EP2817360A1 - Multi-responsive self-healing polymer and gel compositions - Google Patents

Multi-responsive self-healing polymer and gel compositions

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Publication number
EP2817360A1
EP2817360A1 EP13712673.6A EP13712673A EP2817360A1 EP 2817360 A1 EP2817360 A1 EP 2817360A1 EP 13712673 A EP13712673 A EP 13712673A EP 2817360 A1 EP2817360 A1 EP 2817360A1
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EP
European Patent Office
Prior art keywords
alk
group
chr
amino
backbone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP13712673.6A
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German (de)
French (fr)
Inventor
Marie KROGSGAARD
Henrik Birkedal
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Aarhus Universitet
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Aarhus Universitet
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Publication date
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Publication of EP2817360A1 publication Critical patent/EP2817360A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0031—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2379/00—Characterised by the use of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen with or without oxygen, or carbon only, not provided for in groups C08J2361/00 - C08J2377/00
    • C08J2379/02—Polyamines

Definitions

  • the present invention relates to a method of forming a multi-responsive self-healing polymer and the polymer thus obtained.
  • Tissue adhesives have the potential to improve wound treatments and surpass sutures and staples, because they can decrease the risk of inflammation and skin irritation, are less time consuming than alternative treatments and provide superior cosmetic results. Additionally, they do not have to be subsequently removed as they can be engineered to naturally degrade within the body.
  • the tissue adhesives currently commercially available include Fibrin glue, Gelatin- Resorcinol-Formaldehyde (GRF) glue and Cyanoacrylate glue.
  • Fibrin glue The major concern with Fibrin glue is the risk of blood-borne disease transmission from human derived clot precursors, particularly hepatitis and HIV. Furthermore, it is limited in strength. Cyanoacrylate and GRF glue both release formaldehyde upon degradation, which is histotoxic and can cause acute and chronic inflammation. It is therefore necessary to develop improved tissue adhesives.
  • a tissue adhesive should not only be biocompatible and biodegradable, but also waterproof with a consistently high adhesive strength. Most commercial glues lose adhesive strength over time as moisture weakens the adhesive bonds. Furthermore, if the cohesive bonds are broken, they cannot reform, due to the irreversible nature of covalent bonds.
  • a solution to this problem is to mimic the blue mussel's self-healing byssal threads as they have the ability to form strong underwater bonds to a wide range of surfaces, from inorganic to organic materials, including classically adhesion-resistant materials such as Teflon, and even in wet environments.
  • a major advantage to use new materials based on mimicking the blue mussel's self-healing byssal threads is that these new materials are non-toxic, and it is expected that different uses, including medical uses, of such materials are easily granted by national medical agencies, because they are based on compounds, which can be found in the nature.
  • the byssal threads contain Fe(l l l) ions and high amounts of the amino acid 3,4-dihydroxyphenylalanine (also known as DOPA).
  • DOPA has unique properties related to adhesion as well as cohesion and is the main reason why byssal threads are able to attach to surfaces under water.
  • incorporation of Fe(l ll) ions in the byssal threads imparts strength and self-healing properties by the formation of strong, reversible tris-DOPA-Fe(ll l) cross-links.
  • Fe(l ll)-DOPA adhesion system of the blue mussel has been mimicked by Holten- Andersen (WO201 1 /084710) in the formation of adhesive self-healing pH- responsive hydrogels of Fe(lll) ions and DOPA functionalized PEG polymers.
  • WO201 1/084710 discloses the maximum mechanical strength of the polymer obtained by the method disclosed therein to be about 103-104 Pa.
  • improved self-healing bio-adhesives and coatings such as self-healing polymer materials, of which the mechanical strength is increased, self-healing polymer materials of which the mechanical strength can be controlled and / or self-healing polymer materials which can be easily delivered and that solidify in situ to form strong and durable interfacial adhesive bonds and are resistant to the normally detrimental effects of water.
  • Some of the potential applications for such biomaterials include consumer adhesives, bandage adhesives, tissue adhesives, bonding agents for implants and drug delivery. Summary of invention
  • the inventors of the present invention have now, surprisingly, succeeded in inventing a novel method of forming multi-responsive self-healing polymers with a physiological relevant curing pH. Moreover, with the method of the present invention, the pH-optimum for the maximum strength of the multi-responsive self- healing polymers thus obtained can be controlled. It is thus, surprisingly, possible to adjust the mechanical performance of self-healing polymers to match a number of applications. Furthermore, as compared to known self-healing polymers the present invention provides multi-responsive self-healing polymers with improved properties in respect of mechanical strength, e.g. in that the maximum mechanical strength of polymers obtained with the method of the present invention is surprisingly high, namely at least 1000 Pa.
  • hydrogels provided herein are useful in treatment of e.g. open wounds. Such hydrogels protect wounds against infections while the natural skin barrier is disrupted and thus provide protection against e.g. haemorrhaging. Due to fast curing of hydrogels provided herein, immediate treatment and physical closure of the wounds is provided and thus bacterial infection, halt bleeding and facilitate healing may be prevented.
  • Hydrogels which function as tissue adhesives have a potential to improve wound treatments and surpass sutures and staples, because they can decrease the risk of inflammation and skin irritation, are less time consuming than alternative treatments and provide superior cosmetic results. Additionally, some of the hydrogels provided herein do not have to be subsequently removed as they can be engineered to naturally degrade within the body. Some of the hydrogels provided herein are not only biocompatible and biodegradable, but also waterproof with a consistently high adhesive strength. Moreover, the hydrogels provided herein are capable of forming strong under-water bonds to a wide range of surfaces, from inorganic to organic materials, including classically adhesion-resistant materials such as Teflon, and even in wet
  • one aspect of the present invention provides a method of making a hydrogel, said method comprising the steps of:
  • backbone comprises one or more backbone monomer unit(s) comprising an amino group
  • polymer backbone being functionalized with one or more catechol monomer unit(s),
  • said catechol monomer units comprising at least one amino group and/or carboxylate-group
  • hydrogel having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
  • Another aspect of the invention relates to a hydrogel comprising:
  • said polymer backbone being functionalized with one or more catechol monomer unit(s),
  • said catechol monomer units comprising at least one amino group and/or carboxylate-group
  • said hydrogel having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
  • One further aspect of the invention relates to the use of a multi-responsive self- healing polymer provided herein.
  • a multi-responsive self- healing polymer provided herein.
  • self-healing multi-pH responsive hydrogel systems having a cationic nature as is illustrated by the below DOPA functionalized polyallylamine herein below:
  • the polymers are further functionalized in a pH-dependent manner as the number of coordinating catechol monomer units per metal atom depends on pH.
  • each grafted- on catechol monomer unit will be next to an amine or carboxylate functionality.
  • the multi-pH-responsive design of the hydrogels provided herein will facilitate control over the mechanical properties of the hydrogels and the reversible nature of the complex bonds will impart self-healing properties to the materials.
  • the hydrogels provided herein will obtain the maximum mechanical strength when the pH is close to the polymer's pK a value.
  • the polymers When the pH is below the polymer's pK a value, the polymers are highly charged facilitating the formation of a hydrogel.
  • the stoichiometry of the complex bond changes from a mono- to bis- to tris-complexes, when using Fe as example, and the mechanical strength increases.
  • the amines or carboxylates will start to deprotonate. Therefore, the hydrogel structure will collapse at a pH above the polymer's pK a value and consequently, the mechanical strength of the hydrogel decreases.
  • this multi-pH-responsive hydrogel design allows, contrary to existing DOPA:Fe(ll l) systems, for the mechanical properties to be adjusted to match a number of application by selecting the polymer based on its pK a value.
  • Figure 1 shows UV/VIS absorption spectra of the DOPA-polyallylamine Fe(lll)-gel at different values spanning from pH 1 to pH 12.
  • Figure 2 shows the calculated fraction of mono-, bis- and tris-catechol Fe(lll) complexes as a function of pH based on the UV/VIS data provided in Figure 1 .
  • Figure 3 shows the storage modulus G' as a function of strain at a frequency of 1 s "1 measured on a DOPA-polyallylamine Fe(lll)-hydrogel (20 ⁇ NaOH added in the final hydrogel formation step, pH 6).
  • Figure 4 shows a selection of the frequency sweeps on DOPA-polyallylamine Fe(lll)- gels with different amount of NaOH added.
  • Figure 5 shows the storage modulus G' of DOPA-polyallylamine Fe(lll)-gels as a function of the molar amount of NaOH added for the angular frequencies A) 24.8 s "1 , B) 49.8 s "1 , C) 75.6 s ⁇ 1 and D) 100.0 s ⁇ 1 .
  • the least squares refined Gaussian distributions are shown by the bell-formed curves. Measurements performed for the polyallylamine Fe(lll)-solutions at the same concentration as the DOPA-polyallylamine Fe(lll)-gels is indicated by the almost straight horizontal line at about 0.
  • Figure 6 displays the result of a quantitative recovery test performed using a
  • Figure 7 shows photographs of a DOPA-polyallylamine Fe(lll)-hydrogel.
  • Figure 7A is a top view picture of a DOPA-polyallylamine Fe(lll)-hydrogel with a fracture induced by a scalpel. The hydrogel was prepared to have a pH of 8.
  • Figure 7B is a picture of the gel from figure 7A after the two pieces have been brought into contact.
  • Figure 8 shows the self-healing properties through shape recovery over a period of 45 minutes of the DOPA-polyallylamine Fe(lll)-hydrogel from figure 7B.
  • Figure 9 shows the radius of gyration R g as a function of pH, which has been obtained from SAXS data. The data was obtained for cationic polyallylamine and Fe(lll):DOPA- polyallylamine, respectively.
  • Figure 10 shows a self-healing hydrogel of Ca(ll):DOPA-polyallylamine.
  • Figure 1 1 shows a self-healing hydrogel of Zn(ll):DOPA-polyallylamine.
  • Figure 12 shows a self-healing hydrogel of Mn(ll):DOPA-polyallylamine.
  • Figure 13 shows a self-healing hydrogel of AI(lll):DOPA-polyallylamine.
  • Figure 14 shows a self-healing hydrogel of Ga(lll):DOPA-polyallylamine.
  • Figure 15 shows UV/VIS spectra of a AI(lll):DOPA-polyallylamine system in the pH range of 1 -12.
  • the left and right figure shows the wavelength ranges 200-850 and 200- 500 nm, respectively. The individual measurements appear in order given by the labels on the right.
  • Figure 16 shows UV/VIS spectra of a Ga(lll):DOPA-polyallylamine system in the pH range of 1 -12. The individual measurements appear in order given by the labels on the right.
  • Figure 17 shows UV/VIS spectra of a ln(lll):DOPA-polyallylamine system in the pH range of 1 -12. The individual measurements appear in order given by the labels on the right.
  • Figure 18 shows the storage modulus G' as a function of the final pH of the
  • metakDOPA-polyallylamine hydrogels for the angular frequency 25 s ⁇ ⁇ where the metal is Al(lll), Ga(lll) and In(lll), respectively.
  • Figure 19 shows the storage modulus G' for gels made with Fe(lll) as a function of pH for a metakDOPA ratio of 1 :6 and 1 :9.
  • Figure 20 shows a test of de-gelation by competitive binding of Fe(lll) by EDTA performed on Fe(lll)-gel at ratio 1 :3.
  • Figure 21 shows a construct comprising two untreated glass slides, which are adhered together with Fe(lll):DOPA-polyallylamine for use in shear testing.
  • Figure 22 shows a gel, which has been prepared by use 3,4-dihydroxyphenylacetic acid-polyallylamine polymer with Fe(lll).
  • Figure 23 shows the storage modulus G'for Fe(lll): 3,4-dihydroxyphenylacetic acid- polyallylamine gels.
  • Figure 24 shows a 1 H NMR of a DOPA-functionalized chitosan, in which the chitosan oligosaccharide had 5000 Da molecular weight on average.
  • Figure 25 shows a FTIR spectrum of a DOPA-functionalized chitosan, in which the chitosan oligosaccharide had 5000 Da molecular weight on average.
  • Figure 26 shows the storage modulus G'for a Fe(lll):DOPA-chitosan hydrogel having the ratio of 1 :3.
  • Figure 27 shows a test of de-gelation by competitive binding of Fe(lll) by EDTA performed on Fe(lll):DOPA-chitosan gel at a metakDOPA ratio 1 :3.
  • one aspect of the present invention provides a method of making a hydrogel, said method comprising the steps of: 1 . providing a functionalized polymer backbone; wherein the polymer backbone comprises one or more backbone monomer unit(s) comprising an amino group;
  • polymer backbone being functionalized with one or more catechol monomer unit(s),
  • said catechol monomer units comprising at least one amino group and/or carboxylate-group
  • hydrogel whereby a hydrogel is obtained, said polymer having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
  • One embodiment of the invention relates to such method, wherein the second pH value is obtained by addition of a solid, liquid, or gaseous base.
  • gaseous base is advantageous when the method is used in large scale, such as in industrial scale, whereas the use of liquid base is advantageously used in smaller scale, such as in laboratory scale.
  • said base is ammonia, e.g. from ammonium carbonate.
  • said base comprises OH " , such as e.g. a base selected from the group consisting of KOH and NaOH.
  • one or more co-solvent(s) is/are optionally comprised when contacting the polymer with the solution comprising a soluble metal of formula M n+ or any complex thereof at a first pH-value or alternatively at a later stage in the procedure.
  • a mixing step is performed upon contacting the functionalized polymer backbone with the solution comprising a soluble metal of formula M n+ or any complex thereof at a first pH- value.
  • said mixing is performed using a magnetic stir bar.
  • said mixing is done using a mechanic stirrer.
  • said mixing is done using a hand held and auctioned mixer including but not restricted to a spatula.
  • said mixing is done by diffusion and/or convection and/or advection.
  • said mixing is done by aspiration combined with ejection from a suction device such as a pipette.
  • the mixing procedure is performed at temperatures between 0 and 100 °C. In one particular embodiment thereof, said temperature is between 5 and 60 °C. In one further embodiment thereof, said temperature is between 10 and 45 °C. In one further and preferred embodiment thereof, said temperature is between 17 and 33 °C.
  • a hydrogel comprising:
  • said polymer backbone being functionalized with one or more catechol monomer unit(s);
  • catechol monomer units comprising at least one amino group and/or carboxylate-group
  • said hydrogel having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
  • hydrogels obtained with the method provided herein.
  • One further aspect of the invention relates to the use of a multi-responsive self- healing polymer provided herein.
  • C 1-10 -alk(en/yn)yr' means Ci-i 0 -alkyl, C 2 -8-alkenyl or C 2- i 0 -alkynyl; wherein:
  • C 1-10 -alkyl refers to a branched or unbranched alkyl group having from one to ten carbon atoms, including but not limited to methyl, ethyl, prop-1 - yl, prop-2-yl, 2-methyl-prop-l-yl, 2-methyl-prop-2-yl, 2,2-dimethyl-prop-l-yl, but-l- yl, but-2-yl, 3-methyl-but-l-yl, 3-methyl-but-2-yl, pent-1 -yl, [rho]ent-2-yl, pent-3- yl, hex-l-yl, hex-2-yl, hex-3-yl, 2-methyl-4,4-dimethyl-pent-l-yl and hept-1 -yl;
  • C 2-10 -alkeny refers to a branched or unbranched alkenyl group
  • C 2 -io-alkynyl refers to a branched or unbranched alkynyl group
  • C 1-6 -alk(en/yn)yl means C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl; wherein:
  • C 1-6 -alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms, including but not limited to methyl, ethyl, prop-1 - yl, prop-2-yl, 2-methyl- prop- 1 -yl, 2-methyl-prop-2-yl, 2,2-dimethyl-prop- 1 -yl, but- 1 -yl, but-2-yl, 3-methyl-but- 1 - yl, 3-methyl-but-2-yl, pent-1 -yl, pent-2-yl, pent-3-yl, hex-l-yl, hex-2-yl and hex-3-yl;
  • C 2-6 -alkenyl refers to a branched or unbranched alkenyl group
  • C 2-6 -alkynyl refers to a branched or unbranched alkynyl group having from two to six carbon atoms and one triple bond, including but not limited to ethynyl, propynyl and butynyl.
  • C 2-4 -alk(en/yn)yl means C 2-4 -alkyl, C 2-4 -alkenyl or C 2-4 -alkynyl; wherein:
  • C 2-4 -alkyl refers to a branched or unbranched alkyl group having from two to four carbon atoms, including but not limited to prop-1 -yl, prop-2-yl, 2-methyl- prop- 1 -yl, 2-methyl-prop-2-yl, but- 1 -yl and but-2-yl; •
  • C 2 - 4 -alkenyl refers to a branched or unbranched alkenyl group having from two to four carbon atoms and one double bond, including but not limited to ethenyl, propenyl, and butenyl; and
  • C 2 - 4 -alkynyl refers to a branched or unbranched alkynyl group having from two to four carbon atoms and one triple bond, including but not limited to ethynyl, propynyl and butynyl.
  • C 3 -alk(en/yn)yl means C 3 -alkyl, C 3 -alkenyl or C 3 -alkynyl; wherein:
  • C 3 -alkyl refers to a branched or unbranched alkyl group having three carbon atoms, including but not limited to prop-1 -yl and prop-2-yl;
  • C 3 -alkenyl refers to a branched or unbranched alkenyl group having from three carbon atoms and one double bond, including but not limited to propenyl
  • C 3 -alkynyl refers to a branched or unbranched alkynyl group having from two to four carbon atoms and one triple bond, including but not limited to propynyl.
  • amino-Ci-i 0 -alk(an/en/yn)yl refers to "C 1-10 - alk(an/en/yn)yl", “C 1-6 -alk(en/yn)yl", “C 2-4 -alk(en/yn)yl” and "C 3 -alk(en/yn)yl” as defined herein above which is substituted with an amino group (-NH 2 ) in a terminal position of said alk(an/en/yn)yl.
  • polymer backbone' refers to the series of covalently bonded atoms that together create a continuous chain of a polymer molecule.
  • a polymer backbone comprises backbone monomer units, which may be identical or different from each other, and of which at least one comprises one or more amino group(s) or groups that can be functionalized so as to comprise one or more amino group(s).
  • the polymer backbone is cationic.
  • a cationic polymer is a polymer which is positively charged within a given pH range. Common for cationic (and anionic) polymers are that their solubility and structural conformation depend on pH and their pH behaviour is dependent upon the pKa value of their side chains.
  • the polymer backbone comprises one kind of backbone monomer unit(s), only, said backbone monomer unit(s) comprising one or more amino groups. In another embodiment of the invention, the polymer backbone comprises more than one kind of backbone monomer unit(s), wherein at least one kind of backbone monomer units comprises one or more amino groups. In yet another embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are cationic at said first pH value. In yet one further embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are stimuli-responsive.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are thermo-responsive.
  • thermo-responsive as used herein is meant that the polymers undergo a physical change when external thermal stimuli are presented.
  • the polymer backbone comprises one or more backbone monomer(s) which is/are pH-responsive.
  • the polymer backbone comprises one or more backbone monomer(s) which is/are soluble in water.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are selected from the group consisting of:
  • R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of -H, -OH and Ci -6 -alk(an/en/yn)yl wherein Ci -6 - alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and
  • R 7 is selected from the group consisting of -H and -(CO)-Ci -6 - alk(an/en/yn)yl wherein -(CO)-Ci -6 -alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
  • said polymer backbone may comprise any of the backbone polymer units disclosed herein and it may comprise any mixture thereof with other monomer units known to the skilled person.
  • the backbone monomer units comprised in the polymer backbone are identical, such as allylamine.
  • two different kinds of backbone monomer units are comprised in the polymer backbone.
  • three different kinds of backbone monomer units comprised in the polymer backbone such as in a polymer backbone made of chitosan.
  • the polymer backbone comprises one or more backbone monomer unit(s) with a pKa ranging from 4 to 10, such as from 5-10. In a specific embodiment thereof, said pKa ranges from 6-9, such as from 7- 8.
  • the pKa value of the polymer is taken to be the same as the pi of the polymer defined as the pH where half the polymer pH-responsive groups are charged and the other half is uncharged.
  • the method of the present invention is applicable to polymer backbones which in addition to backbone monomer unit(s) comprising one or more amino group(s) may further comprise any other monomer unit(s) known to the skilled person.
  • backbone monomer unit(s) comprising one or more amino group(s)
  • the skilled person will know which backbone monomer units to be incorporated into the backbone polymer.
  • Essential for a purposive selection of backbone monomer units to be incorporated into the backbone polymer is the pKa of the resulting backbone polymer. Accordingly, the pKa of the resulting backbone polymer shall preferably be within the range of a pH which is appropriate for the intended use of the obtained hydrogel.
  • the pKa of the backbone polymer shall preferably be between 6 and 8, such as about 7.
  • the pKa of the backbone polymer shall preferably be below 7.
  • the pKa of the backbone polymer shall preferably be about 7.
  • the pKa of the backbone polymer shall preferably be between 6 and 8, such as about 7.
  • the pKa shall preferably be between 1 and 9, such as about 8.
  • the polymer backbone has a pka between 7 and 9, such as a pKa of about 8. In another embodiment of the invention, the polymer backbone has a pKa of below 7. In one further embodiment of the invention, the polymer backbone has a pKa between 6 and 8, such as at a pKa of about 7. Furthermore, in one embodiment of the invention, the functionalized polymer backbone has a pKa between 7 and 9, such as a pKa of about 8. In another embodiment of the invention, the functionalized polymer backbone has a pka of below 7. In one further embodiment of the invention, the functionalized polymer backbone has a pKa between 6 and 8, such as at a pKa of about 7.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are thermo-responsive and one or more backbone monomer unit(s) selected from the group consisting of:
  • R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of -H, -OH and C 1-6 -alk(an/en/yn)yl wherein C 1-6 - alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and o R 7 is selected from the group consisting of -H and -(CO)-Ci -6 - alk(an/en/yn)yl wherein -(CO)-C 1-6 -alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
  • the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino- C 1-10 -alk(an/en/yn)yl which is/are optionally substituted with one or more
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are thermo-responsive and one or more backbone monomer unit(s) selected from the group consisting of amino-C 1-10 - alk(an/en/yn)yl which is optionally substituted.
  • DOPA is the functionalizing catechol monomer unit which is grafted to the polymer backbone.
  • the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino- Ci- 6 -alk(an/en/yn)yl which is optionally substituted with one or more substituents.
  • the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino- C 2 - 4 -alk(an/en/yn)yl which is optionally substituted with one or more substituents.
  • the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino-
  • the polymer backbone comprises one or more backbone monomer unit(s) of the formula: ⁇ *" .
  • the backbone polymer unit allylamine has a pKa value of about 9.3.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is selected from the group consisting of amino-Ci-i 0 -alk(an/en/yn)yl, amino-Ci -6 -alk(an/en/yn)yl, amino- C 2 - 4 -alk(an/en/yn)yl and amino-C 3 -alk(an/en/yn)yl is selected with one or more substituent(s) selected from the group consisting of -SH, - OH, -COOH, -NH 2 , -S- CH 3 , -O-CH 3 , -CH(OH)-CH 3 and -CH(SH)-CH 3 .
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino acids which occur naturally and which do not occur naturally.
  • said amino acid(s) is/are of the generic formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent.
  • said amino acid(s) is/are of the formula H 2 N-CHR 1 -COOH; wherein R 1 is selected from the group consisting of -H, -C 1-6 -alk(an/en/yn)yl, -C 1-6 -alk(an/en/yn)yl-R 2 , wherein R 2 is selected from the group consisting of -SH, -COOH, C 3 H 3 N 2 , -NH 2 , -S-CH 3 , -CO- NH 2 , -NH-C(NH)NH 2 , - OH, -CH(OH)-CH 3 , -SeH, -C 8 H 6 N, -C 6 H 5 -C 6 H 4 OH, and - C 6 H 3 (OH) 2 .
  • the polymer backbone comprises one or more backbone monomer unit(s) of the formula H 2 N-CHR 1 -COOH which is/are is a naturally occurring amino acid.
  • said amino acid(s) of the formula H 2 N-CHR 1 -COOH is a naturally occurring amino acid which is selected from the group consisting of DOPA, ornithine, lysine, arginine, histidine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine and valine.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being ornithine having a pKa value of about 10.75. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being lysine In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being arginine.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N- CHR 1 -COOH thus being histidine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being aspartic acid. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being glutamic acid.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being serine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being threonine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being DOPA.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N- CHR 1 -COOH thus being asparagine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being glutamine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being cysteine.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N- CHR 1 -COOH thus being selenocysteine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being glycine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being alanine.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N- CHR 1 -COOH thus being isoleucine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being leucine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being methionine.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being phenylalanine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being tryptophan. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N-CHR 1 -COOH thus being tyrosine.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H 2 N- CHR 1 -COOH thus being valine.
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are amide(s).
  • said amide(s) is/are of the formula -(CO)-(NH 2 )-Ci -6 -alk(an/en/yn)yl-NH 2 .
  • the polymer backbone comprises one or more backbone monomer unit(s) which is/are comprising styrene which is optionally substituted. In an embodiment thereof, said styrene is not substituted. In another embodiment thereof, said styrene is substituted with one or more substituents selected from the group consisting of NH 2 -Ci -6 -alk(an/en/yn)yl- and -NH 2 . In one embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of styrene which is substituted with an amino group.
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of styrene which is substituted with NH 2 - Ci- 6 -alk(an/en/yn)yl-.
  • said styrene is further substituted with one or more substituents selected from the group consisting of - SH, - OH, -COOH, -NH 2 , -S-CH 3 , -O-CH 3 , -CH(OH)-CH 3 and -CH(SH)-CH 3 .
  • said substituted styrene is para- NH 2 -Ci -6 - alk(an/en/yn)yl-styrene. In another specific embodiment thereof, said substituted styrene is meta- NH 2 -C 1-6 -alk(an/en/yn)yl-styrene. In another specific embodiment thereof, said substituted styrene is ortho- NH 2 -Ci -6 -alk(an/en/yn)yl-styrene. In one specific embodiment thereof, said substituted styrene is para-amino-styrene.
  • said substituted styrene is meta-amino- styrene. In another specific embodiment thereof, said substituted styrene is ortho- amino-styrene, such as e.g. 4-aminostyrene having a pKa value of about 4.5.
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars.
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are selected from the group consisting of glucosamine, acetyl- glucosamine, galactosamine and sialic acid in their open chain form or in any a- form or ⁇ -form thereof.
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are selected from the group consisting of glucosamine and acetyl- glucosamine in their open chain form or in any a-form or ⁇ -form thereof.
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are glucosamine(s) of the formula:
  • the backbone polymer unit glucosamine has a pKa value of about 6.3-6.5.
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are galactosamine(s) of the formula:
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are acetylglucosamine(s) of the formula:
  • acetylglucosamine being in its open chain form or in any a-form or ⁇ -form thereof.
  • the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are sialic acid of the formula:
  • sialic acid being in its open chain form or in any a-form or ⁇ -form thereof.
  • the polymer backbone comprises at least 3 monomer units selected from the group of amino sugars, wherein 3 amino sugar(s) comprised in the polymer backbone together form chitosan having the formula:
  • the polymer backbone comprises at least 3 backbone monomer units selected from the group of amino sugars, wherein said 3 amino sugars together form chitosan with varying degrees of de-acetylation in its open chain form or in any a-form or ⁇ -form thereof.
  • the polymer backbone comprises at least 3 backbone monomer units selected from the group of amino sugars, wherein said 3 amino sugars together form chitosan which is functionalized with DOPA catechol monomer unit(s).
  • Chitosan is a specific example of a cationic polymer.
  • Chitosan is a linear co-polymer formed from the N-acetyl-D-glycosamine and D-glycosamine:
  • One such chitosan backbone co-polymer has a pKa value of about 6.3-6.5.
  • Chitosan is both thermo- and pH-responsive owing to the ionisable primary amines on the chitosan chain that have a pKa value of about 6.5. Further to the close-to physiological pH, chitosan also has the advantage that it is biocompatible and biodegradable. Hydrogels comprising chitosan as the only backbone monomer unit is thus highly advantageous.
  • Polyallylamine is another specific example of a cationic polymer.
  • Polyallylamine has a pKa value around 9.5.
  • Polyallylamine is a linear homo-polymer formed through polymerization of allylamine.
  • polyallylamine is used as the free base. In another embodiment,
  • polyallylamine is used as the hydrobromide.
  • polyallylamine is used as the hydrochloride, which is highly soluble in water as the amines along the polymer backbone are already protonated:
  • polymer backbones being amino-functionalized polymer backbones with a pKa ranging from
  • the polymer backbone does not comprise polypeptide or it does not comprise one or more backbone monomer unit(s) selected from the group consisting of dopa such as L-DOPA, lysine such as L- lysine, glutamic acid such as L-glutamic acid, serine such as L-serine, alanine such as L-alanine, a-amino acid N-carboxy anhydride such as N-carbobenzyloxy-L- lysine N-carboxyanhydride or dicarbobenzoxy-L-DOPA N-carboxyanhydride or di- acetyl-DOPA- N-carboxyanhydride, and 3,4-dihydroxyphenylalanine.
  • dopa such as L-DOPA
  • lysine such as L- lysine
  • glutamic acid such as L-glutamic acid
  • serine such as L-serine
  • alanine such as L-alanine
  • the polymer backbone does not comprise polypeptide. In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are dopa(s) such as L-DOPA(s). In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are lysine(s) such as L- lysine(s). In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are glutamic acid(s) such as L-glutamic acid(s).
  • the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are serine(s) such as L- serine(s). In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are alanine(s) such as L-alanine(s).
  • the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are a-amino acid N-carboxy anhydride such as N-carbobenzyloxy-L-lysine N- carboxyanhydride or dicarbobenzoxy-L-DOPA N-carboxyanhydride or di-acetyl- DOPA- N-carboxyanhydride.
  • the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are 3,4-dihydroxyphenylalanine.
  • polymer backbone does not comprise an amino acid, such as a histidine analogue.
  • said polymer backbone does not comprise cysteine.
  • polymer backbone does not comprise an acrylamide, such as n-isopropylamide or N,N-dimethylacrylamide.
  • polymer backbone does not comprise polyethylene glycol (PEG) as a backbone monomer unit. In another specific embodiment of the invention, polymer backbone does not comprise polypropylene glycol (PPG) as a backbone monomer unit. In another specific embodiment of the invention, polymer backbone does not comprise polyacrylate. In another specific embodiment of the invention, polymer backbone does not comprise polystyrene. In another specific embodiment of the invention, polymer backbone does not comprise polyvinyl. In another specific embodiment of the invention, polymer backbone does not comprise polypeptide.
  • PEG polyethylene glycol
  • PPG polypropylene glycol
  • polymer backbone does not comprise polyacrylate.
  • polymer backbone does not comprise polystyrene.
  • polymer backbone does not comprise polyvinyl.
  • polymer backbone does not comprise polypeptide.
  • the polymer backbone does not comprise amino-Ci-i 0 -alk(an/en/yn)yl which is optionally substituted. In another specific embodiment of the invention, the polymer backbone does not comprise amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent.
  • the polymer backbone does not comprise amides of the formula -(CO)-(NH 2 )-C 1-6 -alk(an/en/yn)yl-NH 2 .
  • R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of - H, -OH and C 1-6 -alk(an/en/yn)yl wherein C 1-6 -alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and
  • R 7 is selected from the group consisting of -H and -(CO)-Ci -6 -alk(an/en/yn)yl wherein -(CO)-Ci -6 -alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
  • a 'monomer unit used for functionalizing the polymer backbone' is used synonymous with the term a 'functionalizing catechol monomer unit' and refers to a catechol monomer unit which is grafted to a backbone monomer unit of the polymer backbone, i.e. bound to a backbone monomer unit of the polymer backbone via a covalent bond, said catechol monomer unit comprising at least one catechol functional group and further comprising at least one amino group and/or one carboxylate group.
  • Such polymer backbone may be functionalized with one or more catechol monomer unit(s) which are identical to each other or with one or more monomer unit(s) which are not identical to each other.
  • the one or more functionalizing catechol monomer unit(s) comprise(s) at least one amino group.
  • said functionalizing catechol monomer unit(s) comprise(s) exactly one amino group.
  • said one or more functionalizing catechol monomer unit(s) comprise(s) at least one carboxylate-group.
  • said functionalizing catechol monomer unit(s) comprise(s) exactly one carboxylate-group.
  • said one or more functionalizing catechol monomer unit(s) comprise(s) at least one amino group and at least one carboxylate-group.
  • the one or more functionalizing catechol monomer unit(s) comprise(s) at least one amino group and/or one carboxylate- group of the below formula:
  • R 10 is selected from the group consisting of (C 1-6 -alk(an/en/yn)yl) q -COOH and (Ci-6-alk(an/en/yn)yl) r -NH 2 wherein:
  • R 12 is of the formula:
  • q is 0. In another embodiment, q is 1 .
  • r is 0. In another embodiment, r is 1 .
  • R 10 is selected from the group consisting of optionally substituted (C 2 - 4 -alk(an/en/yn)yl) q -COOH and (C 2 - 4 -alk(an/en/yn)yl) r -NH 2 .
  • R 10 is selected from the group consisting of optionally substituted (C 2-4 -alk(an/en/yn)yl)-COOH and (C 2-4 -alk(an/en/yn)yl)-NH 2 wherein -.y
  • R 10 is -COOH.
  • R 10 is -NH 2 .
  • R 10 is optionally substituted (C 2-4 -alk(an/en/yn)yl)- COOH.
  • R 10 is optionally substituted (C 2 - 4 -alk(an/en/yn)yl)-NH 2 .
  • R 11 is -OH.
  • R 11 is H.
  • R 11 is ositioned as indicated herein:
  • R 11 is positioned as indicated herein:
  • R 11 is positioned as indicated herein:
  • the one or more functionalizing catechol monomer unit(s) is/are selected from the group consisting of 3,4- dihydroxyphenylacetic acid (DHPAA),3,4-dihydroxycinnamic acid (DHCA ), 2,4,5- trihydroxybenzoic acid, 3-(3,4-dihydroxyphenyl)propanoic acid, 3-(3,4- dihydroxyphenyl)-2-methyl-alanine, 2,4,5-trihydroxy-phenylalanine, 2-amino-3-(3,4- dihydroxyphenyl)-3-hydroxypropanoic acid, (2R)-3-(3,4-dihydroxyphenyl)-2- ⁇ [(2E)- 3-(3,4-dihydroxyphenyl)-2-propenoyl]oxy ⁇ propanoic acid (Rosmarinic acid), dopamine and L-DOPA and D-DOPA; or any isomers or mixtures thereof.
  • DHPAA 3,4- dihydroxyphenylacetic acid
  • DHCA 3,5- trihydroxybenzoic acid
  • the one or more functionalizing catechol monomer unit(s) is/are selected from the group consisting of 2,4,5- trihydroxybenzoic acid, 3-(3,4-dihydroxyphenyl)propanoic acid, 3-(3,4- dihydroxyphenyl)-2-methyl-alanine, 2,4,5-trihydroxy-phenylalanine, 2-amino-3-(3,4- dihydroxyphenyl)-3-hydroxypropanoic acid, (2R)-3-(3,4-dihydroxyphenyl)-2- ⁇ [(2E)- 3-(3,4-dihydroxyphenyl)-2-propenoyl]oxy ⁇ propanoic acid (Rosmarinic acid), dopamine and L-DOPA and D-DOPA; or any isomers or mixtures thereof.
  • catechol monomer unit(s) is/are selected from the group consisting of 3,4-dihydroxyphenylacetic acid (DHPAA),3,4-dihydroxycinnamic acid (DHCA ) and DOPA; or any isomers or mixtures thereof.
  • DHPAA 3,4-dihydroxyphenylacetic acid
  • DHCA 3,4-dihydroxycinnamic acid
  • DOPA DOPA
  • the one or more functionalizing catechol monomer unit(s) is/are 2,4,5-trihydroxybenzoic acid of the formula:
  • the one or more functionalizing catechol monomer unit(s) is/are 3,4-dihydroxyphen lacetic acid of the formula: In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are 3-(3,4-dihydroxyphenyl)propanoic acid of the formula:
  • the one or more functionalizing catechol monomer unit(s) is/are 3,4-dihydroxycinnamic acid (DHCA ) of the formula:
  • the one or more functionalizing catechol monomer unit(s) is/are 3-(3,4-dihydroxyphenyl)-2-methyl-alanine of the formula:
  • the one or more functionalizing catechol monomer unit(s) is/are 2,4,5-ttrihydroxy-phenylalanine of the formula:
  • the one or more functionalizing catechol monomer unit(s) is/are 2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid of the formula:
  • the one or more functionalizing catechol monomer unit(s) is/are (2R)-3-(3,4-dihydroxyphenyl)-2- ⁇ [(2E)-3-(3,4-dihydroxyphenyl)-2- propenoyl]oxy ⁇ propanoic acid (Rosmarinic acid) of the formula:
  • the one or more functionalizing catechol monomer unit(s) is/are dopamine(s) which is/are linked to the backbone polymer via a di- carboxylic acid or other intermediate linker molecule of the formula:
  • the one or more functionalizing catechol unit(s) is/are L-DOPA of the formula:
  • the one or more functionalizing catechol unit(s) is/are D-DOPA of the formula:
  • DOPA i.e. L-DOPA and/or D-DOPA
  • L-DOPA and/or D-DOPA is a specific example of such monomer unit(s) used for functionalizing the polymer backbone.
  • DOPA is an amino acid, which is widely distributed in nature. It is produced from the amino acid tyrosine through posttranslational modifications by the enzyme tyrosine hydroxylase. DOPA has two different forms; an unoxidized catechol form and an oxidized quinone form :
  • the catecholic moiety must be preserved during the reaction.
  • the functionalizing monomer used herein comprising e.g. a primary amine and/or a carboxylic acid, such as e.g. in DOPA. Both the amine and the carboxylic acid have the capability to participate in peptide bond formation as nucleophile and
  • a polymer backbone as used herein comprising e.g. a secondary and a primary alcohol as well as a primary amine (or an amide if the monomer is acetylated), such as e.g. a polymer backbone comprising chitosan monomer(s), the primary (non-protonated) amine has the most nucleophilic potential, however it is closely followed by the primary alcohol.
  • the primary amines and alcohols on chitosan can participate in nucleophilic attacks.
  • an appropriate approach to conjugate a functionalizing monomer unit as used herein, such as e.g. DOPA, to a backbone polymer as disclosed herein, such as e.g. chitosan or polyallylamine, is through peptide bond formation between the carboxylic acid on DOPA and the primary amines on the polymers.
  • a functionalizing monomer unit comprising a carboxylate-group, such as e.g. DOPA
  • a backbone polymer as disclosed herein, said backbone polymer comprising a primary alcohol group such as e.g. chitosan
  • Ester bonds and especially peptide bonds, due to their resonance stabilization, are strong and relatively non-reactive. Furthermore, they can for example be formed through standard carbodiimide chemistry.
  • the one or more catechol monomer unit(s) is/are attached to the polymer backbone via covalent bond(s).
  • said covalent bonds are ester bonds or peptide bonds or a mixture of ester bonds and peptide bonds.
  • said covalent bonds are a mixture of ester bonds and peptide bonds.
  • said covalent bond is/are peptide bonds.
  • said covalent bond(s) is/are ester bond(s).
  • DOPA such as L-DOPA
  • DOPA is a functionalizing monomer unit.
  • DOPA is not a functionalizing monomer unit.
  • suitable reaction conditions for the synthesis of DOPA- chitosan is determined to be a DOPA to chitosan ratio of 2:1 and a reaction pH of 6.
  • a DOPA to chitosan ratio of 1 .5-2.5 : 0.5-1 .5 e.g. a DOPA to chitosan ratio of 1.8-2.2 : 0.8-1 .2.
  • Catechol and quinone comprised in catechol monomer units as used herein for functionalizing the polymer backbone may participate in e.g. oxidizing metal cross- linking, cross linkage by a Shiff-base-reaction between a quinone-moiety and an amino acid residue, cross-linkage by a Michael-type-reaction between a quinone- moiety and an amino acid residue, creation of an aryloxy-radical followed by an aryl-aryl-coupling, oxidation of the catechol to the quinone form and binding of a catechol to a surface-bound metal.
  • catechol monomer units as used herein for functionalizing the polymer backbone may have an ability to participate in a number of side reactions. For instance, an amine on such catechol monomer unit may make a nucleophilic attack on the carboxylic acid of another catechol monomer unit.
  • Fe(ll l) is the metal, b) Cross linkage of DOPA-proteins by a Shiff-base-reaction between
  • Metals suitable within the present invention are metals that can engage in coordinate bonding. Included are those metals which can have more than one oxidation state.
  • the metal comprised in the self-healing polymer is a transition metal.
  • the metal used in the method of the invention is selected from metals which have a high affinity for coordinate binding to 3,4-dihydroxyphenylalanine.
  • the metal used in the method of the invention is selected from metals which have a high affinity for coordinate bonding to dihydroxybenzene derivatives.
  • the metal is ionic, that is, it does not form a covalent bond with a carbon atom such as would be present in a bond between a platinum atom and a phenyl derivative.
  • the soluble metal of formula M n+ designates such metals wherein n is selected from the group consisting of 2, 3, 4, 5 or 6. In another embodiment thereof, n is selected from the group consisting of 2, 3 and 4. In yet another embodiment thereof, n is 2. In yet another embodiment thereof, n is 3. In yet another embodiment thereof, n is 4.
  • M designates iron, aluminium, titanium, vanadium, manganese, copper, chromium, magnesium, calcium or silicon. In one preferred embodiment thereof, M designates iron. In further embodiments, M designates iron, aluminium, titanium, vanadium, manganese, copper or chromium. In a further embodiment, M designates Ga, Fe, Al, Mn, V, Cr, Ti, Cu, Zn, Mg, Ca, Ag, Au, Ni or Co. In a further embodiment, M designates Ga, Fe, Al, Mn, V, Cr, Ti, Cu, Zn, Mg or Ca.
  • M designates Ga, Fe, Al, Mn, V, Cr, Ti, Cu, Zn, Mg, Ca, In, Ln or Hf, where Ln represents a member of the Lanthanides that includes La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
  • M designates Ga, Fe, Al, Mn, V, Cr, Ti, Cu, Zn, Mg, Ca, Ag or Au.
  • M designates Ga(l ll), Fe(ll l), Al(l ll), Mn(ll), V(l ll), Cr(lll), Ti(IV), Cu(l l), Zn(ll), Mg(l l) or Ca(ll).
  • M designates an octahedrally coordinated metal, such as Ga(l ll), Fe(ll l), Al(ll l), Mn(ll), V(ll l), Ti(IV), Zn(ll), Mg(ll), Ca(l l) or Cr(ll l), e.g.
  • M designates a tetrahedrally coordinated metals, such as Cu(l l).
  • M designates Fe, Al, Mn, Mg or Ca.
  • M designates Fe, Al, or Ca.
  • M designates Fe or Al.
  • M designates iron, titanium, manganese or copper, such as e.g. wherein M n+ designates Fe(ll l), Cu(ll), Ti(IV) or Mn(ll). In a specific embodiment thereof, M designates iron, such as wherein M n+ designates Fe(lll). In a further embodiment thereof, M designates aluminium, such as wherein M n+ designates Al(ll l). In yet a further embodiment thereof, M designates titanium, such as wherein M n+ designates Ti(IV). In yet a further embodiment thereof, M
  • M n+ designates vanadium, such as wherein M n+ designates V(l ll). In yet a further embodiment thereof, M designates manganese, such as wherein M n+ designates Mn(l l). In yet a further embodiment thereof, M designates copper, such as wherein M n+ designates Cu(ll). In yet a further embodiment thereof, M designates chromium, such as wherein M n+ designates Cr(l ll). In one further embodiment, at the second pH, the metal of formula M n+ is coordinated to one, two or three catechol groups comprised in the one or more monomer(s) comprising an amino group and a catechol functional group.
  • the metal of formula M n+ is coordinated to one catechol group comprised in the one or more monomer(s) comprising an amino group and a catechol functional group. In one further embodiment, at the second pH, the metal of formula M n+ is coordinated to two catechol groups comprised in the one or more monomer(s) comprising an amino group and a catechol functional group. In one further embodiment, at the second pH, the metal of formula M n+ is coordinated to three catechol groups comprised in the one or more monomer(s) comprising an amino group and a catechol functional group.
  • the hydrogel of the present invention is for human applications and M n+ preferably designates Fe(l ll). In another preferred embodiment, the hydrogel of the present invention is for human applications and M n+ preferably designates Fe(l ll). In another preferred embodiment
  • the hydrogel of the present invention is for human applications and M n+ preferably designates Fe(lll), Mg(ll), Gd(ll l) or Al(lll).
  • the hydrogel of the present invention is for non- human applications and then the order of preference for M n+ is: Fe(lll), Al(l ll), Ti(IV), Mn(l l), Cu(l l), V(ll l), Cr(l ll), Hf(IV), Ln.
  • the metals may also be able to coordinate to amine groups on the polymer backbone; the tendency for a given metal to do this depends on pH, the relative binding strength of metal to DOPA and metal to amine as well as the molar ratios of amine to catechol in the polymer. This adds to the flexibility of the present invention. Note that interactions between metals and amines can effectively lower the pKa value of the amine.
  • Metals particularly prone to bind amines include but is not restricted to Al(l ll), Fe(ll l), Ga(l ll), Cr(lll), Mg(l l), Ca(l l), Ag(l), Au(l ll).
  • metals are additionally able to catalyze oxidation of amino acids such as lysine (and other amines). This includes iron and copper and the metals may thus also activate e.g. polymer amine groups for covalent crosslinking e.g. through imine formation, a process which is also pH dependent.
  • self-healing hydrogels comprising:
  • catechol monomer comprising an amino group such as DOPA as catechol monomer unit
  • corresponding self-healing hydrogel comprising e.g. Fe(lll) or Mn(l l) as metal source.
  • self-healing hydrogels comprising:
  • catechol monomer comprising an amino group such as DOPA as catechol monomer unit
  • Al(l ll), Mn(l l) and Fe(l ll) will be the fastest recovering hydrogels as compared to corresponding hydrogels comprising Cu(l l) or Cr(ll l) as metal source.
  • self-healing hydrogels comprising:
  • catechol monomer comprising an amino group such as DOPA as catechol monomer unit
  • self-healing hydrogels comprising:
  • catechol monomer comprising an amino group such as DOPA as catechol monomer unit
  • self-healing hydrogels comprising:
  • a polymer consisting of at least 3 backbone monomer units selected from the group of amino sugars, wherein said 3 amino sugars together form chitosan with varying degrees of de-acetylation in its open chain form or in any a-form or ⁇ -form thereof;
  • catechol monomer comprising an amino group such as DOPA as catechol monomer unit
  • self-healing hydrogels comprising:
  • catechol monomer comprising an amino group such as DOPA as catechol monomer unit
  • the Al(lll) functionalized hydrogels displayed much more distinct self-healing properties than the Ca(l l) hydrogels due to the higher number of reversible complex-bonds to covalent bonds in hydrogels comprising Al(l ll).
  • the polymer obtained was a sticky gel.
  • the colour of the resulting hydrogel is predominantly determined by four factors:
  • the metal influences the colour in a manner that depends on the electronic structure of the metal (i.e. the detailed electronic structure).
  • the electronic structure of the metal i.e. the detailed electronic structure.
  • coloured gels are likely to result.
  • the colour and the mechanical strength of the hydrogels will depend on the detail interaction between polymer and metal including the number of catechols bound to the metal, the nature of other counter ions, pH as well as the metal and polymer concentrations and the ratio between them. Coloured gels may be preferred when applied to e.g. a coloured surface. Then the appropriate combination of metals can be employed so that the obtained hydrogel has the same colour as the original surface and blends in with.
  • Uncoloured hydrogels may be preferred for applications where either a transparent gel is needed (e.g. in connection with ophthalmological applications) or where colour is undesired for cosmetic reason (e.g. in connection with certain applications where the hydrogel is visible after application such as may be the case when used on and/or in connection with skin).
  • a coordinate bond is a kind of 2-centre, 2-electron covalent bond in which the two electrons derive from the same atom. The strength of these bonds varies depending on the nature of the metal and ligand as well as external factors including but not limited to pH. For example, DOPA-Ti bonds have bond strengths around 0.8 nN vs about 2 nN for a Si-C covalent bond.
  • a gel is defined as a material that contains polymer subunits that can be cross- linked with each other thus establishing a macroscopic infinite network where all subunits are connected.
  • Gels are viscoelastic materials and they therefore have mechanical properties in between the classical extremes of a solid and a liquid.
  • gels are used synonymous with hydrogels and refer to chemically cross-linked hydrogels.
  • Hydrogels are hydrophilic gels with an ability to absorb and/or comprise high amounts of water, such as e.g. at least 50% of their weight in water. In one embodiment, such hydrogel is capable of absorbing and/or comprising at least 60% of its weight in water.
  • such hydrogel is capable of absorbing and/or comprising at least 70% of its weight in water. In one further embodiment, such hydrogel is capable of absorbing and /or comprising at least 80% of its weight in water. In yet one further embodiment, such hydrogel is capable of absorbing and/or comprising at least comprises at least 90% of its weight in water. In yet one further embodiment, such hydrogel is capable of absorbing and/or comprising at least at least 95% of its weight in water.
  • Hydrogels are widely used as scaffolds in tissue-engineering and drug delivery systems because they, like natural tissue, possess a high degree of flexibility due to their ability to absorb and/or comprise significant volumes of water.
  • Stimuli-responsive hydrogels are hydrogels capable of responding to external triggers like e.g. temperature and pH.
  • temperature-responsive polymers are polymers which undergo a physical change when external thermal stimuli are presented.
  • Stimuli-responsiveness of a hydrogel is an attractive material property in regards to applications in tissue engineering, considering the well-defined temperature and pH ranges of the human body.
  • the multi-responsive self-healing polymers of the present invention are stimuli- responsive hydrogels, hereinafter also referred to as self-healing polymers, multi- responsive polymers, gels or hydrogels. pH-REGULATED MULTIRESPONSIVENESS
  • the hydrogel formation is controlled e.g. by regulation of the pH.
  • the functionalized polymer backbone is charged when the pH is below its pK a value. At low pH, electrostatic repulsion will ensure that the solution remains liquid. At a higher pH, but below the pKa value, a hydrogel may form. As the pH is increased the functionalized polymer backbone amine backbones will gradually become deprotonated and accordingly the functionalized polymer backbones will become less charged. At some pH, in the range of the pK a value of the functionalized polymer backbones, the hydrogel structure may collapse, due to the reduction in the hydrophilicity of the functionalized polymer backbones.
  • said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 4. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 3. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 2.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 0.5.
  • said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 4. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 3. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 2.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 0.5.
  • said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer plus 0.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer plus 1 . In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer plus 2. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer plus 3.
  • said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone plus 0.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone plus 1 . In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone plus 2. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized plus 3.
  • the multi-responsive self-healing polymers provided herein are functionalized in a pH responsive manner by maintaining the first pH value below the pKa value of the polymer, wherein said polymer is functionalized with one or more monomer unit(s).
  • the first pH value is below the pKa value of the polymer backbone, such between 0 and the pKa value, such as within the range of 0 up to the pKa value minus 0.5, or such as within 0 and the pKa minus 1 .
  • the first pH is preferred larger than or equal to 0 and smaller than or equal to 8 or the pKa value of the polymer backbone, whichever is smaller.
  • the first pH is within 0 and 7 or the pKa value of the polymer backbone, whichever is smaller.
  • the first pH is within 1 and the pKa value of the polymer backbone.
  • the first pH value is below the pKa value of the functionalized polymer backbone, such between 0 and the pKa value, such as within the range of 0 up to the pKa value minus 0.5, or such as within 0 and the pKa minus 1 .
  • the first pH is preferred larger than or equal to 0 and smaller than or equal to 8 or the pKa value of the functionalized polymer backbone, whichever is smaller.
  • the first pH is within 0 and 7 or the pKa value of the polymer, whichever is smaller.
  • the first pH is within 1 and the pKa value of the functionalized polymer backbone.
  • the first low pH-value is below 8 or below the pKa value of the polymer backbone amine group. In an embodiment of the invention, the first pH-value is below the pKa value of the backbone polymer. In a preferred embodiment of the invention, the first pH value is below the pKa value of the backbone polymer minus 1 .
  • metal ligand affinity and the ligands metal affinity depend upon pH.
  • mono-complexes are typically formed.
  • the bond stoichiometry of the complex bond is increased thereby establishing an inter- polymer network.
  • An initial binding of the metal ions in the mono-complex at low pH is beneficial to prevent metal oxide or hydroxide precipitation at increased pH as some metal ions have low solubility in alkaline environment.
  • the multi-responsive self-healing polymers obtained with the method provided herein are further functionalized in a pH responsive manner by
  • the second pH value will determine the strength of the obtained hydrogel as further described below.
  • the second pH value is within the range from above the first pH value up to the pKa value of the backbone polymer plus 9; such as within the range from the first pH value plus 0.5 up to the pKa value plus 9.
  • the mechanical strength of the multi-responsive self-healing polymers provided herein is based on two opposing effects, which are an increasing mechanical strength caused by the increase in bond-stoichiometry and a decreasing mechanical strength caused by the break-down of the hydrogel structure.
  • the hydrogels obtained are multi-responsive, e.g. due to their pH-multi-responsiveness.
  • the hydrogels obtained have the potential for their mechanical properties to be adjusted to match a number of applications by selecting the polymer based on its pKa value.
  • the initial binding of the Fe(lll) ions in the mono-complex at low pH is crucial to prevent Fe(l ll) oxide precipitation at increased pH as Fe(ll l) ions have low solubility in alkaline environment.
  • the mono-, bis- and tris- complex formed between catechol-DOPAs and Fe(ll l) ions are shown below.
  • the polymer backbone comprises DOPA functionalized polyallylamine and the metal is Fe(l ll)
  • the mono-complexes dominate in the pH-range of 1 -5.
  • the polymer backbone comprises DOPA functionalized polyallylamine and the metal is Fe(l ll)
  • the bis-complexes dominate in the pH range of 5-10.8.
  • the polymer backbone comprises DOPA functionalized polyallylamine and the metal is Fe(l ll)
  • the tris-complexes dominate in the pH-range above 10.8.
  • Figure 1 shows UV/VIS absorption spectra of the DOPA-polyallylamine Fe(ll l)-gel at different values spanning from pH 1 to pH 12 Moreover
  • Figure 2 shows the calculated fraction of mono-, bis- and tris-catechol
  • the pKa value of the functionalized polymer backbone is in about the same range as the non-modified counterparts. In a specific embodiment thereof, the pKa value of the functionalized polymer backbone is in about the same range as the non-modified counterparts due to low grafting densities of the catechol monomer unit(s) with the polymer backbone.
  • the grafting density refers to the fraction of catechol-functionalizable polymer side chains which are actually functionalized by catechol monomer units. In one embodiment of the invention, the grafting density is between 0.01 % and
  • the grafting density is between 1 % and 20%. In yet one further embodiment of the invention, the grafting density is between 3% and 15%. In one specific embodiment, the grafting densities as estimated through a least squares refinement of potentiometric data are no more than 20%, such as no more than 15%. In a particular embodiment, said grafting density is no more than 10%, such as no more than 5%. In yet further embodiment, said grafting density is no more than 3%, such as less than 1 %. More particularly, said grafting density may be in the range of 5-15%, such as 7-13%.
  • the grafting density is controlled by e.g. the ratio of DOPA:polymer; the efficiency of coupling reaction, the reaction time and the reaction conditions, such as pH, temperature etc.
  • a DOPA grafting density of the DOPA-polyallylamine polymers was estimated through a least squares refinement of potentiometric data and was in the range of 7.8-1 1 .2%.
  • the pKa values of the functionalized polymer backbone is in the same range as the non-modified counterparts such as wherein the difference between the pKa value of the functionalized polymer backbone and the pKa value of a corresponding polymer backbone which is not functionalized is no more than ⁇ 2.0 such as no more than ⁇ 1 .
  • said difference is no more than ⁇ 0.75, such as no more than ⁇ 0.5.
  • said difference will be no more than ⁇ 0.25.
  • the pKa value of the DOPA-polyallylamine backbone amine has been shown to be slightly higher (9.29 ⁇ 0.06 - 9.65 ⁇ 0.09) than that for polyallylamine (8.80 ⁇ 0.19) at the same concentration (-0.01 M).
  • the pH at which the mechanical properties of the hydrogels of the present invention are optimal is adjusted by changing the pKa value of the functionalized polymer backbone and thus of the monomer(s) constituting the polymer backbone (i.e. the backbone monomer unit(s)). That is, at a pH above the pKa value of the functionalized polymer backbone, the hydrogel structure will collapse and phase separation will occur, due to the reduction of the hydrophilicity of the polymers. Consequently, the mechanical strength will decrease.
  • hydrogels provided herein are mechanically strongest at a pH which is in the range of the pKa of the functionalized polymer backbone.
  • the DOPA functionalized chitosan Fe(ll l)-hydrogels is mechanically strongest in the range of the pKa value of chitosan, which is 6.5. Chitosan's pKa value is close to physiological pH and the system will thus be suitable for tissue engineering applications.
  • the DOPA functionalized polyallylamine Fe(lll)-hydrogels are mechanically strongest in the range of the pKa value of polyallylamine, which is approximately 9.5.
  • the below scheme display the obtained DOPA-chitosan and DOPA-polyallylamine polymers (A).
  • B-D highlights the key pH responsive parts of these polymers in the specific case of Fe(l ll) functionalization.
  • the term 'curing pH' refers to the pH at which the maximum storage modulus is obtained.
  • maximum strength and maximum mechanical strength refer to the maximum storage modulus.
  • the mechanical strength of the hydrogels obtained by the method of the present invention was found to display a close-to Gaussian pH-dependency.
  • the pH- dependency of the hydrogels of the present invention fit into the Gaussian model of below Equatio Equation 1
  • y is the storage modulus
  • y 0 is the baseline offset
  • A is the total area under the Gaussian curve from the baseline
  • x c is the center of the peak
  • w is defined by means of the "Full With of Half Maximum" parameter ⁇ FWHM): i Equation 2
  • the maximum mechanical strength of the hydrogel provided herein is obtained at a pH which is in the range of the pKa of the functionalized polymer backbone.
  • the hydrogel obtained has a significant strength, even at pH-levels beyond the pKa of the functionalized backbone polymer.
  • the hydrogel obtained has a significant strength, also at pH-levels above the pKa of the functionalized backbone polymer.
  • the pH value of the maximal strength of the multi-responsive self-healing polymer is determined by the pKa value of the functionalized polymer.
  • the pH value of the maximal strength of the polymer is obtained in the range pKa -6 to pKa +3.
  • said optimal strength is obtained at a pH within the range of pKa -2.5 to pKa +1 .5.
  • said optimal strength is obtained at a pH within the range of pKa -1 to pKa +0.5.
  • the pH value of the maximal strength of the multi-responsive self-healing polymer is identical to the pKa value of the unmodified polymer backbone, i.e. of the polymer backbone prior to
  • the pH value of the maximal strength of the polymer is obtained in the range pKa -6 to pKa +3.
  • said optimal strength is obtained at a pH within the range of pKa -2.5 to pKa +1 .5.
  • said optimal strength is obtained at a pH within the range of pKa -1 to pKa +0.5.
  • the pH value of the maximal strength of the multi- responsive self-healing polymer obtained with the process disclosed herein is determined by properties of other components of the system.
  • said maximal strength is determined by properties of other components of the system where said components comprise copolymer segments not involved in DOPA functionalization.
  • said components comprise copolymer segments not involved in DOPA functionalization.
  • temperature of the maximal strength of the polymer is determined by thermo- responsive properties of the polymer.
  • the mechanical strength of a DOPA- polyallylamine Fe(lll)-hydrogel obtained by the method disclosed herein was found to display a Gaussian pH-dependency.
  • said hydrogel has a maximum strength of about 7000 Pa at pH 9.3 which correspond to the pKa of the DOPA-polyallylamine polymer backbone.
  • said hydrogel has a significant strength at a pH below the pKa of the DOPA- polyallylamine polymer backbone, such as e.g a strength of at least 700 Pa, e.g. of at least 800 Pa.
  • said pH below the pKa of the DOPA- polyallylamine polymer backbone is of.
  • said hydrogel has a mechanical strength of about 820 Pa at pH 6.
  • This embodiment is displayed in figure 3.
  • This material strain hardened above about 30% strain and failed above about 100% strain.
  • the inventors of the present invention found that, hydrogels of the present invention display a non-Newtonian shear-thickening behaviour, which implies that they flow relatively easy at a low applied shear rate and become more resistant to flow when sheared at a high rate.
  • the storage modulus was found to exhibit a strong increase from 0 to 10-15 s "1 after which it stabilized.
  • the loss modulus increases gradually as a function of the angular frequency (figure 4B).
  • the storage moduli of hydrogels of the present invention are at least 1000 Pa, such as within the range from 1000 to 7000 Pa, or within the range from 1 .000 to 40.000 Pa.
  • the hydrogels obtained with the method provided herein has a maximum mechanical strength measured as storage modulus of at least 1000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 2000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 3000 Pa. In a further embodiment
  • the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 4000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 5000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 6000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of about 7000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 10.000 Pa, such as at least 30.000 Pa, e.g. up to 40.000 Pa. In further embodiments of the invention, the hydrogels obtained with the method provided herein has a strength measured as storage modulus at pH 4-8 of at least 500 Pa.
  • the hydrogel has a strength measured as storage modulus at pH 4-8 of at least 700 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 4-8 of at least 1000 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 4-8 of at least 1500 Pa. In a further embodiment, the hydrogel has a measured as storage modulus at pH 4-8 of about 2000 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10-13 of at least 500 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10-13 of at least 700 Pa.
  • the hydrogel has a strength measured as storage modulus at pH 10-13 of at least 1000 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10- 13 of at least 1500 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10-13 of about 2000 Pa.
  • the inventors of the present invention have mapped the mechanical properties of the hydrogels as a function of pH by performing a range of frequency sweeps within the linear viscoelastic deformation range on hydrogels with different final pH. Some of the data obtained are shown in below figure 4.
  • the method of the present invention provides hydrogels having a storage modulus which depends on pH.
  • this has been illustrated in figure 5 that displays the modulus as a function of the amount of NaOH added in the formation of the hydrogels for the four angular frequencies (24.8 s “1 , 49.8 s “1 , 75.6 s "1 and 100 s "1 ).
  • Corresponding pH values are indicated on the graphs.
  • the graphs in Figure 5 result from many individual measurement.
  • the spread of the data points result from the use of a small diameter top-plate in the parallel plate rheological measurements, which are susceptible to non-negligible surface effects. Nevertheless, a consistent and very clear trend is seen.
  • the storage modulus of the DOPA- polyallylamine Fe(lll)-hydrogels display a Gaussian pH-dependency with maximum strength around the polymer's pKa value (pH 9.3-9.7).
  • hydrogels of the present invention have a storage modulus which, regardless of the angular frequency, increases from an initial storage modulus, such as approximately 2000 Pa, at a first low pH-value to its maximum storage modulus, such as approximately 7000 Pa, at a pH-value at about the pKa of the polymer wherein the storage modulus decreases to a storage modulus of about the same strength as the initial storage modulus, such as of approximately 2000 Pa.
  • said hydrogel is a
  • DOPA-polyallylamine Fe(l ll)-hydrogel and said storage modulus increases from an initial storage modulus of approximately 2000 Pa at 10 ⁇ NaOH (pH 4) to approximately 7000 Pa around 35 ⁇ NaOH added (pH 9.3) after which it decreases to approximately the initial value of 2000 Pa at 60 ⁇ NaOH added (pH 12).
  • the corresponding loss moduli at the four angular frequencies show a similar but less clear trend.
  • the storage modulus was also measured on
  • polyallylamine Fe(lll)-samples with similar concentration as for the hydrogel i.e. for polymers not functionalized by DOPA. Data for these are also shown in figure 5.
  • hydrogels of the present invention display a primary elastic behaviour at all pH values (G' > G") at low angular frequencies.
  • the pH 5 hydrogel exhibits a solely viscous response due to prevalence of mono- complexes at pH 5, which implies no cross-linkage of the polymers.
  • the cationic DOPA-polyallylamine Fe(lll)-hydrogels exhibit completely new mechanical properties compared to previous synthesized
  • PEG(DOPA) 4 Fe(ll l)-systems demonstrate a solely increasing mechanical strength as a function of pH with a maximum strength at pH 1 2 where the tris-complex prevails, whereas the DOPA-polyallylamine Fe(l l l)- hydrogels, display a Gaussian mechanical strength distribution that peaks around the polymer's pKa value ⁇ 9.3 - 9.7 (pH 9.3, 33 ⁇ NaOH) where the bis- complexes are abundant.
  • composition W which is a self- healing hydrogel comprising :
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 1 5:1 , such as 50:1 or 1 00:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3: 1 , such as less than 2: 1 , e.g. less than 1 : 1 ; will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 5000 Pa, such as of about 5000-10.000 Pa or about 5000-30.000 Pa.
  • Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i 0 -alk(an/en/yn)yl e.g.
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes, which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 5000 Pa, such as of about 5000-10.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 5000 Pa, such as of about 5000-30.000 Pa.
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-10.000 Pa.
  • composition Y which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa.
  • R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of -H, -OH and Ci -6 -alk(an/en/yn)yl wherein Ci -6 -alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R 7 is selected from the group consisting of -H and -(CO)-Ci -6 -alk(an/en/yn)yl wherein -(CO)-Ci -6 - alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or ⁇ -form thereof as backbone monomer; e.g.
  • glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-40.000 Pa.
  • composition Z which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-40.000 Pa.
  • composition A which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • composition B which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • Such self-healing hydrogels wherein the backbone monomer units are amino-C 1-10 -alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 100 Pa, such as of about 100-5.000 Pa.
  • composition C which is a self- healing hydrogel comprising:
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-10.000 Pa.
  • composition D which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechokmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-10.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-30.000 Pa.
  • composition E which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • Such self-healing hydrogels wherein the backbone monomer units are amino-C 1-10 -alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-5.000 Pa.
  • composition F which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • composition G which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 2.000 Pa, such as of about 2.000-12.000 Pa.
  • composition H which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 500 Pa, such as of about 500-18.000 Pa.
  • composition J which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-5.000 Pa.
  • composition K which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • Such self-healing hydrogels wherein the backbone monomer units are amino-C 1-10 -alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 100-5.000 Pa.
  • composition L which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-10.000 Pa.
  • composition M which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • Such self-healing hydrogels wherein the backbone monomer units are amino-C 1-10 -alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-10.000 Pa.
  • composition N which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-9.000 Pa.
  • composition P which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • Such self-healing hydrogels wherein the backbone monomer units are amino-C 1-10 -alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 100 Pa, such as of about 100-9.000 Pa.
  • composition Q which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-10.000 Pa.
  • composition S which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • Such self-healing hydrogels wherein the backbone monomer units are amino-C 1-10 -alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 100 Pa, such as of about 100-10.000 Pa.
  • composition T which is a self- healing hydrogel comprising:
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-10.000 Pa.
  • composition U which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechokmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • composition AA which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-12.000 Pa.
  • composition AB which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-40.000 Pa.
  • composition AC which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-12.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-40.000 Pa.
  • composition AD which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-40.000 Pa.
  • composition AE which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
  • the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-12.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-40.000 Pa.
  • composition AF which is a self- healing hydrogel comprising:
  • ⁇ amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine,
  • catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
  • the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
  • the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
  • allylamine or amino acids such as of the formula H 2 N-CHR 1 -COOH wherein R 1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa.
  • acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-40.000 Pa. CONTROLLING THE MECHANICAL PROPERTIES
  • the mechanical properties of a multi-responsive self-healing hydrogel of the present invention may be controlled by the degree of cross-linking.
  • cross-linking may be controlled by managing the number of molar equivalents of the metal to catechol monomer units available in the polymer.
  • Cross-linking may also be controlled by managing the number of molar equivalents of base (such as NaOH) added to a composition of the metal and polymer to obtain a pH that favours mono-, bis-, and tris- complexation.
  • base such as NaOH
  • the degree of cross-linking of the self-healing polymer composition may furthermore be controlled by varying the metal to catechol ratio.
  • the amount of base added which ultimately determines the final pH, the polymer concentration, the nature and concentration of co-solvents, the equilibrium concentrations of the deprotonated ligands, and the equilibrium concentrations of all potential coordination complexes, is essential for the polymer gels' properties.
  • the polymer concentration also plays an essential role for properties of the resulting hydrogel. The strength is expected to scale with polymer-concentration at the concentration levels discussed herein.
  • the DOPA grafting density i.e. the fraction of polymer monomer units
  • DOPA DOPA functionalized by DOPA, determines the number of metal-crosslinking sites and hence will be important determinants for strength.
  • Co-solvents, counter ions, and other added components will also allow influencing mechanical properties.
  • the term 'self-healing polymer' refers to a self-healing hydrogel.
  • Hydrogel formation via coordinate-bonds has the advantage of bonds with close-to covalent bond characteristics while still being spontaneously reversible. Such hydrogels are thus capable of repairing themselves spontaneously.
  • the hydrogels obtained with the method provided herein comprise coordinate-bonds and are self- healing.
  • the hydrogels of the present invention thus differ from polymers and gels which have cross-linking from e.g. covalent bonding as those compositions lack coordinate bonding between monomers and a metal.
  • self-healing refers to a property of a material that can undergo such spontaneous repair.
  • self-healing results in restoration of a material to its original chemical structure.
  • self- healing results in restoration of a material to nearly its original chemical structure such as reforming at least one or more coordinate bonds, such as reforming at least two or more coordinate bonds, e.g. at least three or more coordinate bonds.
  • a self-healing polymer according to the invention may have coordinate bonds between a metal and one or more monomer subunits of the polymer. Those coordinate bonds can break from external force and subsequently new coordinate bonds will spontaneously form.
  • the self-healing polymer obtained in the method provided herein undergoes repair by formation of an intermolecular coordinate bond with any catechol-group available, such as with another catechol-group.
  • Self-healing is considered complete when the storage modulus is close to the value prior to fracture such as within 50% or within 70% or within 90%.
  • the inventors of the present invention have succeeded in inventing a method for manufacturing hydrogels which further to a high mechanical strength also possess convincing self-healing properties.
  • the self-healing hydrogels provided with the method of the present invention are capable of reforming upon being cut into pieces. When the pieces are brought into intermediate contact the broken bonds will reform.
  • the hydrogel provided herein will regain at least 75% of its mechanical strength after fracture. In another embodiment thereof, said hydrogel will regain at least 80% of its mechanical strength after fracture. In another embodiment thereof, said hydrogel will regain at least 90% of its mechanical strength after fracture. In yet another embodiment thereof, said hydrogel will regain at least 95% of its mechanical strength after fracture. In yet another embodiment thereof, said hydrogel will regain its original mechanical strength after fracture.
  • the recovery of a DOPA-polyallylamine Fe(l ll)-hydrogel was tested by increasing the amplitude of the oscillation until failure (0.01 -200% strain) at 1 s "1 .
  • the storage modulus (G) was monitored for 8.5 minutes with constant shear (1 %) and constant frequency (1 s "1 ).
  • Figure 6 shows the storage modulus versus % strain and time, respectively. It is seen that the storage modulus is nearly constant until the failure point around 32% strain after which the storage modulus rapidly decreases to zero. After forced fracture the hydrogel recovers faster than 10 s (the first reliable measurement point) to a storage modulus of around 4700 Pa, which is
  • a "forced fracture” is defined as a mechanical fracture of a quantity of material performed by some means, e.g. by using a scalpel, spatula or other tool that is then pressed through the material to separate it into two or more physically distinct parts.
  • the hydrogel of the present invention is capable of recovering its original shape as can be seen in Figure 7 and 8.
  • self-healing will be initiated within 1 second or less after a forced fracture, such as within 1 second. In one embodiment of the hydrogel of the present invention, self-healing is initiated within 30 seconds after a forced fracture. In another embodiment, self-healing is initiated within 2 minutes after a forced fracture. In one embodiment of the hydrogel of the present invention, self-healing will be completed within 2 minutes after a forced fracture, such as within 1 ,5 minutes, e.g. within 1 minute. In one further embodiment, self-healing will be completed within 10 minutes from a forced fracture, such as within 5 minutes. In yet one further embodiment, self-healing will be completed within 120 minutes from a forced fracture, such as within 60 minutes.
  • self-healing is completed within 45 minutes from a forced fracture, such as within 30 minutes from a forced fracture. In preferred embodiments, self-healing is completed within 15 minutes from a forced fracture.
  • Catechol monomer units as used herein for functionalizing the polymer backbone have unique properties related to adhesion.
  • the quinone comprised therein is in part responsible for a binding to organic surfaces and the catechol is responsible for a binding to inorganic surfaces.
  • the two chemical forms of catechol monomer units provide the chemical diversity required to cross-link proteins and adhere proteins to both organic and inorganic surfaces.
  • dopa monomers in both the catechol and quinone form can engage in a range of other non-covalent interactions facilitating adhesion including but not limited to hydrogen bonding, van der Waals interactions, and aromatic surface/substrate interactions.
  • one embodiment of the invention provides control of the adhesive properties of the self-healing polymer provided herein.
  • the adhesive properties of the polymers obtained will be minimized because all catechol-moieties of the catechol monomer units as used herein for functionalizing the polymer backbone will be cross-linked to the metal during complex-formation.
  • the strength of adhesion is measured in a static tensile test as the one disclosed herein below.
  • the self-healing polymer obtained is non-adhesive. In an embodiment thereof, the self-healing polymer obtained is non-adhesive in that it will not join two materials together and resist their separation. In a particular
  • a self-healing polymer having a strength of adhesion which is below 20 kPa is referred to as non-adhesive.
  • the self-healing polymer obtained is non-adhesive due to a stoichiometric ratio of catechol :metal which is below or at 3:1 for octahedrally coordinated metals and below or at 2:1 for tetrahedrally coordinated metals.
  • the self-healing polymer obtained is non-adhesive due to a stoichiometric ratio of catechol :metal is below 3:1 for octahedrally coordinated metals and below 2:1 for tetrahedrally coordinated metals.
  • the self-healing polymer obtained is non-adhesive due to a stoichiometric ratio of catechol :metal is 3:1 for octahedrally coordinated metals and 2:1 for tetrahedrally coordinated metals.
  • a more specific embodiment of the invention provides a self-healing polymer comprising an octahedrally coordinated meta in a stoichiometric ratio of
  • catechohmetal below 3:1 wherein the polymer obtained is non-adhesive in that the strength of adhesion of the self-healing polymer will be less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa.
  • said ratio is below 1 :1 .
  • said ratio is below 2:1 .
  • said ratio is below 3:1 .
  • a more specific embodiment of the invention provides a self-healing polymer comprising an octahedrally coordinated metal in the stoichiometric ratio of catechohmetal of 3:1 wherein the self-healing polymer obtained is non-adhesive in that the strength of adhesion of the self-healing polymer will be less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa. In a particular embodiment thereof, said ratio is about 1 :1 . In another embodiment thereof, said ratio is about 2:1 . In a preferred embodiment of the non-adhesive self-healing polymer, said ratio is 3:1 .
  • catechohmetal below 2:1 wherein the self-healing polymer obtained is non- adhesive in that the strength of adhesion of the self-healing polymer will be less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa. In a particular embodiment thereof, said ratio is below 1 :1 . However in a preferred embodiment thereof, said ratio is below 2:1 .
  • a more specific embodiment of the invention provides a self-healing polymer comprising a tetrahedrally coordinated metals in the stoichiometric ratio of catechokmetal of 2:1 wherein the self-healing polymer obtained is non-adhesive in that the strength of adhesion of the self-healing polymer will be less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa. In a particular embodiment thereof, said ratio is about 1 :1 . In a preferred embodiment of the non-adhesive self-healing polymer, said ratio is 2:1 .
  • the polymers obtained will be adhesive due to the stoichiometric excess of catechol- moieties comprised in the catechol monomer units as used herein as compared to metal.
  • increasing the amount of catechol as compared to metal (molar ratios) will increase the adhesive strength of the self-healing polymer obtained in the process of the present invention.
  • a ratio of catechokmetal of 3:1 or less for octahedrally coordinated metal and of 2:1 or less for trahedrally coordinated metals lead to non-adhesive self-healing polymers such as self-healing polymers which will have a strength of adhesion of less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa.
  • An adhesive hydrogel as used herein refers to a self-healing polymer which can join two materials together.
  • the self-healing polymer obtained is adhesive.
  • the self-healing polymer obtained is adhesive in that it will join two materials together and resist their separation.
  • a particular embodiment of the invention provides a self-healing polymer having a strength of adhesion which is above 20 kPa is referred to as adhesive, such as e.g. above 30 kPa or preferably above 50 kPa or above 100 kPa, e.g. 400 kPa .
  • the adhesives disclosed herein function as glues.
  • the self-healing polymer obtained is adhesive due to a stoichiometric ratio of catechohmetal which is above 3:1 for octahedrally
  • coordinated metals such as Fe(l ll), Al(l ll), Mn(l l), V(lll), Cr(lll), Ti(IV) and Hf(IV) , and above 2:1 for tetrahedrally coordinated metals.
  • the self-healing polymer obtained with the method provided herein is adhesive and the stoichiometric ratio of catechol :metal is above 4:1 for octahedrally coordinated metals and 3:1 for tetrahedrally coordinated metals.
  • the self-healing polymer obtained is adhesive and the stoichiometric ratio of catechohmetal is above or at 6:1 for octahedrally coordinated metals and above or at 4:1 for tetrahedrally coordinated metals.
  • a more specific embodiment of the invention provides a self-healing polymer comprising an octahedrally coordinated metal, in a stoichiometric ratio of catechohmetal above 3:1 wherein the self-healing polymer obtained is adhesive in that the strength of adhesion of the self-healing polymer will be more than 20 kPa, such as e.g. above 30 kPa or preferably above 50 kPa or above 100 kPa, e.g. 400 kPa. In a particular embodiment thereof, said ratio is above 4:1 , such as above or at 6:1 .
  • the self-healing polymer obtained is adhesive in that the strength of adhesion of the self-healing polymer will be more than 20 kPa, such as e.g. above 30 kPa or preferably above 50 kPa or above 100 kPa, e.g. 400 kPa. In a particular embodiment thereof, said ratio is above 3:1 , such as above or at 4:1 .
  • the adhesive properties of the hydrogels of the present invention are illustrated based on complexes formed by Fe(ll l) and DOPA:
  • DOPA:Fe(III) 3: l DOPA:Fe(III) > 3: 1 + pH increase + pH increase
  • the water resistant properties of the hydrogel according to the invention are imparted to a gel material by inclusion of different amounts of amphipathic molecules.
  • amphipathic molecules may include, for example fatty acids such as n-hexanoic acid, palmitic acid and other fatty acids as well as phospholipids.
  • the amphipathic molecules may be added to the polymer prior to pH-induced gelation (addition of alkali to raise the pH).
  • fatty acids for example may be added to decrease the hydration of a polymer matrix and confer water-resistance.
  • amphipathic molecules may be added to decrease the dielectric constant of a polymer matrix, which in turn increases the strength of the metal-catechol coordination bonds.
  • antioxidants may be included to protect catechol from oxidation. Suitable antioxidants include but are not limited to, water-soluble antioxidants such as ascorbic acid, glutathione, mycothiol, trypanothione, ubiquinone, uric acid, lipoic acid, carotene derivatives, such as derivatives of vitamin A, water-soluble derivatives of tocopherols, such as trolox. Also suitable are polyphenolic antioxidants, such as resveratrol. Also suitable are polythiol/thiolates. Also suitable are synthetic antioxidants, such as propyl gallate (PG, E310), tertiary
  • lipid-soluble antioxidants such as tocopherols and tocotrienols (vitamin E), which form a family of structurally related antioxidants, and is known in the art.
  • monomers comprised in the hydrogel according to the invention may comprise functional groups that have polar, non-polar, or both types of groups by covalent linkage.
  • Embodiments include ambifunctional polymers.
  • non-covalent components may be mixed with the polymer that separate into a different phase to form domains within a gel matrix.
  • ambifunctional moieties may assist in excluding water from penetrating a gel, making a more effective coating such as an anti-fouling coating.
  • they could display antioxidant properties.
  • other additives such as anti-microbial and anti-fouling additives may be incorporated to increase the resistance of the polymer to microbial contact.
  • the present invention may carry drugs either through non- covalent encapsulation or by covalent or coordinative bonding. In this embodiment, the present invention has properties desired for a drug delivery system.
  • One aspect of the invention relates to the use of a hydrogel according to the invention.
  • One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as an adhesive, glue, joining, attachment and/or cohesive agent such as e.g. for underwater applications, for dry applications and/or for joining dissimilar substrates such as skin/bandaging and/or rubber/metal.
  • the invention relates to the use of a hydrogel according to the invention as an adhesive or joining agent.
  • said use is as an adhesive.
  • said use is as a consumer adhesive.
  • said use is as a bandage adhesive.
  • said use is as a joining agent.
  • said use is as a glue.
  • said use is for attachment purposes.
  • a hydrogel according to the invention which is suitable for use as an adhesive, glue, joining, attachment and/or cohesive agent such as e.g. for underwater applications, for dry applications and/or for joining dissimilar substrates such as skin/bandaging and/or rubber/metal.
  • said use relates to the use of a hydrogel according to the invention as an adhesive or joining agent.
  • said use
  • said use is as an cohesive agent.
  • said use is for underwater applications.
  • said use is for joining dissimilar substrates such as skin/bandaging and/or rubber/metal.
  • said use is for dry applications.
  • hydrogel formulations comprising compositions W, Y, A, C, E, G, J, L, N, Q, T, AA, AC and/or AE are preferred. More preferred are hydrogel formulations comprising composition W, Y, E, G, L, Q and/or T.
  • hydrogels comprising compositions W, X, Y, Z, A, B,
  • hydrogel formulations comprising compositions Y, G, J, L, Q, AA and/or AE are most preferred.
  • the self-healing and cationic natures of the hydrogel formulations comprising compositions W, X, Y, Z, A, B, C, D, E, F, G, H, J, K, L, M, N, P, Q, S, T, U, AA, AB, AC, AD, AE and/or AF are especially advantageous as are their capability to function underwater.
  • the invention relates to the use of a hydrogel according to the invention as a self-healing material, such as for use as a self- healing coating.
  • a self-healing material such as for use as a self- healing coating.
  • said use is for lining a pipe.
  • the self-healing nature of the hydrogel is essential.
  • Hydrogel formulations comprising compositions A-Z and AA-AF disclosed herein above are all of use in this regard, but preferred are formulations with the highest self-healing capability and strength, e.g. hydrogel formulations comprising compositions B, D, F,
  • hydrogel formulations comprising compositions D, F, H, M, S, U, X and/or Z.
  • the invention relates to the use of a hydrogel according to the invention for under-water purposes.
  • said use is as a sea-water adhesive, an under-water coating or a coating with antifouling capabilities.
  • the hydrogel of the invention is for under-water purposes, the hydrogel comprises a polymer backbone having a maximum mechanical strength at a pH between 7 and 9, such as at a pH about 8.
  • hydrogel formulations comprising any of A-Z and AA-AF are useful, but preferred are formulations comprising polymers with the desired pKa values.
  • hydrogels based on polyallylamine, polyornithine with catechols provided by 3,4-dihydroxyphenylacetic acid (DHPAA),3,4- dihydroxycinnamic acid (DHCA), 2,4,5-trihydroxybenzoic acid, 3-(3,4- dihydroxyphenyl)propanoic acid, 3-(3,4-dihydroxyphenyl)-2-methyl-alanine, 2,4,5- trihydroxy-phenylalanine, 2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid, (2R)-3-(3,4-dihydroxyphenyl)-2- ⁇ [(2E)-3-(3,4-dihydroxyphenyl)-2- propenoyl]oxy ⁇ propanoic acid (Rosmarinic acid), dopamine and L-DOPA and D- DOPA; or any isomers or mixtures thereof will be preferred.
  • DHPAA 3,4-dihydroxyphenylacetic acid
  • DHCA 3,5-trihydroxybenzo
  • the pKa of the polymer can be further optimized by changing its chemical nature as is also illustrated by the explicit examples described herein.
  • hydrogel formulations comprising any of compositions Y, Z, C, D, E, F, J, K, N, P, Q, S, T, U, AA, AB, AC, AD, AE and/or AF are preferred.
  • the invention relates to the delivery of the mixture of step 2 to a location in the body whereby the hydrogel subsequently cure in step 3, due to the increased pH derived from the tissue. This embodiment has the advantage that the need of surgical invasion is minimized. Moreover a high hydrogel strength is obtained.
  • hydrogel formulations comprising any of compositions A-Z are of use in this regards but hydrogel formulation comprising any of compositions W, X, Y, Z, A, B, C, D, G, H, J, K, L, M, Q, S, AA, AB, AC and/or AD are preferred.
  • One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use to glue, attach, adhere and/or join implants to desired locations in the body such as: a. Dental implants; b. Dental filling material be it plastic, polymeric, metal, ceramic or any mixture and/or composite thereof; c.
  • Orthopedic implants including bone and cartilage implants; d. For catheter fixation; e. For fixation of internal medical devices of other kinds, e.g. i) insulin or other pumps; ii) power supplies, motors or computers; and/or iii) artificial heart valves or blood vessels (including auto-, alio- and xeno-grafts).
  • the invention relates to the use of a hydrogel according to the invention as a bonding agent for implants.
  • One embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join dental implants to desired locations in the mouth.
  • Another embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join dental filling material such as plastic, polymeric, metal, ceramic or any mixture and/or composite thereof to a tooth.
  • dental filling material such as plastic, polymeric, metal, ceramic or any mixture and/or composite thereof to a tooth.
  • Using a hydrogel of the invention to glue, attach, adhere and/or join dental filling material is advantageous because the acid step being present in conventional methods can be avoided.
  • Another embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join orthopedic implants such as bone and cartilage implants to desired locations.
  • Another embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join with the purpose of catheter fixation.
  • hydrogel formulations comprising any of compositions W, Y, A, C, E, G, J, L, N, Q and/or T are preferred. More preferred are hydrogel formulations comprising any of compositions W, Y, A, C, G, J, L, Q and/or T.
  • hydrogel formulations comprising any of compositions W, Y, C, G, J, L, Q and/or T.
  • hydrogel formulations comprising any of compositions Y, Z, A,
  • the self-healing and cationic natures of the hydrogels are especially advantageous as are their capability to function underwater.
  • a hydrogel according to the invention which is suitable for use as a drug delivery vehicle, e.g. as an internal nicotine patch or for delivery of any other drug.
  • drug delivery vehicle e.g. as an internal nicotine patch or for delivery of any other drug.
  • such drug delivery vehicle is used in combination with other drug delivery platforms.
  • the invention relates to the use of a hydrogel according to the invention as a drug delivery matrix.
  • said drug delivery matrix comprises a polymer backbone having a maximum mechanical strength at a pH below 7.
  • hydrogels comprising any of compositions A-Z may all be useful when formulated with polymers with pKa values below 7, e.g. chitosan or poly(4-amino styrene) or analogous polymers as starting point. Hydrogels based on chitosan are more preferred. In terms of choice of metals, hydrogel formulations comprising any of compositions W, X, Y, Z, A, B,
  • One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as a tissue adhesive, glue, cohesive agent such as: a.
  • Applications in the oral cavity including tongue, lip or oral cavity surgery, e.g.
  • cheek/gum surgery b. In connection with eye surgery, e.g. cataract operation; in this connection transparent hydrogels; c. In place of existing tissue adhesives either internally or externally i.e. on skin; d. In place of sutures in connection with surgery, e.g. in relation to use as soft tissue sutures and/or biodegradable sutures; and/or d.
  • tissue adhesives either internally or externally i.e. on skin
  • sutures in connection with surgery, e.g. in relation to use as soft tissue sutures and/or biodegradable sutures; and/or d.
  • d for fixation of skin grafts.
  • the use of a hydrogel of the invention is advantageous because the surfaces are glued together and the resulting bond has self-healing properties to protect the joint from wear and tear. Moreover, when used as wound a sealant, the hydrogel of the invention will even obviate suture in surgery.
  • the invention relates to the use of a hydrogel according to the invention as a tissue adhesive.
  • a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications in the oral cavity including tongue, lip or oral cavity (cheek/gum) surgery.
  • a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications in connection with eye surgery, e.g. cataract operation; in this embodiment, transparent hydrogels (such as those based on Ca, Ga, Zn, Al, or Ti) are preferred.
  • Yet another specific embodiment thereof relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications in place of existing tissue adhesives either internally or externally (on skin). Yet another specific embodiment thereof relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications in place of sutures in connection with surgery, e.g. in relation to use as soft tissue sutures and/or biodegradable sutures. Yet another specific embodiment thereof relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications for fixation of skin grafts. In a particular embodiment thereof, said hydrogel comprises a polymer backbone having a pKa of about 7.
  • hydrogel formulations comprising any of compositions W, X, Y, Z, A, C, E, G, J, K, L, M, N, Q, T, AA, AB, AD and AF are preferred. More preferred are hydrogel formulations comprising any of compositions W, Y, A, C, G, J, L, Q, X, Z, AA, AB, AF, AD and/or T. Most preferred are hydrogel formulations comprising any of compositions W, Y, C, G, J, L, Q, X, Z, AD, AF and/or T.
  • hydrogel formulations comprising any of compositions Y, Z, A, G, J, K, L, M, Q, AA, AB and/or AF are most preferred.
  • the self-healing and cationic natures of the present hydrogels are especially advantageous as are their capability to function underwater.
  • hydrogels comprising a polymer backbone having a pKa of about 7 are most preferred; chitosan is one example of such a most preferred polymer backbone.
  • the invention relates to the use of a hydrogel according to the invention as a bio-adhesive.
  • One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as a part of a wound-care product.
  • the hydrogel properties are of special advantage as they support a moist environment.
  • certain combinations will be particularly advantageous such as: a. wound healing applications; b.
  • a hydrogel containing an uncolored ion may be of cosmetic advantage; and/or c.
  • tissue/organ scaffold As tissue/organ scaffold.
  • One specific embodiment relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for wound healing applications wherein the metal is Zn. Such hydrogel is particularly useful for that purpose, because zinc aids wound healing/reduces irritation.
  • Another specific embodiment relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications where the hydrogel is visible to the eye, a hydrogel containing an uncolored ion will be of cosmetic advantage.
  • hydrogels based on Ca, Mg, Ga, Zn, Al, and/or Ti are preferred.
  • a combination of metals will be useful, e.g. the toning the color of the hydrogel by mixing Fe(l ll) with Al(ll l).
  • Another specific embodiment relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent as a tissue/organ scaffold.
  • any of the compositions X, Z, B, D, F, H, K, M, P, S, U, AB, AD, and/or AF may be used.
  • One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use to stop bleeding, such as by: a. Addition of a solution below curing pH, which then cures when in contact with body pH; and/or b. By extracting metals from surrounding medium and then curing.
  • the invention relates to the use of a hydrogel according to the invention to stop bleedings.
  • said hydrogel comprises a polymer backbone having a pKa between 6 and 8, such as at a pKa of about 7.
  • bleeding is stopped by addition of a solution below curing pH, which then cures when in contact with body pH.
  • hydrogel with a strength pH maximum as close to physiological as possible will be advantageous.
  • bleeding is stopped by extracting metals from surrounding medium and then curing.
  • a hydrogel with little to no metal added prior to application may be used and a hydrogel with a strength pH maximum as close to physiological as possible will be advantageous.
  • hydrogel formulations comprising any of compositions X, Z, B, D, F, H, K, M, P, S, U and /or AB are preferred with hydrogel formulations comprising any of compositions X, Z, B, D, H, K, M, S, and/or U being more preferred.
  • One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as metal sorbants, e.g. for removing metals from streams and/or mixtures etc.
  • the metal sorbate is for use for removing metals from liquids such as waste water, blood, radioactive liquids, reaction streams and/or mixtures thereof.
  • the polymer/polymer solution is added to waste water/radioactive liquids/reaction streams and
  • the metals may be removed by complex bonding to the catechol-functionalized polymers and aggregates are formed, which subsequently can be removed by e.g. filtration.
  • the polymer is used in the treatment of patients suffering from iron overload
  • the polymer/polymer solution may be applied in the body and the iron is removed from the blood as it is becomes cross- linked to the catechol-functionalized polymer.
  • the polymer is preferentially attached by chemical bonding to a carrier surface, e.g. a bead, membrane, interior bead surface or other. This allows use in combination with flow-through processing. This embodiment may be used in combination with the previously mentioned embodiments given the added benefit of easy recycling of the polymer.
  • hydrogel formulations comprising any of compositions X, Z, B, D, F, H, K, M, P, S, U, AB, AD and/or AF are preferred.
  • hydrogel formulations comprising any of compositions X, Z, B, D, H, K, M, S, U, AB, AD and/or AF are more preferred.
  • the invention relates to the use of a hydrogel according to the invention as a metal sorbate. In another particular embodiment, the invention relates to the use of a hydrogel according to the invention in removing metals from liquids such as from waste water, blood, radioactive liquids.
  • Composition A of the present invention is particular useful for use in dry
  • Composition B of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition C of the present invention is particular useful for use in dry
  • Composition D of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition E of the present invention is particular useful for use in dry
  • Composition F of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition G of the present invention is particular useful for use in dry applications, for use in contact with the human body, for use underwater, for use in sea-water, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
  • Composition H of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition J of the present invention is particular useful for use in dry
  • Composition K of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition L of the present invention is particular useful for use in dry
  • Composition M of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition N of the present invention is particular useful for use in dry
  • Composition P of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition Q of the present invention is particular useful for use in dry
  • Composition S of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition T of the present invention is particular useful for use in dry
  • Composition U of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition W of the present invention is particular useful for use in dry
  • Composition X of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition Y of the present invention is particular useful for use in dry
  • Composition Z of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition AA of the present invention is particular useful for use in dry applications, for use in contact with the human body, for use underwater, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle and for use to fixate skin grafts.
  • Composition AB of the present invention is particular useful for use underwater, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
  • Composition AC of the present invention is particular useful for use in dry applications, for use in contact with the human body, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
  • Composition AD of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives and for use as metal sorbants.
  • Composition AE of the present invention is particular useful for use in dry
  • Composition AF of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, and for use as metal sorbants.
  • Hydrogels of the present invention may be suitable for use in dry applications.
  • dry applications include as adhesives outside of water, self-healing coatings etc.
  • Particular useful compositions for dry applications are compositions A, C, E, G, J, L, N, Q, T, W, Y, AA, AC and AE.
  • Hydrogels of the present invention may be suitable for use underwater outside the human body.
  • Examples of such uses include antifouling coatings, lining in pipes and gluing and/or adhering two materials under water. Particular useful
  • compositions for underwater applications are compositions A, B, C, D, G, H, J, K, L, M, Q, S, T, U, W, X, Y, Z, AA, AB, AC, AD, AE and AF.
  • Hydrogels of the present invention may be suitable for use in contact with the human body. Examples of use in contact with the human body includes treatment of wounds, materials that stop bleedings, fixation of skin grafts, implant fixation or coating, drug delivery vehicles and/ systems and for use in the mouth cavity.
  • compositions A, B, C, D, G, H, J, K, L, M, Q, S, T, U, W, X, Y, Z, AA, AB, AC, AD, AE, and/or AF are particularly useful compositions A, B, C, D, G, H, J, K, L, M, Q, S, T, U, W, X, Y, Z, AA, AB, AC, AD, AE, and/or AF.
  • Hydrogels of the present invention may be suitable for gluing or adhering two different materials to each other.
  • uses include fixation of skin grafts, fixation of implants or other biomaterials including bandages, tubing, power supplies etc., fixation of rubbers or plastics on metals or glass and fixation of glass on metals.
  • Particular useful compositions for use to gluing/adhering two different materials include B, H, K, M, P, S, U, X, Z, AB, AD and/or AF.
  • Hydrogels of the present invention may be suitable for use as self-healing coatings.
  • Examples of such uses include materials preventing / repairing rupture of a coated material.
  • Particular useful composition use as self-healing coatings are
  • compositions W, X, Y, Z, AA, AB, AC, AD, L and M are particularly useful as advantт.
  • hydrogels comprising Gd(l ll) (or other paramagnetic ions) may be used as a contrast medium in MRI.
  • Any polymer from the claimed group of backbone polymers can have the claimed catechol monomers, comprising at least either an amine or a carboxylate group, grafted there onto. This can be done using standard carbodiimide coupling chemistry. For example using y-ethyl-3-(3-dimethylaminpropyl)-carbodiimide hydrochloride in combination with equimolar amounts of A/-Hydroxysuccinimide.
  • the grafting density can be controlled by the ratio of catechol monomer to backbone polymer. The specific optimal ratio will depend on the choice of backbone polymer used.
  • Hydrogels can be made in the following manner:
  • Step 1 dissolve the catechol functionalized polymer in water at the desired concentration (or by other means than dissolution including dilution from
  • the pH shall be at least 1 pH unit below the pKa of the backbone polymer amine and preferably also low enough to ensure that the metals are soluble; for Fe(l ll) pH should be below ⁇ 6, preferably below 5.
  • an appropriate starting salt could be the chloride, which by itself obtains an acidic solution due to the acidic nature of Fe(lll) aqua complexes; similar considerations hold for many other metals.
  • Step 2 Make a solution of the metal at a concentration leading to the desired molar ratio in the final mixture.
  • the metal to catechol molar ratio should be less than 3:1 for octahedrally bound metals and less than 2:1 for tetrahedrally bound metals.
  • 3 (2) mole metal ion should be used per mole catechol for octahedrally (tetrahedrally) bound metal ions.
  • ⁇ 3 mole metal ion should be used per mole catechol for octahedrally bound metals such as Fe(l ll) and ⁇ 2 mole metal ion per mole catechol for tetrahedrally bound metals, e.g. Cu(l l).
  • 1 -2.9 mole metal ions per mole catechol can be used for octahedrally bound metals (analogously for tetrahedrally bound metals).
  • the pH of the metal solution can be adjusted so that it is also below that of the pKa of the backbone polymer amine. This can be the case if the metal solution is not at the required pH, e.g. if a basic salt has been used as metal source.
  • Step 3 Mix volumes of the polymer and metal, where said volumes are determined to obtain the desired molar ratio of catechol to metal.
  • pH is within the range pKa-5 to pKa+3, where pKa is the backbone polymer pKa value.
  • pH is within the range pKa-2 to pKa+1 or more specifically within pKa-1 .5 to pKa+0.5.
  • the desired volumes of polymer, metal, base solutions are added to a recipient directly and then mixed.
  • a base of high concentration e.g. 1 or 2 M.
  • the final pH, and material properties can be adjusted by adding base and water in the appropriate ratio.
  • Hydrogels can conveniently be made at room temperature. The hydrogels form rapidly, within minutes after mixing, but in most cases, it is advantageous for characterization of properties for let them mature for a set time, e.g. 0.5 h or 1 h to ensure that diffusion has rendered them completely homogenous. It is important for reproducibility that the maturation takes place in a manner reducing solvent evaporation, e.g. by placing the gel in a closed container with a small free air volume.
  • this maturing period can be reduced if so desired, e.g. to 10 min or 5 min or 1 min after mixing.
  • chitosan as the backbone polymer and DOPA as the catechol.
  • Chitosan is dissolved in water and functionalized with DOPA as follows: a quantity of DOPA corresponding to 2 times the number of moles of chitosan amine groups is dissolved in 0.5% TFA continuously degassed with Ar.
  • Step 1 Hydrogels are made by dissolving the DOPA functionalized chitosan polymer in acidic water.
  • Step 2 The desired metal is added at pH -1 -3.
  • Step 3 Thereafter pH is raised using e.g. NaOH as base to obtain hydrogels.
  • DOPA-functionalized polymers DOPA was grafted onto polymers using standard peptide coupling chemistry. 4.2 g DOPA (21 .4 mmole) (Sigma Aldrich, CAS no. 59-92-7) was dissolved in 0.47 L 0.5 % TFA, which was continuously degassed with argon. The dissolution was aided by ultrasonication. Next, 1 g solid polyallylamine hydrochloride (10.7 mmole) (Polysciences Inc., CAS no. 71550-12-4) was added to the reaction mixture in which it dissolved. The pH was adjusted to 6 by a slow addition of 2 M NaOH.
  • Step 1
  • the polymer solution was mixed with 1 /6 final volume (25 ⁇ _) of FeCI 3 -6H 2 0 solution that had a concentration resulting in a final DOPA to Fe(ll l) ratio of 3:1 .
  • Binding Fe(l ll) in stable non-cross-linking mono-DOPA-Fe(lll) complexes allowed base addition (Raising the pH) to favor the formation of bis-, and tris-complexes without precipitation of ferrihydrite or other iron salts.
  • the Fe(ll l)/polymer solutions were always made fresh before any subsequent experiments. Samples with other polymer concentrations can be prepared as well.
  • Mn(l l) gels were obtained by using a Mn(ll) sulfate instead of the iron compound. 3. Synthesis of hydroqels;
  • step 3a Either step 3a or step 3b is employed:
  • the hydrogel was formed by addition of 2/6 final volume NaOH (50 ⁇ _) to the solution described in 2 above at a concentration adjusted to obtain the requested final pH of the hydrogel (Step 3).
  • the gel was mixed until homogenous color and physically state were established (for about 1 minute). After the gels were obtained they were matured in closed containers for 1 h until e.g. the rheology
  • DOPA-polyallylamine in all gels used in the experiments below was 150 mg/mL (15 wt%) with a final molar ratio of DOPA to Fe(l ll) of 3:1 .
  • Samples with other polymer concentrations can be prepared; however, if the concentration is too low gels are not formed and if it is too high the kinetics of gel formation becomes affected and bulk mixing becomes difficult.
  • the pH of gels was measured with a flat surface electrode designed for solids, semi-solids and liquids (Fieldscount Soilstick pH- meter, SpectSpectrum Technologies, Plainfield, Illinois).
  • the gel was created by adding 2/6 final volume (50 ⁇ _) NaOH at a concentration adjusted to get the requested final pH of the gel. (e.g. to get a gel with a final pH of approximately 9, 35 ⁇ _ 2M NaOH + 15 ⁇ _ 1 M NaOH was added).
  • the solution instantaneously changed color from green to wine red and at the edge of the alkaline drop a purple/blue color appeared.
  • the color development can be assigned to the different complexes formed in the sample.
  • the wine-red color in the middle of the basic droplet is due to the formation of tris-complexes at high pH and at the edge of the droplet the purple color appears due to the formation of predominantly bis-complexes.
  • the hydrogel is established by homogenization for a minute with a spatula.
  • the characteristic mono-complex peaks were found to be located at 406 nm, 505 nm and at 660 nm.
  • the characteristic bis- and tris-complex peaks were located at approximately 538.5 ⁇ 1 .3 nm and 418 ⁇ 4 nm, respectively.
  • the relative fractions were obtained by normalizing the areas of the characteristic peaks associated with the different complexes to the maximum area-value for each characteristic peak.
  • a Fe(l ll):DOPA-polyallylamine solution with a DOPA concentration of 0.4 mM and a DOPA to Fe(l ll) ratio of 3:1 was titrated against NaOH, whilst the pH was monitored with a Metrohm pH-meter equipped with a Metrohm Unitrode. The pH was increased in steps of -0.5-1 pH units to a final pH of 12 and the spectral changes were monitored by performing UV-Vis absorption measurements at every step from 200 nm to 800 nm at ambient temperature with a scanning rate of 600 nm/min.
  • the relative abundance of the mono-, bis- and tris-catechol-Fe(l ll) complexes was extracted by fitting a multi- Gauss function in an iterative manner to the collected absorption data and models for characteristic absorption of the mono-, bis- and tris-complex were proposed that could be used to describe all absorption curves.
  • the characteristic mono-complex peaks were found to be located at 406 nm, 505 nm and at 660 nm.
  • the characteristic bis- and tris-complex peaks were located at approximately 538.5 ⁇ 1 .3 nm and 418 ⁇ 4 nm, respectively.
  • the relative fractions were obtained by normalizing the areas of the characteristic peaks associated with the different complexes to the maximum area-value for each characteristic peak. As no constraints on the sum of fractions were imposed in the modeling of the data, it can be used to test the quality of the employed models. The sum of fractions is to a good approximation 1 in the pH range above pH 2. Below pH 2 the sum of fractions is less than 1 , which suggest that some of the Fe(lll) ions are free in the solution. Hence, it can be concluded that the deduced models provide a sufficient description of the absorption data.
  • the mechanical properties of the hydrogels were measured with an Anton Parr MCR 501 Rheometer using parallel plate geometry (8 mm rotating top plate). An Anton Parr evaporation hood equipped with a custom made accessory was employed to prevent solvent evaporation. Prior to each measure the hydrogels were allowed to rest for 1 hour in air tight containers to facilitate complete diffusion and relaxation of the polymer network. Frequency sweeps was performed in the linear viscoelastic range (LVR) at constant strain amplitude of 15 % (LVR is e.g. 0- 30% strain for a pH 9 hydrogel) while the storage and loss modulus was
  • Quantitative recovery test was likewise performed on a hydrogel that had med allowed to rest for 1 hour prior to the measurements.
  • the strain amplitude was increased until failure (0.01 -200% strain) under constant angular frequency (1 s "1 ).
  • the storage modulus was monitored at constant strain (1 %) and angular frequency (1 s "1 ).
  • SAXS Small Angle X-rav Scattering
  • Hydrogels obtained as disclosed herein are applied to a test surface of 25 mm by 25 mm and an identical test surface pressed onto this area. Thereafter the glue is allowed to cure for the chosen time after which a tensile test is run till failure; the force at this point measures the strength of adhesion.
  • the test surface is selected from the following: glass, steel, skin, tissue, bone and cartilage
  • Metal :DOPA-polyallylamine hydrogels may also be prepared by using the below method:
  • polymer backbone comprises one or more backbone monomer unit(s) which is/are selected from the group consisting of:
  • R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of -H, -OH and Ci -6 -alk(an/en/yn)yl wherein Ci -6 - alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and
  • R 7 is selected from the group consisting of -H and -(CO)-Ci -6 - alk(an/en/yn)yl wherein -(CO)-C 1-6 -alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
  • metal shall be added in an amount corresponding to a final concentration of ⁇ / ⁇ .
  • the metal chloride solution in step b. is diluted.
  • the starting solution is concentrated.
  • AICI 3 -6H 2 O (AICI 3 ) was employed as metal source.
  • a transparent faint red/orange gel instantly formed.
  • the prepared hydrogel showed self-healing properties and recovered within minutes after forced fracture as can be seen in the following three pictures. Pictures of the hydrogel are shown in Figure 13.
  • ZnCI 2 was used as metal source. When mixed in the recipe-described proportions an orange/red solution formed. If twice as much Zn(l l) was employed a light purple/white sticky gel was formed. Pictures of the hydrogel are shown in Figure 1 1 .
  • MnCI 2 -4H 2 O was used as metal source.
  • a yellow/green hydrogel formed instantly upon mixing.
  • the hydrogel was very liquid-like and recovered within seconds after forced fracture. Note that a thin skin with a brown shade formed on the surface of the hydrogen and this might possible be explained by DOPA-oxidation. Pictures of the hydrogel are shown in Figure 12.
  • hydrogels were prepared according to the recipe described above with AICI 3 H 2 O, Ga(NO 3 ) 3 -3.12 H 2 O and lnCI 3 -4H 2 O as metal sources in step 2 of the hydrogel formation process.
  • the UV/Vis absorption measurements were performed on metal:DOPA-polyallylamine solutions with a metal:DOPA ratio of 1 :3 and a DOPA concentration of 40 mM using a Helius Alfa double-beam spectrophotometer equipped with disposable UV-Vis cuvettes having a path length of 1 cm.
  • the pH of the solutions was increased in steps of 0.5-1 pH units to a final pH of 12 while the spectral changes were monitored at each pH step.
  • the pH of the AI(ll l):DOPA-polyallylamine system was reduced to pH 1 after having reached pH 12.
  • UV/VIS spectra are shown with the left graph showing the wavelength span from 200-800 nm while the right graph displays a zoom onto the wavelength range 200-500 nm.
  • the bottom curve in the figure below shows the absorption profile measured on the pH 1 solution after having reached pH 12.
  • Absorption bands in the region above 300 nm can still be seen after the pH has been returned to 1 from 1 1 .9; thus, some quinone tanning has occurred in the alkaline pH range and the Al(l ll) ions do not protect the catechol completely from being oxidized. Note that addition of antioxidants may alleviate this effect.
  • UV/VIS spectra were also measured for a corresponding Ga(ll l) solution, which is shown in Figure 16 and for the In(lll) solution in Figure 17.
  • the measured storage modulus G' is plotted as a function of the final pH of the probed metal:DOPA-polyallylamine hydrogels for the angular frequency 25 s "1 .
  • a maximum in the mechanical strength is obtained within a few pH values above neutral pH in all the metal-DOPA-polyallylamine systems again reflecting that a maximum in the mechanical properties is obtained around the polymers pKa value (DOPA-polyalyllamine's pKa value ⁇ 9.5).
  • Example 4 Varying the metal :DOPA ratio

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Abstract

The present invention provides a novel method of forming hydrogels with a physiological relevant curing p H and a polymer thus obtained. With the present invention, the p H-optimum for the maximum strength of the multi-responsive self- healing polymer can be controlled.

Description

Multi-responsive self-healing polymer and gel compositions
Field of invention
The present invention relates to a method of forming a multi-responsive self-healing polymer and the polymer thus obtained.
Background of invention
Patients with open wounds are highly susceptible to infections as their natural skin barrier is disrupted. In the case of severe wounds patients might also suffer from haemorrhaging. Immediate treatment and physical closure of the wounds are therefore crucial in order to prevent bacterial infection, halt bleeding and facilitate healing. Tissue adhesives have the potential to improve wound treatments and surpass sutures and staples, because they can decrease the risk of inflammation and skin irritation, are less time consuming than alternative treatments and provide superior cosmetic results. Additionally, they do not have to be subsequently removed as they can be engineered to naturally degrade within the body.
The tissue adhesives currently commercially available include Fibrin glue, Gelatin- Resorcinol-Formaldehyde (GRF) glue and Cyanoacrylate glue. The major concern with Fibrin glue is the risk of blood-borne disease transmission from human derived clot precursors, particularly hepatitis and HIV. Furthermore, it is limited in strength. Cyanoacrylate and GRF glue both release formaldehyde upon degradation, which is histotoxic and can cause acute and chronic inflammation. It is therefore necessary to develop improved tissue adhesives.
A tissue adhesive should not only be biocompatible and biodegradable, but also waterproof with a consistently high adhesive strength. Most commercial glues lose adhesive strength over time as moisture weakens the adhesive bonds. Furthermore, if the cohesive bonds are broken, they cannot reform, due to the irreversible nature of covalent bonds. A solution to this problem is to mimic the blue mussel's self-healing byssal threads as they have the ability to form strong underwater bonds to a wide range of surfaces, from inorganic to organic materials, including classically adhesion-resistant materials such as Teflon, and even in wet environments. A major advantage to use new materials based on mimicking the blue mussel's self-healing byssal threads is that these new materials are non-toxic, and it is expected that different uses, including medical uses, of such materials are easily granted by national medical agencies, because they are based on compounds, which can be found in the nature.
Adhesive forces in water are severely reduced due to the dielectric constant of the surrounding water. The byssal threads contain Fe(l l l) ions and high amounts of the amino acid 3,4-dihydroxyphenylalanine (also known as DOPA). DOPA has unique properties related to adhesion as well as cohesion and is the main reason why byssal threads are able to attach to surfaces under water. Furthermore, it has been shown that incorporation of Fe(l ll) ions in the byssal threads imparts strength and self-healing properties by the formation of strong, reversible tris-DOPA-Fe(ll l) cross-links.
Fe(l ll)-DOPA adhesion system of the blue mussel has been mimicked by Holten- Andersen (WO201 1 /084710) in the formation of adhesive self-healing pH- responsive hydrogels of Fe(lll) ions and DOPA functionalized PEG polymers.
However, the systems disclosed therein have a curing pH around 12 and it was not shown how to decrease the curing pH of the adhesive towards physiological pH (pH ~ 7.4), therefore their use is restricted. Finally, WO201 1/084710 discloses the maximum mechanical strength of the polymer obtained by the method disclosed therein to be about 103-104 Pa. There is, therefore, an unmet need of improved self-healing bio-adhesives and coatings, such as self-healing polymer materials, of which the mechanical strength is increased, self-healing polymer materials of which the mechanical strength can be controlled and / or self-healing polymer materials which can be easily delivered and that solidify in situ to form strong and durable interfacial adhesive bonds and are resistant to the normally detrimental effects of water. Some of the potential applications for such biomaterials include consumer adhesives, bandage adhesives, tissue adhesives, bonding agents for implants and drug delivery. Summary of invention
The inventors of the present invention have now, surprisingly, succeeded in inventing a novel method of forming multi-responsive self-healing polymers with a physiological relevant curing pH. Moreover, with the method of the present invention, the pH-optimum for the maximum strength of the multi-responsive self- healing polymers thus obtained can be controlled. It is thus, surprisingly, possible to adjust the mechanical performance of self-healing polymers to match a number of applications. Furthermore, as compared to known self-healing polymers the present invention provides multi-responsive self-healing polymers with improved properties in respect of mechanical strength, e.g. in that the maximum mechanical strength of polymers obtained with the method of the present invention is surprisingly high, namely at least 1000 Pa.
Accordingly, hydrogels provided herein are useful in treatment of e.g. open wounds. Such hydrogels protect wounds against infections while the natural skin barrier is disrupted and thus provide protection against e.g. haemorrhaging. Due to fast curing of hydrogels provided herein, immediate treatment and physical closure of the wounds is provided and thus bacterial infection, halt bleeding and facilitate healing may be prevented.
Hydrogels which function as tissue adhesives have a potential to improve wound treatments and surpass sutures and staples, because they can decrease the risk of inflammation and skin irritation, are less time consuming than alternative treatments and provide superior cosmetic results. Additionally, some of the hydrogels provided herein do not have to be subsequently removed as they can be engineered to naturally degrade within the body. Some of the hydrogels provided herein are not only biocompatible and biodegradable, but also waterproof with a consistently high adhesive strength. Moreover, the hydrogels provided herein are capable of forming strong under-water bonds to a wide range of surfaces, from inorganic to organic materials, including classically adhesion-resistant materials such as Teflon, and even in wet
environments. Accordingly, one aspect of the present invention provides a method of making a hydrogel, said method comprising the steps of:
1 . providing a functionalized polymer backbone; wherein the polymer
backbone comprises one or more backbone monomer unit(s) comprising an amino group;
said polymer backbone being functionalized with one or more catechol monomer unit(s),
said catechol monomer units comprising at least one amino group and/or carboxylate-group;
2. contacting said functionalized polymer backbone with a solution comprising a soluble metal of formula Mn+ or any complex thereof at a first pH value, where n is an integer from 1 to 9; and
3. adjusting the pH of the polymer metal solution to a second pH value,
wherein the second pH value is higher than the first pH value;
whereby hydrogel is obtained, said hydrogel having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
Another aspect of the invention relates to a hydrogel comprising:
a. a functionalized polymer backbone; wherein the polymer backbone
comprises one or more backbone monomer unit(s) comprising an amino group;
• said polymer backbone being functionalized with one or more catechol monomer unit(s),
· said catechol monomer units comprising at least one amino group and/or carboxylate-group;
b. a metal of formula Mn+ or any complex thereof;
said hydrogel having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
One further aspect of the invention relates to the use of a multi-responsive self- healing polymer provided herein. In more detail, herein provided are self-healing multi-pH responsive hydrogel systems having a cationic nature as is illustrated by the below DOPA functionalized polyallylamine herein below:
For the polymer itself, an amine side groups or a carboxylate side group and a catechol monomer unit exemplified by DOPA. The catechol/quinone equilibrium both depend on pH. By adding metals, the polymers are further functionalized in a pH-dependent manner as the number of coordinating catechol monomer units per metal atom depends on pH. At reasonably optimal grafting densities, each grafted- on catechol monomer unit will be next to an amine or carboxylate functionality. The multi-pH-responsive design of the hydrogels provided herein will facilitate control over the mechanical properties of the hydrogels and the reversible nature of the complex bonds will impart self-healing properties to the materials.
Accordingly, the hydrogels provided herein will obtain the maximum mechanical strength when the pH is close to the polymer's pKa value. When the pH is below the polymer's pKa value, the polymers are highly charged facilitating the formation of a hydrogel. As the pH is increased the stoichiometry of the complex bond changes from a mono- to bis- to tris-complexes, when using Fe as example, and the mechanical strength increases. Simultaneously, but at a different rate, the amines or carboxylates will start to deprotonate. Therefore, the hydrogel structure will collapse at a pH above the polymer's pKa value and consequently, the mechanical strength of the hydrogel decreases. Thereby this multi-pH-responsive hydrogel design allows, contrary to existing DOPA:Fe(ll l) systems, for the mechanical properties to be adjusted to match a number of application by selecting the polymer based on its pKa value. Description of Drawings
Figure 1 shows UV/VIS absorption spectra of the DOPA-polyallylamine Fe(lll)-gel at different values spanning from pH 1 to pH 12.
Figure 2 shows the calculated fraction of mono-, bis- and tris-catechol Fe(lll) complexes as a function of pH based on the UV/VIS data provided in Figure 1 .
Figure 3 shows the storage modulus G' as a function of strain at a frequency of 1 s"1 measured on a DOPA-polyallylamine Fe(lll)-hydrogel (20 μηιοΙ NaOH added in the final hydrogel formation step, pH 6).
Figure 4 shows a selection of the frequency sweeps on DOPA-polyallylamine Fe(lll)- gels with different amount of NaOH added. A) Storage modulus G' and B) loss modulus G" as a function of angular frequency.
Figure 5 shows the storage modulus G' of DOPA-polyallylamine Fe(lll)-gels as a function of the molar amount of NaOH added for the angular frequencies A) 24.8 s"1 , B) 49.8 s"1 , C) 75.6 s~1 and D) 100.0 s~1. The least squares refined Gaussian distributions are shown by the bell-formed curves. Measurements performed for the polyallylamine Fe(lll)-solutions at the same concentration as the DOPA-polyallylamine Fe(lll)-gels is indicated by the almost straight horizontal line at about 0.
Figure 6 displays the result of a quantitative recovery test performed using a
rheometer. The data shows that the resulting storage modulus is nearly constant (slightly increasing) until the failure point around 32% strain after which the storage modulus rapidly decreases to zero. After forced fracture the hydrogel recovers faster than 10 s (the first reliable measurement point) to a storage modulus of around 4700 Pa, which is approximately the initial value (3800 Pa) when accounting for solvent evaporation. The tests can be repeated several times and recovery after failure remains rapid.
Figure 7 shows photographs of a DOPA-polyallylamine Fe(lll)-hydrogel. Figure 7A is a top view picture of a DOPA-polyallylamine Fe(lll)-hydrogel with a fracture induced by a scalpel. The hydrogel was prepared to have a pH of 8. Figure 7B is a picture of the gel from figure 7A after the two pieces have been brought into contact.
Figure 8 shows the self-healing properties through shape recovery over a period of 45 minutes of the DOPA-polyallylamine Fe(lll)-hydrogel from figure 7B. The side view pictures of the hydrogel shown above, illustrate the recovery of stiffness and cohesiveness after fracture: A): 0 minute after forced fracture, B) 2 minutes after forced fracture, C) 45 minutes after forced fracture. Figure 9 shows the radius of gyration Rg as a function of pH, which has been obtained from SAXS data. The data was obtained for cationic polyallylamine and Fe(lll):DOPA- polyallylamine, respectively.
Figure 10 shows a self-healing hydrogel of Ca(ll):DOPA-polyallylamine.
Figure 1 1 shows a self-healing hydrogel of Zn(ll):DOPA-polyallylamine.
Figure 12 shows a self-healing hydrogel of Mn(ll):DOPA-polyallylamine. Figure 13 shows a self-healing hydrogel of AI(lll):DOPA-polyallylamine.
Figure 14 shows a self-healing hydrogel of Ga(lll):DOPA-polyallylamine.
Figure 15 shows UV/VIS spectra of a AI(lll):DOPA-polyallylamine system in the pH range of 1 -12. The left and right figure shows the wavelength ranges 200-850 and 200- 500 nm, respectively. The individual measurements appear in order given by the labels on the right.
Figure 16 shows UV/VIS spectra of a Ga(lll):DOPA-polyallylamine system in the pH range of 1 -12. The individual measurements appear in order given by the labels on the right.
Figure 17 shows UV/VIS spectra of a ln(lll):DOPA-polyallylamine system in the pH range of 1 -12. The individual measurements appear in order given by the labels on the right. Figure 18 shows the storage modulus G' as a function of the final pH of the
metakDOPA-polyallylamine hydrogels for the angular frequency 25 s~\ where the metal is Al(lll), Ga(lll) and In(lll), respectively.
Figure 19 shows the storage modulus G' for gels made with Fe(lll) as a function of pH for a metakDOPA ratio of 1 :6 and 1 :9.
Figure 20 shows a test of de-gelation by competitive binding of Fe(lll) by EDTA performed on Fe(lll)-gel at ratio 1 :3.
Figure 21 shows a construct comprising two untreated glass slides, which are adhered together with Fe(lll):DOPA-polyallylamine for use in shear testing. Figure 22 shows a gel, which has been prepared by use 3,4-dihydroxyphenylacetic acid-polyallylamine polymer with Fe(lll).
Figure 23 shows the storage modulus G'for Fe(lll): 3,4-dihydroxyphenylacetic acid- polyallylamine gels.
Figure 24 shows a 1 H NMR of a DOPA-functionalized chitosan, in which the chitosan oligosaccharide had 5000 Da molecular weight on average.
Figure 25 shows a FTIR spectrum of a DOPA-functionalized chitosan, in which the chitosan oligosaccharide had 5000 Da molecular weight on average.
Figure 26 shows the storage modulus G'for a Fe(lll):DOPA-chitosan hydrogel having the ratio of 1 :3. Figure 27 shows a test of de-gelation by competitive binding of Fe(lll) by EDTA performed on Fe(lll):DOPA-chitosan gel at a metakDOPA ratio 1 :3.
Detailed description of the invention
In more detail, one aspect of the present invention provides a method of making a hydrogel, said method comprising the steps of: 1 . providing a functionalized polymer backbone; wherein the polymer backbone comprises one or more backbone monomer unit(s) comprising an amino group;
said polymer backbone being functionalized with one or more catechol monomer unit(s),
said catechol monomer units comprising at least one amino group and/or carboxylate-group;
2. contacting said functionalized polymer backbone with a solution comprising a soluble metal of formula Mn+ or any complex thereof at a first pH value, where n is an integer from 1 to 9; and
3. adjusting the pH of the polymer metal solution to a second pH value,
wherein the second pH value is higher than the first pH value;
whereby a hydrogel is obtained, said polymer having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
One embodiment of the invention relates to such method, wherein the second pH value is obtained by addition of a solid, liquid, or gaseous base. The use of gaseous base is advantageous when the method is used in large scale, such as in industrial scale, whereas the use of liquid base is advantageously used in smaller scale, such as in laboratory scale. In one particular embodiment thereof, said base is ammonia, e.g. from ammonium carbonate. In another particular embodiment thereof, said base comprises OH", such as e.g. a base selected from the group consisting of KOH and NaOH.
In one further embodiment, one or more co-solvent(s) is/are optionally comprised when contacting the polymer with the solution comprising a soluble metal of formula Mn+ or any complex thereof at a first pH-value or alternatively at a later stage in the procedure.
In one further embodiment of the method disclosed herein, a mixing step is performed upon contacting the functionalized polymer backbone with the solution comprising a soluble metal of formula Mn+ or any complex thereof at a first pH- value. In one embodiment thereof, said mixing is performed using a magnetic stir bar. In yet one further embodiment of the present invention, said mixing is done using a mechanic stirrer. In yet one further embodiment of the present invention, said mixing is done using a hand held and auctioned mixer including but not restricted to a spatula. In yet one further embodiment of the present invention, said mixing is done by diffusion and/or convection and/or advection. In yet one further embodiment of the present invention, said mixing is done by aspiration combined with ejection from a suction device such as a pipette.
In one embodiment of the method disclosed herein, the mixing procedure is performed at temperatures between 0 and 100 °C. In one particular embodiment thereof, said temperature is between 5 and 60 °C. In one further embodiment thereof, said temperature is between 10 and 45 °C. In one further and preferred embodiment thereof, said temperature is between 17 and 33 °C. Another aspect of the invention relates to a hydrogel comprising:
a. a functionalized polymer backbone; wherein the polymer backbone
comprises one or more backbone monomer unit(s) comprising an amino group;
• said polymer backbone being functionalized with one or more catechol monomer unit(s);
• said catechol monomer units comprising at least one amino group and/or carboxylate-group;
b. a metal of formula Mn+ or any complex thereof;
said hydrogel having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
Also provided are hydrogels obtained with the method provided herein. One further aspect of the invention relates to the use of a multi-responsive self- healing polymer provided herein.
Definitions 1 ^
The expression "C1-10-alk(en/yn)yr' means Ci-i0-alkyl, C2-8-alkenyl or C2-i0-alkynyl; wherein:
• The term "C1-10-alkyl" refers to a branched or unbranched alkyl group having from one to ten carbon atoms, including but not limited to methyl, ethyl, prop-1 - yl, prop-2-yl, 2-methyl-prop-l-yl, 2-methyl-prop-2-yl, 2,2-dimethyl-prop-l-yl, but-l- yl, but-2-yl, 3-methyl-but-l-yl, 3-methyl-but-2-yl, pent-1 -yl, [rho]ent-2-yl, pent-3- yl, hex-l-yl, hex-2-yl, hex-3-yl, 2-methyl-4,4-dimethyl-pent-l-yl and hept-1 -yl;
• The term "C2-10-alkeny refers to a branched or unbranched alkenyl group
having from two to ten carbon atoms and one double bond, including but not limited to ethenyl, propenyl, and butenyl; and
• The term "C2-io-alkynyl" refers to a branched or unbranched alkynyl group
having from two to ten carbon atoms and one triple bond, including but not limited to ethynyl, propynyl and butynyl.
The term "C1-6-alk(en/yn)yl" means C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl; wherein:
• The term "C1-6-alkyl" refers to a branched or unbranched alkyl group having from one to six carbon atoms, including but not limited to methyl, ethyl, prop-1 - yl, prop-2-yl, 2-methyl- prop- 1 -yl, 2-methyl-prop-2-yl, 2,2-dimethyl-prop- 1 -yl, but- 1 -yl, but-2-yl, 3-methyl-but- 1 - yl, 3-methyl-but-2-yl, pent-1 -yl, pent-2-yl, pent-3-yl, hex-l-yl, hex-2-yl and hex-3-yl;
• The term "C2-6-alkenyl" refers to a branched or unbranched alkenyl group
having from two to six carbon atoms and one double bond, including but not limited to ethenyl, propenyl, and butenyl; and
• The term "C2-6-alkynyl" refers to a branched or unbranched alkynyl group having from two to six carbon atoms and one triple bond, including but not limited to ethynyl, propynyl and butynyl.
The term "C2-4-alk(en/yn)yl" means C2-4-alkyl, C2-4-alkenyl or C2-4-alkynyl; wherein:
• The term "C2-4-alkyl" refers to a branched or unbranched alkyl group having from two to four carbon atoms, including but not limited to prop-1 -yl, prop-2-yl, 2-methyl- prop- 1 -yl, 2-methyl-prop-2-yl, but- 1 -yl and but-2-yl; • The term "C2-4-alkenyl" refers to a branched or unbranched alkenyl group having from two to four carbon atoms and one double bond, including but not limited to ethenyl, propenyl, and butenyl; and
• The term "C2-4-alkynyl" refers to a branched or unbranched alkynyl group having from two to four carbon atoms and one triple bond, including but not limited to ethynyl, propynyl and butynyl.
The term "C3-alk(en/yn)yl" means C3-alkyl, C3-alkenyl or C3-alkynyl; wherein:
• The term "C3-alkyl" refers to a branched or unbranched alkyl group having three carbon atoms, including but not limited to prop-1 -yl and prop-2-yl;
• The term "C3-alkenyl" refers to a branched or unbranched alkenyl group having from three carbon atoms and one double bond, including but not limited to propenyl; and
• The term "C3-alkynyl" refers to a branched or unbranched alkynyl group having from two to four carbon atoms and one triple bond, including but not limited to propynyl.
The terms "amino-Ci-i0-alk(an/en/yn)yl", "amino-Ci-6-alk(en/yn)yl", "amino-C2-4- alk(en/yn)yl" and "amino-C3-alk(en/yn)yl" as used herein refers to "C1-10- alk(an/en/yn)yl", "C1-6-alk(en/yn)yl", "C2-4-alk(en/yn)yl" and "C3-alk(en/yn)yl" as defined herein above which is substituted with an amino group (-NH2) in a terminal position of said alk(an/en/yn)yl.
POLYMER BACKBONE
As used herein, the term 'polymer backbone' refers to the series of covalently bonded atoms that together create a continuous chain of a polymer molecule.
Within the context of the present invention, a polymer backbone comprises backbone monomer units, which may be identical or different from each other, and of which at least one comprises one or more amino group(s) or groups that can be functionalized so as to comprise one or more amino group(s).
Preferably, the polymer backbone is cationic. A cationic polymer is a polymer which is positively charged within a given pH range. Common for cationic (and anionic) polymers are that their solubility and structural conformation depend on pH and their pH behaviour is dependent upon the pKa value of their side chains.
In one embodiment of the invention, the polymer backbone comprises one kind of backbone monomer unit(s), only, said backbone monomer unit(s) comprising one or more amino groups. In another embodiment of the invention, the polymer backbone comprises more than one kind of backbone monomer unit(s), wherein at least one kind of backbone monomer units comprises one or more amino groups. In yet another embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are cationic at said first pH value. In yet one further embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are stimuli-responsive. By the term "stimuli-responsive" as used herein is meant that the polymers respond/change conformation when being actuated by a stimuli e.g. pH, temperature, humidity, light etc. In yet one further embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are thermo-responsive. By the term "thermo-responsive" as used herein is meant that the polymers undergo a physical change when external thermal stimuli are presented. In yet one further embodiment of the invention, the polymer backbone comprises one or more backbone monomer(s) which is/are pH-responsive. In yet one further embodiment of the invention, the polymer backbone comprises one or more backbone monomer(s) which is/are soluble in water. In yet one further embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are selected from the group consisting of:
· amino-C1-10-alk(an/en/yn)yl which is optionally substituted;
• amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an
organic substituent;
• amides of the formula -(CO)-(NH2)-Ci-6-alk(an/en/yn)yl-NH2;
• aminostyrenes which are optionally substituted; and
· amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)-(CHR3)-
(CHR4)-(CHR5)-OH; wherein
o R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6- alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and
o R7 is selected from the group consisting of -H and -(CO)-Ci-6- alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
in their open chain form or in the a-form or β-form thereof.
Accordingly, said polymer backbone may comprise any of the backbone polymer units disclosed herein and it may comprise any mixture thereof with other monomer units known to the skilled person. In one preferred embodiment, the backbone monomer units comprised in the polymer backbone are identical, such as allylamine. In another embodiment, two different kinds of backbone monomer units are comprised in the polymer backbone. In yet another embodiment, three different kinds of backbone monomer units comprised in the polymer backbone, such as in a polymer backbone made of chitosan.
In a particular embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) with a pKa ranging from 4 to 10, such as from 5-10. In a specific embodiment thereof, said pKa ranges from 6-9, such as from 7- 8.
In the present context the pKa value of the polymer is taken to be the same as the pi of the polymer defined as the pH where half the polymer pH-responsive groups are charged and the other half is uncharged.
The method of the present invention is applicable to polymer backbones which in addition to backbone monomer unit(s) comprising one or more amino group(s) may further comprise any other monomer unit(s) known to the skilled person. Based on the intended use of the hydrogel obtained, the skilled person will know which backbone monomer units to be incorporated into the backbone polymer. Essential for a purposive selection of backbone monomer units to be incorporated into the backbone polymer is the pKa of the resulting backbone polymer. Accordingly, the pKa of the resulting backbone polymer shall preferably be within the range of a pH which is appropriate for the intended use of the obtained hydrogel. Accordingly, for a hydrogel for human applications, the pKa of the backbone polymer shall preferably be between 6 and 8, such as about 7. In particular, for a hydrogel for a drug delivery matrix, the pKa of the backbone polymer shall preferably be below 7. In particular, for a hydrogel for a tissue adhesive, the pKa of the backbone polymer shall preferably be about 7. In particular, for a hydrogel to stop bleedings, the pKa of the backbone polymer shall preferably be between 6 and 8, such as about 7. Furthermore, for a hydrogel for under-water applications, the pKa shall preferably be between 1 and 9, such as about 8.
Accordingly, in one embodiment of the invention, the polymer backbone has a pka between 7 and 9, such as a pKa of about 8. In another embodiment of the invention, the polymer backbone has a pKa of below 7. In one further embodiment of the invention, the polymer backbone has a pKa between 6 and 8, such as at a pKa of about 7. Furthermore, in one embodiment of the invention, the functionalized polymer backbone has a pKa between 7 and 9, such as a pKa of about 8. In another embodiment of the invention, the functionalized polymer backbone has a pka of below 7. In one further embodiment of the invention, the functionalized polymer backbone has a pKa between 6 and 8, such as at a pKa of about 7.
In one embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are thermo-responsive and one or more backbone monomer unit(s) selected from the group consisting of:
• amino-Ci-io-alk(an/en/yn)yl which is optionally substituted;
· amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent;
• aminostyrenes which are optionally substituted; and
• amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)-(CHR3)- (CHR4)-(CHR5)-OH; wherein
o R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6- alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and o R7 is selected from the group consisting of -H and -(CO)-Ci-6- alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
in their open chain form or in the a-form or β-form thereof.
In one specific embodiment of the present invention, the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino- C1-10-alk(an/en/yn)yl which is/are optionally substituted with one or more
substituents.
In one particular embodiment thereof, the polymer backbone comprises one or more backbone monomer unit(s) which is/are thermo-responsive and one or more backbone monomer unit(s) selected from the group consisting of amino-C1-10- alk(an/en/yn)yl which is optionally substituted. In one specific embodiment thereof, DOPA is the functionalizing catechol monomer unit which is grafted to the polymer backbone.
In one further specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino- Ci-6-alk(an/en/yn)yl which is optionally substituted with one or more substituents. In yet one further specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino- C2-4-alk(an/en/yn)yl which is optionally substituted with one or more substituents. In yet one further specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino-
C3-alk(an/en/yn)yl which is optionally substituted with one or more substituents. In a preferred embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) of the formula: ~^ *" . The backbone polymer unit allylamine has a pKa value of about 9.3.
In an even more specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is selected from the group consisting of amino-Ci-i0-alk(an/en/yn)yl, amino-Ci-6-alk(an/en/yn)yl, amino- C2-4-alk(an/en/yn)yl and amino-C3-alk(an/en/yn)yl is selected with one or more substituent(s) selected from the group consisting of -SH, - OH, -COOH, -NH2, -S- CH3, -O-CH3, -CH(OH)-CH3 and -CH(SH)-CH3. In an embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino acids which occur naturally and which do not occur naturally. In a particular embodiment thereof, said amino acid(s) is/are of the generic formula H2N-CHR1-COOH wherein R1 is an organic substituent. In a more specific embodiment thereof, said amino acid(s) is/are of the formula H2N-CHR1-COOH; wherein R1 is selected from the group consisting of -H, -C1-6-alk(an/en/yn)yl, -C1-6-alk(an/en/yn)yl-R2, wherein R2 is selected from the group consisting of -SH, -COOH, C3H3N2, -NH2, -S-CH3, -CO- NH2, -NH-C(NH)NH2, - OH, -CH(OH)-CH3, -SeH, -C8H6N, -C6H5 -C6H4OH, and - C6H3(OH)2.
In one embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) of the formula H2N-CHR1-COOH which is/are is a naturally occurring amino acid. In one particular embodiment thereof, said amino acid(s) of the formula H2N-CHR1-COOH is a naturally occurring amino acid which is selected from the group consisting of DOPA, ornithine, lysine, arginine, histidine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine and valine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being ornithine having a pKa value of about 10.75. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being lysine In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being arginine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N- CHR1-COOH thus being histidine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being aspartic acid. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being glutamic acid. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being serine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being threonine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being DOPA. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N- CHR1-COOH thus being asparagine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being glutamine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being cysteine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N- CHR1-COOH thus being selenocysteine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being glycine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being alanine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N- CHR1-COOH thus being isoleucine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being leucine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being methionine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being phenylalanine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being tryptophan. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N-CHR1-COOH thus being tyrosine. In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are of the formula H2N- CHR1-COOH thus being valine. In one embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are amide(s). In a particular embodiment thereof, said amide(s) is/are of the formula -(CO)-(NH2)-Ci-6-alk(an/en/yn)yl-NH2.
In one embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) which is/are comprising styrene which is optionally substituted. In an embodiment thereof, said styrene is not substituted. In another embodiment thereof, said styrene is substituted with one or more substituents selected from the group consisting of NH2-Ci-6-alk(an/en/yn)yl- and -NH2. In one embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of styrene which is substituted with an amino group. In one embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of styrene which is substituted with NH2- Ci-6-alk(an/en/yn)yl-. In one particular embodiment thereof, said styrene is further substituted with one or more substituents selected from the group consisting of - SH, - OH, -COOH, -NH2, -S-CH3, -O-CH3, -CH(OH)-CH3 and -CH(SH)-CH3. In one specific embodiment thereof, said substituted styrene is para- NH2-Ci-6- alk(an/en/yn)yl-styrene. In another specific embodiment thereof, said substituted styrene is meta- NH2-C1-6-alk(an/en/yn)yl-styrene. In another specific embodiment thereof, said substituted styrene is ortho- NH2-Ci-6-alk(an/en/yn)yl-styrene. In one specific embodiment thereof, said substituted styrene is para-amino-styrene. In another specific embodiment thereof, said substituted styrene is meta-amino- styrene. In another specific embodiment thereof, said substituted styrene is ortho- amino-styrene, such as e.g. 4-aminostyrene having a pKa value of about 4.5. In one embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars. In one particular embodiment thereof, said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and Ci-6- alk(an/en/yn)yl-(CO)- ; wherein C1-6-alk(an/en/yn)yl-(CO)- is optionally substituted with one or more -OH groups; said amino sugar(s) being in its/their open chain form or in the a-form or β-form thereof.
In one specific embodiment of the invention, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH, HO- (CH2)- and -COO" and HO-CH2-CH(OH)- CH(OH)-.
In one further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R3 and R4 are independently selected from the group consisting of -H and -OH.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R3 is -OH.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R4 is selected from the group consisting of -H and -OH, such as wherein R4 is -H, or wherein R4 is -OH. In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R5 is selected from the group consisting of -(CH2)-OH and -COO".
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R6 is selected from the group consisting of -OH and -CH(OH)- CH(OH)-CH2-OH.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R7 is selected from the group consisting of -H and -(CO)-CH3.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are selected from the group consisting of glucosamine, acetyl- glucosamine, galactosamine and sialic acid in their open chain form or in any a- form or β-form thereof.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are selected from the group consisting of glucosamine and acetyl- glucosamine in their open chain form or in any a-form or β-form thereof.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein: R3 is -OH, R4 is -OH, R5 is HO-CH2-, R6 is -OH, R7 is -H, in its open chain form or in any a-form or β-form thereof. In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are glucosamine(s) of the formula:
said glucosamine being in its open chain form or in any a-form or β-form thereof. The backbone polymer unit glucosamine has a pKa value of about 6.3-6.5.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are galactosamine(s) of the formula:
said galactosamine being in its open chain form or in any a-form or β-form thereof. In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein: R3 is -OH, R4 is -OH, R5 is -CH2-OH, R6 is -OH, R7 is -(CO)-CH3; in its open chain form or in any a-form or β-form thereof.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are acetylglucosamine(s) of the formula:
said acetylglucosamine being in its open chain form or in any a-form or β-form thereof.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein: R3 is -OH, R4 is -H, R5 is -COO", R6 is -CH(OH)-CH(OH)-CH2-OH., R7 is -CO-CH3, in its open chain form or in any a-form or β-form thereof.
In yet a further embodiment, the polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars, said amino sugar(s) is/are sialic acid of the formula:
said sialic acid being in its open chain form or in any a-form or β-form thereof.
In yet a further embodiment, the polymer backbone comprises at least 3 monomer units selected from the group of amino sugars, wherein 3 amino sugar(s) comprised in the polymer backbone together form chitosan having the formula:
in its open chain form or in any a-form or β-form thereof.
In yet a further embodiment, the polymer backbone comprises at least 3 backbone monomer units selected from the group of amino sugars, wherein said 3 amino sugars together form chitosan with varying degrees of de-acetylation in its open chain form or in any a-form or β-form thereof. In a preferred embodiment, the polymer backbone comprises at least 3 backbone monomer units selected from the group of amino sugars, wherein said 3 amino sugars together form chitosan which is functionalized with DOPA catechol monomer unit(s).
Accordingly, chitosan is a specific example of a cationic polymer. Chitosan is a linear co-polymer formed from the N-acetyl-D-glycosamine and D-glycosamine:
One such chitosan backbone co-polymer has a pKa value of about 6.3-6.5.
In chitosan, the D-glycosamine and N-acetyl-D-glycosamine are linked through β- glycosidic bonds:
Chitosan is both thermo- and pH-responsive owing to the ionisable primary amines on the chitosan chain that have a pKa value of about 6.5. Further to the close-to physiological pH, chitosan also has the advantage that it is biocompatible and biodegradable. Hydrogels comprising chitosan as the only backbone monomer unit is thus highly advantageous.
Polyallylamine is another specific example of a cationic polymer. Polyallylamine has a pKa value around 9.5. Polyallylamine is a linear homo-polymer formed through polymerization of allylamine. In one embodiment, polyallylamine is used as the free base. In another
embodiment, polyallylamine is used as the hydrobromide. In one further embodiment, polyallylamine is used as the hydrochloride, which is highly soluble in water as the amines along the polymer backbone are already protonated:
Chemical structure of poly(allylamine hydrochloride)
Within the context of the present invention, preferred are such polymer backbones being amino-functionalized polymer backbones with a pKa ranging from
approximately 4 to 10, preferred 5-10.
In one embodiment of the invention, the polymer backbone does not comprise polypeptide or it does not comprise one or more backbone monomer unit(s) selected from the group consisting of dopa such as L-DOPA, lysine such as L- lysine, glutamic acid such as L-glutamic acid, serine such as L-serine, alanine such as L-alanine, a-amino acid N-carboxy anhydride such as N-carbobenzyloxy-L- lysine N-carboxyanhydride or dicarbobenzoxy-L-DOPA N-carboxyanhydride or di- acetyl-DOPA- N-carboxyanhydride, and 3,4-dihydroxyphenylalanine.
In one specific embodiment of the invention, the polymer backbone does not comprise polypeptide. In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are dopa(s) such as L-DOPA(s). In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are lysine(s) such as L- lysine(s). In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are glutamic acid(s) such as L-glutamic acid(s). In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are serine(s) such as L- serine(s). In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are alanine(s) such as L-alanine(s). In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are a-amino acid N-carboxy anhydride such as N-carbobenzyloxy-L-lysine N- carboxyanhydride or dicarbobenzoxy-L-DOPA N-carboxyanhydride or di-acetyl- DOPA- N-carboxyanhydride. In another specific embodiment of the invention, the polymer backbone does not comprise one or more backbone monomer unit(s) which is/are 3,4-dihydroxyphenylalanine. In another specific embodiment of the invention, polymer backbone does not comprise an amino acid, such as a histidine analogue. In another embodiment, said polymer backbone does not comprise cysteine.
In another specific embodiment of the invention, polymer backbone does not comprise an acrylamide, such as n-isopropylamide or N,N-dimethylacrylamide.
In another specific embodiment of the invention, polymer backbone does not comprise polyethylene glycol (PEG) as a backbone monomer unit. In another specific embodiment of the invention, polymer backbone does not comprise polypropylene glycol (PPG) as a backbone monomer unit. In another specific embodiment of the invention, polymer backbone does not comprise polyacrylate. In another specific embodiment of the invention, polymer backbone does not comprise polystyrene. In another specific embodiment of the invention, polymer backbone does not comprise polyvinyl. In another specific embodiment of the invention, polymer backbone does not comprise polypeptide.
In another specific embodiment of the invention, the polymer backbone does not comprise amino-Ci-i0-alk(an/en/yn)yl which is optionally substituted. In another specific embodiment of the invention, the polymer backbone does not comprise amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent.
In another specific embodiment of the invention, the polymer backbone does not comprise amides of the formula -(CO)-(NH2)-C1-6-alk(an/en/yn)yl-NH2.
In another specific embodiment of the invention, the polymer backbone does not comprise amino-styrenes which are optionally substituted. In another specific embodiment of the invention, the polymer backbone does not comprise amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)-(CHR3)- (CHR4)-(CHR5)-OH; wherein
• R3, R4, R5 and R6 are independently selected from the group consisting of - H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and
• R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
in their open chain form or in the a-form or β-form thereof.
THE FUNCTIONALIZING CATECHOL MONOMER
Within the context of the present invention, a 'monomer unit used for functionalizing the polymer backbone' is used synonymous with the term a 'functionalizing catechol monomer unit' and refers to a catechol monomer unit which is grafted to a backbone monomer unit of the polymer backbone, i.e. bound to a backbone monomer unit of the polymer backbone via a covalent bond, said catechol monomer unit comprising at least one catechol functional group and further comprising at least one amino group and/or one carboxylate group. Such polymer backbone may be functionalized with one or more catechol monomer unit(s) which are identical to each other or with one or more monomer unit(s) which are not identical to each other. Accordingly, in an embodiment of the invention, the one or more functionalizing catechol monomer unit(s) comprise(s) at least one amino group. In a particular embodiment, said functionalizing catechol monomer unit(s) comprise(s) exactly one amino group. In one further embodiment thereof, said one or more functionalizing catechol monomer unit(s) comprise(s) at least one carboxylate-group. In a particular embodiment, said functionalizing catechol monomer unit(s) comprise(s) exactly one carboxylate-group. In yet one further embodiment, said one or more functionalizing catechol monomer unit(s) comprise(s) at least one amino group and at least one carboxylate-group.
In one embodiment of the invention, the one or more functionalizing catechol monomer unit(s) comprise(s) at least one amino group and/or one carboxylate- group of the below formula:
wherein:
• R10 is selected from the group consisting of (C1-6-alk(an/en/yn)yl)q-COOH and (Ci-6-alk(an/en/yn)yl)r-NH2 wherein:
• q and r are independently selected from the group consisting of 0 and 1 ;
• R11 is selected from the group consisting of -OH and -H; and when q or r is 1 then C1-6-alk(an/en/yn)yl is optionally substituted with one or more substituents selected from the group consisting of -CH3, -OH, -NH2 and -CO-C=C-R12 wherein:
• R12 is of the formula:
In an embodiment, q is 0. In another embodiment, q is 1 .
In an embodiment, r is 0. In another embodiment, r is 1 .
In an embodiment, R10 is selected from the group consisting of optionally substituted (C2-4-alk(an/en/yn)yl)q-COOH and (C2-4-alk(an/en/yn)yl)r-NH2.
In another embodiment, R10 is selected from the group consisting of optionally substituted (C2-4-alk(an/en/yn)yl)-COOH and (C2-4-alk(an/en/yn)yl)-NH2 wherein -.y
In one further embodiment, R10 is -COOH.
In another embodiment, R10 is -NH2.
In yet another embodiment, R10 is optionally substituted (C2-4-alk(an/en/yn)yl)- COOH.
In yet another embodiment, R10 is optionally substituted (C2-4-alk(an/en/yn)yl)-NH2.
In an embodiment, R11 is -OH.
In another embodiment, R11 is H.
In yet another embodiment, R11 is ositioned as indicated herein:
In yet another embodiment, R11 is positioned as indicated herein:
R11 In yet another embodiment, R11 is positioned as indicated herein:
In a specific embodiment of the invention, the one or more functionalizing catechol monomer unit(s) is/are selected from the group consisting of 3,4- dihydroxyphenylacetic acid (DHPAA),3,4-dihydroxycinnamic acid (DHCA ), 2,4,5- trihydroxybenzoic acid, 3-(3,4-dihydroxyphenyl)propanoic acid, 3-(3,4- dihydroxyphenyl)-2-methyl-alanine, 2,4,5-trihydroxy-phenylalanine, 2-amino-3-(3,4- dihydroxyphenyl)-3-hydroxypropanoic acid, (2R)-3-(3,4-dihydroxyphenyl)-2-{[(2E)- 3-(3,4-dihydroxyphenyl)-2-propenoyl]oxy}propanoic acid (Rosmarinic acid), dopamine and L-DOPA and D-DOPA; or any isomers or mixtures thereof.
In a more specific embodiment of the invention, the one or more functionalizing catechol monomer unit(s) is/are selected from the group consisting of 2,4,5- trihydroxybenzoic acid, 3-(3,4-dihydroxyphenyl)propanoic acid, 3-(3,4- dihydroxyphenyl)-2-methyl-alanine, 2,4,5-trihydroxy-phenylalanine, 2-amino-3-(3,4- dihydroxyphenyl)-3-hydroxypropanoic acid, (2R)-3-(3,4-dihydroxyphenyl)-2-{[(2E)- 3-(3,4-dihydroxyphenyl)-2-propenoyl]oxy}propanoic acid (Rosmarinic acid), dopamine and L-DOPA and D-DOPA; or any isomers or mixtures thereof.
In an even more specific embodiment of the invention, the one or more
functionalizing catechol monomer unit(s) is/are selected from the group consisting of 3,4-dihydroxyphenylacetic acid (DHPAA),3,4-dihydroxycinnamic acid (DHCA ) and DOPA; or any isomers or mixtures thereof.
In one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are 2,4,5-trihydroxybenzoic acid of the formula:
In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are 3,4-dihydroxyphen lacetic acid of the formula: In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are 3-(3,4-dihydroxyphenyl)propanoic acid of the formula:
In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are 3,4-dihydroxycinnamic acid (DHCA ) of the formula:
In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are 3-(3,4-dihydroxyphenyl)-2-methyl-alanine of the formula:
In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are 2,4,5-ttrihydroxy-phenylalanine of the formula:
In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are 2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid of the formula:
In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are (2R)-3-(3,4-dihydroxyphenyl)-2-{[(2E)-3-(3,4-dihydroxyphenyl)-2- propenoyl]oxy}propanoic acid (Rosmarinic acid) of the formula:
In yet one further embodiment, the one or more functionalizing catechol monomer unit(s) is/are dopamine(s) which is/are linked to the backbone polymer via a di- carboxylic acid or other intermediate linker molecule of the formula:
In yet one further embodiment, the one or more functionalizing catechol unit(s) is/are L-DOPA of the formula:
In yet one further embodiment, the one or more functionalizing catechol unit(s) is/are D-DOPA of the formula:
o DOPA (i.e. L-DOPA and/or D-DOPA) is a specific example of such monomer unit(s) used for functionalizing the polymer backbone. DOPA is an amino acid, which is widely distributed in nature. It is produced from the amino acid tyrosine through posttranslational modifications by the enzyme tyrosine hydroxylase. DOPA has two different forms; an unoxidized catechol form and an oxidized quinone form :
Qumone X)PA
Chemical structures of the two forms of DOPA; Catechol-DOPA and Quinone-DOPA.
FUNCTIONALIZING THE POLYMER BACKBONE
When functionalizing a polymer backbone, the catecholic moiety of the
functionalizing monomer unit as used herein, the catecholic moiety must be preserved during the reaction.
The functionalizing monomer used herein comprising e.g. a primary amine and/or a carboxylic acid, such as e.g. in DOPA. Both the amine and the carboxylic acid have the capability to participate in peptide bond formation as nucleophile and
electrophile, respectively.
Furthermore, in a polymer backbone as used herein comprising e.g. a secondary and a primary alcohol as well as a primary amine (or an amide if the monomer is acetylated), such as e.g. a polymer backbone comprising chitosan monomer(s), the primary (non-protonated) amine has the most nucleophilic potential, however it is closely followed by the primary alcohol. Moreover, in a polymer backbone as used herein comprising e.g. one or more primary amine per monomer, such as e.g. polyallylamine, the primary amines and alcohols on chitosan, can participate in nucleophilic attacks.
Consequently, an appropriate approach to conjugate a functionalizing monomer unit as used herein, such as e.g. DOPA, to a backbone polymer as disclosed herein, such as e.g. chitosan or polyallylamine, is through peptide bond formation between the carboxylic acid on DOPA and the primary amines on the polymers.
Another approach to conjugate a functionalizing monomer unit as used herein, said functionalizing monomer unit comprising a carboxylate-group, such as e.g. DOPA, to a backbone polymer as disclosed herein, said backbone polymer comprising a primary alcohol group such as e.g. chitosan, is through ester bonds.
Ester bonds and especially peptide bonds, due to their resonance stabilization, are strong and relatively non-reactive. Furthermore, they can for example be formed through standard carbodiimide chemistry.
In an embodiment of the invention, the one or more catechol monomer unit(s) is/are attached to the polymer backbone via covalent bond(s). In an embodiment thereof, said covalent bonds are ester bonds or peptide bonds or a mixture of ester bonds and peptide bonds. In a particular embodiment thereof, said covalent bonds are a mixture of ester bonds and peptide bonds. In another particular embodiment thereof, said covalent bond is/are peptide bonds. In another particular embodiment thereof, said covalent bond(s) is/are ester bond(s).
A specific embodiment relates to DOPA functionalized polyallylamine and chitosan as shown below:
Chemical structure of A) DOPA functionalized chitosan and B) DOPA functionalized polyallylamine In one embodiment, DOPA, such as L-DOPA, is a functionalizing monomer unit. In other embodiments, DOPA is not a functionalizing monomer unit.
For illustrative purposes, suitable reaction conditions for the synthesis of DOPA- chitosan is determined to be a DOPA to chitosan ratio of 2:1 and a reaction pH of 6. Such as a DOPA to chitosan ratio of 1 .5-2.5 : 0.5-1 .5 e.g. a DOPA to chitosan ratio of 1.8-2.2 : 0.8-1 .2.
Catechol and quinone comprised in catechol monomer units as used herein for functionalizing the polymer backbone may participate in e.g. oxidizing metal cross- linking, cross linkage by a Shiff-base-reaction between a quinone-moiety and an amino acid residue, cross-linkage by a Michael-type-reaction between a quinone- moiety and an amino acid residue, creation of an aryloxy-radical followed by an aryl-aryl-coupling, oxidation of the catechol to the quinone form and binding of a catechol to a surface-bound metal.
Furthermore, catechol monomer units as used herein for functionalizing the polymer backbone may have an ability to participate in a number of side reactions. For instance, an amine on such catechol monomer unit may make a nucleophilic attack on the carboxylic acid of another catechol monomer unit.
For illustrative purposes, the below scheme provides an overview of some reactions which DOPA can participate in:
Schematic illustration of the reactions DOPA can participate in. Note that the scheme does not provide a complete flowchart, a) Oxidizing metal cross-linking DOPA proteins. In this case
Fe(ll l) is the metal, b) Cross linkage of DOPA-proteins by a Shiff-base-reaction between
quinone-DOPA and an amino acid residue, c) Cross-linkage of DOPA-proteins by a Michael- type-reaction between quinone-DOPA and an amino acid residue, d) Creation of an aryloxy- radical, which can continue reacting by f) an aryl-aryl-coupling of DOPA-proteins. e) Oxidation of the catechol to the quinone form, g) An example of DOPA binding to a surface, M = metal.
From Deming, T. J. Mussel byssus and biomolecular materials. Current Opinion in Chemical Biology 3, 100-105 (1999)
In some instances it may be advisable to prevent side reactions by use of a protection group during functionalization of the backbone polymer with one or more monomer unit(s).
THE METAL
Metals suitable within the present invention are metals that can engage in coordinate bonding. Included are those metals which can have more than one oxidation state.
In one embodiment of the invention, the metal comprised in the self-healing polymer is a transition metal. In another embodiment, the metal used in the method of the invention is selected from metals which have a high affinity for coordinate binding to 3,4-dihydroxyphenylalanine. In yet another embodiment, the metal used in the method of the invention is selected from metals which have a high affinity for coordinate bonding to dihydroxybenzene derivatives. In one further embodiment, the metal is ionic, that is, it does not form a covalent bond with a carbon atom such as would be present in a bond between a platinum atom and a phenyl derivative.
In one further embodiment, the soluble metal of formula Mn+ designates such metals wherein n is selected from the group consisting of 2, 3, 4, 5 or 6. In another embodiment thereof, n is selected from the group consisting of 2, 3 and 4. In yet another embodiment thereof, n is 2. In yet another embodiment thereof, n is 3. In yet another embodiment thereof, n is 4.
In one further embodiment, M designates iron, aluminium, titanium, vanadium, manganese, copper, chromium, magnesium, calcium or silicon. In one preferred embodiment thereof, M designates iron. In further embodiments, M designates iron, aluminium, titanium, vanadium, manganese, copper or chromium. In a further embodiment, M designates Ga, Fe, Al, Mn, V, Cr, Ti, Cu, Zn, Mg, Ca, Ag, Au, Ni or Co. In a further embodiment, M designates Ga, Fe, Al, Mn, V, Cr, Ti, Cu, Zn, Mg or Ca. In a further embodiment, M designates Ga, Fe, Al, Mn, V, Cr, Ti, Cu, Zn, Mg, Ca, In, Ln or Hf, where Ln represents a member of the Lanthanides that includes La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu. In a further embodiment, M designates Ga, Fe, Al, Mn, V, Cr, Ti, Cu, Zn, Mg, Ca, Ag or Au. In a further embodiment, M designates Ga(l ll), Fe(ll l), Al(l ll), Mn(ll), V(l ll), Cr(lll), Ti(IV), Cu(l l), Zn(ll), Mg(l l) or Ca(ll). In one yet further embodiment, M designates an octahedrally coordinated metal, such as Ga(l ll), Fe(ll l), Al(ll l), Mn(ll), V(ll l), Ti(IV), Zn(ll), Mg(ll), Ca(l l) or Cr(ll l), e.g. such as Ga(l ll), Fe(lll), Al(ll l), Mn(l l), V(l ll) or Cr(ll l), In one yet further embodiment, M designates a tetrahedrally coordinated metals, such as Cu(l l). In a specific embodiment, M designates Fe, Al, Mn, Mg or Ca. In a further embodiment, M designates Fe, Al, or Ca. In a preferred embodiment, M designates Fe or Al.
In further embodiments, M designates iron, titanium, manganese or copper, such as e.g. wherein M n+ designates Fe(ll l), Cu(ll), Ti(IV) or Mn(ll). In a specific embodiment thereof, M designates iron, such as wherein Mn+ designates Fe(lll). In a further embodiment thereof, M designates aluminium, such as wherein Mn+ designates Al(ll l). In yet a further embodiment thereof, M designates titanium, such as wherein Mn+ designates Ti(IV). In yet a further embodiment thereof, M
designates vanadium, such as wherein Mn+ designates V(l ll). In yet a further embodiment thereof, M designates manganese, such as wherein Mn+ designates Mn(l l). In yet a further embodiment thereof, M designates copper, such as wherein Mn+ designates Cu(ll). In yet a further embodiment thereof, M designates chromium, such as wherein Mn+ designates Cr(l ll). In one further embodiment, at the second pH, the metal of formula Mn+ is coordinated to one, two or three catechol groups comprised in the one or more monomer(s) comprising an amino group and a catechol functional group. In one further embodiment, at the second pH, the metal of formula Mn+ is coordinated to one catechol group comprised in the one or more monomer(s) comprising an amino group and a catechol functional group. In one further embodiment, at the second pH, the metal of formula Mn+ is coordinated to two catechol groups comprised in the one or more monomer(s) comprising an amino group and a catechol functional group. In one further embodiment, at the second pH, the metal of formula Mn+ is coordinated to three catechol groups comprised in the one or more monomer(s) comprising an amino group and a catechol functional group.
In a preferred embodiment, the hydrogel of the present invention is for human applications and Mn+ preferably designates Fe(l ll). In another preferred
embodiment, the hydrogel of the present invention is for human applications and Mn+ preferably designates Fe(lll), Mg(ll), Gd(ll l) or Al(lll).
In another preferred embodiment, the hydrogel of the present invention is for non- human applications and then the order of preference for Mn+ is: Fe(lll), Al(l ll), Ti(IV), Mn(l l), Cu(l l), V(ll l), Cr(l ll), Hf(IV), Ln.
In all embodiments, the metals may also be able to coordinate to amine groups on the polymer backbone; the tendency for a given metal to do this depends on pH, the relative binding strength of metal to DOPA and metal to amine as well as the molar ratios of amine to catechol in the polymer. This adds to the flexibility of the present invention. Note that interactions between metals and amines can effectively lower the pKa value of the amine. Metals particularly prone to bind amines include but is not restricted to Al(l ll), Fe(ll l), Ga(l ll), Cr(lll), Mg(l l), Ca(l l), Ag(l), Au(l ll). Many metals are additionally able to catalyze oxidation of amino acids such as lysine (and other amines). This includes iron and copper and the metals may thus also activate e.g. polymer amine groups for covalent crosslinking e.g. through imine formation, a process which is also pH dependent. In an embodiment of the invention, self-healing hydrogels comprising:
Ca(ll) as metal source;
- an amino-Ci-io-alk(an/en/yn)yl such as allylamine as backbone
monomer; and
- an catechol monomer comprising an amino group such as DOPA as catechol monomer unit
were obtained relatively slowly, e.g. within 10 minutes from mixing the ingredients. In particular, the recovery obtained was slower than what was seen for a
corresponding self-healing hydrogel comprising e.g. Fe(lll) or Mn(l l) as metal source.
In an embodiment of the invention, self-healing hydrogels comprising:
- Al(ll l), Mn(ll) or Fe(ll l) as metal source;
- an amino-Ci-io-alk(an/en/yn)yl such as allylamine as backbone
monomer; and
- an catechol monomer comprising an amino group such as DOPA as catechol monomer unit
were obtained fast, e.g. fast, e.g. instantly, upon mixing the ingredients. Moreover, recovery was obtained within second(s) after forced fracture. Al(l ll), Mn(l l) and Fe(l ll) will be the fastest recovering hydrogels as compared to corresponding hydrogels comprising Cu(l l) or Cr(ll l) as metal source.
In an embodiment of the invention, self-healing hydrogels comprising:
- Cu(l I) as metal source; - an amino-Ci-io-alk(an/en/yn)yl such as allylamine as backbone monomer; and
- an catechol monomer comprising an amino group such as DOPA as catechol monomer unit
were obtained fast, e.g. within 5 minutes from mixing the ingredients.
In an embodiment of the invention, self-healing hydrogels comprising:
- Cr(ll l) as metal source;
- an amino-Ci-io-alk(an/en/yn)yl such as allylamine as backbone
monomer; and
- an catechol monomer comprising an amino group such as DOPA as catechol monomer unit
were obtained fast, e.g. within 5-10 minutes from mixing the ingredients. In an embodiment of the invention, self-healing hydrogels comprising:
- Fe(l ll) as metal source;
- A polymer consisting of at least 3 backbone monomer units selected from the group of amino sugars, wherein said 3 amino sugars together form chitosan with varying degrees of de-acetylation in its open chain form or in any a-form or β-form thereof; with
- a catechol monomer comprising an amino group such as DOPA as catechol monomer unit
were obtained fast, e.g. fast, e.g. instantly, upon mixing the ingredients and displayed high strength. Moreover, recovery was obtained within second(s) after forced fracture
In an embodiment of the invention, self-healing hydrogels comprising:
- Ca(l I) as metal source;
- an amino-Ci-io-alk(an/en/yn)yl such as allylamine as backbone
monomer; and
- an catechol monomer comprising an amino group such as DOPA as catechol monomer unit
were obtained fast, e.g. within 10 minutes after mixing the ingredients. In an embodiment wherein Ca(l l) was used as metal source, the hydrogel obtained was red apparently due to DOPA oxidation. However, in an embodiment wherein Al(ll l) was used as metal source, the colour of the hydrogel obtained was less pronounced than for the Ca(ll):DOPA-polyallylamine hydrogel. Hence, in this embodiment, Al(lll) was apparently better at protecting DOPA from oxidation than Ca(l l) and consequently, the Al(lll) functionalized gels were apparently held together primarily by reversible complex bonds and not irreversible covalent bonds formed during DOPA-sclerotarization. Consequently, in that embodiment, the Al(lll) functionalized hydrogels displayed much more distinct self-healing properties than the Ca(l l) hydrogels due to the higher number of reversible complex-bonds to covalent bonds in hydrogels comprising Al(l ll).
In an embodiment wherein Zn(l l) was used as metal source, the polymer obtained was a sticky gel.
The colour of the resulting hydrogel is predominantly determined by four factors:
- the nature of the metal,
- the interaction of the metal with catechol and/or amine groups,
- the degree of catechol oxidation, and
- the presence of covalently cross-linked catechol functionalities such as di-catechols, Michael addition products, or imines.
Accordingly, the metal influences the colour in a manner that depends on the electronic structure of the metal (i.e. the detailed electronic structure). For transition metals with unfilled d-orbital shells, such as V, Mn, Ni, Co, Fe, Cu in their various oxidation states, coloured gels are likely to result. The colour and the mechanical strength of the hydrogels will depend on the detail interaction between polymer and metal including the number of catechols bound to the metal, the nature of other counter ions, pH as well as the metal and polymer concentrations and the ratio between them. Coloured gels may be preferred when applied to e.g. a coloured surface. Then the appropriate combination of metals can be employed so that the obtained hydrogel has the same colour as the original surface and blends in with. For main group metals, such as Mg, Ca, Al and Ga in all oxidation states, and metal ions with empty of filled d-shells (or f-shells for f-block metals) such as Zn(l l), Ag(l), Au(lll), Sc(ll I), Hf(IV), La(lll) the only source of colour in the hydrogels will come from the oxidized and/or covalently cross-linked catechols.
Uncoloured hydrogels may be preferred for applications where either a transparent gel is needed (e.g. in connection with ophthalmological applications) or where colour is undesired for cosmetic reason (e.g. in connection with certain applications where the hydrogel is visible after application such as may be the case when used on and/or in connection with skin). Within the context of the present invention, complexes between catechol monomer units as used herein and metal are held together by coordinate bonds. A coordinate bond is a kind of 2-centre, 2-electron covalent bond in which the two electrons derive from the same atom. The strength of these bonds varies depending on the nature of the metal and ligand as well as external factors including but not limited to pH. For example, DOPA-Ti bonds have bond strengths around 0.8 nN vs about 2 nN for a Si-C covalent bond.
Contrary to covalent bonds, the reversible nature of coordinate bonds imparts self- healing properties to the material, which means that the coordinate bonds will spontaneously repair after fracture.
HYDROGELS
A gel is defined as a material that contains polymer subunits that can be cross- linked with each other thus establishing a macroscopic infinite network where all subunits are connected. Gels are viscoelastic materials and they therefore have mechanical properties in between the classical extremes of a solid and a liquid. Within the context of the present invention, gels are used synonymous with hydrogels and refer to chemically cross-linked hydrogels. Hydrogels are hydrophilic gels with an ability to absorb and/or comprise high amounts of water, such as e.g. at least 50% of their weight in water. In one embodiment, such hydrogel is capable of absorbing and/or comprising at least 60% of its weight in water. In one further embodiment, such hydrogel is capable of absorbing and/or comprising at least 70% of its weight in water. In one further embodiment, such hydrogel is capable of absorbing and /or comprising at least 80% of its weight in water. In yet one further embodiment, such hydrogel is capable of absorbing and/or comprising at least comprises at least 90% of its weight in water. In yet one further embodiment, such hydrogel is capable of absorbing and/or comprising at least at least 95% of its weight in water.
Hydrogels are widely used as scaffolds in tissue-engineering and drug delivery systems because they, like natural tissue, possess a high degree of flexibility due to their ability to absorb and/or comprise significant volumes of water.
Stimuli-responsive hydrogels are hydrogels capable of responding to external triggers like e.g. temperature and pH. For exemplification purposes, in more detail, temperature-responsive polymers are polymers which undergo a physical change when external thermal stimuli are presented.
Stimuli-responsiveness of a hydrogel is an attractive material property in regards to applications in tissue engineering, considering the well-defined temperature and pH ranges of the human body. The multi-responsive self-healing polymers of the present invention are stimuli- responsive hydrogels, hereinafter also referred to as self-healing polymers, multi- responsive polymers, gels or hydrogels. pH-REGULATED MULTIRESPONSIVENESS
In the method of the present invention, the hydrogel formation is controlled e.g. by regulation of the pH.
The functionalized polymer backbone is charged when the pH is below its pKa value. At low pH, electrostatic repulsion will ensure that the solution remains liquid. At a higher pH, but below the pKa value, a hydrogel may form. As the pH is increased the functionalized polymer backbone amine backbones will gradually become deprotonated and accordingly the functionalized polymer backbones will become less charged. At some pH, in the range of the pKa value of the functionalized polymer backbones, the hydrogel structure may collapse, due to the reduction in the hydrophilicity of the functionalized polymer backbones.
In one embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 4. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 3. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 2.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer minus 0.5.
In one embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 4. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 3. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 2.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone minus 0.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer plus 0.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer plus 1 . In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer plus 2. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the backbone polymer plus 3.
In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone plus 0.5. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone plus 1 . In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized polymer backbone plus 2. In one further embodiment of the invention, said hydrogel structure collapses at a pH equal to the pKa of the functionalized plus 3.
Accordingly, the multi-responsive self-healing polymers provided herein are functionalized in a pH responsive manner by maintaining the first pH value below the pKa value of the polymer, wherein said polymer is functionalized with one or more monomer unit(s).
In one embodiment of the invention, the first pH value is below the pKa value of the polymer backbone, such between 0 and the pKa value, such as within the range of 0 up to the pKa value minus 0.5, or such as within 0 and the pKa minus 1 . The first pH is preferred larger than or equal to 0 and smaller than or equal to 8 or the pKa value of the polymer backbone, whichever is smaller. In a preferred embodiment, the first pH is within 0 and 7 or the pKa value of the polymer backbone, whichever is smaller. In a more preferred embodiment of the invention, the first pH is within 1 and the pKa value of the polymer backbone.
In one embodiment of the invention, the first pH value is below the pKa value of the functionalized polymer backbone, such between 0 and the pKa value, such as within the range of 0 up to the pKa value minus 0.5, or such as within 0 and the pKa minus 1 . The first pH is preferred larger than or equal to 0 and smaller than or equal to 8 or the pKa value of the functionalized polymer backbone, whichever is smaller. In a preferred embodiment, the first pH is within 0 and 7 or the pKa value of the polymer, whichever is smaller. In a more preferred embodiment of the invention, the first pH is within 1 and the pKa value of the functionalized polymer backbone.
In a particular embodiment of the invention, the first low pH-value is below 8 or below the pKa value of the polymer backbone amine group. In an embodiment of the invention, the first pH-value is below the pKa value of the backbone polymer. In a preferred embodiment of the invention, the first pH value is below the pKa value of the backbone polymer minus 1 . The multi-responsive self-healing polymers provided herein are further
functionalized in a pH responsive manner by the addition of metal. Both the metal ligand affinity and the ligands metal affinity depend upon pH. At the first low pH- value, mono-complexes are typically formed. As the pH increases, the bond stoichiometry of the complex bond is increased thereby establishing an inter- polymer network. An initial binding of the metal ions in the mono-complex at low pH is beneficial to prevent metal oxide or hydroxide precipitation at increased pH as some metal ions have low solubility in alkaline environment.
Accordingly, the multi-responsive self-healing polymers obtained with the method provided herein are further functionalized in a pH responsive manner by
maintaining the second pH value at a pH higher than the first. The second pH value will determine the strength of the obtained hydrogel as further described below.
In one embodiment of the invention, the second pH value is within the range from above the first pH value up to the pKa value of the backbone polymer plus 9; such as within the range from the first pH value plus 0.5 up to the pKa value plus 9.
Hence, the mechanical strength of the multi-responsive self-healing polymers provided herein is based on two opposing effects, which are an increasing mechanical strength caused by the increase in bond-stoichiometry and a decreasing mechanical strength caused by the break-down of the hydrogel structure. Accordingly, the hydrogels obtained are multi-responsive, e.g. due to their pH-multi-responsiveness. Furthermore, the hydrogels obtained have the potential for their mechanical properties to be adjusted to match a number of applications by selecting the polymer based on its pKa value.
For illustrative purposes, taking Fe(lll) ions and catechol-DOPA as a specific example, the initial binding of the Fe(lll) ions in the mono-complex at low pH is crucial to prevent Fe(l ll) oxide precipitation at increased pH as Fe(ll l) ions have low solubility in alkaline environment. The mono-, bis- and tris- complex formed between catechol-DOPAs and Fe(ll l) ions are shown below.
Schematic drawing of the mono-complex, bis-complex and tris-complex, which can form between Fe(l ll) ions and catechol-DOPA. The equilibrium is
displaced towards the right with increasing pH.
Further, for illustrative purposes, the inventors of the present invention have shown that solutions of DOPA-functionalized polymer backbone and Fe(ll l)-ions are dominated by the mono-complexes in the pH range of 1 -5, the bis-complexes in the range of pH 5-10.8 and the tris-complexes in the range of 10.8-12.)
In a specific embodiment wherein the polymer backbone comprises DOPA functionalized polyallylamine and the metal is Fe(l ll), the mono-complexes dominate in the pH-range of 1 -5.
In one further specific embodiment wherein the polymer backbone comprises DOPA functionalized polyallylamine and the metal is Fe(l ll), the bis-complexes dominate in the pH range of 5-10.8.
In one further specific embodiment wherein the polymer backbone comprises DOPA functionalized polyallylamine and the metal is Fe(l ll), the tris-complexes dominate in the pH-range above 10.8.
Figure 1 shows UV/VIS absorption spectra of the DOPA-polyallylamine Fe(ll l)-gel at different values spanning from pH 1 to pH 12 Moreover Figure 2 shows the calculated fraction of mono-, bis- and tris-catechol
Fe(l ll) complexes as a function of pH based on the UV/VIS data provided in Figure 1 . In this Figure it is clearly seen that the mono-complexes dominate in the pH- range of 1 -5, the bis-complexes dominate in the pH-range of 5-10.8 and the tris- complexes dominate in the pH-range above 10.8. In one embodiment of the invention, the pKa value of the functionalized polymer backbone is in about the same range as the non-modified counterparts. In a specific embodiment thereof, the pKa value of the functionalized polymer backbone is in about the same range as the non-modified counterparts due to low grafting densities of the catechol monomer unit(s) with the polymer backbone.
Within the context of the present invention, the grafting density refers to the fraction of catechol-functionalizable polymer side chains which are actually functionalized by catechol monomer units. In one embodiment of the invention, the grafting density is between 0.01 % and
100%. In another embodiment of the invention, the grafting density is between 1 % and 20%. In yet one further embodiment of the invention, the grafting density is between 3% and 15%. In one specific embodiment, the grafting densities as estimated through a least squares refinement of potentiometric data are no more than 20%, such as no more than 15%. In a particular embodiment, said grafting density is no more than 10%, such as no more than 5%. In yet further embodiment, said grafting density is no more than 3%, such as less than 1 %. More particularly, said grafting density may be in the range of 5-15%, such as 7-13%.
In a particular embodiment thereof, the grafting density is controlled by e.g. the ratio of DOPA:polymer; the efficiency of coupling reaction, the reaction time and the reaction conditions, such as pH, temperature etc.
For illustrative purposes, a DOPA grafting density of the DOPA-polyallylamine polymers was estimated through a least squares refinement of potentiometric data and was in the range of 7.8-1 1 .2%. Accordingly, for the purpose of the present invention, the pKa values of the functionalized polymer backbone is in the same range as the non-modified counterparts such as wherein the difference between the pKa value of the functionalized polymer backbone and the pKa value of a corresponding polymer backbone which is not functionalized is no more than ±2.0 such as no more than ±1 . In a particular embodiment, said difference is no more than ±0.75, such as no more than ±0.5. In yet another embodiment said difference will be no more than ±0.25. In a specific embodiment the pKa value of the DOPA-polyallylamine backbone amine has been shown to be slightly higher (9.29 ± 0.06 - 9.65 ± 0.09) than that for polyallylamine (8.80 ± 0.19) at the same concentration (-0.01 M).
The inventors of the present invention have surprisingly found, that the pH at which the mechanical properties of the hydrogels of the present invention are optimal is adjusted by changing the pKa value of the functionalized polymer backbone and thus of the monomer(s) constituting the polymer backbone (i.e. the backbone monomer unit(s)). That is, at a pH above the pKa value of the functionalized polymer backbone, the hydrogel structure will collapse and phase separation will occur, due to the reduction of the hydrophilicity of the polymers. Consequently, the mechanical strength will decrease.
Accordingly, the hydrogels provided herein are mechanically strongest at a pH which is in the range of the pKa of the functionalized polymer backbone.
In a specific embodiment, the DOPA functionalized chitosan Fe(ll l)-hydrogels is mechanically strongest in the range of the pKa value of chitosan, which is 6.5. Chitosan's pKa value is close to physiological pH and the system will thus be suitable for tissue engineering applications.
In one further specific embodiment of the invention, the DOPA functionalized polyallylamine Fe(lll)-hydrogels are mechanically strongest in the range of the pKa value of polyallylamine, which is approximately 9.5. The below scheme display the obtained DOPA-chitosan and DOPA-polyallylamine polymers (A). B-D highlights the key pH responsive parts of these polymers in the specific case of Fe(l ll) functionalization.
Schematic drawing of A) DOPA randomly grafted onto chitosan and polyallylamine. There are several pH responsive parts of the formed polymers (B-D). The amino groups on the polymer backbone are involved in an acid base equilibrium B) with a pKa around 6.5 and 9.5 for chitosan and polyallylamine, respectively. The equilibrium between the catechol and the quinone form of DOPA depends on pH C) and in addition the Fe(lll): DOPA-polymer complex bond change stoichiometry as the pH is altered D).
MECHANICAL STRENGTH As used herein the term 'curing pH' refers to the pH at which the maximum storage modulus is obtained. As used herein, the terms maximum strength and maximum mechanical strength refer to the maximum storage modulus. Within the context of the present invention, the mechanical properties of hydrogels provided herein have been investigated using Dynamic Oscillatory Rheology.
In a particular embodiment of the invention, the mechanical strength of the hydrogels obtained by the method of the present invention was found to display a close-to Gaussian pH-dependency. In a particular embodiment thereof, the pH- dependency of the hydrogels of the present invention fit into the Gaussian model of below Equatio Equation 1
where y is the storage modulus, y0 is the baseline offset, A is the total area under the Gaussian curve from the baseline, xc is the center of the peak and w is defined by means of the "Full With of Half Maximum" parameter {FWHM): i Equation 2
As previously mentioned, the maximum mechanical strength of the hydrogel provided herein is obtained at a pH which is in the range of the pKa of the functionalized polymer backbone. However, with the method provided herein, the hydrogel obtained has a significant strength, even at pH-levels beyond the pKa of the functionalized backbone polymer. Furthermore, with the method provided herein, the hydrogel obtained has a significant strength, also at pH-levels above the pKa of the functionalized backbone polymer.
In an embodiment of the invention, the pH value of the maximal strength of the multi-responsive self-healing polymer is determined by the pKa value of the functionalized polymer. In a specific embodiment thereof, the pH value of the maximal strength of the polymer is obtained in the range pKa -6 to pKa +3. In a preferred embodiment thereof, said optimal strength is obtained at a pH within the range of pKa -2.5 to pKa +1 .5. In a more preferred embodiment thereof, said optimal strength is obtained at a pH within the range of pKa -1 to pKa +0.5.
In a particular embodiment of the invention, the pH value of the maximal strength of the multi-responsive self-healing polymer is identical to the pKa value of the unmodified polymer backbone, i.e. of the polymer backbone prior to
functionalization with one or more catechol monomer unit(s). In a specific embodiment thereof, the pH value of the maximal strength of the polymer is obtained in the range pKa -6 to pKa +3. In a preferred embodiment thereof, said optimal strength is obtained at a pH within the range of pKa -2.5 to pKa +1 .5. In a more preferred embodiment thereof, said optimal strength is obtained at a pH within the range of pKa -1 to pKa +0.5.
In one further embodiment, the pH value of the maximal strength of the multi- responsive self-healing polymer obtained with the process disclosed herein is determined by properties of other components of the system. In further
embodiments, said maximal strength is determined by properties of other components of the system where said components comprise copolymer segments not involved in DOPA functionalization. In still further embodiments, the
temperature of the maximal strength of the polymer is determined by thermo- responsive properties of the polymer.
In a specific embodiment of the invention, the mechanical strength of a DOPA- polyallylamine Fe(lll)-hydrogel obtained by the method disclosed herein was found to display a Gaussian pH-dependency. In an embodiment thereof, said hydrogel has a maximum strength of about 7000 Pa at pH 9.3 which correspond to the pKa of the DOPA-polyallylamine polymer backbone. In a further embodiment, said hydrogel has a significant strength at a pH below the pKa of the DOPA- polyallylamine polymer backbone, such as e.g a strength of at least 700 Pa, e.g. of at least 800 Pa. In a particular embodiment said pH below the pKa of the DOPA- polyallylamine polymer backbone is of. In a specific embodiment, said hydrogel has a mechanical strength of about 820 Pa at pH 6. This embodiment is displayed in figure 3. This material strain hardened above about 30% strain and failed above about 100% strain. The inventors of the present invention found that, hydrogels of the present invention display a non-Newtonian shear-thickening behaviour, which implies that they flow relatively easy at a low applied shear rate and become more resistant to flow when sheared at a high rate. Thus the storage modulus was found to exhibit a strong increase from 0 to 10-15 s"1 after which it stabilized. The loss modulus increases gradually as a function of the angular frequency (figure 4B). Accordingly, in one embodiment of the invention, the storage moduli of hydrogels of the present invention are at least 1000 Pa, such as within the range from 1000 to 7000 Pa, or within the range from 1 .000 to 40.000 Pa.
In an embodiment of the present invention, the hydrogels obtained with the method provided herein has a maximum mechanical strength measured as storage modulus of at least 1000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 2000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 3000 Pa. In a further
embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 4000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 5000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 6000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of about 7000 Pa. In a further embodiment, the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 10.000 Pa, such as at least 30.000 Pa, e.g. up to 40.000 Pa. In further embodiments of the invention, the hydrogels obtained with the method provided herein has a strength measured as storage modulus at pH 4-8 of at least 500 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 4-8 of at least 700 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 4-8 of at least 1000 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 4-8 of at least 1500 Pa. In a further embodiment, the hydrogel has a measured as storage modulus at pH 4-8 of about 2000 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10-13 of at least 500 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10-13 of at least 700 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10-13 of at least 1000 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10- 13 of at least 1500 Pa. In a further embodiment, the hydrogel has a strength measured as storage modulus at pH 10-13 of about 2000 Pa.
The inventors of the present invention have mapped the mechanical properties of the hydrogels as a function of pH by performing a range of frequency sweeps within the linear viscoelastic deformation range on hydrogels with different final pH. Some of the data obtained are shown in below figure 4.
The method of the present invention provides hydrogels having a storage modulus which depends on pH. As a specific example, this has been illustrated in figure 5 that displays the modulus as a function of the amount of NaOH added in the formation of the hydrogels for the four angular frequencies (24.8 s"1 , 49.8 s"1 , 75.6 s"1 and 100 s"1). Corresponding pH values are indicated on the graphs. The graphs in Figure 5 result from many individual measurement. The spread of the data points result from the use of a small diameter top-plate in the parallel plate rheological measurements, which are susceptible to non-negligible surface effects. Nevertheless, a consistent and very clear trend is seen.
In the specific embodiment illustrated in figure 5, the storage modulus of the DOPA- polyallylamine Fe(lll)-hydrogels, display a Gaussian pH-dependency with maximum strength around the polymer's pKa value (pH 9.3-9.7).
In an embodiment of the present invention, hydrogels of the present invention have a storage modulus which, regardless of the angular frequency, increases from an initial storage modulus, such as approximately 2000 Pa, at a first low pH-value to its maximum storage modulus, such as approximately 7000 Pa, at a pH-value at about the pKa of the polymer wherein the storage modulus decreases to a storage modulus of about the same strength as the initial storage modulus, such as of approximately 2000 Pa. In one specific embodiment thereof, said hydrogel is a
DOPA-polyallylamine Fe(l ll)-hydrogel and said storage modulus increases from an initial storage modulus of approximately 2000 Pa at 10 μηιοΐβ NaOH (pH 4) to approximately 7000 Pa around 35 μηιοΐβ NaOH added (pH 9.3) after which it decreases to approximately the initial value of 2000 Pa at 60 μηιοΐβ NaOH added (pH 12). In below figure 5, the corresponding loss moduli at the four angular frequencies show a similar but less clear trend.
For illustrative purposes, the storage modulus was also measured on
polyallylamine Fe(lll)-samples with similar concentration as for the hydrogel, i.e. for polymers not functionalized by DOPA. Data for these are also shown in figure 5.
Regardless of the amount of NaOH added the storage moduli of the polyallylamine Fe(l ll)-samples are zero, which emphasizes the great impact of DOPA grafting as the grafting of DOPA contributes to an enhancement of the polymer performance from zero to 7000 Pa at a pH of 9.3.
The inventors of the present invention have found that, by comparing the measured storage and loss modulus of the DOPA-polyallylamine Fe(ll l)-hydrogels it is evident that hydrogels of the present invention, contrary to the PEG(DOPA)4 Fe(l ll)- hydrogels of WO201 1 /084710, display a primary elastic behaviour at all pH values (G' > G") at low angular frequencies. In the PEG(DOPA)4 Fe(lll)-hydrogel system the pH 5 hydrogel exhibits a solely viscous response due to prevalence of mono- complexes at pH 5, which implies no cross-linkage of the polymers. On the contrary, bis-complexes exist at pH 4 in the DOPA-polyallylamine Fe(ll l)-system ; and thus a significant elastic behaviour is observed even in a 10.0 μηιοΐβ DOPA- polyallylamine Fe(lll)-hydrogel (pH 4).
Hence, the cationic DOPA-polyallylamine Fe(lll)-hydrogels provided herein exhibit completely new mechanical properties compared to previous synthesized
PEG(DOPA)4 Fe(ll l)-systems. The PEG(DOPA)4 Fe(ll l)-hydrogels demonstrate a solely increasing mechanical strength as a function of pH with a maximum strength at pH 1 2 where the tris-complex prevails, whereas the DOPA-polyallylamine Fe(l l l)- hydrogels, display a Gaussian mechanical strength distribution that peaks around the polymer's pKa value ~ 9.3 - 9.7 (pH 9.3, 33 μηιοΐβ NaOH) where the bis- complexes are abundant.
One embodiment of the invention relates to below composition W, which is a self- healing hydrogel comprising :
- Fe(l l l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1 -COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein :
the stoichiometric ratio of backbone monomer unit:metal is at least 1 5:1 , such as 50:1 or 1 00:1 , e.g. from about 15:1 to about 300:1 ;
the stoichiometric ratio of catechohmetal is less than or equal to 3: 1 , such as less than 2: 1 , e.g. less than 1 : 1 ; will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 5000 Pa, such as of about 5000-10.000 Pa or about 5000-30.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes, which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 5000 Pa, such as of about 5000-10.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally
substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 5000 Pa, such as of about 5000-30.000 Pa.
One embodiment of the invention relates to below composition X which is a self- healing hydrogel comprising:
- Fe(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-10.000 Pa or about 1 .000-30.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-10.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-30.000 Pa. One embodiment of the invention relates to below composition Y, which is a self- healing hydrogel comprising:
- Al(ll l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-i o-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa.
Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i 0- alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1- COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-12.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-
(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6- alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g.
glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-40.000 Pa.
One embodiment of the invention relates to below composition Z, which is a self- healing hydrogel comprising:
- Al(ll l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa or about 1 .000-40.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-40.000 Pa.
One embodiment of the invention relates to below composition A, which is a self- healing hydrogel comprising:
- Ca(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of ■ amino-Ci-i o-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-5.000 Pa or about 500-10.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i 0-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-5.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 500 Pa, such as of about 500-10.000 Pa.
One embodiment of the invention relates to below composition B, which is a self- healing hydrogel comprising:
- Ca(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein: - the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-5.000 Pa or about 100-10.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 100 Pa, such as of about 100-5.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 100 Pa, such as of about 1 .000-10.000 Pa.
One embodiment of the invention relates to below composition C, which is a self- healing hydrogel comprising:
- Mn(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine, ■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid; the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-10.000 Pa or about 3.000-30.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-10.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000- 30.000 Pa.
One embodiment of the invention relates to below composition D, which is a self- healing hydrogel comprising:
- Mn(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ; - the stoichiometric ratio of catechokmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-10.000 Pa or about 1 .000-30.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-10.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally
substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-30.000 Pa.
One embodiment of the invention relates to below composition E, which is a self- healing hydrogel comprising:
- Cr(ll l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-5.000 Pa or about 500-10.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-5.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 500 Pa, such as of about 500-10.000 Pa. One embodiment of the invention relates to below composition F, which is a self- healing hydrogel comprising:
- Cr(ll l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-5.000 Pa or about 100-10.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 100 Pa, such as of about 100-5.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 100 Pa, such as of about 100-10.000 Pa.
One embodiment of the invention relates to below composition G, which is a self- healing hydrogel comprising:
- Mg(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and ■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 2.000 Pa, such as of about 2.000-12.000 Pa or about 2.000-18.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 2.000 Pa, such as of about 2.000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 2.000 Pa, such as of about 2.000- 18.000 Pa.
One embodiment of the invention relates to below composition H, which is a self- healing hydrogel comprising:
- Mg(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of ■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 1 .000-12.000 Pa or about 500-18.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally
substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 500 Pa, such as of about 500-18.000 Pa.
One embodiment of the invention relates to below composition J, which is a self- healing hydrogel comprising:
- Zn(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein: - the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-5.000 Pa or about 1 .000-10.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-5.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000- 10.000 Pa.
One embodiment of the invention relates to below composition K, which is a self- healing hydrogel comprising:
- Zn(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-5.000 Pa or about 200-10.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 100-5.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 200 Pa, such as of about 200-10.000 Pa.
One embodiment of the invention relates to below composition L, which is a self- healing hydrogel comprising:
- Ga(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-10.000 Pa or about 3.000-20.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-10.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000- 20.000 Pa.
One embodiment of the invention relates to below composition M, which is a self- healing hydrogel comprising:
- Ga(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 300 Pa, such as of about 500-10.000 Pa or about 300-20.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-10.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6- alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 300 Pa, such as of about 300-20.000 Pa. One embodiment of the invention relates to below composition N, which is a self- healing hydrogel comprising:
- Cu(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-9.000 Pa or about 2.000-20.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-9.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 2.000 Pa, such as of about 2.000- 20.000 Pa.
One embodiment of the invention relates to below composition P, which is a self- healing hydrogel comprising:
- Cu(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-9.000 Pa or about 200-20.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 100 Pa, such as of about 100-9.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 200 Pa, such as of about 200-20.000 Pa.
One embodiment of the invention relates to below composition Q, which is a self- healing hydrogel comprising:
- Ti(IV) as metal source;
- one or more backbone monomer units selected from the group
consisting of ■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-10.000 Pa or about 2.000-20.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-10.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 2.000 Pa, such as of about 2.000- 20.000 Pa.
One embodiment of the invention relates to below composition S, which is a self- healing hydrogel comprising:
- Ti(IV) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein: - the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-10.000 Pa or about 200-20.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 100 Pa, such as of about 100-10.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 200 Pa, such as of about 200-20.000 Pa.
One embodiment of the invention relates to below composition T, which is a self- healing hydrogel comprising:
- V(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine, ■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid; the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-10.000 Pa or about 2.000-20.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 500 Pa, such as of about 500-10.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units areamino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6- alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 2.000 Pa, such as of about 2.000- 20.000 Pa.
One embodiment of the invention relates to below composition U, which is a self- healing hydrogel comprising:
- V(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ; - the stoichiometric ratio of catechokmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-10.000 Pa or about 200-20.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g. allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4- aminostyrene will have a maximum storage modulus of at least about 100 Pa, such as of about 100-10.000 Pa. Contrary thereto, such self-healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6- alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)- C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine will have a maximum storage modulus of at least about 200 Pa, such as of about 200-20.000 Pa.
One embodiment of the invention relates to below composition AA, which is a self- healing hydrogel comprising:
- In(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ; - the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-40.000 Pa. One embodiment of the invention relates to below composition AB, which is a self- healing hydrogel comprising:
- In(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa or about 1 .000-40.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally
substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-40.000 Pa.
One embodiment of the invention relates to below composition AC, which is a self- healing hydrogel comprising:
- A lanthanide ion such as Gd(lll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and ■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-40.000 Pa.
One embodiment of the invention relates to below composition AD, which is a self- healing hydrogel comprising:
- A lanthanide ion such as Gd(lll) as metal source;
- one or more backbone monomer units selected from the group
consisting of ■ amino-Ci-i o-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa or about 1 .000-40.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally
substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-40.000 Pa.
One embodiment of the invention relates to below composition AE, which is a self- healing hydrogel comprising:
- Hf(IV) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein: - the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-C1-10-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally
substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 3.000 Pa, such as of about 3.000-40.000 Pa.
One embodiment of the invention relates to below composition AF, which is a self- healing hydrogel comprising:
- Hf(IV) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa or about 1 .000-40.000 Pa. Such self-healing hydrogels wherein the backbone monomer units are amino-Ci-i0-alk(an/en/yn)yl e.g.
allylamine or amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine or aminostyrenes which are optionally substituted, e.g. 4-aminostyrene will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa. Contrary thereto, such self- healing hydrogels wherein the backbone monomer units are amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and - (CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β-form thereof as backbone monomer; e.g. glucosamine and/or
acetylglucosamine will have a maximum storage modulus of at least about 1 .000 Pa, such as of about 1 .000-40.000 Pa. CONTROLLING THE MECHANICAL PROPERTIES
As mentioned above, the mechanical properties of a multi-responsive self-healing hydrogel of the present invention may be controlled by the degree of cross-linking.
As disclosed herein, cross-linking may be controlled by managing the number of molar equivalents of the metal to catechol monomer units available in the polymer.
Cross-linking may also be controlled by managing the number of molar equivalents of base (such as NaOH) added to a composition of the metal and polymer to obtain a pH that favours mono-, bis-, and tris- complexation.
As is outlined above, the degree of cross-linking of the self-healing polymer composition may furthermore be controlled by varying the metal to catechol ratio.
Furthermore, the amount of base added, which ultimately determines the final pH, the polymer concentration, the nature and concentration of co-solvents, the equilibrium concentrations of the deprotonated ligands, and the equilibrium concentrations of all potential coordination complexes, is essential for the polymer gels' properties. The polymer concentration also plays an essential role for properties of the resulting hydrogel. The strength is expected to scale with polymer-concentration at the concentration levels discussed herein.
The DOPA grafting density, i.e. the fraction of polymer monomer units
functionalized by DOPA, determines the number of metal-crosslinking sites and hence will be important determinants for strength.
Co-solvents, counter ions, and other added components (e.g. surfactants or other polymers) will also allow influencing mechanical properties. SELF-HEALING PROPERTIES
Within the context of the present invention, the term 'self-healing polymer' refers to a self-healing hydrogel.
Hydrogel formation via coordinate-bonds has the advantage of bonds with close-to covalent bond characteristics while still being spontaneously reversible. Such hydrogels are thus capable of repairing themselves spontaneously. The hydrogels obtained with the method provided herein comprise coordinate-bonds and are self- healing. The hydrogels of the present invention thus differ from polymers and gels which have cross-linking from e.g. covalent bonding as those compositions lack coordinate bonding between monomers and a metal.
As used herein, the term "self-healing" refers to a property of a material that can undergo such spontaneous repair. In some embodiments, self-healing results in restoration of a material to its original chemical structure. In some embodiments, self- healing results in restoration of a material to nearly its original chemical structure such as reforming at least one or more coordinate bonds, such as reforming at least two or more coordinate bonds, e.g. at least three or more coordinate bonds. In a specific embodiment, a self-healing polymer according to the invention may have coordinate bonds between a metal and one or more monomer subunits of the polymer. Those coordinate bonds can break from external force and subsequently new coordinate bonds will spontaneously form. Accordingly, when coordinate bonds are broken in the disclosed self-healing polymer compositions, such that the metal has e.g. only one or two coordinate bonds with a catechol-group, the self-healing polymer obtained in the method provided herein undergoes repair by formation of an intermolecular coordinate bond with any catechol-group available, such as with another catechol-group.
Self-healing is considered complete when the storage modulus is close to the value prior to fracture such as within 50% or within 70% or within 90%. As is illustrated below, the inventors of the present invention have succeeded in inventing a method for manufacturing hydrogels which further to a high mechanical strength also possess convincing self-healing properties. Accordingly, the self-healing hydrogels provided with the method of the present invention are capable of reforming upon being cut into pieces. When the pieces are brought into intermediate contact the broken bonds will reform.
In an embodiment of the invention, the hydrogel provided herein will regain at least 75% of its mechanical strength after fracture. In another embodiment thereof, said hydrogel will regain at least 80% of its mechanical strength after fracture. In another embodiment thereof, said hydrogel will regain at least 90% of its mechanical strength after fracture. In yet another embodiment thereof, said hydrogel will regain at least 95% of its mechanical strength after fracture. In yet another embodiment thereof, said hydrogel will regain its original mechanical strength after fracture.
Accordingly, in a specific embodiment, the recovery of a DOPA-polyallylamine Fe(l ll)-hydrogel (pH 9, 30 μηιοΐβ NaOH) was tested by increasing the amplitude of the oscillation until failure (0.01 -200% strain) at 1 s"1. Subsequently, the storage modulus (G") was monitored for 8.5 minutes with constant shear (1 %) and constant frequency (1 s"1). Figure 6 shows the storage modulus versus % strain and time, respectively. It is seen that the storage modulus is nearly constant until the failure point around 32% strain after which the storage modulus rapidly decreases to zero. After forced fracture the hydrogel recovers faster than 10 s (the first reliable measurement point) to a storage modulus of around 4700 Pa, which is
approximately the initial value (3800 Pa) when accounting for solvent evaporation. The tests can be repeated several times and recovery after failure remains rapid.
In the present context, a "forced fracture" is defined as a mechanical fracture of a quantity of material performed by some means, e.g. by using a scalpel, spatula or other tool that is then pressed through the material to separate it into two or more physically distinct parts. In one embodiment of the invention, the hydrogel of the present invention is capable of recovering its original shape as can be seen in Figure 7 and 8.
In one embodiment of the hydrogel of the present invention, self-healing will be initiated within 1 second or less after a forced fracture, such as within 1 second. In one embodiment of the hydrogel of the present invention, self-healing is initiated within 30 seconds after a forced fracture. In another embodiment, self-healing is initiated within 2 minutes after a forced fracture. In one embodiment of the hydrogel of the present invention, self-healing will be completed within 2 minutes after a forced fracture, such as within 1 ,5 minutes, e.g. within 1 minute. In one further embodiment, self-healing will be completed within 10 minutes from a forced fracture, such as within 5 minutes. In yet one further embodiment, self-healing will be completed within 120 minutes from a forced fracture, such as within 60 minutes. In one further embodiment, self-healing is completed within 45 minutes from a forced fracture, such as within 30 minutes from a forced fracture. In preferred embodiments, self-healing is completed within 15 minutes from a forced fracture. ADHESIVE PROPERTIES OF THE GEL
Catechol monomer units as used herein for functionalizing the polymer backbone have unique properties related to adhesion. The quinone comprised therein is in part responsible for a binding to organic surfaces and the catechol is responsible for a binding to inorganic surfaces. Hence, the two chemical forms of catechol monomer units provide the chemical diversity required to cross-link proteins and adhere proteins to both organic and inorganic surfaces. In addition dopa monomers in both the catechol and quinone form can engage in a range of other non-covalent interactions facilitating adhesion including but not limited to hydrogen bonding, van der Waals interactions, and aromatic surface/substrate interactions.
The inventors of the present invention have found that the stoichiometric ratio between the catechol monomer units and the metal ions as used herein for functionalizing the polymer backbone will determine the adhesive properties of the resulting polymer. Accordingly, one embodiment of the invention provides control of the adhesive properties of the self-healing polymer provided herein.
By applying the stoichiometric ratios listed in the below embodiments, the adhesive properties of the polymers obtained will be minimized because all catechol-moieties of the catechol monomer units as used herein for functionalizing the polymer backbone will be cross-linked to the metal during complex-formation.
Whenever mentioned within the context of the present invention, the strength of adhesion is measured in a static tensile test as the one disclosed herein below.
In one embodiment, the self-healing polymer obtained is non-adhesive. In an embodiment thereof, the self-healing polymer obtained is non-adhesive in that it will not join two materials together and resist their separation. In a particular
embodiment of the invention, a self-healing polymer having a strength of adhesion which is below 20 kPa is referred to as non-adhesive.
In one further embodiment the self-healing polymer obtained is non-adhesive due to a stoichiometric ratio of catechol :metal which is below or at 3:1 for octahedrally coordinated metals and below or at 2:1 for tetrahedrally coordinated metals.
In one further embodiment the self-healing polymer obtained is non-adhesive due to a stoichiometric ratio of catechol :metal is below 3:1 for octahedrally coordinated metals and below 2:1 for tetrahedrally coordinated metals.
In one further embodiment the self-healing polymer obtained is non-adhesive due to a stoichiometric ratio of catechol :metal is 3:1 for octahedrally coordinated metals and 2:1 for tetrahedrally coordinated metals. A more specific embodiment of the invention provides a self-healing polymer comprising an octahedrally coordinated meta in a stoichiometric ratio of
catechohmetal below 3:1 wherein the polymer obtained is non-adhesive in that the strength of adhesion of the self-healing polymer will be less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa. In a particular embodiment thereof, said ratio is below 1 :1 . In another embodiment thereof, said ratio is below 2:1 . However, in a preferred embodiment thereof, said ratio is below 3:1 .
A more specific embodiment of the invention provides a self-healing polymer comprising an octahedrally coordinated metal in the stoichiometric ratio of catechohmetal of 3:1 wherein the self-healing polymer obtained is non-adhesive in that the strength of adhesion of the self-healing polymer will be less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa. In a particular embodiment thereof, said ratio is about 1 :1 . In another embodiment thereof, said ratio is about 2:1 . In a preferred embodiment of the non-adhesive self-healing polymer, said ratio is 3:1 .
A more specific embodiment of the invention provides a self-healing polymer comprising a tetrahedrally coordinated metal in a stoichiometric ratio of
catechohmetal below 2:1 wherein the self-healing polymer obtained is non- adhesive in that the strength of adhesion of the self-healing polymer will be less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa. In a particular embodiment thereof, said ratio is below 1 :1 . However in a preferred embodiment thereof, said ratio is below 2:1 . A more specific embodiment of the invention provides a self-healing polymer comprising a tetrahedrally coordinated metals in the stoichiometric ratio of catechokmetal of 2:1 wherein the self-healing polymer obtained is non-adhesive in that the strength of adhesion of the self-healing polymer will be less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa. In a particular embodiment thereof, said ratio is about 1 :1 . In a preferred embodiment of the non-adhesive self-healing polymer, said ratio is 2:1 .
Likewise, by applying the stoichiometric ratios listed in the below embodiments, the polymers obtained will be adhesive due to the stoichiometric excess of catechol- moieties comprised in the catechol monomer units as used herein as compared to metal. In more detail, increasing the amount of catechol as compared to metal (molar ratios) will increase the adhesive strength of the self-healing polymer obtained in the process of the present invention. Accordingly, at a ratio of catechokmetal of 3:1 or less for octahedrally coordinated metal and of 2:1 or less for trahedrally coordinated metals lead to non-adhesive self-healing polymers such as self-healing polymers which will have a strength of adhesion of less than 20 kPa, such as less than 10 kPa, e.g. less than 1 kPa. The lower the catechol :metal ratio comprised in the hydrogel, the lower the strength of adhesion will be.
However, increasing the relative amount of catechol will increase the adhesive strength and lead to adhesive self-healing polymers. Accordingly, at a ratio of catechohmetal of more than 3:1 or more for octahedrally coordinated metal and of more than 2:1 for trahedrally coordinated metalslead to adhesive self-healing polymers such as self-healing polymers which will have a strength of adhesion of more than 20 kPa, such as of above 30 kPa or preferably above 50 kPa or above 100 kPa, e.g. 400 kPa . The higher the catechol :metal ratio comprised in the self- healing polymer, the higher the strength of adhesion will be. An adhesive hydrogel as used herein refers to a self-healing polymer which can join two materials together. In one embodiment the self-healing polymer obtained is adhesive. In an embodiment thereof, the self-healing polymer obtained is adhesive in that it will join two materials together and resist their separation. A particular embodiment of the invention provides a self-healing polymer having a strength of adhesion which is above 20 kPa is referred to as adhesive, such as e.g. above 30 kPa or preferably above 50 kPa or above 100 kPa, e.g. 400 kPa .
In a specific embodiment of the invention, the adhesives disclosed herein function as glues.
In one further embodiment the self-healing polymer obtained is adhesive due to a stoichiometric ratio of catechohmetal which is above 3:1 for octahedrally
coordinated metals, such as Fe(l ll), Al(l ll), Mn(l l), V(lll), Cr(lll), Ti(IV) and Hf(IV) , and above 2:1 for tetrahedrally coordinated metals.
In one further embodiment, the self-healing polymer obtained with the method provided herein is adhesive and the stoichiometric ratio of catechol :metal is above 4:1 for octahedrally coordinated metals and 3:1 for tetrahedrally coordinated metals. In yet one further embodiment, the self-healing polymer obtained is adhesive and the stoichiometric ratio of catechohmetal is above or at 6:1 for octahedrally coordinated metals and above or at 4:1 for tetrahedrally coordinated metals.
A more specific embodiment of the invention provides a self-healing polymer comprising an octahedrally coordinated metal, in a stoichiometric ratio of catechohmetal above 3:1 wherein the self-healing polymer obtained is adhesive in that the strength of adhesion of the self-healing polymer will be more than 20 kPa, such as e.g. above 30 kPa or preferably above 50 kPa or above 100 kPa, e.g. 400 kPa. In a particular embodiment thereof, said ratio is above 4:1 , such as above or at 6:1 .
Another more specific embodiment of the invention provides a self-healing polymer comprising a tetrahedrally coordinated metal in a stoichiometric ratio of
catechohmetal above 2:1 the self-healing polymer obtained is adhesive in that the strength of adhesion of the self-healing polymer will be more than 20 kPa, such as e.g. above 30 kPa or preferably above 50 kPa or above 100 kPa, e.g. 400 kPa. In a particular embodiment thereof, said ratio is above 3:1 , such as above or at 4:1 .
In a specific example, the adhesive properties of the hydrogels of the present invention are illustrated based on complexes formed by Fe(ll l) and DOPA:
DOPA:Fe(III) = 3: l DOPA:Fe(III) > 3: 1 + pH increase + pH increase
Metal cross-l inked self- Melal U M—I inked dher e healiny; hvdr sicls sel l-hcalim. I di u-jel Approaches to the formation of A) Metal cross-linked self-healing hydrogels and B) Metal cross-linked adhesive self-healing hydrogels. Here illustrated for Fe(l ll).
VARIATIONS
In one embodiment of the invention, the water resistant properties of the hydrogel according to the invention are imparted to a gel material by inclusion of different amounts of amphipathic molecules. Such amphipathic molecules may include, for example fatty acids such as n-hexanoic acid, palmitic acid and other fatty acids as well as phospholipids. In one embodiment thereof, the amphipathic molecules may be added to the polymer prior to pH-induced gelation (addition of alkali to raise the pH). In one embodiment, fatty acids, for example may be added to decrease the hydration of a polymer matrix and confer water-resistance. In one embodiment, amphipathic molecules may be added to decrease the dielectric constant of a polymer matrix, which in turn increases the strength of the metal-catechol coordination bonds.
In further embodiments, additional components may be incorporated into a self- healing polymer or hydrogel according to the invention. Such components may be covalently linked to the polymer or included as a non-covalent mixture. In one embodiment, antioxidants may be included to protect catechol from oxidation. Suitable antioxidants include but are not limited to, water-soluble antioxidants such as ascorbic acid, glutathione, mycothiol, trypanothione, ubiquinone, uric acid, lipoic acid, carotene derivatives, such as derivatives of vitamin A, water-soluble derivatives of tocopherols, such as trolox. Also suitable are polyphenolic antioxidants, such as resveratrol. Also suitable are polythiol/thiolates. Also suitable are synthetic antioxidants, such as propyl gallate (PG, E310), tertiary
butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA, E320) and butylated hydroxytoluene (BHT, E321 ). Also suitable are lipid-soluble antioxidants, such as tocopherols and tocotrienols (vitamin E), which form a family of structurally related antioxidants, and is known in the art.
In further embodiments, monomers comprised in the hydrogel according to the invention may comprise functional groups that have polar, non-polar, or both types of groups by covalent linkage. Embodiments include ambifunctional polymers. In some embodiments, non-covalent components may be mixed with the polymer that separate into a different phase to form domains within a gel matrix. In some embodiments, ambifunctional moieties may assist in excluding water from penetrating a gel, making a more effective coating such as an anti-fouling coating. In other embodiments, they could display antioxidant properties. In yet further embodiments, other additives such as anti-microbial and anti-fouling additives may be incorporated to increase the resistance of the polymer to microbial contact. In further embodiments, the present invention may carry drugs either through non- covalent encapsulation or by covalent or coordinative bonding. In this embodiment, the present invention has properties desired for a drug delivery system.
USES OF THE INVENTION
One aspect of the invention relates to the use of a hydrogel according to the invention.
One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as an adhesive, glue, joining, attachment and/or cohesive agent such as e.g. for underwater applications, for dry applications and/or for joining dissimilar substrates such as skin/bandaging and/or rubber/metal. In one particular embodiment, the invention relates to the use of a hydrogel according to the invention as an adhesive or joining agent. In yet another particular embodiment, said use is as an adhesive. In another particular embodiment, said use is as a consumer adhesive. In another particular embodiment, said use is as a bandage adhesive. In another particular embodiment, said use is as a joining agent. In another particular embodiment, said use is as a glue. In another particular embodiment, said use is for attachment purposes. In another particular
embodiment, said use is as an cohesive agent. In another particular embodiment, said use is for underwater applications. In another particular embodiment, said use is for joining dissimilar substrates such as skin/bandaging and/or rubber/metal. In another particular embodiment, said use is for dry applications. In these embodiments, hydrogel formulations comprising compositions W, Y, A, C, E, G, J, L, N, Q, T, AA, AC and/or AE are preferred. More preferred are hydrogel formulations comprising composition W, Y, E, G, L, Q and/or T. In embodiments wherein the hydrogel is for use in contact with the human body, e.g. in relation to use as a bandage adhesive, hydrogels comprising compositions W, X, Y, Z, A, B,
G, H, J, K, L, Q, T, AA, AC and/or AD are especially preferred. For uses that further require uncolored or almost uncolored hydrogels, hydrogel formulations comprising compositions Y, G, J, L, Q, AA and/or AE are most preferred. In these
embodiments, the self-healing and cationic natures of the hydrogel formulations comprising compositions W, X, Y, Z, A, B, C, D, E, F, G, H, J, K, L, M, N, P, Q, S, T, U, AA, AB, AC, AD, AE and/or AF are especially advantageous as are their capability to function underwater.
In one particular embodiment, the invention relates to the use of a hydrogel according to the invention as a self-healing material, such as for use as a self- healing coating. In another embodiment thereof, said use is for lining a pipe. In these embodiments, the self-healing nature of the hydrogel is essential. Hydrogel formulations comprising compositions A-Z and AA-AF disclosed herein above are all of use in this regard, but preferred are formulations with the highest self-healing capability and strength, e.g. hydrogel formulations comprising compositions B, D, F,
H, K, M, P. S, U, X and/or Z. More preferred are hydrogel formulations comprising compositions D, F, H, M, S, U, X and/or Z.
In another particular embodiment, the invention relates to the use of a hydrogel according to the invention for under-water purposes. In a particular embodiment thereof, said use is as a sea-water adhesive, an under-water coating or a coating with antifouling capabilities. In an embodiment wherein the hydrogel of the invention is for under-water purposes, the hydrogel comprises a polymer backbone having a maximum mechanical strength at a pH between 7 and 9, such as at a pH about 8. In this regard, hydrogel formulations comprising any of A-Z and AA-AF are useful, but preferred are formulations comprising polymers with the desired pKa values. In these embodiments, hydrogels based on polyallylamine, polyornithine with catechols provided by 3,4-dihydroxyphenylacetic acid (DHPAA),3,4- dihydroxycinnamic acid (DHCA), 2,4,5-trihydroxybenzoic acid, 3-(3,4- dihydroxyphenyl)propanoic acid, 3-(3,4-dihydroxyphenyl)-2-methyl-alanine, 2,4,5- trihydroxy-phenylalanine, 2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid, (2R)-3-(3,4-dihydroxyphenyl)-2-{[(2E)-3-(3,4-dihydroxyphenyl)-2- propenoyl]oxy}propanoic acid (Rosmarinic acid), dopamine and L-DOPA and D- DOPA; or any isomers or mixtures thereof will be preferred. In particular embodiments, the pKa of the polymer can be further optimized by changing its chemical nature as is also illustrated by the explicit examples described herein. For coatings with antifouling capabilities, hydrogel formulations comprising any of compositions Y, Z, C, D, E, F, J, K, N, P, Q, S, T, U, AA, AB, AC, AD, AE and/or AF are preferred. In another particular embodiment, the invention relates to the delivery of the mixture of step 2 to a location in the body whereby the hydrogel subsequently cure in step 3, due to the increased pH derived from the tissue. This embodiment has the advantage that the need of surgical invasion is minimized. Moreover a high hydrogel strength is obtained. In principle, hydrogel formulations comprising any of compositions A-Z are of use in this regards but hydrogel formulation comprising any of compositions W, X, Y, Z, A, B, C, D, G, H, J, K, L, M, Q, S, AA, AB, AC and/or AD are preferred.
One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use to glue, attach, adhere and/or join implants to desired locations in the body such as: a. Dental implants; b. Dental filling material be it plastic, polymeric, metal, ceramic or any mixture and/or composite thereof; c.
Orthopedic implants including bone and cartilage implants; d. For catheter fixation; e. For fixation of internal medical devices of other kinds, e.g. i) insulin or other pumps; ii) power supplies, motors or computers; and/or iii) artificial heart valves or blood vessels (including auto-, alio- and xeno-grafts). Accordingly, in a particular embodiment, the invention relates to the use of a hydrogel according to the invention as a bonding agent for implants. One embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join dental implants to desired locations in the mouth. Another embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join dental filling material such as plastic, polymeric, metal, ceramic or any mixture and/or composite thereof to a tooth. Using a hydrogel of the invention to glue, attach, adhere and/or join dental filling material is advantageous because the acid step being present in conventional methods can be avoided. Another embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join orthopedic implants such as bone and cartilage implants to desired locations. Another embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join with the purpose of catheter fixation. Another embodiment relates to the use of a hydrogel according to the invention to glue, attach, adhere and/or join with the purpose of fixation of internal medical devices of other kinds, such as: insulin or other pumps; power supplies, motors or computers; and/or artificial heart valves or blood vessels (including auto-, alio- and xeno-grafts). In these embodiments, hydrogel formulations comprising any of compositions W, Y, A, C, E, G, J, L, N, Q and/or T are preferred. More preferred are hydrogel formulations comprising any of compositions W, Y, A, C, G, J, L, Q and/or T. Most preferred are hydrogel formulations comprising any of compositions W, Y, C, G, J, L, Q and/or T. For uses that further require uncolored or almost uncolored hydrogels, hydrogel formulations comprising any of compositions Y, Z, A,
B, G, H, J, K, L, M, Q, S, AA, AB, AE and/or AF are most preferred. In any of these embodiments, the self-healing and cationic natures of the hydrogels are especially advantageous as are their capability to function underwater. One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as a drug delivery vehicle, e.g. as an internal nicotine patch or for delivery of any other drug. In an embodiment, such drug delivery vehicle is used in combination with other drug delivery platforms. Accordingly, in a particular embodiment, the invention relates to the use of a hydrogel according to the invention as a drug delivery matrix. In a particular embodiment thereof, said drug delivery matrix comprises a polymer backbone having a maximum mechanical strength at a pH below 7. In relation to this embodiment, hydrogels comprising any of compositions A-Z may all be useful when formulated with polymers with pKa values below 7, e.g. chitosan or poly(4-amino styrene) or analogous polymers as starting point. Hydrogels based on chitosan are more preferred. In terms of choice of metals, hydrogel formulations comprising any of compositions W, X, Y, Z, A, B,
C, D, G, H, J, K, L, M, Q, S, T, U, AA, AB, AC, AD, AE and/or AF are preferred. One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as a tissue adhesive, glue, cohesive agent such as: a. Applications in the oral cavity including tongue, lip or oral cavity surgery, e.g.
cheek/gum surgery; b. In connection with eye surgery, e.g. cataract operation; in this connection transparent hydrogels; c. In place of existing tissue adhesives either internally or externally i.e. on skin; d. In place of sutures in connection with surgery, e.g. in relation to use as soft tissue sutures and/or biodegradable sutures; and/or d. For fixation of skin grafts. The use of a hydrogel of the invention is advantageous because the surfaces are glued together and the resulting bond has self-healing properties to protect the joint from wear and tear. Moreover, when used as wound a sealant, the hydrogel of the invention will even obviate suture in surgery.
Accordingly, in a particular embodiment, the invention relates to the use of a hydrogel according to the invention as a tissue adhesive. One specific embodiment thereof relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications in the oral cavity including tongue, lip or oral cavity (cheek/gum) surgery. Another specific embodiment thereof relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications in connection with eye surgery, e.g. cataract operation; in this embodiment, transparent hydrogels (such as those based on Ca, Ga, Zn, Al, or Ti) are preferred. Yet another specific embodiment thereof relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications in place of existing tissue adhesives either internally or externally (on skin). Yet another specific embodiment thereof relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications in place of sutures in connection with surgery, e.g. in relation to use as soft tissue sutures and/or biodegradable sutures. Yet another specific embodiment thereof relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications for fixation of skin grafts. In a particular embodiment thereof, said hydrogel comprises a polymer backbone having a pKa of about 7. In these embodiments, hydrogel formulations comprising any of compositions W, X, Y, Z, A, C, E, G, J, K, L, M, N, Q, T, AA, AB, AD and AF are preferred. More preferred are hydrogel formulations comprising any of compositions W, Y, A, C, G, J, L, Q, X, Z, AA, AB, AF, AD and/or T. Most preferred are hydrogel formulations comprising any of compositions W, Y, C, G, J, L, Q, X, Z, AD, AF and/or T. For embodiments relating to uses that further require uncolored or almost uncolored hydrogels, hydrogel formulations comprising any of compositions Y, Z, A, G, J, K, L, M, Q, AA, AB and/or AF are most preferred. For the preceding embodiments, the self-healing and cationic natures of the present hydrogels are especially advantageous as are their capability to function underwater. In these embodiments, hydrogels comprising a polymer backbone having a pKa of about 7 are most preferred; chitosan is one example of such a most preferred polymer backbone.
In another particular embodiment, the invention relates to the use of a hydrogel according to the invention as a bio-adhesive.
One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as a part of a wound-care product. Here the hydrogel properties are of special advantage as they support a moist environment. For specific sup-conditions certain combinations will be particularly advantageous such as: a. wound healing applications; b. For applications where the hydrogel is visible to the eye, a hydrogel containing an uncolored ion may be of cosmetic advantage; and/or c. As tissue/organ scaffold. One specific embodiment relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for wound healing applications wherein the metal is Zn. Such hydrogel is particularly useful for that purpose, because zinc aids wound healing/reduces irritation. Another specific embodiment relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent for applications where the hydrogel is visible to the eye, a hydrogel containing an uncolored ion will be of cosmetic advantage. In this embodiment, hydrogels based on Ca, Mg, Ga, Zn, Al, and/or Ti are preferred. To match the exact color of skin, a combination of metals will be useful, e.g. the toning the color of the hydrogel by mixing Fe(l ll) with Al(ll l). Another specific embodiment relates to a hydrogel which is suitable for use as a tissue adhesive, glue, cohesive agent as a tissue/organ scaffold. For these embodiments relating to the use the use of the hydrogel compositions as a bio-adhesive, any of the compositions X, Z, B, D, F, H, K, M, P, S, U, AB, AD, and/or AF may be used.
One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use to stop bleeding, such as by: a. Addition of a solution below curing pH, which then cures when in contact with body pH; and/or b. By extracting metals from surrounding medium and then curing. In one particular embodiment, the invention relates to the use of a hydrogel according to the invention to stop bleedings. In a particular embodiment thereof, said hydrogel comprises a polymer backbone having a pKa between 6 and 8, such as at a pKa of about 7. In a particular embodiment thereof, bleeding is stopped by addition of a solution below curing pH, which then cures when in contact with body pH. In this embodiment, a hydrogel with a strength pH maximum as close to physiological as possible will be advantageous. In another embodiment, bleeding is stopped by extracting metals from surrounding medium and then curing. In this embodiment, a hydrogel with little to no metal added prior to application may be used and a hydrogel with a strength pH maximum as close to physiological as possible will be advantageous. For these embodiments relating to stopping of bleeding, hydrogel formulations comprising any of compositions X, Z, B, D, F, H, K, M, P, S, U and /or AB are preferred with hydrogel formulations comprising any of compositions X, Z, B, D, H, K, M, S, and/or U being more preferred.
One embodiment of the invention relates to a hydrogel according to the invention which is suitable for use as metal sorbants, e.g. for removing metals from streams and/or mixtures etc. In one particular embodiment, the metal sorbate is for use for removing metals from liquids such as waste water, blood, radioactive liquids, reaction streams and/or mixtures thereof. In an embodiment, the polymer/polymer solution is added to waste water/radioactive liquids/reaction streams and
or/mixtures thereof. In this embodiment, the metals may be removed by complex bonding to the catechol-functionalized polymers and aggregates are formed, which subsequently can be removed by e.g. filtration. In another embodiment, the polymer is used in the treatment of patients suffering from iron overload
(haemochromatosis). In this embodiment, the polymer/polymer solution may be applied in the body and the iron is removed from the blood as it is becomes cross- linked to the catechol-functionalized polymer. In one further embodiment, the polymer is preferentially attached by chemical bonding to a carrier surface, e.g. a bead, membrane, interior bead surface or other. This allows use in combination with flow-through processing. This embodiment may be used in combination with the previously mentioned embodiments given the added benefit of easy recycling of the polymer. For metal sorbate applications, hydrogel formulations comprising any of compositions X, Z, B, D, F, H, K, M, P, S, U, AB, AD and/or AF are preferred. For those embodiments implying contact with the human body, hydrogel formulations comprising any of compositions X, Z, B, D, H, K, M, S, U, AB, AD and/or AF are more preferred.
In another particular embodiment, the invention relates to the use of a hydrogel according to the invention as a metal sorbate. In another particular embodiment, the invention relates to the use of a hydrogel according to the invention in removing metals from liquids such as from waste water, blood, radioactive liquids.
Composition A of the present invention is particular useful for use in dry
applications, for use in contact with the human body, for use underwater, for use in sea-water, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition B of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition C of the present invention is particular useful for use in dry
applications, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition D of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants. Composition E of the present invention is particular useful for use in dry
applications, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body and for use to fixate skin grafts.
Composition F of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition G of the present invention is particular useful for use in dry applications, for use in contact with the human body, for use underwater, for use in sea-water, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition H of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition J of the present invention is particular useful for use in dry
applications, for use in contact with the human body, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition K of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition L of the present invention is particular useful for use in dry
applications, for use in contact with the human body, for use underwater, for use in sea-water, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition M of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition N of the present invention is particular useful for use in dry
applications, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body and for use to fixate skin grafts.
Composition P of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition Q of the present invention is particular useful for use in dry
applications, for use in contact with the human body, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition S of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition T of the present invention is particular useful for use in dry
applications, for use in contact with the human body, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts. Composition U of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition W of the present invention is particular useful for use in dry
applications, for use in contact with the human body, for use underwater, for use in sea-water, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition X of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition Y of the present invention is particular useful for use in dry
applications, for use in contact with the human body, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition Z of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition AA of the present invention is particular useful for use in dry applications, for use in contact with the human body, for use underwater, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition AB of the present invention is particular useful for use underwater, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, for use to stop bleeding and for use as metal sorbants.
Composition AC of the present invention is particular useful for use in dry applications, for use in contact with the human body, for use underwater, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle and for use to fixate skin grafts.
Composition AD of the present invention is particular useful for use in contact with the human body, for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use to adhere implants to locations in the body, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives and for use as metal sorbants. Composition AE of the present invention is particular useful for use in dry
applications, for use underwater, for use in sea-water, for use as antifouling coatings and for use as a drug delivery vehicle.
Composition AF of the present invention is particular useful for use underwater, for use as self-healing coatings, for use in lining of pipes, for use in sea-water, for use as antifouling coatings, for use as a drug delivery vehicle, for use to fixate skin grafts, for use as bio-adhesives, and for use as metal sorbants.
Hydrogels of the present invention may be suitable for use in dry applications.
Examples of dry applications include as adhesives outside of water, self-healing coatings etc. Particular useful compositions for dry applications are compositions A, C, E, G, J, L, N, Q, T, W, Y, AA, AC and AE.
Hydrogels of the present invention may be suitable for use underwater outside the human body. Examples of such uses include antifouling coatings, lining in pipes and gluing and/or adhering two materials under water. Particular useful
compositions for underwater applications are compositions A, B, C, D, G, H, J, K, L, M, Q, S, T, U, W, X, Y, Z, AA, AB, AC, AD, AE and AF. Hydrogels of the present invention may be suitable for use in contact with the human body. Examples of use in contact with the human body includes treatment of wounds, materials that stop bleedings, fixation of skin grafts, implant fixation or coating, drug delivery vehicles and/ systems and for use in the mouth cavity.
Particular useful compositions for use in contact with the human body are compositions A, B, C, D, G, H, J, K, L, M, Q, S, T, U, W, X, Y, Z, AA, AB, AC, AD, AE, and/or AF.
Hydrogels of the present invention may be suitable for gluing or adhering two different materials to each other. Examples of such uses include fixation of skin grafts, fixation of implants or other biomaterials including bandages, tubing, power supplies etc., fixation of rubbers or plastics on metals or glass and fixation of glass on metals. Particular useful compositions for use to gluing/adhering two different materials include B, H, K, M, P, S, U, X, Z, AB, AD and/or AF.
Hydrogels of the present invention may be suitable for use as self-healing coatings. Examples of such uses include materials preventing / repairing rupture of a coated material. Particular useful composition use as self-healing coatings are
compositions W, X, Y, Z, AA, AB, AC, AD, L and M.
Moreover, hydrogels comprising Gd(l ll) (or other paramagnetic ions) may be used as a contrast medium in MRI.
While the terminology used in this application is standard within the art, the following definitions of certain terms are provided to assure clarity.
Units, prefixes, and symbols may be denoted in their International System of Units (SI) accepted form. Numeric ranges recited herein are inclusive of the numbers defining the range and include and are supportive of each integer within the defined range. Unless otherwise noted, the terms "a" or "an" are to be construed as meaning "at least one of." The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.
Examples
Any polymer from the claimed group of backbone polymers can have the claimed catechol monomers, comprising at least either an amine or a carboxylate group, grafted there onto. This can be done using standard carbodiimide coupling chemistry. For example using y-ethyl-3-(3-dimethylaminpropyl)-carbodiimide hydrochloride in combination with equimolar amounts of A/-Hydroxysuccinimide. The grafting density can be controlled by the ratio of catechol monomer to backbone polymer. The specific optimal ratio will depend on the choice of backbone polymer used. For example, for polyallylamine and for chitosan as polymers and DOPA as catechol, molar ratios of 2 mole DOPA per mole backbone polymer amine group, results in -10% grafting density. Conveniently these reactions can run overnight, for example for 18 h, and at room temperature.
Example 1
Hydrogels can be made in the following manner:
Step 1 : dissolve the catechol functionalized polymer in water at the desired concentration (or by other means than dissolution including dilution from
concentrated solution or solvent exchange).
Adjust pH to be well below the pKa of the backbone polymer amine; note that this may have changed due to the addition of catechol monomers to the polymer. The pH shall be at least 1 pH unit below the pKa of the backbone polymer amine and preferably also low enough to ensure that the metals are soluble; for Fe(l ll) pH should be below ~6, preferably below 5. For Fe(l ll), for example, an appropriate starting salt could be the chloride, which by itself obtains an acidic solution due to the acidic nature of Fe(lll) aqua complexes; similar considerations hold for many other metals.
Step 2: Make a solution of the metal at a concentration leading to the desired molar ratio in the final mixture. If the material is to be used in a manner making use of catechols for adhesion, the metal to catechol molar ratio should be less than 3:1 for octahedrally bound metals and less than 2:1 for tetrahedrally bound metals. For non-adhesive hydrogels, 3 (2) mole metal ion should be used per mole catechol for octahedrally (tetrahedrally) bound metal ions. For adhesive hydrogels, <3 mole metal ion should be used per mole catechol for octahedrally bound metals such as Fe(l ll) and <2 mole metal ion per mole catechol for tetrahedrally bound metals, e.g. Cu(l l). For example, 1 -2.9 mole metal ions per mole catechol can be used for octahedrally bound metals (analogously for tetrahedrally bound metals).
If necessary the pH of the metal solution can be adjusted so that it is also below that of the pKa of the backbone polymer amine. This can be the case if the metal solution is not at the required pH, e.g. if a basic salt has been used as metal source.
Step 3: Mix volumes of the polymer and metal, where said volumes are determined to obtain the desired molar ratio of catechol to metal.
Add base, for example NaOH (aq), to increase pH to the desired one. For maximum strength hydrogels, this will typically be close to the pKa of the backbone polymer. For example, the pH is within the range pKa-5 to pKa+3, where pKa is the backbone polymer pKa value. In another example pH is within the range pKa-2 to pKa+1 or more specifically within pKa-1 .5 to pKa+0.5.
In another procedure that may also be used, the desired volumes of polymer, metal, base solutions are added to a recipient directly and then mixed.
In all of the above, it may be convenient to use a base of high concentration, e.g. 1 or 2 M. Then the final pH, and material properties, can be adjusted by adding base and water in the appropriate ratio. Hydrogels can conveniently be made at room temperature. The hydrogels form rapidly, within minutes after mixing, but in most cases, it is advantageous for characterization of properties for let them mature for a set time, e.g. 0.5 h or 1 h to ensure that diffusion has rendered them completely homogenous. It is important for reproducibility that the maturation takes place in a manner reducing solvent evaporation, e.g. by placing the gel in a closed container with a small free air volume. For use of the hydrogels, this maturing period can be reduced if so desired, e.g. to 10 min or 5 min or 1 min after mixing. As a further example, consider the use of chitosan as the backbone polymer and DOPA as the catechol. Chitosan is dissolved in water and functionalized with DOPA as follows: a quantity of DOPA corresponding to 2 times the number of moles of chitosan amine groups is dissolved in 0.5% TFA continuously degassed with Ar. Next two solutions containing respectively 7-ethyl-3-(3- dimethylaminpropyl)-carbodiimide hydrochloride and /V-Hydroxysuccinimide are made so that the molar amount of each of these compounds equal 1 .5 times the molar amounts of DOPA used. The pH of all solutions is adjusted to 6. Then the DOPA solution is added to the chitosan solution. To the resulting solution, the 1- ethyl-3-(3-dimethylaminpropyl)-carbodiimide hydrochloride solution is added and stirred for 15 min. Thereafter, the /V-Hydroxysuccinimide solution is added and the reaction is allowed to proceed in a light-protected bottle under stirring and argon atmosphere at room temperature for e.g. 18 h. The polymer is purified by dialysis against 0.1 M HCI (aq) and isolated by rotary evaporation or freeze drying. Hydrogel formation:
Step 1 : Hydrogels are made by dissolving the DOPA functionalized chitosan polymer in acidic water.
Step 2: The desired metal is added at pH -1 -3.
Step 3: Thereafter pH is raised using e.g. NaOH as base to obtain hydrogels.
1 . Synthesis of DOPA-functionalized polymers: DOPA was grafted onto polymers using standard peptide coupling chemistry. 4.2 g DOPA (21 .4 mmole) (Sigma Aldrich, CAS no. 59-92-7) was dissolved in 0.47 L 0.5 % TFA, which was continuously degassed with argon. The dissolution was aided by ultrasonication. Next, 1 g solid polyallylamine hydrochloride (10.7 mmole) (Polysciences Inc., CAS no. 71550-12-4) was added to the reaction mixture in which it dissolved. The pH was adjusted to 6 by a slow addition of 2 M NaOH. 6.15 g 7-ethyl-3-(3-dimethylaminpropyl)-carbodiimide hydrochloride (32.1 mmole) (Sigma Aldrich, CAS no. 1892-57-5) was dissolved in 14 mL demineralised water and the pH was adjusted to 6 with 10 % TFA. 3.69 g A/-Hydroxysuccinimide (32.1 mmole) (Sigma Aldrich, CAS no. 6066-82-6) was likewise dissolved in 14 mL demineralised water and the pH adjusted to 6 with 2 M NaOH. The N-
Hydroxysuccinimide solution was added to the DOPA/polyallylamine reaction mixture and after 15 minutes the 7-ethyl-3-(3-dimethylaminpropyl)-carbodiimide hydrochloride solution was added. The reaction components were allowed to react for 18 h in a light-protected bottle at room temperature under argon atmosphere and magnetic stirring. The synthesized polymer was purified by dialysis against 0.1 M HCI using Spectra/Por dialysis membranes with a MWCO of 3.5 kDA under vigorous stirring. The polymers were thereafter isolated by rotary evaporation.
2. Synthesis of metal ion/DOPA functionalized polymer complexes;
Step 1 :
22.5 mg of the synthesized DOPA-polyallylamine was dissolved in 75 μΙ_ 0.55 M NaOH to a starting concentration of 300 mg/pL, which corresponds to a DOPA concentration of 136 mM. Step 2:
The polymer solution was mixed with 1 /6 final volume (25 μΙ_) of FeCI3-6H20 solution that had a concentration resulting in a final DOPA to Fe(ll l) ratio of 3:1 . Binding Fe(l ll) in stable non-cross-linking mono-DOPA-Fe(lll) complexes allowed base addition (Raising the pH) to favor the formation of bis-, and tris-complexes without precipitation of ferrihydrite or other iron salts. The Fe(ll l)/polymer solutions were always made fresh before any subsequent experiments. Samples with other polymer concentrations can be prepared as well. In another embodiment, Mn(l l) gels were obtained by using a Mn(ll) sulfate instead of the iron compound. 3. Synthesis of hydroqels;
Either step 3a or step 3b is employed:
Step 3a:
The hydrogel was formed by addition of 2/6 final volume NaOH (50 μΙ_) to the solution described in 2 above at a concentration adjusted to obtain the requested final pH of the hydrogel (Step 3). The gel was mixed until homogenous color and physically state were established (for about 1 minute). After the gels were obtained they were matured in closed containers for 1 h until e.g. the rheology
measurements was performed to ensure complete homogenization and curing of the gels while preventing dehydration of the samples. The final concentration of
DOPA-polyallylamine in all gels used in the experiments below was 150 mg/mL (15 wt%) with a final molar ratio of DOPA to Fe(l ll) of 3:1 . Samples with other polymer concentrations can be prepared; however, if the concentration is too low gels are not formed and if it is too high the kinetics of gel formation becomes affected and bulk mixing becomes difficult. The pH of gels was measured with a flat surface electrode designed for solids, semi-solids and liquids (Fieldscount Soilstick pH- meter, SpectSpectrum Technologies, Plainfield, Illinois).
Step 3b:
The gel was created by adding 2/6 final volume (50 μΙ_) NaOH at a concentration adjusted to get the requested final pH of the gel. (e.g. to get a gel with a final pH of approximately 9, 35 μΙ_ 2M NaOH + 15 μΙ_ 1 M NaOH was added). Locally where the drop hits the polymer solution, the solution instantaneously changed color from green to wine red and at the edge of the alkaline drop a purple/blue color appeared. The color development can be assigned to the different complexes formed in the sample. The wine-red color in the middle of the basic droplet is due to the formation of tris-complexes at high pH and at the edge of the droplet the purple color appears due to the formation of predominantly bis-complexes. The hydrogel is established by homogenization for a minute with a spatula.
Characterization:
UV/Vis absorption spectroscopy;
The abundance of the three different DOPA:Fe(ll l) species (mono-, bis- and tris- complex) as a function of pH was determined using a UV-Visible absorption spectrophotometer. A Fe(l ll):DOPA-polyallylamine solution with a DOPA
concentration of 0.4 mM and a DOPA to Fe(l ll) ratio of 3:1 was titrated with NaOH, whilst the pH was monitored with a Metrohm pH-meter equipped with a Metrohm Unitrode. The pH was increased in steps of -0.5-1 pH units to a final pH of 12 and the spectral changes were monitored by performing UV-Vis absorption measurements at every step from 200 nm to 800 nm at ambient temperature with a scanning rate of 600 nm/min. The relative abundance of the mono-, bis- and tris- DOPA:Fe(lll) complexes was extracted by fitting a multi-Gauss function in an iterative manner to the collected absorption data (Figure 1 ). For quantification, only the region above 400 nm was used as the peaks below this region was severely affected by peak overlap. The characteristic mono-complex peaks were found to be located at 406 nm, 505 nm and at 660 nm. The characteristic bis- and tris-complex peaks were located at approximately 538.5 ± 1 .3 nm and 418 ± 4 nm, respectively. The relative fractions were obtained by normalizing the areas of the characteristic peaks associated with the different complexes to the maximum area-value for each characteristic peak. The results show, Figure 2, that the solutions are dominated by the mono-complexes in the pH range of 1 -5, the bis-complexes in the range of pH 5-10.8 and the tris-complex in the range of 10.8-12. In more detail, the abundance of the mono-, bis- and tris-catechol-Fe(l ll)-species as a function of pH was determined using a UV-Visible absorption spectrophotometer (Helius Alfa double-beam spectrophotometer) equipped with disposable UV-VIS cuvettes having a path length of 1 cm. A Fe(l ll):DOPA-polyallylamine solution with a DOPA concentration of 0.4 mM and a DOPA to Fe(l ll) ratio of 3:1 was titrated against NaOH, whilst the pH was monitored with a Metrohm pH-meter equipped with a Metrohm Unitrode. The pH was increased in steps of -0.5-1 pH units to a final pH of 12 and the spectral changes were monitored by performing UV-Vis absorption measurements at every step from 200 nm to 800 nm at ambient temperature with a scanning rate of 600 nm/min. The relative abundance of the mono-, bis- and tris-catechol-Fe(l ll) complexes was extracted by fitting a multi- Gauss function in an iterative manner to the collected absorption data and models for characteristic absorption of the mono-, bis- and tris-complex were proposed that could be used to describe all absorption curves. For quantification, only the region above 400 nm was used as the peaks below this region was severely affected by peak overlap. The characteristic mono-complex peaks were found to be located at 406 nm, 505 nm and at 660 nm. The characteristic bis- and tris-complex peaks were located at approximately 538.5 ± 1 .3 nm and 418 ± 4 nm, respectively. The relative fractions were obtained by normalizing the areas of the characteristic peaks associated with the different complexes to the maximum area-value for each characteristic peak. As no constraints on the sum of fractions were imposed in the modeling of the data, it can be used to test the quality of the employed models. The sum of fractions is to a good approximation 1 in the pH range above pH 2. Below pH 2 the sum of fractions is less than 1 , which suggest that some of the Fe(lll) ions are free in the solution. Hence, it can be concluded that the deduced models provide a sufficient description of the absorption data.
Recovery test;
These results are described in Figures 6, 7 and 8.
Dynamic Oscillatory Rheoloqy;
The mechanical properties of the gels were measured with an Anton Parr MCR 501 Rheometer using parallel plate geometry (8 mm diameter rotating top plate). All tests were performed at 20 °C after 1 h of sample maturation after gel formation as described above. Water evaporation was minimized using a Anton Parr evaporation hood with a solvent trap. Strain sweeps, Figure 3, were performed at a frequency of 1 s"1. Frequency sweeps were performed at constant strain (15 %) with increasing rate of deformation while measuring storage modulus (G') and loss modulus (G"), Figure 4. The resulting pH-dependent storage moduli are shown in Figure 5, 18, 19, 23 and 26.
In more detail, the mechanical properties of the hydrogels were measured with an Anton Parr MCR 501 Rheometer using parallel plate geometry (8 mm rotating top plate). An Anton Parr evaporation hood equipped with a custom made accessory was employed to prevent solvent evaporation. Prior to each measure the hydrogels were allowed to rest for 1 hour in air tight containers to facilitate complete diffusion and relaxation of the polymer network. Frequency sweeps was performed in the linear viscoelastic range (LVR) at constant strain amplitude of 15 % (LVR is e.g. 0- 30% strain for a pH 9 hydrogel) while the storage and loss modulus was
simultaneously measured, Figure 4.
Quantitative recovery test was likewise performed on a hydrogel that had med allowed to rest for 1 hour prior to the measurements. The strain amplitude was increased until failure (0.01 -200% strain) under constant angular frequency (1 s"1). Subsequently, the storage modulus was monitored at constant strain (1 %) and angular frequency (1 s"1). Some of the points in the beginning of the recovery part has been removed as they are not reliable All measurements were performed at 20 °C. Results are shown in Figure 6.
Small Angle X-rav Scattering (SAXS):
The structural changes that the cationic polyallylamine and Fe(ll l):DOPA- polyallylamine undergo as a function of pH were examined with Small Angle X-ray Scattering, SAXS. 10 ml_ 1 wt% polyallylamine solution and 1 .5 wt% Fe(l ll):DOPA- polyallylamine solution with at DOPA to Fe(lll) ratio of 3:1 (0.1 M HCI as solvent) were prepared. Subsequently, the pH was increased through a potentiometric titration with NaOH. The dilution factor of the samples caused by the addition of base could be neglected due to the small volume used to change the pH. A volume of 200 μΙ_ of the resulting solution was removed at each integer value of pH (e.g. pH 1 , pH 2, pH 3....) and constituted a sample for SAXS.
From the obtained SAXS data the radius of gyration Rg was determined though an indirect Fourier transform and the result is plotted as a function of pH in figure 9. At low pH the size of the polyallylamine polymers are relative constant but as the pH increases above a transition pH of ~8 the size increases. The abrupt increase in size above the transition pH can be explained by an aggregation/change of shape of the polymers caused by the neutralization of the positive charges along the polymer backbone. DOPA-polyallylamine is speculated to undergo the same pH- induced structural transition as polyallylamine just with a slightly higher transition pH as the pKa value of DOPA-polyallylamine is just above that found for polyallylamine. The Fe(lll): DOPA-polyallylamine in general display a much larger sizes, which suggest that Fe(lll):DOPA complexes are indeed formed. Static tensile test:
Hydrogels obtained as disclosed herein are applied to a test surface of 25 mm by 25 mm and an identical test surface pressed onto this area. Thereafter the glue is allowed to cure for the chosen time after which a tensile test is run till failure; the force at this point measures the strength of adhesion. To test the underwater adhesive capabilities, the same procedure is described but now the test surfaces are kept underwater the entire time. The test surface is selected from the following: glass, steel, skin, tissue, bone and cartilage
Example 2
Metal :DOPA-polyallylamine hydrogels may also be prepared by using the below method:
a. 22.5 mg DOPA-polyallylamine with a grafting density of approximately 9% was dissolved in 75 μΙ_ 0.55 M NaOH to give a polymer concentration of 300 mg/ml.
b. 25 μΙ_ metal chloride solution with a concentration chosen to obtain a
DOPA:metal molar ratio of 3:1 was added
c. 50 μΙ_ NaOH solution was added with a concentration adjusted to obtain the desired final pH of the hydrogel. In the below examples a 2 M NaOH solutions was employed.
Analogous synthesis procedures will be used to make hydrogels of other polymers such as polymer backbone comprises one or more backbone monomer unit(s) which is/are selected from the group consisting of:
• amino-C1-10-alk(an/en/yn)yl which is optionally substituted;
• amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent;
• amides of the formula -(CO)-(NH2)-Ci-6-alk(an/en/yn)yl-NH2;
• aminostyrenes which are optionally substituted; and
• amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)-(CHR3)- (CHR4)-(CHR5)-OH; wherein
o R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6- alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and
o R7 is selected from the group consisting of -H and -(CO)-Ci-6- alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
in their open chain form or in the a-form or β-form thereof. However, it is necessary to establish the grafting density using e.g. UV-VIS absorption spectroscopy in each case to decide how much metal to add. For a specific grafting ratio, γ, or a polymer molar mass M, and a polymer concentration of m in units of g/l, the catechol concentration is [catechol] = γτη/Μ. To obtain a desired catechol :metal ratio, of X:1 , metal shall be added in an amount corresponding to a final concentration of γτη/ΜΧ. To make gels with higher DOPA:metal ratios the metal chloride solution in step b. is diluted. To make gels with lower DOPA:metal ratios, the starting solution is concentrated.
All of the below mentioned metal:DOPA-polyallylamine hydrogels were prepared using the recipe given above. In the final base addition step 2 M NaOH was added. All hydrogels were prepared to have a DOPA to metal ratio of 3:1 and were found to have a final pH around 9.5.
Ca(ll):
CaCI2-2H2O was used as metal source. Within 10 minutes a red weakly self-healing hydrogel had been formed. The red color can possibly be explained by DOPA oxidation and subsequently sclerotarization. The pictures of this hydrogel, which is shown in Figure 10, display the slow self-healing of a Ca(ll):DOPA-polyallylamine hydrogel.
Al(lll):
AICI3-6H2O (AICI3) was employed as metal source. A transparent faint red/orange gel instantly formed. The prepared hydrogel showed self-healing properties and recovered within minutes after forced fracture as can be seen in the following three pictures. Pictures of the hydrogel are shown in Figure 13.
Zn(ll):
ZnCI2 was used as metal source. When mixed in the recipe-described proportions an orange/red solution formed. If twice as much Zn(l l) was employed a light purple/white sticky gel was formed. Pictures of the hydrogel are shown in Figure 1 1 .
Mn(ll):
MnCI2-4H2O was used as metal source. A yellow/green hydrogel formed instantly upon mixing. The hydrogel was very liquid-like and recovered within seconds after forced fracture. Note that a thin skin with a brown shade formed on the surface of the hydrogen and this might possible be explained by DOPA-oxidation. Pictures of the hydrogel are shown in Figure 12.
Cr(lll):
CrCI3-6H2O was used as metal source. After 5-10 minutes a squashy light orange hydrogel formed. Cu(ll):
CuCI2-2H2O was used as metal source. After 5 minutes a squashy green hydrogel was formed.
Example 3
Hydrogels with the group II I metals, aluminium, gallium and indium were
synthesized following the general protocol as disclosed in example 2 using the metal ions Al(lll), Ga(l ll), and In(ll l) that all occur in main group II I of the periodic table to the elements. Note that the hydrogels were prepared according to the recipe described above with AICI3 H2O, Ga(NO3)3-3.12 H2O and lnCI3-4H2O as metal sources in step 2 of the hydrogel formation process.
Qualitative testing of the self-healing properties of the Al(lll) and Ga(ll l) gels were made for DOPA-polyallylamine gels with a metahDOPA ratio of 1 :3. The self- healing properties were tested by forced fracture of freshly formed hydrogels (pH 10), which had been allowed to homogenize for 10 min prior to the experiment. The two hydrogel blobs were brought back together and allowed to reform the broken bonds as a function of time. In Figure 13 is shown the recovery of a AI(l ll):DOPA- polyallylamine hydrogel, which was found to recover its original shape within 7 minutes after fracture. The Ga(l ll):DOPA hydrogel was found to recover it original shape within 2 minutes as shown in figure 14. All formed AI(ll l)/Ga(l ll)/ln(l ll):DOPA-polyallylamine gels were transparent regardless of pH. In especially the high pH region they develop a red/orange color. Al(ll l) and Ga(l ll) functionalized hydrogels develops the strongest colors (red- and yellowish, respectively), whereas In(l ll) only display a faint orange shade. The colors suggest that the catechol may have been oxidized. To investigate the abilities of the ions to protect the DOPA functionality from oxidation, UV-Vis absorption measurements were performed and the absorption profiles above 300 nm were compared because absorption in this region is a clear indication of catechol oxidation. The UV/Vis absorption measurements were performed on metal:DOPA-polyallylamine solutions with a metal:DOPA ratio of 1 :3 and a DOPA concentration of 40 mM using a Helius Alfa double-beam spectrophotometer equipped with disposable UV-Vis cuvettes having a path length of 1 cm. The pH of the solutions was increased in steps of 0.5-1 pH units to a final pH of 12 while the spectral changes were monitored at each pH step. To investigate whether irreversible cross-links had been formed as a result of the catechol oxidation, the pH of the AI(ll l):DOPA-polyallylamine system was reduced to pH 1 after having reached pH 12. If absorption bands could still be seen in the region above 300 nm after reaching pH 1 again, this would suggest that quinone- tanning had occurred as a result of the catechol oxidation. In Figure 15 UV/VIS spectra are shown with the left graph showing the wavelength span from 200-800 nm while the right graph displays a zoom onto the wavelength range 200-500 nm. The bottom curve in the figure below shows the absorption profile measured on the pH 1 solution after having reached pH 12. Absorption bands in the region above 300 nm can still be seen after the pH has been returned to 1 from 1 1 .9; thus, some quinone tanning has occurred in the alkaline pH range and the Al(l ll) ions do not protect the catechol completely from being oxidized. Note that addition of antioxidants may alleviate this effect. UV/VIS spectra were also measured for a corresponding Ga(ll l) solution, which is shown in Figure 16 and for the In(lll) solution in Figure 17.
As a reference the same experiment was performed on a DOPA-polyallylamine solution without the addition of metals, and the data suggest that approximately the same amount of oxidation occurs both with and without Al(ll l), Ga(lll) or Fe(lll) added.
Rheoloqy
Gels made with Al(l ll), Ga(ll l), In(l ll) as a function of pH for a metal:DOPA ratio of 1 :3 were investigated by oscillatory rheology with an Anton Parr MCR 501
Rheometer using parallel plate geometry (8 mm rotating top plate). In addition, an Anton Parr evaporation hood equipped with a custom made accessory was employed to prevent solvent evaporation. Prior to each measurement the pH of the hydrogels was measured using a flat Fieldscount Soilstick electrode from Spectrum Technologies Plainfield, Illinois. Afterwards the hydrogels were allowed to rest for 1 hour in air tight containers to facilitate complete diffusion and relaxation of the polymer network. Subsequently, frequency sweeps were performed in the linear viscoelastic range (LVR) with a constant strain amplitude of 15 % while the storage modulus G' and loss modulus G" were measured. All measurements were performed at 20 °C.
In Figure 18 the measured storage modulus G' is plotted as a function of the final pH of the probed metal:DOPA-polyallylamine hydrogels for the angular frequency 25 s"1. A maximum in the mechanical strength is obtained within a few pH values above neutral pH in all the metal-DOPA-polyallylamine systems again reflecting that a maximum in the mechanical properties is obtained around the polymers pKa value (DOPA-polyalyllamine's pKa value ~ 9.5). Example 4: Varying the metal :DOPA ratio
Rheological characterization of mechanical performance for gels made with Fe(ll l) as a function of pH for a metal :DOPA ratio of 1 :6 and 1 :9. Gels were made as described in Example 2 but with a correspondingly lower concentration of the FeCI3 solution in step 2 of the hydrogel formation so that a 1 :6 and 1 :9 metahDOPA ratio was obtained. Both metakDOPA systems display as expected a maximum in the mechanical strength distribution close to the pKa value of polyallylamine (pKa ~ 9.5). With a Fe(lll):DOPA ratio of 1 :6 a maximum strength of 4250 Pa was obtained at pH 9.9 while in the 1 :9 system, the mechanical strength peaked at pH 10.2 with a value of approximately 4500 Pa. The data are represented in figure 19.
Example 5: Reversibility test of adhesion
To test gel reversibility, Fe(ll l):DOPA-polyallylamine gels with a 1 :3 metal:DOPA ratio were made as described in Example 2. pH reversibility was tested by inspection by eye: Addition of acid (0.1 M HCI) lead to dissolution of the gel while subsequent re-addition of base resulting in formation of another gel. This illustrates the pH-reversible nature of the gelation system. The competitive complexation of Fe'" with EDTA was likewise tested. A 37.5 μΙ hydrogel was allowed to rest for 1 h after formation. Thereafter it was embedded in ~3 ml 150 mM EDTA at pH 5.5. The sample was lightly shaken by hand during the first 5 min and thereafter left at rest. After 30 min most of the gel material had dissolved; after 1 1 h only traces of gel-like material could be seen as shown in Figure 20.
Example 6: Qualitative test of adhesion
Qualitative tests of adhesion between two untreated glass slides were made for Fe(l ll):DOPA-polyallylamine with metahDOPA ratios of 1 :3, 1 :6 and 1 :9. The samples were left to cure overnight in air at room temperature. One of the constructs is shown in Figure 21 .
Shear testing by hand did not allow pulling the two glass slides apart indicating that both a good cohesive and adhesive performance was obtained. Example 7: Synthesis of polyallylamine grafted with 3,4-dihydroxyphenyl- acetic acid
3,4-dihydroxyphenylacetic acid was grafted onto polyallylamine using standard EDC coupling chemistry as disclosed in "Catechol-functionalized chitosan/Pluronic hydrogels for tissue adhesives and hemostatic materials", Ji Hyun Ryu, Won Ho Kong, Taek Gyoung Kim, Tae Gwan Park, Haeshin Lee, Biomacromolecules, 201 1 . The chemical structure of 3,4-dihydroxyphenylacetic acid is shown below.
0.55 g polyallylamine (160 ± 40 kDa, Polysciences Inc.) was dissolved in 100 mL H20 (pH 5.5). Next, 1 .09 g 3,4-dihydroxyphenylacetic acid (Sigma Aldrich, CAS no. 102-32-9) and 2.5 g EDC (Sigma Aldrich, CAS no. 1892-57-5) was dissolved in 50 mL H20:ethanol (1 :1 V/V) and added to the polymer mixture. The mixture was allowed to react for 12 h. During the reaction the of the solution was maintained at pH by the addition of 1 M HCI. Afterwards the product were purified by dialysis against 0.1 M HCI using Spectra/Por dialysis membranes with a molecular weight cut off of 3.5 kDa. Subsequently, the catechol functionalized polymers were isolated by rotary evaporation and grinded to give a homogenous light brown powder.
The grafting density determined by UV/VIS spectroscopy using pure 3,4- dihydroxyphenylacetic acid as a standard. From the absorption of the 280 nm peak the grafting density of 3,4-dihydroxyphenyl acetic acid polyallylamine was determined to 5.9%.
The pKa (pi) was determined by potentiometric titration to be approximately pH 9. The titration was performed with a Metrohm 809 Titrando equipped with a calibrated Metrohm Aquatrode and a mechanical Metrohm 802 stirrer. The measurements were conducted under nitrogen atmosphere at 25 °C. 60 mg of 3,4 dihydroxyphenylacetic acid-polyallylamine was dissolved in 50 mL 0.1 M KCI and 0.5 mL 0.1 M HCI was likewise added to decrease the pH to around 2. The solution was titrated at a rate of 0.2 mL/minute with a 0.08 M NaOH. The pKa value of 3,4 dihydroxyphenylacetic acid-polyallylamine was found to be around 9.
Gel formation Gel formation was studied qualitatively with a metahDOPA ratio of 1 :3 according to the following recipe:
a. 1 1 .25 mg polymer was dissolved in 37.5 μΙ_ H20
b. 12.5 μΙ_ 0.174 M FeCI3 6H20 was added to the solution from step a) and the solution turned green due to the formation of mono-complexes at low pH. c. 25 μΙ_ NaOH was added to the solution from step b) leading to formation of the hydrogel.
During step c), a red color appeared due to the formation of tris-complexes at high pH. Upon mixing with a spatula a homogenous dark colored hydrogel was formed. A final gel is shown in Figure 22.
Rheoloqy
Rheological experiments were performed on Fe(ll l): 3,4 dihydroxyphenylacetic acid-polyallylamine hydrogels prepared using the recipe described in the previous section and the experiment were performed as described for DOPA-polyallylamine. The result is shown in Figure 23 and as expected a maximum in the mechanical strength is found around the polymer's pKa value.
Example 8
DOPA-functionalized chitosan was prepared following the recipe described for DOPA-polyallylamine in example 1 with chitosan oligosaccharide (5000 Da molecular weight on average).
The grafting density was determined by UV/VIS spectroscopy using pure DOPA as a standard. From the absorption of the 280 nm peak the grafting density of DOPA- chitosan was determined to 3.3%.
The pKa was determined by potentiometric titration to be approximately 6.7. The DOPA-chitosan polymer was characterized spectroscopically by 1 H NMR and FTIR. In the 1 H NMR spectra of chitosan, peaks stemming from the three aromatic hydrogen atoms situation on the DOPA side chain was detected around 6.6 ppm (see figure 24). In figure 25 the FT-IR spectra of pure and DOPA modified chitosan oligosaccharide are compared. The DOPA functionalized chitosan oligosaccharide has an additional peak at -1715 cm"1 , which can be assigned to the formed amide linkage between the polymer backbone and the DOPA side chain.
Gel formation was studied qualitatively at a metahDOPA ratio of 1 :3 with Fe(l ll) as the metal:
a. 16.88 mg polymer was dissolved in 37.5 μΙ_ H2O
b. 12.5 μΙ_ 0.073 M FeCI3-6H2O was added to the solution from step a) and the solution turned green due to the formation of mono-complexes at low pH. c. 25 μΙ_ NaOH was added to the solution of step b) and a red color appeared due to the formation of tris-complexes at high pH. Subsequently the sample was mixed with a spatula and a homogenous hydrogel was formed
Rheology measurements were done for Fe(ll l):DOPA ration of 1 :3. The measurements were performed as described for DOPA-polyallylamine and the results are shown in Figure 26. As expected, a bell-shaped curve with a maximum close to the pKa value of chitosan (pKa = 6.5), was obtained. The maximum mechanical strength obtained around pH 8 and was
approximately a factor 5 higher than in the Fe(l ll):DOPA-polyallylamine system. This huge increase in hydrogel strength can in part be explained by a 1 .5 times higher polymer concentration in the DOPA-chitosan system than in the DOPA-polyallylamine system. Furthermore, chitosan is a more "bulky" polymer compared to polyallylamine.
De-gelation by the action of EDTA on Fe(ll l):DOPA-chitosan hydrogels were performed for a gel with a metahDOPA ratio of 1 :3. A Fe(ll l):DOPA-chitosan hydrogel with a final pH of 12 was allowed to cure for 1 h, where after it was placed in 150 mM EDTA at pH 5.5. It was found to dissolve within 10 minutes as illustrated in Figure 27 that shows images taken during the first 10 minutes after placing the hydrogel in the EDTA solution.

Claims

Claims 1 . A method of forming a hydrogel, comprising the steps of:
1 . providing a functionalized polymer backbone; wherein the polymer
backbone comprises one or more backbone monomer unit(s) comprising an amino group;
said polymer backbone being functionalized with one or more catechol monomer unit(s),
said catechol monomer units comprising at least one amino group and/or carboxylate-group;
2. contacting said functionalized polymer backbone with a solution comprising a soluble metal of formula Mn+ or any complex thereof at a first pH value, where n is an integer from 1 to 9; and
3. adjusting the pH of the polymer metal solution to a second pH value,
wherein the second pH value is higher than the first pH value;
whereby a hydrogel is obtained, said hydrogel having its maximum mechanical strength at a pH-value in the range of pKa -6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone. 2. The method of claim 1 wherein the second pH value is obtained by addition of a base comprising an OH-group, such as KOH or NaOH.
3. The method of any of claims 1 -2; wherein a mixing step is performed upon contacting the functionalized polymer with the solution comprising a soluble metal of formula Mn+ or any complex thereof at a first pH-value, such as wherein the mixing procedure is performed at temperatures between 5 and 60 °C.
4. The method according to any of claims 1 -3; wherein the polymer backbone comprises one kind of backbone monomer units, only, said backbone monomer units comprising one or more amino groups.
5. The method according to any of claims 1 -4; wherein the polymer backbone comprises more than one kind of backbone monomer units, wherein at least one kind of monomer units comprise one or more amino groups.
6. The method according to any of claims 1 -5; wherein the polymer backbone comprises one or more backbone monomer unit(s) which is/are cationic at said first pH value.
7. The method according to any of claims 1 -6; wherein the polymer backbone comprises one or more backbone monomer unit(s) which is/are stimuli-responsive.
8. The method according to any of claims 1 -7; wherein the polymer backbone comprises one or more backbone monomer unit(s), which is/are thermo- responsive.
9. The method according to any of claims 1 -8; wherein the polymer backbone comprises one or more backbone monomer unit(s), which is/are pH-responsive.
10. The method according to any of claims 1 -9; wherein the polymer backbone comprises one or more backbone monomer unit(s), which is/are soluble in water.
1 1 . The method according to any of claims 1 -10; wherein the polymer backbone comprises one or more backbone monomer unit(s) which is/are selected from the group consisting of:
• amino-C1-10-alk(an/en/yn)yl which is optionally substituted;
• amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an
organic substituent;
• amides of the formula -(CO)-(NH2)-Ci-6-alk(an/en/yn)yl-NH2;
• aminostyrenes which are optionally substituted; and
• amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)-(CHR3)- (CHR4)-(CHR5)-OH; wherein
o R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6- alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and o R7 is selected from the group consisting of -H and -(CO)-Ci-6- alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
in their open chain form or in the a-form or β-form thereof.
12. The method according to any of claims 1 -1 1 ; wherein the polymer backbone comprises one or more backbone monomer unit(s) of the generic formula amino- C1-10-alk(an/en/yn)yl which is optionally substituted with one or more substituents.
13. The method according to any of claims 1 -12; wherein the polymer backbone comprises one or more backbone monomer unit(s) of the formula:
14. The method according to any of claims 1 -12; wherein the polymer backbone comprises one or more backbone monomer unit(s) which is/are selected from the group consisting of amino-C1-10-alk(an/en/yn)yl! amino-C1-6-alk(an/en/yn)yl, amino- C2-4-alk(an/en/yn)yl and amino-C3-alk(an/en/yn)yl is substituted with one or more substituent(s) selected from the group consisting of -SH, - OH, -COOH, -NH2, -S- CH3, -O-CH3, -CH(OH)-CH3 and -CH(SH)-CH3.
15. The method according to any of claims 1 -1 1 , wherein polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino acids which occur naturally and which do not occur naturally.
16. The method according to any of claims 1 -1 1 and 15, wherein said amino acid(s) is/are of the generic formula H2N-CHR1-COOH wherein R1 is an organic
substituent.
17. The method according to any of claims 1 -1 1 and 15-16, wherein said amino acid(s) is/are of the formula H2N-CHR1-COOH;
wherein R1 is selected from the group consisting of -H, -C1-6-alk(an/en/yn)yl, -C1-6- alk(an/en/yn)yl-R2, wherein R2 is selected from the group consisting of -SH, -COOH, C3H3N2! -NH2, - S-CH3, -CO-NH2, -NH-C(NH)NH2, - OH, -CH(OH)-CH3, -SeH, -C8H6N, -C6H5(OH)2! -C6H4OH and -C6H4OH.
18. The method according to any of claims 1 -1 1 and 15-17, wherein said amino acid(s) of the formula H2N-CHR1-COOH is a naturally occurring amino acid which is selected from the group consisting of DOPA, ornithine, lysine, arginine, histidine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine and valine.
19. The method according to any of claims 1 -1 1 , wherein the polymer backbone comprises one or more polymer monomer unit(s) of the formula -(CO)-(NH2)-C1-6- alk(an/en/yn)yl-NH2.
20. The method according to any of claims 1 -1 1 , wherein the polymer backbone comprises one or more backbone monomer unit(s) comprising styrene which is substituted, such as with one or more substituents selected from the group consisting of -NH2 and -C1-6-alk(an/en/yn)yl-NH2.
21 . The method according to any of claims 1 -1 1 and 20, wherein the polymer backbone comprises one or more backbone monomer unit(s) comprising styrene which is substituted with NH2.
22. The method according to any of claims 1 -1 1 and 20, wherein the polymer backbone comprises one or more backbone monomer unit(s) comprising styrene which is substituted with Ci-6-alk(an/en/yn)yl-NH2.
23. The method according to any of claims 1 -1 1 and 20-22, wherein styrene is further substituted with one or more substituents selected from the group consisting of -SH, - OH, -COOH, -NH2, -S-CH3, -O-CH3, -CH(OH)-CH3 and -CH(SH)-CH3.
24. The method according to any of claims 1 -1 1 , wherein the polymer backbone comprises one or more backbone monomer unit(s) comprising styrene which is un- substituted.
25. The method according to any of claims 1 -1 1 , wherein polymer backbone comprises one or more backbone monomer unit(s) selected from the group of amino sugars.
26. The method according to any of claims 1 -1 1 and 25, wherein said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein
• R3, R4, R5 and R6 are independently selected from the group consisting of - H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and
· R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein - -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups;
in their open chain form or in the a-form or β-form thereof.
27. The method according to any of claims 1 -1 1 and 25-26, wherein said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH, -(CH2)-OH and -COO" and -CH(OH)-CH(OH)-CH2-OH.
28. The method according to any of claims 1 -1 1 and 25-27, wherein said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R3 and R4 are independently selected from the group consisting of -H and -OH.
29. The method according to any of claims 1 -1 1 and 25-28, wherein said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R3 is -OH.
30. The method according to any of claims 1 -1 1 and 25-28, wherein said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R4 is selected from the group consisting of -H and -OH, such as wherein R4 is -H, or wherein R4 is -OH.
31 . The method according to any of claims 1 -1 1 and 25-30, wherein said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R5 is selected from the group consisting of -(CH2)-OH and -COO".
32. The method according to any of claims 1 -1 1 and 25-31 , wherein said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R6 is selected from the group consisting of -OH and -CH(OH)- CH(OH)-CH2-OH.
33. The method according to any of claims 1 -1 1 and 25-32, wherein said amino sugar(s) is/are of the generic formula O=CR6-CH(NHR7)-(CHR3)-(CHR4)-(CHR5)- OH; wherein R7 is selected from the group consisting of -H and -(CO)-CH3.
34. The method according to any of claims 1 -1 1 and 25-33, wherein said amino sugar(s) is/are selected from the group consisting of glucosamine,
acetylglucosamine, galactosamine and sialic acid in their open chain form or in any a-form or β-form thereof.
35. The method according to any of claims 1 -1 1 and 25-33, wherein 3 such said amino sugar(s) comprised in the polymer backbone together form chitosan having the formula
in its open chain form or in any a-form or β-form thereof.
36. The method according to any of claims 1 -1 1 and 25-33, wherein said amino sugar(s) comprised in the polymer backbone together from chitosan with varying degrees of de-acetylation in its open chain form or in any a-form or β-form thereof.
37. The method according to any of claims 1 -1 1 and 25-33, wherein the polymer backbones are amino-functionalized polymers with a pKa ranging from
approximately 4 to 10, such as from 5 to10.
38. The method according to any of claims 1 -37, wherein the functionalizing catechol monomer unit(s) with which the polymer backbone is functionalized comprises at least one catechol functional group and further comprising at least one amino group.
39. The method according to any of claims 1 -37, wherein the monomer unit(s) with which the polymer backbone is functionalized comprises at least one catechol functional group and further comprising at least one carboxylate-group.
40. The method according to any of claims 1 -39, wherein the monomer unit(s) with which the polymer backbone is functionalized comprises at least one catechol functional group and further comprising at least one amino group and at least one carboxylate-group.
41 . The method according to any of claims 1 -40, wherein the monomer unit(s) with which the polymer backbone is functionalized comprises at least one catechol functional group and further comprises at least one amino group and/or one carboxylate-group is of the below formula:
wherein: R10 is selected from the group consisting of (Ci-6-alk(an/en/yn)yl)q-COOH and (Ci-6-alk(an/en/yn)yl)r-NH2 wherein:
q and r are independently selected from the group consisting of 0 and 1 ;
R11 is selected from the group consisting of -OH and -H; and when q or r is 1 then Ci-6-alk(an/en/yn)yl is optionally substituted with one or more substituents selected from the group consisting of -CH3, -OH, -NH2 and -CO-C=C-R12 wherein:
o R12 is of the formula:
42. The method according to claim 41 , wherein R10 is selected from the group consisting of optionally substituted (C2-4-alk(an/en/yn)yl)q-COOH and (C2-4- alk(an/en/yn)yl)r-NH2.
43. The method according to any of claims 41 -42, wherein q is 0.
44. The method according to any of claims 41 -42, wherein q is 1 .
45. The method according to any of claims 41 -44, wherein r is 0.
46. The method according to any of claims 41 -44, wherein r is 1 .
47. The method according to any of claims 41 -46, wherein R10 is selected from the group consisting of optionally substituted (C2-4-alk(an/en/yn)yl)-COOH and (C2-4- alk(an/en/yn)yl)-NH2.
48. The method according to any of claims 41 -47, wherein R10 is -COOH.
49. The method according to any of claims 41 -47, wherein R10 is -NH2.
50. The method according to any of claims 41 -47, wherein R10 is optionally substituted (C2.4-alk(an/en/yn)yl)-COOH.
51 . The method according to any of claims 41 -47, wherein R10 is optionally substituted (C2-4-alk(an/en/yn)yl)-NH2.
52. The method according to any of claims 41 -51 , wherein R11 is -OH.
53. The method according to any of claims 41 -51 , wherein R11 is H.
54. The method according to any of claims 41 -51 , wherein R11 of the monomer unit(s) with which the polymer backbone is functionalized comprises at least one catechol functional group and further comprises at least one amino group and/or one carboxylate-group is positioned as indicated in the below formula:
55. The method according to any of claims 41 -51 , wherein R11 of said monomer unit(s) with which the polymer backbone is functionalized comprises at least one catechol functional group and further comprises at least one amino group and/or one carboxylate-group is positioned as indicated in the below formula:
R11
56. The method according to any of claims 41 -53, wherein R11 of said monomer unit(s) with which the polymer backbone is functionalized comprises at least one catechol functional group and further comprises at least one amino group and/or one carboxylate-group is positioned as indicated in the below formula:
57. The method according to any of claims 41 -53, wherein said monomer unit(s) with which the polymer backbone is functionalized is/are selected from the group consisting of 2,4,5-trihydroxybenzoic acid, 3-(3,4-dihydroxyphenyl)propanoic acid, 3-(3,4-Dihydroxyphenyl)-2-methyl-alanine, 2,4,5-Trihydroxy-phenylalanine, 2- amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid, (2R)-3-(3,4- dihydroxyphenyl)-2-{[(2E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]oxy}propanoic acid (Rosmarinic acid), dopamine and L-DOPA and D-DOPA; or any isomers or mixtures thereof.
58. The method according to any of claims 41 -53, wherein said monomer unit(s) with which the polymer backbone is functionalized is L-DOPA of the below formula:
o
59. The method according to any of claims 41 -53, wherein said monomer unit(s) with which the polymer backbone is functionalized is D-DOPA of the below formula:
o
60. The method according to claim 1 -59, wherein the catechol monomer units are attached to the polymer backbone via covalent bonds.
61 . The method according to claim 60, wherein said covalent bonds are ester bonds or peptide bonds or a mixture of ester bonds and peptide bonds.
62. The method according to any of claims 60-61 , wherein said covalent bonds are a mixture of ester bonds and peptide bonds.
63. The method according to any of claims 60-61 , wherein said covalent bonds are peptide bonds.
64. The method according to any of claims 60-61 , wherein said covalent bonds are ester bonds.
65. The method according to any of claims 1 -64, wherein n is selected from the group consisting of 2, 3 and 4.
66. The method according to claim any of claims 1 -65, wherein M designates iron, aluminium, titanium, vanadium, manganese, copper, chromium, magnesium, calcium or silicon, or wherein M designates calcium, manganese, chromium, magnesium, zinc, gallium, copper, titanium, vanadium, iron, aluminium, indium, a lanthanide or hafnium; such as wherein M designates iron.
67. The method according to any of claims 1 -66, wherein M designates iron, titanium, manganese or copper, such as e.g. wherein M n+ designates Fe(l ll), Cu(l l), Ti(IV) or Mn(l l).
68. The method according to any of claims 1 -67, wherein M designates iron, such as wherein Mn+ designates Fe(lll).
69. The method according to any of claims 1 -68, wherein the first pH value is larger than or equal to 0 and smaller than or equal to 8 or the pKa value of the backbone polymer whichever is smaller.
70. The method according to any of claims 1 -68, wherein the first pH value is within 1 and the pKa value of the backbone polymer.
71 . The method according to any of claims 1 -70, wherein the second pH value is within the range from above the first pH value up to the pKa value of the backbone polymer plus 9.
72. The method according to any of claims 1 -71 , wherein the second pH value is; such as within the range from the first pH value plus 0.5 up to the pKa value plus 9.
73. The method according to any of claims 1 -72, wherein, the grafting density, is between 0.01 % and 100%, such as wherein, the grafting density is between 1 % and 20%.
74. The method according to any of claims 1 -73, wherein the pH value of the maximal strength of the polymer the range pKa -6 to pKa +3.
75. The method according to any of claims 1 -74, wherein the pH value of the maximal strength of the polymer the range pKa-1 to pKa+0.5.
76. The method according to any of claims 1 -75, wherein the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 1000 Pa.
77. The method according to any of claims 1 -76, wherein the hydrogel obtained has a maximum mechanical strength measured as storage modulus of at least 4000 Pa.
78. The method according to any of claims 1 -77, wherein the hydrogel obtained has a maximum mechanical strength measured as storage modulus of about 7000 Pa.
79. The method according to any of claims 1 -78, wherein self-healing is initiated within 30 seconds after a forced fracture.
80. The method according to any of claims 1 -79, wherein self-healing is completed within 15 minutes after a forced fracture.
81 . The method according to any of claims 1 -80, wherein self-healing is completed within 45 minutes from a forced fracture.
82. The method according to claim any of claims 1 -81 , wherein the self-heal polymer obtained is adhesive.
83. The method according to any of claims 1 -82, wherein the the stoichiometric ratio of catechohmetal is above 3:1 for octahedrally coordinated metals, such as Fe(l ll), Al(lll), Mn(l l), V(lll), Cr(lll), and Ti(IV), and 2:1 for tetrahedrally coordinated metals.
84. The method according to any of claims 1 -81 , wherein the self-healing polymer obtained is non-adhesive.
85. The method according to any of claims 1 -81 and 84, wherein the stoichiometric ratio of catechohmetal is below or at 3:1 for octahedrally coordinated metals and 2:1 for tetrahedrally coordinated metals.
86. A hydrogel comprising:
a. a functionalized polymer; wherein the polymer backbone comprises one or more backbone monomer unit(s) comprising an amino group;
• said polymer backbone being functionalized with one or more catechol monomer unit(s),
• said catechol monomer units comprising at least one amino group and/or carboxylate-group;
b. a metal of formula Mn+ or any complex thereof;
said polymer having its maximum mechanical strength at a pH-value in the range of pKa minus 6 of the functionalized polymer backbone to pKa +3 of the functionalized polymer backbone.
87. The hydrogel according to any of claims 1 -86, which is for use as an adhesive, glue, joining, attachment and/or cohesive agent e.g. for underwater applications, for dry applications and/or for joining dissimilar substrates such as skin/bandaging and/or rubber/metal; such as a hydrogel which is for use as an adhesive or joining agent.
88. The hydrogel according to any of claims 1 -86, which is for use as a self-healing material, such as a self-healing coating.
89. The hydrogel according to any of claims 1 -86, which is for use for under-water purposes.
90. A delivery of the mixture of step 2 to a location in the body whereby the hydrogel according to any of claims 1 -86, subsequently cure in step 3, due to the increased pH derived from the tissue.
91 . The hydrogel according to any of claims 1 -86, which is for use to glue, attach, adhere and/or join implants to desired locations in the body such as:
a. Dental implants;
b. Dental filling material be it plastic, polymeric, metal, ceramic or any mixture and/or composite thereof;
c. Orthopedic implants including bone and cartilage implants;
d. For catheter fixation;
e. For fixation of internal medical devices of other kinds, e.g.
i) insulin or other pumps;
ii) power supplies, motors or computers; and/or
iii) artificial heart valves or blood vessels (including auto-, alio- and xeno-grafts);
such as for use as a bonding agents for implants.
92. The hydrogel according to any of claims 1 -86, which is for use as drug delivery vehicle, e.g. as a drug delivery matrix, such as an internal nicotine patch or for delivery of any other drug.
93. The hydrogel according to any of claims 1 -86, which is for use to stop bleedings, such as by: a. Addition of a solution below curing pH, which then cures when in contact with body pH; and/or
b. By extracting metals from surrounding medium and then curing.
94. The hydrogel according to any of claims 1 -86, which is for use as a metal sorbant; such as for removing metals from streams and/or mixtures etc. such as for removing metals from liquids such as waste water, blood, radioactive liquids, reaction streams and/or mixtures thereof, e.g. for use in removing metals from liquids such as from waste water, blood, radioactive liquids.
95. The hydrogel according to any of claims 1 -86, which is for use as a part of a wound-care product, such as:
a. wound healing applications;
b. For applications where the hydrogel is visible to the eye, a hydrogel containing an uncolored ion may be of cosmetic advantage; and/or
c. As tissue/organ scaffold.
96. The hydrogel according to any of claims 1 -86, which is for use as a tissue adhesive, glue, cohesive agent such as:
a. Applications in the oral cavity including tongue, lip or oral cavity surgery, e.g. cheek/gum surgery;
b. In connection with eye surgery, e.g. cataract operation; in this connection transparent hydrogels;
c. In place of existing tissue adhesives either internally or externally i.e. on skin; d. In place of sutures in connection with surgery, e.g. in relation to use as soft tissue sutures and/or biodegradable sutures; and/or
d. For fixation of skin grafts.
97. The hydrogel according to claims 86, which is designated composition W, and is a self-healing hydrogel comprising:
- Fe(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine; ■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 5000 Pa, such as of about 5000-10.000 Pa or about 5000-30.000 Pa.
98. The hydrogel according to claim 86, which is designated composition X, and is a self-healing hydrogel comprising:
- Fe(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine, ■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-10.000 Pa or about 1 .000-30.000 Pa.
99. The hydrogel according to claim 86, which is designated composition Y, and is a self-healing hydrogel comprising:
- Al(ll l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine, ■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa.
100. The hydrogel according to claim 86, which is designated composition Z, and is a self-healing hydrogel comprising:
- Al(ll l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa or about 1 .000-40.000 Pa.
101 . The hydrogel according to claim 86, which is designated composition A, and is a self-healing hydrogel comprising:
- Ca(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-5.000 Pa or about 500-10.000 Pa.
102. The hydrogel according to claim 86, which is designated composition B, and is a self-healing hydrogel comprising:
- Ca(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-5.000 Pa or about 100-10.000 Pa.
103. The hydrogel according to claim 86, which is designated composition C, and is a self-healing hydrogel comprising:
- Mn(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-10.000 Pa or about 3.000-30.000 Pa.
104. The hydrogel according to claim 86, which is designated composition D, and is a self-healing hydrogel comprising:
- Mn(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-10.000 Pa or about 1 .000-30.000 Pa.
105. The hydrogel according to claim 86, which is designated composition E, and is a self-healing hydrogel comprising:
- Cr(ll l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-5.000 Pa or about 500-10.000 Pa.
106. The hydrogel according to claim 86, which is designated composition F, and is a self-healing hydrogel comprising:
- Cr(ll l) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula O=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-5.000 Pa or about 100-10.000 Pa.
107. The hydrogel according to claim 86, which is designated composition G, and is a self-healing hydrogel comprising:
- Mg(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 2.000 Pa, such as of about 2.000-12.000 Pa or about 2.000-18.000 Pa.
108. The hydrogel according to claim 86, which is designated composition H, and is a self-healing hydrogel comprising:
- Mg(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and ■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 1 .000-12.000 Pa or about 500-18.000 Pa.
109. The hydrogel according to claim 86, which is designated composition J, and is a self-healing hydrogel comprising:
- Zn(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and ■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and
- one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-5.000 Pa or about 1 .000-10.000 Pa.
1 10. The hydrogel according to claim 86, which is designated composition K, and is a self-healing hydrogel comprising:
- Zn(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-5.000 Pa or about 200-10.000 Pa.
1 1 1 . The hydrogel according to claim 86, which is designated composition L, and is a self-healing hydrogel comprising:
- Ga(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-10.000 Pa or about 3.000-20.000 Pa.
1 12. The hydrogel according to claim 86, which is designated composition M, and is a self-healing hydrogel comprising:
- Ga(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 300 Pa, such as of about 500-10.000 Pa or about 300-20.000 Pa.
1 13. The hydrogel according to claim 86, which is designated composition N, and is a self-healing hydrogel comprising:
- Cu(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-9.000 Pa or about 2.000-20.000 Pa.
1 14. The hydrogel according to claim 86, which is designated composition P, and is a self-healing hydrogel comprising:
- Cu(l I) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-9.000 Pa or about 200-20.000 Pa.
1 15. The hydrogel according to claim 86, which is designated composition Q, and is a self-healing hydrogel comprising:
- Ti(IV) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-10.000 Pa or about 2.000-20.000 Pa.
1 16. The hydrogel according to claim 86, which is designated composition S, and is a self-healing hydrogel comprising:
- Ti(IV) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-10.000 Pa or about 200-20.000 Pa.
1 17. The hydrogel according to claim 86, which is designated composition T, and is a self-healing hydrogel comprising:
- V(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 500 Pa, such as of about 500-10.000 Pa or about 2.000-20.000 Pa.
1 18. The hydrogel according to claim 86, which is designated composition U, and is a self-healing hydrogel comprising:
- V(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 100 Pa, such as of about 100-10.000 Pa or about 200-20.000 Pa.
1 19. The hydrogel according to claim 86, which is designated composition AA, and is a self-healing hydrogel comprising:
- In(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-C1-10-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and C1-6-alk(an/en/yn)yl wherein C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-C1-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa.
120. The hydrogel according to claim 86, which is designated composition AB, and is a self-healing hydrogel comprising:
- In(l ll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa or about 1 .000-40.000 Pa.
121 . The hydrogel according to claim 86, which is designated composition AC, and is a self-healing hydrogel comprising:
- A lanthanide ion such as Gd(lll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa.
122. The hydrogel according to claim 86, which is designated AD, and is a self- healing hydrogel comprising:
- A lanthanide ion such as Gd(lll) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa or about 1 .000-40.000 Pa.
123. The hydrogel according to claim 86, which is designated composition AE, and is a self-healing hydrogel comprising:
- Hf(IV) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-C1-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as 50:1 or 100:1 , e.g. from about 15:1 to about 300:1 ;
- the stoichiometric ratio of catechohmetal is less than or equal to 3:1 , such as less than 2:1 , e.g. less than 1 :1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 3.000 Pa, such as of about 3.000-12.000 Pa or about 3.000-40.000 Pa.
124. The hydrogel according to claim 86, which is designated composition AF, and is a self-healing hydrogel comprising:
- Hf(IV) as metal source;
- one or more backbone monomer units selected from the group
consisting of
■ amino-Ci-io-alk(an/en/yn)yl e.g. allylamine;
■ amino acids such as of the formula H2N-CHR1-COOH wherein R1 is an organic substituent e.g. ornithine,
■ amino sugar(s) such as of the generic formula 0=CR6-CH(NHR7)- (CHR3)-(CHR4)-(CHR5)-OH; wherein R3, R4, R5 and R6 are independently selected from the group consisting of -H, -OH and Ci-6-alk(an/en/yn)yl wherein Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; and R7 is selected from the group consisting of -H and -(CO)-Ci-6-alk(an/en/yn)yl wherein -(CO)-Ci-6-alk(an/en/yn)yl is optionally substituted with one or more -OH groups; in their open chain form or in the a-form or β- form thereof as backbone monomer; e.g. glucosamine and/or acetylglucosamine; and
■ aminostyrenes which are optionally substituted, e.g. 4- aminostyrene; and - one or more catechol monomer units comprising an amino group such as DOPA and/or a carboxylate-group such as 3,4-dihydroxyphenylacetic acid and/or 3,4-dihydroxycinnamic acid;
wherein:
- the stoichiometric ratio of backbone monomer unit:metal is at least 15:1 , such as at least 500:1 or at least 1000:1 , e.g. at least 10.000:1 , or from about 15:1 to about 30000:1 ;
- the stoichiometric ratio of catechohmetal is more than 3:1 , such as at least 4:1 , e.g. at least 6:1 , alternatively at least 10:1 , e.g. at least 50:1 , such as from 3:1 to 100:1 ;
will have a maximum storage modulus at about the pKa of the backbone monomer unit, said maximum storage modulus being of at least about 1 .000 Pa, such as of about 1 .000-12.000 Pa or about 1 .000-40.000 Pa.
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