NL2023358B1

NL2023358B1 - Dopamine-functionalized polymers

Info

Publication number: NL2023358B1
Application number: NL2023358A
Authority: NL
Inventors: Franke Tooren Martin; Antonius Loontjens Jacobus
Original assignee: Polyganics Ip B V; Univ Groningen
Priority date: 2019-06-21
Filing date: 2019-06-21
Publication date: 2021-02-01

Abstract

Title: Dopamine-functionalized polymers Abstract The invention is directed to a tissue-adhesive polymer comprising at least one polymeric chain functionalized with an ArOH group, wherein said ArOH represents a hydroxyl-substituted aromatic group which is bound to said polymeric chain with an amide, urethane, thiourethane or urea bond, optionally Via a spacer. The ArOH can be positioned at one or more termini of said polymeric chain, at the backbone of the polymeric chain according to formula lb, or both. The ArOH can be based on a compound such as dopamine, DL-DOPA, L-DOPA, D-DOPA, tyramine, noradrenaline and/or serotonin. In addition, the invention is directed to a caprolactam blocked hydroxyl-substituted aromatic compound, suitable for the preparation of the tissue-adhesive polymer and to the method for the preparation of the tissue-adhesive polymer.

Description

P122936NL00 Title: Dopamine-functionalized polymers

BACKGROUND OF THE INVENTION The invention is in the field of tissue-adhesive materials. In particular, the invention is directed to tissue-adhesive multi-arm polymer and applications thereof in tissue-adhesive materials such as hydrogels. 'The invention is also directed to the processes to prepare the polymer and the use of a reactive intermediates in this and similar processes.

Tissue adhesives are common practice in the fields of surgery, thereby providing an alternative for the traditionally perforating materials such as sutures and staples. The currently used tissue adhesives have limited adhesive strength (e.g. fibrin-based products) or are relatively toxic (e.g. cyanoacrylate). Examples of adhesive materials include Coseal™, TissuepatchDural™, Hemopatch™ (described in WO2011/079336) and Veriset™. Tissue-adhesive materials that shows improve adhesive properties over these materials are patches described in WO 2019/066657 and WO 2017/171549, the latter being commercially available under the tradename LIQOSEAL™, The patches however, are not fluidic and limited in their application. Hydrogels at the other hand, are fluidic and can therefore be utilize in different applications. Specific examples of known hydrogels include Evicel™, Adherus™, Tisseel/Tissucol™ and DuraSeal™, that is commercially available from Integra LifeSciences Corporation and described in e.g. US5997895. Some of the known hydrogels (e.g. DuraSeal™) are NHS-esters-based hydrogels and show a limited adhesive and burst strength. Alternatively to NHS-based gels, hydrogels have been proposed that are based on dopamine-modified poly(ethylene glycol) polymers (see Liu et al., ACS Applied Materials and Interfaces 6 (2014) 16982-16992). The polymers however, require laborious preparation comprising NHS functionalization of poly(ethylene glycol) polymers followed by coupling with dopamine and dialysis of the dopamine and N-hydroxysuccinimide after this coupling to prevent free dopamine. Another drawback of the dopamine-modified poly(ethylene glycol)

polymers by Liu is the presence of an ester bond, which limits the water resistance of these hydrogels.

BRIEF SUMMARY OF THE INVENTION It is an object of the present invention to provide tissue-adhesive polymers that can be used in tissue-adhesive materials. A particular object of the invention is to apply this polymers for hydrogels that preferably give a higher adhesive strength than known materials. A further or alternative object is that these polymers can be prepared by less laborious methods and/or without the release of free dopamine.

Surprisingly, the present inventors found that the above objects can at least partially be met by a tissue-adhesive polymer comprising at least one polymeric chain functionalized with an ArOH group, wherein said ArOH represents a hydroxyl-substituted aromatic group which is bound to said polymeric chain with an amide, urethane, thiourethane or urea bond, optionally via a spacer. With hydroxyl-substituted aromatic group is meant an aromatic group that is substituted with a hydroxyl.

Thus, the polymer of the present invention is functionalized with the ArOH group via an amide, urethane, thiourethane or urea bond. Advantageously, such a bond is more stable to hydrolytic conditions as ester bonds. Preferably, the ArOH group is bound to the polymer via a urethane, thiourethane or urea bond, as these are even more stable than amide bonds, in particular a urea bond, which is the most stable of the group.

The ArOH group can for instance be based on dopamine, as is explained in more detail herein below. The combination of the ArOH and the aforementioned bond with which the ArOH is bound to the polymeric chain, result is very good adhesive properties and allow the preparation of hydrogels that meet the above- described objects.

The polymer of the present invention may at least partially have a structure according to formula I, wherein X is S, NH and/or O, or absent.

X NH Timea

I In the embodiments wherein X is absent, the polymeric chain is directly bound to the -C(O)-NH-spacer-ArOH group. For sake of clarity it is noted that the polymeric chain may bind more than one -XC(O)-NH-spacer-ArOH groups, even though only one is illustrated in formula I. In addition, in formula I, the -XC(O)-NH-spacer-ArOH may be position at one or more termini of the polymeric chain, at the backbone of the polymerie chain, or both. The present inventors realized that marine mussels adhere to substrates by spinning treads made from proteins which are rich in the catecholie amino acid 3,4-dihydroxyphenyl alanine (DOPA), and that introducing DOPA or other hydroxyl-substituted aromatics results in polymer materials that are water resistant and have good adhesive properties under wet conditions. The present inventors further found that in a particularly preferred embodiment of the present invention, the tissue-adhesive polymer is a multi-arm polymer, comprising a core and two or more polymeric arms of which at least one arm comprises said one polymeric chain functionalized with an ArOH group. It was found that the multi-arm facet of the polymer further results in a particular high adhesive strength towards tissues. Accordingly, in a particularly preferred embodiment of the present invention the present invention is directed to a tissue- adhesive multi-arm polymer comprising a core from which polymeric arms extent, which polymeric arms are substituted with a hydroxyl-substituted aromatic group. The polymer of the present invention can be tailored such that the ArOH group is positioned at one or more termini of said polymeric chain, at the backbone of the polymeric chain, or both. This tailoring is enabled by the provision of various caprolactam blocked hydroxyl-substituted aromatic compounds as building blocks. These building blocks are suitable for the preparation of the tissue- adhesive polymer by a reaction of the caprolactam blocked group with a hydroxyl, amine, and/or sulthydryl group that is present on the other building blocks (e.g. a polymeric chain or chain extender).

Typically, formation of amide, urethane, thiourethane or urea bonds require reactive reagents such as isocyanates that are incompatible with the hydroxyl-substituted aromatic groups and as such require protection of the hydroxyl with a protective group (e.g. an ester). The present inventors however found that such protection is not required when using the caprolactam blocked hydroxyl-substituted aromatic compounds as described herein. Caprolactam blocked isocyanates can be used for isocyanate-free routes to urethane compounds (see e.g. Maier ef al. Macromolecules (2003) 4727-4734).

BRIEF DESCRIPTION OF THE DRAWINGS In Figure 1, gelation times of various multi-arm polymers in accordance with the present invention are depicted.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a tissue-adhesive polymer comprising at least one polymeric chain functionalized with an ArOH group, wherein said ArOH represents a hydroxyl-substituted aromatic group which is bound to said polymeric chain with an amide, urethane, thiourethane or urea bond, optionally via a spacer.

Similar to what is known for DOPA, hydroxyl-substituted aromatic groups can be oxidized, after which the aromatic compound can interact, in particular react with tissue, typically at the ortho-position to the hydroxyl substituent. Hydroxyl-substituted aromatic groups such as catechol groups can be oxidized to quinones. Quinones are electrophilic and capable of reaction with nucleophilic groups (e.g. thiols and amines) that are present in tissue. Other than a reactive interaction, a physical interaction may also be possible. As such, the polymers and materials functionalized with hydroxyl-substituted aromatic groups can used as tissue-adhesive compounds and materials.

Particularly suitable hydroxyl-substituted aromatic groups include phenol, catechol, 3-hydroxyphenol, 4-hydroxyphenol, 2-aminophenol, 3- aminophenol, 4-aminophenol, 4-hydroxyindole, 5-hydroxyindole, 6-hydroxyindole, 7-hydroxyindole. These group are oxidizable and can subsequently interact with tissue. In a preferred embodiment, the hydroxyl-substituted aromatic group is one or more selected from the group of aromatic moieties having one of the following structures: or Cr Or ye OH & % OH & NH, Cy

H Of this group of aromatic moieties, the catechol group is particularly preferred for 5 its presence in several naturally occurring compounds such as DL-DOPA, dopamine, L-DOPA, D-DOPA, and/or noradrenaline. The catechol-group is therefore generally biological well compatible and preferred for medical applications such as tissue-adhesive substances and devices. Accordingly, is a further preferred embodiment, the moiety “NH—spacer—ArOH” (for example in formula Ia below) is based on dopamine, DL-DOPA, L-DOPA, D-DOPA and/or noradrenaline. Other naturally occurring hydroxyl-substituted aromatic compounds such as tyramine and serotonin can also advantageously be used for the moiety “NH-spacer-ArOH”.

ArOH functionalization of polymer at the termini The ArOH group can be attached to the polymer in the backbone, to one or more termini or both. For instance, in case the ArOH is position at one or more termini of the polymer, the polymer may have a structure according to formula II. "omeen fram aon | | Oo n m

II wherein Q represent a core; the polymeric chain comprises one or more polymeric groups; Xrepresents O, S or NH, preferably O; the spacer represents a spacer functionality, preferably a linear or branched C1-Cs hydrocarbon, optionally substituted with one or more OH, SH, halide, amide and/or carboxylate;

ArOH represents a hydroxyl-substituted aromatic group; m represents the number of functionalized polymer arms and is 2 or more, preferably in the range of 3 to 12; and n represents the number of non-functionalized polymer arms and is a number in the range of less than m, preferably 0.

The spacer in the polymer of the invention generally originates from an amine compound comprising the hydroxyl-substituted aromatic group. As will be described herein below, the process to functionalize the polymer with this amine compound is also an aspect of the present invention.

Particularly suitable hydroxyl-substituted aromatic groups include phenol, catechol, 3-hydroxyphenol, 4-hydroxyphenol, 2-aminophenol, 3- aminophenol, 4-aminophenol, 4-hydroxyindole, 5-hydroxyindole, 6-hydroxyindole, 7-hydroxyindole. These group are oxidizable and can subsequently interact (e.g. react) with tissue. In a preferred embodiment, the hydroxyl-substituted aromatic group is one or more selected from the group of aromatic moieties having one of the following structures: oy OH OH ye oH % % 2 u & > - Cy

H Of this group of aromatic moieties, the catechol group is particularly preferred for its presence in several naturally occurring compounds such as DL-DOPA, dopamine, L-DOPA, D-DOPA, and/or noradrenaline. The catechol-group is therefore generally biologically compatible and preferred for medical applications such as tissue-adhesive substances and devices. The hydroxyl-substituted aromatic group present in tyramine and/or serotonin can also favorably be used. Accordingly, is a further preferred embodiment, the moiety “NH—spacer—ArOH” (vide infra) is based on dopamine, DL-DOPA, L-DOPA, D-DOPA, tyramine, noradrenaline and/or serotonin.

In the aforementioned preferred embodiment wherein the moiety “NH- spacer—ArOH” is based on dopamine, DL-DOPA, L-DOPA, D-DOPA, tyramine, noradrenaline and/or serotonin, the spacer may thus be based on C:-alkylene, optionally substituted with a hydroxyl or carboxylate. Variations of this linker may however also be well possible. Esters of the carboxylate can also be applied. In general however, it is preferred to maintain a short linker, without superfluous substituents. As such, the linker is preferably a linear or branched C:-Cs alkylene, preferably C:-C4 alkylene, more preferably C: alkylene, most preferably a linear Cz alkylene. The linker may optionally be substituted with a hydroxyl and/or a carboxylic acid group.

The moiety “NH-spacer—ArOH” is however not necessarily directly based on dopamine, DL-DOPA, L-DOPA, D-DOPA, tyramine, noradrenaline and/or serotonin. It was surprisingly found by the present invention that certain compounds comprising two or more caprolactam blocked groups and the ArOH group, can bifunctionally be used — i.e. for functionalization of the polymer at one or more termini and at the backbone of the polymer. This is explained in more detail herein-below.

The polymeric chain of the polymer may be based on a variety of polymers or polymeric groups and combinations thereof. Good interaction with the tissue (i.e. good adhesion) can in particular be obtained if the tissue-adhesive polymer is based on a hydrophilic polymer. Examples of suitable hydrophilic polymers include hydrophilic polyether, polyester, poly(ester ethers), polycarbonates, polyurethanes, polyetherurethanes, polyurethane urea, poly(vinylpyrrolidone), poly(saccharide), poly(vinyl alcohol), polyoxazoline, or combinations thereof. The polymer preferably comprises polyether, polyester, poly(ester ether), polyamide, polycarbonate, polyurethane or a combination thereof. The presence of a hydrophobic polymeric part is not necessarily excluded, as long as this is not detrimental to the adhesive properties of the tissue-adhesive polymer. For instance, the hydrophobic part can be overruled by a hydrophilic part of the tissue-adhesive polymer such that overall the polymer remains adhesive to tissue.

Particularly preferred polymeric chains include polyether, polyester, polycarbonate such as poly(alkylene glycol) or a poly(lactic acid), poly(caprolactone), polydioxanone, poly(glycolide) or a poly(trimethylene carbonate). Although polyesters such as poly(lactic acid) and poly(caprolactone) show favorable hydrophilic properties, the presence of the ester bonds in the polymers, in particular when combined with ethers, results in a shorter adhesion than the polyether and polycarbonate, probably due to hydrolysis of the ester bonds. Accordingly, even more preferably, the polymer or polymeric group comprises poly(ethylene glycol) (PEG), polycaprolactone (PCL), poly(lactic acid) (PLA), for instance poly(L-lactic acid) (PLLA), a co-polymer of PCL and PLA or a poly(trimethylene carbonate) (PTMC), most preferably PEG.

In the embodiments wherein the backbone of the polymer is functionalized with the ArOH group, the polymeric chain of said polymer preferably comprises a polyurethane (based on -NHC(0O)O-), polythiourethane (based on —-NHC(0)S—) and polyurea (based on —-NHC(O)NH-), synthesized by reacting a chain extender such as respectively a polyol, polythiol or polyamine with a monomeric unit functionalized with the ArOH, in particular with a unit comprising two or more caprolactam blocked groups and the ArOH group. As such, the polymeric chain may have a structure according to formula IT ~E-Z~(R*)~—(RF*%) Zj

II wherein E is based on a chain extender such as a polyol, polythiol or polyamine. In formula III, R+ represents a functionalized monomeric unit functionalized with the ArOH group while R#es represent a regular monomeric unit not functionalized with the ArOH group and g plus p equal 1 while g is not 0 (as such, RA is always present in formula II). The polymeric chain may thus be based on only monomeric units R functionalized by the ArOH group (p = 0, ¢ = 1), or on a combination or RAs and RE (p > 0 and 0 <q < 1). The ratio of RA over Rie is preferably more than 2, more preferably more than 4 and most preferred R#«s is not present. In other words, g/p is preferably at least 0.5, more preferably at least 0.75, most preferably

1.

In formula III, Z represents a urethane, thiourethane and/or urea bond while s represents the number of polymer units of the polymeric chain and proportional to its molecular weight. The s is preferably an integer from 5-500.

The chain extender on which E is based can comprise one or more of the group consisting of Cu-Cio alkylene, optionally substituted with Ci-Cio alkyl or Ci- Cio alkyl groups substituted with halides or protected S, N, P or O moieties and/or comprising S, N, P or O in the alkylene chain, aliphatic polyesters, polyether esters, polyethers, poly(anhydrides), polycarbonates, polyethers or combinations thereof, optionally at least one E comprises a hydrophilic segment. A specific example of a suitable chain extenders includes polyethylene glycol (PEG). The RA moiety in the polymeric chain typically comprises a C2-C alkylene substituted with the ArOH group. The ArOH group and said alkylene can be linked via a spacer. For instance, the RY group may have a structure according to formula VII ArOH ©. HN f # cH 2x CHE

VII wherein the spacer is as defined for formula Ia and provides a linking functionality, ArOH represents the hydroxyl-substituted aromatic group, x and y are integers each between 0 and 8 while x + y being between 3 and 9. In a particular embodiment of the present invention, wherein RA is based on a modified lysine, x is 4 and y is 0.

The present inventors found that the polymer can suitably be prepared with one or more caprolactam blocked hydroxyl-substituted aromatic compounds (abbreviated as CAB-ArOH or CAB:-ArOH). Said caprolactam blocked compound can have a structure according to formula IVa (CAB2-ArOH) or IVb (CAB-ArOH), preferably IVaa or IVba, more preferably [Vab or IVba.

So pas Nu NH gar J I linker |—ArOH oO Oo IVa IVb

ArOH % %. | R2 HN 0 Cl) XY™

OH N NH NH ‚N TH EH © 0 0 © IVaa IVba OH

OH

HO R2 Cr HN, O0 0 N.__NH I _NH 1) NCH (CH) 0 © IVab wherein R* represents the functionalized monomeric unit functionalized with the ArOH group; the linker represents a linear or branched C:-Cs hydrocarbon, optionally substituted with one or more OH, SH, hale, amide and/or carboxylate; R? is H, OH or CO:H or esters thereof such as CO:Me or CO:zEt and x and y are integers each between 0 and 8 while x + y being between 3 and 9, preferably x is 4 and y is 0. The bis-reactive CAB2-ArOH compounds according to structures IVa, IVaa and IVab can be used for the backbone functionalization of the polymer in a polymerization reaction as illustrated in Scheme 1 (shown only for IVa).

CC gpm X s HX-E—XH N NH__Ar-NH _N + sx R + vi Tr tr IVa GS pu 3) SX p My MRR NAN 0 Oo

VIII A R Oo ECR) AR) + 5 NH (111) In Scheme 1, HX—E—XH represent a chain extender wherein XH is a hydroxyl, sulfhydryl and/or amine group and E is as defined for compound III.

In preferred embodiments, the CAB:-ArOH compounds according to structures IVaa and IVab can be used, leading to a polymer comprising at least partially a backbone according formula IIIa and IIb respectively, wherein E, X, Ra, x, y and the linker are as defined for compounds II, IVaa and IVab.

OH

HO ArOH 2 HNO HN, 50 ‚X_ ‚NH I _NH XL ANH xT ~NH_X. KEN CHa CHT EO CH (CHR yr oO o 0 OO | IIIa IIb The conditions for a polymerization reaction according to Scheme 1 typically include elevated temperatures (e.g. higher than 100 °C, such as about 145 °C) and reduced pressure in order to allow caprolactam to evaporate from the reaction mixture. Suitable solvents are organic solvents such as dimethylformamide (DMF). A specific example of a compound according to formula [Vab is the lysine-derived caprolactam blocked lysine diisocyanate functionalized with dopamine (CBDLI-DA), which can be obtained from caprolactam blocked lysine diisocyanate methylester (CBLDI-OMe, see also Yin J. PhD thesis, Lysine based amorphous polyurethanes decorated with pendant bio-active groups. 2012 University library of Groningen, ISBN 9789036756730).

OH Tt oo HN_ 0 Car A © CBLDI-DA The inventors surprisingly found that CAB2-ArOH compounds such as CBDLI-DA can not only suitably be used to obtain backbone ArOH-functionalized polymers through polymerization reaction, but that such compound can also suitable be used to functionalize one or more termini of the polymer. Namely, it was found that CBDLI-DA for example, reacts relatively slowly in a polymerization reaction. Without wishing to be bound by theory, the present inventors believe that the reaction with the caprolactam blocked isocyanate number 2 (as indicated in the structure directly below) is slightly hampered (i.e. it reacts slower than caprolactam blocked isocyanate number 1), possibly due to intra-molecular hydrogen bonding, rendering the carbonyl to be reacted less electrophilic toward the chain extender VI (i.e. HX-E-XH).

OH ie oo HN 2.

CI © CBLDI-DA Accordingly, CABz-ArOH compounds can be used to obtain backbone ArOH functionalized polymers, terminally ArOH functionalized polymers or combinations thereof. By keeping a relatively short reaction time, PEG may for instance be terminally functionalized, while avoiding dimerization or even further polymerization. On the other hand, by using a long reaction time, polymerization can be obtained. For sake of clarity, it is noted that when CABz-ArOH compounds are used to obtain terminally ArOH functionalized polymers, the spacer as used in formulae IT and Ila is thus typically not equal to the linker as used in compound TVaa. In such case, the moiety “NH-spacer—ArOH” is not based on dopamine, DL- DOPA, L-DOPA, D-DOPA, tyramine, noradrenaline and/or serotonin, even if the moiety “NH-linker—ArOH?” is based on these compounds. On the other hand, when a CAB-ArOH compound such as IVb is used to obtain terminally ArOH functionalized polymers according to the invention, the moiety “NH-spacer—-ArOH” is equal to the moiety “NH-linker-ArOH” and both may be based on dopamine, DL- DOPA, L-DOPA, D-DOPA, tyramine, noradrenaline and/or serotonin. The inventors found that both CAB-ArOH and CAB:-ArOH compounds can be used to terminally functionalized polymers with the ArOH group. More in particular, the inventors found that these groups can very suitably be used to provide a tissue-adhesive multi-arm polymer according to formula Ia, wherein m is 3 or more.

In a particular embodiment, the tissue-adhesive multi-arm polymer has a structure according to formula Ila.

HOL 9% of ee NH RT) d RY T oe] ITa Formula Ila is a specification of formula II and the spacer, Q, m and n are accordingly the same for both formulae.

In formula Ib, R* represents linear or branched C:-C4 alkylene and/or —C(0)—C1-C5 alkylene; and k represents the number of polymer units of each arm and is proportional to the molecular weight of each arm.

The number of polymer units of each arm k is typically in the range of 5 to 1000. For example, if the polymer is based on a multi-arm PEG weighing 40 kDa, k is about 114. Preferably % is in the range of 10 to about 250, more preferably 50 to 150 such as about 114 units.

The R! part originates from the monomeric units on which the polymer arm is based.

For instance, in embodiments wherein the arm is based on poly(ethylene glycol) or poly(propylene glycol), R! represents ethylene or propylene while in embodiments wherein the arm is based on a polyester, R! represents — C(O)—alkylene, wherein —C(0O)- is the carbonyl group in the polyester.

In a further preferred embodiment, R! represents -C(O)-CH(CH:)- (i.e. a branched -C(O)-C: alkylene originating from e.g. lactide) -or —C(O)—(CHz)s (i.e. a linear —C(0)—Cs alkylene originating from e.g. e-caprolactone). An yet another particularly preferred embodiment, the tissue-adhesive multi-arm polymer has a structure according to formula IIb. | : HO{ 1-0) a Of -OY “Or ’ "0 OH m Ih

Formula IIb is a specification of formulae II and Ila and Q, m and n are accordingly the same for all formulae. The R! and % for formulae Ib and Ic are also the same. In formula IIb, R2 represents H, OH, CH; or CO:H or ester thereof, preferably H, and typically originates from the amine on which the hydroxyl- substituted aromatic group and spacer is based. Suitable esters of the CO:H group include Ci-Cs alkyl and alkyl esters such as CO:Me and CO:Et.

The length of the arms can be expressed with their molecular weight. Accordingly, on average, the number-average molecular weight (Ma) of each arm is preferably in the range of 500 Da to 50 kDa, more preferably 1-25 kDa, most preferably 2 to 10 kDa. In addition, number-average molecular total weight of the multi-arm tissue-adhesive polymer is preferably in the range of 5 to 100 kDa, more preferably in the range of 10-80 kDa, most preferably in the range of 20-60 kDa. For instance, very good results were obtained with an 8-armed (PEG) having a number-average molecular weight of 40.000 g/mol (i.e. 40 kDa), of which each arm is thus about 5 kDa.

The number-average molecular weight can be determined by known analytical techniques such as size exclusion chromatography (SEC) and/or matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF- MS).

The multi-arm nature of the polymer can be attributed to a core. The number of functionalized arms in the polymer m depends on the selected core and the substitution degree of the arms (i.e. the ratio of functionalized arms to non- functionalized arms). In general, the core may be based on any poly-functional compound to which the polymeric chains (i.e. the arms) can suitably be connected.

In a preferred embodiment, the core is based on a poly-functional compound which is an initiator in polymerization reactions. This enables that the polymeric chain may be grafted from the core. Therefore, the core is preferably based on a polyol that is suitable for initiation polymerization to form polyethers or polyesters. Examples of such polyols include ethylene glycol, glycerol (GL), pentraerythritol (P), hexaglycerol (HG), tripentaerytritol (TP), trimethylolpropane (TMP), dipentaerythritol (DP) and combinations thereof.

As such, in a preferred embodiment, Q of formula Ia, Ib and Ie is based on a polyol comprising m+n hydroxyl groups, preferably Q is based on a polyol of any of structures depicted below, 3 HO 5 5 g Se) O-R R=O O-R 3 R Pa . . . . - . 3.0 Ol 3 . . . . wherein each R3 is individually H or R R ‚each R* is individually H or HO 4 5 4 | O-R « | O-R HO , each R5 is H or HO . The R3, Rt and R5 can be selected based on the amount of desired hydroxyl groups. For instance, hexaglycerol (HG) can be represented as follows.

HO LY 0 Do

HO O OH O

HO O HO = HO

HO In a particular embodiment, the core is the initiator for the preparation of a multi-arm PEG, which is then used as a subsequent initiator in a polymerization reaction with lactide, trimethylenecarbonate, glycolide of caprolacton to form a multiarm block copolymeer comprising a multi-arm PEG segment extended with one or more of these monomers. In a further preferred embodiment, the number of functionalized arms mis 4 to 10, preferably 6 to 8. It was surprisingly found that gelation time decreases with an increasing m. Thus, the gelation time for the polymer wherein m is 6 is less than when m is 4, while for the polymer wherein m is 8, the gelation time is even less than when m is 6. In addition, a higher number of functionalized arms were surprisingly found to result in better adhesive properties as well as in better mechanical properties. As such, pentraerythritol (P), hexaglycerol (HG), tripentaerytritol (TP), trimethylolpropane (TMP) and dipentaerythritol (DP), in particular hexaglycerol (HG), dipentaerythritol (DP), tripentaerytritol (TP) are preferred core structures.

Generally, it is preferred that all arms are functionalized, but it may be that not all arms are substituted with the hydroxyl-substituted aromatic group, e.g. due to limitation in the method for preparation (vide infra) or by design. The substitution degree of the arms as defined by m divided by (m+n) is preferably more than 60%, more preferably more than 80%, even more preferably more than 90%, most preferably about 100%. In general, a higher substitution degree leads to better adhesion and better mechanical properties.

The substitution degree can be determined by !H-NMR in combination with the following mathematical formula substitution degree(%) = _A x ZX Mn x 100% QxR BxMy wherein: A is the area of the peak or peaks corresponding to all the protons of the moiety “NH-spacer-ArOH”; Q is the number of protons in the moiety “NH-spacer-ArOH”; R is the total number of arms of the polymer; B is the area of the peak or peaks corresponding to all the protons of polymer arms; 7Z is the number of protons in the monomer on which the polymeric chain is based; Mu is the molecular weight of monomer on which the polymeric chain is based; Ma is the number-average molecular weight of the polymer without the moiety “NH-spacer-ArOH".

A further aspect of the present invention is a kit of parts comprising a first container comprising the tissue-adhesive polymer and a second container comprising an oxidizing agent. As described herein-above, the tissue-adhesive properties are obtained by oxidizing the hydroxyl-substituted aromatic group. Suitable oxidizing agents are generally known agents capable of oxidizing such groups and include periodates, peroxides, permanganates and the like, such as sodium periodate, potassium permanganate.

By mixing the contents of both containers, a hydrogel is formed that can be injected. Such a hydrogel is another aspect of the present invention.

Advantageously, the hydrogel according to the present invention demonstrates improved adhesion and/or mechanical properties vis-a-vis conventional hydrogels. The hydrogel of the present invention may have a lap shear adhesion strength of more than 0.50 N, preferably more than 0.7, more preferably more than 1, even more preferably more than 1.5, most preferably more than 2 N as determined by ASTM F2255-05.38. The burst pressure may be more than 15 mbar, preferably more than 20 mbar, more preferably more than 25 mbar as determined by ASTM F2392-04.

The tissue-adhesive polymer and the injectable hydrogel of the present invention can be used in a medical treatment of a human or animal, in particular for sealing or closing of tissue, preferably of tissue that is otherwise difficult to treat using conventional methods such applying suture, patches or staples. Due to their typical injectable nature, the polymer and hydrogel of the invention can very suitably be used in laparoscopic treatments. The polymer and hydrogel are thus well suitable for sealing the ventral cavity (including the abdominal, thoracic and pelvic cavities) like liver, lung, pancreas, spleen, bladder, kidney and/or intestine tissues.

Oxidation of the polymer may occur on-site (i.e. after appliance), before appliance, or a combination thereof (e.g. using a syringe comprising two containers corrected to a mixing section wherein the oxidation can at least partially occur).

A particular application for tissue-adhesive polymer and hydrogel is the sealing of dura mater or spinal tissue. Dura mater is the outermost membrane layer that surrounds the brain and spinal cord of the central nervous system. After e.g. trauma or cranial surgery, opened dura mater needs to be sealed to prevent leakage of cerebrospinal fluid. Even when in an operation dura mater is closed by suture, staples and such, cerebrospinal fluid may still leak, in particular through remaining small openings. It is therefore typically required that the dura mater is sealed by a surgical sealant, which preferably, is based on a tissue-adhesive material such that no glue or other type of adhesive is required to apply the sealant and seal the dura mater. Inter alia for these reasons, tissue-adhesive polymer and hydrogel in accordance with the invention is very suitable for use in methods of surgery.

Yet a further aspect of the invention is directed to the preparation of the tissue-adhesive polymer. The present inventors found that the polymer can efficiently be prepared by reacting the non-functionalized polymer, for example a non-functionalized multi-arm polymer with with one or more of the caprolactam blocked hydroxyl-substituted aromatic compounds CAB-ArOH and CAB2-ArOH.

Backbone functionalization can be carried out with CAB2-ArOH as described for and illustrated by Scheme 1.

Functionalization of one or more termini of the non-functionalized polymer can be carried out with CAB-ArOH and CAB2-ArOH for reasons described herein above. It may be appreciated that a combination of backbone and terminal functionalization is also according to the present invention and that this for instance can be obtained by first carrying out a polymerization as illustrated in Scheme 1, followed by a functionalization at one or more termini. Non- functionalized polymer thus refers to the polymer as existing before (further) functionalization and may already be functionalized with the ArOH in a preceding process.

Advantageously, in contrast to Liu et al., ACS Applied Materials and Interfaces 6 (2014) 16982-16992, the present tissue-adhesive polymer can be prepared without the requirement of dialysis or other elaborate and/or cumbersome purification method.

The present inventors found that CAB-ArOH and CAB2-ArOH can be a suitable substitute for isocyanates and offers several advantages. Isocyanates are generally toxic and there is a possibility for incomplete reactions. Furthermore, undesired crosslinking may take place in the presence of moisture and/or elevated temperatures. In contrast, the CAB-ArOH and CAB:s-ArOH is non-toxic and stable up to a temperature of 100°C or more.

Accordingly, a particular aspect of the invention is the preparation of the tissue-adhesive multi-arm polymer of formula I, said method comprising reacting the polymer having a structure according to formula V with the caprolactam blocked hydroxyl-substituted aromatic compounds IVaa or IVb, as illustrated in Scheme 2, wherein XH is a hydroxyl, sulthydryl and/or amine group. ArOH — polymeric chain + ly N NH —NH _N 3 (CH), (CH 2)y YW Oo © IVaa

X NH Gen polymeric chain T p ArOH oo

I IVb Scheme 2 Naturally, in the particular embodiment wherein the polymer is a multi-arm polymer according to formula IT, the process can be carried out similarly, as illustrated in Scheme 3, wherein XH is a hydroxyl, sulfhydryl and/or amine group.

ArOH | — XH Q-1 polymeric chain | + or n+m Va Cx HN, © 0 N NH I —NH ‚N TT CHa (CH), YT Oo © IVaa N_NH_7 Cy Sman © Oo IVb HX | x_ ‚NH polymeric chain rQ | polymeric chain hil {spacer |-AroH | | Oo n m

II Preferably, for terminal functionalization of the polymer, the CAB- ArOH according to any of formulae IVb and IVba is used, as is illustrated in Scheme 4 for IVb. In this embodiment, the linker is equal to the spacer. : — XH N Q-H polymeric chain (A NH, linker |- | | 1 hE linker {—ArOH mm Oo Oo Va IVb

HX X NH polymeric chain + Q- polymeric chain hid {spacer}~AroH Oo n m

II Scheme 4

For all of the reactions illustrated in Schemes 2-4, the reaction of compound V or Va with a compound IV (i.e. one of IVa, IVb, IVaa, IVab and IVba) can be carried out at relatively high temperature because to the good stability of compounds IV. In general, the reaction temperature may be about 100 to 200 °C, preferably between 130 to 180° such as about 145 °C. Full conversion of compound V and Va is then typically obtained in 8 to 24 hours, for instance in about 16 hours. Advantageously, the ArOH moiety remains intact and does not degrade nor interfere with the reaction.

In a preferred embodiment of the method according to the present invention, a compound IV is reacted with the preferred embodiment of the multi- arm polymer according to formula Vb. This results in the formation of the tissue- adhesive multi-arm polymer of formula Ila, as illustrated in Scheme 5 for IVb. 0f{,1.0 TEM Am i on Vb IVb HO{ 1-0) Jefe Ar " n ko 0 Ia Scheme 5 Caprolactam blocked isocyanates are known in the art and are typically used in an isocyanate-free route to urethane compounds (see e.g. Maier et al. Macromolecules (2003) 4727-4734). In a preferred embodiment of the preparation of the tissue-adhesive polymer, the method further comprises preparing the CAB-ArOH and/or CAB:»- ArOH in methods as described herein-below. The CAB-ArOH compound IVb can be readily prepared by a reaction of the compound NHz—spacer—ArOH (compound IX) with carbonylbiscaprolactam

(CBC, or compound X), as illustrated in Scheme 6. This reaction is preferably carried out in the presence of a base such as an organic amine (e.g. triethyl amine). IX oO O © © X IVb Scheme 6 Surprisingly, conditions for the preparation of caprolactam blocked isocyanates of primary amines reported in Maier et al. Macromolecules (2003) 4727-4734 (CHCl, 75°C for 4 hour) did not result in a good yield of the product. It was found that preferably, compound IX is used in excess vis-a-vis CBC (e.g. more than 1.3 molar equivalents such as 1.5 molar equivalents or more). The base is preferably present in an amount of more than 2 molar equivalents with respect to CBC, more preferably 3 molar equivalents or more, especially when compound IX is introduced in the reaction as a salt (e.g. a HCI salt). In addition, it is preferred that compound IX and CBC are reacted at a temperature of more than 80 °C, more preferably 90 °C or more. Typical reaction times range from 8 hours to 14 days, for instance 1 to 12 days and is generally about 7 days.

Advantageously, the hydroxyl substituent at the ArOH moiety does not require a protective group as a chemoselective reaction between the amine and CBC can be utilized.

Specific examples of NH»—spacer-ArOH are dopamine, DL-DOPA, L- DOPA, D-DOPA, tyramine, noradrenaline and serotonin. In preferred embodiments of the present invention as described, CBC is reacted with dopamine, DL-DOPA, D-DOPA, L-DOPA or noradrenaline (compound IXb, wherein R? is respectively H, CO:H or OH), as illustrated in Scheme 7.

R? (A 22 HN OH N. N N___NH “CT . OQ T ® I I “or

OH O O O IXb X IVba OH Scheme 7 It may be appreciated that in a preferred embodiment, compound IVba is reacted with the multi-arm polymer of formula Vb, to provide the tissue-adhesive multi-arm polymer of formula IIb, as illustrated in Scheme 8. aon (A NH v k dm + rn — Vb IVba OH R2 Ho{-O)q eh ’ *o OH m Ib The compound CAB:-ArOH according formula IVaa to can be prepared by reacting an actives ester according to formula XI as illustrated in Scheme 9, wherein x and y are as defined for formula IVaa and LG is a leaving group such as an alcohol radical comprising an electron withdrawing group or an halide such as a iodide bromide or chloride. Suitable examples of alcohol radicals comprising an electron-withdrawing group as the leaving group include alcohol radicals wherein the alcohol is selected from the group consisting of perfluoroalkyl alcohol, p-nitro- phenol, 3,4,5-trichlorophenol, pentafluorophenol, 1-benzotriazolyl alcohol, 1- hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, and N-hydroxysuccinimide alcohol and derivatives thereof such as N-hydroxymaleimide, N- hydroxyphthalimide, endo-N-hydroxy-5-norbornene-2,3-dicarboximide and a N-

hydroxysulfosuccinimide salt, more preferably wherein the alcohol is a N- hydroxysuccinimide alcohol. Sa ( Negen ave aon 0] © XI IX ArOH | x HN.__O o N_ ‚NH I _NH 1) hit (CH), (CHy)y Ne Oo © IVaa Scheme 9 The compound according to XI can be prepared according to a procedure as described in Yin oJ. PhD thesis, Lysine based amorphous polyurethanes decorated with pendant bio-active groups. 2012 University library of Groningen, ISBN

9789036756730.

The CAB-ArOH and CAB2-ArOH may further be used to functionalize materials, which is yet another aspect of the present invention. Typically, such materials require reactive groups to be able to react with the CAB-ArOH. Examples of reactive groups are hydroxyl, sulthydryl and amine reactive groups.

Certain materials (e.g. cellulose) may intrinsically comprise one of more reactive groups, while other typically of materials (e.g. polyesters, polyamide, polyethers, polyurethanes, polyolefins and the like) may require activation (e.g. hydrolysis, aminolysis or electron-beam treatment).

Accordingly, the invention is further directed to a method of functionalizing an activated material A, which surface comprises at least one hydroxyl, sulfhydryl and/or amine reactive group, with a catechol derivative, said method comprising contacting said activated material A with the caprolactam blocked hydroxyl-substituted aromatic compound to provide functional material B, as illustrated in Scheme 10 wherein XH is the hydroxyl, sulfhydryl and/or amine reactive group. ArOH

XH XH XH XH + activated material x o HN. Oo o 1D) or

A I N NH —NH ‚N hi (CH2)x (CHy)y Ir © IVaa ; ArOH

HN

N Gn = © Oo XH X XH xH IVb functional material

B Scheme 10 Examples of materials that can be functionalized in accordance with this method are the polyurethane foams, sheets and materials as for instance described in WO 99/64491 (Biomedical PUs), WO 2004/062704 (Nasal Sponge) WO 2017/171549 (Duraseal) and PCT/NL2018/050649 (Liver sealant), which are all incorporated herein in their entirety.

Accordingly, in a preferred embodiment, the functional material of the present invention comprises a foam structure, a sheet structure, a gel-like structure or combinations thereof.

As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. The term "and/or" includes any and all combinations of one or more of the associated listed items. It will be understood that the terms "comprises" and/or "comprising"

specify the presence of stated features but do not preclude the presence or addition of one or more other features. For the purpose of clarity and a concise description features are described herein as part of the same or separate embodiments, however, it will be appreciated that the scope of the invention may include embodiments having

EXAMPLES The invention can be further illustrated by the following non-limiting examples. Example 1 - synthesis of CBDLI-DA CBLDI-OMe prepared and hydrolyses according to Yin J. (PhD thesis, Lysine based amorphous polvurethanes decorated with pendant bio-active groups. 2012 University library of Groningen, ISBN 9789036756730) was hydrolysed to the acid (CBDLI-COOH) in 72% yield using KOH (pH 13) in a 3:1 mixture of THF and water at room temperature using the procedure described. CBLDI-COOH was activated with dicyclocarbodiimide (DCC) and converted to an N-hydroxysuccinimide (NHS) ester, after which acetonide protected dopamine (prepared according to Liu, Z., Hu, B. H., & Messersmith, P. B. (2010). Acetonide protection of dopamine for the synthesis of highly pure N- docosahexaenoyldopamine. Tetrahedron letters, 51(18), 2403-2405) was added which gave acetonide protected caprolactam blocked lysine diisocyanate. Hydrolysis in trifluoroacetic acid (TFA) in a mixture of chloroform and water provided the desired monomer (CBDLI-DA).

Example 2 — preparation of backbone dopamine functionalized polymer HO. Ay, { rr 8 TT} He H | He H Hy H | pn ; 50 + MIN el Pe 0 4 . H a H pa 5 fn a m i i HO | ì p WE, vam ' 1 SE aw 4 We Be H : i ies Lal: Ly ort . gd n mn WH p A mixture of about 1:1 CBDLI-DA (A) and PEG2000 having a Ma of 2000 (B) was heated at 145 °C for 72 h under vacuum. The results are shown in Table 1. Table 1: Size exclusion chromatography (SEC) results after 72h polymerization at 145°C under vacuum. Entry | A Mol. Mol. eq. | Mn Mw % eq. (g/mol) Unreacted CBDLI- PEG2000 | (g/mol) A

DA 1 CBLDI- | PEG2000 | 1.025 1 3405 3511 1.03 5

DA 2 CBLDI- | PEG2000 | 1.1 1 3411 3518 1.03 6

DA Example 3 — preparation of 8-armed lysine-dopamine functionalized PEG (8-ArmPEG40k-LD)

HMO. RIOT ~C do oO HH, & Fu NT : A” 20 + A= hunagivoasol aoe \ Ao ° 148°C, vacuum

H THQ, fa (> : ‚ ( EE ve ~<A oer He ™ + hi > | OL a § 8-armed lysine-dopamine functionalized PEG (8-ArmPEG40k-LD) was synthesized by end-capping 8-arm PEG (Mn = 42320 g/mol, hexaglycerol core) with CBLDI-DA. The monomer CBLDI-DA was allowed to react with 8-armPEG-OH (Mn = 42320 g/mol, f=8) in a 1:1 molar ratio under vacuum at 145°C for a period of 16h). The reaction time was kept rather short to prevent dimerization: An NMR analysis showed a coupling efficiency of 72% for the obtained hydrogel. Example 4 — Gelation time (min) at various NalO4/Dopamine molar ratios A fast curing time is an important characteristic for biomedical tissue adhesives. Therefore, 8-ArmPEG40k-LD was mixed with NalO4 in order to oxidize the catechol hydroxyl groups, as described in Liu, Z., Hu, B. H., & Messersmith, P. B. (2010). Acetonide protection of dopamine for the synthesis of highly pure N- docosahexaenoyldopamine. Tetrahedron letters, 51(18), 2403-2405. Oxidation results in the formation of reactive quinone moieties which gives intermolecular crosslinking. The curing time depends on the NalO4/Dopamine molar ratio, as can be derived from the results shown in Table 2. The fastest curing time was observed at a NalOa: : dopamine ratio of 0.5: Table 2 : Gelation time (min) at various NalO4/Dopamine molar ratios NalQs: Dopamine Gelation time (min)

Example 5 — Determination of tissue adhesive properties of the 8-ArmPEG40k-LD The tissue adhesive properties of the 8-ArmPEG40k-LD was determined on porcine dura mater.

Lap shear adhesion (ASTM F2255-05.38) and burst pressure testing (ASTM F2392-04) were performed.

The results (Table 3) were compared with commercially available DuraSeal™ (Medtronic Inc.). Results show that the lap shear strength of the 8-ArmPEG40k-LD is much higher (4 times) than with DuraSeal™ (Medtronic Inc.). Table 3 Tissue adhesive Lap shear strength (N) Example 6 — Determination of tissue adhesive properties of the 8-ArmPEG40k-LD The in vitro burst pressure test was performed according to ASTM F2392-04 (Standard Test Method for Burst Strength of Surgical Sealants). The results (Table 4) were compared with commercially available DuraSeal™ (Medtronic Inc.). Results show that the burst pressure of the 8-ArmPEG40k-LD is higher than commercially available DuraSeal™ (Medtronic Inc.).

Table 4 Tissue adhesive Burst pressure (mbar) Example 7 — preparation of a caprolactam blocked dopamine (CABDA) 0 o 0 NH CI 0 OH ? OH 0 At a round-bottom flask was added carbonyl bis caprolactam (1,0 eq; 19,82 mmol; 5,0 g) and dissolved in CHCl3 (50 mL). The mixture was stirred at room temperature until dissolved, and of all times kept under inert conditions.

Dopamine hydrochloride (1,5 eq; 29,73 mmol; 5,64 g) was added to the mixture and heated to 40°C and followed by the addition of triethylamine (3,0 eq; 59,46 mmol; 6,02 g; 8,29 mL). The reaction mixture was heated to 90°C and stirred for 48h in a closed system under nitrogen gas and reflux conditions.

The mixture was slowly cooled to room temperature.

The white precipitation in the mixture was removed by Buchner filtration.

The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate/hexane (2/1; 90 mL). The mixture was treated with a solution of 0,5M HC1/5% CaCl: and 5% NaCl (90mL), 5% CaCl: (90 mL), 1M Na2COs (90 mL) and brine (90 mL). The organic layer was dried with MgSO4 and filtrated.

The solvents were removed in vacuo.

To give a yellow solid (yield 92%).

Example 8 — Functionalization of multi-arm PEG polymers = hexaglycero R = hexaglycerol An 8-arm poly(ethylene glycol) polymer (PEG), 6-arm PEG and 4-arm PEG, having a molecular weight of 40 kDa, 30 kDa and 20 kDa respectively (8- arm-PEG40k, 6-arm-PEG30k and 4-arm-PEG20k respectively) were separately reacted with CABDA (1 equiv.) at 145 °C for 48h under vacuum. Tissue-adhesive multi-arm polymers based on multi-arm-PEG40k and dopamine 8-ArmPEG40k- DA, 6-armPEG30k-DA and 4-armPEG20k-DA were individually obtained.

Example 9 — Gelation time of 8-ArmPEG40k-DA, 6-armPEG30k- DA and 4-armPEG20k-DA The polymers prepared according to Example 8 were mixed with NalOa4 in order to oxidize the catechol hydroxyl groups. This resulted in the formation of reactive quinone moieties which gives intermolecular crosslinking or gelation. The results are depicted in Figure 1.

It was found that faster gelation occurs for 8-ArmPEG40k-DA > 6- armPEG30k-DA > 4-armPEG20k-DA. In addition, faster gelation occurs with increasing relative amounts of oxidation agent NalO..

Example 10 — Lap shear adhesion of 8-ArmPEG40k-DA, 6- armPEG30k-DA and 4-armPEG20k-DA The tissue adhesive properties of the multi-arm PEG-DA polymers prepared according to Example 8 were determined on porcine dura mater. Lap shear adhesion test were carried out according to ASTM F2255-05.38. The results are depicted in Table 5 and are compared with commercially available DuraSeal™, Results show that the lap shear strength of the 8-ArmPEG40k-DA is much higher than with DuraSeal™,

Table 5 6-armPEG30k-DA Example 11 - In vitro burst pressure test of 8-ArmPEG40k-DA, 6- armPEG30k-DA and 4-armPEG20k-DA The tissue adhesive properties of the multi-arm PEG-DA polymers prepared according to Example 8 were determined on porcine dura mater.

The in vitro burst pressure test was performed according to ASTM F2392-04 (Standard Test Method for Burst Strength of Surgical Sealants). The results are depicted in Table 6 and are compared with commercially available DuraSeal™. Results show that the burst pressure of the 8-ArmPEG40k-DA is higher than commercially available DuraSeal™, Table 6 Tissue adhesive material

Claims

Conclusions

A fabric-adhering polymer comprising at least one polymer chain functionalized with an ArOH group, said ArOH group representing a hydroxyl-substituted aromatic group bonded to said polymer chain with an amide, urethane, thiourethane , or urea binding, optionally via a spacer.

A tissue-adhesive polymer according to the preceding claim, wherein said polymer is a multi-branch polymer comprising a core and two or more polymer branches, at least one branch comprising said one polymer chain functionalized with an ArOH group.

A fabric-adhesive polymer according to any one of the preceding claims, wherein said polymer has a structure according to formula IT n m

II Polymeric chain = polymer chain Spacer = spacer where Q represents a core; the polymer chain comprises one or more polymer groups; X represents O, S, or NH, preferably O; the spacer represents a spacer functionality, preferably a linear or branched C 1 -C 8 hydrocarbon, optionally substituted with one or more OH, SH, halide, amide, and / or carboxylate; ArOH represents the hydroxyl-substituted aromatic group;

m represents the number of functionalized polymer branches, and is at least equal to 2, preferably in the range of 3 to 12, more preferably where m is 4 to 10, and most preferably 6 to 8; and n represents the number of non-functionalized polymer branches, and is a number in the range less than m, preferably 0.

A fabric-adhesive polymer according to any preceding claim, wherein said polymer chain functionalized with an ArOH group comprises a structure according to formula ITI (EZRA) LRZ

III where E is based on a chain extender such as a polyol, polythiol, or polyamine, Rr represents a functionalized monomer unit that is functionalized with the ArOH group, RRes represents a common monomeric unit that is not functionalized with the ArOH group, Z represents a urethane, thiourethane, and / or urea bond, s represents the number of polymer units in the polymer chain and is proportional to its molecular weight, where s is preferably an integer from 5 to 500, q plus p is 1; and g is not equal to 0, preferably q / p is at least equal to 0.5, more preferably at least equal to 1s to 0.75, and most preferably equal to 1; where preferably E comprises one or more from the group consisting of C 1 -C 19 alkylene optionally substituted with C 1 -C 19 alkyl or C 1 -C 19 alkyl groups substituted with halides or protecting S-, N-, P-, or O- groups and / or S, N, P, or O in the alkylene chain include aliphatic polyesters, polyetheresters, polyethers, poly (anhydrides), polycarbonates, polyethers, or combinations thereof, wherein optionally at least one E comprises a hydrophilic segment; and / or wherein preferably said Rr comprises a C 1 -C 10 alkylene substituted with the ArOH group, optionally via a spacer, preferably wherein said Rr has a structure according to formula VII ArOH 3 |

SE (chy); (CH cE

VII where the spacer provides a linker functionality, ArOH represents a hydroxyl-substituted aromatic group, x and y are integers each between 0 and 8, while x + y is between 3 and 9, preferably where x is equal is equal to 4, and y is equal to 0.

The tissue-adherent multi-branch polymer of any preceding claim, wherein the ArOH is selected from the group consisting of phenol, catechol, 3-hydroxyphenol, 4-hydroxyphenol, 2-aminophenol, 3-aminophenol, 4-aminophenol, 4-hydroxyindole , 5-hydroxyindole, 6-hydroxyindole, 7-hydroxyindole, and combinations thereof, preferably one or more from the group consisting of aromatic groups having one of the following structures: \ and JJ JOU% NH, N

H.

The tissue-adhesive multi-branch polymer of any one of the preceding claims, wherein the group NH spacer ArOH is based on dopamine, DL-DOPA, L-DOPA, D-DOPA, tyramine, noradrenaline, and / or serotonin.

Multi-branch tissue-adhesive polymer according to any one of the preceding claims, having a structure according to formula IIb, R2 ee | n 3

OH m Ib wherein Q, m, and n are as defined for Formula II; R! represents a linear or branched C 1 -C 4 alkylene and / or -C (O) -C 1 -C 5 alkylene, preferably ethylene; R2 represents H, OH, CH3, or CO: H, or esters thereof, such as CO: Me or CO: Et, preferably H; represents the number of polymer units of each branch, and is proportional to the molecular weight of each branch.

A tissue-adhesive polymer according to any one of the preceding claims, having a number-based average molecular weight in the range of 500 Da to 100 kDa, which is preferably in the range of 10 kDa to 80 kDa, even more preferably in the range of 20 kDa to 50 kDa, such as about 40 kDa.

A kit of parts comprising a first container comprising a tissue-adherent polymer according to any preceding claim, and a second container comprising an oxidizing agent.

An injectable hydrogel, preferably based on an oxidized fabric adhesive polymer according to any one of claims 1 to 8, wherein said hydrogel has an overlap shear bond strength of more than 0.50 N, preferably of more than 0.7 N, yet Better of more than 1 N, still better of more than 1.5 N, and still better of more than 2 N, as determined in accordance with ASTM F2255-05.38, and / or wherein said hydrogel exhibits a burst pressure of more than 15 mbar , preferably greater than 20 mbar, and even more preferably greater than 25 mbar, determined in accordance with ASTM F 2392-04.

A tissue-adhesive polymer according to any one of claims 1 to 8, or an injectable hydrogel according to claim 10, for use in medical treatment, preferably wherein the treatment comprises sealing or closing tissue.

Caprolactame-blocked hydroxyl-substituted aromatic compound (abbreviated as CAB-ArOH or CAB2-ArOH), suitable for the preparation of a tissue-adherent polymer according to any of claims 1 to 8, wherein said caprolactame-blocked compound has a structure according to formula IVa (CAB2-ArOH) or IVb (CAB-ArOH), preferably IVaa or IVba, more preferably IVab or IVba.

OH

HO R2 Os HN 0 Oo N, NH 1 -NH 1D

EE TCH® IVab® wherein RA represents a functionalized monomeric unit that is functionalized with the ArOH group; the linker represents a linear or branched C 1 -C 8 hydrocarbon, optionally substituted with one or more OH, SH, halide, amide, and / or carboxylate; R2 represents H, OH, CH:;, or CO: H, or esters thereof, such as CO: Me or CO: Et, and x and y are integers each between 1 and 8, while x + y is between 3 and 9, wherein x is preferably equal to 4, and y is equal to 0.

A method of preparing a fabric adhesive polymer according to any one of claims 1 to 8, wherein said method comprises reacting a polymer comprising a polymer chain functionalized with XH, as illustrated in Formula V with CAB- ArOH or CAB2-ArOH according to claim 12, ArOH are | | Cet N-NH-NH-Ea CHEN

O © IVaa

X NH NT and J zpeeeri-aox Gh ~ linker | -AroH polymeric chain S 0 Oo

I IVb Polymeric chain = polymer chain Spacer = spacer wherein XH is a hydroxyl, a sulthydryl, and / or an amine group, and wherein the spacer represents a spacer functionality, preferably said tissue-adherent polymer being a multi-branch tissue-adhering polymer according to any one of claims 3 to 8 insofar as dependent on claim 3, and wherein said method comprises reacting a multi-branched polymer having a structure of formula Va with CAB-ArOH or CAB2-ArOH according to claim 12, ArOH

II Polymeric chain = polymer chain Spacer = spacer in which XH is a hydroxyl, a sulfhydryl, and / or an amine group, and the spacer represents a spacer functionality,

A method of functionalizing an activated material A, the surface of which comprises at least one reactive hydroxyl, sulfhydryl, and / or amine group, with a catechol derivative, said method comprising contacting said activated material A with the CAB -ArOH according to claim 12, in order to obtain functional material B, ArOH wt ot QN, NH activated material}, + go r = O 0

A XH X XH XH IVb functional material

B Activated material = activated material Linker = left Spacer = spacer Functional material = functional material in which XH is the reactive hydroxyl, sulfhydryl, and / or amine group.

Functionalized material obtainable by means of a method according to the preceding claim.