WO2024062300A1 - Copolymère élastomère biodégradable - Google Patents

Copolymère élastomère biodégradable Download PDF

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Publication number
WO2024062300A1
WO2024062300A1 PCT/IB2023/058206 IB2023058206W WO2024062300A1 WO 2024062300 A1 WO2024062300 A1 WO 2024062300A1 IB 2023058206 W IB2023058206 W IB 2023058206W WO 2024062300 A1 WO2024062300 A1 WO 2024062300A1
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poly
optionally substituted
group
diisocyanate
copolymer according
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PCT/IB2023/058206
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English (en)
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Iman Manavitehrani
Maryam PARVIZ
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SDIP Innovations Pty Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4269—Lactones
    • C08G18/4277—Caprolactone and/or substituted caprolactone
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/708—Isocyanates or isothiocyanates containing non-reactive high-molecular-weight compounds
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C08G18/12—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step using two or more compounds having active hydrogen in the first polymerisation step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4236—Polycondensates having carboxylic or carbonic ester groups in the main chain containing only aliphatic groups
    • C08G18/4238—Polycondensates having carboxylic or carbonic ester groups in the main chain containing only aliphatic groups derived from dicarboxylic acids and dialcohols
    • C08G18/4241—Polycondensates having carboxylic or carbonic ester groups in the main chain containing only aliphatic groups derived from dicarboxylic acids and dialcohols from dicarboxylic acids and dialcohols in combination with polycarboxylic acids and/or polyhydroxy compounds which are at least trifunctional
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/44—Polycarbonates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
    • C08G18/751—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring
    • C08G18/752—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group
    • C08G18/753—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group containing one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group having a primary carbon atom next to the isocyanate or isothiocyanate group
    • C08G18/755—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing only one cycloaliphatic ring containing at least one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group containing one isocyanate or isothiocyanate group linked to the cycloaliphatic ring by means of an aliphatic group having a primary carbon atom next to the isocyanate or isothiocyanate group and at least one isocyanate or isothiocyanate group linked to a secondary carbon atom of the cycloaliphatic ring, e.g. isophorone diisocyanate
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/069—Vascular Endothelial cells
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2230/00—Compositions for preparing biodegradable polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C12N2533/40—Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers

Definitions

  • an elastic biodegradable biomaterial in particular, copolymers comprising polyester, polycarbonate and polyurethane segments, which may be used for engineered tissue applications (e.g., in vivo and in vitro) and medical devices, or for parts thereof.
  • Tissue engineering has the potential to address the ever-increasing demand of in vitro engineered tissue materials, and to produce medical devices with the capacity for growth.
  • the most recent tissue engineering approach is to use the fundamental characteristics of the self-assembling nature of cells to ultimately form a 3D construct, which is biologically active and possesses growth capacity.
  • Such devices need the mechanical strength to withstand physiological shear stresses. Utilizing a biocompatible material that degrades safely in the body without any risk of thromboembolic and calcific complications is ideal for tissue engineering.
  • Elastomers are a class of polymeric materials that can repeatedly and easily undergo large, reversible deformations with complete recovery. They are usually composed of long-chain molecules, which are extremely flexible due to their ability to reconfigure themselves and dissipate an applied force.
  • the main feature of elastomers also called “biomedical elastomers” or “bioelastomers,” is their viscoelasticity combined with biodegradation, thus making them suitable for medical applications as drug delivery systems, biosensors, artificial organs, materials for regenerative medicine, tissue engineering and veterinary medicine.
  • the polymers are suitable for medical applications due to their great attributes such as a 3D-crosslinked network structure, good mechanical properties, and the possibility of tailoring degradation by introducing resorbable functional groups within the structure.
  • Bioresorbable implants are arms of regenerative medicine that promote the restoration of the normal function of damaged tissues upon resorption of implants.
  • Synthetic biodegradable polymers are considered the most commercially competitive polymers for these applications as they can be produced reproducibly in a cost-effective manner with a wide range of characteristics. They are also biocompatible, and biodegradable polymers used for the manufacturing of different medical devices, such as sutures, plate, bone fixation devices, stent, screws, and tissue repairs, as their physicochemical properties are suitable for a broad range of medical applications.
  • the present disclosure provides a copolymer comprising a polycarbonate segment, a polyester segment, and a polyurethane segment.
  • the polycarbonate segment degrades into benign product(s), such as water and carbon dioxide. It is believed that the use of polypropylene carbonate (PPC) with biologically neutral degradation products, can eliminate the risks associated with conventional biodegradable synthetic polymers.
  • PPC polypropylene carbonate
  • the present disclosure provides a copolymer, which is at least partially biodegradable, the copolymer comprising:
  • the disclosure provides a composition comprising a copolymer which is at least partially biodegradable.
  • the disclosure provides a tissue engineered complex, or a medical device comprising a copolymer which is at least partially biodegradable.
  • FIG. 1 is an illustration of certain chemical reactions, which can be used to synthesize a tri-block elastic copolymer of the present disclosure.
  • FIG. 2 is an illustration of chemical functional groups of the copolymer versus the monomers based on FTIR results.
  • FIG. 3 is an illustration of the thermal properties of the tri-block elastic copolymer based on a DSC test.
  • FIG. 4 illustrates a cell proliferation study by Ki67 immunofluorescence staining FIG. 4A, “no material control”) and FIG. 4B HUVEC cultured on biomaterial). Representative images of HUVECs seeded on tri-block copolymer material surfaces and then stained with Ki67 (cell proliferation marker) and CD31 (endothelial cell marker). Cells were mounted onto glass slides with DAPI. The bar graph FIG. 4C shows quantification of Ki67-positive cells in both the control “no material” and “material”.
  • FIG. 6 is an illustration of in vivo studies. Mouse model histology at 8 weeks post-surgical implantation showing representative H&E staining of (A, B) GoreTex tube and (C, D) tri-block biodegradable elastomer at 4 and 10/, respectively. Neither sample shows evidence of an adverse foreign body response. (Scale bars are 500 pm for panels A and C and 200 pm for panels B and D.)
  • the present disclosure provides a novel class of copolymers comprising a polyester segment, a polycarbonate segment, and a polyurethane segment.
  • the resultant absorbable copolymers are useful for implantable medical devices, fillers, coatings, tissue engineering complexes and scaffoldings, and tissue adhesives.
  • alkanoyl as used herein includes an alkyl-C(O)- group wherein the alkyl group is as defined herein.
  • Representative alkanoyl groups include acetyl, ethanoyl, and the like.
  • alkenyl as used herein includes a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms that contains at least one carbon-carbon double or triple bond. Preferred alkenyl groups have 2 to about 12 carbon atoms. More preferred alkenyl groups contain 2 to about 6 carbon atoms. In one aspect, hydrocarbon groups that contain a carbon-carbon double bond are preferred. In a second aspect, hydrocarbon groups that contain a carbon-carbon triple bond are preferred (i.e., alkynyl). “Lower alkenyl” as used herein includes alkenyl of 2 to about 6 carbon atoms.
  • alkenyl groups include vinyl, allyl, n-butenyl, 2-butenyl, 3-methylbutenyl, n-pentenyl, heptenyl, octenyl, decenyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, and the like.
  • An alkenyl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the alkenyl group e.g., from 1 to 4, from 1 to 2, or 1 may be replaced with a moiety independently selected from the group of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio.
  • alkenylene as used herein includes a straight or branched bivalent hydrocarbon chain containing at least one carbon-carbon double or triple bond.
  • Preferred alkenylene groups include from 2 to about 12 carbons in the chain, and more preferred alkenylene groups include from 2 to 6 carbons in the chain.
  • hydrocarbon groups that contain a carbon-carbon double bond are preferred.
  • hydrocarbon groups that contain a carbon-carbon triple bond are preferred.
  • Alkoxy as used herein includes an alkyl-O- group wherein the alkyl group is as defined herein.
  • Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, heptoxy, and the like.
  • An alkoxy group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the alkoxy group e.g., from 1 to 4, from 1 to 2, or 1 may be replaced with a moiety independently selected from the group of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio.
  • Alkoxyalkyl as used herein includes an alkyl-O-alkylene- group wherein alkyl and alkylene are as defined herein.
  • Representative alkoxyalkyl groups include methoxyethyl, ethoxymethyl, n-butoxymethyl and cyclopentylmethyloxyethyl.
  • Alkoxy carbonyl as used herein includes an ester group; i.e., an alkyl-O-CO- group wherein alkyl is as defined herein.
  • Representative alkoxycarbonyl groups include methoxy carbonyl, ethoxy carbonyl, t-butyloxycarbonyl, and the like.
  • Alkoxycarbonylalkyl as used herein includes an alkyl-O-CO-alkylene- group wherein alkyl and alkylene are as defined herein.
  • Representative alkoxycarbonylalkyl include methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, and the like.
  • Alkyl as used herein includes an aliphatic hydrocarbon group, which may be straight or branched chain, having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. More preferred alkyl groups have 1 to 6 carbon atoms in the chain. “Branched-chain” as used herein includes that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. “Lower alkyl” as used herein includes 1 to about 6 carbon atoms, preferably 5 or 6 carbon atoms in the chain, which may be straight or branched. Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n- pentyl, and 3-pentyl.
  • An alkyl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the alkyl group e.g., from 1 to 4, from 1 to 2, or 1 may be replaced with a moiety independently selected from the group of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio.
  • Alkylene as used herein includes a straight or branched bivalent hydrocarbon chain of 1 to about 6 carbon atoms. Preferred alkylene groups are the lower alkylene groups having 1 to about 4 carbon atoms. Representative alkylene groups include methylene, ethylene, and the like.
  • Alkylthio as used herein includes an alkyl-S- group wherein the alkyl group is as defined herein. Preferred alkylthio groups are those wherein the alkyl group is lower alkyl. Representative alkylthio groups include methylthio, ethylthio, isopropylthio, heptylthio, and the like.
  • Alkylthioalkyl as used herein includes an alkylthio-alkylene- group wherein alkylthio and alkylene are defined herein.
  • Representative alkylthioalkyl groups include methylthiomethyl, ethylthiopropyl, isopropylthioethyl, and the like.
  • Amido as used herein includes a group of formula YIY2N-C(O)- wherein Yi and Y2 are independently hydrogen, alkyl, or alkenyl; or Yi and Y2, together with the nitrogen through which Yi and Y2 are linked, join to form a 4- to 7-membered azaheterocyclyl group (e.g., piperidinyl).
  • Representative amido groups include primary amido (H2N-C(O)-), methylamido, dimethylamido, diethylamido, and the like.
  • “amido” is an -C(O)NRR’ group where R and R’ are members independently selected from the group of H and alkyl. More preferably, at least one of R and R’ is H.
  • amidoalkyl as used herein includes an amido-alkylene- group wherein amido and alkylene are defined herein.
  • Representative amidoalkyl groups include amidomethyl, amidoethylene, dimethylamidomethyl, and the like.
  • Amino as used herein includes a group of formula Y1Y2N- wherein Yi and
  • Y2 are independently hydrogen, acyl, or alkyl; or Yi and Y2, together with the nitrogen through which Yi and Y2 are linked, join to form a 4- to 7-membered azaheterocyclyl group (e.g., piperidinyl).
  • Yi and Y2 are independently hydrogen or alkyl, an additional substituent can be added to the nitrogen, making a quaternary ammonium ion.
  • Representative amino groups include primary amino (H2N-), methylamino, dimethylamino, diethylamino, and the like.
  • “amino” is an - NRR’ group where R and R’ are members independently selected from the group of H and alkyl.
  • at least one of R and R’ is H.
  • aminoalkyl as used herein includes an amino-alkylene- group wherein amino and alkylene are defined herein.
  • Representative aminoalkyl groups include aminomethyl, aminoethyl, dimethylaminomethyl, and the like.
  • Aroyl as used herein includes an aryl-CO- group wherein aryl is defined herein. Representative aroyl include benzoyl, naphth- 1-oyl and naphth-2-oyl.
  • Aryl as used herein includes an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms.
  • Representative aryl groups include phenyl and naphthyl.
  • ‘Aromatic ring” as used herein includes 5-12 membered aromatic monocyclic or fused polycyclic moieties that may include from zero to four heteroatoms selected from the group of oxygen, sulfur, selenium, and nitrogen.
  • Exemplary aromatic rings include benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthalene, benzathiazoline, benzothiophene, benzofurans, indole, benzindole, quinoline, and the like.
  • the aromatic ring group can be substituted at one or more positions with halo, alkyl, alkoxy, alkoxy carbonyl, haloalkyl, cyano, sulfonato, amino sulfonyl, aryl, sulfonyl, aminocarbonyl, carboxy, acylamino, alkyl sulfonyl, amino and substituted or unsubstituted substituents.
  • Carboxy and “carboxyl” as used herein include a HOC(O)- group (i.e., a carboxylic acid) or a salt thereof.
  • Carboxyalkyl as used herein includes a HOC(O)-alkylene- group wherein alkylene is defined herein. Representative carboxyalkyls include carboxymethyl (i.e., HOC(O)CH2-) and carboxy ethyl (i.e., HOC(O)CH2CH2-).
  • Cycloalkyl as used herein includes a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. More preferred cycloalkyl rings contain 5 or 6 ring atoms.
  • a cycloalkyl group optionally comprises at least one sp 2 -hybridized carbon (e.g., a ring incorporating an endocyclic or exocyclic olefin).
  • Representative monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like.
  • Representative multicyclic cycloalkyl include 1 -decalin, norbornyl, adamantyl, and the like.
  • Cycloalkylene as used herein includes a bivalent cycloalkyl having about 4 to about 8 carbon atoms.
  • Preferred cycloalkylenyl groups include 1,2-, 1,3-, or 1,4- cis- or trans-cyclohexylene.
  • Halo or “halogen” as used herein includes fluoro, chloro, bromo, or iodo.
  • Heteroatom as used herein includes an atom other than carbon or hydrogen. Representative heteroatoms include O, S, and N. The nitrogen or sulphur atom of the heteroatom is optionally oxidized to the corresponding N-oxide, S-oxide (sulfoxide), or S,S-dioxide (sulfone). In a preferred aspect, a heteroatom has at least two bonds to alkylene carbon atoms (e.g., -C1-C9 alkylene-O-Ci-C9 alkylene-).
  • a heteroatom is further substituted with an acyl, alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl group (e.g., -N(Me)-; -N(Ac)-).
  • Heteroaroyl as used herein includes a heteroaryl- C(O)- group wherein heteroaryl is as defined herein.
  • Representative heteroaroyl groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, pyridinoyl, and the like.
  • Heterocycloyl as used herein includes a heterocyclyl-C(O)- group wherein heterocyclyl is as defined herein.
  • Representative heterocycloyl groups include N-methyl prolinoyl, tetrahydrofuranoyl, and the like.
  • “Hydroxyalkyl” as used herein includes an alkyl group as defined herein substituted with one or more hydroxy groups. Preferred hydroxyalkyls contain lower alkyl.
  • Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • bioabsorbable refers to a copolymer that readily reacts or enzymatically degrades upon exposure to bodily tissue for a relatively short period of time, thus providing a significant loss of the original material in that short time period.
  • the polymers of the disclosure can be fabricated into medical and surgical devices, bio-adhesives, coatings, etc., which are useful for a vast array of applications requiring complete or partial absorption within the relatively short time periods.
  • the term “elastomer” refers to a material which at room temperature can be stretched repeatedly to at least 1.2X to 5X or even to 10X its original length and, upon immediate release of the stress, will return with force to its approximate original length.
  • polymers are molecules containing multiple copies (e.g., from 2 to 5 to 10 to 25 to 50 to 100 to 250 to 500 to 5000 or more copies) of one or more constituent units, commonly referred to as monomers.
  • monomers may refer to free monomers and to those that have been incorporated into polymers, with the distinction being clear from the context in which the term is used.
  • polymeric segment or “segment” is a portion of a polymer or co-polymer.
  • treatment or “treating” of a wound or skin defect means administration to a patient by any suitable dosage regimen, procedure and/or administration route of a composition, device or structure with the object of achieving a desirable clinical/medical end-point, including attracting progenitor cells, healing a wound, correcting a defect, etc.
  • the term “biocompatible,” refers to a device, scaffold composition, and the like, which is essentially and practically, substantially non-toxic, non-injurious or non- inhibiting or non-inhibitory to cells, tissues, organs, and/or organ systems that would come into contact with the device, scaffold, composition, and the like.
  • the term “polymer composition” is a composition comprising one or more of the present polymers of this disclosure and optionally one or more other polymers.
  • “polymers” includes homopolymers, heteropolymers, copolymers, block polymers, block copolymers and can be both natural and synthetic. Homopolymers contain one type of building block, or monomer, whereas copolymers contain more than one type of monomer.
  • Copolymers in accordance with the disclosure may include, for example, the following segments: a polyester segment, a polycarbonate segment, and a polyurethane segment. Segments can be unbranched or branched. Segments can contain a single type of constituent unit (also referred to herein as “homopolymeric segments”) or multiple types of constituent units (also referred to herein as “copolymeric segments”) which may be present in a periodic (e.g., alternating) distribution.
  • the copolymers disclosed herein are biodegradable and/or bioerodible. Once implanted and in contact with bodily fluids and tissues, or subjected to other environmental conditions, the polymers will degrade either partially or completely through chemical reactions, typically and often preferably over a time period of hours, days, weeks, months or even years. Non-limiting examples of such chemical reactions include acid/base reactions, hydrolysis reactions, and enzymatic cleavage.
  • the copolymers described herein contain labile ester linkages, which are susceptible to esterases. The copolymer can be selected and tailored so that it degrades over a selected time period.
  • the present disclosure provides a biodegradable copolymer, the copolymer comprising:
  • the biodegradable copolymer has feed ratios for the (a) polyester segment: the (b) polycarbonate segment: the (c) polyurethane segment of (0.70 to 0.80): (0.15 to 0.20): (0.015 to 0.030); or (0.75 to 0.80): (0.16 to 0.20): (0.02 to 0.030). These ratios correspond to a: b: c.
  • copolymers disclosed herein contain a polyester segment, which segment contains the polyester functional group when p > 3 having the general formula as follows: wherein Z 1 is defined herein.
  • copolymers disclosed herein contain a polycarbonate segment, which segment contains a polycarbonate functional group when n > 3 having the general formula as follows: wherein Z 4 is defined herein.
  • copolymers disclosed herein contain a polyurethane segment, which segment contains a polyurethane functional group when b > 3 having the general formula as follows: wherein Z 5 is defined herein.
  • the biodegradable copolymer comprises:
  • the biodegradable copolymer is a block copolymer, where each segment is homopolymeric. In certain instances, at least one of the segments (a), (b) or (c) is branched. In certain instances, the copolymer is crosslinked, for example, the polyurethane segment is crosslinked, or the polyester segment is crosslinked, or the polycarbonate segment is crosslinked or some combination thereof.
  • the biodegradable copolymer of the disclosure has Formula I: wherein R 1 is a Ci-Ce alkyl;
  • R 2 to R 4 are each independently a C2-C6 alkylene
  • Z 1 to Z 4 are each independently an optionally substituted C1-C20 alkyl, an optionally substituted C2-C20 alkylene, or an optionally substituted C2-C20 alkenylene, wherein the C2-C20 alkylene group or C2-C20 alkenylene group, is optionally substituted with one or more of a C1-C3 alkyl group, optionally interrupted by a heteroatom or functional group;
  • Z 5 is divalent and is a member selected from the group consisting of an optionally substituted Ci-Cs alkyl, an optionally substituted Ci-Cs alkylene, an optionally substituted C5-C7 cycloalkyl, an optionally substituted aryl, an optionally substituted alkylarylalkyl and an optionally substituted diaryl;
  • Z 6 is divalent and is a member selected from a group consisting of C2-C14 alkylene, optionally interrupted by a heteroatom, optionally substituted C5-C7 cycloalkyl, optionally substituted aryl and a disiloxyl ether; and p, m, n, a, b and c are each an integer independently selected from 2-500 or 2-250, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, and/or 250.
  • Z 1 in the biodegradable copolymer of Formula I is an optionally substituted C2-C15 alkylene, or an optionally substituted C2-C15 alkenylene, wherein the C2-C15 alkylene group or C2-C20 alkenylene group, is optionally substituted with one or more of a C1-C3 alkyl group, optionally interrupted by a heteroatom or ester functional group; and p is 2-250. Each number between 2 and 250 is hereby recited inclusively.
  • the polyester segment Z 1 in the biodegradable copolymer of Formula I is formed from or is a residue of an ester selected from the group consisting of poly(s -caprolactone), poly(P-butyrolactone), poly(S-valerolactone), poly(y- butyrolactone), poly (y- valerolactone), poly(a-angelica lactone), poly(lactic acid), poly(glycolic acid), poly(ortho esters), poly(hydroxyl valerate), poly(ethylene succinate), poly(butylene succinate), poly(butylene succinate adipate), poly(paradioxanone) and poly (decalactone); or a copolymer comprising units selected from the group consisting of: poly(e caprolactone), poly(P-butyrolactone), poly(S-valerolactone), poly(y- butyrolactone), poly (y- valerolactone), poly(a-angelica lac
  • Z 2 is an optionally substituted C2-C15 alkylene.
  • Z 3 is an optionally substituted C2-C15 alkylene and m is 2 to 250.
  • the polycarbonate segment Z 3 is formed from or is a residue of a monomer which is a member selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate.
  • the polycarbonate segment is formed from or is a residue of polypropylene carbonate).
  • Z 4 is an optionally substituted C2-C15 alkylene and n is 2 to 250.
  • the polycarbonate segment Z 4 is formed from or is a residue of a monomer which is a member selected from the group consisting of dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate.
  • the polycarbonate segment Z 4 is formed from or is a residue of polypropylene carbonate).
  • Z 3 is the same as Z 4 .
  • Z 5 is a member selected from the group consisting of an optionally substituted Ci-Ce alkyl, an optionally substituted Ci-Ce alkylene, and an optionally substituted C5-C7 cycloalkyl.
  • the polyurethane segment Z 5 is formed from or is a residue of a compound comprising at least two isocyanate groups which is a member selected from the group consisting of 1,4- diisocyanatobutane, 1,12-diisocyanatododecane, 1,6- diisocyantehexane, 1,8- diisocyanateoctane, 4,4'-methylenediphenyl diisocyanate (MDI), 4,4’- methylenebispyclohexyl diisocyanate) (H12MDI), p-phenylene diisocyanate (p- PDI), m-phenylene diisocyanate (m-PDI) trans-cyclohexane-l,4-diisocyanate (CHDI) or a mixture of the cis and trans isomers, 1,6-hexamethylene diisocyanate (HDI), 2,4- toluene diisocyan
  • the Z 5 segment is formed from or is a residue of isophorone diisocyanate.
  • Z 6 is selected from the group consisting of an optionally substituted C2-C10 alkenylene, an optionally substituted Ci-Ce alkyl C5-C6 cycloalkyl-Ci- Ce alkyl, an optionally substituted Ci-Ce alkyl C5-C6 aryl-Ci-Ce alkyl and a disiloxyl ether.
  • Z 6 is formed from or is a residue of a member selected from the group consisting of 1 ,4-butanediol, 1,6-hexanediol, 1,8- octanediol, 1,9-nonanediol and 1,10-decanediol, 1,4-cyclohexane dimethanol, pxyleneglycol, 1,4-bis (2- hydroxy ethoxy) benzene, 1,12-dodecanediol, 1,3 bis-(4- hydroxybutyl) 1, 1,3,3- tetramethyldisiloxane, N-methyl diethanolamine N-ethyldiethanolamine, N- butyldiethanolamine, N-tert-butyldiethanolamine, 3- diisopropyl-amino-l,2-propanediol, 3-(dimethylamino)-l,2-propanediol,2-propaned
  • Z 6 is formed from or is a residue of N-methyl diethanolamine.
  • the compound of Formula I has the structure: [0089] In certain aspects, the compound of Formula I has a number average molecular weight of (Mn) of about 40 kDa to about 60 kDa or about 50 kDa to about 60 kDa or about 55 kDa to about 60 kDa.
  • the compound of Formula I has a weight average molecular weight of (Mw) about 180 kDa to about 250 kDa or about 200 kDa to about 240 kDa or about 215 kDa to about 230 kDa.
  • the number average molecular weight refers to the mole fraction of molecules in the polymer sample
  • the weight average molecular weight is the weight fraction of molecules in the polymer sample.
  • the ratio of the weight average molecular weight to the number average molecular weight is the Polydispersity Index (or PDI).
  • the disclosure provides a medical implant comprising the copolymer as described herein.
  • the disclosure provides a copolymer a tissue scaffold for tissue grafts.
  • the scaffold holds viable cells.
  • the disclosure provides a copolymer which is at least partially biodegradable.
  • the disclosure provides a method of synthesizing a copolymer, which is at least partially biodegradable, the method comprising the step of combining a polyester chain with a polycarbonate chain to yield a polyester-poly carbonate block copolymer.
  • a one-pot, catalyst-free method was used as an efficient technique to produce the copolymers described herein.
  • the reaction involves a polycondensation of polyester for example PCL, followed by esterification of polycarbonate for example esterification of PPC, formation of the NCO-terminated prepolymer and optionally using an appropriate chain extender.
  • the synthesis of the copolymer includes a polyol such as an alkanediol.
  • the polyol can be for example, a difunctional OH-functional aliphatic polycarbonatediol.
  • the polyol is present and selected from the group consisting of butane- 1,4-diol, pentane- 1,5-diol, hexane- 1,6-diol, 3 -methylpentane- 1,5- diol, and mixtures thereof.
  • the polyol is present and is selected from the group consisting of: polyadipates, polycaprolactones, polyether polyols, polyether polyols based on tetrahydrofuran and propylene oxide, and combinations thereof.
  • the polyol is present and is selected from the group consisting of: polyadipates, polycaprolactones, polyether polyols, polyether polyols based on tetrahydrofuran and propylene oxide, and combinations thereof.
  • polyol is present and is poly(s-caprolactone) diol.
  • the chain extender is selected from the group consisting of: 1,4- butanediol, 1,6-hexanediol, 1,8- octanediol, 1,9-nonanediol and 1,10-decanediol, 1,4- cyclohexane dimethanol, pxyleneglycol, 1,4-bis (2-hydroxy ethoxy) benzene, 1,12- dodecanediol and 1,3 bis-(4- hydroxybutyl) 1,1,3,3-tetramethyldisiloxane.
  • chain extender is an amine comprising at least two hydroxyl groups.
  • the chain extender is selected from the group consisting of: N- methyl diethanolamine Nethyldi ethanolamine, N-butyldiethanolamine, N-tert- butyldiethanolamine, 3- diisopropyl-amino-l,2-propanediol, 3 -(dimethylamino)- 1,2- propanediol, 3- (di ethylamino)- 1,2-propanediol, triethanolamine, tripropanolamine, triisopropanolamine, and mixtures thereof.
  • the chain extender is N-methyl diethanolamine.
  • polyesters suitable for use in the present disclosure for making the polyester segment are in Table 1.
  • polycarbonates suitable for use in the present disclosure for making the polycarbonate segment are in Table 2.
  • the compounds with two isocyanates suitable for use in the present disclosure for making the urethane segment are in Table 3.
  • polyol compounds suitable for use in the present disclosure are in Table 4.
  • the copolymers of this disclosure are useful materials for multitude biomedical applications such as tissue engineering and drug delivery.
  • the polymers disclosed herein can be constructed into tissue engineered scaffolds, which are biodegradable and promote cell growth and tissue regeneration.
  • the disclosed polymers have tunable mechanical and degradation properties to match the regeneration/healing rate of the target tissue.
  • the disclosed polymers can withstand the dynamic in vivo microenvironment and mechanically mimic the native extracellular matrix (ECM) to maintain tissue integrity.
  • ECM extracellular matrix
  • the copolymers disclosed herein find application in a wide variety of applications including engineering of tissues, especially muscle tissue, nerves, artery, and heart valves.
  • the copolymers can be used in the form of tubes, e.g., for peripheral nerve reconstruction.
  • the tube is constructed to withstand pressure of the surrounding tissue and guide the nerve in its outgrowth, substantially unhampered by scar tissue formation.
  • the material be functionalized (e.g., with GRGD) to facilitate the attachment and guidance of Schwann cells.
  • the copolymers disclosed herein can incorporate growth factors into a wound dressing/sealent comprising a composition or material of the present disclosure to recruit cells to a wound site and/or promote specific metabolic and/or proliferative behavior in cells that are at the site and/or seeded within the matrix.
  • Exemplary growth factors include, without limitation, TGF-0, acidic fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor, IGF-I and II, vascular endothelial-derived growth factor, bone morphogenetic proteins, platelet-derived growth factor, heparin-binding growth factor, hematopoietic growth factor, and peptide growth factor.
  • the copolymers can be used to tissue engineer, epithelial, connective, nerve, muscle, organ, and other tissues, as well as artery, ligament, skin, tendon, kidney, nerve, liver, pancreas, bladder, and other tissues.
  • compositions and materials of the present disclosure can be used as the template for mineralization and formation of bone.
  • Tissues typically experience mechanical forces and deformation in daily use, and tissue remodeling is often influenced by mechanical forces.
  • mechanical force stimulates the cells that produce extracellular matrix elements to produce growth factors that promote either the production or degradation of ECM.
  • Use of a substance, like various embodiments of the compositions and materials of the disclosure, that mimics a normal physiological response to mechanical forces can facilitate the regeneration of normal tissue, as mechanical stimulation can be applied early in the culturing of tissue engineered constructs.
  • the copolymer composition of this disclosure is used as a carrier for release of an active agent or drug for therapeutic purposes.
  • the composition is used for release of one or more therapeutic agents within a subject’s body and/or incorporates one or more therapeutic agents.
  • at least one therapeutic agent is added to the composition before it is implanted in the patient or otherwise administered to the patient, for example, a therapeutic agent is added to the described composition by adsorption to or absorption into the scaffold, by chemical crosslinking.
  • the therapeutic agents include any substance that can be coated on, embedded into, absorbed into, adsorbed to, or otherwise attached to or incorporated onto or into the copolymer composition described herein or incorporated into a drug product that would provide a therapeutic benefit to a patient.
  • Non-limiting examples of such therapeutic agents include antimicrobial agents, growth factors, emollients, retinoids, and topical steroids.
  • Each therapeutic agent may be used alone or in combination with other therapeutic agents.
  • a composition comprising neurotrophic agents or cells that express neurotrophic agents may be applied to a wound that is near a critical region of the central nervous system.
  • Example 1 describes the synthesis of the PCL-PPC Polyurethane.
  • PCL-PPC-PU As shown in FIG. 1 and Step 1, to a sealable reaction vessel containing a stir bar is added PCL-triol (102.8 mg) and sebacic acid (14.2 mg). The reaction mixture is heated to 160 °C by an external source, such as an oil bath, and allowed to stir while maintaining temperature for 1 h.
  • PCL-triol 102.8 mg
  • sebacic acid 14.2 mg
  • Step 2 to the reaction mixture is then added polypropylene carbonate derivative (PPC)(1.85 g), and the temperature is increased to 120 °C. The reaction is allowed to stir for 24 h while maintaining temperature. [0119] In Step 3, after 24 h, the reaction temperature is decreased to 90 °C, and to the reaction mixture is added isophorone diisocyante (IPDI) (57 pL) and PCL-Diol (377 mg).
  • PPC polypropylene carbonate derivative
  • IPDI isophorone diisocyante
  • the reaction is allowed to stir for 3 h while maintaining temperature.
  • Step 4 after 3 h, the temperature is decreased to 60 °C, and to the reaction mixture is added MDEA (10 pL) and chloroform (50 mL). The reaction is allowed to stir for 24 h while maintaining temperature. Upon completion, the reaction is allowed to cool to room temperature (about 25 °C). The crude mixture is purified by centrifuging at 8k rpm for 5 min. Pure compound is then subjected to solvent casting under ambient conditions (about 1 atm and about 25 °C) for 3 days. Compound was identified by: J H NMR (CDCh, 500 MHz); 13 C NMR (CDCh, 500 MHz); FTIR; GPC; DSC.
  • the final polymer is optionally further processed to increase uniformity using organic solvents, that may be selected depending on solubility, such as but not limited to chloroform.
  • organic solvents such as but not limited to chloroform.
  • PCL-PCC-PU 800 mg
  • chloroform 20 mL
  • the solution is stirred at 600 rpm for about 10 min to about 2 h under ambient conditions (about 1 atm and about 25 °C).
  • the reaction vessel is then subjected to a stream of N2 gas until dry, leaving uniform polymer.
  • Uniform polymer is then subjected to solvent casting under ambient conditions (about 1 atm and about 25°C) for 3 days.
  • this method of processing comprising dissolving as described herein, stirring as described herein, drying as described herein, and/or solvent casting as described herein, may be repeated to further influence uniformity.
  • Example 2 spectroscopically compares by FTIR the monomers as well as the tri-block copolymer described in the synthesis of the PCL-PPC Polyurethane.
  • FTIR was used to compare spectroscopically the monomers as well as the tri-block copolymer prepared using the process described in FIG. 1.
  • the tri-block copolymer demonstrated broad peaks between 2000 cm-1 and 2300 cm-1.
  • the results demonstrate that the tri-block copolymer is spectroscopically different from that of the monomers used in formulating the tri-block polymer.
  • Example 3 illustrates the results of the chemical composition of the synthesized tri-block copolymer at different stages using NMR and GPC.
  • Proton NMR and GPC showed the chemical composition of the synthesized tir- block copolymer at different stages.
  • the PPC, PCL-PCC, and PCL-PPC-PU were
  • the Table shows that the tri-block copolymer demonstrated a composition of 78 ⁇ 1.03 % PPC, 18.66 ⁇ 1.17 PCL, and 2.59 ⁇ 0.15 % PU by mol% with a PDI of 3.98 ⁇ 0.07.
  • PPC demonstrated a Mn of 51 ⁇ 7.3, a Mw of 152 ⁇ 21.9 and a PDI of 2.98 ⁇ 0.05.
  • the PCLT demonstrated a Mn of 1.02 kDa, a Mw of 1.24 kDa, and a PDI of 1.21.
  • Example 4 illustrates thermal properties of the tri-block elastic copolymer based on DSC test.
  • DSC Differential scanning calorimetry
  • Example 5 evaluates the tensile modulus, ultimate tensile strength, and elongation at break of the biomaterial.
  • the tensile modulus, ultimate tensile strength, and elongation at break were evaluated for the human pulmonary artery wall (comparative example) as well as the monomers and copolymer compositions to understand the similarities in the mechanical properties of a biodegradable copolymer used in medical applications.
  • the copolymer demonstrated similar mechanical properties when compared to the human pulmonary artery wall.
  • the pulmonary artery wall demonstrated a tensile modulus of 1.69 ⁇ 0.36 MPa while the copolymer demonstrated a 0.61 ⁇ 0.12 MPa.
  • the monomers, PPC, and PCL-PPC demonstrated a tensile modulus of 17.12 ⁇ 0.89 MPa and 13.87 ⁇ 0.97 MPa, respectively.
  • the tensile modulus demonstrates that while the monomers are ridged when compared to the human pulmonary artery wall, the copolymer may have a higher elasticity as demonstrated by the lower tensile modulus.
  • the ultimate tensile strength results indicate that the copolymer has comparable characteristics to the human pulmonary artery wall as demonstrated by a 069 ⁇ 0.02 MPa ultimate tensile strength compared the human pulmonary artery with an ultimate tensile strength of 0.71 ⁇ 0.08 MPa.
  • the monomers PPC and PCL-PPC demonstrated a higher ultimate tensile strength of 6.65 ⁇ 1.01 MPa and 3 ⁇ 0.14 MPa, respectively.
  • PCL-PPC-PU 0.61 + 0.12 0.69 + 0.02 880 + 24.3
  • the human pulmonary artery wall demonstrated an elongation at break (%) of 73 ⁇ 0.85.
  • the monomers demonstrated an 8.6 ⁇ 1.8 and 14 ⁇ 0.71 %, respectively, while the copolymer demonstrated an elongation of 880 ⁇ 24.3 %.
  • the copolymer may provide beneficial mechanical properties that more closely resemble the mechanical properties of the human pulmonary artery wall.
  • the copolymer may be more elastic, as demonstrated by the tensile modulus and the elongation at break when compared to the human pulmonary artery wall.
  • Example 6 is an evaluation of cells cultured on the biomaterial.
  • HUVEC cells were seeded onto sterile glass coverslips in treated tissue culture well plates in medium supplemented with 10% FBS in each well. After 24-hours, the culture media was removed, and the cells were washed before the cells were fixed and permeabilized. The cells were incubated with either Ki67 or CD31 primary antibodies. Following incubation, the cells were washed and mounted onto glass slides with DAPI. Slides were cured in the dark for 24 hours under ambient conditions before imaging.
  • Cells undergoing proliferation may have higher expression of Ki67.
  • the protein may be detected exclusively within the nucleus during interphase.
  • the results demonstrate that cells in the control group (FIG. 4A) were actively proliferating before imaging.
  • the endothelial cell marker, CD31 was also detected in the control group cells, indicating some angiogenic behavior.
  • the cells cultured on the biomaterial demonstrated presence of both Ki67 and CD31 (FIG. 4B) as demonstrated by the immunofluorescence images shown in FIG. 4B.
  • the cells grown on the biomaterial also demonstrated that Ki67 was present in the nucleus of the cells (arrows in the merged image) indicating that the cells cultured on the biomaterial were actively proliferative.
  • Example 7 is an evaluation of cells cultured on the biomaterial and comparison for nodes, tubes, and mesh formations.
  • HUVEC cells were seeded onto sterile glass coverslips on Matrigel in treated tissue culture well plates in medium supplemented with 10% FBS in each well. After 8- hours of culture time, the culture media was removed, and the cells were washed before the cells were fixed and permeabilized. The cells were incubated with CD31 primary antibody. Following incubation, the cells were washed and mounted onto glass slides with DAPI. Slides were cured in the dark for 24 hours under ambient conditions before imaging. The CD31 expression and DAPI were imaged for control cells (FIG. 5A) and cells cultured on the biomaterial, FIG. 5B.
  • the control cells and the cells cultured on the biomaterial were compared for nodes (C), tubes (D), and mesh (E) formations in three independent experiments.
  • the control cells and cells cultured on the biomaterial demonstrated comparable number of nodes, tubes and mesh formations per field of view.
  • the number of nodes/field of view were about 60 ⁇ 5 for the control cells while the number of nodes/field of view were about 58 ⁇ 2.
  • the number of nodes/field of view were about 42 ⁇ 2 and 40 ⁇ 3, respectively.
  • the number of meshes/field of view were about 20 ⁇ 1 and about 18 ⁇ 2, respectively.
  • Example 8 shows mouse model histology at 8 weeks post-surgical implantation
  • H&E staining provides a comprehensive set of detection for both nuclear components and cytoplasmic components of cells often used to evaluate the microanatomy of the tissue.
  • FIG. 6 shows a mouse model histology at 8 weeks post- surgical implantation showing representative H&E staining of (A,B) GoreTex tube and (C,D) tri-block biodegradable elastomer at 4 and 10 , respectively.
  • the pathology depicted in FIG. 6 demonstrates that neither sample shows evidence of an adverse foreign body response.

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Abstract

La présente invention concerne un élastomère biodégradable présentant des caractéristiques supérieures comprenant un segment de polyester, un segment de polycarbonate et un segment de polyuréthane.
PCT/IB2023/058206 2022-09-20 2023-08-15 Copolymère élastomère biodégradable WO2024062300A1 (fr)

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