Bioactive polyethylene copolymers, polyethylene polymers and related methods

Abstract

Bioactive polyethylene copolymers having a poly(norbornene) backbone comprising one or more repeat units represented by general formula (I) and one or more repeat units represented by general formula (II) are provided. Also provided are polyethylene polymers, materials comprising the bioactive polyethylene copolymers, methods of preparing the bioactive polyethylene copolymers, and methods of preparing the polyethylene polymers. [Formula 1] JPEG2024501100000068.jpg69126

Description

[Technical field]

[0001] The present disclosure relates generally to bioactive polyethylene copolymers, polyethylene polymers and materials comprising said bioactive polyethylene copolymers. The present disclosure also relates to methods of preparing said bioactive polyethylene copolymers, said polyethylene polymers and said materials. [Background technology]

[0002] background A better understanding of the biology and physiology of living organisms over the years has led to an evaluation of the possibility of using alternative materials to augment or replace existing functions in living systems.

[0003] However, it is often difficult to identify suitable materials that meet both the mechanical and biological requirements to function desirably in or with biological systems.

[0004] This is because bioactive molecules with desirable biological attributes (e.g., collagen, chitosan, etc.) often lack the mechanical strength required for useful biomedical applications. For example, many such bioactive molecules are highly hygroscopic and exist as gels when they absorb moisture, which makes them too weak on their own for use in weight-bearing biomedical applications such as implantable devices.

[0005] On the other hand, synthetic materials with superior mechanical characteristics lack the biological attributes required for them to be used appropriately in applications that require constant interaction with living systems.

[0006] Of particular interest is polyethylene (PE), which is often used in biomedical applications despite its modest biocompatibility. PE is a common plastic frequently used in consumer care and disposable products (e.g., diapers and sanitary products) as well as medical devices (e.g., biliary stents, gastrointestinal stents, arthroplasty implants and joint implants, either in the form of high density polyethylene (HDPE) or cross-linked polyethylene (XPE)) due to properties such as inertness, high mechanical strength, good thermal stability, good / easy material processability, ease of sterilization and low cost.

[0007] However, there are some significant problems associated with the use of polyethylene. For example, polyethylene implants can cause foreign body reactions (FBR) when inserted into the human body. This can result in inflammation and other types of undesirable immune responses being elicited around the implantation site, which would require the administration of immunosuppressants to quell the inflammation. In cases where the administration of immunosuppressants fails, removal of the implant may be necessary along with continued administration of immunosuppressants. In polyethylene-based gastrointestinal and biliary stents, biofouling can also be an issue leading to stent obstruction and the need for restenting. Skin sensitization is also common with polyethylene-based products as a result of friction against the material. For example, diaper dermatitis is the most common skin condition experienced by infants and can lead to ulceration and pustule formation in severe cases. In adults who require diaper wearing for reasons such as incontinence and reduced mobility, dermatitis can also lead to bed sores that often lead to sepsis. Furthermore, working with polyethylene is also difficult, as the synthetic polymer is not only insoluble in most organic solvents, but is also a relatively inert polymer as it is.

[0008] Combining these different materials in the hope that the resulting material can achieve both the desired biological and mechanical properties is also difficult because bioactive molecules such as peptides and carbohydrates are often incompatible with polyethylene due to the hydrophilic nature of the former and the hydrophobic nature of the latter.

[0009] That is, physically blending two different materials together often results in phase separation of the two mutually incompatible materials, rendering the resulting overall material ineffective.

[0010] Their inherent differences in hydrophilicity also make it extremely difficult to chemically synthesize bioactive polyethylene copolymers from these materials, especially when the molecular weights of these materials are relatively high. This is in addition to the various complex chemical hurdles (e.g., low reactivity due to the inertness of polyethylene, unwanted chemical leaching of by-products, etc.) that must be overcome when attempting to chemically combine these two chemically dissimilar types of materials together.

[0011] In view of the above, there is a need to address or at least ameliorate the above-mentioned problems, in particular to provide bioactive polyethylene copolymers, polyethylene polymers, materials comprising said bioactive polyethylene copolymers, and associated methods that address or at least ameliorate the above-mentioned problems. Summary of the Invention

[0012] overview In one aspect, one or more repeat units represented by general formula (I) and one or more repeat units represented by general formula (II):

[0013] [ka]

[0014] (In the formula, R1 is optionally substituted alkyl; R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; R 3 is selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; L is heteroalkylene; X comprises a biologically active moiety selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof; Y comprises polyethylene or a portion thereof; and Z 1 and Z 2 are each independently a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0015] In one embodiment, Y is represented by the general formula (III):

[0016] [ka]

[0017] (In the formula, A is NR c where R cis independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is 10 to 350.

[0018] In one embodiment, n is from 20 to 250.

[0019] In one embodiment, B is present and has the general formula:

[0020] [ka]

[0021] (In the formula, R 6a , R 6b , R 6c and R 6d are independently C, CR a , C.R. a R b , N, N.R. c , O or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and R 7a , R 7b and R 7c are =O, =S, -F, -Cl, -Br, -I, =CR a R b, -CR a R b R c , -OH, -SH, -NH2 or =NR c (which may optionally exist as

[0022] In one embodiment, Y is represented by the following general formula (IIIa), (IIIb) or (IIIc):

[0023] [ka]

[0024] (In the formula, R 5 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 alkylcarbonylalkyl; R 6a and R 6d are independently C, CR a , C.R. a R b , N, N.R. c , O or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 7a are =O, =S, -F, -Cl, -Br, -I, =CR a R b , -CR a R b R c , -OH, -SH, -NH2 or =NR c Optionally present as; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is selected from 10 to 350.

[0025] In one embodiment, Y is represented by the following general formula (IIId), (IIIe) or (IIIf):

[0026] [ka]

[0027] (In the formula, R 5 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is selected from 10 to 350.

[0028] In one embodiment, the repeat units represented by general formula (I) are present in an amount of from 1 to 100 mole % of the copolymer.

[0029] In one embodiment, the molecular weight of general formula (I) does not differ from the molecular weight of general formula (II) by more than 30% of the molecular weight of general formula (II).

[0030] In one embodiment, L is heteroalkylene having from 20 to 300 carbon atoms.

[0031] In one embodiment, L is polyethylene glycol (PEG).

[0032] In one embodiment, L is a polyethylene glycol (PEG) having a number average molecular weight between 500 and 7,000.

[0033] In one embodiment, R 1 is C1-C4 alkyl, and R 2 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl or C3-C 20 alkylcarbonylalkyl.

[0034] In one embodiment, R 1 is a straight or branched C1-C4 alkyl substituent independently selected from methyl, ethyl, n-propyl, 2-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl, and R 2 is methyl, ethyl, n-propyl, 2-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, hexyl, amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl ... linear or branched C1-C alkyl aryl groups independently selected from methylpropyl, 2-ethylpentyl, 3-ethylpentyl, heptyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 5-methylheptyl, 1-methylheptyl, octyl, nonyl, or decyl; 20 It is an alkyl substituent.

[0035] In one embodiment, Z 1 and Z 2 Both are CR a R b where R a and R b are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0036] In one embodiment, X comprises a protein, peptide or carbohydrate selected from the group consisting of a peptide sequence, a laminin derived peptide, an integrin binding peptide, a cell penetrating peptide, a collagen sequence, a collagen mimetic, a collagen fragment, heparin sulfate, glycosaminoglycan (GAG) and derivatives thereof.

[0037] In one embodiment, X is RGD, SRGDS, RGDS, A5G81(AGQWHRVSVRWGC), SVVYGLR, (IRIK)2, (IKKI)3, DGEA, (PHypG) n Type sequence, (PGHyp) n Type Array, (HypGP) n Type Array, (HypPG) n Type sequence, (GHypP) n Type array, (GPHyp) n type sequences, heparin oligosaccharides DP8, DP10, DP12, DP14, DP16 and hyaluronic acid.

[0038] In one aspect, a method of preparing a bioactive polyethylene copolymer disclosed herein comprises: One or more bioactive polymers represented by general formula (IV) are polymerized with one or more polyethylene polymers represented by general formula (V) in the presence of a catalyst to produce a bioactive polyethylene copolymer:

[0039] [ka]

[0040] (In the formula, R 1 is optionally substituted alkyl; R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; R 3 is selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; L is heteroalkylene; X comprises a biologically active moiety selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof; Y comprises polyethylene or a portion thereof; and Z 1 and Z 2 are each independently a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0041] In one embodiment, the catalyst comprises a ruthenium complex.

[0042] In one embodiment, the method comprises ring-opening metathesis polymerization (ROMP).

[0043] In one aspect, for preparing the copolymers disclosed herein, a polyethylene polymer represented by the general formula (VIII):

[0044] [ka]

[0045] (In the formula, R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; Z 2 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; A is NR c where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is from 10 to 350.

[0046] In one aspect, a method for preparing a polyethylene polymer disclosed herein comprises: (i) General formula (IX):

[0047] [ka]

[0048] (In the formula, Z 2 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and (ii) reacting said dicarboxylic anhydride having general formula (IX) with an amine to obtain a polyethylene polymer, wherein the amine has general formula (X):

[0049] [ka]

[0050] (In the formula, R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; A is NR c where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; n is 10 to 350) A method is provided, comprising:

[0051] In one embodiment, the method further comprises, prior to step (ii), (ai) General formula (XIa) or (XIb):

[0052] [ka]

[0053] (In the formula, R 6a and R 6d are independently C, CR a , C.R. a R b , N, N.R. c , O or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 7a are =O, =S, -F, -Cl, -Br, -I, =CR a R b , -CR a R b R c, -OH, -SH, -NH2 or =NR c Optionally present as; R 8 and R 9 are each independently 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; n is 10 to 350; and (bi) reacting said polyethylene having the general formula (XIa) or (XIb) with a diamine HN-R 2 -NH2 or ammonia NH3 to obtain an amine having the general formula (X) Includes.

[0054] In one embodiment, at least one of steps (ii) and (bi) is carried out in the presence of an organic solvent and / or a base.

[0055] In one embodiment, the organic solvent comprises an aromatic solvent; and the base comprises a tertiary amine.

[0056] In one aspect, there is provided a material comprising the copolymers disclosed herein for use in medicine.

[0057] In one embodiment, the material is part of an article selected from the group consisting of consumer care products, wound dressings, skin scaffolds, bone and bone marrow organoid scaffolds, cartilage implants, joint implants and medical devices.

[0058] definition As used herein, the term "polymer" refers to a chemical compound that contains repeating units and is created through the process of polymerization. The units that make up a polymer are typically derived from monomers and / or macromonomers. A polymer typically contains multiple repeats of constitutional units.

[0059] As used herein, the term "monomer" or "macromonomer" refers to a chemical entity that can be covalently bonded to one or more such substances to form a polymer.

[0060] As used herein, the term "bioactivity" refers broadly to a property that has a biological effect, preferably a desirable or positive biological effect on a living organism, tissue, or cell.

[0061] As used herein, the term "biocompatibility" refers broadly to the property of being compatible with a biological system or part of a biological system without substantially or significantly eliciting an adverse physiological response, such as a toxic reaction, an immune reaction, injury, etc. Such biological systems or parts include blood, cells, tissues, organs, etc.

[0062] The term "bond" refers to a linkage between atoms in a compound or molecule. A bond can be a single bond, double bond, or triple bond.

[0063] In the definitions of many of the following substituents, it is stated that "the group may be a terminal group or a bridging group." This is intended to mean that the use of the term is intended to encompass the situation where the group is a terminal group / moiety, as well as the situation where the group is a linker between two other parts of a molecule. Using the term "alkyl" having one carbon atom as an example, it will be understood that when present as a terminal group, the term "alkyl" having one carbon atom can mean -CH3, when present as a bridging group, the term "alkyl" having one carbon atom can mean -CH2-, and so on.

[0064] The term "alkyl" as a group or part of a group refers to a straight or branched chain aliphatic hydrocarbon group having 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Examples of suitable straight and branched alkyl substituents are methyl, ethyl, n-propyl, 2-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, hexyl, amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2 -trimethylpropyl, 1,1,2-trimethylpropyl, 2-ethylpentyl, 3-ethylpentyl, heptyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 5-methylheptyl, 1-methylheptyl, octyl, nonyl, decyl, etc. The groups can be terminal groups or bridging groups.

[0065] The term "alkenyl" as a group or part of a group means an aliphatic hydrocarbon group which contains at least one carbon-carbon double bond and may be straight or branched having 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms in the chain. The group may contain multiple double bonds and the orientation about each double bond is independently E or Z. Exemplary alkenyl groups are ethenyl, vinyl, allyl, 1-methylvinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-pentadienyl, 2,4-pentadienyl, 1,4-pentadienyl. , 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 2-methylpentenyl, 1-heptenyl, 2-heptentyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, etc. The group may be a terminal group or a bridging group.

[0066] The term "alkynyl" as a group or part of a group means an aliphatic hydrocarbon group which contains at least one carbon-carbon triple bond and which may be straight or branched having 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms in the chain. The group may contain more than one triple bond. Exemplary alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, etc. The group may be a terminal group or a bridging group.

[0067] The term "heteroalkylene" as used herein refers to an alkylene having one or more -CH2- replaced with a heteroatom selected from O, NR, Si, P, or S, where R is hydrogen or alkyl as defined herein. The term "heteroalkylene" can be linear, branched, or cyclic and can contain up to 500 carbon atoms.

[0068] The term "alkoxy" as used herein refers to a straight or branched chain alkyloxy group. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and the like.

[0069] As used herein, the term "alkoxyalkyl" is intended to refer broadly to a group containing -RO-R', where R and R' are alkyl as defined herein. The group may be a terminal group or a bridging group.

[0070] As used herein, the term "alkylcarbonyl" is intended to refer broadly to a group containing -RC(=O)-, where R is alkyl as defined herein. The group may be a terminal group or a bridging group.

[0071] As used herein, the term "alkylcarbonylalkyl" is intended to refer broadly to a group containing -RC(=O)-R', where R and R' are alkyl as defined herein. The group may be a terminal group or a bridging group.

[0072] As used herein, the term "carboxylalkyl" is intended to refer broadly to a group containing -C(=O)-OR, where R is alkyl as defined herein. The group may be a terminal group or a bridging group.

[0073] As used herein, the term "oxycarbonylalkyl" is intended to refer broadly to a group containing -OC(=O)-R, where R is alkyl as defined herein. The group may be a terminal group or a bridging group.

[0074] As used herein, the term "alkylcarboxylalkyl" is intended to refer broadly to a group containing -RC(=O)-O-R', where R and R' are alkyl as defined herein. The group may be a terminal group or a bridging group.

[0075] As used herein, the term "alkoxycarbonylalkyl" is intended to refer broadly to a group containing -ROC(=O)-R', where R and R' are alkyl as defined herein. The group may be a terminal group or a bridging group.

[0076] As used herein, the term "oxy" is intended to refer broadly to groups containing --O--.

[0077] As used herein, the term "carbonyl" is intended to refer broadly to groups containing -C(=O)-.

[0078] As used herein, the term "oxycarbonyl" is intended to refer broadly to groups containing -OC(=O)-.

[0079] As used herein, the term "carboxyl" is intended to refer broadly to groups containing -C(=O)-OR, where R is hydrogen or an organic group.

[0080] The term "halogen" refers to chlorine, fluorine, bromine or iodine. The term "halo" refers to chloro, fluoro, bromo or iodo.

[0081] The term "amine group" and the like are intended to refer broadly to groups containing -NR2, where R is independently hydrogen or an organic group. The group can be a terminal group or a bridging group.

[0082] The term "amide group" and the like are intended to refer broadly to groups containing -C(=O)NR2, where R is independently hydrogen or an organic group. The group may be a terminal group or a bridging group.

[0083] The term "heterocycle" as used herein broadly refers to a structure in which two or more different kinds of atoms are bonded to form at least one ring.For example, heterocycle can be formed by carbon atom and at least another atom (i.e., heteroatom) selected from oxygen (O), nitrogen (N) or (NR) and sulfur (S), where R is independently hydrogen or organic group.The term also includes, but is not limited to, saturated and unsaturated 5-membered rings and saturated and unsaturated 6-membered rings. Examples of groups having a heterocyclic structure include furan, thiophene, 1H-pyrrole, 2H-pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, 1-pyrazoline, 2-pyrazoline, 3-pyrazoline, 2-imidazoline, 3-imidazoline, 4-imidazoline, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, disubstituted 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, tetrahydrofuran ... Examples of suitable amines include, but are not limited to, thiophene, pyrrolidine, 1,3-dioxolane, 1,2-oxathiolane, 1,3-oxathiolane, pyrazolidine, imidazolidine, pyridine, pyridazine, pyrimidine, pyrazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 2H-pyran, 4H-pyran, 2-pyrone, 4-pyrone, 1,4-dioxine, 2H-thiopyran, 4H-thiopyran, tetrahydropyran, thiane, piperidine, 1,4-dioxane, 1,2-dithiane, 1,3-dithiane, 1,4-dithiane, 1,3,5-trithiane, piperazine, morpholine, thiomorpholine, and the like.

[0084] The term "optionally substituted," when used to describe a chemical structure or moiety, means that one or more of its hydrogen atoms have been substituted with an alkyl group such as alcohol, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amido (-C(O)NH-alkyl- or -alkylNHC(O)alkyl), amine (such as alkylamino, arylamino, arylalkylamino), aryl, aryloxy, azo, carbamoyl (-NHC(O)O-alkyl- or -OC(O)NH-alkyl), carbamyl (e.g., CONH, as well as CONH-alkyl, CONH "NHCONH-arylalkyl" refers to a chemical structure or moiety that is optionally substituted with a chemical moiety or functional group such as, for example, -NHCONH-arylalkyl, -NH-aryl, -NH-arylalkyl ...

[0085] As used herein, the term "micro" should be interpreted broadly to include dimensions from about 1 micron to about 1000 microns.

[0086] As used herein, the term "nano" should be interpreted broadly to include dimensions less than about 1000 nm, less than about 500 nm, less than about 100 nm, or less than about 50 nm.

[0087] The terms "coupled" or "connected" as used in this description are intended to cover both a direct connection or a connection through one or more intermediary means, unless otherwise stated.

[0088] The term "associated" as used herein when referring to two elements refers to a broad relationship between the two elements. The relationship includes, but is not limited to, a physical, chemical, or biological relationship. For example, when element A is associated with element B, elements A and B may be directly or indirectly attached to each other, or element A may contain element B, or vice versa.

[0089] The term "adjacent," as used herein when referring to two elements, refers to the proximity of one element to another, which may be, but is not limited to, elements that contact each other, or may further include elements that are separated by one or more additional elements disposed between them.

[0090] The term "and / or," e.g., "X and / or Y," should be understood to mean either "X and Y" or "X or Y," and should be interpreted as providing clear support for both meanings or either meaning.

[0091] Further, in the description herein, the word "substantially", whenever used, is understood to include, but is not limited to, "entirely" or "completely", etc. Furthermore, terms such as "comprising", "comprise", etc., whenever used, are intended to be open-ended descriptive language in that they broadly include the elements / components listed after such term, in addition to other components not expressly listed. For example, when using "comprising", a reference to "a" feature is also intended to be a reference to "at least one" of that feature. Terms such as "consisting", "consist", etc., may be considered as subsets of terms such as "comprising", "comprise", etc., in the appropriate context. Thus, in embodiments disclosed herein that use terms such as "comprising", "comprise", etc., it will be understood that these embodiments provide teachings of corresponding embodiments that use terms such as "consisting", "consist", etc. Additionally, the terms "about," "approximately," and the like, whenever used, typically refer to a reasonable variation, such as a + / - 5% variation of the disclosed value, or a 4% variation of the disclosed value, or a 3% variation of the disclosed value, a 2% variation of the disclosed value, or a 1% variation of the disclosed value.

[0092] Furthermore, in the description herein, specific values ​​may be disclosed within a range. The values ​​indicating the end points of the range are intended to illustrate the preferred range. Whenever a range is described, the range is intended to cover and teach all possible subranges as well as the individual numerical values ​​within the range. That is, the end points of the range should not be interpreted as inflexible limitations. For example, a description of a range of 1% to 5% is intended to specifically disclose subranges such as 1% to 2%, 1% to 3%, 1% to 4%, 2% to 3%, etc., as well as values ​​within the range, such as 1%, 2%, 3%, 4%, 5%, etc., individually. It should be understood that the individual numerical values ​​within the range also include integers, fractions, and decimals. Furthermore, whenever a range is described, the range is also intended to cover and teach values ​​from the numerical endpoints indicated to two additional decimal places or significant figures (where appropriate). For example, description of a range of 1% to 5% is intended to specifically disclose the range of 1.00% to 5.00% and also 1.0% to 5.0% and all intermediate values ​​therein (1.01%, 1.02%...4.98%, 4.99%, 5.00% and 1.1%, 1.2%...4.8%, 4.9%, 5.0%, etc.). The above specific disclosure intent is applicable to any depth / breadth of range.

[0093] Furthermore, when describing some embodiments, the present disclosure may disclose a method and / or process as a specific sequence of steps. However, unless otherwise required, it will be understood that the method or process should not be limited to the specific sequence of steps disclosed. Other sequences of steps may also be possible. The specific order of steps disclosed herein should not be construed as unduly limiting. Unless otherwise required, the method and / or process disclosed herein should not be limited to steps performed in the order described. The order of steps may be changed and still be within the scope of the present disclosure.

[0094] Furthermore, while the present disclosure provides embodiments having one or more of the features / characteristics discussed herein, it will be understood that one or more of these features / characteristics may also be disclaimed in other alternative embodiments, and the present disclosure provides support for such disclaimers and these related alternative embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0095] Description of the Preferred Embodiments Exemplary, non-limiting embodiments of bioactive polyethylene copolymers, polyethylene polymers for preparing the bioactive polyethylene copolymers, materials comprising the bioactive polyethylene copolymers, and related methods are disclosed below.

[0096] Bioactive Polyethylene Copolymer One or more repeating units represented by general formula (I) and one or more repeating units represented by general formula (II):

[0097] [ka]

[0098] (In the formula, R 1 is optionally substituted alkyl; R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; R 3 is selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; L is heteroalkylene; X comprises a biologically active moiety selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof; Y comprises polyethylene or a portion thereof; and Z 1 and Z 2 are each independently a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0099] In various embodiments, the repeating units and / or moieties X represented by general formula (I) are bioactive, biocompatible and / or biodegradable. In various embodiments, the repeating units and / or moieties Y represented by general formula (II) have good mechanical strength / hardness / compatibility / miscibility with the base polyolefin material when used as such or as an additive to the base material. In various embodiments, the repeating units and / or moieties Y represented by general formula (II) have higher mechanical strength than the repeating units and / or moieties X represented by general formula (I). Advantageously, the presence of the repeating units represented by general formulas (I) and (II) in the bioactive polyethylene copolymer confers both bioactivity and mechanical strength to the copolymer, leading to a mechanically strong bioactive copolymer. In various embodiments, the copolymer may also be biocompatible. Thus, in various embodiments, the copolymer may be classified as a biomaterial. Advantageously, due to the presence of polyethylene side chains, the bioactive polyethylene copolymer has higher thermal stability than conventional biomolecules or biomaterials such as pure collagen. Even more advantageously, the thermal stability of the bioactive polyethylene copolymers allows embodiments of the copolymers to be suitable for processing at high temperatures, or even for harsh material processing such as melt extrusion and melt blowing above 200° C., making the copolymers ideal / attractive for use in applications such as nonwoven fibers / fabrics, which are important components of biomedical devices or diapers. In various embodiments, the repeating units and / or moieties Y represented by general formula (II) are substantially or completely non-bioactive, or at least less bioactive than the repeating units and / or bioactive moieties X represented by general formula (I).

[0100] In various embodiments, L is a polymer linker that connects the bioactive moiety X to the poly(norbornene) backbone. Advantageously, L is designed to be adjustable and / or customizable based on the size of the bioactive moiety X and the size / length of the synthetic polymer (i.e., polyethylene) present in Y. In various embodiments, the physical properties of the copolymer can be altered or adjusted depending on the length of L (e.g., PEG chain) in the macromonomer or polymer. The molecular weight and / or length of the polymer linker L can be customized to suit the molecular weight and / or length of the synthetic polymer (i.e., polyethylene) selected for the bioactive moiety X and Y depending on the application in which the copolymer will be used. In various embodiments, the molecular weight of Y is about 5,000 or less. For applications that do not require high strength, such as nonwoven cloth for wound dressings and diapers, a molecular weight PE of less than 5,000 can be used because the resulting copolymer will be blended with a medium molecular weight PE for fiber production. In other embodiments, the molecular weight of Y is greater than about 5,000. For example, for applications requiring high mechanical strength such as cartilage and joint implants, where the copolymer would be blended with ultra-high molecular weight polyethylene (UHMWPE) for implant production, the molecular weight of Y is 5,000 or greater.

[0101] In various embodiments, Y is represented by the general formula (III):

[0102] [ka]

[0103] (In the formula, A is NR c where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; and T is a terminal group selected from the group consisting of hydrogen and methyl.

[0104] In various embodiments, Y is represented by the general formula (III-1):

[0105] [ka]

[0106] (In the formula, A is N or NR c where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; the dotted lines represent any chemical bond.

[0107] In various embodiments, the dotted line between A and B represents an optional second chemical bond. 5 The dotted line between represents an optional second chemical bond.

[0108] In various embodiments, the original PE backbone has an even number of carbons.

[0109] In various embodiments, n is from about 10 to about 350, from about 20 to about 250, or from about 25 to about 100. In various embodiments, PE with repeat units (n) of about 10 to about 350 is suitable for use as a starting material. In various embodiments, PE with repeat units (n) of about 20 to about 250 or repeat units (n) of about 25 to about 100 is also suitable for use / handling in macromonomer synthesis and polymerization. In these n ranges, polyethylene (PE) has good mechanical properties and compatibility with / in the base polyolefin material while maintaining sufficient reactivity during macromonomer synthesis and copolymerization. In various embodiments, n is at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 105, at least about 110, at least about 115, at least about 120, at least about 125, at least about 130, at least about 135, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 210, at least about 220, at least about 230, at least about 240, at least about 250, at least about 260, at least about 270, at least about 280, at least about 290, at least about 300, at least about 310, at least about 320, at least about 330, at least about 340, at least about 350, at least about 360, at least about 370, at least about 380, at least about 390, at least about 40 ... At least about 145, at least about 150, at least about 155, at least about 160, at least about 165, at least about 170, at least about 175, at least about 180, at least about 185, at least about 190, at least about 195, at least about 200, at least about 210, at least about 220, at least about 230, at least about 240, at least about 250, at least about 260, at least about 270, at least about 280, at least about 290, at least about 300, at least about 310, at least about 320, at least about 330, at least about 340, or at least about 350. In various embodiments, it will be understood by those skilled in the art that the value of n represents the average number of repeat units present in the polymer or polymer mixture. In various embodiments, n also represents the degree of polymerization.

[0110] In various embodiments, in general formula (III-1), A is present while B is absent. In such embodiments, Y is represented by general formula (III-2):

[0111] [ka]

[0112] It is represented by:

[0113] In various embodiments, A is N or NR c where R c is H, optionally substituted C1-C 20 Alkyl, optionally substituted C-C 20 Alkenyl or optionally substituted C-C 20 alkynyl. In various embodiments, A is independently selected from R 5 For example, A is -NH- and -AR 5 is -NH-R 5 In various embodiments, A can be linked to R 5 For example, A is -N= and -A=R 5 is -N=R 5 It could be.

[0114] In various embodiments, B is present as a 5- or 6-membered heterocycle with at least one N heteroatom in the ring. In various embodiments, the heterocycle with at least one N heteroatom also has at least one C atom in the ring that is N or NR c In various embodiments, B is also understood to mean replaced with one nitrogen-containing substituent / group selected from N (or NR c ), as a 5- or 6-membered heterocycle with up to 3 C atoms in the ring, optionally replaced with heteroatoms selected from the group consisting of O and S.

[0115] In various embodiments, B has the following structure:

[0116] [ka]

[0117] (In the formula, R 6a , R 6b , R 6c and R 6d are independently C, CR a , C.R. a R b , N, N.R. c , O or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and R 7a , R 7b and R 7c are =O, =S, -F, -Cl, -Br, -I, =CR a R b , -CR a R b R c , -OH, -SH, -NH2 or =NR c is a 5-membered heterocycle represented by the formula:

[0118] In various embodiments, R 6a and R 7a , R 6b and R 7b , and R 6c and R 7c The dotted line between represents any single or double chemical bond. 6a is connected to R via a single bond. 7a Adheres to R 6b is connected to R via a single bond. 7b Adhering to and / or R 6c is connected to R via a single bond. 7c For example, R6a is C and R 7a When is -Br, then R 6a R 7a is C-Br. In various embodiments, R 6a is connected to R via a double bond. 7a Adheres to R 6b is connected to R via a double bond. 7b Adhering to and / or R 6c is connected to R via a double bond. 7c For example, R 6a is C and R 7a =O, then R 6a R 7a is C=O.

[0119] In various embodiments, B is selected from the group consisting of succinimide (or pyrrolidine-2,5-dione), thiosuccinimide (or 5-thioxopyrrolidin-2-one), dithiosuccinimide (or pyrrolidine-2,5-dithione), pyrrolidine, pyrrole, pyrazolidine, maleimide (or pyrrole-2,5-dione), 1,2,3-triazole, 1,2,4-triazole, and imidazole.

[0120] In various embodiments, only one of A and B is present in general formula (III). For example, when A is present in general formula (III), B is not present in general formula (III), and vice versa.

[0121] In various embodiments, in general formula (III), B is present while A is absent. In such embodiments, Y is represented by general formula (IIIa):

[0122] [ka]

[0123] It can be expressed as:

[0124] In various embodiments, in general formula (III), A is present while B is absent. In such embodiments, Y is represented by general formula (IIIb):

[0125] [ka]

[0126] It can be expressed as:

[0127] In various embodiments, in general formula (III), A and B are both absent. In such embodiments, Y is represented by general formula (IIIc):

[0128] [ka]

[0129] It can be expressed as:

[0130] In various embodiments, R 5 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 In various embodiments, R 5 is a straight chain or branched C1-C3 alkenyl. For example, R 5 can be ethenyl, allyl, or propenyl. In various embodiments, R 5 is a straight or branched C1-C3 alkyl. For example, R 5 can be methyl, ethyl, n-propyl, 2-propyl, or isopropyl. In various embodiments, when Y is represented by the general formula (IIIc), R 5 is methyl.

[0131] In various embodiments, T is a terminal group selected from the group consisting of hydrogen and methyl.

[0132] In various embodiments, Y is represented by the following general formula (IIIg), (IIIh) or (IIIi):

[0133] [ka]

[0134] where n is selected from 10 to 350.

[0135] In various embodiments, Y includes one or more of the following properties: inertness; long shelf life; mechanical strength; impact resistance; thermal stability; elasticity; elastic recovery; smoothness; lightweight; low or non-toxic; and miscibility, compatibility or affinity with lipophilic compounds / polymers.

[0136] In various embodiments, Y is substantially free of polyalkylene glycols, such as polyethylene glycol.

[0137] In various embodiments, the total molecular weight of general formula (II) is kept below about 50,000, below about 45,000, below about 40,000, below about 35,000, below about 30,000, below about 25,000, below about 20,000, below about 15,000, or below about 10,000. It will be appreciated that when the total molecular weight of general formulas (I) and (II) is too high, copolymerization may become inefficient.

[0138] In various embodiments, the molecular weight and / or length of the polymer linker L is selected such that the overall molecular size of the repeating unit represented by general formula (I) is similar / comparable to the molecular size of the repeating unit represented by general formula (II). For example, if polyethylene with a molecular weight of 4,000 is selected as the synthetic polymer of choice for Y, and a peptide with a molecular weight of about 400 to about 500 is selected as the biologically active moiety X of choice, then L may be designed to include a molecular weight of about 3,400. It will be understood that in various embodiments, it is the length of L that is adjusted to match the molecular weight of general formula (I) to the molecular weight of general formula (II). In other embodiments, the molecular weight and / or length of the polymer linker L is selected such that the overall molecular size of the repeating unit represented by general formula (I) is different from the molecular size of the repeating unit represented by general formula (II).

[0139] In various embodiments, the molecular weight of the general formula (I) is equivalent / substantially similar to the molecular weight of the general formula (II). In various embodiments, the molecular weight of the general formula (I) does not differ from the molecular weight of the general formula (II) by more than 30% of the molecular weight of the general formula (II), or vice versa. For example, the molecular weight of the general formula (I) can be up to about 30% more than or up to 30% less than the molecular weight of the general formula (II), or vice versa. The molecular weight of the general formula (I) can not differ from the molecular weight of the general formula (II) by more than about 30%, more than about 25%, more than about 20%, more than about 15%, more than about 10%, more than about 5%, more than about 4%, more than about 3%, more than about 2%, or more than about 1%, or vice versa. In various embodiments, the molecular weight of the general formula (I) does not differ from the molecular weight of the general formula (II) by more than about 20% of the molecular weight of the general formula (II), or vice versa. For example, the molecular weight of the general formula (I) can be up to about 20% more or up to 20% less than the molecular weight of the general formula (II), or vice versa. Advantageously, the repeating unit with the biologically active moiety has a molecular size / weight / length similar to that of the repeating unit with polyethylene, thereby extending the length of the biologically active moiety X, thereby allowing X to be "visible", available for binding to cells or accessible to its target physiological site for the desired biological activity, i.e., not buried in a sea / matrix of polyethylene chains. In other embodiments, the molecular weight of the general formula (I) is not equivalent / substantially similar to the molecular weight of the general formula (II). In various embodiments, the molecular weight of the general formula (I) differs from the molecular weight of the general formula (II) by more than 30% of the molecular weight of the general formula (II), or vice versa. For example, the molecular weight of the general formula (I) can be about 30% more or 30% less than the molecular weight of the general formula (II), or vice versa.The molecular weight of general formula (I) can differ from that of general formula (II) by more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, more than about 55%, more than about 60%, more than about 65%, more than about 70%, more than about 75%, or more than about 80% or vice versa.

[0140] In various embodiments, the molecular weight of general formula (I) is kept below about 50,000, below about 45,000, below about 40,000, below about 35,000, below about 30,000, below about 25,000, below about 20,000, below about 15,000 or below about 10,000. In various embodiments, the molecular weight of general formula (I) is from about 100 to about 15,000, from about 200 to about 14,000, from about 300 to about 13,000, from about 400 to about 12,000, from about 500 to about 11,000, from about 1,000 to about 10,000, from about 1,500 to about 9,500, from about 2,000 to about 9,000, from about 2,500 to about 8,500, from about 3,000 to about 8,000, from about 3,500 to about 7,500, from about 4,000 to about 7,000, from about 4,500 to about 6,500, from about 5,000 to about 6,000 or about 5,500. In various embodiments, when X includes longer peptides containing more than 10 amino acids and the molecular weight of L is about 6,000, then the molecular weight of general formula (I) is greater than about 7,000. In various embodiments, when X includes larger peptides having a molecular weight of about 5,000 or more and the molecular weight of L (e.g., polyethylene glycol) is about 6,000, then the molecular weight of general formula (I) can be up to about 12,000.

[0141] In various embodiments, the molecular weight of general formula (II) is kept below about 50,000, below about 45,000, below about 40,000, below about 35,000, below about 30,000, below about 25,000, below about 20,000, below about 15,000 or below about 10,000. In various embodiments, the molecular weight of general formula (II) is from about 100 to about 15,000, from about 200 to about 14,000, from about 300 to about 13,000, from about 400 to about 12,000, from about 500 to about 11,000, from about 1,000 to about 10,000, from about 1,500 to about 9,500, from about 2,000 to about 9,000, from about 2,500 to about 8,500, from about 3,000 to about 8,000, from about 3,500 to about 7,500, from about 4,000 to about 7,000, from about 4,500 to about 6,500, from about 5,000 to about 6,000 or about 5,500.

[0142] In various embodiments, the total molecular weight of general formula (I) and general formula (II) is kept to about 300,000, about 300,000 or less, about 200,000 or less, about 100,000 or less, about 90,000 or less, about 80,000 or less, about 70,000 or less, about 60,000 or less, about 50,000 or less, about 45,000 or less, about 40,000 or less, about 35,000 or less, about 30,000 or less, about 25,000 or less, about 20,000 or less, or about 15,000 or less to facilitate copolymerization.

[0143] In various embodiments, L is hydrophilic. Because L is adjustable, the hydrophilicity and / or swellability of the repeating unit represented by general formula (I), as well as the overall hydrophilicity and / or swellability of the bioactive polyethylene copolymer, can be adjusted as desired. Advantageously, the presence of L increases the hydrophilicity of the repeating unit represented by general formula (I), as well as the overall hydrophilicity of the bioactive polyethylene copolymer. Even more advantageously, the presence of L increases the hydrophilicity and waxiness of the bioactive polyethylene copolymer, thus softening the highly hydrophobic and crystalline polyethylene chains (for high molecular weight PE), making the copolymer less rigid after processing. In various embodiments, L allows for adjustment of the hydrophilicity of the overall copolymer to provide water uptake. In various embodiments, L also allows for adjustment of the waxiness of the overall copolymer to provide lubricity. It will be understood by those skilled in the art that the bioactive moieties and polyethylene are typically not compatible with each other, since individual bioactive moieties are generally hydrophilic, while polyethylene is generally hydrophobic. It has been advantageously shown that the use of L in the repeating unit represented by general formula (I) can achieve a balance between the hydrophilicity (of the bioactive component) and the hydrophobicity (of the synthetic component, i.e., polyethylene), increasing their compatibility with each other.

[0144] In various embodiments, L is amorphous. Advantageously, the presence of L increases the amorphousness and / or decreases the crystallinity of the bioactive polyethylene copolymer, making it useful for creating softer or less stiff plastics.

[0145] In various embodiments, L is a heteroalkylene having at least 20 carbon atoms, at least 30 carbon atoms, at least 40 carbon atoms, at least 50 carbon atoms, at least 60 carbon atoms, at least 70 carbon atoms, at least 80 carbon atoms, at least 90 carbon atoms, at least 100 carbon atoms, at least 150 carbon atoms, at least 200 carbon atoms, at least 250 carbon atoms, or at least 300 carbon atoms. 20 -C 300 It is a heteroalkylene or a heteroalkylene having from 20 carbon atoms to 300 carbon atoms.

[0146] In various embodiments, L has a number average molecular weight between about 500 and about 7,000. L can have a number average molecular weight of about 600, about 700, about 800, about 900, about 1,000, about 1,500, about 2,000, about 2,500, about 3,000, about 3,500, about 4,000, about 4,500, about 5,000, about 5,500, about 6,000, about 6,500 or about 7,000. In various embodiments, the number average molecular weight of L is from about 1,000 to about 6,000.

[0147] In various embodiments, the heteroatom in L is O. In various embodiments, L is a polyalkylene glycol. In various embodiments, L is a poly(C2-C4 alkylene glycol). L may be selected from the group consisting of polyethylene glycol (PEG), polypropylene glycol (PPG), polytetramethylene glycol (PTMG), polybutylene glycol (PBG), and the like. Advantageously, the use of polyalkylene glycol such as PEG may increase the hydrophilicity of the macromonomer and the resulting copolymer. In various embodiments, polyalkylene glycol such as PEG is used as a spacer, linker, or linking group in the overall polymer, instead of as a terminal group.

[0148] In various embodiments, L is a polyalkylene glycol having at least about 10 repeat units, at least about 15 repeat units, at least about 20 repeat units, at least about 21 repeat units, at least about 22 repeat units, at least about 23 repeat units, at least about 24 repeat units, at least about 25 repeat units, at least about 30 repeat units, at least about 40 repeat units, at least about 50 repeat units, at least about 60 repeat units, at least about 70 repeat units, at least about 80 repeat units, at least about 90 repeat units, at least about 100 repeat units, at least about 150 repeat units, at least about 200 repeat units, or at least about 250 repeat units. In various embodiments, L comprises about 10 monomers / repeat units to about 250 monomers / repeat units. Unlike conventional polymers that use short PEG chains, the bioactive polyethylene copolymer embodiments disclosed herein incorporate long polyalkylene glycol chains of at least 20 repeat units in L.

[0149] In various embodiments, L is PEG. 500 , PEG 600 , PEG 700 , PEG 800 , PEG 900 , PEG 1000 , PEG 1100 , PEG 1200 , PEG 1300 , PEG 1400 , PEG 1500 , PEG 2000 , PEG 2500 , PEG 3000 , PEG 3500 , PEG 4000 , PEG 4500 , PEG 5000 , PEG 6000 and mixtures thereof.

[0150] In various embodiments, X has the following configuration: -R 1-L-NR 3 -C(=O)-X is attached to the poly(norbornene dicarboximide) backbone through the carboxylic acid functionality in X. Advantageously, by linking X through the carboxylic acid functionality, the amine end groups in X are completely free to deliver their bioactivity, thus ensuring the bioavailability of X. It will be appreciated that since the amine groups confer bioactivity, it may not be desirable to use up the amine groups in the bioactive moiety for polymer attachment.

[0151] In various embodiments, X is a peptide / amide bond, i.e., -NR 3 The amide bond is attached to the poly(norbornene dicarboximide) backbone via -C(=O)-. Advantageously, the bioactive polyethylene copolymers disclosed herein are significantly stronger and / or more stable than conventional polymers containing ester bonds. Without being bound by theory, it is believed that the amide bond is stronger than the ester bond because the ester bond is more susceptible to hydrolysis, which can release the bioactive moiety into the bloodstream and lead to premature metabolism of the bioactive moiety.

[0152] In various embodiments, one or more of the H atoms in the alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylcarbonyl and alkylcarbonylalkyl are optionally replaced by hydroxy, hydroxyalkyl, halogen, haloalkyl, cyano, cyanoalkyl and nitro.

[0153] In various embodiments, R 1 is C1-C 20 Alkyl is selected from C1-C 20Alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, hexyl, amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, R may be a straight chain or branched substituent selected from 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, 2-ethylpentyl, 3-ethylpentyl, heptyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 5-methylheptyl, 1-methylheptyl, octyl, nonyl, decyl, and the like. 1 may be a straight chain or branched C1-C4 alkyl substituent. In various embodiments, R 1 The length of R is the same as the length of the repeat unit in L. For example, if L is poly(butylene glycol), then R 1 is butyl. In another example, when L is poly(ethylene glycol), then R 1 is ethyl. In various embodiments, R 1 It will be appreciated that is carefully designed to match L.

[0154] In various embodiments, R 3 , H, C1-C 20 Alkyl, C2-C 20 Alkenyl or C2-C 20 alkynyl.

[0155] In various embodiments, Z 1 and Z 2 are each independently a Rb , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl. The poly(norbornene) backbone may be selected from the group consisting of poly(norbornene-imide), poly(norbornene-dicarboximide), poly(5-norbornene-2,3-dicarboximide), poly(7-oxanorbornene), poly(oxanorbornene-imide), poly(oxanorbornene-dicarboximide), and the like. In various embodiments, Z 1 and Z 2 are each independently a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently H, C1-C 20 Alkyl, C1-C 20 Alkenyl and C1-C 20 In various embodiments, Z is selected from the group consisting of alkynyl. 1 is CH2. In various embodiments, Z 2 is CH2.

[0156] In various embodiments, X comprises a biologically active moiety selected from a protein, a peptide, a carbohydrate, a therapeutic / drug molecule and a derivative thereof. In various embodiments, the protein, peptide, carbohydrate or therapeutic / drug molecule or a derivative thereof comprises a protein, peptide, carbohydrate or therapeutic / drug molecule that is optionally modified or modified to contain one carboxylic acid terminal group. In some embodiments, the biologically active moiety contains only one carboxylic acid terminal group.

[0157] In various embodiments, the biologically active moiety comprises monocarboxylic acid.Advantageously, the use of a biologically active moiety with a monocarboxylic acid end group avoids the possibility of undesired cross-linking that may otherwise occur when there are two or more carboxylic acids.Accordingly, in various embodiments, the biologically active moiety X is substantially free of two or more carboxylic acid end groups, for example, dicarboxylic acid or tricarboxylic acid.

[0158] In various embodiments, X comprises a protein or peptide. X can be a peptide sequence, a laminin-derived peptide, an integrin-binding peptide, a cell-penetrating peptide, a collagen sequence, a collagen mimetic or a collagen mimetic peptide or a collagen fragment. In various embodiments, X comprises 2 to 50 amino acid residues, 2 to 40 amino acid residues, or 2 to 20 amino acid residues of any sequence. In various embodiments, X comprises 7 amino acid residues, including 50 amino acid residues, 40 amino acid residues, 30 amino acid residues, 25 amino acid residues, 20 amino acid residues, 15 amino acid residues, 10 amino acid residues, 9 amino acid residues, 8 amino acid residues, 6 amino acid residues, 5 amino acid residues, 4 amino acid residues, or 3 amino acid residues of any sequence. The amino acid residues may be selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, asparagine, glutamine, glycine, serine, threonine, serine, asparagine, glutamine, tyrosine, cysteine, lysine, arginine, histidine, aspartic acid and glutamic acid. In various embodiments, X is a peptide sequence comprising 3 to 20 natural amino acids. X may be an integrin-binding peptide selected from the group consisting of arginine-glycine-aspartic acid (RGD), SRGDS and RGDS; a laminin-derived peptide A5G81 (AGQWHRVSVRWGC); an osteopontin-derived peptide SVVYGLR; a cell-permeable / antimicrobial peptide selected from IRIK or (IRIK)2 or (IKKI)3. In various embodiments, X is a collagen sequence containing 3 to 20 units of glycine (G), proline (P) and hydroxyproline (Hyp) in any sequence or permutation. X is (PHypG) n Type sequence, (PGHyp) n Type Array, (HypGP) n Type Array, (HypPG) n Type sequence, (GHypP) n Type array, (GPHyp) nThe collagen fragment may have a type sequence or a collagen mimetic DGEA.

[0159] In various embodiments, X comprises a carbohydrate. In various embodiments, X comprises a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide. In various embodiments, X comprises 2 to 50 saccharide units, 2 to 40 saccharide units, 2 to 20 saccharide units, or 10 to 14 saccharide units. In various embodiments, X comprises 50 saccharide units, 40 saccharide units, 30 saccharide units, 25 saccharide units, 20 saccharide units, 15 saccharide units, 14 saccharide units, 13 saccharide units, 12 saccharide units, 11 saccharide units, 10 saccharide units, 9 saccharide units, 8 saccharide units, 7 saccharide units, 6 saccharide units, 5 saccharide units, 4 saccharide units, or 3 saccharide units, or 2 saccharide units. X can be heparan sulfate (HS) or glycosaminoglycan (GAG). In various embodiments, X is a heparin oligosaccharide selected from the group consisting of DP8, DP10, DP12, DP14 and DP 16. In various embodiments, X is hyaluronic acid, the simplest form of glycosaminoglycan (GAG).

[0160] In various embodiments, X is chemically linked to the remainder of general formula (I) via its hydroxy group. For example, when X is a carbohydrate / sugar, oxidation and / or reductive amination reactions can be carried out on the hydroxy of the carbohydrate to link X to general formula (I). The -CH2OH on the sugar can be oxidized to -C(=O)H, which subsequently undergoes reductive amination using the -NH2 terminus on L to create a peptide bond.

[0161] In various embodiments, X comprises a carbohydrate / sugar that contains or has been modified to contain a carboxylic acid end group. Modification by one or more chemical reactions, such as oxidation, may be performed on the carbohydrate / sugar to create a carboxylic acid group. In various embodiments, the modification is performed on a hydroxyl group originally present in the carbohydrate / sugar. In various embodiments, the -CH2OH on the carbohydrate / sugar is completely oxidized to -C(=O)OH, which subsequently reacts with the -NH2 terminus on L to create a peptide bond linking the carbohydrate / sugar to the remainder of general formula (I): XC(=O)-NH-L-. However, it will be understood that if a carboxylic acid is naturally present in the carbohydrate / sugar, no modification to the carbohydrate / sugar is / may not be required.

[0162] In various embodiments, X comprises a therapeutic / drug molecule. In various embodiments, X comprises an antibiotic, an antimicrobial, an antibacterial, a blood thinner, or an anti-inflammatory. X can be penicillin, amoxicillin, amphotericin, ciprofloxacin (CIF), atorvastatin, aspirin, or an aminoglycoside molecule selected from streptomycin, ribostamycin, or gentamicin. It will be understood that X can be any therapeutic or drug molecule that contains a carboxylic acid group.

[0163] In various embodiments, X is chemically bonded to the remainder of general formula (I) through one of its chemical moieties selected from the group consisting of -COOH, -CHOH, -CHNH and =CHNH. For example, -CHNH or =CHNH on a drug molecule may be bonded to a small dicarboxylic acid before reacting with the -NH terminus on L to create a peptide bond linking the drug molecule to the remainder of general formula (I): XC(=O)-NH-L-.

[0164] In various embodiments, X comprises a therapeutic / drug molecule that contains or has been modified to contain a carboxylic acid end group. Modification by one or more chemical reactions, such as oxidation, may be performed on the therapeutic / drug molecule to create a carboxylic acid group. In various embodiments, the modification is performed on a hydroxyl group that is originally present in the therapeutic / drug molecule. For example, in various embodiments, when X is ribostamycin or gentamicin, the -CH2OH on the drug molecule is completely oxidized to -C(=O)OH, which subsequently reacts with the -NH2 terminus on L to create a peptide bond that links the drug molecule to the remainder of general formula (I): XC(=O)-NH-L-. However, it will be understood that if a carboxylic acid is already present in the therapeutic / drug molecule, no modification to the therapeutic / drug molecule may be required / necessary.

[0165] In various embodiments, the biologically active moiety is modified or has been modified to contain one carboxylic acid end group.For example, if no carboxylic acid end group is present in the carbohydrate or therapeutic / drug molecule, the carbohydrate or therapeutic / drug molecule can be modified to add a carboxylic acid to one of the termini of the carbohydrate or therapeutic / drug molecule.The modification can include an oxidation reaction to convert a hydroxy group in the carbohydrate to a carboxylic acid.

[0166] In various embodiments, the repeat unit represented by general formula (I) is present in an amount of about 1 mol% to about 100 mol%, about 2 mol% to about 99 mol%, about 3 mol% to about 98 mol%, about 4 mol% to about 97 mol%, about 5 mol% to about 96 mol%, about 10 mol% to about 95 mol%, about 15 mol% to about 90 mol%, about 20 mol% to about 85 mol%, about 25 mol% to about 80 mol%, about 30 mol% to about 75 mol%, about 35 mol% to about 70 mol%, about 40 mol% to about 65 mol%, about 45 mol% to about 60 mol%, or about 50 mol% to about 55 mol% relative to the copolymer. In various embodiments, the repeat unit represented by general formula (I) is present in an amount of about 1 mol% to about 10 mol% relative to the copolymer. In various embodiments, the bioactive moiety is about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, or about 10 mol% of the bioactive polyethylene copolymer. In some embodiments, the repeating units represented by general formula (I) are present in an amount of about 10 mol% or less relative to the copolymer. It will be appreciated that in some embodiments, the bioactive moiety is relatively insoluble in non-polar solvents, making it difficult to include more than 10% of general formula (I) in the copolymer without using a large excess of general formula (I), which would be expensive to manufacture.

[0167] In various embodiments, R 2 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl or C3-C 20 alkylcarbonylalkyl. C1-C 20Alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, hexyl, amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2 The substituents may be straight chain or branched and selected from 1,2,3-trimethylpropyl, 2-ethylpentyl, 3-ethylpentyl, heptyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 5-methylheptyl, 1-methylheptyl, octyl, nonyl, decyl, and the like.

[0168] In various embodiments, the ratio of the number of repeat units represented by general formula (I) to the number of repeat units represented by general formula (II) in the bioactive polyethylene copolymer is from about 1:1 to about 1:100, from about 1:2 to about 1:99, from about 1:3 to about 1:98, from about 1:4 to about 1:97, from about 1:5 to about 1:96, from about 1:6 to about 1:95, from about 1:7 to about 1:90, from about 1:8 to about 1:85, from about 1:9 to about 1:80, from about 1:10 to about 1:75, from about 1:15 to about 1:70, from about 1:20 to about 1:65, from about 1:25 to about 1:60, from about 1:30 to about 1:55, from about 1:35 to about 1:50, or from about 1:40 to about 1:45. In various embodiments, the ratio of the number of repeating units represented by general formula (I) to the number of repeating units represented by general formula (II) in the bioactive polyethylene copolymer is about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45 or about 1:50.

[0169] In various embodiments, the number of repeat units represented by general formula (I) in the copolymer is from about 10 to about 1,000. In various embodiments, the number of repeat units represented by general formula (II) in the copolymer is from about 10 to about 1,000.

[0170] In various embodiments, the bioactive polyethylene copolymer has a number average molecular weight (Mn) of about 2,000 to about 300,000, about 3,000 to about 200,000, about 4,000 to about 150,000, about 5,000 to about 100,000, about 10,000 to about 90,000, about 20,000 to about 80,000, about 30,000 to about 70,000, about 40,000 to about 60,000, or about 50,000.

[0171] In various embodiments, the bioactive synthetic copolymer has a polydispersity index (PDI) of about 1.0 to about 10.0. In various embodiments, the PDI of the bioactive synthetic copolymer is about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5 or about 10.0. In various embodiments, the bioactive polyethylene copolymer has a polydispersity index (PDI) of about 1.0 to about 3.0, about 1.05 to about 2.95, about 1.1 to about 2.9, about 1.2 to about 2.8, about 1.4 to about 2.6, about 1.6 to about 2.4, about 1.8 to about 2.2 or about 2.0. In various embodiments, the bioactive polyethylene copolymer has a PDI of 1.50 or less.

[0172] In various embodiments, one or more repeat units represented by general formula (I) and one or more repeat units represented by general formula (II) are designed to be linked to the poly(norbornene) backbone at least via covalent interactions. In various embodiments, each repeat unit represented by general formula (I) is covalently attached to the poly(norbornene) backbone and / or each repeat unit represented by general formula (II) is covalently attached to the poly(norbornene) backbone. Advantageously, since the bioactive moiety (in general formula (I)) is covalently attached to the bioactive polyethylene polymer, the bioactivity is localized. In various embodiments, the bioactive moiety, such as a biomolecule, does not leach out of the polymer, thus preventing undesirable / unwanted side effects caused by the biomolecule entering the circulatory system and / or reaching unintended parts of the body system. The bioactive polyethylene copolymer embodiments thus overcome the problems faced by conventional biomolecules administered as drugs that may be prematurely metabolized before a therapeutic effect is achieved. In various embodiments, the biologically active moieties, such as drug molecules, do not leach into the medium that may leak into the environment if disposal is improperly managed.

[0173] It will be appreciated that other interactions, such as van der Waals interactions, may also be present within the copolymer.

[0174] In various embodiments, the bioactive polyethylene copolymer comprises a brush, bottle-brush, block, comb, or graft copolymer structure. In various embodiments, the repeat units may be randomly distributed / arranged within the polymer.

[0175] In various embodiments, one or more repeat units represented by general formula (I) contain two or more different types of biologically active moieties X. In various embodiments, one or more repeat units represented by general formula (I) contain 2, 3, 4, 5, 6, 7 or 8 different types of biologically active moieties X. For example, within a bioactive polyethylene copolymer, there may be a repeat unit represented by general formula (I) that contains a peptide as X and a repeat unit represented by general formula (I) that contains a carbohydrate as X. Advantageously, in various embodiments, the bioactive polyethylene copolymer confers two or more different types of biological activity.

[0176] In various embodiments, the bioactive polyethylene copolymer is a random polymer or a block copolymer.In some embodiments, the block polymer is a diblock or triblock polymer.For example, the copolymer can have or be composed of two or three different polymer blocks.In some embodiments, the multiblock copolymer comprises more than three polymer blocks.The blocks can be randomly distributed / arranged within the polymer.

[0177] In various embodiments, the bioactive polyethylene copolymer is selected from one of the following: (GPHyp)3 in general formula (I) and (SA-t-PE) comprising succinic acid terminated polyethylene in general formula (II). p -[(GPHyp)3] q copolymers; SA-t-PE-RGD copolymers comprising RGD in general formula (I) and succinic acid terminated polyethylene in general formula (II); and amine terminated PE-RGD copolymers comprising RGD in general formula (I) and amine terminated polyethylene in general formula (II).

[0178] Advantageously, the bioactive polyethylene copolymers disclosed herein are highly customizable. Depending on the intended application of the bioactive polyethylene copolymer, X with the desired bioactivity can be selected and combined with Y with the desired physical attributes to finally obtain a bioactive polyethylene copolymer with the desired repeating units represented by the general formulas (I) and (II). For example, for stents that face the problem of biofouling, antimicrobial peptides can be incorporated into the stent material to target biofouling. For joint implants (e.g. knee joint implants), polyethylene can be made more biocompatible by incorporating peptides that bind to integrins for cartilage regeneration, such as RGD peptides, or oligosaccharides that mimic the cartilage environment and promote the attachment of chondrocytes. Some possible oligosaccharides can include hyaluronic acid fragments and sulfated sugars.

[0179] In various embodiments, the bioactive polyethylene copolymer is blended with a base polymer for further use. In various embodiments, the base polymer is similar or of the same type as the synthetic polymer Y used in general formula (II). For example, the base polymer can be a polyalkylene / polyolefin, such as polyethylene, ultra-high molecular weight polyethylene, polypropylene, copolymers of ethylene and α-olefins. In various embodiments, a medical grade polymer is used for the substrate, while low molecular weight polyethylene is used in the synthetic side chain of the bioactive polyethylene copolymer. Advantageously, the embodiment of the bioactive polyethylene polymer allows biomolecules to be blended into the base material, which is similar to the polyethylene side arm of the copolymer, without phase separation. Advantageously, in various embodiments, the hydrophilic PEG chains are well dispersed in / within the copolymer structure, thus obtaining better blending results when blending synthetic polyethylene (PE)-peptide copolymer with hydrophobic base material.

[0180] In various embodiments, the following copolymers: A) General formula (III-1):

[0181] [ka]

[0182] (In the formula, A is N or NR c where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; the dotted line represents an optional chemical bond; n is 10 to 350;

[0183] B) General formula (VIII-1):

[0184] [ka]

[0185] (In the formula, R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; Z 2 CR a R b , O, N.R. c , SiR a Rb , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; A is N or NR c where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; the dotted line represents an optional chemical bond; n is 10 to 350); and

[0186] C) A copolymer derived from an intermediate described in the process for preparing a polyethylene polymer disclosed herein, the process comprising: (i) General formula (IX):

[0187] [ka]

[0188] (In the formula, Z 2 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b, and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and (ii) reacting said dicarboxylic anhydride having general formula (IX) with an amine to obtain a polyethylene polymer, wherein the amine has general formula (X-1):

[0189] [ka]

[0190] (In the formula, R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; A is N or NR c where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; the dotted line represents an optional chemical bond; and n is 10 to 350) Copolymers including is also provided.

[0191] In various embodiments, copolymers A)-C) have desirable properties similar to the other copolymers disclosed herein.

[0192] In various embodiments, the bioactive polyethylene copolymers comprising general formula (III-1) have the same desirable characteristics as the bioactive polyethylene copolymers comprising general formula (III).

[0193] In various embodiments, bioactive polyethylene copolymers prepared from polyethylene polymers represented by general formula (VIII-1) have desirable characteristics similar to those of bioactive polyethylene copolymers prepared from polyethylene polymers represented by general formula (VIII).

[0194] In various embodiments, bioactive polyethylene copolymers derived from amines represented by general formula (X-1) have desirable characteristics similar to those of bioactive polyethylene copolymers derived from amines represented by general formula (X).

[0195] method A method for preparing a bioactive polyethylene copolymer is provided, the method comprising: polymerizing one or more bioactive polymers represented by general formula (IV) with one or more polyethylene polymers represented by general formula (V) to obtain a bioactive polyethylene copolymer:

[0196] [ka]

[0197] (In the formula, R 1 is optionally substituted alkyl; R 2is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; R 3 is selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; L is heteroalkylene; X comprises a biologically active moiety selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof; Y comprises polyethylene; and Z 1 and Z 2 are each independently a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0198] Advantageously, in various embodiments, the methods for preparing bioactive polyethylene copolymers disclosed herein are also modular methods for designing bioactive polyethylene copolymers.

[0199] Also provided is a modular method for designing bioactive polyethylene copolymers, comprising: selecting one or more polymers from a first module based on a desired biological activity, the first module consisting of a library of norbornene dicarboximide-containing bioactive polymers represented by general formula (IV) having known biological activity; selecting one or more polymers from a second module based on a desired physical attribute, the second module consisting of a library of norbornene dicarboximide-containing polyethylene polymers represented by general formula (V) having known physical attributes; and polymerizing the one or more polymers selected from the first module with the one or more polymers selected from the second module to obtain a bioactive polyethylene copolymer.

[0200] [ka]

[0201] Advantageously, the methods disclosed herein allow for rapid customization and rapid development / construction of bioactive polyethylene copolymers with desired bioactivity and physical properties.

[0202] In various embodiments, the polymerization reaction comprises one or more olefin metathesis chain-growth polymerization steps. The olefin metathesis chain-growth polymerization can be ring-opening metathesis polymerization (ROMP). In various embodiments, the ROMP reaction occurs at the reactive portion of the macromonomer, for example, at the olefin / alkene / C=C portion. ROMP can include many different approaches, including "arm-first" ROMP, "brush-first" ROMP, "graft-to" ROMP, "graft-from" ROMP, "graft-through" ROMP, or combinations thereof. Advantageously, ROMP allows for the rapid development / construction of well-defined polyethylene polymers with desired biological activity. In various embodiments, depending on the target application, a biomolecule with the desired biological activity represented by general formula (I) can be selected and copolymerized together with the polyethylene represented by general formula (II) using ROMP.

[0203] In various embodiments, the polymerization reaction is carried out in the presence of a polymerization initiator / catalyst / accelerator. In various embodiments, the polymerization initiator / catalyst / accelerator comprises a metal complex. The metal complex can be a ruthenium, molybdenum or tungsten complex. In various embodiments, the ROMP is carried out in the presence of a ruthenium complex. Advantageously, compared to other transition metals (e.g., W and Mo), Ru is more stable in the presence of polar functional groups, thereby making Ru a suitable olefin metathesis catalyst for ROMP reactions involving biologically active moieties selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules and their derivatives. In various embodiments, Ru is commercially available on a large scale while being air-stable (i.e., stable in air) and thermally stable (i.e., stable at high temperatures), which allows the ROMP to be carried out at high temperatures. The ruthenium complex can comprise a Grubbs catalyst selected from a first generation Grubbs catalyst, a second generation Grubbs catalyst, a Hoveyda-Grubbs catalyst, a third generation Grubbs catalyst or derivatives thereof.

[0204] In various embodiments, R 1, R 2 , R 3 , L, X, Y, Z 1 and Z 2 contains one or more features and / or shares one or more properties that are similar to those described above.

[0205] In various embodiments, the polymerization reaction includes: a) mixing one or more bioactive polymers represented by general formula (IV) with one or more polyethylene polymers represented by general formula (V) to obtain a solution; b) adding a catalyst to the solution from a); and c) precipitating the bioactive polyethylene copolymer.

[0206] In various embodiments, the polymerization reaction involves mixing one or more bioactive polymers represented by general formula (IV) with one or more polyethylene polymers represented by general formula (V) in a ratio of about 1:1 to about 1:10. In various embodiments, one or more bioactive polymers represented by general formula (IV) are added to one or more polyethylene polymers represented by general formula (V) in a ratio of about 1:5.

[0207] In various embodiments, step a) and / or step b) are carried out or tackled at a temperature ranging from about 20° C. to about 180° C. In various embodiments, step a) and / or step b) are carried out or tackled at a temperature just below the boiling point of the solvent used, for example, the boiling point of 1,2-dichlorobenzene. The temperature at which step a) and step b) are carried out may be independently selected from temperatures of about 20° C., about 25° C., about 30° C., about 35° C., about 40° C., about 50° C., about 60° C., about 70° C., about 80° C., about 90° C., about 100° C., about 110° C., about 120° C., about 130° C., about 140° C., about 150° C., about 160° C., about 170° C., or about 180° C. In various embodiments, high temperature reaction conditions are required when dealing with higher molecular weight polyethylene (PE).

[0208] In various embodiments, step a) and / or step b) are performed or engaged for a period ranging from about 30 minutes to about 3 days. The period for performing step a) and step b) may be independently selected from a period of about 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 20 hours, 1 day, 2 days, or 3 days.

[0209] In various embodiments, step a) and / or step b) are carried out in the presence of an organic solvent. In various embodiments, the organic solvent for step a) and step b) is a non-polar solvent independently selected from the group consisting of benzene, toluene, dichlorobenzene, etc., and combinations thereof. In various embodiments, non-polar solvents such as benzene and / or toluene may be used, especially for PE-based materials. In various embodiments, the organic solvent used is the same for steps a) and b). It should be understood that the type of solvent used depends on the type of reactants used and is not limited to the above. In some embodiments, benzene can dissolve general formula (I) and (II) at high temperatures compared to toluene.

[0210] In various embodiments, step c) is carried out in a mixture of organic solvents. The mixture of organic solvents may contain one or more aprotic organic solvents and one or more protic organic solvents. In various embodiments, the mixture of organic solvents for step c) is selected from the group consisting of tetrahydrofuran (THF), benzene, toluene, acetonitrile (ACN), dichloromethane (DCM), dimethylsulfoxide (DMSO), acetone, methyl ethyl ketone (MEK), ethyl vinyl ether, methanol, ethanol, butanol, etc., and combinations thereof. It should be understood that the type of solvent used depends on the type of reactants used and is not limited to the above. In various embodiments, ethyl vinyl ether is used to quench the catalyst added in step b). Only a few drops of ethyl vinyl ether may be added / used. In various embodiments, step c) is carried out by adding a large amount of a protic solvent, such as methanol, into the reaction mixture obtained from steps a) and b).

[0211] Advantageously, by conducting the polymerization under the above carefully designed / controlled conditions, embodiments of the methods disclosed herein successfully overcome the widely varying and / or opposing properties of the individual components (e.g., L, X, Y components) to construct the bioactive polyethylene copolymers disclosed herein.

[0212] Also provided is a method for preparing a bioactive homopolymer, the method comprising: polymerizing one or more bioactive macromolecules represented by general formula (IV) to obtain a bioactive synthetic homopolymer:

[0213] [ka]

[0214] (In the formula, R 1 is optionally substituted alkyl; R 3is selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; L is heteroalkylene; X comprises a biologically active moiety selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules, and derivatives thereof; and Z 1 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0215] Also provided is a method for preparing a polyethylene homopolymer, the method comprising: polymerizing one or more polyethylene polymers represented by general formula (V) to obtain a polyethylene homopolymer:

[0216] [ka]

[0217] (In the formula, R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; Y comprises polyethylene; and Z 2 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b and R care each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0218] bioactive polymer Also provided is a bioactive polymer for preparing the copolymers disclosed herein, represented by the general formula (IV):

[0219] [ka]

[0220] (In the formula, R 1 is optionally substituted alkyl; R 3 is selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; L is heteroalkylene; X comprises a biologically active moiety selected from proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof; and Z 1 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

[0221] In various embodiments, R 1 , R 3 , L, X and Z 1 contains one or more features and / or shares one or more properties similar to those already described above.

[0222] In various embodiments, the bioactive polymer undergoes self-polymerization or copolymerization, in various embodiments of which the bioactive polymer also behaves as a bioactive macromonomer.

[0223] In various embodiments, X has the following configuration: -R 1 -L-NR 3 -C(=O)-X is linked to norbornene dicarboximide through a carboxylic acid functionality. Advantageously, by linking X through a carboxylic acid functionality, the amine end group in X is completely free to deliver its bioactivity, thus ensuring the bioavailability of X. It will be appreciated that since the amine group confers bioactivity, it may not be desirable to use up the amine groups in the bioactive moiety for polymer attachment.

[0224] In various embodiments, X is a peptide / amide bond, i.e., -NR 3 The linkage is to norbornene dicarboximide via -C(=O)-. Advantageously, the bioactive polymers disclosed herein are significantly stronger and / or more stable than conventional polymers containing ester bonds. Without being bound by theory, it is believed that amide bonds are stronger than ester bonds because ester bonds are more susceptible to hydrolysis, which can release the bioactive moiety into the bloodstream and lead to early metabolism of the bioactive moiety.

[0225] Also provided is a method for preparing a bioactive polymer disclosed herein, comprising: (i) a compound of general formula (VI):

[0226] [ka]

[0227] (In the formula, Z 1 CR a R b , O, N.R. c , SiR a R b , P.R.a or S, where R a , R b and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; (ii) reacting said dicarboxylic anhydride having the general formula (VI) with a diamine R 4 R 3 NLR 1 -NH2 to form a compound of the general formula (VII):

[0228] [ka]

[0229] (In the formula, R 1 is optionally substituted alkyl; R 3 and R 4 are each independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, where R 3 and R 4 at least one of is H; L is heteroalkylene; Z 1 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and (iii) reacting said amine having general formula (VII) with an acid-containing biologically active moiety XC(=O)OH to obtain a biologically active macromolecule, where X comprises a biologically active moiety selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof.

[0230] In various embodiments, R 1 , R 3 , L, X and Z 1 contains one or more features and / or shares one or more properties that are similar to those described above.

[0231] In various embodiments, R 3 and R 4 are each independently H, C1-C 20 Alkyl, C2-C 20 Alkenyl or C2-C 20 alkynyl, where R 3 and R 4 At least one of is H.

[0232] In various embodiments, step (ii) comprises providing a diamine R for attaching X to the norbornene dicarboxylic anhydride. 4 R 3 NLR 1 The diamines used may be commercially available. Advantageously, the method is a simple reaction and does not require poly(ethylene glycol) amino carboxylic acids, which are not commercially available and are difficult to prepare synthetically. In various embodiments, the method therefore does not require tedious multi-step and / or low-yield synthetic procedures. In various embodiments, the diamine R 4 R 3 NLR 1 -NH2 is an amine having the general formula (VII) bonded to norbornene dicarboximide on the two ends (otherwise diamine R 4 R 3 NLR 1 Use a slight excess to ensure that the -NH2 will be the linker instead of the terminal group.

[0233] In various embodiments, the diamine is a poly(ethylene glycol) diamine, where L is poly(ethylene glycol).

[0234] In various embodiments, the method further comprises purifying the amine having general formula (VII) to isolate the product and / or remove impurities prior to step (iii). In various embodiments, the purification step comprises washing with at least one of an acid or a base. The purification step may comprise washing with at least one of an acid or a base at least once, at least twice, at least three times, at least four times, at least five times, at least six times, at least seven times, or at least eight times to neutralize the amine having general formula (VII). In various embodiments, the purification step comprises a double neutralization step. In one embodiment, the double neutralization is carried out to remove unreacted diamine R. 4 R 3 NLR 1 The method includes a first step of washing with an acid to remove -NH2 and a second step of washing with a base to neutralize the amine having the general formula (VII). 4 R 3 NLR 1It will be appreciated that since -NH2 is basic, adding an acid to the diamine will neutralize the diamine for removal from the amine having general formula (VII). It will also be appreciated that a first step of washing with an acid may protonate the amine having general formula (VII) at the amine end, but a subsequent second step of washing with a base or excess base will convert the protonated form to its free amine form. The acid used for the first neutralization step may be selected from the group consisting of HCl, HNO3, H2SO4, and H3PO4. The base used for the second neutralization step may be selected from the group consisting of NaOH, KOH, NH4OH, and Ca(OH)2. In various embodiments, the second neutralization step includes washing with a base at least once, at least twice, at least three times, or at least four times to fully extract the amine having general formula (VII) for maximized yield. In one embodiment, the second neutralization includes washing with a base twice. Without being bound by theory, it is believed that up to 30% of the protonated form of the amine having general formula (VII) may be present in the aqueous phase during extraction. In various embodiments, the step of washing with base thus includes washing the aqueous phase once with base and washing the organic phase once with base to completely extract the amine having general formula (VII) from both the aqueous and organic phases. Advantageously, by using a double neutralization step after coupling to obtain free amine ends, the method eliminates the need for any additional steps, such as a protection / deprotection step. It will be understood by those skilled in the art that the use of diamines, particularly polyethylene glycol diamines, is extremely difficult and typically requires protection of one amine end to couple to norbornene dicarboxylic anhydride. Indeed, in various embodiments, polyalkylene glycols such as PEG are used as spacers, linkers or linking groups in the entire polymer instead of as terminal groups. That is, it may seem intuitive to consider protecting one amine end of the PEG diamine and coupling it to norbornene dicarboxylic anhydride. The protecting group can then be removed to expose the amine terminus for further reactions.However, this would add an extra step to the reaction and therefore may not be desirable. Embodiments of the present disclosure successfully overcome this problem in the synthesis and purification process by performing a double neutralization step after conjugation to provide a free amine terminus for further conjugation to the peptide.

[0235] Polyethylene Polymer Also provided are polyethylene polymers represented by general formula (VIII) for preparing the copolymers disclosed herein.

[0236] [ka]

[0237] In various embodiments, the polyethylene polymer has the general formula (VIII-1):

[0238] [ka]

[0239] It is represented by:

[0240] In various embodiments, in general formula (VIII-1), A is present while B is absent. In such embodiments, the polyethylene polymer has the general formula (VIII-2):

[0241] [ka]

[0242] It is represented by:

[0243] In various embodiments, the polyethylene polymer has the following general formula (VIIIa), (VIIIb), or (VIIIc):

[0244] [ka]

[0245] It can be represented by one of the following:

[0246] In various embodiments, Z 2 , R 2 , R 6a , R 6d , R 7a , R c , A, B, R 5 and T contain one or more features and / or share one or more properties similar to those already described above.

[0247] Also provided is a method for preparing the polyethylene polymer disclosed herein, comprising: (i) providing a polyethylene polymer having general formula (IX):

[0248] [ka]

[0249] (In the formula, Z 2 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and (ii) reacting said dicarboxylic anhydride having general formula (IX) with an amine to obtain a polyethylene polymer, wherein the amine has general formula (X):

[0250] [ka]

[0251] (In the formula, R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; A is NR c where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 alkylcarbonylalkyl; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is 10 to 350) Includes.

[0252] In various embodiments, the amine has the general formula (X-1):

[0253] [ka]

[0254] It is represented by:

[0255] In various embodiments, in general formula (X-1), A is present while B is absent. In such embodiments, the amine has the general formula (X-2):

[0256] [ka]

[0257] It is represented by:

[0258] In various embodiments, the general formula (X) has the following general formula (Xa), (Xb) or (Xc):

[0259] [ka]

[0260] (In the formula, R 2 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; R 5 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 alkylcarbonylalkyl; R 6a and R 6d are independently C, CR a , C.R. a R b , N, N.R. c , O or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 7a are =O, =S, -F, -Cl, -Br, -I, =CR a Rb , -CR a R b R c , -OH, -SH, -NH2 or =NR c optionally present as T is a terminal group selected from the group consisting of hydrogen and methyl.

[0261] In various embodiments, the method further comprises, prior to step (ii), (ai) General formula (XIa) or (XIb):

[0262] [ka]

[0263] (In the formula, R 6a and R 6d are independently C, CR a , C.R. a R b , N, N.R. c , O or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 7a are =O, =S, -F, -Cl, -Br, -I, =CR a R b , -CR a R b R c , -OH, -SH, -NH2 or =NR c Optionally present as; R 8 and R 9 are each independently 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C20 Alkylcarbonyl and C3-C 20 alkylcarbonylalkyl; and T is an end group selected from the group consisting of hydrogen and methyl; and (bi) reacting said polyethylene having the general formula (XIa) or (XIb) with a diamine HN-R 2 -NH2 or ammonia NH3 to obtain an amine having the general formula (X) Includes.

[0264] In various embodiments, -A=R in general formula (X-1) or (X-2) 5 The bond is a polyethylene having the general formula (XIb) (e.g., PE-aldehyde or PE-CHO) bonded to H2N-R 2 -It is produced by reacting with NH2.

[0265] Also provided is a method for preparing a polyethylene polymer represented by general formula (VIII-1) or (VIII-2), comprising: (i) General formula (XIb):

[0266] [ka]

[0267] (In the formula, R 9 is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C1-C 20 Alkoxy, C1-C 20 Alkoxyalkyl, C2-C 20 Alkylcarbonyl and C3-C 20 and T is an end group selected from the group consisting of hydrogen and methyl; and (ii) reacting said polyethylene having general formula (XIb) with norbornene dicarboximide containing pendant NH to obtain a polyethylene polymer, wherein norbornene dicarboximide has general formula (XII):

[0268] [ka]

[0269] (In the formula, R 10 is selected from a single bond, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyalkyl, optionally substituted alkylcarbonyl, or optionally substituted alkylcarbonylalkyl; and Z 2 CR a R b , O, N.R. c , SiR a R b , P.R. a or S, where R a , R b , and R c are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl. Includes.

[0270] In various embodiments, at least one of steps (ii) and (bi) is carried out in the presence of an organic solvent and / or a base.

[0271] In various embodiments, step (ii) and / or step (bi) are carried out in the presence of an organic solvent. The organic solvent can be a non-polar solvent. In various embodiments, the organic solvent for step (ii) and / or step (bi) is an aromatic solvent such as toluene. Advantageously, in various embodiments, the removal of water from the condensation reaction is more efficient when toluene is used as the solvent. In various embodiments, a non-polar solvent such as benzene, toluene, p-xylene, tetralin or decalin can be used. In various embodiments, the organic solvent for step (ii) and / or step (bi) is a halogenated solvent. The halogenated solvent can be a chlorinated solvent such as dichlorobenzene. In various embodiments, the organic solvent used is the same for steps (ii) and (bi). It should be understood that the type of solvent used depends on the type of reactants used and is not limited to the above.

[0272] In various embodiments, step (ii) and / or step (bi) are carried out in the presence of a base. The base can be an organic base selected from a tertiary amine or pyridine. In various embodiments, the tertiary amine is selected from triethylamine.

[0273] In various embodiments, step (ii) and / or step (bi) are carried out or undertaken at a temperature ranging from about 80° C. to about 200° C. The temperature at which step (ii) and step (bi) are carried out may be independently selected from temperatures of about 80° C., about 90° C., about 100° C., about 110° C., about 120° C., about 130° C., about 140° C., about 150° C., about 160° C., about 170° C., about 180° C., about 190° C., or about 200° C.

[0274] In various embodiments, step (ii) and / or step (bi) are performed or engaged for a period of time ranging from about 30 minutes to about 3 days. The period of time for performing step (ii) and step (bi) may be independently selected from the following periods: about 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 20 hours, 1 day, 2 days, or 3 days.

[0275] Materials containing bioactive polyethylene copolymers Also provided is a material comprising the copolymer disclosed herein for use in medicine.In various embodiments, the material is part of or used on a device selected from the group consisting of consumer care products such as diapers and sanitary products, wound dressings, skin scaffolds, bone scaffolds, bone and bone marrow organoid scaffolds, implants such as joint implants and cartilage implants, medical devices such as intestinal stents.For example, the material can be a scaffold, wound dressing or medical device for tissue regeneration comprising the bioactive polyethylene copolymer disclosed herein.The material can be a material suitable for increasing the biocompatibility of polyethylene used in medical devices through stimulation of collagen production.The material can be a material suitable for promoting wound healing.The material can be a material for skin tissue regeneration (by incorporating a bioactive moiety such as RGD or collagen).The material can be a knee joint implant for cartilage regeneration (by incorporating a bioactive moiety such as hyaluronic acid or RGD).The material can be an antimicrobial material suitable for use in wound dressings or tissue and serum handling devices. The material can be one for increasing comfort in skin contacting products such as diapers by incorporating collagen.

[0276] In various embodiments, the materials are processed via electrospinning, melt extrusion, hot melt extrusion, injection molding, fused filament fabrication or fused deposition modeling type three dimensional printing, meltblowing, and the like.

[0277] In various embodiments, the material or bioactive polyethylene copolymer, when used on / in the human or animal body, is compatible with a living system or part of a living system without substantially or significantly eliciting an adverse physiological response, such as a toxic reaction / response, an immune reaction / response, injury, etc. In various embodiments, the polymer is substantially free of substances that elicit an adverse physiological response.

[0278] Methods of accelerating / stimulating / promoting cell proliferation or tissue regeneration, such as regeneration of cartilage or skin tissue, or wound healing are also provided, which methods comprise administering / applying the bioactive copolymers or materials disclosed herein to the human or animal body.

[0279] There is also provided the use of a bioactive polyethylene copolymer or material disclosed herein in the manufacture of a medicament for accelerating / stimulating / promoting cell proliferation or tissue regeneration, or wound healing, such as the regeneration of cartilage or skin tissue.

[0280] For example, embodiments of the bioactive polyethylene copolymers or materials disclosed herein may be useful in promoting the healing of wounds (e.g., diabetes-related wounds or wounds) on diabetic patients, such as diabetic foot ulcers. Advantageously, embodiments of the bioactive polyethylene copolymers or materials disclosed herein may be useful in creating dressings with the necessary stimulation within the material itself to promote skin cell regeneration for enhanced recovery rates. Such materials would not only be useful for wound dressings, but also in other medical devices that require enhanced tissue regeneration for improved healing outcomes. Some such applications may include cartilage implants, where the deposition of collagen around the implant by chondrocytes aids in recovery from implantation.

[0281] Use of the bioactive polyethylene copolymers or materials disclosed herein for biofilm eradication is also provided.

[0282] In various embodiments, the bioactive polyethylene copolymer is substantially free of stem cells and / or growth factors, hi various embodiments, the bioactive polyethylene copolymer is non-biofouling.

[0283] In various embodiments, the biologically active moiety is directly chemically linked to the copolymer, hi various embodiments, the biologically active moiety is not encapsulated in the polymer matrix.

[0284] In various embodiments, the biologically active moiety (eg, a peptide) is not attached to the norbornene dicarboximide via an aminobutyric acid spacer.

[0285] In various embodiments, the bioactive portion comprises structurally well-defined collagen having a specific sequence, hi various embodiments, the bioactive portion is substantially free of animal-derived collagen, which has a broad molecular weight distribution and / or an ill-defined structure, and / or is known to illicit a negative immune response in the human body.

[0286] In various embodiments, polyethylene glycol is not used as a monomer as such, for example, in various embodiments, ethylene glycol units are not present as end groups in the copolymer / polymer.

[0287] Embodiments of the bioactive polyethylene polymers and / or methods disclosed herein do not include any release of bioactive molecules, such as drug molecules, from the copolymer upon activation, such as photoactivation.Embodiments of the bioactive polyethylene polymers are substantially free of photocleavable groups. [Brief description of the drawings]

[0288] [Figure 1] FIG. 1 is a schematic diagram 100 of a bioactive polyethylene polymer according to various embodiments disclosed herein. [Diagram 2]FIG. 2 shows thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) graphs of pure RGD peptide ("RGD(PURE)"), NBPEG1000RGD macromonomer ("NB PEG1000RGD"), NBPE homopolymer ("PE"), and succinic acid terminated polyethylene (SAt-PE)-PEGRGD copolymer ("(RGD)ROMP"). [Figure 3A] FIG. 3A is a graph showing the biocompatibility of PE-peptide based materials prepared according to various embodiments disclosed herein compared to a control. Results were obtained from cell viability tests on human keratinocytes cultured on a human epidermis-free dermis model. 3D printed sheets of bioactive PE blended with medical grade polypropylene were applied to the skin model for 24 and 48 hours, where macromonomers of six peptides (SRGDS, RGDS, (IRIK)2, (GPHyp)3, DGEA and RGD) were copolymerized with macromonomers of PE. Comparative examples are the commercially available dressings Allevyn (i.e. polyurethane foam) and Acticoat (i.e. silver-based polypropylene nonwoven dressing). The control used includes poly(norbornene dicarboximide) with PE and mPEG1000 as side chains. [Figure 3B] FIG. 3B is a graph showing the biocompatibility of PE-peptide-based materials prepared according to various embodiments disclosed herein compared to a control. Results were obtained from cell viability studies on a human epidermis-free dermis model as an ex vivo human skin model, where macromonomers of six peptides (SRGDS, RGDS, (IRIK)2, (GPHyp)3, DGEA and RGD) were copolymerized with macromonomers of PE, and the bioactive copolymers were blended with polypropylene, extruded into filaments, 3D printed into sheets, and then applied to the human skin model. Comparative examples are the commercially available dressings Allevyn (i.e. polyurethane foam) and Acticoat (i.e. silver-based polypropylene nonwoven dressing). The control used includes poly(norbornene dicarboximide) with PE and mPEG1000 as side chains. [Figure 4]Figure 4 shows cross-sectional hematoxylin and eosin (H&E) stained images of human skin samples obtained from a preliminary ex vivo wound closure study 3 days after material application. The comparative example is the commercially available dressing Allevyn (i.e., a polyurethane-based dressing). The control used includes poly(norbornene dicarboximide) with PE and mPEG1000 as side chains. [Diagram 5] Figure 5 shows cross-sectional hematoxylin-eosin (H&E) stained images of human skin samples from a preliminary ex vivo wound closure study after 3 days of application of the PE-peptide-based material, a PE macromonomer copolymerized with 6% RGD macromonomer, and the final bioactive polyethylene copolymer was blended with medical grade polypropylene at blend ratios of 0.1%, 1% and 3%. [Figure 6] FIG. 6 shows the thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) graphs of bioactive amine-terminated polyethylene (PE)-RGD copolymers. [Figure 7] 7 is a graph showing the biocompatibility of PE-peptide based materials prepared according to various embodiments disclosed herein compared to commercial wound dressings Acticoat and Allevyn. Results were obtained from viability testing of Hs27 human dermal fibroblast cells on PERGD copolymer blended with PLA in a 1:4 ratio. PERGD copolymer blended with medical grade PLA was electrospun into nanofibers for biocompatibility testing with Hs27 human fibroblast cells grown in DMEM with 10% FBS and 1% Pen / Strep. EXAMPLES

[0289] The exemplary embodiments of the present disclosure will be better understood and readily apparent to those skilled in the art in conjunction with the following examples, tables and, where applicable, drawings. It should be understood that other modifications related to structural and chemical changes can be made without departing from the scope of the present invention. The exemplary embodiments are not necessarily mutually exclusive, since some may be combined with one or more embodiments to form new exemplary embodiments. The exemplary embodiments should not be interpreted as limiting the scope of the disclosure.

[0290] Example 1: Modular approach to constructing bioactive polyethylene copolymers A general strategy for the construction of bioactive macromonomers containing either peptides, carbohydrates or drug molecules has been developed. A simple two-step synthesis allows for the rapid construction of a broad library of bioactive macromonomers of various chain lengths, which allows for the rapid development of synthetic polymers (i.e. polyethylene) with the desired bioactivity required in the target application. By matching the bioactive macromonomers with synthetic polymeric macromonomers (i.e. polyethylene) with the desired physical properties, this library allows for a modular approach to construct desired macromolecules to suit a variety of applications. Rapid polymer customization can be achieved.

[0291] A modular building block system for designing / constructing desired bioactive materials has been developed, as shown in Scheme 1. Once the target medical application is identified, a "plug-and-play" approach (Scheme 1) can be used to create the desired bioactive polyethylene material that not only has a therapeutic effect, but also possesses the necessary mechanical properties for easy storage and handling.

[0292] [ka]

[0293] By using a modular approach, macromonomers consisting of bioactive molecules at the end of the monomer can be created and copolymerized with other synthetic polymers (i.e. polyethylene) to create bioactive polyethylene copolymers with targeted bioactivity. The desired polymers are highly customizable using the strategies developed according to the various embodiments disclosed herein by switching the bioactive molecule to any peptide or carbohydrate with a carboxylic acid group. This allows for the rapid synthesis of bioactive polymers once the target application is identified. The bioactive polymers created can have properties ranging from skin cell regeneration, bone cell regeneration, antibacterial activity, cartilage tissue regeneration, wound healing, collagen production, anti-inflammation to cholesterol synthesis inhibition (e.g., using atorvastatin as the drug) and can be made to be mechanically robust, depending on the needs. Modular synthesis therefore makes the matching of the polymer properties to the application much simpler and more effective.

[0294] Example 2: Method for preparing bioactive polyethylene copolymers The method of preparing bioactive polyethylene copolymers according to various embodiments disclosed herein involves creating macromonomers of bioactive molecules and polyethylene separately, and linking these otherwise mutually incompatible molecules together using ring-opening metathesis polymerization (ROMP) techniques. The result is a brush polymer with both the bioactive molecule and polyethylene for the overall mechanical strength of the material (Scheme 2). By creating the macromonomers separately, the inventors can build a library of macromonomers with different properties for clinicians or medical technology companies to choose from, and materials with the desired therapeutic effect can be easily and quickly constructed to suit the targeted application. By creating the macromonomers separately, the inventors can also build a library of macromonomers and final copolymers for rapid testing of efficacy in the biomedical laboratory. Various combinations of these macromonomers (MM) can also generate a library of well-defined brush copolymers containing different bioactive molecules for rapid screening of bioactivity in the laboratory.

[0295] In the following examples, brush polymers were created that contain pendant arms of bioactive molecules tethered onto polyethylene and polyethylene glycol (PEG) moieties. Bioactive molecules can include biomolecules selected from peptide sequences of any combination of the 20 natural amino acids from 3-20 amino acid residues, carbohydrates such as glycosaminoglycans, or drug molecules containing a carboxylic acid terminus such as certain antibiotics. Biomolecules can also include collagen mimetic peptides from 3-20 amino acid residues of any sequence, such as DGEA, (Gly-Pro-Hyp)3, and (Pro-Hyp-Gly)3. Depending on the application, biomolecules with the desired bioactivity can be selected and copolymerized together with polyethylene using the brush polymer technology disclosed herein by ring-opening metathesis polymerization.

[0296] The resulting polymers exhibit the biological activity of the biomolecules involved while possessing much better physical and mechanical properties for better material handling and processability.

[0297] The bioactive polyethylene copolymer can be subsequently blended with a polymer similar to that on the pendant arm (e.g., polyethylene or polypropylene) to create a bioactive material for use in biomedical devices such as catheters, wound dressings, tissue scaffolds, plastic surgery implants, prosthetic components, cartilage joint implants, and the like.

[0298] A synthetic route for preparing bioactive polyethylene copolymers according to various embodiments disclosed herein is illustrated in Scheme 2.

[0299] [ka]

[0300] Example 3: Bioactive Macromonomers and Methods of Synthesis A general strategy for the synthesis of bioactive macromonomers according to various embodiments disclosed herein was developed. Polyethylene glycol diamines of various chain lengths (e.g., M W =1,000-6,000) is reacted with cis-norbornene-exo-2,3-dicarboxylic anhydride to generate the primary macromonomer entity, namely, a macromonomer entity containing norbornene dicarboximide and polyethylene glycol (NBPEG) (Scheme 3.1). Once the NBPEG is generated, various peptides, carbohydrates, or drug molecules are then reacted with these NBPEG chains to generate bioactive macromonomers with desired therapeutic properties.

[0301] With the body of the macromonomer, any peptide, carbohydrate or drug molecule (R) can be used, with the carboxylic acid terminus on the bioactive molecule being used, via a condensation reaction to form a peptide / amide bond between the amine group on the NBPEG-NH2 and the carboxylic acid terminus of the carbohydrate or peptide (Scheme 3.2). Examples of drug molecules include antibiotics such as amoxicillin or ciprofloxacin. In various embodiments, R is a copolymer of antimicrobial peptides (IRIK)2 or (IKKI)3; heparin oligosaccharides DP10, DP12, DP14, extracellular matrix peptides COL or RGD, where COL is DGEA, (GPHyp) n or (PHypG) n , or (PGHyp) n In various embodiments, R is a carbohydrate or drug molecule having a CO2H group or a peptide sequence of 3 to 20 amino acid residues formed from the 20 naturally occurring amino acids. In various embodiments, R is DP12, DP14, COL or RGD, where COL is DGEA or (GPHyp) n Or it can be any combination of P, Hyp and G. If the carbohydrate does not have a carboxylic acid group, modification of the carbohydrate to include one may be necessary. Alternatively, the amine substitution reaction or reductive amination reaction can also be performed on a hydroxy or carbonyl group of the carbohydrate.

[0302] [ka]

[0303] [ka]

[0304] Example 4: Polyethylene Macromonomers and Methods of Synthesis Polyethylene (PE) macromonomers can be created with succinic acid or primary amine ends.

[0305] To create succinic acid terminated PE macromonomers, low molecular weight and polydispersity vinyl terminated polyethylene is reacted with maleic anhydride to give succinic acid terminated polyethylene (SA-t-PE), which can then be reacted with hexamethylenediamine (HMDA) and finally cis-norbornene-exo-2,3-dicarboxylic anhydride to create the desired PE macromonomer (Scheme 4.1).

[0306] To obtain primary amine termini on polyethylene (PE) for macromonomer formation, hydroaminomethylation of vinyl-terminated PE is performed in a one-pot, two-step process in which it is first converted to a linear carbonyl via hydroformylation followed by reductive amination in the presence of hexamethylenediamine (HMDA) (Scheme 4.2). After obtaining the amine-terminated PE, condensation with cis-norbornene-exo-2,3-dicarboxylic anhydride affords the PE macromonomer (Scheme 4.3), which can be used in the formation of brush polymers with either itself or other macromonomers.

[0307] [ka]

[0308] [ka]

[0309] [ka]

[0310] Example 5: Ring-opening metathesis polymerization catalyst Using both the bioactive and synthetic polymer (i.e., PE) macromonomers, the final bioactive polyethylene copolymers are prepared by ROMP using Grubbs-type catalyst 1 (Scheme 5).

[0311] [ka]

[0312] Example 6: Examples of bioactive polyethylene copolymers FIG. 1 shows a bioactive polyethylene copolymer 100 designed according to various embodiments disclosed herein. The bioactive polyethylene copolymer 100 comprises a poly(norbornene dicarboximide) backbone 102, pendant arms of polyethylene 104a, 104b, and 104c, and pendant arms of bioactive molecules 106a, 106b, and 106c tethered to PEG chains 108a, 108b, and 108c. As shown in the schematic diagram, the pendant arms are attached to the poly(norbornene dicarboximide) backbone 102. 106a, 106b, and 106c can be the same or different types of bioactive moieties.

[0313] Examples of biologically active molecules include biomolecules selected from peptide sequences of 3-20 amino acid residues formed from the 20 naturally occurring amino acids, collagen mimetic peptides from 3-20 amino acid residues of any sequence such as DGEA, (Gly-Pro-Hyp)3 and (Pro-Hyp-Gly)3, (Hyp-Pro-Gly)3, (Gly-Hyp-Pro)3, (Hyp-Gly-Pro)3 and (Pro-Gly-Hyp)3, carbohydrates such as glycosaminoglycans or drug molecules containing a carboxylic acid terminus such as certain antibiotics.

[0314] Collagens are popular materials in the skin care and wound care industries due to their skin compatibility and reported ability to regenerate skin tissue. Moreover, they are gentle enough to prevent overly active tissue regeneration, which can lead to cancer. The hydrophilic nature of collagen itself makes it an attractive material for skin care products, as its ability to retain moisture in the skin prevents dermatitis resulting from overly dry skin. Therefore, the use of collagen fragments and collagen mimics can be used in PE to create polymers for blending into polypropylene substrates for diaper manufacturing.

[0315] Naturally occurring biopolymers such as hyaluronic acid (HA) and collagen (COL) have been shown to support cell growth and proliferation. Several studies have shown that HA significantly improves the healing rate of diabetic foot ulcers (DFUs). HA has been reported to promote cartilage regeneration. Collagen gels or freeze-dried collagen pads are commercially available for wound treatment. Integra, a collagen scaffold made of bovine collagen, is currently the gold standard for burn treatment. Collagen's ability to regenerate skin tissue and being a highly biocompatible material makes it a very attractive material for wound healing.

[0316] Besides HA and COL, arginylglycylaspartic acid (RGD) peptide is yet another interesting peptide that has been reported to promote the proliferation of both bone, cartilage and skin cells. The RGD sequence is the minimal binding domain of fibronectin, a high molecular weight glycoprotein of the extracellular matrix (ECM) that binds to ECM components such as collagen and fibrin. The RGD peptide sequence is known to regulate cell activity by interacting with cell surface integrins that contribute to the wound healing process. Materials modified with RGD peptides have been reported to promote cell adhesion, spreading and wound healing. RGD also enables integrin binding for transforming growth factor (TGF-β) activation, which is required for the regulation of cartilage development. Therefore, RGD is an important peptide to consider in the development of materials for wound healing and cartilage repair.

[0317] An example would be the development of a wound dressing material for the treatment of chronic wounds where rapid skin re-epithelialization is required. RGD is a peptide sequence that can bind to integrins for cell attachment, migration and proliferation. Therefore, a macromonomer of RGD is created (Scheme 6a). Since the dressing is required to be inert while having a long shelf life and good mechanical strength, a polyethylene-containing macromonomer is paired with this RGD-containing macromonomer to create the final copolymer of RGD and PE (Scheme 6b). The material has been tested to be biocompatible and promotes re-epithelialization using a human skin equivalent model.

[0318] [ka]

[0319] Since RGD is a good integrin binder and bone growth factor binder, it can also be paired with PE macromonomers to create bioactive copolymers for use as substrates or scaffolding materials for bone and bone marrow organoid generation. Such a modular approach in constructing polymers allows the matching of various bioactive macromonomers with synthetic macromonomers to rapidly create mechanically strong therapeutic materials based on target applications.

[0320] RGD can be replaced with any peptide sequence via its acid terminus, or any carbohydrate or any drug molecule such as amoxicillin or ciprofloxacin that has a carboxylic acid functionality.

[0321] For example, glycosaminoglycans (GAGs), such as heparan sulfate (HS) chains of between 5 and 10 disaccharide units, may be used as bioactive moieties. Without being bound by theory, it is believed that HS chains are active against bone morphogenetic proteins (BMPs), particularly BMP-2, which can transdifferentiate myoblasts into osteoblasts. Without being bound by theory, it is believed that DP12, an HS fragment with six disaccharide units, has the highest binding affinity for BMP-2.

[0322] Bioactive materials can also be created with collagen fragments and mimetics. Bone is a mineralized collagen tissue that remodels itself throughout the human life cycle to adapt to mechanical stresses and maintain the integrity of the skeletal tissue. Current bone scaffolds are typically made of collagen sponges, sometimes mineralized with some calcium phosphate ceramics such as tricalcium phosphate or hydroxyapatite. Collagen's biocompatibility and its similarity to bone and cartilage tissues make it an ideal scaffold material for bone and cartilage. Some collagen mimetics that may be used include DGEA and collagen fragments with various lengths of glycine, proline, and hydroxyproline sequences. Without being bound by theory, it is believed that DGEA supports mesenchymal stem cell attachment and differentiation into osteoblasts. Additionally, without being bound by theory, it is believed that collagen would also be an excellent skin scaffold material because the extracellular matrix (ECM) is primarily a collagen material. Other ECM peptides that have been studied include the laminin-derived peptide A5G81, which has been reported to promote wound healing in rats.

[0323] Besides tissue regeneration biomolecules, cell penetrating peptides such as (IRIK)2 and (IKKI)3 can also be used as bioactive moieties for incorporation into non-biofouling materials. Biofouling is a serious problem in biomedical devices such as catheters, intestinal stents and even wound dressings. The ability to target biofilm-forming bacteria such as Pseudomonas aeruginosa while not being toxic to humans makes such peptides attractive candidates for biomedical device materials.

[0324] Drug molecules such as antibiotics can also be incorporated into the brush polymers. In theory, any drug molecule with a carboxylic acid end would allow for the creation of these bioactive synthetic polymers. Some of the drug molecules that have been successfully polymerized include amoxicillin and ciprofloxacin. Brush polymers have also been created for use in antibacterial devices.

[0325] In summary, by using a modular approach to polymer design and synthesis, we developed a general strategy to create bioactive macromonomers for the rapid construction of bioactive polyethylene copolymers. Such a modular approach to therapeutic materials synthesis allows for therapeutic customization to suit the needs of each patient, thus approaching the ideal situation of personalized medicine.

[0326] In summary, a series of polymers with polyethylene bearing PEGylated biomolecules as side chains on a poly(norbornene dicarboximide) backbone were developed via ROMP technology. The biocompatibility and skin cell viability of some of these polymers were also tested, demonstrating the ability of the materials to withstand harsh material processing temperatures without loss in bioactivity. The general strategy presented herein forms a method to create bioactive polyethylene copolymers for use as bioadditives in materials for biomedical devices, where the bioadditives can be blended with base polymers of similar type as the polymer side chains on the poly(norbornene dicarboximide) backbone. The polyethylene side chains help make the biomolecules more compatible with the base synthetic polymer, allowing them to be blended together without phase separation. The formation of brush polymers also allows the biomolecules to have better structural integrity compared to the natural biomolecules themselves, which tend to be extremely hygroscopic, resulting in their poor handling and poor processability as materials.

[0327] Example 7: Succinic acid-terminated polyethylene (SA-t-PE)-peptide copolymer 7.1.(SA-t-PE) p -[(GPHyp)3] q Copolymer This example demonstrates the development of a new strategy to incorporate collagen fragments or mimetics into polyethylene by brush polymer synthesis for use in consumer products such as diapers. The bioactive polyethylene produced can be blended into medical grade polypropylene (PP) for nonwoven fiber production, which typically occurs by melt extrusion at 220°C. Other peptides, such as arginyl-glycyl-aspartic acid (RGD), known to enhance skin biocompatibility, can also be made using a similar strategy.

[0328] Succinic acid terminated polyethylene (SA-t-PE) was obtained according to literature methods (Macromolecules 2009, 42, 4356-4358; following the second example in the Supporting Information).

[0329] 7.1.1.PE macromonomer An amine handle was first created on the SA-t-PE using hexamethylenediamine (HMDA), and then the aminated PE was connected to a norbornene dicarboxylic anhydride linker (cis-norbornene-exo-2,3-dicarboxylic anhydride) to create the PE macromonomer (Scheme 7.1).

[0330] 7.1.2. Peptide macromonomers Peptide macromonomers were prepared by reacting PEG diamines (MW 1,000–6,000) with cis-norbornene-exo-2,3-dicarboxylic anhydride on one amine terminus, followed by a second condensation reaction with the appropriate peptide on the other amine terminus of the PEG diamine (Scheme 7.2).

[0331] Macromonomers of collagen fragments such as (GPHyp)3 and (PGHyp)3, collagen mimetics such as DGEA, and extracellular matrix peptides such as RGD and SRGDS were also prepared using this general strategy.

[0332] 7.1.3. PE-Peptide Copolymers Once both macromonomers were synthesized, ring-opening metathesis polymerization was carried out on the macromonomers using Grubbs' catalyst (Scheme 5, catalyst 1) to give the desired PE-peptide copolymer (Scheme 7.3).

[0333] The synthesized copolymers showed an average of 6% peptide incorporation into the polymer despite a 5:1 PE:peptide monomer ratio. This is likely due to the poor solubility of the peptide macromonomer in benzene. Other non-polar solvents such as toluene performed the worst, with less than 2% RGD incorporation. Polar solvents generally do not dissolve PE.

[0334] Upon synthesis, the polymer is checked for residual metals from Grubbs catalyst using inductively coupled plasma mass spectrometry (ICP-MS) to ensure that the metal content is less than 0.1 ppm. The FDA allowable inhalation limit for Ru in class 2B medical devices is 0.1 μg / g. For a 5 kg baby, this corresponds to 0.5 mg of Ru. Assuming that each disposable diaper uses 10 g of non-woven PE-COL sheet as its cover and the blend ratio of PE-COL in PP is 3%, there is 0.3 g of PE-COL in the material. At 0.1 ppm Ru, the amount of Ru detected in 0.3 g of material is 0.03 μg. This is far below the FDA limit for class 2B devices. For applications such as diapers, such Ru limits are insignificant.

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[0336] [ka]

[0337] [ka]

[0338] 7.2.SA-t-PERGD Copolymer This example demonstrates the development of brush polymers with PEGylated biomolecules such as RGD, HA and collagen fragments, with polyethylene side chains on a poly(norbornene dicarboximide) backbone for applications in wound healing and cartilage repair.

[0339] Succinic acid terminated polyethylene (SA-t-PE) was prepared by literature methods (Macromolecules 2009, 42, 4356-4358; following the second example in Supporting Information). The PE used to make SA-t-PE is in the MW range of 1,400-5,000, suitable for use in creating macromonomers that may be grafted onto linker units such as norbornene and further polymerized into brush polymers containing such PE side chains.

[0340] 7.2.1.PE macromonomer An amine handle was first created on the SA-t-PE using hexamethylenediamine (HMDA), and then the aminated PE was connected to a norbornene dicarboxylic anhydride linker (cis-norbornene-exo-2,3-dicarboxylic anhydride) to create the PE macromonomer (Scheme 7.1).

[0341] 7.2.2. Peptide Macromonomers Peptide macromonomers were prepared by reacting PEG diamine (MW 1,000–6,000 depending on the MW range of PE) with cis-norbornene-exo-2,3-dicarboxylic anhydride on one amine terminus, followed by a second condensation reaction with the appropriate peptide on the other amine terminus of the PEG diamine (Scheme 7.2).

[0342] 7.2.3. PE-Peptide Copolymers Once both macromonomers were synthesized, ring-opening metathesis polymerization was carried out on the macromonomers using Grubbs' catalyst (Scheme 5, catalyst 1) to give the desired PE-RGD copolymer (SA-t-PERGD) (Scheme 7.4).

[0343] The synthesized copolymers showed an average of 6% RGD incorporation in the polymer despite a 5:1 PE:RGD monomer ratio. This is likely due to the poor solubility of the RGDPEGNB macromonomer in benzene. Other non-polar solvents such as toluene performed the worst, with 2% or less RGD incorporation. Polar solvents generally do not dissolve PE.

[0344] Upon synthesis, the polymer is checked for residual metals from Grubbs' catalyst using ICPMS to ensure the metal content is less than 0.1 ppm. Assuming each cartilage implant (osteochondral plug) uses 1 g of PE for fabrication, at a 10% bioactive PE blend ratio, there is 0.1 g of bioactive PE in the implant material. At 0.1 ppm Ru, the amount of Ru found in 0.1 g of bioactive PE is 0.01 μg. This is well below the FDA daily oral exposure limit of 100 μg / day or 1 μg / day by inhalation.

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[0346] 7.3.Thermal stability After ICP-MS, thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) measurements were obtained on pure RGD, NBPEGRGD, NBPE homopolymer and PE-co-PEGRGD copolymer (PE-RGD) to confirm the thermal stability of the polymers. The DSC curves show that the materials undergo single-phase degradation / weight loss at >450 °C (467 °C), a temperature much higher than the typical melt processing temperatures of PE or PP for either 3D printing or nonwoven fiber fabrication. Hence, enhanced thermal stability of the materials was demonstrated despite the incorporation of biomolecules.

[0347] Pure RGD is the macromonomer NBPEG. 1000 It was observed to degrade at temperatures (150-250 °C) lower than RGD (250-400 °C) and even much lower than its PE-RGD copolymer (400-500 °C). NBPEGRGD showed a two-phase degradation (weight loss) where the initial degradation was due to loss of RGD groups, followed by degradation of the PEG chains from about 250 °C. The PE-RGD copolymer only underwent a 50% weight loss at 466 °C, which allows the use of most material processing methods such as melt extrusion or filament melt fabrication (FFF / FDM) to process the polymer into usable devices. A significant enhancement in the thermal stability of RGD upon attachment to PEG and subsequent copolymerization with PE via ROMP on the norbornene dicarboximide backbone is thus evident here.

[0348] Biocompatibility The bioactive PE was blended with medical grade polypropylene powder in various ratios ranging from 0.1 to 10% to create formulations. The formulations were then melt extruded at 190 °C using a twin-screw filament extruder to create fused filament (FFF) printer quality filaments, which were then molded into 1.5 × 1.5 mm 3D shapes for ex vivo testing on a human skin model. 2 2×2cm with pores 2 The sheet of material was fed into a printer to produce a sheet of material.

[0349] To demonstrate the bioactivity of the polymers designed according to various embodiments disclosed herein, human skin tests were conducted using some of the polymers with peptides attached on the biomacromonomer. The bioactive synthetic polymers were blended with medical grade PP as the substrate, which has a higher melting point of 179°C. The polymer blends were extruded into filaments at 220°C using a filament extruder, followed by FFF printing to obtain sheets with incorporated pores. The sheets were then tested on a human skin model, and it was clear that the materials designed according to various embodiments disclosed herein showed much better skin cell viability compared to commercial dressings such as Allevyn (polyurethane foam) and Acticoat (silver-based nonwoven dressing) (Figures 3A-3B). These are the two most commonly prescribed wound dressings in hospitals for chronic wound patients. These skin data demonstrated the effectiveness of the bioactive synthetic polymers and their ability to withstand harsh material processing temperatures (220°C). The bioactivity of the attached biomolecules is not lost even at such temperatures, demonstrating the ability of the present disclosure to create bioactive polymers with high stability for material processing and bioavailability for a variety of therapeutics.

[0350] Biocompatibility testing was performed in the SRIS Human Tissue Laboratory using human dermis to reconstruct a skin model by re-growing the epidermis using keratinocytes obtained from a skin bank. Testing was performed according to the reported standard protocol according to Topping, G. et al. (Primary Intention: The Australian Journal of Wound Management, 2006, 14(1), 14-21), the contents of which are fully incorporated herein by reference. Briefly, dressing materials were applied onto the skin model with a medium provided to the skin to support skin viability. The dressings were removed at 24 hours (FIG. 3A) and 48 hours (FIG. 3B), and the skin samples were stained with Alamar Blue and incubated for 90 minutes, respectively, and the staining was analyzed by fluorescence spectroscopy to check the amount of viable cells.

[0351] Copolymers were created using PE as the synthetic polymer and a range of peptides of different properties as bioactive macromonomers, namely antimicrobial peptide; IRIK; collagen fragment (GPHyp)3: GPHyp; collagen mimetic: DGEA and integrin binding peptides: RGD, SRGDS and RGDS. The copolymers were subsequently blended with polypropylene, 3D printed into sheets and tested for cell viability and biocompatibility against commercially available wound dressings such as Allevyn and Acticoat.

[0352] Ex vivo studies show that both collagen-based materials, (GPHyp)3 and DGEA, showed enhanced cell viability compared to the control at 24 hours. SRGDS also slightly outperformed the control (Figure 3A). At 48 hours, both SRGDS and GPHyp retained good cell viability, demonstrating their biocompatibility with human skin (Figure 3B). Even bioactive PE made with antimicrobial peptides such as (IRIK)2 showed reasonable biocompatibility compared to the commercially available antimicrobial dressing, Acticoat.

[0353] Cross-sectional hematoxylin and eosin stained (H&E) images of human skin samples from a preliminary ex vivo wound closure study after 3 days of application of the PE-peptide based material are provided in Figures 4 and 5. The comparative example is the commercially available dressing Allevyn (i.e., a polyurethane-based dressing). The control used was a PE and mPEG-based dressing with PE and mPEG as side chains. 1000 The PE-peptide based materials are PE macromonomers copolymerized with RGD macromonomers and blended with polypropylene at ratios of 0.1%, 1% and 3% of PE-RGD copolymer, respectively.

[0354] In summary, using PEG and norbornene dicarboximide linkers, copolymer materials of PE with various peptides including collagen fragments, collagen mimetics, antimicrobial peptide (IRIK)2, and extracellular matrix peptides such as RGD and SRGDS were prepared. The materials showed enhanced thermal stability as well as good biocompatibility data. In general, peptides of any sequence length from 3 to 20 amino acids and oligosaccharides up to 14 sugar units can be used.

[0355] 7.5. Conclusion Through the incorporation of PEGylated peptides and collagen fragments into brush polymers containing polyethylene (PE) side chains, bioactive polyethylenes were created for use in consumer products and nonwoven fibers for polyethylene or polypropylene-based medical devices. To create prototypes for testing, these polymers were blended as powders into medical grade polypropylene and melt extruded into sheets at 220 °C using an FDM printer. The polymer sheets were tested ex vivo on a human skin model and demonstrated excellent biocompatibility with human skin. Other PEGylated peptides also demonstrated good biocompatibility upon incorporation into PE. As shown in the examples, the thermal stability of peptides improved dramatically upon incorporation into PE-based brush polymers. Peptides of any sequence length from 3 to 20 amino acids and oligosaccharides of up to 14 sugar units can generally be used.

[0356] Polymeric materials containing PEGylated collagen fragments or peptides were developed with polyethylene as a brush polymer using a polynorbornene dicarboximide backbone. The polymers demonstrated the bioactivity of the peptides in terms of biocompatibility and enhanced cell viability using an ex vivo human skin model. At the same time, the polymers also demonstrated improved thermal stability as evident from the TGA-DSC curves, which showed a 50% material weight loss only at 467°C. The polymers did not show any loss in bioactivity when melt extruded at 220°C and tested on human skin, demonstrating the capability in developing bioactive polyethylene materials with both thermal stability and bioactivity like that of collagen. The materials can be melt processed by conventional material processing methods, which makes them useful materials for consumer products such as diapers. They also demonstrated good mechanical properties like those of polyethylene.

[0357] Through the incorporation of PEGylated biomolecules known to improve wound healing into polyethylene, a novel material was created that possesses both the bioactivity of the biomolecules used as well as the physical properties of polyethylene. Extracellular matrix peptides such as RGD, collagen and laminin-derived peptides such as A5G81 are known to enhance skin cell proliferation and wound healing. Brush polymers were created with these peptides on a polynorbornene dicarboximide backbone, along with polyethylene side chains, and on PEGylated side chains. The material was then 3D printed into sheets using an FFF printer and tested on a human skin model. Ex vivo testing of the material showed improved cell viability compared to a commercial dressing as a control.

[0358] Brush polymers with polyethylene side chains and PEGylated peptides were created for use in tissue regeneration materials such as wound dressings and other medical devices. By incorporating peptides into the polyethylene, bioactivity was created in the otherwise inert polyethylene. At the same time, the thermal stability of peptides such as collagen fragments and RGD was dramatically enhanced. The peptides also did not phase separate from the PE. This allowed the bioactive PE to be blended into base polypropylene (PP) for non-woven fiber production in wound dressing manufacturing. Bioactive PE can also be blended into PE for the creation of other biomedical devices such as joint implants and stents to improve recovery rates in patients receiving implants as a result of using more biocompatible PE.

[0359] 7.6. Materials and Methods 7.6.1 General Procedure Ring-opening metathesis polymerization reactions and RGD macromonomer synthesis were carried out in a Vacuumu Atmosphere glove box under nitrogen atmosphere. SA-t-PE macromonomer was synthesized under ambient conditions. All solvents used - anhydrous benzene and anhydrous methanol from Alfa Aesar, were used as purchased in a glove box. Grubbs second generation catalyst was purchased from Sigma Aldrich, and all peptides (including RGD peptide) were purchased from Biomatik Inc. HMDA and PEG diamine were purchased from Alfa Aesar. All purchased reagents were used without further purification. Succinic acid terminated polyethylene (MW 15,000 or less) was prepared according to the literature (Macromolecules 2009, 42, 4356-4358; following the second example in Supporting Information).

[0360] 1 H NMR spectra were recorded on a Jeol 500 MHz NMR spectrometer. GPC chromatograms show * PLgel Mixed B column (300 × 7.5 mm, particle size 10 μm) and 1* The data were recorded on an Agilent Infinity II High Temperature GPC system equipped with a PLgel Mixed B guard column (50×7.5 mm). The eluent was TCB with a flow rate of 1 ml / min and an oven temperature of 160° C. Polystyrene was used as the calibration standard.

[0361] 7.6.2. Synthesis of SA-t-PE macromonomer (SA-t-PEHMDANB) for PE MW 1,400-5,000 SA-t-PE (6 mmol) was weighed into a 250 ml round bottom flask (rbf) and then toluene (120 ml) was added. HMDA (18 mmol) and triethylamine (6 mmol) were then added. The mixture was then stirred overnight under reflux with a dean stark trap attached for water removal. The mixture was then cooled and concentrated, after which MeOH was added to give a beige precipitate. The mixture was filtered and the residue was washed with MeOH and dried in a vacuum oven overnight to quantitatively obtain SA-t-PEHMDA.

[0362] SA-t-PEHMDA (6 mmol) was added to a 250 ml rbf followed by cis-norbornene-exo-2,3-dicarboxylic anhydride (6.5 mmol), toluene (120 ml) and triethylamine (6 mmol). The mixture was then refluxed overnight with a dean stark trap attached for water removal. The mixture was then cooled and concentrated before adding MeOH to give a beige precipitate. The mixture was filtered and the residue was washed with MeOH and dried in a vacuum oven overnight to quantitatively obtain SA-t-PE macromonomer (SA-t-PEHMDANB). 1 H NMR(C7D8)δ=5.88-5.85(m, 2H), 5.16-5.47(m, 2H), 3.41-3.36(m, 5H), 2.97-3.36(m, 4H), 2.64(bs, 2H).

[0363] 7.6.3. NBPEG macromonomer (H 2 N-PEG-NH 2 Synthesis of 1,000 to 6,000 PEG diamine (1 g) and cis-norbornene-exo-2,3-dicarboxylic anhydride (1 eq) were added to a 100 ml rbf followed by toluene (50 ml). Triethylamine (1 eq) was added and the mixture was stirred overnight at reflux with a Dean-Stark trap attached for water removal. The resulting solution was evaporated to dryness and dichloromethane (40 ml) was added followed by 0.1 M HCl (40 ml). The organic layer was extracted and washed with 0.1 M NaOH (50 ml). 0.1 M NaOH (50 ml) was added to the aqueous fraction from the acid wash followed by CH2Cl2 (30 ml). The organic layers were extracted, combined, washed with saturated NaCl and dried over Na2SO4. The material was evaporated to dryness to give a pale orange oil for PEG diamine 1,000 and a beige solid for NBPEG and PEG diamines 3,400 and 6,000. 1 H NMR (MeOD): δ = 6.36 (t, 2H, NB), 3.67 (s, PEG), 3.21 (s, 2H, NB), 2.74 (s, 2H, NB), 1.92 (s, 2H).

[0364] 7.6.4. NBPEG as a representative preparation for PEG 1,000-6,000 1000 Synthesis of RGD RGD (with one carboxylic acid on the aspartic acid protected with OMe) (0.0937 g, 0.26 mmol) was dissolved in MeOH (2.5 ml) in a 4 ml vial in a glove box. i Pr2EtN (91 μL, 0.52 mmol) was added and the mixture was stirred (A). HOBT (0.0353 g, 0.26 mmol) and HBTU (0.0992 g, 0.26 mmol) were dissolved in MeOH (12.5 ml) in a 20 ml vial at 40° C., after which the RGD solution from (A) was added to obtain solution (B). Solution B was then dissolved in NBPEG in a 40 ml vial. 1000(0.25 g, 0.218 mmol) and stirred at room temperature overnight. The resulting mixture was then evaporated to dryness and the oil was added to diethyl ether (50 ml). The diethyl ether solution was chilled in a freezer for 48 hours and decanted. MeOH (5 ml) was added to the residue to give an orange solution with white ppts. The mixture was passed through a syringe filter and the clear filtrate was evaporated to dryness to give an orange oil of RGDPEGNB in ​​95% yield. 1 H NMR (MeOD): δ=7.74(dd), 7.35-7.42(m), 6.32(t), 4.39(s), 4.20(s), 3.63(brs), 3.60(d), 3.17(t), 2.70(d). MALDI-MS:661.3([M-NB]+2H + ).

[0365] 7.6.5. NBPEG as a representative preparation for PEG 1,000-6,000 1000 Synthesis of DGEA DGEA (with two carboxylic acid termini protected with OMe) (0.109 g, 0.26 mmol) was dissolved in MeOH (2.5 ml) in a glove box. i Pr2EtN (91 μl, 0.52 mmol) was added and the mixture was stirred as solution A. HOBT (0.0353 g, 0.26 mmol) and HBTU (0.0992 g, 0.26 mmol) were dissolved in MeOH (12.5 ml) at 40° C., and then solution A was added to obtain suspension B. Suspension B was then added to NBPEGNH2 (0.25 g, 0.218 mmol) and stirred at room temperature for 24 h. The resulting pale yellow mixture was then concentrated by solvent evaporation to obtain a yellow oily mixture. The mixture was dispersed in Et2O and the solution was placed in a freezer for 48 h. The Et2O layer was removed and MeOH was added to the residue to obtain a yellow suspension. Filtration and solvent evaporation gave the yellow oily product NB-PEG-DGEA (0.28 g, 73% yield). 1H NMR (CD3OD, 500MHz, 25℃): δ7.80(d, 1H), 7.71(d, 1H), 7.44-7.38(m, 2H), 6.33(s, 2H), 4.40(s, 2H), 4.22(s, 1H), 3.95(s, 1H), 3.68(m , 6H), 3.64(m, 84H), 3.57(m, 4H), 3.18(s, 2H), 2.82(s, 2H), 2.72(s, 2H), 2.47(m, 2H), 2.14(m, 1H), 1.96(m, 1H), 1.48-1.41(dd, 2H).

[0366] 7.6.6. NBPEG as a representative preparation of collagen fragments of glycine, proline, and hydroxyproline with various sequences and chain lengths up to n=6, PEG 1000-6,000 1000 (GPHyp) 3 Synthesis of (GPHyp)3 (0.213 g, 0.26 mmol) was dissolved in MeOH (2.5 ml) in a glove box. i Pr2EtN (91 μl, 0.52 mmol) was added and the mixture was stirred (solution A). HOBT (0.0353 g, 0.26 mmol) and HBTU (0.0992 g, 0.26 mmol) were dissolved in MeOH (12.5 ml) at 40° C., after which solution A was added to give suspension B. Suspension B was then added to NBPEGNH2 (0.25 g, 0.218 mmol) and stirred at room temperature for 24 h. The resulting pale yellow mixture was then concentrated by solvent evaporation to give a beige mixture. The mixture was dispersed in Et2O and frozen for 48 h. The Et2O layer was removed and MeOH was added to the residue to give a beige suspension. Filtration and solvent evaporation gave the beige oily product NB-PEG-(GPHyp)3 (0.25 g, 50% yield).

[0367] 1 H NMR (CD3OD, 500MHz, 25℃): δ6.33(s, 2H), 4.73-4.44(br, 4H), 3.65(m, 84H), 3. 57(m, 4H), 3.18(s, 2H), 2.72(s, 2H), 2.39-1.80(br, 8H), 1.44-1.37(dd, 2H).

[0368] 7.6.7.NBPEG as a representative preparation for PEG 1,000-6,000 1000 (IRIK)2 Synthesis of (IRIK)2 (with one Boc-protected amine) (0.100 g, 0.0875 mmol) was dissolved in MeOH (1.0 ml) in a glove box. i Pr2EtN (31 μl, 0.175 mmol) was added and the mixture was stirred as solution A. HOBT (0.012 g, 0.0875 mmol) and HBTU (0.033 g, 80.0875 mmol) were dissolved in MeOH (1.5 ml) at 40° C., followed by addition of solution A to obtain suspension B. Suspension B was then added to NBPEGNH2 (0.0835 g, 0.073 mmol) and stirred at room temperature for 24 h. The resulting pale yellow mixture was then concentrated by solvent evaporation to obtain a yellow oily mixture. The mixture was dispersed in Et2O and the solution was placed in a freezer for 48 h. The Et2O layer was removed and MeOH was added to the residue to obtain a yellow suspension. Filtration and solvent evaporation gave a yellow sticky solid product (0.14 g, 70% yield). The solid was dissolved in dichloromethane (3.0 ml) and trifluoroacetic acid (0.5 ml) and stirred at room temperature for 24 hours. The resulting pale yellow mixture was then concentrated by solvent evaporation and washed with Et2O to give a pale yellow solid. The solid was redissolved in dichloromethane (2.0 ml) and MeOH (1.0 ml). Et3N (200 μl) was added and the mixture was stirred at room temperature for 24 hours. The resulting pale yellow mixture was then concentrated by solvent evaporation and washed repeatedly with Et2O to give a pale yellow solid NB-PEG-IRIK (0.12 g, 63%). 1 H NMR (CD3OD, 500MHz, 25℃): δ6.32(s, 2H), 4.50-4.10(m, 7H), 3.64(m, 84H), 3.25-3.10( m, 4H), 3.00-2.80(m, 5H), 1.90-1.30(m, 30H), 1.25-1.15(m, 4H), 1.05-0.85(m, 24H).

[0369] 7.6.8. Procedures for ROMP of SA-t-PE Macromonomers and RGD Peptide Macromonomers as Representative Procedures for SA-t-PE-Peptide Copolymers for Peptide Lengths of 3-20 Amino Acids of Any Sequence RGD peptide macromonomer (0.0342 g, 0.0023 mmol) was weighed into a 20 ml vial, followed by the addition of SA-t-PE (0.2 g, 0.12 mmol). Benzene (2.3 ml) was added and the mixture was stirred at 75° C. until a clear solution was obtained. A solution of catalyst 1 in benzene (1.25 mol%, 0.05 M) was added to the solution and the reaction was stirred at 75° C. for 22 hours. Ethyl vinyl ether was added to the reaction mixture, followed by MeOH (15 ml) to give a beige precipitate. The mixture was filtered and the residue was washed five times with methanol and dried in a vacuum oven overnight.

[0370] Regarding SA-t-PERGD copolymer, 1 H NMR: 6.0 (s, unreacted SA-t-PE), 5.62-5.38 (m), 3.65 (PEG), 1.46 (t, CH2), 1.02 (PE CH3).

[0371] Example 8: Amine-terminated polyethylene (PE)-peptide copolymers 8.1. Amine-Terminated PE-RGD Copolymers This example demonstrates a one-pot, two-step strategy for generating primary amine termini on polyethylene and their subsequent use in macromonomer synthesis and subsequent copolymerization with biomacromonomers to form bioactive polyethylene copolymers. In this method, linear primary amines are generated using polyethylene via hydroaminomethylation and subsequently used in macromonomer formation with cis-norbornene-exo-2,3-dicarboxylic anhydride. Bioactive polyethylene can be generated by copolymerizing this PE macromonomer with a biomolecule-containing macromonomer. PE-RGD copolymers are reported here as examples of bioactive PE compatible with human dermal fibroblasts.

[0372] 8.1.1.PE macromonomer To obtain primary amine termini on polyethylene (PE) for macromonomer formation, hydroaminomethylation of vinyl-terminated PE was carried out in a one-pot, two-step process in which it was first converted to a linear carbonyl via hydroformylation followed by reductive amination in the presence of hexamethylenediamine (HMDA) or NH3 gas (Scheme 4.2). The linear-to-branched ratio here was excellent, and no branched carbonyls or amines were detected. Negligible amounts of linear alcohols (<1%) were detected in the crude product.

[0373] After obtaining the amine-terminated PE, condensation with cis-norbornene-exo-2,3-dicarboxylic anhydride affords the PE macromonomer (Scheme 4.3), which could be used in the formation of brush polymers either with itself or with other macromonomers.

[0374] 8.1.2. PE-Peptide Copolymers To demonstrate the formation of bioactive PE using PE macromonomers, PE macromonomers were reacted with PEGylated RGD macromonomers using ring-opening metathesis polymerization (ROMP) with Grubbs catalyst to give copolymers of PE and PEGylated RGD (Scheme 8.1).

[0375] [ka]

[0376] 8.2.Thermal stability The PERGD copolymer was checked for thermal stability before undergoing material processing. TGA analysis of the copolymer showed that the polymer underwent 50% weight loss at 465°C, indicating its high thermal stability compared to pure RGD itself, which has a decomposition temperature below 200°C (Figure 6).

[0377] Biocompatibility Subsequently, the PERGD copolymer was blended with medical grade PLA and electrospun into nanofibers for biocompatibility testing with Hs27 human fibroblast cells grown in Dulbecco's Modified Eagle Medium (DMEM) with 10% FBS and 1% Pen / Strep. Cell viability testing on electrospun samples for 72 hours shows that PERGD exhibits little cell proliferation compared to the negative control or pure PLA at 25% PERGD / PLA blend ratio, as well as much better cell viability than commercial wound dressings Acticoat and Allevyn (Figure 7). Live cells are essential for cell proliferation.

[0378] In conclusion, amine-terminated PE was successfully produced using a one-pot, two-step hydroaminomethylation reaction in the presence of HMDA, and PE macromonomers were constructed using it. Bioactive PE copolymers were also produced, using PERGD as an example, and successfully tested for human skin biocompatibility.

[0379] 8.4. Materials and Methods 8.4.1 General Procedure Ring-opening metathesis polymerization reactions and RGD macromonomer synthesis were carried out in a Vacuumu Atmosphere glove box under nitrogen atmosphere. PEHMDANB macromonomer was synthesized under ambient conditions. PEHMDA synthesis was carried out in a Hastelloy pressure reactor equipped with a PTFE gasket from Parr Instrument. All solvents used - anhydrous benzene and anhydrous methanol from Alfa Aesar, were used as purchased in a glove box. Grubbs second generation catalyst was purchased from Sigma Aldrich and all peptides were purchased from Biomatik Inc. [Rh(acac)(CO)2], [Ir(COD)Cl]2, Xantphos, HMDA, triethylamine and PEG diamine were purchased from Alfa Aesar. All purchased reagents were used without further purification. Vinyl-terminated PE (MW 1,400-5,000) was obtained according to literature methods (Macromolecules 2009, 42, 4356-4358; following the second example in Supporting Information).

[0380] 1 H NMR spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer. GPC chromatograms were * PLgel Mixed B column (300 × 7.5 mm, particle size 10 μm) and 1 * The data were recorded on an Agilent Infinity II High Temperature GPC system equipped with a PLgel Mixed B guard column (50×7.5 mm). The eluent was TCB with a flow rate of 1 ml / min and an oven temperature of 160° C. Polystyrene was used as the calibration standard.

[0381] PERGD copolymer was blended with PLA in a 1:4 ratio and electrospun into sheets of fibers, which were then sterilized with 70% ethanol, dried, incubated with fibroblasts Hs27 for 72 hours and checked for cell viability using the Celltitre-Glo assay.

[0382] 8.4.2. Synthesis of PEHMDA Vinyl-terminated PE (0.35 g, 0.25 mmol) and Xantphos (0.0036 g, 6.25 μmol) were weighed into a 25 ml pressure reactor, followed by the addition of toluene (3.5 ml). Rh(acac)(CO)2 was then (0.5 ml, 0.65 mg / ml, 1.25 μmol) was added to the mixture. The vessel was sealed, flushed five times with CO / H2(g) (1:1), and pressurized to 45 bar with gas. The mixture was stirred at 100° C. for 12 hours and then cooled. HMDA (0.0581 g, 0.5 mmol) was dissolved in toluene (1 ml) and added to the cooled mixture, followed by the addition of [Ir(COD)Cl]2 (1 ml, 0.84 mg / ml). The vessel was sealed, flushed five times with H2(g), and pressurized to 20 bar with gas. The mixture was stirred at 135° C. for 4 h, cooled, and then MeOH was added to give a white precipitate. The precipitate was filtered and the residue was washed repeatedly with MeOH and then dried in a vacuum oven to give a white solid product of PEHMDA in 68% yield. 1 H NMR (toluene-d8, 90° C.): δ=0.91 (t, 3H), 1.36 (br, s, 148H), 1.47-1.44 (m), 2.61-2.54 (m, 6H at 68% conversion).

[0383] 8.4.3.PECH 2 NH 2 Synthesis of Vinyl-terminated PE (0.35 g, 0.25 mmol) and Xantphos (0.0036 g, 6.25 μmol) were weighed into a 50 ml pressure reactor, after which toluene (3.5 ml) was added. Rh(acac)(CO)2 was then added (0.5 ml, 0.65 mg / ml, 1.25 μmol) to the mixture. The vessel was sealed, flushed five times with CO / H2(g) (1:1), and pressurized to 45 bar with gas. The mixture was stirred at 100° C. for 12 hours and then cooled. [Ir(COD)Cl]2 (1 ml, 0.84 mg / ml) was added to the cooled mixture, the vessel was sealed, flushed five times with NH3(g), and pressurized to 3 bar with NH3(g). The vessel was further pressurized with an additional 20 bar of H2(g). The mixture was then stirred at 135° C. for 3 h, cooled, and then MeOH was added to give a white precipitate. The precipitate was filtered and the residue was washed repeatedly with MeOH and then dried in a vacuum oven to give the white solid product of PECH2NH2 in 61% yield. 1 H NMR (toluene-d8, 90 °C): δ = 0.90 (t, 3H), 1.34 (br, s, 194H), 2.58 (t, 2H in 61% yield).

[0384] Synthesis of PEHMDANB PEHMDA and PECH2NH2 cannot be separated from the unreacted PE and are used as a mixture. The amounts of PEHMDA and PECH2NH2 used are calculated based on their respective percentages in the sample mixture containing unreacted PE.

[0385] PEHMDA (0.2 mmol) and cis-norbornene-exo-2,3-dicarboxylic anhydride (0.04 g, 0.25 mmol) were weighed into an rbf followed by the addition of toluene (20 ml) and Et3N (28 μL, 0.2 mmol). The flask was equipped with a dean stark trap and the mixture was refluxed for 12 h. The reaction was cooled and MeOH was added to the mixture to give a white precipitate in a pale yellow solution. The mixture was filtered and the residue was washed repeatedly with MeOH to give an off-white product. 1H NMR (toluene-d8, 90 °C): 5.89(s), 5.87(s), 3.42(t), 3.01(t), 2.53-2.60(m), 2.19(s), 1.37(br s), 0.92(t). The product exists as a mixture of PEHMDANB and unreacted PE.

[0386] 8.4.5. Procedures for ROMP of PEHMDANB Macromonomers and RGD Peptide Macromonomers as Representative Procedures for PE-Peptide Copolymers, for Peptide Lengths of 3-20 Amino Acids of Any Sequence RGD peptide macromonomer (0.0342 g, 0.0023 mmol) is weighed into a 20 ml vial, followed by the addition of PEHMDANB (0.12 mmol). Benzene (2.3 ml) is added and the mixture is stirred at 75° C. until a clear solution is obtained. A solution of Grubbs catalyst (2nd generation) in benzene (1.25 mol%, 0.05 M) is added to the solution and the reaction is stirred at 75° C. for 22 hours. Ethyl vinyl ether is added to the reaction mixture followed by MeOH (15 ml) to give a beige precipitate. The mixture is filtered and the residue is washed five times with MeOH and dried in a vacuum oven overnight. For PERGD, 1 H NMR (toluene d8, 90 °C): δ = 5.88 (s), 5.85 (s) (unreacted PEHMDANB), 5.46-5.42 (m), 3.53 (br s, PEG), 3.4 (t), 2.57-2.53 (m), 1.36 (br s, PECH2), 0.91 (br s, PECH3). The sample contains unreacted PE.

[0387] Example 9: Uses The present disclosure provides a new modular synthesis method to create softer, more biocompatible PE / PP blends. The bioactive polyethylene copolymer embodiments disclosed herein exhibit the following properties: Non-toxic to skin; Increased thermal stability for material processing compared to pure collagen, which denatures at 37°C; and Increased structural integrity compared to pure collagen, oligopeptides or oligosaccharides present in gels or hygroscopic crystals has one or more of the following.

[0388] Advantageously, embodiments of the bioactive polyethylene copolymers disclosed herein allow for the blending of biomolecules (e.g., collagen) into synthetic polymer base materials similar to the synthetic polymer side arms of the copolymer (e.g., polypropylene) without phase separation, despite the incompatible material properties that exist between the hydrophobic PP and hydrophilic collagen.

[0389] The bioactive polyethylene copolymer embodiments disclosed herein have demonstrated good thermal stability and biocompatibility data. Advantageously, the bioactive polyethylene copolymer embodiments disclosed herein can be used to manufacture consumer care products such as diapers and feminine care products, or biomedical devices such as joint implants, intestinal stents, wound dressings, cartilage implants, etc.

[0390] The present disclosure provides a new modular synthetic method to rapidly generate bioactive macromonomers for the construction of bioactive copolymers with optimal bioactive molecules depending on the target application or required bioactivity. Bioactive macromonomers can be easily copolymerized with polyethylene to form biopolyethylene copolymers with desired physical and mechanical properties. Advantageously, there is increased stability of the bioactive molecules upon attachment to the polymer linker. The embodiments of the strategy disclosed herein allow any peptide, carbohydrate or drug molecule to be used in polymer synthesis without loss of bioactivity. The embodiments of the strategy disclosed herein also allow for the rapid construction of bioactive macromonomer libraries. Any bioactive molecule with a carboxylic acid group may be used. In summary, the present disclosure provides a highly versatile strategy for the customization of biomedical materials.

[0391] Embodiments of the methods disclosed herein allow for the pairing of macromonomers with synthetic polymers of choice to create bioactive polymers that have both the mechanical and physical properties of the synthetic polymer and the biological activity of the bioactive molecule.

[0392] An embodiment of the method disclosed herein is a simple strategy to create various types of bioactive polymers that are chemically linked, instead of physically blending, bioactive molecules into synthetic polymers.

[0393] Advantageously, non-cellular or growth factor based bioactivity is provided on the polymers disclosed herein. The bioactive polyethylene copolymer embodiments disclosed herein have both bioactivity to enhance therapeutic effects such as tissue regeneration, biofilm eradication, and also polymer-like structural integrity and mechanical strength. The bioactive polyethylene copolymer embodiments disclosed herein allow biomolecules to be blended into the synthetic polymer base material as well as the synthetic polymer side arms of the copolymer without phase separation. The method embodiments disclosed herein allow polyethylene to become biocompatible with human tissue upon modification with biomolecules. The method embodiments disclosed herein allow a wide range of biomolecules to be used to achieve any desired therapeutic effect. The method embodiments disclosed herein also allow a wide range of synthetic polymers to be used to achieve the various mechanical and physical properties required in the material for the targeted biodevice.

[0394] Embodiments of the bioactive polyethylene copolymers disclosed herein may be used as bioadditives for biomedical devices, allowing the device material itself to provide a therapeutic effect.

[0395] Embodiments of the methods disclosed herein use non-cell-based or growth factor-based therapies, which allow for a long shelf life of materials such as devices or scaffolds and prevent undesirable or uncontrolled bioactivity (e.g., tissue regeneration).

[0396] Embodiments of the bioactive polyethylene copolymers disclosed herein may be used as bioadditives for wound dressings, cartilage implants or bone scaffolds to create the stimulation needed for the regeneration of skin, cartilage or bone tissue.

[0397] It will be appreciated by those skilled in the art that other variations and / or modifications may be made to the embodiments disclosed herein without departing from the spirit or scope of the present disclosure as broadly described. For example, features of the various exemplary embodiments described herein may be mixed, combined, substituted, incorporated, adopted, modified, included, etc. across the various exemplary embodiments. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive.

Claims

1. One or more repeating units represented by general formula (I) and one or more repeating units represented by general formula (II): 【Chemistry 1】 (In the formula, R １ is an optionally substituted alkylene; R ２ is selected from a single bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alkyleneoxyalkylene, optionally substituted alkylenecarbonyl, or optionally substituted alkylenecarbonylalkylene; R ３ is selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; L is polyethylene glycol (PEG) having a number average molecular weight between 500 and 7,000; X comprises a biologically active moiety selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof; Z １ and Z ２ are each independently ａ R ｂ , O., N.R. ｃ , SiR ａ R ｂ , P.R. ａ or S, where R ａ , R ｂ , and R ｃ are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and Y is represented by the general formula (III): 【Chemistry 2】 (In the formula, A is optionally present as NR c , where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is selected from optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alkyleneoxyalkylene, optionally substituted alkylenecarbonyl, or optionally substituted alkylenecarbonylalkylene; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is 10 to 350. (represented by A bioactive polyethylene copolymer having a poly(norbornene) backbone comprising:

2. The copolymer of claim 1 , wherein n is from 20 to 250.

3. B is present and has the general formula: 【Chemistry 3】 (In the formula, R ６ａ , R ６ｂ , R ６ｃ and R ６ｄ are each independently C, CR ａ , C.R. ａ R ｂ , N.R. ｃ , O or S, where R ａ , R ｂ , and R ｃ are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and R ７ａ , R ７ｂ and R ７ｃ is ═O, ═S, -F, -Cl, -Br, -I, ═CR ａ R ｂ , -CR ａ R ｂ R ｃ , -OH, -SH, -NH ２ Or = NR ｃ 3. The copolymer of claim 1 or claim 2, wherein

4. Y is represented by the following general formula (IIIa), (IIIb) or (IIIc): 【Chemistry 4】 (In the formula, R ５ is C １ -C ２０ Alkylene, C ２ -C ２０ Alkenylene, C ２ -C ２０ Alkynylene, C １ -C ２０ Alkyleneoxy, C １ -C ２０ Alkyleneoxyalkylene, C ２ -C ２０ Alkylenecarbonyl and C ３ -C ２０ alkylenecarbonylalkylene; R ６ａ and R ６ｄ are each independently C, CR ａ , C.R. ａ R ｂ , N.R. ｃ , O or S, where R ａ , R ｂ , and R ｃ are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ７ａ is ═O, ═S, -F, -Cl, -Br, -I, ═CR ａ R ｂ , -CR ａ R ｂ R ｃ , -OH, -SH, -NH ２ Or = NR ｃ Optionally present as T is a terminal group selected from the group consisting of hydrogen and methyl; and n is 10 to 350. The copolymer of claim 1 , wherein the copolymer is selected from the group consisting of

5. Y is represented by the following general formula (IIId), (IIIe) or (IIIf): 【Chemistry 5】 (In the formula, R ５ is C １ -C ２０ Alkylene, C ２ -C ２０ Alkenylene, C ２ -C ２０ Alkynylene, C １ -C ２０ Alkyleneoxy, C １ -C ２０ Alkyleneoxyalkylene, C ２ -C ２０ Alkylenecarbonyl and C ３ -C ２０ alkylenecarbonylalkylene; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is 10 to 350. The copolymer of claim 1 , wherein the copolymer is selected from the group consisting of

6. 6. The copolymer of claim 1, wherein the repeat unit represented by general formula (I) is in an amount of from 1 to 100 mol % relative to the copolymer.

7. 7. A copolymer according to any one of claims 1 to 6, in which the molecular weight of the compound of general formula (I) does not differ from that of the compound of general formula (II) by more than 30% of the molecular weight of the compound of general formula (II).

8. R １ C １ -C ４ alkylene, and R ２ C １ -C ２０ Alkylene, C ２ -C ２０ Alkenylene, C ２ -C ２０ Alkynylene, C １ -C ２０ Alkyleneoxy, C １ -C ２０ Alkyleneoxyalkylene, C ２ -C ２０ Alkylenecarbonyl or C ３ -C ２０ 8. The copolymer of claim 1 , wherein the alkylene group is selected from alkylene carbonyl alkylene.

9. R １ is a linear or branched C independently selected from methanediyl, ethanediyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, 2-methylpropane-1,3-diyl, 1-methylpropane-1,3-diyl, or 1,1-dimethylethanediyl １ -C ４ is an alkylene substituent, and R ２ methanediyl, ethanediyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, 2-methylpropane-1,3-diyl, 1-methylpropane-1,3-diyl, 1,1-dimethylethanediyl, hexane-1,6-diyl, 1,2-dimethylpropane-1,3-diyl, 1,1-dimethylpropane-1,3-diyl, pentane-1,5-diyl, 3-methylbutane-1,4-diyl 4-methylpentane-1,5-diyl, 1-methylpentane-1,5-diyl, 2-methylpentane-1,5-diyl, 3-methylpentane-1,5-diyl, 2,2-dimethylbutane-1,4-diyl, 3,3-dimethylbutane-1,4-diyl, 1,2-dimethylbutane-1,4-diyl, 1,3-dimethylbutane-1,4-diyl, 1,2,2-trimethylpropane-1,3-diyl, 1,1,2-trimethylpropane-1,3-diyl, 1,3-dimethylpropane-diyl, 2-ethylpentane-1,5-diyl, 3-ethylpentane-1,5-diyl, heptane-1,7-diyl, 1-methylhexane-1,6-diyl, 2,2-dimethylpentane-1,5-diyl, 3,3-dimethylpentane-1,5-diyl, 4,4-dimethylpentane-1,5-diyl, 1,2-dimethylpentane-1,5-diyl, 1,3-dimethylpentane-1,5-diyl linear or branched C independently selected from 1,4-dimethylpentane-1,5-diyl, 1,2,3-trimethylbutane-1,4-diyl, 1,1,2-trimethylbutane-1,4-diyl, 1,1,3-trimethylbutane-1,4-diyl, 5-methylheptane-1,7-diyl, 1-methylheptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, or decane-1,10-diyl; １ -C ２０ 9. The copolymer of claim 1, wherein the substituent is an alkylene.

10. Z １ and Z ２ Both are CR ａ R ｂ where R ａ and R ｂ 10. The copolymer of claim 1, wherein each is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

11. 11. The copolymer of any one of claims 1 to 10, wherein X comprises a protein, peptide, or carbohydrate selected from the group consisting of peptide sequences, laminin-derived peptides, integrin-binding peptides, cell-penetrating peptides, collagen sequences, collagen mimetics, collagen fragments, heparan sulfate, glycosaminoglycans (GAGs), and derivatives thereof.

12. X is RGD, SRGDS, RGDS, A5G81 (AGQWHRVSVRWGC), SVVYGLR, (IRIK) ２ , (IKKI) ３ , DGEA, (PHypG) ｎ Type sequence, (PGHyp) ｎ Type sequence, (HypGP) ｎ Type sequence, (HypPG) ｎ Type sequence, (GHypP) ｎ Type sequence, (GPHyp) ｎ 12. The copolymer of claim 1 , wherein the copolymer is selected from the group consisting of heparin oligosaccharides DP8, DP10, DP12, DP14, DP16 and hyaluronic acid.

13. 13. A method for preparing a bioactive polyethylene copolymer of any one of claims 1 to 12, comprising: One or more bioactive polymers represented by general formula (IV) are polymerized with one or more polyethylene polymers represented by general formula (V) in the presence of a catalyst to produce a bioactive polyethylene copolymer: 【Chemistry 6】 (In the formula, R １ is an optionally substituted alkylene; R ２ is selected from a single bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alkyleneoxyalkylene, optionally substituted alkylenecarbonyl, or optionally substituted alkylenecarbonylalkylene; R ３ is selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; L is polyethylene glycol (PEG) having a number average molecular weight between 500 and 7,000; X comprises a biologically active moiety selected from the group consisting of proteins, peptides, carbohydrates, therapeutic / drug molecules and derivatives thereof; Z １ and Z ２ are each independently ａ R ｂ , O., N.R. ｃ , SiR ａ R ｂ , P.R. ａ or S, where R ａ , R ｂ , and R ｃ are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and Y is represented by the general formula (III): 【Chemistry 7】 (In the formula, A is optionally present as NR c , where R c is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R 5 is selected from optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alkyleneoxyalkylene, optionally substituted alkylenecarbonyl, or optionally substituted alkylenecarbonylalkylene; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is 10 to 350. (represented by The method of claim 1, further comprising:

14. The method of claim 13 , wherein the catalyst comprises a ruthenium complex.

15. 15. The method of any one of claims 13 to 14, wherein the method comprises ring-opening metathesis polymerization (ROMP).

16. For preparing the copolymer of any one of claims 1 to 12, a polyethylene polymer represented by the general formula (VIII): 【Chemistry 8】 (In the formula, R ２ is selected from a single bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alkyleneoxyalkylene, optionally substituted alkylenecarbonyl, or optionally substituted alkylenecarbonylalkylene; Z ２ is CR ａ R ｂ , O., N.R. ｃ , SiR ａ R ｂ , P.R. ａ or S, where R ａ , R ｂ , and R ｃ are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; A is NR ｃ where R ｃ is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R ５ is selected from optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alkyleneoxyalkylene, optionally substituted alkylenecarbonyl, or optionally substituted alkylenecarbonylalkylene; T is a terminal group selected from the group consisting of hydrogen and methyl; and n is from 10 to 350).

17. 17. A method for preparing the polyethylene polymer of claim 16, comprising: (i) General formula (IX): 【Chemistry 9】 (In the formula, Z ２ is CR ａ R ｂ , O., N.R. ｃ , SiR ａ R ｂ , P.R. ａ or S, where R ａ , R ｂ , and R ｃ are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and (ii) reacting said dicarboxylic anhydride having general formula (IX) with an amine to obtain a polyethylene polymer, wherein the amine has general formula (X): 【Chemistry 10】 (In the formula, R ２ is selected from a single bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alkyleneoxyalkylene, optionally substituted alkylenecarbonyl, or optionally substituted alkylenecarbonylalkylene; A is NR ｃ where R ｃ is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; B is optionally present as a 5- or 6-membered heterocycle having at least one N heteroatom in the ring; R ５ is C １ -C ２０ Alkylene, C ２ -C ２０ Alkenylene, C ２ -C ２０ Alkynylene, C １ -C ２０ Alkyleneoxy, C １ -C ２０ Alkyleneoxyalkylene, C ２ -C ２０ Alkylenecarbonyl and C ３ -C ２０ alkylenecarbonylalkylene; T is a terminal group selected from the group consisting of hydrogen and methyl; n is 10 to 350. (represented by A method comprising:

18. Prior to step (ii), (ai) General formula (XIa) or (XIb): 【Chemistry 11】 (In the formula, R ６ａ and R ６ｄ are each independently C, CR ａ , C.R. ａ R ｂ , N.R. ｃ , O or S, where R ａ , R ｂ , and R ｃ are each independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ７ａ is ═O, ═S, -F, -Cl, -Br, -I, ═CR ａ R ｂ , -CR ａ R ｂ R ｃ , -OH, -SH, -NH ２ Or = NR ｃ Optionally present as R ８ and R ９ are each independently １ -C ２０ Alkylene, C ２ -C ２０ Alkenylene, C ２ -C ２０ Alkynylene, C １ -C ２０ Alkyleneoxy, C １ -C ２０ Alkyleneoxyalkylene, C ２ -C ２０ Alkylenecarbonyl and C ３ -C ２０ alkylenecarbonylalkylene; T is a terminal group selected from the group consisting of hydrogen and methyl; n is 10 to 350. providing a polyethylene having (b-i) Treating the polyethylene having the general formula (XIa) or (XIb) with a diamine H ２ N-R ２ -NH ２ or ammonia NH ３ to obtain an amine having the general formula (X) 20. The method of claim 17, further comprising:

19. The process according to claim 17 or 18, wherein at least one of step (ii) and step (bi) is carried out in the presence of an organic solvent and / or a base.

20. 20. The method of claim 19, wherein the organic solvent comprises an aromatic solvent; and the base comprises a tertiary amine.

21. A material comprising a copolymer according to any one of claims 1 to 12 for use in medicine.

22. 22. The material of claim 21, wherein the material is part of an appliance selected from the group consisting of consumer care products, wound dressings, skin scaffolds, bone and bone marrow organoid scaffolds, cartilage implants, joint implants and medical devices.

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