Lubricating block copolymers and their use as biomimetic interfacial lubricants

Abstract

The present invention relates to a method of lubricating a biological tissue (such as a joint, bone, eye tissue, nasal tissue, tendon, tendon sheath, and vaginal tissue) by contacting the biological tissue with an effective amount of a block copolymer lubricating composition, the function of the block copolymer lubricating composition being at least equal to or superior to that of lubricin. In a particular embodiment, the method is used for treating osteoarthritis. In a specific embodiment, the block copolymer has a polymer block containing ammonium and a nonionic hydrophilic polymer block, or the copolymer has a polymer block containing carboxylic acid and a non-acidic nonionic hydrophilic polymer block.

Description

[0001] This application is a divisional application of a Chinese patent application with the application number 201780074895.5, the filing date of October 4, 2017, and the invention title of "Lubricating Block Copolymers and Their Use as Biomimetic Interfacial Lubricants". The original application is a national stage application of an international application with the international application number PCT / US2017 / 055057. This international application claims the priority of a US provisional patent application with the filing date of October 4, 2016 and the application number 62 / 403,962, the entire content of which is incorporated herein by reference. Field of the Invention

[0002] The present invention mainly relates to pharmaceutically acceptable lubricating compositions and their use in methods for lubricating biological tissues (especially joints, cartilage, and bone surfaces). The present invention more particularly relates to polymer compositions that mimic the action of lubricin, and more specifically to methods of using such compositions to treat various conditions (such as osteoarthritis), where the effect of lubrication on treating and improving the disease or condition is particularly beneficial. Background Art

[0003] Lubricin is a glycosylated protein present in synovial fluid that plays a key role in joint boundary lubrication and the prevention of osteoarthritis. Lubricin reduces the coefficient of friction (COF) of articular cartilage in the boundary mode by up to 70% (Gleghorn, J.P. et al., J. Orthop. Res. 2009, 27(6), 77). This effective lubricating ability stems from the structure of lubricin: the central mucin-like domain of lubricin consists of a core protein that is extensively glycosylated, which attracts and retains water in the vicinity of the molecule; the C-terminus of lubricin binds the protein to the cartilage surface (Zappone, B. et al., Langmuir 2008, 24(4), 1495). This structure is crucial for the boundary mode lubrication of articular cartilage, as denaturation of any domain of lubricin will result in partial or complete loss of lubricating ability.

[0004] In developed countries, more than 50 million people suffer from osteoarthritis (OA), and this number is expected to increase with the growth of the median age and life expectancy. In the United States alone, the annual economic impact of treating osteoarthritis exceeds $30 billion. The economic burden and other factors (i.e., quality of life, lost work hours, etc.) have motivated the development of more effective treatments.

[0005] Current treatments for osteoarthritis (OA) include non-steroidal anti-inflammatory drugs, intra-articular corticosteroid injections, and chondroitin sulfate or glucosamine supplements. However, they have little or no effect on disease progression. A recent approach to treating OA is the intra-articular injection of native synovial glycosaminoglycans, hyaluronic acid (HA) (e.g., Mabuchi et al., (1994) J. Biomed. Mat. Res. 28:865–70), and HA is known to increase the viscosity of synovial fluid (e.g., viscosupplementation) to reduce the coefficient of friction in hydrodynamic mode lubrication (e.g., Tadmor et al., (2002) J. Biomed. Mat. Res. 61:514–23). Another major lubricating component in synovial fluid is lubricin, a high molecular weight glycoprotein that reduces the coefficient of friction in boundary mode lubrication.

[0006] In damaged cartilage, it is well known that lubricin production by chondrocytes is impaired and boundary mode lubrication is reduced. Natural lubricants in nature, such as proteoglycan aggregates and mucins (e.g., lubricin), keep natural surfaces hydrophilic. In a disease model of rats, intra-articular injection of lubricin as a supplement and a truncated recombinant lubricin construct LUB:1 slowed the progression of OA (e.g., Jay et al., (2010) Arthritis Rheum. 62:2382–91; Flannery et al., (2009) Arthritis Rheum. 60:840–7). However, to date, large-scale recombinant production of lubricin and LUB:1 remains challenging, due to multiple amino acid repeats in the core structure of the above proteins and their high glycosylation (e.g., Jay (2004) Curr. Opin. Orthop. 15:355–359; Jones et al., (2007) J. Orthop. Res. 25:283-292). In cases where direct bone-to-bone contact may occur in the late stages of osteoarthritis, effective bone lubricants are also separately required. Therefore, an effective lubricant that can provide the same or similar boundary lubrication effect as lubricin or LUB:1 would be a significant advancement in this field. Summary of the Invention

[0007] The present disclosure relates to the design, synthesis, and use of specific block copolymers having a lubricin-mimicking structure, and which provide significant lubricating ability under boundary mode lubrication conditions. In certain embodiments, the block copolymer contains a lubricating block (e.g., M n ~200 kDa), which mimics the mucin-like domain of lubricin, and a smaller cartilage-binding block (e.g., M n~3 kDa), which mimics the hemopexin-like domain. As disclosed below in this application, application of this type of polymer to bovine articular cartilage or bone lacking lubricin results in a significant reduction in the coefficient of friction (COF) compared to untreated controls.

[0008] In one aspect, the present invention relates to a block copolymer having the following structure:

[0009]

[0010] wherein: R 1 、R 2 and R 3 are independently selected from hydrocarbon groups having at least 1 and at most 12 carbon atoms; X and X' are independently selected from –NR'–, –O– and a bond, where R' is selected from a hydrogen atom and hydrocarbon groups having at least 1 and at most 6 carbon atoms; Y is selected from polyalkylene glycols, sugars and polyols; the subscripts a and b are independently integers of at least 3; and the subscript c is an integer of at least 1. According to the laws of chemistry, the block copolymer is capped at each end with end groups, and the total positive charge of the quaternary ammonium groups in the copolymer is offset by an equal amount of total negative charge provided by anions associated with the ammonium groups.

[0011] In another aspect, the present invention relates to a block copolymer having the following structure:

[0012]

[0013] wherein: X is selected from –NR'–, –O– and a bond, where R' is selected from a hydrogen atom and hydrocarbon groups having at least 1 and at most 6 carbon atoms; Y is selected from polyalkylene glycols, sugars and polyols; R is a hydrogen atom, a hydrocarbon group having 1-12 carbon atoms (R) or a cartilage-binding domain; the subscripts d and e are independently integers of at least 3; and the subscript f is 0 or an integer of at least 1. In the formula, the hydrogen atom on the shown carboxylic acid group is optionally replaced by a positively charged metal ion or a positively charged organic group. According to the laws of chemistry, the end of the block copolymer opposite to the thiol group is capped with an end group.

[0014] In another aspect, the present invention relates to a method of imparting an appropriate level of lubricity to biological tissue, the method comprising contacting the biological tissue with a sufficient amount of a lubricating composition to increase the lubricity of the biological tissue. The lubricating composition can be, for example, any of the block copolymers described above. The biological tissue can be selected from, for example, joints, bones, eye tissues, nasal tissues, tendons, tendon sheaths and vaginal tissues. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1: General representation of an exemplary diblock copolymer of the invention, identifying the binding block and the lubricating block portions.

[0016] Figure 2 : Graphs describing the coefficient of friction (COF) of phosphate buffered saline (PBS) solution, Figure 1 the diblock copolymer, the binding block only and the lubricating block only.

[0017] Figure 3 : As part of the competitive binding study, graphs describing how the COF of the solution varies with the ratio of the binding block to the diblock copolymer.

[0018] Figure 4 : Describing Figure 1 the COF of the diblock copolymer and the random copolymer form of the diblock copolymer (i.e., having the same monomer units, but inserted into the copolymer in a random rather than block form), the latter synthesized by random RAFT copolymerization of the two block monomers followed by quaternary ammonium conversion.

[0019] Figure 5A , 5B: Figure 5A is a graph describing COF as Figure 1 a function of the concentration of the diblock copolymer in Figure 5B is a graph describing COF as a function of incubation time, with the copolymer at 1 mg / mL for different durations. The resulting graph can be considered a binding kinetic curve.

[0020] Figure 6A , 6B: Figure 6A and Figure 6B are graphs respectively describing the COF of trabecular bone and subchondral bone samples treated with a diblock copolymer (3) solution (10 mg / mL for 2 hours or 1 mg / mL for 1 hour) or PBS solution. DETAILED DESCRIPTION OF THE INVENTION

[0021] In a first aspect, the invention relates to a block copolymer that mimics lubricin, which mimics is effected by having a mucin-like domain and a C-terminal hemopexin-like (PEX-like) domain. The copolymer can for example comprise a polymer block containing a positively or negatively charged side group, and a polymer block containing a nonionic hydrophilic side group, particularly a hydrophilic group containing an ether and / or hydroxyl functional group. In the case where the side group is a polymer, the copolymer can be further classified as a graft brush copolymer. As used in this application, the term "copolymer" means that there are at least two polymer blocks. The copolymer can be for example a diblock copolymer, a triblock copolymer, a tetrablock copolymer or a more multi-block copolymer.

[0022] The first type of block copolymer considered in this application includes the following general formula structure:

[0023]

[0024] The substituent R in formula (1) 1 , R 2 and R 3 are independently selected from hydrocarbyl groups (R) having at least 1 and at most 12 carbon atoms. In some embodiments, the substituents R 1 , R 2 and R 3 can be more specifically defined as having exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, or a specific range of carbon atoms therein, such as 1 - 10, 1 - 8, 1 - 6, 1 - 4, 1 - 3, 2 - 12, 2 - 10, 2 - 8, 2 - 6, 2 - 4, 3 - 12, 3 - 10, 3 - 8 or 3 - 6 carbon atoms. In some embodiments, R 1 , R 2 and R 3 are exactly the same, while in other embodiments R 1 , R 2 and R 3 are not exactly the same (or at least two of R 1 , R 2 and R 3 are different). The hydrocarbyl group R can be saturated or unsaturated, straight-chain (linear) or branched, and cyclic or acyclic.

[0025] In one set of embodiments, R 1 , R 2 and R 3at least one, two or all of which are selected from hydrocarbon groups consisting only of carbon and hydrogen. The hydrocarbon groups consisting only of carbon and hydrogen can be, for example, alkyl groups, alkenyl groups, cycloalkyl groups, cycloalkenyl groups (aliphatic) or aromatic groups. Some examples of straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Some examples of branched-chain alkyl groups include isopropyl (2-propyl), isobutyl (2-methylprop-1-yl), sec-butyl (2-butyl), tert-butyl, 2-pentyl, 3-pentyl, 2-methylbut-1-yl, isopentyl (3-methylbut-1-yl), 1,2-dimethylprop-1-yl, 1,1-dimethylprop-1-yl, neopentyl (2,2-dimethylprop-1-yl), 2-hexyl, 3-hexyl, 2-methylpent-1-yl, 3-methylpent-1-yl and isohexyl (4-methylpent-1-yl), where the “-1-yl” suffix represents the point of attachment of the group. Some examples of straight-chain alkenyl groups include vinyl, prop-1-en-1-yl (allyl), 3-buten-1-yl (CH2=CH-CH2-CH2-), 2-buten-1-yl (CH2-CH=CH-CH2-), butadienyl and 4-penten-1-yl. Some examples of branched-chain alkenyl groups include prop-2-en-1-yl, 3-buten-2-yl (CH2=CH-CH.-CH3), 3-buten-3-yl (CH2=C.-CH2-CH3), 4-penten-2-yl, 4-penten-3-yl, 3-penten-2-yl, 3-penten-3-yl and 2,4-pentadien-3-yl, where the dot in the foregoing exemplary formula represents a radical (i.e., the point of attachment of the group). Some examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl group can also be a polycyclic (e.g., bicyclic) group having a bond (e.g., dicyclohexyl) or shared (i.e., fused) side chains (e.g., decahydronaphthalene and norbornane) between two ring groups. Some examples of cycloalkenyl groups (aliphatic) include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl and cyclooctatetraenyl. Some examples of aromatic groups include phenyl and benzyl. The unsaturated cycloalkyl group can also be a polycyclic (e.g., bicyclic or tricyclic polyaryl) group having a bond (e.g., biphenyl) or shared (i.e., fused) side chains (e.g., naphthalene, anthracene, phenanthrene, fluoranthene or indene) between two ring groups.

[0026] In another set of embodiments, R 1 , R 2 and R 3at least one of which is selected from hydrocarbon groups containing at least one heteroatom (i.e., non-carbon and non-hydrogen atoms), such as one or more heteroatoms selected from oxygen, nitrogen, sulfur, and halogen atoms, and groups containing one or more of these heteroatoms (i.e., heteroatom-containing groups). In some embodiments, the hydrocarbon group does not contain hydrogen atoms (e.g., all hydrogen atoms therein are replaced by heteroatoms, such as in -CF3), while in other embodiments, the hydrocarbon group contains at least one hydrogen atom. Some examples of oxygen-containing groups include hydroxyl (OH), alkoxy (OR), carbonyl-containing groups (e.g., carboxylic acid, ketone, aldehyde, carboxylic acid ester, amide, and urea functional groups), nitro (NO2), carbon-oxygen-carbon (ether), sulfonyl, and sulfinyl (i.e., sulfoxide group). Some specific examples of alkoxy (-OR) include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenoxy, benzyloxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, vinyloxy, and allyloxy. In the case of an ether group, the ether group can also be a polyalkylene oxide (polyalkylene glycol) group, such as a polyethylene oxide group. Some examples of nitrogen-containing groups include primary amine, secondary amine, tertiary amine (i.e., -NR’2 or NR’3 + , where R’ is independently selected from H and the above hydrocarbon groups), nitrile (CN), amide (i.e., -C(O)NR’2 or -NRC(O)R’, where R’ is independently selected from a hydrogen atom and the above hydrocarbon groups), imine (e.g., -CR’=NR’, where R’ is independently H or a hydrocarbon group), urea (-NR’-C(O)-NR’2, where R’ is independently H or a hydrocarbon group), and carbamate group (-NR’-C(O)-OR’, where R’ is independently H or a hydrocarbon group). Some examples of sulfur-containing groups include mercapto (i.e., -SH), thioether (i.e., sulfide, e.g., -SR), disulfide (-R-S-S-R), sulfoxide (-S(O)R), sulfone (-SO2R), sulfonate (-S(=O)2OR”, where R” is H, a hydrocarbon group, or a cationic group), and sulfate group (-OS(=O)2OR”, where R” is H, a hydrocarbon group, or a cationic group). Some examples of halogen atoms include fluorine, chlorine, bromine, and iodine. One or more of the above-described heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) can be inserted between the carbon atoms of any of the above-described hydrocarbon groups (e.g., in the form of -O-, -NR’-, or -S-). Alternatively, or additionally, one or more heteroatom-containing groups can be used to replace one or more hydrogen atoms on the hydrocarbon group. In some embodiments, any one or more of the above groups are excluded.

[0027] The variables X and X’ in formula (1) are independently selected from –NR’–, –O–, and a bond, where R’ is selected from a hydrogen atom and a hydrocarbyl group having at least 1 and at most 6 carbon atoms (selected from the R groups). In some embodiments, R’ is particularly selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, or more specific selections thereof.

[0028] In the first case, the variable Y in formula (1) is or comprises a polyalkylene glycol group. The polyalkylene glycol group can be conveniently represented by the following structure: (-CR’2CR’2O-) n R’, where for each instance of R’, R’ is independently selected from a hydrogen atom and a hydrocarbyl group (e.g., methyl or ethyl), and n is at least 2, 3, 4, 5, or 6 and at most, for example, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500, or n is in the range defined by any two of the foregoing values, where each of the foregoing values corresponds to the number of alkylene oxide (-CR’2CR’2O-) monomer units. In certain embodiments, the polyalkylene glycol is a polyethylene glycol or polypropylene glycol group. Additionally, the polyalkylene glycol group may or may not be incorporated into a copolymer, such as a copolymer containing polyethylene glycol and an anionic polymer moiety, such as polyacrylic acid (PAA), polyglutamic acid, or polyaspartic acid.

[0029] In the second case, the variable Y in formula (1) is or includes a glycosyl group. As used herein, the term "sugar" includes monosaccharides (containing one monosaccharide unit) and saccharides containing at least or more than two monosaccharide units, such as disaccharides, trisaccharides, oligosaccharides (e.g., at least 4 and up to 20, 30, 40, 50 or 60 monosaccharide units), and polysaccharides (usually more than 60, 70 or 80 monosaccharide units, and up to, for example, 100, 200, 300, 400, 500 or 1000 monosaccharide units). Saccharides can also be derivatized in such a way (e.g., esterification, etherification, amination or halogenation) that the derivatized form can still be reasonably classified as a sugar by those skilled in the art. Some examples of monosaccharides include glucose, galactose, fructose, mannose, sialic acid, glucosamine, N-acetylglucosamine and galacturonic acid. Some examples of disaccharides include lactose, sucrose, maltose, trehalose, cellobiose and mannotriose. Some examples of oligosaccharides include fructooligosaccharides (FOS), galactooligosaccharides (GOS) and mannan oligosaccharides (MOS). Some examples of polysaccharides include dextran, dextran sulfate, starch (e.g., amylose or amylopectin), cellulose, hemicellulose, polysialic acid, pectin, glycogen, mannan, galactomannan, xylan, pullulan, xanthan gum, carrageenan, guar gum, polygalacturonic acid, poly(N-acetylgalactosamine), heparin, hyaluronic acid and chondroitin sulfate. In some embodiments, the saccharides are selected to have a total anionic charge, such as those saccharides having carboxylic acid, carboxylate, sulfate or sulfonate groups. The glycosyl group may or may not be incorporated into the copolymer, such as a copolymer containing an oligosaccharide moiety and an oligopeptide or polyacrylic acid moiety. In some embodiments, the copolymer containing saccharides contains a saccharide moiety and an anionic polymer moiety, such as polyacrylic acid (PAA), polyglutamic acid or polyaspartic acid.

[0030] In a third case, the variable Y in formula (1) is or includes a polyol group. As used herein, the term "polyol" refers to a non-saccharide group having multiple (i.e., at least 2, 3, or 4) hydroxyl groups. The polyol can be, for example, a sugar alcohol or a polyhydric alcohol. Some examples of sugar alcohols include erythritol, xylitol, mannitol, glycerol, and sorbitol. The saccharide or polyol (Y) is typically attached to the block copolymer of formula (1) through a hydroxyl group in its deprotonated form, where X' can represent the oxygen atom of the Y group; or X' can represent a bond, and Y represents a saccharide or polyol that is bound to the indicated C(O) group through its oxygen atom; or X' is –NR'–, and Y represents a saccharide or polyol that is bound to the –NR'– group through its carbon atom. In other embodiments, the polyol is a polymer containing hydroxyl groups. The polymer containing hydroxyl groups can contain, for example, at least 2, 3, 4, 5, or 6 and up to, for example, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 monomer units. Some examples of such polymers include polyvinyl alcohol, poly(2-hydroxyethyl methacrylate), and poly(2-hydroxypropyl methacrylate). The polyol group may or may not be incorporated into the copolymer, such as a polyvinyl alcohol-polyacrylic acid (PVA-PAA) copolymer. In some embodiments, the copolymer containing a polyol contains a polyol moiety and an anionic moiety, which can be an anionic polymer moiety, such as polyacrylic acid (PAA), polyglutamic acid, or polyaspartic acid.

[0031] The subscripts a and b in formula (1) are independently integers of at least 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, or 50. In some embodiments, the subscripts a and b independently do not exceed 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1500, 1800, or 2000. In some embodiments, the selected subscript a is less than subscript b. For example, subscript a can be in the range of 3 - 10, 3 - 20, 3 - 30, or 3 - 40, while subscript b is in the range of 30 - 500, 40 - 500, 50 - 500, or 60 - 500. In other embodiments, the selected subscript a is greater than subscript b. For example, subscript a can be in the range of 30 - 500, 40 - 500, 50 - 500, or 60 - 500, while subscript b is in the range of 3 - 10, 3 - 20, 3 - 30, or 3 - 40.

[0032] The subscript c in formula (1) is an integer of at least 1. In various embodiments, c is exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or c is within the range defined by any two of the foregoing values. The value of c corresponds to the number of methylene groups to which c corresponds. That is, when the subscript c is 1, a CH2 linker is present between X and the quaternary ammonium group shown in formula (1); and when the subscript c is 2, a CH2CH2 linker is present between X and the quaternary ammonium group shown in formula (1).

[0033] Although not shown in formula (1), the structure shown in formula (1) necessarily (i.e., by chemical laws) includes terminal groups at each of the two ends of the copolymer. The terminal groups are independently selected from, for example, hydrogen atoms, hydrocarbon radicals R or groups containing heteroatoms (such as-OH,-OCH3), alkyl groups containing nitrile (such as provided by free radical initiators or chain transfer agents), sulfhydryls (-SH) or dithioester groups (provided by RAFT chain transfer agents). In some embodiments, at least one terminal group is a sulfhydryl group. The terminal groups generally correspond to the groups initially present in the precursor reactants for synthesizing block copolymers, so the type of terminal groups generally depends on the chemical substances used to synthesize block copolymers. However, the terminal groups can be suitably adjusted by reacting the block copolymers initially produced to add specific terminal groups (for example, cartilage binding domains (for example, containing peptide groups)), and the specific terminal groups help to bind the block copolymers to the desired biological tissues. In some embodiments, the cartilage binding domains are attached to the block copolymers by-S-joints, such as RS-forms, wherein R is the cartilage binding domains. Moreover, although also not shown in formula (1), the total positive charge of the quaternary ammonium groups in the copolymer shown in formula (1) is offset by an equivalent amount of total negative charge provided by anions associated with the quaternary ammonium groups. The anions can be selected from any acceptable species for use in organisms, such as halides (e.g., chlorides, bromides, or iodides), carbonates, bicarbonates, sulfates, bisulfates, bisulfites, carboxylates (e.g., acetates, propionates, butyrates, maleates, and citrates), and sulfonates (e.g., methanesulfonates).

[0034] The second class of block copolymers contemplated in this application is encompassed by the following general structure:

[0035]

[0036] In formula (2), the variables X and Y in formula (2) are defined as provided above in formula (1). The variable R is a hydrogen atom, a hydrocarbon group (R) having 1-12 carbon atoms (or more specifically, at least 4, 5 or 6 and up to 7, 8, 9, 10, 11 or 12 carbon atoms), or a cartilage binding domain. When R is a hydrocarbon group having 1-12 carbon atoms, more specifically, the hydrocarbon group can be a linear or branched alkyl or alkenyl group. In some embodiments, the cartilage binding domain is a peptide-containing group (or "peptide"), which can be a monopeptide, a dipeptide, a tripeptide, or an oligopeptide containing at least 4 and up to 5, 6, 7, 8, 9 or 10 peptide units. The cartilage binding peptide can be, for example, TKKTLRT, SQNPVQP, WYRGRL, SYIRIADTN, or CQDSETRFY (SEQ ID. NOs: 1-5, respectively), cholesterol or other sterol moieties, or any other moiety for binding the block copolymer to biological tissue. Conjugation chemistry for attaching cartilage binding domains, hydrophobic alkyl chains, sterols, or other substances to block copolymers is well known to those skilled in the art. Although not shown, the structure in formula (2) must also contain an end group opposite the RS-end group. Other end groups can be as described above as described below in formula (1).

[0037] In formula (2), subscripts d and e are independently an integer of at least 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, or 50. In some embodiments, subscripts d and e are independently no more than 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1500, 1800, or 2000. In some embodiments, subscript d is selected to be smaller than subscript e. For example, subscript d can be in the range of 3-10, 3-20, 3-30, or 3-40, while subscript e is in the range of 30-500, 40-500, 50-500, or 60-500. In other embodiments, subscript d is selected to be greater than subscript e. For example, subscript d can be in the range of 30-500, 40-500, 50-500, or 60-500, while subscript e is in the range of 3-10, 3-20, 3-30, or 3-40.

[0038] The subscript f in formula (2) is an integer of at least 1. In various embodiments, f is exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or f is within the range defined by any two of the foregoing values. When the subscript f is 1, a CH2 linker is present. When the subscript f is 2, a CH2CH2 linker is present.

[0039] In formula (2), the hydrogen atom on the carboxylic acid group shown may (i.e., optionally) be substituted with a positively charged metal ion or a positively charged organic group. Some examples of positively charged metal ions include lithium ion, sodium ion, and potassium ion. Some examples of positively charged organic groups include ammonium ions such as dimethyl, trimethyl, or tetramethyl ammonium ions.

[0040] The above block copolymer can be synthesized by any suitable polymerization method. In a particular embodiment, the block copolymer is synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, which is well known in the art. In the RAFT process, in the presence of a polymerization initiator (e.g., 4,4'-azobis(4-cyanovaleric acid), i.e., ACPA), a first polymer block is produced by reacting a first functionalized vinyl monomer (e.g., 2-(dimethylamino)ethyl acrylate, i.e., DMAEA) with a RAFT transfer agent (e.g., dithiobenzoic acid 4-cyanopentyl ester, i.e., CPADB). Then, in the presence of a polymerization initiator, the first polymer block is reacted with a second functionalized vinyl monomer (e.g., poly(ethylene glycol) methyl ether acrylate) so as to attach the polymerized second functionalized vinyl monomer block to the first polymer block.

[0041] The following route shows an exemplary RAFT process:

[0042]

[0043] In another aspect, the present invention relates to a pharmaceutical formulation comprising one or more block copolymers of the present invention and a pharmaceutically acceptable carrier (i.e., excipient or diluent). The pharmaceutical formulation can be made suitable for various delivery forms for use, including for intra-articular, intranasal, intravaginal or ophthalmic delivery. As used in the present application, the phrase "pharmaceutically acceptable carrier" or equivalent terms refers to a pharmaceutically acceptable material, composition or vehicle, which can be a liquid (diluent or excipient) or a solid filler. The phrase "pharmaceutically acceptable" means a compound, material, composition and / or dosage form that, within the scope of reasonable medical judgment, is suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reaction or other problems or complications, and meets a reasonable benefit / risk ratio. In a pharmaceutical composition, the compound is usually dispersed in a physiologically acceptable carrier, which is achieved by mixing (e.g., mixing in solid form with a solid carrier) or dissolving or emulsifying in a liquid carrier. The carrier should be compatible with the other components of the formulation and be safe for the subject physiologically. Any carrier known in the art is suitable for the present application, depending on the mode of administration. Some examples of suitable carriers include aqueous solutions, gelatin, fatty acids (e.g., stearic acid) and their salts, talc, vegetable fats or oils, gums and diols, starch, dextran, etc.

[0044] The pharmaceutical composition may also contain one or more adjuvants, such as stabilizers, surfactants, salts, buffers, additives or combinations thereof, all of which are well-known in the pharmaceutical field. Stabilizers can be, for example, oligosaccharides (e.g., sucrose, trehalose, lactose or dextran), sugar alcohols (e.g., mannitol) or combinations thereof. Surfactants can be any suitable surfactant, including, for example, those containing polyalkylene oxide units (e.g., Tween 20, Tween 80, Pluronic F-68), which are usually included in an amount from about 0.001% (w / v) to about 10% (w / v). Salts or buffers can be any suitable salts or buffers, such as sodium chloride or sodium phosphate or potassium phosphate, respectively. Some examples of additives include, for example, glycerol, benzyl alcohol and 1,1,1-trichloro-2-methyl-2-propanol (e.g., chlorobutanol or chlorobutanol). If necessary, the pH of the solution can be appropriately adjusted by including a pH regulator. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, emulsions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily matrices, thickeners, etc. may be necessary or desired. The pharmaceutical formulation can be in the form of a sterile aqueous solution containing one or more buffers, diluents and / or other suitable additives, such as, but not limited to, permeation enhancers and carrier compounds.

[0045] In another aspect, the present invention relates to a method of imparting lubricity to biological tissues (such as joints, cartilage, and bone) by using the biomimetic copolymers described in Formulas (1) and (2) above. In the case of bone, the biomimetic copolymers can reduce the discomfort, pain, and additional damage caused by direct bone-to-bone contact that sometimes occurs in the late stages of osteoarthritis. According to the method, a biological tissue is contacted with a sufficient (i.e., effective or therapeutically effective) amount of any of the biomimetic copolymers described in Formulas (1) and (2) above to enhance lubricity or impart an appropriate level of lubricity to the biological tissue. When a biological tissue slides relative to the same tissue or another substance, an increase in the lubricity level generally corresponds to a decrease in the friction level (i.e., the coefficient of friction, or COF). The coefficient of friction can be measured using a tribometer and the surface lubrication can be evaluated by linear oscillation of the sample at variable speeds (usually 0.1, 0.3, 1, 3, and 10 mm / s) and variable compressive normal stresses (usually 250 to 300 kPa).

[0046] The terms "sufficient amount", "therapeutically effective amount", and "effective amount", which are used interchangeably in this application, refer to an amount of the copolymer composition of the present invention that is sufficient to achieve the following results: to endow a biological tissue with sufficient lubricity, or to prevent the development, recurrence, or onset of a disease or condition (such as osteoarthritis) or one or more of the above symptoms, to enhance or improve the preventive effect of another therapy, to reduce the severity and duration of a disease or disorder, to relieve one or more symptoms of a disease or disorder, to prevent the development of a disease or disorder, and / or to enhance or improve the efficacy of an additional treatment.

[0047] A therapeutically effective amount can be administered to a patient in one or more doses, the dose being sufficient to mitigate, relieve, stabilize, reverse, or slow the progression of the disease or disorder, or to reduce the pathological consequences of the disease or disorder, or to reduce the symptoms of the disease or disorder. The relief or reduction need not be permanent, but can be for a period of time ranging from at least one hour, at least one day, or at least one week or more. The effective amount is generally determined by a physician on a case-by-case basis, which is within the skill of the art. When determining the appropriate dose to achieve an effective amount, several factors are usually considered. These factors include the age, sex, and weight of the patient, the condition being treated, the severity of the condition, as well as the route of administration, dosage form, and regimen and the desired outcome. In certain embodiments of the invention, the therapeutically effective amount is an amount that can effectively treat osteoarthritis, achieve pain relief, improve joint mobility and flexibility, reduce friction in the joint, or improve other acceptable osteoarthritis metrics over a period of time. In an exemplary embodiment, the dose level ranges from injecting a volume of 0.1 - 10 mL at a concentration of 0.1 - 10 mg / mL (for humans), and more typically injecting a volume of 0.1 - 3 mL at a concentration of about 1 - 5 mg / mL.

[0048] The biological tissue to be lubricated can be contacted with any block copolymer of formula (1) or (2) by any method well known in the medical field. The block copolymer can be delivered directly into or onto the biological tissue or indirectly into the biological tissue surrounding the tissue to be lubricated, such as by injection, infusion, implantation, spraying or coating, so that the biological tissue is contacted with the block copolymer. Generally, contacting the biological tissue refers to delivering the block copolymer to the tissue by any method of coating the surface with the copolymer or soaking the tissue. In certain embodiments, the composition is injected or infused into the joint space to contact the tissue, resulting in the coating of the cartilage and / or meniscus present in the joint space. Moreover, the volume used depends at least in part on the type of tissue contacted, whether to fill the space or coat the surface, which can be determined by those skilled in the medical field.

[0049] In a particular embodiment, the block copolymer is injected or infused into or onto an arthritic or injured joint or bone to improve the lubricity of the joint or bone. Thus, the copolymer provides boundary lubrication. This treatment can be specifically used to treat or prevent osteoarthritis. Treatment of osteoarthritis or an injured joint, cartilage or bone preferably results in the following: alleviating symptoms, improving mobility, reducing joint pain and generally inhibiting disease progression, or preventing in the case of joint injury. The method may also include administering one or more of the above block copolymers and simultaneously or sequentially administering another composition that acts to enhance or work with the block copolymer and is outside the scope of formulas (1) and (2). The enhancing (i.e., adjuvant) composition can be selected from, for example, hyaluronic acid, lubricin, synovial fluid, glycosaminoglycan or other adjuvants. These other agents can also be administered, for example, by injection or infusion. In some embodiments, these other agents can act synergistically with one or more of the above block copolymers to provide enhanced lubrication and wear protection.

[0050] In certain embodiments, the biological tissue is a joint, cartilage, or bone, more typically an injured or arthritic joint, cartilage, or bone. In some embodiments, the joint is a weight-bearing joint such as the hip, knee, or ankle joint. Many different joints can benefit from an increased level of lubrication, including the shoulder, elbow, wrist, hand, finger, and toe joints. However, the lubricated biological tissues are not limited to joints, cartilage, and bone. Other biological tissues, including eye tissue, nasal tissue, and vaginal tissue, can be lubricated by using the disclosed block copolymers. Thus, by using the block copolymers described herein, various conditions other than those associated with joints, cartilage, and bone can be treated. Some of these other conditions include, for example, dry eye, dry nose, postmenopausal vaginal dryness, carpal tunnel syndrome, and the like. One of ordinary skill in the medical arts can determine the appropriate delivery routes and methods for contacting specific biological tissues. For example, for dry eye, contact can be achieved by instilling drops; for dry nose, contact can be achieved by nasal spray; for carpal tunnel syndrome, contact can be achieved by injecting near or around the inflamed tendon and capsule; and for postmenopausal vaginal dryness, a pill, lozenge, or suppository can be placed or implanted in the vagina. Thus, the method can be used to achieve boundary mode lubrication in any of a variety of biological tissues that can benefit from additional lubrication.

[0051] Also included herein are the following embodiments:

[0052] Embodiment 1. A block copolymer having the following structure:

[0053]

[0054] Wherein:

[0055] R 1 、R 2 and R 3 are independently selected from hydrocarbon groups having at least 1 and at most 12 carbon atoms;

[0056] X and X' are independently selected from –NR'–, –O–, and a bond, where R' is selected from a hydrogen atom and a hydrocarbon group having at least 1 and at most 6 carbon atoms;

[0057] Y is selected from polyalkylene glycols, sugars, and polyols;

[0058] The subscripts a and b are independently integers of at least 3; and

[0059] The subscript c is an integer of at least 1;

[0060] Wherein, according to the laws of chemistry, the block copolymer is capped at each end with end groups, and the total positive charge of the quaternary ammonium groups in the copolymer is offset by an equal amount of total negative charge provided by the anions associated with the ammonium groups.

[0061] Embodiment 2. The block copolymer according to Embodiment 1, wherein Y is a polyalkylene glycol.

[0062] Embodiment 3. The block copolymer according to Embodiment 2, wherein the polyalkylene glycol is polyethylene glycol.

[0063] Embodiment 4. The block copolymer according to Embodiment 1, wherein the sugar is a monosaccharide.

[0064] Embodiment 5. The block copolymer according to Embodiment 1, wherein the sugar contains at least two monosaccharide units.

[0065] Embodiment 6. The block copolymer according to Embodiment 1, wherein the polyalkylene glycol, sugar or polyol is composed of at least 2 and at most 500 monomer units.

[0066] Embodiment 7. The block copolymer according to Embodiment 1, wherein the polyalkylene glycol, sugar or polyol is composed of at least 2 and at most 200 monomer units.

[0067] Embodiment 8. The block copolymer according to Embodiment 1, wherein the polyalkylene glycol, sugar or polyol is composed of at least 2 and at most 100 monomer units.

[0068] Embodiment 9. The block copolymer according to Embodiment 1, wherein the polyalkylene glycol, sugar or polyol is composed of at least 2 and at most 20 monomer units.

[0069] Embodiment 10. The block copolymer according to Embodiment 1, wherein R 1 , R 2 and R 3 are independently selected from alkyl groups having at least 1 and at most 12 carbon atoms.

[0070] Embodiment 11. The block copolymer according to Embodiment 1, wherein at least one of the end groups is a mercapto group.

[0071] Embodiment 12. A block copolymer having the following structure:

[0072]

[0073] Wherein:

[0074] X is selected from –NR'–, –O– and a bond, where R' is selected from a hydrogen atom and a hydrocarbon group having at least 1 and at most 6 carbon atoms;

[0075] Y is selected from polyalkylene glycols, sugars and polyols;

[0076] R is a hydrogen atom, a hydrocarbon group having 1 to 12 carbon atoms (R), or a chondronectin domain;

[0077] The subscripts d and e are independently integers of at least 3; and

[0078] The subscript f is 0 or an integer of at least 1;

[0079] wherein the hydrogen atom on the shown carboxylic acid group is optionally replaced by a positively charged metal ion or a positively charged organic group; and

[0080] wherein, according to chemical laws, the end of the block copolymer opposite to the thiol group is capped with an end group.

[0081] Embodiment 13. The block copolymer according to Embodiment 12, wherein Y is a sugar.

[0082] Embodiment 14. The block copolymer according to Embodiment 13, wherein the sugar is a monosaccharide or a polysaccharide.

[0083] Embodiment 15. The block copolymer according to Embodiment 12, wherein R is a chondronectin domain.

[0084] Embodiment 16. A method for imparting an appropriate level of lubricity to a biological tissue, the method comprising contacting the biological tissue with a sufficient amount of a composition to impart an appropriate lubricity, the composition comprising a block copolymer having the following structure:

[0085]

[0086] wherein:

[0087] R 1 、R 2 and R 3 are independently selected from hydrocarbon groups having at least 1 and at most 12 carbon atoms;

[0088] X and X' are independently selected from –NR'–, –O– and a bond, where R' is selected from a hydrogen atom and a hydrocarbon group having at least 1 and at most 6 carbon atoms;

[0089] Y is selected from a polyalkylene glycol, a sugar and a polyol;

[0090] The subscripts a and b are independently integers of at least 3; and

[0091] The subscript c is an integer of at least 1;

[0092] wherein, according to chemical laws, the block copolymer is capped with end groups at each end, and the total positive charge of the quaternary ammonium groups in the copolymer is offset by an equal amount of total negative charge provided by the anions associated with the ammonium groups.

[0093] Embodiment 17. The method according to embodiment 16, wherein at least one of said end groups is a thiol group.

[0094] Embodiment 18. The method according to embodiment 16, wherein said biological tissue is selected from joints, bone, eye tissue, nasal tissue, tendon, tendon sheath, and vaginal tissue.

[0095] Embodiment 19. A method of imparting a suitable level of lubricity to a biological tissue, the method comprising contacting the biological tissue with a sufficient amount of a composition to impart a suitable lubricity, the composition comprising a block copolymer having the following structure:

[0096]

[0097] X is selected from –NR'– and –O–, wherein R' is selected from a hydrogen atom and a hydrocarbon group having at least 1 and at most 6 carbon atoms;

[0098] Y is selected from polyalkylene glycols, sugars, and polyols;

[0099] R is a hydrogen atom, a hydrocarbon group having 1-12 carbon atoms (R), or a chondroitin-binding domain;

[0100] The subscripts d and e are independently integers of at least 3; and

[0101] The subscript f is 0 or an integer of at least 1;

[0102] wherein the hydrogen atom on the indicated carboxylic acid group is optionally replaced by a positively charged metal ion or a positively charged organic group; and

[0103] wherein, according to the laws of chemistry, the end of the block copolymer opposite the thiol group is capped with an end group.

[0104] Embodiment 20. The method according to embodiment 19, wherein R is a chondroitin-binding domain.

[0105] Embodiment 21. The method according to embodiment 19, wherein said biological tissue is selected from joints, bone, eye tissue, nasal tissue, tendon, tendon sheath, and vaginal tissue.

[0106] For illustrative purposes, examples are listed below and the best mode of the present invention as currently known is described. However, the scope of the present invention is not limited in any way by the examples described in this application. Examples

[0107] Synthesis and Characterization of Lubricating Diblock Copolymers

[0108] To mimic the structure of lubricin, the present application prepared a diblock copolymer, which copolymer comprises a larger lubricating block (M n ~200 kDa) mimicking the mucin-like domain of lubricin and a smaller cartilage-binding block (M n ~3 - 10 kDa) mimicking the C-terminal domain. Figure 1 Exemplary compositions showing the two mimicking domains are provided in Figure 1 The lubricating domain of the diblock copolymer shown in Figure 1 comprises a polyacrylic acid backbone grafted with poly(ethylene glycol) (PEG) brushes. The foregoing features contribute to the hydration and compression resistance of the polymer.

[0109] The synthesis of the diblock copolymer starts with reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(dimethylamino)ethyl acrylate to synthesize a "pre-binding" block. By using the "pre-binding" block as a macroinitiator for subsequent RAFT polymerization of poly(ethylene glycol) methyl ether acrylate (M n 480), the lubricating block is added to the copolymer. Then, by treating the block copolymer with an excess of ethyl bromide, the tertiary amine in the "pre-binding" block is converted into a quaternary ammonium group to obtain the final product (M n ~200 kDa, PDI = 1.8). The general route is described as follows (where R and R' represent moieties provided by the RAFT chain transfer agent):

[0110]

[0111] Synthesis of poly(2-(dimethylamino)ethyl acrylate) (1) with a degree of polymerization (DP) of 24

[0112] 2-(Dimethylamino)ethyl acrylate (DMAEA) (4.30 g, 30 mmol) was added to a 5 mL anisole solution containing 14.0 mg (0.05 mmol) of 4,4'-azobis(4-cyanopentanoic acid) (ACPA) and 139.5 mg (0.5 mmol) of 4-cyanopentanoic acid dithiobenzoate (CPADB). The mixture was deoxygenated by five freeze-thaw cycles and then heated to 70 °C for 48 hours. Then, the reaction was quenched by freezing with liquid nitrogen, and the residue was purified by inducing precipitation with hexane (repeated 5 times). The structure of the purified product was confirmed by 1 1H NMR to have the above structure:

[0113]

[0114] Synthesis of block copolymer (2) by adding a PEG block to (1)

[0115] The methoxy-capped PEG(9)-acrylate (3.46 g, 7.2 mmol) was added to a 6 mL anisole solution containing 30.9 mg (0.009 mmol) of (1) and 0.5 mg (0.0018 mmol) of ACPA. The mixture was deoxygenated by five freeze-thaw cycles and then heated at 65 °C for 8 hours. Then, the reaction was quenched by freezing with liquid nitrogen, and the residue was purified by inducing precipitation by adding hexane (repeated 5 times). The structure of the purified product was confirmed by 1 1H NMR and GPC to have the following structure:

[0116]

[0117] Synthesis of quaternary ammonium derivative (3) of block copolymer (2)

[0118] At 0 °C, 0.3 mL of ethyl bromide was added dropwise to a 3 mL acetone solution containing 865.9 mg of (2). The mixture was stirred at room temperature for 48 hours and then quenched by evaporating the solvent using a nitrogen stream. The residue was dissolved in dichloromethane, and the product was initially purified by inducing precipitation by adding hexane (repeated 5 times). Then, the product (3) was dissolved in a solution containing 0.01 M PBS (phosphate buffer solution), further purified by dialysis in 0.01 M PBS for 24 hours and then in deionized water for another 48 hours, and subsequently lyophilized. The structure of the purified product (3) was confirmed by 1 1H NMR and GPC to have the following structure:

[0119]

[0120] Evaluation of the cartilage lubricating ability of block copolymer (3)

[0121] To evaluate the diblock copolymer (3) as a synthetic lubricant, a custom-made cartilage glass tribometer (Gleghorn, J.P. et al., J. Orthop. Res. 2009, 27(6), 77) was used to evaluate the tribological behavior of the copolymer. Cartilage samples were obtained from the patellofemoral groove of the posterior knee joint of neonatal calves and incubated in 1.5 M NaCl to remove lubricin. The samples were incubated in PBS and then in the polymer solution for 120 minutes to saturate the cartilage surface. After incubation, the samples were loaded onto the tribometer and placed in a PBS bath and under boundary conditions (30% compressive strain and 0.3 mm / s linear oscillation speed). To demonstrate the importance of the diblock structure, single blocks of only the binding block and only the lubricating block were also tested under the same conditions. Figure 2This is a graph depicting the coefficient of friction (COF) results of PBS, diblock copolymer (3), the binding-only block, and the lubrication-only block. In vitro boundary lubrication test results showed that the COF decreased from 0.391 ± 0.020 to 0.088 ± 0.039 (n = 4 - 11, *p < 0.0001), which was comparable to the results of the lubricin-treated group ( Figure 2 the dashed line in

[0122] COF = 0.093 ± 0.011) (Gleghorn et al., ibid.). It is worth noting that no similar trend of COF reduction was observed with the treatment of any single block, indicating that boundary lubrication of articular cartilage requires both the binding block and the lubrication block. Figure 3 This is a graph depicting the COF of solutions of the binding block and the diblock copolymer (3) at different ratios. As Figure 3 shown by the data in Figure 3 the COF of the samples showed dose-response behavior. As expected, a high concentration of the binding domain effectively inhibited the lubrication of the diblock copolymer, indicating that the effective binding of the polymer to the surface is crucial for its successful lubrication of cartilage. As 2 shown in 50 this behavior followed an S-shaped dose-response (R

[0123] = 0.87, IC Figure 4 = 13.45, n = 4 - 6). Figure 4As shown by the results in, the ability of random copolymers to lubricate articular cartilage is significantly lower than that of block copolymers. In the same test, random polymers were unable to lubricate articular cartilage, which confirmed the importance of the combined blocks for providing significantly improved lubricating ability. In the boundary lubrication mode, the frictional properties are mainly controlled by solid-solid interactions and thus depend largely on the physical and chemical properties of the opposing surfaces. For boundary mode lubricants, it is crucial to form a molecular layer that effectively coats the cartilage surface to support the normal load. The randomly distributed individual positively charged quaternary ammonium groups in the polymer backbone cannot effectively interact with the cartilage surface, which again demonstrates the importance of the diblock structure.

[0124] Next, some key lubrication parameters of the diblock copolymer were evaluated and compared with native lubricin. Briefly, dosing studies were performed using cartilage samples that had been treated with solutions of (3) in a concentration range from 0.01 to 10 mg / mL. Figure 5A is a graph depicting the COF as a function of the concentration of the diblock copolymer (3). As Figure 5A shown in, the COF of the samples showed a dose-response behavior (R 2 = 0.89), where high concentrations of the copolymer (3) led to effective lubrication of the cartilage (EC 50 = 0.404 mg / ml), which was at a level comparable to that of lubricin (under similar conditions, EC 50 > 0.030 mg / mL). Figure 5B is a graph depicting the COF as a function of incubation time, for different durations with the diblock copolymer (3) at 1 mg / mL. The resulting graph can be considered a binding kinetic curve. The concentration was selected using the inflection point of the sigmoidal dose curve. When fit to a model of single-phase decay followed by plateauing (R 2 = Figure 5B 0.95), the binding kinetic curve (

[0125] showed a binding time constant (τ) of 7.19 minutes, which was comparable to that of native lubricin (∼9 minutes), e.g., Gleghorn et al., supra. 50(0.404 mg / mL) and the binding time constant (7.19 minutes) are comparable to the corresponding parameters of lubricin (>0.03 mg / mL, ~9 minutes). Like lubricin, the excellent tribological properties of this diblock copolymer can be explained by its molecular structure. In particular, the effective binding of this polymer to articular cartilage has been shown to be crucial for effective lubrication. The diblock copolymer (3) has unexpectedly shown to have at least the lubricating ability of lubricin, indicating its significant clinical potential.

[0126] Evaluation of the bone lubricating ability of block copolymer (3)

[0127] In this study, the same diblock copolymer (3) was tested for its lubricating ability on bone. Bone samples were obtained from the femoral condyles of neonatal bovine posterior knee joints. Bone plugs were extracted from the cartilage layer to the growth plate using a 6-mm diameter drill bit and trimmed to a height of 2 mm. The subchondral surface was exposed by removing the cartilage layer, and trabecular bone plugs were obtained by cutting the medial portion of the drilled bone plugs. The bone samples were incubated in PBS solution and then in a polymer solution containing (3) (10 mg / mL for 2 hours or 1 mg / mL for 1 hour). Tribological properties were measured on a custom-built bone-glass tribometer (Gleghorn et al., ibid.) at a normal load of 450 g and linear oscillation speeds of 0.3, 1, and 3 mm / s. The coefficient of friction was calculated by dividing the average shear force during sliding by the normal force. One-way ANOVA and Student's t-tests with a matched sliding speed were used to determine the statistical significance between treatments.

[0128] It is well known that the coefficient of friction (COF) of trabecular bone and subchondral bone is significantly higher than that of cartilage under the same conditions. Figure 6A and 6B are graphs depicting the COF of trabecular bone and subchondral bone samples treated with a diblock copolymer (3) solution (10 mg / mL for 2 hours or 1 mg / mL for 1 hour) or PBS solution, respectively. Also shown is the COF of cartilage in PBS in the boundary mode or synovial fluid. As Figure 6A and 6B The data in show that, compared to the PBS control, the bone plug samples incubated in the polymer solution showed significantly lower COF (ΔCOF for trabecular bone ~ -0.2, p < 0.05; ΔCOF for subchondral bone ~ -0.15, p < 0.05). It can also be seen from Figure 6A and 6BThe data in [reference] indicate that better lubrication is achieved using polymer solutions at higher concentrations (e.g., greater than 1 mg / mL, or at least 2, 5, or 10 mg / mL) and / or longer incubation times (e.g., greater than 1 hour, or at least 1.5 or 2 hours). The results show that the block copolymers described in the present application can effectively lubricate cartilage or bone to a level equivalent to or even superior to the COF of cartilage in PBS in the boundary mode. Without being bound by theory, it is believed that the diblock copolymers of the present invention interact strongly with the negatively charged mineral components of cartilage or bone and resist positive compression by virtue of the bottlebrush-like structure.

[0129] Although the presently considered preferred embodiments of the invention have been shown and described, various changes and modifications can be made by those skilled in the art, and such changes and modifications are still within the scope of the invention defined by the appended claims.

Claims

1. A block copolymer having the following structure: Wherein: R 1 、R 2 and R 3 are independently selected from hydrocarbon groups having at least 1 and at most 12 carbon atoms; X and X' are independently selected from –NR'–, –O–, and a bond, where R' is selected from a hydrogen atom and a hydrocarbon group having at least 1 and at most 6 carbon atoms; Y is selected from polyalkylene glycol, sugar, and polyol; The subscript a is an integer in the range of 3 - 40; The subscript b is an integer in the range of 30 - 500; and The subscript c is an integer of at least 1; Wherein, according to chemical laws, the block copolymer is capped at each end by end groups, and the total positive charge of the quaternary ammonium groups in the copolymer is offset by a total negative charge of an equal magnitude provided by anions associated with the quaternary ammonium groups.

2. The block copolymer according to claim 1, wherein Y is polyalkylene glycol.

3. The block copolymer according to claim 2, wherein the polyalkylene glycol is polyethylene glycol.

4. The block copolymer according to claim 1, wherein the sugar is a monosaccharide.

5. The block copolymer according to claim 1, wherein the sugar contains at least two monosaccharide units.

6. The block copolymer according to claim 1, wherein the polyalkylene glycol, sugar, or polyol is composed of at least 2 and at most 500 monomer units.

7. The block copolymer according to claim 1, wherein the polyalkylene glycol, sugar, or polyol is composed of at least 2 and at most 200 monomer units.

8. The block copolymer according to claim 1, wherein the polyalkylene glycol, sugar, or polyol is composed of at least 2 and at most 100 monomer units.

9. The block copolymer according to claim 1, wherein the polyalkylene glycol, sugar, or polyol is composed of at least 2 and at most 20 monomer units.

10. The block copolymer according to claim 1, wherein R 1 , R 2 and R 3 are independently selected from alkyl groups having at least 1 and at most 12 carbon atoms.

11. The block copolymer according to claim 1, wherein at least one of the end groups is a thiol group.

12. A block copolymer having the following structure: Wherein: X is selected from –NR'–, –O–, and a bond, where R' is selected from a hydrogen atom and a hydrocarbon group having at least 1 and at most 6 carbon atoms; Y is selected from polyalkylene glycol, sugar, and polyol; R is a hydrogen atom, a hydrocarbon group having 1 - 12 carbon atoms, or a chondroitin-binding domain; The subscript d is an integer in the range of 3 - 40; The subscript e is an integer in the range of 30 - 500; and The subscript f is 0 or an integer of at least 1; Wherein the hydrogen atom on the indicated carboxylic acid group is optionally replaced by a positively charged metal ion or a positively charged organic group; and Wherein, according to chemical laws, the end of the block copolymer opposite the thiol group is capped by an end group.

13. The block copolymer according to claim 12, wherein Y is a sugar.

14. The block copolymer according to claim 13, wherein the sugar is a monosaccharide or a polysaccharide.

15. The block copolymer according to claim 12, wherein R is a chondroitin-binding domain.

16. A method of imparting an appropriate level of lubricity to a biological tissue, the method comprising contacting the biological tissue with a sufficient amount of a composition comprising a block copolymer having the following structure: Wherein: R 1 、R 2 and R 3 are each independently selected from hydrocarbyl groups having from at least 1 to at most 12 carbon atoms; X and X' are independently selected from –NR'–, –O– and a bond, where R' is selected from a hydrogen atom and a hydrocarbyl group having at least 1 and at most 6 carbon atoms; Y is selected from polyalkylene glycols, sugars and polyols; The subscript a is an integer in the range of 3 - 40; The subscript b is an integer in the range of 30 - 500; and The subscript c is an integer of at least 1; wherein, according to the laws of chemistry, the block copolymer is capped at each end with end groups, and the total positive charge of the quaternary ammonium groups in the copolymer is offset by an equal magnitude of total negative charge provided by anions associated with the quaternary ammonium groups.

17. The method according to claim 16, wherein at least one of said end groups is a thiol group.

18. The method according to claim 16, wherein said biological tissue is selected from joints, bone, eye tissue, nasal tissue, tendon, tendon sheath and vaginal tissue.

19. A method of imparting a suitable level of lubricity to a biological tissue, the method comprising contacting the biological tissue with a sufficient amount of a composition to impart a suitable lubricity, the composition comprising a block copolymer having the following structure: X is selected from –NR'– and –O–, where R' is selected from a hydrogen atom and a hydrocarbyl group having at least 1 and at most 6 carbon atoms; Y is selected from polyalkylene glycols, sugars and polyols; R is a hydrogen atom, a hydrocarbyl group having 1 - 12 carbon atoms or a chondroitin-binding domain; The subscript d is an integer in the range of 3 - 40; The subscript e is an integer in the range of 30 - 500; and The subscript f is 0 or an integer of at least 1; wherein the hydrogen atom on the indicated carboxylic acid group is optionally replaced by a positively charged metal ion or a positively charged organic group; and Among them, According to the laws of chemistry, the end of the block copolymer opposite the thiol group is capped with an end group.

20. The method according to claim 19, wherein R is a chondroitin-binding domain.

21. The method according to claim 19, wherein said biological tissue is selected from joints, bone, eye tissue, nasal tissue, tendon, tendon sheath and vaginal tissue.

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