WO2016061145A1

WO2016061145A1 - Synthetic proteoglycans for preventing tissue adhesion

Info

Publication number: WO2016061145A1
Application number: PCT/US2015/055396
Authority: WO
Inventors: Nathan BACHTELL
Original assignee: Symic Biomedical, Inc.
Priority date: 2014-10-13
Filing date: 2015-10-13
Publication date: 2016-04-21

Abstract

This disclosure provides compositions and methods for treating and/or preventing tissue adhesion, such as abdominal or pelvic adhesion, tendon adhesion or cardiac tissue adhesion in a patient in need thereof by applying a pharmaceutical composition on an unnaturally exposed tissue of an abdominal organ, tendon or cardiac tissue respectively, wherein the composition contains a synthetic proteoglycan capable of binding to collagen.

Description

SYNTHETIC PROTEOGLYCANS FOR PREVENTING TISSUE ADHESION

Cross Reference to Related Application

[0001] This application claims the benefit under 35 U.S.C. 119(e) to U.S. Provisional Application Ser. No. 62/063336, filed on October 13, 2014, the entirety of which is incorporated herein by reference.

Field

[0002] This disclosure provides a method of treating and/or preventing tissue adhesion, such as abdominal or pelvic adhesion, tendon adhesion or cardiac tissue adhesion in a patient in need thereof by administering to the patient a composition containing a synthetic peptidoglycan (or proteoglycan) of the present disclosure.

Background

[0003] Adhesions are fibrous connections that form between tissues and/or organs, which join surfaces in abnormal locations. Adhesions commonly develop in the inflammation healing and repair process and are caused by the entanglement of extracellular matrix molecules which are deposited in the formation of granulation tissue or a scar. Adhesions form in response to various types of injury or tissue disturbances such as surgery, trauma, infection, chemotherapy, radiation, foreign objects or cancer. When adhesions are accompanied by clinical problems, complications and/or pain, then surgical intervention is necessary to remove the adhesion, which may further exacerbate the problem.

[0004] Abdominal adhesions are a common occurrence with abdominal and pelvic surgery. Of the patients who undergo abdominal surgery, an estimated 93% develop abdominal adhesions, compared with only 10% of patient who had never had a previous abdominal operation (Menzies D., Ellis, H. Ann R. Coll. Sur. Engl. 1990; 72: 60-63.). Of all cases of small bowel obstruction, 60-70% of cases involve adhesions (Ellis, H. Eur. J. Surg. Suppl. 1997: 5-9). Abdominal adhesions cause severe life-long clinical problems and complications (Diamond, M. P., Freeman, M. L. Eur. Soc. Human. Repro. Embryo. 2001; 7(6): 567-576). A large surgical workload and cost to health care systems is attributable to abdominal adhesions.

[0005] Cardiac adhesions are a common complication of pediatric cardiothoracic surgical procedures. Such adhesions can cause severe clinical problems and/or pain for the child. The most severe pediatric cardiac adhesion-related clinical problem is difficulty with sternal re-entry to carry out staged cardiac repair, a common necessity in children with congenital heart disease. Estimates of the incidence of injury to cardiac structures upon restemotomy in patients with adhesions range from 2% to 10% of operations (Napoleone CP, Oppido G, Angeli E, Gargiulo G. Restemotomy in pediatric cardiac surgery: CoSeal initial experience. Interact CardioVasc Thorac Surg 2007;6:21-23.). In addition, cardiac adhesions may cause a restriction in cardiac output due to constriction and non-compliance of the pericardium (Russell JL, Le Blanc JG, Sett SS, Potts JE. Risks of repeat sternotomy in pediatric cardiac operations. Ann Thorac Surg 1998;66:1575-1578).

[0006] The clinical problem of flexor tendon injuries can be complicated when healing results in adhesions forming between the tendon and the surrounding tendon. Although difficult to predict following surgical repair, adhesions have long been accepted as a cause of restricted tendon movement. The formation of adhesions leads to impairment of digit flexion through inhibiting normal tendon gliding.

Summary

[0007] It is contemplated that the synthetic proteoglycans as described herein may be useful in treating and/or preventing tissue adhesions, such as abdominal and pelvic adhesions, tendon sheath adhesion or cardiac tissue adhesion by providing a protective hydrating layer, providing lubricity to the tissues and/or organs, protecting damaged tissue from degradation and promoting epithelial migration and epithelial proliferation. Accordingly, provided herein is a method of treating and/or preventing tissue adhesion in a patient in need thereof by administering to the patient a composition comprising a synthetic proteoglycan described herein. The composition can be administered directly to the exposed tissue, organ, or area of injury.

[0008] In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tissue of an organ. In one embodiment, the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 1 to about 80 collagen binding peptide(s) bonded to the glycan. An "unnaturally exposed tissue" refers to a tissue that is exposed to a new environment that is not seen under normal, healthy conditions. Such environments include, but are not limited to a disease, an injury, or a medical procedure. [0009] In certain embodiments, the tissue is abdominal or pelvic tissue or tendon or cardiac tissue.

[0010] In some aspects, the tissue is exposed due to surgery, trauma, infection,

chemotherapy, radiation, foreign body, or cancer. In one aspect, the tissue is surgically exposed.

[0011] In some aspects, the composition is applied as a spray, or brushed on, poured on, or applied with a dropper or applied in a sheet. In some aspects, the tissue is a peritoneal membrane tissue.

[0012] In certain embodiments, the glycan of the synthetic proteoglycan comprises dextran, chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparan sulfate, heparin, keratin, keratan sulfate, or hyaluronic acid.

[0013] In certain embodiments, the peptide(s) of the synthetic proteoglycan are covalently bonded directly to the glycan. In certain embodiments, the peptide(s) of the synthetic proteoglycan are covalently bonded to the glycan via a linker. In certain embodiments, the linker is N-[P-maleimidopropionic acid]hydrazide (BMPH). In certain embodiments, the linker is 3-(2-pyridyldithio)propionyl hydrazide (PDPH).

[0014] In certain embodiments, the collagen binding peptide is

RRANAALKAGELYKSILY (SEQ ID NO: 1) or a peptide having at least about 80% sequence identity to RRANAALKAGELYKSILY (SEQ ID NO: 1) and capable of binding to collagen.

[0015] In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion by administering a composition comprising a synthetic

proteoglycan and a pharmaceutically acceptable carrier. In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion by administering an anti-adhesion composition. In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion via a film, gel, patch or liquid solution.

Detailed Description

[0016] It is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0017] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a peptide" includes a plurality of peptides.

1. Definitions

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein the following terms have the following meanings.

[0019] As used herein, the term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others.

"Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) claimed. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0020] The term "about" when used before a numerical designation, e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by (+) or (-) 10%, 5% or 1%.

[0021] The following abbreviations used herein have the following meanings.

DS Dermatan Sulfate

ECM Extracellular Matrix

EDTA Ethylenediaminetetraacetic Acid

ELISA Enzyme-Linked Immunosorbent Assay

FGF Fibroblast Growth Factor

Fmoc 9-Fluorenylmethoxycarbonyl

GAG Glycosaminoglycan

Hep Heparin

HEPES 2- [4- (2-hydroxyethyl)piperazin- 1 - yl]ethanesulfonic acid

HLB Hydrophile/Lipophile/Balance

HPC Hydroxyl Propylcellulose

HPMC Hydroxypropylmethyl Cellulose

ITC Isothermal Titration Calorimeters

kDa KiloDalton

kg Kilogram

MES 2-ethanesulfonic acid

mg Milligram

mL Milliliter

MOPS 3-(N-morpholino)propanesulfonic acid mOsm Milliosmole

mV Millivolt

ng Nanogram

Ox-CS Oxidized Chondroitin Sulfate

PBS Phosphate buffered saline

PDPH 3-(2-pyridyldithio)propionyl hydrazide

PIPES piperazine-N,N'-bis(2-ethanesulfonic acid)

QD Administered Once Daily

SILY RRANAALKAGELYKSILY (SEQ ID NO: 1)

SPR Surface Plasmon Resonance

TAPS 3-[[l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl]amino]propane-l-sulfonic acid

TES 2-[[l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl] amino] ethanesulfonic acid

Tris 2- Amino-2-hydroxymethyl -propane- 1 ,3-diol w/w Weight/Weight

w/v Weight/Volume [0022] As used herein, the term "treating and/or preventing" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of a traumatic injury state, disease progression or other abnormal condition.

[0023] As used herein, the term "adhesion" refers to a type of banding or scarring that forms an abnormal connection between two parts of the body. Adhesion formation involves a complex interaction of cytokines, growth factors, cell adhesion molecules, neuropeptides, and numerous other factors secreted by cells in or near the area of trauma. The early balance between fibrin deposition and degradation (i.e., fibrinolysis) is an important factor in the pathogenesis of adhesions. Adhesion occurs in response to various types of injury or tissue disturbances, for example, such as surgery, trauma, infection, chemotherapy, radiation, foreign body, or cancer. In one embodiment, adhesion refers to the fibrous bands that connect tissues and/or organs not normally connected. In another embodiment, adhesion is the result of surgery. In one embodiment, adhesion is the result of trauma. In one

embodiment, adhesion is the result of infection. In another embodiment, adhesion is the result of chemotherapy, radiation, foreign body, or cancer. In one embodiment, adhesion form without apparent cause.

[0024] As used herein, the term "abdominal adhesion" refers to bands of fibrous tissue (or scarring) that forms between abdominal tissues and/or organs. In some embodiments, abdominal adhesion refers to a band of scar tissue that connects abdominal tissues and/or organs not normally connected.

[0025] As used herein, the term "tendon adhesion" refers to fibrous tissue that forms between tendon and soft tissue, multiple tendons or tendon and tendon sheath.

[0026] As used herein, the term "cardiac adhesion" refers to fibrous tissue that binds the outer membrane of the heart to the surrounding tissue. Typically, these are bands of scar tissue that develop after surgery or other trauma.

[0027] As used herein, the term "patient" refers to a subject (i.e., human) at risk for or suffering from a disease state, disease progression or other abnormal or deleterious condition.

[0028] As used herein, the term "administering" or "administration" refers to the delivery of one or more therapeutic agents to a patient. [0029] As used herein, the term "amino acid" refers to either a natural and/or unnatural or synthetic amino acid, including glycine and both the D and L optical isomers, amino acid analogs and peptidomimetics.

[0030] A "peptide" is a chain of two or more amino acid monomers linked by peptide (amide) bonds. A peptide of three or more amino acids is commonly called an oligopeptide if the peptide chain is short. If the peptide chain is long, the peptide is commonly called a polypeptide or a protein. As used herein, the term "peptide" is intended to refer a linear or branched chain of amino acids linked by peptide (or amide) bonds. In one embodiment, the peptide comprises from about 3 to about 120 amino acids, or from about 3 to about 110 amino acids, or from about 3 to about 100 amino acids, or from about 3 to about 90 amino acids, or from about 3 to about 80 amino acids, or from about 3 to about 70 amino acids, or from about 3 to about 60 amino acids, or from about 3 to about 50 amino acids, or from about 3 to about 40 amino acids, or from about 5 to about 120 amino acids, or from about 5 to about 100 amino acids, or from about 5 to about 90 amino acids, or from about 5 to about 80 amino acids, or from about 5 to about 70 amino acids, or from about 5 to about 60 amino acids, or from about 5 to about 50 amino acids, or from about 5 to about 40 amino acids, or from about 5 to about 30 amino acids, or from about 5 to about 20 amino acids, or from about 5 to about 10 amino acids.

[0031] As used herein, the terms "peptidoglycan," "proteoglycan," "proteoglycan mimetic," and "synthetic proteoglycan" are used interchangeably and refer to a synthetic conjugate that comprises a glycan and one or more optionally synthetic peptides covalently bonded thereto. The glycan portion can be made synthetically or derived from animal sources. The peptides can be covalently bonded directly to the glycan or via a linker. For methods of conjugating hyaluronic acid binding peptides to glycans, see, e.g., WO

2012/162534. For methods of conjugating collagen binding peptides to glycans, see, e.g., US 2013/0190246, US 2012/0100106, and US 2011/0020298, the disclosures of which are incorporated herein by reference in their entirety. In one embodiment, the molecular weight range for the synthetic proteoglycan is from about 13 kDA to about 1.2 MDa, or from about 500 kDa to about 1 MDa, or from about 20 kDa to about 90 kDa, or from about 10 kDa to about 70 kDa.

[0032] As used herein, the term "glycan" refers to a compound having a large number of monosaccharides linked glycosidically. In certain embodiments, the glycan is a

glycosaminoglycan (GAG), which comprise 2-aminosugars linked in an alternating fashion with uronic acids, and include polymers such as heparin, heparan sulfate, chondroitin, keratin, and dermatan. Accordingly, non-limiting examples of glycans which can be used in the embodiments described herein include alginate, agarose, dextran (Dex), chondroitin, chondroitin sulfate (CS), dermatan, dermatan sulfate (DS), heparan sulfate, heparin (Hep), keratin, keratan sulfate, and hyaluronic acid (HA). In one embodiment the molecular weight of the glycan is a key parameter in its biological function. In another embodiment the molecular weight of the glycan is varied to tailor the effects of the synthetic proteoglycan mimic (see e.g., Radek, K. A., et al., Wound Repair Regen., 2009, 17: 118-126; and Taylor, K. R., et al., J. Biol. Chem., 2005, 280:5300-5306). In another embodiment, the glycan molecular weight is about 46 kDa. In another embodiment, the glycan is degraded by oxidation and alkaline elimination (see e.g., Fransson, L. A., et al., Eur. J. Biochem., 1980, 106 :59-69) to afford degraded glycan having a lower molecular weight (e.g., from about 10 kDa to about 50 kDa). In some embodiments, the glycan is unmodified.

[0033] In one embodiment, the GAG is dermatan sulfate (DS) or dermantan (D). The biological functions of DS are extensive, and include the binding and activation of growth factors FGF-2, FGF-7, and FGF-10, which promote endothelial cell and keratinocyte proliferation and migration. In one embodiment, the DS molecular weight is about 46 kDa. In another embodiment, the DS is degraded by oxidation and alkaline elimination (see e.g., Fransson, L. A., et al., Eur. J. Biochem., 1980, 106:59-69) to afford degraded DS having a low molecular weight (e.g., 10 kDa). In some embodiments, the weight range of the DS is from about 10 kDa to about 70 kDa.

[0034] As used herein, the terms "bonded" and "covalently bonded" can be used interchangeably, and refer to the sharing of one or more pairs of electrons by two atoms. In one embodiment, the peptide is bonded to the glycan. In one embodiment the peptide is covalently bonded to the glycan, with or without a linker. In one embodiment the peptide is covalently bonded to the glycan via a linker. In one embodiment the peptide is directly bonded to the glycan.

[0035] In one embodiment, the synthetic proteoglycans of the disclosure bind, either directly or indirectly to collagen. The terms "binding" or "bind" as used herein are meant to include interactions between molecules that may be detected using, for example, a hybridization assay, surface plasmon resonance, ELISA, competitive binding assays, isothermal titration calorimetry, phage display, affinity chromatography, rheology or immunohistochemistry. The terms are also meant to include "binding" interactions between molecules. Binding may be "direct" or "indirect". "Direct" binding comprises direct physical contact between molecules. "Indirect" binding between molecules comprises the molecules having direct physical contact with one or more molecules simultaneously. For example, it is contemplated that synthetic proteoglycans of the disclosure directly bind and interact with either collagen and can be used to treat and/or prevent tissue adhesion. This binding can result in the formation of a "complex" comprising the interacting molecules. A "complex" refers to the binding of two or more molecules held together by covalent or non- covalent bonds, interactions or forces.

[0036] As used herein, the term "collagen binding peptide" refers to an optionally synthetic peptide comprising a collagen binding sequence (or domain or unit). "Collagen binding" indicates an interaction with collagen that could include hydrophobic, ionic (charge), and/or Van der Waals interactions, such that the compound binds or interacts favorably with collagen. This binding (or interaction) is intended to be differentiated from covalent bonds and nonspecific interactions with common functional groups, such that the collagen binding peptide would interact with any species containing that functional group to which the peptide binds on the collagen. See, e.g., Li, Y., et al., Current Opinion in Chemical Biology, 2013, 17: 968-975, Helmes, B.A., et al., J. Am. Chem. Soc. 2009, 131, 11683-11685, and

Petsalaki, E., et al., PLoS Comput Biol, 2009, 5(3): el000335.

[0037] In one aspect, the collagen binding peptide binds to one or more of collagen type I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIIII, or XIV. In one aspect, the collagen biding peptide promotes or inhibits fibrillogenesis upon binding to collagen. In one aspect, the collagen biding peptide does not promote or inhibit fibrillogenesis upon binding to collagen. In some embodiments, the peptide binds to type I collagen. In other embodiments, the peptide binds to type IV collagen. In certain embodiments, one or more peptide(s) having a specified binding affinity for collagen can be used in the proteoglycan mimetics described herein. For example, the synthetic proteoglycans can comprise at least one peptide which has binding affinity to type I collagen and at least one peptide which has binding affinity to type IV collagen. In another embodiment, the peptides have binding affinity to type I collagen. In another embodiment, the peptides have binding affinity to type IV collagen. In certain embodiments, the peptides have binding affinity to type II collagen. In certain embodiments, the peptides have binding affinity to type III collagen. In certain embodiments, the peptide binds to more than one type of collagen, where the relative affinity to each collagen type may vary. [0038] Further, the peptides as used herein may comprise more than one binding unit, where the binding unit can be the same or different. For example, in certain embodiments, the peptide comprises two or more collagen-binding units, where the collagen-binding units are the same. In another embodiment, the peptide comprises two or more collagen-binding units, where the collagen-binding units are different.

[0039] The collagen binding peptide can have amino acid homology with a portion of a protein normally or not normally involved in collagen fibrillogenesis. In one embodiment, the collagen binding peptide comprises from about 5 to about 40 amino acids, or from about 5 to about 20 amino acids, or from about 5 to about 10 amino acids. In some embodiments, these peptides have homology or sequence identity to the amino acid sequence of a small leucine-rich proteoglycan, a platelet receptor sequence, or a protein that regulates collagen fibrillogenesis. In various embodiments, the collagen binding peptide comprises an amino acid sequence selected from: i) RRANAALKAGELYKSILY (SEQ ID NO: 1), RLDGNEIKR (SEQ ID NO: 2), AHEEISTTNEGVM (SEQ ID NO: 3), GELYKSILY (SEQ ID NO: 4),

NGVFKYRPRYFLYKHAYFYPPLKRFPVQ (SEQ ID NO: 5), CQDSETRTFY (SEQ ID NO: 6), TKKTLRT (SEQ ID NO: 7), GLRSKSKKFRRPDIQYPDATDEDITSHM (SEQ ID NO: 8), SQNPVQP (SEQ ID NO: 9), SYIRIADTNIT (SEQ ID NO: 10), KELNLVYT (SEQ ID NO: 11), GSITTIDVPWNVGC (SEQ ID NO: 12), GSITTIDVPWNV (SEQ ID NO: 13), RRANAALKAGELYKCILY (SEQ ID NO: 14), GELYKCILY (SEQ ID NO: 15),

GQLYKSILY (SEQ ID NO: 16), or RRANAALKAGQLYKSILY (SEQ ID NO: 17); or ii) a peptide comprising a sequence with at least about 80% sequence identity to the amino acid sequence of i) and capable of binding to collagen.

[0040] In certain embodiments, the collagen binding peptide comprises an amino acid sequence that has at least about 80%, or at least about 83%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 100% sequence identity with the collagen binding unit(s) of the von Willebrand factor or a platelet collagen receptor as described in Chiang, T.M., et al. J. Biol. Chem., 2002, 277: 34896-34901, Huizinga, E.G. et al., Structure, 1997, 5: 1147-1156, Romijn, R.A., et al., J. Biol. Chem., 2003, 278: 15035-15039, and Chiang, et al., Cardio. & Haemato. Disorders-Drug Targets, 2007, 7: 71-75, each incorporated herein by reference. A non-limiting example is

WREPSFCALS (SEQ ID NO: 18), derived from vWF. [0041] Various methods for screening peptide sequences for collagen-binding affinity (or a collagen-binding unit) are routine in the art. Other peptide sequences shown to have collagen-binding affinity (or a collagen-binding unit) which can be used in the proteoglycans and methods disclosed herein include but are not limited to, pAWHCTTKFPHHYCLYBip (SEQ ID NO: 19), pAHKCPWHLYTTHYCFTBip (SEQ ID NO: 20),

PAHKCPWHLYTHYCFT (SEQ ID NO: 21), etc., where Bip is biphenylalanine and βΑ is beta-alanine (see, Abd-Elgaliel, W.R., et al., Biopolymers, 2013, 100(2), 167-173),

GROGER (SEQ ID NO: 22), GMOGER (SEQ ID NO: 23), GLOGEN (SEQ ID NO: 24), GLOGER (SEQ ID NO: 25), GLKGEN (SEQ ID NO: 26), GFOGERGVEGPOGPA (SEQ ID NO: 27), etc., where O is 4-hydroxyproline (see, Raynal, N., et al., J. Biol. Chem., 2006, 281(7), 3821-3831), HVWMQAPGGGK (SEQ ID NO: 28) (see, Helms, B.A., et al., J. Am. Chem. Soc. 2009, 131, 11683-11685), WREPSFCALS (SEQ ID NO: 18) (see, Takagi, J., et al., Biochemistry, 1992, 31, 8530-8534), WYRGRL (SEQ ID NO: 29), etc. (see, Rothenfluh D.A., et al., Nat Mater. 2008, 7(3), 248-54), WTCSGDEYTWHC (SEQ ID NO: 30),

WTCVGDHKTWKC (SEQ ID NO: 31), QWHCTTRFPHHYCLYG (SEQ ID NO: 32), etc. (see, U.S. 2007/0293656), STWTWNGSAWTWNEGGK (SEQ ID NO: 33),

STWTWNGTNWTRNDGGK (SEQ ID NO: 34), etc. (see, WO/2014/059530),

CVWLWEQC (SEQ ID NO: 35) (see, Depraetere H., et al., Blood. 1998, 92, 4207-4211; and Duncan R., Nat Rev Drug Discov, 2003, 2(5), 347-360), CMTSPWRC (SEQ ID NO: 36), etc. (see, Vanhoorelbeke, K., et al., J. Biol. Chem., 2003, 278, 37815-37821),

CPGRVMHGLHLGDDEGPC (SEQ ID NO: 37) (see, Muzzard, J., et al., PLoS one. 4 (e 5585) I- 10), KLWLLPK (SEQ ID NO: 38) (see, Chan, J. M., et al., Proc Natl Acad Sci U.S.A., 2010, 107, 2213- 2218), and CQDSETRTFY (SEQ ID NO: 6), etc. (see, U.S.

2013/0243700), wherein each is hereby incorporated by reference in its entirety.

[0042] Additional peptide sequences shown to have collagen-binding affinity (or a collagen-binding unit) which can be used in the proteoglycans and methods disclosed herein include but are not limited to, LSELRLHEN (SEQ ID NO: 39), LTELHLDNN (SEQ ID NO: 40), LSELRLHNN (SEQ ID NO: 41), LSELRLHAN (SEQ ID NO: 42), LRELHLNNN (SEQ ID NO: 43) (see, Fredrico, S., Angew. Chem. Int. Ed. 2015, 37, 10980-10984).

[0043] In certain embodiments, the peptides include one or more sequences selected from the group consisting of RVMHGLHLGDDE (SEQ ID NO: 44), D-amino acid

EDDGLHLGHMVR (SEQ ID NO: 45), RVMHGLHLGNNQ (SEQ ID NO: 46), D-amino acid QNNGLHLGHMVR (SEQ ID NO: 47), RVMHGLHLGNNQ (SEQ ID NO: 48), GQLYKSILYGSG-4K2K (SEQ ID NO: 49) (a 4-branch peptide), GSGQLYKSILY (SEQ ID NO: 50), GSGGQLYKSILY (SEQ ID NO: 51), KQLNLVYT (SEQ ID NO: 52),

CVWLWQQC (SEQ ID NO: 53), WREPSFSALS (SEQ ID NO: 54),

GHRPLDKKREEAPS LRPAPPPISGGG YR (SEQ ID NO: 55), and

GHRPLNKKRQQAPSLRPAPPPISGGGYR (SEQ ID NO: 56).

[0044] As used herein, the term "sequence identity" refers to sequence homology (i.e., similarity) between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence, which may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. A peptide (or a polypeptide or peptide region) has a certain percentage (for example, at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 83%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98% or at least about 99%) of "homology" or "sequence identity" to another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences. This alignment and the percent homology or sequence identity can be determined using software programs known in the art (e.g., BLAST), and for example, those described in Ausubel et al. eds. (2007) Current Protocols in Molecular Biology.

[0045] In any of the embodiments described herein, any one or more of the synthetic peptides (e.g., the collagen binding peptide) may have a spacer sequence comprising from one to about five amino acids. It is contemplated that any amino acid, natural or unnatural, can be used in the spacer sequence, provided that the spacer sequence does not significantly interfere with the intended binding of the peptide. Exemplary spacers include, but are not limited to, short sequences comprising from one to five glycine units (e.g., G, GG, GGG, GGGG, or GGGGG), optionally comprising cysteine (e.g., GC, GCG, GSGC, or GGC) and/or serine (e.g., GSG, or GSGSG), or from one to five arginine units (e.g., R, RR, RRR, etc.). The spacer can also comprise non-amino acid moieties, such as polyethylene glycol (PEG), 6-aminohexanoic acid, or combinations thereof, with or without an amino acid spacer. The spacer can be attached to either the C-terminus or the N-terminus of the peptide to provide a point of attachment for a glycan or a glycan-linker conjugate. In certain embodiments, the spacer comprises more than one binding site (may be linear or branched) such that more than one peptide sequence can be bound thereto, thus creating a branched construct. The binding sites on the spacer can be the same or different, and can be any suitable binding site, such as an amine or carboxylic acid moiety, such that a desired peptide sequence can be bound thereto (e.g. via an amide bond). Thus in certain embodiments, the spacer contains one or more lysine, glutamic acid or aspartic acid residues. Such constructs can provide peptides having more than one collagen-binding unit of the formula P_nL, where P is a collagen-binding unit, L is a spacer and n is an integer from 2 to about 10, or from 2 to 8, or from 2 to 6, or from 2 to 5, or from 2 to 4, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10. For example, the spacer L can be an amino acid sequence such as KGSG, KKGSG, or KKKGSG, etc., providing 2, 3, or 4 binding sites, respectively. Exemplary collagen-binding constructs include, but are not limited to, (GELYKSILYGSG)₂KGSG (SEQ ID NO: 57), (GELYKSILYGSG)₃KKGSG (SEQ ID NO: 58), (GELYKSILYGSG)₄KKKGSG (SEQ ID NO: 59), (GQLYKSILYGSG)₂KGSG (SEQ ID NO: 60 ), (GQLYKSILYGSG)₃KKGSG (SEQ ID NO: 61 ), and (GQLYKSILYGSG)₄KKKGSG (SEQ ID NO: 62).

[0046] Accordingly, in certain embodiments, the peptide is RYPISRPRKRGSG (SEQ ID NO: 63), RRANAALKAGELYKSILYGC (SEQ ID NO: 64), or GELYKSILYGC (SEQ ID NO: 65).

[0047] In any of the embodiments described herein, a peptide (e.g., a collagen binding peptide) comprises any amino acid sequence described in the preceding paragraph or an amino acid sequence having at least about 80%, or at least about 83%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 100% homology to any of these amino acid sequences. In various embodiments, the peptide components of the synthetic proteoglycan described herein can be modified by the inclusion of one or more conservative amino acid substitutions. As is well-known to those skilled in the art, altering any non-critical amino acid of a peptide by conservative substitution should not significantly alter the activity of that peptide because the side-chain of the replacement amino acid should be able to form similar bonds and contacts to the side chain of the amino acid which has been replaced.

[0048] As is well-known in the art, a "conservative substitution" of an amino acid or a "conservative substitution variant" of a peptide refers to an amino acid substitution which maintains: 1) the secondary structure of the peptide; 2) the charge or hydrophobicity of the amino acid; and 3) the bulkiness of the side chain or any one or more of these characteristics. Illustratively, the well-known terminologies "hydrophilic residues" relate to serine or threonine. "Hydrophobic residues" refer to leucine, isoleucine, phenylalanine, valine or alanine, or the like. "Positively charged residues" relate to lysine, arginine, ornithine, or histidine. "Negatively charged residues" refer to aspartic acid or glutamic acid. Residues having "bulky side chains" refer to phenylalanine, tryptophan or tyrosine, or the like. A list of illustrative conservative amino acid substitutions is given in Table 1.

Table 1

[0049] As used herein, the term "extracellular matrix" refers to the extracellular part of tissue that provides structural and biochemical support to the surrounding cells.

[0050] As used herein, the term "linker" refers to chemical bond, atom, or group of atoms that connects two adjacent chains of atoms in a large molecule such as a peptide, synthetic proteoglycan, protein or polymer. In various embodiments, the linker comprises two or more chemically orthogonal functionalities on a rigid scaffold (e.g., any suitable bifunctional linker, such as N-[P-maleimidopropionic acid]hydrazide (BMPH), 3-(2- pyridyldithio)propionyl hydrazide (PDPH)), or the peptide GSG.

[0051] As used herein, the term "composition" refers to a preparation suitable for administration to an intended patient for therapeutic purposes that contains at least one pharmaceutically active ingredient, including any solid form thereof. The composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier. In certain embodiments, the composition is formulated as a film, gel, patch, or liquid solution. In another embodiment, the composition is administered topically to tissues and/or organs. As used herein, the term "topically" refers to administering a composition non-systemically to the surface of a tissue and/or organ (internal or, in some cases, external) to be treated, for local effect. In one embodiment, the synthetic proteoglycans are administered topically to the tissues and/or organs in the form of a composition comprising a synthetic proteoglycan and a

pharmaceutically acceptable carrier.

[0052] As used herein, the term "pharmaceutically acceptable" indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile.

[0053] As used herein, the term "pharmaceutically acceptable earner" refers to

pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any supplement or composition, or component thereof, from one organ, or portion of the body, to another organ, or portion of the body, or to deliver an agent to the surface of the tissues and/or organs.

[0054] As used herein, the term "formulated" or "formulation" refers to the process in which different chemical substances, including one or more pharmaceutically active ingredients, are combined to produce a dosage form. In certain embodiments, two or more pharmaceutically active ingredients can be coformulated into a single dosage form or combined dosage unit, or formulated separately and subsequently combined into a combined dosage unit. A sustained release formulation is a formulation that is designed to slowly release a therapeutic agent in the body over an extended period of time, whereas an immediate release formulation is a formulation that is designed to quickly release a therapeutic agent in the body over a shortened period of time.

[0055] As used herein, the term "delivery" refers to approaches, formulations,

technologies, and systems for transporting a pharmaceutical composition in the body as needed to safely achieve its desired therapeutic effect. In some embodiments, an effective amount of the composition is formulated for delivery into the abdominal cavity of a patient in need thereof prior to, during, or after surgical intervention to treat and/or prevent symptoms of abdominal adhesion.

[0056] As used herein, the term "abdominal cavity" refers to largest body cavity in humans and many animals, which holds the bulk of the internal organs. Organs of the abdominal cavity include the stomach, liver, gallbladder, spleen, pancreas, small intestine, kidney, large intestine, and adrenal glands. In some aspects, abdominal cavity also includes the pelvic cavity and all organs within the pelvic cavity (e.g., uterus, bladder, ovaries, fallopian tubes).

[0057] As used herein, the term "film" refers to an absorbable thin-film dosage form.

Thin-films used for drug delivery are well known in the art and comprise non-toxic, non- irritant hydrophilic polymers devoid of leachable impurities, such as polysaccharides (e.g., cellulose, maltodextrin, etc.). In some embodiments, the film described herein adheres to tissues to which it is applied, and is slowly absorbed into the body over a period of about a week. In certain embodiments, the film contains a lubricity-enhancing agent.

[0058] As used herein, the term "gel" refers to a solid, jelly-like dosage form that can have properties ranging from soft and weak to hard and tough. As is known in the art hydrogels are a type of gel which comprises a network of polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the dispersion medium. In some embodiments, the gel comprises a natural or synthetic polymeric network. In some embodiments, the gel possesses a degree of flexibility very similar to natural tissue. In certain embodiments, the gel contains a lubricity-enhancing agent.

[0059] As used herein, the term "patch" refers a drug eluting dosage form comprising a biocompatible polymeric matrix. Drug eluting patch dosage forms are well known in the art and can have one or more desirable properties (e.g., porosity, uniformity, thickness, strength, and/or flexibility) that are well known in the art and highly beneficial for the treatment and/or prevention of tissue adhesion. In some embodiments, the patch is biocompatible. In certain embodiments, the patch comprises a hydrophilic polymeric material. In other embodiments, the patch comprises a natural or biocompatible synthetic material. In certain embodiments, the patch contains a lubricity-enhancing agent.

[0060] As used herein, the term "liquid solution" refers to solutions, suspensions, emulsions, drops, ointments, liquid wash, sprays, liposomes which are well known in the art. In some embodiments, the liquid solution contains an aqueous pH-buffering agent which resists changes in pH when small quantities of acid or base are added. In certain

embodiments, the liquid solution contains a lubricity-enhancing agent.

[0061] As used herein, the term "polymer matrix" or "polymeric agent" refers to a biocompatible polymeric material. The polymeric material described herein may comprise, for example, sugars, peptides, protein, laminin, collagen, hyaluronic acid, ionic and non-ionic water soluble polymers; acrylic acid polymers; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulosic polymers and cellulosic polymer derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methyl cellulose, carboxymethyl cellulose, and etherified cellulose; poly(lactic acid), poly(glycolic acid), copolymers of lactic and glycolic acids, or other polymeric agents both natural and synthetic.

[0062] As used herein, the term "absorbable" refers to the ability of a material to be absorbed into the body. In certain embodiments, the polymeric matrix is absorbable, such as, for example collagen, polyglycolic acid, polylactic acid, polydioxanone, and caprolactone. In other embodiments, the polymer is non-absorbable, such as, for example polypropylene, polyester or nylon.

[0063] As used herein, the term "pH buffering agent" refers to an aqueous buffer solution that resists changes in pH when small quantities of acid or base are added to it. pH buffering solutions typically comprise of a mixture of weak acid and its conjugate base, or vice versa. For example, pH buffering solutions may comprise phosphates such as sodium phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate, disodium hydrogen phosphate dodecahydrate, potassium phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate; boric acid and borates such as, sodium borate and potassium borate; citric acid and citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate; carbonates such as sodium carbonate and sodium hydrogen carbonate, etc. pH adjusting agents can include, for example, acids such as hydrochloric acid, lactic acid, citric acid, phosphoric acid and acetic acid, and alkaline bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and sodium hydrogen carbonate, etc. In some embodiments, the pH buffering agent is a phosphate buffered saline (PBS) solution (i.e., containing sodium phosphate, sodium chloride and in some formulations, potassium chloride and potassium phosphate).

[0064] As used herein, the term "concurrently" refers to simultaneous (i.e., in conjunction) administration. In one embodiment, the administration is coadministration such that two or more pharmaceutically active ingredients, including any solid form thereof, are delivered together at one time.

[0065] As used herein, the term "sequentially" refers to separate (i.e., at different times) administration. In one embodiment, the administration is staggered such that two or more pharmaceutically active ingredients, including any solid form thereof, are delivered separately at different times.

2. Methods of Treating and/or Preventing Tissue Adhesion

[0066] The methods of the invention are useful in a variety of applications related to tissue adhesions, such as abdominal or pelvic adhesion, tendon adhesion or cardiac tissue adhesion. It is contemplated that the methods of the invention would be useful in treating and/or preventing these persistent defects or recurrent injury.

[0067] An adhesion is a band of fibrous scar tissue that abnormally binds tissues and/or organs that are not normally connected. Adhesions develop in response to various types of injury or tissue disturbances, for example, such as surgery, trauma, infection, chemotherapy, radiation, foreign body, or cancer.

[0068] Abdominal and pelvic adhesions are a common complication of abdominal surgical procedures. Abdominal adhesions can cause severe clinical problems and/or pain. For example, abdominal adhesion-related clinical problems may include small-intestinal obstruction, secondary female infertility, ectopic gestation, chronic abdominal and pelvic pain, and difficult and hazardous re-operations (Diamond, M. P., Freeman, M. L. Eur. Soc. Human. Repro. Embryo. 2001; 7(6): 567-576). Abdominal adhesions may cause pain by tethering tissues and/or organs not normally connected and causing traction of nerves. If the bowel becomes obstructed then distention will causes pain. Accordingly, abdominal adhesions may cause intestinal disturbances and bowel obstruction or blockage. In extreme cases, abdominal adhesions may form fibrous bands around a segment of an intestine that constricts blood flow and leads to tissue death.

[0069] Standard treatment of abdominal and pelvic adhesions that cause the above clinical problems and/or pain is surgical intervention. However, surgical intervention carries the risk of additional abdominal adhesions and further complications. Therefore, alternative treatment and/or prevention options for abdominal adhesions would be beneficial in treating and/or preventing abdominal adhesions in patients in need thereof.

[0070] Cardiac adhesions are a common complication of cardiothoracic surgical procedures, specifically, in pediatric cardiothoracic surgical procedures. Such adhesions can cause severe clinical problems and/or pain for the child. Therefore, alternative treatment and/or prevention options would be beneficial in treating and/or preventing cardiac tissue adhesions in patients in need thereof.

[0071] Tendon adhesions have long been accepted as a cause of restricted tendon movement and alternative treatment and/or prevention options would be beneficial in treating and/or preventing tendon adhesions in patients in need thereof.

[0072] In one aspect, trauma to the abdominal tissue or organs results in fibrous tissue band formation between abdominal tissues and/or organs. It is contemplated that the methods described herein would be useful in treating and/or preventing said abdominal adhesion. Also, it is contemplated that the methods described herein would be useful in treating and/or preventing cardiac tissue adhesion or tendon adhesion.

[0073] It is contemplated that the synthetic proteoglycans provided herein will provide a protective hydrating layer to minimize pain, protect tissue and/or organ collagen from degradation, and promote epithelial migration and epithelial proliferation.

[0074] In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tissue of an organ. In one embodiment, the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 1 to about 80 collagen-binding peptide(s) bonded to the glycan.

[0075] In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tissue of an organ, wherein the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 5 to about 40 collagen-binding peptide(s) bonded to the glycan. In certain embodiments, the tissue is abdominal tissue, tendon or cardiac tissue. In some embodiments, the tissue is pediatric cardiac tissue.

[0076] In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tissue of an organ, wherein the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 5 to about 40 collagen-binding peptide(s) bonded to the glycan, wherein the glycan comprises dermatan sulfate. In certain embodiments, the tissue is abdominal tissue, tendon or cardiac tissue. In some embodiments, the tissue is pediatric cardiac tissue.

[0077] In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tissue of an organ, wherein the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 5 to about 40 collagen-binding peptide(s) bonded to the glycan, wherein the glycan comprises dermatan sulfate and the collagen-binding peptide(s) comprises an amino acid sequence of RRANAALKAGELYKSILY (SEQ ID NO: 1). In certain embodiments, the tissue is abdominal tissue, tendon or cardiac tissue. In some embodiments, the tissue is pediatric cardiac tissue.

[0078] In certain embodiments, the disclosure provides a method of treating and/or preventing tissue adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tissue of an organ, wherein the pharmaceutical composition comprises a synthetic proteoglycan, wherein the glycan comprises dermatan sulfate and the collagen-binding peptide(s) comprises an amino acid sequence of

RRANAALKAGELYKSILY (SEQ ID NO: 1). In certain embodiments, the tissue is abdominal tissue, tendon or cardiac tissue. In some embodiments, the tissue is pediatric cardiac tissue.

[0079] In some aspects, the tissue is exposed due to surgery, trauma, infection,

[0080] In some aspects, the pharmaceutical composition is applied as a spray or an ointment or a wash or a gel. In some aspects, the tissue is a peritoneal membrane tissue. [0081] The compositions and methods of the present disclosure are also contemplated to be useful for reducing or preventing orthopedic adhesions, such as during hand or finger surgeries.

[0082] In some embodiments, the methods can further include other methods known in the art in reducing or preventing adhesion, such as the use of a mesh surrounding a tissue.

[0083] The synthetic proteoglycans provided herein can be used to treat and/or prevent tissue adhesion in a patient in need thereof by administering to the patient a synthetic proteoglycan that targets extracellular matrix components of the tissues and/or organs. It is contemplated that the synthetic proteoglycans provided herein can be tailored with respect to the peptide identity, the number of peptides attached to the glycosaminoglycan (GAG) backbone, and the GAG backbone identity to promote tissue vascularization. Thus, a number of molecular design parameters can be engineered to optimize the target effect.

[0084] The synthetic proteoglycans provided herein can be used as an adjunct in surgery to prevent or reduce tissue adhesion. During surgery, the synthetic proteoglycans can be delivered to the tissues or organs that are potentially adhesiogenic. It is contemplated that such an administration will help in preventing and/or reducing the post-operative adhesions. In one embodiment, this disclosure provides a method for decreasing or preventing postsurgical adhesions, wherein the method comprises delivering the synthetic proteoglycans provided herein to a surgical site. In another embodiment, the synthetic proteoglycans provided herein can be useful in surgical procedures such as laparoscopic surgery. In a further embodiment, the synthetic proteoglycans provided herein can be delivered through a laparoscope to the tissues or organs that are potentially adhesiogenic.

[0085] It is contemplated that the treatment with the synthetic proteoglycan DS-SILY or other proteoglycan as described herein will treat and/or prevent tissue adhesion by binding to the area of injury, providing a protective hydrating layer to minimize pain, protecting the tissue and/or organ collagen from degradation, and promoting epithelial migration and epithelial proliferation. It is further contemplated that the DS-SILY or other proteoglycan as described herein will persist in the injured area so that multiple treatments per day are not necessary.

[0086] In one embodiment, the molecule configuration consists of a dermatan sulfate (DS) GAG backbone with attached collagen binding peptide(s). DS may be useful in tissue adhesion applications because of its ability to promote epithelial cell migration and proliferation.

[0087] It is contemplated that other variants of GAG-peptide provided herein are also capable of inhibiting platelet activation through binding to type I collagen. In one

embodiment the synthetic proteoglycans provided will treat and/or prevent abdominal adhesion by enabling the GAG backbone to be tethered to the site of injury through the collagen-binding peptide(s) (e.g., RRANAALKAGELYKSILY (SEQ ID NO: 1), referred to as "SILY").

[0088] In another embodiment, the synthetic proteoglycan comprises collagen binding peptide(s) (SILY) conjugated to GAG backbones comprising heparin (Hep-SILY), dermatan sulfate (DS-SILY), or dextran (Dex-SILY) (see, e.g., US 2011/0020298 and 2013/0190246).

[0089] DS-SILY refers to the synthetic proteoglycan having about 5-20 SILY peptide(s) conjugated to dermatan sulfate (DS). In some embodiments, the synthetic proteoglycan comprises 5-10 SILY pepetide(s) or 10-15 SILY pepetide(s) or 5-20 SILY peptide(S) conjugated to dermatan sulfate. In some embodiments, the synthetic proteoglycan comprises from about 1 to about 75 percent (%) functionalization, or from about 5 to about 30 percent ( ) functionalization, wherein the percent ( ) functionalization is determined by a percent of disaccharide units on the dermatan sulfate which are functionalized with SILY peptide(s). DS-SILY optionally contains a linker between the SILY peptide(s) and DS.

[0090] The compositions of the present disclosure can be administered during open surgery or via a Laparoscope or via any instrument that allows for access to the surgical site.

3. Synthetic Proteoglycans

[0091] In various embodiment described herein, the synthetic proteoglycan comprises a combination of collagen-binding peptides bonded to the glycan. It is contemplated that the synthetic proteoglycan comprising a combination of collagen-binding peptides covalently bonded to the glycan that will treat and/or prevent tissue adhesion in a patient in need thereof.

[0092] In one embodiment, the present disclosure is further directed to a method of preventing and/or treating tissue adhesion in a patient in need thereof, comprising the step of administering to the tissue and/or organ of said patient an effective amount of the synthetic proteoglycan and a pharmaceutically acceptable carrier. [0093] In one embodiment, the synthetic proteoglycan comprises a glycan having from about 1 to about 80 collagen-binding peptide(s) bonded to the glycan.

[0094] In various embodiments of the methods disclosed herein, the synthetic proteoglycan binds to the extracellular matrix of the tissues and/or organs.

[0095] In various embodiments of the methods disclosed herein, the synthetic proteoglycan is administered in a combination, a) and b); a) and c); or b) and c) as described above. In various embodiments of the methods disclosed herein, the glycan is dextran, chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparan sulfate, heparin, keratin, keratan sulfate, or hyaluronic acid. In some embodiments the glycan can be any glycan (e.g., glycosaminoglycan or polysaccharide). In some embodiments, the glycan is dextran. In some embodiments, the glycan is chondroitin. In other embodiments, the glycan is chondroitin sulfate. In some embodiments, the glycan is dermatan. In some embodiments, the glycan is dermatan sulfate. In other embodiments, the glycan is heparan sulfate. In other embodiments, the glycan is heparin. In other embodiments, the glycan is keratin. In some embodiments, the glycan is keratan sulfate. In other embodiments, the glycan is hyaluronic acid. Various glycans may be employed including, a wide range of molecular weights, such as from about 1 kDa to about 2 MDa, or from about 10 kDa to about 2 MDa. In some embodiments, the glycan is from about 3 to about 5 MDa. In some embodiments, the glycan is up to about 3 MDa, or up to about 5 MDa, or up to about 60 MDa.

[0096] The peptide(s) can be bonded to the glycan directly or via a linker. In some embodiments, the linker can be any suitable bifunctional linker, e.g., Ν-[β- maleimidopropionic acid] hydrazide (BMPH), 3-(2-pyridyldithio)propionyl hydrazide (PDPH), and the like. In any of the various embodiments described herein, the sequence of the peptide may be modified to include a glycine-cysteine (GC) attached to the C-terminus of the peptide and/or a glycine-cysteine-glycine (GCG) attached to the N-terminus to provide an attachment point for a glycan or a glycan-linker conjugate. In certain embodiments, the linker is N-[P-maleimidopropionic acid] hydrazide (BMPH). In certain embodiments, the linker is 3-(2-pyridyldithio)propionyl hydrazide (PDPH). In some embodiments, the peptide to linker ratio is from about 1 : 1 to about 5: 1. In other embodiments, the peptide to linker ratio is from about 1:1 to about 10: 1. In other embodiments, the peptide to linker ratio is from about 1:1 to about 2:1, from about 1:1 to about 3:1, from about 1:1 to about 4:1, from about 1:1 to about 5:1, from about 1 : 1 to about 6:1, from about 1:1 to about 7: 1, from about 1 :1 to about 8:1, or from about 1 :1 to about 9:1. In one embodiment, the peptide linker ratio is about 1: 1. In one embodiment, the peptide linker ratio is about 2:1. In one embodiment, the peptide linker ratio is about 3:1. In one embodiment, the peptide linker ratio is about 4:1. In one embodiment, the peptide linker ratio is about 5:1. In one embodiment, the peptide linker ratio is about 6:1. In one embodiment, the peptide linker ratio is about 7: 1. In one embodiment, the peptide linker ratio is about 8: 1. In one embodiment, the peptide linker ratio is about 9: 1. In one embodiment, the peptide linker ratio is about 10:1.

[0097] Depending on the desired properties of the synthetic proteoglycan, the total number of peptides bonded to the glycan can be varied. In certain embodiments, the total number of peptides present in the synthetic proteoglycan is from about 2 to about 160, or from about 10 to about 160, or from about 20 to about 160, or from about 30 to about 160, or from about 40 to about 160, or from about 40 to about 150, or from about 40 to about 140, or from about 10 to about 120, or from about 20 to about 110, or from about 20 to about 100, or from about 20 to about 90, or from about 30 to about 90, or from about 40 to about 90, or from about 50 to about 90, or from about 50 to about 80, or from about 60 to about 80, or about 10, or about 20, or about 30, or about 40, or about 50, or about 60, or about 70, or about 80, or about 90, or about 100, or about 110, or about 120. In certain embodiments, the synthetic proteoglycan comprises less than about 50 peptides. In various embodiments , the synthetic proteoglycan comprises from about 5 to about 40 peptides. In some embodiments, the synthetic

proteoglycan comprises from about 10 to about 40 peptides. In other embodiments, the synthetic proteoglycan comprises from about 5 to about 20 peptides. In various

embodiments, the synthetic proteoglycan comprises from about 4 to about 18 peptides. In certain embodiments, the synthetic proteoglycan comprises less than about 20 peptides. In certain embodiments, the synthetic proteoglycan comprises less than about 18 peptides. In certain embodiments, the synthetic proteoglycan comprises less than about 15 peptides. In certain embodiments, the synthetic proteoglycan comprises less than about 10 peptides. In certain embodiments, the synthetic proteoglycan comprises about 20 peptides. In certain embodiments, the synthetic proteoglycan comprises about 40 peptides. In certain

embodiments, the synthetic proteoglycan comprises about 18 peptides. In certain

embodiments, the synthetic proteoglycan comprises from about 5 to about 40, or from about 10 to about 40, or from about 5 to about 20, or from about 4 to about 18, or about 10, or about 11, or about 18, or about 20 peptides.

[0098] In any of the embodiments described herein, the number of peptides per glycan is an average, where certain proteoglycans in a composition may have more peptides per glycan and certain proteoglycans have less peptides per glycan. Accordingly, in certain embodiments, the number of peptides as described herein is an average in a composition of proteoglycans. For example, in certain embodiments, the proteoglycans are a composition where the average number of peptides per glycan is about 5. In other embodiments, the average number of peptides per glycan is about 6, or about 7, or about 8, or about 9, or about 10, or about 11, or about 12, or about 13, or about 14, or about 15, or about 16, or about 17, or about 18, or about 19, or about 20, or about 25, or about 30. In certain embodiments, the number of peptides per glycan may be described as a "percent (%) functionalization" based on the percent of disaccharide units which are functionalized with peptide on the glycan backbone. For example, the total number of available disaccharide units present on the glycan can be calculated by dividing the molecular weight (or the average molecular weight) of a single disaccharide unit (e.g., about 550-800 Da, or from about 650-750 Da) by the molecular weight of the glycan (e.g., about 25 kDa up to about 70 kDa, or even about 100 kDa). For example, in some embodiments, the number of available disaccharide units present on the glycan is from about 10 to about 80, or from about 10 to about 70, or from about 15 to about 70, or from about 20 to about 70, or from about 30 to about 70, or from about 35 to about 70, or from about 40 to about 70, or from about 10 to about 75, or from about 15 to about 75, or from about 20 to about 75, or from about 30 to about 75, or from about 35 to about 75, or from about 40 to about 75, or from about 10 to about 50, or from about 20 to about 50, or from about 25 to about 50, or from about 10 to about 35, or from about 15 to about 35, or from about 20 to about 35, or from about 10 to about 30, or from about 15 to about 30, or from about 20 to about 30, or about 15, or about 20, or about 25, or about 30, or about 35, or about 40, or about 45, or about 50, or about 55, or about 60, or about 65, or about 70.

[0099] Therefore, in certain embodiments, the glycan comprises from about 1 to about 50, or from about 5 to about 30% functionalization, or about 25% functionalization, wherein the percent (%) functionalization is determined by a percent of disaccharide units on the glycan which are functionalized with peptide. In some embodiments, the percent (%)

functionalization of the glycan is from about 1% to about 50%, or from about 3% to about 40%, or from about 5% to about 30%, or from about 10% to about 20%, or about 1%, or about 2%, or about 5%, or about 10%, or about 15%, or about 20%, or about 25%, or about 30%, or about 35%, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%, or about 100%.

[0100] In one aspect, the collagen-binding peptide has binding affinity to one or more of collagen types I, II, III, or IV. In some embodiments, the collagen-binding peptide binds to type I collagen. In other embodiments, the collagen-binding peptide binds to type IV collagen. In certain embodiments, one or more collagen-binding peptide having a specified binding affinity can be used in the synthetic proteoglycans described herein. For example, the synthetic proteoglycans can comprise at least one collagen-binding peptide which has binding affinity to type I collagen and at least one collagen-binding peptide which has binding affinity to type IV collagen. In another aspect, the collagen-binding peptides have binding affinity to type I collagen. In another aspect, the collagen-binding peptides have binding affinity to type IV collagen. In certain aspects, the collagen-binding peptides have binding affinity to type II collagen. In certain aspects, the collagen-binding peptides have binding affinity to type III collagen.

[0101] Suitable collagen-binding peptides are known (see, e.g., US 2013/0190246, US 2012/0100106, and US 2011/0020298, the disclosures of which are incorporated herein by reference in their entirety) or can be found by methods known in the art. In certain embodiments, the collagen-binding peptide comprises from about 5 to about 40 amino acids. In some embodiments, these peptides have homology to the amino acid sequence of a small leucine-rich proteoglycan, a platelet receptor sequence, or a protein that regulates collagen fibrillogenesis.

[0102] In various embodiments, the collagen-binding peptide comprises an amino acid sequence selected from: i) RR AN A ALK AGELY KS ILY (SEQ ID NO: 1), RLDGNEIKR (SEQ ID NO: 2), AHEEISTTNEGVM (SEQ ID NO: 3), GELYKSILY (SEQ ID NO: 4),

[0103] In certain embodiments, the collagen binding peptide(s) is

RR AN A ALKAGEL Y KS IL Y (SEQ ID NO: 1) or a peptide having at least about 80% sequence to RRANAALKAGELYKSILY (SEQ ID NO: 1) and capable of binding to collagen. In some embodiments, the peptide sequence comprises a sequence with at least about 80% sequence identity, or at least about 83% sequence identity, or at least about 85% sequence identity, or at least about 90% sequence identity, or at least about 95% sequence identity, or at least about 98% sequence identity to the amino acid sequence of i) and capable of binding to collagen. In certain embodiments, the collagen-binding peptide is at least about 80%, or at least about 83%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 100% homologous with the collagen-binding unit(s) of the von Willebrand factor or a platelet collagen receptor as described in Chiang, T. M. et al. J. Biol. Chem., 2002, 277: 34896-34901 ; Huizinga, E.G. et al., Structure, 1997, 5: 1147-1156; Romijn, R. A. et al., J. Biol. Chem., 2003, 278: 15035-15039; and Chiang, et al, Cardio. & Haemato. Disorders-Drug Targets, 2007, 7: 71-75, each incorporated herein by reference. A non-limiting example is WREPSFCALS (SEQ ID NO: 18), derived from vWF.

[0104] In various embodiments, the collagen-binding peptide comprises an amino acid spacer. Accordingly, in certain embodiments, the collagen-binding peptide comprises an amino acid sequence selected from: i) RRANAALKAGELYKSILYGC (SEQ ID NO: 64), RLDGNEIKRGC (SEQ ID NO: 66), AHEEISTTNEGVMGC (SEQ ID NO: 67), GCGGELYKSILY (SEQ ID NO: 68), NGVFKYRPRYFLYKHAYFYPPLKRFPVQGC (SEQ ID NO: 69), CQDSETRTFYGC (SEQ ID NO: 70), TKKTLRTGC (SEQ ID NO: 71),

GLRSKSKKFRRPDIQYPDATDEDITSHMGC (SEQ ID NO: 72), SQNPVQPGC (SEQ ID NO: 73), SYIRIADTNITGC (SEQ ID NO: 74), KELNLVYTGC (SEQ ID NO: 75),

GSITTIDVPWNVGC (SEQ ID NO: 12), GCGGELYKS ILYGC (SEQ ID NO: 76) or GELYKSILYGC (SEQ ID NO: 65); or ii) a peptide comprising a sequence with at least about 80% sequence identity to the amino acid sequence of i) and capable of binding to collagen. In some embodiments, the peptide sequence comprises a sequence with at least about 80% sequence identity, or at least about 83% sequence identity, or at least about 85% sequence identity, or at least about 90% sequence identity, or at least about 95% sequence identity, or at least about 98% sequence identity to the amino acid sequence of i) and capable of binding to collagen.

[0105] In one embodiment, the synthetic proteoglycan comprises dermatan sulfate having from about 5 to about 40 collagen-binding peptide(s) bonded thereto and wherein the collagen-binding peptide(s) is RRANAALKAGELYKSILY (SEQ ID NO: 1) or a peptide having at least about 80% sequence identity to RRANAALKAGELYKSILY (SEQ ID NO: 1) and capable of binding to collagen.

[0106] In one embodiment, the synthetic proteoglycan comprises chondroitin sulfate having from 5 to about 40 collagen-binding peptide(s) bonded thereto and wherein the collagen-binding peptide(s) is RRANAALKAGELYKSILY (SEQ ID NO: 1) or a peptide having at least about 80% sequence identity to RRANAALKAGELYKSILY (SEQ ID NO: 1) and capable of binding to collagen.

[0107] A peptide derived from a phage display library selected for collagen binding can be generated. The peptide can be synthesized and evaluated for binding to collagen by any of the techniques such as SPR, ELISA, ITC, affinity chromatography, or others known in the art. An example could be a biotin modified peptide sequence (e.g., SILY_bi_oti_n) that is incubated on a microplate containing immobilized collagen. A dose response binding curve can be generated using a streptavidin-chromophore to determine the ability of the peptide to bind to collagen.

[0108] In various embodiments described herein, the peptides described herein can be modified by the inclusion of one or more conservative amino acid substitutions. As is well known to those skilled in the art, altering any non-critical amino acid of a peptide by conservative substitution should not significantly alter the activity of that peptide because the side-chain of the replacement amino acid should be able to form similar bonds and contacts to the side chain of the amino acid which has been replaced. Non-conservative substitutions may too be possible, provided that they do not substantially affect the binding activity of the peptide (i.e., hyaluronic acid or collagen binding affinity).

4. Synthesis of Synthetic Proteoglycans

[0109] The peptides used in the method described herein (i.e., the collagen-binding peptides) may be purchased from a commercial source or partially or fully synthesized using methods well known in the art (e.g., chemical and/or biotechnological methods). In certain embodiments, the peptides are synthesized according to solid phase peptide synthesis protocols that are well known in the art. In another embodiment, the peptide is synthesized on a solid support according to the well-known Fmoc protocol, cleaved from the support with trifluoroacetic acid and purified by chromatography according to methods known to persons skilled in the art. In other embodiments, the peptide is synthesized utilizing the methods of biotechnology that are well known to persons skilled in the art. In one embodiment, a DNA sequence that encodes the amino acid sequence information for the desired peptide is ligated by recombinant DNA techniques known to persons skilled in the art into an expression plasmid (for example, a plasmid that incorporates an affinity tag for affinity purification of the peptide), the plasmid is transfected into a host organism for expression, and the peptide is then isolated from the host organism or the growth medium, e.g., by affinity purification. Recombinant DNA technology methods are described in Sambrook et al., "Molecular Cloning: A Laboratory Manual", 3rd Edition, Cold Spring Harbor Laboratory Press, (2001), incorporated herein by reference, and are well-known to the skilled artisan.

[0110] In certain embodiments, the peptides are covalently bonded to the glycan directly (i.e., without a linker). In such embodiments, the synthetic proteoglycan may be formed by covalently bonding the peptides to the glycan through the formation of one or more amide, ester, ether, or imino bonds between an acid, aldehyde, hydroxy, amino, or hydrazo group on the glycan. All of these methods are known in the art. See, e.g., Hermanson G.T.,

Bioconjugate Techniques, Academic Press, pp. 169-186 (1996), incorporated herein by reference. As shown in Scheme 1, the glycan (e.g., chondroitin sulfate "CS") can be oxidized using a periodate reagent, such as sodium periodate, to provide aldehyde functional groups on the glycan (e.g., "ox-CS") for covalently bonding the peptides to the glycan. In such embodiments, the peptides may be covalently bonded to a glycan by reacting a free amino group of the peptide with an aldehyde functional groups of the oxidized glycan, e.g., in the presence of a reducing agent, utilizing methods known in the art.

[0111] In embodiments where the peptides are covalently bonded to the glycan via a linker, the oxidized glycan (e.g., "ox-CS") can be reacted with a linker (e.g., any suitable

bifunctional liker, such as 3-(2-pyridyldithio)propionyl hydrazide (PDPH) or Ν-[β- maleimidopropionic acid] hydrazide (BMPH)) prior to contacting with the peptides. The linker typically comprises about 1 to about 30 carbon atoms, or about 2 to about 20 carbon atoms. Lower molecular weight linkers (i.e., those having an approximate molecular weight of about 20 to about 500) are typically employed. In addition, structural modifications of the linker are contemplated. For example, amino acids may be included in the linker, including but not limited to, naturally occurring amino acids as well as those available from conventional synthetic methods, such as beta, gamma, and longer chain amino acids.

[0112] As shown in Scheme 1, in one embodiment, the peptides are covalently bonded to the glycan (e.g., chondroitin sulfate "CS") by reacting an aldehyde function of the oxidized glycan (e.g., "ox-CS") with N-[P-maleimidopropionic acid]hydrazide (BMPH) to form an glycan intermediate (e.g., "BMPH-CS") and further reacting the glycan intermediate with peptides containing at least one free thiol group (i.e., -SH group) to yield the synthetic proteoglycan. In yet another embodiment, the sequence of the peptides may be modified to include an amino acid residue or residues that act as a spacer between the HA- or Collagen- binding peptide sequence and a terminating cysteine (C). For example a glycine-cysteine (GC) or a glycine-glycine-glycine-cysteine (GGGC) or glycine-serine-glycine-cysteine (GSGC) segment may be added to provide an attachment point for the glycan intermediate.

Scheme 1. Synthesis of CS -BMPH -Peptide _n

"BMPH-CS"

[0113] Accordingly, in one embodiment, the synthetic proteoglycans is provided by a) oxidizing at least one vicinal diol group of a glycan to provide a glycan having at least two aldehyde functional groups; b) optionally reacting the glycan with a linker; and reacting the glycan with from about 1 to about 80 collagen binding peptide(s). 5. Compositions

[0114] In one embodiment, the synthetic proteoglycan is administered in a composition. The present disclosure provides compositions comprising a synthetic proteoglycan and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known to one having ordinary skill in the art may be used, including water or saline. As is known in the art, the components as well as their relative amounts are determined by the intended use and method of delivery. The compositions provided in accordance with the present disclosure are formulated for delivery, for example, into the abdominal cavity. Diluent or carriers employed in the compositions can be selected so that they do not diminish the desired effects of the synthetic proteoglycan. Examples of suitable compositions include aqueous solutions, for example, a solution in isotonic saline, 5% glucose. Other well-known pharmaceutically acceptable liquid carriers such as alcohols, glycols, esters and amides, may be employed. In certain embodiments, the composition further comprises one or more excipients, such as, but not limited to ionic strength modifying agents, solubility enhancing agents, lubricity enhancing agents, pH buffering agent, surfactants, stabilizing polymer, preservatives, and/or co-solvents.

[0115] In certain embodiments, the composition provided herein is an anti-adhesion composition. Anti-adhesion compositions administered according to the present invention may act as a adhesion barrier, or physical barrier separating the tissues and/or organs while the body's healing repair mechanisms respond to tissue disturbances (e.g., trauma, surgery, infection, etc.). Alternatively, compositions according to the present invention may act as anti-adhesion agents to promote or enhance the body's healing mechanisms and which have local effect on the tissue vascularization. Anti-adhesion compositions provided herein may be formulated as films, gels, foams, patches, liquid solutions, suspensions, emulsions and other dosage forms for topical administration to tissues and/or organs. In certain

embodiments, the composition comprises an aqueous solution. Aqueous solutions are suitable for use in composition formulations based on ease of formulation, as well as an ability to easily administer such compositions by means of instilling the solution in. In certain embodiments, the compositions are suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. In some embodiments, the composition is in the form of foams, ointments, liquid wash, gels, sprays and liposomes, which are very well known in the art. Alternatively, the topical administration is an infusion of the provided synthetic proteoglycan to said tissues and/or organs via a device selected from a pump- catheter system, a continuous or selective release device, or an adhesion barrier. In certain embodiments, the composition is a solution that is directly applied to or contacts tissues and/or organs. In some embodiments, the composition comprises a polymer matrix. In other embodiments, the composition is absorbable. In certain embodiments, the composition comprises a pH buffering agent. In some embodiments, the composition contains a lubricity enhancing agent.

[0116] In certain embodiments, a polymer matrix or polymeric material is employed as a pharmaceutically acceptable carrier or support for the anti-adhesion composition. The polymeric material described herein may comprise natural or unnatural polymers, for example, such as sugars, peptides, protein, laminin, collagen, hyaluronic acid, ionic and non- ionic water soluble polymers; acrylic acid polymers; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers and cellulosic polymer derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methyl cellulose, carboxymethyl cellulose, and etherified cellulose; poly(lactic acid), poly(glycolic acid), copolymers of lactic and glycolic acids, or other polymeric agents both natural and synthetic. In certain embodiments, the anti-adhesion compositions provided herein is formulated as films, gels, foams, or and other dosage forms for topical

administration to tissues and/or organs.

[0117] Suitable ionic strength modifying agents include, for example, glycerin, propylene glycol, mannitol, glucose, dextrose, sorbitol, sodium chloride, potassium chloride, and other electrolytes.

[0118] In certain embodiments, the solubility of the synthetic proteoglycan may need to be enhanced. In such cases, the solubility may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing compositions such as mannitol, ethanol, glycerin, polyethylene glycols, propylene glycol, poloxomers, and others known in the art.

[0119] In certain embodiments, the composition contains a lubricity enhancing agent. As used herein, lubricity enhancing agents refer to one or more pharmaceutically acceptable polymeric materials capable of modifying the viscosity of the pharmaceutically acceptable carrier. Suitable polymeric materials include, but are not limited to: ionic and non-ionic water soluble polymers; hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, gelatin, chitosans, gellans, other proteoglycans or polysaccharides, or any combination thereof; cellulosic polymers and cellulosic polymer derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,

hydroxypropyl methylcellulose phthalate, methyl cellulose, carboxymethyl cellulose, and etherified cellulose; collagen and modified collagens; galactomannans, such as guar gum, locust bean gum and tara gum, as well as polysaccharides derived from the foregoing natural gums and similar natural or synthetic gums containing mannose and/or galactose moieties as the main structural components (e.g., hydroxypropyl guar); gums such as tragacanth and xanthan gum; gellan gums; alginate and sodium alginate; chitosans; vinyl polymers;

hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; carboxyvinyl polymers or crosslinked acrylic acid polymers such as the "carbomer" family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol™ trademark; and various other viscous or viscoelastomeric substances. In one embodiment, a lubricity enhancing agent is selected from the group consisting of hyaluronic acid, dermatan, chondroitin, heparin, heparan, keratin, dextran, chitosan, alginate, agarose, gelatin, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methyl cellulose, carboxymethyl cellulose, and etherified cellulose, polyvinyl alcohol,

polyvinylpyrrolidinone, povidone, carbomer 941, carbomer 940, carbomer 971P, carbomer 974P, or a pharmaceutically acceptable salt thereof. In one embodiment, a lubricity enhancing agent is applied concurrently with the synthetic proteoglycan. Alternatively, in one embodiment, a lubricity enhancing agent is applied sequentially to the synthetic proteoglycan. In one embodiment, the lubricity enhancing agent is chondroitin sulfate. In one embodiment, the lubricity enhancing agent is hyaluronic acid. The lubricity enhancing agent can change the viscosity of the composition.

[0120] For further details pertaining to the structures, chemical properties and physical properties of the above lubricity enhancing agents, see e.g., U.S. 5,409,904, U.S. 4,861,760 (gellan gums), U.S. 4,255,415, U.S. 4,271,143 (carboxyvinyl polymers), WO 94/10976 (polyvinyl alcohol), WO 99/51273 (xanthan gum), and WO 99/06023 (galactomannans). Typically, non-acidic lubricity enhancing agents, such as a neutral or basic agent are employed in order to facilitate achieving the desired pH of the formulation.

[0121] In some embodiments, the synthetic proteoglycans can be combined with minerals, amino acids, sugars, peptides, proteins, vitamins (such as ascorbic acid), or laminin, collagen, fibronectin, hyaluronic acid, fibrin, elastin, or aggrecan, or growth factors such as epidermal growth factor, platelet-derived growth factor, transforming growth factor beta, or fibroblast growth factor, and glucocorticoids such as dexamethasone or viscoelastic altering agents, such as ionic and non-ionic water soluble polymers; acrylic acid polymers; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers and cellulosic polymer derivatives such as

hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,

hydroxypropyl methylcellulose phthalate, methyl cellulose, carboxymethyl cellulose, and etherified cellulose; poly(lactic acid), poly(glycolic acid), copolymers of lactic and glycolic acids, or other polymeric agents both natural and synthetic.

[0122] Suitable pH buffering agents for use in the anti-adhesion compositions herein include, for example, acetate, borate, carbonate, citrate, and phosphate buffers, as well as hydrochloric acid, sodium hydroxide, magnesium oxide, monopotassium phosphate, bicarbonate, ammonia, carbonic acid, hydrochloric acid, sodium citrate, citric acid, acetic acid, disodium hydrogen phosphate, borax, boric acid, sodium hydroxide, diethyl barbituric acid, and proteins, as well as various biological buffers, for example, TAPS, Bicine, Tris, Tricine, HEPES, TES, MOPS, PIPES, cacodylate, or MES. In certain embodiments, an appropriate buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) is added to the composition to prevent pH drift under storage conditions. In some embodiments, the buffer is a phosphate buffered saline (PBS) solution (i.e., containing sodium phosphate, sodium chloride and in some formulations, potassium chloride and potassium phosphate). The particular concentration will vary, depending on the agent employed. In certain embodiments, the pH buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) is added to maintain a pH within the range of from about pH 4 to about pH 8, or about pH 5 to about pH 8, or about pH 6 to about pH 8, or about pH 7 to about pH 8. In some embodiments, the buffer is chosen to maintain a pH within the range of from about pH 4 to about pH 8. In some embodiments, the pH is from about pH 5 to about pH 8. In some embodiments, the buffer is a saline buffer. In certain embodiments, the pH is from about pH 4 and about pH 8, or from about pH 3 to about pH 8, or from about pH 4 to about pH 7. In some embodiments, the composition is in the form of a film, gel, patch, or liquid solution which comprises a polymeric matrix, pH buffering agent, a lubricity enhancing agent and a synthetic proteoglycan wherein the composition optionally contains a preservative; and wherein the pH of said composition is within the range of about pH 4 to about pH 8.

[0123] Surfactants are employed in the composition to deliver higher concentrations of synthetic proteoglycan. The surfactants function to solubilize the inhibitor and stabilize colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension.

Suitable surfactants comprise c polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, triton, and sorbitan monolaurate. In one embodiment, the surfactants have hydrophile/lipophile/balance (HLB) in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as TritonX114 and tyloxapol.

[0124] In certain embodiments, stabilizing polymers, i.e., demulcents, are added to the anti- adhesion composition. The stabilizing polymer should be an ionic/charged example with precedence for topical tissue and/or organ use, more specifically a polymer that carries negative charge on its surface that can exhibit a zeta-potential of (-) 10-50 mV for physical stability and capable of making a dispersion in water (i.e. water soluble). In one

embodiment, the stabilizing polymer comprises a polyelectrolyte or polyelectrolytes if more than one, from the family of cross-linked polyacrylates, such as carbomers and Pemulen®, specifically Carbomer 974p (polyacrylic acid), at a range of about 0.1% to about 0.5% w/w.

[0125] In one embodiment, the composition comprises an agent which increases the permeability of the synthetic proteoglycan to the extracellular matrix of the abdominal cavity. Preferably the agent which increases the permeability is selected from benzalkonium chloride, saponins, fatty acids, polyoxyethylene fatty ethers, alkyl esters of fatty acids, pyrrolidones, polyvinylpyrrolidone, pyruvic acids, pyroglutamic acids or mixtures thereof.

[0126] The synthetic proteoglycan may be sterilized to remove unwanted contaminants including, but not limited to, endotoxins and infectious agents. Sterilization techniques which do not adversely affect the structure and biotropic properties of the synthetic proteoglycan can be used. In certain embodiments, the synthetic proteoglycan can be disinfected and/or sterilized using conventional sterilization techniques including propylene oxide or ethylene oxide treatment, sterile filtration, gas plasma sterilization, gamma radiation, electron beam, and/or sterilization with a peracid, such as peracetic acid. In one embodiment, the synthetic proteoglycan can be subjected to one or more sterilization processes.

Alternatively, the synthetic proteoglycan may be wrapped in any type of container including a plastic wrap or a foil wrap, and may be further sterilized. [0127] In some embodiments, preservatives are added to the composition to prevent microbial contamination during use. Suitable preservatives added to the anti-adhesion compositions comprise benzalkonium chloride, benzoic acid, alkyl parabens, alkyl benzoates, chlorobutanol, chlorocresol, cetyl alcohols, fatty alcohols such as hexadecyl alcohol, organometallic compounds of mercury such as acetate, phenylmercury nitrate or borate, diazolidinyl urea, diisopropyl adipate, dimethyl polysiloxane, salts of EDTA, vitamin E and its mixtures. In certain embodiments, the preservative is selected from benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, or polyquarternium- 1. In certain embodiments, the ophthalmic compositions contain a preservative. In some embodiments, the preservatives are employed at a level of from about 0.001% to about 1.0% w/v. In certain embodiments, the ophthalmic compositions do not contain a preservative and are referred to as "unpreserved". In some embodiments, the unit dose compositions are sterile, but unpreserved.

[0128] In one embodiment, a method of treating and/or preventing tissue adhesion is provided comprising administering a composition comprising a synthetic proteoglycan and a pharmaceutically acceptable carrier.

[0129] In some embodiments, separate or sequential administration of the synthetic proteoglycan and other agent is necessary to facilitate delivery of the composition into, for example, the abdominal cavity, or topical administration to the tissues and/or organs. In certain embodiments, the synthetic proteoglycan and the other agent can be administered at different dosing frequencies or intervals. For example, the synthetic proteoglycan can be administered daily, while the other agent can be administered less frequently. Additionally, as will be apparent to those skilled in the art, the synthetic proteoglycan and the other agent can be administered using the same route of administration or different routes of

administration.

[0130] Any effective regimen for administering the synthetic proteoglycan can be used. For example, the synthetic proteoglycan can be administered as a single dose, or as a multiple-dose daily regimen. Further, a staggered regimen, for example, one to five days per week can be used as an alternative to daily treatment.

[0131] In certain embodiments, a synthetic proteoglycan is administered to a patient (e.g., a patient in need of treatment to treat and/or prevent abdominal adhesion). In various embodiments, the synthetic proteoglycan can be administered topically, such as by film, gel, patch, or liquid solution. In some of the embodiments, the compositions provided are in a buffered, sterile aqueous solution. In certain embodiments, the solutions have a viscosity of from about 1 to about 100 centipoises (cps), or from about 1 to about 200 cps, or from about 1 to about 300 cps, or from about 1 to about 400 cps. In some embodiments, the solutions have a viscosity of from about 1 to about 100 cps. In certain embodiments, the solutions have a viscosity of from about 1 to about 200 cps. In certain embodiments, the solutions have a viscosity of from about 1 to about 300 cps. In certain embodiments, the solutions have a viscosity of from about 1 to about 400 cps. In certain embodiments, the solution comprises the composition which is dispensed in the abdominal cavity in the form of an injectable liquid solution. In other embodiments, the compositions are formulated as viscous liquids, i.e. viscosities from several hundred to several thousand cps, gels or ointments. In these embodiments, the synthetic proteoglycan is dispersed or dissolved in an appropriate pharmaceutically acceptable carrier.

[0132] Exemplary compositions for use with the synthetic proteoglycans for catheter-based delivery may comprise: a) a synthetic proteoglycan as described herein; b) a pharmaceutically acceptable carrier; c) a polymer matrix; d) a pH buffering agent to provide a pH in the range of about pH 4 to about pH 8; and e) a water soluble lubricity enhancing agent in the concentration range of about 0.25% to about 10% total formula weight or any individual component a), b), c), d) or e) or any combinations of a), b), c), d) or e).

[0133] In certain embodiments, the proteoglycan, or a composition comprising the same, is lyophilized prior to, during, or after, formulation. Accordingly, also provided herein is a lyophilized composition comprising a proteoglycan or composition comprising the same as described herein.

6. Pharmaceutical Formulations

[0134] Formulations contemplated by the present disclosure may also be for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present disclosure. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0135] Sterile injectable solutions are prepared by incorporating the component in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0136] In making pharmaceutical compositions that include synthetic proteoglycans described herein, the active ingredient is usually diluted by an excipient or carrier and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of films, gels, patches, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compounds, soft and hard gelatin films, gels, patches, sterile injectable solutions, and sterile packaged powders.

[0137] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. [0138] In any of the embodiments, the composition is formulated for delivery into, for example, the abdominal cavity. In some embodiments, the composition is formulated as a film, gel, patch, or liquid solution.

[0139] Films used for drug delivery are well known in the art and comprise non-toxic, non- irritant polymers devoid of leachable impurities, such as polysaccharides (e.g., cellulose, maltodextrin, etc.). In some embodiments, the polymers are hydrophilic. In other

embodiments, the polymers are hydrophobic. The film adheres to tissues to which it is applied, and is slowly absorbed into the body over a period of about a week. Polymers used in the thin-film dosage forms described herein are absorbable and exhibit sufficient peel, shear and tensile strengths as is well known in the art. In some embodiments, the film is administered topically to tissues and/or organs of a patient in need thereof. In some embodiments, the film is injectable. In certain embodiments, the film is administered to the patient prior to, during or after surgical intervention.

[0140] Gels are used herein refer to a solid, jelly-like material that can have properties ranging from soft and weak to hard and tough. As is well known in the art, a gel is a non- fluid colloidal network or polymer network that is expanded throughout its whole volume by a fluid. A hydrogel is a type of gel which comprises a network of polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are highly absorbent and can contain a high degree of water, such as, for example greater than 90% water. In some embodiments, the gel described herein comprises a natural or synthetic polymeric network. In some embodiments, the gel comprises a hydrophilic polymer matrix. In other embodiments, the gel comprises a hydrophobic polymer matrix. In some embodiments, the gel possesses a degree of flexibility very similar to natural tissue. In certain embodiments, the gel is biocompatible and absorbable. In some embodiments, the gel is administered topically to tissues and/or organs of a patient in need thereof. In certain embodiments, the gel is administered to the patient prior to, during or after surgical intervention.

[0141] Patch as used herein refers a drug eluting biocompatible polymeric matrix as is well known in the art. As provided herein the patch can have one or more desirable properties (e.g., porosity, uniformity, thickness, strength, and/or flexibility) that are well known in the art and highly beneficial for the treatment and/or prevention of tissue adhesion. In some embodiments, the patch is biocompatible. In some embodiments, the patch provides controlled or sustained release of synthetic proteoglycans over a prolonged period of time, such as a week. In some embodiments the patch is an absorbable hydrogel or polymeric material providing sustained or controlled release of synthetic proteoglycans at the site of application. In certain embodiments, the patch is biocompatible and absorbable. In some embodiments, the patch is conformable with the tissue and/or organs, meaning that it can create adapt to the shape of the tissue and/or organ on which it is applied. In some embodiments, the patch is implanted surgically to tissues and/or organs of a patient in need thereof. In certain embodiments, the patch is administered to the patient during or after surgical intervention.

[0142] Liquid solution as used herein refers to solutions, suspensions, emulsions, drops, ointments, liquid wash, sprays, and liposomes which are well known in the art. In some embodiments, the liquid solution contains an aqueous pH buffer agent which resists changes in pH when small quantities of acid or base are added. In some embodiments, the liquid solution is administered topically to tissues and/or organs of a patient in need thereof. In certain embodiments, the liquid solution is administered to the patient prior to, during or after surgical intervention. In certain embodiments, the liquid solution is administered as an infusion of the provided synthetic proteoglycan to said tissues and/or organs via a device selected from a pump-catheter system, a continuous or selective release device.

[0143] In some embodiments, an effective amount of the composition is administered in the form of film on the external surface of the tissues and/or organs which has a local effect on the tissue vascularization. In some embodiments, an effective amount of the composition is administered in the form of a gel on the external surface of the tissues and/or organs which has a local effect on the tissue vascularization. In other embodiments, an effective amount of the composition is administered in the form of a patch on the external surface of the tissues and/or organs which has a local effect on the tissue vascularization. In other embodiments, an effective amount of the composition is administered in the form of a liquid solution on the external surface of the tissues and/or organs which has a local effect on the tissue

vascularization.

[0144] Exemplary formulations for delivery into the abdominal cavity may comprise: a) synthetic proteoglycan as described herein; b) pharmaceutically acceptable carrier; c) polymer matrix; and d) pH buffering agent to provide a pH in the range of about pH 4 to about pH 8, wherein said formulation has a viscosity of from about 3 to about 30 cps for a liquid solution. In certain embodiments, the solutions have a viscosity of from about 1 to about 100 centipoises (cps), or from about 1 to about 200 cps, or from about 1 to about 300 cps, or from about 1 to about 400 cps. In some embodiments, the solutions have a viscosity of from about 1 to about 100 cps. In certain embodiments, the solutions have a viscosity of from about 1 to about 200 cps. In certain embodiments, the solutions have a viscosity of from about 1 to about 300 cps. In certain embodiments, the solutions have a viscosity of from about 1 to about 400 cps.

[0145] Alternatively, exemplary formulations for delivery into the abdominal cavity may comprise: a) synthetic proteoglycan as described herein; b) pharmaceutically acceptable carrier; and c) hydrophilic polymer as matrix network, wherein said compositions are formulated as viscous liquids, i.e. viscosities from several hundred to several thousand cps, gels or ointments. In these embodiments, the synthetic proteoglycan is dispersed or dissolved in an appropriate pharmaceutically acceptable carrier.

7. Dosing

[0146] Suitable dosages of the synthetic proteoglycan can be determined by standard methods, for example by establishing dose-response curves in laboratory animal models or in clinical trials and can vary significantly depending on the patient condition, the disease state being treated, the route of administration and tissue distribution, and the possibility of co- usage of other therapeutic treatments. The effective amount to be administered to a patient is based on body surface area, patient weight or mass, and physician assessment of patient condition. In various exemplary embodiments, a dose ranges from about 0.0001 mg to about 10 mg. In other illustrative aspects, effective doses ranges from about 0.01 μg to about 1000 mg per dose, or 1 μg to about 100 mg per dose, or from about 100 μg to about 50 mg per dose, or from about 500 μg to about 10 mg per dose, or from about 1 mg to 10 mg per dose, or from about 1 to about 100 mg per dose, or from about 1 mg to 5000 mg per dose, or from about 1 mg to 3000 mg per dose, or from about 100 mg to 3000 mg per dose, or from about 1000 mg to 3000 mg per dose. In any of the various embodiments described herein, effective doses ranges from about 0.01 μg to about 1000 mg per dose, 1 μg to about 100 mg per dose, about 100 μg to about 1.0 mg, about 50 μg to about 600 μg, about 50 μg to about 700 μg, about 100 μg to about 200 μg, about 100 μg to about 600 μg, about 100 μg to about 500 μg, about 200 μg to about 600 μg, or from about 100 μg to about 50 mg per dose, or from about 500 μg to about 10 mg per dose, or from about 1 mg to about 10 mg per dose. In other illustrative embodiments, effective doses can be about 1 μg, about 10 μg, about 25 μg, about 50 μg, about 75 μg, about 100 μg, about 125 μg, about 150 μg, about 200 μg, about 250 μg, about 275 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 550 μg, about 575 μg, about 600 μg, about 625 μg, about 650 μg, about 675 μg, about 700 μg, about 800 μg, about 900 μg, 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 100 mg, or about 100 mg to about 30 grams. In certain embodiments, the dose is from about 0.01 mL to about 10 mL.

[0147] In some embodiments, the compositions are packaged in multidose form.

Preservatives are thus required to prevent microbial contamination during use. In certain embodiments, suitable preservatives as described above can be added to the compositions. In some embodiments, the composition contains a preservative. In certain embodiments the preservatives are employed at a level of from about 0.001% to about 1.0% w/v. In some embodiments, the unit dose compositions are sterile, but unpreserved.

[0148] In one embodiment, the anti-adhesive compositions provided herein are intended for administration to a human patient suffering from tissue adhesion or symptoms thereof. In another embodiment, the compositions provided herein are intended for administration to a patient to treat and/or prevent tissue adhesion, i.e. prior to, during or after surgical intervention. In one embodiment, the doses used for the above described purposes will vary but will be in an effective amount to prevent, eliminate or improve tissue adhesion or symptoms thereof. In another embodiment, the anti-adhesive compositions are administered from once to many times per day. In one embodiment, the anti-adhesive compositions are administered once (QD) or twice (BID) daily.

[0149] In one embodiment, an effective amount of a composition comprising a synthetic proteoglycan and pharmaceutically acceptable carrier is administered to a patient in need to eliminate and/or improve tissue adhesion or symptoms thereof.

Example 1. Synthesis of DS-SILY

[0150] Dermatan sulfate (DS) was dissolved in 0.1 M sodium phosphate buffer at pH 5.5 to make a solution of a concentration of 20 mg/mL. The degree of functionalization was controlled by the concentration of the periodate. Periodate solutions of various

concentrations were prepared by dissolving it in 0.1 M sodium phosphate buffer at pH 5.5 according to the following table.

[0151] The DS solution was mixed with the periodate solution in a ratio of 1:1 (V:V) for two hours at room temperature to provide the oxidized DS, which was purified using Biogel P6 column with phosphate buffer saline. SILY peptide having a terminal GSG-NHNH₂ bound thereto (i.e., RRANAALKAGELYKSILYGSG-NHNH₂ (SEQ ID NO: 77)) was dissolved in water to provide a concentration of 1 mg/mL using sonication if needed. The SILY peptide was slowly added to the oxidized DS at room temperature and stirred for about 2 hours protecting it from light. The pH of the reaction mixture was maintained above 6. Optionally, one mole of similarly functionalized SILYbioti_n (biotin-labeled peptide) can be reacted with one mole of DS and then unlabeled SILY peptide can be added up (molar equivalent- 1 ) to the number of aldehydes expected. For example, for DS-SILY₂₀, 1 mole of SILYbiotin and 19 moles of SILY unlabeled were added. However, the addition of SILYbiotin was optional. DS-SILY₂o was also prepared by adding 20 moles of SILY-unlabeled to one mole of DS. The product was purified with water to provide the desired DS-SILY.

Example 2. Synthetic Proteoglycan In Preventing or Reducing Post-operative

Peritoneal Adhesions

[0152] A clinical test is designed to evaluate the ability of a synthetic proteoglycan, DS- SILY, in preventing or reducing post-operative peritoneal adhesions.

[0153] Several approved devices when applied to sites of potentially adhesiogenic tissue in the abdominopelvic cavity serve as a temporary barrier and thus reduce adhesions.

Unfortunately, no anti-adhesion products are approved for laparoscopic administration, thus a growing percent of abdominal procedures lack options for adhesion prophylaxis.

[0154] This example proposes a randomized, multi-center, safety and effectiveness pilot study of DS-SILY administered in the peritoneal cavity to reduce adhesions at the time of laparoscopic abdominal surgery.

[0155] Patients undergoing laparoscopic abdominal surgery involving colectomy are followed by ileal pouch anal anastomosis and formation of a temporary loop ileostomy. The primary objectives will be to (1) assess the overall safety profile of intraperitoneal DS-SILY treatment at the time of laparoscopic abdominal surgery and (2) assess the effectiveness parameters (reducing the incidence, extent and severity of postoperative adhesions) of DS- SILY for this indication.

[0156] This is a 2-arm, parallel, multicenter, double-blind, randomized clinical study.

Following the primary procedure, 5-10 ml of DS-SILY or saline will be delivered (as a spray) through the laparoscope to organs and tissues that are potentially adhesiogenic. The patient and the surgeon will be blinded to the investigative study treatment. Follow up assessment will occur at ileostomy takedown (second look). 60 patients can be enrolled, with a 2:1 randomization, 30 treated with DS-SILY and 30 with saline control.

[0157] Key inclusion criteria will be age over 20 willing to provide consent. Key exclusion criteria are neoadjuvant or adjuvant chemo or radio within 30 days, existing intra-abdominal infection, or gross fecal contamination during procedure. Visiting schedule can be weekly until ileostomy takedown, then quarterly until month 12.

[0158] During the test, adhesion scoring at ileostomy takedown will be taken. In addition, safety assessments include ascertainment of adverse events (AEs) and Serious AEs (SAEs) and laboratory studies.

[0159] The primary endpoint will be postoperative adhesion incidence during ileostomy takedown (3-6 weeks post primary procedure).

[0160] The second endpoints include adhesion severity (1 = filmy thickness, avascular; 2 = moderate thickness, limited vascularity and 3 = dense thickness, vascularized), adhesion extent (0 = no adhesions, 1 = <25% of location's total area, 2 = covering 26% to 50% of location, 3 = covering >50% of location) and effectiveness in reducing bowel obstructions during one year follow up.

Claims

What is Claimed is:

1. A method of treating and/or preventing tissue adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tissue of an organ, wherein the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 1 to about 80 collagen binding peptide(s) bonded to the glycan.

2. A method of treating and/or preventing abdominal or pelvic adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tissue of an abdominal or pelvic organ, wherein the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 1 to about 80 collagen binding peptide(s) bonded to the glycan.

3. The method of claim 1 or 2, wherein the tissue is exposed due to surgery, trauma, infection, chemotherapy, radiation, foreign body, or cancer.

4. The method of claim 1 or 2, wherein the tissue is surgically exposed.

5. The method of claim 1 or 2, wherein the pharmaceutical composition is applied as a spray.

6. The method of claim 2, wherein the tissue comprises a peritoneal membrane tissue.

7. The method of any preceding claim, wherein the glycan is dextran, chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparan sulfate, heparin, keratin, keratan sulfate, or hyaluronic acid.

8. The method of any preceding claim, wherein the peptide(s) are covalently bonded to the glycan via a linker.

9. The method of claim 8, wherein the linker is N-[P-maleimidopropionic acid]hydrazide (BMPH), 3-(2-pyridyldithio)propionyl hydrazide (PDPH) or the peptide GSG.

10. The method of claim 8, wherein the peptide(s) to linker ratio is from about 1:1 to from about 5:1.

11. The method of any preceding claim, wherein the synthetic proteoglycan comprises less than about 50 peptides.

12. The method of claim 10, wherein the synthetic proteoglycan comprises from about 5 to about 40 peptides.

13. The method of any preceding claim, wherein the collagen -binding peptide has binding affinity to one or more of collagen types I, II, III, or IV.

14. The method of any preceding claim, wherein the collagen-binding peptide comprises an amino acid sequence selected from: i) RRANAALKAGELYKSILY (SEQ ID NO: 1), RLDGNEIKR (SEQ ID NO: 2), AHEEISTTNEGVM (SEQ ID NO: 3), GELYKSILY (SEQ ID NO: 4),

15. The method of any preceding claim, wherein the pharmaceutical composition is formulated as a film, gel, patch, liquid solution or aerosol.

16. The method of claim 15, wherein the pharmaceutical composition comprises a polymer matrix.

17. The method of claim 16, wherein the pharmaceutical composition is absorbable.

18. The method of any preceding claim, wherein the pharmaceutical composition further comprises a pH buffering agent.

19. A method of treating and/or preventing cardiac tissue adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed cardiac tissue, wherein the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 1 to about 80 collagen binding peptide(s) bonded to the glycan.

20. A method of treating and/or preventing tendon adhesion in a patient in need thereof, comprising applying a pharmaceutical composition on an unnaturally exposed tendon, wherein the pharmaceutical composition comprises a synthetic proteoglycan comprising a glycan having from about 1 to about 80 collagen binding peptide(s) bonded to the glycan.

21. The method of any preceding claim, wherein the collagen-binding peptide(s) is RRANAALKAGELYKSILY.

22. The method of claim 21, wherein the glycan is dermatan sulfate.

23. The method of claim 21, wherein the glycan is heparin.