CA2423990C - Bone replacement materials utilizing bioabsorbable liquid polymers - Google Patents

Abstract

The present invention is directed to bone replacement device and compositions containing a synthetic, bioabsorbable, biocompatible liquid polymer that is the reaction product of a polybasic acid or derivative thereof, a polyol and a fatty acid, the liquid polymer having a melting point less than about 40°C, as a determined by differential scanning calorimetry.

Description

BONE P ,C `Z MATERIALS UTILIZING

FU OF THE I ION

The present invention relates to bone replacement devices and materials that utilize bioabsorbable and biocompatibie polymeric liquids.

aACKG O ) OF TRZ INVENTION

Both natural and synthetic polymers, including is homopolytn.ers and cosolymers, which are both biocompati.ble and absorbable in vivo are. known for use in the manufacture of medical devices that are implanted in body tissue and absorb over time. Examples of such medical devices include suture anchor devices, sutures, staples, surgical tacks, clips, plates and screws, drum delivery devices, adhesion prevention films and foams, and tissue adhesives-Natural polymers may include catgut, cellulose derivatives and collagen. Natural polymers typically absorb by an enzymatic degradation process in the body.
Synthetic polymers may include aliphatic polyesters, polyanhydrides and poly (orthoes _er) s .
Synthetic absorbable polymers typically degrade by a hydrolytic mechanism. Such synthetic a:bsorb.able polymers include homopolymers, such as poly(glycclide), I

poly(lactide) , poly(z-caprolactone) tone), poly (triT,~kethylene carbonate) and poly (p-dioxanone) , and copolymers, such as poly (lactide-co-glycol ide) , poly(s-caprolactone-co-glycolid.e), and poly(glycolide-co-trimethylene carbonate). The polymers may be statistically random copolymers, segmented copol,yccmers, block copolymers or graft copolymers.
Several injectable, bi,oa.bsorbable liquid copolymers suitable for use in parenteral applications as well as hard and soft tissue repair or augmentation materials in animals have been described. These liquid polymers contain lactone repeating units, including s-caprolact.one tr methylene carbonate, ether lactone, glycolide, lactide, p-dioxanone, and combinations i5 thereof. These liquid copolymers, however, are slow to degrade, taking over six months to be absorbed by the body.
Alkyd-type polyesters prepared by the polycondensation of a polyol, polyacid and fatty acid 2C are used in the coating industry in a variety of products, including chemical resins, enamels, varnishes and paints. These polyesters also are used in the food industry to make taxturized oils and emulsions for use as fat substitutes.
25 There is a great need for polymers for use in drug delivery and medical devices that permit solvent-free processing techniques in preparation of medical devices and compositions and that biodegrade within 6 months S ARY OF E. 'L IO N' The present invention is directed to bone replacement devices and compositions comprising a synthetic, bioabsorbable, biocompatible liquid polymer comprising the reaction product of a pol.ybasic acid or derivative thereof, a fatty acid and a polyol, the liquid polymer having a melting point less than about 4OoC, as determined by di,fferen ial scanning io calorimetry.

DETAILED DESCRIPTION of THE I I:oN
Alkyd polymers have been prepared by several known methods. For example, alkyd-type polymers were prepared is by Van . emmelen (J. Prakt. Chem., 69 (1856) 84) by condensing succinic anhydride with glycerol- In the "Fatty Acid" method (see Parkyn, et al- Polyesters (1967), Iliffe Books, London, Vol- 2 and Patton, In, Alkyd Resins Technology, Wiley-Interscjence New York 20 (1962)), a fatty acid, a polycl and an anhydride are mixed together and allowed to react, The 'natty Acid-Monoglyceride" method includes a first step of esterifying the fatty acid with glycerol and, when the first reaction is comp.l ete, adding an acid anhydride 25 The reaction mixture then is heated anti the polymerization reaction takes place. in the " Oil-Monog:ly ceride" method, an oil is reacted with glycerol to form a mixture of mono-, di-, and triglycerides.

This mixture then is polymerized by reacting with an acid anhydride.
The synthetic, bioabaorbable, bi ocompatible liquid polymers utilized in the present: invention are the reaction product o a polybasic acid or derivative thereof, a fatty acid, and a po=youl, and may be classified as alkyd polyester liquids. Preferably, the liquid polymers of the present invention. are prepared by the polycondensation of a polybasic acid or derivative thereof and a monoglyceride, wherein the monoglyceride comprises reactive hydroxy groups and fatty acid groups-The expected hydrolysis byproducts are glycerol, dicarboxylic acid(s), and fatty acid(s), all of which are biocompatible. Preferably, the liquid polymers is utilized in the present invention will have a3 weight average molecular weight between about 1,000 daltoris and about 100,000 daltons, as determined by gel permeation chromatography. The liquid polymers comprise an aliphatic polyester backbone with pendant fatty acid ester groups that exhibit relatively lcw melting points, e.g. less than about 40CC, preferably less than about C.
Fatty acids used to prepare liquid polymers utilized in the present invention may be saturated or 25 unsaturated, and may vary in length from C4 to C12 for saturated fatty acids, and C. to C22 for unsaturated fatty acids. Examples of such fatty acids include, without limitation, stearic acid, palmitic ,acid, el mvrisitic acid, caproic acid, decanoic acid, lauric acid, linoleic acid and oleic acid.
Polyols that can be used to prepare the liquid polymers include, without limitation, glycols, polyglycerols, polyglycerol esters, glycerol, sugars and sugar alcohols, Glycerol is a preferred polyhydric alcohol due to its abundance and cost.
Monoglycerides which may be used to prepare liquid polymers utilized in the present invention include, without limitation, monostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol, monoo? eoyl glycerol, and combinations thereof. Preferred monoglycerides include monocaproyl glycerol, monodecaaoyl glycerol, monolauroyl glycerol, =Tiolinoleoyl glycerol, and monoo: eoyl glycerol.
Polybasic acids that can be used include natural multifunctional carboxylic acids, such as succinic, glutaric, adipic, pimelic, suberic, and sebacic acids;
hydroxy acids, such as diglycolic, malie, tartaric and citric acids; and unsaturated acids, such as fumaric and maleic acids. Polybasic acid derivatives include anhydrides, such as succific anhydride, diglycolic anhydride, glutaric anhydride and maleic anhydride, mixed anhydrides, esters, activated esters and acid halides. The mul t.? functional carboxylic acids listed above are preferred.

C

In certain embodiments of the invention, the liquid polymer may be prepared from the polybasic acid or derivative thereof, the monoclyceride and, additionally, at least on additional polyol selected from the group consisting of ethylene glycol, 1,2-propylene glycol, 1,3-propanediol, bis-2-hydroxyethyl ether, 1,4-butanediol, 1,5-pentanadiol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, 1, 12-dodecanediol, other diols, linear poly(ethylene glycol), branched poly(ethylene glycol), linear poly(propylene glycol), branched poly(propylene glycol), linear poly(ethylene-co-propylene glycol)s and branched poly(ethylene-co-propylene glycol)s.
In an embodiment, the liquid copolymer comprises the reaction product of said polybasic acids or derivative thereof, and at least two monoglycerides selected from the group consisting of monostearoyl glycerol, monopalmitoyl glycerol, monomyristitoyl glycerol, monocaproyl glycerol, mondecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol.
In preparing the liquid polymers utilized in the present invention, the particular chemical and physical properties required of the liquid polymer for a particular use must he considered. For example, changing the chemical composition can vary the physical properties, including absorption times.
Copolymers can be prepared by using mixtures of diols, trial, polyols, diacids, triacids, and different monoalkanoyl glycerides to match a desired set of properties. Similarly, blends of two or more alkyd polyesters may be prepared to tailor properties for different applications.
Alkyd polyester liquids of the present invention can be made more hydrophobic by increasing the length of the fatty acid side chain or the length of the diacid in the backbone, or by incorporating a long chain diol.

Alternatively, alkyd polyester liquids of the present invention can be made more hydrophilic or amphiphilic by employing hydroxy acids, such as malic, tartaric and citric acids, or some oxadiacids, in the composition, or by employing poly(ethylene glycols or copolymers of polyethylene glycol and polypropylene glycol, commonly known as Pluronic5, in the formation of segmented block copolymers.
Copolymers containing other linkages in addition to an ester linkage also may be synthesized; for example, ester-amides, ester-carbonates, ester-anhydrides and ester urethanes, to name a few.
Functionalized liquid polymers can be prepared by appropriate choice of monomers. Polymers having pendant hydroxyls can be synthesized using a hydroxy acid such as malic or tartaric acid in the synthesis. Polymers with pendent amines, carboxyls or other functional groups also may be synthesized. A variety of biologically active substances, hereinafter referred to as bioactive agents, can be covalently attached to these functional liquid polymers by known coupling chemistry to give sustained release of the bioactive agent. As used herein, bioactive agent is meant to include those substances or materials that have a therapeutic effect on mammals, e.g_ pharmaceutical compounds.
In another embodiment, the polymers of the present invention may be endcapped in a variety of ways to obtain the desired properties. Endcapping reactions convert the terminal and pendant hydroxyl groups and terminal carboxyl groups into other types of chemical moieties. Typical endcapping reactions include but are not limited to alkylation and acylation reactions using common reagents such as alkyl, alkenyl, or alkynyl halides and sulfonates, acid chlorides, anhydrides, mixed anhydrides, alkyl and aryl isocyanantes and alkyl and aryl isothiocyantes. Endcapping reactions can impart new functionality to the polymers of this invention. For instance, when acryloyl or methacryloyl chloride is used to endcap these polymers, acrylate or methacrylate ester groups, respectively, are created that can subsequently be polymerized to form a crosslinked network. In one embodiment, the terminal and pendant chemical moieties are selected from the group consisting of ethers, esters, anhydrides, mixed anhydrides, sulfonates, and urethanes.
One skilled in the art, once having the benefit of the disclosure herein, will be able to ascertain particular properties of the liquid polymers required for particular purposes, and readily prepare liquid polymers that provide such properties.
The polymerization of the alkyd polyester liquids preferably is performed under melt polycondensation conditions in the presence of an organometallic catalyst at elevated temperatures. The organometallic catalyst preferably is a tin-based catalyst e.g. stannous octoate.
The catalyst preferably will be present in the mixture at a molar ratio of polyol and polycarboxylic acid to catalyst in the range of from about 15,000/1 to 80,000/1.
The reaction preferably is performed at a temperature no less than about 120 C. Higher polymerization temperatures may lead to further increases in the molecular weight of the copolymer, which may be desirable for numerous applications. The exact reaction conditions chosen will depend on numerous s factors, including the properties of the polymer desired, the viscosity of the reaction mn,ixtuse, and melting temperature of the polymer. The preferred reaction conditions of temperature, time and pressure can be readily determined by assessing these and other factors-Generally, the reaction mixture will be maintained at about 180 v. The polymerization reaction can be allowed to proceed at this temperature until the desired molecular weight and percent conversion is achieved for the copolymer, which typically will take from about 15 minutes to 24 hours. Increasing the reaction temperature generally decreases the reaction time needed to achieve a particular molecular weight, In another embodiment, copolymers of alkyd polyester liquids can be prepared by forming an alkyd polyester prepolycmer polymerized under melt polycondensation conditions, then adding at least one lactone monomer or lactone prepolymer. The mixture then would be subjected to the desired conditions of temperature and time to copolymerize the prepolymer with the lactose monomers.
The molecular weight of the prepolyrmer, as well as its composition, can be varied depending on the desired characteristic that the prepolynmer is to impart to the copolymer. Those skilled in the art will recognize that the alkyd polyester prepolymers describer herein can also be made from mixtures of more than one diol or dioxycarboxylic acid.
One of the beneficial properties of the alkyd polyester liquids of this invention is that the ester linkages are hydrolytically unstable, and therefore the polymer is bioabsorbable because it readily breaks down 1o into small segments wheri exposed to moist body tissue.
In this regard, while it is envisioned that co-reactants could be incorporated into the reaction mixture of the poly,asic acid and the diol for the formation of the alkyd polyester, it is preferable that the reaction mixture does not contain a concentration o- any co-reactant which would render the subsequently prepared polymer nonabsorbable. Dreferably, the reaction mixture is substantially free of any such co-reactants if the resulting polymer is rendered n.onabsorba;ble.
In one embodiment of the invention, the alkyd polyester liquids of the present invention can be used as a pharmaceutical carrier in a drug delivery matrix, or as a cell-based carrier in a tissue r=ngineering application. To form the matrix, the liquid polymer would be mixed with an effective amount of a bioactive agent to form the matrix. The variety of bioactive agents that can be used in conjunction with the liquid polymer of the invention is vast. In general. bioactive ~0 agents which may be administered via pharmaceutical compositions of the invention include, without limitation, antiinfectives, such as antibiotics and antiviral agents; analgesics and analgesic combinations,.-anorexics; antihelmintics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals; antihistamines; antii.nfiammatory agents; antimigraine preparations; antinauseants;
antineoplastics; antiparkinscinism drugs; alit ipr-uri tics;
ao antipsychotics; antipyretics, antispasmodics;
anticholinergics; sympathomirnetics; xant:hine derivatives; card iovascu._ar preparations including calcium channel blockers and beta-blockers such as pindolol and anti.arrhytha*tics; antihypert:ensives;
T5 diuretics; vasodilators, including general coronary, peripheral and cerebral; central nervous system stimulants;, cough and cold preparations, including decongestants; hormones, such as estradiol and other steroids, including corticosteroids; hypnotics;
20 immunosuppressivee; muscle relaxants;
parasyrtapatholytics,; psychzostimulants; sedatives;
tranquilizers; naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins; oligonucleot,ides, antihodies, antigens, 25 cholinergics, chemotherapeutics, hemostatics, clot dissolving agents, radioactive agents and cystostatics.

Raparrycin, risperidone, and er'ythrcpoietin are several bioactive agents that may be used in drug delivery matrices of the present invention.
In two particularly preferred embodiments the s bioactive agents for administration in conjunction with the bioerodible polymers of the invention are antibacterial agents for the treatment of deep wounds, and antibiotics for periodontal treatment (e.g., tetracycline or the like) . Other preferredõ drugs for use with the presently disclosed polymers include proteinaceous drugs such as growth factors or growth hormones The drug delivery matrix may be administered in any suitable dosage form suct as parenterals, bioerodible 5 ointments, gels, creams, and similar soft dosage forms adapted for the parenteral or topical administration of bioactive agents. Other modes of administration (e.g. , transderm.al) and compositional forms (e :: g _ , more rigid transdermal forms) are within the scope of the inventio as well.
Paren,tera.l administration of a bioerodible composition of the invention can be effected by either subcutaneous, or intramuscular injection. Parenteral formulations of the copolymer may be formulated by mixing one or more pharmaceuticals with a .liquid copolymer- Other suitable parenteral additives may be formulated with the copolymer and pharmaceutical active.
However, if water is to be used it should be added immediately before administration- The b ioercdible ointment, gel or cream may also be injected as is or in combination with one or more suitable auxiliary components as described below_ Parente-re delivery is preferred for administration of prote,inscecus drugs such as growth factors, growth hormone, or the like.
The bioerodible ointments, gels and creams of the invention will include an ci ntntent, gel or cream base comprising one or more of the copolymers described herein and a selected bioactive agent. The bicactive agent, whether present as a. 1~c aid,, a finely divided solid, or any other physical form, is dispersed in the ointment, gel or cream base. Ty- ically, but optionally, the compositions include one or more other components, is a-9., nontoxic auxiliary substances such, as colorants, diluents, odorants, carriers, excipients,, stabilizers or the like-The quantity and type of copolymers incorporated into the parenteral, ointment, gel, cream, etc., is variable. For a more viscous composition, a higher molecular weight polymer is used. if a less viscous composition is desired, a, lower molecular weight polymer can be employed. The product may contain, blends of the liquid or low melting point copolymers to provide the desired release profile or consistency to a given formulation-While not essential for topical or :r. ansdermal administration of many drugs, i may in some cases, with ii some drugs, be preferred that a skin permeation enhancer be coadminister'ed therewith. -An'y, number of the many skin permeation enhancers known in the art may be used Examples of suitable enhancers include ddmeth.yisulf oxide (DSO), dimethylforroamide (DMF), L3, N-dimethylacetamide (DMA), cesl?~methylsu.! foxide-, et!-,ano9, eu.L s pto , lecithin, and the 1i.-N-dodecylcyclazaeycloheptan--2-ones..
Depending on dosage fo ^rm, the pharmaceutical compositions of the present invention may be i0 administered in different ways, i.e., parenterally, topically, or the like- Preferred dosage forms are liquid dosage forms that can be administered parenterally.
The amount of bioact.ive agent will be dependent i5 Upon the particular drug employed and medical condition being treated. Typically, the amount of drug represents about 0.001% to about 70%-, more typically about 0.001%
to about 50%, most typically about 0.001% to about 20%
by weight of the matrix.
20 The quantity and type of a:'Ayd polyester liquid incorporated into the parentera-, ointment, gel or cream will vary depend i ng on the release profile desired and the amount of drug employed- The product may contain blends of polyesters to provide the desired release 25 profile or consistency to a given formulation.
The alkyd polyester liquid, upon contact with body fluids including blood or the like, undergoes gradual degradation, mainly through hydrolysis, with concomitant release of the dispersed drug for a sustained or extended period, as compared to the release from an isotonic saline solutionõ This can result in prolonged delivery, e.g. over about I to about 2,00C .ours, preferably about 2 to about 800 hours) of effective amounts, e.g. 0.0001. mg/kg/hour to 10 mci/kg/hour) of the drug. This dosage form can be administered as is necessary depending or the subject being treated, the severity of the affliction, the judgment off the prescribing physician, and the like Individual formulations of drugs and alkyd, polyester liquid may be tested in appropriate in vitro and in vivo models to achieve t. e desired drug release profiles. For example, a drug could be formulated with an alkyd polyester l i uic and parenterally administered to an animal- The drug release profile could then be monitored by appropriate meanas, such. as by taking blood samples at specific times and assaying the samples for drug concent ration. Following ahis or s .mi 1a.r procedures, those skilled in the art will be able to formulate a variety of fonnula.tions.
In a further embodiment of the present invention the injectable liquid polymers can be used for a variety of soft tissue repair and augmentation p.; oced.ures For example, the liquid polymers can be used. in facial tissue repair or augmentation including out not limited to camouflaging scars, filling depressions, smoothing out irregularity, correcting asymmetry in facial hemiatrophy, second, branchial 'arch syndrome, facial lipodystrophy and camouflaging age-related wrinkles as well as augmenting facial eminences (lips, brow, etc.).
Additionally, these injectable liquid polymers can be used to restore or improve sphincter function such as for treating stress urinary incontinence. Other uses of these injectable liquid polymers may also include the treatment of vesicoureteral ref lux (incomplete function of the inlet of the ureter in children) by subureteric 3.0 injection and the application of these liquid polymers as general purpose fillers in the human body.
Surgical applications for injectable:, biodegradable liquid polymers include,, but are not limited to, facial contouring (frown or glabellar line, acne scars, cheek depressions, vertical or peri oral lip lines, marionette lines or oral commissures, worry or forehead lines, crow's feet or periorbital lines, deep smile lines or nasolabial folds, smile lines, facial scars, lips and the like); periurethral injection including injection into the submucosa of the urethra along the urethra, at or around the urethral-bladder ;!unction to the external sphincter; ureteral injection for the prevention of urinary reflux; injection into the tissues of the gastrointestinal tract for the : ailk.ing of tissue to ?5 prevent reflux; to aid in sphincter muscle coaptation, internal or external, and for coaptation, of an enlarged lumen; intraocala.r inject ion for the replacement of vitreous fluid or maintenance of intraoculaz pressure for retinal detachment; injection into anatomical ducts to temporarily plug the outlet to prevent re:clux or infection propagation; larynx rehabilitation after surgery or atrophy and any other soft tissue which can be augmented for cosmetic or therapeutic affect.
Surgical specialists who would use such a product include, but are not limited to, plastic and reconstructive surgeons, dermatologists, facial plastic surgeons, cosmetic surgeons, otolaryngologists, urologists, gynecologists, gast:roenterol.og .st.s, ophthalmologists and! any other physician qualified to utilize such a product.
The liquid copolymers can be administered with a syringe and needle or a variety of devices. It is also envisioned that the liquid polymers could be sold in the farm of a kit comprising a device containing the liquid, polymers_ The device having an outlet for said liquid polymers, an ejector for expelling the liquid polymers and a hollow tubular member fitted to the outlet for administering the liquid polymers into an an.imnal.
Additionally, the liquid polymer's, when sterilized, are useful as adhesion prevention barriers.
In another embodiment, the :iquid polymer is used to coat a surface of a surgical article to enhance the lubricity of the coated surface. The polymer may be applied as a coating using conventional techniques it is contemplated that numerous surgical articles, including but not limited to sutures, needles, orthopedic pins, clamps, screws, plates, clips, e.g. f+or-vrena cava, staples, hooks, buttons, snaps, bone substitutes, e.g. as mandible prosthesis, intrauterine devices, e.g. as spermicidal devices, draining or s testing tubes or capillaries, surgical instruments, vascular implants or supports, ae.g. stents or grafts, or combinations thereof, vertebral discs, extracorporeal tubing for kidney and heart-lung machines, artificial skin, and supports for cells in tissue engineering 3-0 applications, can be coated with the liquid polymers of this invention to improve the surface properties of the article.
in yet another embodiment, the.medical device comprises a bone replacement material comprising the is liquid polymer. The bone replacement materials may further comprise liquid polymer mixed with a bioactive agent in a therapeutically effective amount, such d growth factor, to facilitate growth of bone tissue.
Examples of bioactive agenta suitable for use with the 20 present invention include cell attachment mediators, such as peptide-containing variations of the "RGD11 integrin binding sequence known to affect cellular attachment, biologically active ligands, and substances that enhance or exclude particular varieties of cellular zs or tissue ingrowth.. Examples of such substances include integrin binding sequence, ligands, bone morphogenic proteins, epidermal growth facto..--, IGF-I, IGF-II, 2GF-P
I-III, growth differentiation factor, parathyroid hormone, vascular endothelial growth factor, hyaluroni c acid, glycoprotein, lipoprotein, bFGF, TGF8 superfamily factors, BMP-2, BMP-4, BMP-G, BMP-12, sonic hedgehog, GDFS, GDF6, GDFS, POGF, small molecules that affect the uprerulacion of-specific growth factors, tanascin-C, fibronectin, thromboalastin, thrombin-de: ived peptides, heparin-binding domains, and the like- Furthermore, the bone replacement material may comprise liquid polymer mixed with a biologically derived substance selected Ao from the group consisting of dernineralized bone matrix (DBM) : platelet rich plasma, bone marrow aspirate and bone fragments, all of which may be from au`ogenic, allogeaic, or xenogenic sources.
Alternatively, the bone replacement material may comprise liquid polymer mixed with an inorganic filler-The inorganic filler may be selected fro=th alpl-aa-t.ricalcium phosphate, beta-tricalcium phosphate, calcium carbonate, barium carbonate, calcium sulfate, barium sulfate, hydroxyapatite, and mixtures thereof- in certain embodiments the inorganic filler comprises a polymorph of calcium phosphate. Preferably, the inorganic filler is hydroxyapatite.
The bone replacement materials may still further comprise liquid polymer mixed with a bioactive agent is a therapeutically effective amount and an inorganic filler.
In still yet another embodiment, the bone replacement material may comprise liquid polymer mixed wish appropriate cell types prior to implantation.
Cells which can be seeded or cultured in the liquid polymers of the current invention include, but are not limited to, bone marrow cells, mesenchymal cells, stromal cells, stem cells, embryonic stem cells, osteoblasts, precursor cells de-rived from adipose tissue, bone marrow derived progenitor cells, peripheral blood progenitor cells, stem cells isolated from adult tissue, and genetically transformed cells, or 10combinations of the above-The bone replacement liquid polymers of the present invention may be used i, applications such as the filling of trauma defects. Alternatively, they may be coated on orthopaedic devices to facilitate bone regeneration.
IS Such devices include, but are not limited to plates, nails, screws, rods, and suture anchors.
Furthermore, the bone replacement liquid. polymers may be injected into, or coated on, naturally or synthetically derived tissue engineering scaffolds and 20 spinal cages. Naturally derived tissue engineering scaffolds include those formed from small intestinal submucosa, collagen, hyalur-onic acid, chitosan, and alginates. These scaffolds may be is the form of porous materials such as foams or sponges, or in fibrous form, 25 such as weaves, braids, or nonwovens.
The relative amounts of liquid polymer, bioactive agent, cells, and inorganic filler may be determined readily by one skilled in the art by routine experimentation after having the benefit of this disclosure.
The examples set forth below are for illustration purposes only, and are not intended to limit the scope of the claimed invention in any way. Numerous additional embodiments within the scope and spirit of the invention will become readily apparent to those skilled in the art.
In the examples below, the synthesized polymeric to waxes were characterized via differential scanning calorimetry (DSC), gel permeation chromatography (GPC), and nuclear magnetic resonance (NMR) spectroscopy- DSC
measurements were performed on a 2920 Modulated Differential Scanning Calorimeter from TA Instruments is using aluminum sample pans and sample weights of 5-10 mg. Samples were heated from room temperature to 100 C
at 10 C/minute; quenched to -40 C at 30 C/minute followed by heating to 100 C at 10 C/minute. For GPC, a Waters System with Millennium 32 Software and a 410 20 Refractive Index Detector were used. Molecular weights were determined relative to polystyrene standards using THE as the solvent, Proton NMR was obtained in deuterated chloroform on a 400MHz NMR spectrometer using Varian software-Example 1: Synthesis of Poly(glyceryl monolinoleate-succinate) 29.97 gm (84.5 mmoies) of glyceryl monol inoleate were added to a dry 100 ml, single neck, round bottom flask. A football stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed into a room temperature oil bath and a nitrogen blanket was applied. The oil bath temperature was raised to 140 C. Once at 140 C, 8.47 gm (84.6 mmoles) succinic anhydride were added and the temperature was raised to 200 C. Heat tape was wrapped around the outside of the top of the flask and adapter to keep the succinic anhydride from subliming. The reaction was continued for 3 ho ,rs at 2000C. The flask was removed from the oil bath and allowed to cool to room temperatur e . The polymer was a pale yellow, viscous I5 licruid.
For purification, the polymer was dissolved in Ethyl acetate (5.0 gm polymer in 20 mis Eto.Ac) and added to a separatoi-j- funnel. The solution was washed three times with 20 mis of a very dilute sodium bicarbonate solution. The funnel was agitated very slightly (in order to avoid forming an emulsion). The solution was then washed three times with a saturated sodium chloride solution. The polymer solution was decanted and dried over magnesium sulfate.. The solution was gravity filtered and evaporated to give a viscous yellow liquid.
The polymer was dried in the vacuum oven, where the oven was set around 40 C, for 48-72 hours.

GPC measurement determined a number average molecular weight of 2,264, and a weight average molecular weight of 3 , 935 daltots.

Example 2: Syr-thesis of Poly(glyceryl monol inol.eate-succinate) The same procedure as Example 1 was used, except the reaction was maintained at 200 C for 24 hours.
GPC measurement determined a number average molecular weight of 6,624, and a weight average molecular weight of 83 , 214 datons _ 3bc le 3t Synthesis of 'oly (glyceryl monooleate-succinate) is 30.0 gm (84_l mmoies) of glyceryl monooleate were added to a dry 100 ml, single neck, round bottom flask-A football stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed into a room temperature oil bath and a nitrogen blanket was applied. The oil bath temperature was raised to 140 C.
Once at 140 C, 8.42 gm (84.1 mmoles) succinic anhydride was added and the temperature was raised to 2000C. Heat tape was wrapped -around the outside of the top of the flask and adapter to keep the succinic anhydride from subliming. The reaction was continued for 3 hours at 200 C. The flask was removed from the oil bath and allowed to cool to room temperature. The polymer was a pale yellow, viscous liquid_ For purification, the polymer was dissolved in Ethyl acetate (5.0 gm polymer in 20 mis "tOAc) and added to a separatory funnel- The solution was washed three times with 20 mis of a very dilute sodium bicarbonate solution. The funnel was agitated very slightly (in order to avoid forming an emulsion) . The solution was then washed three times with a saturated sodium chloride solution- The polymer solution was decanted and dried, over magnesium sulfate. The solution was gravity ae filtered and evaporated to give a viscous yellow liquid.
The polymer was dried in the vacuum oven., where the oven was set around 40 C, for, 48-72 hours, GPC measurement determined a number average molecular weight of 2,145, and a weight average is molecular weight of 3 , 659 d.altons.

Example 4: Synthesis of ?oly(glyceryl monoaleate-succina,te ) The same procedure as Example 3 was used, except 20 the reaction was maintained at. 200 C for 24 hours.
GPC measurement determined a number average molecular weight of 3,246, and a weight average molecular weight of 29,303.

25 ple 5! Synthesis of 50:50 Poly(monostearoyl glycerol-co-glyce:r yl monolinc l eate-succ ,nate) 25.D gm (70-5 mmoles) of glycerol monolinoleate and 2S_3 gm (70.5 mmoles) of m'onostear 3yl glycerol were added to a dry 100 ml: single neck, round bottom flask.
A football stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed into a room temperature oil bath and a nitrogen blanket was applied. The oil bath temperature was raised to 140 C.
Once at la0 C, 14.1, gm (141.0 Enrnoles) succinic anhydride were added and the temperature was raised to 200 C.
Heat tape was wrapped around the outside of the top of the flask and adapter to keep the succinic anhydride 1G from subliming. The reaction was continued for 3.0 hours at 200 C. The flask was removed from the oil bath and allowed to cool to room temperature, The polymer crystallized to an off white pasty solid.
DSC measurements found a melting point of 32.43 C, and a specific heat of 33.33 Jig. UPC measurement determined a number average molecular weight: of 2, 500, and a weight average molecular weight- of 3,964.

Ex le 6.- Synthesis of 50:50 Poly(monostearoyl glycerol -co-glycen:-yl 25.0 gm (10.1 mmoles) of glyceryl monocleate and 25.2 gin (70.1 mmoles) of monostearoyl glycerol were added to a dry 100 ml, single neck, round bottom flask.
A football stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed into a room temperature oil bath and a nitrogen blanket was applied. The oil bath temperature was raised to 140 C.
Once at 140 C, 14.0 gin (140-2 mmoles) succinic anhydride were added and the temperature was raised to 200 C_ Heat tape was wrapped around the outside of the top of the flask and adapter to keep the succinic anhydride from subliming- The reaction was continued for 3.0 s hours at 200 C. The flask was removed from the of l bath and allowed to cool to room temperature. The polymer crystallized to an off-white pasty solid DSC measurements found a melting point of 29.31 C, and a specific heat of 32.43 0"/g. GPC measurement determined a number average molecular weight of 2,406, and a weight average molecular weight of 3,-t39 daltons Example 7: Synthesis of 25:75 Poly(monostearoyl glycerol-'co-glycerol mono3. õn oleate-succinate) i5 37.49 gm (105-8 mmoles) of cg' ly cery'f monolinoleate and 12.64 gm (35.3 mmoles) of monostearoyl glycerol were added to a dry 100 ml, single neck, round bottom flask.
A football stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed into a room temperature oil bath and a nitrogen blanket was applied- The oil bath temperature was raised to 140 C.
Once at 1400C, 14, l got (141.0 mmoles) succinic anhydride were added and the temperature was raised to 200 C_ Heat tape was wrapped around the outside of the top of the flask and adapter to keep the succinic anhydride from subliming, The reaction was continued for 3.0 hours at 200 C. The flask was removed from the oil bath and allowed to cool to room temperature. The polymer was a very viscous, light amber liquid.
Por purification, the polymer was dissolved in Ethyl acetate (5.0 gm polymer in 20 mls EtOAc) and added to a separatory funnel- The solution was washed three times with 20mis of a very dilute sodium bicarbonate solution. The funnel was agitated very slightly (in order to avoid forming an emulsion) . The solution was then washed three times with a saturated sodium chloride iv solution. The polymer solution was decanted and dried over magnesium sulfate. The solution was gravity filtered and evaporated down to give a viscous yellow 'liquid. The polymer was dried in the vacuum oven, where the oven was set around 400C, for 46-7a hours-I5 DSC measurements found a melting point of about 200C. QPC measurement determined a number average molecular weight of 2,115, and a weight average molecular weight of 3,3>26 daltons _ 20 Example 8: Synthesis of 25:75 Poly(monostearoyl glycerol-co-glycerol monooleate-succinate) 44.12 gm (123.8 mroles) of glycerol monooleate and 14.79 gm (41.3 mmoles) of monostearoyl glycerol were added to a dry 130 ml, single neck, round bottom flask.
25 A football stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed into a room temperature oil bath and a nitrogen blanket was applied. The oil bath temperature was raised to 140"C-Once at 1400C, 16.51 gm, (i65.C) mmoles) succini^
anhydride was added and the temperature was raised to 200CC. Heat tape was wrapped around the outside of the top of the flask and adapter to keep the succinic anhydride from subliming. The reaction was allowed to cook for 3.0 hours at 200 C. The flask was removed from the oil bath and allowed to cool to room temperature-The polymer was a pale yellow, viscous liquid.
For purification, the polymer was dissolved in Ethyl acetate (5.0 9-in polymer in 20 mis EtOAc) and added to a separatory funnel. The solution was washed three times with 20 mis of a very dilute sodium bicarbonate solution. The funnel was agitated very slightly (in order to avoid forming an emulsion) The solution was Is then washed three times with a saturated sodium chloride solution. The polymer solution was decanted and dried over magnesium sulfate for approximately one hour. The solution was gravity- filtered and rotovapped down to give a viscous yellow liquid- The polymer was dried in the vacuum oven., where the oven was set arouõa.d 4000, for 48-72 hours. An 'R NMR was taken. to make sure all of the solvent was removed.
DSC measurements found a melting pint of 18.130C, and a specific heat of 18.29 J'/g- GPC measurement determined a number average molecular weight of 1,933, and a weight average molecular weight of 7,122 daltons.

Example 9: Synthesis of Poly(eonodecanoyl glycerol-co-succiriate) 15.0 gm (60.9 mmoles) monod.ecan yl-rac-glycerol were added to a dry 50 ml, single neck, round bottom flask. A teflon football stirbar was added and a nitrogen inlet adapter was attached. The reaction flask was placed in a room temperature oil bath and a nitrogen gas blanket was started. The reaction temperature was increased to 1400C. once at 1406C, 6.09 gm (60.9 mmoles) of suceinic anhydride was added. The temperature was raised to 2000C and maintained at this temperature for three hours. The reaction was removed from the oil bath and allowed to cool to room temperature.. The polymer was a light amber liquid, Crystallites began to form within ten days.
GPC measurement determined a number average molecular weight of y , 4 60 , and. a weight average molecular weight of 3,929 dalt_ons. The 'H iR. showed the following peaks: 6 0.86 triplet (3H), 1.34 multiplet (12H), 1- 62 multiplet (2H), 2.32 multiples (2H), 2-72 multiples (2H), 4-15 multiplet (2H), 4.35 m?altiplet (2H) , 5.29 multiplet (1.H) .

Exile 10: Synthesis of Poly :monolau oyl-rac-glycerel-co-succinate) 14.0 gm (50 mmoles) mono:Lauroyl glycerol were added to a dry 50 ml, single neck, round bottom flask- A stir bar was added and a nitrogen inlet adapter was attached-The reaction flask was placed in a room temperature oil bath and a nitrogen gas blanket was applied. The flask was heated to 140 C. Once at 140 C, 5.0 gm (50 rnmoles) of succinic anhydride were added. The temperature was raised to 200 C and maintained at this temperature for 3 hours. After 3 hours the reaction flask was removed from the oil bath and allowed to cool to room temperature- The polymer was a dark yellow liquid.
Crystallites began to form within seven days.
3.0 GPC measurement determined a number average molecular weight of 1,284, and a weight; average molecular weight of 21,198. The 1H NMR showed, the following peaks: 8 0.85 triplet (3H), 1.171 multiplet (16H), 1.6 multiplet (2H), 2.29 multip:Let (2H), 2-6 is multiplet (4H) , 4.23 multiplet (4W) , S..27 multiplet (2W) .

Example 11: Synthesis of Poly(monocaproyl glycerol-co-siucci hate) 20 15.0 gm (68.7 mmoles) reonocaprylo,yl glycerol were added to a dry 50 ml, single neck, round bottom flask.
A stir bar was added and a nitrogen inlet adapter was attached- The reaction flask was placed in a room temperature oil bath and a nitrogen blanket was applied.
a_5) The flask was heated to 140 C and then 6.88 gm (68.7 mmoles) of succinic anhydride were added. the temperature was raised to 200 C and the sol,4tior. was held at this temperature for 3 hours. After 3 hours the =0 flask was removed from the oil bath and allowed to cool to room temperature. The polymer was a light: yellow viscous liquid. The polymer began to cW'ystallize very slowly in 7-10 days.
S GPC measurement dete r m ned a number average molecular weight of !,349, and a weight average molecular weight of 2,301 daltons. The sH NMR showed the following peaks o 6 0.66 triplet. (3H) , I .25 multiplet (8K) , 1.6 multiple, (2H) 2.30 multiples (2HH) , 2.65 its mult.iplet (4K) , 4 .:L3 multip' et (2K) , 4.33 tmulti,plet (2K) , 5.26 multiplet (I.K) ,.

Example 12: Synthesis of Poly (monostearoyl glycerol -co-succinate) Room Temperature Solid 15 8.0 gm. (22.3 rnmolea) of r:onostearo l gff.ycerol were added to a dry 50 mL, single neck, round bottom flask.
A stir bar was added and a nitrogen inlet adapter was attached. The reaction fl-ask was placed in a room temperature oil bath and a nitrogen ga. blanket was 20 started. The flask was heated to 140 CL' and 4,46 gm (44.6 mmoles) of st,uccini c anhydride were added. The temperature was raised to 200 C and maintained for 22.5 hours. The flask was removed from the oil bath to cool to room temperature. Once the solution crystallized, it 25 was deglassed and cleaned of any glass fragmente_ The polymer was an amber colored solid.
DSO measurements found a melt temperature of 48.41 C and a specific heat of 73 _ 98LTfgg; _ GPO

measurement determined a number average molecular weight of 2,546, and a weight average molecular w; ght of 43,002 daltons.

Rxan- le 13: Poly (inonostear=oyl glycerol -co- glyceryl monolinoleate-succinate) liquid polymer as a bone replacement material A bone replacement study was performed in male New Zealand white rabbits using poly(monostearoyl glycerol-co-glyceryl. monoliaoleate--succinate) liquid. The animals utilized in this study were handled and maintained in accordance with current recniirements of the Animal Welfare Act. Compliance with the above Public Laws was accomplished by adhering to the Animal is Welfare regulations (9 CFR) and conforming to the current standards promulgated in the Qu:Lde for the Care and Use of Laboratory Axnimals.
Liquid poly (monostearoyl glycero { .-co-glyceryl monolinoleate-succ`_nate) was prepared as described in 20 Example 7. The polymer was heat sterilized in glass vials sealed with a crimped aluminum seal and a septum, The vials were heated to 160 C in an oven for 2 hours.
The outside of the vials were then cleaned using a 70/30 mix of isopropariol and deionized water before the Vial 25 was introduced into a sterile, laminar flow hood. The polymer was then loaded into 3cc sterile syringes in a sterile hood and injected into the radial defect (2 -2.5 cm) of four rabbits until the defect was filled Explants were taken at 8 weeks.
In two of the four defects, bone regeneration or bone bridging was observed. 1 -aeiog. rap]htic data showed gradual healing of the defect in these two cases. In the case that resulted in bone bridging, this result appeared to be fully achieved within four weeks. By eight weeks, the bone appeared to be re-corticalized which was confirmed by gross histology.

Ex le 14 Poly (monostea-royl glycerol-co-glycerol monolinoleate-succinate) liquid polymer mixed with demineralized bone matrix (DBM) as a bone replacement material is A bone replacement study was performed in male New Zealand white rabbits using a cixture of poly(menostearoyl glycerol-co-glyceryl monolinoleate-succinate) liquid polymer and demineralized bone matrix (DBM). The animals utilized in this study were handled 20 and maintained in accordance with current requirements of the Animal Welfare Act. Compliance with the above Public Laws was accomplished by adhering to the Animal Welfare regulations (9 CFR) and conforming to the current standards promulgated in the Guide for the Care 25 and Use of Laboratory Animals.
Liquid poly(monostearoyl glycerol-co-glycerol monolinoleate-succinate) was prepared as described in Example 7. The polymer was heat sterilized in glass vials sealed with a. crimped aluminum seal and a septum-The vials were heated to 1600C in an oven for 2 hours.
The outside of the vials were 1- hen cleaned using a 70/30 mix of isopropanol. and deionized water before the vial.
was introduced into a sterile, laminar flow hood. Also loaded into the sterile hood were 2, 1 cc -packets of rabbit DEN prepared by - TS inc. (Kent, WA) _ The liquid polymer was mixed wi h DEN in a sterile petri dish with the aid of a stainless steel spatula at a DBM to polymer carrier ratio of 2 ratio forming a paste-like formulation of 67 weight percent DBMMi_ The formulation was then loaded into sterile syringes with cut ends.
The filling volume was 05 cc and each syringe was packaged in a pre--autoclaved sterile pouch before removal from the sterile hood.
The surgical procedure for implantation of these samples into defects in the radii of 5 rabbits is as follows, A longitudinal skin t acisiox, was made over the middle one third of the right front leg, The periosteum was then separated from the muscle and s, 17 mm osteo-periosteal defect was made in the radius. The radial segment was cat using an. air powered mini driver equipped with an oscillati~ig saw attachment- The defect was located approximately 2.0 to 2.5 cm proximal to the r'adilocarpal joint, No additional fixation or hardwar was necessary to stabilize the limb due to the strutting of the forelimb by the ulna. The samples were implanted by injecting the polymer into the radial' defect from the above prepared syringes until the defect was filled (-O.3 cc) All incisions were closed with multiple layers of resorbabie suture upon completion of the operation.
Radiographic data was taken every two weeks to monitor the implant site. Explants were taken at 6 weeks and in all 5 cases hone bridging occurred. The defect sites in three of the five cases were sunken and in general, the sites reflected a diffuse pattern with no organized structure. As early as 2 weeks, the defect site was cloudy, emphasizing the osteoinductivity of the DBM .

Example IS: 25:75 Pol ,r (monostearoyl glycerol -co-glyceryl_ monooleate-succinate) liquid polymer minced with demineralized bone matrix (Dl3M) as a bone replacement material A bone replacement study was performed in male New Zealand white rabbits using a mixture of 25:75 poly(monostearoyl glycerol -co-ulyceryl monooleate-succin.ate) liquid polymer and demineralized bone matrix (tEM) -Liquid 2S:75 poly(monost,ea.royl glycerol-co-glyceryl monooleate-succinate) was prepared as described in Example 8. The polymer was heat sterilized, mixed with DSM and implanted into defects made in the radii of 5 rabbits following the procedure used in 'xample 14.
Radiographic data was taken every two weeks to monitor the implant site. Exp`.ants were taken at 8 weeks and in all 5 cases, bone bridging occurred- As in Example 14, some of the defect sites had a sunken appearance but, in general, the radiographic data s indicated a slightly more orga:nized cancellous appearance to the newly formed bone. At 2 weeks, the defect site was cloudy, emphasizing the osteoinductivity of the DEM.

Example 16 Poly(glyceryl monocleate-succinate) liquid polymer mixed with demineralized bone matrix (DBM) as a bone replacement material A bone replacement study was performed in male New Zealand white rabbits using a mixture of poly (glyceryl.
is monooleate succinate) liquid polymer and, dernineralized bone matrix (OEM) Liquid poly(glyceryl monooleate-succinate) was prepared as described in Example 3_ The polymer was heat sterilized, mixed with OEM and implanted into defects made in the radii of 5 rabbits following the procedure used in Example 14.
Radiographic data was taken every two weeks to monitor the implant site. Expl.ants were taker, at 8 weeks and, in all 5 cases, bone bridging occurred. The observed healing was advanced in comparison to that observed in Examples 14 and 15. Three of the defect sites showed not only complete bridging, but also clear evidence of recorticalization. In one case, there was evidence of restoration of the marrow cavity. At 2 weeks, the defect site was cloudy, emphasizing the osteoii ductivity of the DEM. The extent to which this cloudiness was visible was more pr ominenr than in the other Examples 14 and 15.

Example 17: Poly(glyceryl mcnooleate-suceinate) liquid polymer end-capped with ol.eoyl chloride A polymer was prepared following the procedure in 1.0 Example 3, except using 253.12 g (0.71 mci) of glycerol moncoleate and 70.05 g (0 . 7 mol) of succinic anhydride in a 500 gal single neck, round bottom flask. GPC
measurement determined a number average molecular weight of 2,280 and a weight average molecular weight of 4,040 35 daltons, An end-capping procedure was performed by dissolving 25.2 g of the polymer in 75 ;ml of methylene chloride in a three necked, 300 ml, round bottom flask, to which 3.35 grams of triethyl amine was added as an 20 acid scavenger. The flask was equipped with a glass stirrer with a teflon paddle, a thermometer, and a septum with N2 inlet/outlet needles. The flask was placed in a ice/NaC1 slush bath, and the reaction mixture was allowed to chill to 0 C. A nitrogen blanket 25 was placed over the reaction through the septum.
In the glove box, 9.74 g o>leoyl c bride Was weighed in a gas-tight syringe, and the needle was stoppered using a grubber stopper. The oleoyi chloride was added to the chilled reaction mixture through the septum in a dropwise fashion so as to keep the reaction temperature between 2 and 7 C, as read on the thermometer. After complete addition of the oleoyl chloride, the reaction was allowed to continue stirring for another 2 hours. While still stirring, the slush bath was removed and the reaction mixture was allowed to come to room temperature at which point 2 ml of ethanol was added to the solution and let stir for 1 hour to react with any excess oleoyl chloride. The stirring was stopped, and the reaction was stoppered and allowed to sit in the refrigerator overnight.
The triethylamine hydrochloride salt was removed by vacuum filtration and the filtercake was washed twice with 25 ml of cold methylene chloride. The product-containing methylene chloride solution was transferred to a 500 ml separatory funnel and washed twice with equal volumes of 1.0 M HCL followed by two washings with equal volumes of brine solution. The organic layer was then dried over magnesium sulfate.
The magnesium sulfate was removed by vacuum filtration over Celite. Finally, the methylene chloride was removed by evaporation on a rotary evaporator leaving behind the end-capped polymer which was allowed to dry in a vacuum oven at room temperature until it exhibited constant weight.

H1 N'MR. showed the following peaks: S 0.84 triplet, 1.29 doublet, 1.63 multiple" 2.01 multiplet, 2.30 multiplet, 2.45 triplet, 2.63 multiplet, 4.23 multiplet, and 5.34 multiplet. Following the end capping reaction, the peaks assigned to the terminal hydroxyl endgroups at S 3-5 - 3.8 on the starting polymer were not resolvable above the baseline, indicating that the terminal hydroxyl groups were converted into asters-The polymer was heat sterilized for 2 hours at 160 C and mixed with DBM following the procedure used in Example 14 in order to make a bone replacement material.
Ex le lam Poly(g7yCeryl mono(;leate-succinate) liquid polymer end-capped with acetyl chloride i5 ~Ioly(glyceryl monooleate-succinate) liquid polymer was prepared following the method of Example 17.
An end-capping procedure with 2.6 g acetyl chloride was performed using the same procedure as described in Example 17, except using 25.04 g of the polymer in methylene chloride, to which 3.35 grams of triethyl amine was added as an acid scavenger. The end-capped polymer product which was allowed to dry in a vacuum oven at 80 C until it exhibited constant weight.

H1 NMR showed the following peaks: & 0.S3 triplet, 1.30 doublet, 1.61 multiplet:. 2,02 multi. lot, 2.32 multiplet, 2.62 multiplet, 4.23 multiplet, and 5.33 multiplet. Following the end capping reaction, the peaks assigned to the terminal hydroxyl endgroups at 8 3,5 -3-8 on the starting polymer were not resolvable above the baseline, indicating that the terminal hydroxyl groups were converted into esters.

Example 19. End-capped poiy(monooleate-si,,ccinate) liquid polymer mixed with demineralized bone matrix (DBMM) as a bone replacement rocaterial_ A bone replacement study was performed in male New Zealand white rabbits using a mixture of the end-Gapped liquid polymer as described in Example 1-8 and demineralized bane matrix (D-SIC .
The polymer was heat sterilized for 2 hours at 16O C and. mixed with D3M, and the sterile samples were implanted into defects made in the radii of 5 rabbits as in Example 14.

Claims (39)

1. A medical device, comprising: a bone replacement material, said bone replacement material comprising a synthetic, bioabsorbable, biocompatible, liquid polymer comprising the reaction product of a polybasic acid or derivative thereof, a fatty acid, and a polyol, said liquid polymer having a melting point less than about 40°C, as determined by differential scanning calorimetry.

2. The medical device of claim 1 wherein said liquid polymer comprises the reaction product of said polybasic acid or derivative thereof and a monoglyceride, said monoglyceride comprising the reaction product of said fatty acid and said polyol.

3. The medical device of claim 2 wherein said polybasic acid or derivative thereof is selected from the group consisting of succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid, diglycolic anhydride, glutaric acid, glutaric anhydride, adipic acid, pimelic acid, suberic acid, sebacic acid, fumaric acid, maleic acid, maleic anhydride, mixed anhydrides, esters, activated esters and acid halides.

4. The medical device of claim 2 wherein said monoglyceride is selected from the group consisting of monostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproyl, glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol.

5. The medical device of claim 4 wherein said polybasic acid derivative is succinic anhydride.

6. The medical device of claim 4 wherein said polybasic acid is succinic acid.

7. The medical device of claim 1 wherein said liquid polymer comprises a liquid copolymer.

8. The medical device of claim 7 wherein said liquid copolymer comprises the reaction product of said fatty acid, said polyol, and at least two of said polybasic acids or derivatives thereof selected from the group consisting of succinic acid, succinic anhydride, malic acid, tartaric acid, citric acid, diglycolic acid and diglycolic anhydride.

9. The medical device of claim 7 wherein said liquid copolymer comprises the reaction product of said polybasic acid or derivative thereof, and at least two monoglycerides selected from the group consisting of monostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol.

10. The medical device of claim 7 wherein said liquid copolymer comprises the reaction product of said polybasic acid or derivative thereof, a monoglyceride selected from the group consisting of monostearoyl glycerol, monopalmitoyl glycerol, monomyrisitoyl glycerol, monocaproyl glycerol, monodecanoyl glycerol, monolauroyl glycerol, monolinoleoyl glycerol and monooleoyl glycerol, and at least one additional polyol selected from the group consisting of ethylene glycol, 1,2-propylene glycol, 1,3-propanediol, bis-2-hydroxyethyl ether, 1,4-butanediol, 1,5-pentanediol, 1,6- hexanediol, 1,8-octanediol, 1,10-decanediol, 1, 12-dodecanediol, other diols, linear poly(ethylene glycol), branched poly(ethylene glycol), linear poly(propylene glycol), branched polypropylene glycol), linear poly(ethylene-co-propylene glycol)s and branched polylethylene-co-propylene glycol)s.

11. The medical device of claim 1 further comprising an inorganic filler.

12. The medical device of claim 11 wherein said inorganic filler is selected from the group consisting of alpha-tricalcium phosphate, beta-tricalcium phosphate, calcium carbonate, barium carbonate, calcium sulfate, barium sulfate and hydroxyapatite.

13. The medical device of claim 11 wherein said inorganic filler comprises a polymorph of calcium phosphate.

14. The medical device of claim 11 wherein said inorganic filler is hydroxyapatite.

15. The medical device of claim 11 further comprising a bioactive agent.

16. The medical device of claim 15 wherein said bioactive agent is a growth factor.

17. The medical device of claim 16 wherein said growth factor is selected from the group consisting of cell attachment mediators, biologically active ligands, integrin binding sequence, bone morphogenic proteins, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, IGF-I, IGF-II, TGF-.beta.I-III, growth differentiation factor, parathyroid hormone, vascular endothelial growth factor, bFGF, TGF.beta.
superfamily factors, sonic hedgehog, GDF5, GDF6 and GDF8.

18. The medical device of claim 11 further comprising a biologically derived substance selected from the group consisting of demineralized bone, platelet rich plasma, bone marrow aspirate and bone fragments.

19. The medical device of claim 1 further comprising at bioactive agent.

20. The medical device of claim 19 wherein said bioactive agent is a growth factor.

21. The medical device of claim 20 wherein said growth factor is selected from the group consisting of cell attachment mediators, biologically active ligands, integrin binding sequence, bone morphogenic proteins, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, IGF-I, IGF-II, TGF-.beta.I
III, growth differentiation factor, parathyroid hormone, vascular endothelial growth factor, bFGF, TGF.beta.
superfamily factors, sonic hedgehog, GDF5, GDF6 and GDF8.

22. The medical device of claim 1 wherein the polymer further comprises terminal and pendant chemical moieties prepared by suitable endcapping reactions.

23. The medical device of claim 22 wherein said terminal and pendant chemical moieties are selected from the group consisting of ethers, esters, anhydrides, mixed anhydrides, sulfonates, and urethanes.

24. The medical device of claim 22 further comprising an inorganic filler.

25. The medical device of claim 24 wherein said inorganic filler is selected from the group consisting of alpha-tricalcium phosphate, beta-tricalcium phosphate, calcium carbonate, barium carbonate, calcium sulfate, barium sulfate and hydroxyapatite.

26. The medical device of claim 24 wherein said inorganic filler comprises a polymorph of calcium phosphate.

27. The medical device of claim 24 wherein said inorganic filler is hydroxyapatite.

28. The medical device of claim 24 further comprising a bioactive agent.

29. The medical device of claim 28 wherein said bioactive agent is a growth factor.

30. The medical device of claim 29 wherein said growth factor is selected from the group consisting of cell attachment mediators, biologically active ligands, integrin binding sequence, bone morphogenic proteins, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, IGF-I, IGF-II, TGF-.beta.I-III, growth differentiation factor, parathyroid hormone and vascular endothelial growth factor.

31. The medical device of claim 22 further comprising a biologically derived substance selected from the group consisting of demineralized bone, platelet rich plasma, bone marrow aspirate and bone fragments.

32. The medical device of claim 22 further comprising a bioactive agent.

33. The medical device of claim 32 wherein said bioactive agent is a growth factor.

34. The medical device of claim 33 wherein said growth factor is selected from the group consisting of cell attachment mediators, biologically active ligands, integrin binding sequence, bone morphogenic proteins, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, IGF-I, IGF-II, TGF-.beta.I-III, growth differentiation factor, parathyroid hormone and vascular endothelial growth factor.

35. A bone replacement composition, comprising: a liquid polymer comprising the reaction product of a polybasic acid or derivative thereof, a fatty acid and a polyol, said liquid polymer having a melting point less than about 40°C, as determined by differential scanning calorimetry; and demineralized bone matrix.

36. The medical device of any one of claims 17 and 21, wherein the bone morphogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-6 and BMP-12.

37. The medical device of any one of claims 15 and 19, wherein the bioactive agent is selected from the group consisting of hyaluronic acid, glycoprotein, lipoprotein, tenascin-c, fibronectin, thromboelastin and thombin-derived peptides.

38. The medical device of any one of claims 28 and 32, wherein the bioactive agent is selected from the group consisting of hyaluronic acid, glycoprotein and lipoprotein.

39. The medical device of any one of claims 1-34 and 36-38, wherein the melting point of said liquid polymer is less than about 25°C.