KREBS CYCLE ACID POLYESTERS AND USE THEREOF

Abstract: The invention is directed to high molecular weight polymers for use as bioresorbable bone cements for orthopedic and periodontal applicators, wound dressings, adhesives, and drug delivery devices.

Description: KREBS CYCLEACIDPOLYESTERS ANDUSETHEREOF This application is a continuation-in-part of U.S. Serial No. 08/110,074 filed August 20, 1993. Field of the Invention The present invention relates to biodegradable polymers and methods and apparatus for making such polymers. Embodiments of the present invention feature batch and continuous methods employing condensation polymerization. The apparatus and methods feature greatly increased yield of high molecular weight polymers and improved reproducibility. High molecular weight polymers are incorporated in formulations having desirable strength and stiffness features. These formulations can be used as bone cements, adhesives and wound dressings, and can be used to make devices for delivery of drugs. Background of the Invention Biodegradable, bioresorbable polymers have applications in medicine and surgery. The term "biodegradable", in the context of the present invention, means capable of being decomposed by natural biological processes in situ. The term "bioresorbable" means capable of being decomposed and utilized by natural processes in situ with little residue. The applications include bone replacement, cements, adhesives, sutures, wound dressings and drug delivery systems. Typically, biodegradable, bioresorbable polymers are derived from compositions which form part of the normal metabolism of the organism into which the material is to be placed. The acids of the Krebs cycle, also known as the tricarboxylic acid cycle, have been used to form biodegradable, bioresorbable polymers. However, use of some Krebs cycle-type polymers has been limited due to the lack of reproducibility of the polymerization process, insufficient yields of high molecular weight polymer and difficulty in limiting undesired cross linking reactions during the initial polymerization process when synthesizing unsaturated polyesters. Various materials, such as plastics and ceramics have been evaluated for use in bone repair procedures for decades. Bone cements are materials which can be molded or formed in a desired shape, with hardened in situ. Bone cements are used to substitute for diseased bone or bone which has been lost through accident or the like. Bone cements are employed in such areas as maxillofacial repair and reconstruction, total joint replacement, bone void fill, fracture and some repair dental applications. For over 30 years, orthopaedic surgeons have been using mainly acrylic cements for bone repair. Acrylic materials are not biodegradable, and remain in the body, subject to fatigue and wear. The methyl methacrylate based commercial acrylic cements are brittle in nature. Acrylic cement cracking is a well-known problem that can lead to failure of a cemented artificial joint. Acrylic cement systems are very exothermic on cure, often reaching 80 °C or greater. These temperatures can be damaging to surrounding tissue. A biodegradable, bioresorbable bone cement preferably should allow bone ingrowth into the repaired area. This ingrowth of bone strengthens the repaired area over time. Biodegradable, bioresorbable cements do not remain in the body, and are replaced with natural bone or tissue. Thus, the biodegradable cements are not available for fatigue wear over prolonged time periods. However, biodegradable cements have met with limited success due to poor material strength. Most biodegradable, bioresorbable cements do cure quickly or are not readily moldable. Summary of the Invention One embodiment of the present invention features a biogradable polymer and methods and apparatus for making such polymers. One embodiment of the present invention features a biodegradable polymer represented by Formula I below: Fornmla I As used above, X is a C 2 -C 3 divalent paraffinic group or divalent olefinic group, and Y is a C,-C divalent paraffinic group or divalent olefinic group or a single bond between the carbon atoms to which it is adjacent. R 1 , R 2 , R 3 and R 4 taken independently are hydrogen, or a C,-C 5 divalent paraffinic group or C*-C 5 divalent olefinic group. The letter "n" represents an integer consistent with the weight average molecular weight(M w )and number average molecular weight (M n ) of the polymer. The polymers of the mixture generally have a number average molecular weight (M n ) of 3,000 - 20,000 and a weight average molecular weight (M w ) of 8,000 - 60,000 g/mole. The final polymer being a distribution of polymer chains (species) of various chain lengths, the number average and weight average molecular weight may be obtained as follows: the number average molecular weight is formed by summing the products of the mole fraction of each species and its molecular weight; the weight fraction is formed by summing the products of the weight fraction of each species times its molecular weight. The value of "n" for each polymer molecule of a sample will vary providing a distribution of "n" values. The majority of "n" values will be 20 to 120 in a polymer resulting in a M π of generally greater than 3,000 and a (Mw) of 8,000 to 60,000 g/mole for polymers in which the repeating unit Mo (in polymer (Mo)n) has a molecular weight between 100 and 200 g/mole, for example. Preferably the polymer has a M w of 10,000 - 50,000 g/mole. Even more preferred, the polymer has a M w greater than or equal to 20,000 g/mole. Preferably the polymer has a number average molecular weight (M n ) of 3,000 to 20,000 g/mole. Even preferable more the polymer has a M n greater than 5,000 g/mole. Preferably, X is a C 2 divalent olefinic group and Y is a C, divalent paraffinic group or a single bond between adjacent carbons. Preferably R 1 , R 2 , R 3 and R 4 are hydrogen, or not more than one R 1 , R 2 , R 3 , and R 4 is a C, alkyl and the remaining R 1 , R 2 , R\ and R 4 are H. The polymers of the present invention where X as an olefinic group are reactive. One embodiment of the present method comprises the steps of forming a biodegradable polymer represented by Formula I above. The method comprises forming a reaction mixture comprising a first monomer and a second monomer. The first monomer is represented by the Formula II set forth below: Formula II «. ' R.H μO- - Y- C - ^ ^ As used above, Y and R'-R 4 are consistent with Y and R'-R 4 above. The second monomer is represented by the Formula III below: Formula III wherein X is consistent with X above, and R 5 and R 6 taken independently are hydrogen, or a C]-C 3 alkyl or alkenyl. The method further comprises the step of imposing reaction conditions on the reaction mixture to form a first reaction product. The reaction conditions comprise a temperature in the range of 80° to 250°C under an inert gas. The first reaction product comprises an alcohol by-product which is removed and a first product. The first product is represented by the formula IV below: Formula IV H O- O H As used above, Y and X are. as set forth above with respect to Formulas I, II and III, and R 7 through R 10 and R 11 through R 14 are each R 1 through R 4 . The method further comprises the step of removing the alcohol by-product and imposing second reaction conditions on the first product. Second reaction conditions comprise a temperature in the range of 80© to 250°C and a pressure of 0.1 -760 torr to form a second reaction product. The second reaction product comprises the first monomer (which is now a by-product) and polymer represented by Formula I above. The second reaction product contains an excess of the first monomer. The method further comprises the step of removing the excess first monomer from the second reaction product using heat and vacuum to form a high molecular weight biodegradable polymer. The polymer has a M w of 8,000 - 60,000. As used herein, the term "biodegradable polymer" refers to polymers which are capable of being resorbed or degraded with minimal residue when placed in a body. Typically such polymers are formed with one or more compositions represented by Formula I or Formula II. A preferred first monomer comprises physiologically acceptable polyhydroxy alcohols. Preferred polyhydroxy alcohols comprise glycol (1, 2-propanediol), 1, 3-propanediol and ethylene glycol. A preferred polyhydroxy alcohol is propylene glycol. Preferably, the second monomer is selected from the group of 6 Krebs cycle acids consisting essentially of acotinic acid, isocitric acid, α-keto-glutaric acid, succinic acid, malic acid, oxaloacetic acid, citric acid, fumaric acid and derivatives thereof. Preferred derivatives are the C r C 3 alkyl esters of such acids. A preferred second monomer is fumaric acid and derivatives thereof, including without limitation, diethyl fumarate. Preferably, the first and second monomers form a reaction mixture having a mole ratio of 2.2:1 Formula II composition to Formula III composition. For preferred monomers comprising propylene glycol and diethyl fumarate the mole ratio comprises a first monomer in a concentration of 40 to 60 weight percent and a second monomer in a concentration of 40 to 60 weight percent. As used herein, the term inert gas refers to gases which are substantially unreactive to the reaction mixture. The term specifically excludes carbon monoxide, carbon dioxide and atmospheric air. One preferred inert gas is nitrogen. Preferably, the inert gas is applied as a continuous sweep across the reaction mixture during the first stage of the reaction. Preferably, the alcohol by-product (produced from the release of the alkoxy groups of the second monomer) is distilled from the reaction mixture. Preferably, second reaction conditions comprise reheating the first reaction product to 195° to 250oC under vacuum to promote further polymerization by removing excess first monomer. The vacuum facilitates removal of excess first monomer promoting further polymerization. As used herein the term "vacuum" means a pressure which is less than normal atmospheric pressure. Preferably, the vacuum is less than 1 mm of mercury. Preferably, the second reaction conditions are maintained for 30 to 90 minutes. A further embodiment of the present method comprises reaction conditions which include the presence of a catalyst. Preferably, the catalyst is selected from one or more catalysts set forth in Table 1 below: Table 1 1. Lithium, sodium, potassium, calcium, beryllium, magnesium, zinc, cadmium, strontium, aluminum, lead, chromium, molybdennum, manganese, iron, cobalt, germanium, nickel, copper, silver, mercury, tin, platinum, boron, antimony, bismuth, palladium, and cerium as the metal, oxide, hydride, formate, acetate, alcoholate, or glycolate or halide salt. 2. Zinc and lead perborates and borates. 3. Zinc, manganous, cobalt, magnesium, and cadmium succinate, butyrate, adipate, etc. or enolate of a diketone. 4. Calcium, zinc, aluminum, and strontium chlorides and bromides. 5. Lanthanum dioxide and titanate. 6. Neodymium chloride. 7. Double salts of antimony, such as potassium antimonyl tarnate, and salts of antimony acids, such as potassium pyroantimonate. 8. Lithium, zinc, or manganese salts of dithiocarbonic acids. 9. Titanium tetrafluoride or tetrachloride. 10. Alkyl orthotitanates. 11. Titanium tetrachloride-ether complexes. 12. Quaternary ammonium salts containing a titanium hexalkoxy radical; titanium tetralkoxides; alkali or alkaline earth metal compounds with aluminum, zirconium, or titanium alkoxides. 13. Magnesium metal plus free iodine. 14. Organic quaternary ammonium, sulfonium, phosphonium, and oxonium hydroxides and salts. 15. Antimony trioxide, p-toluene sulfonic acid, sulfuric acid, hydrochloric acid, pyrogallol. 16. Acid catalysts and Lewis acid catalysts; carbonates, alkanoates, hydrides, alkoxides of alkali metals. Preferred metal catalysts comprise compounds of magnesium, zinc, manganese, cobalt and titanium. Even more preferred metal catalysts comprise those of the transition metals, such as zinc and titanium. These metal catalysts promote polymerization to high molecular weight polymers at lower temperatures than acid catalysts and have less tendency towards cross linking. Preferred acid catalysts are sulfuric acid, sulfonic acids, hydrochloric acids. A preferred acid catalyst comprises sulfuric acid or paratoluene sulfonic acid. Preferred catalysts include para-toluene-sulfonic acid, and zinc and titanium salts and alkoxides. Preferred zinc and titanium salts and alkoxides include zinc chloride, zinc acetate and titanium tetrabutoxide. Preferably, the catalyst is present in the reaction mixture prior to heating the mixture. In order to control cross linking by free radical reactions, a free radical inhibitor is preferably present prior to heating the reaction mixture. Free radical inhibitors comprise chloranil, benzoquinone and hydroquinone. A preferred free radical inhibitor is hydroquinone. Embodiments of the present method are suitable for continuous processing. One embodiment of the present method features imposing first reaction conditions upon a reaction mixture in a flow-through reactor to form a first reaction product. The reaction mixture comprises a first monomer and second monomer represented by Formulas II and III as set forth previously. The first reaction product is comprised of an alcohol by-product and a first product. The first product is represented by Formula IV as set forth previously. The first reaction product and reaction mixture are received in a second reactor and second reaction conditions are imposed to form a second reaction product. The second reaction product comprises the first monomer and a polymer represented by Formula I as set forth previously. Preferably, the first reactor is in continuous communication with the second reactor in the sense that the reaction mixture and reaction product flow through the first reactor with only limited interruption. Preferably, the second reactor is in continuous communication with one or more vessels for receiving the second reaction product. First reaction conditions comprise a temperature of 50° to 250°C, and most preferably 80o to 250©C. Preferably, second reaction conditions comprise a pressure of 0.1 to 760 torr and a temperature of 150-250°C. Preferably, second reaction conditions comprise a temperature which is at least 5oC higher than the first reaction conditions. Preferably, reaction conditions comprise continuous stirring, mixing or agitation. Preferably, following the imposition of second reaction conditions, the second reaction product is devolatilized under devolatilization conditions. Devolatilization conditions comprise a temperature of 180° to 250°C and a pressure of 0.1 to 10 torr. Preferably, the volatile gases are removed from the reaction mixture under devolatilization conditions in a devolatilization vessel in communication with the second vessel. Preferably, the second reaction product is preheated in a separate flow-through heating vessel prior to introduction to the devolatilizer vessel. One preferred devolitilization vessel is a falling strand devolatilizer. Embodiments of the present invention are able to recycle first and second monomers which are not incorporated in the polymer. A further embodiment of the present invention features an apparatus for making biodegradable polymers represented by Formula I described previously. One embodiment of the apparatus features a first reactor for receiving and containing a reaction mixture comprising at least one monomer selected from the group of first and second monomers consisting essentially of a first monomer and a second monomer. The first monomer and the second monomer are represented by the Formulas II and III, respectively, as described previously. The reactor is capable of imposing reaction conditions on the reaction mixture. Reaction conditions comprise a temperature in the range of 80° to 250°C under an inert gas to form a first reaction product comprising an alcohol by-product and a first product. The first product is represented by the Formula IV described previously. The first reactor is in communication with removal means for removing the alcohol by-product. Following the removal of the alcohol by-product, second reaction conditions are imposed on the first product. Imposition of second reaction conditions on the first product forms a second reaction product comprising a first monomer represented by Formula II above and a polymer represented by Formula I above, having a distribution of molecular weights. The second reaction conditions comprise reheating the polymer to 195° to 250°C under vacuum to promote further polymerization by removal of excess first monomer. Preferably, the vacuum is less than 1 mm mercury. Preferably the second reaction conditions are maintained from 30 to 90 minutes. Preferably, the apparatus further comprises a source of inert gas. A preferred inert gas is nitrogen. Preferably, removal means comprise distillation apparatus. One embodiment of the present invention features a second reactor in fluid communication with the first reactor. As used herein, the term "fluid communication" means connected to by suitable means such as pipes, conduits, tubing, and the like to allow fluids to flow from one vessel to another. The second reactor is capable of imposing second reaction conditions on the reaction mixture to promote further polymerization. Preferably, the first reactor and the second reactor are capable of receiving catalysts and a free radical inhibitor. Preferably, catalysts and the free radical inhibitors are added to the reaction mixture prior to imposition of reaction conditions in the first reactor. One embodiment of the present apparatus features a source of catalyst in communication with the first reactor. The catalyst is selected from the group of catalysts set forth in Table I. Particularly preferred catalysts include para-toluene sulfonic acid, zinc salts and alkoxides and titanium salts and alkoxides. Preferred reaction conditions comprise temperatures of 195° to 250°C. Preferably, the first and second monomers are present in a mole ratio of 2.2: 1. For preferred first and second monomers propylene glycol and diethyl fumarate such ratio results in concentrations of 40 to 60 weight percent for each monomer. A preferred embodiment of the present invention features a flow-through apparatus for making biodegradable polymers represented by Formula I as set forth above. The apparatus comprises a first reactor and a second reactor. The first reactor and second reactor are in fluid communication. The first reactor is capable of receiving a reaction mixture comprising a first monomer and a second monomer represented by Formulas II and III respectively, as set forth above. The first reactor is capable of imposing first reaction conditions to form a first reaction product. The first reaction product comprises an alcohol by-product and a first polymer represented by Formula IV above. First reaction conditions comprise a temperature of 80 to 250°C The second reactor is capable of receiving the first product from the first reactor and imposing second reaction conditions to form a second reaction product. Second reaction conditions comprise a pressure of 0.1 to 760 torr and a temperature of 80 to 250oC. The second reaction product comprises a polymer represented by Formula I and the first monomer. The pressure is 0.1 to 760 torr, generally vacuum conditions removes the excess first monomer during the second reaction. Preferably, the second reactor has a temperature which is at least 5° higher than the first reactor. Preferably, the apparatus comprises a devolatilizer assembly for removing volatile gases from the second reaction product following the second reactor. One embodiment of the present apparatus features a devolatilization assembly in fluid communication with the second reactor. The devolatilization assembly is capable of imposing removal conditions. Removal conditions comprise temperatures of 150o to 250°C and a pressure less than or equal to 10 torr. A preferred apparatus further comprises a falling strand devolatilizer in fluid communication with a preheater vessel. The preheater vessel is in fluid communication with the second reactor for heating the second reaction product and directing the second reaction product to the falling strand devolatilizer. The first and second monomers which are not incorporated into the final polymer, are recycled. The first polymer may be purified further if desired. Embodiments of the present invention provide methods and apparatus for producing polymers of a high molecular weight range with little or no cross linking. The M w of the polymers comprises about 8,000 to about 60,000 grams/mole. The continuous process, utilizing a first reactor and a second reactor, allows the process to be scaled to commercial needs and is highly reproducible. A further embodiment of the present invention comprises a bioresorbable material comprising a polymer represented by the Formula V below: Formula V 0 0 R 1 R A (-0-C-X a -C-0-C-Y-0-) n R R 3 wherein Y, R 1 , R 2 , R 3 and R 4 are as previously described, and Xa is a C 2 -C 3 divalent paraffinic group, or a C 2 -C 3 divalent olefinic group, or a divalent paraffinic group represented by Formula VI below: Formula VI wherein Q is a single bond between carbon atoms to which it is adjacent, or - CH 2 -, and U and W, taken independently are H or M k Z, wherein M is represented by Formula VII below: Formula VII wherein L 1 , L 2 , L 3 , and L 4 taken independently are H, carboxyl, C,-C 3 esters of carboxyl C,-C 6 alkyl, C,-C 6 haloalkyl C,-C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C,-C 6 thiol, amine, ketone or hydroxy substituted alkyl or the group represented by Formula VIII below: FormuJa VIII ^. ^l<o and R 15 and R 16 taken together with N are a five to six member ring in which the members consist of carbon, nitrogen, sulfur or oxygen, and such carbon members of said ring are alkyl, nitrosoalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, said nitrogen members of said ring are imides, amines or amides and said sulfur members of said ring are sulfonyls and sulfones, or R 15 and R 16 taken independently or H, C r C 6 alkyl, haloalkyl C,-C 6 hydroxyalkyl, Cj- alkoxyalkyl, C,-C 6 , or thiol amine substitute alkyl; and k is an integer of 1 or greater and Z is H or u or w of Xb, wherein Xb is consistent with the description of Xa but is not Xa or, U or W if U and W are taken together to form a ring of M k and n is an integer greater than 1. Preferably, Xa is a divalent paraffinic group and Q is a single bond between adjacent carbon atoms. Preferably, at least three of L 1 , L 2 , L\ L 4 are H and at least one of L 1 , L 2 , L 3 and L 4 is the group represented in Formula VIII. Referring to Formula VIII, preferably, R 15 and R 16 together with the nitrogen to which they are attached are represented by the group depicted in Formula IX below: Formula IX In the alternative, L 1 and L 3 are H, L 2 is methyl and L 3 is a carboxylate group - C00H or C,-C 3 alkyl ester thereof. Preferably, the bioresorbable material further comprises a filler. As used herein, the term "filler" refers to material which occupies space and provides bulk. The filler also provides strength and stiffness reinforcement to the final system. Other features of the present method allow curing of the polymer to take place in vivo. Embodiments of the present invention are capable of curing to a rigid fixed composition in an amount of time that depends on the exact formulation. This cure time can be adjusted to provide hardening in a few minutes or in several hours. In this system, the exothermic curing reaction results in a maximum cure temperature of not more than 45 °C with starting materials at room to body temperature. A preferred filler for bone and periodontal applications is a calcium salt or ground bone products. Examples of calcium salts comprise calcium chloride, calcium phosphate, calcium carbonate, and calcium sulphonate. Ground bone products, include without limitation, pulverized bone and hydroxyapatite. The bioresorbable material of the present invention with calcium salts or ground bone products as a filler has a compressive strength of 25 Mpa and, preferably, greater than 40 Mpa. The bioresorbable material of the present invention with calcium salts or ground bone products as a filler exhibit a compressive modules of 300 MPa and, preferably greater than 800 MPa. A preferred filler for soft tissue application and wound dressing is a bioresorbable polymer or ground cartilage. Preferably, the bioresorbable polymer used as a filler is incapable of further polymerization reactions. A bioresorbable polymer as described in Formula 1, wherein X is a C 2 -C 3 paraffinic group is a suitable filler. The bioresorbable polymer of Formula V is a suitable filler. However, these polymers may need to be reduced to small particle sizes. The polymer of Formula I can be used as a filler with other polymers. One embodiment of the present invention comprises the polymer of Formula I wherein X is a C 2 -C 3 divalent parafinic group, and Y is a C,-C 5 divalent parafinic or a single bond between adjacent carbons. This nonreactive polymer is combined with a monomer of Formula X. In this situation, the monomer forms a second polymer of M k . In this situation k is an integer of one or greater and has a distribution of values for all M, which distribution of values is consistent with a weight average molecular weight of 6,000 to 500,000 and M n of 3,000 to 100,000. The value of k is normally 15-1,000. Preferably, the filler and the polymer define a ratio of two parts filler to one part polymer. Preferably, the bioresorbable material comprises a drug. The drug may be released slowly from the biosorbable polymer as the polymer is acted upon in vivo. Preferred drugs comprise antibiotics, bone growth factors, tissue growth factors. The high molecular weight polymers of the present invention are particularly useful for applications as biologically compatible cements, grouts and adhesives. The term adhesive is used to suggest mechanical adhesion achieved by flow of the uncured material into pores of the remaining tissue/bone, then hardening in place. As used herein, the term "cement" or "grout" is used in the sense of a mechanical adhesive with higher strength and stiffness. That is, the cement or grout can be used to fill voids and provide strength. However, the terms "adhesive" "cement" and "grout" are not mutually exclusive and reflect, to a substantial degree, general ranges of a spectrum of flow characteristics which embodiments of the present invention are capable of. A further embodiment of the present invention features a method of making a bioresorbable material as described in Formula V. The method comprises the steps of forming an admixture of a reactive polymer and a monomer. The reactive polymer is as described in Formula I, wherein X is a C 2 - C 3 olefinic group. The monomer is represented by Formula X below: Formula X L* \ i - 1 c * wherein L', L 2 , L 3 and L 4 are consistent with Formula VII. The reactive polymer and monomer are polymerized by imposing polymerization conditions on the admixture. Preferably, polymerization conditions comprise the addition of a polymerization activator and a polymerization initiator to the admixture. Preferably, the monomer is maintained in the presence of a polymerization inhibitor until polymerization condition are imposed to prevent reactions from occurring prior to polymerization. Preferably, the monomer is a solvent or partial solvent for the polymer. Thus, forming an admixture comprises dissolving the polymer in the monomer to allow the resultant bioresorbable material to have a consistent composition throughout the form. Preferably, the admixture further comprises a filler. The filler provides strength and stiffness reinforcement to the final material, and may act as a heat sink during the polymerization reaction. The presence of only a small amount of monomer polymerizing in the presence of a large amount of filler allows the admixtures to cure generating a maximum temperature of only about 45 °C. Preferably, for rigid, hard tissue application the admixture forms a moldable dough-like material which can be used as bone cement or grout. This material upon curing forms a rigid hard mass. In the event the material is used as a wound dressing, adhesive, drug delivery system, or as a soft tissue repair material, a filler of bioresorbable polymer is used. The admixture retains a more liquid flowable consistency prior to curing and upon curing is more flexible and pliable. One embodiment further comprises a method of making a bioresorbable material as described in Formula I wherein the polymer of Formula I is nonreactive. In such polymer X is a C 2 - C 3 divalent paraffinic group, and Y is a C, - C 5 divalent paraffinic group or a single bond between adjacent cartons. This non-reactive polymer is combined with the monomer of Formula X. A second polymer is formed of M k . In this situation k is an integer of 1 or greater and has a distribution of values consistent with a weight average molecular weight of 6,000 to 500,000 and a M n of 3,000 to 100,000. The majority of k will be 15 to 1,000. A further embodiment of the present invention comprises a kit for making a bioresorbable material described in Formula V. The kit comprises a reactive polymer and or nonreactive polymer and a monomer. The monomer and polymer are contained in one or more vessels for forming an admixture and imposing polymerized conditions. Preferably, the monomer and polymer are contained in separate vessels with polymerization inhibitors to avoid premature reactions. A preferred inhibitor is a quinone as set forth in Formula XI below: Formula XI or hydroquinone as set forth in Formula XII below: Formula Xfl ς^ Z, P where R' l 22 are H or a C,-C 4 alkyl group. Preferably, the kit comprises means for initiating a free radial polymerization reaction. Preferably, such means comprise a peroxide, such as benzoyl peroxide. Preferably, the kit comprises a polymerization activator. Preferred activators comprise amines,sulfides and phosphines. A particularly preferred activator is N, N, dimethyl-p-toluidine. Preferably, the kit further comprises a filler. Preferred fillers comprise calcium salts, ground bone products and polymers of the type represented by Formula I. Bone repair applications of such a material include, but are not limited to, supplying internal support to weakened and brittle bones of patients with osteoporosis, fracture repair, facial reconstruction and space filling (in areas of tumor removal or damaged bone removal), fixation of total joint prostheses (hip and knee replacement), and the preparation of pre-molded plates, pins, and screws for orthopaedic mending of bone parts. Veterinary applications further comprise hoof repairs. Most animals with severely damaged hooves are destroyed. This material provides means for effecting repairs of hooves, which due to its fast and low temperature curing and bioresoφtion, poses little to no harm to the nearby source, and allows healing. Dental applications of the material include but are not limited to use as a performed resobable film for covering a repaired area of gum or tooth in dental or peridontal surgery, and use of a fast-curing cement form for use as a dry delivery device to allow and encourage regrowth of the alveolar bone when a bone growth factor is incoφorated. Other features and advantages of the present invention will be apparent from the following description which, by way of illustration, shows preferred embodiments of the present invention and the principles thereof and what is now considered to be the best mode to apply these principles. Brief Description of the Drawings FIG. 1 is a schematic of an apparatus for making biodegradable polymers for a first stage of processing; FIG. 2 is a schematic of the apparatus of FIG. 1 modified for a second stage of processing; FIG. 3 is a schematic representation of a flow-through apparatus for the continuous production of biodegradable polymers; FIG. 4 is a depiction of a polymer network according to the present invention; and, FIG. 5 is a depiction of a kit for making a bioresorbably material in accordance with the present invention. Detailed Description Part 1 : Preparation of the Polymer Embodiments of the present invention will be described in detail as a batch process for the manufacture of Krebs cycle-type polymers. Individuals skilled in the art will readily recognize that the present invention is subject to modifications and alterations, and the discussion should not be construed as a limitation of the invention but merely an exemplification of the features and advantages. Turning now to FIG. 1, an apparatus, generally designated by the numeral 11, for making Krebs cycle-type polymers, is comprised of the following major components: a reaction vessel 13, a column 15, a distillation head 17, a receiving assembly 19, and a heating assembly 21. Reaction vessel 13 has a opening 23 in communication with a source of nitrogen gas (not shown). Reaction vessel 13 receives nitrogen gas through opening 23 which nitrogen gas flows through the column 15 and distillation head 17 and receiving apparatus 19. Receiving apparatus 19 has a cooperating opening 25 for removing nitrogen gas from the assembly (i.e., outlet for nitrogen gas). The entire apparatus 11 is operated under a continuous nitrogen sweep. Reaction vessel 13 has a second opening 27 for receiving a first monomer and a second monomer. The first monomer and second monomer and optional catalyst and radical inhibitor are combined in vessel 13 to form a reaction mixture. Preferred monomers comprise diethyl fumarate and propylene glycol. The formation of a reaction mixture of uniform consistency is aided by agitation, mixing, and stirring. Reaction vessel 13 is equipped with a stirring bar 31 representing stirring means. Vessels of an industrial size will normally have other stirring equipment (not shown) such as paddles, turbines and the like. Reaction vessel 13 is held within the heating assembly 21. Heating assembly 21 comprises a heater 37 and an oil bath 39 for maintaining reaction vessel 13 at a predetermined temperature. Individuals skilled in the art will recognize that heating assembly 21 can be altered to suit the scale of the reaction process. Reaction vessel 13 is in communication with column 15. Column 15 is equipped with temperature sensing means, such as a thermometer 41 to monitor the temperature of polymerization reactions in the column 15 and reaction vessel 13. Column 15 is in communication with distillation head 17. Distillation head 17 is equipped with a water jacket 43 for cooling the interior chamber of the distillation head 17. Cooling of the distillation chamber 17 condenses an alcohol by-product of the polymerization reaction. Distillation head 17 is in communication with receiving assembly 19. Receiving assembly 19 comprises a housing 45 and a receiving vessel 47. Housing 45 defines a inner chamber having a plurality of openings. One of the openings in housing 45 comprises opening 25 for removal of nitrogen. A further opening is in communication with a receiving vessel 47 for collecting the alcohol by-product produced during the reaction process. A further opening 49 is equipped with a valve 51. Opening 49 allows the contents of receiving assembly 19 to be removed from the apparatus 11. During the first reaction stage, apparatus 11 has a configuration as illustrated in FIG. 1. During the first stage a first monomer, such as propylene glycol, and a second monomer, such as diethyl fumarate, are added to the reaction chamber with a catalyst such as zinc chloride and a free radical inhibitor such as hydroquinone, to form a reaction mixture. The propylene glycol and diethyl fumarate are combined (in a 2.2:1 mole ratio). Under a continuous nitrogen sweep, the reaction vessel 13 is heated by the heating assembly 27 to a temperature of approximately 230oC, over 3 hours. As the oil bath temperature reaches 195°C the temperature at the head of the column 15, as measured by thermometer 41, begins to climb with a steady, rapid distillation of the alcohol by-product. As the alcohol evolution becomes rapid, the head temperature will reach well over 78 °C, sometimes as high as 160°C, due to superheating by vapors of the higher boiling monomers being carried up the column by the rapidly distilling ethanol. As the oil bath temperature reaches 230°C, the distillation of by-products will slow as the theoretical amount of ethanol is recovered into the receiving vessel 47. On the completion of the reaction of the first stage, typically after maintaining the temperature at 230 °C for one hour, heating is discontinued and the reaction vessel 13 allowed to cool to below 100°C under a continuous nitrogen sweep. The first reaction stage combines the first and second monomers to form a first reaction product. The first reaction product comprises the alcohol by-product and a first product represented by Formula IV as previously described. The reaction assembly 11 is now modified for the second stage reaction as generally depicted in FIG. 2. Reference numerals assigned in stage 1 and described with respect to FIG. 1 are maintained in FIG. 2. The apparatus 11 is modified in FIG. 2. The receiving assembly 15 is replaced with a vacuum pump-dry ice-acetone trap assembly, generally designated by numeral 59. Opening 23 of vessel 13 is closed to allow apparatus 11 to operate under vacuum. Vacuum pump-dry ice-acetone trap assembly 59 is comprised of the following elements, a housing 45 a, receiving vessel 47 and a cold trap vessel 61. Housing 45a has an opening 25a. Opening 25a is connected to a conduit 63. Conduit 63 communicates with a nitrogen source (not shown) through conduit 65 or conduit 63 is closed. The apparatus 11 operates substantially under vacuum and a nitrogen source is not necessary. Conduit 63 is also in communication with a cold trap vessel 65. Cold trap vessel 65 is capable of being chilled by dry ice or other refrigerating means. The cold trap vessel 65 is in communication with a vacuum source (not shown) via a conduit 67 to allow the apparatus 11 to operate under vacuum. A vacuum gauge (not shown) is in communication with the vacuum source to monitor the vacuum level. In operation, during stage 2, the system is attached to a vacuum pump by conduit 61. Reaction vessel 13 and its contents are reheated as rapidly as possible (usually over two hours) to 220°C under a vacuum of approximately 1mm. mercury. Additional distillate is collected in receiving vessel 47a and cold trap vessel 65 as the vessel 13 is heated. The temperature is maintained between 220°C and 225 °C for 30-90 minutes (timeframe dependent on reaction scale). The melt within the reaction vessel 13 becomes more yellow and viscous during the latter stages. As high-boiling by-products are removed, the distillation temperature may reach 150° or higher. After 45 minutes, heating is discontinued and the reaction vessel 13 is removed from the heat assembly 21. Cooling is continued under evacuation followed by nitrogen backfilling of the cool system and the clear yellow-gold glassy polymer is dissolved in methylene chloride and precipitated into a 5-fold excess of ethyl ether. In the stage II reaction, first product formed in stage I undergoes further condensation to form a second reaction product. The second reaction product comprises a polymer represented by formula I and first monomer as previously described. The apparatus and methods of FIGS. 1 and 2 are further described with respect to Example 1 discussed later in t his application. The apparatus and methods of FIGS. 1 and 2 are further described with respect to Example 1, discussed later in the application. One embodiment of the present invention features a continuous process and flow through apparatus. Turning now to FIG. 3, an apparatus, generally designated by the numeral 111, for the continuous manufacture of Krebs cycle-type polymers is illustrated. The apparatus 111 has the following major elements: a first reactor 113, a second reactor 115, a preheater 117 and a devolatilizer 119. First reactor 113 has a jacket 121 which may be heated by steam, hot oil or pressurized hot water. The first reactor 113 is capable of imposing first reaction conditions on a reaction mixture. First reaction conditions comprise temperatures from 50°C to 250°C and, preferably, from 80°C to 250°C. First reaction conditions also comprise a pressure from 400 to 760 torr under an inert atmosphere of nitrogen. The first reactor 113 is in communication with a source of a first monomer 123 via a conduit 125 and pump 125a. Similarly, the first reactor 113 is in communication with a source of a second monomer 127 via a conduit 131 and pump 131a. The first reactor is also in communication with a source of catalyst and free radical inhibitor 133 via a conduit 137 and pump 137a. The first monomer, second monomer, catalyst and free radical inhibitor are added to the first reactor 113 to form a reaction mixture. The first monomer is represented by formula II and the second monomer is represented by formula III as previously described. The first and second monomers are combined in a mole ratio of 2.2:1. The reaction mixture in the first reactor is stirred by suitable stirring and mixing means such as turbines, anchors, paddles and screw conveyors (not shown). Reactions conditions are imposed on the reaction mixture in first reactor 113 by increasing the temperature to 250 °C. The residence time in the first reactor is approximately one to six hours and typically converts about 35% to 75% and more preferably 50% to 60% of the monomers to a first reaction product, comprising a first product, and an alcohol by-product. The first product is represented by formula IV as previously described. First reactor 113 is in communication with a condenser 143 via conduit 145. The condenser 143 receives volatile gases comprising the alcohol by-product from the first reaction vessel. The condenser condenses such gases into liquids. The liquids formed with the condenser 143 are piped to a holding tank (not shown) via conduit 147. To the extent possible unreacted first and second monomers are recovered and recycled. First reaction vessel 113 is in communication with a second reaction vessel 115 via a pump 151 and a conduit 153. The first product, formed within the first reactor 113, is pumped to the second reactor 115. Second reactor 115 is capable of imposing second reaction conditions to form a second reaction product. The second reaction product comprises a polymer represented by formula I as previously described and first monomer. Second reactor vessel 115, like the first reactor vessel 113, has a jacket 155 for receiving steam, hot oil or pressurized hot water to set the second reactor 115 at second reaction condition temperatures. Second reaction conditions comprise a temperature in a range from 150°C to 250 °C and a pressure of 0.1 to 720 torr. More preferably, the operating temperature is 185°C to 235°C. Preferably, the temperature is 5° to 10° higher than the temperature of the first reactor 113. Preferably, the pressure is 0.1 - 10 torr. First reactor 113 operates under an inert atmosphere of nitrogen. Second reactor 115 substantially operates under a vacuum under a nitrogen atmosphere carried from the first reactor 113. Second reactor 115 is in communication with a second condenser 161 via conduit 163. Condenser 161 receives volatile gases comprising any alcohol by-product carried to the second reactor 115 and first monomer from the second reaction within second reactor 115. Condenser 161 condenses such volatile gases to liquids. The liquids formed are piped to a storage tank (not shown) via a conduit 165. To the extent possible, unreacted first and second monomers are recycled. Second reactor 115 is in communication with preheater 117 by means of a pump 167 and a conduit 169. Preheater 117 is capable of receiving a mixture of polymer and first monomer. Preheater 117 is capable of imposing devolatilization conditions. Preheater 117 has suitable heating means such as electric heating coils, hot oils, hot water or steam. Preferably, preheater 117 is equipped with static mixer or a screw conveying means (not shown) to provide a more uniform product. Devolatilization conditions comprise temperatures up to 250 °C. Typically, the preheater will be heated to about 180°C to 210°C. The polymer has a residence time in the preheater of .5 to 15 minutes. Preferably, the time is kept as short as possible to minimize polymer degradation and/or depolymerization or cross-linking. The pressure in the preheater ranges from 0.1 to 10.4 torr and most preferably is maintained at 1 to 2.4 torr. Preheater 117 is in communication with the devolatilizer vessel 119 by conduit 171. Devolatilizer vessel 119 operates at a temperature of approximately 150°C to 250°C. Preferably, devolatilizer vessel 119 operates at a temperature of 220°C to 240°C. The internal pressure in the devolatilizer vessel 119 is maintained at a pressure typically less than 10.4 torr, and most preferably less than about 5 torr. Preferably, the devolatilizer vessel 119 is a falling strand devolatilizer. The mixture of second polymer and first monomer is received in the devolatilizer vessel 119 and falls through the inner chamber of devolatilizer vessel 119 as strands from top to bottom. As the mixture descends to the bottom of the devolatilizer vessel 119, any unreacted monomers and by-products of the first and second reactions evaporate from the reaction product and are withdrawn from the devolatilizer vessel 119 via a conduit 173. The unreacted monomers and by-products exiting conduit 173 are received by a third condenser 181. Condenser 181 cools and condenses the alcohol by-product and first and second monomer. The condensation product is conveyed via conduit 183 to a storage vessel (not shown). To the extent possible, unreacted first and second monomers are recycled. The finished polymer is removed from the devolatilizer vessel 119 via a pump 185 and a conduit 187. Individuals skilled in the art will readily recognize that the present apparatus is capable of modification and alteration. Indeed, more than one devolatilizer vessel 119, preheater 117, or additional reaction vessels 113 and 115 may be used. The resulting polymer may be extruded as strands, cooled and chopped into pellets or washed with non-solvents to further purify the polymer. The polymer resulting from the process described with respect to the FIG. 3 has a M w of about 8,000 to 60,000 grams per mole. These and other features and advantages of the present invention will be described with respect to the following example. Example 1 The following example features formation of a Krebs cycle-type polymer from diethyl fumarate and propylene glycol by transesterification using zinc chloride or zinc acetate as a catalyst. As illustrated in Fig. 1, a reaction vessel 13, a two-liter round-bottom flask containing a stir bar 31, is fitted with a 25 cm Vigreaux column 15 and a water-cooled distillation head 17. A typical reaction mixture of 344 g diethyl fumarate and 332 g propylene glycol (representing a 2.2: 1 glycol:ester ratio) was added to the flask, along with 0.15 g zinc chloride and 0.05 g hydroquinone. The system was completely flushed with nitrogen, and a nitrogen sweep continued over the reaction during the entire first (atmospheric pressure) stage, by means of an opening 23 on one flask neck and an exit opening 25 at the end of the receiving assembly 19. The flask 13 was heated by means of an oil bath 39, the temperature slowly being raised to 230°C over three hours. When the oil bath temperature reached about 195°C, the temperature at the head of the distillation column 15 began to climb, with the steady rapid distillation of ethanol by-product. When ethanol evolution was quite rapid, the head temperature reached well over 78°C, sometimes climbing as high as 160oC due to superheating by vapors of the higher boiling monomers being carried up the column by the rapidly distilling ethanol. The rate of heating of the oil bath 39 was monitored to assure controlled distillation of the ethanol. By the time the oil bath temperature reached 230°C, the distillation of by-product was slow, the theoretical amount of ethanol usually having completely distilled into the receiver. Some carryover of small amounts of higher boiling materials (monomer) may have occurred. Once the oil bath temperature reached 230oC, it was maintained at this temperature for one hour. Heating was then discontinued, and the reaction flask 13 allowed to cool to below lOOoC under a continuous nitrogen sweep. At this point, the opening 23 was plugged with a stopper and the system was attached to a vacuum pump, dry ice/acetone trap assembly 59, as can best be seen in Fig. 2. The reaction mixture was rapidly reheated to 220°C under a vacuum of approximately 1 mm Hg. Additional distillate was collected as the flask was heated. The temperature was maintained between 220 and 225 oC for 45 minutes. The melt became more yellow and viscous during these latter stages. As high boiling by-products were removed, the distillation temperature reached 150oC or higher. Stirring was maintained for product uniformity. After 45 minutes, heating was discontinued, and the flask 13 was removed from the oil bath 39. After cooling under continuous evacuation, the clear yellow-gold glassy polymer was either isolated or processed further by dissolving in 200-300 mL methylene chloride and precipitated into a 5-fold excess of ethyl ether. The resulting suspension and precipitate in ether is stored in a freezer overnight. After rewarming to room temperature, the supernatant was decanted, and the precipitation process was repeated. The final precipitate was vacuum dried at room temperature for several days. A typical batch process yields 170-200 g (66-75% yield) of poly (propylene fumarate) having a M w of > 20,000 g/mole. Part II: Preparation of the Bioresorbable Material This section describes the preparation and use of a bioresorbable material featuring the polymer of Formula I. The bioresorbable material has applications as a bone cement, adhesive wound dressing or as a drug delivery device. To perform further polymerization reactions with the polymer of Formula-I, a reactive polymer is used. A reactive polymer is defined by X where X is a C 2 - C 3 olefinic group. Preferrably, the polymer is poly (propylene fumarate). The polymer is combined with a monomer to form an admixture. Preferably, the monomer is a liquid in which the polymer is soluble or partly so. The polymer of Formula I is a solid at room temperature. Preferred monomers are n-vinyl-2-pyrrolidone,acrylamide, acrylic acid, methacrylic acid, and methyl methacrylate. The use of methyl methacrylate may result in bioresorbable material which is less water swellable and permeable. Preferably, a radical inhibitor is maintained with the monomer, as an admixture to prevent premature polymerization of the monomer. This inhibitor may be of the quinone or hydroquinone family as set forth in Formula XI and XII. The bioresorbable material is made by imposing polymerization conditions on the admixture. Polymerization conditions comprise the addition of polymerization activator and a polymerization initiator to the admixture. Preferably, the polymerization activator is an amine or any other compound capable of transferring an electron to a peroxide bond to facilitate the redox reaction resulting in the production of free radicals at room temperature. The polymerization initiator consists of any one of the peroxide or hydroperoxide classes of initiators of radical polymerization. The polymerization initiator and activator, in combination in the polymer-monomer admixture produce free radicals at ambient temperature. Examples of a peroxide initiators are dibenzoyl peroxide dintert-buxyl peroxide and dicumylperoxide. Examples of hydroperoxide initiators are t-buxyl hydroperoxide, and benzoyl/hydroperoxide. A preferred initiator is benzoyl peroxide. The monomer is preferably a liquid capable of solubilizing the polymer or wetting it well. The monomer is biocompatible or capable of being well tolerated by the body for the time the monomer will be in an incompletely polymerized state in vivo. The resultant polymer, referring now to Formula V, in the case where Xa is a C 2 paraffinic group and M is represented by Formula XIII below: Formula XIII and Z is Xb or H, is illustrated in Fig. 4. This Figure illustrates a crosslinked network of poly(propylene fumarate) with poly(viny pyrrolidone). It will be understood by those of ordinary skill in the art that the number of units of polyvinylidene pyrrolidone linking the poly(propylene fumarate) chain will vary within a single network. Preferably, the bioresorbable material comprises a filler. The filler and the first reactive polymer are combined as powders. Preferably, the filler comprises 50-80% of the total powder volume. Preferred fillers are inorganic materials, such as calcium sulfate, calcium phosphate, calcium carbonate or hydroxyapatite, or other biocompatible calcium salts. Powdered Krebs cycle acid polymers, such as those described by Formula I or powdered or morselized bone can also be used as filler. A preferred polymer filler is poly(propylene fumarate). Other polymers based on other Krebs cycle acids are described in U.S. Patent No. 3,978,203 and 4,722,948. Polymers used as fillers can be prepared from reactions between acids such as citric, acotinic, succinic, malic, oxaloacetic, isocitric and α-ketogluteric and biologically compatible alcohols such as ethylene glycol, glycerol, mannitol, sorbitol, and additional alcohols. A preferred bioresorbable material has applications as a bone cement. This material is made with the polymer of Formula I wherein X is a C 2 olefinic group, Y is a single bond between adjacent carbons and R'-R 3 are H and R 4 is methyl. This polymer is a solid which is reduced to a powder. The powder is combined with powdered calcium phosphate and the polymerization initiator. This powder admixture composition can be premixed and stored. The powder admixture composition typically comprises 20-50% by weight polymer, 50-80% by weight filler and 0.05-1.5% by weight polymerization initiator. Wound dressing may comprise 0-50% by weight filler. The preferred monomer, n-vinyl-α-pyrolidone is a liquid. The preferred polymerization inhibitor, N,N-dimethyl-p-toluidine are combined to form a liquid admixture. A typical formulation comprises 99% by volume n-vinyl-α-pyrolidone, .01 -.4% by volume hydroquinone; and .001-0.5% by volume N,N-dimethyl-p-toluidine. When the powder and liquid components are mixed together, the mixture becomes a moist dough that can be readily molded and shaped as desired. This allows working time for the cement dough to be placed as desired at the bone repair site, followed by in vivo completion of the cure to form a hard, bioresorbable cement. Cure time is adjusted by altering the amount of activator, or of activator and initiator, and can be adjusted to allow for curing times of 3-5 minutes to 2-3 hours. Most preferably, the curing time is 15 minutes. The powder components and the liquid components can be conveniently packaged as kits. A kit, generally designated by the numeral 11, is illustrated in FIG. 5. Kit 11 comprises the following major components: a package 17, a first vessel 21 and a second vessel 23. Package 17 may comprise a wrap or box for keeping first vessel 21 and second vessel 23 together. Individuals skilled in the art are able to make modifications and alterations to package 17 to suit particular needs. First vessel 21 contains a powdered admixture, comprising first polymer, filler and a polymerization initiator. These components can be maintained in separate vessels (not shown) if desired. Second vessel 23 contains a liquid admixture comprising monomer, a polymerization inhibitor and polymerization activator. The components may be maintained in separate vessels (not shown), if desired. Preferably the kit 11 further comprises instructions (not shown). Example 2 This example describes the making of a bone cement in accordance with the present invention. The cement was made by combining a powdered admixture with a liquid admixture. The powdered admixture has the following formulation where percentages are weight percentages: Preferred poly(proρylene fumarate) 25-50% 25% calcium salt(s) 50-75% <75% benzoyl peroxide 0.1 -.75% .1% The liquid admixture has the following formulation: N-vinyl-pyrolidone >99% hydroquinone <1% N,N-dimethyl-p-toludine .001 -.5% The powdered admixture and the liquid admixture were combined to form a reaction mixture. This reaction mixture is capable of curing to a hard mass within a few minutes and full hardness within a 24-hour period. Cure time may be adjusted over a wide range by altering the amount of activator and initiator. This material was formed into cylinders measuring 6 mm in diameter and 12 mm in length. These cylindrical samples were leached in phosphate buffered saline (pH 7.4) to mimic biological body fluids. At various times the leaching was stopped and the samples tested for compression strength and stiffness according to ASTM F451. The results are summarized in Table 2 below. Table 2 Compression Strength Compression Stiffness Time (days) (Mpa") (Mpa 0 42 ± 4 1730 ± 250 1 20 ± 1 410 ± 130 3 20 ± 1 330 ± 40 7 24 ± 1 680 ± 150 14 22 ± 2 460 ± 70 1 month 26 ± 1 550 ± 100 3 months 17 ± 7 430 ± 260 4 months 21 ± 3 670 ± 80 6 months 12 ± 1 220 ± 50 These in vitro results indicate that, while the material undergoes an initial strength and stiffness decrease probably due to hydration and swelling of the orgamc matrix, a plateau level is then reached. The material then maintains a strength and stiffness greater than the average strength of trabecular bone (5 Mpa and 50 Mpa respectively). This indicates maintenance of sufficient strength for bone repair. Example 3 The bioresorbable bone cement made in accordance with the formulation of Example 2 was also tested for use as a fixative for an intramedullary rod. This is an alternative to the use of interlocking intramedullary nails. The use of nails has many difficulties, among them proper fixation of the distal end of the rod. A bioresorbable cement is ideal for such a situation, as temporary fixation of the rod is all that is required for fracture repair. All marrow was removed from the medullary canal of 25 bovine femurs. An intramedullary rod was inserted into the canaled pocket and affixed with either a commerical polymethylmethacrylate cement or the bioresorbable bone cement. The bioresorbable bone cement was made in accordance with the formulation of Example 2. The polymethylmethacrylate cement was purchased from zimmer and made in accordance with manufacturer's instructions. The cements were mixed to the dough stage, and hand packed and pressurized into the canal of the femur, followed by insertion of the intramedullary rod to a depth of 10 cm. The femurs were allowed to continue to cure for 24 hours at 37 °C. All mechanical testing was conducted using an Instron test machine. The distal portion of the specimen was potted in a rectangular mold and held in place by a low melting metal. Cyclic compression was performed for 10 cycles between 0 and 100 N. Then the specimen was reoriented for application of torque. Angular rotation was measured with a rotational transducer on the rod. The rod was rotated to failure, after a "preconditioning" of 10 cycles between 100 and 200 N. Failure was defined as the first drop in load. Table 3 sets forth results, where PPF indicates poly(propylene fumurate) are PMMA indicates polymethylmethacylate: Table 3 Torque at Rotation at Compressive Torsional Failure (Nm) Failure (°) Stifrhess(N/rnrn) Stiffness(Nm/°) PPF cement 120 ± 70 9.0 ± 9 4800 ± 700 32 ± 7 PMMA 160 ± 40 4 ± 1 4900 ± 700 46 ± 8 These results indicate poly(propylene fumerate) bone cements have sufficient strength for fixation of an intramedullary rod. Example 4 This example explores in vivo evaluation of bioresorbability and bone healing following cortico-medullary grafting in a rat tibial model. Two formulations of sterilized bioresorbable bone cement were studied: one containing 25% poly(propylene fumarate), 75% calcium sulfate • 2H 2 O in the powder component, and one containing 33% poly(propylene fumerate) and 67% calcium sulfate. The liquid formation of Example 2 was used to form a reaction admixture in the manner of Example 2. One control animal (empty hole) was used at each time point out to 8 weeks. A 2 mm defect was created in the proximal end of the right tibia on the cranial-medial surface. A smooth, circular defect was created through the cortex and continuing to the endosteal surface on the caudal-lateral side. Cement was inserted (in the dough state) to fill the entire defect. Twenty rats per formulation were employed. Four rats were later sacrificed for each formulation at each of five timeframes: 1, 2, 4, 8 and 16 weeks. After euthanasia, from each group of 4 rats, 2 rats were subjected to hematoxylin-eosin stain and, in some cases, stains for hydroxyapatite (Vankossa) or cartilage (alcian blue) for studying bone moφhologic changes. Two rats had their hind limbs perfused with microfil barium and red latex rubber by established techniques, allowing visualization of neovascularization. Two rats also had previously received xylenol orange 8 days before sacrifice (intravenously) and calcein 4 days before sacrifice to allow fluorochrome dye analysis after euthanasia. In this manner, new bone deposition was followed over the course of the study. Results verified that vascular ingrowth into the cement begins cortically between 1 and 2 weeks, with resoφtion of cement and bone remodeling cortically being nearly complete in 4 weeks. In the medullary area, decalcification was complete in 8 to 16 weeks, while the material remaining (medullary) at 16 weeks was heavily vascularized. The resorbable bone cement is osteoconductive, readily allowing new bone growth. No evidence of an inflammatory response or systemic toxicity was evident at any time. The formulations of the present invention feature rapid curing times adjustable to anywhere from 3-5 minutes to 2-3 hours and achieving compression strengths of greater than 25 Mpa, and preferably greater than 40 Mpa. The formulations cure in an exothermic reaction, however due to the low percentage of polymerizing monomer, maximum cure temperatures do not exceed 45 °C. The bioresorbable material has applications as bone cements, wound dressings, peridontal disease treatment and adhesives. For veterinary applications, the bone cement is useful as a hoof repair material. What is claimed is:

Claims: CLAIMS 1. A biodegradable bioresorbable matrial comprising a first polymer represented by the formula below: wherein X is a C 2 -C 3 divalent paraffinic group or divalent olefinic group, and Y is a C,-C 5 divalent paraffinic group or divalent olefinic group or a single bond between adjacent carbons, and R 1 . R 2 , R 3 , R 4 taken independently are hydrogen, or a C,-C 5 alkyl or alkenyl and n is an integer consistent with the weight average molecular weight of said polymer, said polymer having a weight average molecular weight of 8,000-60,000. 2. The biodegradable material of claim 1 wherein said weight average molecular weight is greater than or equal to 10,000, and preferrably greater than 20,000 g/mole. 3. The biodegradable material of claim 1 wherein: X is a C 2 divalent olefinic group, and Y is a C, divalent paraffinic group, or a single bond between the adjacent carbons, and R 1 . R 2 , R 3 and R 4 are hydrogen, or not more than one of R 1 , R 2 , R 3 and R 4 is a C- alkyl and the remaining R 1 , R 2 , R 3 and R 4 are hydrogen. 4. The biodegradable material of claim 1 wherein: X is a C 2 -C 3 divalent paraffinic group, and Y is a C,-C 5 divalent paraffinic group or a single bond between adjacent carbons. 5. The biodegradable material of claim 4 further comprising: a second polymer of M k , wherein M is represented by the formula below: L l L2 t I (-C— C-) L3 wherein L 1 , L 2 , L 3 , and L 4 taken independently are H, carboxyl, C,-C 3 esters of carboxyl, C r C 6 alkyl, - haloalkyl, C,-C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C r C 6 thiol, amine, ketone or alcohol substituted alkyl, or the group represented by the formula below: -N and R 15 and R 16 taken together with N are a five to six member ring in which the members consist of carbon, nitrogen, sulfur or oxygen, and such carbon members of said ring are alkyl, nitrosoalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, said nitrogen members of said ring are imides, amines or amides and said sulfur members of said ring are sulfonyls and sulfones, or R 15 and R 16 taken independently or H, C,-C 6 alkyl, haloalkyl C,-C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C,-C 6 , or equal to thiol amine substitute alkyl, and k is an integer greater than or equal to 1 consistent with a weight average molecular weight of M of 6,000 to 500,000. A method of making a biodegradable polymer represented by the formula below: i ; / 3 r wherein X is a C 2 -C 3 alkyl or alkenyl, and Y is a C C 5 alkyl or alkenyl or a single bond between adjacent carbons, and R 1 , R 2 , R 3 and R 4 taken independently are hydrogen, or a C,-C 5 alkyl or alkenyl and n is an integer consistent with a weight average molecular weight of 8,000 to 60,000, comprising: (a) forming a reaction mixture comprising a first monomer and a second monomer wherein said first monomer is represented by the formula: , - l wherein Y and R 1 , R 2 , R 3 and R 4 are as described above and said second monomer is represented by the formula: D O 0 - C - χ - C - 0 - < wherein X is described above and R 5 and R 6 taken independently are H, or a C, - C 3 alkyl or alkenyl; (b) imposing reaction conditions on said reaction mixture, said reaction conditions comprising a temperature in the range of 80° - 250°C, and an atmosphere of inert gas, to form a first product comprising an alcohol by-product and a first polymer having a formula: wherein Y and X are as set forth above, and R 7 through R 10 are R 1 through R 4 and R" through R 14 are each R 1 through R 4 ; (c) removing the alcohol by-product from the reaction mixture; (d) subjecting the first product to second reaction conditions comprising a temperature in the range of 80 - 250°C and a pressure of 0.1 -760 torr to form a second reaction product comprising the first monomer and mixture of a second polymers having the formula of said biodegradable polymer, said mixture of second polymers having a weight average molecular weight of 8,000-60,000. 7. The method of claim 6 wherein said second polymer has a weight average molecular weight of greater than or equal to 10,000 g/mole, and preferably greater than or equal to 20,000 g/mole. 8. The method of claim 6 wherein said first monomer and second monomer of said reaction have a mole ratio of 2.2: 1. 9. The method of claim 6 wherein said inert gas is nitrogen. 10. The method of claim 6 wherein said alcohol by-product is distilled for the reaction mixture. 11. The method of claim 6 wherein said pressure is 0.1 - 10 torr. 12. The method of claim 6 wherein said second reaction conditions comprise a temperature of 185 - 235°C. 13. The method of claim 6 wherein at least one of said first and second reaction conditions include the presence of a catalyst. 14. The method of claim 13 wherein said catalyst is present prior to imposing first reaction conditions. 15. The method of claim 13 wherein said catalyst is selected from the group of catalyst consisting essentially of acid catalysts, Lewis acid catalysts or transition metal catalysts. 16. The method of claim 13 wherein said catalyst is selected from the group of catalysts consisting essentially of para-toluene sulfonic acid, salts and acetates of zinc, and titanium alcoholates. 17. The method of claim 16 wherein said catalyst is selected for the group consisting essentially of zinc chloride, zinc acetate, and titanium tetrabutoxide. 18. The method of claim 6 wherein at least one of said reaction conditions include the presence of a free radical inhibitor. 19. The method of claim 16 wherein said free radical inhibitor is present prior to imposing first reaction conditions. 20. The method of claim 6 wherein said reaction conditions comprise temperatures of 195 - 250oC. 21. The method of claim 6 wherein said first monomer is selected from the group of monomers comprising 1,2 propanediol, 1,3 propanediol, and ethylene glycol. 22. The method of claim 6 wherein said second monomer is diethyl fumarate. 23. The method of claim 6 wherein said first monomer is 1,2 propanediol and said second monomer is diethyl fumarate. 24. The method of claim 23 wherein said first monomer is present in a concentration of 40-60 weight percent and second monomer is present in a concentration of 40-60 weight percent. 25. The method of claim 6 wherein said reaction conditions are imposed in a first flow through reactor having an operating pressure of 0.1 to 760 torr. 26. The method of claim 6 wherein said second reaction conditions are imposed in a second flow-through reactor. 27. The method of claim 26 wherein said second reactor has a temperature which is at least 5°C higher than said first reactor. 28. The method of claim 6 wherein said volatile gases are removed from the second product under removal conditions, said removal conditions comprising a temperature of 180°C - 250 °C and a pressure less than or equal to 10 torr. 29. The method of claim 28 wherein said removal conditions comprise a temperature of 150° - 250 °C and a pressure of 0.1 to 10 torr. 30. The method of claim 28 wherein said removal conditions ar imposed within a falling strand devolatizer. 31. The method of claim 6 wherein said reaction mixture is continuously stirred. 32. The process of claim 6 wherein said first and second monomers which are not incoφorated in said polymer are recycled. 33. An apparatus for making biodegradable polymers represented by the formula set forth below: wherein X is a C 2 -C 3 alkyl or alkenyl, and Y is a C]-C 5 alkyl or alkenyl or a single bond between adjacent carbons, and R 1 , R 2 , R\ R 4 taken independently are hydrogen, or a C,-C 5 alkyl or alkenyl and n is an integer greater than or equal to 1 and consistent with an M n of greater than 3,000 and with a M w of 8,000 to 60,000 g/mole: a first reaction vessel, a second reaction vessel, and a devolatizer assembly, said first reaction vessel for receiving and containing a reaction mixture comprising a first monomer and a second monomer wherein said first monomer is represented by the formula below: Λ' •t *1 - c- H HO " - ft "1 - wherein Y, R 1 , R 2 , R\ R 4 are as described above and said second monomer is represented by the formula: O Q O - c - - < - O - a. wherein X is as described above and R 5 and R 6 taken independent are H, or a C, - C 3 alkyl or alkenyl; said first reaction vessel capable of imposing first reaction conditions on said reaction mixture, said reaction conditions comprising a temperature in the range of 80° - 250 °C, and an atmosphere of inert gas, to form a first reaction product comprising an alcohol by-product and a first product, said first product having a formula as set forth below: π.' a * £ -' (in • < « ' * i < H o -c - y -t -o - - * - - o- -r-c- o t-t said second reaction vessel capable of receiving said first product and imposing second reaction conditions, said second reaction conditions comprising a temperature in the range of 250 °C at a pressure of 0.1 - 720 torr to form a mixture of second product having the formula of said biodegradable polymer and containing excess first monomer, said polymer having a weight average molecular weight of 8,000 - 60,000 g/mole. 34. The apparatus of claim 33 wherein said pressure vacuum is 0.1 - 10 torr. 35. The apparatus of claim 33 wherein said second reaction conditions comprise a temperature of 185 - 235 °C. 36. The apparatus of claim 33 wherein at least one of said first and second reaction conditions include the presence of a catalyst. 37. The apparatus of claim 33 wherein said inert gas is nitrogen. 38. The apparatus of claim 33 wherein said first monomer and second monomer are present in said first reaction mixture in a mole ratio of 2.2: 1. 39. A bioresorbable polymer represented by the formula: 0 0 Rl R (- 0 - C - X a - C - 0 - C - Y - c -)„ R2 3 wherein Y is a C r C 5 divalent paraffinic group or divalent olefinic group or a single bond between adjacent carbons, and R 1 , R 2 , R 3 , R 4 taken independently are hydrogen, or a C-^C s alkyl or alkenyl and Xa is a C 2 - C 3 divalent parafinic group, or a C 2 - C 3 divalent olefinic group, or Xa is a divalent parafinic group represented by the formula: μ «J wherein Q is a single bond between the carbon atoms to which it is adjacent or Q is -CH 2 -, wherein U and W, taken independently are H, or M k Z wherein M is represented by the formula: ' L 2- 1 1 • C - - c_ - / / z_* L^ wherein L 1 , L 2 , L 3 , and L 4 taken independently are H, C,-C 6 alkyl, C,-C 6 haloalkyl, C--C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C,-C 6 thiol, amine, ketone or hydroxy substituted alkyl, or the group represented by the formula - N X R 1 * 0 wherein R 15 and R 16 taken together with the nitrogen are a five to six member ring in which the members consist of carbon, nitrogen, sulfur, or oxygen and the carbon members of the ring are alkyl, or nitrosoalkyl, or hydroxyalkyl, said nitrogens are imides, amines or amides and said sulfurs are sulfonyls or sulphones, and R, 5 and R, 6 taken separately are C,-C 6 alkyl or nitrosoalkyl or hydroxyalkyl or alkoxyalkyl or nitrogen, oxygen or sulfur substitutions thereof and k is an integer of 1 or greater; and Z is H or u or w of Xb wherein Xb is as described with respect to Xa but is not Xa or u or w of Xa if u and w are taken together to form a ring of M k ; n is an integer greater than 1. 40. The bioresorbable polymer of claim 37 wherein said polymer forms a matrix and said polymer further comprising a filler, said filler occupying space within said matrix to alter strength characteristics of said polymer. 41. The bioresorbable polymer of claim 39 wherein said filler provides strength and rigidity to said polymer for use in bone and periodontal repairs. 42. The bioresorbable polymer of claim 41 wherein said filler is selected from the group comprising calcium salts and ground bone products. 43. The bioresorbable polymer of claim 40 wherein said polymer is flexible for use in the repair of soft tissue and as a wound dressing or as a drug delivery device. 44. The bioresorbable polymer of claim 39 wherein said filler is ground up polymer or ground up cartilage. 45. The bioresorbable polymer of claim 39 further comprising a drug. 46. The bioresorbable polymer of claim 45 wherein said drug is an antibiotic, bone growth factors, tissue growth factors. 47. The bioresorbable polymer of claim 39 wherein X is a C 2 divalent parafinic group or a C-, divalent olefinic group, or X is a divalent parafinic group represented by the formula: M H -i - L - - \ I H W wherein Q is a single bond between carbon atoms to which it is adjacent. 48. The bioresorbable polymer of claim 39 wherein L„ ,, L 3 , are H and L 4 is represented by the formula below: ^ l5 49. The bioresorbable polymer of claim 47 wherein R 15 and R 16 , together with the nitrogen to which they are attached are represented by the formula below: . , ^ 50. The bioresorbable polymer of claim 39 wherein said weight average molecular weight is greater than, or equal to 10,000, and preferably greater than 20,000 g/mole. 51. The bioresorbable polymer of claim 40 wherein said polymer has a compression strength of at least 25 MPa. 52. The bioresorbable polymer of claim 40 wherein said polymer has a compression strength of at least 40 MPa. 53. The bioresorbable polymer of claim 40 wherein said polymer has a compressive modulus of at least 300 Mpa. 54. The bioresorbable polymer of claim 39 wherein said polymer has a compressive modulus of at least 800 Mpa. 55. A kit for forming a bioresorbable polymer comprising: a. a polymer represented by the formula set forth below: o 12.1 - c - ' \ *~\ w- <^ wherein X is a C 2 -C 3 divalent paraffinic group or divalent olefinic group, and Y is a C r C 5 divalent paraffinic group or divalent olefinic group or a single bond between adjacent carbons, and R 1 , R 2 , R\ R 4 taken independently are hydrogen, or a C,-C 5 alkyl or alkenyl and n is an integer consistent with the weight average molecular weight of said polymer from 20 to 120, said polymer having a weight average molecular weight of 8,000-60,000; b. a monomer represented by the formula: A. t. I c C / \ C wherein L 1 , L 2 , L 3 , L 4 taken independently are H, C,-C 6 alkyl, C,-C 6 haloalkyl, C r C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C,-C 6 thiol or amine substituted alkyl, or the group represented by the formula - R> wherein R I5 and R 16 taken together with the N are a five to six member ring in which the members consist of carbon, nitrogen, sulfur, or oxygen and the carbon members of the ring are alkyl, or nitrosoalkyl, or hydroxyalkyl or alkoxyalkyl and said nitrogens are imides, amines or amides and said sulfurs are sulfonyls or sulphones, and wherein R ]5 and R 16 taken separately are C,-C 6 alkyl or, nitrosoalkyl or hydroxyalkyl or nitrogen, oxygen or sulfur substitutions thereof. 56. The kit of claim 53 further comprising means for initiating a free radial polymerization reaction. 57. The kit of claim 56 wherein said means for initiating a free polymerization reaction is a peroxide. 58. The kit of claim 55 further comprising a polymerization inhibitor. 59. The kit of claim 57 wherein said polymerization inhibitor is a quinone or hydroquinone. 60. The kit of claims 55-59 further comprising a polymerization activator. 61. The kit of claim 60 wherein said polymerization activator is an amine, sulfide or phosphine. 62. The kit of claim 61 wherein said polymerization activator is N,N dimethyl-p- toluidine. 63. The kit of claim 55 further comprising a filler. 64. The kit of claim 63 wherein said filler is selected from the group consisting of calcium salts, ground bone products and polymers. 65. The kit of claim 55 wherein said reactive polymer is a powder and said monomer is a liquid capable of dissolving or partially dissolving said polymer. 66. The kit of claim 65 wherein said liquid and powder have weights defining a powder/liquid ratio of 2/1 to 15/1. 67. A method of making a bioresorbable polymer comprising the steps of: a. forming an admixture with a reactive polymer and a monomer, said reactive polymer represented by the formula set forth below: wherein X is a C 2 -C 3 divalent paraffinic group or divalent olefinic group, and Y is a C,-C 5 divalent paraffinic group or divalent olefinic group or a single bond between adjacent carbons, and R\ R 2 , R\ R 4 taken independently are hydrogen, or a C,-C 5 alkyl or alkenyl and n is an integer equal to or greater than 1 consistent with the weight average molecular weight of said polymer of 8,000-60,000,and said monomer is represented by the formula: wherein L 1 , L 2 , L 3 , and L 4 taken independently are H, C,-C 6 alkyl, C,-C 6 haloalkyl, C,-C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C,-C 6 thiol, amine, ketone or hydroxyl substituted alkyl, or the group represented by the formula n ,^. X ^ '^ wherein R, 5 and R, 6 taken together with the nitrogen are a five to six member ring in which the members consist of carbon, nitrogen, sulfur, or oxygen and the carbon members of the ring are alkyl, or nitrosoalkyl, or hydroxyalkyl, said nitrogens are imides, amines or amides and said sulfurs are sulfonyls or sulphones, and R I5 and R )6 taken separately are C,-C 6 alkyl, C,-C 6 nitrosoalkyl, C-- hydroxyalkyl, C,-C 6 alkoxyalkyl, or nitrogen, oxygen or sulfur substitutions thereof; b. initiating a free radical polymerization reaction to form a product/product having the formula: o Q , fc «χ H - o -c- ^- - o - - a - - where Xa is consistent with X or Xa is a divalent parafinic group represented by the formula: 1 I H v wherein Q is a single bond between the carbon atoms to which it is adjacent or Q is -CH 2 -, wherein U and W, taken independently are H. or M k Z wherein M is represented by the formula: J ι (- 4 - - ) wherein L 1 , L 2 , L 3 , and L 4 taken independently are H, C,-C 6 alkyl, C,-C 6 haloalkyl, C,-C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C,-C 6 thiol, amine, ketone or hydroxy substituted alkyl, or the group represented by the formula - N ---R I 1 f 6 *, wherein R 15 and R 16 taken together with the nitrogen are a five to six member ring in which the members consist of carbon, nitrogen, sulfur, or oxygen and the carbon members of the ring are alkyl, or nitrosoalkyl, or hydroxyalkyl, said nitrogens are imides, amines or amides and said sulfurs are sulfonyls or sulphones, and R, 5 and R 16 taken separately are C r C 6 alkyl, C,-C 6 nitrosoalkyl, C,-C 6 hydroxyalkyl,C r C 6 alkoxyalkyl, or nitrogen, oxygen or sulfur substitutions thereof and k is an integer of 1 or greater; and Z is H or u or w of Xb wherein Xb is as described with respect to Xa but is not Xa or u or w of Xa if u and w are taken together. 68. A method of making a bioresorbable material comprising the steps of: a. forming an admixture with a polymer and a monomer, said polymer represented by the formula set forth below: © o 1 < n-' ftv « → ■ L O - c- x. c - o - c 1 - v - wherein X is a C 2 -C 3 divalent paraffinic group, and Y is a C,-C 5 divalent paraffinic group or divalent olefinic group or a single bond between adjacent carbons, and R 1 , R 2 , R 3 , R 4 taken independently are hydrogen, or a C Cj alkyl or alkenyl and n is an integer equal to or greater than 1 consistent with the weight average molecular weight of said polymer of 8,000-60,000,and said monomer is represented by the formula: t c 1 - c ' . wherein L 1 , L 2 , L 3 , and L 4 taken independently are H, C,-C 6 alkyl, C,-C 6 haloalkyl, C,-C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C,-C 6 thiol, amine, ketone or hydroxy substituted alkyl, or the group represented by the formula: (\ ts ~ — * " wherein R 15 and R 16 taken together with the nitrogen are a five to six member ring in which the members consist of carbon, nitrogen, sulfur, or oxygen and the carbon members of the ring are alkyl, or nitrosoalkyl, or hydroxyalkyl, said nitrogens are imides, amines or amides and said sulfurs are sulfonyls or sulphones, and R 15 and R 16 taken separately are C r C 6 alkyl, C,-C 6 nitrosoalkyl, C--C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, or nitrogen, oxygen or sulfur substitutions thereof; b. initiating a free radical polymerization reaction to form a second polymer/product having the formula M k wherein M is represented by the formula: ) wherein L 1 , L 2 , L 3 , and L 4 taken independently are H, C,-C 6 alkyl, C,-C 6 haloalkyl, C r C 6 hydroxyalkyl, C,-C 6 alkoxyalkyl, C r C 6 thiol, amine, ketone or hydroxy substituted alkyl, or the group represented by the formula wherein R )5 and R 16 taken together with the nitrogen are a five to six member ring in which the members consist of carbon, nitrogen, sulfur, or oxygen and the carbon members of the ring are alkyl, or nitrosoalkyl, or hydroxyalkyl, said nitrogens are imides, amines or amides and said sulfurs are sulfonyls or sulphones, and R, 5 and R 16 taken separately are C,-C 6 alkyl, C r C 6 nitrosoalkyl, C,-C 6 hydroxyalkyl,C,-C 6 alkoxyalkyl, or nitrogen, oxygen or sulfur substitutions thereof and k is an integer of 1 or greater consistent with a weight average molecular weight of 6,000 to 500,000.

Inventors: CAYWOOD GRETCHEN A, KHARAS GREGORY B, CAYWOOD, GRETCHEN, A., KHARAS, GREGORY, B.
Applicants: DYNAGEN INC, DYNAGEN, INC.
Application year: 1996
Main classification: C08G63
IPC codes: C08F283, C08G63, C08L67, C09J4, C09J167