WO2009046418A1

WO2009046418A1 - Chemical vapor deposition (cvd) polymerization onto nucleophilic surfaces

Info

Publication number: WO2009046418A1
Application number: PCT/US2008/078937
Authority: WO
Inventors: Jody Redepenning
Original assignee: Board Of Regents Of The University Of Nebraska
Priority date: 2007-10-04
Filing date: 2008-10-06
Publication date: 2009-04-09

Abstract

A method of preparing a composite comprising a bioabsorbable polymer or copolymer of one or more lactone monomers and a substrate, includes initiating polymerization or copolymerization by ring-opening of the lactone. The initiation of polymerization or copolymerization of the lactone may bε conducted by a chemical vapor deposition method. The substrate may be positioned within a chemical vapor deposition reactor and exposed to a vapor of the lactone monomers under conditions effective to initiate ring-opening polymerization or copolymerization of the lactone by the substrate and deposition of the polymer or copolymer on the substrate.

Description

PCT APPLICATION FOR

CHEMICAL VAPOR DEPOSITION (CVD) POLYMERIZATION ONTO NUCLEOPHILIC SURFACES

Inventor:

Jody Redepenning

920 Manchester Drive

Lincoln, NE 68528

CHEMICAL VAPOR DEPOSITION (CVD) POLYMERIZATION ONTO NUCLEOPHILIC SURFACES

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. Provisional Patent

Application No. 60/977,503, filed October 4, 2007, entitled CHEMICAL VAPOR DEPOSITION (CVD) POLYMERIZATION ONTO NUCLEOPHILIC SURFACES, which document is hereby incorporated by reference to the ex lent permitted by law.

BACKGROUND OFTHE INVENTION

[0002] The successful design of a prosthetic device to replace or repair skeletal tissue requires knowledge of the structure and mechanical properties of bone and an understanding of the means by which such prostheses become incorporated into the body. This information can then be used to define desirable characteristics of the implant to ensure that the graft functions in a manner comparable to organic tissue.

[0003] The mechanical properties of bone are related to the internal organization of the material, as reviewed by Roesler, H., 'The History of Some Fundamental Concepts in Bone Biomechanics," Journal of Biomechanics, 20, 1025-34 (1987). Cortical bone is classified as a material of less than 30% porosity, as described by Keaveny, T. M. and W. C. Hayes, "Mechanical Properties of Cortical and Trabecular Bone*" in Bone Volume 7: Bone Growth-B^ B. K. Hall, ed,, Boca Raton: CRC Press, 285-344 (1992), as a "solid containing a series of voids (Haversian canals, Volkmann's canals, lacunae and canaltculi). The porosity of cortical bone tissue (typically 10%) is primarily a function of the density of these voids." In contrast, cancellous/trabecular bone is "a network of small, interconnected plates and rods of individual trabeculae with relatively large spaces between the trabecule." Trabecular bone has a porosity of 50-90% which is a function of the space between the trabeculae.

[0004] The material properties of bone are based on determinations of the elastic modulus, compressive arid tensile strengths. As a general rule,, bone is stronger in compression than in tension and cortical is stronger than trabecular bone. Ranges of reported elastic modulus have been from 10 MPa to 25 GPa (10 MPa to 2 GPa for cancellous bone; 4 to 25 GPa far cortical and cancellous bone); compressive strength between 40 and 280 MPa (40 to 280 MPa for cancellous bone; 138 So 193 MPa for cortical bone); and tensile strength between 3.5 MPa and 150 MPa (3.5 to 150 MPa for cancellous bone; 69 to 133 MPa for cortical bone) (Friedlaender and Goldberg, Bone and Cartilage Allografts Park Ridge: American Academy of Orthopedic Surgeons 1991; Jarcho, "Calcium Phosphate Ceramics as Hard Tissue Prosthetics" Clin. Orthopedics and Related Research 157, 259-278 1981; Gibson, "The Mechanical Behavior of Cancellous Bone" J, Biomcchan. 18(5), 317-328 1985; Keaveny and Hayes 1992).

[0005] Mechanisms by which bone may fail include brittle fracture from impact loading and fatigue from constant or cyclic stress. Stresses may act in tension, compression, or shear along one or more of the axes of the bone- A synthetic bone substitute must resist failure by any of these stresses at their physiological levels. A factor of safety on the strength of the implant may ensure that the implant will be structurally sound when subject to hyperpliysiofogicai stresses.

[0006] A graft may be necessary when bone fails and does not repair itself in the normal amount of time or when bone loss occurs through fracture or tumor. Bone grafts must serve a dual function: to provide mechanical stability and to be a source of osteogenesis. Since skeletal injuries are repaired by the regeneration of bone rather than by the formation of scar tissue, grafting is a viable means of promoting healing of osseous defects, as reviewed by Friediaeadef, G. £., "'Current Concepts Review: Bone Grafts," Journal of Bone and Joint Surgery, 69A(S), 786-790 (1987). Osteoinduction and osteoconduction are two mechanisms by which a graft may stimulate the growth of new bone, ϊn the former case, inductive signals of little- understood nature lead to the plienotypic conversion of connective Ussuc cells to bone cells. In the latter, the implant: provides a scaffold for bony ingrowth.

[0007] The bone remodeling cycle is a continuous event involving the resorption of pre-existing bone by osteoclasts and the formation of new bone by the work of osteoblasts. Normally, these two phases are synchronous and bone mass remains constant. However, the processes become uncoupled when bone defects heal and grafts are incorporated. Osteoclasts resorb the graft, a process which may take months. More porous grafts revascularize more quickly and graft resorption is more complete; After graft has been resorbed, bone formation begins. Bone mass and mechanical strength return to near normal.

[0008] Present methods for the repair of bony defects include grafts of organic and synthetic construction. Three types of organic grafts are commonly used: autografts, allografts, and xenografts. An autograft is tissue transplanted from one site to another In the patient. The benefits of using the patient's tissue are that the graft will not evoke a strong immune response and that the material is vascularized, which allows for speedy incoiporation. However, using an autograft requires a second surgery, which increases the risk of infection and introduces additional weakness at the harvest site. Further, bone available for grafting may be removed from a limited number of site, for example, the fibula, ribs and iliac crest. An allograft is tissue taken from a different organism of the same species, and a xenograft from an organism of a different species. The latter types of tissue are readily available in larger quantities than autografts, but genetic differences between the donor and recipient may lead to rejection of the graft.

[0009] Synthetic implants may obviate many of the problems associated with organic grafts. Further, synthetics can be produced in a variety of stock shapes and sizes, enabling the surgeon to select implants as his needs dictate, as described by Coombes, A. D. A. and J. D. Heckjnan, "Gel Casting of Resorbable Polymers: Processing and Applications," Biomaterials, 13(4), 217-224 (1992). Metals, calcium phosphate ceramics and polymers have all been used in grafting applications.

[0010] Calcium phosphate ceramics are used as implants in the repair of bone defects because these materials are non-toxic, nott-immunogenic, and are composed of calcium and phosphate ions, the main constituents of bone_r in an apatitic structure (Jarcho, 1981; Frame, J. W., "Hydroxyapatite as a biomaterial for alveolar ridge augmentation," M. J. Oral Maxillofacial Surgery, 16, 642-55 (1987); Parsons, et al. "Osteoconductive Composite Grouts for Orthopedic Use," Annals N.Y. Academy of Sciences, 523, 190-207 (1988)). Both tricalehim phosphate (TCP) tCa₃(PO₄)₂ ] and hydroxyapatite (HA) [Ca₁₀(PO₄)₆(OH₂] have been widely studied for this reason. Calcium phosphate implants are osteoinductive;, and have the apparent ability to become directly bonded to bone, as reported by Jarcho 1981, As a result, a strong bone-implant interface is created.

[0011] Calcium phosphate ceramics have a degree of bioresorbability which is governed by their chemistry and material structure, High density HA and TCP implants exhibit little resorption, while porous ones are more easily broken down by dissolution in body Ωuids and resorbed by phagocytosis. However, TCP degrades mure quickly than HA structures of the same porosity in vitro. In fact, FTA is relatively insoluble in aqueous environments. The use of calcium phosphates in bone grafting has been investigated because of the chemical similarities between the ceramics and the mineral matrix found in the teeth and bones of vertebrates. This characteristic of the material makes it a good candidate as a source of osteogenesis. However, the mechanical properties of calcium phosphate ceramics make them ill-suited to serve as a structural element. Ceramics are brittle and have low resistance to impact loading.

[0012] Biodegradable polymers are used in medicine as suture and pins for fracture fixation. These materials are well suited to implantation as they can serve as a temporary scaffold to be replaced by host tissue, degrade by hydrolysis to non-toxic products, and be excreted, as described by Kulkami, et al, J. Biomedical Materials Research, 5, 169-81 (1971); Hotlinger, J. O. and G. C. Battistoπc, "Biodegradable Bone Repair Materials." Clinical Orthopedics and Related Research, 207, 290-305 (1986).

[0013] Four polymers widely used in medical applications are ρoly(paradioxaπone)

(PDS), poly(lactie acid) (PLA), poly(glycolic acid) (PGA), and PLAGA copolymers. Copolynierization enables modulation of the degradation time of the material By changing the ratios of crystalline to amorphous polymers during polymeπzatioru properties of the resulting material can be altered to suit the needs of the application. For example, PLA is crystalline and a higher PLA content in a PLAGA copolymer results in a longer degradation time, a characteristic which may be desirable if a bone defect requires structural support for an extended period of time. Conversely, a short degradation time may be desirable if ingrowth of new tissue occurs quickly and new cells need space to pro Ii ferate within the implant, [0014] Coombes and Heckman 1992 and HoHinger 1983 have attempted to create poly(lactide-co-glycolide) [(C₃H₄O₂)x(C₂H₂O₂)_y] implant as bone substitute. HoHinger used a PLAGA of high inherent viscosity (0«92 dl/g) prepared by a solvent-non-solvent casting method. Plugs of this material were implanted in tibial defects of Walter Reed rats, and humeral defects were created as control sites in which no polymer was implanted. Examination of the defects after sacrifice of the animals at 7, 14, .21 , 28 and 42 days suggested that polymer may aid in osteoinduction in the early bone repair process. However, by 42 days, the rate of repair was equivalent in controls and experimental defect sites. Coombes and Heckman described a gel casting method for producing a three-dimensional PLAGA matrix. Success of this method, i.e., creation of a strong, rubbery gel, was dependent upon high inherent viscosity of the polymer (0.76-0.79 dl/g). Material properties of the polymer matrix through a degradation cycle were the focus of the research. The modulus of the PLAGA implant before degradation was 130MPa, equivalent to that of cancellous bone. After eight weeks degradation in phosphate buffered saline (PBS), the strength of the material had deteriorated significantly. Moreover, the microporous structure (pores 205 .mu.m in diameter) has been shown io be too small to permit the ingrowth of cells, as reported by Friedfaender and Goldberg 1991 and Jarcho 1981. From a mechanical as well as a biological standpoint, this matrix is not ideal for use as a substitute bone graft material.

[0015] Other workers in this field have formed composites of various forms of hydroxyapatite and numerous polymers or other supplementary materials such as, e.g., collagen, glycogen, cnitin, celluloses, starch, keratins, silk, nucleic acids, demtneralized bone matrix, derivativized hyaluronic acid, polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, and copolymers thereof. In particular, polyesters of .alpha.-hydroxycarboxylic acids, such as poly(L-lactide) (PLLA), poly(D.L-lactide) (PDLLA),. polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly^D.L-lactide-co-trimethylene carbonate), and polyhydroxybutyrate (PHB), and polyanhydrides, such as poly(anhydride-co-imide) and co-polymers thereof are known to bioerode and are suitable for use in the present invention. In addition, bioacfive glass compositions, such as compositions including S1O2, Na^O, CaO, PiOs, AI₂O3 and/or CaFs, maybe used. Other useful bioerødible polymers may include polysaccharides, peptides and fatty acids.

[0016] Bioerodible polymers are advantageously used in the preparation of bioresorbable hardware, such as but not limited to iπteπnedulary nails, pins, screws, plates and anchors for implantation at a bone site, in preferred bioresorbable hardware embodiments, the supplementary material itself is bioresorbable and is added to the PCA calcium phosphate in particulate or fiber form at volume fractions of 1 -50% and preferably, 1 -20 wt %. In some preferred embodiments, the bioresorbable fiber is in the form of whiskers which interact with calcium phosphates according to the principles of composite design and fabrication known in the art. Such hardware may be formed by pressing a powder particulate mixture of the PCA calcium phosphate and polymer. In one embodiment, a PCA calcium phosphate matrix is reinforced with PLLA fibers, using PLLA fibers similar to those described by Tormala el al., which is incorporated herein by reference, for the fabrication of biodegradable self reinforcing composites (Clin. Mater. 10:29-34 (1992)).

[0017] The implantable bioceramic composite may be prepared as a paste by addition of a fluid, such as water or a physiological fluid, to a mixture of a PCA calcium phosphate and a supplemental material. Alternatively, a mixture of the supplementary material with hydrated precursor powders to the PCA calcium phosphate can be prepared as a paste or putty, [n cases where the supplementary material is to be dispersed within or reacted with a PCA calcium phosphate matrix, water maybe added to one of the precursor calcium phosphates to form a hydrated precursor paste, the resulting paste is mixed with the supplementary material, and the second calcium phosphate source is then added. Alternatively, the calcium phosphate sources which make up the PCA calcium phosphate precursor powder may be premixed, water may then be added and then the supplementary material is added. In those cases where it is desirable to have the supplementary material serve as the matrix, the fully hardened PCA calcium phosphate will be prepared in the desired form which will most often be of controlled particle size, and added directly to the matrix forming reaction (e.g., to gelling collagen). These materials may then be introduced into molds or be otherwise formed into the desired shapes and hardened at temperatures ranging from about 35-100° C. A particularly useful approach is to form the composite precursor paste into the approximate shape or size and then harden the material in a mαsst environment at 37° C, The hardened composite may then be precisely milled or machined to the desired shape for use in the surgical setting. The amount of particular PCA caicium phosphate to be incorporated into the supplemental material matrix will most often be determined empirically by testing the physical properties of the hardened composite according to the standards known to the art.

[0018] It has been proposed to formulate composites comprising a bioabsorbable polymer or copolymer of a lactone monomer or mixture thereof and a ceramic, the composite having been prepared by the ceramic initiated ring-opening polymerization or co polymerization of the lactone monomer, wherein the ceramic is an apatitic calcium phosphate or an osteoinductive, bioabsorbable derivative thereof.

[0019] Composites comprising a porous, inorganic bone matrix derived from hone tissue and a compatible, bioabsorbable polymer or copolymer of a lactone monomer or mixture thereof have also been proposed wherein the composite is preferably prepared by the apatitic calcium phosphate, or an osteoinductive, bioabsorbable derivative thereof, initiated ring-opening polymerization or copolymerization of the lactone monomer within the pores of the porous inorganic bone matrix.

[0020] It is an object of the present invention to provide a novel method for preparing composites such as those described above.

BRIEF SUMMARY OF THE INVENTION

[0021 ] in its broadest embodiment, the invention relates to the chemical vapor deposition (CVD) polymerization or copoiyrnsrization of monomers onto nucleophiiic substrates that initiate or catalyze the polymerization of the monomers to form an adherent surface layer of the polymer or copolymer on the substrate A specific example of the method of the invention comprises the polymerization of a cyclic lactone such as L-lactide onto a nucleophilic substrate such as hydroxyapatite. The mechanisms of chemical vapor deposition methods are, of course, well known in the art ["Chemical Vapor Polymerization: The Growth and Properties of ParySene Thin Films," J. B. Forttn and T.-H. Lu, Kluwer Academic Publishers, New York, 2004]. [0022] Generally speaking, the method of the invention involves heating the monomer (e.g., L-lactide) under vacuum in the presence of the substrate (e.g., hydroxyapatite), In contrast, to earlier procedures for preparing such composites wherein the substrate and the liquid monomer are placed in direct contact with each other, in the method of the present invention, the substrate is in contact only with the gas phase of the monomer. The method of the invention forces gas phase monomer to collide with the nucleophilic surface. Upon collision, the monomer can either react with the substrate or remain in the gas phase. After the reaction is initiated, thin films of low molecular weight polymer are formed on the substrate surfaces exposed to the chemical vapor. As the reaction proceeds for longer times, both the thickness of the polymer coating and the molecular weight generally increase,

DETAILED DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

[0023] The method of the invention is particularly efficacious for porous samples wherein it is desired to provide a thin coating of polymer on the surface, but not to fit i the pores thereof. Because liquid monomer does not come in contact with the surface to be coated, there is no need to remove excess monomer from the surfaces of the final product. If porous samples are placed in contact with liquid monomer, the monomer has a tendency to stay within the pores due to capillary forces. In the CVD polymerization, method of the invention, the small amount of excess monomer remaining in the gas phase upon completion of the process is conveniently trapped in the monomer reservoir by cooling the reservoir before cooling the coated sample, As a result, the gas-phase monomer condenses into the monomer reservoir, not onto the sample,

[0024] However, it will be understood by those skilled in the art that the method of the invention is also applicable where it is desired to form coatings of the polymer within the pores of the substrate, as is demonstrated below. [0025] The lactone monomers that may be polymerized or copolymcrized according to the method of the invention include those having the formula:

wherein: X == nil (i.e., resulting in a single bond connecting (C)_v and (C)_-4), -0-, or !

-R.4 may be the same or different and are H₅ C1-C₁6 straight or branched chain alkyl or HOCH₂-.

[0026] Suitable lactone monomers that may be employed in the practice of the invention include any that form abioabsorbable polymer or copolymer such as, but not limited to caprolactone, t-butyl caprolactone, zeta-enantholactone, deltavalerolactones, the monoalkyl- dclta-valerolactones, e.g., the monomethyl-, monoethyl-, monohexyl-deltavalcroiactoncs, and the like; the nonalkyl, dialkyl, and trialkyl-epsilon-caprotactones, e g., the monomethyl-, monoethyl-, monohexyl-, dimethyl-, di-n-propyl-, di-n-hexyl-, trimethyl-, trielhyl-, tri- n-epsilon caprolactones, 5-nonyl-oxepan-2-one, 4,4,6- or 4,6,6-trimethyl-oxepan-2-one, 5-hydroxyτnethyloxepan-2-one_s and the like; beta-lactones, e.g., beta-propiolactone. beta-butyrolactone gamma-lactones, e.g., gammabutyrolactone or pivalolactone, dilactones, e.g., lactide, dilactides, glycoHdes^ e.g., tetramethyl glycolidcs, alkyl derivatives thereof and the like, ketodioxanones, e g> l ,4-dioxan-2-one, i,5-dioxepan-2-one, and the like. The lactones can consist of the optically pure isomers or two or more optically different isomers or can consist of mixtures of isomers. [0027] Any suitable substrate may be coated according to the CVD method described herein; e.g., those described herein below, as well as any nucleophilic surface that will initiate the cyclic lactone polymerization (metal oxides such as magnesium oxide), hydroxyapatite surfaces (including coralline, coral, bone, trabecular bone and bone that has been treated to convert at least apart of the surface thereof to calcium carbonate), BioGlass, and nucleophilic surface of biological sources of CaCO3, including for example nacre from gastropods (such as snails and abalone), cephalopoda (such as nacre from nautilus or cutilebone from cuttlefish), bivalve nacre (from scallops, clams, oysters or mussels), lobster shells, crab shells, and chicken egg shells, it will be understood by those skilled in the art that any of the nucleophilic surfaces described herein may also comprise derivatives wherein some fraction, of the native carbonate has been OH~exchanged with oxide, alkoxide or alkanoic acid, such as, but not limited to alkoxide, e.g., methoxide or ethoxidc or alkanoic acid such as oeianoic acid to enhance initiation of the CVD polymerization process, ϊn some embodiments, the substrate may be selected from one or more of hydroxyapatite, hydroxyapatite with nυcleophϋic substitutions, such as oxyapatitc, fluoride, and alkoxides, hydroxyapatite with nucleophilic adorbates, biological sources of hydroxyapatite, including mammalian bone and coralline hyrdroxyapatite, nucleophilic glasses or ceramics such as Bioglass(R), nucleophilic oxides including, but not limited to: LiO₅ MgO₁ CaO, ZnO, and AJ2O3, nucleophilic hydroxides including, but not limited to: JJOH. Mg(0H)2, Ca(0H)2, and Zn(OH)2. It should also be noted that a variety of non-nucleophilic substitutions could be mad to hydroxyapatite and that the surface would still initiate polymerization of cyclic iaciones from the gas phase. Such substitutions could include alkali metal ions (such as iilhium ions, sodium ions, and potassium ions), alkaline earth ions (such as magnesium Ions, strontium ions, and barium ions), transitions rnetal ions such as ferric ions, halide ions

(such as chloride, bromide and iodide), nitrate, sulfate, carbonate, silicate, and borates. Other non-nucleophilic substitutions may be present without preventing the substrate from effectively enabling the ring opening polymerization. [0028] Tiie rate of the CVD polymerization reaction is controlled by, inter alia, temperature. At least two mechanisms are believed to be involved. First, the vapor pressure of the monomer, i.e., the concentration of the monomer in the gas phase, is controlled by the temperature. The relationship between the vapor pressure of the monomer and the temperature is generally described by the well-known Clausius-ClapeyroB equation. Briefly, the vapor pressure of the gaseous monomer increases as the temperature increases. As the vapor pressure of the monomer increases, the number of collisions between the monomer and the substrate increase.

[0029] As is true for many chemical reactions, the rate of the CVD polymerization increases with temperature because at high temperatures molecules accelerate at a faster rate from the reactant, through the transition state, and then to product. Generally speaking, the influence of temperature on reaction rate is described by the well-known Arrhenius equation.

[0030] It will be understood by those skilled in the art that, although it is preferred to carry out the method of lhe invention under "vacuum", that term is not intended to imply or mandate that an "absolute vacuum" is required or even that a vacuum is required at all. The method may also be conducted, for example, in an environment containing an inert gas. The presence of an inert gas would not disable the CVD process or the reaction mechanism; although, it would probably influence mass transfer of the monomer hi the gas phase, and it would change the mean free path thereof It is far easier to carry out the reaction by sealing the vessel "under so-called vacuum" and then warming the entire vessel up to a point where the vapor pressure of the monomer is large enough to make the reaction proceed at a reasonable rale. Carrying out the reaction in the presence of an inert gas may alter the resulting coating morphology and the rate of polymerization might well be somewhat different. Moreover, the rate of reaction would almost certainly be slower in the presence of an inert gas; depending, of course, on the amount of inert gas present.

[0031] Figure 1 shows a simple reaction vessel that can be used to perform the CVD polymerization of L-lactide onto hydroxyapatite. In this manifestation the reaction vessel is a glass tube that is ultimately sealed while the contents are under vacuum just prior to initiating the process. In a typical reaction L-lactide is place in the bottom of the glass tube containing a constriction. The sample to be coated via CVD polymerization is then added to the top of the glass tube, but the constriction in the tube prevents the sample from coming in contact with the solid L-lactide at the bottom of the vessel. The glass tube is then sealed under vacuum. The entire reaction vessel is then introduced into a convection oven that maintains the vessel (and its contents) at a constant temperature. For certain applications it might be desirable to ramp the temperature. The temperature at which the reaction is performed is often above the melting temperature of the monomer, but the reaction is not limited thereto. Temperatures below the melting point may also be used.

[0032] The reaction is often run isothermally so that the vessel, the liquid (or solid) monomer, the sample, and the gas phase monomer moleeiiles are nominally at the same temperature. The sample to be coated may, if desired, be held at a temperature higher than that of the monomer, If the temperature of the sample is lower than that of the monomer source, condensation of monomer may occur on the sample. When this occurs, the reaction is no longer a CVD procedure, but involves a physical deposition thai may be followed by ring opening events that are the same as those described above, One skilled in the art will recognize that a variety of reaction vessel dimensions and sample configurations will produce CVD polymerizations in a manner that is consistent with the CVD polymerizations produced using the configuration shown in Figure I .

[0033] Biomet, Inc. markets ®Pro Osteon, a coralline hydraxyapatite that resembles the porous structure of trabecular bone. Pro Osteon, which is produced by converting a fraction of the calcium carbonate in goniopora coral to hydroxyapatite, is utilized as a substrate in the following examples to investigate the parameters necessary to control the CVD polymerization of L-lactide onto a porous surface. It will be understood, however, that the method of the invention is applicable to the CVD coating of any suitable porous surface. Figure 2 shows a scanning electron micrograph (SEM) of as received coralline hydroxyapatite. Figure 3 shows coralline hydroxyapatite after a thin coat of poly-L-lactide (PLLA) has been applied using the CVD polymerization method of the invention. Note that a relatively thin, but uniform coating of PLLA has been successfully applied by the method of the invention to this highly irregular substrate.

[0034] The polymerization occurs within and throughout the macroscopic pores of the coralline hydroxyapatite because these pores are large compared to the mean free path of the gas phase monomer. In other words, the pores of the coralline hydroxyapatite are filled with gas phase monomer during the course of the reaction. The concentration of monomer in ihe gas phase is far lower than what is observed for liquid phase reactions and reactions from a melt, but the concentration in the gas phase is high enough to make the CVD polymerization viable. EXAMPLE i provides additional details for one set of reaction conditions that are sufficient to execute CVD polymerizations of L-lactide onto coralline hydroxy apatite.

[0035] EXAMPLE 2 shows that the rate at which coralline hydroxyapatite can be coated with PLLA (by CVD polymerization) can be accelerated by heating the coralline hydroxyapatite to a temperature that is sufficient to convert a fraction of any residual calcium carbonate to calcium oxide. The resulting mixture of hydroxyapatite, calcium oxϊde_r and residual calcium carbonate (in those cases where the conversion of calcium carbonate to calcium oxide is not driven to completion) serves as an effective nucleophilic surface for the CVD polymerization of L-lactide.

[0036] EXAMPLE 3 shows that goniopora coral can be dried at 400 C and then coated with PLLA (via CVD polymerization) without being converted to hydroxyapatite, as is done, for example, to produce Pro Osteon. Although pure calcium carbonate is not a good nucleophilic surface for the polymerization of L-lactide, and although calcium carbonate is, by far, the predominant inorganic constituent in goniopora coral, it was found that goniopora coral is an effective heterogeneous initiator for the polymerization of L-lactide. The reasons it is effective are not presently clear, One possible reason is that goniopora coral, once it is dried, naturally contains a nucIcophiJc that is present at concentrations sufficient to initiate the polymerization at a rate that is useful. A possible alternative is that approved procedures for isolating and processing goniopora corai introduce an effective nucleophile.

[0037] EXAMPLE 4 demonstrates that goniopora coral cars be thermally processed at elevated temperatures so that it can be coated rapidly with PLLA via the CVD polymerization method of the invention. The process (described in more detail below) involves heating the goniopora coraf to a temperature sufficient to drive off carbon dioxide and convert some of the calcium carbonate to calcium oxide, The resulting oxide is a very strong nucleophile that is highly effective in initiating the desired ring opening polymerizations, [0038] EXAMPLE 5 shows that the CVD polymerization of cyclic lactones is not limited to samples of goniopora coral or to samples derived from goruopora coral. EXAMPLE 5 describes conditions that are efficacious for the CVD polymerization of L-Iactide into trabecular (porous) bone derived from bovine femurs.

[0039] One skilled in the art will recognize that the CVD polymerizations we describe here are not limited to hydroxyapatite or to L-lactide. Other cyclic lactones [e.g., racemic lactide, glycolide, dioxanone and ε-eaprolactøne] will also react via lhis mechanism, as will other πυcleophi Hc surfaces.

EXAMPLE 1

CVD Polymerization of PLLA onto dried coralline hydroxyapatite 500R

[0040] Cylindrical rods of coralline hydroxyapatite (6 mm diameter by 12 mm length) were heated for approximately two hours at 400° C to remove residual water. The samples were then cooled to room temperature under vacuum in a desiccator. In an inert atmosphere box under nitrogen, approximately 0,1 to 0,5 g of L~lactidc was placed in the bottom of c.a. S mm diameter glass tubes. The coralline hydroxyapatite was supported inside the tube atop a constriction in the wall of the tube (See Figure 1.) This constriction prevented direct contact between the coralline hydroxyapatite samples, which remained above the constriction, and the solid (or liquid) L-lactide below the constriction in the bottom of the tube The tubes were sealed under vacuum and then heated at temperatures that typically ranged from 75° C to 180° C for periods that typically ranged from 1 day to 10 days. At the end of the reaction period the samples were cooied to room temperature and then opened to give samples of coralline hydroxyapatite that were coated with poly-L-!actide, An SEM image of a coralline hydroxyapatite sample before it was coated with PLLA is shown in Figure 2. An SEM image of a coralline hydroxyapatite sample after it is coated with PLLA is shown in Figure 3. CVD polymerization of PLLA onto the sample of coralline hydroxyapatite sample shown in Figure 3 was conducted at 166° C until the mass increase due to PLLA was approximately 40% of that for the original sample. These conditions produced the relatively ihin, but uniform coating of PLLA that is evident in Figure 3. The molecular weight of the polymer deposited under these conditions was 7300. Generally speaking, molecular weights were found to increase at lower ] deposition temperatures, and when the % mass increase due to PLLA is increased. EXAMPLE 2

CVD Polymerization of PLLA onto coralline hvdroxyapatite for which a fraction of the residual CaCO₃ is converted to CaO

[0041 ] The calcium carbonate that may be fo und in cαrall ine hydroxyapatite is a weak nucleophile that is not an efficacious initiator of L-lactide polymerization. CaO is a very strong nucleophile that readily initiates the ring opening polymerization of L-lactide to PLLA. Thermal processing of calcium carbonate can be used to convert it to CaO. At 600° C in air, the calcium carbonate in coralline hydroxyapatite is slowly converted to calcium oxide. By controlling the amount of time that coralline hydroxyapatite is subjected to 600° C in air, the amount of calcium oxide that is produced can be controlled. Consequently, thermal processing can be used to increase the number of sites in coralline hydroxyapatite that can initiate L-lactide polymerization. A specific example is described below.

[ 0042 ] A cylindrical rod of coralline hydroxyapatite (6 mm diameter by 12 mm length, 0.277 g) was heated to 600° C for a period of approximately 68 hours to remove deleterious water and to convert the majority of the CaCO₃ to CaO. At the end of this time the sample, which weighed 0.169 g,, was removed from the heating oven and allowed to cool in a desiccator under vacuum. In an inert atmosphere box under nitrogen, approximately 0.3 g samples of L-lactide were placed in the bottom of c.a. 8 mm diameter glass tubes. The coral was supported inside the tube atop a constriction in the wail of the tube. (See Figure 1.) This constriction prevented όfrsct contact between the coralline hydroxyapatite, which remained above the constriction, and the solid (or liquid) L-lactide below the constriction in the bottom of the tube. The tube was sealed under vacuum and was beated for approximately 20 hours at 130° C. At the end of the reaction period the sample was cooled to room temperature and then opened to give a sample of coralline hydroxyapatite containing a thick coating of pσly-L-lactide. The weight of the coated sample was 0,420 g. An SEM image of coralline hydroxyapatite after it is coated with PLLA is shown in Figure 4. An image of the coated sample obtained using light microscopy is shown in Figure 5. NMR analysis of die resulting polymer (Figure 6) shows that the deposit was 95% polymer and 5% monomer. The molecular weight of the polymer deposited under these conditions was determined (by gel permeation chromatography) to be 23,000.

EXAMPLE 3

CVD Polymerization of PLLA onto goniopora coral

[0043] A specific example of a reaction that can be used to produce coral/PLLA composites is described below. Cylindrical rods of goniopora coral (6 mm diameter by 12 mm length) were heated to 400° C for a period of 3 hours to remove deleterious water. At the end of this time the samples were removed from the healing oven and allowed to cool in a desiccator under vacuum, In an inert atmosphere box under nitrogen, approximately 0.4 g samples of L-lactide were placed in the bottom of c.a. S mm diameter glass tubes. The corai was supported inside the tube atop a constriction in the wall of the tube. (See Figure 1.) This constriction prevented direct contact between the corai samples, which remained above the constriction, and the solid (or liquid) L-lactide below the constriction in the bottom of the tube. The lubes were sealed under vacuum and could be heated for up to several days over a temperature range that was typically between 100° C and 180° C. At the end of the. reaction period the samples were cooled to room temperature and then opened to give samples of goniopora coral that were coated with poly-L-Iactide. An SEM image of goniopora coral before it is coated with PLLA is shown in Figure 7. An SEM image of goniopora coral after it is coated with PLLA is shown in Figure 8, For the sample shown in Figure 8, the reaction was carried out at 130° C until the mass increase due to PLLA (0.102 g) was approximately 40% of thai for the original sample (0,256 g). These conditions produced the relatively uniform coating of PLLA that is evident in Figure 8. The molecular weight of the polymer deposited under these conditions was determined (by gel permeation chromatography) to be 45,000.

EXAMPLE 4

CVD Polymerization of PLLA onto gonio ora coral for which a fraction of the CaCO₃ ( calcium carbonate) has been converted to CaO (calcium oxide) [0044] A cylindrical rod of goniopora coral (6 mm diameter by 12 mm length, 0.281 g) was heated for one hour (successively) at each of the following temperatures: 75° C, 200° C, 300° C, 400° C, and 500° C. It was then heated to 600° C for 12 hours. At the end of this time the sample was cooled to 400° C, and then transferred to a vacuum desiccator where it was allowed to cool to room temperature, During this time the sample experienced a 30% mass loss, which indicates that approximately two thirds of the original calcium carbonate had been converted to calcium oxide. In an inert atmosphere box under nitrogen, approximately 0.35 g of L-lactide were placed in the bottom of c.a. 8 mm diameter glass tubes. The coral was supported inside the tube atop a constriction in the wall of the tube. (See Figure. 1.) This constriction prevented direct contact between the coral samples, which remained above the constriction, and the solid (or liquid) L-lactide below the constriction in the bottom of the tube. The tubes were sealed under vacuum and then heated for approximately 40 hours at 130° C, At the end of the reaction period the sample vessel was cooled to room temperature and then opened Io provide goniopora coral that was coated with poly-L-lactide. An SEM image of this sample after it was coated with PLLA is shown in Figure 9. The mass increase for this particular sample was 0.180 g (64%). The molecular weight of the polymer deposited under these conditions was determined (by gel permeation chromatography) to be 54,500.

[0045] Figure 10 shows the time dependent weight loss observed upon heating goniopora coral to 600° C in air. The nominally constant rate of the weight loss between t ™ 0 hr and approximately t = 20 hr indicates that at this temperature the process is a zero order reaction for which the weight decreases by approximately 2% for each hour the sample is heated. The reaction continues to proceed at this rate until the mass loss nears 44%, at which point the vast majority of CaCO₃ originally present has been converted to CaO. Figure 10 serves only as an example. The rate of conversion cars be controlled by controlling the temperature. Generally speaking, temperatures higher than 600° C produce faster rates of conversion than the rate shown in Figure 10. Temperatures lower than 600° C produce slower rates of conversion than the rate shown in Figure 10. Below 500° C the rate of the reaction is slow enough to render the reaction ineffectual on the time scale of approximately 12 hours, [0046] Figure 11 shows a sample of gonϊopora com! for which the CaCO₃ has been converted, effectively completely, to CaO, The porosity of this material on a length scale less than 10 μm is particularly noteworthy,

EXAMPLE 5

CVD Polymerization of PLLA onto bovine trabecular boneΛ

[0047] Cylindrical plugs (6 mm dia and 20 imrt length) of trabecular bone were cut from the proximal end of a bovine femur. These sections were placed in a soxhlet extractor to remove the majority of the organic material from the bone. The solvent mixture used in the soxhlet extractor was 80% ethylcnediamine (240 ml) and 20% deionized water (60 ml). This mixture was observed to reflux at 118-120° C, The samples were extracted for approximately 40 hours, over which time at least one hundred extraction cycles were executed, At the end of this time, the extracted organic material ethylenediamine/water mixture was removed from the soxhlet extractor and replaced with deionized water. Soxhlet extraction of trabecular bone using water was continued until washings from individual extractions were found to be neutral. At this point the samples were white to the unaided eye,, but a few percent organic material (by weight) remained. The remaining organic material was removed by heating the extracted sample to 600° C in air for approximately 40 hours. The samples were then cooled to room temperature under vacuum in a desiccator. The desiccator was brought into a nitrogen box.

[0048] In an inert atmosphere box under nitrogen, approximately 0.3 g of L-lactide was placed in the bottom of c.a. 8 mm diameter glass tube. The trabecular bone was then supported inside the tube atop a constriction in the wall of the tube. (See Figure 1.) This constriction prevented direct contact between the trabecular bone, which remained above the constriction, and the solid (or liquid) L-lactidc below the constriction in the bottom of the tube. The tubes were sealed under vacuum and than healed at temperatures that typically ranged from 130° C for approximately 90 hours. At the end of the reaction period the samples were cooled to room temperature and then opened Io give samples of trabecular bone that were coated with poly-L-lactide. During the course of this reaction, this sample experienced a mass increase of nearly 100%. The molecular weight of the polymer deposited under these conditions was 21 ,000. A representative SEM image is provided in Figure 12. [0049] Although a few exemplary embodiments of the present invention have been shown and described, the present invention is not limited to the described exemplary embodiments, instead, it would be appreciated by those skilled hi the art that changes may be made to these exemplary embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

[0050] The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0052] It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the Figures. [0053] Moreover, it will be understood that although the terms first and second are used herein to describe various features, elements, regions, layers and/or sections, these features, elements, regions, layers and/or sections should not be limited by tliese terms. These terms are only used to distinguish one feature, element, region, layer or section from another feature, element, region, layer or section. Thus, a first feature, element, region, layer or section discussed below could be termed a second feature, element, region, layer or section, and similarly, a second without departing from the teachings of the present invention.

[0054] It will also be understood that when an element is referred to as being

"connected" or "coupled" to another element, it can be directly connected or coupled to the other element or intervening elements may be present In contrast, when an element is referred to as being "directly connected" or "directly coupled" to another element, there are no intervening elements present. Further, as used herein the term "plurality" refers to at least two elements. Additionally, like numbers refer to like elements throughout. Thus, there has been shown and described several embodiments of a novel invention. As is evident from the foregoing description, certain aspects of the present invention are not limited by the particular details of the examples illustrated lierein, and it is therefore contemplated that other modifications and applications, or equivalents thereof, will occur to those skilled in the art. The terms '"having" and "including" and similar terms as used in the foregoing specification are used in the sense of "optional" or "may include" and not as "required". Many changes, modifications, variations and other uses and applications of the present construction will, however, become apparent to those skilled in the art after considering the specification and the accompanying drawings. All such changes, modifications, variations and other uses and applications which do not depart from the spirit and scope of the invention are deemed to be covered by the invention which is limited only by the claims which follow. The scope of the disclosure is not intended to be limited to the embodiments shown herein, but is to be accorded the Ml scope consistent with the claims, wherein reference to an element in the singular is not intended to mean "one and only one" unless specifically so stated, but rather "one or more." All structural and functional equivalents to the elements of the various embodiments described throughout this disclosure that are known or later come to be known to those of ordinary skill in the art are expressly incorporated herein fay reference and are intended to be encompassed by the claims.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of preparing a composite comprising a bioabsσrbable polymer or copolymer of one or more lactone monomers and a nucleophilic substrate, the method comprising;

initiating polymerization or copolymerization by ring-opening of said lactone,

wherein the step of initiating polymerization or eopolymerizalion of said lactone is conducted by a chemical vapor deposition method including providing said substrate within a chemical vapor deposition reactor; providing a vapor of βaid lactone raonomer(s) or a source of said vapor in said reactor under conditions effective to initiate ring-opening polymerization or copolymerization of said lactone by said substrate and deposition of said polymer or copolymer on said substrate,

2. The product of the method of claim 1.

3. The method of claim 1, wherein the one or more lactone monomers are selected from the group consisting of caprolactone, t-butyl caprolactone, zeta-enantholactoπe, dehavalerolactones, rnonoalkyl- delta-valero lactones, beta-lactones, gamma-lactoties, diϊactones. derivatives and mixtures thereof.

4. The method of claim 1 , wherein the substrate comprises a material selected from the group consisting of hydroxyapatite, hydroxypatite with nucleophilic substitutions, hydroxyapatite with nucleophilic adorbaies, nucleophilic oxides, micleophilic hydroxides_* and mixtures thereof.

5. The method of claim 1 , wherein the substrate comprises a nucleophilic surface that will initiate the cyclic lactone polymerization selected from the group consisting of metal oxides, hydroxyapatite, BioGlass, and biological sources of CaCO₃.