FI123935B

FI123935B - Composite containing polymer and additive and its use

Info

Publication number: FI123935B
Application number: FI20116327A
Authority: FI
Inventors: Kimmo Laehteenkorva; Esa Suokas; Mikko Huttunen
Original assignee: Conmed Linvatec Biomaterials Oy Ltd
Priority date: 2011-12-28
Filing date: 2011-12-28
Publication date: 2013-12-31
Also published as: AU2012360738B2; FI20116327A; EP2797639A1; CA2858501A1; WO2013098481A1; AU2012360738A1

Abstract

The present invention relates to bioabsorbable polymer composite materials, which contain a polymer matrix component composition including one or more multimonomer-polymers and one or more biocompatible additives, as well as a process for their manufacture. Further, the invention relates to surgical devices, such as pins, screws, plates, tacks, bolts, intramedullary nails, suture anchors, wedges, wires, filaments, sutures or staples, containing said composite, and a process for their manufacture.

Description

COMPOSITE CONTAINING POLYMER AND ADDITIVE AS WELL AS ITS USE

Back2round of the Invention 5 Field of the Invention

The present invention concerns biocompatible and bioabsorbable composite materials containing multimonomer-polymers and/or their blends together with one or more additive, as well as a method for manufacturing said composites. These composite materials have 10 the required properties tailored to be suitable for use in implantable surgical devices.

Description of Related Art

In orthopaedic surgery, either biostable or biodegradable devices, such as pins, fixation 15 screws, plates, tacks, bolts, intramedullary nails, interference screws, suture anchors, or staples, are used in various applications.

Most biostable devices are made of metallic alloys. However, there are several disadvantages in the use of metallic implants, such as the bone resorption caused by the 20 bone plates and screws (Wolffs law), which carry most of the external loads, as well as debris formation and the possibility of corrosion. Therefore, surgeons are recommended to remove metallic implants in a second operation to be carried out once the fracture has healed.

co o 25 Therefore, bioabsorbable (i.e. biodegradable and resorbable) surgical devices, generally σ> made from polymers, are commonly used in surgical fixation. The advantages of these cd devices include that the materials are absorbed in the body and the degradation products x exerted via metabolic routes. Hence, a further implant removal operation is not required.

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Additionally, the strength of the bioabsorbable polymeric devices decreases gradually as co 30 the device is degraded, whereby the bone is progressively loaded. This, in turn, promotes g bone regeneration.

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Synthetic biodegradable polymers have many advantages in the medical applications. They can be tailored to fulfill specific needs of a particular application. The hydrophobicity, 2 crystallinity, degradability, solubility and thermal properties (glass transition and melting temperature) of polymer can be easily modified by copolymerization or by changing polymerization conditions. Another feasible route to modify polymer properties is physical blending.

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Biodegradable polymers are typically synthetic aliphatic polyesters. Most commonly used aliphatic polyesters are poly-a-hydroxy acids such as polyglycolides (PGA), polylactides (PLA) and their copolymers produced by polycondensation or ring-opening polymerization. Biocompatible and bioabsorbable surgical devices are normally made of 10 these polymers. Glycolide/L-lactide copolymers (PLGA) and glycolide trimethylene carbonate copolymers (PGA/TMC) are examples of glycolide based copolymers. Lactide based copolymers may comprise lactones (acid dimers) such as L-lactide (L), D-lactide (D), D,L-lactide (DL), glycolide (G), ε-caprolactone (CL), trimethylene carbonates (TMC), /?-dioxanone (PD), 2-methyl glycolide (MG), 2,2-dimethyl glycolide (DMG), 1,5-15 dioxapane-2-one (DOX-5), para-dioxapane-2-one (DOX-4), 3,3-dimethyltrimethylene carbonate (DMTMC), glycosalicylate (GS), and morpholine-2,5-dione (MD) as comonomer. In these aliphatic polyesters described, n-alkylene, alkylene oxide or alkylene carbonate linking groups may consist more than 5 carbon atoms in backbone (-CH2-). n-Alkylene may also be substituted (side-chain polymers) or branched (star polymers).

20 Copolymers of L-lactide and D-lactide are also able to form stereocomplexes (stereopolymers), which behavior is resulting from the enantiomer character of a single lactic acid. Polyhydroxyalkanoates (PHA), polyhydroxybutyrates (PHB), polyhydroxyvalerate (PHV) and poly(hydroxybutyrate-co hydroxyvalerate) (PHBV) are belonging to polyhydroxyalkanoates (bacterial polyesters) produced by bacterial 25 biosynthesis. Other possible biodegradable polymers are poly(ortho esters), ^ polyanhydrides, polyamides, polydioxanones, polyoxylates, polyoxamates, polyacetals, ^ “pseudo”-poly(amino acids) such as tyrosine-derived polycarbonate, polypropylene fumarates), poly(butylenes adipate-co-terephthalate), polyesteramides, pocarboantes,

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polyiminocarbonates, polyurethanes, poly(alkyl cyanoacrylates), polyphosphazenes, cm 30 polyphosphoesters.

co o w Copolymers of lactides have been chemically prepared to modify the properties of homopolymer. For instance co-monomers such as L-lactide (L), D-lactide (D) or racemic D,L-lactide (DL) disrupt the crystallinity of L-lactide block, which is resulting to reduced 3 crystallinity and also sometimes to accelerated degradation process. The semi-crystalline homopolymer poly(L-lactide) has a modulus about 25% higher than copolymer poly(D,L-lactide). The amorphous copolymer poly(L-lactide-co-D,L-lactide) may have higher elasticity due to lack of crystallinity.

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Biodegradable polyesters decompose mostly by hydrolysis after having been exposed to moisture. Normally, there exists a sequence of phenomena; a decrease in molecular weight, strength, and mass during the hydrolysis of biodegradable polymers. Crystalline blocks of semi-crystalline polylactide are more resistant to hydrolytic degradation than the 10 amorphous phase. Time required for certain polylactide implants to be totally absorbed is relatively long and depends on polymer quality, processing conditions, implant site, and physical dimensions of the implant. For instance PLA degrades in vivo to form lactic acid which is normally present in the body. This acid enters tricarboxylic acid cycle and is exerted as water and carbon dioxide.

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Bioceramics are attractive as biological implants because of their biocompatibility. During the last three decades ceramic materials have become widely used in many medical applications such as hip prosthesis, cardiac valves and dental implants. Among the biomaterials available, medical ceramics or bioceramics, exhibit some of the most 20 interesting properties. Calcium phosphates have been used in the form of artificial bone. Calcium phosphate ceramics (CPC) have been synthesized and manufactured to various forms of implants and coatings. Calcium phosphate ceramics exhibit non-toxicity to tissues (biocompatibility), bioreseption and osteoinductive property. Calcium hydroxyapatite (HA) and tricalcium phosphates (TCP) are the most typical bioceramics used in medical

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o 25 devices. Tricalcium phosphate exits in two different whitlockite crystallographic g configurations, namely as α-TCP and as the more stable β-TCP. The biodegradation rate of σ) TCP is greater than that of HA, because the differences in the crystalline structures. Glass- x ceramics (AAV glasses) were developed in the early 1960s. The basic components in most bioactive glasses are S1O2, Na20, CaO and P2O5. Bioglass and glass-ceramics are non-

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co 30 toxic and are able chemically bond to bone. The primary advantage of bioactive glasses is £ their quick rate of surface reaction resulting in fast bonding.

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In its most basic form a composite material is one, which is composed of at least two elements working together to produce material properties that are different to the properties 4 of those elements on their own. The mechanical properties of polymers can be improved by the addition of the particulate or fiber reinforcement.

A wide variety of bioabsorbable homo- and copolymers containing implantable prior art 5 materials and devices have been made and described for instance in the following publications:

Eur.Pat.No. 0011528 and U.S. Pat.No. 4,279,249 describe osteosynthesis parts made of absorbable polymer composition consisting of a matrix of lactic acid homopolymer, or 10 copolymer very high in lactic acid units, having discrete reinforcement element embedded therein. The reinforcement elements are made of glycolic acid homopolymers or copolymers predominant in glycolic acid units. Osteosynthesis part made of said polymer compositions containing a charge constituted by a material containing at least one ion selected from: calcium, magnesium, sodium, potassium, phosphate, borate, carbonate and 15 silicate. Such a composition may be shaped with minimum of polymer degradation into osteosynthesis parts exhibiting good resilience, shock resistance, and tensile strength. One mentioned example is a composite part prepared by compression-molding employing as the polymer the PLA charged with tricalcium phosphate.

20 Eur.Pat. No. 0204931 and U.S. Pat. No. 4,743,257 describe surgical osteosynthesis composite material, which is self-reinforced. This material is formed about the absorbable polymer or copolymer matrix which is reinforced with absorbable reinforcements units which have the same chemical element percentage composition as the matrix has.

Osteosynthesis material is characterized in that the absorbable matrix and reinforcement co o 25 units are manufactured of polylactide or a lactide copolymer. Other main material σ> combination is the one, where the absorbable matrix and reinforcement units are 0 σ> manufactured of polyglycolide or a glycolide copolymer. The absorbable matrix and 1 reinforcement units can be also manufactured of glycolide/lactide copolymer. Self-

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reinforcement in these patents means that the polymeric matrix with the reinforcement co 30 element or materials (such as fibers) which the same chemical element composition as ^ does the matrix, and then preferred processing method is compression-molding.

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U.S. Pat. No. 4,968,317 and Eur.Pat. No.0854734 describes surgical material of resorbable polymer, copolymer, or polymer mixture containing at least partially fibrillated structural 5 units, and use thereof. Homopolymer and copolymer materials are typically composed of the absorbable matrix and reinforcement units are manufactured of polylactide or a lactide copolymer. Self-reinforcing in these patents means orientation of the molecular structure of absorbable polymeric materials in such a way that they are at least partially fibrillated.

5 U.S. Pat. No. 6,406,498, andEur.Pat. No. 1109585 describe a bioactive, biocompatible, bioabsorbable surgical composite that is fabricated bioabsorbable polymers, copolymers or polymer alloys that are self-reinforced and contain ceramic particles or reinforcement fibers, and also can be porous. Polymers matrix is typically composed of poly-a-hydroxy 10 acid based absorbable polymers or copolymers such as polylactide or a lactide copolymer. Typical ceramic additive is belonging to calcium phosphate ceramic family, and then the most typical additive is beta-tricalcium phosphate (β-TCP). The composite of the invention can be formed into devices with the suitable property profile depending on the indication.

15 Eur.Pat. No. 1009448 and U.S.Pat.No. 7,541,049 describe surgical osteosynthesis composite materials which has three components, namely biodegradable polymer reinforcement, bioceramic or bioglass filler reinforcement and biodegradable polymer matrix. The invention introduces the composites that have two different reinforcing phases and one matrix phase. One reinforcing element is referred as the polymeric reinforcing 20 element and the other as the ceramic reinforcing element. Typical matrix polymers are poly-a-hydroxy acid based absorbable polymers or copolymers such as polylactide or a lactide copolymer.

^ U.S.Pat. No. 6,206,883 and U.S.Pat.No. 6,716,957 describe a bioabsorbable material such g 25 as a terpolymer of poly-(L-lactide/D-lactide/glycolide). The claims of the former patent is g relating to an implantable medical device and the ones of the latter to a material <5 comprising terpolymer. The material may consist of 85 molar percent L-lactide, 5 molar percent D-lactide, and 10 molar percent glycolide. The material may hay tensile strength

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retention at 26 weeks of incubation at least 50%, and tensile strength retention at 52 weeks

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g 30 of incubation of at most about 25%. The material may be used in implantable devices such q as bone fixation devices.

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U.S.Pat.No. 6,747,121 describes implantable, resorbable copolymers containing L-lactide and glycolide repeat units, and in particular to terpolymers containing L-lactide, glycolide, 6 and one other type of repeat unit selected from the group consisting of D-lactide, D,L-lactide, and ε-caprolactone. Medical devices for in vivo implantation applications containing such implantable, resorbable copolymers have also been described, as well as methods for making such co- and terpolymers and devices.

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Surgeons prefer using devices that eventually are resorbed and disappear from the body after they have served their purpose. However, in many cases sufficient strength properties are difficult to achieve using bioabsorbable polymeric devices, particularly since the strength must be maintained for a sufficient period of time, even after the absorption of the 10 material has started. A common way to overcome this challenge is to manufacture bioabsorbable medical implants with as high initial molecular weight as possible. Another commonly used route is to choose materials having long degradation time. The result in both cases is unfortunately prolonged total bioabsorption time, which can be in certain cases 5-10 years. Therefore the optimized biodegradation kinetics is needed. The 15 optimized kinetics means here long enough strength retention time to guarantee tissue healing while biodegradation occurs in reasonable time scale to guarantee the lack of negative tissue responses caused by degradation products of polymeric or composite device.

20 For some surgical applications there are challenges to achieve sufficient strength properties by using non-reinforced bioabsorbable polymers and composites. For those cases the use of various reinforcing techniques is a feasible way to guarantee required initial strength properties. Self-reinforced polymeric composites have been developed that show enhanced strength compared to conventional polymeric surgical materials (see e g. EP 1109585).

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o 25 However, even these do not provide the preferred advantageous properties bioabsorption σ> kinetics of the materials of the present invention.

o σ> x Several publications describe the use of composite materials in surgical devices, such as EP 0011528, EP 1009448and EP 1109585. However, none of these solutions describe the I"'' co 30 use of preferred terpolymers of this invention in these materials and devices.

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Copolymers have been described extensively as polymer materials examples (e g. in EP 0423155). U.S.Pat. No. 6,206,883, U.S.Pat.No. 6,716,957 and U.S.Pat.No. 6,747,121 are depicting bioabsorbable polymers such as terpolymer of poly-(L-lactide/D- 7 lactide/glycolide), which is used in implantable devices such as bone fixation devices. These three patents are not claiming any absorbable composite materials or medical devices made of said composite materials.

5 It has been attempted to mix various additives into the bioabsorbable polymers to modify their properties and to yield devices having useful properties. The initial mechanical strength of surgical materials has been improved by applying reinforcement units having the same chemical composition as matrix such as absorbable fibers by mixing mechanically together and then compression-molded (see e.g. Example 5 in EP 0204931).

10 The reinforcement fibers typically have a fiber length of lpm to 10mm. However, if the chemical structure or the element composition of the reinforcement units differ from that of the matrix material (e.g., EP 0011528), the resulted structures cannot generally form strong bonds between each other, which, in turn, leads to poor adhesion. Adhesion promoters, such as silanes or titanates, cannot be applied in surgical materials due to their 15 toxicity. The poor interface adhesion has been solved by orientation of the molecular structure of absorbable polymeric material in such a way that it is at least partially fibrillated because of molecular orientation of polymer by means of self-reinforcing process (EP 0854734 and EP 1109585).

20 The self-reinforced materials described in EP 0204931 and EP 0854734 are composed of plain polymer/polymers, and therefore they lack direct bone-bonding properties. To overcome this challenge the composite properties have been modified by additives including bioceramics, which optionally can be bioactive (such as in EP 1009448). These additives can be in various forms including particle fillers, fibers, etc., and these additives

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o 25 can promote osteoconductivity, i.e. such bioabsorbable bone fracture fixation devices can cb create direct contact with the bone tissue.

o o x A general problem with addition of said ceramic particles has been the brittleness of the formed composites, since the addition of ceramic fillers into the polymeric matrix changes Γ"» co 30 most thermoplastic polymers from tough and ductile to brittle in nature. This is a ^ consequence of lack of adhesion between said ceramic particles and polymer matrix. This 00 is evidenced by a significant reduction in both the elongation at break and the impact strength. Moreover, even non-filled bioabsorbable thermoplastic polymer devices can be 8 brittle in their mechanical behavior. The brittleness can be a severe limitation on bioabsorbable devices, leading to premature breaking or other adverse behavior.

Thus, there remains a need for non-toxic bioabsorbable composite materials having 5 sufficient strength retention properties during the degradation, reasonable estimated total bioabsorption time and osteoconductive potential. The osteoconductive potential means here a good adhesion particularly to solid contact with bone tissue.

Summary of the Invention 10

It is an object of the present invention to provide a biocompatible, bioabsorbable polymer composite material suitable for use in surgical devices.

Particularly, it is an object of the present invention to provide such bioabsorbable polymer 15 composites for surgical devices, which provide these devices with an improved bioabsorption kinetics at the same time maintaining equivalent strength compared to the prior art. The improved bioabsorption kinetics means here long enough strength retention time to ensure mechanical support during the required healing period and short enough degradation in terms of decline of molecular weight (or inherent viscosity) to guarantee 20 faster total bioabsorption than plain PLLA polymer.

Further, it is an object of the invention to provide said surgical devices, the strength of which can be maintained on a sufficiently high level for a required healing time compared to the prior art. co δ 25

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cd Likewise, it is a particular object of the invention to provide said improved and prolonged cd strength retention without significantly impairing the adhesion of the surgical devices to x bone and without prolonged total mass loss time.

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h- g 30 These and other objects, together with the advantages thereof over known polymer g composites (as well as compositions, devices and manufacturing processes), are achieved cm by the present invention, as hereinafter described and claimed.

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Thus, the present invention concerns a biodegradable composite material for use in surgical devices, which composite contains a biocompatible polymer matrix composition and one or more biocompatible additives, preferably in the form of bioceramics. Further, the invention concerns a surgical device containing said composite, and a process for its 5 manufacture.

More specifically, the composite material of the present invention is characterized by what is stated in the characterizing part of Claim 1.

10 Further, the process for manufacturing said composite is characterized by what is stated in Claim 8, the surgical device containing said composite is characterized by what is stated in Claim 12, and the process for manufacturing the device is characterized by what is stated in Claim 14.

15 The preferred embodiments of the invention relating to bioabsorbable composite materials and medical devices made of them, as well as methods for manufacturing said devices, comprise: (a) compositions of multi monomer-polymer and/or their blends as matrix, wherein one 20 or more additives are dispersed; (b) multimonomer-polymer matrix encompasses repeat units, which are derived from lactone-based monomers as a primary matrix component; (c) multimonomer-polymer matrix consists the lactone-based repeat unit compositions, which are composed of more than two co-monomers (biopolymers),

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o 25 namely the ones of three monomers (terpolymers), or the ones of four monomers σ> (quaterpolymers), or the ones of five monomers (quinterpolymers), etc. as a σ> secondary matrix components; x (d) multimonomer-polymer matrix consists of the blends of polymers, which are

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composed of more than two co-monomers (biopolymers), namely the ones of three co 30 monomers (terpolymers), or the ones of four monomers (quaterpolymers), or the ^ ones of five monomers quinterpolymers, etc. as a tertiary matrix components; cm (e) additive component encompasses bioceramics, which are selected from calcium phosphate ceramics and/or bioactive glasses and glass-ceramics as one or more primary additives; 10 (f) additive component encompasses one or more assistive additives in addition to one or more primary additive; (g) said composite materials are manufactured by mixing (molten or solution) selected one or more bioabsorbable matrix and selected one or more additive components 5 with each other in molten or solution phase, the preferred manufacturing process is molten; (h) bioabsorbable medical devices are manufactured from said preferred one or more composite compositions by means of one or more continuous or non-continuous processes depending on the product application; 10 (i) medical devices made of said composite materials are used in selected indications.

Considerable advantages are obtained by means of the invention. Among others, the present invention provides an optimized bioabsorption profile, i.e. the material exhibits a fast enough rate of absorption (i.e. reduced total mass loss time) while maintaining its 15 strength for a sufficiently long time. Particularly the shear strength provides the advantages that are significant in manufacturing surgical devices.

The composite materials of this invention can be further processed by means of various orientation techniques such as self-reinforcing. By orientating preferred polymer matrix 20 components of this invention, high ceramic contents can be added to matrix polymer matrix without resulting to brittle composite material. Such high ceramic contents as 50wt-% can lead to composite structures which are hand malleable at room temperature.

Next, the invention will be described more closely with reference to the attached drawings co δ 25 and a detailed description.

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σ> 0 σ> Brief Description of the Drawings cn □_

Figure 1 shows the bending of self-reinforced 50-wt-% beta-TCP containing terpolymer g 30 composite without breakage.

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Figure 2 shows the bending of injection molded terpolymer composites without breakage.

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Figure 3 shows the eyelet strength of self-reinforced terpolymer (85L/5D/10G PLDGA) and terpolymer composite (85L/5D/10G PLDGA + TCP) suture anchors

Figure 4 shows the torsion strength of self-reinforced terpolymer (85L/5D/10G PLDGA) 5 and terpolymer composite (85L/5D/10G PLDGA + TCP) suture anchors.

Figure 5 shows the eyelet strength of various injection molded terpolymer and terpolymer composite suture anchors 10 Figure 6 shows the torsion strength of various injection molded terpolymer and terpolymer composite suture anchors

Figure 7 shows the estimated total biodegradation time for composites of this invention.

15 Detailed Description of the Preferred Embodiments of the Invention

The present invention concerns a biocompatible, bioabsorbable composite material for use in surgical devices, containing one and more multimonomer-polymers and/or their blends together with one or more additives, as well as a method for manufacturing said 20 composites. Particularly, the composite material comprises a bioabsorbable polymer composed of three or more lactone-based repeat units as a matrix, wherein one or more biocompatible ceramics are dispersed as said one or more additive components.

These bioabsorbable composite materials include a bioabsorbable matrix polymer, which

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o 25 preferably is composed of three chemically differing repeat units, i.e. it is a terpolymer, a) and where the ceramic is bioabsorbable and bone adhesion promoting as well as, 0 cd preferably, bone growth promoting, bioceramic additive.

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Tailor-made medical devices, such as interference screws and suture anchors, may be I''» g 30 manufactured of said bioabsorbable composite materials.

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The bioabsorbable polymeric matrix of the invention may be selected from a diversity of synthetic bioabsorbable polymers. Such synthetic biocompatible, bioabsorbable polymers are preferably aliphatic polyesters such as poly-a-hydroxy acids. These multimonomer 12 based polymers as a matrix contain preferably repeat units selected from lactones (cyclic acid dimers) such as L-lactide (L), D-lactide (D), D,L-lactide, glycolide (G), ε-caprolactone (CL), trimethylene carbonates (TMC), />dioxanone (PD), 2-methyl glycolide (MG), 2,2-dimethyl glycolide (DMG), l,5-dioxapane-2-one (DOX-5), para-dioxapane-2-5 one (DOX-4), 3,3-dimethyltrimethylene carbonate (DMTMC), glycosalicylate (GS), and morpholine-2,5-dione (MD). However, in the primary embodiment of the invention terpolymer matrix consists of lactide and glycolide repeat units, particularly including a terpolymer of a L-lactide repeat unit (L), a D-lactide repeat unit (D), and glycolide (G), optionally also containing a racemic D,L-lactide repeat unit (D,L) . The bioabsorbable 10 composite contains preferably only one terpolymer as a matrix component.

The additive component of the invention can be selected from bioceramic and glass groups such as hydroxyapatite (HA) and tricalcium phosphates (a- and β-TCPs), but also from other calcium phosphates such as monocalcium phosphate monohydrate (MCPM), 15 monocalcium phosphate anhydrate (MCPA), dicalcium phosphate dehydrate (DCPD, i.e., brushite), dicalcium phosphate anhydrate (DCPA, i.e., monenite), octacalcium phosphate (OCP), amorphous calcium phosphate (ACP), calcium-deficient hydroxyapatite (CDHA) and tetracalcium phosphate (TTCP), Bioglass, Cerevital bioactive glass-ceramics, alumina, zirconia, bioactive gel-glass, bioactive glasses and glass ceramics. However, the 20 bioceramic additive material component of the composite is preferably beta-tricalcium phosphate (beta-TCP) or a mixture of hydroxyapatite and beta-tricalcium phosphate (HA/TCP) in the primary embodiment of the invention. Particularly, at least a portion of the additives are always selected from biominerals, providing a composite structure at least partially to resemble the bone matrix.

1 25 g The optimized biodegradation kinetics of the composite materials of this invention <y> comprises long enough strength retention time typically 6-26 weeks to guarantee tissue x healing depending on the application and reasonable total bioabsorption time 1.5-4 years.

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Too quick bioabsorption may cause negative tissue responses because of high

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g 30 concentration of degradation products. Therefore, in this invention preferable composite £ compositions are introduced to avoid too quick degradation and not compromise

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mechanical performance.

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According to a preferred primary embodiment of the invention, the composite material is composed of polymer matrix, preferably a terpolymer PLDGA of L-lactide, D-lactide and glycolide (G), particularly of the type 70-90 mol% L / 1-20 mol% D / 1-20 mol% G PLDGA, or a blend thereof, mixed with 1-90 wt% biocompatible ceramic additive. More 5 preferably, the composite material is formed from 80mol% L /5-15 mol% D / 5-10 mol% G PLDGA, or a blend thereof, and 10-60 wt% biocompatible additives.

According to a preferred primary embodiment of the invention, the additive is a bioceramic material, which may be selected from any biocompatible ceramic material such as a 10 calcium phosphate and bioactive glass. Most suitably, the ceramic material is beta-tricalcium phosphate (beta-TCP) or a mixture of HA/TCP. Ceramic additive is mainly inducing osteoconductivity to composite.

In another embodiment of the invention, the polymer matrix consists of more than three 15 lactone-based repeat units in addition to L-lactide, D-lactide and glycolide (PLDGA) such as trimethylene carbonate (TMC), ε-caprolactone (CL) and/or p-dioxanone (PD) or a blend thereof, mixed with 1-90 wt% biocompatible ceramic additive.

In still another embodiment of the invention, the composite material is composed of colorant containing polymer matrix, preferably a terpolymer PLDGA of L-lactide, D- 20 lactide and glycolide (G), particularly of the type 70-90 mol% L / 1-20 mol% D / 1-20 mol% G PLDGA, or a blend thereof, mixed with 1-90 wt% biocompatible ceramic additive and with 0.01-0.3 wt-% colorant such as l-hydroxy-4-[(4-methylfenyl)amino]- 9,10-antrasenedione (D&C Violet #2) or 9,10-anthracenedione, l,4-bis[(4- £2 methylphenyl)amino] (D&C Green 6). More preferably, the composite material is formed o ^ 25 from 80 mol% L /5-15 mol% D / 5-10 mol% G PLDGA, or a blend thereof, and 10-60

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? wt% biocompatible additive with 0.01-0.3 wt-% colorant such as 1-hydroxy-4-[(4- o methylfenyl)amino]-9,10-antrasenedione (D&C Violet #2) or 9,10-anthracenedione, 1,4-

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£ bis[(4-methylphenyl)amino] (D&C Green 6).

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>- 30 In further another embodiment of the invention the composite matrix may contain a δ ^ physical blend of two or more terpolymers, or a physical blend of one or more terpolymer with one or more copolymer or homopolymer or both. Most suitable, the terpolymer 14 composition consists of a single terpolymer mixed with said one or more biocompatible preferred ceramic additives.

In a further embodiment of the invention the bioactive glasses optionally employed as 5 primary ceramic additives are based on a network former and at least one additional additive component. The network former can, for example, be P2O5. The additional components typically provide the resulting composite with a further advantageous function, such as change its rate of solubility, whereby these are also called functional additives.

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One group of additional additives include alkali and alkaline earth metal oxides, such as sodium oxide, potassium oxide, calcium oxide and magnesium oxide, and their respective carbonates and phosphates.

15 Particularly, the bioactive glasses of this embodiment include both alkali metal oxides (or their respective carbonates or phosphates, or a mixture thereof) and alkaline earth metal oxides (or their respective carbonates or phosphates, or a mixture thereof). As a general rule, the rate of solubility is increased by increasing the proportion of alkali metal oxides, and is decreased by increasing the proportion of alkaline earth metal oxides.

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The second group of the additional additives, i.e., functional additives can be selected from organic or inorganic bioactive substances such as osteoconductive agents, antibiotics, chemotherapeutic agents, agents activating the healing of wounds, growth factors, bone morphogenic proteins and anticoagulants. Such agents provide the additional advantage of

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0 25 promoting tissue healing.

σ> o σ> The third group of additional additives can be, for example, additives for facilitating x processing of the material or for altering its properties, such as adhesion promoters,

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stabilizers, antioxidants and plasticizers, or for facilitating its handling, such as colorants.

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co 30 co ^ Some preferred exemplary composite compositions include: - 78 wt-% or 50 wt-%(85 mol%L / 5 mol%D / 10 mol%G) PLDGA+ 22 wt-%TCP or 50 wt-%TCP, 15 - 78 wt-% or 50 wt-%(85 mol%L / 10 mol%D / 5 mol%G)PLDGA + 22 wt-%TCP or 50 wt-%TCP, and - 78 wt-% or 50 wt-%(90mol%L / 5 mol%D / 5 mol%G)PLDGA + 22 wt-t%TCP or 50 wt-%TCP).

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The composite is manufactured by mixing the ceramic additive with the composite matrix component. The additive can be used in any form, preferably as a powder, flakes, granules, cut-off fibers or continuous fibers. However, the addition of additive to the composite matrix component is preferably carried out with the components heated to a molten state 10 (melt processing) or dissolved in a suitable solvent, such as an aqueous solution, more preferably with the polymeric matrix components in molten state.

After the addition of the additive to the composite polymer matrix component, the composite material is subjected to mechanical treatment step to form the final composite 15 structure. This treatment step preferably includes injection molding, extrusion followed by machining and/or the use of some orientation technique, such as self-reinforcing.

The addition of the primary and/ or secondary additive components to the polymer matrix component can be carried out gradually, in several steps. However, the final content of 20 additive in the composite, after addition of the final portion of additive, is 1 to 90 wt-%. Additional additives may be added in a selected step suitable for process methods used.

The mechanical treatment can be divided into two parts, whereby, in the first part, the polymer raw material, with additives, is melted with a continuous process, such as o 25 extrusion, or with a noncontinuous process, such as injection or compression molding, or g maintained in a molten state after mixing its components. The melted material is cooled so σ) that it solidifies to an amorphous or partially crystalline (crystallinity typically 0-60%) perform. The cooling is carried out, for example, inside a mold, on a cooling belt or in a

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cooling solution.

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s 30 ^ A feasible way of carrying out the second part of the mechanical deformational treatment

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is by orientation. This optional orientation can be carried out using a temperature (T) that is above the glass transition temperature (Tg) of the polymer matrix material, but below its melting temperature, particularly if it is partially crystalline (semi-crystalline), and by 16 drawing the above melt-processed, non-oriented billet or preform (such as a rod, a plate or a film) to a typical drawing ratio of 1.1 to 7 in the direction of the longitudinal axis of the preform, such as billet.

5 The drawing can be done freely by fixing the ends of the preform into fixing clamps of a drawing machine, tempering the system to the desired drawing temperature, and increasing the distance between the fixing clamps so that the preform is stretched and oriented structurally. This type of orientation is mainly uniaxial.

10 The drawing can also be done through a conical die, which can have, e.g., a circular, an ellipsoidal, a square, a star-like, a rectangular or other suitably shaped cross-section. When the cross-sectional area is circular like in the polymer billet, which is to be drawn through the die, is bigger than the cross-sectional area of the die outlet, the billet is deformed and oriented uni- or biaxially (or both) during drawing, depending on the geometries of the die 15 and the billet. The ratio of the cross-sectional areas of the undrawn and drawn billet defines the draw ratio (DR or λ).

Also pushing deformation can be carried out, e.g. using a piston as an effective force. Further, it is possible to create orientation by shearing the flat billet between two flat 20 plates, which glide in relation to each other, or by rolling a rod-like or plate-like preform between rollers, which flatten the preform to a desired thickness, simultaneously orienting the material biaxially. Fleating can be used in all these methods.

As a result of the drawing, the molecular chains or parts thereof are directed increasingly to

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o 25 the draw direction, wherein the strength and toughness of the material are growing in the cb draw direction. After the drawing, the drawn billet is cooled under stress to room o cd temperature, and can be further shaped into various surgical implants or other structures, x Suitable processes for further shaping include machining, stamping, turning, milling,

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shearing, compression molding and thermoforming.

OU ΛΛ co 30 co ^ Toughening of composite materials described in the invention can be also attained, when

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the final products of this invention are manufactured by injection molding after which they may also contain flow induced orientation of polymer chains. This will result in more ductile mechanical behavior as described in Example 3 and Figure 2 of the invention.

17

The composites of the invention can be treated also by using so called solvent methods, wherein at least a part of the polymer matrix material is dissolved or dispersed into a suitable solvent and/or mixed with additives, or softened by the solvent and/or mixed with 5 additives, whereafter the formed dispersion or paste is compressed into a suitably shaped object using pressure and, optionally, heat. The dispersed or softened composite and/or polymer matrix material then functions as a glue to maintain the given shape of the object, from which the solvent can be removed, e.g., by evaporating.

10 After finishing, cleaning and drying, the surgical devices of the present invention are ready for transportation and use. Thus, they can be packed, and the packages sealed. Since these products are to be used in surgery, they are also required to be sterilized before use.

The following non-limiting examples are intended to merely illustrate the properties of 15 certain preferred embodiments of the invention.

Examples

Example 1 20

Various samples were prepared using the terpolymer 85 mol%L/5 mol%D/10 mol%G and from composites of said terpolymer and beta TCP. Mechanical properties of such composites are shown in the following Table 1.

co o 25 Table 1 CM ______ σ> o ^ Composition Sample Measured Strength x 85L/5D/10G Diameter Draw Shear Strength

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PLDGA beta-TCP (mm) ratio (Mpa) StDev r--______ m 100 0 2.38 1 55.6 1.2 co______ ^ 100 0 1.45 2.5 99.5 0.9 o CM------ 100 0 1.18 4.4 128.7 2.6 Ί00 ö TÖ5 ~4 96^8 2.1 18 "78 22 % 13.95 [TT ΓδϊΤ Π~8 Τδ 22% TT Ti "öL7 "Ö8 50 50% 5.4 2.2 TTT 02

Example 2 A self-reinforced rod containing the terpolymer 85L/5D/10GPLDGA of Example 1 and 50 5 wt-% beta-TCP was subjected to manual bending in room temperature. This composite material of the invention could be shaped in room temperature without any additional equipment such a way without showing any signs of breaking or tearing (as shown in Figure 1).

10 Example 3

Injection molded composite samples composed of three different terpolymers (85L/10D,L/5G PLDGA, 75L/20D,L/5GPLDGA and 85L/5D/10G PLDGA) and 22-50 wt-% TCP was subjected to manual bending. The material could be shaped in such a way 15 without showing any signs of breaking or tearing (as shown in Figure 2). 22 wt-% beta-TCP containing specimens could be bent to sharp angle and 50 wt-% beta-TCP containing specimens could be bent to mellow angle without any signs of breakage. After heating above glass transition temperature the test samples shrank, which indicate molecular orientation relaxation.

20 co Example 4 δ c\j o Various composites were prepared by means of self-reinforcement and they were further ^ shaped into suture anchors. The terpolymer used was 85L/5D/10G PLDGA and it was ϊ 25 mixed with 0 wt-%, 22 wt-% and 50 wt-% TCP. The eyelet strength and the torsion yield h- strength of the resulting composites are shown in Figures 3 and 4.

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19

Example 5

Various composites were prepared by means of injection molding into suture anchors. The terpolymers used were PLDGA, 75L/20D,L/5G PLDGA and 85L/5D/10G PLDGA and 5 was mixed with 22 wt-% and 50 wt-% beta-TCP. The eyelet strength and the torsion yield strength of the resulting composites are shown in Figures 5 and 6.

Example 6 10 A terpolymer of the invention (85L/5D/10G PLDGA) was self-reinforced (DR=4.5). The biodegradation (particularly the rate of biodegradation) of the formed terpolymer structures was monitored. The degradation study was made in 37°C in phosphate buffer saline (PBS). During the degradation the shear strength and inherent viscosity of the structures was measured at different points of time. These formed structures of the invention showed 15 strength retention over 18 weeks without remarkable strength loss. Results of shear strength and inherent viscosity during the degradation are presented in Tables 2 and 3.

Example 7 20 A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 22% ceramic (TCP) and self-reinforced (DR=4.5) into composite structures.

The same tests were carried out as in Example 6. These composite structures of the invention showed strength retention over 16 weeks without grammatical strength loss.

δ 25 c\j g These composite structures of the invention showed strength retention over 16 weeks cd without remarkable strength loss. Results of shear strength and inherent viscosity during x the degradation are presented in Tables 2 and 3.

O- oo 30 Example 8 δ c\j A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 22 wt-% ceramic (TCP) and self-reinforced (DR=4.4) into composite structures.

20

The same tests were carried out as in Examples 6 and 7. These composite structures of the invention showed strength retention over 20 weeks without grammatical strength loss.

These composite structures of the invention showed strength retention over 20 weeks 5 without remarkable strength loss. Results of shear strength and inherent viscosity during the degradation are presented in Tables 2 and 3.

Example 9 10 A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 22 wt-% ceramic (TCP) and the resulting composite was self-reinforced (DR=2.5) into surgical structures.

The same tests were carried out as in Examples 6-8.These composite structures of the invention showed strength retention over 18 weeks without remarkable strength loss.

15

Example 10 A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 22% ceramic (TCP) and the resulting composite was self-reinforced (DR=2.5) into surgical structures.

20 The same tests were carried out as in examples 6-9. These composite structures of the invention showed strength retention over 22 weeks without remarkable strength loss.

Example 11

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o 25 A terpolymer of the invention (85L/5D/10G PLDGA) was mixed with 50 wt-% ceramic cb (TCP) and the resulting composite was self-reinforced (DR=2.2) into surgical structures.

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x The same tests were carried out as in examples 6-10. These composite structures of the 0_ invention showed strength retention over 20 weeks without remarkable strength loss.

C\J o r\ co 30 co ^ Example 12 c\j A terpolymer of the invention (85L/10D,L/5G PLDGA) was mixed with 22 wt-% ceramic (TCP) and the resulting composite was injection molded into surgical structures.

21

The same tests were carried out as in examples 6-11. These composite structures of the invention showed strength retention over 6 weeks without remarkable strength loss.

5 Example 13 A terpolymer of the invention (85L/10D,L/5G PLDGA) was mixed with 22 wt-% ceramic (TCP) and the resulting composite was injection molded into surgical structures.

10 The same tests were carried out as in examples 6-12 .These composite structures of the invention showed strength retention over 6 weeks without remarkable strength loss.

Example 14 15 A terpolymer of the invention (75L/20D,L/5G PLDGA) was mixed with 22 wt-% ceramic (TCP) and the resulting composite was injection molded into surgical structures.

The same tests were carried out as in examples 6-13 These composite structures of the invention showed strength retention over 6 weeks without remarkable strength loss.

20

Example 15 A terpolymer of the invention (75L/20D,L/5G PLDGA) was mixed with 22 wt-% ceramic (TCP) and the resulting composite was injection molded into surgical structures.

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0 25 c\j σ> The same tests were carried out as in examples 6-14 .These composite structures of the σ> invention showed strength retention over 6 weeks without remarkable strength loss. 1 cc

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Example 16 CM

co 30 co ^ A terpolymer composite of this invention will demonstrate total biodegradation (i.e. total

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mass loss) within 1.5-4 years biodegradation in physiological conditions (Figure 7). The total biodegradation time depends on terpolymers chemical structure, amount of additive material, type of additive, temperature, moisture, patient related factors, etc.

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Claims

A biocompatible and bioabsorbable composite material for use in surgical devices, characterized in that it comprises a bioabsorbable polymer consisting of a PLDGA terpolymer of the type 60-90 mol% L / 1-20 mol% D / 1 -20 mol% G containing from 1 to 99% by weight of the biocompatible additive, based on the weight of the composite, wherein the biocompatible additive comprises one or more biocompatible ceramics dispersed as one or more additive components. 10

The composite material of claim 1, wherein the biocompatible additive component comprises one or more biocompatible ceramics selected from calcium phosphate ceramics including hydroxyapatite (HA), alpha-tricalcium phosphate, beta-tricalcium phosphate, monocalcium monohydrate, monocalcium monobasic DCPD, or brushite), dicalcium phosphate anhydrate (DCPA, or monenite), octa-calcium phosphate (OCP), amorphous calcium phosphate (ACP), calcium-deficient hydroxyapatite (CDHA), and tetracalcium phosphate tricalcium phosphate 20 (beta-TCP).

Polymer composite material according to any one of the preceding claims, containing one or more additives which facilitate the processing of the material or alter its properties, such as stabilizers, antioxidants, adhesion promoters and plasticizers, or facilitate its handling, such as colorants, wherein the additive σ> is preferably a dye. i O)

Composite material according to any one of the preceding claims, formed from a mixture of 80 mol% L / 5-15 mol% D / 5-10 mol% G PLDGA g 30 and 10-60% biocompatible additive. δ C \ J

A polymeric composite according to any one of the preceding claims, selected from: - a mixture of 85 mol% L / 5 mol% D / 10 mol% G PLDGA and 22% w / w tricalcium phosphate (TCP) based on the weight of the composite , - a mixture of 85 mol% L / 5 mol% D / 10 mol% G PLDGA and 50% wt TCP, 5. mixture containing 85 mol% L / 10 mol% D / 5 mol% G PLDGA plus 22 wt% TCP, - a mixture of 85 mol% L / 10 mol% D / 5 mol% G PLDGA and 50 wt% TCP mixture containing 90 mol% L / 5 mol% D / 5 mol% G PLDGA and 22% w / w TCP, and - a mixture containing 90 mol% L / 5 mol% D / 5 mol% G PLDGA, and 50 wt% TCP.

The polymeric composite according to any one of the preceding claims, which is a mixture of 85 mol% L / 5 mol% D / 10 mol% G PLDGA and 22% TCP, based on the weight of the composite.

A surgical device capable of at least partial absorption under tissue conditions, characterized in that it comprises a bioabsorbable composite material according to any one of claims 1 to 6.

The surgical device of claim 7, which is a spike, screw, interference screw, plate, stud, bolt, core nail, suture anchor, wedge, wire, thread, co suture, or wound hook. ^ 25

A process for making a surgical device according to claim 7 or 8, wherein one or more additives according to claim 2 or claim 3, or both, are mixed and performed in the composite material composition. mechanical treatment, characterized in that the mechanical treatment is selected from injection molding, C \ J CO 30 extrusion, self-reinforcement, other deformation solid state orientation techniques and pultrusion.

The method of claim 9, wherein the mechanical treatment is carried out by drawing the composite blank at a temperature higher than its glass transition temperature but lower than its melting point to obtain a pull ratio of 1.01-20.

The method of claim 10, wherein the drawn structure is cooled to room temperature under tension.

The method of any one of claims 9 to 11, wherein the structure which has undergone mechanical treatment is further shaped by machining, stamping, turning, milling, cutting, molding, thermoforming or a solvent method. co δ c \ j i O) o O) X cc CL 1 ^ C \ l CO CO δ CM