CA1261991A

CA1261991A - Method of producing biodegradable prosthesis and products therefrom

Info

Publication number: CA1261991A
Application number: CA000469900A
Authority: CA
Inventors: Richard L. Dunn; Robert A. Casper
Original assignee: Southern Research Institute
Current assignee: Southern Research Institute
Priority date: 1983-12-19
Filing date: 1984-12-12
Publication date: 1989-09-26
Also published as: EP0146398A3; US4655777A; EP0146398A2; JPS60153868A

Abstract

ABSTRACT OF THE DISCLOSURE
Method of producing biodegradable prostheses comprising a composite of resorbable fibers reinforcing a biodegradable polymer matrix and the use thereof in medical applications such as bone plates and other orthopedic devices. The fibers include ceramic powders, .beta.-TCP and CaAl and a biodegradable glass, CMP.

Description

.
l~
BACKGROUND O~ THE INVENTION
The need for improved methods and materials to manage severe maxillofacial injuries is well recognized, In such cases, ~be surgeon faces the dual problem o~ restoring ~unction and appearance. The patient su~erlng ~rom an extenslve ma~illo~acial in~ury is typically confronted with dis~igurement, impaired speech, and eating di~iculties as well as the psychological trauma resulting ~rom the injury.
Ideally, ~ixation applicances should maintain the ~ractured bone se~ments in close approximation ior the promotion oi primary union Qnd heal1ng~ provide su~icient strength and rigidity to prevent disruption o~ the primary union by external ~orces, and as the union becomes ~urther osslfied, trans~er an ~ncreasing proportion oi the external load to the healing bone so that it wlll be strained and exercised. The iulPillment o~ these crlteria is necessary i'or the Yormation o~ healthy, hard tissue that has properties commensurate with those o~ virgin bone.
Implant materials used ~or such in~uries over the years belong to three traditional classes: metals, c~ramics, and polymere. The choice of material ior the particular application depends on the type and magnltude of applied loads which the lmplant is expected to experience in vivo and whether the implant ~is to be a permanent or a temporary augmentation. When trying to make repairs to the skeletal system, surgeons and engineers must ~tlemp~ to replicate the static and dynamic responBes o~ bone.

` ~ ~
~.,., I , :~

-Bone consists of a ~ramework of collagenous fibers, a m1neral matri~ consisting primarily o~ calcium hydroxyapatite, and a small amount of polysaccharides. Although bone is stronger and less deformable than polymeric materials, it is weaker than metals.
Historically, metals have received wide application for the construction of devices for fixing fractures. Metals exhibit high values of tensile strength and compressive modulus; they can be fabricated into flxation hardware by a variety of conventional techniques; and they provide excellent resistance to the in vivo environment. Met~ls and alloys now used as surglcal implants include 31~ stainless steel, several cobalt-chromlum alloys, titanium, zirconium alloys and tantalum.
In mandlbular i'racture repair, one o~ the major disadvantages with metal implants is atrophy oi' ~he healing bone as a result of the stress-protectlcn eP~ect o~ the rigid metal plate. Other drawbacks with metal fi~ation appliances are that they may cause local ln~lamation and maY corrode with age.
Among the metallic materials, tantalum is superior in resistance to corrosion and has been extensively employed as i'ixation plates i'or ~ractured bones and as implants. The metal is, however, difficult to process. In contrast, ceramic materlal6 show good affinity to bones often with bone tissue penetrating into the fine pores of the ceramic to produce a strong ~i~ation.
Bone and tissue compatibility with ceramics is e~cellent. The main disadvantage of ceramic materials is their poor impact strength as they are oi'~en brittle. This conditlon is quite evident with the more porous ceramic~ and leads to poor durabili~y o~ ceramic implant6 and fixation devices. On the other hand, polymeric materials provide excellent impact strength, good biocompatibillty, and they are easlly molded to the desired shape;

¦however, they do not possess the requlred strength and stifPnes6 ~¦~or bone fi~ation.
,~ Those materials and many o~ the prior art materials ¦Isufi'er from the common drawback of being permanent. In many ;lapplications, such as a fixation appliance holding ~ fracture together while it heals, it is highly desirable if the implant can be resorbed by the body. Such an implant would biodegrade over Q
period of weeks or years, and be gradually replaced by natural bone growth. Such materials eliminate the need for a second surgery to remove the implant. However, homogenous fixation plates previously fabricated ~rom biodegradable polymers have been shown to possess 1nsu~icient strength and rigidlty i'or lnitial iracture fixation. Porous resorbable ce~amics have also been used in bone repair, but they must be used in con~unction with other support because o~ their fragile nature.
The prior art includes U.S. Patent No. 3,929,971 which discloses a synthetic material (either hydroxapatite or whitlockite) that may ~e used with other materlals, such as organic polymers, to iorm a composite substance which could be use~ul in constructing a degradable prosthetic implan~; U.S0 Patent No. 3,905,047 which discloses a blodegradable prosthesis containing an eutectic or metal pyrophosphate and high-modulus ~ibers ~ormed o~ a reYractory metal oxide; U.S. Patent 4,330,514 is directed to a process ior preparing a hydroxyapatite ceramic which is used in a nondegradable implant comprising the ceramic and an organic bindin~ ma~erial; and U.S. Patent 4,356,572 which is directed to a porous biodegradable bone implant which utilizes calcium carbonate ln crystalline ~orm.

, ~, ..

?~:~

SUMMAHY ()F Tl~ lNV~N'r~N

~ he disadvantages of -the prior art are overcome by the present invention comprising biodegradable, high-strength, rigid fixation systems formed of composites of biodegradable polymers reinforced with resorbable fibers, particularly calcium phosphate fibers; the degradation products of the composites of the present invention are nontoxic and harmless to the host. The preferred polymers include polyglycolide (~GA), poly(~L-lactide) (~L-PLA), poly(DL-lactide-co-glycolide) (DL-PLG), poly(L-lactide) (L-PLA), poly(L-lactide-c~-glycolide) (L-PLG), polycaprolactone (~CL), polydioxanone, polyesteramides, copolyoxalates and the polycarbonates because of t~eir degradation times and their degree of control of degradation.
'rhe relnforcing fibers include the ceramic or the preferred glass forms of calcium phosphate. The ceramic fibers include those comprising R-tricalcium phosphate. These fibers may be prepared by wet-spinning mixtures of the powders with different polymeric binders, such as polyacrylonitrite (PAN-A), and solvents, such as dimethyl suifoxide (~MS~). Ceramic loading, oxidative pretreatment, coupling agents and sintering conditions affect spinnability and fiber properties. ~`ibers of phosphate-free calcium aluminate (CaAl) produced by the same process may also be used although the resulting fibers are fragile and may fracture easily.
Due to the highly porous and fragile nature of the fibers produced from the ceramic powders, the preferred fibers of the present invention are glass fibers. Smooth, uniform fibers of calcium metaphosphate ~Ca(PO3)2](CMP), a bioabsorbable glass, may be prepared by extruding or pulling filaments from a melt and air quenching. ~ibers can also be prepared by the same process from a partially bioabsorbable glass compbsed of a mi~ture of silicon dioxide, sodium oxide, calcium oxide and phosphorous pentoxide.
It is preferred to use continuous filament fibers so that a high ratio of length to cross sectional area is ob-tained, the length to diameter or aspect ratio ranging from 10:1 to 1,000,000:1.
The invention in one broad aspect pertains to a method of producing a biodegradable prosthesis, comprising the steps of encasing an effective amount of resorbable fibers 10 selected from the group consisting of calcium phosphate and calcium aluminate in a matrix ofa biodegràdable synthetic polymer to form a composite, the effective amount ranging from 10 - 90% by volume and the aspect ratio of said fibers ranging from 10:1 to 1,000,000:1, and forming the composite to the desired prosthetic shape.
Another aspect of the invention pertains to a method of producing a biodegradable fracture-fixation appliance reinforcement, comprising the steps of preparing resorbable calcium phosphate fibers having an aspect ratio of 10:1 to 20 1,000,000:1, incorporating from 10 - 90~ by volume of the fibers within a nontoxic biodegradable polymer to form a composite, and fabricating the reinforcement from the composite.
Another aspect of the invention comprehends a bio-degradable prosthesis, comprising a biodegradable polymer matrix and fibers selected from the group-consisting of calcium phosphate and calclum aluminate incorporated within the matrix in an amount ranging from 10 - 90% by volume and the fibers having an aspect ratio of 10:1 to 1,000,000:1.
Still further, the invention comprehends a method of 30 producing a totally biodegradable composite material for :~ pros~hetic and implant devices, comprising the step of encasing an effective amount of a reinforcing material in the form of fibers selected from the group consisting of calcium :: ~
:.

,:,, d ~ !~ u phosphate and calcium aluminate in a matrix of a polymer selected from the group consisting of polyglycolide, poly(DL-lactide) r poly(L-lactide), polycaprolactone, polydioxanone, polyesteramides, copolyoxalates, polycarbonate, poly(glutamic-co-leucine) and blends, copolymers and terpolymers thereof.
Yet another aspect of the invention pertains to a totally biodegradable composite material for prosthetic and implant devices, comprising from 10 - 90% by volume of a reinforcing material in the form of fibers selected from the group consisting of calcium phosphate and calcium aluminate, and a polymer encasing the reinforcing material, the polymer being selected from the group consisting of polyglycolide, poly~DL-lactide), poly(L-lactide), poly-caprolactone, polydioxanone, polyesteramides, copolyoxalates, polycarbonate, poly~ylutamic-co-leucine) and blends, copolymers and terpolymers thereof.

- 7a -'~: J
. ,.

~ 7~

D~TAIL~ UE~CRIPTI~N OF TH~ ILI.USTRATIV~ M~OI)IMLNT

The present invention relates to the incorporation ofhigh-strength, high-modulus, biodegradable fibers in biodegradable' polymers to form totally absorbable fracture-fixation plates or devices. The use of two bioabsorbable ceramic powders, ~-TCP and CaAl, and a bioabsorbable glass, CMP, is described.

A. Preparation of Ceramic Materials -~ one contains a matrix of calcium hydro~yapatite, a resorbable ceramic material, in callagen. The calcium hydroxyapatite provides rigidity and the same material, when incorporated into biodegradable polymers, should provide the necessary reinforcement for use as fixation plates or devices. A
variety of` ceramic forms of hydroxyapatite [CalO(~4)~(~H)~l and tricalcium phosphate [CA3(P04)~l have been reported in the literature. Recent evidence indicates that ceramic forms of hydroxyapatite ar~ inert as implant materials while those of tricalcium phosphate (Whitlockite) are bioabsorbable. The strength, durabllity, and absorption kinetics of tricalcium phosphate ceramics depend on the phasic nature of tbe final product, the lattice structure of the phases present, and the porosity and total surface area.
Preparation of a calcium phosphate ceramic of high purity and single-phase nature is accomplished by the precipitation method of Salsbury and Doremus for pro~uction of ~-Whitlockite (~-TCP), as follows:
A solution of calcium nitrate (1.40 moles) in 900 mL of distilled water is brought to pH 11 to 1~ with concentrated .. . . . .. ... .. . .. ...

ammonium hydroxide and thereafter diluted to 1~00 mL. A solution of ammonium phosphate (1.00 moles) in 150n mL distilled water is brought to pH 11 to 12 with concentrated ammonium hydroxide and thereafter diluted to 3~00 mL to dissolve the resulting precipitate. The pH is again checked and additional concentrated ammonium hydroxide is added if necessary.
The calcium solution is vigorously stirred at room temperature, and the phosphate solution is added ln drops over 30 to 40 minutes to produce a milky, somewhat gelatinous precipitate which is then stirred overnight (more than 1~ hours). The reaction mixture is then centrifuged, and the clear supernatant fluid decante~. The resulting mineral sludge is homogeneously resuspended in distilled water to serve as a feedstock.
To produce green states which should afford lOU%
~-Whitlockite ceramics, aliquots of the feedstock are recentrifuged, homogeneously suspended in two volumes of dilute a~ueous ammonium sulfate (1 to 2%) and then filtered on a Buchner funnel with application o~ mild suction and a rubber dam. After filtration for several hours, the compact clay-like cake is drie~
intact at 9~C for 15 hours to prodllce directly the green state.
~intering conditions, of course, may vary with the material and the phase or phases desired in the final productO
For the production o~ ~-Whitlockite, the green cake may be placed on an alumina dish and initially heated to 60UC over 0.5 hours.
The temperature is then raised quickly to 1150C, the cake is slntered isothermally at llS0C for 1 hour, the temperatllre is reduced to 900C, and the ceramic is cured at 900C for 4 hours.
Calcium aluminate is another resorbable ceramic material. Calcium aluminate of a 50:5U Ca/Al wt % composition [CaAl204] (CaAl) was 6U% resorbed after one year implantation in monkeys, The Ca/Al rntio can he varied to produce several ,,,, , . . ....... .. _ ¦~combinat~ons of crystallographic phases and the various phases ~hydrolyze at varying rates providing a method ~or controlling the l¦rate of ceramic dissolution. CaAl can be purchased ~rom Pialtz &
¦¦~auer, Inc~, Stamford, CT consisting o~ CaA1204 with quantities o~ Al203 and Cal2All4022 as impurities.

. Preparation of Fine-Particle Sized Ceramic Powder ~ o prepare rei~orclng ceramic iibers, especially with small diameters, it is necessary that the ceramic material con6i~t of small particlee. The s~all part1cles allow the estru~lon Or small-diameter ceramic ilament~, and the finer particle 6ize results in greater densliicatlon on sintering. Greater den~iiication and t~e ~ssoclated reduction ln void volume oi ~ormed articles produces ceramic products, whether ln pellet, rod or ~iber ~orm, with greater 6trength and structural rigidity. In addition, the bre~kinB strength oi sintered cer~mlc ~ibers ~6 usually inversely proportional to the diameter o~ the ~lber; thus, the smaller the ~lber, the stronger lt i~ per unit ~ize. The sa~e relationship has been iound with ~lntered TCP ~ibers.
One method to reduce the ceramic powder to small 20 particles is the use o~ a Megapack high-energy vibrAtory mill.
The system employs the u~e o~ ~mall-diameter steel balls vlbratlng at high ~requencles ~or grlnding o~ ceramic powders. The procedure u~ed to grind ceramlc ~amples to ~lne partlcle ~izes wi:th thls mlll is a6 ~ollows: A slurry oi TCP (or phocphate-~ree C~Al) ln WQter ~as added to the vibratory mill, and the mlll ~a6 activRted and allowed to run ~or 4 hour~. During that tlme, ~ample~ were take~ a~ periodia intervals and e~amined by scanning electron microscopy ~SEM) to determine particle-slze range. A
m111ing time o~ 4 hOUr6 W~6 ~ound to be sui~i~lent to yteld ~ particles in the l- t~ 2-~m range. At the end o~ that time, the *trademark ~ ~1 slurry was removed from the mill and centrifuged for 30 minutes at 100 g. The supernatant was decanted and dimethyl acetamide was added to the centrifuge bottle; the contents were then agitated to resuspend the compacted ceramic powder. This process was repeated several times until all of the water was replaced by dimethyl acetamide.
The vibratory milling technique allowed preparation of slurries of ceramic powder in the appropriate polymer solvent both effect~vely and ef~iciently. Ceramic particles in this size ranKe were appropriate ~or use in the wet-spinning o~ ~ine diameter iilaments.

C. Wet-~pinnin~ of_C_ramic Fibers Usi_g Polymeric Binders Of the number o~ methods for use in the production o~
ceramic fibers e~amined, i'iber production by wet-spinning appears to be the most success~ul method, Sim~listically fipeaking, ~iber production by wet-spinning involves extruding a mlxture o~ cera~ic powder, binder (PAN-A), and solvent (DMSO) into a trough or bath contalning a non-solvent ~or the binder. During extruslon into the non-solvent bath, the mixture coagulates to ~orm a ~iber or ~ilament. For s~1ccess fn making fibers by wet spinning, the solvent ~or the binder must be soluble in the coagulating bath, which must be ~ non~solvent for the binder.
The fibers or ~ilaments are subsequently drawn from the coagulating bath using a series oi water-~lushed, heated godets to rinse and evaporate the remaining solvent. A~ter passing through the rlnsing and drying system, the ~bers are taken up on a winding reel. The collected ~ibers are then soaked in dlstilled water to assure complete solvent removal and are, therea~ter, drled in an alr-circulating oven to produce the final dried i'lber.
For the production o~ fibers ~rom both ~-TCP and phosphate-~ree ' ' '':

~CaAl, it is necessary to sinter the dried fibers ln an inert atmosphere (nitrogen) maintained above 1150C to achieve coalesence and densification of the ceramic particles.
l. Polymeric Blnders As a consequence of the elevated temperature required for proper sintering of both~-TCP and phosphate-~ree CnAl, polymeric binders with superior thermal stability are required for use in the wet-spinning process. Although no resin yet produced is capable of withstanding these temperatures, three highly thermally stable resins ~ere examinéd to see i~ they mlght effectively bind the ceramic powders together in ~iber form until preliminary sinterlng (lower temperature) was achieved. These binders were Bare~ 210 (Vistron Corp., Chemicals Dlvision, Cleveland, OH), a terpolymer mostly composed o~ acrylonitrile;
Polyacrylonitrile Type A (PAN-A) (Du Pont, Wllmlngtsnl DE); and Ethocel ~1 Standard (Dow Chemical Co., Mldland, UI), an ethylcellulose material.
The thermal stability o~ PAN-A and, hence, the spun fiber, may be enhanced by subJecting the material to an o~idative pretreatment. The pretreatment lmproves thermal stability by forming a ladder polymer. Ethyl cellulose o~ered s~mllar thermal stability without the necessity o~ a pretreatment step, although the fibers prepared ~ith ethyl celluloæe are lnierior to tho~e ~ith PAN-A as a binder.

2. Dlspersin~ agents In wet spinning o~ ceramic ~ibers, dispersing agents are o~ten used to prevent clumping o~ the ceramic particles and plugging o~ the in-llne ~ilter screen. Nuosper~e, obtalned Yrom Tenneco Chemlcals (Plscat~way, NJ) is more compatlble wlth the spinnlng solvent, D~SO, than Tamol 9~0 and Tamol SN fro~ Rohm and Haas tPhiladelphia, PA). It was successi'ul in preventlng clumping * Trademarks ~ .,, ¦¦of the ceramic particles, and its addition to the spinning dope ¦improved the spinnability of the ceramic mater~als.

3. ~TCP fibers TCP powder ~repared as described previously was wet sieved using No. 6~ (250-~m) and No. 140 (160-~m) sieves. The fine particle cut was used to make the spinning dope. TCP was mixed with a solution of PAN-A in DMS0 to make up the spinnlng composition~ Care was taken to remove any entrapped air bubbles.
The final spinning dope consisted of 7.4% TCP, 1.8~ PAM-A, and 90.8% DMS0 on a weight basis.
Fibers were prepared by wet extrusion using a hypodermic syrlnge and hypodermic needles of varlous sizes. The needles ranged from 15 G (1~37 mm ID) to 27 G (002 mm ID). Distilled water at room temperature was used as the coagulating medium. The spinning dope was loaded into the syringe barrel, and the tip o~
the needle was placed below the surface o~ the coagulating fluid.
Pressure was applied until a bead of coagulum formed at the needle's tip. The bead was grasped with a pair of tweezers and pressure was reapplied to the syringe barrel. Fibers were extruded ~or the length o~ the coagulating bath. Fibers prepared using the smaller diameter needles were considerably more difficult to extrude than ~lbers prepared uslng the larger ~eedles. The extruded fibers were removed irom the coagulatln8 bath and placed iD another water bath and allowed to soak to remove solvent. After soaking for a su~ficlent time, the fibers were removed from the bath with tweezers and placed on Teflon sheeting to dry in air overnight. The smaller fibers were easier to handle and exhibited more struc~ural integrity. This was probably due to a higher resldual solvent content in the larger ~lbers.

B -TCP fibers were also prepared on wet~spinning equipment designed ~or production o~ rayon fibers. A spinning dope consisting of 10% R-Tcp~ 15% ~arex 210 ~crylic polymer, and 75~ N,N-dimethylacetamide was loaded into a cylindrical, stainless steel iee(i pot. The feed po~ was pressurized with compressed air ~0 psi), and the spinning dope was $orced from the feed pot through stainless steel tubing (0.25-in.-0~, type 304) to a Zenith gear pump driven by a Zenith Model QM drive motor. The Zenith pump delivered the spinning dope (at 0.~ cm~ per revolution;
1.45 cm3/min) to a spinneret with an orarice diameter o~ 0.020 in. The spinneret was submerged in a water bath. As the spinnin~
dope came in contact with the water, it coagulated to form a fiber. After traversing the coagul~tion bath (1~ in.), the ~iber was taken up by the fir~t godet. This godet (80 ~t/min sur~ace speed; 107F) was equlpped with a tap water spray to remove solvent ~rom the ~iber. The iiber was then taken up on a second heated gode~ ~84 ~t/min suriace speed; 97F) and rinsed with a warm water spray. The iiber was passed around a third heated godet (87 ft/min sur~ace speed; 105F) and collected on a Leesona Model 955 take-up winder.
The fibers were then sub~ected to oxidatiYe pretreatment to promote the formation Or a ladder polymer and enhance the thermal stability of the binder matrix. Pretreatment was accomplished by placing the fibers in an air-circulatlng oven maintained at 200C for 3~ minutes. Pyrex test tubes were used to contain ~he fibers during the pretreatment process. The ~ibers changed from white to tan during pretreatment.
After pretrea~ment, the ~ibers were sintered in a Lindberg ~levi-Duty SB oven* The oven was malntained a~ 1~00C and~
purged with nitrogen for the duration of the sintering cycle. The *Trademark .' 1 1~7~
sintered ~ibers were light yellcw. A~ter sinterlng, soma of the ~ibers shrank to less than 40% oi their original diameter.
The ~lbers were tested gor breaking strength on an Instron*Model TUS Serlal 72 testing machine. The ~ibers were prep~red ~or testing by mounting on cardboard tnbs. The ~inest fibers were attached to the t&bs wlth p~ra~in, aDd the larger fibers were attached with sealing wax. Samples were pulled at a rate of 1 in./min. until ~racture occurred and the ~orce at break was determined. After being tested, the samples ~ere removed ~rom the Instron, the dlameter at the $racture point was determined with a micrometer and used to calculate the brea~ing strengtb in terms of ~orce per unit area. The ~racture suriacea were the~
e~amined by SEM. The test results are presented in the iollo~ing table:

B~EAKING STRENG~H OF TRICALCIU~ PHOSPHATE FIBERS
. , _ . .
Average diameter Breaklng strength mm _ psi 0.508 353 0.~5~ 6~
0.124 419 0.122 477 0.074 1607 There is a dramatic e~ect o~ ~lber diameter on tensile strength. As ~iber dlameter decreases, the Rtrength incre~ses.
Such behavior is commonly ~ound in the preparation o~ ceramic Sibers. Results shown in the table reflect the average o~ test results ~or ~lve specimens o~ each ~ibsr diameter. One sample o~
~ the smallest diameter fiber had a tensile strength o~ 2500 psl.
SE~ photos showed voids and irregularities at the ~racture sur~ace of all specimens. In general, larger voids were asaociated wlth lo~er breaking strength, reilecting the streS~-cODCentrating effect~ o~ the irregularities.
trademark ~ 15 -; ~, .'r.. '' "'~ ~ `.

4. CaAl fibers Fibers of phosphate-free calcium aluminate were prepared following the procedures used for ~-TCP ~iber production and usin~
the same solvent and binder. A~ter sintering, the fibers were quite fragile.
Calcium aluminate (Pfaltz & 13auer, Inc., Stamford, CT) was used to prepare the fibers. X-ray diffraction analysis revealed that the powder consisted of CaAl~O~ but also contained significant amounts of Al2()~ and Cal2Al1~l0~. 'rhe CaAl ~as dry sieved through a No. 100 sieve (150-~m) to break up any clumps and remove any large particles.
! The spinning dope had a ceramic-to-binder ratio of ~0:2() and consisted by weight of 25% CaAl, ~% ~AN-A, and 6~% UMSO.
Fibers were extruded from a hypodermic syringe and needle, as were the TCP fibers. Needle siz~es 15 G through 25 G were used to form fibers, The 27 G needle proved to be too fine for the CaAl dope.
The fibers were coagulated in a tap-water bath at ambient temperatures. The coagulated fibers were quite rigid and easier to handle ~han the TC~ ~ibers at this stage. CaAl fihers were also prepared by the pilot-scale equi~ment used for the ~-TC~
fiber production. A 70:30 by wt blend of CaA1 and Barex 210 in a suspension in N,N-dimethylacetamide was extruded at a rate of 1.75 cm3/min into tap water at 70~F. The ~irst and second godets were operating at a speed of 94 ftJmin and the third godet at a speed of 96 ft/min. The temperatures were 110, 115, and 115F for the three godets respectively. The fibers were dried at ambient conditions overnlght. Oxidative pretreatment was performed in a circulating-air oven at 200C for 30 minutes. ~rior to oxidation the fibers were white. Aft~r oxidation the fibers turned brown.
The fihers were then placed in an oven under a nitrogen purge, heated at 1200C, held for 1 ho~lr, .

: ::

l . ~
and allowed to cool overn~ght. When the fiber~ were removed ~rom the oven, they wers ~ound to be e~tremely ~ragile.
¦D. Fiber Production ~rom Blod~ radable Glas6es Although sintering oi ceramic particles produces bioabsorbable ceramic ~ibers, the volds still preeent ln the ~ibers c~use them to be somewh~t ~ragile and ~eak. A void-~ree ceramic ~iber produced by melt~ng and extrusion o~ a bloabsorbable glass gives a stronger and more durable ~iber ~or u~e ln polymer reinforcement. Gla~ses are converted to ilbers by drawlng ~iber~
~rom hot melts. The high ~ur~ace tension and 810w r~te o~ change oi' viscosity wlth temperature o~ melted glass permit6 ~ormation oi stable meniscuses and enables ~ibers to be ~ormed and drawn irom a suitable crucible aYter the natural ~lo~ o~ molten glass downward by gravity. Both marble melt and direct melt proceæses are used to produce gla88 ~ibers.
1. ~io~l~ss ~ibers Bioglass i8 a partially biodegr&dabl~ gla66 composed o~
~5% silicon dlo~ide, and various metallic o~ideR (sodium o~ide, calcium oxide and pho~phorous pe~toxide). Only the sllicon dioxide portion of the glass is non-absorbable.
Fibers ~ere prepared from the Bioglas~ by heating the material in a crucible until it beca~e molten (900 C) a~d ~ithdrawing Yilaments wlth a stainless steel rod. Fibers ~ere produced by thls procedure, but there was considerable varlation in both ~iber dlameter ~rom sample to s~mple and unirorm~ty o~
dlameter throughout the length o~ a given ~ampl~. Samples o~ the glass ~ibers were mounted and tested ln the same manner as the ceramic iibers. Breaking strength oi the gla~s iibers varied ~rom 9000 to 50,000 psi~ This variation ~as to be expected in view oi the lack of uni~ormity from one sample to the ne~t. However, the iormation o~ iibers ~ith hlgh ten~ile strength~ was evident.

*trademark Fibers prepared in the fashion described above were tested for bioabsorption. Samples of the fibers were cut into 2-in~ lengths for breaking strength detemination, and the 2-in.
lengths were weighed, Some fibers were mounted and broken to determine initial breaking strength. Their average initial breaking strength was about 45,000 psi, and their average diameter was ~.026 mm. The remaining fibers were placed in phosphate-buffered saline a~ a pH of 7.2 in a 37 C oven for 18 ! days, The fibers were then removed Yrom the saline, dried, I reweighed, and broken to determine final breaking strength, Their ;, average wei~ht loss was about 5%, and their average breaking strength was less then 200 psi.
2. ~MP fibers CMP is known as a hydrolytically unstahle glass, Consisting of calcium and phosphorous, it degrades within the body to harmless components of normal body fluid. CMP, however, must be properly purifled before it can be spun into fibers for use in reinforcin~ biodegradable polymers~ F'ollowing the procedure g1ven in U.~. Patent No, 4,~)4~,779, CMP of sufricient purity ~or fiber formation is obtained. One liter of a 3-molar solution of phosphoric acid was prepared. One hundred grams of CaCo3 was then slowly dissolved in the acid solution. Impurities were removed by precipitating with 2,5 g of ammonium 1-pyrrolidine dithiocarbamate dissolved in 50 mL of water. The resulting grey precipitate was then removed by filtration. The supernatant was concentrated by evaporation, and the pure CMP was precipitated.
The precipitate was ~iltered and washed with acetone to remove any residual phosplloric acid. Th~ whit~ material was then placed in ~ an alumina dish and baked in an oven at 600C ~or 24 hours, 800C

for 7~ hours, and cool~ slowly to room temperature. l`he baking ' ' : '. :

i steps allow the CMP salt to be chemically condensed and i polymerized to produce the CMP glass.
The resulting grey, foamed, brick-llke substance is then placed in an alumin~ or platinum crucible, heated in an oven at 600~C for 2 hours, at 800C ~or 16 hours, and at 1000C for 2 hours, after which time the crucible is removed from the oven and trans~erred to the ~iber drawing apparatus. This equipment consists of an oxygen/natural gas heating source ~or the crucible and a 3.75 in, -OD stainless steel take-up spool ~or drawing the ~ibers, The speed o~ the spool can be controlled to produce flbers with the desired diameters. A typical draw speed of 7.2 in./sec. is used. The spool is also heated with a natural gas ~lame. By insertlng the tip o~ a stainless steel rod into the molten glass, a ~iber c~n be drawn from the melt and passed around the take-up spool. IP the melt is maintained at the proper temperature (~1000C), a very fine glass ~iber can be wound on the take-up spool. The resulting ~ibers have good strength and uniformity. A typical ~iber has a tensile ~trength oi approximately 51,0~0-110,000 psi, an initial modulus o~ 5 x 106psi, a diameter of about 5 mils, and ~ density o~ 2,67 g/cm3. These properties are comparable to commercial glass flbers.
In vitro studies o~ the CMP ~ibers in 0.9% U~P sallne at 37C show the fiber begins to dissolve irom the surface after only lO days, and they are completely dlssolved a~ter 30 day6.

D. Biode~radable COmDOSiteS
For the hlgh-strength, high-modulus, bioabsorbable ceramic or glass flbers to be useful, they must be incorporated lnto a biodegradable polymer matrix. The matrix protects the flbers from abrasion and breakage, and they provide a structure 3~
I for bone-fixation plates. The fibers in return provide the structural rigidity needed for the polymer plate or device to maintain support.

1. Biodegradahle Polymers The following polymers (with their approximate degradation times) are all candidates for the biodegradable composite of the present inventlon~ These polymers are all biodegradable to water-soluble, nontoxic materials which can be eliminated from the body. All are well known for use in humans and ~heir safety has been demonstrated and approved by the FDA.
Although these polymers are normally linear, crosslinked reslns can be prepared from these materials by those skilled in the art, and these materials are also included as suitable biodegrudable polymer matrices.

Polymer Polycaprolactone 24-36 Poly(L-lactide) 24 Poly(DL-lactide) 12-18 Polyglycolide 3-4 95:5 Poly(~L-lactide-co-glycolide) 12 9O:lO Poly(DL-lactide~co-glycolide) 10 85:15 Poly(DL-lactlde-co-glycolide) 9 75:25 Poly(DL-lactide-co-glycolide) S
50:50 Poly(DL-lactide-co-glycolide) 2 9O:10 Poly~DL-lactlde-co-caprolactone) 9 75:25 Poly(DL-lactlde-co-caprolactone) 6 50:50 Poly(~L-lactlde-co-caprolactone) 2 Polydioxanone 12 Polyesteramides 4-12 Copolyoxalates 4-12 Polycarbonates 2-12 Polg(glutamic-co-leucine) 2~-48 The pre~erred polymers are the poly(DL~lactide-co-glycolide) materials because of the degradation times and their degree of control of degradation. The poly(L-lactide-co-glycolide) materlals not mentioned ln the table should give similar results. Poly(DL-lactide) is also pre~erred as are the polydioxanone, polyesteramides, copolyoxalates and ~he polycarbonates, Polycaprolactone, poly(L-lactide), and the l poly(glutamic-co-leucine) are less preferred because of their long ¦¦degradation times.
With a composite formed from a biodegradable polymer and resorbable fibers, the strength decreases with resorptlon time within the body. This decrease in strength is important because the ~ixation plate trans~ers the load with time to the healing bone and prevents stress protection atrophy. The loss o~ strength of the polymer plates rein~orced with biodegradable ~ibers will depend primarily upon the degradation rate of the polymer because the polymer completely encases the fibers. The degradation rate o~ the polymeric matrix depends upon the type o~ polymer used. It should be noted th~t the degradation times set iorth above are ~or complete disappearance from the polymer. The time ~or s~rength loss in the composite will be considerably less and can be approximated as one hal~ the total polymer degradation tlme.
Composltes which lose their strength in one month will be use~ul as well as those that last up to about one year. ~he preferred tlmes will be three to six mon~hs. It should also be noted that the biodegradation times of the polymers and the correspondlng ~trength losses of the composites will depend upon polymer molecular weights. The values given in the table are ~or normal molecular weights. Higher molecular weight polymers will last longer and those lower in molecular weight will degrade ~aster.
The degradation rate o~ the polymer can be changed by control o~
molecular weight, by the type of biodegradable polymer, and by controlllng the ratio of lactide to glycolide in co-polymers.

2. Reinforcin~ Flbers The term "~iber" as used herein is deflned as any l material that has a high ratio o~ length to cross sectional area ¦ with minimums suggested as 10:1 to 100:1, and a maximum cross sectional area o~ 7085 x 10-5 in.2 and a maximum transverse dimension of 0.010 in. ~ith continuous iilament fibers which are preferred, the length to diameter (a~pect ratio) is maximized to give the best rein~orcement. However, the composites can be made with chopped or shorter lengths o~ ~ibers. With these, the aspect ratio is lower and the level o~ reiniorcement is less. Thus, the aspect ratio can range ~rom 10:1 up to really high numbers such as 1,000,000:1. The pre~erred range is 10~:1 to 1,000,000:1.

3. Composite_Fabrication The Pibers can be incorporated lnto the polymer matrices by several method6. In one approach, the ~ibers can be chopped lnto small pieces, mixed with the molten polymer, and formed into the desired shape by injection molding, compression moldlng, or e~trusion. In another procedure, the chopped iibers can be mixed with a solutlon of the polymer and the mi~ture cast into a ~ilm with evaporation o~ the solvent. The ~ilms can then be laminated or molded to the desired shape. The preferred method, ho~ever, 1 to use contlnuous ~ilaments o~ the fiber to provlde maximum s~rength and regldlty. There~ore, the ceramic or gla6s ~ibers are wrapped around a ~ylar- or Teilon-coated ma~dril and dlpped into or spra~ed wlth a ~olution o~ the polymer in a suitable solvent.
The solvent is evaporated, and the dipping or spraylng repeated to obtai~ a composite ~ilm o~ the de~lred thickneæ~. The ~ilm ls then removed from the mandril, and pre~sed under pre~sure and heat to provide ~lat, bubble-iree shéets. These sheets are then lamin~ted wlth other sheets oi,the same compos~tion or with polymer sheets containing no ~ibers to produce the ~ixation plate.
* Trademarks ~ . ,.

, r 11 As an example, films o~ DL~PLA were prepared from purified polymers having inherent viscosities from 0.58 dL/g to 1~27 dL/g measured in chloroform at 30C. Either ceramic or glass fibers are wrapped around a Mylar-coated mandril and sprayed with a solution of the same l)L-I'LA in p-dloxane. After the solvent evaporates, the spraying is then repeated to obtain a composite film of the desired thickness. When the appropriate thickness is obtained, the film is removed from the mandril, cut, and pressed with ~ hydraulic pI'eSS maintained at 70C and 29,000 psi to provide flat, bubble-free sheets. These sheets are then laminated with sheets of the same polymer containing no fibers to produce a plate. ~'ive sheets of fiber-reinforced material are combined with four sheets of polymer.
~ n another procedure, a hot-pressed film of PLA is placed in a mold and the film is brushed with solvent until it is tacky. Then a layer of the CMP fiher is placed lengthwise along the film taking care not to overlap the fibers which causes breakage. Additional solvent is then brushed over the fiber and another polymer film is placed over the fibers to which it readily adheres. The ~op of the new ~ilm is then wetted, more CMP fibers placed onto it, and the process repeated until 6 layers of fiber are laminated between 7 layers of film to give a composite with ; 40% by volume of CM~ fiber. The solvent is allowed to dry completely, and the laminate is heat-pressed at 60C and 20,000 psi for 15 minutes. This gives better lamination of the ~ilms and removes any residual solvent bubbles.
The plates produced hy this procedure were evaluated in three-point bending tests (AST~ D790). Flexural strengths of 6,0()0-10,()0() psi and fl~xural moduli of about 1 x 106 psi were found. 'rhese compare favorably with those values obtained for nonbiodegradable polymer/fiber composites, and they show the iml)rovements over non-reinforced biodegradable polymer plates.

Flexural Flexural Materials ~treng~h, psi Modulus, psi ~one 10,000-20,0~0 l to 3 x 106 ~teel 75,00() 3() x 1()6 ~L-~LA ~,000-4,~00 ().3 x 106 ! ~arbon-reinforced l)L-YLA 20,000-40,00() l to 4 x 1~6 10, C~-reinforced ~L-PLA ~,00~-1(),00~ l x 1 4. ~olvents for ~iodegradable Polymers The following table sets forth what solvent(s) will dissolve the biodegradable polymers useful in the present invention: ;

Polymers Solvent Polycaprolnctone dichloro~ethan0, 90:l~ ~oly(l)L-lactide-co-eaprolactone) chloroform, toluene 75:~5 poly(~l.-lactide-eo-caprolaetone) xylene, p-di~xane, and 50:5() poly(~L-laetide-co-eaprolactone) TI~F.
poly(~L-lactide) ~5:5 poly(DL-laetide-eo-glycolide) ~():10 polY(l)L-lactide-co-glycolide) ~5:15 poly(~L-lactide-co-glycolide)

5~:50 poly(l)L-lactide-eo-glycolide) HFIP
(hexafluoroisopropanol) and ~FASH
(hexafluoroacetone-; sesquihydrate) : polydixanone tetrachloroethane and chloroform ~-polyesterarnides cresol : copolyoxalates chloroform . polycarbonates ketones, esters and : partially chlorinated hydrocarbons poiy(glutamie-co-leueine) benzene .

' _ 24 -... .. .. , .. . ~ . . . . . .
,

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of producing a biodegradable prosthesis, comprising the steps of a) encasing an effective amount of resorbable fibers selected from the group consisting of calcium phosphate and calcium aluminate in a matrix of a biodegradable synthetic polymer to form a composite, said effective amount ranging from 10 - 90% by volume and the aspect ratio of said fibers ranging from 10:1 to 1,000,000:1; and b) forming said composite to the desired prosthetic shape.

2. A method as defined in Claim 1 wherein said fibers are calcium phosphate fibers and comprised of .beta. -tricalcium phosphate.

3. A method as defined in Claim 1 wherein said fibers are calcium phosphate fibers and comprised of calcium metaphosphate.

4. A method as defined in Claim 1 wherein said effective amount is preferably 30 - 80% by volume.

5. A method as defined in Claim 1 wherein said polymer is selected from the group consisting of poly-caprolactone, poly(L-lactide), poly(L-lactide-co-glycolide), poly(DL-lactide), polyglycolide, 95:5 poly(DL-lactide-coglycolide), 90:10 poly(DL-lactide co-glycolide), 85:15 poly(DL-lactide-co-glycolide), 75:25 poly(DL-lactide-co-glycolide), 50:50 poly(DL-lactide-co-glycolide), 90:10 poly(DL-lactide-co-caprolactone), 75:25 poly(DL-lactide-co-caprolactone), 50:50 poly(DL-laatide-co-caprolactone), polydioxanone, polyesteramides, copolyoxalates, poly-carbonates, and poly(glutamic-co-leucine).

6. A method of producing a biodegradable fracture-fixation appliance reinforcement, comprising the steps of a) preparing resorbable calcium phosphate fibers having an aspect ratio of 10:1 to 1,000,000:1, b) incorporating from 10 - 90% by volume of said fibers within a nontoxic biodegradable polymer to form a composite; and c) fabricating said reinforcement from said composite.

7. A method of producing a biodegradable prosthesis comprising the steps of:
a) preparing a film of a biodegradable, nontoxic polymer comprising dissolving said polymer in a suitable nontoxic solvent, spin casting the dissolved polymer to form said film, and removing said solvent from said film;
b) incorporating an effective amount of resorbable calcium phosphate fibers into said film;
c) repeating steps a) and b) a preselected number of times so as to form a composite having a predetermined number of layers of said film; and d) shaping said composite into said prosthesis.

8. A method as defined in Claim 7 wherein said solvent is selected from the group consisting of p-dioxane, dimethyl sulfoxide, dichloromethane, chloroform, toluene, xylane, THF, acetone, hexafluoroisopropanol, hexafluoroacetone ses-quihydrate, tetrachloroethane, n-cresol, ketones, esters, partially chlorinated hydrocarbons, water and benzene.

9. A biodegradable prosthesis, comprising a) a biodegradable polymer matrix and b) fibers selected from the group consisting of calcium phosphate and calcium aluminate incorporated within said matrix in an amount ranging from 10 - 90% by volume and said fibers having an aspect ratio of 10:1 to 1,000,000:1.

10. A biodegradable prosthesis as defined in Claim 9 wherein said polymer is selected from the group consisting of polycaprolactone, poly(L-lactide), poly(L-lactide-co-glycolide), poly(DL-lactide), polyglycolide, 95:5 poly (DL-lactide-co-glycolide),90:10 poly(DL-lactide-co-glycolide), 85:15 poly(DL-lactide-co-glycolide), 75:25 poly(DL-lactide-co-glycolide), 50:50 poly(DL-lactide-co-glycolide), 90:10 poly(DL-lactide-co-caprolactone), 75:25 poly(DL-lactide-co-caprolactone), 50:50 poly(DL-lactide-co-caprolactone), poly-dioxanone, polyesteramides, copolyoxalates, polycarbonates, and poly(glutamic-co-leucine).

11. A biodegradable prosthesis as defined in Claim 9 or 10 wherein said matrix is a film of said polymer and said prosthesis comprises a predetermined number of alternating layers of said film and said fibers.

12. A method of producing a totally biodegradable prosthesis or implant comprising the steps of a) encasing an effective amount of fibers selected from the group consisting of calcium phosphate and calcium aluminate in a matrix of a polymer selected from the group consisting of polyglycolide, poly(DL-lactide), poly(L-lactide), polycaprolactone, polydioxanone, polyesteramides, copoly-oxalates, polycarbonate, polylglutamic-co-leucine) and blends, copolymers and terpolymers thereof to form a composite; and b) forming said composite to the desired shape.

13. A method as defined in Claim 12 wherein said calcium phosphate fibers are comprised of .beta.-tricalcium phosphate.

14. A method as defined in Claim 12 wherein said calcium phosphate fibers are comprised of calcium metaphosphate.

15. A method as defined in Claim 12 wherein said effective amount ranges from 10 - 90% by volume.

16. A method as defined in Claim 12 wherein said effective amount is preferably 30 - 80% by volume.

17. A method as defined in Claim 12 wherein the aspect ratio of said fibers ranges from 10:1 to 1,000,000:1.

18. A biadegradable prosthesis or implant, comprising (a) a matrix formed from a polymer selected from the group consisting of polyglycolide, poly(DL-lactide), poly(L-lactide), polycaprolactone, polydioxanone, poly-esteramides, copolyoxalates, polycaxbonate, poly(glutamic-co-leucine) and blends, copolymers and terpolymers thereof;
and (b) fibers selected from the group consisting of calcium phosphate and calcium aluminate incorporated within said matrix in an amount ranging from 10 - 90% by volume and said fibers having an aspect ratio of 10:1 to 1,000,000:1.

l9. A biodegradable prosthesis or implant as defined in Claim 18 wherein said matrix is a film of said polymer and said prosthesis or implant comprises a predetermined number of alternating layers of said film and said fibers.

28

20. A method of producing a totally biodegradable composite material for prosthetic and implant devices, comprising the step of encasing an effective amount of a reinforcing material in the form of fibers selected from the group consisting of calcium phosphate and calcium aluminate in a matrix of a polymer selected from the group consisting of polyglycolide, poly(DL-lactide), poly (L-lactide), polycaprolactone, polydioxanone, polyesteramides, copolyoxalates, polycarbonate, poly(glutamic-co-leucine) and blends, copolymers and terpolymers thereof.

21. A totally biodegradable composite material for prosthetic and implant devices, comprising:
(a) from 10 - 90% by volume of a reinforcing material in the form of fibers selected from the group consisting of calcium phosphate and calcium aluminate;
and (b) a polymer encasing said reinforcing material, said polymer being selected from the group consisting of polyglycolide, poly(DL-lactide), poly(L-lactide), polycaprolactone, polydioxanone, polyesteramides, co-polyoxalates, polycarbonate, poly(glutamic-co-leucine) and blends, copolymers and terpolymers thereof.