CA2031529A1

CA2031529A1 - Biodegradable composites for internal medical use

Info

Publication number: CA2031529A1
Application number: CA002031529A
Authority: CA
Inventors: Alma U. Daniels; Jorge Heller
Original assignee: Individual
Current assignee: SRI International Inc; University of Utah
Priority date: 1989-04-27
Filing date: 1990-04-25
Publication date: 1990-10-28
Also published as: EP0422208A1; WO1990012605A1; JPH03505541A; US5108755A

Abstract

A family of composites suitable for use as materials of construction for implantable medical devices is disclosed. In the most preferred embodiment, the substrate polymer is an ortho ester polymer formed by the reaction of a ketene acetal having a functionality of two or more with a polyol. Also in the most preferred embodiment, the reinforcement material in the composites is calcium-sodium metaphosphate ("CSM") fibers. In other embodiments, the composites may replace either (but not both) of the substrate or the reinforcement with materials of the art.

Description

WO 90/12605 ~ ~ 3 1 ~ 2 ~ PCr/VS9~/0~2~1 _ l_ BIODEGRADA~LE COMPOSITES FOR INTERNAL MEDICAI USE

BACRGROUND OF THE INVENTION

Field of the Invention This invention rela~es to biodegradable 15 composites for internal use. That is, it relates to ~mpo~ites made up of biodegradable substrate and a bio-degradable reinforcement which ~an be used inte~nally in the body of a human or animal for bone fixation or the like. In this use, the composites ~radually completely degrade to ~oluble products. In preferred embodiments, this invention relates to the use ~f poly ( ortho esters ) as the erodible substrate ~nd o the u~e:of calcium-cndium me~aphosphate fibers as the reinforcement in such ~omposites.
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l~etal plates, pin~, rod~ nd screws are used for rigid internal fixa~ion of bones and tendons which h~ve been damaged by trauma:or reconfigured surgically to correct defe~s occurri~g;co~genitally, developmentally or ~s the result of disease.: These dev ces are most co~monly fabri~:ated from stainless ~teel and align bone fragmerlts by bringing their edges into ~lose prox~mity. Due to ~device structural stiffness they control rel~tive motion ; 3S to allow bon~ un~on. ~or healing, the stabilization must perslst for ~-voral weeks~or ~onth~ wi~hout devlce break- .

:., , ' ~ . .-WO9~ 605 ~ 3 1 ~ 2 ~ PCT/US90/02281 ~

~ge or loosening. While the level of relati~e motion tha~
can be tolerated has not been thoroughly determinedr it is understood that gross motion at the fracture 6 ~ te will result in non-union of the bone fragments.
Hhile metal devices of the type well known in the ~rt can hold fragments in close proximity, they may at ~imes interfere with proper healing. Thi.s has been traced to their extreme rigidity. It has been demonstrated that completion of healing is prevented by permanent highly 10 rigid ~ixation of the bone fragments. This is because --much of the load that is normally carried by the bone is txansferred across the fracture site by the implant. This load transf~r is brought about by a mismatch between the elastic modulus o~ the bone and the metal implant (Ebone =
6-20 Gpa and Emetal = 100-200 Gpa). The stress-shielded bone heals incompletely or may even remodel 60 t~at the ~hielded area is susceptible to refracture when:the implant is removed.
Another problem inherent in the metal ~ixation -Lmplants used heretofore is that they generally need to be surgically removed aft~r they have served their desired function. This is done to eliminate pain (which can~be c~used by local corrosion, tis~ue pressure or friction related to loosening), or at the suggestion of the surgeon where he or she believes this represents the patientis best interest. This removal involves a second surgery, wi~h its attendan~ costs and risks.
Some attempts ~t reducing the rigidity of fixation implants havo included the use of permanent impl~nts made from titanium alloys, polymers and carbon-reinforced polymers such a5 nylon, polyether sulphone and polymethylmethacrylate. These implants lessen stress shielding but ~till may need to be removed after the bone he~ls.
Begi~ning in 1971, investigators reported the p~ssibility ~f employing implants fabricated from materi-.

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W~90/12605 -~ 3 ~ ~ ~ 9 PCT/US90/0228]

als which gr~dually break down or dissol~e when placed in the body. An implant formed of a biodegradable matexial, which meets basic design criteria, including biocompatibility (sterilizabil.ity and low toxicity), 5 compatibility for intraoperati~re reshaping ~where needed) and sufficient initial strengtll and stiffness, has two major advantages over conventional implants: (a) I~ al-lows gradual load transfer to the healing bone as it degrades and (b) It eliminates the need for surgical removal.
The earliest reported use of an resorbable polymer for fracture fixation was described by Kulkarni et al. in the J. Mater. Res. 5, pp. 169-181 (1971). He suc-cessfully ~sed extruded rods of poly(lactic acid) to lS reduce mandibular fractures in dogs.
Hore recently the number of reports dealing with the use of biodegr~dable polymers and compo~ites for fracture fixation has increased dramatically. At least 63 articles on the sub~ect have appeared as of the date of this application. The mcst ~ommon materials of construc-tion for these articles are poly(lactic acid) and poly(glycolic acid). Other materials also have been used.
Ty'pical references in the literature and the materials they describe include: : :
H. Alexander et al. ~Development of new methods ~ -for phal~ngeal frac~ure fixation," J. Biomech., 14(6), pp.
377-387 (1981) - poly(levo lactic acid~ "PLLA" rods; :
P. Christel et al. "Biodegradable composites for internal fixation,'~ in Advances in Biomaterials 3 Biomaterials 1980, ed. G.D. Winter et al. 3, l9B~, pp.
271-200 - combinations of poly(d~l lactic acid) ~'PDLLA~
a~d PLhA, ~s well as polyglycolic acid "PGA";
M.~Vert et al. "Bioresorbable plastic materials for bone ~urgery," Macromolecular 8iomaterials ed.
Nastings et ~l. 1984, pp. 120-I42 combina~ions of n PDLL~ nd ~p~LA;

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WO90tl~05 2 ~ 3 1 5 2 ~ PCT/US90/02281 -D. Lewis et al. ~Absorbable fixation plates with fiber r~inforcement", Trans. Soc. Biomater., 4, p. 61 (1981) - PDLLA r~infiorced with alumina, alumina-boria-silica and carbon; ..
~. Xilpikari et al '~Ccirbon fibr~ reinforced bio-degradable and non-biodegradabl~ polymers as bone plate materials, n ~rans. Soc. Biomat~r~, 7, p. 242 (19~4) - PGA/
PLA copolymers with ~nd without carbon reinforcement;
L. Claes et al. ~Refixati~n of osteochondral fragments with resorbable polydioxanone pins in animal experiments~, Trans. Soc. Biomater., 8, p. 163 l1985) -the poly(ethyl ether) polydioxanone, R.H. Wehrenberg, ~Lactic acid polymers: stro~g, degradable thermoplastics," Mater._Eng., 94 (3)l pp. 63-66 (1981) - ~opolymers ~f L-lactide and epsilon-caprolactone, 8s well ~s polycaprolactone "PCL";
X.D. Feng et al. "Synthesis ~nd evaluation of biodegradable block copolymers of epsilon-caprolactone and d,l-lactide," J. Polym. Sci.: Polym. Letters Ed., 21, pp.
593-600 (1983) - PCL and various PCLtPDLLA copolymers;
V. Sknondia et al. "Chemical and physicomechanical aspects of biocompatible orthopedic .
polymer (BOP) in bone ~urg~ry,'i J. Int. Med. Res., 15 (5), : -- pp. 293-302 (1987) - N-vinylpyrollidone/ :~
methylmethacrylate copoly~ers;
A.C. Ibay ~t al. ~Synthesis and properties of polymers for biode~r~dable implants," ~glY~
En~., 53, pp. 505-507 (1985)- polypropylene fumarate;
J. ~ohn et al. "Poly(iminoc~rbonates) as potential biomaterials.~ Eiom~teri~ls, 7(3), pp. 176-lB2 86) - polyiminocarbonate;
. A.J. owen, "Some dynamic mechanical properties ~ .
of microbially produced poly beta-hydroxybutyrate/beta-hydroxyvaler~t,e copolymers," Colloi~_~ Polymer S~ience, 263, pp. 79~-803 (1985), among ~everal - copolymers of p~lyhydroxybutrate/polyhydroxyvalerate;

2 ~ 3 ~L ~i 2 ~ PCT/US90/02281 S.~. Shalaby et al. "Absorbable polyesters with stru~ture modulated biological properties,~ Trans. Soc.
Biomater., 8, p. 212 (1985) - polyalkylene oxalates; and L. Claes et. al. "Resorbable implants for the txeatment ~f bone defects," Tralns. Soc. 3iomater., ll, p.4g9 (l988) - polyester-amide.
TypicGl fibers used as reinforcements in these composites are carbon fibers and other nondegradable materials, biodegradable inorganic polymers and biodegradable organic polymers. Some of the r~inforcements u~ed in these prior studies have been nonerodible - for example, carbon fibers, glass filaments and the like. While ~hese materials can give drama~ic increases in initial strength to ~omposites over their polymer matrix alone they have the medically unacceptable problem of leaving behind finely di~ided nondegradable debris when the substrate disappears and also:sometimes gi~ing rise to rapid losses of strength during environmental exposure. Typical ~iodegradable p~lymers include ~elf-reinforcement where the reinforcement is made of polymers of the same material as the polymer matrix but with the reinforcing polymer ha~ing a high degree of orientation of polymer chains ~or increased strength. In other cases one organic material, for ~xample poly(glycolic acid) fibers, can be used in another organic material ~uch as poly~lactic acid).
While th~ advantages of biodegradable supports are quite cle~r, especially their elimination of the need to perform a second surgical procedure to remove them, there are ~t~ dv~nces to be made. A majox area of : interest invoIves identifying materials which have a proper b~lance of~strength and bioerosion.
This balance is a fine one. For example, much ~ -of the work c~rried out her2tofoxe has focused on PLLA and 3~ PDLhA. These two materials,~while chemically closely rel~ted, with one~a pure material and the other a mixture .
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Wo90tl2605 2 ~ 3 ~ PC~'/V~90/0228~ ~~

of two enantiomers of the ~ame compound, illustrate the bal~nce point. Pure PLLA is quite strong, h~ving a tensile strength of sbout 60 MPa in one type of test.
PDLLA has a ten~ile strength of about 40 MPa in the same 5 test, with copolymers falling b~tween these two values.
Thus, one could achieve different lPvels of ~trength by v~rying the ratio of the cOmOnOJner units. The erosion properties of these material-~ a:Lso vary as a function of composition. Pure PLLA is very durable, or nondegradable, depending on the user's point of view. It retains nearly a~l of its physical integrity after 150 d~ys of implanta-tion. The same s~udy reported that a 50-50 PLLA-PDLLA
copolymer degraded to 314 of its initial strength in 30 days of impl~nt~tion. Many work rs in the field have looked at the physical and erosion properties of erodible or degradable polymers, each seeking a composite system which will have physical support properties which lead to optimal healing and degradation properties which lead ~o prompt clearance of the implant from the ~ystem with~ut any premature degr~dation which would compromise the desired physical properties.

STATEMENT OF THE INVENTION
We now have found a f~mily of composites which offer ~ubstantial promise as materials of c~nstruction for implantable devises. In the most preferred ~mbodiment, the substrate polymer is an ortho ester formed by the re-~ction of a ketene acetal having a functionality of two or more with a polyol, whi~h term includes alcohols and phenols. Al~o in the most preferred embodiment, the re~
inforcement ~aterial in the ~omposites is calcium-sodium metaphosphate (~CSM") ~iber~.
Thus, in one aspect this in~ention eoncerns implantable composites made fro~ these ~wo materials.

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WO9U/12605 ~ 2 ~ PCT/US90/02281 In ~nother aspect, this invention concerns implantable composites fabricated fr~m these ortho ester substrate polymers and an erodible reinforcement, gener-ally.
In a further aspect, this invention ~oncerns implantable composites fabricatled from the CSM fiber materials and erodible substrates of the art.
In yet another aspe~t, this invention ~oncerns implantable reinforcement devices fabricated from ~hese ::
materials.
In yet a further ~spect, this invention relates to a method of treating the CSM fibers, and the-produc~
thereof to make them more ~ompatible with the poly(ortho ester) substrates.

DETAILED DESCRIPTION OF THE INVENTION

Brief Description of the Drawin~s This invention will be described with reference being made to the appended drawings. In these drawings ~igure l is a graph illus~rating the degradation of certain c~mposites of this invention in simulated intern~l medi~ as determined by measuring flexural strength;
Figure 2 is a graph illus~rating the degradation of certain composites of this invention in simulated internal ~edia ns determined by measuring flexural modulus;
Figure 3a is a ~raph illustrating the degrada-tion of cortain composites o f this in~ention as weli as materi~ls not in accord with this invention in simul~ted internal media as determined by measuring compressive ætrength;
: 35 Figure 3b is a graph illustrating the degrada-tion of cert~ln composiees of this in~ention as well as WO90/1260S 2 ~ 3 ~ ~ 2 9 PCT/VS90/0228~ ~

materials not in ~ccord with this invention in simulated internal media as determined by measuring compressive modulus;
Figure 4a is a graph i.llustrating the degrada-tion of cert~in composites of this invention as well asmaterials not in accord with thi.s invention in simulated internal media as determined by measuring tensile ~trength;
Fi~ure 4b is a graph illustrating the degrada-tion of certain composites of this invention as well asmaterials not in accord with this invention in simulated internal media as determined by measuring tensile modulus;
Figures 5a and Sb are bar graphs illustrating the improvement in properties of POE materials achieved with reinforcement; and Figures 6a and 6b are bar graphs illustrating the improvement in properties of poly(lactic acid) materials achieved with reinforcement.
Definitions This invention involves ~ioerodible composites.
The terms ~degradablel~, "erodible', ~absorbablell, and llresorbablell are used somewhat in~erchangeably in ~he literature of this field, with or without the prefix 2S ~bio~. In this application, these terms will be used interchangeably to des~ribe material~ broken down and yradually ~bsorbed or eliminated by the body, whether degradation is due mainly to hydrolysis or mediated by metabolic processes.
: Ortho _ ter Substrates : :One preferred group of substrate materials for use in the composites of this invention are the poly(ortho es~er) materi~ls formed from ketene ~cetals and polyols.
Th~se materi~ re:described in United States patent number 4,304,767. This patent is incorporated herein by .
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Wo 90~1260~ 2 ~ 3 ~ 'J 2 ~ PCr/UiS90/022~1 reference. Thes~ ortho e~ter polymer hA~re re~eating m~r units represented by the gene:ral formula~
, S
17~ 8 -- ; 0 ~C~ R6--CH /C~ O ~Rs--- _ Rl------R2 R3~ --R4 n wherein n i3 an integer ~;ubstzlntially grea~cer thzln 10;
wherein Rl, R2 ~ R3 and R4 are th~ Bam~ dif ferent 15 e.~selltially hydroc~rbon grollp~ ~ R1 and R2 b~ing ~eparate group~ or p~rt~ o~ a cyclie group and R3 ancl: R4 being ~eparate group~ or parts of a cyclic group; R5 i~ ~n e~entially hydrocarbon yroup which i8 tha re~idu6~ of a polyol R5 t OH ) n wher~in n i~ an ~nteg~r equal to ~wo or 20 more, such polyol baing ~ ~ingle molecul~r ~peci~ or a mixturQ of molecular spec:~e~; RS i~ a valencel bond or an e~3entially hydrocarbon group; R7 ancl R8 ar~ hydr~g~n or e~ent~ally hydrocarbon groups wlt~ich may b~ p~r~t~
group~ or may fonn part~ of a cyclic group; ancl whe~rein 25 ~uch linear~ chaln~ may be ~ro~ nked to ~ llar ch~in~

and ~O~ O--R~

R/---R2 R3~ R.~ ~
n :

SUBSTITUTE 8HE~

WO90/12605 2 ~ 3 ~ ~ 2 ~ PCT/US90/02281 ~^

wherein n is an integer substantially greater than 10;
wherein Rl and R2 are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; ~ is a quadrivalent organic grouping; R3 and R4 are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; R5 is an essentially hydrocarbon group which is the residue of a polyol R5(0H)a wherein a is an integer equal to two or more, such polyo? ~eing a single molecular species or a mixture of molecular species; and wherein such linear chain may be crosslinked with other similar chains.
These ortho ester polymers are preferably formed by a condensation reaction between ketene acetals having a functionality of two or more and hydroxyl compounds having a functionality of two or more. The term "func~ionality", as applied to a ketane acetal, is meant a ketene acetal group ~t\ ~0--, C-C~ . -O--or ~0 1 C=c Thus, a di-ketene acetal has a functionality of two, a tri-ketene acetal has a functionality of three, etc. Similarly, where the term "functionality~ is used in connection with a polyol, it refers to the hydroxyl groups - present in the~polyol.

~ The kotene acetals are of two types.

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~ ~ 3 ~
WO90/12605 . . PCT/VS90/02281 ~11--- Tho ir~t ~ a~ follow~

, \ / ~ \ / R TypeIMonomc~

R O O \ R

whereln t~o ~ermln~l R ~roup~ ~re t~e ~m~ or diffeEent, ~nd can b~ H or ~8~nti~11y hydrocarbon ~roup30 pri~arily ~lkyl, ~ryl, cy~loallphatic or ar~lkyl group~, ~nd m~y be ~atur~ted or un~aturat~d, and R 1~ a qu~dr~val~nt group-lng or ~om.
By ~s~enti~lly hydroc~rbonU ~ meant th~t the group~ R ~y contain he~ero ~tom~ provlded th~y do not .
inhibit poly~eriz~tion w~t~ ~ polyol eo ~n unacoeptable d~gree, do not ln~iblt degr~d~tion of ~he polym~r to an unaccopta~l~ d~grae ~nd do not gi~ r$~ to toxic or dif-~icultly ~et~oliz~bl~ degr~dation produ~t~. The fonmula-20 tion R-R indicate~ that th~ ~wo R groupB may be ~oined toge~h~r to fs~ cycllc ~roup o~ may be separ~t~
unconnQct~d s~oup~.
Th~ ~cond type of k~tene aoetal 1~ as follow~:

. \ R~ R / O - R Typc~ Monom~
~ C~3C R"- C~C \
R - O R
3q w~rql~ t~o tl~rmin~l R groupo are~thQ aam~ or di~f~rent o~o~nti~lly hydr~carbon 9~0up3, th~ R' group~ Rr~ hydrog~n:
or ~s~ntl~lly hydroear~on~g~oup~ and R~ blv~l~nt o~anle group~ng whlch ~0 ~l~o es~ntlally hydroc~sbon.
~.
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`: SUBSTITUT@ $HE@T

WO 90/12605 2 ~ 3 1 5 2 ~ P~/USgO/0228l -The~ Type I monomers condens~ with diols HO--R-~ -OH, ~ b~ing ~n assenti~lly hyd:rocarbon, to produce linear polymers a~ follows s L R~ - R R~-~ R ~ D
where$n R is derived from th~ pc lyol and n i8 an ~nteger 10 gre~t~r tha~ on~ and u~ually lV0 to 300 or gr~ater.
The Typ~ SI monomes polymerize with dlol~ to produce~ lin~Ar polymer~ ~ followsO
1.... 1 --O--~C~ R' C~C~ _ R--~-- R R-~ n where R and n ~re similarly def ined .
Ie will be understood that where the p~lyol ~ndf 20 or the ket~n~ acetal ha~ or ha~r~ fun~t~on~litieY ~reater ~han two, crosslirlked polymer~ will re~ul~. AR noted below cro3slinklng may alRO be ~chi~ved by other cro~linking ag~nt~.
Cartain of the d~k~'cen~ ~cetal~ which c~n be 25 us~d in tha pr~nt lnventlon ~re de~cribed ~n T~ble I.

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35~

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g~U~3ST~T~TE ~ F

~3~ 3 WO 90/12605 PCI/US90/022~1 TABL}: 1 , ~O--CH2 /~H2--Q\ Compound I
CH2--C~ /C-GCH2 O--~H2 ~H2_O

/ ~~\ Compound II
CH2~ ~ /C=CH2 O O

/O--CH2 C~2--O~ COmPOUDd III
--C ' ' /C~CH2 O-- \ /CH--Q
t~H2--CH2 ~-/C=c\ X~o/ ~ Compound lY

C~2~H3 CH2C~3 Compound V
O- C~I2 ~H2-- .
~H3--t '--C\ ~ /~\ \f~ ~ ~_~3 O CH? ~H2_O

Compo ~C=C~ 2 / 2 \~ c~ 3 C~I3/ b_ CH2/ \CH2--O CH3 : ~.
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$llBSTlTWTE SHE~T

2~31~2~
WO 90/~2605 ~ PCr/US90/02281 1 3!2 TABLE :l (cont ' d . ) ~3f f~3 Compound ~II
i =CH; CH--Cl O_ _{) Compound VIII

0- 1 ~ ~ ' .
CH3o\ ~ /~3 Compound IX
~C=C ~C
CH3O \--/ OCH3 ~.

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\C ~ CH ~ / Compound X
~: ~ ~2-- ~=~ C\O_~ ~H2 : ~:
;

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SUBS~IT~ 4~EFF ~ ~

WO 90/12605 ~ ~ 3 ~ PCI/US~0/02~1 Exemplary polyol~ ~u~t~bl~v ~q r~ctar~ts include dlol~, triols, ~nd th~ llke th~st c~n ~nter int~ the polymeriz~tion reactlon without adver~ly ~f f~t~ng it or th~ polym~r~ c product . Tha po.lyols are known to the ~rt 5 in reported ~ynthe~is and th~y ~re ~ommer~ially av~ilable.
Generally, they include ~liphatlc diol~, trlols and the like of ~ch~ straight or branched ch~in type.
Repre~ent~ive polyol~ 2IrE~ z~lk~ne polyol3 ha~ring a terminal llydroxyl group at the terminu~ of an ~lkylene 10 chain of the $ormula HO--Rl--OH
(O~
wherein R i~ an alkylene ~h~in of 2 to 12 carbon atom~ and y i~ O to 6 . Typical diol~ I named a~ the glyools, include 1, 2-propyl~ne glyeol, 1, 5-pentyl~rl0 glycol, 3, 6-diethyl 1, 9-nonylene glycol, tran~-cy~lohexAne~imeth~nol and the like.
Polyol3 containlng ms:~re th~n 2 reactive hydroxyl radical~ ~uitabl~ for u~e here~n include polyhydroxyl compound~ ~uch ~8 1, ~, 3, 4, 5, 6 h~x~nehexol; 1, 2, 3-propsnetr~ ol; 1, 5 ,12-dodecanatriol 1, 2, 6-hexanetriol and the likeO
- 25 Other poiyol~ ~uitabl~ for ~ynthesizing the poly(ortho e~ter~) in~lud~ polyqlycole cont~nlng a repeating glycol monoether molety -a:H2(C~12?pO~ wherein p 1 to 5. .
Addieion~l polyols th~t c~n b~ u~ed in the poly~ ortho e~t~r~ ) Ar~ polyhydroxyl compouncl~ having 2 or - more re~ctl~ hydroxyl group3 uch ~ pentaerythritol and ~ .
di penéaerythrltol .
Al~o phenolic polyol~ (ewo or more phenolic hydroxyl grQup~ ) and mix~d phenoli~-Al~oholi~ polyol3 m~y be amploy~d. ~l~o m~x'curQR o two or mor~ polyols may be ~mployed. -Fxample~ o~ polyol~ and of mix~d phenoloic-~lcoholic polyolJ ~re ~o follow~ ~

,' ~ErF .r~L~ Y~

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Woso/1260s ~ 0 3 ~ ~ 2 3 PCT/US90/02281 ~

4,4'-isipropylidenediphenol (bisphenol A);
4-hydroxybenzylalcohol; and non-phenolic polyols having aromatic linking groups between the hydroxyl gr~ups, e.g.
1,4-dihydroxymethylbenzene. ~urtheremore, tri- (and higher) hydric phenols may be used such as pyrogallol;
hydroxyhydroquinone; phloruglucinol; ~nd propyl gallate.

Other_Substrate Pol~ners In 6sme embodiments of this invention the composites may include substrate polymers other Shan the above-described ortho esters. These substrate materials include poly(lactic acid) including "PLLA', "PDLLA" and combinations of "PLLA" and "PDLLA"; poly(glycolic acid) ("PGA") copolymers of L-lactide and epsilon-caprolactone;
polycaprolactone ("PCL"); PCL~PDLLA copolymers;
polypropylene fumarate; polyiminocarbonate; copolymers of polyhydroxybutrate/polyhydroxyvalerate; poly(alkylene oxalates); poly(ester-amide) ~nd the polyanhydrides described by ~.W. Leong et al., J. Biomed. Res. Yol 19 pp.941-955, (1985) incorporated by reference. These alternate substrate materials are described in the ~ references included in the Background section of this application which references are incorporated herein by - reference.
The CSM Reinforcements ~ _ .
In certain embodiments, the composites of this - invention employ calcium-sodium-methaphosphate ("CSM") ~ibers as reinforcements. CSM is described in the United States Patent 4,346,828, which patent is herein in- -corporated by reference. This patent teaches the prepara-tion a~d use of asbestiform calcium-sodium-methaphosphate ~"CSM") crystals as reinforcement-filler materials. This material has been promoted by and is Available a~ a developmental 6cale chemical from Monsanto Company ~St.
~ouis, ~issouri) and has been proposed as use as a WO90/l~605 ~ 3 1 ~ 2 ~ PCT/US90/02281 reinforcer and filler in flooring and roofing materials, friction material6, plastic materials, plastic~, resins and elastomers, insulating mat~erials and biomedical materials. The u~e of these m,~terials in erodible 5 composites for internal medical use is I to our understand-ing, not di~closed in the lite:r~ture.
The CSM materials we:re proposed as an alterna-tive to asbes~os. As described by Bruce Monzyk in September-October l9B6, Plastics Compoundin~, pp. 42-46, 10 this material was developed as an insoluble fiber that would degr~de naturally if ingested or inhaled. This material, an inorganic covalently bonded polyphosphate having sodium and calcium cations ad~acent to and ionically bonded to the polym~r can generally be used as 15 distributed by Monsanto. However, when used in combina-tion with the orthoesters, this material may lead ~o pre-mature breakdown of the orthoester because it tends to have an acidic surface. This can be easily prevented by blocking some of the acidic functions on the raw f iber ~u~h as by treating with a silylating agent as will be demonstr~ted in the preparation &ection.
The composites of this :invention contain at least two materials: ~ ~ubstrate polymer and a fibrous reinforcement. The nmount of rein~orcement should be an 2~ effecti~e reinforcing amount or l~vel. An ~effective re-inforcing" amount i8 such as to not be ~o great as to destroy the continuous phase p~ssented by the polymer matrix and thus degrade the mechanical properties of the composite but large enough to effectively reinforce the - 30 ~ubstrate. Typically, the weight ratio of substrate to reinforGement is from about 90:10 to about lO:90 with more preferred materials having a ratio of from about ~0: 20 to about 20:80. -. The composites m~y contain additional materials : 35 a~ well, a5 lon~ as these additional materials ~re nontoxic and bioco patible end have physical a~d ' `

WO90/]2605 2 ~ 3 ~ ~ 2 9 PCT/US90/02281 -degradation properties consistent with the intended uses of these composites in erodible implants. Therefore, these compo~ites could contain pharmaceutically acceptable plasticizers, mold release agents, radioimaging materials, or the like. Other materials can be present as well, including excipients to promot.e or regulate erosion and degradatio~, and pharmaceutic~lly active materials such as bone yrowth factors, drugs such as antibio~ics or the like.
The composites are typically formed by admixing the reinforcement, which is most commonly in a loose fiber form but which could also be in the form of fabrics, felts, or the like, if desired and if Gompatible with the properties of the reinforcement, with the substrate polymer or a polymer precursor in a fluid state. This material can them be east into shapes desired.for medical reinforcement applications or it can be cast into billets from which the desired ~hapes can be machined.
Alternatively the ~ubstrate and fiber can be dry-mixed and formed in~o ~he desired shapes by in~ection molding, hot-pressing, transfer molding and the like. The actual forming techniques employed ~re known in the art and will depend upon whether the polymer is thermoplastic or thermorigid and also will depend upon whether it is the polymer it~elf whi~h is being formed or rather a fluid precur~or whi~h is then ~olidi~ied by curing or the like.
The~final form of the reinforcements produced n~ording to the in~ention can include the various shapes described heretofore for medi~al reinforcement purposes.
These shapes include, without limitation, rods, pins, screws, plates and the like.

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WO90/l260~ 2 0 3 ~ ~ 2 9 PCT/US90/022Bl ~18-Descriptaon of Preferred Embodiments This invention will be further described by the following ex~mples and represent~tive preparations. These are presented to exemplify the practice of this in~ention and are no~ to be construed as limiting ~t~ ~cope.
A study was carried out investigating the suit-ability of poly(ortho esters) as composite substrates and the 5uitability of CSM as a composite reinforcement. The polymer investigated was lin~r poly(ortho ester) (POE) 10 prepared from 3,9-bis-( ethylidene 2,4,8,10-te~raoxa-8piro[5.5]-undecane) and a 60:40 mole ratio of rigid rans-cyclohexanedimethanol and ~lexible 1,6-hexane-diol.
Equivalent, and sometimes ~uperior, results wer~ achie~ed with the ~me ~ystem and a 90:10 r~tio of these alcohols.
A typical preparation of a test quantity of a CSM-reinforced POE composite is as follows:

l. CSM Fiber PreParation - Removal of ImPuri-ties:
- add 25 g of calcium-~odium metapho phate (CSM) fibers (Monsanto) to a 1000 ml be~ker with a stirring bar - add 500 ml of deionized water ~nd boil for 4 . .
- hours, maintain volwme level of water as needed : :
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- filter the hot 3u~pension with a Buchner fun-nel under VACUU

- wash fibers with room temperature deionized wat~r - ~ry in a vacuum oven at 90-100 C for 24 hours.
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WO90tlZ605 2 0 3 ~ PCT/VS90/02281 ~`

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2. Modification of CSM Fiber Surface:
Since the raw fiber ~surface is slightly acidic and the r~te of hydrolysis of poly(ortho ester) (POE) increases with increasing acid:ity, it is preferred to cre-5 ate a basic fiber ~urface. To make the CSM fiber more 1.
~ompatible with the POE polymer a basic coupling agent, ~uch as a diamine silane (Dow Corning, Z-6020) may be bonded to the CSM fiber surface. This m~y be carried out as follows:
- in a 250 ml beaker add 99.7 ml of methanol tEM
Science, OmniSolv) and O . 3 ml of the diamine silane (Dow Corning, Z-6020~ to produce a 0. 3% solution by volume - 510wly add 25 9 of washed CSM fibers to the ~bove solution nnd stir,- using a magnetic stirring bar, until a slurry is formed - filter the above suspension with a Buchner funnel under ~acuum - dry the residue in an ov~n for 3.5 hours at 90-100 C, using an air flow, to cure the coupling agent to the fiber - cool to room temperature and sieve the sized fibers through a 100 mesih Ty1er sieve screen using a ~ototap - ~olvent wash the siz d fibers with methanol to remove r~idual coupling agent - ~ry Eized fibers in a vacuum oven at:90-100 C
for several hours.

3. Pretreatment of Poly(ortho ester ? Polvmer:
- A linear ortho ester polymer (PO~) is prepared from 3,9-bis-(ethylidene 2,4,8,10-tetraoxa-Eipiro[5.51-undecane) a~d a 60:40 mole ratio of rigid trans-~yclohexanedimethanol and flexible 1,6-hexane-diol ~sing the ~eneral methods set forth in the examples of 35 United States patent number 4,304,767. One of the Reveral repeat prepar2ltions is carried out as follows:
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WO90/12605 2 i~ 3 ~ 5 ~ ~ PCT/U~90/02281 Into a 5-L, three-ne!cked flask equipped with an overhead stirr~r, an argon inlet tube and a condenser are placed B6.54 9 (0.60 mole) trans-cyclohexan~dimethanol and 47.33 ~ (0.40 mole 1,6-hexanediol and 1.8 L of distilled tetrahydrofuran. The mixture is stirred until all solids have dissolved; then 212.31 g (1 mole) of 3,9-bi6(ethylidene 2,4,8,10-tetraoxaspiro [5,5]
undecane) is added. The polymerization is initia~ed ~y the addition of 2 ml of a solution of p-toluenesulfonic acid (20 mg/ml) in tetrahydrofuran.
The polymeri2ation temperature rapidly rises to the boiling point of tetrahydrofuran, then gradually decreases. Stirring is continued ~or about 2 hr., 10 ml of tri~thylamine stabilizer added, and the re- -action mixture then very slowly poured with vigorous 6tirring into about 15 gallons of methanol ~ontaining 100 ml of triethylamine.
The precipitated polymer is collected by vacuum filtration and dried in a ~acuum oven at 60C for 24 hrs. The waight o~ the dried polymer was 346.03 (98.8% yield). The molecular weight determined by light scat~ering was 95,300.
To make a 90~10, use 129.81 g (0.90 mole~
trans-cyclohexanedimethanol, 11.83 (0.10 molej l,Ç-hexanediol and 212.31 g (1 mole) 3,9-bis (ethylidene 2~4~10-tetraoxaspiro [5,5~ undecane).
- mill the POE polymer through a 40 mesh screen l~sing a Thomas ~ y Mill (Thomas Scientific) - as a precau~ion after milling, dry the milled :
- polyme,r in a vaeuum o~en at 50C for 24 hours be~ore using.
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4. Preparation of comPosites:
Mixing of the powdered POE polymer ~nd the sized CSM fibers i6 achieved by simply dry-mixing the oppropri-,' :
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WO90/12605 ~ 3 ~ PCT/US90/02281 ate amounts of ~iber and polymer depending on the desired fiber loading.
For example to prepare 5 composite samples, at a fiber-volume fraction equal to 30~, for flexure testing according the ASTM Standard D-790 for proced~re and sample size, the following ~teps are carried out:
- in a narrow diameter bot le (dia = 2") add 2.B5 9 of ~ized CSM fibers - sprinkle in a milled POE polymer, 3.15 g total, while blending the fibers with the impell~r of a stirring assembly - use low to medium speed.

5. Hot-Pressinq of ComPosites - ~et and heat the platens of a Carver Press to - fill the s~eel die with 1.20 g of ~he dry-mixed composite - transfer the die into the spa~e between the platens and apply 500 lbs-f as a preload - insert the thermocouple temperature probe into the die - heat the die to 130C
~ when the die temperature reaches 130C apply 2000 psi to the mold - ~he tempera~ure and pressure will remain constant - after 5 minutes turn on the cold water to cool ~he platens and the die; make sure the pressure i6 at 2000 psi - when ~he die ~emperature decreases to 45C or less shut off the water, release the pressure and remove ~::
the mold and sample - this yields a compositè sample 1-1~2~ x 1/2" x 1~16" which is ready for flexure testing.

WO90/12~05 ~ ~ 3 ~ ~ 7, 9 PCT/US90/02281 Similar processing with other substrates such as other orth~ esters or ortho est.ers having differing ratios of diols, say 90:l0 instead of 60:40, or with other types of substrate or reinforcement would yield similar products.

~ restina of Materials Acute toxicity screening was performed on .
ethylene oxide 5terilized ~amples. Cytotoxicity was determined ~y agar overlay assay of direct samples. VSP
- ~oxicity Class YI tests (systemic and intracutaneous in~ection of extracts, 37C for 9 hours) and USP Implanta-tion XXI tests (intramuscular implantation, foll~wed by gross and macroscopic examination) were conducted.
lS . FlexuraI mcdulus and flexural strength were measured in accordance with ASTM Standard D 790-8l (3 pt.
bend). Specimens were immersed in Tris-buffered saline, ~H 5.0 and 7.4 (aerated~, at 37C and tested after 1, 3, ~nd 6 weeks exposure. Another set of specimens was ir-radiated with 2.5 Mrad of g~mma radiation and exposed toaerated Tris-buffered saline, pH 7.4, at 37C. All mechanical testing was perfcrmed in triplicate.
CytotoxiGity, toxicity, and implantation tests indicated that 60s40 POE i-8 non-toxic, with test r~sponses ~omparable to negative ~ontrols. The initial ~lexural strength and modulus were 65 ~Pa and l.6 GPa. The effects of exposurP to ~aline, pH 5.0 and 7.4, at 37C ~re shown in Figures l and 2. POE retained approximately 90% of its initial flexural strength and modulus at 6 weeks in ~itro, and the two pH levels produced no significant di~ference : in the rate of mechanical property degradation. Radiation : sterilization reduced initial flexural strength by 60~, had a negligihle effect on initial modulus, and m~rkedly in~reased the degradation rate.

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W~90/12605 2 ~ 3 ~ ~ 2 ~ PCT/US90/02281 -POE shows low toxicity and retains excPllent mechanical properties for 6 or more weeks in vitro.
Radiation ~terilization appears to severely compromise its mechanical properties.
Additional studies detailed the initial hist~-logic~l ~nd mechanical properties of the following bio-degr~dable polymer composites: poly~ortho ester) (POE) and copolymers of epsilon-caprolactone/L-lactide (CLLA), in 90:l0 and l0:90 ratios, reinforced with degradable glassy ~odium-calcium-aluminum-polyphosphate (NCAP) and crys~al-line calcium-sodium-metaphosphate ~CSM~, in the form of randomly oriented short fibers.
NCAP fiber snd CSM fiber samples were submitted for ~cu~e toxicity screening by standard Tissue Culture Agar ~verlay Assay (cytotoxicity), ~SP Class VI (systemic and intracutaneou~ toxicity) and USP XXI (intramuscular implantation) protocols.
Six composite types were prepared by reinforcing each of 3 polymers (CLLA l~:90, CLLA 90:l0 and POE) with either NCAP or CSM fibers and were implanted into New Zealand Rex rabbits to assess the effect of materials on both muscle and bone. ASTM Standards, F496-78 and F361-80 - .:
were adopted for muscle ~nd bone implant methodology - respectively. Animals wexe sacrificed at 4, 12 and 26 week~ with ta~dard histological analysis performed on retrieved implant/tissue ~pecimens.
Par~ l in vitro mechanical degradation ~tudies were performed by immersing composite ~amples in phosphate buffered ~aline, pH 7.4, at 37C, for periods of 6, 12 and 26 weeks. Tensile ~nd compressive mechanical properties were determined in ~riplicate ~or each exposure period.
Both NCAP and CSM fibers were rated nontoxic in the cytotoxic~ty, systemic and intracutaneous toxicity and intramuscular implantation. Responses were comparable to negative controls.

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WOgO/12605 2 ~ 3 ~. ~ 2 9 PCT/USgO/02281 After muscle implantal:ions, necrotic foci were observed in 12 of 22 NCAP-conta.ining specimens, while only 2 of 14 CSM-containing specimens and 2 of 11 CLLA 90:10 copolymer specimens showed necrosis. However, the necrosis was localized and associated with the fibrous capsule. None of the implanted sites exhibited the uniform zone associated with gross leeching of toxic substances from the implant material.
Bone histoloqiç examination revealed a mild proliferation of fibrous connective ti~sue on the periosteal surface for all specimens. This tissue varied in thickness and contained lymphocytes and macrophages.
The bone showed no evidence of necrosis or toxicity.
All in vi~o and in ~itro samples were s~erilized with 2.5 MRads of gamma radiation prior to usage. All of the ~amples containing NCAP fibers showed some dis-coloration after irradiation, and therefore possibly some degradation. .
Figuxes 3a and 3b show compressive strength and stiffness after in vitro exposure. CLLA 10:90 and POE
polymers with NCAP fibers started out much stiffer and stronger than the rest, but degraded quickly.
Figures 4a ~nd 4b show tensile strength and stiffness after in vitro exposure. Both C~LA lO:90iNCAP
and POE~CSM st~rted out with relatively high stifness and strength, but only POE/CSM:retalned significant strength at 6 and 12 weeks. CLLA 10:90/NCAP had the hi~hest modulus initially, but at 6 weeks, POE/CSM was several times stiffer than all other materials. ::
~0 Other results of mechanical tests on pure ortho ester and la~tic acid sustrates and reinforced composites based on these substrates are presented in Figures 5a, 5b, 6a and 6b. These results show that the CSM fibers ' ' ', W090/12605 2 0 ~1 S 2 9 PCT/US90/02281 ~

effectively reinforce both sys1:ems and that treating the CSM ~urface with silane coupling agen~ improves composite in~egrity with the poly(lactic acid) materials and with the POE materials.

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Claims

What is claimed is:

1. A reinforced bioerodible composite having a polymer substrate phase and dispersed therethrough a fiber reinforcement phase, the substrate phase being selected from the group consisting of poly(ortho ester), poly(levo lactic acid), poly(d/l lactic acid), poly(glycolic acid), the poly(ethyl ether) polydioxanone, L-lactide, epsilon-caprolactone, polycaprolactone, polyanhydrides, polypropylene fumarate, polyiminocarbonate, polyhydroxybutrate, polyhydroxyvalerate, poly(alkylene oxalate) and poly(ester-amide) and mixtures and coplymers thereof and the reinforcement phase being selected from the group consisting of calcium-sodium metaphosphate, calcium phosphate, oriented poly(glycolic acid), oriented poly(lactic acid), sodium-calcium-aluminum polyphosphate, and mixtures thereof, subject to the proviso that when the substrate is other than poly(ortho ester), the reinforcement must include calcium-sodium metaphosphate and that when the reinforcement is other than calcium-sodium metaphosphate, the substrate must include poly(ortho ester).

2. A reinforced bioerodible composite having a poly(ortho ester) substrate phase and dispersed therethrough a fiber reinforcement phase.

3. The reinforced bioerodible composite of claim 2 wherein the polymer substrate phase is a poly(ortho ester) of polyols and ketene acetals each hav-ing a functionality of two or more.

4. The reinforced bioerodible composite of claim 3 wherein the poly(ortho ester) has the formula wherein n is an integer substantially greater than 10;
wherein R1, R2, R3 and R4 are the same or different essentially hydrocarbon groups, R1 and R2 being separate groups or parts of a cyclic group and R3 and R4 being separate groups or parts of a cyclic group; R5 is an essentially hydrocarbon group which is the residue of a polyol R5 (OH)n wherein n is an integer equal to two or more, such polyol being a single molecular species or a mixture of molecular species; R6 is a valence bond or an essentially hydrocarbon group; R7 and R8 are hydrogen or essentially hydrocarbon groups which may be separate groups or may form parts of a cyclic group; and wherein such linear chains may be crosslinked to similar chains.

5. The reinforced bioerodible composite of claim 3 wherein the poly(ortho ester) has the formula wherein n is an integer substantially greater than 10;
wherein R1 and R2 are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; ? is a quadrivalent organic grouping; R3 and R4 are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; R5 is an essentially hydrocarbon group which is the residue of a polyol R5(OH)a wherein a is an integer equal to two or more, such polyol being a single molecular species or a mixture of molecular species; and wherein such linear chain may be crosslinked with other similar chains.

6. A reinforced bioerodible composite having an erodible polymer substrate phase and dispersed therethrough a calcium-sodium metaphosphate fiber re-inforcement phase.

7. In a medical implant for use within the body and formed of a reinforced bioerodible composite capable of undergoing bioerosion within the body, the improvement comprising employing as said reinforced bioerodible composite a material of claim 1.

8. In a medical implant for use within the body and formed of a reinforced bioerodible composite capable of undergoing bioerosion within the body, the improvement comprising employing as said reinforced bioerodible composite a material of claim 2.

9. In a medical implant for use within the body and formed of a reinforced bioerodible composite capable of undergoing bioerosion within the body, the improvement comprising employing as said reinforced bioerodible composite a material of claim 3.

10. In a medical implant for use within the body and formed of a reinforced bioerodible composite capable of undergoing bioerosion within the body, the improvement comprising employing as said reinforced bioerodible composite a material of claim 4.

11. In a medical implant for use within the body and formed of a reinforced bioerodible composite capable of undergoing bioerosion within the body, the improvement comprising employing as said reinforced bioerodible composite a material of claim 5.

12. In a medical implant for use within the body and formed of a reinforced bioerodible composite capable of undergoing bioerosion within the body, the improvement comprising employing as said reinforced bioerodible composite a material of claim 6.

13. Calcium-sodium metaphosphate fibers particularly adapted for incorporation into poly(ortho ester) substrated composites, said fibers having been treated to block acidic sites present on their surface.