CA2650955A1 - Malleable implants containing demineralized bone matrix - Google Patents

Abstract

Described are malleable medical compositions such as pastes or putties that include solids combined with a liquid carrier. The solids can include particulate collagen and particulate demineralized bone matrix. The liquid carrier includes an aqueous medium comprising one or more polysaccharides. Also described are methods for making and using such medical compositions.

Description

MALLEABLE IMPLANTS
+C.+c'3NTAI.1I.1(-z DEMI.llERAI_:.1.~'lED B()N EMA7'Rl'~
BACKGRC3L` l! I) TiIe present 117\,'e17.t1t)Il relates gf'IIerall'LY to P.I"1ed1Gal.
IPI"Ipl:`s.11"it.s. In Ii1~.?rc particular aspects, the present :rrrverrtion relates to ost:eoiÃ-adr.ictÃve implant i'ormWations containing demineralized baitie rnatr Ãr;.
lf.) A wide variety of inZplairt tormulat.ioirs have been suggested in Ãlre art f'Qr'the treatment o.fi bone detects. .In rld(litiorr to traeiitional bone grr7.ftirrg,,a rit.rrriber ofi synthetic boz~e graft substitutes have been rÃSed or explored, including some materials t:}rat ccnrtaiÃr demin~.~ralizecl bone matrix.. Demineralized bone matrix. has been showI-I to exhibit the ability to ilidu~e andr`or conduct the formation of bozre, It is thus desar-ableto implant and tiiaisr.tairi e$o mirieralire(l boiie matrix at a site at wrtric}i horic growt}i i;; dc;;;ired.

Ho-wcyc;r-, th~,~ beneficial nature of delnirlc;raliz~,'ci bone matrix is <rÃ5ceptsble to disruption by the incorporation fyf irrcoIrrpalible rlra7.t.er-ia(s or techniques wlier2 .fiizrrlrralatyng tiie rnedirral Ãmplanà material. At the sarxre tirne, eff`'err=t:ive inip1aziÃ
compositions must e-Nfubit proprv.Ã t:ies t1iat retain the tfeIn:irreralized borle rrratrix at t}re izrrplatlt site, arlcf that lrairdle wel1 in the oprvr=atir2g rv.rxvi.r=o2-rmerrÃ, As we1l, it is of corisidet-afalrv cor2-rtlrrvrcial significance that the forinulation be. Ãnant~~~acturatrle Without rrrrdu.c cost, equifarrlent. or matera al burdens.

In view of the lracfS:wwrotirlcf in the area oi'cfer2-rirrerali~ed bc}rie matrix:f=ortrrulatior2s, there exiSt needs for product, f:Qr'inulatior1s wlrieh exlribit tlre a.f..~ilitV to irrduce arZdf~.~r support bone gr(iwth through a desired re~,~ic3r2, wIr.ickr are readily r7~amrt`tlc;tra.rab1e, rlri(l wliicfl demonstrate acceptable handling properties for sr7rgoons.

SUMMARY

ln one aspect, the present iÃaventÃori paovides a demineralized bone rllatrÃx composit.ion. The composition compr-ises l;aioresorbable solids taclrtiixe;d witl7 a licltiic.l carrier Ãc) forni a rYral1eafalrv implant r:.or-nposition, .:vith the bioresorbable solids present at a level of abc}ut. 0lgram w pà retibic centsrriet.er(g(p"cc) fo about 0, 7g/c:~.
o~~fli~~ ~~c~rril~c~sitir~Ãl.
`l'lie bÃorescarlaable sol`Ãds :rnclrlde a part:rcrilat.e solid eolla-en material and a particulate solid demineralazed bone mat:rix material, with the particulate sr?lid collagen material present in a weight ratio rio1ess t:h<~~i about 1:1 ~~ arid no greater t}iat1 aborit 1:2 relative to the particulate s~.~licf ciem in eralizecf bone riiatrix material. The liquid carrier comprises an aqueous gel iaic,lt.r(iiiig a biocon-ipaÃible poly;;acc.haride, with the bic3c;or-iipr7.tib1e polysaccharicie present at a level of ffbor.it 0.01 to about 0.5 g/cc of the coniposition, and in certaiii. f'orms aborrt t.~ 1_a'cc to abotià 05 g,tc.c of the coniposition.
The solid demineralized 17taJie n7attix:materiaJ incorporated in the ctampositioJi can exhibit ostetainductivity. 1n certain forrr-is, ;;ticli iaiallc;alale compositions areflowablc; paste materials M w1-iic.h tlie l?.ioresorfadble solicls are present at a level c}f about 0. 1 4;;`ec to dbor.rt 0.25 gr'c.c of the composition. fflid the polysaccl1aiicic is presciit at a level of a.bor.it Ct.t.~1 }.,jcc tcx about 0.03 <~rL~:: c~t'tl~e composition. In other ixi~~exiiic.~e c:r~~Y~~~~iir~~rer~.t.s, stiLl~ rrt~.lleal~le c~c~~t~fz~Tsi~Eiczr~s are shapearetaÃnin{~ putties in whÃch the bioresorable solids are present at a level of about 0 2 (~r`cc, to afaorrt 0.4 g/cc ot`Ãhe c.otiipositiori, arid the polysaccharide is present at a level of afaorrt 0.0- to about U.:? ~wI'cc, c-ir-rd in c.ert:ainliorms about U.f,l2 gl.'cc Ã:oabout 0.05 .o.rrr:,e of the coÃs~posibon. Tho poly saccharidÃ; M fhese inventive ComposiÃions caÃi bc ari al' gwÃiat:Ã , pectin or cli:rtosa:ri mat.era;d, or a blerid of any or all of these, wit='li a.lgiriates provid`Ãrig piaÃ-ticuliarl.y advantageous osteoinductive p:~st~,~s ar-ici puÃties.
In atiother embocfimetiÃ, tlie irZverZtiQri provides a demineralized 1otie inatrix composition that. contains a liqt$Eid carrier c;c3n1priSi11~,~ aD atlUeOUs C.Yel ir7cludi11~,~ a lalcx:onipatibl~ polysaccbaricic, the aqueous gcl in admixture with solids to fors~l a niall~.~able composition. The solids of this c;n-iboflsr~ier-it c;ompri;s~.~ a chemically croasslinkcfl.
particulate collagen material, and a particulate de:mineral:Ãzed bone mat,ria;
inaÃerial. "I'lie )0 demineralized boneiliAitrix composition cati esliibit osteoindractivit-y, In ffliotlicr- er~boclimeiit, th~,~ invention prryvi,des a demineralized laoiic matri:~
corrtfac>siiirTrr that includes a liquid u3r r'aer compris:ixrw ari akltrcotrs -,e1 inc.lrrdixrw a bioecrmpatÃ1}le po1~sa~~~,i~aride; the aqueous ~;el being in ~.drx~i~.tr.ire with particulate solÃd~
to form a arialleable corriposityc3ri. The particulate so.lids include ta .{1~agn7er7tecf lair:rresc}rf?able sp(arige material and a tler-nineralized borie zrlatr-ix material. 'I'he fragmented brcrresorbablt; spoiigc Ãnat:Ã;rial Cttn comprise a ~potige silaterial that has beeri rciidct-ed to a part:ieLdate form, such as a razi~.~orzilv fragmented (e.g. milled) sporrge ma.t:erial.

I11 -another rv.rnf?odi.rnent:, the present invention provides a dezrlirleraliretl f?or-rrv nzat.rix composition that includesa. liquid carrier conzprisingan aqxreoxrS
gel irlcluciinga.
po1t~~~accl7ar-ide, t.lic aqueous gel beirrg in admixture witl7 derniareralizt:ei borren7atrix material, wherein the demineralized b(yrie matrix material is in the forin aif ribbons l~avino a mediarl c\.-idth of at least abotià t? `'nr.m, and in certaiai form5 at least about 0.5mm. In certain embodiments, the ribbons have a.Ãnedian width in tlie range of about O.?mrn to Aibcrrrt.3nrrn (tyior~e preferably about t?-Srnra tc) about 3rrrityi}, a iirediar~i lerigt}i iir ttie r=atrge of about 5mtii to abotit. 20zrlm, arld a nietliarr thir:,k_r-rrvss in the .r=arrcFe of about 0.02nim tc} about 0.2mm. In cc;rtainaciditional embodiments, the pol?~sac:cliaridc is asi algiiiate and/or-tlle 1zolz s:rccha7.ride lias a7 rrtrTlecu1ar x.~eigl-a of at. least about '?
l:ilodaltorrs, e.g. in tl-.te rarr:;e of ~botrt '-)toat)out IOU0lE.ilodaltcrri,.~,_ lÃr fuather aspects, crri a dry weig}it basis, the aÃbbon-form demir-rrv.Ã=alirecl borre matrix cari coristituÃe about 70% to about 98%
of t1-rrv ac}rY~poSiÃi(ari: more preferab1y alaorrt: 90% to dbor:rt 98%, arid the polysaccharide Carr compriwe. about 2% to about 30% of the composition, iilorÃ; preferably about 10% to '"%.
()pticarrally, other- insoluble solic~-, can be Ãrrclrided irr tl-w ccarr-apcasition, including for example demineralized l=son~.~ matriz miaterial.havirlg other shapes and/or piaÃ-ticrÃliate ac}lIacFerr.

hi further eiirbodiiirearis, the invention provides methods c.Yf nrakir7g anci metlioeiS o.{.
Lrsiiig malleable implant compositions as described hereiii, and rlieclicai proclr.ac;ts iiicir.aciing su.clr. compositions or materials for niakiaig th~.~n~ packaged in a sterile condition.
hr. still frrrtkrer~ embotfinietrts of t:lrc; invention, the demirreralired horie iaratrix paÃ-ticJes in ariy or all emlaodimer-rÃs deSr:.rif?ed herein cari f?e c(-ra.Ãacterized aS, or repIaced with a1iv othc r particulate collk~u enous material entraining ~~~-ie or niore fzolie nior~~ogeiiic proÃeiiis., sucli zis BMP-? or f3NM:f'k4, Tf:.~l;'-beta 1, IGl"-l., or aiiv c:ombinaiion ot'sorrte or all of these wt:}i factors.

Additional embodimetiÃ:s as well as features -and atla~ant~.~wes of the itlvetrtic~ii will be rcadil~~ apparent totlio:o crforciinatZr skill in the art ft-oisi the descriptions hereir'i.
BRIEF DESCRIPTit}N7 OF I'Hk; FIGURES

FIt:f. I provides a persf.~eGtive, view of a medical product of the invent.ioFn iiicludi~~g a medical paste o.r ptitty of the invention packaged witliina tc:rmiiitallv siefli liz:eci ;;yriitge device.

FIG. 2 provides a perspective view of a dry dÃsraxptable bodv t17.at can l~~
ussed to prepare iaiallc;al;ale iri-ipl~sit compositions of t.hc; inve;-ntion=

DETAILED I3ESCR1 PTl:0N

For the pLiriioses of promoting an understanding of the pr'ancÃples of tiie SÃaventioÃl, reference will now be made to ceztaiii embodin-~ents a~id spec.ific language will be risecl to describe the s-anie. 1Ã will nevertheless be riiiclerstood that tio lam:itat.i~~~i of the scope of the invcntion is ti~oreby intended, st-c.l~ alterations arici fibr-tlier modifications in the illustratf>ci device, and suc.li firrtfaer applicaticans of tl-ae principles of Tfae invention as deseCibed hereill b~,'ii-ig contemplated as would ~-iornially occur to one skillecl in the iaÃ-t to which the invention relates.

As disclosed ab(ive, in certain aspc.cts< ttie pre:;erit. iitveitti~ii relates to implantable r~ieclical formulations, asid to mc;thocis for niakiaif.~~ and tasiiig the formulati~~i-is, In particular embocii:nnen.ts, tlic present invention provides nieti.ical formu.latic~i-is tliat M.cludc; a niszlleable composition comprised of solids aJiel a liquid carrier, sucli as paste (aJ~
putty for:Ã~lutations.
The solids ii~icltatfe;- a substantial level of demune;-ra:lized bone matfi:~
particles. I.n partic;talarly ad~~antageous embodimerits, the dezrlitleralizetl bone niat.Ã=:ix partic.les.vill be effective to render the formulation ost~.~oi:nciue.tive when implantecl in a mammalian patient, including a lru.tnarr 1zatierrt. The liquid ca7.rrier advantageously arrclrades an aqueous rxiedir.rm containing a polysacclra:ricle, and especÃal1y a water soluble alg-Snate. Further, certain advantageous r-irc;ciictal formulations irrclti(ie particulate collagen, srrcl7 as collagen fibers or rtaridor7ily ff~a):Mrv.rrt:ed collagerr sponge, m 'cirr 'arrrorrni that is relatively less Ãh-arr the amourit of partYcuWe D1:3M oÃt a ciry weight basis. The irivetitivr; forr.rit.-laticrrrw desirably retain the DBM
in a bicaacÃ:rve, osteoinductive ccarrditiozi, while also provÃding beriefiicial lrandliÃ~garrd amplarrt properties.

4'lalleable irnplatià fQrrnulatior1s of the irrvent.iorl will include an amoLÃ.rrt of insoluble solids coml:rirre(l x.6t.h. i17e liqui(l carr-ier n7aterial. `I':hc; so'li(ls include a pariic;talate-t`orm demfneralized bozie rliatrÃr; material, or another par-tictrlateat-:c?rm collagenous material entraining gr(-)c\.-th factors that iiatively occur in bone, strclr. as orr~.~
or more bone morplioger-iic proteins, especially B?v:l.l'_2 a:Ãrdrior BMl'rc4, Ã:ransf(ar-nin4,~ growth factcrrrcbeta---1 (l'Gl"-beta 1), iristrliri-lil;e ~;rod.sIli factor-l. (IC3T-l), or Ainy cornbirtation of':ome or all of't}iese, Iri t.lri:
reg-ard-, as used herein, the tertrr < clemi.rrerafi~ed b(arre matrix" refers to a. rrratriN riraterial prepared by demincr-alizirrg any bor-ie sotirce; iiiclr.acling cortical and/or cancellous bone.
Desirable derxiiner-a7lased bone ma7trix maieria7ls will contain less tlrarr about 5% bv weaglrt of residual ca1cir.irn. The source bcyrre caar be from aÃay, suitable source including autogenic, alloo.enic., aricl;'or Nerrogerric bo.rre. Wtlerr usedln desc;rilaino; a derrrirreralixed la(arre ma:trix.
(-D1=3M) material, the teÃ-rir ``oste6irrclrrctive'-retrvrs to the ability of Ã:he Dl3M.material to iiid~ice bcrr.re gro~~-tl.r. A(teniat.ively, D1:3M materials cari be.
larovide(i lacl:lÃlg ostcoitidGac.tive iJiara.cter, azi~.~ rrortetlreless be used as osteor:.c?rrclricÃÃve materials that provÃde a scaffold capable of receiving bolie. gr-owtli indtÃc~,'ci by natur-al bealilig processes or other materials irr-rplar-rted in the paÃierit.

1)13Mt17'aterials for t.rse in the pr-e;seiit invention ctari be obtained c;c3rtir-irc:rc;ially or C'ar7 be prepiared by known teclrnif7tÃcs. in. g~,'neral, advantageous, osteoinductive DBM materials can b~.~ prepared by clecalt:ificEitiorr. of't:ortical and/or casic~.~llotis bone, ofter~ by acid ~.~xtrszctiorr.
)0 'I'l7is process can be condLÃcted so as to leave collagen, nonco1:lageJrcrus proteins, and growth factors tcr~;etlier in a si.ilicf r~trataxx. Meihcrcf::f-br prepAiring:wc:.h bioactive;- ciemisicralired bone trraÃriN ar e well lS.rrow rr, in respect of wlr:ictl rrvte.Ãenc,e carr be made to U.S. Patent Nc}s.

5,t.~73,3>73õ 5,484;601; and 5;2284,655, as ~,~xanr.plcs, DBN-1: prodLicts ar~,~ also :vs,ailable it~Lluc~ir~:; t:or insta7nc.e. .[:rcrm strrarc.~~ sLzch as Regeneration `I'eLhnczltrgies, l:ric.
tA1ac1~ua; FL'l, The American Red Cross (A:rlingt(yn, VA), and others. DBM
ma:terÃals that are solely Osteoconc.luc;trve c"aar be pre;pareei tisir7g sirrnihar tec}rr7iques that }rave beerr r-irodit.it:ei or supplemented to renioz e or inactivate (e. ;. by crosslinking or otherwise denaturing) cornpcrnerlls in the borie matrix respor-isibl.c. for crstecrinciuc:livity, C)stcoindu.cti.vf~ and/Or c?steocc?nclriet'tve DBM materials rised in the pz-esezià inventiozi can desirably be derived frorzi human dnzic?r tÃssue, especially in regard toiznplazià clevic,es inteÃa~ed for use in liumaÃr subjects. t_à will be LirldersÃoorl, however, that DBM niat:erials can also be derived from nwiw 1t3 hxrinan arrimal sources arrd tised in irnplaiits irrtended for trse in htimatis or other aiiirirals.

:fÃr cerÃam eÃxibodiÃxiezits, tlie partictilate fJBN1: materia.l can have an average particle size of less than abotit 1,t3~.~t? Lim. For instance, the DBM materia1 can hEive pari-icl~.~ sizes in the range of 50 to 850 gm.
In additional einbodiinents. the part:iculat:e DBM material carl be iti the forrii of eIorigate particles, stÃch as fibers or ribbotrs. DBMribb~~i-is havifligamcdi:~n wi,clthof grc:~ter th~l-I
a7bczLzt 0.5 mm are preferred, in certain embodiments witlr rrierl.izr.xr lengths in t(ic range of ~botit 5 nim to al}out 20 nim and mediaai thicknesses in the range of about 0.02 to about 0.22 mm. I:l:ltrstratively, t1ie I]:BM ribfa(ari cornpositions cari f~ave median wirltlis from afaorit 0.5 mm to afaorit 3 mni, r-~~edian1engths of dbor:rt 5 nim tc} about 20 nim, andir~edian thickrlesses of atiotÃÃ 0..02 to about 0.2 mm, Su.cli r'i.btrortwfrortn DBM laar-lic;les c.art be made, for examp(e, by ÃitÃilint, off ribbons of bc?ne from ~.~onor (e_g. ltuntan aIlc?{,~ra.ft}
tissue, and t'lierr demineralizing the bolie ribborls. Sr.acih milling can be c~~i-icfr.ac;tr~d with a side-cutting bit.
Alt:erna:tivelv or in addition, such DBM ribbons carr be made bvinillinww or 4.~:rating the ribbons from a piece of denZineralized cortical bor1e. Where r'ibborZ-forni DBNi particles as ciescri~l.~ed 1iereiar are used, effective for-mulations car7 be prepared wkricli contain Iower amouarts 1't.he collagem particles, or which are eveai firc~.~ fronr. the coltage~~ particles.
Thr.as, in certain embocii:nnents of the invention, the coniposition will comprise ri~bon-forni DBN-1: particlc;s Eis described herein, in combination with a. liquid subs-tatice c.omprisin4,) a polysaccharide and prefe;-rably ai-i aquoous iiieciitiri-i e~:omprisirrgAi pi.ilv~sac;clraricie, especially an algiirate. Such compositions iirav comprise collagen particles or iira~F 1:~e:t:ree frcar~-~
~.~~lla~~e~-~~:r~~> substances other than DBM. Tlic elongate ribbon forni th~,~ of DBN1 particles promotes entanglenr.eÃr.t.
MuLlr, along witlà the tl-uLkexr.irÃ:; and biÃrdi.Ãr- M3tÃ.Ãre O.f the PO14~S,-LLClÃ~3ride,-ccznta:trÃarrg liqÃrid earr`~aer, caxl be used to provide paste crr ptÃtÃy cnrnpcrsitions of good corÃsistericy ax~d Cohe;;iirene;;s, aard in particular putty corrrpositi ars lvitlr berief.icial resistance to detor-mtatiorr=

In additional eÃnbociiÃnent.s, ~tlie particulate DBM incoÃporatcd i.r~to the iÃivcsiÃive eompc?sÃticarà can iric;lude a substantial r:.oÃrÃponent of relatively larger D.B.It1 particles i11 combination wÃtli relatively smaller D:l~N-l particles. lÃa certain aspects, the particulate DB:M caii be constituted at least 10 weiwwht'1% by paÃ-ticJes l-ravirrc, aÃrÃtIMMUM dimension of greater t.lrarr abotit 22 mnz, or greater t.lrarr abotit 3mm (e.g. irr the range of about 3 mrn to abotit ? rrrari) anc1 at least 10 weiglre.,f; bv particles 1ias irrt, a maxirÃ-ium d.iaricrisioar of Ie,"
than al}out 1 mm. lrà fr.irther aspects, the particulate DRN-1 can be constituted at least 20 weiglÃ&o by particles haviÃ-ig a nra:xirnr7m dirliensiorl ofgre-at~.~r than aboÃ.at2mm, or grc;ater than about 3 mm (e.& in the range of aboLÃt 3 mrn to about 5 rnrt~) ar7tl at least ?Ct weight%
by par-kic:.les 1~aviÃr.4.~ a rnaxirÃ-wrn dimension of less tkrari about l.rrrÃni. In still further embodirÃients, tFie particulate DBM caÃi l?e constituted abÃ:rLÃt l.(#
weight%a to about 40 weiglÃN by particles haviÃ~g a nraximr7sn climcnsioÃ-i of greater tlÃaÃ-i abotit 2)nim, or greater than ab(iut rrirri. Wu . iri the ran4.~e of ab~Tu~E :+ rÃ~rr~. to about 5 rr~rrt~ ) ~3rÃ~~ about 90 ~z~ ei :;lrt%
to about 60 weÃglatN by particles having a mammum dirneÃasicyri of less than abotit 1. nirÃr_ It .:vill be understood tt-rat particles as described above may have the giverl di.ÃrÃerÃsions aJorlg orle axis (ar ailong; twc) or three axes. Rela.tive:l~F volrÃmet.Ã=ic, part:icle,,,c,arl brv rÃsrvd, fi:rr iÃistwice hav=ing shapes t-asigirtg froÃil geriera(ly round to generally c.Ã.Ãboicial. ProcitÃcts havizi(õ suel~ Dl=3M particle size and/or shape distri butions can be prepared, for exa:rÃ-aple, by Wending sÃ~parat~,~ DBN-1: proclÃ.Ãcts having the respective piarticle size clistÃ"ibÃ,itioÃr.s. The presence of relatively large DBM particles in cornbirratiÃ:rnw it(-r sÃiralIrvr particles can ~.~rovide an overall cornpositiQrr that resists conzpressioÃz LÃ:poÃz impitigement.~l.~y sot~ t.isstÃ~s at aÃi irÃ-iplant site, and that also can exhibit lrerre-t.icial lraard:lirÃg and osteoinductive pr-operties.

3l3 Insoluble colla,~
4er7 material for use in the iJiventi~~t~ caJi be derived from natural tissue scrrÃr=ces c;.g. x criogetric, allogetric, or atatogearic relative to t}ic Ã-ee~.ipie;-Ãr.t }irÃr-rÃarà or other patierrt) or zecwnlainaÃ-rtly prepared (q);. recombinant hr:rrÃian collagen).
Co1lagerrs can be ~
subclassified ir-it~~ several different types depending r.apoii their amino iacid seeluence>
carbolr4d.rai~e content arid tlae presence or absence czt'disr.rl#ide crossl:iriks. Types laticl I1:1 collagen are two of the most commozt subtypes of colla;yezt_ Tvpe Icc?llkgen is preserit in skin, tetid r~ ~iid borie, wlieretas Type 11:1 coll~~ger7 i;; Ãotand priniar'ily ir7 skir7, The coll~geri Lr~ed in cc}rYrpc}siti(aris oi'the invention catr be obtained from skin, bone, tendon, or c~rtil<~ge aricl pr.-Ã-Ãficd by rnetlwds well k-r.~owri in the art and ir-relr.-:try.
Sor,rr-ecs other tl-rari boiie are.
pr-eferred, in ce:rt.airt erribod`ÃrneÃ-itsz t'c?:r tl-ie ccall kaen component of compositions of the invention. Alternatively, the collagen Can be purchased from commercial sor.trces_ Type I
bovine collagen is preferred for use irr the invention.
The Collagen ctari bc. atelopejyticle c:ollager7 r7.iidr'r.}r telopeptide coIlta~,~en'ai7d Can be essentially free t'ront protein ziia:terÃalS other tlia.ri er?llageÃa. Still further, either or botli of ztons tibrill,szr and tÃbrillEir coll,szgen can be used. N-on-fibrillar collageri is c;ollagc;n that has been solrÃbilizeel atid has ziÃ~t been recottstittratetl into its native tibritlar l't~:rn7.
Suitable c,ollatw.rx t)roduct:s are availal?le cornrrlercially, including fo.Ã= exariiple frcani Kensey Nash Corporatioii (EMon, PA), which manufactures a. fibrous collagc;n knowr-i as Senierl.:la, t:r`c>rxi bovine li:ides Collagen rxiat:e.r-:ials derived fi-c>rxi bolvine liide are also manufactured bv I.ztÃegra Life, Scieztce Holding Corporation (Plainsboro, NJ), Natura11v-derived or recc}rYtbirlarrt htt.~n-an collagerr materials are also suitable f(ar tise in the iriverrtiori.
(llr:rstrativek,: zecc}rYÃbirrarit httrnan collagerr products are ava:ildble krc}rYr 1<ifarc}gwn: :(nc. (Sarr Francisco, CA).

The solid particulate c:ollagen incorporated ir-itcx the inventive c..ompositi.ons caai be irI
the fo~rm oi'iritact or recorlstitrit:ecl t~rfaers, o.Ã= randomly-shaped particles. for e.Nample. In certairi beneficial enil.~odinzerzts, the S~.~lid paÃticrÃ.laÃe collagen will be in the forrn ot-~.~a.rt-ic.les derived from a spc3tige materia), for examp1e by r-ar~~~~rnly trtagmentir7g the spc3rigen7aterial by, milling, shreclclir-ig or other similiar operations. Strch particulated sponge material cffli have a r~
average niazimrrm particle dianictc;r of less than about 6 nim., more. pr-ef~.~rably less than aborit 3 rnm, atid advantageously in the rar~~~e of aliout 0.5 m.Ãn to -2 mm. Such :Ãtiateri als can, for )o example, be obtairrecl by millir~g or grii-iclii-ic-, a porous sfsorige rnateria;l and siovirig the ri-iille(l or (fror:rrld rrxateriai1 through a screen having openings Sixedabout 6 nim o.Ã= sinaJIez, desirab1v about 0.5 nim to abor.it 2 mm. Retch grinders wit1~ associated sieves are sr,lit.able for these purposes. The .r-~sulÃirr:; small spon4.~e particles are r~~3rr~~~~ztrl~~
ic~rri~rerl. and have gerreraI(y irregular shapes ANrith remnant structures from tlte sponge materÃa1, and ar~:
hi;Jyh1v beneficial fc3r tasciaittialle,-tl)1ecor~~positi~iis:~uc:haspa:,,;tesor lyuttiesoftlieiriveri,tiori. hi this regard, t(-rrv rrse of such part:ic.ulat:ed sponge niaterials in combir-raÃ:i(an zh~ith D>i3M materials in r.iialleablc compositions is considered as ari inventive aspcct disclosed lir;reiti also whercin tl~c.
spcange material is made all or in pa.:rt frcarn a bioresorbable material otlter- t'ltan ccallkaen. For example, the, particulated spozt;ye mateaial can be ntade from any of the otlier natural or synthetir:, pc}lyniers disclosecf :l-rrvrein. Likewise, in these part:iculated sponge embodiments, the liquid carrier cari be a poly saccharicie-c~.~riÃairling sxrbsÃance a.s disclosed lier'eiii or another suitable anat.c.rial, iiiclrrd.iaig aqueous ati(l ric3tt-atlueous licltiicl aiteditirtis, ariei the par`ticu:lated ~~~nge z~iaterial can optioÃaally be used in Ãlie sa.rne relative amc?unts, disclosed }iereizt for the collager-i solids materials. Further, a ~porige starting material liaS been c1iemic:szlly crosslinked Withan aIdelivde crtasslin:ker such as farr7ialdehyde or giutaraldehyele, or another suitable chemical cro:slinker such as a e~.Airbodiimidc;, or by other tecliriiclties srrch as elehyclrutlierr~na:l or racfiat.ic}rirc:iricluced r:.ross:lanking. the particulated r:,ollagen. or otlier biorrvswt able material retair-is tlic chemical crosslinking .~ncl provides ar-i advantageous;
lasting scaffold for bolie in4~rowth Other sources c>I'chem.icall~r crosslinked, particulate ~.c~ila7t~ez~, it~ fiber, irre<.~L~la7.r or other shalies, cazt also be used to significant advantage, and their use Ãs, consi der ed tt) be -another aSperrt of the preserlt .iriveritiorl. `i':l-rrvse crc}sslir-rked particulate materials can be provided as starting materials for preparing compos:itiorrs as tlisclosed l-rrv.rein: and therefore as incorporated M the device tlleso part1c.1cS are. individrrally, crosslitikf>el. As well, crosslinked solid collagen particles cazt be rlsed in ocambiriat:ron with non-crosslinked collagen in c;onipositions of the ir-iver-itioli, whc;r~,'ir-i the rion-c:rosSlinked c:ollagerl cffli b~.~ solid (insoluble) or soluble r:.ollao,.en, or combinations thereof. Such crossl:iriked arid non-crosslinked collagen mixtures can be used, for ex-ar1~pleY to modulate t.lie residerice time of the collager1 portion of the irnplat7t compositions in viv-o.

In otheracivantagecra.~s embodiments, the particulate ccrllagen, crosslinked and/or rion-croSs-linked, can be in the foa:Ãti of elongate particles, sucli as fibers or ribbozis. Col:lagen ribbons having a me;e$iari width of greaier than about 0.2mr~ti are preferrocl, moro preferably greater thari afaotrt 0.5 rixm, in certain rvr-nl?odi.rnents with r~~ediarl lengths in the range of afaotrt 5 mm to abou.t. 20 mm and/or median thicknesses in the range of about t.~.t7' mr1i to about 0.2 rxirÃa. 1:llrrst.rativelY, the collagen ribbotis can have mecliati Nkl7dths frorÃt abotit 0.2mm to abotit 3mm (more preferably 0.5 mm to about 3 mzii}, riiediarà lengths of about 5 rnnt to abotit 20 r-11Ã1Ã, aDd ariedian tliick.Ãiesses t'abotÃt 0.02 tti rn to abotit 0,21 n7rtÃ. Whensuc;he'lorÃgate 5 collagen ribbon cozrlpositic}t~s -arrr used, potentially in coÃljuÃict:ic}ti w:itfi siÃii.ilarly-sized DBM
riblioii compositions, or other DBM coiilpositsoà described hereiii or otlierwi.se, :1Ã1 a:dva:ri t.ageou s tztrwr:.ltari:rcal eÃ-ata.:rtg(emerÃt of tztaterials :rri t'ltrw form ulatioÃt cart be achieved.
AclvariÃ:agrrorÃs ocarÃ-~positiorls of t(-re invention caÃi comprise bioresorbable solids at a 10 level of abottt. 0.1 .;r~ins per cttl.~ic cerit-inz et:er ~~'cc) Ã~.~
aboLÃt 0,7 g/cc of the overall composition. For extar-iiple, flow-able paste compositions canbefor-mtÃ1ateei w1Ãicli contain bioresorbffble sa?licis at a. level of ffbor.it 0.1 g/cc to about: O.1'>
_Ricc, more typically in flter~nge of abotit t.~.1 5 g,tc.t: to about 0.22 pp`cc;. SLÃc.h flowable formulations can be configured as it1jectab:le materiats, e.g, soas to be injectable thror.Ãg1i a zieedle that is 16 gauge or smaller.
C'eriaiÃis1it1)c-retaiÃiirig putty coÃnposit:ions cari be forma,alAitee$ w1-iich contain bioresorbable solids a:t a level of about 0.2 grcc to about 0.5 more typicailly in the range of about 0.25 cc to about 035 g.{cc.

As noted above, malleable fomttÃ1ati(yris of certa:irà embodiments of the ÃnveztÃi0r) include -arà amount of collager1 as -arà insoluble solicls Ãnaterial. The collagerl w ill desirably l?e irÃc(arpo.rater:l in a substantial, scaffold-providing amount, but in ari azrlc}urià less than tFlat of the partie.ulat.e DBM oti a weig.~ht ~-t~Ã~-~~~~~;.i~.~~}~~~ bawis. lin certain ~.~Ãts~~~~~si~~ic~}r~a( ~~r~~bc~}r~.im ents of t'ltrw irÃverÃtÃott, t(trw baoresorbab(e scalicls include the particulate solid collagen material and fl-w DBM material at a collag on matcria1 DBNI material weight ratio t.clr-~t basis) of about '1:122 tcx about 1.2. M(arrr desirab1v, said we.iv:~,hÃ: ratio is in the range of about 1;12 to ifbo>.:rt 1:5, or abottt. i;1 0 to about 1:5. Particular iiiveiitive enil.~ocl.imeÃzts are provided wherein said weight ratio is in the rarÃge of aboa,at t:S to about. l.:5, '1:'1iese riÃalleab1e irÃIplaDt c;OrItPc3sitiOns thus include significant amounts of the collagen solids, w1Ãicb provide a local sc;atfolcl miaterial. for c:ellLÃlar infiltration and eventual n~.~-w bone vola.rm.e. Typically, the particles of sÃÃch collag~.~n solitls are less dense than the 13B:M parÃicles, which has not only been found to improved the pliysical handling and ir~tiplant properties of ilic iriveritive;- tiiaterials bt.rt: cai-i also provide a local ;cafTold rrrÃvirc}rurlrrrrt that is rnore sLÃserrptible tc) cellular :inf:ÃltraÃicarà than tfie I3L3M

1l.
piarticlcs alone. Thes~,~ factors, combiiicd with the biologicially-triondly r~ .~turÃ~ of a thfckelled po1ysa7.Lclraride carrier, lzr(ivide ostCOiDdtac,tive materials fyf particular benefit to 1~ea.l.tla care provi clers and patÃen ts.

'1'he licltiid combined with the solids of the .iriveritive medical formulations can be an aqueous subsiarice, wid c.aii comprise sierile w~4et-, physiologic.al saline, phosphate buffered sa(ine, blcaorl, borte rraarrca-~v, laone marrow :f`.ractiorts or other liquid me~.~iunisz emulsions or suspensi oÃas that provide adequate NN.ettiÃag characteristics to form pastes, putt:ies, and other simi1-ar malleab1e materials. B:Ãc}c,c}mpatible organic liquids cat1 'be used in certain forms of the pr'eserit irzverztiQri, alone or in combination with water. A wide variety of biQc.oFirtpatible liquids are kr7OlV-Ti arldstaitable for these ptarposes, iticlrrt-I.ir7g for imstance liqt# iel polyols sucli as glycerol.

CoJnposit-ions of ttie inventiÃ~ti can be prepared in certain embotlaJnents by mixing tlle irisoluble solid components ink) the liquid material(s), preferably so as to provide a sribstatrtially homogenous compos:it:iori ovrv.Ã=all. :Ir-r ttris regard, any order of addition of t(-rrv sol:id corlipoiicnts may be used. As an additional preparative technielue:
after iiicorporatson of the solacl c.ompori~iit.s ixito the liqtiid, the olverall c.omlaczsition can be heated, desirably to a temperaturethat does not significantly deor~detiie ostec?iriductive character of`'t:he .DBlLrl:.
material, wheri sucli a :E]I_3M material is employed. 'I'emperaÃures below fr(l"C w.ill be. desired for these ptirpc}ses, for example in the range of about :3 )U"(Y to about 60"C, ni(are prrv:f=erably in the rar~~~~~ of about 45"C to about 55'C. The heating can be conducted for any striiablc perioel of t:rrne, in certa.Ãri eiiibo~.~iiiierits for a period of up to about 12 lic?ur-s, and raiore preterkly in the range of about 'l 0 miiiu.tes to about l8Ct nainutcs. Wher~,~ elongate particle tornis of DB41:
a:nd./'c}r collagerl are Lrtilizrvrl iti the cornpositior-rs, sur:,:(-r a:(-rrvat:ing strvl) cari be coriducterl so as to tliic-keri the composition, everi in the presence of the liquid carrier and in the abserice of any liquid loss. Witlic3t.rt intending to be botandb4 i17eort, it is believed that sucli a heatingstep creates a fu.rtlicr association of the elongate DBM aaicl;'or collagon materials in the c;oniposition wi.th. oiic another, leading to Ei more viscous consistency of the malleable compositioJi. Thus, such heating steps can be beneficial in the preparation of generally )0 r-nalle;able or f1owable c 01-1tpositic~rIs.

The liquid phase of the medical implant c~~ipositions in accordance with certain aspects frfÃlre invent.io.rr will cc>rxipn'se an amount of a polysacc.har-:ide. Preferred are iczrr.ie polvsacelra:ricles tiiat are capable of forming thermallv irreversible ionically-crosslinked (; Rs trpor7 cor-irbirratic3ri x.0t.h divalcir.t or other polyvalent cati<raricn7alerials. St$Eitable strch ;~ polysaccharides include, as ~xazrrples: plarrt--clerived polysacc,}rarides suc,}r as <~lgiriates and pectins, arid gc(yformirrg cierivat1ve: tliercof. AqGaeoGas soluticrr.rs of such i011ic.
plysacelra:ricles forrr-a ÃonÃcally-crosslinlt:ed -els upon ccarrtact w:rthaqueoLrs scalritÃorrs of countersi(yrrs. For instance, usefr.rl a;yeÃats for iorrically crosslirrlw.irrg a1oinate and pectin polysaccharides include cationic -;rvllim) a wwents, prefrv.Ã=a1.?ly ir-rr:,ltrdirrc, divalerrt or trivalent cations. UsefLÃ.1 divalent cations for these ptrrpQses irrcltrde t.lre alkalirie earÃlr metals, especially c;alcitarn arrti str-or7tytrrti. Altar-irirrt# iir is a use;ftrl c;rc3ssliarl4.iarg trivalent cation. I'lrese ionic crosslinkiÃag kgerrts will usually be proviried by salts. Useful anionic cor.irrter-ioÃas for the ca1c:itrm or other salts are desirably selected from pharmacer7tic.ally-acccptable anions such as chlorides, ;y:luconates. fluorides, c.it-rates, p17osphates, ta:r-trates, sulphates, acetates.
borates, atrd the like;-. .:~i-i especially preferred ionic crossliiikir~ig agent for tase with an alginate or pectin compound is prov.Ãdedby caJcitr.rrr chloÃ-ide. 'I'tle ic}riic polysaccharide cbitosffli caar also be rrsecl (for example a1or-ie or iar conibinatiotr. with aar a1giarat~,~ and/or a lzec;tiri), and c:arr be:iorricallv c~rtrsslixrl~ed with mtr(tivalexrt, anionic gelli.rr~ a.gerits. Srrelr agyeÃrts irrclude metal po1yphosphaÃes, suc}r as an alkali ziretal (rr arxrmc?nium po1yphosphaÃe, pyroptlc}sphat:es c}z mrvtapfiosptlates. Citrates c-arr also be Lrsed.
'1`fiese aiiic}riic erossliriltiri;.) gerrts will also usually be prc}videcl by salts. 'I'}re ca.tionic courrter-ior-r for tf~e po1yp:lrr:rsplrate a or other salt c.ar-i be any suitable, biocompatitrl.e or pl.r:tr-rl-itt~outica11v-~accr;ptable, cation iziclud`Ãrrg for- in starice sodiwrr, poÃa.ssiurn, or a.rrrmc?nÃum. IN-:ta:rry other bÃocc?mpatÃb(e polysace.haricies, including plant-derived and animal-derived matcrials, .~ncf star-iclarcl and thickened polr~sa~.c,}raritle~;, as well as corresE~c~r~.dir-~~;, .i~~rri~.~
czc~sslirilt~iriw, ~.~FerrÃs, are ltrr~~~:~ti and can als~.~ be l.ased in aspects of t.lre present irrverrtion. 1Ã will be l.anderstQod that a sirz gle pcrl4sacc;harit-1e, or a blet7d ul tw-(.) or more different poly saccliaridc.s, can be taseci in compositions of the ir-iver-itiotr.. In this regard, in. the case of combinations of diffcrc;rrt polysacc.haricies, ~.~ach. polysacc.haricie c.ar-i indivfciLrally be trs~.~ci in the amounts, ratios, ranges or levels for the po:lysacc.l7aride ccrmpozier7t disclosed herein (Ãtruss potentially leading to highe;-r values than ttioso set :fortfr }iereiii w1-ie;-ii the poly sac;crtraricies are corisidereci on an addit:ize basi;), or the tota;l amourit of pc}lysaccharidrvs f.co.rrsiderrvd c}rr ari adcl:itive basis3 c:ari l:a~,~ controlled to be witliin the aniounts, raticas, ranges or levels f'or the pol~sacchan,dÃ~
corrtlac>nerrt rl.i sc(osed he.r-eirl.

N:1etiical grade polysaccl7aricles switab1e tc3r trse ir7 aspects of the invention can be prepared usil-r ;14.riowri techniques or purc,liased from commercial sources.
lllust:ratively, p ~~~~i~~cation techniques for larelaaririg meciica( grade po(~saccharides may iriclu.de.
eoriveritional separa.tiort techniques such as chr-oma.tcag-raphy, membrane filtration, precipitation, extrarr?=taonz or other suitable t:eclarriqrres, t1edical grade sodium al;yinate ziia.v be commercially obtair~ed. :f=or eNamplrv, from M_edipol SA (:Lausal-me SwiÃzerlanrl), or t:rotrl \ovwklaÃrix FMC BiopolynZer (l'hilacfelphia, 1'enrls}rlvania, t'_.ltrapxrre PRONOVA brand (er7dotoxin Ie;ve;l <' 100 e;nc.lc3toxin rrnits per gran7 )).

Alginszt:c; polymers contain larg~.~ variatiolis in. the total c:ontelit ofM
szr-icl G, and the relative c(aritent of sequencesÃ:rurrtua~s also varies largely (Grfalocks, M-blocks atid MG
Ailtorr) atil-ic: ;;eqt.lel-icaes) as well as t}ic lerigt}i of the seqraerrce;-s along tlie polymer chairr. In some embodiments, orle or more algirlate pc}lyniers of the r~ialleab1e composition carl c,c}ritairi more thali 50% alpha-L-guluronic acicl. In sosiie cnibodirlients, osic or more a1ginate polymers ot'the c.omlaczsition can conti3in more than 60% allal-mr t:,r grrllaronic ac~id. Il~ son-re embodiments, one or rnore alg-irraÃe polymers of`'t:he rr.ornposiÃÃc?n cazi contain 60% to 80%
alptla-l=-.- ~r:ll~rrc}r~ic ~.~;~itl.

l:ri certain ersibodirsicsitw, a(girWe polymer`s r.-:ed in compositions as ciescrit~ed herein may have average molecular we:rglits ranging frcarn 2 to 1000 '1;.Ãlc?daltorrs (W)_ 'Tlie molecrÃliar weight ofalgiiiates Cffll atTect tlic propcr-iies of th~,~
malleable coniposition, Generally, lower molecular weic,:(-rà al~;inates will be more biocfep,radable.
:I.l-r sotrie ernbQdirnentsY the alginate polynZers have ari average InQlecr.rle weight of frorii 5 to -350 kl_3.
iri ;;or7ie eriibotiiriieiit;;, the algiiiate pc31yr-iie;r;; have ~ii averta~,~e rri lect# Ie iveiglrt of from 2 to 100 1;-D. in some c;nibod1r~ier-its, the al.gÃnat:c; p{llymers have all average rliolÃ'cu.le w~,~Ã<-,ht of froiii 5t.~ to 500 I:-I?. ln sor~ie ~.~nil=sodsnielits, the alginat~.~
polymers have sznws,~.~rage rliolecu.lc;
weight of from loo to 10170 k:>:=3. "f he molecular weights identified in tliis Paaa.gaaph can similAirly apply to other polysaccaharides w1-ie;-l-i used iri t:lic iiiver~rkioli.

The algi31ate, whf?31 14sed, may possess a viscosity ina 1% solutit7n r11f?as1.]r~,'cj at 2~.~
degrees centigrade of from 25 to 1.000 rxiPa:s :rircl M soriie ert~boClimenÃs, 50 to 1000 rxiPzis (11NO
solution, ?t?T).

Whi1e the Lrse of those ic}riic po1ysacch-arides t(-rat are capab1e of forming tfrermallyr ir-reversible gr,.ls is prefcrTr;dK ii will be understood that in the prescslt invention these polysaccharides will lae ionic,a.lly r:.:rosslinkeclz if at a.ll. carily to an extent that does not eliminate the nialleable nature of the putty, paste or other similar implant material of t(-rrv present invrvntic}n. '1'hus, w it(-rin aspects of the preserrt invention, no or subsÃantiaillv rio ionic crosslinking agent Nvill be added, oFr irz some cases only a relatively small am~.~r.rnt of i:or7ic cr'osslinking or gellir~g cari beac.lclecl in c3rcler to increase the viscositv of the overtal l formulation. Ori Ãlie other hand, in other aspects of the ftrvetrtiozi, malleable rr:oziipositic?Ãis as described h~.~reiri can be contactecl w ith. an aniorrnt of a liquid rlieclia.rm. containing an ionic crosslinking agent immediately prior to, dtarin4.), or after implantation of the material into a patient, Illtrstrativelv, a ma11eAible; corr-ipositiorr as described herein c:~~si bo c;o-a.tlr-ninisterecl with a liquid r-r~edir:rni of ic}riic c,rosslinker, as in the case of a tlual-ba.rrrvl syringe administration ~y wliich the niall~,~able conipositior~ and crosslinker are admixed as thev exit the syringe. A(iernatively, a lareviously-imlalarrted zi.rxic>rrnt fTfÃhe rna.lleab(e Lomposition can be was}iecl -,v~ith a solr.itioÃt or other liqrÃici medirÃrn coziÃainitrg an appropriate i(yriie c;rosslinl;.in4~ <~~;erit to sÃ:ifferr the i.r~il:~larrted r~l~.ter:ial ir-r .~itrl.

The polysaccharido will :omciitsir;s be incorporated into mallcable.
fomlrrlatioi~s of t-lic invention at a. relatÃvely low level. AccordiÃ-agly, irt certaÃri inveraive varÃants, the niall~,~able implant cor~positioris of th~,~ invention contain the pol.ysaccharide at a 1evel of about 0.01 ww/cc to about. 0.5 cF.`c,c of ttle overall ac}rYrpositkan., somrvtinies abotit. 0.01 w;`cc, to aborrt 0. l s;:=cc of the Qverall composition, and in certain forrlis at a leN,=el of about 0.0-1 g'cc to ab rri 0.07 g/c~c. In clesirable i'l(awable past.c. L rmultat.ion;;, the overall cor7~posiiion can c;ontain the pol~sacch .~nde at a lcvc;l of iabor7t 0.01 _g/c:c to about 003) niore preferably aborrt O.Ct 1 i toaborit C3.t3"-)5;,~r'co. ln cc;rtsziri. desirable shszpe-retaining putty formr.rlatlons, the oN~eratl composition can uantain the polymccl7aride at a. level of aliorit 0.02 grcc to about 0Sg. e::c:.. 1i-i additional emboclirnc;nts, the (iverall caor~tipositii.~l-i Carr co'ritair~i the poly saccharide at a level c}f about 0.02 o,,'r:,e to about 0.07 g./cr:,, abotit. 0.[}2 4;;`ec to dbor:rt 0, 05 gi`cc, or about 0.02 ( g: cc to about t3,04 ~;/c:~.. It will be trt~.c~~yrstr~c~cl that tl~.r~ propc;rticS of a specific aigiriate comlzos.iticzn titilizecl will impact its effect t.tpc>xi the cliaraLteristiLs of the overall malleable coanpnSitiora, and that the amtit.tÃat or level of a1gSraaÃe in inventive composit.ions niay vary, in certain embodiments, from those ;;~eci.{ied here;ir7, C'oiilpt3sitsot of the present iriveiitit3ai c.aii be rnanuf~it;tura;ci in a ready-to-use forrnat and paiAa{~ed in a medically acceptable container for wetted malleable Ãiia.t:etials_ fn soÃiie embodiments, as illtÃsÃrat:ed in FIG. I. the ready-to-use medical procltÃct can be a prodracà II including a syringe device 1_ containing aai aaYtoraait of a. malleable cornposition 13 of the 10 in-venÃion. -fhe coanpositiQai is contained within syria~ge, barrel 14, and is Ãransfer-a~l.~le from the barrel 14 by actuating a plur~ger 15.

Compositions of the invention cati also be prepared on-site, at or near the time of surgery. For ia7stance, elav anaÃerials can be provided in the apprt~ptiate amounts, aÃa.da.
15 suitable liqt.aitl! such asAtbtaffere;e$ Atqtacc)ta::oltatiott caai be combined with the cfr-Y r-nateria;ls and mixed to fo~rtti aYtal1eafale ittiplatit compositions. Witli referetice to >i 1G, 2. :in orle form, ffli i:nvt'ntive prodaÃct." l includes a body 22 of clm> materials i:ncluding the DB~,.1 materiial, c,olla~er~ t~tatEeri~tl, ~ricl lzolysatcchatide is provided. Bodz. ?? taii olat.ionallz tie.["rte a reservoir 23 for receiN=Ãng, and retaiaiing aÃxiouzits tif the liquid ziiedir.ian to be combined -,v~ith t:}le dry, materials as it soaks ittto t}ie body 22. The body 22 r:.aii tf-terea.fter be cfisrupt:ed, e.g;, by zrlarlrtal lS.t~~adirlg: zrliNirtg or otherwise, to form the n-talleable cottipositioai.

in re-a.rd to the incorlioraÃed materials considered ori a d:av we:aght.
laasis; in cert.aizl embodiments, tlic piarticaÃliate DBM material cati c:onststa,ate about 40% to about 90% of the inventive c(ari-tlx}sitiorls, aiiore preferably abouà 5t}% to about t301 ,-,it, arld most preferably about.
60% to alrsottt 85% by weight, in a sianilar vein, preferred inventive fQrantÃ.laÃions can contain about. to about :')Mr~ by weight insoluble collagen particulate onat a:lTy x-veit.~lit batsis', rtlt:}re preft'rab1v alaotrt 9% to al=sotat 10%, and most preferably about 10% to about -1 5%'; aalcl can c;ontsziii the polySszct;han,de at a. level of about 1% to abot.at ~0% t:xal a dry %reight basis, mcrre.
p.refe-ralily about 5% to aliotit 15%, and most preferably about 8% to about 11%. it wi l l be )0 understood, lic~wever, that ot}ittr am otant: o.ftliestt aaia te;rials caai be tisttci withia t}itt b roael_er aspects of the present irtverttioa-a.

f.rr further embodimerrts., on a drL=~ weialr.t basis, ribbori-fc>rm DBM as described ttere:ixr can coÃrstitut:e about 70% to about 98% of'the composition, more pref'erably about 90% to abotrt. 98'N, air.cf t17e pc3lysac;cbar-ide caar c;c3mpri:~eatrout 2% to ab(aut 30% Ot t17e COMPO;;itiOrr, rirr:rre preferably about. 10% to I'M. In c}rie specitic rvml?odi.rnerrt, c}r~
a dry we:iglrt basis, the rltrbonrforri-i Df3N-1c.an constitute about 96% of the ~omposition, asid the polysac.cliarlcic can eorrstitute about. 4% of the composition. SLrclr ocarr-apositions cazi be free from ariy eoilagenous material otlrer than MtI, and/or cazi incorporate aar algirrate as the pc?lysaccharide.

l~trrt.lrer-, when considered as a solvated corirf.,~.~rierz t of'Ãhe liquid phase of tlre c.:omfr<rsitiorr (i.e, excluding the w-eiglr.t oI'the; solids), the polysaccharide can for extar-irple be presezià as aÃr about 1 wi% to abotrt 40s~-t% solutioÃr, azid in certain ernbodirneÃats about a 1.
\v-t% to aborrt 5 we%~ solution. Illustrative pastes can ccrr-itasn the polysac.chszride in th~.~ liquid phase as ar7 about l wt% toabout 3'wt%, solution, more preferably about 1.5 to 2.5 wt%.
Illustrative, ;;liape;--re;tair~ui-ic-, ptatties cart contain the polysae::charide in the liquid phase as arr about 3 ) ~vi% to S ,w-9. /"0 sc}lr:rtiori, more preferably about 15 M% to 4.5 wt%. Additional shape-retaining putties catr contain the polysaccharide at higher levels, for example about a 5 wt%y to alic>rri40 Nvt. ,~~t solution, in certain embtrrl.iztrerrts about a. 5 wt% to about 15 wt%
solrÃtion, and in other embodiments abotrt a 15 wloy~ to abotrt 40 wt%
soluticyrr.

In desirable variarits, the liquid carrier of the inventive c(arr-rpositiorls is essentially or ~ompldely free from any" Organic compound that is a liffttid at atsibiertt or rrsf~ (e,g. about :'17 'C) teÃitpen lr.ires. `I'lrcrs, the use of orgaÃ-aie sc?lverrts cazi be avoided, and the liquid r:.a:rrier Ãrr certain tornis cffli consist or colisfst essentially of an aqtieor.is solr7tion (potentially buffered) of c}r~e or .rnore lx}lysacchw-irles that is/are effective to provide t(-rrv desired consistency to t(-rrv firral l'~.~rrtrulation. With respect to tlre a.drrrixed solids, these can be at least largely rirade up (e.& at letast about 60%, at least abotat S.VIv, or at letast abotat 90% bv weight) by the solid collagc;rl particles fflid the solid DBM particles, and in. certain embodiments the lnsolrÃblc;
solids in the composition can consist or consist essentially of'the Col1agc;r1 particles fflid DBM
part-ic.:les. A~ vve11, in desirable embodiments of the invention, a1:l of the solids in the composition will be bioresorbable. it will bo t.rricierstood, however, that these paraariete;-rs are ri~ot necessary to all aspects oi'tfr.e invention.

C'ertain ac1vanla4.~eczus malleable Lompositions o#'the invention X.Yfl( corita7.in a particulate DBM material at a level of at least about. 5% by weight overall, and typically within tite range of al;aotit 5% t,oabout 30%~ Sucli cc3mpositions c;aD contain the partycuhate solid c;c3llageri riiatefia1 at a level of aà Ieast: about 0.5%a by weight overall arld typically iri the rain;e ol'dbor:rt 05% by w-eiglit to about. 5%, and the po(~sacchaÃ-ieleaf a level of at lf>aq about 0.1% by weight ca~~erall azt~.~ typically in the range of about 0. l% toabout. 20%, and in certa.'tti forzns about 0.5% to 5%, tlore specific iraverative malleable coÃx) posiÃÃc?ns incorporate the paÃ-tic,rilate DBM material at a level of about 10% to about ? 5%a by weight ~~~~ eraJ l, the partierÃ.1aÃe solid collageti material at a level of about 1% to about 5% bv weight overall, arld the polysaccharide at a level ot-about 1% to ab(aut 20%b4 tiveigbt overtall aiid in some fc}rrtis about 1 % to abotÃt 5% by weiglit overall, rr17.e bulk densities ol't17.e inventive compos:itions can var), atid depel7t1 upon the clerisities of tkre rnaierials in the c orn positic~sis. li~i certain embodiments, the bulk tle;-sisity of the irrvetiÃive malleable c(ariipc}siÃ-ior1will be in the range of about 1 1g./cc to about 15 gt'cc, more tvpica11v irl tlic range of alaotÃt l,1 g.'t:c to about l.4 g,tcc. These ciensities may vail', laoivever., with the dexisitaes of additional r~taÃerials :incorpora7.tecl into the rrtalleable compositÃozts. For inst:ance,bri1k densities within these razt;yes or higher may be exhibited wf~~ii amc}urrts of derise solids such as particulate mineralized borle or ceramics are inc(arporated :iiitc} t(ie kc}rrnulat.iorrs.

IN-:ta.lleable Ãmplarit material.s of the invention may also contain other benefie'lal su.bst~~-ices including for example preservatives, cosolvents, sL7~peaicliaig agc;nts, viscosity enharicing awwenÃs, ioriicstrenw,~-th aiicl c}smo1aJat:y atljusters and,r'or other excipients. Suitable buffering agents can also be used an iricltide but are riot limited toalkali~~~ earth metal carl~~iiates, pkosphates, bicarbonates, c.itrates, boraies, acetates, succinates, or (atliers Illustrative specific bufferi~~g agents include for iaist~~-ice soditÃm phosphate, sociiuni citrate, sodium borate, sodiL7m acetate, soclium bic;szrbonate, soclir.ani carlaoiiate, szaicl sodium tromethanine (TRIS). 'I'liese ag;ent, s can be inclttded inamounts that are effective to maitiÃain the pf-l: of'the system at a biologic:all~~ acceptable level, for ii-isiai-ic;c; maintAiirmi<.~ a p)<T hetd:s~ee;-a about 6 ~iid about 8 and preferably near rietitral.

Tlretn:rllcable inalalant maÃeraals disc(osed bereiri u3rr also .irrclude otfier biczc.omfaatible and pref~rably bioresorbable substances. These materialS rnay Ãnclucle, for eNaziiple, natural pol4nie r; ;ticfi as proteiris arid polypeptides, gly COSart`1iDOt~1vC,'R175 Prc~t~:c3(,~14c;aD;;, ela'Stin, f~valurorric acid, tferriia:tari sr.rlfat:e: o.Ã= riiixÃurrvS c)r c(ariifx}sites t(-rrvreof. Syrithetic polymers r.riav also 1ie incorporaÃeci iiito the r.rial(eab1e itsiplaitt materia1S.
Tlle:o include, for exam.plc bÃodegm, da.lale synfl-wÃ:rc faofviiier-s sriiJi as polylar:.ticaeÃd,pofyglycolÃde; polylactic polyglycolic acid wpolymers (":f'LGA."}, polyrraprolactorae ("K:U).
poly(dioxanone), poly(trir-~~ettlvlene carfawiatrv) copc}lyniers., po1vc,:1yconate, fx}ly(propy lerie. fLrma.r=ate), poly(etliylene terepht.hal-ate), poly(butylene terepht.llalate), pol4ethy1eriegfyeQ1, po1vcapr-oltactone c;opol4nier;;,po1yhydrc3xybrriyrate, poly liy(lr-ox;,va1er=atc., ttr-olsirie-clerivc.t-1 polyearbonate;; aÃid any random or ( Ãn ulti-)bloc1;. wpolymers, such as, bipolymer, terpolymer, quaterpolymer, etc., that c;szai be potymerized from the mort.crmcrS related to previorrS1y-1iStcd h(aJnor and copotymers.
I'tle malleable implant materials of the invention. c-an also include a rii:irieraJ
compolieti.t.. The mineral tased c;ari include a lia.tL7raf or ~Nmthetsc;
mineral that is ef'fcctive to fzr(ivacfe a seai'fold.fior boiie in.grc>wth. l:llrrstraiic elv. the riiiireral ma.irixztray be selected fr(yrn rizle or more materials fr(rrn tlle ;yrorxp consisting of bone particles, .BÃogylass`~', tricalcitirii phosphate, biphasic calcium phospha:te, fi_ydrc~xvapaÃ:ite, co.Ã
raline hydroNyapatite, arid bioco.rnpa:tible ceramics. Biphasic, calcium phosphate is a particularly deSirablo sviiÃhofYc cerwili:e for trwc in the MvcnÃion, StÃch bipllasic calciusil phosphate can have a tr:rcalcir.rrn fa(it-)sf)hve:hy~.~rcaNva:f),itÃte weigl-a ratio c?:f`fflaor.it 50_50 to about 95:5;
nior~,~ preferably a.botit 70:30 to about 95:5, e~,~,en more preferably about 80;20 to about 90:10, and most prekerably about 85;1 5. '1'hetiiiriezaf mi:teÃ-iaf cirifaea('r,-Lr-rtilaz particulate having an average particle cii~n-ieter betv-men a.bout 0.2 arid 5.0 min, rnore tvpicall;r betweert abotat 0.4,and >.f) mr7i, aii(l desirably laet~~~eeii abotat 0A aalt-1 10 mari.

In ffliotlicr aspect of tlic invention, tlic niiliera1 material can iriclrrde lson~.~ particles, )l3 possibly rrancellÃ~uss but preferably cortical, ground to provide an averaye particle diameter aationg those (lrscrassecl above for t:lic particulate rniacral rnateria;l.
Both human ar~i(f non-hunian~ources ofborie are Suitable for uw iri the instant invention, and the borie may be aux a~;ratt, allograft or xc~ograt't, ilr rlatÃire relative to the mamrrral to receive tlrc inrplatrt.
Alzprc>pr-iate lare-Erea7trxients known arr the art may l~e used to rxiiriimize the risks of disease t:ransÃxrission and/or imziruztogenic rearr?=t:i~~ Avlrerr trsirrg bcyrre par-ticles as or in the Ãxrirreral rna teri al, In orie crnbcrciirnentK xcit.o(.wnic bone that lt~~ ~eerr preÃ.rea1ed to redttcc or removc its irtrrtru.n~~ezti~.ie4~ :r ~; s used to laz-o4,i~.~e a porous rr-aiztera.l Ãiia.trix in the irztplartt eompositiorl.
For example, the bone can be calcined or deproteirrized to redr.rce the risks of im.rrrtr.rrooenic reactions to the implant matez:ial.
f3iotac;tive ~gearts <:~~ii be cleliver=ed x.6Ã.Ii rrralleable irtIplaDt r~r~t~r7~71s Of t.lle irrverrtion. These bioactive kgents rnay, include, for eNaÃxrple, antirxricrobials, antibiotics, antimyobacterial, antsft7nga1s, antivi:rals, antineoplastic agents, antitu.mor agents, agents attect-ittg tlie im.Ãrrune res-pozise, bIoocl rrafcium replato:rs, a4.~ents Useful in 4~Itracose regrrlat:iorr, aartic:oagt.rlasr.ts,, ant:it}iroml;aotics, aritil-iyperlipicfetiuc a<;ent:s, carcliac tfr-Ligs, tlrN,zornurr-reÃ:ic arrd arltitfivroid dztr~F~;, adrerler4.~~i~.s, ~.r~tilr~:l~aerter~sid~rv a~:er~.ts, cl~~alr~er ~:ir:,s, anticholinergics; anti spasm oclics, ar-ititÃleer agents, skeletal .~ncf smooth muscle relaxatrts:
lzrosi.i3g1aridiir.s. general irrlribitczrs fyf the a7.llergic response, aritihistarrriries., local aztestlaetics; aaral;yesics, rrarcotic aÃatkgoztÃsts, antÃÃussives, sedativeahypnotic kgerrts, -arrtir:,or-rvulsarrts, -arrtipsychoÃics, arlti-a.rxxiety agerrÃs, antidepressant ag;ents, an(aretiio;enlcs, rror-r-steroitla;l antircirrf7.anxrnat(arv a;er-rÃs, steroidal arrtr-irrfl-arr-rmaÃozy agerits, arltiox.ida.rrt:s, vascryactivÃ; agciiÃw, borle-actsve agÃ;r.ri:. osleogerii~ ~~acÃors, an'fiarillritics, statins, M_lArC"D..
Rr11' (nrelan(arr-aa-Ãrrltibiting activity/cartilage-derÃved retinoic acicl-sensiÃÃve proteÃrr}, and diagnostic agents.

f3ic~acÃive agents may als~.~ be provided bv tissue materials incorporated into the r-iralleab1e irrrplarit material, iir.clrrcliarg for instance tautolotyc3t.rs or a'llogerric; tysstre; rr-iaterital;;, which are incorporated into the material to be implianted in the patient.
SLrch Ãssstae materials can include blcrocl or blood fractions, laoiic marrow or bone marrow t'rae.tions, cartilage, andr'or other sources of'ce:lls or oflier beneficial tissue caJnparreJrts derived fia~n7 the pat:ierit to be treated or aarot:lrc;r= stritahle anurnal source.

Bioactl~,,e agents stÃch as those described hereiri. can be ilicorporated h0t~~~~~CDeOriSlz~ Or r'ea;ional(y iiito the implant material by sinalale aclrr~ixtrare or ottterevase FtirÃlaer, ti~ev may be iÃac,orpcyrated a1oÃae or in coxllunction with another carrier tairÃai or r-iie;d.irrm swc17 r7.s.microspherr;;; or "inother t17icroparticu.late i rm rrlat.ion. Suitable 5 t:ec,liriiques for kc}rzrririg m:icrc}p-articles are well 'known iri the a.Ã=t, aricl can be tisecl to entrain or enc.a~st-1aÃe bioaclYve. ageiits, wliercaf'ter` the mic:ropariic.(e: caii be elislacr`seci wilhiri the malleable iniplanta.ble material ulaort or after it-, preparation.

III aeriairi eiiibodiiiieriÃs, a niaIleable imp1ant cc~inposit.ion of t(-re invention will 10 iticlude one or moFre substances, additional to the osteoinductive DBM
niaterial, that iritirrce or ger7erat.e; the forniation ofi bone. 4t# ittable; oste ~;er7i:c materials can iric;lrade; a grow'th tactcyr Ãliat is effective in inducing tormation of bone. Desirably, the gros~-tla factor will be ti-cxm a class of proteias kno-wri. generally as bone morphogenic proteilis (BNI:1?'s), atid can in certain e:mbodÃ:ments be recombinant 17u:Ãiian (rh) B?v.lf's.
Tl~es-e B:Ml' prÃ~teins, 15 w1-iiclt are knod:sri to have osteo<;enic, e:.hontlrogenuc ai~i(l other growth aricl clii'f:er~sitiatioti activities, iriclude rliBMP-2, rh>iiM:l?-<3. HiBM:l'4 (also referred to as rt1f3M:1?w2:E3), rh>i3M:l?..
5, rhB41;t?-6; rhBN~IP-"? ('rhO1?'-1), rhBMP-8, rl~BMf'-9, rl~BMP-12, rhBN-1;t?-1 3, rhBM_t?'-15;
rlif3NI;1?-1 6, rl-.tBM:P- l?., z-b:BMP-l8. rIrCYDF- zhGD1"-7., rhGDF-8, rhGDF-9, rhGDF- 10, rhGDF-11, rhGDl~'a1'21, rhGDF- 14. For example, BMP-2, 20 BMI'-:-) L3M:1' 1B:MI'-5, >i3M_l?r6 and BMf'-7, clisc,l~~ed in U.S. 1'a:t.
Nos. 5.108,972:
5,t31 3,649, 5,116,738; 5,106,748; 5.,187,076; arid 5:141:905: E3:MP-8, disclosed in PC1' publication W091:'18098; and BMPr9, disclosed M PCT publication W093/00432, f3N,-1_I?-l 0z d'Iselcased iÃ-a U. S. I'a.t.. V o. 5z63 ) 7z480; BMP-11, clisclosed in U. S. 1'a.t. `~o. 5,63 )9,63 ) 9, or B4IP-12 or B~,I1'-1.3, disclosed in U.S. Pat. ~:~o 5,658.882, BMP-1 S.
disclosed U.S. t?iat.
No. 5,635,372 and BMP-16, disclosed in U.S. 1?a:tent Nos. 5,9655403 and 6,331,61 -. Otfier compositions whicli inay also be useÃiil irlcll.ade Vgrs22, aild any of the growth ailci differentiation factors iiic1rrd.iaig tkose descflibec.l in 1)(71'r7.pplictation;;
WE~~94/ 1~~~65, W094/ 15~-J49, W095/ c31 801, WE~~95/ 018022, W094/ '? 1 681, WQ~-J4/ 159ti6, W095,`10539õ W096/t.~'1845; W096102559 and others. A1sous~.~fiil in the preseiit ~l3 invention :may be R11', disclosed in W094,'t} I 557; H1110[}269. diSctoSed in JP Public~tiat~
i-iur-aher: 7-250688; aricl M.P-52, disclosed inPCT application W093/ 16099.
The disclosuzes ol'aIl of these Patents arid applicatiorrs are lierelay inco.Ãporat.ed fiereiri by .

r~,'ference, AIso usc;fi71 in the present invention are heteroclimers of tl~~
~~ove and modifi~,'cl proÃems or izart.ial deleÃ:ic>n farcxfricts thereof. These ~roÃeins ca7.t~ ~~e usecl individua11y or in mixtures of two or more, rhBMPa2 is preferred.

S `I'he >i3M:l? r~~ay be .reac}mbirlantly produr:.ecl, or purif:recf from a farotein comfaos:itaon. '1'he f3M1'may be homodirs~eric:, or may be heterodsrrierie wiill ot.lter f3M;1?`w (eg,, a het.erodimer compc?secl c?f one monomer each of BMP-2 and BMP-6) or with cather members of tl~e TGF'sheta sr.rperfamÃlyz sr.rch as activins, inhihins and TGF-beta. 1 (e.g., a heteaodÃmer composed of or-re monozrler eactl of a 13M=1' ancl a.relatecl membez c}f t(-rrv 1'GF-beta superfamil}r). Examples Qf such heterodÃmeric prot.eins are cfeseribed for example in Publi;;lied PC"I' Pateni Applic;aiion Wf;3 93t'09229, the specificat.ion 1'w~hicl7 i;; he;reby incorporated herein by reference_ `1"f~~ amoÃrnt of osÃeogenic protein usefrÃl lterein is tha:t amorrnt effective to stimulate inc:reasecl osteogenic activity of infiltratirlg pr~ogenitor cells, attd wilt depe:nd upon several factors includitt4y the size attd natrÃre ofthe defect being 1 5 treateci, aricf the; c:arrier= anzl partic:t.rlar farotein beirig e;mployed.

Other ther~~peutic; growth factor-s or substances may also be usc;cf in mallc;able implanE mate.ria1s oftl presenE :inveniion, esfaecially thczse that may he rrsed to stimri1aEe bnne formaticrn. Such proteÃns aae knowÃa a:nd iÃaclude, for exa:rnple, plateletsderived 2() g.rowtt1 fac.tors, insrrlin-lil4e 4?,rowt.h t`actors, carti1a4?;e-dera~~ed morphoge.nic protrvins, g.rowtt1 diffe.rentiatic}n kactors sucl~ ~s g.rowth diffezentiatic}n farrÃoz 5 (GDt'rc5), a.nd t~~ansforrriing growtll factorw, includirtg TCiFac~ and TGCyft The osteogenic proteins or other biologic;ally active ag~,'nts, when used irl the pr-c;sent 25 invention, car-r f?e prozicfed in liquid foz.mulatior-rs, fo.r example fauffered aclueous formulations. In certain embocfimenÃs, suclz liql.aid formulations can be mixed wifh, receivecf trpc3n and{or wiil7in, or otlierwise combined with a dried iariplant materital c;ontainirlg solicf ingredierlts in orcler to prÃ~pare an osteogenic, malleab1e implant material ofthe invention. One suitable rhBMf'-2 fcrrmulation is availafrle fi=crm Medtronic Sofamor-30 Dattek, MeJnphrs., TN, w:ith its INFi_JSE Botte Graffi protluct, Altea:nativel~, srÃch 1:Ãqu:Ãel iiormt.rla.ticaris o:fbioloc;irally ac:tivc; age;nts e::Ain be c:ornhine;e$
with an alreae$y-prepare;d, wettecl maIleable implant composition of tlxrv inventio.rx.

C)StCOiDdrac.tiveztrecfica7l lza:~~te, lzLrtt.y or otlaer malleable eorr~posiiions c>I'the fareserit iriveritiotr rr:aai also comprise progeriitor arid{c?r steni cells derived froni embryonic or adult tis;-,ue s(aurces ~iid/'c:}r takeri frc3m c~trlt.tare. 1lltistrat.ively, compositions t'tlle iriverition, Cari incorporate cells clerid:rvd fro.rn blood, bone marrow, or otlier t.issrre sorrraes from the patient to 1ie treated (autologous cells) or fr-oiil asuittrble allogcsiie. or xer~ogcriic donor source. In certain ertiboc1Ãrtienis of the i nverition, the confcarrnalal e eompos:rti oris inccrrporat:e aai enriched borie marrow fract:iorr, paepa.recl for exaanple as descril~ed in US
Patent Publ:icat.ioti No. 2005/0130301 to McKay et aJ. prrblisl~ed Jutie 16, 22(#05, pr:rblisliirlg U.S. t'aÃent. Application Serial No. 10/887,275 filed July S, 2004, which is hereby mcoq)or-ated her-eiri b4 r-eforerice in its eritir-e;iy, '1:`lit.rs, implantable niaterials c~ii inccyrporat:e a bone marrow fractioÃa enriched in connective tissue gr~Avth components, that is prepared by centrifuging a biological sample (e.g. frorn the patient to be treated) to separate t`t~~ sample aritta fractions including a fraetion rich in ctarir7ective tissue ;yrtawth cornponerits. The f:ract-iori ricrti in connective tisstic; growth components can itrer~i be isolatetf i:Ã=orri the separated samp1e, atld incorporated irito ttle .rnaJleable iniplar-rt material, c.g. by r.asiiig the frac.ticxri in or as a wetting niedirÃm in coiiibfnatiori. with a dry particulate or dried bod4 including the otlier in4~re~.ier~i~.s c~I't(~re rrt~.(le~.l~le t:~~rrxiul~.t:ic>r~.

In still fLrrtfrer erYrbodinients, the present invention provides rYÃett-rods for treating paÃierits that irivolve implanting in the patients a rYral1eafalrv implant r~iaterial as described herein. :(n such tisesK a paste, putty or other- malleable ir.riplan.t composition of the invention can be iÃl-rplari.t:eci at, a sit:e at whic,l-.i tissue growfl-.i is desÃred; e.g. to treat a disease, defect or loeaticari of tra.crrria, and/or in some instances to promote artificial arthrodesis. The rlieclical compositions c .~n be used as or in surgical ir~iplarrts at., in, on, or .r~ear fa(arie rle:f=ect sites, cartilage repair sites, or other musculoskeletal sites. Alternatively, the compositions of the invetlti~.~ti may be applied to larger segments of bc~ii~~ artificial ir7ipl~iit;;, or r7.rr4 otlier kiiid of stargical impltarit.. 7~1'17e ni'alle;al_ale character of th~,~ compositions can eriabl~,~ their introduction, shapiiig and/or moldiiig within voids, defects or other areas in wliicll new tissue gro-wth is desired, szricl,r'crr in cortair~
embodiments in whic17 tt~e deliveav of a bioacti~~~ agent is desired. in sÃ~n7~ advantageous emboe$inierits, tho rnalleable maierial d:sill be a pt.rtty liAiving sliAipe-ret:airiirrg properties that desirdbly p.Ãovidrv sufficient ttrree-tfimensiona;1 ir-rtegrity to resisÃ
suf.?stant:ial compression wher-r `?..i impinged by aclja.c~,'nt soft tissÃ,~~~s of the bocly at a boÃiv implant site.
In other aclvantageoÃ,~s embodiments, the rxial(eable rrtat:erial will be a rxiore tlowable paste, tttereby I~:Ãcililat:irÃ:; it:s iritroductiorà Ãnt:o reziirite implant sites using SyrÃng;es, rieedles, tu~~s, or other elong;ate delivery clevices. IaÃ-jec;table pastes, tor c;ÃTe;CtiVC f r rr-IjeCtiOrl tl7rOtÃgh,`R
16 gatÃge rÃeecfle;, Ãor7il prefeÃ-Ã-ed past eÃiibotliÃn eriÃs of the iriverrtioÃi. It. will be understood, l-roiN-ever, tfiat not all pastes or ryGaltio~ of tl~e.i.riveri~fior-iÃ~~edbe.ijcctablctl-ir(-iGaghrela.ti.~~elySmal.l dev1ce.sSGachaw Ã~eeciles, as other ~.~el:rver), mo~.~~-, or devÃce-, Ãht-ouglà open or rÃiirÃiÃ-aially ÃrÃvasive suÃlger-Ães will be, ao:aÃlfflale.
IlluSt.Ã=ative bone repai.Ã= sites that can be treated with medical cotiipositioÃis of the inN=enÃion include, for iiisÃaiice, those resulting froÃii iqjur-y, defects brought about dtaring the course of strrgery, int:ectior7, Malignr7.ncy or developmental aritalfiorrtiatior7 'l:'1ie malleable ccrrnposit:ionS can be rÃsed in a. '%.Nli~e variety of orthopedic, periodontal, lieu.rosrÃrgicEi1 and oral and Ã~axi11cÃfszcial stirgical procedures iÃiclÃ.acling, but not limited to:
tlie repair of saJnple and rron7pound fractLÃr~s and norlruzi:Ãozis; external atid .Ãr7terrlal f-ixAitioÃis, JoirÃt reconstructions suchAis arthrodesis; ge;-Ãieral a:rtkÃroplasty; c;tap arttÃroplAisN=
of the bip; trv.Ãno.Ã=al arirl hu.Ãneral head rrvp:lacer-nerit; :f=ezrlc}raJ
head sur:faae Ã=eplacrv.ÃnerÃt arirl total joint rc;placem~,'nt; repairs of the vertcbral. colLÃnin including spinal. fusion fflid interiial fi xa7ia~~rÃ; irÃ.Ã~~c~Ã s~ix4~~r~ ,~.:;,, clet.icit.fiiling; d:iscectoinz, lamixÃeetoÃtw, excision of Slzina71 cord tumors; anterior cervical and thoracic operatiorÃs; repairs of spinal iÃajÃ.rrÃes; scoliosis, lc}rclosis and 14vphosis treatrYÃerits; .intermaxillc-try iixa.tioÃi of fractrires; zrlerrtoplasty;
ternpororÃiandibuIar j61 rit replar:.ezrlent; aIvrvo:l-ar ridge augmeritaÃi(arà and recorÃstructiorl., inlay osteOintplar.Ãi:; implant placement wid revl:ioÃt; sinus lifts; cosmetic enlianecsileÃlt;
etc. Specific bozies whic;li can be repaired or replaced with ihe malleable ccarÃ-aposition or arÃ
implant compriSirig the compositioÃi. include, bÃ.Ãt iarc Ãiot limited to: the othrliofci; fi=oÃ-ita1;
nasal: occ,ipital., parietal., temporal; maÃ-rtlible., Ãnaxilla, zygomatic;
cervical vertebra;
thoracic vertebra; lumbar vertebra; sacrrÃin; rib, sternum; c.lavicle, scaptala, humerus;
raclitÃs; u(r7a: carpal laone;s; r7ietac.tarptal bones; p17alantfe;;; ilit#
ÃiÃ; i;;c;liit# ÃiÃ; pt.Ãbiss fen7u.t;
tibiar fibula; patella; ca1caneLÃs tarsal anci metatarsal bones.

In accordance with certain aspec.Ãs ofthe invention, the paste, ptitty or other rnalle;able implaÃ~it compositions o.f"the;- invention can be tÃsed as bone void filler:, or catà be aÃ-rcorporatecl in, on or arouÃid a. load 1~eariÃii) :implaÃits sucfi as spinal implarÃts, hip iÃiiplaiits (e.g. in or aror.and implant stems and/or- lsehilrcl aeetabu.liar cups), knec;
implants (e.g. in or W-OUDdsterrts). In inventive variani.s, the malleable itriplarrl cc>rxipositaoris o.[`ttte invention can be iÃacorpcYrated in, on nr arouncl a load-bearing spÃtral implant device lra.ving a coir.rprc.;,sive strength of at least ab(aut .l 000fl'ti, suchaS aÃiasiorr cage, dowel, or oÃlrer device potentially tlaviii~~: a pocket, chamber or other cavity for containing arr osteoinductive c.crmpcrsitiorr, aÃlci usoci in a slai.rral ftiwioii wuchas ari irrter`trody ftiwioii.. f3rrc illustraÃive such use is in cotr_jLizrctiart with a load-bearing interbody spir.4l spacer t.o achieve iÃateal}ody fusicyzr. In these applications, the malleable implant coniposition caar be placed in arlcl!or around the spacer to facilitate the fusiori.
Illtts,trative C"ar-tylage repair sites that carr be'trer7.te(l witli mallealrle compositions of the invention include, as exaÃarlr(es, ar-tictilar cartila;ye surf~ces occurring in articular_jointS
lraviiig iat least two rriEijor bolreS. Exaniples ilrclr7dc., btit are not limited to th~.~ elbow, wriSt;
phalanx, knee, and aJr1S.le. AdelitiÃ~na:lly, cartilageSurfac.eS within slrÃ~ulder and hip joints c:.ai-i be ti-eatecl.

The present inv~,'nti~~i-i also provides rrieclical lc.its that i~-iclu.de; or tlriat can be r.asc~ to prepare, mzr.llezrble :irxiplant corrr.posityoris oft1re invention. Suc:h kilS
can iricltrde a dried mater"aal contaizring tl~~ solid ingredients of tiie znalleable f4rnlr.ilaÃioxr alozl;Jy with an aqueotrs irredir:rrr-r or otlrer biocor-nlratible wetting; lirlLtitl for cc}mbiriatiorr witlr the dried material to forrr-r a.malleable wetted maÃeria;l, or cari include the formulated, weÃ-tetl malleable irrrplarit niat.erial i.rr a stritablc container such as a syringe or vial (c.g terrnisra11y, sterilizecl). arid:'Or afrot.lrer iterr-a srieh as a load-bea:ring inrplant (e.g. a spiÃ-.4l spacer), an. ct1or a transfer cl~,~~vicc su.cb as a syritrge, and/or a therapeutic sr7bStan.cc;, for ~~amplc alr Osteqg;en.ic, Substarrc,e sr:rcfi as a:BMP. :Ione specific f(arrYi, such airredical kit can irlclrrtle a ciried rrlaÃerial, sLÃ.clr as a. parÃic.ulate or dried body, a BM_I) in 1yoplrilized forirl (e.g, rMNIP-2), aDd arr atltaeotas r-trc.d.itrffl f(.)r= WOD;;titUtyc3ri of tlre (3MP to prepare tanatluc.ous formr7lat.ion. that can then be added to the dri~,'cl material in. the process of preparing aar osteogenic putty, paste or other malleable implant materiat of the irlvcnti.on.

The invention will lrmv- be more particularly described with rcf~,'renc:e to t1lc fOll:OWiD- specific exartrlales. ft will be trÃiderstood tha7t these eNartrizles are :illustr-ati~~e aÃr.d not limiting of the embodimenÃs of the irrveÃrtion.

Example I
PREPARA-'I'ION OF OSTE+C31ND[ CT'lVE PUTTY :F'ORMULATI.ON

1'-~1.9 ~; E~t sr~dÃuzir a1{~ixr~:te(~~S:1' {~rade, Spectrum Chemical) were combined s~~~iÃlr :3 ) 25 cc of phoslr:(-rate britTered salirle in a blerider. Tlremateria;1s werrv rr-rixrvd irl the blender tÃrltil all of the als;iÃrate was iÃrc.orpora:ted. The coÃtrlrsirZed PBS/alginate material Nvas then trarisferr-ed t,oa Ãr.rixer bc~c~l aÃr.dtr7i:sirig was iriititat.e;d. 16.1 '-"~gof ariille(l, cr<r,"liÃr.kecl collagen sponge were slowly added to the mixer boANrl while mixing, aztd tlre resulting materials rriixed to torrrr a unitorrrr mixttire. The milled collagen was obtained by grinding a crosslÃ.Ãr:l1ed colla,~
4ezr spon4~e material available from Collagen Niiatri\, (rrc. (Franklin I..al,es, NJ) asr.d k.ir.~~wrt as Collagear Matrix Spcxrge, A retcli grinder operating at 8000rpsar with a 1 rr-rm sieve was used for t(-iis purpose, .r=esult:irrg in the collerrÃicarr of the randomized sp~nge partiotrlatc as a wislsy mass. 1t3~.~ g of'clenr.ineralizcd bone matrix lraiing a pas-ticle size of 55-850 gÃr.r we.r-e, then slowly added to the bczevl while rrr.i.xin-1 wlr.ic}r X.~,as allc>wed to prrirr?=eecl r.rÃatil a uniform mixture was nbtaÃÃied. The resulting mass of'ptrtÃy was packed into a 60 cc syr inge, arrcl a s rin4?;e c(arrrrector was at:taclrrvd. 'I'}re 60 cc syringe was cc}rrrrected in sequerlce to smaller sy~ringes f(ar final pack~.~w:ing. In partic,rÃlar, Scc of the putty product were traÃlstcrrcd itit~~ 6 cc syringes, arici=oÃ' 10 cc oi`tlle putty pÃ'odtrc;i xvere trarrsterred Ãrrt:o l~? cc syr:rrrges. 'i'lre top ot'tlrc srtra.ller syz-in{~~
was then capped tÃglttlyz and the capped syringe was insert~,'cl into an inner pouch paclc.apgc c\.-bic..h was vacuunr.
sealed. Appropriate labels were applied to the iÃ-iner pouches wliiclr were then iriserted iÃrto outer packaging pouches aÃrd theÃi heat sealeci. Tlre packaged syringe prQdtrcts were terrrriritally stefl* Iiz:ed with f:-betarn to a level of2:? l:ilc3Gr-ay4(k.Gy}, The osteoinductive putties prepared as above c:ontsziiicd, oar a cfry weight basis, 77.5% DBN.1 (particle size 5-5-850 Lrm), 10.0% a14y.Ãnate, and 12.5% collagen.
f3n a. wet )o weiglrk basis, the prrttic;: ccxrtaisr.ed 21.41r~'o D.13M, 2.8"~'o sodium algiarate;-, 3.4% ccrllagc;rt-and 722,4% phosphate buffered saliÃ-ie. Th~,~ compositions were. of good pLÃtty quality and would retain their slaape fi.ÃrÃless kÃr&3ckeck or presseck Ã,ÃporÃ.

E1AMPilE 2 .PREI'ARA 1'.lON OF OSl'E O[;'eÃDUCI'1VE PASTE FORM.[`-IiA'['1ON

`I'kre procedures c?i'ExarÃrple I were repeated except utilizÃÃrg 660 cc of plrc?spkrate buffered saline instead tif 315 cc. The resr.iltin{,~ paodÃ.Ãcts NN.ere of a paste character and ozl a dry weight 'basis contained the sarÃ-re 1eve1s of I]:W. sodiLÃm afgirrate., -arÃd col1ager1 as the pxÃtties, prepared in Example 1. 011 a wet weight basis, the paste contained 12.7% DBM, 16{'r~ sod.itÃrtà r7.lgir7ale, '?.(3 `/O c<rllage;rr- arrd 83.7r~ phosphate btÃi'fer-ed ;;taliare, 'k:'Ir.c eorripc?sÃtinzr had a bezietzcfal paste consistency and Avas manually ÃÃr_jectab(e through a 16 gauge needle.

SPINAL FUSION STUDY
WITH OS7'Et):tNDCICTIVE PASTES AND PCIT'CCrS

In tkris stfi.Ãdv., the osteoiÃr.dLÃc~tive paste and putty rÃ-taterials czt Ex:Ãrrtfalc s 1arrd 2 were evalr.iated for tiieia abikit-y, to izidtÃce spinal vertebral fusion w}rerl bilaterally irÃ-rplanÃed in t}Ãe.Ãrutke ra:t nÃockel.

Ath,vrnic iiÃ.-cie rats (kZNUr'kZ,N'U) ranging M wcight iroÃn 2, 12-3000 grarns were obtained frorri Harlan Labcaratories. 'Test rats were div'ide~.~ Ãrrt:o `.õrcacÃps eorrlprised of 6 anima1s according to weight. CoÃ-itro1 animals received sbani stargc;ry (no test impkant).
For arrest.lresia, animals were pkaced iÃZ a clramber and indLÃ~ed with isoflura:Ãre iÃZ
c3:~~~gerà (0.5 rrigrBkg) was administered pre-ofrertativeky fc}r analgesiaK asid 027 ml orrrot'1omicin was administorrcd subcutaneously for antimicrobial pr-op1iv 1ax is prior- to sa.rrgem=.
.A e$orsal rr:Ãa(lliÃr.c skin iÃ-icai;;ioÃ-i was rnacfo trorr-i t-}ic rogioir o:f'I:1-? c;xtericfirig caudal approN irr-Ãat:ely 3 -4 erYr to jtist caudal to t(-Ãe ileac crest:s. 1?-aramediaii iÃicisioÃ-Ãs of `?7 approximately 2 crli were miacic over the par-aspiiial fascia, and muscles were separated witlr a corrtliiriat.ion oI'blurit and slrzrrp clissectyori. Seil-reEainixrw retractors were placed to retract tlie rnr.iscle to eNpose the traÃrsverse vertebral processes. The traÃrsverse prcrcesses of the 4111 aard 5t}r lia.n7bar vertebrae wer`c icier7ti#.ied tarit~ adhe;r-c:art s l-I tissue cleaned from the d(arsal surfaces, 'I'l~e operative sites were both flushed with approximately 1.5 niI salirle. A
small, motorized bur-r was then used to clecot'tscate the transverse processes to the laoi.n'f that blee~.~in`.õ boz~c was observed. 'I'he paste or putty was thenapla(ied to t'lic sites. f3.~..~ nrl of paste or putty compositions were applied to each site in direct cnntact Avit.la the ~ecorÃ:icaÃecl transverse processes aricf spanned the distance between t.lrezrl, 4trrgic,a1 closure was performed ill i-wc} layers tisir7g r110110filarrierrl polvgl;rcotlate suture (4-0 Maxon. `l-"yco :H:ealthcare). After clnstire, a povidone iodizie nintment. was placed oai the %rourld, followreci by application of a Tcgacl~.~rn1 (=3'~~
H~;~iltl~c.~re)tr~arlspszr~y~r.t.
dressin(;. A dorsorcvezitral radiograph was taken, andan:Ãmals were placed ina. sterilized polyc,arbcxrate; cage witkr a stezxle towel bed for anesthesia recovery.
Trtre;;e;- c:agesd:svre placed over a circulating warm wat:er'baÃh to provide suppleinent:al 1ieaÃ
during tlle recovery process. After several hours of observation, thc;), were retLir-rlc;cl to snr.glc hor.asing ori :irrzr.diated becldarig in sairityred c~a7ges. Buprexrorlatirie wzrs administered twice daily I~or t-,.N~o davs azid ozi the moanin{,~ of ttie third dav. Enrc?l7crxa.ciÃa was adziiiriister~d ozl t:}le everrinof sr:rqger~ c-ititf tlie mo.Ã ning; of posÃ-operaÃive day 1. Sutures ~~ ere remod ed at appro:xiinate1y 7 days postrsuroeÃ-y, aricf rats were then pair housed f(ar the studv duration.
The anirrrals on study were observ-ecl elaily. Post-operative radiographs were taf~eri, 1) either immediat:c;l.~~ after sr.ar~ert or at ~ppro\imately I week post-surgaery, ?3 at.
-appro:xiinate1y three weeks post-surgery aricf ?) a:t: sacrifice (appro.xiinately 6 weeks postw sLargery), All animal radiographs were dor~~-venÃral views centered on the lower lLÃ.mbar spirrc.
Euthanasia was p~,'rforiii~,'(f appro\i:nrat~,'1y 6 weeks post-operatsv~,'1y.
Anlnials were weighc;cl., c;r7thani.zed. in a, CO2 chamber and radiographed. The necropsy cc~i-isist~.~ci of )l3 explanting; the lumbar spine from -f 13 to approximately S l or S2. A rab evas left on T13 to aid the }iistcr-tec;lr.riiciati tli site oriotrtat:ioir. Excessive soft tiss-ued:s~as rernove;e$ aricl the operaÃ:ive site ident:ifietl. A piece of braided sLittire was placed od e.Ã
the opera:t:ive site to aid the histo-technician with site identification, The operative segment %ras manually palpated for rnotion. After tlae site was palpated, tl-.te slzirr.e wzr.s placed iri 101!4, ir.etrtrzr.l buffered foaÃxralÃÃr. Fres}r forina1.Ãn was exchanged 34 days, a:ller the necropsies were completecl,ar7d the sarirples slripped f:cx- histc3ptatholog4 proce,"irig and interpretation.

Tlie formalin fi-c-eci ltrmbar- spines wcr-e rrrcrc.esscd (Leica TP10-50 tissue Processor)>
embedded itt paraffizi, sectioned, mourited orr slide~ and slides were stained wit.lr hernatoxvfiÃr and eosin {ME} in azi a.tÃtnznaÃed st:aizier (Leica AtÃtnstaaner XL) usizi;y standard :l1istolo~;;~~ .~~retlr.~clc}l~a~~ . lf&:E: stained slides were examined bv a veterinary pathologist. Coronal Secti~.~tis of tlre s~pirles were takerr Ã~.~ include the T4 anci T5 ('.( :::tr-aarsverse processes), and t}re I-.4 tarid 1-,5 vertebra.
Spe;cirtieais x.vere evaluated fcyr inflammatory aesponse, whiclr was present in all graitips, and was minimal to mild in most sites. Specimens were also evszltratecl for th~.~ presence of ftisiorl of T4 to Ti, tlie p,-eser7~e of r7ew bo:Ãre, the pres-erlce of original DB.M, aJrel tlie p,-eser7~e of carrier. -I'}re restrlts are :howir iti Talales 1(l?utty test wlajt:c;t.), 2(PAistt: test sulajt:cts) aard 3(Slraaris), iir wfiiclr 'l = '1'.Ã=arrsverse process. :ft ~ RiglrÃ, L -__: Left, I3L3M - Der-nineralizecl br:rrle zrlatl-ix, P
t?r~,~scrlt, AND A WAbsciit, FtÃsi~~i-i %ras defined as briclgii-ig bone, c~.-ith or withou.t c.zrriil~we. betweerr the transverse processes T4 aiid T5.

TalErle I [Put#v, oi:' Exx3mLi1e 1) ------ ---- -------- ------ - ----------------------Ac3ima1 4: 1 2 3 4 5 6 ---------------Group: Putty Putty lla utta lla ut# y Ptt##~ pu#t~>
::- :::- :::-New Bc~~ie (R) p p p p p p - ......... ----------------------- -----------------;----- ------------------------- . ---------------------. ...................... .....................
New BE?Ãie (L) P P p 1' 1' A

= t -------- ---- ------ -------- ---- t------ -t -------- ~-------- -- --- ---- , Fusaon of T4 to P P p p p p T~i (R) Fusion of T~ to p p p p p p T~ (L) t~r7~;iiY~.l1~ ~' p p :l' ~' f_'ar'rier A A A A A A

`?q Table 2 (Paste of Example 2) Animal #: 1 2 3 4 5 6 C~xroul3: Paste Paste :~as#e~ Paste Paste Paste .
.
z- _ - x <- - , <- - -~ _ -r 1Ron~'R) f? p p f' p f' Newr Bone (L) p p 1? p p p , , =
-------- ------- ------ ------------------=----------~---------;----------- ---------------------- -- --- - k---------------------- ---------------------- Fusion of `T'4 to `T'5 f? A A A P

=
(R) Ftisioii of `I'4 ko `I'5 A A A p f' A
~l }

Orioi nal DBM p I' I' p f' ------ --------------------------------------------- ---------------------- ---------------------- ---------------------- ---------------------- ---------------------- ----------------------~ ~trÃer A A A A A A

'1"able 3 {Sh~~ml -------- -------- ------- ------ ------ ------ --- -- ------- --- ---- --Animal 9: 1 2 3 4 5-1 6 ------- -------- t t ----- ------ ---- ------- ~---- ------- ---- ----GrOup: ~~~~~~ Sham Shain Sham ~hain Sbain A ....
--.... ---=
::.- ::.- 1. - ---_:-- --k:::.- ---.- --------- -NGw Boaic (R) A A A A A A
...............................................................------------------- -------------------- , ---------------, . , ~Ic~~~= Bc~ti~: (L) A A A ~ A A
.-----------------------------------------------------------------................... .................... ....................
.................... -------------------- --------------------;
l~tz~lt~ti of ~I''t to "f-5 (1-31) A A A A A A
.-----------------------------------------------------------------.
........................................ ....................
.................... -------------------- --------------------l:' u.sl t~.l~ of ~I 4 to "I-5 (L) A A A A A A
Original D.BM A A A A A
.---------------------------------------------------------------- -------------Cai"rlei A A A A A A

As cffli b~.~ secti, bilateral new bon~,~ %r~s observed in ta11 six artimals, ffroiii M. each of t`tie paste aj7d putty, g.roups. Either uJiiiateral or bilateral ffision of 'I=4 to T-5 was observed in all six .~nimals from tlic putty grotip. Ui-iilateral ftision only (of T4 to T5) was observed in five of six aiiiixialsixi tl~e paste 4.~r~Tuf~ 1:t should be tic~ted that ti~~liile l~i:~~ErTlcz<.~y Iar~T~.=ides aai accurate meazts, ol'eva.lr.iatin{~ bone forznaÃÃon, it is possÃble to mis-, bridging bone that r-iiiglià c;rc3sS out cA the plane cA sec;ti ai tii7tfer evalu'ation.

TlieSpi~~c explants dewcribeci in the c~periÃnent.al above wcre also evaluated by manual palpatic?n after han~est.. 'aw resu(ts are set tortl-.1 Ãfl ,l,.ab(e 4 belca~k,.

'[`able 4 Ir7ipl ~iit Fusion by N1.antaa:l Palpat.ion Rat I Rcià : Ra.à :> K-at. 4 :Kaà ;~ Kat 6 Ftisic}ri U.xan1p1e 1 Putty YeS Yes Yes Yes Yes Yes 100%
Example 2 Paste YCs Yes Yes Yes Yes Yes 100%
Sttr.g.ic:al Shc-irii No No I~~~ No No No 0%
The results de:monstrcxte that tllC il7veM:iV~ pUt.ty aÃicl paste koraxlulat:ions sLiccessf'tally acFiieverl fusion in t(ie atlxymic, rat:tixodel as assessed by zrlatiua1 paJpat:ioll.
E1:.l.'4:1PLE4 Il.VALUX1':lON OF OS"t'~[:E}FN l)l:Ã I':t:V1`[`Y

'I'Ite aÃ1i;,~iliie rat is a widely~ accepted animal ctlode1 .for testin;?
t~.~r ~~stec~iit~:ia~,ti~.re actsvitv in DBM procitie.tS. Tllis model was Lasecl to eval.uate the inductivity pLltqr formulations prepared as in Exianip1e '1 and paste torniu1ati.ons prc;piared as in E~~t-np1~,~ 2.

The rats in the stt.acly were screened for general health before enroll:mt;nt The rats were anesthetized with isok'lLtr~iie ttrrotr~F:l-~~:~~~t the s~~r~ical l~ar~acedrire to maintain the proper 2-i anesthetic lc;vc;l.. Impl .~nts wer~.~ p1aced singularly in the muscle pc~~ich of each hind limb through a0.5 caxi MCas.iOD. Iaxiplant:; were placed n ear ili e #em ur to a11ow for b1ooci saipply .3 1but liot acljacc;rlt to the botr.e. For the putty and paste implants. 0.1 cc;
of material was used per site. Ixrcisions were c~losed W7th srat.trre.

At 28 days post-operative, the rats were ;;tacrificecf via carbon dioxide ir7lralati ar.
~ '1'he rr-rusctrlati.ire wliereirr the sairrple was placed was paIpaÃed to locate the iirrplarrt arrcl cir.ceÃ'i.r any tarrgi.ble .ivris oi`calcrlicati:oÃl. A11 ii.rilalar-it.s xvere harvested, prescrviiig record of loeaticarr. E, xplants were piaced irt labeled hist:olcagy ea.ssetÃes in 10% neutral brif:tere~.~
l'ormaliÃa.

lf) Satiiples were decalcifiecl, eirrl~edded in p-araktirl, sectic~iied &
stainecl. Three sectiorrs per inz plant.z .vcre taken at 100 ~trr-i int.crvals arid stained with H& E. Sampl~swcre scored serni-cluantstati.vely according to the t~~bl~~ lzcl ~~c~ A score. of otic or grc;atc;r is indicative of a a score of zero is a fail for the sample. Scores are avera;yed to deterrnin~,~ if th~,~ group is a pass or f:ffl, Tlic scoririg key was as tollows.

SemiaQuantitative Histol<ogic 4cOritig Score Histologic Appearance 0 No tiew bone formation r~,; of and/or , .
l l-~.,.x % t~f seutr~.xal area is new bone uarta c~.t,~e~~.xr~~a~t~on m 25-50 % of seciic3ri area is arew la~iie taridlc3r cartil~~ge fc3rrtiatior7 3 5075 % of sectiorl area is aiew bone and/or cartllag c formation.
4 75-100 ~ t~f`s~:c~ti~~~. ~ir`ca is rre~~ bone and/or ctar~ilta4~e I~~r~~r~~ti~}r~
15 The results are set fottli in Table 5 belÃ~i.N--, Table 5 lltrplaart k:Tate;rial lmplant Scores fmplarrt 1 Irrilrlant 2 :lmplant _') l:mplaxrt 4 Avera4.~e L:x.c-iriiple 1 f'titt:v Fail :13ass Pass Pass I?ass lv-:x:ampte 2 f'aste Fail Pass Pass l'a ss I1"Iss Tlius, the invent:ive Zzutt.y aricl Zzas-tc formulat:ions wereshown to be osi.eoaridtrctive.

FXA. MP1. F 5 E"R>liaI'ARAT:1C3N +EJhF

AD1317'I1:lAL MALLEABLE DBM 1FORML`.lAT:t.O1lS
=f Tii~~ preparativÃ;pÃ'ocf>dt-Ã'es deSc.Ãibed in ~~anip(e I wet'c used to pr~~arc additional formulations of DBM. ln particular, a sodium a.lg:inate Solution at a given concentration 47, was preliared, and to this solution were added 0.3 ol'collaget~ and ~.~ of DBM

paÃ-ticJes. `I' le alginates employed were a rnedicaJ grade a1wwina:tesavith a1ow endoÃo:xin level (less than 1 t30 EUt'gY U-It.raFureNlignate, '='~~~~~inatrix, lnc.,.).
The 1'ormtilati~.~i~s Prepar-ed wer=e as follov'-;;.
Table 6 ----- ------ ---------- ----- -- --- ------------- -------- ------ -------Component % Solution =F/cc overtall Dry wt"=~
= , , ..................................................... .......................
. - = ------------------------- - ------------------ --------------------- --- -- ------------------------ - ------- ---Sodium E~.lgat~aÃ~% 0.035 I0=1 3 ----- --------- -------- ------ ------ ------ -------- ~-- ------------- --------- t -------- ------ ---------Collkgwil fl{a 0.043 12=46 = , .
. , = =
............................................ -----...........
...............................................................................
........................... ----------------------------------------------------I~B -N, 1. 0.267 77A1 L --------------------------------------------------- ..----------------------------------------------------z----------------------------------------------------`=
FC)1~ U,~LA 5B
----------------------------------------------------------- ---------------------------------------------------- - ---------------------------------------------------- - ----------------------------------------------------Compoz~ent % Sailutiozl gg;'cc overall Dry AN t%
Sodiu.xtl AloinaÃe 6%} 0.[35 " 1 U.?6 Col l agel7 ai;'a 0. 043 8.67 I]WN4 n/a 0.4 8037 1;'[)RMI J:I:.A 5C

Coniposicnt % SolLition -gr'cc ovcra1.1 Dn, d~l%
-------- ______- ----_____- t__- ________- ____-SociimuA1paa.te" 7. 5 .. v 0. 065 17,44 =
=
f____- - t--- - - t ----- ------ ------ --------Collag~~n n. 0.04~ 11.45 _____ _________ _________ _________ ________ _________ _________ ---____-________- _______- ________- _______- ________- _________ _____ ~BM nlii 0267 71Al , , = , , ------------------------------------------------------------........................ -----------------------------'--...................................................
.................................................... FOR'L'1.ULA. 5D

--.... ..... ...... ......... ........ ....... .......
F ..... ......... ...... ........ ......... ....... ........ ---- ------- -- ---- -- t conipnzient % SoltitÃozi ~rcc overall Ditr m%
-----,- ---- ---~oditim Al~ ina:te 10% OM7 41 1.98 ----------------------------------------------------------------------------------------------------------------------------------------------------------------('o11a~.~en rr;'a 0.043 l (#.81' D B N-1: ri/a7. 0.2) 6 7 67 .2 *Apparent viscositv 500 niPa's {21 O C, 1% solution}
"Apparent viscosity 270 mPa's (20 C;; 1% solr.rtÃt?n.) SPINAL FC.ISiON ST'C.IDY WlT'I] OSTEOINDUCTIVE ll?ORWI11AT.1.ONS
Formulmons prepared iis in Example 5 wer~.~ used in aspirtal fusion stLrdy in the ziude rat rrrodel ~3s generally described in Example 3, alongside a sirnilar amount of the ac}rYrnierciaJ prodLrct. Acael (.'on.r-rextis putty Oso 1'is SA, 701,.'it Df3N4: in a reverse pfrase carrier). Microscopic examination I't.he rIghtantf left posterolateral sites betiveeti the transverse processes of lurn'bar vertebra L4 ar-rdL5 caf rats from the tt-eatrtlerlt grorips was c.oÃlciucieel to detr;r-mine tht,~ r;fle;c:fivesir;ss cyfÃbe implaÃll f%irsmu.lalYoris in promotsna borlt,~
formatiorr. Eac}i of t.}ie torrnrilatinris of E, xample 5 demoristrat:ed the capacity to forrzt bone. No signitieant bozte formation was tfbsem ecl in the sham surgery.
Forrnr.ila 5C was observed to cause the liigliest average of borie formation (79%). Formula 5:E3 caused only slightly less 6t.xnÃ, forrnatit.xn (76% average). Of the remaining treatments, turmLrla 5D
caused 69`?r~ bor7e formation, ar7d Foriiiula 5A caused 67% br.}rie formation, on average.
Accell ('onztexus ptrtÃv caused aÃi avera~ye of 38% bone torrnation.
Tkreinventive c:oinpc:xsitio:tis %rere thrrs demonstrated to have highly berteticial levels of'ost~.~oirrdrrctiarity useful for qpinal fusion.

T.XAMPI..T. 7 EVALUATION OF OSTEO+C'(3NDU+l~:`TlViTY

IN RABBIT FEMORAL CC)N T3p'4'LE DEFECT S1"U T3p'4' 2~!
In tl7is exaitiple, the bc3tie-t'cx-ming capacities ol' fibtar itiveritivc.
#i.}rttiulatiOns were evaluated arid compared to the corrYnierci,'fl product Ifealos1?or-re W aft rmaterial (li~rcir~t~~:y~apaiitr;-e:t~:~~f~ytl. ~:r~llageri microfibers) ati~l sl~atsi srrt~~~~yt~~ ~~~li~~r~ i.r~i.pl~sitt,'ci at a.
vnlritztc of about 0.15 cc's Ãrtto a 5 rtarii cfiaÃitet:er def:rct created in the cancellous bone of the distolateral temora.l condyle in rabbits. The test formulations were a.s follows:

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - .
.l~ (:3RNi ULA 7A
_____- ______- _______- ----- ---- ---- ------- -- -- -- -- t ------- ----- --.__- ---------- --------- -------- ------ -------Conipnzient % SoltttÃoti ~r~,e overall ---- ------ ---- ----- ------- ------ -------- ----------- ------ --------- = ------ ------ -------- -;
Sodium M{2% t3_017 5.3 3 Co11aget`a t~~a 0.043 13= 1:.i . , , . ------------------------------------------ - ---- - ------------------------- -------------------------------------------------------- ----;^-----------------------1~1::-~~~ tlfa t ~. "~i7 81.54 F 0 ttN1I >L A 7 B

Component % ~ Sc~lt~t.i~~tl ~^_'`cc c~v~,rtall Dt-~,~ ~~Ã v S~.~ditarti A.Iginake" 4% 0.035 10.7 ----- --------- ------- ---- ~-------- ------- -------- ;-- --------- ---- --------- t -------- ----- -------- _ Collage;n r-1/a O.t343 12.4 , , =
=----- --------- --------- --------- ~-------- --~-- t , , --------- --------- --------- ------ --------- -------- --------U3B ~,I nt'a. 0.267 7&9 ---------------------.................................................... ,- ----------- ---- ----------.------- ------Corrrporlerit % Soluiiorr a-ce Over 0l1 Dry Aa t%
, , =
----- ---- --- ---- ------ -------- ------ - --------- ----- --------- ------------ -------. . =
`~t?dtut~t E~l~,ar~~Ã~ ~ 8.5% ~ U.t374 19.32 =----------------------------------------------r--:---:------~--------------------------- ..-----------------------;----------------------------------------------------,-----------------------------------------------------=
C'oItagen. r-1r`a, 0.043 11,19 DB't't (}.?6' [.~9J
.
`=
.----------------------------------------------------....................................................
~~ORMLIx1. 5D
----------------------------------------------------------- ---------------------------------------------------- - ---------------------------------------------------- - ----------------------------------------------------CoÃxipotietit % Solution ~.`cc overall Dry ~.vtf ~
gg/cc Al4.~irtaÃtr.' 10% 0.087 2 1.98 Cnl Ia gen O. t34:~ 10.82 DBM t71l'a 0.267 6 7.2) ----- ------- ------ ----- --- --------- -----'^Appar~ent viscosity 2270 r~Pa s (201C,K 1% solution.) 15 rabbits were tasetl in Ihe sttrciy, to pc=ovicio a total of 30 defect sites. 1;:.ac.>ll. test composition was implanted irt :? defect sites, zanclornlv ass:igt~ed. Six weeks after implant, tissues were. h:-trvt,'sted tr~oni the defce.i sites ar-ict decialcifit~d fflid processed for microscopic study. Three slides were examined per each dc,fiet:1 site. The initial evaluation Wfts conducted in a "blin~ed" fashion so the treatment status of each experimental group was unknown to tfte pathologist. Otrce Ãlr~ evaluation was co.t~ipleted, the ex.perinretrtal groups l~) were t:heti "unlalinded" so that the test compoSit.ic}tiS -and the s:(-ta.tn su.Ãg;ical pzoceduze were lat-~~cr(y ident1I-if:d pr-ior- to Ãht<, re.portin~~ of the. eflec;ts of'eac(i. lrf:aÃment. Wbt;re applicable, niicr-oScopic findings were giveri ia sea~~en't~ score based upon the following sc,zile: ;..0,.. _:: wiÃh:iri riormal limits, 1 . :::: rninimal "T" ::: rrtild ;<V' .::: rrtoclerat:e., and'44,':::.
markecl. Parameters were evaluated as follows:

5 raL3caneItc}rrYration percentage of 'borle seeri bet-ween existent vertebral tr-ar~sverSe proceSscs or percentage crfte:t site (lhat. may include remodeled trari:vcr~se pr-ocesses) Ãha.t a.fal~ears t:o'lae bone ;QualiÃy of Bone prvr=c.entage of bc}rie that is either irrnnature woven fawie or 10 Ma:txrr'e compact boiie W %Car=tsl,szge = pc;rc.er-it~.~;e oft~.'st site that contains cEirtilage that is undergoing transformation to bÃ~ne * Irii7.atrir~iatior1 SeveriÃv rati.rx, of irrcfivitlLral infla.rnmatory cell types. if present, ranging froi~i a niiriimal. grade of;..lõ to a mar-kcd gr-Eicle of "4" or ``t?"z if iiot present.

o Soft 'I'is~u~ ~e~rrÃi~ar~ =- severity rating as farevic~uslv cited of the fc~ll~a~~ir~~F
findings, if present: p1g1iit;Iit, filjr't3s1s, hC;nIC?rrhagE;, and/or ne-C3v`s.lSculat"1zi-1t1C)17.

~: Pliagocyti.zed. ~,-Iatedal = tlic pr-c;scnc~.~ of debris soc;n in the cytoplEtsr~i of rnar:,ropfra~;,e~;

Res,ults and Dr scussi on:

Gc;n~.~rEil Obs~.~rvations. Tliere were a fec\.- sites that lacked bcrth.
laoiic szricl soft tissue )0 responses. 'I'lie lack of f`:Ãr7dir7gs ir~ t`liese instances e~~as presumed to l~e due to inadequate sar-apling of the ie;-;-4 sites aii(l not ireatmerrt. As such, group aver~~~s were calculated for ,ill sites (ur-ra4jtrstecl-) arld orrly those sites t(-raà fratl some form of borre and./'c}r soft tissue r~,~spolis~,~ (adjusted). Acljustecl av~,'rages were viewed as a nior-~,~
accurate evaluation of bone for'rxiation.

Cor-irpac.t bc3tie.formatyc3ti was by far the prc:donrir7arrt type c3fborie observed lvitlr veÃ-y limited amount of im.ma:ture, woven bonefaeing;preSent..
'I'issueresfonses typicaJly found in assor;lat.ion witll the r-f>ar;tiy-e bone fcrrrrration consisted Ãl-iaiiilv of macrophage ar-iel multiztric;'leated giarit cell ÃrrfiiltratÃon arid prolifera.tiort of ccarrrrective tissue (fiÃbrosis).
Additional ce11u1ar infiltration c(yrnntonly observ-ecl included heterophils and 1ympl~~cyteS.
l;izrlited amounts of laoc~rly m.iner;alizecf borÃe iÃaww.~nerrts were at times preserrt in areas of reactive bone. A fewSites for several different treatments had fair1v diStirlct foci of what appeared to be lliiid or.fil=:ar-ir7ou;; acc:urr-iuIr7.tior7S.

Tr~.~atmc;rrt-R~.~l,szt:c;cf Observations. Wben comparing unadaust:c;cf group avera~sr~S, the least ati7Ã~unt of bor7e formation (] 1%) was found in femoral defects of the ]H:~~los treatment rabbits. Iri contrast, the greatest ar~trot.rr~it o.fborre torinatiort (65" ) was detected in the Formu1a 7C t:zeatiirerit rab'brts. Next gr~eateSt.borre f(arrr-rat:iorr (53%) was:f=buncf irr the Forsiitila 7A treatment rabbits. Comparabl~,~ bone for-mation %ras detected for Surgery Slrarrt 4401!40, l;'orriir.rla 7B (4 l%) aricl :Formula i:f3 {461':fi}
t.realrnenÃs.

Wtleri t.akirlg into account a4justetl averages ofborie i=o.Ã=mation, treat:ment-re:la:tetl effects were as tollowS: Fortirtila 7C {69%)}., :E{(arrr-rula 7A (66%), Fortirtila 7>i3 (6-2%).
Comltila 7B (5 1%), Su.rgerlr Slrars~ (50%) and l;-lealos ('' 3%). Based on ft-Ã-flrer su~jec;tive c,rÃteraa of appearance, derrstty, a:rrd corrs'tstency of boztc development, the quality of boztc was dcc;r~iecl bighcst for tlic Forr~nula 7C fflid Formula 7L? trea.tnients, Lower than ajrticipated leveIs of borie fOFrrr-iatiorz for >"~.~rnrula 7B may have been due to greater` variability of sarr-ipling. In addition, greater` amounts of reactive borie formation may have be~~~-i attributed tc) the SrarLy ,~,~n., sham procedure cfr7ring the blinded phase bec.atr~~~ of niisii-iterpret>itiori of existing bolie due to vari,szbillty in orierr.t.ation of ~0 bÃ~ne sectiÃ~ns. Notwithstanding any potential erroneous bias regarding the s~Ãrt~er~l str~.a~r iireltic;ed response, tliere;- was clearly a bearefacial of:'foet of bone i0rinaticrrr relatecf to the;-in~~ent:ive for-rriLtiati(arrs.

In srÃmrxiary, the microScc>pie~ ex.Ãrr-unaÃic>xà (-Yf dn'll defects M the riw1ià and left femurs of 15 rabbits was cozidÃ_.ÃcÃed to deterrÃiÃrie tiie efficacy of'inventive DBM inip1aÃit COMpOSit.iOrIS iD t]ls;: pÃ-OrIÃOÃiOr7 cA bc3nefornÃatyc3n. ThissttÃc14 was conducted ina blinde;d ~ l='aslÃi(arà so the actual identity of eacli treaÃ:merit group was UnkrÃown prior to the final i~i), ofdaia. Tho results of tl.Ãi::ttÃdy cieÃnoÃlSÃrafed tl.Ã.4 the inventive DBN,-1' eompc?sÃticarÃs were et~ective :rrà prorÃicatizr`.õ tlÃe fiomiaticarà of borÃe_ E:'4AM_PLE: 8 lÃ} lf'`R11!:I' ARATIC.}N OF DE1;4.1..FC3RMÃYLA'1"IC3N
WITH BLENDED DBM PARTICLE SIZE DlS'I'~~BUTION'S

This example clesc:ribes the preparation of a.Df3M putty c;oniposition wi.th.
stiperior handlinganel mrftarmanrve upon implant. A robtist, firn7 pr_Ãtty ~~~~as-prepared using the 15 gpieral proe::ecitÃres and iiigre;elietÃts ciese::ril~e(l ir) Exarnple 1.
The c;ornposition o.f tlie ptÃtt-y was;

l-" ORMl_:'I. A SA
Cc3mporÃent. ; (4/CC c3verall Dry wt%
-------------- --- --------- ~ ~ -- -----------SÃ.rclr ur~r-Ã _~l gi r7at~~ -------- ----~~ ,38 CC?ll.clgen. 0.10 8A
---------------------------------------------------- -----------------------------------------------------D B 1,~7. 0..67 58.6 ------ ....................................................
............................................... -- -----------------------------------------*ApparerÃt vÃScosity270 ni1'a s (~~'C, 1% solr.ità oÃa) rl'1le ~B.%-r l Ã.rsecf in this torn1r_Ãlaton was a blend of sma11er arici large;r particle size products. Pa.rtsc;les were. first ground and screened for 22-4rlnrr-à sizes. A
portion of tlic 22-4111m size was, reserved, and the remaiaÃng; DBl,i was grourÃcl aÃid screeriecl for a f 25a710 r-nierc~n size. These twr(-) grotrps were ttren mi.x-etl at the tinie of final product manufacturing. 'I'lie proportions of these two riiixes were 38% 2r4mm sizrv-, aiicl 62% 1 22:?-7 f. t3 micron size.

The r~,'sultii-ig pLitty was cohesive and suffIci~,'ntly firrli to resist compression r.apoil arrilzin4.~em nt by soft tissues at a bony arripla7nà s:ile.

Ta'X':'\.'F.i.T L1Ta' 9 PRll:l'A RA't'~[CIlN O1E? DBM .!<ORM Ã=i-aA'l I{~N
WITH BIPHASIC CALCIUM PHOSPHATE GRANULES

'I-his example descrÃbes the preparation aif a fJBM: paste compositÃozi also including a significant ocanipwient ot granules of osteocoridrictive biphasic c,alcirim phosphate (B('P) with a. tricalciuin phosphate.h4cl.r~~xyapatite ratio of al.~olat 40M. -I-he paste was prepared ~ene;ra1 prc3c;e;dt# re;; aaid irigr'e(lieiit;; described in :[:xample I in a(ltiiti~ii to t:he;
using the tg Bt'fa oraraules. The composition of the material was:

~..~~~~t~i~c~t~e~~it (F/~.e:: ~~~~er~.ll Dry ~c~t-~3:n .........................................................
...............................................................................
..............................
Sodium Alginate 0.() 1; 5,1 ----- ------------ -----------------~"~~11 a~;Ã i 1 -------- 0,018 ------- --- --------- 6.] 2 .
------------------------------------------------------------~ ---------------------------------------------------- -------------------------------- --------------------I~f~1. 0.109 ; ;7 t_=
---------------------- -------- -------- ------------------------ --------- ------ ------------------- ----------------------E3C:1? Gzanules 0,148 5 1.02 ------------------------------------------------------------ ----------------------------------------------------------------------------------------------------------l`i The resulting paste a4ras cohesive ancl coalta:ined both ino:r~ganic {cerarilic t,~rantal:es}
and organic. (coll~~,~en) os~teocoriduct.ive r-iiateTials along x.6tliai7 c3sie(Anduct.ive 1):[M
pr-od.uct.

The ti4es of'the ternis a" and an' anLi "the" and siniilar refcrences in the eonte-'a of describing Ãlie :inventican (especially in the coritext of the kollo-v~,irig elairns) are t{} be c~~iistr-Lied to cover both the sin4~.u1a.Ã= arld the plural, tiriless other.vise indicated herein or clearly contradicted by conlext- ReciÃalion o.f ranges of iralues liereiri are r~ierely iDterieied to serve as a shorthand riiethod cat-r~eferxing iiidividrially to eaclY separate value failiArwF within the ra1ige, unless otherw1st,', indicated hf',relli, and each separate vc']lliE', is incorporated into the specifica:tion, as if':ii were irldividual:(v recited :(-~erein, All inethocls described herein carr be perfcyrined in aziv suitable tirder unless otherwise indicated herein or otherzvise clearly c;ontradictecl by contem. The L~se of any ~i-ic1 a11 examples, or ~~xempliart~
las~~sti~.~sr~ (Ã~.~;., "such . L
as") rolvided herein, is intended riiere1v to better il(utiunate tlae invention :~~id clc>es riot pose a limitation t?n the scailie ol'the iÃaveÃation unless othei-NvÃse claimed. Nt?
1angyuktge in tlle speci#.icatioti should be construed as indicating aiiy non-claiaried element as e;;;sei7tyal to t}lc practice oi'the irivetrtic~ii.

Wli'lle the inventionbas been illust:r~.te~.~ and described Ãfi deta.'tl 'Iti the clrawÃ~igs a:fid foregoing description, the saziie is to be considered as illustrative and not restrictive in c:(la.Ã=acter, it beino, understood that ~~iilv preferred embodin-~ents have been shown at1d desc.fil.~eci aiid that all changes aiid modifications that come within the s~pirit Ql'the inventioil ar-e desired to be pr' tecÃeei, In addition, all publications cited lierein are lier'eby incorporated by refereÃace in tliefr entirety.

Claims (38)

1. A demineralized bone matrix (DBM) composition, comprising:
bioresorbable solids admixed with a liquid carrier to form a malleable implant composition, said bioresorbable solids present at a level of about 0.1 grams per cubic centimeter to about 0.7 grams per cubic centimeter of said composition;
said bioresorbable solids comprising a particulate solid collagen material and a particulate solid DBM material, said particulate solid collagen material present in a weight ratio no less than about 1:12 and no greater than about 1:2 relative to said particulate solid DBM mineral; and said liquid carrier comprising an aqueous gel of a biocompatible polysaccharide, wherein said biocompatible polysaccharide is present at a level of about 0.0 1 grams per cubic centimeter to about 0.5 grams per cubic centimeter of said composition.

2. The composition of claim 1, wherein said polysaccharide is selected from the group consisting of alginate, pectin and chitosan.

3. The composition of claim 1, wherein said polysaccharide is alginate.

4. The composition of claim 1, wherein said weight ratio is in the range of 1:12 to 1:5.

5. The composition of claim 1, wherein said weight ratio is in the range of 1:10 to 1:5.

6. The composition of claim 1, wherein:
said bioresorbable solids are present at a level of about 0.1 g/cc to about 0.25 g/cc of said composition;

said polysaccharide is present at a level of about 0.01 g/cc to about 0.03 g/cc of said composition; and said composition is a flowable paste.

7. The composition of claim 1, wherein:
said bioresorable solids are present at a level of about 0.2 g/cc to about 0.4 g/cc of said composition;
said polysaccharide is present at a level of about 0.01 to about 0.5 g/cc of said composition; and said composition is a shape-retaining putty.

8. The composition of claim 6, wherein said polysaccharide is an alginate.

9. The composition of claim 7, wherein said polysaccharide is an alginate.

10. The composition of claim 8, wherein said weight ratio of collagen material to DBM material is in the range of 1:10 to 1:5.

11. The composition of claim 9, wherein said weight ratio of collagen material to DBM material is in the range of 1:10 to 1:5.

12. The composition of claim 1, wherein said particulate solid collagen material comprises a chemically crosslinked collagen material.

13. The composition of claim 12, wherein said particulate solid collagen material comprises a particulated sponge material.

14. The composition of claim 1, also comprising a mineral material selected from synthetic ceramic granules or mineralized bone chips.

15. The composition of claim 1, wherein said solid DBM material in said composition exhibits osteoinductivity.

16. A demineralized bone matrix (DBM) composition, comprising:
a liquid carrier comprising an aqueous gel of a biocompatible polysaccharide, said aqueous gel in admixture with solids to form a malleable composition;
said solids comprising a chemically crosslinked, particulate collagen material, and said solids comprising a particulate DBM material.

17. The DBM composition of claim 16, wherein said polysaccharide is selected from the group consisting of alginate, pectin, and chitosan.

18. The DBM composition of claim 16, wherein said polysaccharide is an alginate.

19. The DBM composition of claim 16, wherein said particulate DBM material is osteoinductive.

20. The DBM composition of claim 19, wherein said particulated sponge material has an average particle size less than about 2 mm.

21. The DBM composition of claim 16, wherein said particulate collagen material is present in a weight ratio no less than about 1:12 and no greater than about 1:2 relative to said particulate DBM material.

22. The DBM composition of claim 21, wherein said weight ratio of particulate collagen material to particulate DBM material is in the range of 1:10 to 1:5

23. The DBM composition of claim 21, wherein said polysaccharide is an alginate.

24. The DBM composition of claim 16, wherein said solids are present at a level of about 0.1 g/cc to about 0.25 g/cc of said said polysaccharide is present at a level of about 0.01 g/cc to about 0.03 g/cc of said composition; and said composition is a flowable paste.

25. The DBM composition of claim 16, wherein:
said solids are present at a level of about 0.2 g/cc to about 0.4 g/cc of said composition;
said polysaccharide is present at a level of about 0.01 g/cc to about 0.5 g/cc of said composition; and said composition is a shape-retaining putty.

26. A method for treating a patient, comprising:
implanting an amount of a composition according to claim 1 in the patient at a location at which bone growth is desired.

27. A method for making a demineralized bone matrix (DBM) composition, the method comprising:
forming an admixture including bioresorbable solids and a liquid carrier, said bioresorbable solids present at a level of about 0.1 grams per cubic centimeter to about 0.7 grams per cubic centimeter of said composition;
wherein said bioresorbable solids comprise a particulate solid collagen material and a particulate solid DBM material, said particulate solid collagen material present in a weight ratio no less than about 1:12 and no greater than about 1:2 relative to said particulate solid DBM material; and wherein said liquid carrier comprises an aqueous gel of a biocompatible polysaccharide, with said biocompatible polysaccharide present at a level of about 0.01 grams per cubic centimeter to about 0.5 grams per cubic centimeter of said composition.

28. A method for making a demineralized bone matrix (DBM) composition, the method comprising:

forming an admixture including a liquid carrier and solids, said liquid carrier comprising an aqueous gel of a biocompatible polysaccharide;

wherein said solids comprise a chemically crosslinked, particulate collagen material; and wherein said solids comprise a particulate DBM material.

29. A demineralized bone matrix (DBM) composition, comprising:
a liquid carrier comprising an aqueous gel including a biocompatible polysaccharide, said aqueous gel in admixture with particulate solids to form a malleable composition;
said particulate solids comprising a particulated bioresorbable sponge material; and said particulate solids comprising a DBM material.

30. The DBM composition of claim 37, wherein said particulated bioresorbable sponge material comprises collagen.

31. The DBM composition of claim 37, wherein said polysaccharide is selected from the group consisting of alginate, pectin and chitosan.

32. The DBM composition of claim 39, wherein said polysaccharide is an alginate.

33. The DBM composition of claim 37, wherein said sponge material is chemically crosslinked.

34. The DBM composition of claim 37, wherein said DBM material is osteoinductive.

35. A method for preparing a demineralized bone matrix (DBM) composition, comprising:
admixing particulate solids with a liquid carrier comprising an aqueous gel including a biocompatible polysaccharide to form a malleable composition;
wherein said particulate solids comprise a particulated bioresorbable sponge material; and wherein said particulate solids comprise a DBM material.

36. The composition of claim 1, wherein said particulate solid DBM material includes elongate particles having a width of at least about 0.2 mm.

37. The DBM composition of claim 16, wherein said particulate solid DBM
material includes elongate particles having a width of at least about 0.2 mm.

38. The DBM composition of claim 37, wherein said particulate solid DBM
material includes elongate particles having a width of at least about 0.2 mm.