CA2205104A1

CA2205104A1 - Device for incorporation and release of biologically active agents

Info

Publication number: CA2205104A1
Application number: CA002205104A
Authority: CA
Inventors: Eugenia Ribeiro De Sousa Fidalgo Leitao; Joost Dick De Bruijn; Hai-Bo Wen; Klaas De Groot
Original assignee: Individual
Current assignee: Chienna BV
Priority date: 1996-05-10
Filing date: 1997-05-12
Publication date: 1997-11-10
Also published as: DE69716505D1; ATE235927T1; DE69716505T2; US6146686A; ATE226453T1; US6069295A; DE69720316T2; CA2205107A1; DE69720316D1; ES2196252T3; ES2185861T3

Abstract

The invention provides an implantable device coated with a layer of calcium phosphate and optionally one or more biologically active substances such as growth factors, lipis, (lipo)polysaccharides, hormones, proteins, antibiotics or cytostatics. The device can be obtained by a nanotechnology process comprising subjecting a substrate to a surface treatment until a surface roughness with an average peak distance (Ra value) between 10 and 1,000 nm and subjecting the roughened surface to precipitation of calcium phosphate from a solution containing calcium and phosphate ions with optional coprepitation of the biologically active substance.

Description

' HO4~ CA 0220S104 1997-05-22 Db~ceror ~nCOrpOra~ODiand relcase of blol~c~ly ac~e ~gcn~

The present invcntion ~elatcs lo i~ ~mpLaDtable devicc with a sjpecific sur~ace rwgbIle~ that hcilita~s in vi~o roll ~;on of 8 solution IP~diatcd co~tuy~ n ~e caldum ~r~ ,c, m w~ ic~a~r~lly iaccivc s ~:t: ~ s can bc copr~i-s tated. T~e prcscllt ;~r~ furthcr rcliates to a ~nocess of ~ .g suc~ a de~icc iandto the 1, ~ ' use of sucll a devicc.
US Patent 5,456,723 l YI ~es a~ ilnplant ~ a p~us ~netallic smface , ~vhichhas becn ~rcated by ~ e and ~Cli~._ acid etch~ng rcsulting in a sur~ace mi~o-r~uPhn~ SC ~g a .~ m~ pealc-to-vallcy height o~ about ~0 to 30 ~ d 0 a lou~l~nes; spaci~lg Of about 1-5 ,~m. The eA~ cly 6harp, comb-~ike ~Ct~lC ~S~sal~ m ordcr to achicve . rf;oP h~ si ~ bctwecn thc implant aIld the ~)ati~g matc~ial Q.y~ho~ti~) fonned on it by ~ g t~e L~L~A~a~Jditt m thc jm~p~nt A J~ of most L~J~o.~.~ite coatod l..~pl~ ~lc ~ that the ~ ~ of h ~ UA~d~itC oDtothC implant nequ~ ~ pn~ e ~ p~ sl whkh limit ~c oice of ~ e ~ c and result in higher p~ g c06ts. lnc ~ iol~ly e~.led tfrh i.l~.., for coatin~ implant mq~ with h~l,oJL~.p~t;te is plaslna ~3~5.1;" ~ (far a review, sec P. ~ ;ql~, in Hydrarylap~tite f~tir<~ in Ordl~poa~i~
Sl rgcry, Ed Gees~lc and Ma~ley, ~aven Pre6s ~Y, 1993, p~ 81-87). Anothcr dis-ad~ t~,~ of the plasma ~lep~ ~ tr h ~ e, iII afl~litinn to ~e hi~h temperaturcs ed, lesides in the rclatively la~gc particle size, m the ûrdCI of 30-7U ~D.
Ihe aim of the prcsellt inYention is to provide a coated i~p~t?~le dcvice that caD be uscd ;D a wide va~cty of b~ m~ plicatiolls (surgcry, bO~ C~ t-~t, y~ r~O~ S etc.). Thc devioe should g~e ise to effective boDc f~ orl and ~' 'I ;~~rly rcsult iJI a dcsired b.~o"i~A~ effcct, suc~ ssistlng bo~c fnnnAtion, 25 plG~-oti~g i..fi ~ l-n . or l~jjr~l jo~ dunng or after implantation, illduccd by thc ~5~ ~
of biCl~ y active sub5tances, such as protcins, grovvth-facto~, lipids, Qipo)poly-5~ lcs, cytostatic agcnts, ~.~io s) antibiotic~ or other biological agents. 1~
a de~ble coat~ng is ~ ~ d, degIadatio~ of said coatiDg due to solutioD Pledia~d p~ s or cdl m ~i-~d prOce6sGs s~ould result in a fi~cr e~,po~u.c or tcleasc of' 30 b;t~'~rJ~lly activc aven~. Thc ~IU~ r. of the device ~nd the t~ at which it ~s p~duced s~ould not have a~ adver~ cffect on t~c biological activity of sa~d agcnts.

~O41299 CA 02205104 1997-05-22 Thc aim is achievcd b~ a sbaped artide sllitablc as an implaDt of a solid, i.c.
noll-fluid, po~ous ~ non~ s matcnal ha~ing a su~ naDo r~Eh~ees, gi~ rise to thc ~-~inn of a composite coati~lg whcl~ plaoed ~~ t~;q Said solutio~sooDtaiD, but are ~ot li~ited to calcium and ~ e ion~, aud biologically active a~ents s (e.g pn)teiDs, grow~ cto~s, lipids, (lipo)~l~s?~ 5~ c~rt~l~tic agcllts, l~n~ 011~ 5~
A.~ I .;O~i~j a~d ~nay be s ~h--~l~ or 5;1. ~ w~t~ d, but may i~lso be rela~ely dilutcd.
The 0a~ng can lh~cr~c bc ~~--r d of both ~ orgauic phasc, such ias the biologtcally activc a~ent and an inorganic (c.g. calcium 1~'~~ ~) phase. lhe un;~ about thc plescnt L~llio~ is dlat b;l~lo~r~ y activc ag~nts cart bc 0 s~ i't~ ly co y~ ildted du~ g the f~m~r~ of dlc soludon ~n-' - d coating.
As a rcsult, a spt~ 1 arca in the coating or the whole Ih r~ of sa~d coati~g ca~be loa~ed with the biologically active agerlt(s), that cxpresses itsi use when c ~ or ,~lc-~scd at tbe surfacc. n~ ~ ~~ on the time at whicll the biolo~tcally activc agent is addod to thc ~l~ 'q eaid a~sent can be a~urately co ~ wbere Ih~ t tbe Ih rL~ ss of the co~ g, as thc coating f~ -- is a time-~ y.,/~ proc~s ande~ ;on o~ said agent f~om the solution rc6ults ~n thc formation of an ~o.~nic coatin~ (i.e. a cilaum p}l~.h~ coati~g). Utiliz:ing such a co-~ ~ip~ t~h~ C
wbere bir'~ 'ly aaiYc agents ca~ cither or not be co ylcC;~ h~ at L~,..i,lt timepoints and witJ~ ~;rr~ c~ r~ 1ion~, can rcsult in a wide vanety of coatin~s, from 20 lcilati~,ly simple e~;--~,c in whicb a hr~m~en~ c~nn~ tion of a 0 ~ ;p~ d biologiully activc a~ent is prescnt, to a vcry complex ooatiDg c~ inine, ar l;r~ e.~t le~els, ~irfe~llt co~ onc of L~ t ~ r~lly active agcnts.
Ihe 6urfsce rou~hness is an ;..,l~,t~ factos of the devioc according to the in~ention. Ihe sulfacc lO~ ghness is dcfme~ herein by the averagc pcak distance, i.e the~5 average spa~ng bchveen ~lo~Usiolls on the sud~ce (Ra value). This aversge pcak e c~n be 5h~ d e.g. b~r means of ~ ~ , FIPct~J~ b~ic o .~ (SEM). Ln general~ ~e average pcak dista~ce may be 1,000 mn or less, dawn to 10 mn. Thc mo~t suitable luuE)~Ilr- - de~cnds on thc nature of the materia~ of the article. F~ articles made of ti'~ u" the average peal~ distancc can bc e.g. ~om 10 to ~ or pol~uwic Inatcnal, thc ~,e$,~,d peak distance is ~om 20 to S00 Dm, .. hv,~s ~or ~ n1r~s steel the pa~k distancc is adv~nf~c~D~ y betwecn 50 and 1,00. 0 nm. In gcneral, thc ~,.vfe average pca~ r~ ~angc is between 2 an~ 500 ~n.

~041299 CA 02205104 1997-05-22 I

Ibe dcpth of thc 6urf~ce roughncss of the ~tidc is less ~tical th~m thc peak dis~ce. Il~ 4, a ~um depth is dec~able, in par~cular a pe~ heigbt - with ~espect to t~e doepest sitcs on thc s~ce - of at lcal;t 20 , up to ~bout 2,000 mn.
~ ~. f~"~ svcIage dcpth is of thc same order of ~hde 8~; the avera~c pcalc s~1 A~r~ and is in p0rt~ om 50 Dm to 1,000 . ~e B~erage depth caU also bc .1. s.~-l ;~A by means of Sca~ng F~ on ~;. .06cop~.
~hc ~-,~n~ of tbe impla~lt articlc can bc of various matc~ials. Ihese iDdud~
mctals, in pa~ticular bioc~mpatible metals such as titanium, tantalum, niobium, ~c~,.i.~ and alloys t~eof, as wcll as s~ c~ stecl. A~oUIcr usefill dass of bio-10co~patible matcrials compriscs or~amc natural and synt~etic ~ol~ as poly-ethylene, polypropylcne, pol~t~ h~n~)o~ h~len~ CIefloD~), whidl may also bc bio-deg~adable pol~ ,6 such ~s poly~l~coUc ~id, polylactic acid or ce~tain poly-~ -OGI~ 5 Ccramic matcrials sllch as calchlm phosphatc, ~ mirq or bioglq~, as well as ~ r~ ~ at~ials, can also be used as aD implant substrate. Thc ~ ] may bc 5pomus or ~ ~us. W~ere it is porous, thc pore6 arc disl;-~u~1 ~d ftom the valleys of the ~facc ~ue~-.-,sj by the deptb: i.c. ~e pores have d~pths sllbstantially greater fflan 2 ~ d thc su~face nDu~ may be ~ .r~ rnC~d on ~hc pore walls.
The ~!bS~h- havi lg t~e desircd ~urhce rough~ ~ss am ~rr~ bc coated ~n vi~ro with a laycr of a calcium I~h~,~e and one or more biologically aaive agcnts.
~IC C~ o- h~ coating caIl be relativdg ~i~, iD the order of froPI a e.g. ~0 nrn to 20U
m, especially &om 1 to S0 ~m. lhe calcium phosphate ~,~ f~ , foTms s~ crystals, .ing an - p}' D~6 likc strucmre. Thc calciurn phosphatc csn be any combination of calciun~ and phospbatc ior~, opt~ y bL,C_~h~ with c.g. h~dlu~idc, ch1or~
sulphate, n~tratc ctc. aDio~s or hy~i~.O- ~, sodium, p01t s;i~ , magnesium etc. cations. For 2sa fastcr process, the d~pa~-:' ;on step can be ~.,v~A~A by a ~ t ~ 1 stcp using a solution of calcium and phosphate ions, or two ~lyl;~...c c .-~ calcium ions and phosphate iolls ~a~ t;.vl~ and applied c~ - - - Jtivdy. The b;~ ' ~rs11y acti~e agc~t in the a)ating ;~ ,dFs, but is ~ot limited to, 6illgle or clJ ~ ;n~l6 of E~rotei~s, lipids~
Qipo)~d~s..~ides, g~owth-factors, ~ytr~ldlic agent~s, 1~ - s, ~d ~ ~; P~s.
30 E~amplcs of so~b agents ar bonc morphogcnctic protcin~ (BMP'6), basic ~ib.obl~st growth i~ctor (bFGE3, h~o ~n~, g~ factor ~GF~), ~ , nic g~h peptide (OGP), et cetera. Ihe r' ~ -' ~ ~ wcight of said biologically active agents call vary from B~D4~5q~ CA 0220S104 1997-OS-22 scvcral tens Of ~lto~c, tO i' ~ ~n~c of Idlo-Daltons.
The calc~um c~ating c~m be applied ~om a solutioD contaming calcium a~d pbo6phatc joDs ant one w mo~e dissolvcd biologically ac~e age~ts. I~c ~l~ may be saturatod w cvc~ supcr-satu~ated, but it may ~Iso be ~elatively dilutcd. This is an 5 ~ ~6~ Of tlle prcscnt il~ Sillcc it allows thc for~ation of a calcium phosp~ate coa~ng hom p¢actically a~ly solution c~ calcium a~-d ph~ io~~and tJe ~ '~F:-'IY activc agcnt. ~e pH n~D~e of thc cal~um phosphate ,....1_:..;,.,.
~olution may be bch veen 4 aIId ~0, ~ ti~l1y betwecD 6 aDd 8. The l~ad~g ~atc ofthc cwting w~ the bioloE~GIlly active ~gerlt(s) can va~y ~m several pn~milles to 60 0 pcrccnt (in wcight w1th rcspect to thc coating) and depcnds on the c~ ti ~whic~ it ~..~ its biololpcal activjty. ~bis a~ bc esl~blisJ~d by va~y~ng thc " ..~ation of ~e biologically activc age~t in the ~Illho~ he ~ ;t~ coabng canbe ~,u.l~,~J to dc~rsde due to solution ~ d or cell mediated l~lo~ s, or can be ~,G~d as a sbble coa~g that shows littlc or no dcgra~htion.
lS Ihe ;~ Jt~ hlc dcvioe unth the calcium phosp~ate ~nd biologically active agent w--~ e coating can give rise to the ~r~ c~h~ e- ~ or; A~JC ~ of e formation when implanted wben thc ~iolo~ir~ly active agcnt is co-~ d of an ,a ~ ' tive protein, c~ gtowth faaors.
Thc ;~l~v.~tion also ~vvides a process of pl~Cil~ a dcvice as d~ d abovc, b~t sub~ecting a solid matcrial to a suIface 1-- 't"" ~~1 U~ a ~urface roughncsswith thc ~ u---,d avera~e peak distance (R8 value) iS ~l3t, ~ d, and L ;~, -ntly coating thc dcvice with calcium ph~rh~e, o~t;nr-'ly tOO~ with a biologically acltive sub6taDce.
Ihe ~ 1 may e.g. bc a sanding or ~coring treatment USiDg z5 con~ tiol.al sa~paper, cmery papcr or glass paper havin~ an applul,l~t~, fincness, e.g.
grade 4000, optinn~lly i~ the ~ CG of.watcr or oth-r fluid6. Diamond paste can also bc uscd in t~e ~--- h~ 1 surface t--~U---- ~ Ihe sur~ace ro~Jg~ r~ can fu~her bc,d by powder ~ nr u6in~ç suitablc fine pu..d~,,s. I~e surface roughI~ess may also bc ~ by a ~ h~ ....f_l 1 -- ~' ~- with a strong, ~ v~bl~ mmeral, a¢id sol ~tinn~
30 optinn~lly follanved by ~ n~ agents sucll as hydrogen IJC. u~;~, optioDally followud by hcu'Q~ g steps.
rne coated i..~p1-p"t~1)le devices ~co.di~ to the ~ tiol. are ~~n('~' for -' BO4~g CA 02205104 1997-05-22 bi~P~ir~t use, i.e. as a bonc subs~tute, a joint p,.~ . s~6, a dc~t~l impla~t (~
dontics), a ~-11c'- ~ ' ~plant, a ~ ' surgG~ d, a t~ .,t~ device (stoma a~d thc lilce) and othcr mcdical or CPC'~ ~ de~ a~ scrve a6 a bone ~P,nt ar ~e ~ l, but also a~i a mea~ f ~, a de~ice to a pa~ticular s bone.
EXAMPIE 1.

Ti-6Al~V alld rl-Al-2 SPe samples, 9.15 mm a~d 5 mr~ in diameter ~spec~cly and 1.~ mm thick, werc used. They wcre ground ~at in SiC pap~s, 1200, 4000 grit a~d o ~ poli~hed down to 1 ,um. 316~ P-- steel ;amples, ca. 80 mm~, were also g~nd iD SiC pape~s, 120~ and 4~00 g~it. All samples were ~ ;r_11y cleal~cd u~
~0~0 ethanol for 20 ~ utes followed by a ~û-minute doublc nPSC with d~stilled watcr and dried under a nOw of hot air. The s~ ~o~g' . ~: ~ wcre meas~ed with a laser ~rfi'l~Pt~r (Eerlcin Elmcr). Tablc 1 show~. t~.e results of the following ~o~n~c ~s paramete~s: Ra - aLi~h ~'~;~ m~ of thc ~ ,s~ hd~çht, ~z - mean pcak-t~v.dley hei~ht and Rma,~ o ~ n~ s~ depth.
~ftcr surfa_c ~li~J ~ d ck~ ;~ all saD~plcs werc ;~ --"s~. in HBSS at 37~C f~r 14 days in ~ep~T.~te pol~ lc~.e ~ 't~~ To allow a ~ .~pply of sn~tinn this was ch~ ~A every 48 hou~s. Empty pol~ Icll_ n~ V~ s we~e used as rcfere~oe. A
zo c~mple of ea~ l~h;e~d s.olution was stored iD 2 mL F,~ .. t~T at 4~~. Ca and P
concent.~ations ill d~cse 8~1L~ r ~ u~ by atomic 7.~s~ t;~ sp~hO
met~ (Yarian SpectAA 300) and 6~~:t,s~ 0.. t~ (Vitalab 21, ~italab ~ t;fic), ~w~i~d~r. All the Iesults are the avera~e of at least three ~ t~.
All su~r~s ~Ivere obs~"~, befose alld after ;~ o~ by sC~nT1ilu dectIon micro-25 scopy (Philips SE~ 52~ and analysed by XR~ oyager X~MA syste~ NOR~N
I~struments): X~D OE'bilips ll~-film XRD) ~as u~ed to d(t~ , the ~u~ of the y~ te la~ APM was used to.obselve its ~n~ h~logy o~l pnl;~h,tl t;~ . "

alloys.
Res~ts ~ discussion 30 Pig. 1 ~hows t~e Ca c~ ltratio~s as a L- ~in,~ of time. 1~ the sv'~ ~ir - that we~c in c~tact ~ith the alloys, a ~ oun~ ;C dccrcasc of tbe c~ tinn~ of Ca was cl~ h~ ~- A
The samc ~ v ol~ was also obs~ d for the lr~ e~ SS. Until day 5 all aurves _ave similar fo~ms b-lt aftcr day S a highe~ d~sL f~r the 1~-6Al-4V 1 ~ ~ s ,t which ~ cs 123 ~1.5 ppm. ~or both Ti-6AI-4V 4000 a~d r~ 25Fc ampks thc Ca ~ A' ation ~ ai~ d more rapitly aftcr day 7 ;~ttaining similar final C:a upt~ko co ~ ations, 61 2.3 and 63-1.5 ppm"~~ . All othe~ r~ s , e~bited Ca upl~e values ~t~ 5 alld 20 ppm.
S ~Ig. 2 thows the P L ~r ~tio~ ~s a filn~i~ of ~me. Thc P uptake culvcs, li~e the Ca ;01~6, al~o showed a ~cc,~ as a F~ r.l on of timc. I~c r~-6AI-4V 4000 a~d 1 llm and thc ~-Al-25Fc 1 llm shawed thc highess P uptakc; 29 ~2~1, 34+1.S ant 58 ~ ~ ~ 7 ppm, ~ . Thcsc findings suggcst that a Ca and P ric~ } ~ isformed ou all the sur~ ~m thc HBSS. In fact, it was possible to seo a white fiL~lO ~ thc pol~ k~c, tbat coJItactcd ~nth thc ~SS. rl--Al--25Fc 4000 and 1~0 showed the lowest Ca and P uptake. rrhe decl ~- ~ ~ in both C:a and P w~ ~ lt~ A
to the gro~ ~f p~ -;p"~'~ nuclei on the su~faces f~m thc HBSS sol~io~l Similar b~ho~r;u~ was fou~d by Ii er a~ [4] after i.. -,,sio~ of silica-gel and gcl-dc~ived titania il~ a ~im~ ed Body Fluid; ~adin e~ a~ 12] also lcl,oll~.d a decrcase in Ca and 15 P ~ dljO~ sS5d Ph~;c'D~ Sol~lbr~n after the immcr~on of cersmic Fig. 3 shaws SEM ~ o ~;~Ao~-aphs of tbe metal s~ ces after immersion i~ HBSS.
~n~ ;np t~c ph~t~ on Fig. 3 it can be seen tbat the l~ t~ layer has a platc mc p~ ,y on which "~obl~les" and/or crystals grow. ~A rcvealed a higher 20 qud.ltil~ of Ca and P on these palticles tban m the plate 1~ c;~ It was t~ ' l to obse~ve that thc plates Laclu.~d on some of ~e clllf,-~5, namcly Ti-6Al-4V 1200 and 1 llm, h-AI-~.SFe 1 ~n and s~ lPss ~teel 1;~ hc o~ ~ of the rr~ .,s docs not secm to depend ~n the (~prts~j~ of t~e ~ntling fl~ws as it is "csi:~k to obser~e a ra~dom c~-~ L ;-,4 of the plates. The ~ ate formed on Ti-~1-4V 40ûO ~hows a ous te~e at the 6a~e n~aS~ ni as thc othcr O~ dlions. It was only possl~le to detcct L~s OD thcse ~ 6 On thc Ca and P rich layer, at ~,.~.. r;.~,.. ~ higher than 2400 x.
Ii et al. [4] p-~fo~) ~ a series of ,~.J).~ t~ in which silica-gd was i..~ $-,d in S~F Ihey suggest t~at the lr~ inn of apatite growth is relatcd to thc Ca/P molar ~atio 30 o~ the fluids. F~.~,u.h;-u e~ a~ [1] obtained .I;r~ HA ..~ h~ci~s b~ p Fc and 15 in Ca(cdta)2~-~aH2PO4 s~lutinn Vanous ~v-~r "~t~5 of Ca(edta)~ had a direct effcct on the mo~phology of the L~LuA~aydtil~ film.
Ihe SEM o~,v~ions s~ggest tbat the ~o~bol~~y of thc ~lL.,;~i~tC lay~ seems to be~iu.n~ both on ~ ~ l and surface fi~i5~in~ as thc i~ ,r.ri~n fluid was the salDe ~ .lD9 CA 02205104 1997-05-22 in all ~
Pig. 4 sbows an AFM photo.ui~ rh ~om a 1~ 1-25E~c 1 llm sample. It is ~p~ t tl~ thc calaum phosp~ate ~iC]l c~atin~ is con6titutcd by the ~ ,sbon of sphcrical particles. Simila~ r~sults ~Ivere dlt'~ F~3 fo5 thc Ti-6AI-4~ ~ - r ~-,S. It soemS that s t}~c F~ of tbc coatin~ starts with h~,t~ ic- of nuclci ~vhi~h gathcr with time unh1 all the su~face ~s cove~d.
It was nDt;c~ that t~e r~ 2~sFe allo~ surf~c6 4000 a~d 1~00 did not e~hibit plate pqccipitates. lt w~s only possl~le to obse~vc small scatteret dçposi~s which had a umilar ,..n.yh- I~l!Y to c~ystals. ~RMA a~is~ on the nat g~o~ howed 0 thc presence of no Ca or P. The 6amC ar~ ;t jn OII the ay6tals showed the ~ ~ .t e of t~e alloy clr....~ 1s, ~a ;md P, associatcd ~vith Si. Si sccms to act as a Ducleus for ~e prcdpitatio~ and ~h of the c~ystals. Th~6 illl~JUlit~l k probably dne to thc SiC cmcry paper used duI~ng thc ~ur~acc J _. atiO.,. Eithcr the d~ .g and cle~ L of thc su~c~ was not sufficieDt, oll thcsc s~f~rs, to ~:move the SiC or somc SiC particles 15 might be ancho~d in the alloy's surfacc as ri-~-2.s~ is a softcT matcrial than thc otber allo~s.
Fig. 5 e~hibits ~RMA spectra ac4ui..,d ~D a IS-6AI~V 40W 6ample ~cfa~c a~d afteron in HBSS. Ol~e can obsave the 1~ v c of the alloy el~ e ~ as weU as ve~y well dcfilled Ca ~d P pea~ on thc aftc~ he r7~ S't~ atio iS 1.56~0.03 which ;- ~ t~s that tbe ~ r~ pluWI~. consists mainly of tncalcium l.h~SI,}, ~1A
F1g. 6 shows ~ spect~a ~cquilcd o~ non~ d (A) and ;~
4V 1 ,~ ff On the: ~ v.~,d samples ope can observe the arp~ of a well defincd [002] peal~ d a broader peak which seems to be ~ ;L,I-,d by the jun~uo~J~s of pea~ [211] aDd [112] indicat~ng the as~o.~hous c~ n~ s of t~c calcium Jh~,h ~te. Thcse rcsults suggest that thc ple~ipitate laye~ has an 9~ *C~l:c apatite-like ~hu~lu.~. S~lar ~SultS werc ~ajn~ for thc Ti-Al-25Pe 1 ,um sa~Dples.
Tllc ~ hIf ~r of this layer was prcviously d~te~Inincd by SEM obsc"-~io~s and is ca.
5 ~Im. Ii ct al. E4] I -o~t~l~,d tbe d~Io~ --- ")t of h~u~apalilc ~l~tc 011 gel-denved 30 titania, as a r-,.. ~;o., of time, after - - - in ~ Body Fluid. 11l the ini~al stages thcy d t~ . d precipihteS all Over the suIfacc wbi~h in~ - - - ' in numbcr snd si~ until, e.~ t~ 'Iy, all the su~face wa6 covcrcd by a lO l~m coating. D~ ,.c etal. ~ c~Jo-ted the r~l f~t;o - of small dcposits on titanium discs aftcr 1-day CA~U~C;
toaS ~ 9t~ ~lSollltjnn l'wo wecksof.lifr."~ ti~ wcrcnccded ~0 41299 CA 02205104 1997-05-22 to ~,.~c~ an apatite laycr wi~ a ~ C_ of 1 ,um.
~imawa et ~ 13] ~lso IL~ A that apatitc is ~mlly fonncd on tit~ wbe titanium i6 i~ d m a solu~on whose pH is similar to ~at of tbc ~ rid Ihey b d a Ih~ of 7 ~n of t~c apatitc f;lm grown on 1~ 4V wllicb make~ it s impo5siblc for this laycr to e~hib* ;Iny ~r ~ s of cal~um ~ e in this en~mllcnt. ~-The pra;e~t ~rsults iDdicate that a calcium phosphate with a~ atite-l~e ~hu.l~..c is nah~a~y foImed ~ the surfaccs of ~olisl~ A ti~ m alloys. Thc Ih;- L ~-- P~ of tbis laye~
n~alces it a suitable ~ce for bone ~udu~lio~ ~rs~es of at least 1 ~ re needed 0 for thc calcillm phosphate to show its p.uç~ 1; s a~d cause bonc ;,,-~ ,, [51, Concl~lls The mo.~ y of calcium ~h~ t~ s depends on the metal DV~ t~ and its s~acc ~ h ~; ~cs It is possible to pro~ce a naturally formcd calcium phosphatc coatmg by ;.. -.~ P metsls such ~ titanium alloys and ~I-;'fl~SS steel iII HBSS.
S Ti-6Al-4V 4000 secms to bc thc surhce that is most f~vvu~ ~'e to producc a ~..1;...~..C and more "~ t apatitc-liXc costiDg capable of bone . ~ ;o E~XAMPLE2. Deter~iDation of cah~u~ pho, b7 dept~ dist~ibuffon on a titaDium al10~ subst~te uslug x-~y ~ nt~ ~! f~tron spectroscopy Ihis e . m~ '- illustIates the ~rt~ tion of thc dcpth ~ j~h il /l~1 ;o~s of selected ~ s ~o iD a ~r - n rh~ k~ous and oxya~ c~ E! coatiDg on a ti1- ~ alloy sample using deplh rrt-filin~ X-ray PhOlOGlG~Ilo.. S~lu~ XPS o~ ~SCA).
Mat~rials The s~n~plPc were titanium alloy plates that had becn surfacc ~ated ~cro,d~ , to the of E~ca~ple 1 to p~ducc a calcium pho phate co~llg when . . . ~s d in 25 cal~ ;r;- 1~;t~" 501 ~icr. or simulated body fluid~ c samples we~c ..ou~ ectly to a ~ PS sample holde~ usi~ a spnng clip -~ ~ge~çnt~ with no p~e~l~ t Ihe outc~ coa~g surface was ~ r;~ y r1r~h;~ y co~A~ 1J~ that no clc~l~ldtic char~ing ".~b'~ - were encountacd durine X-ray ;~t~ tioo or ion beam ctchin~. All analy6is we~c camed out using a Su~face Sciencc ~t~u.,.c~ts (SSI) ~ ~lobL o~ .~tioP
30 ata b~ J.e~ e of 3~10-~ taIr.
M~thods A s~c~r ~ wss .~,co.~i ~om tbe "as ~;v~l surface, to d~,t~ , the surfaoe c~ ~si1 io~ o~ e co~ting and ll~.crol~ ~h t~, ... ;. .-, the elr~n~ to bc Aloni~ ed B0~1299 CA 02205104 1997-05-22 for ~hc depth profilc. Ihe XPS depth profile was o~ by -'t-~ ; argon ion sF ~ ring (ovcr an area of apprm. 2 ~ 2 m~n) and data ~rr~ ;n~ om an aIea of aRra~. 300 ~lm ~ -,tt.r oe~ ~ etchcd crater). ~ ts aDal~ed ~erc c~rbon, o~ cD, calcium, phosphoms, magncsil~m a~d ~dtaniu~. Etcl~ time per step was vaqiablc s f~om 15 to 120 seco~ds pcr qrcle and t~e etch ratc was 3 mnhnin using a total sputtcr time of 4470 ~r~
R~su~
~e surf~ce cbemical ~ ;OI~ (~ atomic pc~t) of the "as ,~;~ 1 ooating was:
car~on 44.99~, o~ygen 33.8%, calcillm 10.5%, ph~y~ ,us 8.8%, n~ ... 2.0%
0 and t;~ -- 0% (figurc 7). Ibe depth p~ofilc of thc coating lC~ a gradual t~a~sitio~ of cslcium aDd ~br ~ ~u from thc coating to thc svb~ dicd~ g thc tion of these elcmen~ in the surfaoe (~dc layer), aDd thu~ a ~ .,~ t bnn~i-tg ~ ~n coating and ~ tc (figurc 8). The ~alcium - o~ygcn - ~hn~ ous laye~
(calc:iu~n phosphatc) is ~ as bcing 9~ r ~~ PJy 90 nm~ "~~'"";~C a sputt~r ratc S of 3 nm pcr minute as ~~ on a t~ IO~ f film on t9rltS~ d that the "interface" ~s defin_d as the point whcrc the ~ m re~ches approx. 50% of its final value. A thin layer of ti~ .: .. oxide S~-.~ thc calcium ~Qq~h~ lay~ from thc t;t~rJ; ~ alloy SUti~hat~' Tbc j~t~..fs~. betvveen t~e cal~ium phl~c~ .- and li~-.;..n~
shows chaDges in the o~ygen, ~hc~ olls, c~lcium and l;~ Cl~e S~ Thc XPS
20 pealc bind~ ~-- ~vs of calciu~ and rhn~ph~ous d~ea~c at thc interface ~n~h the .;.. whe~e a ~ ., o~ide layer is found. An Intt,~ region is likely to oocur at the bou~,d~y and o~ygcn has been d Llet~ ~om t~e calcium ~ pk~1~ to form tj~ - dio~ide at the interface. hl~tallj~ titanium is present below the region. ~ is d~,tec~ at 2 - 4 atomic pcrcent ~hlou~hout t~e calaum pho6phatc ~5 layer aDd i~ slightly in cn~ .. with depth towards thc interface with the t;~ ide). Carbon is found in tbc bulk of the tit~i~m rDriCi-lSi The calcium phospbate layer that is folmed on the titaui~ alloy ~ is fl ~ " ~_lly bound to thc s~ - via it6 surface oside laycr 30 E:~AMPlE 3. Prepamtion of biomimetic c~lclum phosphate coatings on metallic implants and co precipibtion of proteins This c ~u~ C illu~trates a new tw~step ch~ raJ treatmcnt for p~epanng an implantw~t_ a specific sur~ce lu-.J-~ , resultin~ in a met:~ic surface that allows k~t ~041299 CA 02205104 1997-05-22 of bi, m~ calcium ~ e (Ca--P) coat~ngs from i/l vi~o sa~ated c~ in~ 601~liO.-r (SCS). Tbc presen~ method bas the ~dlowiIIg adva~ages over tbe ~.I._~;o~ u~c for the ooa~g a~ ;nn- tuc to thc 6pccific su~ e b: im~t-r CO~ ectly inducod ~om SCS arc s ~ t~,d to bc c~ ;c~lly bound to metallic 6~1~t 1 5 a~d to ~ow bi~her bone-bonding ability, (ii) tbe ~ ca~ be y ~ /o~ onto CO~Dpla~ F' 9~ md~or maa~
p~ imp~ d (~) it i~ a coD~ollablc alld cost~E~li-,_ way to acq~ C~a-P
coatillgs. To ~ thc pot~Si9~ of bi~ he calcium phospbatc coatings as drug-nclcase r~ p~> bovine se~um ~Ibumin (BSA) aDd Ca-P ..~..~ we~c co ~itated 0 on tbc trated ~ " -- s...r~ by immcrsi~ in the SCS ~ , 0~% wt. BSA
The BSA/Ca-P coa~ i are ~ c~l~ to 6e~vc as a pOh.~ Irug-relcase systcm.
Matcru~ls and Mcthods A ncwly dcvcloped two-~tep chemical ~ ~Ga~ c ~l w~ ~,fo,~ d on thc mctallic implant matcrials, ie. comme~ally p~re btanium (cp.T~ al~d Ti6A14V and pOIIOUS
5 tantalum CIa), to p~duce a s~ific surface r~l~n~sC. Du~i~g ~is t~catment, two sene6 Of .1~ ,C.It~ were used for titanium (cp.Ti and Ti6A14V) and ~ Dplant~atenals, ~ , t~at ~sulted in ~e ~ r of thc specific s~lrfacc roughness o~rc~ for the ~ ?,tio~ of thc coating. For the f~mcr, the samples -w~e t~eatod with a mi~hrc of ~Cl and H2S04, followed by '~ Q in a NaO~I sol~ ~ior~, Tbe 20 ~s l~ samples vvere treated ~th a mi~ctwe of Ha, H2S04 and E~, followcd by i---- ~ in Hz02.
~wo kinds of SCSs with J;~c~t Ca a~ld P coa~ , fast calfifir~tjl~n s~ tinn ~CS) and w~ uuv.ci~l Hanks' ~~ r~ salt solubon (HBSS), wcrc uscd for p~paring eti~ P rr~ To ~,o~otc tl~ Ca-P n~ n o~ the m~t~ c~ $,~S a p~ecalc;r;~ Ca) p,~ - c was performcd o~ half t~c trcatcd samplcs bcforc -- ~io~ ill the SCS. The Prv-C~ was ca~ried out by in~ubati~ the ~nplcs ~n 05N
~a2HPO4 o.~ ht and tben t~ v fr l; g them into saturated Ca(OH)2 for 5 h. The rolution for eo p~ ;pit~ n of BSA ~nd G-P eoati~gs ~vas ~ o;v~g 0.2g6wt. BSA into FCS. Thc u~ metals wcre also i",....,,s~ as 0lltrols. Ibe FY~S30 solution vol~me used for ir..~ was 1~ ml per cm2 of sample surf~oe aTea. The samplcs w~c i- --~ in scalcd ~ sl~ vials at 37~C ~n a e~lihmtcd ~atcr-bath ~ g C~ n.icl~, (SEM) togcther with cncrgy ~~ X-r~y (ED~) analy~es, X-ray dif~raction (XRD) and in~ared (I~) ~tlvl!hr~ t.~ we~ used to ch~P~i7r the oL~ Ca-P coat~ C

Ibe biamimctic Ca-P coa~ngs were fast preapitatcd on thc ~eated cp.n and Ti6A14Vsamples by ~ in both F~S and HI~SS no mattcr ~.hclh.,. the ~Ca pl~lh.e WaS p' f~ or ~t. But thc ~ ould ~b-~ lly ~pccd-up thc 5 prec~ta~on ratc of the Ca-P ooatin~s as listed in tablc ~
Figurc 9 shows that a bi~etic Ca-P coatiDg, a~o~' ately 16 ~ k, was fonned oll treated cp.Ti aftcr 16 hou~ of :~v~ in FCS with Pre-G. The coat~g got thicker wid~ . t~me as iudicated by EDX (figure 10) a~ld XRD (figure 11) ~sults. I~e ~",e.-~it~ ate of ~e Ca-P co~ng in BSS is dowcr than that m FCS
lO Blt ~c caati~g ~m HBSS (f~u~e 12) was m~ch dcnscr than that ~om FCS. Thc coat~ng from HBSS mainly e- ~ ~~ d of apatitc (figurc 13). Bio~imetic Ca-P :4 ~t~
could also bc ~ cip~ on porous ra samples (figurc 14) after the ~eatme~t. Thc surf~e contcnt ~hange of the sample w;~s ~tcd by E~X as show~ in figurc 15 It isro~ that no ~ .iQ~ was ob~c~ d on any ulltreated samplcs after 2 weeks s of ;~ .e.si~ F~S or ~IBSS, even u~i~ Pre-Ca. Ihe f~". ,t;~" Of a spccific tit~a~d t7~RlU-rl onde la~er after thcir trcatmcnts is p.ob~bly thc m~n reas~m for the i~i~., pl~ ti~lJ of Ca-P coatin~s by meaDs of in vitro ;---u~ in SCS. The ~, vc~l~c of the t~ n~tc for tit~ m impl-~lts ~nd t~r~t~lll~ could not bc ~ ~h~ ~g~-d ~h~w~ ~ no Ca-P coatin~ was ~ui,~d. It is i~t-,.c;,.".~, to find that thc rcsults of co-,c~ ~'in~l Of BSA and Ca-P coatmg we~e positivc. The iR a,~ Jrs (figurc 16) ind1cated thc obvious ~ r~ of BSA in the Ca-P coating oql cp.Ti aftcr ~,-- .-:
in F~S. Relcase e ~of BSA from BSA/Ca-P coatings are ~i~d in Example 4.
Conclusior s Thc ~esults of this b;~ ~ calau3~ ~s~lk ~ coating and protein co p,~ .it ;~
stuty have show~ that:-. The ~e vly d-,~,lo~d t~o-step rh-omir~l t~ is an cff~;~ mcthod to prcparc bioact~ve m~t~llic ~ t s~ g f~t ~ Iy ~ - of a~ Gllt b~
Ca-P c~';~,s by L~l vi~o immersion in SCS. IhG chcmical ~agellts pccdcd for ~c ~ of ~ nplant m~ c and tantalum are dirr~ om ~ othcr.
. rpe prccipitation of C~-P c~dti~,Es could be ~ ly ~ cd by mcan~ of pIe-calcifyin~ thc trcated samples bcfor~ thc i~ion .
. I~e ~ io~ latc and c~ u~ -- of the Ca--P C07'~S Can be, 1~: d by cont~lling thc cv ~ n~ ~ of the SCSs (FCS or HBSS) for ~ e.~

1~

. Somc p~ lL~e BSA can be co p~ d w~th bio ~ ;f Ca-P coatill~s. Such composiSe ooatings, with other - bioactive - - 1~ ,1~1 ~c molecul~ t~
to be able so scn~e as pot~t~sl ~Lug ~ systems.
EXAMrlE 4. Rel~se OI Bo~i~c Senlm Albumi~ tB~) f~om calclum p ~ -(Ca_P~lBSA ~flt:r~g~ on sur~ace-treate~ commercially pun~ titanium Co ,Iccip*~io~ orBS4 Coq~mucially ~ lqr blocks il~ size 1~ x lO x 2 mln were used as su~ates. Ihc two-step l-c ~ 1 and y~ ;r~\tiQn weFc ~.ron~ the m~ls ~s d ~ s e "1~ 3. Ihe ~ ratcd r91- ;r.~ -- 60lUtioD used fa~ ~crsion was y~ U~
0 by d;5sol~ u~g O~9~o BSA into 0.8 ACS. ~11 the samples we~e im~e~cd in 37~C water-bath for nvo days.
I~elcas~ c~peruncn~s ~he BSA contcnt in solution was measured by mcans of total organic carbon (TOC~)me~od. Four blocks w~th Ca-P/BSA roa~in~c were compl~tely diss~lved by 40 ml of 05 ~ HCI solution to d~tect thc ~ tiO1~ of BSA in Ca-PlBSA coat~n~ Four . were i,~ ,d in 20 ml of 0.01 M PBS at pH 4 (adjustcd Usi~lg Ha) at 37~C.
At ccrtain interval6 of time, 5 ml of the i~ solll~ion was takcn for TOC
meas~lc~"t at ccltain ~nterval and then ref~ll to 20 ml ~ith new E'BS at pH 4 evcry time.
ZO R~su~
B54 co/~ tion in C~-P/~ coanng ~he Ca-P/BS~ coatings on five sample~ w~e peded off complctcly and then ~ v;gh~
using a bsll~n~c The weight of the Ca-P/BSA coati~ on each samplc can bc ~
to be a mcsn of 15 mg. The ca~bon ~.- - --t,~ in tbe coating was r~J~ ~ to be 15 % and thc BSA ~c~ ti~ was about 30% be~use thc carbon ~ r~ ti~A i~
BSA was ~l~t~t~d to be around 50% by thc same method.
BS~ ~leasc cun~e T~C a~ount of BSA ~ s~ into PBS was plotted agaillst tbc ;..~ time as shown m Flgurc 17. It is ~dicated that undcr thcsc c ..~ ditions, BSA was, ..l~s 30 ,~il~ti~ tast m thc first two days of the ~ n and the~ thc n:lease latc lcvcllcd off so~ . Thc main reason could be that thc PBS was very acidic ~H - 4) at tbc b~ e stage and the coating was diss~l~cd vcry fast. After certain time of i.. ..the pH bcc~nc bighcr. Thc pH values of PBS at thc 7th and 14th were ~ s~ ~ to be 1~041299 CA 02205104 1997-05-22 ~3 ;

5.628 aDd ~.S84".i~ . p~ ~ t~ese rcsults to the act~al in vivo s;~
where tbe pH valuc will be around 7, these Iesults indicatc that a dual, slow ~elease sy~tam ~s obt~ ssuming that t~e 48 hours ~DcuWon in ~m ~cidic ~Ai~
comparable to 6cvc~al weeks, if not months impl~tation in a C~ r--Ihis c~mel~t shaw~ that p~otems such a6 BSA ca~l be co ~r~ A in a calcium phos~atc coa~g ;md that it ca~ r~ Al~ be le~ d ~om thc coatiI~g. ~
BSA was uscd to ~.~,.",;~r, the fC~ jlity of ~his techniquc, it is clear that a Ca-Ph -'~ 'ly ac~ve agent c~ coating can be used as sort of a dmg deliv~y 10 system and bas lh_.efo,G ,x ~s lti~l ~n the mcdical field.

Iable 1- Su~ce ~ou~uc~ xs~

SuIfa¢e fiIIisbl Ra (~Im) Rz (~m) ~ (llm) 1-4V 1200 grit 0.47 ~ 0.01 3.74:1;0.04 5.13 ~ 0.08 6Al-4V4000grit 0.24~0.03 1.91_0.~1 2.4~054 Ti-6AI-4V 1 llm 0.03+0.00 0 ~5 ~ o.n~ 0.48~0.03 Ti~ 2.5Fe 1200 gnt 0.42~0.03 2.97~0.35 3.47~0A8 Ti-AI-2.5F~ 4000 gnt 0 ~.3+0 01 1.97 ~ 0.18 2.46~0.34 Ti-AI-25Fc 1 llm 0.04_0.01 0.~&0.11 0.36_0.19.
316 L 1200 gnt 0.3 ~ 0.06 2.32~0.47 2.96:~:0.03 2~ 316 L4000 ~nt ~ 01 0.35_0.1 0.46~0.1 Table 2 - Iist of Ca2+ a~ld HPO4~ c~l.it~jo~ rate a~d c- vl - ' of Ca-P coatings on cp.Ti a~d Ti6A14V.

Concentration (m~ Ca2+ 3.0 1.26 HPO 2- 1.87 0.78 Prccipitation rate ofNo P~C~ 0.5 ~hr 1 ~wk coat~g Prc-Ca 1 ~r 3 l~/wlc n of coa~i~g apatitc, OCP apatitc 1~0 41~99 CA 02205104 1997-05-22 l~lgore c-ptiou5 Figuse 1--Ca conce~tian as a R.--r I ;- -. of time ~gu~e 2--P c ~--r~ aS a fi~ tinn of t~ne Figu~e 3 - SEM photan~ctogtaphs of the maal sur~ces after Lmma~iion m EIBSS. A:
~ 4V 1200; B~ 4V 4000; C: r~ 4V 1 ~; D~ 25Fc 1 ,um; E: rl-Al-2~Fe 4000; F- st~inle~s steel lW
Pigurc 4 - AFM ~\h~ a~h of a n~ 25Fe 1 ~lm sample a~t~; ~ ~ Q~
HBSS. I~c~easillg ~na~~ h~ from ficld O to 3. Sc~mi~g le~ ~om field 3: 15 ~m.
lo Figure S - XRMA spec~ cd on z 1~-6A1 4V 4000 sample be*~e (A) and &
~e~;sion (B) in H~SS.
F~c 6 - ~ pcctra a~ d on a "o~ r~C~,d (A) u~d imme~ (B) 1~-6AI-~V 1 llm surface Figure 7. Surface ch~ os;l io (iD atomic percent) of tbe "as ~ coating.
15 Figure 8. ~epth profile of the coating, ~om coating to substrate.
E;igure 9. Sca~ing electron ".ic~o~; ~h of the Ca-P u~ating (C~ p~ecipitated on cp.Ti cr~) a~ter 16 hours of; -- ~ A ~;OJ) in F~ vith Pre-Ca.
Fig~c 10. ED~ spectra of t~ cp.Ti surfaces non-treated, treated and i~ ?A m E~CSwith Pre-Ca for dir~ t hou~s. The choulder of O ka pcak is clearly secn 2~ after the ~-A~ l The Ca and p rr"~t~.. h, iuclG.~3~,d ~ith ~be inclc--- of ~ersion time.
Fi~e 11. X~ pattems of thc c~.Ti surfac~s afte~ di~ nl houIs of ;~ in FCS
with Pre-Ca. Tbc count~ of apatite peaks get bigher l~vith incrcased i..~
times. Oc~a-calcium ~ (OCP) starts to bc fo~med at around 8 houls.
~5 ~ue 1~ Scannin~ clectron ~ic.~,, . } of a de~e Ca-P coa~ng (CP) p. ~ ~ ' on cp.Ti ~om HBSS after 1 week of ;"~ r.~ vith Pre-Ca The layer b~h._aA
coating and ~ C~tC iS t~c titanium o~nde layer (OL), fonncd ss a result of the t~eatment. ~ote the surface roughness of thc implant on which the calcium phosphate coating bas bccn formed.
~0 Fgure 13. Thin-film XRD pattern of a dalse Ca-P coating ~ I by immcrsion in HBSS with P~-Ca ~ veek.
Figme 14. ~ elec~.o~ ~nicrograph of po~ous ~ ~a) aftcr 2 days ;- ~ e.~ . in FCS wit~ Pre-Ca. ~hc coating is fonncd thro~E h~t thc porous 1~ 1 ~04~ CA 02205l04 l997-05-22 F~e 15. EDX spcctr~ of (a) non-trca~d, (b) t~ed, a~d (c) Prc-Ca trca~cd, 2 day FCS i~ porou6~ a) s~nplc.
~i~ue 16. IR ~pectra of BSA (a) and ~p.n surfaces afte~ 2 days of ;----- "cj~
CrJJ~ , 02%~vt. BS~ d E:CS only (c). ~e cSi6teDcc of four s ab~ ~tio . ba~s of BSA in ~ s thc c, ~ n of BSA
~Rith tbc biomimedc calaum p~D~p.~te coati~g.
F~e 17. Thc amou~t of ~SA released into P~ as a result of ~c ;~ -- e.~ on t~e Liter~ture ~treDces 1. Y. F~ishiro, T. Sato and A. Ohlwalci, "Coa~g of h~J~u.~ , ou mehl plates 0 ~g thc~mal dissûciation of ~Icium -I~DTA chelate in F~k~~ t~ so~ ~l:n ,~ under h,~ hr- ~-~9~ jl ;n~.c", J. h~te~. Sc: Mater in Ucd, 6, pp. 172-176, 1995 2. S.R Radin and P. D~ , J. Bion~ Mater. Kes." 27, pp. 35, 19~3 3. T. Ha~avv~, "Titsnium a~ld its o~dc film: a r~ ,t for fo~ming apatite", in Proc.
of thc Bone }~ ' al Intcrfsce ~V~n~ n~, To~ to, Dec. 199~ J.~. Davies ed., Univ. Toronto P~css, pp. 49-61,1991 4. Ii, P, P~D. thesis Lcidcn U~u~J~Sit~ (1993) 5. P. D~ , S. Radin and K. ~ ikawa, ' The ratc of calciu~ ~
o~ on metal aPd cc.~i~, aDd ~c rrl tiQ~-h;l~ to bioactivity", in Bonc ~ Ai~ n~ ;9~S, p. D~ .e, T. ~okubo & CA, va~ Blitte~svrijk (eds), Rccd H~71thr~ m~nic~atio~ pp. 213-21~ 1992.

Claims

1. An implantable device of a material having a surface roughness with an average peak distance (Ra value) between 10 and 1,000 nm, said surface being coated with a layer comprising calcium ions and phosphate ions.

2. An implantable device according to claim 1, wherein said layer further comprises a growth factor, a lipid, a (lipo)polysaccharide, a cytostatic agent, a hormone, an antibiotic, a protein and/or another biologically active agent.

3. An implantable device according to claim 1 or 2, having a surface roughness with an average depth between 20 and 1,000 nm.

4. An implantable device according to any one of claims 1-3, wherein said layer of calcium phosphate has a thickness of 50 nm - 200 µm, in particular of between 1000 nm and 50 µm.

5. An implantable device according to any one of claims 1-4, wherein said material is a metal, a metal alloy, a ceramic material, a natural or synthetic polymer or a composite of any of these materials.

6. A process for producing an implantable device, comprising subjecting a porous or non-porous material to a surface treatment until a surface roughness with an average peak distance (Ra value) between 10 and 1,000 nm is obtained, and subsequently subjecting the surface to precipitation of calcium phosphate from a solution containing calcium and phosphate ions.

7. A process according to claim 6, wherein said solution has a pH of 4-10, preferably 6-8.

8. A process according to claim 6 or 7, wherein said solution further contains agrowth factor, a lipid, a (lipo)polysaccharide, a hormone, a cytostatic agent, an antibiotic, a protein and/or another biologically active agent.

9. A process according to any one of claims 6-8, wherein said subjecting to precipitation of calcium phosphate is carried out in two stages.

10. Use of a device according to any one of claims 1-5, or produced according to any one of claims 6-9, as a bone substituted, a joint prosthesis, a dental implant, a maxillofacial implant, a vertebral surgery aid, a transcutaneous device or any other hard-tissue-related device.