Europäisches Patentamt *EP000987032B1* (19) European Patent Office Office européen des brevets (11) EP 0 987 032 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61L 27/00, A61L 27/10, of the grant of the patent: A61L 27/32, A61P 19/08 01.12.2004 Bulletin 2004/49 (21) Application number: 99202992.6 (22) Date of filing: 14.09.1999 (54) Ceramic material for osteoinduction comprising micropores in the surface of macropores Keramikmaterial zur Osteoinduktion enthaltend Mikroporen an der Öberfläche von Makroporen Matériau céramique pour l’ostéoinduction comprenant des micropores à la surface de macropores (84) Designated Contracting States: (74) Representative: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Prins, Adrianus Willem, Mr. Ir. et al MC NL PT SE Vereenigde, Nieuwe Parklaan 97 (30) Priority: 15.09.1998 EP 98203084 2587 BN Den Haag (NL) (43) Date of publication of application: (56) References cited: 22.03.2000 Bulletin 2000/12 EP-A- 0 267 624 EP-A- 0 410 010 FR-A- 2 697 243 US-A- 4 195 366 (73) Proprietor: IsoTis N.V. US-A- 4 629 464 US-A- 5 017 518 3723 MB Bilthoven (NL) US-A- 5 355 898 US-A- 5 531 794 US-A- 5 549 123 US-A- 5 766 618 (72) Inventors: • de Bruijn, Joost Dick • YOKOZEKI H ET AL: "Influence of surface 2517 AG Den Haag (NL) microstructure on the reaction of the active • de Groot, Klaas ceramics in vivo" JOURNAL OF MATERIAL 2101 EL Heemstede (NL) SCIENCE: MATERIALS IN MEDICINE, vol. 9, no. • Huipin, Yuan 7, July 1998 (1998-07), pages 381-384, 3706 AA Zeist (NL) XP002093992 • van Blitterswijk, Clemens Antoni • PEELEN JGJETAL:"Sintered Hydroxylapatite 3467 PD Hekendorp (NL) as a bioceramic" PHILIPS TECHNICAL REVIEW, vol. 37, no. 9/10, 1977, pages 234-236, XP002093993 Philips BV, Eindhoven, NL Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 987 032 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 0 987 032 B1 2 Description bone filling material composed of a sintered hydroxya- patite with micropores of 0.02-0.1 mm, macropores of [0001] The invention relates to an osteoinductive ma- 0.2-2.0 mm, and a porosity of 40%. The material is pre- terial and to a process for preparing said material. pared by sintering a slurry of hydroxyapatite in the pres- [0002] Calcium phosphates such as hydroxyapatite 5 ence of hydrogen peroxide at a temperature of are known to be osteoconductive, or bioactive. This 1100-1300°C. means that they act as a template along which bone [0011] The present invention aims to provide a mate- growth can occur. Further, bone formation can directly rial having an improved osteoinductivity. It is an object take place at the surface of the material, and a strong of the invention to provide a material that is suitable to bond is obtained with bone tissue. Osteoinductivity, on 10 be used as an implant in living organisms and to function the other hand, is regarded as a property of materials as a (temporary) substitute for bone tissue. Thus, the that induce the formation of bone tissue. In the past, this material should be both biocompatible and biodegrada- property has only been described in connection with ma- ble. terials that contain osteoinductive, proteinaceous fac- [0012] Surprisingly, it has been found that this object tors such as bone morphogenetic proteins (BMP's). 15 is achieved by the provision of a ceramic material having [0003] Recently, however, several studies have been both macropores and micropores of specific sizes. reported that indicate a possible osteoinductive capacity Hence, the invention relates to an osteoinductive bio- of calcium phosphates when implanted intramuscularly material, which is based on a ceramic material and in dogs or baboons. Generally, it is assumed that the which has a total porosity of 20 to 90%, wherein macro- presence of a porous structure and a specific geometry 20 pores are present having a size ranging from 0.1 to 1.5 of the implant plays a crucial role in the osteoinductive mm, and wherein micropores are present in the surface character of the implant. of the macropores, said micropores having a size rang- [0004] Yamasaki et al., in Biomaterials 1992, vol. 13, ing from 0.05 to 20 µm. no. 5, 308-312, have described to have found hetero- [0013] The material of the invention shows excellent topic bone formation around porous hydroxyapatite ce- 25 osteoinductive behaviour in living tissue. The formation ramic granules, but not around dense granules. The po- of bone tissue at the surface of the material of the in- rous granules had a size between 200 and 600 µm, and vention assists in a favourable acceptation of an implant a continuous and interconnected microporosity ranging made of said material. Moreover, the formation of the in diameter from 2 to 10 µm. bone tissue accelerates the recovery of any damage in [0005] European patent application 0 267 624 dis- 30 the bone structure, which forms the reason for applying closes a porous calcium phosphate based bone pros- the implant. thesis having open pores with an average size of [0014] An osteoinductive biomaterial according to the 0.01-2,000 µm and closed pores with an average size invention is based on a ceramic material. The biomate- of 0.01-30 µm. The prosthesis is said to have both good rial may for instance be a medical implant formed of a workability and an adequate degree of biocompatability. 35 ceramic material. It is also possible that the biomaterial [0006] United States patent 5,017,518 discloses a is a medical implant of a different material, such as a process for producing calcium phosphate ceramics hav- metal or a polymeric material, on which the ceramic ma- ing a porous surface. The process comprises preparing terial is present in the form of a coating. Another possi- untreated calcium phosphate ceramics, which compris- bility is described by M.L. Gaillard and C.A. van Blitter- es a mixture of hydroxyapatite and tricalcium phos- 40 swijk in J. Mater. Sci., Materials in Medicine, 5:695-701 phate, and treating said untreated ceramics with an (1994). This possibility concerns a copolymer having hy- acidic solution to selectively dissolve the tricalcium drogel-like properties, which may be calcified in the phosphate in the surface of the ceramics. presence of calcium and phosphate ions. [0007] In the Journal of Material Science: Materials in [0015] In principle, any ceramic material that is both Medicine, vol. 9, no. 7, July 1998, pages 381-384, 45 sufficiently biocompatible and sufficiently biodegrada- Yokozeki et al. have described a bone graft of beta-tri- ble to be used as an implant in living tissue can be used. calcium phosphate. The graft is prepared by sintering at Preferably, the ceramic material is capable of providing 900°C and has micropores of 0.2-0.5 µm and macropo- a calcium phosphate surface, either in vitro or in vivo, res of 0.15-0.4 mm, and a porosity of 60%. which has the present specific surface structure. It is fur- [0008] European patent application 0 410 010 dis- 50 ther preferred that the ceramic material is capable of ad- closes a hydoxyapatite bone implant with micropores sorbing biologically active agents, such as growth fac- having a size below 5 µm, macropores having a size tors (BMP's etc.), either in vitro or in vivo. Suitable ex- above 100 µm, and a porosity of up to 80%. amples of ceramic materials include calcium phos- [0009] United States patent 4,195,366 discloses a phates, glass ceramics and materials containing calci- polycrystalline whitlockite ceramic in either pore-free or 55 um phosphates and/or glass ceramics. porous form. The ceramic has a crystallite size of 0.3-3 [0016] Preferably, the ceramic material is a calcium µm. phosphate. Preferred calcium phosphates are octacal- [0010] United States patent 4,629,464 discloses a cium phosphate, apatites, such as hydroxyapatite and 2 3 EP 0 987 032 B1 4 carbonate apatite, whitlockites, such as α-tricalcium move chemical surface impurities. phosphate and β-tricalcium phosphate, and combina- [0026] Subsequently, the material is treated with an tions thereof. aqueous solution of an acid. Suitable acids in this regard [0017] An important aspect of the invention is the are any etching acids, i.e. any acids which lead to a physical structure of the osteoinductive biomaterial. The 5 slight dissolution of the calcium phosphate based ma- material comprises both macropores and micropores. terial. The use of the following acids has been found to The total porosity ranges from 20 to 90%, preferably lead to extremely favourable results: maleic acid, hydro- from 40 to 70%. chloric acid, phosphoric acid, and combinations thereof. [0018] The macropores of the material have a size of The concentration of the acid in the solution is preferably from 0.1 to 1.5 mm. Preferably, the size of the macro- 10 chosen such that the pH of the solution lies between 0 pores lies between 0.2 and 1 mm. It has been found that and 4, more preferably between 1 and 3. the indicated sizes of the macropores have a significant [0027] After the acid treatment, which preferably lasts beneficial influence on the osteoinductive character of between 3 and 15 minutes, the ceramic material is the material.