Method for manufacturing a fiber-reinforced bioactive ceramic implant

The invention relates to a method for manufacturing a fiber-reinforced bioactive ceramic implant, wherein a base form is made from fibrous material and interspaces between the different fibers are filled using chemical vapor phase infiltration. The fibrous material is coated with a composition which optimizes the bonding with the infiltrant. Preferably, a calcium-phosphate compound is brought between the fibers, which are preferably of the continuous-fiber type.

FIELD OF THE INVENTION
 This invention relates to a method for manufacturing a fiber-reinforced
 bioactive ceramic composite material, and to the use of this material as
 implant.
 BACKGROUND OF THE INVENTION
 In the prior art different materials have already been proposed for making
 implants therefrom for incorporation into animal bodies, and in particular
 into the human body. Such materials are required to meet various, highly
 stringent standards.
 In the first place, these materials must be biocompatible, in order that
 rejection phenomena in the body do no occur or do so to the least possible
 extent.
 Further, certain mechanical properties are required, specific mention being
 made of a high toughness of fracture and a low modulus of elasticity
 comparable to that of human bone tissue.
 Many of the bone implants used heretofore are made of metal. Apart from the
 mechanical properties of metal, which do not correspond to a desirable
 extent with those of animal bone tissue, such implants must be replaced
 after 10 to 15 years owing to corrosion, which is an evident disadvantage.
 The current generation of polymeric materials which have been developed for
 implantation purposes possess a desired toughness. However, the
 biocompatibility of these materials leaves to be desired, so that
 rejection phenomena cannot be precluded.
 Certain ceramic materials, by contrast, are eminently biocompatible. This
 holds in particular for calcium-phosphate-ceramics. However, ceramic
 materials have as a disadvantage that they have a brittle fracturing
 behavior.
 It has been proposed in the prior art to improve the toughness of fracture
 of ceramic material by incorporating fibers. It is this field that the
 present invention resides in.
 The known methods for manufacturing fiber-reinforced ceramic material for
 implantation purposes have a number of evident disadvantages associated
 with the filling of the spaces between the fibers with ceramic material.
 This filling of the spaces between the fibers with ceramic material will
 be designated in this description by the term "densification".
 According to the first methods for manufacturing fiber-reinforced ceramic
 material, a fiber construction was contacted with powdered precursor
 material for forming ceramics. Then this whole was subjected to a
 sintering step, with ceramic being formed from the precursor material.
 This sintering step, however, has as an important disadvantage that it
 entails much shrinkage and hence deformation of the product contemplated.
 This occurrence of shrinkage makes the near-net-shape formation of the
 implants considerably more difficult. Indeed, it is of great importance
 for the bio-implant to have exactly the right dimensions, especially so
 because the finished ceramic product does not readily allow of any
 mechanical processing operation.
 A general description of this type of conventional techniques for
 manufacturing ceramic matrix composites is given in K. K. Chawla, "Ceramic
 matrix composites", Chapman & Hall, London (1993), Chapter 4: "Processing
 of ceramic matrix composites". Further, reference is made to T. N. Tiegs,
 P. F. Becker, "Sintered Al.sub.2 O.sub.3 -SiC-whisker composites",
 Am.Ceram.Soc.Bull. 66 [2] (1987) 339-342. In this article Al.sub.2 O.sub.3
 powder is mixed with SiC whiskers (monocrystal fibers of a diameter of
 about 0.6 .mu.m and a length of 10-80 .mu.m) and other additions. A liquid
 medium is added, followed by drying, pressing and sintering under an argon
 atmosphere (1 atm.) at 1700-1800.degree. C. The shrinkage and deformation
 problem to which reference is made, is discussed, for instance, in the
 standard ceramic processing reference J. S. Reed, "Introduction to the
 principles of ceramic processing", John Wiley & Sons, New York (1988),
 Chapter 26: Firing processes.
 A densification technique which has been developed to solve the problem of
 shrinkage is the so-called "hot pressing". In this technique the sintering
 step is carried out under such pressure that volume contraction hardly
 occurs, if at all. However, hot pressing is applicable to a limited extent
 only, because only simply shapes can be manufactured. Again, reference is
 made to Chapter 26 of the Reed textbook.
 In addition, it is known that fibrous structures can be densified by the
 sol/gel technique. In such a technique the fibrous material is contacted
 with a colloidal solution of the starting materials for the ceramic
 densification material. By evaporation this solution is converted to a
 homogeneous gel. The gel is then converted to a solid material by heating
 at high temperatures in the presence of oxygen.
 These steps must be repeated a number of times because the respective
 transitions from sol to gel to solid successively entail volume
 reductions. In practice, it has been found that it is not possible with
 this technique to fully close the spaces between the fibers. This gives
 rise to weak spots in the fiber-reinforced ceramic material, which can
 cause fracture upon loading. (A. Nazeri, E. Bescher, J. D. Mackenzie,
 "Ceramic composites by the sol-gel method: a review", Ceram. Eng. Sci.
 Proc. 14 [11-12] (1993) 1-19)
 In addition, techniques are known for applying a ceramic layer to a shaped
 substrate. For instance, in the article by Spoto et al. in J. Mater. Chem.
 4 (1994) 1849-1850 and in the article by Allen et al. in Nuclear
 Instruments & Methods in Physics Research, Section B: Beam Interactions
 with materials and Atoms, p. 116 (1996) pages 457-460, methods are
 described for coating a substrate with hydroxyapatite by Chemical Vapor
 Deposition (CVD). Thus a coating is formed which consists of a different
 material than the substrate to which it has been applied. In such products
 which possess a layered structure, the bond between the different
 materials remains a critical point. All this limits the use of these
 products for implantation purposes.
 In fact, in the body many implants are exposed to a high degree of loading,
 with a large number of different forces acting on the implant. Owing to
 differences in the mechanical properties of the materials applied onto
 each other, the bond is thereby weakened. The bond may even be broken,
 with all adverse consequences for a patient.
 SUMMARY OF THE INVENTION
 The object of the present invention is to provide a homogeneous
 fiber-reinforced bioactive ceramic product that can be used for
 implantation purposes, and which does not present the problems of the
 prior art. The term `bioactive implant` in this description and the
 appended claims is understood to mean an implant provoking a specific,
 biological reaction at the interface between the tissue of an organism and
 the implant material, which reaction results in the formation of a bond
 between the tissue and the implant material. Physical characteristics of
 bioactive implant include a mechanically strong bond with surrounding,
 living tissue and provide a means of helping a body in a recovery process.
 This object is achieved by densifying a fiber structure using chemical
 vapor phase infiltration.
 Accordingly, the invention relates to a method for manufacturing a
 fiber-reinforced bioactive ceramic material, wherein a base form is made
 from a fibrous material and interspaces between the different fibers are
 filled using chemical vapor phase infiltration, wherein the fibrous
 material is coated with a composition which optimizes the bonding with the
 infiltrant.
 DETAILED DESCRIPTION
 Using the method according to the invention the densification of a fiber
 preform is carried out with chemical vapor phase infiltration (CVI). Since
 this technique does not entail any sintering step, the problem of
 shrinkage does not arise. Moreover, by starting from a fibrous material
 comprising a specific coating, optimized bonding between the fibrous
 material and the material with which the interspaces between the different
 fibers are filled, is achieved.
 In this technique the ceramic material is brought between the fibers on a
 molecular level. Strength problems arising through the introduction of
 liquid or gel-like media, in particular the unintended and uncontrolled
 creation of (macro)pores, can therefore be prevented.
 It is noted that the chemical vapor phase deposition process is known per
 se. This technique has been developed from the CVD process. While in the
 CVD process a layer is applied to the substrate, in CVI a substrate is
 uniformly impregnated. Fibers are coated with material deposited from a
 vapor until the spaces between the fibers are filled up.
 Such a technique has been described by Y. G. Roman and R. A. Terpstra in a
 review article in Ceramic Technology International 1996, 113-116, Ed. Ian
 Birkby; Sterling Publications Ltd. London. This article describes ceramics
 reinforced with continuous fibers and presently used in the aerospace
 industry.
 In CVI a porous substrate, for instance a fiber structure, is infiltrated
 with a gas phase in a reactor. In this gas phase the components are
 present which are needed for the ceramic product to be formed. Then the
 elements in the gas phase are excited in such a manner that they react to
 form a solid product on the fiber surface.
 An important condition for carrying out CVI is finding suitable reaction
 conditions under which a uniform deposition can be achieved at acceptably
 high reaction rates in the complete volume between the fibers of a
 preform.
 It is preferred to use a starting substance which contains all matrix
 elements. In the case of a SiC-matrix the starting material is, for
 instance, SiCH.sub.3 Cl.sub.3.
 For forming a biocompatible bioactive ceramic material, in particular
 calcium-phosphate compounds, suitable single-source precursors are not
 available. Specifically, calcium- and phosphorus-containing compounds are
 not volatile enough, not stable enough and/or unsuitable in composition to
 deposit a desired compound.
 Little is known about depositing metal phosphates by chemical vapor phase
 reactions, using a single-source precursor. As far as is known, only the
 deposition of chromium, molybdenum and tungsten phosphates from the
 complex of the formula M(CO).sub.5 (PH).sub.3, wherein M represents Cr, Mo
 or W, has been described (I. M. Watson et al. Thin Solid Films 201 (1991),
 337). Corresponding complexes of calcium are not known.
 According to the present invention, presently suitable gas mixtures and
 suitable reaction conditions have been found which enable the manufacture
 of fiber-reinforced bioactive ceramics, with the spaces between the fibers
 being densified with calcium-phosphate compounds.
 The ceramic material that is used according to the invention to density the
 spaces between the fibers are salts of the general formula
EQU Ca.sub.p (PO.sub.4).sub.q (CO.sub.3).sub.r (OH).sub.s F.sub.t
 wherein p.gtoreq.1 and q, r, s and t.gtoreq.0, and wherein 2p=3q+2r+s+t.
 When p=10, q=6, r=0, s=2 and t=0, the above-mentioned formula gives the
 structural formula of hydroxyapatite, which is preferably used. If p=1,
 q=0, r=1 and s=0 calcium carbonate is represented; and when, for instance,
 p=9, q=5, r=1 and s=1 and t=0 a carbonate-containing hydroxyapatite is
 obtained. (E. J. Donahue, D. M. Schleich, Mat. Res. Bull. 26 (1991)
 1119-1126, describe vapor phase processes whereby CaO and CaCO.sub.3 are
 deposited from Ca(dpm).sub.2 (=Ca(tmhd).sub.2)
 From the prior art CVD processes are known whereby specifically
 calcium-containing superconductive materials, such as Tl.sub.2 Ba.sub.2
 CaCu.sub.2 O.sub.x and Bi.sub.2 Sr.sub.2 CaCu.sub.2 O.sub.x, are deposited
 from the vapor phase. The calcium precursors used here, viz. fluorine-free
 and fluorine-containing Ca-.beta.-diketonates, are also usable in the
 method according to the invention.
 In this light reference can be made to L. M. Tone, D. W. Richeson, T. J.
 Marks, J. Zhao, J. Zhang, B. C. Wessels, H. O. Marcy, C. R. Kannewurf,
 "Organometallic chemical vapor deposition--Strategies and progress in the
 preparation of thin films of superconductors having high critical
 temperatures", Adv. Chem. Series 226 (1990), 351-368. Here a
 calcium-.beta.-diketonate, Ca(dpm).sub.2, is used as calcium precursor for
 the deposition of the systems Tl--Ba--Ca--Cu--O and Bi--Sr--Ca--Cu--O. The
 separate known fluorine-free and fluorine-containing Ca-.beta.-diketonate
 precursors can be used separately in the method according to the present
 invention.
 In a preferred embodiment the starting material is a gas mixture in which
 either Ca(tmhd).sub.2 (calcium bis-2,2,6,6-tetramethyl-3,5-heptanedionate;
 identical to Ca(dpm).sub.2, calcium dipivaloylmethane), or Ca(hfac).sub.2
 (calcium bis-1,1,5,5,5-hexafluoro-2,4-pentanedionate), preferably
 Ca(hfac).sub.2 -triglyme or Ca(hfac).sub.2 -tetraglyme, is used as calcium
 precursor.
 Ca(tmhd).sub.2 contains only calcium, carbon, oxygen and hydrogen atoms.
 This compound is preferably used for the formation of hydroxyapatite. From
 this product CaO is deposited. Ca(tmhd).sub.2 is commercially available,
 for instance from Aldrich. However, the inventors have found that the
 quality of this commercially available product is not sufficient for
 depositing a pure product. A prior purification by sublimation, whereby
 the sublimate is maintained under a dry nitrogenous atmosphere is
 therefore desired. For that matter, it is also possible to synthesize
 Ca(tmhd).sub.2 under dry conditions from pure CaH.sub.2 and Htmhd.
 Ca(hfac).sub.2, in triglyme or tetraglyme form, also contains fluorine
 atoms and deposits CaF.sub.2. It is useful for depositing fluorapatite.
 These products can be synthesized by a one-on-one reaction of
 Ca(hfac).sub.2 with triglyme and tetraglyme, respectively, for instance
 according to European patent application 90201485.1.
 Other suitable precursors of calcium are fluorine-free and
 fluorine-containing Ca-.beta.-diketonate compounds and triglyme and
 tetraglyme complexes thereof such as Ca[RC(O)CHC(O)R'].sub.2,
 Ca[RC(O)CHC(O)R'].sub.2.triglyme and Ca[RC(O)CHC(O)R'].sub.2.tetraglyme,
 wherein, for instance, (fluorine-free) R=R'=CH.sub.3 ; R=R'=t-Bu;
 R=CH.sub.3, R'=tBu; and, for instance (fluorine-containing) R =R'=CF.sub.3
 ; R=CH.sub.3, R'=CF.sub.3 ; R=n-C.sub.3 F.sub.7, R'=tBu. See: European
 patent applications 90201485.1 and 92307490.0.
 As already indicated hereinabove, not much is known about the vapor
 deposition of metal phosphates. In the above-mentioned article by Spoto et
 al. in J. Mater. Chem. P.sub.2 O.sub.5 is used as source of phosphorus.
 This compound has an evaporation temperature of 270.degree. C.
 Phosphorus precursors that have a lower evaporation temperature are alkyl
 phosphites of the general structure P(OR).sub.3 or alkyl phosphates of the
 general structure OP(OR).sub.3, wherein R represents a low, C.sub.1-6
 saturated or unsaturated and/or branched alkyl group, and preferably
 methyl or ethyl. In addition, the chlorine-containing compounds PCl.sub.3
 and POCl.sub.3 can be used as phosphorus precursor, although these
 compounds are rather hydrolysis-sensitive.
 By starting from pure starting materials, very pure bioceramics can be
 made.
 In the method according to the invention first a base form of fibrous
 material is made. This base form determines the eventual shape of the
 implant to be manufactured. The spaces between the fibers are filled up.
 In fact, any fibrous material that is compatible with the ceramics to be
 infiltrated and that is stable during the reaction conditions during the
 CVI step can be used. Specifically, ceramic fibers, glass fibers, carbon
 fibers and organic polymeric fibers are suitable, preferably fibers of
 carbon, hydroxyapatite, aluminum oxide, zirconium oxide, glass or metal
 fibers, such as inter alia Fecralloy.RTM..
 The method according to the invention makes it possible to employ long or
 continuous fibers as fibrous material. This provides great advantages as
 regards the mechanical properties, in particular toughness, of the implant
 to be manufactured.
 At the relatively high sintering temperature such as it is employed in the
 known sintering technique, by contrast, the continuous fibers lose a large
 part of their mechanical properties owing to growth of granules and creep.
 If during such a densification in addition high pressures (hot pressing)
 are employed, the fibers will further be subjected to mechanical loading
 as well and consequently fracture and sustain damage. Obviously, this is
 not beneficial to the properties of the composite.
 Through a suitable choice of the type and the orientation of the fibrous
 material, the stiffness (modulus) of the implant can be optimized in any
 desired direction.
 The base form, which must possess a certain dimensional stability, can be
 manufactured in a conventional manner, for instance using textile
 techniques. See, for instance, F. K. KO, "Preform fibre architecture for
 ceramic matrix composites", Ceramic Bulletin 68 [2] (1989) 4021-413.
 In order to optimize the bonding between the fibrous material and the
 infiltrant, the fibers are particularly or completely coated with a
 specific composition. Suitable compositions in this regard comprise
 carbon, boron nitride, zirconium oxide, monazite (LaPO.sub.4), hydroxy
 apatite, aluminum oxide, such as .beta.-aluminum oxide, alumina silicates,
 mica, clay, or combinations thereof. In case boron nitride is used, it is
 preferred that it is employed in combination with silicon carbide.
 Further, it is preferred that the coating is porous to provide dissipation
 of energy, e.g. under circumstances of mechanical stress.
 The coating can be applied to the fibers in any known manner. A preferred
 way of coating the fibers is based on chemical vapor infiltration, i.e.
 the same technique that is used for filling the base form. Gaseous
 reactants are forced to flow to the fibrous base form, and react on the
 surface of the fibers to form a solid. Examples of gaseous reactants are
 natural gas, methane or ethylene, which form a carbon coating at high
 temperatures under non-oxidizing conditions. Boron nitride coatings can
 for instance be deposited using chemical vapor infiltration from gaseous
 mixtures containing boron trichloride, ammonia and hydrogen at 5 kPa
 reactor pressure and 1100.degree. C., as is described in R. A. Lowden, K.
 L. More, O. J. Schwarz, N. L. Vaughn,, "Improved fiber-matrix interlayers
 for Nicalon/SiC composites", in High Temperature Ceramic Matrix
 Composites, ed. R. Naslain, J. Lamon, D. Doumelngts, Woodhead Publ. Ltd.,
 1993. Zirconium oxide may for instance be deposited by the deposition
 reaction between zirconium tetrachloride vapor and water vapor at 200 Ps
 and 800-1000.degree. C., as is described by H. W. Brinkman in his PhD
 thesis "Ceramic membranes by (electro)chemical vapor deposition", PhD
 thesis University of Twente, The Netherlands, 1994. Monazite may for
 instance be deposited using chemical vapor infiltration from mixtures
 containing P.sub.2 O.sub.5 vapor and La-.beta.-diketonate vapor. Aluminum
 oxide coatings can be deposited by thermal decomposition of aluminum
 tr-sec-butoxide at atmospheric pressure at 300-400.degree. C., as
 described by V. A. C. Haanappel in his PhD thesis "Alumina films on
 metallic substrates by MOCVD", PhD thesis University of Twente, The
 Netherlands, 1994.
 The coating thus applied preferably has a thickness between 0.1 and 1
 .mu.m.
 In the reactor, in which a base form from fibrous material is present,
 gaseous precursors for the ceramics are introduced. By choosing the
 pressure of the gas streams and the reactor temperature to be favorable,
 the gases diffuse through the base form of fibrous material. In the base
 form the gases react to form a solid. It is of great importance here that
 the conditions are selected such that the matrix deposits homogeneously in
 the entire volume of the fibrous substrate with acceptable rates.
 The method according to the invention, wherein a base form from fibrous
 material is densified with a ceramic material, has as an advantage that it
 is carried out under mild conditions, such as a relatively low
 densification temperature. As a result, the fibrous structure is not, at
 least less readily, damaged. The infiltration or densification temperature
 in the CVI reactor is between 200 and 1200.degree. C., preferably between
 300 and 900.degree. C., most preferably between 350 and 800.degree. C. The
 infiltration or densification temperature can be set at a value during the
 reaction, that is, can follow a gradient. The pressure in the CVI reactor
 is preferably between 1 mbar-5 bar (absolute), preferably between 1 mbar
 and 1 bar (absolute). The precursor mole fraction is preferably between
 0.05 and 1, preferably between 0.5 and 1, while the total gas flow regime
 is preferably between 1 ml/min to 10,000 ml/min (STP) and more preferably
 between 100 and 1000 ml/min (STP).
 It is noted that international patent application 90/087415 discloses a
 method in which a form part based on pyrocarbon is manufactured. This form
 part, which can be used in cardiac valves, is manufactured by coking
 carbon fibers at 800-1200.degree. C. and subsequently infiltrating this
 product with pyrocarbon at about 1100.degree. C., whereafter the product
 is sealed with a layer of pyrocarbon at a temperature of between 1300 and
 1800.degree. C. Such carbon-carbon composites cannot actively participate
 in processes in the body and are therefore not bioactive. Further, during
 the high infiltration temperatures the fibers lose a great part of their
 mechanical properties, so that the composite end product is not comparable
 in terms of properties with the products that are obtained according to
 the invention.
 The method of the invention makes it possible to control the porosity of
 the infiltrated material without the mechanical properties being adversely
 affected. In particular, this occurs by slowly growing a ceramic coating
 on the fibers. According as the infiltration lasts longer, the coating
 grows on longer, until the complete porosity is filled up. By ending the
 infiltration process prematurely, the composite still retains a certain
 porosity. Moreover, by selecting the proper process conditions, the manner
 in which the growth proceeds in terms of pore size distribution can be
 controlled as well. Some degree of porosity provides that a better bonding
 between the implant and tissue is accomplished. In particular, some degree
 of porosity provides the possibility of systemic tissue growing in.
 According to a preferred embodiment, the fibrous material is densified in
 two steps, the first step consisting in carrying out a sol/gel technique,
 and the second step consisting in carrying out CVI. This embodiment
 provides a method which allows the densification to be carried out faster.
 First a coarse infiltration with a sol/gel technique, for instance that
 described in the publication of Takahashi et al. in Eur. J. Solid State
 Inorg. Chem. 32 (1995) 829-835, is carried out, whereafter the coarse
 structure is further densified using CVI.

The present invention will now be elucidated in and by the following,
 non-limiting examples.
 EXAMPLE 1
 Use is made of the apparatus described in Chapter 3 of the above-mentioned
 thesis by Roman. Two-dimensional wovens of carbon fibers (Toray Industries
 Inc.; Torayra T-300) are wetted with acetone to prevent breakage of the
 fibers. Thereafter these wovens are cut to size and stacked onto each
 other, with the successive layers having a different orientation relative
 to each other (turned through 45.degree. relative to the preceding layer),
 in order to obtain as much isotropy as possible. These stacked layers
 constitute the preform. The preform is placed in a graphite holder.
 In the underside of this preform holder, holes have been drilled to lead
 gaseous/vaporous reactants into the preform. The top of the preform
 holder, which is open in known applications, is closed off with a
 (graphite) cover in which holes have been drilled to lead unreacted
 reactants and gaseous/vaporous reaction products out of the preform. The
 cover can be screwed fixedly to the preform holder, with the preform
 itself being compressed. Then the preform holder/preform combination is
 washed with acetone three times for 30 minutes, after which the
 combination is dried under vacuum, at a good 150.degree. C. for three
 hours. Then the preform holder/preform combination is mounted on the gas
 injector, in such a manner that gas from the injector can only flow
 through the preform holder. The reactor chamber in which the preform is
 disposed is evacuated by suction, and the reactor chamber is brought to
 the desired temperature of 850.degree. C. via the surrounding oven at a
 constant heating rate of 2.degree. C./min.
 When the reactor chamber has reached the desired temperature (measured with
 thermocouples), the pressure in the chamber is Aadjusted to the desired
 value of 50 Torr. Ethylene, coming from a gas bottle located outside the
 reactor chamber, is forced to flow through the porous preform for 30
 minutes with a flow rate of 100 ml/min and is converted into a thin carbon
 coating on the surface of the fibers. After this application of the
 interfacial layer, the hydroxy apatite matrix is applied. The separate
 calcium precursor Ca(tmhd).sub.2 and fluorine precursor
 P(OCH.sub.3).sub.3, which are located outside the reactor chamber, are
 heated to 210.degree. C. and 80.degree. C., respectively, so that their
 vapor pressures are sufficiently high. The carrier gas is passed through
 the precursors. The vapor flow is controlled with a calibrated "vapor
 source controller". Then the gas/vapor mixture is passed to the injector
 at a flow rate of 500 ml/min. Under the influence of the high temperature
 the vaporous reactants are converted to a solid material, precipitated on
 the fibers of the preform. Standard analyses show the precipitate formed
 consists substantially of hydroxyapatite.