Title of Invention	"TITANIUM BASED BIOCOMPOSITE MATERIAL USEFUL FOR ORTHOPAEDIC AND OTHER IMPLANTS AND A PROCESS FOR ITS PREPARATION"
Abstract	Titanium based composite material for use as prosthetic implant has been developed by powder metallurgy process which has interconnected porosity and is bioactive in nature. Titanium base powders are mixed with powder precursors of calcium and phosphorus, blended, milled and compacted. These compacts when calcined at 600-1200°C under various atmospheres form in situ calcium-phosphatic bioactive phases distributed uniformly in bioinert titanium phases. The calcined compacts are crushed, compacted to shape and vacuum sintered at 1000-1250°C to obtain appropriate interconnected porosity and strength. Immersion of the biocomposite in simulated body fluids, led to precipitation of bioactive phases like calcium hydroxyapatite, tricalcium phosphate, sodium calcium phosphate and calcium hydrogen phosphates on the surface, indicating biocompatibility of the implantable material having required interconnected porosity for facilitating tissue growth. The composite material thus developed by such process is noncytotoxic, has adequate corrosion properties, mechanical strength and can be used for orthopedic and other implants.

Title of Invention

"TITANIUM BASED BIOCOMPOSITE MATERIAL USEFUL FOR ORTHOPAEDIC AND OTHER IMPLANTS AND A PROCESS FOR ITS PREPARATION"

Abstract

Titanium based composite material for use as prosthetic implant has been developed by powder metallurgy process which has interconnected porosity and is bioactive in nature. Titanium base powders are mixed with powder precursors of calcium and phosphorus, blended, milled and compacted. These compacts when calcined at 600-1200°C under various atmospheres form in situ calcium-phosphatic bioactive phases distributed uniformly in bioinert titanium phases. The calcined compacts are crushed, compacted to shape and vacuum sintered at 1000-1250°C to obtain appropriate interconnected porosity and strength. Immersion of the biocomposite in simulated body fluids, led to precipitation of bioactive phases like calcium hydroxyapatite, tricalcium phosphate, sodium calcium phosphate and calcium hydrogen phosphates on the surface, indicating biocompatibility of the implantable material having required interconnected porosity for facilitating tissue growth. The composite material thus developed by such process is noncytotoxic, has adequate corrosion properties, mechanical strength and can be used for orthopedic and other implants.

Full Text	FIELD OF INVENTION: The present invention relates to novel titanium based biocomposite material useful for orthopaedic and other implants and a process for its preparation. More particularly, the present invention relates to novel titanium-based composite materials, which are bioactive and are useful as bio implants as bone substitutes. The term bioactive means that the nature of composite material of the present invention is such that it is not rejected by human body (biocompatible) when it is implanted, for example, as a substitute for damaged bone1 (biocomposite) and, in addition actively interacts with the body environment. More particularly, the present invention relates to novel titanium-based composite material which when implanted as a replacement for a damaged portion, for example damaged portion of a bone, integrates with the undamaged tissues of the bone actively (bioactive) such that it behaves as if it is a part of human body itself. One of the primary applications of the composite material of the present invention is in orthopaedics, as substitute for damaged bones or damaged portions of bones. Prior art The use of prosthetic devices for treatment of bone injuries / illnesses is continuously expanding with an increasingly active and aging population. Titanium and the alloy Ti-6AI-4V are widely used as materials for orthopedic implants because of their superior mechanical properties and nontoxic behaviour [Benjamin, D., editor. Metals handbook, 9th ed., Vol. 3, Metals Park, Ohio: American Society for Metals, 1980, 372-406, Dobbs, H. S., Fracture of titanium orthopedic implants, J. Mater. Sci., 1982; 17: 2398-2340]. However, one of the main drawbacks of using metallic implants is that they are bio inert and become encapsulated by dense fibrous tissue inside the body. This impedes proper stress distribution at the 'implant-bone' interface, which can result in an interfacial failure and loosening of the implant with the possible consequence of fracture in the adjacent bone [Hench, L. L, Bioceramics: from concept to clinic, J. Am. Ceram. Soc, 1991; 74 :1487-1510, Suchanek, W. et al., Processing and properties of hydroxyapatite-based biomaterials for use as hard tissue replacement implants, Mater. Res.,1998, 13; 94-117]. Thus the use of bone replacements for bone fractures, removal of bone, or the use of supports for weakened bone requires that the artificial bone replacement form a strong joint with natural bone to ensure the integrity of the structure. Secure tissue-prosthesis attachment is a necessary requirement for the successful performance of most surgical implants. Load-bearing orthopedic implants for bone and joint replacement are effective only if they can be firmly fixed with the host bone. Until the 1970s, poly methyl methacrylate (PMMA) bone cement was the predominant means of fixing a joint-replacement implant to the skeletal system. This fixation is primarily mechanical. Cement penetrates into the bone and locks onto small surface irregularities on the implant. Shrinkage of the cement during curing also locks the cement onto the stem of the device. However, over time, the implant may become loose within the cement. This is particularly true for younger, more physically active patients. In some cases, this loosening may either cause pain or increased stress on the implant and subsequent implant failure. Both of these effects may necessitate re-operation [David J.R editor, Handbook of Materials for Medical Devices; Chapter 9, 2003, ASM International, Materials Park, Ohio, USA, 179 -194]. To overcome the above problem, alternative approaches for implant fixation to bone were investigated, which included the use of porous-coated implants made of metal, polymer (porous poly sulfone and polyethylene), or polymer-based composites (carbon-fiber- filled polytetra-fluoroethylene - PTFE). This has led to the introduction of porous coated joint replacement implants, principally porous metal-coated hip- and knee-joint implants. Porous metal-coated implants provide enhanced fixation through either cement interlocks with the porous structure or fixation via ingrowth of bone tissue. Studies have shown that the minimum pore size for load-bearing implants, such as artificial hips and porous coatings can be highly varied and require different technologies to obtain. For example, cobalt-chromium and titanium porous coatings can be produced from spherical metal powders, wires or fibers that are formed into porous pads A major concern with the use of porous-coated implants in highly loaded applications is the effect of the porous surface layer on the mechanical properties of the implants, particularly on fatigue strength. Further, the complex high temperature metallurgical process used for bonding the coating to the implant can be challenging since strong bonds between the powder particles among themselves as well as between the coating and the implant are required without significantly degrading the strength and corrosion resistance of the component [Smith T, The Effect of Plasma-Sprayed Coatings on the Fatigue of Titanium Alloy Implants, J. Mat., (1994,Feb), 54-56] Coating calcium hydroxyapatite (HA), Caio(P04)6(OH)2, as well as other calcium phosphatic (Ca-P) salts on a bioinert metallic implant surface is one method of obtaining a bioactive coating on implants[Khor K.A, Cheang P, Wang Y., Plasma Spraying of Combustion Flame Spheroidized Hydroxyapatite Powders, J. Therm. Spray Technol., June 1998, 254-260]. Some biological advantages of HA/CaP coatings are enhancement of bone formation, accelerated bonding between the implant surface and surrounding tissues, and the reduction of potentially harmful metallic ion release [Bernard F, Georges W, Rudi C, Titanium release from dental implants: an in vivo study on sheep, Materials Letters, 43 (2000,April), 159-165]. HA/CaP coated titanium has been used in many implants such as hip and dental implants, because the coating establishes strong interfacial bonds with titanium implants, attributed to chemical bonding between the coating and the titanium substrate [Khor K.A, Cheang P, Wang Y., Plasma Spraying of Combustion Flame Spheroidized Hydroxyapatite Powders, J. Therm. Spray Technol., June 1998, 254-260]. Hydroxyapatite coatings have been applied by the plasma spray process, vapour deposition processes, ion-beam-assisted deposition (IBAD), bond coating process etc. [Smith T, The Effect of Plasma-Sprayed Coatings on the Fatigue of Titanium Alloy Implants, J. Mat., (1994,Feb), 54-56] Functionally graded coatings (FGMs) based on calcium phosphate materials have a gradient compositional change from the surface to the interior of the material. With the unique microstructure of FGMs, materials for specific function and performance requirements can be designed [Wang Y, Khor K.A, and Cheang P, Thermal Spraying of Functionally Graded Calcium Phosphate Coatings for Biomedical Implants, J. Therm. Spray Technol., March 1998, 50-57]. Calcium phosphates have different phases. Hydroxyapatite, one of its phases, has excellent chemical bonding ability with natural bone. Tricalcium phosphates (TCP), are biosorbable and dissolve gradually in body fluid, with a new bone eventually replacing it. Of the two types of TCP, a and p, the solubility of a -TCP is higher than that of p -TCP [Wang Y, Khor K.A, and Cheang P, Thermal Spraying of Functionally Graded Calcium Phosphate Coatings for Biomedical Implants, J. Therm. Spray Technol., March 1998, 50-57]. From among the extensive work reported on different methods of coating, plasma-sprayed coatings seem to provide a faster adaptation of the bone to the implant and an appreciable improvement of the interfacial strength at the early stages. However, there is still some lack of information about the long-term efficiency of the plasma-sprayed coatings. Usually, the plasma-sprayed coatings consist of a mixture of amorphous and crystalline phases. The fast dissolution of the amorphous phase and some of the crystalline products like tricalcium phosphate degrade the stability of the coating. Further heat treatment to improve the crystallinity often results in cracking and loss of adhesion. Finally, plasma spray is a "line of sight" technique, which is not entirely suitable for coating implants that have complex shapes [Smith T, The Effect of Plasma-Sprayed Coatings on the Fatigue of Titanium Alloy Implants, J. Mat., (1994,Feb), 54-56]. Some of the methods other than plasma coating technique, which could give better performance (for example, ion beam impingement), are very costly. Powder metallurgical processing offers excellent flexibility to obtain interconnected porous network in a complex shaped components with unique control over pore size and shape. In order to allow tissue growth into such porous network, it is necessary to render the internal surface of the porous network bioactive. Numerous patents published in the area cover solely surface coatings on bulk implants. A few of such patents representing coating on titanium implants are discussed below in brief: US patent no 005730598 describes a process for obtaining an implant having a highly pure crystalline coating of Hydroxyapatite (HA) on Ti substrate. The HA is coated using plasma spraying technique and then subjected to a 2 stage process, including a hydrothermal treatment and leaching stage which results in osseointegration. During plasma spray process, a stream of mixed gases passes through a high temperature electric arc that ionizes the gases into a plasma flame. Thereafter, crystalline HA feedstock powder is fed into the stream and then impinged in a molten state onto the outer surface of the implant. The spray adheres to the surface and forms a relatively thin coating on the surface of the Ti substrate. Though plasma coating is widely used, one of its primary limitations is that plasma-sprayed coatings usually consist of a mixture of amorphous and crystalline phases. The fast dissolution of the amorphous phase and some of the crystalline products like tricalcium phosphate, degrade the stability of the coating and any further heat treatment to improve the crystallinity often results in cracking and loss of adhesion. To overcome these limitations, in this US patent, the coating is further subjected to additional processing steps, including a hydrothermal treatment and leaching stage to remove amorphous HA phase as well as other calcium phosphatic phases which readily dissolve in body fluids. Such a process results in the said highly pure bioactive crystalline HA which is stable to allow bone tissues to grow into it so that the implant gets integrated with the healthy bone (osseointegration). However such integration is limited to the surface of the Ti substrate and not throughout the substrate. The consequences of such surface integration is that, due to unequal stress distribution, delamination of the coated HA surface on the Ti substrate occurs resulting in loosening of the implant. The implant obtained by this process is also not porous as the Ti substrate used has no porosity and Ti is bio inert by nature. Russian patent No. 2146535C1 describes a process wherein the Ti matrix is sprayed with multilayers of HA by plasma spraying process. The layers have varying composition. The innermost layer (immediately surrounding the Ti matrix has minimum amount - almost 0% of HA. The percentage of HA increases gradually in the coated layers away from the Ti matrix at the center reaching 100% HA at the outer most layer of the implant where the implant is in intimate contact with the body fluids The implant obtained by this process, though has better osseointegration, lacks in mechanical strength due the higher content of HA There is also a mismatch due to the thermal expansion coefficient of HA and Ti. In addition the process is also complicated The porosity of the implant obtained is limited to the coated HA portion and body tissue cannot grow into the Ti substrate as TI is bio inert and is not porous. Japanese patent No. 04221553A2 relates to a method of increasing the bond strength between Ti matrix and HA coating to overcome another important limitation of conventional plasma coating where-in, after prolonged exposure to body fluids in vivo, the plasma sprayed HA layer on Ti can peel off, drastically reducing the bioactivity of the implant, at the same time, exposing Ti matrix to body fluids leading to accelerated corrosion of Ti with prolonged exposure. The Japanese patent cited overcomes this limitation by providing a thin titanium dioxide layer between the Ti matrix and HA coating by high vacuum plasma coating process. This # prevents the possibility of peel off of HA layer even after prolonged exposure to body fluids because the bond between titanium dioxide and HA is ceramic-ceramic bond (against metallic-ceramic bond in case of direct HA coating on Ti) which is stronger and more stable under adverse ambient conditions. Here also the porosity of the implant obtained is limited to the coated HA portion and cannot grow into the Ti substrate as Ti is bio inert and is not porous even though the longevity of the implant is increased US patent No. 5872159 describes a method for preparing bone implants where-in a calcium phosphatic material, namely, tricalcium phosphate (TCP) and titanium dioxide in powder form are mixed uniformly with a suitable thermoplastic polymer (as binder) so that the mix can be subjected to plastic injection moulding or extrusion to obtain required bone shaped product. The product is further subjected to special thermal cycling procedure such that TCP gets converted to the more stable HA, which can be then implanted in the body The main advantage of this process is that it is not a line-of-sight process like plasma coating process, another limitation of the process which makes plasma coating on complex shapes almost impossible. The process described in the cited patent allows direct manufacture of complex shapes. Though the implant obtained is porous but due to the employment of the plastic injection moulding or extrusion process, the use of binder results in large volume of pores which cannot be used for load bearing applications. US patent no 5242706 relates to an invention wherein a biocompatible material is deposited onto a substrate by pulsed laser beam deposition or ion assisted pulsed laser beam deposition. Pulsed laser ablation and deposition is probably the simplest among all thin film growth and deposition techniques. It consists of a target holder and a substrate holder housed in a vacuum chamber. A high-power laser is used as an external energy source to vaporize materials and to deposit thin films. A set of optical components is used to focus and raster the laser beam over the target surface. The process creates an ejected plume of material from any target (for example crystalline HA). The vapor (plume) is collected on a substrate (for example Ti) placed a short distance from the target. Though the actual physical processes of material removal are quite complex, one can consider the ejection of material to occur due to rapid explosion of the target surface due to superheating. This process provides better bond strength between Ti and HA layer (metal-ceramic bond) and longer life in vivo than plasma coating process. However, the implant is not porous. Japanese patent no 04334318A2 discusses a process where-in a bioactive Ti based implant can be made by coating on Ti an organic acid like citric acid and malic acid, phosphoric acid and a bivalent ion chelating agent. These coated implants can be directly implanted in the body as substitute for damaged bone. After implantation, the bivalent ion chelating agent, in conjunction with phosphoric acid, precipitates HA from the body fluids while citric acid stabilizes the precipitated HA. Malic acid's "free alcoholic functions" allow biological molecules to bond to Ti substrate. The implant obtained is also not porous. From among the extensive work reported on different methods of coating, plasma-sprayed coatings seem to provide a faster adaptation of the bone to the implant and an appreciable improvement of the interfacial strength at the early stages. However there are certain disadvantages inherent in the plasma spray coating process. • Plasma-sprayed coatings usually consist of a mixture of amorphous and crystalline phases. The fast dissolution in the body fluids of the amorphous phase as well as some of the crystalline products like tricalcium phosphate degrade the stability of the coating. • Any further heat treatment to improve the crystallinity often results in cracking and loss of adhesion. • After prolonged exposure to body fluids in vivo, the plasma sprayed HA layer can peel off drastically reducing the bioactivity of the implant while exposing Ti matrix to body fluids leading to accelerated corrosion of Ti with prolonged exposure. • Plasma spray is a "line of sight" technique, which is not entirely suitable for coating implants that have complex shapes. The important point to note is that in the above coating technologies (including plasma coating technology) the bone tissue growth is limited to the surface of the implant (into the bioactive HA/CaP surface coated layer). An important limitation of this approach is the integrity of the surface coated bioactive layer over prolonged exposure to body fluids in-vivo. The layer can crack or peel off due to fatigue and stress corrosion. Such an eventuality would mean loosening of the implant and all the attendant complications. It would be observed from the prior art discussed above, that the implants obtained by the various processes are not porous and / or only partly porous which make them unsuitable for their use as good implants. Therefore there is a need for the development of a porous implant having bioactive phases. No tissue growth occurs into uncoated wrought titanium implants because of complete absence of interconnected porosity in the implant. Even if interconnected porosity is provided, tissue cannot grow into titanium because it is bioinert. In addition there is a general reluctance to make porous titanium implants because they exhibit poor fatigue strength. There have been no studies reported on the effect of bone tissue growth into a porous titanium implant. It is expected that fatigue strength will improve with bone tissue growth into the interconnected pores. Further, by allowing tissue growth into the implant, the whole implant becomes an integral part of the bone under repair, whereas a mere bioactive surface layer on the implant can at best provide integration up to the thickness of the layer. On this basis, a porous titanium implant material has been developed wherein the surfaces of the pore channels are rendered bioactive to allow tissue growth into the implant leading to the present invention claimed. OBJECTIVES OF THE PRESENT INVENTION: Therefore, the main objective of the present invention is to provide novel titanium based composite bioactive material useful as prosthetic implant as against conventional processes where-in the bioactive phases, usually calcium phosphatic chemicals, are present on the surface of the bioinert Ti. Another objective of the present invention is to provide novel titanium based bioactive composite, which is biocompatible in nature and useful as prosthetic implant Yet another objective of the present invention is to provide novel titanium based bioactive composite which can enable through and through integration with the healthy bone tissue (when it replaces damaged bone) by allowing tissue growth deep into the composite as against the conventional Ti based surface-coated implants which enable only surface integration because of the presence of bioactive phase only on the surface allowing tissue growth only at the surface of the implant, limited to the thickness of the bioactive coated phase. A further objective of the present invention is to provide novel titanium based bioactive composite, which when implanted in place of a damaged bone, can locate itself securely at the implantation site by virtue of the fact that it enables through and through integration with the healthy bone, thus completely avoiding any possibility of the implant getting loosened. Such loosening of the implant is possible with conventional Ti based surface-coated implants where-in the surface coated layer can peel off after prolonged exposure to body fluids. Still another objective of the present invention is to provide novel titanium based composite which can be processed starting from powders such that powder metallurgy (PM) processing is possible which enables production of complex shapes (human bones have varieties of complex shapes). A further objective of the present invention is to provide novel titanium based composite is to obtain, within the Ti matrix, interconnected porous network which is 'bioactive. Still another objective of the present invention is to provide a process for the preparation of novel titanium based composite material useful as prosthetic implant as against conventional processes where-in the bioactive phases, usually calcium phosphatic chemicals, are coated only on the surface of the bioinert Ti. Another objective of the present invention is to make the Ti based biocompatible material capable of extracting out biological HA from the body fluids when the material is implanted as a substitute for a damaged bone. Despite its excellent biocompatibility and bioactivity, synthetic HA prepared from chemicals cannot be considered to be 100% similar to biological HA. In addition to microstructural differences between the two, in biological HA the sizes of individual particles are more uniform. In the context of longevity of the implant, it is better to have more amount of biological HA in the implant and reduce the amount of synthetic HA. Titanium oxide and certain calcium phosphatic and chemicals, which get formed in the present invention, have the potential to precipitate out biological HA from body fluids. This fact is proved by immersing the implant in SBH. The above objectives of the present invention have been achieved by choosing, titanium (Ti) as the main matrix material because it has been long established that Ti is not rejected by human body (biocompatible). However Ti, by itself does not allow body tissue growth into itself; it is bioinert, not bioactive. By virtue of this bioinert nature, Ti, when directly implanted in the body (for example, as a substitute for a damaged part of a bone), gets surrounded by a flexible fibrous tissue within which the Ti implant is loosely located, unanchored. This could lead to micro-movements of the implant leading to dangerous consequences (like leading to further fracture of the same bone). In order to get Ti implant properly anchored, the implant should be made amenable to allow body tissues (bone tissues in case of bone implant) to grow into it. This can be done by modifications in the Ti implant through the presence of other materials, which allow tissue growth into them (bioactive materials). For example, calcium phosphatic materials like hydroxyapatite (HA), allow bone tissue growth. Thus, when such materials are added to Ti, the result is a bioactive biocomposite. In the present invention, such materials, which bring about the said modifications are not added directly (for example hydroxyapatite (HA) is not added directly) but, are added in the form of chemicals (precursor chemicals), which, during processing get converted into the required bioactive materials (phases) similar to HA. The precursor chemicals as well as the matrix material Ti, are taken in the form of powders, providing the advantage of mixing the powders in required proportions, pressing the mixed powders in a die under pressure into required shapes and thermally treating the pressed compacts to increase their strength, i.e, following powder metallurgy (PM) processing. During PM processing, particularly during thermal treatment, the precursor chemicals get converted into bioactive phases within the Ti matrix (in-situ) and get distributed uniformly throughout the volume of the said matrix. In addition, the biocomposite having the in-situ formed bioactive phases, when implanted in the body, has the inherent capacity to precipitate further bioactive phases (calcium phosphatic chemicals) from the body fluids circulating around the implant. This is proved in vitro by preparing simulated body fluid (SBF) having chemical composition similar to that of body fluids and immersing the said biocomposite in it; further precipitation of calcium phosphate phases from SBF occurs and the precipitates get bonded to the surface of the biocomposite. Further, the different phases formed during the thermo-chemical processing, according to the present invention, impart additional superior strength, superior corrosion resistance and improved wear resistance properties as well as enable faster precipitation of bioactive and bioresorbable phases from body fluids, Further, the processing conditions employed in the process of the present invention are such that the titanium based bioactive materials have remnant porosity to facilitate tissue growth into the implant. This permits better anchorage to host tissues. When any component is PM processed, by virtue of the fact that the starting materials are in powder form, which are compacted and thermally treated to be made into components, it is possible to control the processing parameters such that the component can have closely controlled interconnected porosity. The surface interconnected porosity can be bioactive because the chemicals that are added to produce the bioactive phases during processing are intimately mixed with Ti powder. So, the presence of bioactive phases on the internal surface of the interconnected porous network is highly probable. This helps in allowing the tissue growth into the volume of the implant. DESCRIPTION OF INVENTION: Accordingly, the present invention provides a novel titanium based composite bioactive interconnected porous material useful as prosthetic implant comprising - . ' ' " ' bioactive phases of calcium hydroxyapatite, octacalcium phosphate, tricalcium phosphate, calcium hydrogen phosphate and calcium titanate, together with bioinert phases based on titanium or its compounds or its alloys , the bioactive phases distributed uniformly throughout the bio inert phases. In a preferred embodiment of the invention the source of Ti used is selected from its compound Ti hydride, elemental Ti or its alloys. The alloys which can be used are selected from high-strength alloys of titanium like Ti-6AI-4V, Ti-6AI-7Nb, Ti-5AI-2.5Fe, Ti-5Sn-4Nb-2Ta-0.2Pd or Ti-15Zr-4Nb-4Ta-0.2Pd According to another embodiment of the present invention there is provided a process of making a novel titanium based composite bioactive interconnected porous material, useful as prosthetic implant which comprises (i) Mixing Ti or its compounds or its alloys in powder form (bio inert phase) and calcium and phosphorous salts in high energy mill to get an uniform and intimate blend (ii) Compacting the blend into any desired shape at a pressure in the range of 100 to 250 MPa (iii) Calcining the compacts obtained in an atmosphere which will facilitate in situ formation of the bioactive phases between calcium and phosphorous salts present in the compact at a temperature in the range of 600 to 1000°C for a period in the range of 2 to 6 hrs (iv) Crushing the calcined compacts by known methods to get powder (v) Further compacting the powder at a pressure in the range of 300 to 600 MPa and (vi) Sintering the compacts in vacuum at a temperature in the range of 1000 to 1250°C for a period in the range of 1 to 2 hrs Following the above steps results in titanium based composite bioactive interconnected porous material having bioactive phases of different forms of calcium hydroxyapatite, octa-calcium phosphate phases, calcium hydrogen phosphate, tricalcium phosphate, and calcium titanate along with bioinert phases of titanium and titanium compound phases like titanium hydride, titanium oxide, titanium nitride and titanium phosphide The following factors of the process of the present invention are unique as compared to the prior art which impart novelty to the invention 1. The bioactive phases are not directly added to Ti, but added in the form of salts of calcium and phosphorus which during processing, convert into different bioactive phases within the bio inert Ti in situ - thereby ensuring proximity of the bioactive phases thus formed with the Ti phase. 2. An additional advantage of forming the bioactive phases in situ is that it obviates the problem of procurement of biological grade bioactive materials like HA from the market. The high cost is due to the complex packing and transporting system, which is mandatory to prevent dangers to the living body due to contamination. 3. All the ingredients used in the present invention, taken in powder form, undergo ball milling as well as high-energy milling. Both these processes, particularly high-energy milling process, ensure intimate contact between the ingredients being mixed. 4. One of the prerequisites of uniform distribution of a set of ingredients in the composite is density parity between the ingredients and the matrix material. The said parity does not exist between Ti metal powders and the precursor chemical powders. To establish the required parity, Ti is added preferably in the form of titanium hydride. 5. Production of Ti hydride is a well-established process in which Ti sponge is made to react with hydrogen to obtain hydride in a particular set of temperature and pressure conditions, under which any impurities present in Ti sponge do not react with hydrogen. Under different set of temperature and pressure conditions, Ti hydride dissociates into pure Ti and hydrogen. The process is called hydride-dehydride process. 6. In addition to establishing density parity, the hydride-dehydride process ensures availability of highly pure and cheap Ti powder. During actual processing, the titanium based material used can be selected from pure titanium, titanium hydride, titanium based alloy such Ti-6AI-4V or Ti-6AI-7Nb, Ti-5AI-2.5Fe, Ti-15Sn-4Nb-2Ta-0.2Pd and Ti-15Zr-4Nb-4Ta—0.2Pd in powder form having size less than 250>m; The percentage of titanium based material in the composite can be varied from 60 to 95 weight %. The calcium containing precursors can be selected from among calcium chloride, calcium carbonate, calcium nitrate and their combinations while the phosphorus containing precursors, from among di-ammonium hydrogen orthophosphate, sodium hydrogen orthophosphate, phosphoric acid and their combinations. The quantities of calcium and phosphorus containing precursors in titanium matrix are varied from 5 to 40 wt%. The calcium and phosphorus containing precursors are taken such that the calcium and phosphorus content in the precursors are varied in the ratio of 1.3:1 to 2.1:1 The composite having different weight percentages of titanium or titanium compounds or titanium alloys and precursor contents of calcium and phosphorus, the ratio of calcium and phosphorus being further varied in different ratios, the resulting bio composite having the required nucleating points for further nucleation and precipitation of natural hydroxyapatite when immersed in the body fluids. The material has transverse rupture strength value in the range 30 MPa to 80 MPa. The biocomposite is active in nature when exposed to body fluids The biocomposite has the requisite interconnected porosity in the range of 4-15% and the required pore size 3 - 17^m. The biocomposite has superior corrosion resistance of corrosion rate of 0.175775 - 4.7 mills per year(MPY). The biocomposite is non toxic in nature when subjected to in vitro cytotoxicity tissue culture tests ie the biocomposite allows the growth of bone substitute material from the body fluids Titanium oxides are also formed during processing as per the present invention which provide better bonding with calcium phosphatic chemicals than pure titanium. Further, titanium nitride is also formed during processing providing good corrosion and wear resistance to the implant. Calcium titanate is also formed during processing which imparts hardness to the implant in addition to playing an important role in precipitating calcium phosphatic phases from body fluids. In a preferred embodiment of the present invention, titanium is preferably used as titanium hydride for subsequent conversion into titanium powder during processing and the said hydride powder was produced from high purity titanium sponge powder through thermal treatment in hydrogen atmosphere and characterized for phase analysis, particle size and chemical analysis. The chemical assay of the powder is shown in table - 1 Table 1: Properties of Ti-Hydride (Table Removed) The mean particle size of the titanium hydride powder used was chosen to be between 50 to 250 µm, more preferably between 150 to 250 µm. In another embodiment of the present invention the size of the hydride powder was finalized at -250 µm. To make the Ti based biocompatible material capable of extracting out biological HA from the body fluids when the material is implanted as a substitute for damaged bone. Despite its excellent biocompatibility and bioactivity, synthetic HA prepared from chemicals cannot be considered to be 100% similar to biological HA. In addition to microstructural differences between the two, in biological HA the sizes of individual particles are more uniform. In the context of longevity of the implant, it is better to have more amount of biological HA in the implant and reduce the amount of synthetic HA. Titanium oxide and certain calcium phosphatic and chemicals, which get formed in the present invention, have the potential to precipitate out biological HA from body fluids. This fact is proved by immersing the implant in SBH. All the ingredients used in the present invention, taken in powder form, undergo ball milling as well as high-energy milling. Both these processes, particularly high-energy milling process, ensure intimate contact between the ingredients being mixed. In another embodiment of the present invention, the ratio of calcium-phosphatic precursor to titanium based matrix was varied at 5,10, 15, 20, 25 and 30 wt% salt. The said calcium and phosphorus containing chemicals were added in the proportion Ca:P::1.3-2.1:1, appropriate ratios for formation of hydroxyapatite (HA). The mixing was undertaken in a ball mill or pot mill with a ball to charge ratio of 2:1 for 10-40 minutes using stainless steel balls of 10-30mm diameter. The charge thus obtained after the said addition of precursor chemicals in the said proportions of titanium hydride powder, mixing was undertaken in a ball mill or pot mill with a ball to charge ratio of 2:1 for 10-40 minutes, where in the said balls are using stainless steel balls of 10-30mm diameter which help thorough mixing of ingredients in the charge. The uniformly ball milled charge is further subjected to high energy milling using stainless steel balls to bring about intimate contact and bonding between the different ingredients in the charge, the said high energy milling being undertaken in a planetary mill under argon atmosphere to prevent oxidation, if any, of any of the ingredients, while maintaining a ball to charge ratio in the range 5 -15 : 1, 10 -15 : 1 being the preferred ratio. The high-energy milled powder is then compacted in an appropriate die in a press at 200 -300 MPa so as to obtain compacts of 10 mm in diameter and 6 mm in length. The pressed compacts are further calcined at 400 to 1000°C, the preferred temperature being 750 to 1000°C, such that titanium hydride gets converted to pure titanium and also to facilitate the precursor chemicals to react with Ti as well amongst themselves to form different bioactive phases in-situ. The said calcination is done in hydrogen, argon and vacuum atmospheres. Having obtained the requisite bioactive phases during the said calcination step, the phases have to be stabilized, the HA formed has to be converted into pure crystalline state and on the whole the strength of the compact has to be increased. To fulfill the above three requirements, the calcined compacts are again crushed into powder and then pressed at 600- 800 MPa to compacts of size of 31.5mm x 12.75mm x 6mm and subsequently sintered at 800 to 1250°C under a vacuum of 5x10-4 torr. In another preferred embodiment of the present invention, for bioactivity studies, the biocomposites were immersed in simulated body fluid (SBF) and change in concentration of elements like Ca, P, Mg, Na and P in SBF were measured using inductively coupled plasma atomic energy spectroscopy (ICP-AES) after immersion periods of 7, 14, 21 and 28 days. Characterization of the sintered compacts 1. Bioactivity The primary objective of the present invention being production of Titanium based bioactive materials, which can be used as orthopaedic implants, characterizing the bioactivity is important and it is done in vitro using simulated body fluid (SBF) prepared using chemicals such that the chemistry of SBF matches that of biological body fluids. Sintered samples are immersed in SBF for different periods, i.e, 7, 14, 21 and 28 days and the movement of ionic species of calcium, phosphorous, magnesium, and sodium and potassium between the sample and SBF is monitored by subjecting the SBF (after a specific period of immersion is accomplished) to analysis for measuring the quantities of the said elements in it. The analysis is done using inductively coupled plasma atomic energy spectroscopy (ICP-AES). If depletion of the said elements of calcium and phosphorus in SBF is observed, it can only mean that the said elements have been precipitated out of the SBF by the bioactivity of the sample. Such depletion was in fact observed and, in addition, the samples were found with freshly deposited materials validating the fact that the process followed indeed provides bioactivity. To further confirm the bioactivity of the sintered samples, the freshly deposited materials on the samples after immersion in SBF, were scrapped off and the scrapped materials were subjected to Fourier transform infrared spectroscopy (FTI-R), X-ray diffraction (XRD), Scanning Electron Microscopy (SEM) and EDS, to ascertain their exact nature. Carbonate (CO32), phosphatic (PO43) and hydroxyl (OH) species were observed in the deposits, further confirming the bioactivity of the sintered samples. 2. Cytotoxicity An important requirement of any material that is to be implanted in human body is that the implant should not be toxic to different types of cells (should not be cytotoxic) in the body. To ascertain whether the sintered biocomposite exhibits cytotoxicity or not, standard in vitro-cytotoxicity tests were performed and it was confirmed that the biocomposite produced by the process of this invention is non- cytotoxic. 3. Mechanical strength Since the biocomposite produced by the process of the present invention is intended as a bone implant, its mechanical strength is of prime importance. Transverse rupture strength (TRS) measured by 3-point bend test is a good measure of the mechanical strength. Such test was performed and the adequate strength was obtained. The details of the invention are given in the Examples which are provided to illustrate the invention and therefore should not be construed to limit the scope of the invention. EXAMPLE 1 52.08 g of Ti hydride powder (-250nm) and 61.69 g of calcium chloride and 45.93 g of diammonium hydrogen orthophosphate were ball milled for 30 minutes with ball to powder ratio of 2:1, milled in a Fritsch planetary mill for 30 min with ball to powder ratio of 15:1, compacted at 250 MPa to specimens of size 9mm diameter and 15mm height. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa. The compacts were sintered at 1000°C in a vacuum of 10"5 torr for 1h. The bioinert phases obtained in the composite as analysed by x-ray diffraction (XRD) were found to be titanium, titanium hydride and the bioactive phases were as analysed by XRD calcium hydroxyapatite, tricalcium phosphate and calcium titanate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture(MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 2(a and b). Table 2(a) (Table Removed) Table 2(b) (Table Removed) EXAMPLE 2 50 g of Ti powder (-250nm) and 61.69 g of calcium chloride and 45.93 g of diammonium hydrogen orthophosphate were ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9mm dia and 15mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for1h, crushed and compacted at 600Mpa to the same specimen size as said above. The compacts were sintered at 1000°C in a vacuum of 10'5 torr for 1h. The bioinert phases obtained in the composite were found to be titanium, titanium hydride with bioactive phases such as calcium hydroxyapatite, tricalcium phosphate and calcium titanate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture(MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 3(a and b). Table 3(a) (Table Removed) Table 3(b) (Table Removed) EXAMPLE 3 90 g of Ti powder (-250 µm) and 4.3 g of calcium carbonate and 5.7 g of di ammonium hydrogen orthophosphate were mixed with Ca:P ratio of 1.32 and ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9mm dia and 15mm height at 250 MPa. The compacts were calcined in hydrogen at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were sintered at 1150°C in a vacuum of 10~5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture(MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 4(a and b). Table 4(a) (Table Removed) Table 4(b) (Table Removed) EXAMPLE 4 70 g of Ti powder (-250nm) and 12.9 g of calcium carbonate and 17.1 g of di ammonium hydrogen orthophosphate were mixed with Ca:P ratio of 1.32:1 and ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 200 MPa. The compacts were calcined in argon at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The various phases obtained as studied by XRD are bioinert phases of titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive phases of calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The compacts were sintered at 1150°C in a vacuum of 10-5 torr for 1h. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 5(a and b). Table 5(a) (Table Removed) Table 5(b) (Table Removed) EXAMPLE 5 An experiment with 80 wt% titanium hydride 20 wt % of calcium carbonate and di ammonium hydrogen orthophosphate with Ca:P ratio of 1.32:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10"5 torr for 1h to evaluate the interconnected porosity of the sintered composites. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 6(a and b). Table 6(a) (Table Removed) Table 6(b) (Table Removed) EXAMPLE 6 An experiment with 90% titanium hydride and 10% of calcium carbonate and di ammonium hydrogen orthophosphate with Ca:P ratio of 2:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10-5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 7(a and b). Table 7(a) (Table Removed) Table 7(b) (Table Removed) EXAMPLE 7 An experiment with 90g of titanium hydride with 4.3g of calcium carbonate and 5.7 g of di ammonium hydrogen orthophosphate varying from 10 to 30% with Ca:P ratio of 1.32:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 200 MPa. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10-5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 8(a and b). Table 8(a) (Table Removed) The above composite was weighed to find the change in weight upon immersing in SBF for different time periods. Table 9 shows the change in weight of the composite indicative of the fact that the composite is bioactive in nature as dissolution of ions takes place when the composite and the SBF are in continuous interaction. Table 9: Weight change of composite as detailed in EXAMPLE 7 upon immersion in SBF (Table Removed) All the functional groups characteristic of hydroxyapatite are present namely OH", C032", P043". This confirms that the deposits on the surface of the composite are calcium hydroxyapatite which is further confirmed by XRD spectrum. EXAMPLE 8 In this experiment, 80g of of titanium hydride with 8.6g of calcium carbonate and 11.4g of di ammonium hydrogen orthophosphate with Ca:P ratio of 1.32:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 200 MPa. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10~5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 10(a and b). Table 10(a) (Table Removed) Table 10(b) (Table Removed) The above composites were weighed to find the weight change of composites upon immersing in SBF for different time periods. Table 11 shows the change in weight of the composites indicative of the fact that the composites are bioactive in nature as dissolution of ions takes place when the composite and the SBF are in continuous interaction. Table 11: Weight changes of composites as detailed in EXAMPLE 9 upon immersion in SBF (Table Removed) The growth of deposits on the composite surface was studied using XRD and FTIR for examining the phases and the nature of the functional groups characteristic of HA. The bioactive phases are analysed as different forms of calcium hydroxyapatite and other phases like calcium carbonate, sodium calcium phosphate, sodium calcium carbonate and calcium hydrogen phosphate which are intermediate stages of formation of calcium hydroxyapatite. EXAMPLE 9 An experiment with 70g of titanium hydride with 12.9g of calcium carbonate and 17.1g ammonium hydrogen orthophosphate with Ca:P ratio of 1.32:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 250 MPa. The compacts were calcined in hydrogen at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10-5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioantive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 12(a and b). Table 12(a) (Table Removed) Table 12(b) (Table Removed) Also bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find change in chemical composition on surface of the composite by EDAX. A typical EDAX analysis of composite made of 70% titanium hydride with 30% Ca-P precursor is given in table 13 showing that the content of Ca, P and O is increasing on the surface while concentration of titanium decreases. The increase of Ca, P and O on the composite surface indicates that the precipitation of Ca-P deposits are taking place from the SBF. Table 13: EDAX multipoint analysis of the surface of composite containing 70% titanium hydride with 30% chemicals consisting of calcium carbonate and di-ammonium hydrogen orthcohosphate calcined in hydrogen and sintered in vacuum before and after immersion in SBF for 7 days. (Table Removed) EXAMPLE 10 70 g of Ti powder (-250jxm) and 12.9 g of calcium carbonate and 17.1 g of di ammonium hydrogen orthophosphate were mixed with Ca:P ratio of 1.32:1 and ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 250 MPa. The compacts were calcined in hydrogen at 1000°C for 1h, crushed and compacted at 600 Mpa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10~5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 14(a and b). Table 14(a) (Table Removed) Table 14(b) (Table Removed) EXAMPLE 11 90g of Ti powder (-250fam) and 4.3 g of calcium carbonate and 5.62 g of di-ammonium hydrogen orthophosphate were mixed with Ca:P ratio of 1.3:1 and ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15 mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for 2h, crushed and recompacted at 600 MPa to the same specimen size as said above. The compacts were sintered at 1150°C in a vacuum of 10'5 torr for 1h. The phases obtained in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 15(a and b). Table 15(a) (Table Removed) Table 15(b) (Table Removed) In-vitro cytotoxicity tests were done for establishing biocompatibility and the results were positive which proved that the composite was non-toxic in nature. Table 16 shows the in vitro cytotoxicity of 90% titanium hydride with 10% chemicals consisting of calcium and phosphorus with Ca:P as 1.3:1, calcined and sintered in vacuum. Table 16: Qualitative evaluation of in vitro cytotoxicity tests (Table Removed) EXAMPLE 12 90 g of Ti powder (-250\|am) and 5.05 g of calcium carbonate and 4.95 g of di-ammonium hydrogen orthophospliate were mixed with Ca:P ratio of 1.7:1 and ball milled for 30 minutes with ball to powder ratio of 2.1:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9mm dia and 15mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for 2h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were sintered at 1150°C for 1 h in a vacuum of 10"5 torr. The phases obtained in the composite were found to be bioinert phases of titanium, titanium oxides, titanium hydride, calcium titanate, titanium nitride, titanium phosphides and bioactive calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 17(a and b). Table 17(a) (Table Removed) Table 17(b) (Table Removed) The in vitro cyto toxicity tests were done for establishing biocompatibility and the results were positive which proved that is the composite was non-toxic in nature. Table 18 shows the invitro cytotoxicity of 90% titanium hydride with 10% chemicals consisting of calcium and phosphorus with Ca:P as 1.7 :1 calcined and sintered in vacuum. Table 18: Qualitative evaluation of in vitro cytotoxicity tests (Table Removed) EXAMPLE 13 An experiment with 90% titanium hydride with 10% chemical content (calcium carbonate and di ammonium hydrogen orthophosphate), wherein the ratio of Ca:P was 2.1:1, was ball milled for 30 minutes with ball to powder ratio of 2.1:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9mm dia and 15mm height at 300 MPa. The compacts were calcined in vacuum at 1000°C for 2h, crushed and compacted at 550 MPa to the same specimen size as said above. The compacts were sintered at 1150°C for 1h in a vacuum of 10-5 torr. The phases obtained in the composite were found to be bioinert phases of titanium, titanium oxides, titanium hydride, calcium titanate, titanium nitride, titanium phosphides and bioactive calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 19(a and b). Table 19(a) (Table Removed) Advantages of the process: 1. Starting materials are inexpensive and easily available. 2. Inherent advantage of getting any complicated shape and size by PM processing 3. No delamination of the ceramic and metal interface in the composite 4. Uniform and higher strength throughout the composite 5. The pore size can be controlled because of the PM processing to values suitable for facilitating natural tissue growth. 6. In-situ formed seeds of calcium hydroxyapatite and the bioactive phases results in faster nucleation and growth of natural hydroxyapatite from the body environment. 7. Minimises the requirement of synthetic hydroxyapatite. 8. More corrosion resistant because of the presence of the titanium nitride phase formed in situ. We claim, 1. A novel titanium based bioactive interconnected porous composite material for use as prosthetic implant comprising of bioactive phases consisting of calcium and phosphorous salts in the range varied from 5 to 40 weight % and is selected from calcium hydroxyapatite, octacalcium phosphate, tricalcium phosphate, calcium hydrogen phosphate and calcium titanate, together, and bio tolerant or bioinert phases consisting of titanium or its compounds or its alloys and the percentage of Ti based material in the composite is varied from 60 to 95 weight%., and the said bioactive phases distributed uniformly throughout the bio inert phases 2. A process for the preparation of Novel titanium based bioactive interconnected porous material composite for use as prosthetic implant as claimed in claim 1 which comprises (i) Mixing Ti or its salts or its alloys in powder form (bio inert phase) and calcium and phosphorous salts in high energy mill to get an uniform and intimate blend (ii) Compacting the blend into any desired shape at a pressure in the range of 100 to 250 MPa (iii) Calcining the compacts obtained in an atmosphere to facilitate in situ formation of the bioactive phases between calcium and phosphorous salts present in the compact at a temperature in the range of 600 to 1000°C for a period in the range of 2 to 6 hrs (iv) Crushing the calcined compacts by known methods to get powder (v) Further compacting the powder at a pressure in the range of 300 to 600 MPa and (vi) Sintering the compacts in vacuum at a temperature in the range of 1000 to 1250°C for a period in the range of 1 to 2 hrs 3 A process as claimed in claim 2 wherein the salt of Ti used is Ti-hydride. 4. A process as claimed in claims 2 & 3 wherein the calcined compact is crushed to powder and compacted to a shape in a die using mechanical or hydraulic press, or in a mould using cold isostatic press at a pressure of 100-600 MPa and is subjected to vacuum sintering at 1000-1250°C, resulting in a titanium based biocomposite having bioactive phases of different forms of calcium hydroxyapatite, octa-calcium phosphate phases, calcium hydrogen phosphate, tricalcium phosphate, and calcium titanate along with titanium and titanium compound phases like titanium hydride, titanium oxide, titanium nitride and titanium phosphide 5. A process as claimed in claims 2 to 4 wherein the titanium based material is selected from pure titanium, titanium hydride, titanium based alloy such as Ti-6AI-4V or Ti-6AI-7Nb, Ti-5AI-2.5Fe, Ti-15Sn-4Nb-2Ta-0.2Pd and Ti-15Zr-4Nb-4Ta—0.2Pd in powder form having size less than 250µm. 6. A process as claimed in claims 2 to 5 wherein the salts of calcium is selected from among calcium chloride, calcium carbonate, calcium nitrate and their combinations while the phosphorus containing precursors, from among di-ammonium hydrogen orthophosphate, sodium hydrogen orthophosphate, phosphoric acid and their combinations. 7. A process as claimed in claim 2 to 6 wherein the salts of calcium and phosphorus are taken such that the calcium and phosphorus content in the composite are varied in the ratio of 1.3:1 to 2.1:1 8. A process as claimed in claims 2 to 7 wherein the composite material has transverse rupture strength value in the range 30 MPa to 95 MPa, the requisite interconnected porosity in the range of 10-35%, the required pore size 5 - 20µm and the superior corrosion resistance of corrosion rate in the range of 0.175775 - 4.7 mills per year(MPY). 9. A novel titanium based composite bioactive interconnected porous material and a process for the preparation of novel titanium based composite bioactive interconnected porous material as prosthetic implant substantially as herein described with reference to the Examples 11 to 12.

Full Text

FIELD OF INVENTION:
The present invention relates to novel titanium based biocomposite material useful for orthopaedic and other implants and a process for its preparation. More particularly, the present invention relates to novel titanium-based composite materials, which are bioactive and are useful as bio implants as bone substitutes.
The term bioactive means that the nature of composite material of the present invention is such that it is not rejected by human body (biocompatible) when it is implanted, for example, as a substitute for damaged bone1 (biocomposite) and, in addition actively interacts with the body environment.
More particularly, the present invention relates to novel titanium-based composite material which when implanted as a replacement for a damaged portion, for example damaged portion of a bone, integrates with the undamaged tissues of the bone actively (bioactive) such that it behaves as if it is a part of human body itself.
One of the primary applications of the composite material of the present invention is in orthopaedics, as substitute for damaged bones or damaged portions of bones.
Prior art
The use of prosthetic devices for treatment of bone injuries / illnesses is continuously expanding with an increasingly active and aging population. Titanium and the alloy Ti-6AI-4V are widely used as materials for orthopedic implants because of their superior mechanical properties and nontoxic behaviour [Benjamin, D., editor. Metals handbook, 9th ed., Vol. 3, Metals Park, Ohio: American Society for Metals, 1980, 372-406, Dobbs, H. S., Fracture of titanium orthopedic implants, J. Mater. Sci., 1982; 17: 2398-2340]. However, one of the main drawbacks of using metallic implants is that they are bio inert and become encapsulated by dense fibrous tissue inside the body. This impedes proper stress distribution at the 'implant-bone' interface, which can result in an interfacial failure and loosening of the implant with the

possible consequence of fracture in the adjacent bone [Hench, L. L, Bioceramics: from concept to clinic, J. Am. Ceram. Soc, 1991; 74 :1487-1510, Suchanek, W. et al., Processing and properties of hydroxyapatite-based biomaterials for use as hard tissue replacement implants, Mater. Res.,1998, 13; 94-117]. Thus the use of bone replacements for bone fractures, removal of bone, or the use of supports for weakened bone requires that the artificial bone replacement form a strong joint with natural bone to ensure the integrity of the structure. Secure tissue-prosthesis attachment is a necessary requirement for the successful performance of most surgical implants. Load-bearing orthopedic implants for bone and joint replacement are effective only if they can be firmly fixed with the host bone.
Until the 1970s, poly methyl methacrylate (PMMA) bone cement was the predominant means of fixing a joint-replacement implant to the skeletal system. This fixation is primarily mechanical. Cement penetrates into the bone and locks onto small surface irregularities on the implant. Shrinkage of the cement during curing also locks the cement onto the stem of the device. However, over time, the implant may become loose within the cement. This is particularly true for younger, more physically active patients. In some cases, this loosening may either cause pain or increased stress on the implant and subsequent implant failure. Both of these effects may necessitate re-operation [David J.R editor, Handbook of Materials for Medical Devices; Chapter 9, 2003, ASM International, Materials Park, Ohio, USA, 179 -194]. To overcome the above problem, alternative approaches for implant fixation to bone were investigated, which included the use of porous-coated implants made of metal, polymer (porous poly sulfone and polyethylene), or polymer-based composites (carbon-fiber- filled polytetra-fluoroethylene - PTFE). This has led to the introduction of porous coated joint replacement implants, principally porous metal-coated hip- and knee-joint implants. Porous metal-coated implants provide enhanced fixation through either cement interlocks with the porous structure or fixation via ingrowth of bone tissue. Studies have shown that the minimum pore size for load-bearing implants, such as artificial hips and porous coatings can be highly varied and require different technologies to obtain. For example, cobalt-chromium and titanium porous coatings can be produced from spherical metal powders, wires or fibers that are formed into porous pads

A major concern with the use of porous-coated implants in highly loaded applications is the effect of the porous surface layer on the mechanical properties of the implants, particularly on fatigue strength. Further, the complex high temperature metallurgical process used for bonding the coating to the implant can be challenging since strong bonds between the powder particles among themselves as well as between the coating and the implant are required without significantly degrading the strength and corrosion resistance of the component [Smith T, The Effect of Plasma-Sprayed Coatings on the Fatigue of Titanium Alloy Implants, J. Mat., (1994,Feb), 54-56]
Coating calcium hydroxyapatite (HA), Caio(P04)6(OH)2, as well as other calcium phosphatic (Ca-P) salts on a bioinert metallic implant surface is one method of obtaining a bioactive coating on implants[Khor K.A, Cheang P, Wang Y., Plasma Spraying of Combustion Flame Spheroidized Hydroxyapatite Powders, J. Therm. Spray Technol., June 1998, 254-260]. Some biological advantages of HA/CaP coatings are enhancement of bone formation, accelerated bonding between the implant surface and surrounding tissues, and the reduction of potentially harmful metallic ion release [Bernard F, Georges W, Rudi C, Titanium release from dental implants: an in vivo study on sheep, Materials Letters, 43 (2000,April), 159-165]. HA/CaP coated titanium has been used in many implants such as hip and dental implants, because the coating establishes strong interfacial bonds with titanium implants, attributed to chemical bonding between the coating and the titanium substrate [Khor K.A, Cheang P, Wang Y., Plasma Spraying of Combustion Flame Spheroidized Hydroxyapatite Powders, J. Therm. Spray Technol., June 1998, 254-260].
Hydroxyapatite coatings have been applied by the plasma spray process, vapour deposition processes, ion-beam-assisted deposition (IBAD), bond coating process etc. [Smith T, The Effect of Plasma-Sprayed Coatings on the Fatigue of Titanium Alloy Implants, J. Mat., (1994,Feb), 54-56] Functionally graded coatings (FGMs) based on calcium phosphate materials have a gradient compositional change from the surface to the interior of the material. With the unique microstructure of FGMs, materials for specific function and performance requirements can be designed [Wang Y, Khor K.A, and Cheang P, Thermal Spraying of Functionally Graded Calcium Phosphate Coatings for Biomedical Implants, J.

Therm. Spray Technol., March 1998, 50-57]. Calcium phosphates have different phases. Hydroxyapatite, one of its phases, has excellent chemical bonding ability with natural bone. Tricalcium phosphates (TCP), are biosorbable and dissolve gradually in body fluid, with a new bone eventually replacing it. Of the two types of TCP, a and p, the solubility of a -TCP is higher than that of p -TCP [Wang Y, Khor K.A, and Cheang P, Thermal Spraying of Functionally Graded Calcium Phosphate Coatings for Biomedical Implants, J. Therm. Spray Technol., March 1998, 50-57].
From among the extensive work reported on different methods of coating, plasma-sprayed coatings seem to provide a faster adaptation of the bone to the implant and an appreciable improvement of the interfacial strength at the early stages. However, there is still some lack of information about the long-term efficiency of the plasma-sprayed coatings. Usually, the plasma-sprayed coatings consist of a mixture of amorphous and crystalline phases. The fast dissolution of the amorphous phase and some of the crystalline products like tricalcium phosphate degrade the stability of the coating. Further heat treatment to improve the crystallinity often results in cracking and loss of adhesion. Finally, plasma spray is a "line of sight" technique, which is not entirely suitable for coating implants that have complex shapes [Smith T, The Effect of Plasma-Sprayed Coatings on the Fatigue of Titanium Alloy Implants, J. Mat., (1994,Feb), 54-56]. Some of the methods other than plasma coating technique, which could give better performance (for example, ion beam impingement), are very costly.
Powder metallurgical processing offers excellent flexibility to obtain interconnected porous network in a complex shaped components with unique control over pore size and shape. In order to allow tissue growth into such porous network, it is necessary to render the internal surface of the porous network bioactive.
Numerous patents published in the area cover solely surface coatings on bulk implants. A few of such patents representing coating on titanium implants are discussed below in brief: US patent no 005730598 describes a process for obtaining an implant having a highly pure crystalline coating of Hydroxyapatite (HA) on Ti substrate. The HA is coated using plasma spraying technique and then subjected to a 2 stage process, including a hydrothermal

treatment and leaching stage which results in osseointegration.
During plasma spray process, a stream of mixed gases passes through a high temperature electric arc that ionizes the gases into a plasma flame. Thereafter, crystalline HA feedstock powder is fed into the stream and then impinged in a molten state onto the outer surface of the implant. The spray adheres to the surface and forms a relatively thin coating on the surface of the Ti substrate.
Though plasma coating is widely used, one of its primary limitations is that plasma-sprayed coatings usually consist of a mixture of amorphous and crystalline phases. The fast dissolution of the amorphous phase and some of the crystalline products like tricalcium phosphate, degrade the stability of the coating and any further heat treatment to improve the crystallinity often results in cracking and loss of adhesion. To overcome these limitations, in this US patent, the coating is further subjected to additional processing steps, including a hydrothermal treatment and leaching stage to remove amorphous HA phase as well as other calcium phosphatic phases which readily dissolve in body fluids.
Such a process results in the said highly pure bioactive crystalline HA which is stable to allow bone tissues to grow into it so that the implant gets integrated with the healthy bone (osseointegration). However such integration is limited to the surface of the Ti substrate and not throughout the substrate. The consequences of such surface integration is that, due to unequal stress distribution, delamination of the coated HA surface on the Ti substrate occurs resulting in loosening of the implant. The implant obtained by this process is also not porous as the Ti substrate used has no porosity and Ti is bio inert by nature.
Russian patent No. 2146535C1 describes a process wherein the Ti matrix is sprayed with multilayers of HA by plasma spraying process. The layers have varying composition. The innermost layer (immediately surrounding the Ti matrix has minimum amount - almost 0% of HA. The percentage of HA increases gradually in the coated layers away from the Ti matrix at the center reaching 100% HA at the outer most layer of the implant where the implant is in intimate contact with the body fluids

The implant obtained by this process, though has better osseointegration, lacks in mechanical strength due the higher content of HA There is also a mismatch due to the thermal expansion coefficient of HA and Ti. In addition the process is also complicated The porosity of the implant obtained is limited to the coated HA portion and body tissue cannot grow into the Ti substrate as TI is bio inert and is not porous.
Japanese patent No. 04221553A2 relates to a method of increasing the bond strength between Ti matrix and HA coating to overcome another important limitation of conventional plasma coating where-in, after prolonged exposure to body fluids in vivo, the plasma sprayed HA layer on Ti can peel off, drastically reducing the bioactivity of the implant, at the same time, exposing Ti matrix to body fluids leading to accelerated corrosion of Ti with prolonged exposure.
The Japanese patent cited overcomes this limitation by providing a thin titanium dioxide layer between the Ti matrix and HA coating by high vacuum plasma coating process. This # prevents the possibility of peel off of HA layer even after prolonged exposure to body fluids because the bond between titanium dioxide and HA is ceramic-ceramic bond (against metallic-ceramic bond in case of direct HA coating on Ti) which is stronger and more stable under adverse ambient conditions. Here also the porosity of the implant obtained is limited to the coated HA portion and cannot grow into the Ti substrate as Ti is bio inert and is not porous even though the longevity of the implant is increased
US patent No. 5872159 describes a method for preparing bone implants where-in a calcium phosphatic material, namely, tricalcium phosphate (TCP) and titanium dioxide in powder form are mixed uniformly with a suitable thermoplastic polymer (as binder) so that the mix can be subjected to plastic injection moulding or extrusion to obtain required bone shaped product. The product is further subjected to special thermal cycling procedure such that TCP gets converted to the more stable HA, which can be then implanted in the body
The main advantage of this process is that it is not a line-of-sight process like plasma coating process, another limitation of the process which makes plasma coating on complex shapes

almost impossible. The process described in the cited patent allows direct manufacture of complex shapes. Though the implant obtained is porous but due to the employment of the plastic injection moulding or extrusion process, the use of binder results in large volume of pores which cannot be used for load bearing applications.
US patent no 5242706 relates to an invention wherein a biocompatible material is deposited onto a substrate by pulsed laser beam deposition or ion assisted pulsed laser beam deposition. Pulsed laser ablation and deposition is probably the simplest among all thin film growth and deposition techniques. It consists of a target holder and a substrate holder housed in a vacuum chamber. A high-power laser is used as an external energy source to vaporize materials and to deposit thin films. A set of optical components is used to focus and raster the laser beam over the target surface. The process creates an ejected plume of material from any target (for example crystalline HA). The vapor (plume) is collected on a substrate (for example Ti) placed a short distance from the target. Though the actual physical processes of material removal are quite complex, one can consider the ejection of material to occur due to rapid explosion of the target surface due to superheating.
This process provides better bond strength between Ti and HA layer (metal-ceramic bond) and longer life in vivo than plasma coating process. However, the implant is not porous. Japanese patent no 04334318A2 discusses a process where-in a bioactive Ti based implant can be made by coating on Ti an organic acid like citric acid and malic acid, phosphoric acid and a bivalent ion chelating agent. These coated implants can be directly implanted in the body as substitute for damaged bone. After implantation, the bivalent ion chelating agent, in conjunction with phosphoric acid, precipitates HA from the body fluids while citric acid stabilizes the precipitated HA. Malic acid's "free alcoholic functions" allow biological molecules to bond to Ti substrate. The implant obtained is also not porous.
From among the extensive work reported on different methods of coating, plasma-sprayed coatings seem to provide a faster adaptation of the bone to the implant and an appreciable improvement of the interfacial strength at the early stages.

However there are certain disadvantages inherent in the plasma spray coating process.
• Plasma-sprayed coatings usually consist of a mixture of amorphous and crystalline phases. The fast dissolution in the body fluids of the amorphous phase as well as some of the crystalline products like tricalcium phosphate degrade the stability of the coating.
• Any further heat treatment to improve the crystallinity often results in cracking and loss of adhesion.
• After prolonged exposure to body fluids in vivo, the plasma sprayed HA layer can peel off drastically reducing the bioactivity of the implant while exposing Ti matrix to body fluids leading to accelerated corrosion of Ti with prolonged exposure.
• Plasma spray is a "line of sight" technique, which is not entirely suitable for coating implants that have complex shapes.
The important point to note is that in the above coating technologies (including plasma coating technology) the bone tissue growth is limited to the surface of the implant (into the bioactive HA/CaP surface coated layer). An important limitation of this approach is the integrity of the surface coated bioactive layer over prolonged exposure to body fluids in-vivo. The layer can crack or peel off due to fatigue and stress corrosion. Such an eventuality would mean loosening of the implant and all the attendant complications.
It would be observed from the prior art discussed above, that the implants obtained by the various processes are not porous and / or only partly porous which make them unsuitable for their use as good implants. Therefore there is a need for the development of a porous implant having bioactive phases.
No tissue growth occurs into uncoated wrought titanium implants because of complete absence of interconnected porosity in the implant. Even if interconnected porosity is provided, tissue cannot grow into titanium because it is bioinert. In addition there is a general reluctance to make porous titanium implants because they exhibit poor fatigue strength. There have been no studies reported on the effect of bone tissue growth into a porous titanium implant. It is expected that fatigue strength will improve with bone tissue growth into the interconnected pores. Further, by allowing tissue growth into the implant, the whole

implant becomes an integral part of the bone under repair, whereas a mere bioactive surface layer on the implant can at best provide integration up to the thickness of the layer.
On this basis, a porous titanium implant material has been developed wherein the surfaces of the pore channels are rendered bioactive to allow tissue growth into the implant leading to the present invention claimed.
OBJECTIVES OF THE PRESENT INVENTION:
Therefore, the main objective of the present invention is to provide novel titanium based composite bioactive material useful as prosthetic implant as against conventional processes where-in the bioactive phases, usually calcium phosphatic chemicals, are present on the surface of the bioinert Ti.
Another objective of the present invention is to provide novel titanium based bioactive composite, which is biocompatible in nature and useful as prosthetic implant
Yet another objective of the present invention is to provide novel titanium based bioactive composite which can enable through and through integration with the healthy bone tissue (when it replaces damaged bone) by allowing tissue growth deep into the composite as against the conventional Ti based surface-coated implants which enable only surface integration because of the presence of bioactive phase only on the surface allowing tissue growth only at the surface of the implant, limited to the thickness of the bioactive coated phase.
A further objective of the present invention is to provide novel titanium based bioactive composite, which when implanted in place of a damaged bone, can locate itself securely at the implantation site by virtue of the fact that it enables through and through integration with the healthy bone, thus completely avoiding any possibility of the implant getting loosened. Such loosening of the implant is possible with conventional Ti based surface-coated implants where-in the surface coated layer can peel off after prolonged exposure to body fluids.

Still another objective of the present invention is to provide novel titanium based composite which can be processed starting from powders such that powder metallurgy (PM) processing is possible which enables production of complex shapes (human bones have varieties of complex shapes).
A further objective of the present invention is to provide novel titanium based composite is to obtain, within the Ti matrix, interconnected porous network which is 'bioactive.
Still another objective of the present invention is to provide a process for the preparation of novel titanium based composite material useful as prosthetic implant as against conventional processes where-in the bioactive phases, usually calcium phosphatic chemicals, are coated only on the surface of the bioinert Ti.
Another objective of the present invention is to make the Ti based biocompatible material capable of extracting out biological HA from the body fluids when the material is implanted as a substitute for a damaged bone. Despite its excellent biocompatibility and bioactivity, synthetic HA prepared from chemicals cannot be considered to be 100% similar to biological HA. In addition to microstructural differences between the two, in biological HA the sizes of individual particles are more uniform. In the context of longevity of the implant, it is better to have more amount of biological HA in the implant and reduce the amount of synthetic HA. Titanium oxide and certain calcium phosphatic and chemicals, which get formed in the present invention, have the potential to precipitate out biological HA from body fluids. This fact is proved by immersing the implant in SBH.
The above objectives of the present invention have been achieved by choosing, titanium (Ti) as the main matrix material because it has been long established that Ti is not rejected by human body (biocompatible). However Ti, by itself does not allow body tissue growth into itself; it is bioinert, not bioactive. By virtue of this bioinert nature, Ti, when directly implanted in the body (for example, as a substitute for a damaged part of a bone), gets surrounded by a flexible fibrous tissue within which the Ti implant is loosely located, unanchored. This could

lead to micro-movements of the implant leading to dangerous consequences (like leading to further fracture of the same bone). In order to get Ti implant properly anchored, the implant should be made amenable to allow body tissues (bone tissues in case of bone implant) to grow into it. This can be done by modifications in the Ti implant through the presence of other materials, which allow tissue growth into them (bioactive materials). For example, calcium phosphatic materials like hydroxyapatite (HA), allow bone tissue growth. Thus, when such materials are added to Ti, the result is a bioactive biocomposite.
In the present invention, such materials, which bring about the said modifications are not added directly (for example hydroxyapatite (HA) is not added directly) but, are added in the form of chemicals (precursor chemicals), which, during processing get converted into the required bioactive materials (phases) similar to HA. The precursor chemicals as well as the matrix material Ti, are taken in the form of powders, providing the advantage of mixing the powders in required proportions, pressing the mixed powders in a die under pressure into required shapes and thermally treating the pressed compacts to increase their strength, i.e, following powder metallurgy (PM) processing. During PM processing, particularly during thermal treatment, the precursor chemicals get converted into bioactive phases within the Ti matrix (in-situ) and get distributed uniformly throughout the volume of the said matrix. In addition, the biocomposite having the in-situ formed bioactive phases, when implanted in the body, has the inherent capacity to precipitate further bioactive phases (calcium phosphatic chemicals) from the body fluids circulating around the implant. This is proved in vitro by preparing simulated body fluid (SBF) having chemical composition similar to that of body fluids and immersing the said biocomposite in it; further precipitation of calcium phosphate phases from SBF occurs and the precipitates get bonded to the surface of the biocomposite.
Further, the different phases formed during the thermo-chemical processing, according to the present invention, impart additional superior strength, superior corrosion resistance and improved wear resistance properties as well as enable faster precipitation of bioactive and bioresorbable phases from body fluids,

Further, the processing conditions employed in the process of the present invention are such that the titanium based bioactive materials have remnant porosity to facilitate tissue growth into the implant. This permits better anchorage to host tissues.
When any component is PM processed, by virtue of the fact that the starting materials are in powder form, which are compacted and thermally treated to be made into components, it is possible to control the processing parameters such that the component can have closely controlled interconnected porosity.
The surface interconnected porosity can be bioactive because the chemicals that are added to produce the bioactive phases during processing are intimately mixed with Ti powder. So, the presence of bioactive phases on the internal surface of the interconnected porous network is highly probable. This helps in allowing the tissue growth into the volume of the implant.
DESCRIPTION OF INVENTION:
Accordingly, the present invention provides a novel titanium based composite bioactive
interconnected porous material useful as prosthetic implant comprising - . ' ' "
' bioactive phases of calcium hydroxyapatite, octacalcium phosphate, tricalcium
phosphate, calcium hydrogen phosphate and calcium titanate, together with bioinert phases based on titanium or its compounds or its alloys , the bioactive phases distributed uniformly throughout the bio inert phases.
In a preferred embodiment of the invention the source of Ti used is selected from its compound Ti hydride, elemental Ti or its alloys. The alloys which can be used are selected from high-strength alloys of titanium like Ti-6AI-4V, Ti-6AI-7Nb, Ti-5AI-2.5Fe, Ti-5Sn-4Nb-2Ta-0.2Pd or Ti-15Zr-4Nb-4Ta-0.2Pd
According to another embodiment of the present invention there is provided a process of making a novel titanium based composite bioactive interconnected porous material, useful as prosthetic implant which comprises

(i) Mixing Ti or its compounds or its alloys in powder form (bio inert phase) and calcium
and phosphorous salts in high energy mill to get an uniform and intimate blend (ii) Compacting the blend into any desired shape at a pressure in the range of 100 to 250
MPa (iii) Calcining the compacts obtained in an atmosphere which will facilitate in situ formation of the bioactive phases between calcium and phosphorous salts present in the compact at a temperature in the range of 600 to 1000°C for a period in the range of 2 to 6 hrs (iv) Crushing the calcined compacts by known methods to get powder (v) Further compacting the powder at a pressure in the range of 300 to 600 MPa and (vi) Sintering the compacts in vacuum at a temperature in the range of 1000 to 1250°C for a period in the range of 1 to 2 hrs
Following the above steps results in titanium based composite bioactive interconnected porous material having bioactive phases of different forms of calcium hydroxyapatite, octa-calcium phosphate phases, calcium hydrogen phosphate, tricalcium phosphate, and calcium titanate along with bioinert phases of titanium and titanium compound phases like titanium hydride, titanium oxide, titanium nitride and titanium phosphide
The following factors of the process of the present invention are unique as compared to the prior art which impart novelty to the invention
1. The bioactive phases are not directly added to Ti, but added in the form of salts of calcium and phosphorus which during processing, convert into different bioactive phases within the bio inert Ti in situ - thereby ensuring proximity of the bioactive phases thus formed with the Ti phase.
2. An additional advantage of forming the bioactive phases in situ is that it obviates the problem of procurement of biological grade bioactive materials like HA from the market. The high cost is due to the complex packing and transporting system, which is mandatory to prevent dangers to the living body due to contamination.

3. All the ingredients used in the present invention, taken in powder form, undergo ball milling as well as high-energy milling. Both these processes, particularly high-energy milling process, ensure intimate contact between the ingredients being mixed.
4. One of the prerequisites of uniform distribution of a set of ingredients in the composite is density parity between the ingredients and the matrix material. The said parity does not exist between Ti metal powders and the precursor chemical powders. To establish the required parity, Ti is added preferably in the form of titanium hydride.
5. Production of Ti hydride is a well-established process in which Ti sponge is made to react with hydrogen to obtain hydride in a particular set of temperature and pressure conditions, under which any impurities present in Ti sponge do not react with hydrogen. Under different set of temperature and pressure conditions, Ti hydride dissociates into pure Ti and hydrogen. The process is called hydride-dehydride process.
6. In addition to establishing density parity, the hydride-dehydride process ensures
availability of highly pure and cheap Ti powder.
During actual processing, the titanium based material used can be selected from pure titanium, titanium hydride, titanium based alloy such Ti-6AI-4V or Ti-6AI-7Nb, Ti-5AI-2.5Fe, Ti-15Sn-4Nb-2Ta-0.2Pd and Ti-15Zr-4Nb-4Ta—0.2Pd in powder form having size less than 250>m;
The percentage of titanium based material in the composite can be varied from 60 to 95 weight %.
The calcium containing precursors can be selected from among calcium chloride, calcium carbonate, calcium nitrate and their combinations while the phosphorus containing precursors, from among di-ammonium hydrogen orthophosphate, sodium hydrogen orthophosphate, phosphoric acid and their combinations.
The quantities of calcium and phosphorus containing precursors in titanium matrix are varied from 5 to 40 wt%.

The calcium and phosphorus containing precursors are taken such that the calcium and phosphorus content in the precursors are varied in the ratio of 1.3:1 to 2.1:1
The composite having different weight percentages of titanium or titanium compounds or titanium alloys and precursor contents of calcium and phosphorus, the ratio of calcium and phosphorus being further varied in different ratios, the resulting bio composite having the required nucleating points for further nucleation and precipitation of natural hydroxyapatite when immersed in the body fluids. The material has transverse rupture strength value in the range 30 MPa to 80 MPa. The biocomposite is active in nature when exposed to body fluids
The biocomposite has the requisite interconnected porosity in the range of 4-15% and the required pore size 3 - 17^m. The biocomposite has superior corrosion resistance of corrosion rate of 0.175775 - 4.7 mills per year(MPY). The biocomposite is non toxic in nature when subjected to in vitro cytotoxicity tissue culture tests ie the biocomposite allows the growth of bone substitute material from the body fluids
Titanium oxides are also formed during processing as per the present invention which provide better bonding with calcium phosphatic chemicals than pure titanium. Further, titanium nitride is also formed during processing providing good corrosion and wear resistance to the implant. Calcium titanate is also formed during processing which imparts hardness to the implant in addition to playing an important role in precipitating calcium phosphatic phases from body fluids.
In a preferred embodiment of the present invention, titanium is preferably used as titanium hydride for subsequent conversion into titanium powder during processing and the said hydride powder was produced from high purity titanium sponge powder through thermal treatment in hydrogen atmosphere and characterized for phase analysis, particle size and chemical analysis. The chemical assay of the powder is shown in table - 1

Table 1: Properties of Ti-Hydride
(Table Removed)

The mean particle size of the titanium hydride powder used was chosen to be between 50 to 250 µm, more preferably between 150 to 250 µm. In another embodiment of the present invention the size of the hydride powder was finalized at -250 µm.
To make the Ti based biocompatible material capable of extracting out biological HA from the body fluids when the material is implanted as a substitute for damaged bone. Despite its excellent biocompatibility and bioactivity, synthetic HA prepared from chemicals cannot be considered to be 100% similar to biological HA. In addition to microstructural differences between the two, in biological HA the sizes of individual particles are more uniform. In the
context of longevity of the implant, it is better to have more amount of biological HA in the implant and reduce the amount of synthetic HA. Titanium oxide and certain calcium phosphatic and chemicals, which get formed in the present invention, have the potential to precipitate out biological HA from body fluids. This fact is proved by immersing the implant in SBH.
All the ingredients used in the present invention, taken in powder form, undergo ball milling as well as high-energy milling. Both these processes, particularly high-energy milling process, ensure intimate contact between the ingredients being mixed.
In another embodiment of the present invention, the ratio of calcium-phosphatic precursor to titanium based matrix was varied at 5,10, 15, 20, 25 and 30 wt% salt. The said calcium and phosphorus containing chemicals were added in the proportion Ca:P::1.3-2.1:1, appropriate ratios for formation of hydroxyapatite (HA).
The mixing was undertaken in a ball mill or pot mill with a ball to charge ratio of 2:1 for 10-40 minutes using stainless steel balls of 10-30mm diameter.
The charge thus obtained after the said addition of precursor chemicals in the said proportions of titanium hydride powder, mixing was undertaken in a ball mill or pot mill with a ball to charge ratio of 2:1 for 10-40 minutes, where in the said balls are using stainless steel balls of 10-30mm diameter which help thorough mixing of ingredients in the charge.
The uniformly ball milled charge is further subjected to high energy milling using stainless steel balls to bring about intimate contact and bonding between the different ingredients in the charge, the said high energy milling being undertaken in a planetary mill under argon atmosphere to prevent oxidation, if any, of any of the ingredients, while maintaining a ball to charge ratio in the range 5 -15 : 1, 10 -15 : 1 being the preferred ratio.
The high-energy milled powder is then compacted in an appropriate die in a press at 200 -300 MPa so as to obtain compacts of 10 mm in diameter and 6 mm in length.
The pressed compacts are further calcined at 400 to 1000°C, the preferred temperature being 750 to 1000°C, such that titanium hydride gets converted to pure titanium and also to facilitate the precursor chemicals to react with Ti as well amongst themselves to form different bioactive phases in-situ. The said calcination is done in hydrogen, argon and vacuum atmospheres.
Having obtained the requisite bioactive phases during the said calcination step, the phases have to be stabilized, the HA formed has to be converted into pure crystalline state and on the whole the strength of the compact has to be increased. To fulfill the above three requirements, the calcined compacts are again crushed into powder and then pressed at 600- 800 MPa to compacts of size of 31.5mm x 12.75mm x 6mm and subsequently sintered at 800 to 1250°C under a vacuum of 5x10-4 torr.
In another preferred embodiment of the present invention, for bioactivity studies, the biocomposites were immersed in simulated body fluid (SBF) and change in concentration of elements like Ca, P, Mg, Na and P in SBF were measured using inductively coupled plasma atomic energy spectroscopy (ICP-AES) after immersion periods of 7, 14, 21 and 28 days.
Characterization of the sintered compacts 1. Bioactivity
The primary objective of the present invention being production of Titanium based bioactive materials, which can be used as orthopaedic implants, characterizing the bioactivity is important and it is done in vitro using simulated body fluid (SBF) prepared using chemicals such that the chemistry of SBF matches that of biological body fluids. Sintered samples are immersed in SBF for different periods, i.e, 7, 14, 21 and 28 days and the movement of ionic species of calcium, phosphorous, magnesium, and sodium and potassium between the sample and SBF is monitored by subjecting the SBF (after a specific period of immersion is accomplished) to analysis for measuring the quantities of the said elements in it. The analysis is done using inductively coupled plasma atomic energy spectroscopy (ICP-AES). If depletion of the said elements of calcium and phosphorus in SBF is observed, it can only mean that the said elements have been precipitated out of the SBF
by the bioactivity of the sample. Such depletion was in fact observed and, in addition, the samples were found with freshly deposited materials validating the fact that the process followed indeed provides bioactivity. To further confirm the bioactivity of the sintered samples, the freshly deposited materials on the samples after immersion in SBF, were scrapped off and the scrapped materials were subjected to Fourier transform infrared spectroscopy (FTI-R), X-ray diffraction (XRD), Scanning Electron Microscopy (SEM) and EDS, to ascertain their exact nature. Carbonate (CO32), phosphatic (PO43) and hydroxyl (OH) species were observed in the deposits, further confirming the bioactivity of the sintered samples.
2. Cytotoxicity
An important requirement of any material that is to be implanted in human body is that the implant should not be toxic to different types of cells (should not be cytotoxic) in the body. To ascertain whether the sintered biocomposite exhibits cytotoxicity or not, standard in vitro-cytotoxicity tests were performed and it was confirmed that the biocomposite produced by the process of this invention is non- cytotoxic.
3. Mechanical strength
Since the biocomposite produced by the process of the present invention is intended as a bone implant, its mechanical strength is of prime importance. Transverse rupture strength (TRS) measured by 3-point bend test is a good measure of the mechanical strength. Such test was performed and the adequate strength was obtained.
The details of the invention are given in the Examples which are provided to illustrate the invention and therefore should not be construed to limit the scope of the invention.
EXAMPLE 1
52.08 g of Ti hydride powder (-250nm) and 61.69 g of calcium chloride and 45.93 g of diammonium hydrogen orthophosphate were ball milled for 30 minutes with ball to powder ratio of 2:1, milled in a Fritsch planetary mill for 30 min with ball to powder ratio of 15:1, compacted at 250 MPa to specimens of size 9mm diameter and 15mm height. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa. The compacts were sintered at 1000°C in a vacuum of 10"5 torr for 1h. The bioinert phases obtained in the composite as analysed by x-ray diffraction (XRD) were found to be titanium,

titanium hydride and the bioactive phases were as analysed by XRD calcium hydroxyapatite, tricalcium phosphate and calcium titanate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture(MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 2(a and b).
Table 2(a)
(Table Removed)

Table 2(b)
(Table Removed)

EXAMPLE 2
50 g of Ti powder (-250nm) and 61.69 g of calcium chloride and 45.93 g of diammonium hydrogen orthophosphate were ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9mm dia and 15mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for1h, crushed and compacted at 600Mpa to the same specimen size as said above. The compacts were sintered at 1000°C in a vacuum of 10'5 torr for 1h. The bioinert phases

obtained in the composite were found to be titanium, titanium hydride with bioactive phases such as calcium hydroxyapatite, tricalcium phosphate and calcium titanate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture(MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 3(a and b).
Table 3(a)
(Table Removed)

Table 3(b)
(Table Removed)

EXAMPLE 3
90 g of Ti powder (-250 µm) and 4.3 g of calcium carbonate and 5.7 g of di ammonium hydrogen orthophosphate were mixed with Ca:P ratio of 1.32 and ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9mm dia and 15mm height at 250 MPa. The compacts were calcined in hydrogen at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were sintered at 1150°C in a vacuum of 10~5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and

bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture(MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 4(a and b).
Table 4(a)
(Table Removed)

Table 4(b)
(Table Removed)

EXAMPLE 4
70 g of Ti powder (-250nm) and 12.9 g of calcium carbonate and 17.1 g of di ammonium hydrogen orthophosphate were mixed with Ca:P ratio of 1.32:1 and ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 200 MPa. The compacts were calcined in argon at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The various phases obtained as studied by XRD are bioinert phases of titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive phases of calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The compacts were sintered at 1150°C in a vacuum of 10-5 torr for 1h. The

bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 5(a and b).
Table 5(a)
(Table Removed)

Table 5(b)
(Table Removed)

EXAMPLE 5
An experiment with 80 wt% titanium hydride 20 wt % of calcium carbonate and di ammonium hydrogen orthophosphate with Ca:P ratio of 1.32:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10"5 torr for 1h to evaluate the interconnected porosity of the sintered composites. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites

upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 6(a and b).
Table 6(a)
(Table Removed)

Table 6(b)
(Table Removed)

EXAMPLE 6
An experiment with 90% titanium hydride and 10% of calcium carbonate and di ammonium hydrogen orthophosphate with Ca:P ratio of 2:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10-5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and

bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 7(a and b).
Table 7(a)
(Table Removed)

Table 7(b)
(Table Removed)

EXAMPLE 7
An experiment with 90g of titanium hydride with 4.3g of calcium carbonate and 5.7 g of di ammonium hydrogen orthophosphate varying from 10 to 30% with Ca:P ratio of 1.32:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 200 MPa. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10-5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium

nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 8(a and b).
Table 8(a)
(Table Removed)

The above composite was weighed to find the change in weight upon immersing in SBF for different time periods.
Table 9 shows the change in weight of the composite indicative of the fact that the composite is bioactive in nature as dissolution of ions takes place when the composite and the SBF are in continuous interaction.

Table 9: Weight change of composite as detailed in EXAMPLE 7 upon immersion in SBF
(Table Removed)

All the functional groups characteristic of hydroxyapatite are present namely OH", C032", P043". This confirms that the deposits on the surface of the composite are calcium hydroxyapatite which is further confirmed by XRD spectrum.
EXAMPLE 8
In this experiment, 80g of of titanium hydride with 8.6g of calcium carbonate and 11.4g of di ammonium hydrogen orthophosphate with Ca:P ratio of 1.32:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 200 MPa. The compacts were calcined in vacuum at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10~5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 10(a and b).

Table 10(a)
(Table Removed)

Table 10(b)
(Table Removed)

The above composites were weighed to find the weight change of composites upon immersing in SBF for different time periods. Table 11 shows the change in weight of the composites indicative of the fact that the composites are bioactive in nature as dissolution of ions takes place when the composite and the SBF are in continuous interaction. Table 11: Weight changes of composites as detailed in EXAMPLE 9 upon immersion in SBF
(Table Removed)

The growth of deposits on the composite surface was studied using XRD and FTIR for examining the phases and the nature of the functional groups characteristic of HA. The bioactive phases are analysed as different forms of calcium hydroxyapatite and other phases like calcium carbonate, sodium calcium phosphate, sodium calcium carbonate and calcium hydrogen phosphate which are intermediate stages of formation of calcium hydroxyapatite.

EXAMPLE 9
An experiment with 70g of titanium hydride with 12.9g of calcium carbonate and 17.1g ammonium hydrogen orthophosphate with Ca:P ratio of 1.32:1 was ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 250 MPa. The compacts were calcined in hydrogen at 1000°C for 1h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10-5 torr for 1h. The phases obtained as analysed by XRD in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioantive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 12(a and b).
Table 12(a)
(Table Removed)

Table 12(b)
(Table Removed)

Also bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find change in chemical composition on surface of the composite by EDAX. A typical EDAX analysis of composite made of 70% titanium hydride with 30% Ca-P precursor is given in table 13 showing that the content of Ca, P and O is increasing on the surface while concentration of titanium decreases. The increase of Ca, P and O on the composite surface indicates that the precipitation of Ca-P deposits are taking place from the SBF.
Table 13: EDAX multipoint analysis of the surface of composite containing 70% titanium hydride with 30% chemicals consisting of calcium carbonate and di-ammonium hydrogen orthcohosphate calcined in hydrogen and sintered in vacuum before and after immersion in SBF for 7 days.
(Table Removed)

EXAMPLE 10
70 g of Ti powder (-250jxm) and 12.9 g of calcium carbonate and 17.1 g of di ammonium hydrogen orthophosphate were mixed with Ca:P ratio of 1.32:1 and ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15mm height at 250 MPa. The compacts were calcined in hydrogen at 1000°C for 1h, crushed and compacted at 600 Mpa to the same specimen size as said above. The compacts were then sintered at 1150°C in a vacuum of 10~5 torr for 1h. The phases obtained as analysed by XRD in the composite were

found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 14(a and b).
Table 14(a)
(Table Removed)

Table 14(b)
(Table Removed)

EXAMPLE 11
90g of Ti powder (-250fam) and 4.3 g of calcium carbonate and 5.62 g of di-ammonium hydrogen orthophosphate were mixed with Ca:P ratio of 1.3:1 and ball milled for 30 minutes with ball to powder ratio of 2:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9 mm dia and 15 mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for 2h, crushed and recompacted at 600 MPa to the same specimen size as said above. The compacts were sintered at 1150°C in a

vacuum of 10'5 torr for 1h. The phases obtained in the composite were found to be bioinert titanium, titanium oxides, titanium hydride, titanium nitride, titanium phosphides and bioactive calcium titanate, calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 15(a and b).
Table 15(a)
(Table Removed)

Table 15(b)
(Table Removed)

In-vitro cytotoxicity tests were done for establishing biocompatibility and the results were positive which proved that the composite was non-toxic in nature. Table 16 shows the in vitro cytotoxicity of 90% titanium hydride with 10% chemicals consisting of calcium and phosphorus with Ca:P as 1.3:1, calcined and sintered in vacuum.

Table 16: Qualitative evaluation of in vitro cytotoxicity tests
(Table Removed)

EXAMPLE 12
90 g of Ti powder (-250|am) and 5.05 g of calcium carbonate and 4.95 g of di-ammonium hydrogen orthophospliate were mixed with Ca:P ratio of 1.7:1 and ball milled for 30 minutes with ball to powder ratio of 2.1:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9mm dia and 15mm height at 250 MPa. The compacts were calcined in vacuum at 1000°C for 2h, crushed and compacted at 600 MPa to the same specimen size as said above. The compacts were sintered at 1150°C for 1 h in a vacuum of 10"5 torr. The phases obtained in the composite were found to be bioinert phases of titanium, titanium oxides, titanium hydride, calcium titanate, titanium nitride, titanium phosphides and bioactive calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 17(a and b).
Table 17(a)
(Table Removed)

Table 17(b)
(Table Removed)

The in vitro cyto toxicity tests were done for establishing biocompatibility and the results were positive which proved that is the composite was non-toxic in nature. Table 18 shows the invitro cytotoxicity of 90% titanium hydride with 10% chemicals consisting of calcium and phosphorus with Ca:P as 1.7 :1 calcined and sintered in vacuum.
Table 18: Qualitative evaluation of in vitro cytotoxicity tests
(Table Removed)

EXAMPLE 13
An experiment with 90% titanium hydride with 10% chemical content (calcium carbonate and di ammonium hydrogen orthophosphate), wherein the ratio of Ca:P was 2.1:1, was ball milled for 30 minutes with ball to powder ratio of 2.1:1, milled in planetary mill for 30 min with ball to powder ratio of 15:1, compacted to specimens of size 9mm dia and 15mm height at 300 MPa. The compacts were calcined in vacuum at 1000°C for 2h, crushed and compacted at 550 MPa to the same specimen size as said above. The compacts were sintered at 1150°C

for 1h in a vacuum of 10-5 torr. The phases obtained in the composite were found to be bioinert phases of titanium, titanium oxides, titanium hydride, calcium titanate, titanium nitride, titanium phosphides and bioactive calcium hydroxyapatite, tricalcium phosphate. The bioactivity studies of composites upon immersing in SBF for different time periods were undertaken to find the change in chemical composition. The results of sintered density, interconnected porosity, pore size, transverse rupture strength (TRS) for finding Modulus of Rupture (MOR), phase analysis, bioactivity studies in SBF and FTIR studies to find the growth of HA and calcium phosphatic phases from SBF onto the composite materials upon immersion in body fluids for different time periods are given in Table 19(a and b).
Table 19(a)
(Table Removed)

Advantages of the process:
1. Starting materials are inexpensive and easily available.
2. Inherent advantage of getting any complicated shape and size by PM processing
3. No delamination of the ceramic and metal interface in the composite
4. Uniform and higher strength throughout the composite
5. The pore size can be controlled because of the PM processing to values suitable for facilitating natural tissue growth.

6. In-situ formed seeds of calcium hydroxyapatite and the bioactive phases results in faster nucleation and growth of natural hydroxyapatite from the body environment.
7. Minimises the requirement of synthetic hydroxyapatite.
8. More corrosion resistant because of the presence of the titanium nitride phase formed in situ.

We claim,
1. A novel titanium based bioactive interconnected porous composite material for use as prosthetic implant comprising of bioactive phases consisting of calcium and phosphorous salts in the range varied from 5 to 40 weight % and is selected from calcium hydroxyapatite, octacalcium phosphate, tricalcium phosphate, calcium hydrogen phosphate and calcium titanate, together, and bio tolerant or bioinert phases consisting of titanium or its compounds or its alloys and the percentage of Ti based material in the composite is varied from 60 to 95 weight%., and the said bioactive phases distributed uniformly throughout the bio inert phases
2. A process for the preparation of Novel titanium based bioactive interconnected porous material composite for use as prosthetic implant as claimed in claim 1 which comprises
(i) Mixing Ti or its salts or its alloys in powder form (bio inert phase) and calcium and
phosphorous salts in high energy mill to get an uniform and intimate blend
(ii) Compacting the blend into any desired shape at a pressure in the range of 100 to 250
MPa (iii) Calcining the compacts obtained in an atmosphere to facilitate in situ formation of the
bioactive phases between calcium and phosphorous salts present in the compact at a
temperature in the range of 600 to 1000°C for a period in the range of 2 to 6 hrs (iv) Crushing the calcined compacts by known methods to get powder (v) Further compacting the powder at a pressure in the range of 300 to 600 MPa and (vi) Sintering the compacts in vacuum at a temperature in the range of 1000 to 1250°C for
a period in the range of 1 to 2 hrs 3 A process as claimed in claim 2 wherein the salt of Ti used is Ti-hydride. 4. A process as claimed in claims 2 & 3 wherein the calcined compact is crushed to powder and compacted to a shape in a die using mechanical or hydraulic press, or in a mould using cold isostatic press at a pressure of 100-600 MPa and is subjected to vacuum sintering at 1000-1250°C, resulting in a titanium based biocomposite having bioactive phases of different forms of calcium hydroxyapatite, octa-calcium phosphate phases, calcium hydrogen phosphate, tricalcium phosphate, and calcium

titanate along with titanium and titanium compound phases like titanium hydride, titanium oxide, titanium nitride and titanium phosphide
5. A process as claimed in claims 2 to 4 wherein the titanium based material is selected from
pure titanium, titanium hydride, titanium based alloy such as Ti-6AI-4V or Ti-6AI-7Nb, Ti-5AI-2.5Fe, Ti-15Sn-4Nb-2Ta-0.2Pd and Ti-15Zr-4Nb-4Ta—0.2Pd in powder form having size less than 250µm.
6. A process as claimed in claims 2 to 5 wherein the salts of calcium is selected from among calcium chloride, calcium carbonate, calcium nitrate and their combinations while the phosphorus containing precursors, from among di-ammonium hydrogen orthophosphate, sodium hydrogen orthophosphate, phosphoric acid and their combinations.
7. A process as claimed in claim 2 to 6 wherein the salts of calcium and phosphorus are taken such that the calcium and phosphorus content in the composite are varied in the ratio of 1.3:1 to 2.1:1
8. A process as claimed in claims 2 to 7 wherein the composite material has transverse rupture strength value in the range 30 MPa to 95 MPa, the requisite interconnected porosity in the range of 10-35%, the required pore size 5 - 20µm and the superior corrosion resistance of corrosion rate in the range of 0.175775 - 4.7 mills per year(MPY).
9. A novel titanium based composite bioactive interconnected porous material and a process for the preparation of novel titanium based composite bioactive interconnected porous material as prosthetic implant substantially as herein described with reference to the Examples 11 to 12.

Documents:

2490-del-2005-abstract.pdf

2490-del-2005-claims.pdf

2490-del-2005-complete specification (granted).pdf

2490-del-2005-correspondence-others.pdf

2490-del-2005-correspondence-po.pdf

2490-del-2005-description (complete).pdf

2490-del-2005-form-1.pdf

2490-del-2005-form-13.pdf

2490-del-2005-form-18.pdf

2490-del-2005-form-2.pdf

2490-del-2005-form-9.pdf

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Patent Number

228353

Indian Patent Application Number

2490/DEL/2005

PG Journal Number

08/2009

Publication Date

20-Feb-2009

Grant Date

03-Feb-2009

Date of Filing

14-Sep-2005

Name of Patentee

INDIAN INSTITUTE OF TECHNOLOGY (IIT),BOMBAY

Applicant Address

IIT, POWAI, MUMBAI-400-076, MAHARASHTRA INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	BHAGWATI PRASAD KASHYAP	IIT, POWAI, MUMBAI-400-076, MAHARASHTRA INDIA
2	TALLAPRAGADA RAJA RAMA MOHAN	IIT BOMBAY, POWAI, MUMBAI 400 076, INDIA
3	RANGANATHAN SUNDARESAN	ARCI, POST; BALAPUR RR DISTRICT HYSERABAD-500005, AP, INDIA
4	MALOBIKA KARANJAI	ARCI, POST; BALAPUR RR DISTRICT HYSERABAD-500005, AP, INDIA

PCT International Classification Number

B22F 3/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA