PMC:2871132 / 122792-137128 JSONTXT

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Composite Coating\nBioactive calcium phosphate (CaP) coatings were produced on titanium by using phosphate-based glass (P-glass) and hydroxyapatite (HA), and their feasibility for hard tissue applications was addressed in vitro by Kim et al. [207]. P-glass and HA composite slurries were coated on Ti under mild heat treatment conditions to form a porous thick layer, and then the micropores were filled in with an HA sol-gel precursor to produce a dense layer. The resultant coating product was composed of HA and calcium phosphate glass ceramics, such as tricalcium phosphate (TCP) and calcium pyrophosphate (CPP). It was reported that the coating layer had a thickness of approximately 30–40 μm and adhered to the Ti substrate tightly, (ii) the adhesion strength of the coating layer on Ti was as high as about 30 MPa, (iii) the human osteoblastic cells cultured on the coatings produced by the combined method attached and proliferated favorably, and (iv) the cells on the coatings expressed significantly higher alkaline phosphatase activity than those on pure Ti, suggesting the stimulation of the osteoblastic activity on the coatings [207]. Maxian et al. [208] evaluated the effect of amorphous calcium phosphate and poly-crystallized (60% crystalline) HA coatings on bone fixation of smooth and rough (Ti-6Al-4V powder sprayed) Ti-6Al-4V implants after four and 12 weeks of implantation in a rabbit trascortical femoral model. Histological evaluation of amorphous versus poorly crystallized HA coatings showed significant differences in bone apposition and coating resorption that were increased within cortical compared to cancellous bone. The poorly crystallized HA coatings showed the most degradation and least bone apposition. Mechanical evaluation, however, showed no significant differences in push-out shear strengths. Significant enhancement in interfacial shear strengths for bioceremic coated, as compared to uncoated implants, was seen for smooth-surfaced implants (3.5–5 times greater) but not for rough-surfaced implants at four and 12 weeks. Based on these results, it was suggested that once early osteointegration is achieved biodegradation of a bioactive coating should not be detrimental to the bone/coating/implant fixation [208]. Plasma sprayed HA coatings on titanium alloy substrates have been used extensively due to their excellent biocompatibility and osteoconductivity. However, the erratic bond strength between HA and Ti alloy has raised concern over the long-term reliability of the implant. Accordingly, Khor et al. developed HA/yttria-stabilized-zirconia (YSZ)/Ti-6Al-4V composite coatings that possess superior mechanical properties to conventional plasma sprayed HA coatings [209]. Ti-6Al-4V powders coated with fine YSZ and HA particles were prepared through a unique ceramic slurry mixing method. The composite powder was employed as feedstock for plasma spraying of the HA/YSZ/Ti-6Al-4V coatings. The influence of net plasma energy, plasma spray standoff distance, post-spray heat treatment on microstructure, phase composition, and mechanical properties were investigated. It was found that (i) coatings prepared with the optimum plasma sprayed condition showed a well-defined splat structure, (ii) HA/YSZ/Ti-6Al-4V solid solution was formed during plasma spraying, which was beneficial for the improvement of mechanical properties, (iii) the microhardness, modulus of elasticity, fracture toughness, and bond strength increased significantly with the addition of YSZ, and (iv) post-spray heat treatment at 600 °C and 700 °C for up to 12 h was found to further improve the mechanical properties of coatings [209]. Yttria stabilized zirconia (YSZ) is often used as reinforcement for many ceramics because it has the merits of high strength and enhanced toughening characteristics during crack-particle interactions [210–213].\nYamada et al. [214] utilized the Cullet method for which (1) the mixture of HA powder and glass frits are sintered at 900–1000 °C for from 5 to 10 min to prepare well homogenized coating powder, whereas the conventional method is just mixing and not sintering, and (2) the time of etching treatment, through which the bioactive surface is formed using the mixed solution of HNO3 and HF, is relatively short (within 1 min) compared to the conventional method. Through this method, functionally gradient HA/Ti composite implants were successfully fabricated with higher quality compared with the conventional method [214]. Suzuki et al. [215] coated titanium dioxide onto silicone substrates by radio-frequency sputtering. It was reported that silicone coating with titanium dioxide enhanced the breakdown of peroxynitrite by 79%. Titanium dioxide-coated silicone inhibited the nitration of 4-hydroxy-phenylacetic acid by 61% compared to aluminum oxide-coated silicone and 55% compared to uncoated silicone. Titanium dioxide-coated silicone exhibited a 55% decrease in superoxide compared to uncoated silicone, and a 165% decrease in superoxide compared to uncoated polystyrene [215]. Titanium dioxide-coated silicone inhibited IL-6 production by 77% compared to uncoated silicone. Based on these findings, it was concluded that the anti-inflammatory properties of titanium dioxide can be transferred to the surfaces of silicone substrates [215].\nHA coatings with titania addition were produced by the high velocity oxy-fuel spray process by Li et al. [216]. It was found that (i) the addition of TiO2 improves the MOE, fracture toughness, and shear strength of high velocity oxy-fuel sprayed HA-based coatings, (ii) the incorporation of the secondary titania phase is found to have a negative effects on the adhesive strength of high velocity oxy-fuel sprayed HA coatings, (iii) the titania is found to inhibit the decomposition of HA at evelated temperatures lower than 1,410 °C, at which point the mutual chemical reaction occurs, and (iv) a small amount of TiO2 added into high velocity oxy-fuel sprayed HA coatings with less than 20 vol% is therefore recommended for strengthening of HA-coatings [216]. Lu et al. [217] fabricated a two-layer hydroxyapatite (HA)/HA + TiO2 bond coat composite coating (HTH coating) on titanium by the plasma spraying technique. The HA + TiO2 bond coat (HTBC) consists of 50 vol% HA and 50 vol% TiO2 (HT). The as-sprayed HT coating consists mainly of crystalline HA, rutile TiO2 and amorphous Ca-P phase, but the post-spray heat treatment at 650 °C for 120 min effectively restores the structural integrity of HA by transforming non-HA phases into HA [216]. It was found that there exists interdiffusion of the elements within the HTBC, but no chemical product between HA and TiO2, such as CaTiO3 was formed. The toughening and strengthening mechanism of HTBC is mainly due to TiO2 as obstacles resisting cracking, and the reduction of the near-tip stresses resulting from stress-induced microcracking [217]. Ng et al. [218] mimicked bio-mineralization of bone by applying an initial TiO2 coating on Ti-6Al-4V by electrochemical anodization in two dissimilar electrolytes, followed by the secondary calcium (CaP) coating, subsequently applied by immersing the substrates in a simulated body fluid (SBF) with three times concentration (SBF × 3). Electrochemical impedance spectroscopy (EIS) and DC potentiodynamic polarization assessments in SBF revealed that the anodic TiO2 layer is compact, exhibiting up to a four-fold improvement in in vitro corrosion resistance over unanodised Ti-6Al-4V. X-ray photoelectron spectroscopy analysis indicates that the anodic Ti oxide is thicker than air-formed ones with a mixture of TiO2–x compound between the TiO2/Ti interfaces. The morphology of the dense CaP film formed, when observed using scanning electron microscopy, is made up of linked globules 0.1–0.5 μm in diameter without observable delamination. It was also found that (i) the calculated Ca:P ratios of all samples (1.14–1.28) are lower than stoichiometric hydroxyapatite (1.67), and (ii) a duplex coating consisting of a compact TiO2 with enhanced in vitro corrosion resistance and bone-like apatite coating can be applied on Ti-6Al-4V by anodization and subsequent immersion in SBF [218].\nKnabe et al. [219] investigated the effects of novel calcium titanium, calcium, titanium zirconium phosphates suitable for plasma spraying on CpTi substrate on the expression of bone-related genes and proteins of human bone-derived cells, and compared the effects to that on native Ti and HA-coated Ti. Test materials were acid etched and sand-blasted, plasma-sprayed HA, and sintered CaPO4 with Ti, Zr, TiO2, and ZrO2. Human bone-derived cells were grown on these surfaces for 3, 7, 14, and 21 days, counted and probed for various mRNAs and proteins. It was reported that (i) all surfaces significantly affected cellular growth and the temporal expression of an array of bone-related genes and proteins, (ii) at 14 and 21 days, cells on sintered displayed significantly enhanced expression of all osteogenetic mRNAss, and (iii) surfaces of 55CaO·20TiO2·31P2O5 and CaTi4(PO4)6 had the lost effect on osteoblastic differentiation inducing a greater expression on an array of osteogenetic markers than recorded for cells grown on HA, suggesting that these novel materials may possess a higher potency to enhance osteogenesis [219]. Shtansky et al. [220] performed a comparative investigation of multicomponent thin films based on the systems Ti-Ca-C-O-(N), Ti-Zr-C-O-(N), Ti-Si-Zr-O-(N) and Ti-Nb-C-(N). TiC0.5 + 10%CaO, TiC0.5 + 20%CaO, TiC0.5 + 10%ZrO2, TiC0.5 + 20%ZrO2, Ti5Si3 + 10%ZrO2, TiC0.5 + 10%Nb2C and TiC0.5 + 30%Nb2C composite targets were manufactured by means of self-propagating high-temperature synthesis, followed by DC magnetron sputtering in an atmosphere of argon or in a gaseous mixture of argon and nitrogen. The biocompatibility of the films was evaluated by both in vitro and in vivo experiments. The in vitro studies involved the investigation of the proliferation of Rat-1 fibroblasts and IAR-2 epithelial cells on the tested films, morphometric analysis and actin cytoskeleton staining of the cells cultivated on the films. In vivo studies were fulfilled by subcutaneous implantation of Teflon plates coated with the tested films in mice and analysis of the population of cells on the surfaces. It was reported that (i) the films showed high hardness in the range of 30–37 GPa, significant reduced modulus of elasticity, low friction coefficient down to 0.1–0.2, and low wear rate in comparison with conventional magnetron-sputtered TiC and TiN films, (ii) no statistically significant differences in the attachment, spreading, and cell shape of cultured IAR-2 and Rat-1 cells on the Ti-Ca-C-O-(N), Ti-Zr-C-O-(N) (TiC0.5+10%ZrO2 target), Ti-Si-Zr-O-(N) films and the uncoated substrata was detected, and (iii) the adhesion and proliferation of cultured cells in vitro was perfect at all investigated films. Based on these findings, it was concluded that the combination of excellent mechanical properties with non-toxicity and biocompatibility makes Ti-Ca-C-O-N, Ti-Zr-C-O-N, and Ti-Si-Zr-O-N films promising candidates as tribological coatings to be used for various medical applications like total joint prostheses and dental implants [220]. Von Walter et al. [221] introduced a porous composite material, named “Ecopore”, and described in vitro investigation of the material and its modification with fibronectin. The material is a sintered compound of rutile TiO2 and the volcanic silicate perlite with a macrostructure of interconnecting pores. In an in vitro model, human primary osteoblasts were cultured directly on Ecopore. It was reported that human osteoblasts grew on the composite as well as on samples of its single constituents, TiO2 and perlite glass, and remained vital, but cellular spreading was less than on tissue culture plastic. To enhance cellular attachment and growth, the surface of the composite was modified by etching, functionalization with aminosilane and coupling of fibronectin, resulting in greatly enhanced spreading of human osteoblasts. It was therefore concluded that (i) Ecopore is non-toxic and sustains human osteoblasts growth, cellular spreading being improvable by coating with fibro-nectin, and (ii) the composite may be usable in the field of bone substitution [221].\nDifferent biomaterials have been used as scaffolds for bone tissue engineering. Rodrigues et al. [222] characterized biomaterial composed of sintered (at 1,100 °C) and powdered hydroxyapatite and type I collagen (both of bovine origin) designs for osteoconductive and osteoinductive scaffolds. Collagen/HA proportions were 1/2.6 and 1/1 by weight, with particle sizes ranging from 200 to 400 μm. X-ray diffraction and infrared spectroscopy showed that the sintered (1,100 °C) bone was composed essentially of HA with minimum additional groups as surface calcium hydroxide, surface and crystal water, free carbon dioxide, and possibly brushite. It was reported that osteoblasts adhered and spread on both the HA particle surface and the collagen fibers, which seemed to guide cells between adjacent particles [222], suggesting that this biocomposite can be considered as ideal for its use as scaffold for osteoconduction and osteoinduction. Cheng et al. [223] prepared electrochemically a bovine serum albumin (BSA) protein-containing AP coating on a HA coated Ti-6Al-4V. It was reported that (i) the method resulted in a 70-fold increase in BSA inclusion compared to simple adsorption, and was subsequently released by a slow mechanism (15% loss over 70 h), and (ii) thus, this technique provides an efficient method of protein incorporation at physiological stem, with a potential for sustained release of therapeutic agents, as may be required for metallic implant fixation [223].\nRedepenning et al. [224] prepared another type of biocomposite coatings containing brushite (CaHPO4·2H2O) and chitosan by electrochemical deposition. The brushite/chitosan composites were converted to hydroxyapatite/chitosan composites in aqueous solutions of sodium hydroxide. The coatings ranged from about 1 to 15% chitosan by weight. It was mentioned that qualitative assessment of the coatings showed adhesion significantly improved over that observed for electrodeposited coatings of pure HA [224]."}

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Composite Coating\nBioactive calcium phosphate (CaP) coatings were produced on titanium by using phosphate-based glass (P-glass) and hydroxyapatite (HA), and their feasibility for hard tissue applications was addressed in vitro by Kim et al. [207]. P-glass and HA composite slurries were coated on Ti under mild heat treatment conditions to form a porous thick layer, and then the micropores were filled in with an HA sol-gel precursor to produce a dense layer. The resultant coating product was composed of HA and calcium phosphate glass ceramics, such as tricalcium phosphate (TCP) and calcium pyrophosphate (CPP). It was reported that the coating layer had a thickness of approximately 30–40 μm and adhered to the Ti substrate tightly, (ii) the adhesion strength of the coating layer on Ti was as high as about 30 MPa, (iii) the human osteoblastic cells cultured on the coatings produced by the combined method attached and proliferated favorably, and (iv) the cells on the coatings expressed significantly higher alkaline phosphatase activity than those on pure Ti, suggesting the stimulation of the osteoblastic activity on the coatings [207]. Maxian et al. [208] evaluated the effect of amorphous calcium phosphate and poly-crystallized (60% crystalline) HA coatings on bone fixation of smooth and rough (Ti-6Al-4V powder sprayed) Ti-6Al-4V implants after four and 12 weeks of implantation in a rabbit trascortical femoral model. Histological evaluation of amorphous versus poorly crystallized HA coatings showed significant differences in bone apposition and coating resorption that were increased within cortical compared to cancellous bone. The poorly crystallized HA coatings showed the most degradation and least bone apposition. Mechanical evaluation, however, showed no significant differences in push-out shear strengths. Significant enhancement in interfacial shear strengths for bioceremic coated, as compared to uncoated implants, was seen for smooth-surfaced implants (3.5–5 times greater) but not for rough-surfaced implants at four and 12 weeks. Based on these results, it was suggested that once early osteointegration is achieved biodegradation of a bioactive coating should not be detrimental to the bone/coating/implant fixation [208]. Plasma sprayed HA coatings on titanium alloy substrates have been used extensively due to their excellent biocompatibility and osteoconductivity. However, the erratic bond strength between HA and Ti alloy has raised concern over the long-term reliability of the implant. Accordingly, Khor et al. developed HA/yttria-stabilized-zirconia (YSZ)/Ti-6Al-4V composite coatings that possess superior mechanical properties to conventional plasma sprayed HA coatings [209]. Ti-6Al-4V powders coated with fine YSZ and HA particles were prepared through a unique ceramic slurry mixing method. The composite powder was employed as feedstock for plasma spraying of the HA/YSZ/Ti-6Al-4V coatings. The influence of net plasma energy, plasma spray standoff distance, post-spray heat treatment on microstructure, phase composition, and mechanical properties were investigated. It was found that (i) coatings prepared with the optimum plasma sprayed condition showed a well-defined splat structure, (ii) HA/YSZ/Ti-6Al-4V solid solution was formed during plasma spraying, which was beneficial for the improvement of mechanical properties, (iii) the microhardness, modulus of elasticity, fracture toughness, and bond strength increased significantly with the addition of YSZ, and (iv) post-spray heat treatment at 600 °C and 700 °C for up to 12 h was found to further improve the mechanical properties of coatings [209]. Yttria stabilized zirconia (YSZ) is often used as reinforcement for many ceramics because it has the merits of high strength and enhanced toughening characteristics during crack-particle interactions [210–213].\nYamada et al. [214] utilized the Cullet method for which (1) the mixture of HA powder and glass frits are sintered at 900–1000 °C for from 5 to 10 min to prepare well homogenized coating powder, whereas the conventional method is just mixing and not sintering, and (2) the time of etching treatment, through which the bioactive surface is formed using the mixed solution of HNO3 and HF, is relatively short (within 1 min) compared to the conventional method. Through this method, functionally gradient HA/Ti composite implants were successfully fabricated with higher quality compared with the conventional method [214]. Suzuki et al. [215] coated titanium dioxide onto silicone substrates by radio-frequency sputtering. It was reported that silicone coating with titanium dioxide enhanced the breakdown of peroxynitrite by 79%. Titanium dioxide-coated silicone inhibited the nitration of 4-hydroxy-phenylacetic acid by 61% compared to aluminum oxide-coated silicone and 55% compared to uncoated silicone. Titanium dioxide-coated silicone exhibited a 55% decrease in superoxide compared to uncoated silicone, and a 165% decrease in superoxide compared to uncoated polystyrene [215]. Titanium dioxide-coated silicone inhibited IL-6 production by 77% compared to uncoated silicone. Based on these findings, it was concluded that the anti-inflammatory properties of titanium dioxide can be transferred to the surfaces of silicone substrates [215].\nHA coatings with titania addition were produced by the high velocity oxy-fuel spray process by Li et al. [216]. It was found that (i) the addition of TiO2 improves the MOE, fracture toughness, and shear strength of high velocity oxy-fuel sprayed HA-based coatings, (ii) the incorporation of the secondary titania phase is found to have a negative effects on the adhesive strength of high velocity oxy-fuel sprayed HA coatings, (iii) the titania is found to inhibit the decomposition of HA at evelated temperatures lower than 1,410 °C, at which point the mutual chemical reaction occurs, and (iv) a small amount of TiO2 added into high velocity oxy-fuel sprayed HA coatings with less than 20 vol% is therefore recommended for strengthening of HA-coatings [216]. Lu et al. [217] fabricated a two-layer hydroxyapatite (HA)/HA + TiO2 bond coat composite coating (HTH coating) on titanium by the plasma spraying technique. The HA + TiO2 bond coat (HTBC) consists of 50 vol% HA and 50 vol% TiO2 (HT). The as-sprayed HT coating consists mainly of crystalline HA, rutile TiO2 and amorphous Ca-P phase, but the post-spray heat treatment at 650 °C for 120 min effectively restores the structural integrity of HA by transforming non-HA phases into HA [216]. It was found that there exists interdiffusion of the elements within the HTBC, but no chemical product between HA and TiO2, such as CaTiO3 was formed. The toughening and strengthening mechanism of HTBC is mainly due to TiO2 as obstacles resisting cracking, and the reduction of the near-tip stresses resulting from stress-induced microcracking [217]. Ng et al. [218] mimicked bio-mineralization of bone by applying an initial TiO2 coating on Ti-6Al-4V by electrochemical anodization in two dissimilar electrolytes, followed by the secondary calcium (CaP) coating, subsequently applied by immersing the substrates in a simulated body fluid (SBF) with three times concentration (SBF × 3). Electrochemical impedance spectroscopy (EIS) and DC potentiodynamic polarization assessments in SBF revealed that the anodic TiO2 layer is compact, exhibiting up to a four-fold improvement in in vitro corrosion resistance over unanodised Ti-6Al-4V. X-ray photoelectron spectroscopy analysis indicates that the anodic Ti oxide is thicker than air-formed ones with a mixture of TiO2–x compound between the TiO2/Ti interfaces. The morphology of the dense CaP film formed, when observed using scanning electron microscopy, is made up of linked globules 0.1–0.5 μm in diameter without observable delamination. It was also found that (i) the calculated Ca:P ratios of all samples (1.14–1.28) are lower than stoichiometric hydroxyapatite (1.67), and (ii) a duplex coating consisting of a compact TiO2 with enhanced in vitro corrosion resistance and bone-like apatite coating can be applied on Ti-6Al-4V by anodization and subsequent immersion in SBF [218].\nKnabe et al. [219] investigated the effects of novel calcium titanium, calcium, titanium zirconium phosphates suitable for plasma spraying on CpTi substrate on the expression of bone-related genes and proteins of human bone-derived cells, and compared the effects to that on native Ti and HA-coated Ti. Test materials were acid etched and sand-blasted, plasma-sprayed HA, and sintered CaPO4 with Ti, Zr, TiO2, and ZrO2. Human bone-derived cells were grown on these surfaces for 3, 7, 14, and 21 days, counted and probed for various mRNAs and proteins. It was reported that (i) all surfaces significantly affected cellular growth and the temporal expression of an array of bone-related genes and proteins, (ii) at 14 and 21 days, cells on sintered displayed significantly enhanced expression of all osteogenetic mRNAss, and (iii) surfaces of 55CaO·20TiO2·31P2O5 and CaTi4(PO4)6 had the lost effect on osteoblastic differentiation inducing a greater expression on an array of osteogenetic markers than recorded for cells grown on HA, suggesting that these novel materials may possess a higher potency to enhance osteogenesis [219]. Shtansky et al. [220] performed a comparative investigation of multicomponent thin films based on the systems Ti-Ca-C-O-(N), Ti-Zr-C-O-(N), Ti-Si-Zr-O-(N) and Ti-Nb-C-(N). TiC0.5 + 10%CaO, TiC0.5 + 20%CaO, TiC0.5 + 10%ZrO2, TiC0.5 + 20%ZrO2, Ti5Si3 + 10%ZrO2, TiC0.5 + 10%Nb2C and TiC0.5 + 30%Nb2C composite targets were manufactured by means of self-propagating high-temperature synthesis, followed by DC magnetron sputtering in an atmosphere of argon or in a gaseous mixture of argon and nitrogen. The biocompatibility of the films was evaluated by both in vitro and in vivo experiments. The in vitro studies involved the investigation of the proliferation of Rat-1 fibroblasts and IAR-2 epithelial cells on the tested films, morphometric analysis and actin cytoskeleton staining of the cells cultivated on the films. In vivo studies were fulfilled by subcutaneous implantation of Teflon plates coated with the tested films in mice and analysis of the population of cells on the surfaces. It was reported that (i) the films showed high hardness in the range of 30–37 GPa, significant reduced modulus of elasticity, low friction coefficient down to 0.1–0.2, and low wear rate in comparison with conventional magnetron-sputtered TiC and TiN films, (ii) no statistically significant differences in the attachment, spreading, and cell shape of cultured IAR-2 and Rat-1 cells on the Ti-Ca-C-O-(N), Ti-Zr-C-O-(N) (TiC0.5+10%ZrO2 target), Ti-Si-Zr-O-(N) films and the uncoated substrata was detected, and (iii) the adhesion and proliferation of cultured cells in vitro was perfect at all investigated films. Based on these findings, it was concluded that the combination of excellent mechanical properties with non-toxicity and biocompatibility makes Ti-Ca-C-O-N, Ti-Zr-C-O-N, and Ti-Si-Zr-O-N films promising candidates as tribological coatings to be used for various medical applications like total joint prostheses and dental implants [220]. Von Walter et al. [221] introduced a porous composite material, named “Ecopore”, and described in vitro investigation of the material and its modification with fibronectin. The material is a sintered compound of rutile TiO2 and the volcanic silicate perlite with a macrostructure of interconnecting pores. In an in vitro model, human primary osteoblasts were cultured directly on Ecopore. It was reported that human osteoblasts grew on the composite as well as on samples of its single constituents, TiO2 and perlite glass, and remained vital, but cellular spreading was less than on tissue culture plastic. To enhance cellular attachment and growth, the surface of the composite was modified by etching, functionalization with aminosilane and coupling of fibronectin, resulting in greatly enhanced spreading of human osteoblasts. It was therefore concluded that (i) Ecopore is non-toxic and sustains human osteoblasts growth, cellular spreading being improvable by coating with fibro-nectin, and (ii) the composite may be usable in the field of bone substitution [221].\nDifferent biomaterials have been used as scaffolds for bone tissue engineering. Rodrigues et al. [222] characterized biomaterial composed of sintered (at 1,100 °C) and powdered hydroxyapatite and type I collagen (both of bovine origin) designs for osteoconductive and osteoinductive scaffolds. Collagen/HA proportions were 1/2.6 and 1/1 by weight, with particle sizes ranging from 200 to 400 μm. X-ray diffraction and infrared spectroscopy showed that the sintered (1,100 °C) bone was composed essentially of HA with minimum additional groups as surface calcium hydroxide, surface and crystal water, free carbon dioxide, and possibly brushite. It was reported that osteoblasts adhered and spread on both the HA particle surface and the collagen fibers, which seemed to guide cells between adjacent particles [222], suggesting that this biocomposite can be considered as ideal for its use as scaffold for osteoconduction and osteoinduction. Cheng et al. [223] prepared electrochemically a bovine serum albumin (BSA) protein-containing AP coating on a HA coated Ti-6Al-4V. It was reported that (i) the method resulted in a 70-fold increase in BSA inclusion compared to simple adsorption, and was subsequently released by a slow mechanism (15% loss over 70 h), and (ii) thus, this technique provides an efficient method of protein incorporation at physiological stem, with a potential for sustained release of therapeutic agents, as may be required for metallic implant fixation [223].\nRedepenning et al. [224] prepared another type of biocomposite coatings containing brushite (CaHPO4·2H2O) and chitosan by electrochemical deposition. The brushite/chitosan composites were converted to hydroxyapatite/chitosan composites in aqueous solutions of sodium hydroxide. The coatings ranged from about 1 to 15% chitosan by weight. It was mentioned that qualitative assessment of the coatings showed adhesion significantly improved over that observed for electrodeposited coatings of pure HA [224]."}