Beta-tricalcium phosphate is prepared by sintering precipitated Ca deficient apatite with Ca to P molar ratio of 1.5 or by solid-state reactions at high temperature 70,98 Vitoss™ (Orthovita, Inc, Philadelphia, PA) is one of the commercial beta-tricalcium phosphate.
Biphasic calcium phosphate of varying hydroxyapatite to beta-tricalcium phosphate weight ratios is obtained by sintering precipitated calcium deficient apatite (Ca/P molar ratio < 1.67) 12,68,77 Commercial biphasic calcium phosphate products include:Triosit™ (Biomatlante Ltd, Nantes, France), MBCP™ (Biomatlante Ltd), and Osteosynt™ (Einco Biomaterial Co Bella Horizonte, Brazil).
Calcium deficient apatite is prepared either by precipitation at temperatures 25° to 100° C (depending on the desired crystallinity) or by hydrolysis of amorphous calcium phosphate, dicalcium phosphate dihydrate, alpha-tricalcium phosphate, or octacalcium phosphate. 71 An example of commercial unsintered apatite product is Osteogen™ (Impladent Co, Long Island, NY) advertised as resorbable hydroxapatite. 73,134
Noncommercial CaP materials also recommended for bone grafts include octacalcium phosphate, 52 whitlockite, or Mg-substituted tricalcium phosphates, 40 Znsubstituted tricalcium phosphate, 53 carbonate-substituted apatites, 108 and fluoride-substituted apatites. 38,40,55,99 Substitution in the betatricalcium phosphate or apatite structure affects the crystal and dissolution properties of the CaP. For example, carbonate substitution causes the formation of smaller and more soluble apatite, whereas fluoride incorporation has the opposite effects. 66,70,88,91–93,100,140 Magnesium incorporation in apatite is limited but causes reduction in crystallinity (smaller crystal size) and increases its extent of dissolution. 66,70,78,81,91 Strontium causes an increase in solubility. 70 Magnesium or Zn substitution in the beta-tricalcium phosphate structure also affects the properties. 70,74,107
The rationale for the development of hydroxyapatite-coated orthopaedic and dental implants is to combine the demonstrative bioactive properties of hydroxyapatite and the strength of the metal, usually Ti or Ti alloy. 8,51,63,70,82,83 Plasma-spray technique is the method used for depositing the coating. Although the source material used is pure hydroxyapatite, the plasma-sprayed coatings are not pure hydroxyapatite but a mixture of crystalline (principally hydroxyapatite) and the noncrystalline component, or amorphous calcium phosphate. 63,82,86 Other minor crystalline components that may be present include alpha- or beta-tricalcium phosphate, tetracalcium phosphate, and sometimes CaO. The hydroxyapatite component can make up approximately 95% of the crystalline component; however, the hydroxyapatite to amorphous calcium phosphate ratio of the coating can vary from 30 to 70 to 70 to 30 and this ratio is higher in the layer closest to the metal compared with the outermost layer. 63,70,86 Accelerated skeletal attachment and a stronger bone-implant interface have been reported for hydroxyapatite-coated implants compared with the uncoated ones implants. 20,42 Bloebaum et al 11 reported implant failure attributed to the hydroxyapatite coating that resorbs or delaminates before bone can attach to it. It is speculated that the hydroxyapatite to amorphous calcium phosphate ratio is critical to the stability of the coating and also may affect the stability of the implant. 82 Coating with a low hyroxyapatite to amorphous calcium phosphate ratio is expected to be more soluble because the amorphous calcium phosphate component preferentially will dissolve. 70,72,82 An alternative to the plasma-spray method of depositing CaP coating is electrochemical deposition. This allows deposition of the desired coating of homogeneous composition. Dicalcium phosphate dihydrate, octacalcium phosphate, or apatite coatings have been obtained using this method. 64,123,133
The concept of developing apatitic cement or CaP cements first was introduced by LeGeros et al 75 and Chow et al. 17,18 CaP cements consist of solid and liquid components. A combination of CaP with or without other calcium compounds make up the solid components and the liquid component may be inorganic (sulfuric acid, phosphoric acid) or organic acids (lactic acid, tartaric acid) or NaP solutions. 17–19,35,62,75 Calcium phosphate compounds that have been used include: amorphous calcium phosphate, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, monocalcium phosphate monohydrate, alpha-tricalcium phosphate, beta-tricalcium phosphate, calcium deficient apatite, and tetracalcium phosphate. The products obtained after setting depends on the solid and liquid reactants. Setting products include: calcium deficient apatite, carbonate apatite, dicalcium phosphate dihydrate. Commercial CaP cements presently available are αBSM™ (Etex Corporation, Boston, MA) consisting of amorphous calcium phosphate and dicalcium phosphate dihydrate mixed with saline solution;62 Bonesource™ (Orthofix Inc, McKinney, TX) consisting of tetracalcium phosphate and anhydrous dicalcium phosphate mixed with phosphate solution or water, 17,18 and monocalcium phosphate monohydrate and CaCO3 mixed with water. 35 Some of these cements are injectable. 41,96
The extent of dissolution of coralline hydroxyapatite is much higher than that of ceramic hydroxyapatite. 73,90 This difference can be attributed to the difference in crystal size and composition (Table 2): coralline apatite crystals are much smaller (Fig 6) and contain magnesium and carbonate ions that cause an increase in the dissolution of apatite. 70,81,93
For substituted apatites, the type and extent of substitution affects the solubility: carbonate substitution contributes to increasing the solubility and F substitution to decreasing the solubility of apatite. 71,86,101 Comparing unsubstituted apatite with carbonate- or Fsubstituted apatite, carbonate-substituted apatite is most soluble, and F-substituted apatite, the least souble. With biphasic calcium phosphates, the dissolution property depends on the hydroxyapatite to beta-tricalcium phosphate ratio: the higher the ratio, the lower the extent of dissolution. 77
In vivo data confirm the in vitro observations on comparative degradation of CaP biomaterials. The factors that influence dissolution properties in vitro (composition, surface area, surface topography, microporosity and macroporosity) also were operative in vivo. Therefore, it is possible to use an appropriate CaP material with the biodegradation desired for particular clinical applications. With biphasic calcium phosphates, control of biodegradation (and bioactivity) by adjusting the hydroxyapatite to beta-tricalcium phosphate ratio was suggested. 77
In vitro studies on bone cell culture models are used routinely to determine biocompatibility and to investigate bone and biomaterial interactions. Osteoblastlike cells (responsible for bone formation) are used most frequently 1,6,27,28,38,43,54,105,139 and osteoclasts (cells responsible for bone resorption) are used less frequently. 29,121,136,138 Interaction with periodontal ligament cells also has been reported. 3,21,125 Cell proliferation, attachment, and phenotypic expression seem to be influenced by composition, surface roughness, or topography of the CaP biomaterial. 21,38,72,109,120,125,138,139 In vitro, no difference in cell proliferation was observed between coralline hydroxyaptite and synthetic (ceramic) hydroxyapatite. 80 Fluoride-treated bovine bone seemed to stimulate cell activity including proliferation and collagen production (Fig 7) compared with the nontreated bone. 38 Fluoride also seems to inhibit osteoclastic resorption of F-treated bone 136 or F-containing apatite. 38,55,121 In vivo, implanted F-substituted apatite showed higher levels of osteoblastic activity at the bone-biomaterial interface compared with F-free apatite. 55
Bioactivity is defined as the property of the material to develop a direct, adherent, and strong bonding with the bone tissue. 45,46,110 This property was observed first by Hench et al 45,46 with silica-based glasses with special formulation referred to as bioactive glass and associated with a CaP-rich layer that forms between the bioactive glass and the bone tissue. In vitro, bioactivity has been attributed to materials that have the ability to form carbonate hydroxyapatite on its surface when exposed to simulated body fluid. 45,59,77 Therefore, Ti, formerly described as biotolerant and not bioactive, 110 can be treated chemically (with NaOH) to form a TiOH layer that allows a formation of a bioactive carbonatehydroxyapatite layer when exposed to simulated or natural body fluid, imparts a bioactive property to the Ti implant. 59
In vivo, microcrystals were observed to be associated with ceramic CaP biomaterials (hydroxyapatite or biphasic calcium phosphate) implanted in osseous 9,39,77,79,80,129 or nonosseous sites. 47 These microcrystals were identified as carbonatehydroxyapatite intimately associated with an organic matrix. 47,77,79,80 In vivo, the formation of carbonatehydroxyapatite on surfaces of CaP biomaterials at the bone-biomaterial interface (Fig 8) is thought to be a cellmediated dissolution and precipitation processes. 13,77,79,80 Cellular activity induces partial dissolution of the CaP biomaterials and liberation of Ca and P ions onto the microenvironment. In addition to the Ca and P ions, other ions (Mg, CO3) from the biologic fluid become incorporated in the carbonatehydroxyapatite microcrystals that form in intimate association with an organic component on the surfaces of the much larger crystals of the CaP biomaterial (Fig 8). This initial action may trigger a mineralization of the ECM leading to bone formation. The enrichment of Ca and P ions in the microenvironment seem to promote bone mineralization and enhance bone formation. 16,77,80
Formation of carbonatehydroxyapatite on surfaces of calcium phosphate biomaterials in vitro and in vivo seems to be related to the extent of dissolution of the calcium phosphate biomaterials. When exposed to serum, carbonatehydroxyapatite formed after a shorter time on the coralline hydroxyapatite surfaces compared with that on ceramic hydroxyapatite. 80,90 Biphasic calcium phosphates with lower hydroxyapatite to beta-tricalcium phosphate ratios (more soluble) showed greater abundance of the carbonatehydroxyapatite microcrystals. 24,77
Bioactive materials allow attachment of cells and their differentiation directly on the surface to result in intimate bonding with the newly-formed bone creating a uniquely strong interface. 46,110 Cohesive failure of the material, bone tissue, or both, occurred with bioactive materials (CaP materials, bioactive glasses, hydroxyapatite-coated implants) and not at the bone-material interface, whereas failure occurred at the bone-material interface with nonbioactive materials (metals, polymers). Failure observed at the bone-Ti interface in the case of uncoated Ti implant, and at the coating-Ti interface in the case of hydroxyapatite-coated implant, is attributable to the stronger bond between the bone and the bioactive coating compared with that between the Ti and the coating. 23 The bone-CaP biomaterial interface is a dynamic one with the CaP biomaterial interacting with and becoming part of the newly forming bone.
CaP biomaterials have a high affinity for proteins, making them ideal carriers for bioactive peptides, bone growth factors, or MSCs. 106,113,127 It generally is accepted that CaP biomaterials are osteoconductive but not osteoinductive (property to form bone when implanted in nonbony sites). However, there are reports of its possible osteoinductive properties. 58,116,128 This osteoinductive property was found to be associated with specific geometry of the CaP biomaterial. 113,116 Reddi 113 attributed this phenomenon to the binding of an optimum amount of endogenous BMP in circulation to the CaP biomaterial allowing the biomaterial to become osteoinductive. Kuboki et al 58 concluded that the geometry of the BMP carrier is one of the important factors controlling the efficacy of the phenotype induction. These investigators determined that the optimal pore size of porous blocks of hyroxyapatite as BMP carriers to induce direct bone formation was 300 to 400 μm.
Commercial CaP biomaterials used as bone substitutes in several orthopaedic and dental applications generally differ from bone in mechanical strength and physicochemical properties. 30,51,69,85 They cannot be used in load bearing applications because of their low fracture strength. 30,51 Used as coatings on orthopaedic and dental metal (Ti or Ti alloy) implants, CaP biomaterials impart bioactivity to the metal substrate enhancing and accelerating skeletal fixation. 8,30,42,51 The bioactive and osteoconductive properties of CaP biomaterial allow direct and intimate apposition of the newly formed bone to their surfaces resulting in formation of a uniquely strong interface. With the appropriate geometry, CaP biomaterials can serve as carriers of bone growth factors (BMPs), bioactive peptides, or MSCs that allow regeneration of hard tissues using tissue engineering. 58,106,113,116
The author thanks Drs R. Craig, G. Daculsi, C. Frondoza, A. Gatti, M. Heughebaert, R. Kijkowska, J.P. LeGeros, D. Mijares, S. Lin, E. Nery, I. Orly, R. Rohanizadeh, T. Sakae, and M. Okazaki for professional collaboration and Dr. M. Retino, Ms. Bleiwas, and Mr. J. Wong for technical collaboration in the author’s work cited in this review.
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Thomas W. Bauer, MD, PhD; and George F. Muschler, MD—Guest Editors