Chemistry of inorganic compounds – Phosphorus or compound thereof – Oxygen containing
Reexamination Certificate
1995-12-27
2001-02-06
Raymond, Richard L. (Department: 1209)
Chemistry of inorganic compounds
Phosphorus or compound thereof
Oxygen containing
C423S309000, C423S311000, C544S273000
Reexamination Certificate
active
06183711
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to making and using apatite crystals, both in vitro and in vivo, and to the mitigation of the effects of hard tissue diseases.
Natural Sources of Apatite
Calcium hydroxyapatites, a complex calcium phosphate (Ca
5
(PO
4
)
3
OH) in crystalline form, occur naturally as geological deposits and in normal biological tissues, principally bone, cartilage, enamel, dentin, and cementum of vertebrates and in many sites of pathological calcifications such as blood vessels and skin. Essentially none of the geological and biological apatites are “pure” hydroxyapatite since they contain a variety of other ions and cations and may have different ratios of calcium to phosphorous than the pure synthetic apatites. In general, the crystals of pure synthetic apatites, geological apatites and many impure synthetically produced apatites are larger and more crystalline than the biological crystals of bone, dentin, cementum and cartilage.
The terms “crystal” and “crystallite” may be used interchangeably in most respects; “crystallite” simply means a small crystal. A crystal is a homogeneous, solid body of a chemical element, compound, or isomorphous mixture, having a regular repeating atomic arrangement of atoms that may or may not be outwardly expressed by planar faces.
The calcium-phosphate crystals of the bones of essentially all vertebrates have the basic crystal structure of hydroxyapatite as determined by X-ray diffraction. Indeed, the calcium-phosphate crystals of essentially all of the normally mineralized tissues of vertebrates, including enamel, dentin, cementum, and calcified cartilage, have the same general crystal structure. For the purposes of the present invention, these tissues are called “hard tissues”.
However, the crystals of calcium phosphate found in hard tissues such as bone also contain other atoms and ions such as acid phosphate groups (H
2
PO
4
), and carbonate ions, which do not occur in pure, synthetic hydroxyapatite. There is also good evidence that bone crystals either do not contain hydroxyl groups, or contain only very few such groups (Rey et al. (1995) Hydroxyl groups in bone mineral, Bone 16: 583-586) and is therefore more appropriately referred to as “apatite” rather than “hydroxyapatite.” Moreover, many of the carbonate and phosphate groups in bone crystals are, from the structural and physical chemical points of view, unstable and very reactive, thus providing certain physical chemical and biological functional and chemical features important in the formation and dissolution of the crystals in biological tissues.
Recent
31
P-nuclear magnetic resonance spectroscopy studies have demonstrated that the short-range order or environment of the H
2
PO
4
groups in bone crystals are distinctly different than the H
2
PO
4
groups in synthetic apatites and other related calcium-phosphate crystals (Wu, Ph.D. thesis M.I.T., “Solid state NMR study of bone mineral,” Aug. 1992). These differences in chemical, structural, and short range order of the bone crystals compared with pure, synthetic hydroxyapatite also reflect significant differences in their reactivity and hence in their potential function in a biological environment.
The crystals of bone, dentin and cementum are very small, irregularly shaped, very thin plates whose rough average dimensions are approximately 10 to 50 angstroms in thickness, 30 to 150 angstroms in width, and 200 to 600 angstroms in length. This results in their having a very large surface area to present to the extracellular fluids which is critically important for the rapid exchange of ions with the extracellular fluids. This “ion-reservoir” function of the inorganic crystals is very important for a number of critical biological functions.
For a description of the determination of the size of bone crystals, see Ziv, V., and Weiner, S. (1994) Bone Crystal Sizes: A comparison of transmission electron microscopic and X-ray diffraction line width broadening techniques. Connective Tissue Research, 30: 165-175; also Azaroff, L. V. (1968) Elements of X-Ray Crystallography, McGraw-Hill; also Hurlbut, C. S., & Klein, C. (1977) Manual of Minerology, 19th ed., John Wiley & Sons. Most investigators of bone structure prefer to rely on measurements of X-ray diffraction reflection line widths. This parameter is directly related to coherence length, that is the average distance between lattice dislocations in a given direction.
Synthetic Sources of Apatite
Synthetic apatites are highly diverse. For example, the characterization of four commercial apatites was reported by Pinholt, et al., J. Oral Maxillofac. Surg. 50(8), 859-867 (Aug. 1992); J. Cariofac. Surg. 1(3), 154-160 (Jul. 1990) reports on a protein, biodegradable material; Pinholt, et al., Scand. J. Dent. Res. 99(2), 154-161 (Apr. 1991) reports on the use of a bovine bone material called BiO-OSS.™.; Friedman, et al., Arch. Otolaryngol. Head Neck Surg. 117(4), 386-389 (Apr. 1991) and Costantino, et al., Arch. Otolaryngol. Head Neck Surg. 117(4), 379-384 (Apr. 1991) report on a hydroxyapatite cement; Roesgen, Unfallchirurgie 258-265 (Oct. 1990), reports on the use of calcium phosphate ceramics in combination with atogeneic bone; Ono, et al., Biomaterials 11(4), 265-271 (May 1990) reports on the use of apatite-wollastonite containing glass ceramic granules, hydroxyapatite granules, and alumina granules; Passuti, et al., Clin. Orthop. 248, 169-176 (Nov. 1989) reports on macroporous calcium phosphate ceramic performance; Harada, Shikwa-Gakuho 89(2), 263-297 (1989) reports on the use of a mixture of hydroxyapatite particles and tricalcium phosphate powder for bone implantation; Ohgushi, et al., Acta Orthop. Scand. 60(3), 334-339 (1989) reports on the use of porous calcium phosphate ceramics alone and in combination with bone marrow cells; Pochon, et al., Z-Kinderchir. 41(3), 171-173 (1986) reports on the use of beta-tricalcium phosphate for implantation; and Glowacki, et al., Clin. Plast. Surg. 12(2), 233-241 (1985), reports on the use of demineralized bone implants.
Apatite-Forming-Systems
Synthetic calcium hydroxyapatite is formed in the laboratory either as pure Ca
5
(PO
4
)
3
(OH) or hydroxyapatite that is impure, containing other ions such as carbonate, fluoride, chloride for example, or crystals deficient in calcium or crystals in which calcium is partly or completely replaced by other ions such as barium, strontium and lead. Systems for forming apatite by precipitating solutes are known from the literature. In these processes, hydroxyapatite precipitates in very finely crystalline form in nearly all solutions.
Some examples of methods for the precipitation of hydroxyapatite, the properties of the apatite product, and possible applications are discussed below. For the purposes of this invention, the term “apatite” signifies any of the forms of apatite in which the hydroxyl groups are replaced by other anions.
It is known from U.S. Pat. No. 4,274,879, for example, to prepare hydroxyapatite by mixing milk of lime with at least 60% phosphoric acid in stoichiometric amounts at temperatures of 80° C.-85° C., and a pH of the reaction solution of about 9.0-11.0 in a continuous reaction. The products obtained are suitable for preparing bone replacement parts by sintering at temperatures of 700° C. They are unsuitable as tooth-cleaning substances on account of their fineness. Additional examples of such methods, products, and applications are disclosed in U.S. Pat. Nos. 4,324,772 and 4,849,193.
Apatites in which the OH.
—
is replaced with simple anions, including F
—
, Br
—
, I
—
, or carbonate, may be prepared by modifying the process for preparing hydroxyapatite. Apatite derivatives in which calcium is replaced by metal ions, such as paramagnetic, radiopaque, or radioactive metal ions, may also be prepared and used within the scope of the present invention. Useful apatites may also be prepared by replacing phosphate with oxyanions or tetrahedral anions containing radiopaque or radioactive metal species. Stoichiometric pure hydroxyapati
Falster Alexander U.
Nakamoto Tetsuo
Simmons, Jr. William B.
Murray Michael L.
Nakamoto Tetsuo
Raymond Richard L.
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