Paste compositions capable of setting into carbonated apatite

Details Paste compositions capable of setting into carbonated apatite Paste compositions capable of setting into carbonated apatite

1999-04-01

2002-01-01

Marcantoni, Paul (Department: 1755)

Compositions: coating or plastic

Coating or plastic compositions

Dental

C106S690000, C106S691000, C423S308000, C423S309000

Reexamination Certificate

active

06334891

ABSTRACT:

TECHNICAL FIELD
The field concerns the preparation of substantially pure compositions of carbonate-substituted forms of hydroxyapatite, and the biomedical use of such compositions.
BACKGROUND
A number of calcium phosphate minerals, such as hydroxyapatite, fluorapatite, octacalcium phosphate, whitlockite, brushite and monetite may have application as biocompatible materials. The various crystalline forms of the calcium phosphate minerals can confer different physical properties that may be more or less desirable for a specific biomedical application. For instance, octacalcium phosphate and whitlockite are less resorbable than brushite or monetite (Brown and Chow,
Ann. Rev. of Materials Science
(1976) 6:213-236).
Of particular interest are the apatites. Apatite is a general term for a wide range of compounds represented by the general formula M
2+
10
(ZO
4
3−
)
6
Y
−
2
, where M is a metal atom, particularly an alkali or alkaline earth atom, ZO
4
is an acid radical, where Z may be phosphorous, arsenic, vanadium, sulphur, silicon, or may be substituted in whole or in part by carbonate (CO
3
2−
), and Y is an anion, usually halide, hydroxy, or carbonate. When ZO
4
3−
is partially or wholly replaced by trivalent anions (such as CO
3
2−
) and/or Y is partially or wholly replaced by divalent anions, then charge balance may be maintained in the overall structure by additional monovalent cations (such as Na
+
) and/or protonated acid radicals (such as HPO
4
2−
).
Hydroxyapatite (HAp), as well as its various forms, has been the focus of substantial interest because it is a major structural component of biological tissues such as bone, teeth, and some invertebrate skeletons. There are many situations where bone has been broken, surgically removed, destroyed, degraded, become too brittle, or been subject to other deteriorating effects. In many of these situations it would be desirable to be able to replace the bone structure or strengthen the bone structure. In providing materials to substitute for natural bone, teeth, or other calcified tissues, there are a number of restraints on the natural composition of the material.
Dental applications might prefer a fluoride substituted hydroxyapatite, i.e. francolite, that would reduce solubility and increase resistance to decay.
The material should ideally possess certain characteristics that facilitate the production, storage life, and biomedical application of the material. Specifically, a material which could be a material which could be fingerpacked in an open surgical procedure or percutaneously injected as a flowable composition to fill voids or completely fill-in areas deficient of hard bone is very desirable. Where the material is to be placed in the body and formed and hardened in situ, a variety of considerations come to the fore. For example, the rate at which hydroxyapatite forms as well as the extent to which the formation of hydroxyapatite is exothermic or may generate gas can also be important. Where the reaction is highly exothermic, it may cause thermal necrosis of the surrounding tissue.
As the final form of the material must be stable under physiological conditions, so must the form in which the material is introduced be stable while it is hardening in the environment to which it is introduced, as must be any intermediate products of the formation reaction.
The material should also be physiologically acceptable at all phases of curing to the final product, so as to avoid the initiation of clotting, inflammatory responses, and the like. Two different forms of apatite are particularly desirable: One being an hydroxyapatite or a fluoridated derivative thereof that is non-resorbable in vivo; the other includes forms of apatite that are substantially resorbable in vivo. In addition, both forms of apatite must usually be strong and non-friable. Furthermore, there should be a strong adhesion between the material and the remaining bone or calcified tissue. Also, the material should desirably be able to substitute some of the other functions of natural bone such as: accommodating stem cells; allowing infiltration by cells normally resident in natural bone such as osteoclasts, osteoblasts, and the like; allowing remodeling of the material by the infiltrating cells followed by new bone in-growth; and acting in metabolic calcium exchange in a manner similar to native bone.
Carbonate has been shown to inhibit crystal growth of HAp (Blumenthal, et al.,
Calcif. Tissue Int
. (1984) 36:439-441; LeGeros, et al., “Phosphate Minerals in human tissues”, in
Phosphate Minerals
(Berlin), J. Nriagu (eds): Springer, 1984, pp. 351-385; LeGeros, et al.,
J. Dent. Res
. (1989) 68:1003; Nauman and Neuman, The Chemical Dynamics of Bone Mineral, University of Chicago Press, Chicago, (1958); Newesley,
Arch. Oral Biol
. (1961) 6:174-180; Posner,
Clin. Orthop
. (1985) 200:87-99). Carbonates are present in the apatites of hard tissues, and their presence alters the properties of stoichiometric apatite. Carbonate has been described as causing: 1) a reduction in crystallite size, 2) changes in the morphologies of the mineral phase from needles and rods to equi-axis crystals (spheroids), 3) contraction of the a-axis, as well as an expansion in the c-axis, 4) internal strain, and 5) chemical instability (LeGeros, et al., supra , 1984; LeGeros, et al., supra, 1989). All of these factors lead to higher solubilities of carbonate-substituted HAp. The x-ray diffraction patterns as well as the radial distribution function are changed considerably in that as the concentration of carbonate increases, the patterns become more amorphous in character (LeGeros et al., supra 1989; Glimcher, M. J., “Recent studies of the mineral phase in bone and its possible linkage to the organic matrix by protein-bound phosphate bonds”,
Phil. Trans. R. Soc. London Ser. B.,
304, 479-508). The line broadening observed in the diffraction pattern is caused by decreasing crystallite size and crystallinity. In addition to inhibiting HAp crystal growth, carbonate substitution markedly increases the solubility of HAp (Nelson, et al.,
Ultramicroscopy
(1986) 19:253-266. Another interesting experimental finding was that, whether the carbonates are structurally bound within, or absorbed onto HAp, differences in dissolution behavior were observed. This suggests that dissolution increased in HAps containing structurally bound carbonates, while decreasing in HAps with absorbed CO
3
2−
. The decrease in dissolution was explained by the fact that hydronium ions had to compete for the surface of HAp, hence the deposition of the CO
3
2−
layer was required.
The extent of carbonate uptake during HAp precipitation under normal physiologic conditions is approximately 1% by weight CO
3
2−
(Posner, supra, 1985). Bone consists of approximately 4% by weight CO
3
2−
. Thus, HAp precipitation reactions in air generally contain relatively low concentrations of carbonate. Bone mineral apatite with a level of carbonate between 2% and 10% by weight has been referred to by convention as dahllite (McConnell,
J. Dent. Res
. (1952) 31:53-63 and McConnell,
Clin. Orthopaed
. (1962) 23:253-268).
Carbonates can substitute in both the Z and Y sites of the apatite structure, and it is generally accepted that carbonates substitute for PO
4
3−
groups during precipitation reactions leading to HAp formation. More specifically, HAp products formed at lower temperature exhibit carbonate substitution at the phosphate sites, and due to its smaller size, a decrease in the a-axis of the apatite results (LeGeros, et al., supra, 1984 and LeGeros, et al., supra, 1989). Conversely, in most high temperature apatites, the carbonates are found in the vicinity of the six fold axis, where they replace hydroxyl ions. Since the carbonate is larger than the hydroxyl ion, an increase in the a-axis results (Brown and Chow, (1986), supra).
The skeleton is the reservoir for almost all of the body's calcium and most of its phosphorus and magnesium (Avioli and Krane

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