Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Derived from musculoskeletal system – other than cardiac muscle
Reexamination Certificate
2002-06-26
2004-12-14
Tate, Christopher R. (Department: 1654)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Derived from musculoskeletal system, other than cardiac muscle
C435S378000, C435S284100
Reexamination Certificate
active
06830763
ABSTRACT:
FIELD OF THE INVENTION
The invention is a process for producing demineralized osteoinductive bone, and demineralized osteoinductive bone produced thereby. The process achieves demineralization of bone by subjecting bone, including for example ground bone, bone cubes or strips, and essentially intact bone, to a continuous exchange of acid. The process allows bone to be rapidly demineralized to a precise and specific desired residual calcium level, without sacrificing osteoinductivity.
BACKGROUND OF THE INVENTION
Demineralized freeze-dried bone allograft is widely used in the repair of skeletal defects and periodontal disease. It is known that the implantation of acid demineralized bone in the form of a powder in extraskeletal sites may stimulate new bone formation. Various groups including Syftestad, 1982; Urist et al., 1967; Urist and Strates, 1979; Urist and Strates, 1971; Urist et al., 1983; have suggested that a noncollagenous protein or proteins present in demineralized bone has the ability to induce new bone formation when present within the implanted bone matrix.
Current procedures used to demineralize ground bone involve the use of ethanol to remove lipids and hydrochloric acid to remove the mineral components of bone. These known methods are problematic in that they require prohibitively long periods of time for processing resulting in a very low demineralization rate; require excessive handling of the ground bone being processed; are capable of processing only small amounts of ground bone; and result in a demineralized bone product which exhibits inferior osteoinductivitiy caused by excessive exposure of bone inducing proteins in the bone to harsh acids over extended periods of time.
SUMMARY OF THE INVENTION
The invention achieves high demineralization rates by subjecting bone, for example ground cortical bone, to rapid and continuous exchanges of acid. Suitable acids include both highly ionized and/or weak acids. The inventors have discovered that the acid neutralization rate of bone mineral apatite is highly dependent upon the bone surface concentration of the acid and the demineralization reaction products. The initial reaction rate of the acid at the surface of the bone particle is very rapid and quickly terminates, due to boundary layer resistance caused by the increasing concentrations of the reaction by-products, if the residual reaction products are not promptly removed. Since the bone is subjected to the demineralizing acid for very brief periods of time, bone-inducing proteins are not adversely affected, thus resulting in a bone product, which achieves maximum potential osteoinductivity. The process also allows the demineralization of an entire single donor's tissue volume in a single batch.
The invention provides a rapid demineralization process for producing osteoinductive bone, including subjecting bone to continuous exchange of acid to produce demineralized bone.
The invention also provides a rapid demineralization process for producing osteoinductive bone, including subjecting bone to a continuous exchange of a predetermined volume of one or more demineralizing acid solutions under conditions effective to produce demineralized bone.
The invention further provides a rapid demineralization process where acid is continuously exchanged by recirculating a volume demineralizing acid solution from the reaction chamber containing bone to be demineralized, through an ion exchange media to remove calcium thereby producing regenerated acid, and returning the regenerated acid to the reaction chamber, where recirculation is carried out for an interval of time corresponding to a desired residual calcium level.
The invention also provides a rapid demineralization process for producing osteoinductive demineralized bone, including placing an amount of bone to be demineralized into a substantially closed container, and subjecting the bone to a continuous exchange of a demineralizing acid solution to produce osteoinductive demineralized bone.
The invention provides a rapid demineralization process where the step of subjecting includes agitation including for example, stirring, shaking, orbital shaking, and/or sonicating.
The invention further provides a rapid demineralization process where the ion exchange media is agitated during processing for example by stirring, shaking, orbital shaking, and/or sonicating.
The invention provides a rapid demineralization process for demineralizing bone by subjecting bone to a continuous exchange of a demineralizing acid solution, under conditions sufficient to achieve a demineralization rate of from about 1.5 g demineralized bone per minute to about 30.0 g per minute, preferably form about 5.0 g per minute to about 30.0 g per minute, more preferably from about 8.0 g per minute to about 25.0 g per minute, even more preferably from about 10.0 g demineralized bone per minute to about 22.0 g per minute, most preferably about 20.0 g demineralized bone per minute.
The invention further provides a rapid demineralization process for demineralizing bone (preferably to about 2.0 wt % residual calcium) where the continuous exchange of acid is carried out over intervals of from about 1.0 minutes to about 30 minutes, preferably from about 2.0 minutes to about 25.0 minutes, and more preferably from about 3.0 minutes to about 20.0 minutes, and most preferably about 4.0 minutes to about 11.0 minutes to achieve about 2.0 wt % residual calcium.
The invention also provides a rapid demineralization process for demineralizing bone by subjecting bone to a continuous exchange of acid, where the bone is demineralized until a specific desired residual calcium level is achieved.
The invention provides a rapid demineralization process for demineralizing bone where calcium is continuously removed from the demineralizing acid solution.
The invention provides a rapid demineralization process for demineralizing bone where calcium and phosphate are continuously removed from the demineralizing acid solution.
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Reddi et al. 1972. Proc. Nat. Acad. Sci. USA. vol. 69, No. 6, pp. 1601-1605.
O'Leary Robert K.
Wolfinbarger, Jr. Lloyd
Zajdowicz Jan
Hale and Dorr LLP
LifeNet
Tate Christopher R.
LandOfFree
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