Methods for carbonate surface coating and related bone void filler compositions

Abstract

Methods for preparing bone void filler substrates with carbonate surface coatings to promote bone growth.

Claims

1. A method of preparing a bone void filler substrate comprising calcium component particles thereon, said method comprising: providing a carbonatable calcium salt precursor component having a water solubility; applying said precursor component to a bone void filler substrate; and treating said applied precursor component with a transformation component selected from alkali metal hydroxide and alkali metal carbonate to provide on said substrate a calcium component having a water solubility less than the water solubility of said precursor component, said calcium component selected from calcium hydroxide and calcium carbonate particles.

2. The method of claim 1 wherein said calcium salt precursor component is selected from calcium chloride, calcium oxide and calcium acetate.

3. The method of claim 1 wherein said transformation component is selected from sodium hydroxide and sodium carbonate.

4. The method of claim 1 wherein said calcium component is calcium hydroxide, and said transformation component is sodium hydroxide.

5. The method of claim 4, further comprising contacting said substrate with a carbon dioxide source to provide calcium carbonate particles thereon.

6. The method of claim 5 wherein said carbon dioxide source, optionally in the presence of water, is selected from gaseous carbon dioxide, liquid supercritical carbon dioxide and sodium carbonate.

7. The method of claim 6 wherein the presence of water is selected from atmospheric water vapor about said substrate and water applied to said substrate.

8. The method of claim 1 wherein said bone void filler substrate comprises a material selected from calcium salts, collagen, natural mammalian bone, polymers, metals and combinations thereof.

9. The method of claim 1 wherein said carbonatable calcium precursor component is provided as an aqueous solution thereof, and application of said carbonatable calcium precursor component is selected from dipping, soaking and spraying said substrate therewith.

10. The method of claim 1 wherein said substrate is applied to a mammalian bone void.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

(1) As demonstrated by certain non-limiting embodiments, the present invention provides a method to form particles or crystals of calcium carbonate dispersed about the surface (including inside pores) of a biocompatible BVF substrate, such as but not limited to a bone implant. As such, fabrication is simplified and scaffold effectiveness is increased because the material is all one phase rather than a mixture of different materials that may segregate.

(2) The calcium carbonate surface treatment of this invention can be applied to substrates comprising materials known to those skilled in the art (e.g., without limitation implant materials) such as calcium salts including but not limited to calcium phosphates (e.g., hydroxyapatite), collagen based materials, anorganic bone, allograft bone, polymers, and metals/alloys. Any such substrate/material coated with precipitated calcium carbonate particles/crystals, as described herein, can be considered in the context of this invention.

(3) Calcium carbonate has a very low solubility (about 0.013 g/1000 ml water), and it is impractical to soak a BVF substrate in a calcium carbonate solution for the purposes of obtaining a coating. A preferred process, in accordance with certain non-limiting embodiments of this invention, starts with a more soluble calcium compound (salt) that is transformed to a calcium carbonate precipitate on a substrate surface. In accordance with broader aspects of this invention, there are many possible routes to obtain this result. The choice of what route to use is limited only by the chemical and/or physical properties of a BVF substrate to be treated.

EXAMPLES OF THE INVENTION

(4) The following non-limiting examples and data illustrate various aspects and features relating to the methods/compositions and/or devices of the present invention, including the preparation of various substrates comprising calcium carbonate coatings. In comparison with the prior art, the present methods, compositions and/or devices provide results and data which are surprising, unexpected and contrary thereto. While the utility of this invention is illustrated through the use of several carbonatable calcium precursor components, BVF substrates and reagents which can be used therewith, it will be understood by those skilled in the art that comparable results are obtainable with various other precursor components, BVF substrates and reagents, as are commensurate with the scope of this invention.

Example 1a

(5) With reference to the equations, below, one approach involves soaking, spraying, or dipping a bone void filler material/substrate in a calcium chloride solution; and soaking dipping, or spraying the calcium chloride wetted substrate with a sodium hydroxide solution to transform the calcium chloride to relatively insoluble calcium hydroxide (and soluble sodium chloride, NaCl). The treated substrate can then be dried (optional) and rinsed with water to remove the NaCl. The final step is to expose the sodium hydroxide treated substrate to a carbon dioxide (CO.sub.2) source to transform the hydroxide into carbonate. Alternatively, such a washing step to remove NaCl can be carried out after carbonate transformation. An advantage is that the carbonate is less soluble than the hydroxide, and such an alternative can provide more carbonate on the bone void filler substrate.

(6) Calcium hydroxide has a higher solubility than calcium carbonate, but it is still very low (about 1.8 g/1000 ml water). Calcium chloride has a solubility of about 740 g/1000 ml water which is over 400 times greater than that of calcium hydroxide and so provides a better route than direct treatment with calcium hydroxide to cover the substrate surface with a calcium salt. Sodium hydroxide has a very high water solubility (about 1100 g/1000 cc water), and can be used very sparingly to transform a calcium chloride coated substrate to a calcium hydroxide precipitate coating without washing away much of the calcium chloride. The transformation to carbonate is preferably done by exposure to gaseous CO.sub.2, although liquid supercritical CO.sub.2 can be used. The surface of the substrate to be treated is preferably damp, or water vapor can be introduced with the CO.sub.2 to provide a humid conversion atmosphere.

(7) The end result is a dispersion of nano-sized calcium carbonate crystals over the BVF substrate surface. The surface architecture is unique and cannot be duplicated by depositing a pre-formed calcium carbonate material on the device surface.
Calcium chloride+sodium hydroxide.fwdarw.calcium hydroxide+salt
CaCl.sub.2(aq)+NaOH(aq).fwdarw.Ca(OH).sub.2(s)+2NaCl(aq)
Calcium hydroxide+carbon dioxide.fwdarw.calcium carbonate+water
Ca(OH).sub.2(s)+CO.sub.2(g).fwdarw.CaCO.sub.3(s)+H.sub.2O(aq)

Example 1b

(8) With reference to the preceding, an alternative route uses an organic calcium salt such as calcium acetate (solubility is about 340 g/1000 ml water), followed by treatment with sodium hydroxide to obtain calcium hydroxide and sodium acetate. Carbonation, as described above, provides the desired calcium carbonate particles/crystals.

Example 2

(9) Another approach is to cover a BVF substrate surface with calcium acetate (by soaking, dipping, or spraying a calcium acetate solution), then treating the substrate with a sodium carbonate solution (solubility about 340 g/1000 cc water) to transform the calcium acetate to calcium carbonate and soluble sodium acetate that can be rinsed away.
calcium acetate+sodium carbonate.fwdarw.calcium carbonate+sodium acetate
Ca(C.sub.2H.sub.3O.sub.2).sub.2(aq)+Na.sub.2CO.sub.3(aq).fwdarw.CaCO.sub.3(s)+2NaC.sub.2H.sub.3O.sub.2(aq)

Example 3

(10) Another approach is to cover a BVF substrate surface with calcium chloride (by soaking, dipping, or spraying a calcium chloride solution), then treating the substrate with a sodium carbonate solution to transform the calcium chloride to calcium carbonate along with the formation of soluble sodium chloride that can be rinsed away.
Calcium chloride+sodium carbonate.fwdarw.calcium carbonate+sodium chloride
CaCl.sub.2(aq)+Na.sub.2CO.sub.3(aq).fwdarw.CaCO.sub.3(s)+2NaCl(aq)

Example 4

(11) Another approach is to transform calcium oxide or another such carbonatable precursor component present in/on a corresponding BVF substrate to calcium carbonate by an aqueous reaction with sodium carbonate. Such a transformation may be a two-step reaction where the calcium oxide is first transformed to calcium hydroxide which then reacts with the sodium carbonate to produce calcium carbonate and sodium hydroxide. The sodium hydroxide is very water soluble and can be rinsed away.
Calcium oxide in water.fwdarw.calcium hydroxide
CaO(s)+H.sub.2O.fwdarw.Ca(OH).sub.2(s)
Calcium hydroxide+sodium carbonate.fwdarw.calcium carbonate+sodium hydroxide
Ca(OH).sub.2(s)+Na.sub.2CO.sub.3(aq).fwdarw.CaCO.sub.3(s)+2NaOH(aq)

(12) Overall reaction:
Calcium oxide+sodium carbonate.fwdarw.calcium carbonate+sodium chloride
CaO(aq)+H.sub.2O+Na.sub.2CO.sub.3(aq).fwdarw.CaCO.sub.3(s)+2NaOH(aq)

(13) While the principles of this invention have been described in conjunction with certain embodiments, it should be understood clearly that these descriptions are provided only by way of example and are not intended to limit, in any way, the scope of this invention. For instance, in conjunction with comparative carbonate salt solubilities, a transformation component such as an alkali metal hydroxide or carbonate can have a solubility greater than that of a carbonatable calcium precursor component. Likewise, methods and resulting compositions of the present invention can be considered in conjunction with various bone implant materials known to those skilled in the art, including but not limited to a mammalian biocompatible anorganic bone mineral matrix produced by removal of organic components. Alternatively, such substrates can be autologous bone from an implant recipient or allograft bone, such as that obtained from a bone bank. Other advantages and features will become apparent from the claims hereinafter, with the scope of such claims determined by reasonable equivalents as would be understood by those skilled in the art and made aware of this invention.