Production of nanosized calcium phosphate particles as powder or coating via bifunctional precursors

Abstract

Method of producing calcium phosphate particles, such as hydroxyapatite particles, in the form of a powder or coating on a solid support comprising an oxide surface or a polymer surface, such as titanium, titanium alloys, stainless steel, zirconia, glass and poly(styrene), poly(ether ether ketone) (PEEK), and poly(imide) is described. The method comprises I) providing a water solution containing calcium ions and water-soluble organic compound(s) comprising at least two functional groups, II) providing another water solution containing phosphate ions and water-soluble organic compound(s) comprising at least two functional groups, followed by III) mixing the solutions of (I) and (II) to create calcium phosphate particles coated with said water-soluble organic compounds. After washing and drying, the coated particles may be used as scaffolds or for production of a powder of calcium phosphate particles or crystals.

Claims

1. A calcium phosphate particle comprising a water-soluble amino acid, said water-soluble amino acid comprising at least two functional groups comprising a negatively charged group and a positively charged group, wherein said negatively charged group of said water-soluble amino acid is attached to said calcium phosphate particle, thereby providing a coated calcium phosphate particle, and said positively charged group of said water-soluble amino acid is attached to a solid support comprising an oxide surface or a polymer surface so that said water-soluble amino acid is simultaneously attached to said solid support and said calcium phosphate particle, thereby providing said coated calcium phosphate particle in the form of a coating on said solid support.

2. The calcium phosphate particle of claim 1, wherein the particle is in crystalline form.

3. The calcium phosphate particle of claim 2, wherein the negatively charged group is selected from the group consisting of COOH, OPO.sub.3H.sub.2 and OSO.sub.3H groups and the positively charged group is an amine group.

4. The calcium phosphate particle of claim 2, wherein the calcium phosphate particle is hydroxyapatite.

5. The calcium phosphate particle of claim 2, wherein the water-soluble amino acid is selected from the group consisting of water-soluble amino acids with three functional groups.

6. The calcium phosphate particle of claim 2, wherein the water-soluble amino acid is selected from the group consisting of neutral amino acids, basic amino acids and acidic amino acids.

7. The calcium phosphate particle of claim 1, wherein the negatively charged group is selected from the group consisting of COOH, OPO.sub.3H.sub.2 and OSO.sub.3H groups and the positively charged group is an amine group.

8. The calcium phosphate particle of claim 1, wherein the calcium phosphate particle is hydroxyapatite.

9. The calcium phosphate particle of claim 1, wherein the water-soluble amino acid is selected from the group consisting of water-soluble amino acids with three functional groups.

10. The calcium phosphate particle of claim 1, wherein the water-soluble amino acid is selected from the group consisting of neutral amino acids, basic amino acids and acidic amino acids.

11. The calcium phosphate particle of claim 1, wherein the water-soluble amino acid is aspartic acid or lysine.

12. A calcium phosphate particle comprising a water-soluble amino acid, wherein said water-soluble amino acid is monomeric and comprises at least two functional groups comprising a negatively charged group and a positively charged group, wherein said negatively charged group of said water-soluble amino acid is attached to said calcium phosphate particle, thereby providing a coated calcium phosphate particle, and wherein said positively charged group of said water-soluble amino acid is attached to a solid support comprising an oxide surface or a polymer surface, thereby providing said coated calcium phosphate particle in the form of a coating on said solid support.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows a Scanning Electron Microscope (SEM) image of a titanium surface coated with nanocrystalline HA. Scale bar=200 nm. As seen from this Figure, the HA crystals are needle-shaped, 50-150 nm long and 5-10 nm wide.

(2) FIG. 2 shows an X-ray diffractogram of heat treated nanocrystalline HA powder. As seen in the Figure, there is a considerable peak broadening due to the small particle size.

(3) FIG. 3 shows an X-ray Photoelectron Spectroscopy (XPS) spectrum of a titanium surface coated with nanocrystalline HA. As can be seen from this Figure, the titanium content is 1.3%.

(4) FIG. 4 shows an X-ray Photoelectron Spectroscopy (XPS) spectrum of a poly(styrene) disk coated with coated calcium phosphate particles.

EXAMPLES

Example 1

(5) A) In a typical experiment, 10.4 g of gamma-amino butyric acid (GABA) was dissolved in 150 ml H.sub.2O. 2.82 g of CaO was added to the solution and allowed to stir for 10 minutes. This solution had a pH of 11.7. Solution 2 was prepared by adding 9.3 g GABA to 150 ml H.sub.2O. 3.45 g of H.sub.3PO.sub.4 was added to this solution and allowed to stir for 10 minutes. This solution had a pH of 4.50. Solution 1 was subsequently mixed with solution 2, and a crystallisation resulted. The crystallisation was carried out at ambient temperature, and the pH of this mixture was measured to 9.12.

(6) B) The crystals were washed extensively with a H.sub.2O-isopropanol mixture and dried at 120? C. for 12 hours. The crystals were then heated in an oven at 400? C. for 5 hours in order to remove organic compounds. The specific surface area, as measured with a Micromeritics TriStar instrument using the BET algorithm, was 180 m.sup.2/g. The powder was analyzed with a Siemens D5000 powder X-ray diffractometer with CuK?-radiation, and the diffractogram is shown in FIG. 2.

Example 2

(7) In another experiment, 11.5 g of 6-amino hexanoic acid was dissolved in 150 ml H.sub.2O. 2.82 g of CaO was added to the solution and allowed to stir for 10 minutes. The pH of this solution was 12.0. Solution 2 was prepared by adding 13.2 g of 6-amino hexanoic acid to 150 ml H.sub.2O. 3.45 g of H.sub.3PO.sub.4 was added to this solution, and allowed to stir for 10 minutes. The pH of this solution was 4.70. Solution 1 was mixed with solution 2, and crystallisation resulted. The crystallisation was carried out at ambient temperature, and the pH was measured to 9.53. The crystals were washed, heated to 400? C. and dried according to Example 1B. The specific surface area was 160 m.sup.2/g.

Example 3

(8) In another experiment, solution 1 consisted of 2.82 g CaO, 6.70 g L-aspartic acid and 150 ml H.sub.2O. The pH of this solution was 10.1. Solution 2 consisted of 3.45 g H.sub.3PO.sub.4, 6.65 g L-Lysine and 150 ml H.sub.2O. The pH of this solution was 6.46. The solutions were mixed at ambient temperature, and the pH was measured to 8.10. The precipitated crystals were washed with H.sub.2O, dried and heated to 400? C. The specific surface area was 159 m.sup.2/g.

Example 4

(9) In another experiment, the crystals were precipitated according to example 1A. The solution containing nanocrystalline HA particles with the amphoteric GABA molecule attached to the surface of the particles, was used as a coating solution. A titanium disk was dipped into the solution, removed and allowed to dry at room temperature for 1 hour. The disk was then heat treated for 5 minutes in air at 300? C. The disk was allowed to cool to room temperature and washed extensively with water and isopropanol. A crystal layer was visible on the surface of the disk. The titanium disk was analyzed in a LEO ULTRA 55 SEM and a micrograph is shown in FIG. 1. As seen from the figure the crystals on the disk are fibrillar with a length of 50-150 nm, and a diameter of 5-10 nm. EDS measurement revealed a Ca/P ratio of 1.65, close to the theoretical value of natural HA, 1.67. An XPS spectrum, done with a Perkin-Elmer PHI 5000C instrument, of the coated titanium disk is shown in FIG. 3. As seen from this figure, the amount of titanium is 1.3%, which indicates an almost complete HA crystal coverage of the disk.

Example 5

(10) In another experiment, the crystals were precipitated according to example 1A. The solution containing nanocrystalline HA particles with the amphoteric GABA molecule attached to the surface of the particles, was used as a coating solution. A poly(styrene) disk was dipped into the solution, removed and allowed to dry at 80? C. for 1 hour. The disk was then washed extensively with water. A crystal layer was visible on the surface of the disk. The disk was analysed with a Perkin-Elmer PHI 5000C instrument, and the result from this measurement is shown in FIG. 4. As seen from this Figure, the calcium and phosphor content is 13.7 and 9.0%, respectively.

REFERENCES

(11) 1. Reis R and Weiner S, Learning From Nature How to Design New Implantable Biomaterials, Kluwer Academic Publishers, London, 90-92 (2004). 2. Lowenstam H A and Weiner S, On biomineralization, Oxford University Press, New York (1989). 3. Guo et al, J. Biomed. Mater. Res. A, DOI 10.1002/jbm.a.31200 4. Wei J et al, Compos. Part B. Eng., 38, 3, 301-305 (2007); Ramay H R R and Zhang M, Biomaterials 25, 21, 5171-5180 (2004). 5. Mullin J W, Crystallization, Elsevier Butterworth-Heinemann, Oxford, 320-325 (2001). 6. Ying J et al, USRE 39196E; Senna M et al, U.S. Pat. No. 6,592,989 B1. 7. Wang A et al, Mater. Lett. 61, 10, 2084-2088 (2007). 8. Kuriakose T A et al, J. Cryst. Growth 263, 1-4, 517-523 (2004). 9. Koumoulidis G C et al, J. Colloid Interf. Sci. 259 2, 254-260 (2003). 10. Bose S and Kumar Saha S K, Chem. Mater., 15, 4464-4469 (2003). 11. Kjellin P and Andersson M, EP 1781568; Uota M. et al, Langmuir 21, 10, 4724-4728 (2005). 12. Uota M et al, Langmuir 21, 10, 4724-4728 (2005). 13. Story B, Burgess A, U.S. Pat. No. 5,730,598 14. Sun L et al, J. Biomed. Mater. Res. A, 58, 5, 570-592 (2001). 15. Wei-Qi Yan et al, Biomaterials, 18, 17, 1185-1190 (1997). 16. Nishimura I et. al, CA 2563 299. 17. Stupp S I et al, US 2004/0258726A1. 18. Gonzalez-Mcquire R et al, J. Mater. Chem., 14, 2277-2281 (2004). 19. Hidalgo-?lvarez R et al, Adv. Colloid Interface Sci., 67, 1-118 (1996). 20. Weidenhammer P and Jacobasch H-J, J. Colloid Interf. Sci., 180, 232-236 (1996).