Polymeric Resorbable Composites Containing an Amorphous Calcium Phosphate Polymer Ceramic for Bone Repair and Replacement

Abstract

A method for making bioresorbable composites of a non-crystalline calcium phosphate ceramic synthesized within encapsulating microspheres of bioresorbable polymeric material for use in bone repair and replacement is provided. The composites include microspheres and scaffolds produced therefrom.

1 . A method for producing a bioresorbable composite comprising:
 (a) contacting a basic aqueous calcium salt solution and a basic aqueous phosphate salt solution in a non-polar immiscible solvent containing at least one bioresorbable polymeric material at a temperature; and   (b) emulsifying the mixture with sufficient energy for a time and at a temperature sufficient to provide for the reaction between the calcium and phosphate salts to form a non-crystalline or amorphous calcium phosphate composition encapsulated within encapsulating microspheres of the bioresorbable polymer.   
   
   
       2 . The method of  claim 1  wherein the calcium salt is calcium nitrate, or a hydrate thereof. 
   
   
       3 . The method of  claim 1  wherein the phosphate salt is ammonium hydrogen phosphate, or a hydrate thereof. 
   
   
       4 . The method of  claim 1  wherein the basic calcium salt solution, the basic phosphate salt solution, or both comprise ammonium hydroxide. 
   
   
       5 . The method of  claim 1  wherein the non-polar immiscible solvent is methylene chloride. 
   
   
       6 . The method of  claim 1  wherein the pH of the calcium salt solution is about 10. 
   
   
       7 . The method of  claim 1  wherein the pH of the phosphate salt solution is about 10. 
   
   
       8 . The method of  claim 1  wherein the at least one bioresorbable polymeric material comprises a polylactic acid, a polyglycolic acid, a poly(lactic acid-glycolic acid), a polyanhydride, a poly(phosphazene), a poly(orthoester), a poly(caprolactone), a polyhydroxybutyrate, a polyanhydrideco-imide, a polypropylene fumarate, a polydiaxonane, or a polyurethane polymer, or any copolymer or mixture thereof. 
   
   
       9 . The bioresorbable composite of  claim 1 , wherein the bioresorbable polymeric material comprises a polylactic acid, a polyglycolic acid, a poly(lactic acid-glycolic acid) polymer or any copolymer or mixture thereof. 
   
   
       10 . The method of  claim 1  wherein the temperature is below room temperature. 
   
   
       11 . The method of  claim 1  wherein the temperature is about −70° C. 
   
   
       12 . The method of  claim 1  further comprising adding the emulsion to a mixed solution of a surfactant and a calcium salt. 
   
   
       13 . The method of  claim 12  wherein the surfactant is poly(vinyl alcohol). 
   
   
       14 . The method of  claim 1  further comprising separating the encapsulated microspheres of bioresorbable polymer from unencapsulated calcium phosphate and unencapsulating microspheres. 
   
   
       15 . The method of  claim 1  wherein the calcium phosphate composition is characterized by an x-ray diffraction pattern indicative of an amorphous or poorly crystalline material. 
   
   
       16 . The method of  claim 1 , wherein the calcium phosphate composition is characterized as having a stoichiometry approximately that of hydroxyapatite, calcium phosphate, tricalcium phosphate, tetracalcium phosphate, bone apatite, or any combination thereof. 
   
   
       17 . The method of  claim 1 , wherein the calcium phosphate composition is characterized as having a stoichiometry approximately that of bone apatite. 
   
   
       18 . The method of  claim 1 , wherein the calcium phosphate composition additionally comprises carbonated calcium phosphate. 
   
   
       19 . The method of  claim 1  wherein the bioresorbable microspheres are characterized as having a diameter between about 100 and about 250 microns. 
   
   
       20 . The method of  claim 1  wherein the bioresorbable polymeric microsphere contain approximately 28 weight percent or more of the non-crystalline, poorly crystalline, or amorphous calcium phosphate ceramic relative to the mass of the entire composite. 
   
   
       21 . The method of  claim 1  further comprising joining a plurality of the encapsulating microspheres of the at least one bioresorbable polymeric material to form a porous three-dimensional scaffold. 
   
   
       22 . The method of  claim 1  wherein the plurality of the encapsulating microspheres of the at least one bioresorbable polymeric material are joined by sintering at a temperature above the melting point of at least one of the bioresorbable polymeric materials. 
   
   
       23 . The method of  claim 22  wherein sintering temperature is about 150° C. 
   
   
       24 . The method of  claim 21  wherein the majority of pores in the three-dimensional scaffold are characterized as having diameters of at least 100 microns. 
   
   
       25 . The method of  claim 15  wherein the porosity of the three-dimensional scaffold is about 75%. 
   
   
       26 . The method of  claim 1  or  21  wherein the bioresorbable composite is suitable for tissue repair and/or replacement applications. 
   
   
       27 . The method of  claim 26  wherein the tissue is bone.