Production of moldable bone substitute

Abstract

Composites and methods of producing a mouldable bone substitute are described. A scaffold for bone growth comprises nanocrystalline hydroxyapatite (HA), a bioresorbable plasticizer, and a biodegradable polymer. Plasticizers of the invention include oleic acid, tocopherol, eugenol, 1,2,3-triacetoxypropane, monoolein, and octyl-beta-D-glucopyranoside. Polymers of the invention include poly(caprolactone), poly(D,L-Lactic acid), and poly(glycolide-co lactide). Methods of regulating porosity, hardening speed, and shapeability are also described. Composites and methods are described using nanocrystalline HA produced with and without amino acids. The scaffold for bone growth described herein displays increased strength and shapeability.

1 . A scaffold for bone growth comprising:
 nanocrystalline hydroxyapatite (HA);   a bioresorbable plasticizer; and   a biodegradable polymer.   
   
   
       2 . The scaffold of  claim 1  wherein the plasticizer is a lipophilic substance. 
   
   
       3 . The scaffold of  claim 2  wherein the plasticizer is selected from the group consisting of oleic acid, tocopherol, eugenol, and 1,2,3-triacetoxypropane. 
   
   
       4 . The scaffold of  claim 1  wherein the plasticizer is an amphiphilic substance. 
   
   
       5 . The scaffold of  claim 4  wherein the plasticizer is selected from the group consisting of monoolein and octyl-beta-D-glucopyranoside. 
   
   
       6 . The scaffold of  claim 1  wherein the polymer is a biodegradable polyester. 
   
   
       7 . The scaffold of  claim 1  wherein the plasticizer is tocopherol and the polymer is poly(caprolactone). 
   
   
       8 . The scaffold of  claim 1  wherein the plasticizer is eugenol and the polymer is poly(D,L-lactic acid). 
   
   
       9 . A method of inducing bone growth in a bone defect comprising applying an effective amount of the composition of  claim 1  to the site of the bone defect. 
   
   
       10 . A method of producing a scaffold for bone growth according to  claim 1  comprising:
 1) mixing together a solution comprising:   a first solution of a calcium compound and amino acids; and   a second solution of a phosphoric acid compound and amino acids, wherein a dispersion of suspended nanocrystalline HA particles of the size 10-20 nm long and amino acids attached to the surface of calcium phosphate crystals is formed;   2) using heat to dissolve a matrix of polymers with one or more plasticizers to form a third solution;   3) adding the HA particles of step 1) to the solution of step 2); and   cooling this mixture to room temperature whereby a shapeable composite is formed, and wherein the resultant composite can be shaped by hand for at least thirty minutes.   
   
   
       11 . A method of producing a scaffold for bone growth according to  claim 1  comprising:
 1) mixing together a solution comprising:   a first solution of a calcium compound; and   a second solution of a phosphoric acid compound, wherein   a dispersion of suspended nanocrystalline HA particles of the size 10-20 nm long is formed;   2) using heat to dissolve a matrix of polymers with one or more plasticizers to form a third solution;   3) adding the HA particles of step 1) to the solution of step 2); and   cooling this mixture to room temperature whereby a shapeable composite is formed, and wherein the resultant composite can be shaped by hand for at least thirty minutes.   
   
   
       12 . The method of  claim 10 , wherein the amino acids are removed after step 1). 
   
   
       13 . The method of  claim 10 , wherein the porosity is lowered by the addition of an amphiphilic substance. 
   
   
       14 . The method of  claim 10 , wherein the hardening speed is increased by increasing the amount of nanocrystalline HA added in step 3). 
   
   
       15 . The method of  claim 10 , wherein the hardening speed is decreased by increasing the amount of plasticizer. 
   
   
       16 . The method of  claim 10 , wherein the one or more plasticizers includes tocopherol and eugenol and wherein the hardening speed is decreased by increasing the ratio of eugenol to tocopherol. 
   
   
       17 . The bone growth scaffold of  claim 1 , further comprising a biologically active factor selected from the group consisting of an antibiotic, chemotherapeutic, bone cell inducer, bone cell stimulator, tissue promoting factor, tissue decomposition inhibitor, and growth factor. 
   
   
       18 . The method of  claim 10 , wherein the amino acids of step 1) comprise L-aspartic acid and L-lysine. 
   
   
       19 . A scaffold for bone growth comprising:
 calcium phosphate compound(s);   bioresorbable plasticizer; and   biodegradable polymer.   
   
   
       20 . The bone growth scaffold of  claim 19 , wherein the calcium phosphate compound(s) is selected from tricalcium phosphate, octacalcium phosphate, tetracalcium phosphate and dicalcium phosphate.