Enhancement of fracture repair in rats with streptozotocin-induced diabetes by a single injection of biodegradable microcapsules containing a bone formation stimulant, TAK-778

The feasibility of using microcapsules containing a bone formation stimulan t, (2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4,5 -tetrahydro-4me thyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (TAK-778) to enh ance fracture repair was assessed in rats with streptozotocin-induced diabe tes. The release profile of the microcapsules was designed to mimic a dosin g regimen of multiple injections of TAK-778 solution. The solution was inje cted locally every third day from day 0 (the day of operation) to day 27 ac cording to several dosing regimens, and fracture repair was assessed at day 28. The production of callus was most prominent when TAK-778 solution was injected so that 50-75% of the total dose (5 mg TAK-778/site) was administe red during the first half of the treatment period. Thus, injectable microca psules of 30 mu m in mean diameter were prepared in order to release TAK-77 8 over 4 weeks using a biodegradable polymer, poly(d,l-lactic/glycolic) aci d, with a copolymer ratio of 85:15 (mol/mol) and an average molecular weigh t of 14,000. A single local injection of the microcapsules markedly enhance d fracture repair, which resulted in recovery of destructive bending streng th of the bone at day 28. Histologically, the injection of TAK-778 microcap sules stimulated both fibrous and cartilaginous proliferation and periostea l ossification in the callus at day 7;bony bridge formation was observed at day 28. At day 56, the callus was remodeled and cortical bony union was ev idenced in the microcapsule-treated fractures compared with the controls, w hich showed only fibrous union. (C) 2000 John Wiley & Sons, Inc. J Biomed M ater Res, 51, 299-306, 2000.