Enhancement of fracture repair in rats with streptozotocin-induced diabetes by a single injection of biodegradable microcapsules containing a bone formation stimulant, TAK-778
T. Hoshino et al., Enhancement of fracture repair in rats with streptozotocin-induced diabetes by a single injection of biodegradable microcapsules containing a bone formation stimulant, TAK-778, J BIOMED MR, 51(3), 2000, pp. 299-306
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.