Controlled release of osteogenic factors from injectable biodegradable composite materials for bone tissue engineering
Hedberg, Elizabeth LeBleu
Mikos, Antonios G.
Doctor of Philosophy
Composite materials based on the synthetic polymer poly(propylene fumarate) (PPF) were developed and characterized for use as porous controlled release scaffolds in bone tissue engineering. Through the use of poly(DL-lactic-co-glycolic acid) (PLGA) microparticles, the osteogenic peptide TP508 (Chrysalin RTM) was incorporated into the polymer phase of PPF-based scaffolds, creating a composite material that could act as a scaffold for guided tissue ingrowth as well as a vehicle for targeted drug delivery. Alteration of formulation parameters such as the TP508 loading of the microparticles, the microparticle to PPF ratio, and the initial leachable porogen content lead to variation in the release kinetics of the incorporated peptide in vitro. Inclusion of the microparticles into the scaffolds as well as changes in the scaffold formulation parameters did not alter the scaffolds in vitro degradation profile through 26 weeks. Using results from the in vitro studies, two distinct release kinetic profiles were selected for further evaluation in vivo . Composite formulations exhibiting either a large initial burst release or a minimal initial burst release of 200 mug TP508 were implanted in 15.0 mm segmental defects in rabbit radii. Radiography, micro-computed tomography, and histomorphometry were used to elucidate the effect of varied release kinetics on bone formation at 12 weeks post-operative. Results showed that composite scaffolds exhibiting a large burst release of TP508 resulted in the greatest amount of bone. Analysis showed that bone formation was characterized by growth both into the pores of the scaffold as well as guided across the defect along the surface of the implant. Further investigation revealed minimal degradation of the polymer after 18 weeks in vivo. The studies presented here demonstrate the potential of PPF/PLGA composite materials for use in bone tissue engineering. These composite scaffolds offer controlled, targeted delivery of bioactive molecules as well as structural support for cellular infiltration and bone formation within osseous defects. Additional work was conducted in the area of controlled release of polysaccharide oligomers. Initial experiments established that hyaluronan oligomers could be incorporated into PLGA microparticles and that parameters including PLGA molecular weight, hyaluronan molecular weight, and hyaluronan loading influenced the oligomer release kinetics.