The effect of simultaneous, controlled release of angiogenic and osteogenic growth factors on the enhancement of osteogenesis within craniofacial defects
Mikos, Antonios G.
Doctor of Philosophy
Successful translation of experimental therapeutics to the clinical setting will require development of challenging in vivo models which mimic oral and craniofacial wound healing environments, and can accurately assess a construct's angiogenic and osteogenic performance. With the intent of developing an easily accessible and reproducible, non-healing alveolar bone defect in the rabbit, 10-mm diameter partial- and full thickness cylindrical defects were created in the premolar/molar region of the mandible. Microcomputed tomography (micro-CT) and histological analysis of the partial thickness defect demonstrated significant bone formation at 8 weeks, and complete union and contour regeneration at 16 weeks. In contrast, the full thickness defect was never able to bridge itself and only exhibited partial bone regeneration by 16 weeks, demonstrating the potential of the mandibular full thickness defect as a test bed for tissue engineering constructs. A subsequent study examined the use of contrast-enhanced micro-CT to characterize neovascularization in the rabbit alveolar bone defect model. Scaffold-implanted groups were found to have differences in vessel network morphology versus empty defects. These results suggest the rabbit alveolar bone defect model in conjunction with micro-CT imaging is a robust system for evaluating the angiogenic and osteogenic potential of tissue engineering constructs. Lastly, the scale-up to larger human applications will require rapid and adequate vascularization throughout implanted scaffolds, perhaps necessitating simultaneous delivery of angiogenic and osteogenic growth factors with specific release kinetics and dosages for effective tissue regeneration. A final study investigated the dose effect of simultaneous delivery of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) for bone regeneration in a critical size rat cranial defect at 12 weeks. A dose-dependent decrease in percent bone formation was observed as BMP-2 alone decreased from 2 microg to 0.5-1 microg. The addition of VEGF in amounts of 6-12 microg was unable to reverse this decrease in bone formation, although improvements in bony bridging were seen in some of the dual release groups. Thus, further optimization of the growth factor doses and release kinetics may be required to observe long-term benefits over single growth factor release in this particular animal model.