The complex process of critically-sized load-bearing bone defect healing is poorly understood. The interplay between revascularization of the injured tissue and regeneration of a functional bone structure is critical to survival of the limb. The central goal for this dissertation is to establish a novel in vivo model of segmental bone defect repair and to assess the ability of tissue-engineered scaffolds using a growth factor codelivery strategy to heal these defects.

Traditional assessment of large bone defect healing has relied entirely on radiography and histology/histomorphometry. The animal model designed in this thesis enables the investigator to use in vivo X-ray and quantitative micro-CT imaging of the defect to assess mineralized matrix deposition, and to easily free the defect from the stabilization device for mechanical testing of samples post-mortem. Additionally, a hindlimb vascular perfusion procedure was developed to facilitate micro-CT quantification of vascular structures within the defect.

These methodologies were applied to assess functional bone repair resulting from co-delivery of osteogenic (BMP-2), chondrogenic (TGF-β3), and angiogenic (VEGF) growth factors. The dose-dependence effects of and interactions between these growth factors were assessed using micro-CT and mechanical testing methods. There was a dosedependent response to co-delivery of BMP-2/TGF-β3 in terms of mineralized matrix deposition and restoration of mechanical properties. An additive interaction was determined between the two growth factors.

Delivery of VEGF alone did not result in a dose-dependent beneficial effect on bone formation or revascularization of the defect. Modification of the implanted porous polymer structural scaffolds to contain a macroscopic cored center and 10% ceramic component enhanced revascularization of the defects. Co-delivery of VEGF with ΒΜΠ−2/TGF−β3 did not incur any benefit over delivery of only BMP-2/TGF-β3.

In conclusion, this work has yielded a novel, reproducible and robust small animal model of osseous nonunion and quantified the ability of low dose sustained release growth factor co-delivery to enhance functional bone repair.