Synthesis and Characterization of Novel, In Situ-Forming, Biodegradable Hydrogels for Cellular Delivery in Craniofacial Bone Tissue Engineering
Watson, Brendan M
Mikos, Antonios G.
Doctor of Philosophy
Extensive trauma, tumor resection or congenital abnormalities can lead to craniofacial bone defects that require intervention for repair. These defects are often treated with autologous grafts, which are limited in supply, often result in donor site morbidity, and are difficult to mold to appropriately match craniofacial contours. This thesis focused on the synthesis and characterization of a novel, in situ-forming biodegradable hydrogel for cellular delivery in craniofacial bone tissue engineering. To generate these hydrogels, a novel, thermogelling macromer containing pendant phosphate groups was synthesized and subsequently modified by the attachment of chemically cross-linkable methacrylate groups. The components of these macromers varied to evaluate the effects of differing components on macromer properties. This information was used to select two formulations of macromers that were shown to remain in solution at room temperature and undergo dual thermo and chemical gelation to form stable hydrogels at physiologic temperature. The hydrogels formed from these macromers were characterized for cytotoxicity and rate of degradation, which was found to be accelerated in the presence of alkaline phosphatase, an enzyme that is upregulated in newly formed bone. Furthermore, they were shown to support encapsulated mesenchymal stem cells for up to 28 days and undergo cellular induced mineralization under osteogenic conditions. These gels were then evaluated for their ability to generate bone in a critical-size rate cranial defect. The hydrogels demonstrated degradation within the defect and subsequent bone growth into the defect. Finally, the effects of incorporation of inorganic hydroxyapatite nanoparticles into the gels on cellular interaction and hydrogel physiochemical properties were evaluated. This research demonstrated the potential for thermogelling macromers to be designed to form degradable hydrogels that can be used to deliver cells into craniofacial bone defects.