Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an elusive disease that presents as exposed necrotic bone following tooth extraction. It occurs in patients undergoing bisphosphonate therapy for metastasizing cancers and osteoporosis. Experts believe the condition is caused by a defect in bone remodeling—the process by which osteoclasts resorb bone and osteoblasts form new bone—within the oral cavity. Its complexity requires a multicellular model to address the net effects of two key risk factors: tooth extraction (overload) and inflammation associated with bacterial infection.
In this work, a system comprised of a deformable polymeric chip and mechanical loading device is used to expose bisphosphonate-treated osteocytes, the mechanosensing bone cells, to overload. Osteocyte viability is evaluated as a function of load, and soluble activity is assessed. Effects of these factors on bone resorption by osteoclasts and bone formation by osteoblasts are quantified. Osteoclast activity is also quantified in the presence of inflammatory agents, lipopolysaccharide and interferon gamma. Results support a role for osteocyte mechanotransduction in suppressing osteoblast bone formation within a BRONJ environment. They also suggest inflammation may inhibit resorption of necrotic bone by osteoclasts. These findings provide insights into BRONJ that may contribute to its elucidation.
This dissertation also lays the foundation for a biomimetic lab-on-a-chip platform for the study of bone turnover and remodeling-related disease. Fabrication techniques are developed, and osteocyte, osteoclast and osteoblast characterizations are performed on relevant substrates within microfluidic devices. Culture conditions, including seeding densities, feeding requirements and time points for analyses are determined. This work will enable the development of a controlled multicellular lab-on-a-chip capable of quantifying the aggregate response of bone cells to disease cofactors
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