Quantifying the Roles of Stimulated Osteocytes and Inflammation in Bone Remodeling

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

Year	Entry
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2006	Nicolella DP, Moravits DE, Gale AM, Bonewald LF, Lankford J. Osteocyte lacunae tissue strain in cortical bone. J Biomech. 2006;39(9):1735-1743.
2014	Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw: 2014 update. J Oral Maxillofac Surg. October 2014;72(10):1938-1956.
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2012	Verbruggen SW, Vaughan TJ, McNamara LM. Strain amplification in bone mechanobiology: a computational investigation of the in vivo mechanics of osteocytes. J R Soc Interface. October 7, 2012;9(75):2735-2744.
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Year

Entry

2011

Russell RGG. Bisphosphonates: the first 40 years. Bone. July 2011;49(1):2-19.

2006

Nicolella DP, Moravits DE, Gale AM, Bonewald LF, Lankford J. Osteocyte lacunae tissue strain in cortical bone. J Biomech. 2006;39(9):1735-1743.

2014

Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw: 2014 update. J Oral Maxillofac Surg. October 2014;72(10):1938-1956.

2007

Rath Bonivtch A, Bonewald LF, Nicolella DP. Tissue strain amplification at the osteocyte lacuna: a microstructural finite element analysis. J Biomech. 2007;40(10):2199-2206.

2012

Verbruggen SW, Vaughan TJ, McNamara LM. Strain amplification in bone mechanobiology: a computational investigation of the in vivo mechanics of osteocytes. J R Soc Interface. October 7, 2012;9(75):2735-2744.