In response to mechanical stimulus, osteocytes release various signaling molecules that regulate other bone cells during bone modeling and remodeling. Solute transport through LCS is thus essential for osteocytes not only to perform their regulatory functions but also to maintain their viability. However, the solute transport in the LCS of loaded bone has not been well understood due to technique challenges. In this dissertation, I have developed mathematical models at multiple levels to simulate fluorescence recovery after photobleaching (FRAP) experiments, and to obtain new data and knowledge regarding the microenvironments of osteocytes.
At the cellular-level, I developed a three-compartment model to numerically solve the diffusion-convection equation for a typical FRAP experiment. I found that fluorescence recovery during FRAP experiments in a dynamically loaded bone is characterized by an exponential process e-kt, where the transport rate k increases with higher loading magnitude and lower frequency. Mechanical load is predicted to enhance transport of all tracers relative to diffusion, with the greatest enhancement for medium-sized tracers. The large tracers have high reflection coefficients through the pericellular matrix (PCM) that reduce the convective effect. The reflection coefficient which represents the resistance of PCM on the solute flux was then analytically formulated with a 3D orthogonal fiber network model, and found to increase with increasing fiber volume fraction and decreasing fiber radius.
By applying these multiple-level models to our FRAP experiments, the peak fluid velocity in a mouse tibia under intermittent compressive load with peak magnitude at 3 N, resting period at 4 s and loading period at 2 s was quantified as ∼60 μm/s, the reflection coefficient of parvalbumin was quantified as 0.092, and the fiber volume fraction in the PCM was estimated as 2.1–17.2% depending on fiber radius varied from 1 nm to 3 nm.
The work described in this dissertation forms a solid foundation for future studies on solute transport and molecular signaling around osteocytes, especially in disease conditions where the LCS anatomy and/or PCM are altered. These investigations will transform our understanding of bone health and pathology and help develop efficient treatments or countermeasures of bone diseases and conditions.
|Commitee:||Advani, Suresh G., Kirn-Safran, Catherine B., Lu, Xin L., Wang, Lian-Ping, Wu, Qianhong|
|School:||University of Delaware|
|Department:||Department of Mechanical Engineering|
|School Location:||United States -- Delaware|
|Source:||DAI-B 73/07(E), Dissertation Abstracts International|
|Keywords:||Bone fluid flow, Frap, Mechanotransduction, Osteocyte, Pericellular matrix, Solute transport, Transport enhancement|
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