Shearing Oscillatory Interstitial Fluid Flows affect Solute Transport and Osteogenesis in Cortical Bone

Bone, is a dynamic tissue that is continually being renewed at a rate dependent on the health of its cells, which is linked to nutrient availability and other incompletely understood factors. It is known that weight-bearing exercise can noticeably affect bone density and has been hypothesized as a mechanism for increased nutrient delivery in bone. To date the only model for mass transport in bone is passive diffusion, which insufficiently meets bone cell metabolic requirements and is independent of mechanical stress. The objective of this research was to: 1) propose a theoretical model for enhanced mass transport in cortical bone due to shearing oscillatory fluid flow dependent on molecular size, strain magnitude, and frequency; 2) demonstrate experimentally that oscillating fluid flows affect the mass transport of particles in sheep cortical bone; 3) prove that increased nutrient levels influence bone cell osteogenesis and metabolism in-vitro; 4) develop calcium phosphate nano-carriers for nutrients and drugs deliverable through the new mechanism. The theoretical model predicted transport enhancements of up to 100 fold for molecules larger than 7 nm in diameter. In sheep cortical bone, for 20 and 40 nm sized solutes, for frequencies of 1-3 Hz and 20 kHz, experimental diffusivity enhancements of respectively 40-550 and 150 were observed, in accordance with model predictions. The rate of bone deposition, related to nutrient level by Michaelis-Menten kinetics for human fetal osteoblast, was measured by in-vitro experiments, which showed that if passive diffusion in bone was increased by 1000 using oscillatory flow mechanisms, then kinetic and diffusional rates would be equal, and bone deposition would be an ideally tuned biological transformation. In addition, in-vitro experiments showed that bone cell osteogenesis was affected by core-shell and mesoporous calcium phosphate nano-carriers. The transport of these carriers in bone was theoretically predicted by the model. In conclusion, a new model describing oscillatory fluid shear-effects can enhance solute transport in cortical and osteoporotic bone by repetitive strains generated during physical activity and acoustic healing. The model gives new insights into the mechanisms behind bone functional adaptation and is the basis for a strain-based therapy involving bioactive 'smart' osteoconductive nano-device.