Infoscience

Thesis

Effect of Micromotion on Morphogen Dynamics in Peri-Implant Healing

The primary stability of cementless femoral components is crucial for the long-term success of total hip arthroplasty. We know that the healing phase after surgery is a complex biological process, which is affected by the mechanical environment. Implant loading indeed induces local micromotion at the bone-implant interface, generating strain within the peri-implant tissue. Evidence indicates that the cells involved in the apposition of bone around the implant are mechano-sensitive. To eventually reduce the failure rate of such implants, we thus need to better characterize the peri-implant mechanical environment. Current experimental technics of micromotion measurement are however restrained to a limited number of simultaneous measuring points. A characterization of the tissue strain is thus impossible. In this work, we have developed an original method to simultaneously measure micromotion, gap size and strain in a large number of points at the bone-implant interface. This technique was used to compare a straight and anatomical design of the femoral stem. In the next step, we need to predict the cell response to the strain level. Since the peri-implant tissue is porous, micromotion induces fluid flow. Many phenomenological and mechano-biological models have been proposed. Both are based on strain and flow. In this work, we propose an original model based on soluble morphogens, which govern the differentiation of mesenchymal stromal cells. The morphogens are ligands that bind reversibly to transmembrane receptors of the cell. They initiate signal transduction cascades, which regulate the differentiation pathway of the cell. The time and space distribution of morphogens in the peri-cellular region determine the number of morphogens bound to the cell receptors. The developed theoretical model predicts the free and cell bound concentration of morphogens. In the model, the morphogens are released by the cells, have a constant decay rate and bind to receptors on the cell surface. Using physiological parameters for morphogen reaction rates and diffusivities, we have numerically simulated an experimental flow chamber setup. We have showed that cells may sense peri-cellular flow that is high enough to disturb these concentrations. We have obtained a transition in the fraction of bound receptors, which depends on the ratio between the thickness of the boundary diffusive layer and the characteristic distance of the secreted ligand's profile. This ratio depends directly on the fluid flow rate, the fluid viscosity, the flow chamber height, and the ligand decay rate. We therefore conclude that the response of mesenchymal stromal cells to flow rate and flow viscosity can be explained by the advection of morphogens. Finally, we have designed an experimental method to validate the model predictions.

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