Mechanobiological regulation of early stage bone repair

Abstract

Each year in the United States alone, several hundred thousand people suffer skeletal fractures that do not heal from the original treatment, resulting in non-union. To improve patient outcomes, there is a clinical need for therapeutic strategies that stimulate bone repair. The skeleton dynamically adapts its structure and composition to mechanical loads, and controlled loading via rehabilitation represents a non-pharmacologic target with the potential to stimulate endogenous bone regeneration. The primary objectives of this thesis were to develop technical approaches to longitudinally monitor dynamic mechanical cues during bone healing and elucidate how specific magnitudes promote repair. Our overall hypothesis was that moderate mechanical stimulation exerted via periodic walking could enhance bone regeneration. To test this hypothesis, we engineered a fully implantable wireless strain sensor platform that enabled real-time non-invasive monitoring of mechanical cues in a pre-clinical model of skeletal repair. We discovered that early-stage strain magnitudes correlated with significantly improved healing outcomes. We also observed that osteogenic mechanical loading exerted effects on early stage biological processes that precede mineralization, including immune cytokine signaling and angiogenesis. At the conclusion of the experiments, we attained a deeper understanding of how specific mechanical cues regulate bone repair, and established a novel sensor platform to further investigate mechanobiology. The knowledge gained by this thesis aids the development of integrative therapeutic strategies that stimulate bone repair via functional rehabilitation. In addition, the technological outcomes of this thesis serve as foundational support for the expanded development of implantable medical sensor technologies with broad implications to enhance diagnostics, therapeutic development, and interventional surveillance.