BioE PhD Defense Presentation- Brett Klosterhoff

Advisors:

Bob Guldberg, Ph.D. (University of Oregon)

Nick Willet, Ph.D. (Atlanta VA Hospital/Emory Orthopaedics)

Thesis Committee Members:

Ed Botchwey, Ph.D. (Georgia Tech)

Scott. Hollister, Ph.D. (Georgia Tech)

Keat Ghee Ong, Ph.D. (Michigan Technological University)

Jeff Weiss, Ph.D. (University of Utah)

Mechanobiological Regulation of Early Stage Bone Repair

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. Patients with non-unions are afflicted with prolonged disability and often undergo multiple costly surgeries. To improve outcomes, there is a clinical need for therapeutic strategies that mitigate non-union risk by stimulating bone repair. As the primary load-bearing tissue, the skeleton dynamically adapts its structure to mechanical loads, and controlled loading via rehabilitation represents a non-pharmacologic target to stimulate bone formation. However, the study of mechanobiology in vivo has largely remained qualitative because the mechanical environment in the regenerative niche is difficult to monitor. This technical limitation hinders the ability to investigate mechanobiology and exploit it for therapeutic purposes.

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. To this end, 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 used the sensor platform and image-based finite element analyses to quantify the progression of mechanical cues during gait under varying degrees of load sharing. We discovered that early-stage strain magnitudes correlated with significantly improved healing outcomes. Furthermore, strain magnitudes correlated with the status of healing, demonstrating feasibility of strain sensing techniques as an X-ray-free healing assessment. Remarkably, we also observed that osteogenic mechanical loading exerted previously unexplored effects on early stage biological processes that precede mineralization, including immune cytokine signaling and angiogenesis.

The knowledge gained by this thesis aids the development of integrative therapeutic strategies that stimulate bone repair via rehabilitation. In addition, this thesis serves as foundational support for the expanded development of implantable sensors with broad implications to enhance diagnostics, therapeutic development, and interventional surveillance.