BME PhD Dissertation Defense: Timothy Josephson

Title: “A MULTISCALE MECHANOBIOLOGICAL INVESTIGATION OF SCAFFOLD DESIGNS FOR BONE TISSUE ENGINEERING”

Advisory Committee: Brian Connizzo PhD-BME (Chair) Elise Morgan, PhD-BME Keith Brown, PhD-ME Jeroen Eyckmans, PhD-BME Michael Smith, PhD-BME

Abstract: Bone fractures and loss of bone caused by tumors and infections often require surgical intervention and reconstruction to ensure proper healing. Autografts, bone grafts taken from elsewhere in the patient's skeleton, are considered the gold standard for treatment; however, autografts are limited in supply, and harvesting them can lead to infection, loss of function, and persistent pain. These downsides motivate the field of bone tissue engineering to develop biomaterial scaffolds as bone graft substitutes that can meet or exceed the performance of autografts. A critical but understudied aspect of that development is advancing understanding of how skeletal cells respond to the multitude of cues - mechanical and biochemical - they receive from their environment, such that researchers can tailor scaffold materials and architectures to provide favorable microenvironments for enhanced osteogenesis. Many materials have been investigated for the potential to facilitate bone regeneration. Of these, hydroxyapatite (HA), the calcium phosphate ceramic that constitutes the inorganic phase of bone tissue, has shown significant promise. Advancements in additive manufacturing have made possible the production of high quality hydroxyapatite scaffolds with precisely controlled architectures. Scaffolds produced with this technology are attractive candidates for bone tissue engineering and the study of how skeletal cells interact with their local microenvironments. This dissertation presents a multiscale effort to characterize and design additively manufactured hydroxyapatite scaffolds for bone tissue engineering. At the material-level, a study was undertaken to examine the effects of material processing on microscale features smaller than 10 μm, such as crystal grains and micropores, and their subsequent impact on biological processes. At the structure-level, an optimization framework was developed to arrange the material into features larger than 100 μm, such as walls and struts, generating porous scaffold architectures with maximal abundance of mechanical microenvironments thought to be osteogenically favorable. To enable consideration of both material and structure together, an agent-based model was developed to predict how cues derived from both levels can influence the growth and differentiation of skeletal tissues within a scaffold. Taken together, this work presents the foundations of a holistic strategy for development of HA scaffolds and emphasizes that choices made in both the design and manufacturing of scaffolds can influence their overall performance. While much remains to be understood about what conditions are optimal for osteogenesis, this work lays out strategies for tuning both the material-level and structure-level design, and contributes a computational framework capable of generating and testing hypotheses of how skeletal cells respond to cues from their environment.