PROJECT SUMMARY/ABSTRACT Poor healing of large bone defects remains one of the biggest challenges in human orthopedic medicine, affecting more than 1.5 million Americans per year and often leading to infections and other clinical complications, reoperations, poor functional outcomes, and ultimately, all too often, limb loss. The current gold- standard treatment is large metal plate fixation, which is prone to infection and remains in the patient’s body for life. Thus, there is a critical need to address this challenge in human medicine. Researchers have been working on tissue engineered solutions for decades, using scaffolds made of tri-calcium-phosphate (TCP) due to their excellent bioactivity (osteoinduction, osteoconduction and osseointegration), tunable degradation rate and promising drug delivery capabilities. However, despite excellent bone regeneration properties, these scaffolds are not strong enough to support significant loads, especially in critical defects. A viable solution to healing critical defects requires fast, natural bone growth, vascular development, and mechanical integrity to support loads while the new bone grows. Numerous trace elements that are found in bone, such as Zn, Mg, Sr, Si and Mn, have been added to TCP scaffolds (a.k.a. “doping”) to improve mechanical properties and bioactivity, and accelerate new bone formation. Many other trace elements may also play a role in bone development but have yet to be explored. Unfortunately, an intractable combination of studies is required when one considers all combinations of trace elements found in bone and ideal concentrations of each. No amount of funding will be enough to evaluate all these combinations in bone healing. This virtually unlimited set of variants leads to a hypothesis that natural bone may already contain the ideal mineral composition, after many millions of years of trial and error. Rather than trying to re-engineer the mineral composition of bone, this proposal seeks to fabricate and fully characterize bone regeneration scaffolds composed of naturally derived bone powder and test these scaffolds in a pilot ovine in vivo study. We lean on mother nature to provide a possible solution. The novelty of our approach is that we’re testing a new biomimetic biomaterial. No study to date has tested naturally derived bone mineral in bone regeneration scaffolds. Our approach depends on a naturally derived material that would be associated with lower regulatory burden, therefore, should be easier to translate to human medicine. We hope to extend this work to develop similar methods using naturally derived human bone mineral for healing human critical defects. If successful, this project could enable higher porosity structures to accelerate bioactivity and vascularization, both of which would have a significant impact on critical defect bone healing. Our long-term goal is to enable removal of all metal fixation, leaving only endogenous bone as we expect our naturally deri...