PROJECT SUMMARY My long-term goal is to reconstruct limbs that have lost function due to injury or disease. To achieve this goal, my research program combines surgical and mechanical design in a paradigm called anatomics, in which body and machine are co-engineered in pursuit of superior bionic performance. In this proposal, I apply an anatomics- centered approach to the surgical treatment of limb pathology. The human body is made up of compliant (“flexible”) structures that are fundamental to basic function. Joints, the highly-compliant structures that link bones together, are perhaps the most important of these structures for human movement. The nuanced relationships between load and deformation (called “compliance”) in joint tissues dictate how internal and external forces are converted to limb motion. Disruption of inherent biological compliance is often devastating to the body’s ability to move in a healthy way. This disruption can occur as a result of injury or disease, or even the reconstructive procedures intended to alleviate limb pathology. In severe cases, the pain and disability caused by changes to limb compliance are so intense, and treatment options so limited, that patients choose to amputate their viable but dysfunctional limb in search of relief. Unfortunately, there is currently no way to correct the compliance of biological joints and tissues when they are disrupted; this creates enormous challenges for the increasing number of patients with limb pathology, who are often left to live with limbs that are viable but non- functional. In response to this need, I propose a novel class of compliant implantable prostheses that would enable pathological joint compliance to be corrected, and function restored. With support from the New Innovator Award, I will advance a novel compliant limb reconstruction (CLR) pipeline capable of generating joint-and- pathology-specific implant mechanics, and apply this pipeline to design implants for two limb pathologies with urgent unmet clinical needs. I will then fabricate and validate these implants, collecting critical data to support early feasibility studies in human subjects. This work will form the foundation for future initiatives supporting refinement of the CLR pipeline, and is the first step toward a research program that uses the approach to target many different pathologies across all of the body’s joints. I expect that the proposed research will transform the clinical paradigm for treatment of limb pathology, opening the door to revolutionary new salvage options that alleviate pain, restore function, and prevent amputation.

PROJECT NARRATIVE Injury or disease in the bones and joints can fundamentally alter the mechanical behavior of human limbs, leading to painful, unnatural movements. In many cases, the state-of-the-art treatments that are intended to treat these conditions can leave patients with a limb that is alive and attached to their body, but unable to support even basic function. My approach combines new surgical techniques with innovative mechanical design to restore the mechanical properties of damaged limbs, thereby eliminating joint pain, restoring function and quality of life, and preventing unnecessary amputation.