PROJECT SUMMARY The overarching objective of this proposal is to determine if transfemoral osseointegrated prostheses have a positive influence on the etiology of hip osteoarthritis (OA). The two leading causes of disability following transfemoral amputation are chronic skin pathologies due to poor socket fit (e.g., ulceration) and OA due to habitually altered joint loading. Osseointegrated prostheses are a recent clinical intervention to treat socket related pathologies by directly mounting the prosthesis to the residual limb through a bone anchored implant, providing a more normative load transmission from the ground to residual limb. This proposal will determine if this improved load transmission has positive role on the pathogenesis of hip OA differently than socket prostheses. This will be accomplished through a longitudinal study design that will compare the most common biomechanical etiological factors to OA progression at two timepoints (baseline and 12-months) between two groups (patients with osseointegrated prostheses and patients who successfully use a traditional socket prosthesis). In Aim 1, we will quantify bilateral hip muscle quality using fat fraction quantitative magnetic resonance imaging (MRI). Using these images, we will quantify 3D muscle volume and levels of fatty infiltration on the bilateral hip musculature. This will elucidate if the known atrophy and poor composition due to disuse in a socket prosthesis, both of which are known to progress OA, can be reversed following prosthesis osseointegration. In Aim 2, we will quantify dynamic cartilage loading mechanics using motion capture and a subject-specific musculoskeletal contact model. Because altered cartilage loading is a primary instigator and factor in OA onset and progression, these results will determine if cartilage mechanics are normalized during activities of daily living following osseointegration. Although muscle composition and cartilage mechanics are etiological factors to OA development, we seek to assess the role of osseointegration on the clinical progression of OA. Thus, in Aim 3, we will quantify cartilage health using T2 quantitative MRI, which is currently the most sensitive methodology to assess early osteoarthritic changes in-vivo. Ultimately, we seek to use our multi-domain approach to better inform targeted interventions aimed at improving outcomes following osseointegration. The candidate’s overarching career goal is to utilize engineering-based tools to better elucidate the mechanisms to secondary pain conditions that can be used to improve targeted interventions. This proposal builds on the candidate’s current expertise by providing new training in quantitative MRI, advanced imaging post- processing tools, longitudinal research design and implementation, and links between biomechanics and clinical factors of joint disease. The mentoring team consists of physical therapists, radiologists, bioengineers, and orthopaedic surgeons who are experts in imaging, clinical interventions, and OA. This proposal will provide preliminary data for an R01 focused on key factors that affect long-term outcomes with varying prosthesis types.

PROJECT NARRATIVE Osseointegrated prostheses are a novel alternative to a socket that directly mount the prosthesis to the residual limb via a bone anchored implant providing more normative load transmission between the ground and residual limb; yet its effect on the mechanical environment of the joint remains unknown. This project will be the first to rigorously investigate the longitudinal effects of osseointegrated prostheses across multiple biomechanical domains using medical imaging and computational modeling. By quantifying its effect on muscle composition, cartilage loading mechanics, and cartilage health, we can begin to determine if prosthesis osseointegration plays a positive role of osteoarthritis progression in this population differently than a socket, which has vast clinical implications including informing targeted rehabilitation and patient eligibility criteria.