PROJECT SUMMARY Mitral valve regurgitation is one of the most prevalent valvular heart diseases worldwide and is a significant cause of global morbidity and mortality. Although mitral repair operations were first described several decades ago, numerous new repair techniques have been developed in recent years. However, these techniques were described primarily based on anatomic principles and guided by valvular appearance and function, mostly via visual assessment and echocardiography. The biomechanical engineering principles and fundamentals underlying various mitral valve repair techniques have rarely been investigated, and repair strategy remains largely based on surgeon’s preference. With evolving guidelines advocating earlier, more aggressive intervention with mitral valve repair whenever possible, especially for regurgitant lesions, the goal of this proposal is to establish a solid understanding of mitral valve repair biomechanics for primary mitral regurgitation. This is essential for optimizing these complex mitral valve repair operations to enhance valve repairability, expand valve repair technique adoptability, and improve repair durability. Aim 1 will characterize and optimize our novel 3D- printed mitral annuloplasty ring prototype with selective flexibility. Using healthy human cardiac MRI marker tracking and fatigue testing results, the annuloplasty ring design will be perfected to facilitate the native mitral annular motion and enhance durability. Next, primary mitral regurgitation models with leaflet prolapse and annular dilation will be created and assessed. Current clinically employed repair operations, namely triangular resection, neochordal reconstruction, and ring annuloplasty using our novel design and other annuloplasty rings with varying flexibility, will be tested on these primary mitral regurgitation models. Innovative biomechanical sensors and advanced cardiac imaging technologies will facilitate the detailed analysis of the engineering principles underlying these operations and annuloplasty ring designs. Aim 2 will validate findings from the ex vivo experiments in pre-clinical ovine models. The effect of annuloplasty rings’ flexibility on natural mitral annular motion and left ventricular vortex flow pattern after ring annuloplasty will be investigated in healthy ovine models without mitral regurgitation. The mitral valve repair operations will be evaluated on the ovine models with chronic primary mitral regurgitation generated by posterior leaflet chordal transection. The results will be compared to the ex vivo studies. The experiments proposed herein have great clinical applicability. Findings from this study can help surgeons gain substantial understanding of mitral valve repair biomechanics thereby translating directly to patient care in the operating room.