Saturday, December 21, 2024
12/21/2024
PROJECT SUMMARY Each year, at least 20% of women who give birth vaginally sustain an avulsion of the pubovisceral muscle enthesis (PVME) at the pubic bone, substantially predisposing to pelvic organ prolapse (POP) and associated disorders later in life. POP, a chronic disease unique to women, represents a major public health burden since 12.6% of US women will undergo a major surgical repair of POP by age 80, at an estimated cost of > $10 billion annually. Currently, our inability to repair PVME avulsions, either at the time of injury or later in life when POP has occurred, severely undermines the outcomes of current POP surgeries. PVME injuries are rarely recognized at vaginal birth, and given that there is no viable treatment, there is little incentive to change this standard of care. Lack of fundamental and longitudinal data on the pathophysiologic events that follow PVME avulsion and the related biomechanical consequences further hinders the design of interventions. Bridging this knowledge gap, the current proposal will first investigate the structure and function of native PVME and the pathophysiologic events following injury, so as to inform the design of a composite scaffold that orchestrates an integrative repair. We hypothesize that a surgically placed bioinspired composite scaffold with pre-engineered biomimetic spatial cues in structure and composition will enable enthesis regeneration that will be superior to suture repair. To test this, we develop a comprehensive framework for defining PVME injury and repair based on transperineal ultrasound to 1) improve the identification of patients who will have persistent levator avulsion and are candidates for repair; and 2) guide the development of design parameters for an effective repair using a bioinspired graft. Statistical shape models derived from 3D MRI models will be used as a gold standard to inform the diagnostic interpretation of corresponding shape models established from transperineal ultrasound (TPUS) in women with and without PVME injury. These analyses will be further informed by finite element simulations predicting functional deficits after PVME injury and subsequent parametric studies of enthesis repair to enable the establishment of basic design criteria for a scaffold based repair. In parallel, we perform cell culture and small animal studies (Aim 2) to investigate matrix attributes, cell populations, and molecular and mechanical cues involved in enthesis repair to further refine scaffold design and define needs for durable repair. With its high capacity for biomimicry, a nanofiber-based bilayer scaffold with a mineralized component for osteointegration and a nonmineralized portion for tendon formation already established to regenerate a functional tendon-bone interface in rotator cuff repair will be adapted for PVME. Fiber diameter, alignment, and mineral content will be readily optimized in Aim 2 to guide the cell response and direct enthesis healing. Finally, a nonhuman primate model will be employed in a preclinical study that compares scaffold to suture repair and uninjured enthesis (Aim 3). We firmly believe that development of this bioinspired composite scaffold for PVME repair will lead to a paradigm shift in the treatment of traumatic childbirth to the benefit of women world-wide.
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