Prevention of pelvic floor muscle dysfunction with extracellular matrix hydrogel

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PROJECT SUMMARY Maternal childbirth injury is the leading risk factor for pelvic floor muscle dysfunction and the resultant pelvic floor disorders, which include pelvic organ prolapse and urinary and fecal incontinence. Despite high prevalence, significant morbidities, and economic burden associated with pelvic floor disorders, preventative strategies are almost non-existent, and the available treatments are delayed and compensatory as they do not directly target the underlying pathophysiology. Thus, our long-term goal is the development of new, minimally invasive tissue- engineered therapies for the prevention and treatment of pelvic muscle dysfunction. Our pilot studies of pelvic floor muscle morphometric properties in parous women with pelvic organ prolapse and the rat model of simulated birth injury demonstrate substantial degeneration, specifically cell death, myofiber atrophy and fibrosis. The above alterations render muscles insensitive to rehabilitation and are associated with poor clinical outcomes. We developed a novel tissue-specific injectable extracellular matrix hydrogel, derived from decellularized porcine skeletal muscles, which promotes muscle regeneration. This proposal is centered around the overall hypothesis that the skeletal muscle matrix hydrogel, which contains tissue-specific cues, can be delivered alone at the time of birth injury to prevent pelvic floor muscle dysfunction or following a maladaptive post birth injury recovery to reverse pelvic floor muscle dysfunction. We will test this hypothesis in our translationally-relevant pregnant model by comparing untreated and treated pelvic floor muscle phenotypic, functional, and transcriptional signatures at multiple time points following birth injury and determining mechanisms by which the extracellular matrix hydrogel enhances regeneration. Collectively, this innovative study will provide comprehensive and functionally relevant assessments of the role of this low-cost acellular minimally invasive regenerative therapy in pelvic floor muscle recovery following birth injury and the fundamental knowledge of the biological processes involved in the regulation of pelvic floor muscle regeneration. The above has a high potential for the development of novel preventative and therapeutic strategies to counteract pelvic muscle dysfunction and the related pelvic floor disorders.