Prevention of pelvic floor muscle dysfunction with extracellular matrix hydrogel

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.

Grant Number: 5R01HD102184-05
NIH Institute/Center: NIH
Principal Investigator: Marianna Alperin