Injectable Tissue-Specific Extracellular Matrix Hydrogel for Pelvic Skeletal Muscle Regeneration Following Birth Injury

University Of California, San Diego, La Jolla CA

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Abstract

PROJECT SUMMARY Maternal childbirth injury is the leading risk factor for pelvic floor muscle (PFM) dysfunction and the resultant pelvic floor disorders (PFD), which include pelvic organ prolapse (POP) and urinary and fecal incontinence. Collectively PFD represent a major public health concern given their extreme prevalence, associated morbidities and economic burden. Despite this, preventative strategies for maternal birth trauma continue to be limited to Cesarean sections and the existing treatments offer marginal promise at best. Our studies of PFMs' morphometric properties in parous women with POP demonstrate substantial degeneration, specifically cell death and fibrosis, in these muscles. The above alterations render muscles insensitive to rehabilitation and are associated with poor clinical outcomes. To establish a mechanistic link between birth injury and PFM dysfunction, we utilized the rat model, whose PFMs are anatomically and architecturally similar to human. We found that simulated birth injury leads to PFM fiber atrophy and fibrosis, similar to the degenerative changes observed in human PFMs, as well as functional alterations. The primary goals in female pelvic medicine are to preserve or restore normal pelvic floor function. Unfortunately, the current treatments are delayed and compensatory, as they do not directly target and, therefore, do not reverse the pathways responsible for PFM dysfunction. We developed a novel tissue-specific injectable extracellular matrix (ECM) hydrogel, derived from decellularized porcine skeletal muscle, which promotes muscle regeneration by increasing vascularization and recruitment of muscle progenitors, and reducing cell death. These findings lead to our overall theoretical framework for a high impact intervention aimed at therapeutic void preventing injured PFMs' degeneration and We propose that regenerative signals initiated around the time of birth injury will potentiate muscle recovery by stimulating tissue-specific reparative processes. We will test these hypotheses in 2 independent but interrelated Aims, using the rat model of birth injury. In Aim 1, we will determine whether PFM degeneration can be prevented by ECM hydrogel administration at the time of birth injury. We will assess the acute histological, protein, and gene expression changes and subacute physiological, histological, and protein changes of the injured PFMs in response to this novel intervention. In Aim 2, we will test if skeletal muscle ECM hydrogel administered 4 weeks post birth injury can reverse PFMs' degeneration and restore physiological properties. The major outcomes of these innovative studies will be comprehensive and functionally relevant assessments of this low-cost acellular minimally invasive regenerative therapy on PFM recovery following birth injury. These findings will provide the foundation for future clinical investigations. If successful, such strategies could shift the current clinical paradigm towards prevention of PFM dysfunction following birth trauma and treatments that restore postpartum function of injured muscles, both of which are essential for meaningful advances to occur in female pelvic medicine. bridging the existing by preserving muscle function.