Prevention of Urethral and Anal Sphincters Dysfunction with an Acellular Biomaterial

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Project Summary A quarter of the United States female population is affected by pelvic floor disorders (PFDs). They include pelvic organ prolapse, and urinary and fecal incontinence. The most prevalent PFDs include stress urinary incontinence with an estimated rate of 15-17%, followed by fecal incontinence with 9.4% prevalence. PFDs represent a major public health issue given their high prevalence, negative impact on quality of life and associated economic burden. Maternal birth injuries to the external urethral sphincter (EUS) and external anal sphincter (EAS) are a critical event in the pathogenesis of PFDs. While vaginal childbirth doubles the risk for developing PFDs compared to elective cesarean section, this last mode of delivery is associated with high risks of morbidity and costs. Although, there is a continuous progress in the treatment of both conditions, currently available standards approaches continue to be delayed and compensatory, as they do not directly target the pathways responsible for muscle dysfunction, and in consequence do not address the etiology of the disease development. Cell based therapies have resulted in poor cell survival, increase connective tissue layer thickness, preventing myofiber regeneration. The Christman lab has previously demonstrated that an acellular, pro- regenerative skeletal muscle extracellular matrix (mECM) hydrogel, promotes muscle regeneration by increasing vascularization, enhancing the recruitment and differentiation of muscle progenitors and reducing cell death. Therefore, the proposed research hypothesize that mECM hydrogel promotes EUS and EAS regeneration and prevents long-term sphincteric muscle dysfunction following birth injury. To test this hypothesis, we aim to: Aim 1: Evaluate the efficacy of mECM on the myogenic regenerative pathways and on the functional recovery of EUS following birth injury. Aim 2: Evaluate the impact of mECM on the myogenic regenerative pathways and on the functional recovery of EAS following birth injury. This project will use a diverse multi-scale tools, including biomaterial fabrication techniques, in vivo small animal models, in vivo pressure measurements and ex vivo muscle force generation, immunohistochemistry, and bioinformatics. These techniques are essential for accomplishing the proposed aims and develop the PI for a career in scientific research. With women giving birth every day, the incidence of PFDs increases, being expected to increase by 43 million by 2050. In conclusion, this research has the potential to reduce this extreme outcome through mechanistic understanding of minimally invasive, injectable, low cost, easily fabricated decellularized material.