Development of a Novel Bioinspired Pelvic Organ Prolapse Repair Graft

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Surgical treatments for pelvic organ prolapse (POP) suffer from high complication and reoperation rates, with 70% of native tissue repair operations failing within five years and the FDA halting commercial use of graft materials for transvaginal procedures. Many of these problematic grafts are repurposed from non- gynecologic procedures and cannot mimic the properties of the vagina. Recent cell- or protein-enhanced experimental grafts also do not bridge the technological gap due to mechanical failure and immunogenic DNA retention. Given the gap in knowledge regarding engineering POP repair grafts less susceptible to failure, our objective is to obtain novel data on healthy, non-prolapsed vaginal extracellular matrix (vECM) structure and function to inform devel-opment of a synthetic biomimetic graft. We will define contributions of collagen and elastin fibers to the mechan-ical behavior of vaginal tissue and use these data as constraints for iterative design of elastomeric, biocompatible graft components that provide mechanical support and cell adhesion. Then, we will probe for fibroblast adhesion and absence of pathologic myofibroblast differentiation on these materials. Our proposed product design is com-posed of a non-degradable 3D printed elastomer mesh encapsulated by a 3D printed hydrogel coating that can be remodeled by surrounding cells. The goal of this proposal is to test our hypothesis that mechanical and biochemical cues provided by vECM drive cellular organization and structure of the healthy vagina and can be replicated in a mechanically competent biomimetic POP repair graft. This hypothesis will be tested via experi-mental techniques in biomechanics, imaging, additive manufacturing, and bioreactor cell culture. Aim 1 will fur-ther define the relationship between vaginal elasticity and vECM proteins and produce an elastomeric mesh that minimizes pathologic myofibroblast transformation by mimicry of vECM fiber mechanics. This aim will be achieved through vECM elasticity profiling, 3D printing of biocompatible elastomers to form a mesh with similar mechanical properties, and assessment of cellular response to this mesh in a tension bioreactor. Aim 2 will define tissue-specific cell adhesion dynamics and produce a composite 3D printed material capable of partial degradation embedded with physiologic distributions of key extracellular matrix proteins to promote cell adhe-sion. This aim will be achieved via microscopy and proteomic analysis of vECM, 3D printing of a partially de-gradable coating mimicking vECM microstructure and protein distribution, and assessment of cellular adhesion to this coating in a tension bioreactor. The work detailed through this proposal will answer critical questions regarding the structure-function properties of vECM and produce two novel materials with therapeutic potential for POP repair when used together or separately as potential enhancements to commercially available materials. This research is inspired by my own interests in pathology, surgical outcomes, and host response to engineered biomaterials. Completing this proposal will provide me with intellectual and technical skills that are essential for my future work as a physician-scientist at the intersection of biomaterials, pathology, and reconstructive surgery.