Overcoming complications of polypropylene prolapse meshes: Development of novel elastomeric membranes

PROJECT SUMMARY Pelvic organ prolapse (POP) is a common, costly condition in women with a lifetime risk of surgical repair of 12.6%. Of those undergoing a native tissue repair, 70% will fail by 5 years prompting surgeons to turn to biomaterials, most commonly polypropylene mesh (PPM). Unfortunately, POP meshes were never designed specifically for the vagina and are hampered by complications. Our studies show that implantation of PPM leads to degeneration, atrophy, and loss of function of the vagina. The high material stiffness of polypropylene dictates that meshes manufactured from this polymer are knitted, leading to a device that undergoes pore collapse, wrinkling, and permanent deformation upon tensioning. These changes result in an increased mesh burden, a heightened foreign body response, and poor outcomes. To overcome the limitations of current PPMs, we have manufactured an elastomeric membrane (EM) from polycarbonate urethane (PCU) for use in POP repair surgeries. The EMs are 3D printed (to afford rapid prototyping) with a material stiffness that is on the same order of magnitude as that of the vagina, a geometry that favors stable pores, and minimal wrinkling with tensioning. In vivo assessment of physicochemical properties of small EM constructs (2x1cm2) demonstrated a markedly improved host response as compared to similarly sized PPMs. In this renewal application, we propose to expand our in vivo evaluation to full length EMs in a nonhuman primate POP repair model (sacrocolpopexy) and to improve our product based on potential limitations. First, softer devices, while better for host response, can lead to surgical failure under lower loads, necessitating thicker devices or devices that are spatially graded to provide increased mechanical support in certain locations such as mesh anchor points. Second, our current EMs do not bioactively interact with the vagina which is compromised in individuals with POP. To address these issues, we propose to develop the next generation of mechanically graded and functionally interactive EMs, hypothesizing they will improve long-term tissue viability and reduce the host response to the implanted device. We test this hypothesis in 3 aims. In Aim 1, we develop tunable membranes that are mechanically graded with less material over the vagina and increased material in stem that forms a bridge to the sacrum. This design feature will decrease risk of failure at the sacrum and in the bridge and facilitate tacking or sewing into the device without negatively impacting the vaginal host response. In Aim 2, we take advantage of our expertise in polymer synthesis to develop an EM that is functionalized with synthetic peptides designed to promote interaction/integration into the host extracellular matrix and to overcome some of the negative impacts of biomaterials on host tissues. In both Aims 1 and 2, we evaluate the host response in vivo to the small EM constructs using a rabbit vaginal implantation model. In Aim 3, we implant the final iterations of the EM prototypes developed in this and our previous application in a nonhuman primate prolapse repair model for a final preclinical assessment. We look forward to this opportunity to improve outcomes for women with POP.