Pelvic organ prolapse (POP) results in 225,000-300,000 surgical procedures per annum and with costs exceeding $1 billion in the United States. Native tissue repair of POP is associated with high recurrence rates. Therefore, synthetic mesh, originally intended for abdominal wall hernias, has been increasingly used in repair of pelvic organ prolapse to improve anatomic success. However, surgeries which include mesh, such as the 'gold standard'abdominal sacralcolpopexy and the newer vaginal mesh procedures are associated with high rates of patient morbidity including higher rates of fistula formation, erosion, infection, and pain. The rates of these complications are significant enough to warrant FDA warnings in 2008 and 2011. Many of these complications has been directly attributed to the immune response of the host to the synthetic mesh. There is a lack of rigorous scientific studies characterizing the effects of this host response in the vagina and the design of mesh materials largely relies on data generated in abdominal hernia repair. As a result, clinicians may select products based upon the recommendations of a vendor or institution, leading to the use of mesh in women on a trial and error basis. Macrophages have recently been classified as having diverse and plastic phenotypes between M1 (classically activated;pro-inflammatory) and M2 (alternatively activated;regulatory, homeostatic) extremes. Increasingly, macrophage polarization and plasticity are being shown to play important, and determinant, roles in disease pathogenesis and tissue remodeling. The timely modulation of macrophage phenotype appears to be a crucial event in the tissue remodeling process. An increasing number of studies in the field of biomaterials have begun to apply these paradigms and concepts, and have shown that macrophage phenotype is a predictor of integration following placement. Briefly, the early macrophage response following implantation of biomaterials is a necessary and essential component of a beneficial response and that strategies which incorporate and modulate the host macrophage response rather than seek to avoid it result in improved tissue incorporation and long term-functional outcomes as a result. We, therefore, propose to investigate the role of macrophage polarization following placement of synthetic mesh in an in vivo transvaginal model to further elucidate how both individual mesh characteristics and modulation of macrophage phenotype in the immediate postoperative period can determine long term incorporation or complications related to synthetic mesh placement. Completion of these studies on the evaluation and modulation of the host tissue response to synthetic mesh used in pelvic organ prolapse has the potential to inform the selection of mesh materials and to significantly affect the design of next generation mesh materials leading to improved patient outcomes.
Synthetic mesh is widely used in pelvic organ prolapse repair to improve anatomic outcomes, despite the known complications of inflammation, scarring, pain and infection. This host response to synthetic materials should be predictable based on pore size, mesh type, and area of placement, but limited studies to date have sought to distinguish the role of the macrophage in this response and its related effects on long-term outcomes of either functional incorporation or prolonged chronic inflammation. This project seeks to develop a greater understanding of the mechanisms by which differences in synthetic meshes direct macrophage polarization and their downstream effects, how this differs between abdominal and transvaginal implantation, and to determine how modulation of the M1/M2 phenotype ultimately affects the integrity of the post-implantation tissues.