Macrophage Phenotype as a Determinant of Outcome in Pelvic Organ Prolapse Repair

描述（由申请人提供）：在美国，盆腔器官脱垂（POP）每年导致225，000 - 300，000例外科手术，费用超过10亿美元。POP的自体组织修复与高复发率相关。因此，最初用于腹壁疝的合成补片越来越多地用于盆腔器官脱垂的修复，以提高解剖成功率。然而，包括补片的手术，如“金标准”腹部骶骨阴道固定术和较新的阴道补片手术，与高患者发病率相关，包括瘘形成、糜烂、感染和疼痛的发生率较高。这些并发症的发生率足以在2008年和2011年引起FDA的警告。这些并发症中的许多直接归因于宿主对合成补片的免疫反应。目前还缺乏严格的科学研究来描述这种宿主反应在阴道中的影响， 补片材料很大程度上依赖于腹疝修补术中产生的数据。因此，临床医生可能会根据供应商或机构的建议选择产品，导致在试验和错误的基础上在女性中使用补片。巨噬细胞最近被分类为具有M1（经典激活;促炎）和M2（交替激活;调节，稳态）极端之间的多样性和可塑性表型。越来越多的研究表明，巨噬细胞的极化和可塑性在疾病发病机制和组织重塑中起着重要的决定性作用。巨噬细胞表型的及时调节似乎是组织重塑过程中的关键事件。越来越多的研究领域的生物材料已经开始应用这些范例和概念，并已表明，巨噬细胞表型是一个预测器的整合后放置。简而言之，植入生物材料后的早期巨噬细胞反应是有益反应的必要和基本组成部分，并且掺入和调节宿主巨噬细胞反应而不是寻求避免其的策略导致改善的组织掺入和长期功能结果。因此，我们建议在体内经阴道模型中研究植入合成补片后巨噬细胞极化的作用，以进一步阐明个体补片特征和术后即刻巨噬细胞表型的调节如何确定与合成补片植入相关的长期融合或并发症。完成这些关于评价和调节宿主组织对盆腔器官脱垂中使用的合成补片反应的研究，有可能为补片材料的选择提供信息，并显著影响下一代补片材料的设计，从而改善患者结局。

DESCRIPTION (provided by applicant): 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.