Mesh complications: The role of local mechanical stresses on tissue remodeling following mesh implantation

项目摘要 盆腔器官脱垂（POP）是一种常见的使人衰弱的疾病，困扰着世界各地的妇女。12.6%的 仅在美国，女性在80岁之前就将接受大手术来修复POP。现行做法 使用轻质、针织、宽孔聚丙烯支撑，以改善与 自体组织修复然而，补片的使用受到并发症的限制，最常见的是补片暴露 通过阴道上皮和疼痛，发生在约10%的情况下。此前，使用体外试验和 计算模型，我们表明，大多数POP网格的孔隙几何形状是显着不稳定的， 很容易在施加少量张力的情况下变形，导致收缩的孔隙和褶皱。相比之下，Square 多孔补片稳定，几乎没有变形，转化为整体结构和功能的改善 与几何形状不稳定的补片相比的体内结果。然而，通过旋转方孔网格， 45o到不稳定的钻石配置和故意引入皱纹，我们成功地复制了 并发症最明显的是与底层变薄和退化相关的网格暴露 表明有压力遮挡一个更微妙的发现是在邻近地区，我们观察到密集的 胶原/基质沉积和组织增厚与纤维化一致，这是一种合理的疼痛机制。 肌成纤维细胞通常不存在于健康组织中，但在补片区域中显著增加 变形，特别是纤维化明显的地方，强烈表明机械信号，发生在一个 高度地方一级，是东道国反应的主要驱动力。因此，虽然我们以前的研究集中在 免疫反应立即在该地区的网状纤维，我们赞赏，更有影响力的事件 在POP生物材料结果中，由成纤维细胞驱动的可能更为关键。总体假设 这一建议是，由补片的张紧和生理负荷引起的局部应力变化，信号 阴道成纤维细胞的增殖与降解反应与静止， 机械提示为了解决这一假设，在目标1中，我们定义了阴道成纤维细胞对改变的 在a）体内家兔阴道固定模型和B）体外模型中，补片随时间施加的机械应力 使用提供成纤维细胞机械信号传导的功能化合成可调基质。在目标2中，我们测试 假设过度张拉稳定的孔隙网格对主机响应有负面影响， 应力变异性而高应力区域将诱导肌成纤维细胞增殖和基质/胶原沉积 随着收缩，亚生理（屏蔽）应力区域将导致基质降解和成纤维细胞凋亡。 在目标3中，我们解释了从患有并发症的女性中取出补片的先前目标的结果， 将正常结合的扁平补片中的成纤维细胞和免疫反应与变形补片中的成纤维细胞和免疫反应进行比较， 网格我们主张，确定目前并发症的机制基础是关键和必要的一步， 迭代过程，以改善目前的网格和开发未来的新设备的POP修复。

PROJECT SUMMARY Pelvic organ prolapse (POP) is a common debilitating disease afflicting women throughout the world. 12.6% of women in the United States alone will undergo a major surgery to repair POP by age 80. Current practice supports using lightweight, knitted, wide pore polypropylene to improve the high failure rates associated with native tissue repair. However, mesh use has been limited by complications, most commonly mesh exposure through the vaginal epithelium and pain, occurring in ~10% of cases. Previously, using ex vivo tests and computational models, we showed that the pore geometries of most POP meshes were markedly unstable, easily deforming with small applications of tension, resulting in collapsed pores and wrinkling. In contrast, square pored meshes were stable showing little deformation, translating into overall improved structural and functional outcomes in vivo as compared to meshes with unstable geometries. However, by rotating square pored meshes 45o to an unstable diamond configuration and intentionally introducing wrinkles, we successfully reproduced complications. Most obvious were mesh exposures associated with thinning and degeneration of the underlying vagina indicative of stress shielding. A more subtle finding was in adjacent areas where we observed dense collagen/matrix deposition and tissue thickening consistent with fibrosis, a plausible mechanism of pain. Myofibroblasts, not typically present in healthy tissues, were dramatically increased in areas of mesh deformation, particularly where fibrosis was evident, strongly suggesting that mechanical signals, occurring at a highly local level, were a primary driver of the host response. Thus, while our previous studies had focused on the immune response immediately in the area of the mesh fiber, we appreciated that more impactful events driven by fibroblasts were perhaps even more critical in POP biomaterial outcomes. The overall hypothesis of this proposal is that local stress variations induced by tensioning and physiologic loading of mesh, signal vaginal fibroblasts toward a proliferative vs degradative response vs quiescence based on local mechanical cues. To address this hypothesis, in Aim 1, we define the response of vaginal fibroblasts to altered mechanical stresses imposed by mesh over time in a) an in vivo rabbit colpopexy model; and b) an in vitro model using a functionalized synthetic tunable matrix that affords fibroblast mechanosignaling. In Aim 2, we test the hypothesis that over tensioning a stable pore mesh has negative impact on the host response by increasing stress variability. While high stress areas will induce myofibroblast proliferation and matrix/collagen deposition with contraction; subphysiologic (shielded) stress areas will lead to matrix degradation and fibroblast apoptosis. In Aim 3, we interpret findings from the previous aims in mesh removed from women with complications by comparing the fibroblast and immune responses in normally incorporated flat mesh to that found in deformed mesh. We advocate that defining the mechanistic basis of current complications is a key and necessary step in the iterative process toward improving current meshes and developing future novel devices for POP repair.