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

项目总结 盆腔器官脱垂(POP)是困扰世界各地女性的一种常见的衰弱疾病。12.6% 仅在美国，女性就将在80岁之前接受修复POP的大型手术。现行做法 支持使用轻质、针织、宽孔聚丙烯，以改善与以下设备相关的高故障率 天然组织修复。然而，网眼的使用受到并发症的限制，最常见的是网眼暴露。 通过阴道上皮和疼痛，发生在~10%的病例。此前，使用体外试验和 计算模型表明，大多数POP网格的孔道几何结构明显不稳定， 张力小，容易变形，导致毛孔塌陷和起皱。相比之下，正方形 孔洞网格稳定，变形小，结构和功能得到全面改善 与几何结构不稳定的网格相比，体内的结果。然而，通过旋转方形孔洞网格 45o到不稳定的钻石配置并故意引入皱纹，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状暴露 阴道表明有压力屏蔽作用。一个更微妙的发现是在邻近的区域，在那里我们观察到密集的 胶原/基质沉积和组织增厚与纤维化相一致，这是疼痛的合理机制。 通常不存在于健康组织中的肌成纤维细胞在网状区显著增加。 变形，特别是在纤维化明显的地方，强烈表明机械信号，发生在 很高的地方水平，是宿主反应的主要驱动力。因此，虽然我们之前的研究主要集中在 免疫反应即刻在网状纤维的区域，我们体会到更具冲击力的事件 由成纤维细胞驱动，可能对POP生物材料的结果更为关键。的总体假设 这一建议是由网眼的张拉和生理载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期的局部比较 机械的暗示。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反应 在a)活体兔固定模型和b)体外模型中网格随时间施加的机械应力 使用可提供成纤维细胞机械信号的功能化合成可调基质。在目标2中，我们测试 假设过度拉伸稳定的孔网对宿主的反应有负面影响，因为 压力变异性。而高应力区会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，我们解释了从有并发症的妇女中摘除网片的先前目标的发现。 比较正常结合的扁平网眼和变形网眼的成纤维细胞和免疫反应 网状。我们主张，确定当前并发症的机制基础是关键和必要的步骤 改进现有网格和开发用于POP修复的未来新设备的迭代过程。

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.