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

网片并发症：网片植入后局部机械应力对组织重塑的作用

• 批准号: 10687194
• 负责人: STEVEN D ABRAMOWITCH
• 金额: $ 59.79万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687194
• 关键词: Address; Advocate; Age; Apoptosis; Area; Biocompatible Materials; Cells; Collagen; Complication; Computer Models; Data; Deposition; Deterioration; Development; Devices; Diamond; Disease; Disparate; Distant; Encapsulated; Epithelium; Event; Excision; Exposure to; Failure; Fiber; Fibroblasts; Fibrosis; Future; Geometry; Grant; Immigration; Immune response; In Vitro; Inflammatory; Injury; Macrophage; Mechanical Stress; Modeling; Modification; Molecular; Motion; Myofibroblast; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Polypropylenes; Process; Proliferating; Research; Role; Rotation; Signal Transduction; Site; Smooth Muscle; Stress; Surgeon; Symptoms; Testing; Thinness; Time; Tissues; Translating; United States; Vagina; Variant; Woman; design; functional outcomes; implantation; improved; in vitro Model; in vivo; light weight; mechanical signal; millimeter; nonhuman primate; novel; pelvic organ prolapse; repaired; response; soft tissue; surgery outcome; tissue repair; Address; Advocate; Age; Apoptosis; Area; Biocompatible Materials; Cells; Collagen; Complication; Computer Models; Data; Deposition; Deterioration; Development; Devices; Diamond; Disease; Disparate; Distant; Encapsulated; Epithelium; Event; Excision; Exposure to; Failure; Fiber; Fibroblasts; Fibrosis; Future; Geometry; Grant; Immigration; Immune response; In Vitro; Inflammatory; Injury; Macrophage; Mechanical Stress; Modeling; Modification; Molecular; Motion; Myofibroblast; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Polypropylenes; Process; Proliferating; Research; Role; Rotation; Signal Transduction; Site; Smooth Muscle; Stress; Surgeon; Symptoms; Testing; Thinness; Time; Tissues; Translating; United States; Vagina; Variant; Woman; design; functional outcomes; implantation; improved; in vitro Model; in vivo; light weight; mechanical signal; millimeter; nonhuman primate; novel; pelvic organ prolapse; repaired; response; soft tissue; surgery outcome; tissue repair

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.

项目摘要 骨盆器官脱垂（POP）是一种常见的使人衰弱的疾病，困扰着全世界的妇女。 12.6％ 仅美国的妇女就会在80岁之前进行大规模手术，以修复流行。 使用轻巧，针织，宽孔聚丙烯的支持，以提高与 天然组织修复。但是，网格的使用受到并发症的限制，最常见的是网状曝光 通过阴道上皮和疼痛，发生在约10％的病例中。以前，使用离体测试和 计算模型，我们表明大多数流行网格的孔几何形状显着不稳定， 张力的小应用很容易变形，从而导致毛孔塌陷和皱纹。相反，正方形 填充网稳定显示几乎没有变形，转化为整体改进的结构和功能 与具有不稳定几何形状的网格相比，体内结果的结果。但是，通过旋转正方形的围网 45o到不稳定的钻石配置并有意引入皱纹，我们成功地复制了 并发症。最明显的是与底层变薄和变性相关的网格暴露 阴道指示应力屏蔽。一个更微妙的发现是在我们观察到密集的邻近地区 胶原蛋白/基质沉积和组织增厚与纤维化一致，纤维化是一种合理的疼痛机制。 在网状区域中，肌纤维细胞通常不存在于健康组织中 变形，特别是在明显纤维化的情况下，强烈表明机械信号发生在A 高度局部水平是主机响应的主要驱动力。因此，尽管我们以前的研究集中于 立即在网状纤维区域的免疫反应，我们赞赏更具影响力的事件 在成纤维细胞的驱动中，在流行生物材料结果中可能更为重要。总体假设 该建议是，网格的张力和生理负荷引起的局部应力变化，信号 阴道成纤维细胞朝着基于局部 机械提示。为了解决这一假设，在AIM 1中，我们定义了阴道成纤维细胞对改变的反应 随着时间的流逝，网格施加的机械应力在a）体内兔子copopexy模型中施加的机械应力； b）体外模型 使用具有成纤维细胞机械信号的官能化合成可调矩阵。在AIM 2中，我们测试 假设稳定的孔网张紧稳定的孔通过增加对宿主反应的负面影响 压力变异性。高应力区域会诱导肌纤维细胞增殖和基质/胶原蛋白沉积 收缩；亚物理（屏蔽）应力区域将导致基质降解和成纤维细胞凋亡。 在AIM 3中，我们解释了以前目的的发现，从具有并发症的女性中移除的网格中。 比较正式合并的扁平网格中的成纤维细胞和免疫反应与变形 网。我们提倡定义当前并发症的机理基础是关键和必要的步骤 改善当前网格和开发未来新颖的流行设备以进行流行维修的迭代过程。