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

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.

项目总结

项目成果

Dysregulated wound healing in the pathogenesis of urogynecologic mesh complications.

• DOI: 10.1038/s41598-023-48388-8
• 发表时间: 2023-12-05
• 期刊: Scientific reports
• 影响因子: 4.6

T regulatory cells and TGF-β1: Predictors of the host response in mesh complications.

T调节细胞和TGF-β1：网格并发症中宿主反应的预测指标。

• DOI: 10.1016/j.actbio.2020.07.051
• 发表时间: 2020-10-01
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Artsen AM;Liang R;Meyn L;Rytel M;Palcsey S;Abramowitch SD;Moalli PA
• 通讯作者: Moalli PA

Exploring the basic science of prolapse meshes.

• DOI: 10.1097/gco.0000000000000313
• 发表时间: 2016-10
• 期刊: Current opinion in obstetrics & gynecology
• 影响因子: 2.1
• 作者: Liang R;Knight K;Abramowitch S;Moalli PA
• 通讯作者: Moalli PA

Characterization of the T-cell response to polypropylene mesh in women with complications.

患有并发症的女性中 T 细胞对聚丙烯网片反应的表征。

• DOI: 10.1016/j.ajog.2018.11.121
• 发表时间: 2019
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: Tennyson,Lauren;Rytel,Matthew;Palcsey,Stacy;Meyn,Leslie;Liang,Rui;Moalli,Pamela
• 通讯作者: Moalli,Pamela

Impact of Polypropylene Prolapse Mesh on Vaginal Smooth Muscle in Rhesus Macaque.

• DOI: 10.1016/j.ajog.2019.05.008
• 发表时间: 2019-05
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: R. M. Shaffer;R. Liang;K. Knight;C. Carter-Brooks;S. Abramowitch;P. Moalli