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
基本信息
- 批准号:10298638
- 负责人:
- 金额:$ 64.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdvocateAgeApoptosisAreaBiocompatible MaterialsCellsCollagenComplicationComputer ModelsCuesDataDepositionDeteriorationDevelopmentDevice or Instrument DevelopmentDevicesDiamondDiseaseDistantEncapsulatedEpithelialEventExcisionExposure toFailureFiberFibroblastsFibrosisFutureGeometryGrantImmigrationImmune responseIn VitroInflammatoryMechanical StressMechanicsModelingModificationMolecularMyofibroblastOperative Surgical ProceduresOryctolagus cuniculusOutcomePathologicPathway interactionsPatientsPhenotypePhysiologicalPolypropylenesProcessResearchRoleSignal TransductionSiteSmooth MuscleStressStructureSurgeonSymptomsTestingThinnessTimeTissuesTranslatingUnited StatesVaginaVariantWomanbasedesignfunctional outcomesimplantationimprovedin vitro Modelin vivolight weightmacrophagemillimeternonhuman primatenovelpelvic organ prolapserepairedresponsesoft tissuesurgery outcometissue repair
项目摘要
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.
项目概要
盆腔器官脱垂(POP)是一种困扰全世界女性的常见衰弱性疾病。 12.6%的
仅美国女性就会在 80 岁时接受一次修复 POP 的大手术。 目前的做法
支持使用轻质、针织、大孔聚丙烯来改善与
原生组织修复。然而,网片的使用受到并发症的限制,最常见的是网片暴露
穿过阴道上皮并产生疼痛,约 10% 的病例会发生这种情况。此前,使用离体测试和
计算模型,我们表明大多数 POP 网格的孔隙几何形状明显不稳定,
施加很小的张力就容易变形,导致毛孔塌陷和起皱。相比之下,正方形
多孔网格稳定,几乎没有变形,转化为结构和功能的整体改进
与具有不稳定几何形状的网格相比的体内结果。然而,通过旋转方孔网格
45o 到不稳定的钻石构型并故意引入皱纹,我们成功地再现了
并发症。最明显的是与底层变薄和退化相关的网格暴露
阴道指示压力屏蔽。一个更微妙的发现是在我们观察到密集的邻近区域
胶原/基质沉积和组织增厚与纤维化一致,这是一种可能的疼痛机制。
肌成纤维细胞通常不存在于健康组织中,但在网状区域显着增加
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
高度本地化,是主机响应的主要驱动力。因此,虽然我们之前的研究重点是
免疫反应立即发生在网状纤维区域,我们意识到更具影响力的事件
由成纤维细胞驱动的可能在 POP 生物材料结果中更为关键。总体假设为
该建议是,由网格的张紧和生理负荷引起的局部应力变化,信号
基于局部的阴道成纤维细胞的增殖反应、降解反应与静止反应
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反应
a) 兔体内阴道固定模型中网片随时间施加的机械应力; b) 体外模型
使用提供成纤维细胞机械信号传导的功能化合成可调谐基质。在目标 2 中,我们测试
假设过度张紧稳定的孔网会对宿主反应产生负面影响,因为
应力变异性。而高压力区域会诱导肌成纤维细胞增殖和基质/胶原蛋白沉积
伴随着收缩;亚生理(屏蔽)应激区域将导致基质降解和成纤维细胞凋亡。
在目标 3 中,我们解释了先前目标中从患有并发症的女性身上移除网片的结果:
将正常合并的扁平网格中的成纤维细胞和免疫反应与变形网格中的成纤维细胞和免疫反应进行比较
网。我们主张,明确当前并发症的机制基础是解决这一问题的关键和必要步骤。
改进当前网格和开发未来 POP 修复新颖设备的迭代过程。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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STEVEN D ABRAMOWITCH其他文献
STEVEN D ABRAMOWITCH的其他文献
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{{ truncateString('STEVEN D ABRAMOWITCH', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 64.75万 - 项目类别:
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:
10462766 - 财政年份:2021
- 资助金额:
$ 64.75万 - 项目类别:
Overcoming Complications of Polypropylene Prolapse Meshes: Development of Novel Elastomeric Auxetic Devices
克服聚丙烯脱垂网的并发症:新型弹性拉胀装置的开发
- 批准号:
9917810 - 财政年份:2019
- 资助金额:
$ 64.75万 - 项目类别:
Overcoming Complications of Polypropylene Prolapse Meshes: Development of Novel Elastomeric Auxetic Devices
克服聚丙烯脱垂网的并发症:新型弹性拉胀装置的开发
- 批准号:
10372098 - 财政年份:2019
- 资助金额:
$ 64.75万 - 项目类别:
Overcoming Complications of Polypropylene Prolapse Meshes: Development of Novel Elastomeric Auxetic Devices
克服聚丙烯脱垂网的并发症:新型弹性拉胀装置的开发
- 批准号:
10613362 - 财政年份:2019
- 资助金额:
$ 64.75万 - 项目类别:
Porosity and tensioning: Critical factors to consider when choosing a prolapse mesh
孔隙率和张力:选择脱垂网片时要考虑的关键因素
- 批准号:
9205246 - 财政年份:2016
- 资助金额:
$ 64.75万 - 项目类别:
Porosity and tensioning: Critical factors to consider when choosing a prolapse mesh
孔隙率和张力:选择脱垂网片时要考虑的关键因素
- 批准号:
9030077 - 财政年份:2016
- 资助金额:
$ 64.75万 - 项目类别:
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