Comprehensive Evaluation of Prolapse Meshes by an Interdisciplinary Research Team

描述(申请人提供)：每年大约有200,000名美国妇女接受手术修复盆腔器官脱垂(6，7)。生物网片和合成网片被广泛应用于脱垂修复中，以改善解剖结果，而天然组织修复目前的失败率超过30%。然而，到目前为止，几乎没有科学数据来指导外科医生选择特定的产品。因此，网眼是根据当地供应商的建议使用的，因此，在试验和错误的基础上放置在妇女身上。然而，越来越多的证据表明，与网片脱垂相关的并发症会导致不可接受的高发病率，包括感染、网片收缩、网片侵蚀、网片外露、盆腔、直肠和膀胱疼痛以及性功能障碍。这些并发症已经变得足够严重，以至于FDA最近发布了关于使用网片的警告，特别是当它被经阴道放置时。因此，在这项提案中，我们的目标是建立一个跨学科的科学家团队，致力于对以前或新上市的脱垂网片进行全面测试，并基于特定的科学标准开发下一代移植物材料。在研究的第一阶段，我们确定脱垂的阴道的生化和结构变化如何影响被动和主动的机械行为，从而形成一个网状结构，在其中修复或补偿这些缺陷，使我们能够将脱垂的阴道恢复到非脱垂的状态。在第二阶段，我们假设目前的脱垂网格的缺点是它们太硬了。虽然这会导致拉伸强度增加的修复，但它的发生是以组织功能为代价的，组织收缩加速，弹性和顺应性降低，平滑肌功能恶化。为了验证我们的假设，我们使用黄金标准的外科手术(腹部固定术)将常用的合成脱垂网片植入患有脱垂的非人灵长类动物的阴道，然后在植入后6个月确定对阴道的细胞、生化和生物力学影响。最终，我们将经阴道植入网状物，以表征宿主对这种手术方式的不同反应。在第三阶段，我们探讨了未来脱垂手术移植物的发展。我们推测，由于其生物诱导作用，在恢复阴道结构和功能方面，生物/合成网片将优于单独使用合成网片。我们认为，脱垂修复的一个关键但不发达的部分是重建平滑肌的反应性，因此，测试在实现这一过程中使用临时的生物活性支架。通过这种方式，这项拨款提案提供了一种机制，以建立第一支科学家团队，致力于对脱垂网状物进行全面、公正的评估，作为一种手段，教育当前和未来的脱垂外科医生，以及公众与某些材料相关的潜在问题。事实上，发展这样一个群体对于保护妇女的健康是必不可少的。 公共卫生相关性：盆腔器官脱垂(即异常下垂)是一种常见的代价高昂的疾病，对全世界数百万妇女的生活产生了负面影响。由于解剖学结果优于天然组织修复，生物和合成网状物经常用于脱垂的外科修复；但几乎没有科学数据来选择特定的产品。不幸的是，与某些网片相关的并发症导致不可接受的高发病率，包括感染、组织收缩、阴道分泌物和疼痛。在这项建议中，我们的目标是建立一个全面的网目测试中心，在那里可以对以前或新上市的脱垂网目进行客观测试，并根据特定的科学标准开发下一代脱垂网目。

DESCRIPTION (provided by applicant): Each year roughly 200,000 U.S. women undergo a surgery to repair pelvic organ prolapse (6, 7). Biologic and synthetic meshes are widely used in prolapse repairs to improve anatomical outcomes over native tissue repairs which currently have a failure rate of over 30%. To date, however, there is little scientific data to guide surgeons in the selection of a particular product. As a result, meshes are used based on the recommendations of a local vendor and consequently, are placed in women on a trial and error basis. There is growing evidence, however, that the complications associated with prolapse meshes cause unacceptably high rates of morbidity including infection, mesh shrinkage, mesh erosion, mesh exposure, pelvic, rectal and bladder pain and dyspareunia. Such complications have become significant enough for the FDA to recently release a warning about mesh use, especially when it is placed transvaginally. In this proposal, we therefore, aim to establish an interdisciplinary team of scientists dedicated to the comprehensive testing of previously or newly marketed prolapse meshes and for the development of the next generation of graft materials based on specific scientific criteria. In the first phase of the study, we determine how biochemical and structural changes in the prolapsed vagina impact passive and active mechanical behavior so as to develop a mesh in which these deficiencies are repaired or compensated for, allowing us to restore the prolapsed vagina to the nonprolapsed condition. In the second phase, we hypothesize that the shortcoming of current prolapse meshes is that they are too stiff. While this results in a repair with increased tensile strength, it occurs at the expense of tissue function with accelerated tissue contraction, decreased elasticity and compliance, and deterioration of smooth muscle function. To test our hypothesis, we implant commonly used synthetic prolapse meshes into the vagina of nonhuman primates with prolapse using the gold standard surgical procedure (the abdominal sacrocolpopexy) and then define the cellular, biochemical and biomechanical impact on the vagina at 6 months post implantation. Eventually, we will implant meshes transvaginally to characterize the distinct host response to this surgical approach. In the third phase, we explore the development of future grafts for prolapse surgery. We hypothesize that because of its bioinductive effects, a combined biologic/synthetic mesh will be superior to a synthetic mesh alone in restoring vaginal structure and function. We propose that a key yet poorly developed component of prolapse repairs is the re-establishment of smooth muscle reactivity and therefore, test the use of a temporary biologically active scaffold in achieving this process. In this way, this grant proposal provides a mechanism to establish the first team of scientists dedicated to the comprehensive unbiased evaluation of prolapse meshes as a means of educating both current and future prolapse surgeons, and the public regarding potential problems associated with certain materials. Indeed, the development of such a group is imperative for protecting the health of women. PUBLIC HEALTH RELEVANCE: Prolapse (i.e., abnormal descent) of the pelvic organs is a common costly condition that negatively impacts the lives of millions of women world-wide. Biologic and synthetic meshes are often used in the surgical repair of prolapse due to improved anatomical outcomes over native tissue repairs; but with little scientific data on which to base the selection of a particular product. Unfortunately, the complications associated with certain meshes cause unacceptably high rates of morbidity including infection, tissue contraction, vaginal discharge, and pain. In this proposal, we aim to establish a comprehensive mesh testing center in which previously or newly marketed prolapse meshes can be objectively tested and the next generation of prolapse meshes can be developed based on specific scientific criteria.