Pelvic Organ Prolapse Mesh Replacement: Evaluation of Mesh Elasticity and Pore Geometry on Cell Responses and Mesh Degradation

非技术概要：盆腔器官脱垂(POP)是指盆腔肌肉力量下降导致盆腔器官(如膀胱或卵巢)膨胀到阴道内，导致严重疼痛和不适，导致生活质量下降。直到最近，POP还通过使用合成的聚丙烯网状物机械支撑和支撑盆腔器官的手术方式来解决。然而，聚丙烯的生物和力学性能与盆腔器官有很大的不同。因此，这种差异造成了盆腔组织的炎症和损伤，进而导致网状物的氧化，最终导致它们的破坏。这种循环会导致最终的器官损伤和慢性疼痛。由于大量女性出现这样的并发症，FDA已经撤回了对POP使用这种网片的许可，目前还没有可用于POP的外科网片。因此，迫切需要研究替代聚丙烯的替代材料，并了解导致有害反应的网状材料的特征。这项研究将设计和3D打印一套聚酯和聚氨酯网状物作为聚丙烯网状物的替代品。随后，将对这些网格进行测试，以确定细胞对网格化学和几何特征的反应。此外，还将在对网孔造成氧化损伤的条件下对网孔处理前后的机械强度和弹性进行检查。这样的系统研究将使人们更深入地了解影响生物反应的网状材料的化学和物理特性。这项研究的结果也将有助于FDA对POP网状物的评估和监管。技术摘要：高龄或多胎分娩增加了盆腔器官脱垂(POP)的可能性，POP是由于盆底肌肉和结缔组织的削弱而将盆腔器官突出到阴道内。美国每年约有24万例脱垂手术，11%的女性将在有生之年接受矫正手术以解决脱垂问题。直到最近，丙烯网片还被用来通过附着在骶棘韧带和/或筋膜弓上来支撑膨胀的盆腔器官。然而，聚丙烯网片与盆腔的软组织和弹性组织在生物和机械上都是不相容的，而且已被证明会促进炎症反应，最终导致网片失败。由于生物力学依从性差，以及由此导致的慢性疼痛、器官穿孔和反复感染等并发症，FDA已禁止使用现有的手术网片进行经阴道POP修复。因此，对POP网状物的需求尚未得到满足，这种网状物将在不引起炎症反应或盆腔器官损伤的情况下提供机械支持。该项目将比较一套生物材料和网状结构，以确定影响机械稳定性和细胞响应的关键参数，目的是为POP修复材料的设计提供更深入的了解。通过这项研究产生的数据将有助于FDA评估和监管作为聚丙烯替代品的合成材料。一组悬挂功能化的聚酯和聚氨酯将被用来制造具有伸展几何形状的3D打印网格，并将用于评估成纤维细胞在网格上的增殖和细胞相容性。此外，将评估巨噬细胞的行为和在网状物存在时ROS的产生。假设由于外部氧化剂或生物氧化剂导致的网孔的氧化，导致网孔的机械性能的灾难性损失。因此，将评估网格暴露于外部氧化剂之前和之后的机械性能。此外，网状降解产品将通过包括高效液相、核磁共振、UV-VIS、ATR-FTIR和扫描电子显微镜在内的各种方法进行表征。该奖项反映了NSF的法定使命，并已通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Non-Technical Summary: Pelvic organ prolapse (POP) occurs when decreased pelvic muscle strength results in pelvic organs such as the bladder or ovary, distending into the vagina, causing significant pain and discomfort and leading to a lower quality of life. Till recently, POP was addressed surgically by the use of synthetic polypropylene meshes to mechanically support and hold up the pelvic organs. However, the biological and mechanical properties of polypropylene are very different from those of pelvic organs. Hence, this difference created inflammation and damage of the pelvic tissues, which in turn caused oxidation of the meshes leading to their eventual breakdown. This cycle of events leads to eventual organ damage and chronic pain. Due to such complications in a large number of women, the FDA has withdrawn permission for the use of such meshes for POP and currently there are no surgical meshes available for POP. Hence, there is a critical need for examination of alternative materials as replacements for polypropylene and to understand the features of the mesh materials that lead to deleterious reactions. This study will design and 3D print a set of polyester and polyurethane meshes as alternatives for polypropylene meshes. Subsequently, these meshes will be tested to determine how cells react to the mesh chemistry and geometrical features. In addition, the mechanical strength and elasticity of the meshes will be examined before and after treating them in conditions that cause oxidative damage to the meshes. Such systematic studies will provide a deeper understanding of the chemical and physical features of mesh materials that affect biological reactions. The results from this study will also be useful for the FDA in their evaluations and regulation of POP meshes. Technical Summary: Advancing age or multiple childbirths increase the probability of pelvic organ prolapse (POP), which is the herniation of the pelvic organs into the vagina due to the weakening of the pelvic floor muscles and connective tissues. Each year, about 240,000 prolapse procedures are performed in the United States and 11% of women will undergo corrective surgery in their lifetime to address prolapse. Till recently, propylene meshes were used to support the distending pelvic organs by attachment to the sacrospinous ligament and/or the arcus tendineus fascia pelvis. However, polypropylene meshes are both biologically and mechanically incompatible with the soft and elastic tissues of the pelvic cavity and have been shown to promote inflammatory reactions leading to eventual mesh failure. Due to the poor biomechanical compliance and resultant complications such as chronic pain, organ perforation and recurrent infections, the FDA has banned the use of existing surgical meshes for transvaginal POP repair. Hence, there is an unmet need for POP meshes that will provide mechanical support without causing inflammatory reactions or pelvic organ damage. The project will compare a set of biomaterials and mesh architectures to identify critical parameters that influence mechanical stability and cellular responses with the aim of providing a deeper understanding for the design of materials for POP repair. The data generated through this study will be useful for the FDA for the evaluation and regulation of synthetic materials as replacements for polypropylene. A set of pendant functionalized polyesters and polyurethanes will be used to fabricate 3D printed meshes with auxetic geometries and these will be used to evaluate proliferation and cytocompatibility of fibroblasts on the meshes. Furthermore, macrophage behavior and ROS production in presence of the meshes will be evaluated. It is hypothesized that oxidation of the meshes, either due to external or biological oxidants, result in catastrophic loss of mechanical properties of the meshes. Hence, the mechanical properties of the meshes, both before and after exposure of the meshes to external oxidants will be evaluated. In addition, the mesh degradation products will be characterized through various methods including HPLC, NMR, UV-Vis, ATR-FTIR and SEM.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.