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

非技术总结：盆腔器官脱垂（POP）发生时，骨盆肌肉力量下降导致盆腔器官，如膀胱或卵巢，膨胀到阴道，造成显着的疼痛和不适，并导致生活质量下降。直到最近，POP通过使用合成聚丙烯补片机械支撑和支撑盆腔器官的手术解决。然而，聚丙烯的生物学和机械性能与盆腔器官的生物学和机械性能有很大不同。因此，这种差异造成盆腔组织炎症和损伤，进而导致补片氧化，最终导致其损坏。这种循环导致最终的器官损伤和慢性疼痛。由于大量女性出现此类并发症，FDA已撤回此类补片用于POP的许可，目前没有可用于POP的外科补片。因此，迫切需要检查替代材料作为聚丙烯的替代品，并了解导致有害反应的补片材料的特征。本研究将设计和3D打印一组聚酯和聚氨酯补片，作为聚丙烯补片的替代品。随后，将对这些补片进行测试，以确定细胞对补片化学和几何特征的反应。此外，在对补片造成氧化损伤的条件下处理补片之前和之后，将检查补片的机械强度和弹性。这种系统的研究将提供对影响生物反应的网状材料的化学和物理特征的更深入的理解。本研究的结果也将有助于FDA评估和监管POP补片。技术总结：随着年龄的增长或多胎分娩增加了盆腔器官脱垂（POP）的概率，POP是由于盆底肌肉和结缔组织的减弱导致盆腔器官疝入阴道。每年，在美国进行约240，000例脱垂手术，11%的女性将在其一生中接受矫正手术以解决脱垂。直到最近，丙烯补片被用于通过连接到骶棘韧带和/或骨盆筋膜腱弓来支撑扩张的骨盆器官。然而，聚丙烯补片在生物学和机械学上与盆腔的软组织和弹性组织不相容，并且已被证明会促进炎症反应，导致最终补片失效。由于较差的生物力学顺应性和由此产生的并发症，如慢性疼痛、器官穿孔和复发性感染，FDA已禁止使用现有的外科补片进行经阴道POP修复。因此，对POP补片存在未满足的需求，其将提供机械支撑而不引起炎症反应或盆腔器官损伤。该项目将比较一组生物材料和网状结构，以确定影响机械稳定性和细胞反应的关键参数，目的是为POP修复材料的设计提供更深入的了解。通过本研究生成的数据将有助于FDA评估和监管合成材料作为聚丙烯替代品。一组侧基官能化聚酯和聚氨酯将用于制造具有拉胀几何形状的3D打印补片，这些将用于评价补片上成纤维细胞的增殖和细胞相容性。此外，将评价补片存在时的巨噬细胞行为和ROS产生。假设由于外部或生物氧化剂导致的补片氧化导致补片机械性能的灾难性损失。因此，将评价补片暴露于外部氧化剂之前和之后的力学性能。此外，补片降解产物将通过各种方法进行表征，包括HPLC、NMR、UV-Vis、ATR-FTIR和SEM。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值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 Due to such complications in a large number of women, the FDA has withdrawn permission for the use of such meshes for POP and currently there are no surgical meshes available for POP.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.