Development of a Novel Bioinspired Pelvic Organ Prolapse Repair Graft

新型仿生盆腔器官脱垂修复移植物的开发

基本信息

批准号：
10678635
负责人：
Morgan Lee Egnot
金额：
$ 4.9万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678635
关键词：
3-Dimensional 3D Print Adhesions Adhesives Adult Behavior Biochemical Biocompatible Materials Biological Assay Biomechanics Biomimetics Bioreactors Cell Adhesion Cell Culture Techniques Cell Differentiation process Cell-Matrix Junction Cells Characteristics Clinical Collagen Fiber Complication Cues DNA Data Development Elastases Elasticity Elastin Fiber Elastomers Encapsulated Engineering Enzyme-Linked Immunosorbent Assay Etiology Excision Exhibits Extracellular Matrix Extracellular Matrix Proteins Failure Fiber Fibroblasts Fibrosis Foundations Future Goals Graft Enhancements Gynecologic Human Hydrogels Image Immune response In Vitro Knowledge Measures Mechanical Stress Mechanics Microscopic Microscopy Modeling Myofibroblast Nulliparity Operative Surgical Procedures Oryctolagus cuniculus Pathologic Pathology Peptides Phenotype Physicians Physiological Polypropylenes Population Porosity Postoperative Complications Predisposition Procedures Property Proteins Proteomics Ptosis Public Health Reconstructive Surgical Procedures Repair Material Repeat Surgery Research Role Sales Scientist Side Site Structure Technical Expertise Techniques Technology Testing Therapeutic Tissues Training Transference Vagina Work biomaterial compatibility biomechanical test cell transformation collagenase defined contribution design elastomeric experience experimental study immunogenic immunogenicity implant material in vitro testing interest iterative design manufacture mechanical behavior mechanical properties mimicry multiphoton microscopy nonhuman primate novel operation pelvic organ prolapse protein distribution prototype repaired response scaffold skills success surgery outcome tissue repair

项目摘要

Surgical treatments for pelvic organ prolapse (POP) suffer from high complication and reoperation rates, with 70% of native tissue repair operations failing within five years and the FDA halting commercial use of graft materials for transvaginal procedures. Many of these problematic grafts are repurposed from non- gynecologic procedures and cannot mimic the properties of the vagina. Recent cell- or protein-enhanced experimental grafts also do not bridge the technological gap due to mechanical failure and immunogenic DNA retention. Given the gap in knowledge regarding engineering POP repair grafts less susceptible to failure, our objective is to obtain novel data on healthy, non-prolapsed vaginal extracellular matrix (vECM) structure and function to inform devel-opment of a synthetic biomimetic graft. We will define contributions of collagen and elastin fibers to the mechan-ical behavior of vaginal tissue and use these data as constraints for iterative design of elastomeric, biocompatible graft components that provide mechanical support and cell adhesion. Then, we will probe for fibroblast adhesion and absence of pathologic myofibroblast differentiation on these materials. Our proposed product design is com-posed of a non-degradable 3D printed elastomer mesh encapsulated by a 3D printed hydrogel coating that can be remodeled by surrounding cells. The goal of this proposal is to test our hypothesis that mechanical and biochemical cues provided by vECM drive cellular organization and structure of the healthy vagina and can be replicated in a mechanically competent biomimetic POP repair graft. This hypothesis will be tested via experi-mental techniques in biomechanics, imaging, additive manufacturing, and bioreactor cell culture. Aim 1 will fur-ther define the relationship between vaginal elasticity and vECM proteins and produce an elastomeric mesh that minimizes pathologic myofibroblast transformation by mimicry of vECM fiber mechanics. This aim will be achieved through vECM elasticity profiling, 3D printing of biocompatible elastomers to form a mesh with similar mechanical properties, and assessment of cellular response to this mesh in a tension bioreactor. Aim 2 will define tissue-specific cell adhesion dynamics and produce a composite 3D printed material capable of partial degradation embedded with physiologic distributions of key extracellular matrix proteins to promote cell adhe-sion. This aim will be achieved via microscopy and proteomic analysis of vECM, 3D printing of a partially de-gradable coating mimicking vECM microstructure and protein distribution, and assessment of cellular adhesion to this coating in a tension bioreactor. The work detailed through this proposal will answer critical questions regarding the structure-function properties of vECM and produce two novel materials with therapeutic potential for POP repair when used together or separately as potential enhancements to commercially available materials. This research is inspired by my own interests in pathology, surgical outcomes, and host response to engineered biomaterials. Completing this proposal will provide me with intellectual and technical skills that are essential for my future work as a physician-scientist at the intersection of biomaterials, pathology, and reconstructive surgery.

盆腔器官脱垂（POP）的手术治疗并发症和再手术率较高， 70% 的天然组织修复手术在五年内失败，FDA 停止了其商业用途用于经阴道手术的移植材料。许多有问题的移植物都是从非妇科手术并且无法模仿阴道的特性。最近的细胞或蛋白质增强由于机械故障和免疫原性 DNA，实验移植物也无法弥合技术差距保留。鉴于有关设计不易失败的 POP 修复移植物的知识差距，我们目的是获得有关健康、非脱垂阴道细胞外基质 (vECM) 结构和功能为合成仿生移植物的开发提供信息。我们将定义胶原蛋白的贡献和弹性蛋白纤维对阴道组织的机械行为的影响，并使用这些数据作为迭代设计的约束提供机械支撑和细胞粘附的弹性体、生物相容性移植组件。然后，我们将探测这些材料上的成纤维细胞粘附和病理性肌成纤维细胞分化的缺失。我们提出的产品设计由不可降解的 3D 打印弹性体网格组成，该网格由 3D打印的水凝胶涂层可以被周围的细胞重塑。该提案的目标是测试我们的假设是，vECM 提供的机械和生化信号驱动细胞组织，健康阴道的结构，并且可以在具有机械能力的仿生 POP 修复中复制接枝。这一假设将通过生物力学、成像、添加剂等方面的实验技术进行检验。制造和生物反应器细胞培养。目标1将进一步定义阴道弹性之间的关系和 vECM 蛋白并产生弹性网，最大限度地减少病理性肌成纤维细胞转化通过模拟 vECM 纤维力学。这一目标将通过 vECM 弹性分析、3D 打印生物相容性弹性体以形成具有相似机械性能的网格，并评估在张力生物反应器中细胞对这种网格的反应。目标 2 将定义组织特异性细胞粘附动力学并生产出一种复合 3D 打印材料，该材料能够部分降解，嵌入促进细胞粘附的关键细胞外基质蛋白的生理分布。这个目标将是通过 vECM 的显微镜和蛋白质组学分析、部分可降解涂层的 3D 打印实现模拟 vECM 微观结构和蛋白质分布，并评估细胞对该涂层的粘附力在张力生物反应器中。本提案详细介绍的工作将回答有关以下方面的关键问题： vECM 的结构-功能特性并产生两种具有 POP 治疗潜力的新型材料一起或单独使用时可作为市售材料的潜在增强剂进行修复。这研究的灵感来自于我自己对病理学、手术结果和宿主对工程改造的反应的兴趣生物材料。完成这项提案将为我提供必要的知识和技术技能我未来的工作是作为一名医师科学家，从事生物材料、病理学和重建的交叉领域外科手术。