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

• 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
• 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

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)的外科治疗具有较高的并发症和再手术率， 70%的天然组织修复手术在五年内失败，FDA停止了对 用于经阴道手术的移植材料。这些有问题的移植物中有许多是从非 妇科手术，不能模仿阴道的特性。最近细胞或蛋白质增强 实验移植物也不能弥合由于机械故障和免疫原dna造成的技术鸿沟。 留存。考虑到关于工程POP修复移植物不太容易失败的知识差距，我们的 目的是获得关于健康、非脱垂的阴道细胞外基质(VECM)结构和 用于通知开发合成仿生移植物的功能。我们将定义胶原蛋白和 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 提供机械支持和细胞黏附的弹性体、生物相容的移植物组件。然后，我们 将探讨成纤维细胞在这些材料上的黏附和无病理性肌成纤维细胞分化的情况。 我们建议的产品设计是由不可降解的3D打印弹性体网格组成的，该网格由 3D打印水凝胶涂层，可由周围细胞重塑。这项提案的目标是测试 我们的假设是，vECM提供的机械和生化线索推动细胞组织和 健康阴道的结构，并可在机械胜任的仿生POP修复中复制 嫁接。这一假设将通过生物力学、成像、添加剂等实验技术进行验证 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，并产生弹性网状物，最大限度地减少病理性肌成纤维细胞的转化 通过模仿vECM纤维力学。这一目标将通过vECM弹性分析实现，3D 生物相容弹性体的印刷，以形成具有相似机械性能的网状物，并评估 在张力生物反应器中，细胞对这种网状物的反应。目标2将定义组织特异性细胞黏附 并生产能够部分降解的复合3D打印材料，嵌入 促进细胞黏附的关键细胞外基质蛋白的生理分布。这一目标将是 通过显微镜和蛋白质组分析vECM实现，3D打印部分可降解的涂层 模拟vECM的微观结构和蛋白质分布，并评估细胞在该涂层上的粘附性 在一个张力生物反应器中。通过这项提案详细介绍的工作将回答有关 血管内皮细胞基质的结构-功能特性及制备两种具有治疗潜力的POP新材料 一起使用或单独使用时进行修复，作为对商业可用材料的潜在增强。这 这项研究的灵感来自于我自己对病理学、手术结果和宿主对基因工程的反应的兴趣 生物材料。完成此建议书将为我提供基本的智力和技术技能 我未来的工作是成为一名内科科学家，从事生物材料、病理学和重建学的交叉学科 做手术。