Highly Elastic Biomaterial Development for Urethral Application

项目总结 这是儿科泌尿外科助理教授Renea Sturm博士最初提交的K08申请 在加州大学洛杉矶分校(UCLA)。 候选人：Sturm博士在这项建议中的主要培训目标是：1.填补现有的知识空白 材料科学与建模的相互作用2.学习材料制造的科学方法 3.发展研究设计和科学沟通技能4.发展管理和 独立调查员职业生涯所需的领导技能。斯特姆博士将通过以下方式完成这些活动 指导，专注于课程作业，并参与选定的研讨会/会议。这将由以下人员支持 她的主要导师宋丽博士，加州大学洛杉矶分校生物工程系主任，细胞材料专家 互动和共同导师Nasim Annabi博士，可修改弹性水凝胶方面的专家。她会走得更远 由独立的泌尿外科医生兼科学家导师Isla Garraway医学博士支持。她的外部建议 委员会将通过Ali Khademhosseini包括专注的材料科学和组织工程专业知识， 由阿伦·夏尔马提供的下尿路组织工程专业知识博士。 研究：需要进行尿路成形术的儿童和成人继发于先天性， 创伤性的、传染性的和恶性的。目前用于尿路置换术的组织来源受限于 供体部位发病率和缺乏支持终生排尿和阴茎勃起的最佳组织特征。一个 随之而来的短期和长期尿路成形术并发症的高风险突出了改善 具有生物灵感设计的组织替代品。这项提议的目标是建立一名独立的外科医生- 拥有专注的材料专业知识的科学家，以及创造和评估高度弹性的、 支持细胞化的生物力学性能逐层优化的仿生尿路支架 其次是细胞外基质(ECM)沉积。研究计划涉及关键的设计要求：1) 优化的机械性能，2)可重复的合成方法，以及3)伤口愈合和血管形成。 我们的总体假设是，一种由水凝胶和类弹性蛋白组成的新型支架 设计符合目标机械和结构参数的多肽将改善可缝合性，早期排尿 与包皮或未植入支架的尿路成形术相比，肌束功能和局部组织重建术。 在目标1中，复合电纺支架的设计将具有以下机械和结构性能 模仿天然的尿路组织。在目标2中，体外评估将阐明机械生态位在 细胞行为和细胞外基质沉积。在目标3中，功能和解剖学发现的体外评估 在应用种子移植物和非种子移植物后，将发生与标准护理相比的包皮尿路成形术。 总而言之，这一研究战略将利用目标机械来设计精细调整的弹性仿生支架 以及从尿路组织分析得出的结构参数，以最大限度地提高未来的临床可译性。

PROJECT SUMMARY This is an initial submission of a K08 application by Dr. Renea Sturm, an Assistant Professor of Pediatric Urology at the University of California, Los Angeles (UCLA). Candidate: Dr. Sturm’s primary training objectives in this proposal are to: 1. Fill existing knowledge gaps in the interaction between materials science and modeling 2. Learn scientific methodologies in material fabrication and evaluation 3. Develop study design and scientific communication skills 4. Develop management and leadership skills for a career as an independent investigator. Dr. Sturm will accomplish these activities through mentorship, focused coursework, and participation in select workshops/conferences. This will be supported by her primary mentors Song Li, PhD, Chair of Bioengineering at UCLA and an expert in cellular-materials interactions and co-mentor Nasim Annabi, PhD, an expert in modifiable elastic hydrogels. She will be further supported by mentor Isla Garraway, MD, PhD, an independent urologic surgeon-scientist. Her external advisory committee will include focused materials science and tissue engineering expertise through Ali Khademhosseini, PhD with expert knowledge of tissue engineering for the lower urinary tract provided by Arun Sharma, PhD. Research: Urethral defects requiring urethroplasty occur in children and adults secondary to congenital, traumatic, infectious, and malignant conditions. Current tissue sources for urethral replacement are limited by donor site morbidity and lack of optimal tissue characteristics to support lifelong voiding and penile erections. A subsequent high risk of short- and long-term urethroplasty complications highlights the need for an improved tissue alternative with a bioinspired design. The goal of this proposal is to establish an independent surgeon- scientist with focused materials expertise and a track record of creating and evaluating a highly elastic, biomimetic urethral scaffold with optimized biomechanical properties by layer to support cellularization followed by extracellular matrix (ECM) deposition. The research plan addresses key design requirements: 1) optimized mechanical properties, 2) reproducible synthesis methods, and 3) wound healing and vascularization. Our overall hypothesis is that a novel scaffold with the proposed combination of a hydrogel and elastin-like peptide designed to meet targeted mechanical and structural parameters will improve suturability, early urinary tract function, and local tissue recapitulation as compared to preputial or unseeded scaffold urethroplasties. In Aim 1, composite electrospun scaffolds will be engineered with mechanical and structural properties that mimic native urethral tissue. In Aim 2, an in vitro evaluation will elucidate the role of the mechanical niche in cellular behavior and ECM deposition. In Aim 3, an ex vivo evaluation of functional and anatomic findings following application of seeded and unseeded grafts will occur versus standard of care preputial urethroplasty. Put together, this research strategy will engineer finely tuned elastic biomimetic scaffolds with target mechanical and structural parameters derived from urethral tissue analyses to maximize future clinical translatability.