Highly Elastic Biomaterial Development for Urethral Application

项目摘要 这是由儿科泌尿学助理教授Renea Sturm博士首次提交的K 08申请 在加州大学，洛杉矶（UCLA）。 候选人：Sturm博士在本建议书中的主要培训目标是：1。填补现有的知识空白， 材料科学与建模之间的相互作用2.学习材料制造的科学方法 评价3。发展研究设计和科学沟通技巧4.发展管理和 作为一名独立调查员的领导技能。斯特姆博士将通过以下方式完成这些活动 指导，重点课程，并参加选定的研讨会/会议。这将得到以下方面的支持： 她的主要导师是加州大学洛杉矶分校生物工程系主任、细胞材料专家李松博士 相互作用和共同导师Nasim Annabi博士，可改性弹性水凝胶专家。她会更进一步 由导师Isla Garraway，MD，PhD，一位独立的泌尿外科医生科学家支持。她的外部顾问 委员会将包括通过阿里·哈德姆侯赛尼， 具有下尿路组织工程专业知识的博士，由Arun Sharma博士提供。 研究：需要尿道成形术的尿道缺陷发生在儿童和成人中， 创伤性、传染性和恶性疾病。目前用于尿道置换的组织来源受到以下限制： 供区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 随后的短期和长期尿道成形术并发症的高风险强调了改善 具有生物灵感设计的组织替代品。这项提案的目标是建立一个独立的外科医生- 一位专注于材料专业知识的科学家， 具有优化的生物力学性能的仿生尿道支架 随后是细胞外基质（ECM）沉积。该研究计划解决了关键设计要求：1） 优化的机械性能，2）可再现的合成方法，和3）伤口愈合和血管形成。 我们的总体假设是，一种新的支架与水凝胶和弹性蛋白样的组合， 设计为满足目标机械和结构参数的肽将改善可缝合性、早期尿流率、 尿道功能和局部组织再生。 在目标1中，复合电纺支架将被设计成具有机械和结构特性， 模仿天然尿道组织在目标2中，体外评价将阐明机械小生境在以下方面的作用： 细胞行为和ECM沉积。在目标3中，对功能和解剖学结果进行了离体评价 在应用接种和未接种移植物后，将发生与标准护理包皮尿道成形术相比的情况。 总之，这项研究策略将工程师微调弹性仿生支架与目标机械 以及从尿道组织分析中获得的结构参数，以最大化未来的临床可平移性。

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.