Biomaterial Strategies for Tissue Engineering Pediatric Valves

描述（由申请人提供）：心脏缺陷发生在所有活产婴儿的近1%，通常包括半月心瓣膜的异常。处理阀门缺陷的选择很少；即便如此，这些矫正也只是治标不治本，并不能排除患者在以后的生活中再次对瓣膜进行手术的需要。活体、自体、儿童组织工程心脏瓣膜（TEHV）的发展将彻底改变这些患者的预后。开发tehv的一个主要障碍是制造一种具有类似阀门的材料性能和微观结构的支架。此外，大多数关于心脏瓣膜的研究都集中在实现适合成人心脏瓣膜的设计目标，而不是婴儿和儿童心脏瓣膜的设计目标。半月瓣（主动脉瓣和肺动脉瓣）的主要微观结构特征是其各向异性和层状结构，这为瓣膜间质细胞（vic）提供了异质性的细胞周围环境。目前所研究的脱细胞小叶支架不具备这些特性，而且对于生产脱细胞小叶支架的最佳策略也没有达成共识。包括我们在内的许多团队已经研究了用于VIC生物学和病理学研究的天然和合成凝胶基支架，但这些支架通常是在均匀结构内部或顶部植入VIC。因此，我们假设可以使用生物材料制造方法制备新型水凝胶基支架，以生成模拟儿童半月瓣复杂结构、机械功能、生物异质性和抗血栓性质的TEHV支架。水凝胶生物材料具有生物相容性、结构和力学可调、生物功能化、易包封细胞等特点。此外，儿童心脏瓣膜在机械、微观结构和细胞基础上与成人瓣膜不同。此外，尽管完整的内皮被认为是tev成功的必要条件，但对儿童心脏瓣膜的内皮却知之甚少。我们的实验室在进行这项研究方面具有独特的优势，因为我们已经描述了先天性畸形儿童半月瓣在力学和微观结构以及组织和细胞方面的年龄相关差异。我们还在PEGDA水凝胶中生成了新的结构和不同材料行为的区域。我们的目标是应用先进的生物材料策略来创建儿科tehv。我们建议采用模式和准分层方法来开发具有定制结构特征的水凝胶TEHV生物材料支架，以复制儿童半月瓣的微结构、材料特性、机械功能和耐用性（Aim 1）。为了促进儿童tev的瓣膜样内皮涂层，我们将评估儿童半月瓣的内皮特性并修改支架表面（目的2）。采用这些先进的水凝胶/生物材料策略将产生一种新的TEHV支架，模仿天然半月瓣的生物学和力学异质性，并加速这种改变儿童瓣膜性心脏病患者生活的疗法的转化。

DESCRIPTION (provided by applicant): Heart defects occur in almost 1 percent of all live births and usually include abnormalities of the semilunar heart valves. Few options exist for treating valve defects; even so, these corrections are only palliative and do not preclude the need for re-operation on the valve later in the patient's life. The prognosis for these patients would be revolutionized by the development of a living, autologous, pediatric tissue engineered heart valve (TEHV). A major hurdle in the development of TEHVs is creating a scaffold with valve-like material behavior and microstructure. Furthermore, most research on TEHVs has focused on achieving design goals that are appropriate for adult heart valves, not those of infants and children. The primary microstructural attributes of the semilunar heart valves (aortic and pulmonary) are their anisotropic nature and their layered structure, which provide valvular interstitial cells (VICs) with heterogeneous pericellular environments. These characteristics are not provided by the polymer mesh scaffolds being investigated for TEHVs, and there is little consensus about optimal strategies to produce acellular leaflet scaffolds. Many groups including ours have investigated natural and synthetic gel-based scaffolds for studies of VIC biology and pathology, but these have generally seeded VICs within or atop homogeneous structures. Therefore, we hypothesize that novel hydrogel-based scaffolds can be prepared using biomaterial fabrication methods to generate TEHV scaffolds that mimic the complex structure, mechanical function, biological heterogeneity, and anti-thrombotic nature of pediatric semilunar valves. Hydrogel biomaterials are biocompatible, have tunable structure and mechanics, can be biofunctionalized, and can easily encapsulate cells. In addition, pediatric heart valves are distinct from adult valves on a mechanical, microstructural, and cellular basis. Furthermore, little is known about the endothelium of pediatric heart valves, even though an intact endothelium is considered necessary for success of TEHVs. Our lab is uniquely positioned to perform this research, as we have characterized age-related differences in valve mechanics and microstructure as well as of tissues and cells from congenitally malformed pediatric semilunar valves. We also have generated novel structures and regions of differential material behavior within PEGDA hydrogels. Our objective is to apply advanced biomaterial strategies for creating pediatric TEHVs. We propose to apply patterning and quasi-layering approaches to develop hydrogel TEHV biomaterial scaffolds with customized structural features that replicate the micro-architecture, material properties, mechanical function, and durability of pediatric semilunar valves (Aim 1). To promote a valve-like enthothelial coating of the pediatric TEHV, we will then evaluate the endothelial characteristics of pediatric semilunar valves and modify the scaffold surface (Aim 2). Employing these advanced hydrogel/biomaterial strategies will generate a novel TEHV scaffold that mimics the biological and mechanical heterogeneity of native semilunar valves, and hasten the translation of this life-changing therapy for pediatric patients with valvular heart disease.