Biomaterial Strategies for Tissue Engineering Pediatric Valves

描述(申请人提供)：心脏缺陷发生在几乎1%的活产儿中，通常包括半月形心脏瓣膜的异常。治疗瓣膜缺陷的选择很少；即便如此，这些矫正只是姑息性的，并不排除在患者以后的生活中重新手术瓣膜的需要。这些患者的预后将随着活体、自体、儿科组织工程心脏瓣膜(TEHV)的发展而发生革命性的变化。TEHs发展的一个主要障碍是创造一种具有瓣膜状材料行为和微观结构的支架。此外，大多数关于TEHV的研究都集中在实现适合成人心脏瓣膜的设计目标，而不是婴儿和儿童的心脏瓣膜。半月形心脏瓣膜(主动脉瓣和肺瓣)的主要微结构特征是其各向异性和层状结构，这为瓣膜间质细胞(VIC)提供了异质的细胞周围环境。这些特性不是由正在研究的用于TEHV的聚合物网状支架提供的，并且对于生产无细胞小叶支架的最佳策略几乎没有共识。包括我们在内的许多小组已经研究了用于VIC生物学和病理学研究的天然和合成凝胶支架，但这些支架通常在均质结构内或之上种植VIC。因此，我们假设新型水凝胶支架可以通过生物材料制备方法来生成模拟儿童半月瓣的复杂结构、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、易于包埋细胞等特点。此外，儿童心脏瓣膜在机械、微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TEHs成功的必要条件，但对儿童心脏瓣膜的内皮细胞知之甚少。我们的实验室是进行这项研究的独特条件，因为我们已经表征了瓣膜力学和微观结构以及先天性畸形儿童半月瓣的组织和细胞与年龄相关的差异。我们还在PEGDA水凝胶中产生了新的结构和不同的材料行为区域。我们的目标是将先进的生物材料策略应用于创建儿科TEHV。我们建议应用图案化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(目标1)。为了促进儿童TEHV的瓣膜状内皮涂层，我们将评估儿童半月瓣的内皮特性并修改支架表面(目标2)。采用这些先进的水凝胶/生物材料策略将产生一种新型的TEHV支架，模拟天然半月瓣的生物和机械异质性，并加速这种改变生命的治疗方法在儿科瓣膜心脏病患者中的应用。 与公共卫生相关：心脏瓣膜缺陷是最常见的出生缺陷之一，但可用于外科修复这些瓣膜的选择并不理想，需要儿童每隔几年重复手术一次。我们建议开发一种基于水凝胶的支架，用于组织工程学，用于先天性瓣膜缺陷儿童的心脏瓣膜置换。我们的目标是以这样一种方式准备这种支架，以重建儿童心脏瓣膜的复杂结构，测试这些支架的耐用性，并在支架表面覆盖内皮细胞，以防止血栓形成。

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. PUBLIC HEALTH RELEVANCE: Heart valve defects are among the most common birth defects, but the available options for surgical repair of these valves are not ideal and require children to have repeat surgery every few years. We propose to develop a hydrogel-based scaffold to be used in tissue engineering a replacement heart valve for children with congenital valve defects. Our goal is to prepare this scaffold in such a way to recreate the complex structure of pediatric heart valves, test the durability of these scaffolds, and coat the surface of the scaffold with endothelial cells to prevent blood clots from forming.