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异常。治疗瓣膜缺陷的选择很少;即便如此，这些纠正措施也只是姑息性的，并不排除在患者生命后期对瓣膜进行再次手术的需要。通过开发活体、自体、儿科组织工程心脏瓣膜（TEHV），这些患者的预后将发生革命性变化。开发TEHV的主要障碍是创建具有瓣膜样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设计目标。半月心脏瓣膜（主动脉瓣和肺动脉瓣）的主要显微结构属性是其各向异性性质和分层结构，这为瓣膜间质细胞（VIC）提供了异质的细胞周围环境。正在研究的用于TEHV的聚合物网状支架没有提供这些特征，并且关于生产无细胞瓣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天然和合成凝胶基支架用于维克生物学和病理学研究，但这些研究通常将VIC接种在均匀结构内或顶部。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，以生成模拟儿科半月瓣的复杂结构、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，具有可调的结构和力学，可以生物功能化，并且可以容易地封装细胞。此外，小儿心脏瓣膜在机械、显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TEHV成功所必需的，但对儿科心脏瓣膜的内皮知之甚少。我们的实验室是进行这项研究的独特位置，因为我们已经表征了瓣膜力学和微观结构以及先天畸形儿科半月瓣组织和细胞的年龄相关差异。我们还在PEGDA水凝胶中产生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制造儿科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，这些结构特征可复制儿科半月瓣的微结构、材料特性、机械功能和耐久性（目标1）。为了促进儿科TEHV的瓣膜样内皮涂层，我们将评价儿科半月瓣的内皮特征并修改支架表面（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患有心脏瓣膜病的儿科患者中的转化。

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.