Biomaterial Strategies for Tissue Engineering Pediatric Valves

组织工程儿科瓣膜的生物材料策略

• 批准号: 8178833
• 负责人: KATHRYN JANE GRANDE-ALLEN
• 金额: $ 18.37万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8178833
• 关键词: Adult; Architecture; Autologous; Behavior; Biocompatible; Biocompatible Materials; Biological; Biological Process; Biomimetics; Bioprosthesis device; Blood; Blood Clot; Blood coagulation; Cardiopulmonary Physiology; Cardiovascular Physiology; Cells; Cellular biology; Characteristics; Child; Childhood; Climacteric; Complex; Congenital Abnormality; Congenital Heart Defects; Consensus; Defect; Development; Disease; Encapsulated; Endothelial Cells; Endothelium; Environment; Extracellular Matrix Proteins; Gel; Goals; Heart; Heart Valve Diseases; Heart Valves; Heterogeneity; Hydrogels; Infant; Life; Ligands; Live Birth; Lung; Mechanics; Methods; Nature; Operative Surgical Procedures; Pathology; Patients; Pattern; Performance; Polymers; Population; Positioning Attribute; Property; Repeat Surgery; Research; Stem cells; Structure; Structure-Activity Relationship; Surface; Testing; Time; Tissue Engineering; Tissues; Translating; Translations; age related; aortic valve disorder; base; design; heart valve replacement; hemodynamics; interstitial cell; next generation; novel; operation; outcome forecast; palliative; poly(ethylene glycol)diacrylate; prevent; repaired; scaffold; semilunar valve; success; surface coating

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.

描述（由申请人提供）：几乎 1% 的活产婴儿会出现心脏缺陷，通常包括半月形心脏瓣膜异常。治疗瓣膜缺陷的选择很少；即便如此，这些矫正也只是姑息性的，并不排除患者在以后的生活中需要再次进行瓣膜手术。活体自体儿童组织工程心脏瓣膜 (TEHV) 的开发将彻底改变这些患者的预后。 TEHV 开发的一个主要障碍是创建具有类似阀门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（主动脉瓣和肺动脉瓣）的主要微观结构属性是它们的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环境。正在研究的用于 TEHV 的聚合物网状支架并未提供这些特性，并且对于生产无细胞小叶支架的最佳策略几乎没有达成共识。包括我们在内的许多团体已经研究了天然和合成的基于凝胶的支架来研究 VIC 生物学和病理学，但这些支架通常将 VIC 接种在均质结构内或之上。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，具有可调节的结构和力学，可以生物功能化，并且可以轻松封装细胞。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 TEHV 成功所必需的，但人们对儿科心脏瓣膜的内皮知之甚少。我们的实验室在开展这项研究方面具有独特的优势，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的组织和细胞与年龄相关的差异。我们还在 PEGDA 水凝胶中生成了具有不同材料行为的新颖结构和区域。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，以复制儿科半月瓣的微结构、材料特性、机械功能和耐用性（目标 1）。为了促进儿科 TEHV 的瓣膜样内皮涂层，我们将评估儿科半月瓣的内皮特征并修改支架表面（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，该支架可模仿天然半月瓣膜的生物和机械异质性，并加速这种改变生命的疗法对瓣膜性心脏病儿科患者的转化。 公众健康相关性：心脏瓣膜缺陷是最常见的出生缺陷之一，但这些瓣膜的手术修复可用选择并不理想，需要儿童每隔几年重复进行一次手术。我们建议开发一种基于水凝胶的支架，用于组织工程为患有先天性瓣膜缺陷的儿童替代心脏瓣膜。我们的目标是制备这种支架，以重建儿科心脏瓣膜的复杂结构，测试这些支架的耐用性，并用内皮细胞覆盖支架表面以防止血栓形成。