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）：心脏缺陷发生在几乎所有活生生中的1％，通常包括半道路心脏瓣膜的异常。治疗瓣膜缺陷的选择很少。即便如此，这些校正仅是姑息性的，并且不排除在患者一生后期对阀门进行重新操作的必要性。这些患者的预后将通过生存，自体，小儿组织工程心脏瓣膜（TEHV）的发展革新。 TEHVS开发的一个主要障碍是用类似阀门的材料行为和微观结构创建脚手架。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。半肺心瓣（主动脉和肺部）的主要微观结构属性是它们的各向异性性质及其分层结构，它们提供了瓣膜间质细胞（VIC），并具有异质性周围的周围环境。这些特征不是由针对TEHV进行研究的聚合物网状支架提供的，并且关于生产小叶片支架的最佳策略几乎没有共识。包括我们在内的许多群体都研究了基于自然和合成凝胶的支架，用于研究VIC生物学和病理学研究，但是这些基于均匀的结构内或均匀的VIC。因此，我们假设可以使用生物材料制造方法来制备新颖的基于水凝胶的支架，以产生模仿小儿半肺阀的复杂结构，机械功能，生物异质性和抗栓性性质的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，可以被生物功能化，并且可以轻松封装细胞。此外，小儿心脏瓣膜在机械，微结构和细胞基础上与成年瓣膜不同。此外，尽管认为完整的内皮对于TEHV的成功所必需，但对小儿心脏瓣膜的内皮知之甚少。我们的实验室是执行这项研究的独特位置，因为我们表征了与年龄相关的瓣膜力学和微观结构以及先天性畸形的小儿半道路阀的组织和细胞的差异。我们还产生了PEGDA水凝胶中差异物质行为的新结构和区域。我们的目标是应用先进的生物材料策略来创建小儿TEHV。我们建议采用模式和准层次方法来开发具有自定义结构特征的水凝胶TEHV生物材料支架，这些特征复制了小儿半路阀的微体系结构，材料特性，机械功能和耐用性（AIM 1）。为了促进小儿TEHV的类似瓣膜样涂层，我们将评估小儿半隆瓣的内皮特征并修改脚手架表面（AIM 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，该脚手架模仿天然半路星的生物学和机械异质性，并加快为瓣膜心脏病儿科患者而改变这种改变生活的疗法的翻译。 公共卫生相关性：心脏瓣膜缺陷是最常见的先天缺陷之一，但是这些瓣膜手术修复的可用选择并不理想，要求儿童每隔几年重复手术。我们建议开发一种基于水凝胶的支架，用于组织工程的替换心脏瓣膜，用于先天性瓣膜缺陷的儿童。我们的目标是以一种重新创建小儿心脏瓣膜复杂结构，测试这些脚手架的耐用性，并用内皮细胞覆盖脚手架的表面以防止血凝块形成的脚手架。