Biomimetic micro-structured hydrogel scaffolds for tissue engineered heart valves

用于组织工程心脏瓣膜的仿生微结构水凝胶支架

• 批准号: 8086246
• 负责人: KATHRYN JANE GRANDE-ALLEN
• 金额: $ 36.61万
• 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: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8086246
• 关键词: Adhesions; Advanced Development; American; Anisotropy; Behavior; Biocompatible Materials; Biological; Biological Process; Biomimetics; Cells; Cellular biology; Characteristics; Chemicals; Chemistry; Complex; Consensus; Data; Diffuse; Diffusion; Disease; Encapsulated; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Fiber; Functional disorder; Gel; Generations; Goals; Heart Valve Diseases; Heart Valves; Hospitalization; Hyaluronan; Hydrogels; In Vitro; Investigation; Lasers; Ligands; Mechanics; Methodology; Methods; Modeling; Molecular Weight; Nature; Pathology; Pattern; Peptides; Photons; Polymers; Positioning Attribute; Printing; Process; Production; Proteins; Research; Shapes; Signal Transduction; Solutions; Stress; Structure; Structure-Activity Relationship; Testing; Time; Tissue Engineering; Tissues; Translating; Work; absorption; aortic valve; base; cell behavior; heart valve replacement; improved; interstitial cell; mechanical behavior; monomer; next generation; novel; poly(ethylene glycol)diacrylate; scaffold

DESCRIPTION (provided by applicant): Heart valve diseases require hospitalization of more than 90,000 Americans each year, but there are very few options for treating heart valve dysfunction, and even less is known about the mechanisms the underlie valve disease. The essential function of heart valves is made possible by the unique microstructural arrangement of fibrous extracellular matrix proteins within the valve leaflet tissue, but these valvular structure- function relationships have not been translated into the next generation of valve tissue engineering investigations and for in vitro analyses of valvular cell biology and disease. The primary microstructural attributes of aortic valves are their anisotropic nature and their interconnected, 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 tissue engineered heart valves (TEHVs), and there is little consensus about optimal strategies to produce a cellular 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. Electrospinning can produce layered structures and anisotropy, but this approach is highly sensitive to operating parameters. We propose to integrate these heterogeneous structure and material characteristics of heart valves into hydrogel biomaterials. Hydrogel biomaterials (particularly poly ethylene glycol diacrylate, PEGDA) are appealing for use as TEHV scaffolds because they have tunable structure and mechanics, can be readily bio- functionalized, and can easily encapsulate cells. Research concerning these materials; however, has generally been focused on their biological activities, as opposed to the development of advanced material behavior. The goal of the proposed work is to apply novel patterning and layering methodologies to generate advanced 3D hydrogels that mimic the complex microstructure and material behavior of aortic valve tissues. We are ideally positioned to generate these materials, having expertise in the characterization of heart valve microstructure, material behavior, and mechanobiology as well as the use of patterning to govern biological ligand presentation and more recently to generate novel structures and regions of differential material behavior within PEGDA hydrogels. These advanced structures will have tremendous impact on the next generation of TEHV scaffolds and could also be used as more faithful biomimetic platforms for 3D investigations of valvular cell biology and disease mechanisms. The following aims will be performed to accomplish this goal: 1. Compare electrospinning, laser printing photolithography, and 2-photon absorption confocal patterning approaches to generate anisotropic hydrogels demonstrating a valve-like biological-shape stress-strain curve. 2. Optimize semi-interpenetrating approaches to develop composite laminate hydrogel scaffolds. 3. Pattern interconnecting structures into the layers of the composite laminate hydrogels. PUBLIC HEALTH RELEVANCE: More than 90,000 Americans each year are hospitalized for heart valve disease, but there are very few options for treating valve disease. In order to grow replacement heart valves, we propose to develop new materials that mimic the complicated interior structure and mechanical behavior of heart valves, and also have the potential to guide normal heart valve cell behavior. These new material structures may also help us understand why ordinarily durable heart valves become diseased.

描述（由申请人提供）：每年有超过 90,000 名美国人因心脏瓣膜疾病需要住院治疗，但治疗心脏瓣膜功能障碍的选择很少，而且对瓣膜疾病的潜在机制知之甚少。心脏瓣膜的基本功能是通过瓣叶组织内纤维细胞外基质蛋白的独特微观结构排列实现的，但这些瓣膜结构-功能关系尚未转化为下一代瓣膜组织工程研究和体外分析瓣膜细胞生物学和疾病。主动脉瓣的主要微观结构属性是它们的各向异性性质和它们相互连接的层状结构，这为瓣膜间质细胞（VIC）提供了异质的细胞周环境。正在研究的用于组织工程心脏瓣膜（TEHV）的聚合物网状支架并未提供这些特性，并且对于生产细胞瓣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。静电纺丝可以产生层状结构和各向异性，但这种方法对操作参数高度敏感。 我们建议将心脏瓣膜的这些异质结构和材料特性整合到水凝胶生物材料中。水凝胶生物材料（特别是聚乙二醇二丙烯酸酯，PEGDA）作为 TEHV 支架很有吸引力，因为它们具有可调节的结构和力学，易于生物功能化，并且可以轻松封装细胞。有关这些材料的研究；然而，通常关注的是它们的生物活性，而不是先进材料行为的发展。 拟议工作的目标是应用新颖的图案化和分层方法来生成先进的 3D 水凝胶，模拟主动脉瓣组织的复杂微观结构和材料行为。我们处于生产这些材料的理想位置，在心脏瓣膜微观结构、材料行为和机械生物学的表征以及使用图案化来控制生物配体呈现方面拥有专业知识，并且最近在心脏瓣膜内生成差异材料行为的新颖结构和区域PEGDA水凝胶。这些先进的结构将对下一代 TEHV 支架产生巨大影响，也可以用作瓣膜细胞生物学和疾病机制 3D 研究的更可靠的仿生平台。为了实现这一目标，将执行以下目标： 1. 比较静电纺丝、激光印刷光刻和 2 光子吸收共焦图案化方法，以生成展示阀门状生物形状应力应变曲线的各向异性水凝胶。 2.优化半互穿方法开发复合层压水凝胶支架。 3.将互连结构图案化到复合层压水凝胶的各层中。 公共卫生相关性：每年有超过 90,000 名美国人因心脏瓣膜疾病住院，但治疗瓣膜疾病的选择很少。为了生长替代心脏瓣膜，我们建议开发新材料来模仿心脏瓣膜复杂的内部结构和机械行为，并且有可能指导正常的心脏瓣膜细胞行为。这些新材料结构还可以帮助我们理解为什么通常耐用的心脏瓣膜会患病。