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: 8663737
• 负责人: KATHRYN JANE GRANDE-ALLEN
• 金额: $ 7.08万
• 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/8663737
• 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; public health relevance; 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.

描述（由申请人提供）：心脏瓣膜疾病每年需要超过90,000名美国人住院，但是治疗心脏瓣膜功能障碍的选择很少，对于基础瓣膜疾病的机制知之甚少。通过在瓣膜小叶组织中纤维外基质基质蛋白的独特微观结构排列使心脏瓣膜的基本功能成为可能，但是这些瓣膜结构关系尚未转化为下一代瓣膜组织工程研究和体外分析的下一代。瓣膜细胞生物学和疾病。主动脉瓣的主要微观结构属性是其各向异性性质及其相互联系的分层结构，它们提供瓣膜间质细胞（VIC）具有异质性周围环境。这些特征不是由正在研究组织工程阀（TEHV）的聚合物网状支架提供的，并且关于生产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。静电纺丝可以产生分层结构和各向异性，但是这种方法对工作参数高度敏感。 我们建议将心脏瓣膜的这些异质结构和材料特征整合到水凝胶生物材料中。水凝胶生物材料（尤其是聚乙二醇二丙烯酸酯，PEGDA）呼吁用作TEHV支架，因为它们具有可调的结构和力学，可以轻松地通过生物功能化，并且可以轻松封装细胞。有关这些材料的研究；但是，与先进物质行为的发展相反，通常专注于其生物学活动。 拟议的工作的目的是应用新颖的图案和分层方法来生成高级的3D水凝胶，以模拟主动脉瓣组织的复杂微观结构和物质行为。理想情况下，我们可以生成这些材料，在心脏瓣膜微观结构，材料行为和机械生物学的表征方面具有专业知识，以及使用图案来控制生物配体呈现的使用，并在最近产生新颖的结构和差异化材料行为的区域。 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，也可以用作更忠实的仿生平台，用于对瓣膜细胞生物学和疾病机制进行3D研究。将执行以下目的来实现此目标：1。比较电纺丝，激光打印光刻和2光子吸收共聚焦构图方法，以产生各向异性水凝胶，以显示瓣膜样生物形状应激曲线。 2。优化半际训练方法，以开发复合层压层水凝胶支架。 3。将结构互连到复合层压水凝胶的层。