MICROFABRICATED 3D VASCULARIZED CARDIAC TISSUE CONSTRUCTS

微型 3D 血管化心脏组织结构

• 批准号: 8526165
• 负责人: Mehdi Nikkhah
• 金额: $ 3.3万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526165
• 关键词: Achievement; Address; Adhesiveness; Adhesives; Affect; Architecture; Biocompatible Materials; Biologic Characteristic; Biological; Biomechanics; Biomedical Engineering; Biomimetics; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Communication; Cells; Coculture Techniques; Complex; Development; Encapsulated; Endothelial Cells; Engineering; Functional disorder; Gelatin; Heart; Hydrogels; Lead; Mechanical Stimulation; Mechanics; Mesenchymal Stem Cells; Methacrylates; Microfabrication; Natural regeneration; Nude Mice; Organ Transplantation; Pattern; Pharmaceutical Preparations; Play; Property; Research; Research Personnel; Role; Smooth Muscle Myocytes; Stem cells; Stretching; Structure; Techniques; Technology; Testing; Tissue Engineering; Tissues; Training; Vascularization; Work; base; cytotoxicity; design; experience; improved; in vivo; injured; innovation; mouse model; nanofabrication; public health relevance; repaired; scaffold; stem cell differentiation; tissue regeneration

DESCRIPTION (provided by applicant): Cardiovascular diseases caused by the loss or dysfunction of cardiomyocytes (CMs) are the leading cause of death and affect millions of people worldwide. Tissue engineering holds great promise for the repair of injured hearts but requires the engineering of functional tissue constructs. Some of the key limitations of current cardiovascular tissue engineering approaches include the inability to generate cell-laden and cell- adhesive biomaterials, engineer vascularized tissues, and mimic the biological complexity and microarchitecture of cardiac tissues. To address these challenges, we aim to combine innovative microscale technology and advanced biomaterials (i.e. hydrogels) to create cell-laden hydrogels and develop 3D vascularized cardiac tissue constructs with controlled physical and biological properties. We will primarily use natural-based photocrosslinkable hydrogels (gelatin methacrylate, GelMA) to develop highly organized 3D vascularized networks. Specifically, we will co-culture endothelial cells (ECs) and mesenchymal stem cells (MSCs) within the patterned hydrogel construct and induce MSCs differentiation toward smooth muscle cells and develop biomimetic vasculature with controlled geometrical features and biological characteristics. Then, we will encapsulate cardiomyocytes within another layer of hydrogel and combine it with the pre- developed vascularized networks to generate cardiac tissue constructs with variable configurations and controlled complexities. Through the triple-culture of CMs with aligned ECs and MSCs, we will extensively study the biological properties of the tissue construct. In addition, we will test the functionality of the developed vascularized construct under cyclically stretched conditions. Finally, we will assess the functional properties of the engineered cardiac tissue construct in vivo. Achievements in this project will be important for cardiovascular tissue regeneration where the matrix material properties and configuration play an important role in maintaining native structural architecture of cardiac and vascular tissues. In addition, the developed constructs can be used as an integrative platform for drug cytotoxicity studies.

描述（由申请人提供）：由心肌细胞（CM）损失或功能障碍引起的心血管疾病是导致死亡的主要原因，影响着全世界数百万人。组织工程对于修复受伤的心脏有着巨大的希望，但需要功能性组织结构的工程设计。当前心血管组织工程方法的一些关键局限性包括无法生成充满细胞和细胞粘附的生物材料、无法设计血管化组织以及无法模拟心脏组织的生物复杂性和微结构。为了应对这些挑战，我们的目标是将创新的微型技术和先进的生物材料（即水凝胶）结合起来，创建充满细胞的水凝胶，并开发具有受控物理和生物特性的 3D 血管化心脏组织结构。我们将主要使用天然光交联水凝胶（甲基丙烯酸明胶，GelMA）来开发高度组织的 3D 血管化网络。具体来说，我们将在图案化水凝胶结构内共培养内皮细胞（EC）和间充质干细胞（MSC），诱导MSC向平滑肌细胞分化，并开发具有受控几何特征和生物学特征的仿生脉管系统。然后，我们将心肌细胞封装在另一层水凝胶内，并将其与预先开发的血管网络结合起来，生成具有可变配置和受控复杂性的心脏组织结构。通过将 CM 与对齐的 EC 和 MSC 进行三重培养，我们将广泛研究组织构建体的生物学特性。此外， 我们将在循环拉伸条件下测试所开发的血管化结构的功能。最后，我们将评估工程心脏组织构建体的体内功能特性。该项目的成就对于心血管组织再生非常重要，其中基质材料的特性和配置在维持心脏和血管组织的天然结构方面发挥着重要作用。此外，开发的构建体可用作药物细胞毒性研究的综合平台。