Scaffold-Free Tissue-engineered Cardiac Patch Processed with a novel 3D Bio-Printer for Myocardial Restoration

使用新型 3D 生物打印机处理无支架组织工程心脏补片，用于心肌修复

• 批准号: 9525949
• 负责人: Takeyoshi Ota
• 金额: $ 8.1万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9525949
• 关键词: 3-Dimensional; Acute myocardial infarction; Animal Model; Biocompatible Materials; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cells; Cellular Spheroids; Cellular Structures; Cessation of life; Clinical; Connexin 43; Data; Deformity; Device Designs; Dimensions; Electrophysiology (science); Encapsulated; Endothelial Cells; Environment; Euthanasia; Family suidae; Fibroblasts; Future; Geometry; Goals; Gold; Health; Heart; Heart Diseases; Heart Transplantation; Heart failure; Histologic; Human; Imagery; Implant; In Situ; Lead; Left; Life Expectancy; Life Style; Liver; Location; Magnetic Resonance Imaging; Mechanics; Medical; Methods; Modeling; Motion; Myocardial; Myocardium; Myosin Heavy Chains; Natural regeneration; Needles; Operative Surgical Procedures; Organ; Outcome; PECAM1 gene; Patients; Perfusion; Polymerase Chain Reaction; Preparation; Prevalence; Process; Quality of life; Recovery; Recovery of Function; Research; Reverse Transcription; Right ventricular structure; Rupture; Shapes; Side; Site; Smooth Muscle Actin Staining Method; Survivors; System; Techniques; Technology; Testing; Thrombosis; Tissue Engineering; Tissues; Transcript; Treatment Failure; Troponin; Troponin T; United States; Ventricular; Ventricular Cardiac alpha-Myosin; Ventricular Remodeling; alpha Actinin; base; beta-Myosin; biomaterial compatibility; cardiac implant; cardiac tissue engineering; clinical application; design; experience; functional restoration; heart function; implantation; improved; improved outcome; in vivo; left ventricular assist device; mechanical properties; new technology; non-muscle myosin heavy chain-B; novel; restoration; robotic system; scaffold; surgery outcome; three dimensional structure; ventricular assist device; von Willebrand Factor

ABSTRACT The ultimate goal of this project is to develop a tissue-engineered heart to treat patients of end-stage heart failure by replacing the diseased heart. As the initial step, we are developing a tissue-engineered cardiac patch to promote in-situ myocardial regeneration and functional restoration. Heart failure is a major health problem with increasing prevalence, caused in part by increased survivors from acute myocardial infarction, increased life expectancy, and lifestyle choices. There are 53,000 deaths per year related to heart failure. While heart transplantation is currently a gold standard therapy for the treatment of severe heart failure, it only serves for about 2,000 patients per year in the United States due to a shortage of donors. Mechanical support technologies such as left ventricular assist device (LVAD) have been developed for treatment of advanced heart failure as an alternative to heart transplant. A major issue for LVAD therapy is that LVADs are designed to support the left-side heart only but not for right-side heart and that currently there is no durable long-term right ventricular assist device available. Another surgical technique called Surgical Ventricular Restoration (SVR) is also an important strategy for heart failure treatment. Most SVR techniques utilize a large synthetic cardiac patch to restore the geometry of the heart. However, the large inert patches are rapidly encapsulated by the host and do not restore myocardial function, which limit recovery of heart functions. In order to improve the outcomes of surgical treatments and the quality of life of advanced heart failure patients, it is critical to develop a new biomaterial that contributes restoring the heart function. Recently, a novel three dimensional (3D) bio-printer has been invented. The 3D bio-printer is a robotic system that facilitates the fabrication of 3D cellular structures by placing cell spheroids in needle arrays based on pre- designed 3D data. This system allows to create any shape of 3D structure using any desired cells/biomaterials in any coordinate location. No study has been done using this system in the field of cardiac surgery while several applications in other organs (e.g. blood vessel, liver) have started showing promising results. In this proof-of-concept study, we will create a scaffold-free 3D tissue-engineered cardiac patch. The patch will consist of 3 layers: endothelial cells, cardiomyocytes, and adventitial fibroblasts. The patches will be tested in a porcine right ventricular patch replacement model and assessed with Electromechanical mapping, Cardiac Magnetic Resonance Imaging, as well as histological examinations. The goal of this preliminary study is to demonstrate that the new tissue-engineered patch 1) provides the decent durability and strength in a porcine preparation, 2) provides enhanced site-specific host cell repopulation, and 3) restores functional myocardium. At the conclusion of the proposed study and future studies of the project, we could provide a promising material for in-situ myocardial regeneration, which could eventually save over 50,000 patients dying every year from advanced heart failure.

抽象的 该项目的最终目标是开发组织工程心脏来治疗终末期心力衰竭患者 通过更换患病的心脏。作为第一步，我们正在开发一种组织工程心脏补片 促进心肌原位再生和功能恢复。 心力衰竭是一个主要的健康问题，其患病率不断增加，部分原因是心力衰竭幸存者的增加 急性心肌梗塞、预期寿命延长和生活方式选择。每年有 53,000 人死亡 与心力衰竭有关。虽然心脏移植目前是治疗严重心脏疾病的金标准疗法 由于捐赠者短缺，该项目在美国每年只能为大约 2,000 名患者提供服务。 左心室辅助装置 (LVAD) 等机械支持技术已开发用于 作为心脏移植的替代方案治疗晚期心力衰竭。 LVAD 治疗的一个主要问题是 LVAD 的设计仅支持左侧心脏，不适用于右侧心脏，目前还没有 提供耐用的长期右心室辅助装置。另一种手术技术称为心室手术 恢复（SVR）也是心力衰竭治疗的重要策略。大多数 SVR 技术利用大量 合成心脏补片可恢复心脏的几何形状。然而，大的惰性斑块很快就会消失。 被宿主包裹，不能恢复心肌功能，限制了心脏功能的恢复。为了 为了改善晚期心力衰竭患者的手术治疗结果和生活质量， 对于开发有助于恢复心脏功能的新生物材料至关重要。 最近，发明了一种新型三维（3D）生物打印机。 3D生物打印机是一个机器人系统 通过将细胞球体放置在基于预制的针阵列中，促进 3D 细胞结构的制造 设计3D数据。该系统允许使用任何所需的细胞/生物材料创建任何形状的 3D 结构 在任意坐标位置。目前还没有在心脏手术领域使用该系统进行研究，但有一些研究 在其他器官（例如血管、肝脏）中的应用已开始显示出有希望的结果。 在这项概念验证研究中，我们将创建一个无支架的 3D 组织工程心脏补片。补丁 由3层组成：内皮细胞、心肌细胞和外膜成纤维细胞。补丁将被测试 在猪右心室补片替换模型中，并通过机电测绘、心脏功能评估 磁共振成像以及组织学检查。这项初步研究的目的是 证明新的组织工程补片 1) 在猪身上提供了良好的耐用性和强度 准备，2) 提供增强的位点特异性宿主细胞再增殖，3) 恢复功能性心肌。 在拟议的研究和该项目的未来研究的结论中，我们可以提供一个有前途的研究 用于原位心肌再生的材料，最终每年可以挽救超过 50,000 名死亡患者 来自晚期心力衰竭。

项目成果

In Situ Myocardial Regeneration With Tissue Engineered Cardiac Patch Using Spheroid-Based 3-Dimensional Tissue.

使用基于球体的 3 维组织的组织工程心脏补片进行原位心肌再生。

• DOI: 10.1016/j.atssr.2023.11.014
• 发表时间: 2024
• 期刊: Annals of thoracic surgery short reports
• 作者: Koda,Yojiro;Watanabe,Tatsuya;Kawaji,Keigo;Mo,Fei;Beaser,AndrewD;Vaicik,Marcella;Hibino,Narutoshi;Ota,Takeyoshi
• 通讯作者: Ota,Takeyoshi