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

摘要 该项目的最终目标是开发一种组织工程心脏来治疗终末期心力衰竭患者。 通过替换患病的心脏。作为第一步，我们正在开发一种组织工程心脏贴片，以 促进原位心肌再生和功能恢复。 心力衰竭是一个主要的健康问题，随着患病率的增加，部分原因是来自 急性心肌梗死、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重症心脏病的黄金标准疗法 心力衰竭，由于捐赠者短缺，它在美国每年只为大约2000名患者服务。 机械支持技术，如左心辅助装置(LVAD)已被开发用于 晚期心力衰竭的治疗作为心脏移植的替代方案。LVAD治疗的一个主要问题是 LVAD的设计只支持左侧心脏，但不支持右侧心脏，目前还没有 可提供耐用的长期右室辅助装置。另一种被称为外科脑室的外科技术 恢复(SVR)也是心力衰竭治疗的重要策略。大多数SVR技术使用大量的 合成心脏补片以恢复心脏的几何形状。然而，巨大的惰性斑块正在迅速地 被宿主包裹，不能恢复心肌功能，限制了心功能的恢复。按顺序 为了改善手术治疗的结果和晚期心力衰竭患者的生活质量， 对于开发一种有助于恢复心脏功能的新生物材料至关重要。 最近，一种新型的三维(3D)生物打印机被发明出来。3D生物打印机是一个机器人系统 这有助于通过将细胞球体放置在基于预制棒的针阵列中来制造3D细胞结构 设计了3D数据。该系统允许使用任何所需的细胞/生物材料来创建任何形状的3D结构 在任何坐标位置。在心脏外科领域还没有使用该系统的研究，虽然有几个 在其他器官(如血管、肝脏)的应用已经开始显示出令人振奋的结果。 在这项概念验证研究中，我们将创建一种无支架的3D组织工程心脏补片。补丁 将由3层组成：内皮细胞、心肌细胞和外膜成纤维细胞。这些补丁将进行测试 在猪右室补片替换模型中，并通过机电标测评估心脏 磁共振成像，以及组织学检查。这项初步研究的目标是 证明新的组织工程贴片在猪身上提供了相当好的耐用性和强度 制备，2)提供增强的部位特异性宿主细胞再繁殖，以及3)恢复功能心肌。 在拟议的研究和对该项目的未来研究的结论中，我们可以提供一个有前途的 用于原位心肌再生的材料，最终每年可挽救50,000多名死亡患者 死于晚期心力衰竭。

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.