Despite significant efforts in the study of cardiovascular diseases (CVDs), they persist as the leading cause of mortality worldwide. Considerable research into human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has highlighted their immense potential in the development of in vitro human cardiac tissues for broad mechanistic, therapeutic, and patient-specific disease modeling studies in the pursuit of CVD research. However, the relatively immature state of hPSC-CMs remains an obstacle in enhancing clinical relevance ofengineered cardiac tissue models. In this study, we describe development of a microfluidic platform for 3D modeling of cardiac tissues, derived from both rat cells and hPSC-CMs, to better recapitulate the native myocardium through co-culture with interstitial cells (specifically cardiac fibroblasts), biomimetic collagen hydrogel encapsulation, and induction of highly anisotropic tissue architecture. The presented platform is precisely engineered through incorporation of surface topography in the form of staggered microposts to enable long-term culture and maturation of cardiac cells, resulting in formation of physiologically relevant cardiac tissues with anisotropy that mimics native myocardium. After two weeks of culture, hPSC-derived cardiac tissues exhibited well-defined sarcomeric striations, highly synchronous contractions, and upregulation of several maturation genes, including HCN1, KCNQ1, CAV1.2, CAV3.1, PLN, and RYR2. These findings demonstrate the ability of the proposed engineered platform to mature animal- as well as human stem cell-derived cardiac tissues over an extended period of culture, providing a novel microfluidic chip with the capability for cardiac disease modeling and therapeutic testing.

尽管在心血管疾病 (CVD) 的研究中付出了巨大努力，但它们仍然是全世界死亡的主要原因。对人类多能干细胞衍生心肌细胞 (hPSC-CM) 的大量研究凸显了它们在体外开发中的巨大潜力人类心脏组织，用于广泛的机械、治疗和患者特异性疾病建模研究，以追求 CVD 研究。然而，hPSC-CM 相对不成熟的状态仍然是增强工程心脏组织模型临床相关性的障碍。在这项研究中，我们描述了用于心脏组织 3D 建模的微流体平台的开发，该平台来源于大鼠细胞和 hPSC-CM，通过与间质细胞（特别是心脏成纤维细胞）、仿生胶原水凝胶的共培养更好地概括原生心肌封装和诱导高度各向异性的组织结构。所呈现的平台通过以交错微柱的形式结合表面形貌进行精确设计，以实现心肌细胞的长期培养和成熟，导致形成具有模拟天然心肌的各向异性的生理相关心脏组织。经过两周的培养，hPSC 衍生的心脏组织表现出明确的肌节条纹、高度同步的收缩和几种成熟基因的上调，包括 HCN1、KCNQ1、CAV1.2、CAV3.1、PLN 和 RYR2。这些发现证明了所提议的工程平台能够在长时间的培养中使动物和人类干细胞衍生的心脏组织成熟，从而提供一种具有心脏病建模和治疗测试能力的新型微流控芯片。高度同步收缩，以及几种成熟基因的上调，包括 HCN1、KCNQ1、CAV1.2、CAV3.1、PLN 和 RYR2。这些发现证明了所提议的工程平台能够在长时间的培养中使动物和人类干细胞衍生的心脏组织成熟，从而提供一种具有心脏病建模和治疗测试能力的新型微流控芯片。高度同步收缩，以及几种成熟基因的上调，包括 HCN1、KCNQ1、CAV1.2、CAV3.1、PLN 和 RYR2。这些发现证明了所提议的工程平台能够在长时间的培养中使动物和人类干细胞衍生的心脏组织成熟，从而提供一种具有心脏病建模和治疗测试能力的新型微流控芯片。