Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues
Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues
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DOI：
10.1039/c5lc01356a
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发表时间：
2016-02-07
期刊：
影响因子：
6.1
通讯作者：
Rasponi, Marco
中科院分区：
文献类型：
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作者：
Marsano, Anna;Conficconi, Chiara;Rasponi, Marco
在过去的几年里，基于微流控技术的技术已经开发出微型模型，概括了典型的天然心肌的关键物理和生物学线索。然而，将受控的生理单轴循环应变应用于定义的三维细胞环境还不可能。重点研究了二维机械刺激，忽略了复杂的三维细胞-细胞和细胞-基质相互作用。为此，我们开发了一个心脏芯片平台，它概括了细胞在自然心肌中经历的生理机械环境。该装置包括用于限制细胞负载凝胶的悬柱阵列，以及用于在培养过程中将均匀的单轴循环应变诱导到3D细胞结构的气动驱动系统。该设备被用于从新生大鼠和人诱导的多能干细胞来源的心肌细胞(hiPSC-CM)中培养成熟的高功能微工程心脏组织(MU ECT)，有力地表明了我们的工程心脏微生态位的健壮性。我们的结果表明，循环应变是有效的、高度单轴的、均匀地转移到培养细胞中的。与对照组相比，刺激的MUECTs表现出更好的心脏分化，以及电和机械耦合，这是由于连接复合体显著增加所致。机械刺激也促进了早期自发同步搏动和更好的对电起搏的收缩能力。对异丙肾上腺素受控给药的HiPSC-CM结构的起搏分析表明，我们的平台在药物发现、递送和毒理学领域有进一步的应用前景。所提出的单芯片心脏装置代表了该领域的相关进展，提供了一个标准的功能性三维心脏模型，可能通过机械和生化共刺激预测心脏表型肥厚变化的迹象。
In the past few years, microfluidic-based technology has developed microscale models recapitulating key physical and biological cues typical of the native myocardium. However, the application of controlled physiological uniaxial cyclic strains on a defined three-dimension cellular environment is not yet possible. Two-dimension mechanical stimulation was particularly investigated, neglecting the complex three-dimensional cell-cell and cell-matrix interactions. For this purpose, we developed a heart-on-a-chip platform, which recapitulates the physiologic mechanical environment experienced by cells in the native myocardium. The device includes an array of hanging posts to confine cell-laden gels, and a pneumatic actuation system to induce homogeneous uniaxial cyclic strains to the 3D cell constructs during culture. The device was used to generate mature and highly functional micro-engineered cardiac tissues (mu ECTs), from both neonatal rat and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), strongly suggesting the robustness of our engineered cardiac micro-niche. Our results demonstrated that the cyclic strain was effectively highly uniaxial and uniformly transferred to cells in culture. As compared to control, stimulated mu ECTs showed superior cardiac differentiation, as well as electrical and mechanical coupling, owing to a remarkable increase in junction complexes. Mechanical stimulation also promoted early spontaneous synchronous beating and better contractile capability in response to electric pacing. Pacing analyses of hiPSC-CM constructs upon controlled administration of isoprenaline showed further promising applications of our platform in drug discovery, delivery and toxicology fields. The proposed heart-on-a-chip device represents a relevant step forward in the field, providing a standard functional three-dimensional cardiac model to possibly predict signs of hypertrophic changes in cardiac phenotype by mechanical and biochemical costimulation.