Generation and Culture of Cardiac Microtissues in a Microfluidic Chip with a Reversible Open Top Enables Electrical Pacing, Dynamic Drug Dosing and Endothelial Cell Co‐Culture

Abstract

Cardiovascular disease morbidity has increased worldwide. Organs‐on‐chips and human pluripotent stem cell (hPSC) technologies aid to overcome some of the limitations in cardiac in vitro models. Here, a bi‐compartmental, monolithic heart‐on‐chip device that facilitates porous membrane integration in a single fabrication step is presented. Moreover, the device includes open‐top compartments that allow facile co‐culture of hPSC‐derived cardiomyocytes and human adult cardiac fibroblast into geometrically defined cardiac microtissues. The device can be reversibly closed with a glass seal or a lid with fully customized 3D‐printed pyrolytic carbon electrodes allowing electrical stimulation of cardiac microtissues. A subjacent microfluidic channel allowed localized and dynamic drug administration to the cardiac microtissues, as demonstrated by a chronotropic response to isoprenaline. Moreover, the microfluidic channel can also be populated with human induced pluripotent stem‐derived endothelial cells allowing co‐culture of heterotypic cardiac cells in one device. Overall, this study demonstrates a novel heart‐on‐chip model that systematically integrates an open‐top device with a 3D printed carbon electrode for electrical pacing and culture of cardiac tissues while enabling active perfusion and dynamic drug dosing. Advances in the engineering of human heart‐on‐chip models represent an important step towards making organ‐on‐a‐chip technology a routine aspect of preclinical cardiac drug development.

Fluidic circuit board with modular sensor and valves enables stand-alone, tubeless microfluidic flow control in organs-on-chips

“…To validate the system, we used a HoC device in which three-dimensional cardiac tissues containing human pluripotent stem cell-derived cardiomyocytes were co-cultured with endothelial monolayers of HUVECs, as we have previously reported. 44 In the present study, the cardiac tissues' beat rate and compaction were comparable to our previous study. Due to the constant medium perfusion, we were able to maintain cardiac cell cultures for a longer period of time without requiring a medium exchange.…”

Vascularization Strategies in 3D Cell Culture Models: From Scaffold-Free Models to 3D Bioprinting

“…As a result, microfluidic-based systems are often incorporated in tissue models owing to the ease of fabrication and compatibility of integrating external parameters. Vivas et al developed a novel bi-compartmental, monolithic heart-on-a-chip device, capable of integrating 3D carbon electrodes for electrical pacing and the culture of cardiac tissue [ 94 ]. Vascularization was introduced via the active perfusion between the two microcompartments separated by a semi-permeable membrane.…”

“…Each layer accommodated a certain tissue type of either cardiac tissues or endothelial cells, making possible dynamic fluid flow through the endothelial layer without risking shear stress on the cardiac tissues. The device featured an open-top compartment in the top layer, allowing cardiac cell suspensions, medium sampling, and cardiac microtissue retrieval to be obtained, and an electronic lid was introduced for cardiac pacing ( Figure 5 (I)) [ 94 ]. Electromechanical stimulations, the presence of an endothelial monolayer, and selective perfusion promoted the maturation of hPSC-derived cardiomyocytes for the accurate recapitulation of the cardiac tissue microenvironment.…”

“…Electromechanical stimulations, the presence of an endothelial monolayer, and selective perfusion promoted the maturation of hPSC-derived cardiomyocytes for the accurate recapitulation of the cardiac tissue microenvironment. The heart-on-a-chip model provides an approach for modeling cardiac physiology via heterotypic cell interaction, electrical actuation, and biochemical cues [ 94 ].…”

Organs-on-Chips Platforms Are Everywhere: A Zoom on Biomedical Investigation

“…In the same line, the coupling of microfluidics and 3D cell cultures allowed a tremendous step in the field of cell biology research, reflecting an imminent improvement of emulating the in vivo cell microenvironment. Such amalgamation adds multiple dimensions to cell research at diverse scales, encompassing miniaturization, adaptability towards a high throughput design, easiness of use, high sensitivity and robustness [ 48 ]. Here comes the technology of organ-on-a-chip.…”