Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues

Abstract

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 (μECTs), 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 μECTs 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 co-stimulation.

Tissue Engineering and Regenerative Medicine: New Trends and Directions—A Year in Review

“…Nevertheless, each tissue and organ is unique and has very welldefined functions, and therefore, the challenge in recreating such living environments while considering a particular fabrication technology is overwhelming. Although microfluidic systems still enable quite simple models of the enormous complexity of human tissues and organs, they have contributed to significant developments in brain, 53 kidney, 54 heart, 55,56 or neural 57 modeling, providing more complex systems with well-defined architectures mimicking more closely cellular environments of a physiological niche to understand biological mechanisms.…”

“…55 Another heart-on-a-chip platform focusing on the physiologic mechanical environment experienced by cells in the native myocardium was used to generate mature and highly functional micro-engineered cardiac tissues (mECTs), from both neonatal rat and human-induced pluripotent stem (hiPS) cell-derived cardiomyocytes stimulated by homogeneous uniaxial cyclic strains. 56 The mechanically stimulated cardiac micro-niche that was developed showed superior cardiac differentiation, as well as electrical and mechanical coupling. Moreover, cells evidenced early spontaneous synchronous beating and better contractile capability in response to electric pacing, being able to respond on biochemical treatments with isoprenaline.…”

“…Moreover, cells evidenced early spontaneous synchronous beating and better contractile capability in response to electric pacing, being able to respond on biochemical treatments with isoprenaline. 56 The feasibility of a 3D model with axonal properties resembling structural features of brain tissue was demonstrated by the establishment of a 3D neural network in a microfluidics chip under a continuous flow. 57 In the neural circuit fabricated, the ECM fibers aligned due to the influence of the hydrostatic pressure over the crosslinking density patterns of the hydrogels, the growth of cortical neurons, and the formation of axon bundles.…”

Applications of cell culture studies in pharmaceutical technology

“…In a recent study by Ribas et al, 2016, the authors created a vascular microenvironment of the heart for drug development 85 . In another recent study by Marsono et al, 2016, human iPSC-derived cardiomyocytes were used to stimulate 3D construction of myocardium 86 .…”

Stem Cells in Translation versus Innovative Biomaterials and /or Nanomaterials

“…Microengineering for obtaining differentiated human pluripotent stem cells on a chip is one of the approaches to enhance the functional properties of differentiated cells along with ensuring the microcirculation [2][3][4][5][6][7][8] . Contrarily, in the case of cancer stem cells (CSCs), nanomaterials might be helpful especially while targeting such cells or else for imaging.…”