Microfluidic heart on a chip for higher throughput pharmacological studies

Abstract

We present the design of a higher throughput “heart on a chip” which utilizes a semi-automated fabrication technique to process sub millimeter sized thin film cantilevers of soft elastomers. Anisotropic cardiac microtissues which recapitulate the laminar architecture of the heart ventricle are engineered on these cantilevers. Deflection of these cantilevers, termed Muscular Thin Films (MTFs), during muscle contraction allows calculation of diastolic and systolic stresses generated by the engineered tissues. We also present the design of a reusable one channel fluidic microdevice completely built out of autoclavable materials which incorporates various features required for an optical cardiac contractility assay: metallic base which fits on a heating element for temperature control, transparent top for recording cantilever deformation and embedded electrodes for electrical field stimulation of the tissue. We employ the microdevice to test the positive inotropic effect of isoproterenol on cardiac contractility at dosages ranging from 1 nM to 100 μM. The higher throughput fluidic heart on a chip has applications in testing of cardiac tissues built from rare or expensive cell sources and for integration with other organ mimics. These advances will help alleviate translational barriers for commercial adoption of these technologies by improving the throughput and reproducibility of readout, standardization of the platform and scalability of manufacture.

Microfluidic Genipin Deposition Technique for Extended Culture of Micropatterned Vascular Muscular Thin Films

“…Proper cut length should be refined through repeated experiments. Implementation of a laser engraving system, as in Agarwal et al, can improve upon repeatability and quality of MTF cutting 28 .…”

3D Miniaturization of Human Organs for Drug Discovery

“…Microcontact printing in combination with extracellular matrix glycoproteins improved cellular alignment thus the differentiation of myotubes as well as muscular contraction following electrical stimulation. [36] In addition, muscular thin films (MTFs) have shown promise to assays muscle contractility. [78] Following seeding of muscle cells on a thermally sensitive polymer MTFs can be released through heat application to the substrate.…”

“…High-throughput pharmacological study [36,78] 3D bioprinting Primary feline H1 cardiomyocytes First rhythmic beating of 3D printed structure [93][94][95] Lung Microfabrication Epithelial cells Use of porous membrane to mimic lung functions [31,37] 3D bioprinting A549 cells and EA hy926 cells World's first 3D bioprinted lung tissue [101] Bone 3D bioprinting BMSCs High viability in microextrusion-based bioprinting [108,109,158,159] Cancer Self-assembled Intestinal stem cells Discovery of LGR5+ intestinal stem cells [52,62] Microfabrication Breast cancer cells Perfusable human microvascularized bone-mimicking (BMi) microenvironment [81,168] 3D bioprinting OVCAR-5 and MRC-5 cells Insight into complex cell-cell communication in 3D [113][114][115][116][117] Multi Self-assembled Liver, gut, vessel cells High throughput hanging drop [30,[49][50][51][52] Microfabrication Liver, heart, and vessel cells Automated control of perfusion [11,19,27,32] 3D bioprinting NPC and HCT-116 cells Multiorgan bioprinted model [30,122] a)…”

“…For example, cellular components can be integrated by co-culturing multiple cell types in defined physical arrangements, 3D organization can be mimicked with biomaterial scaffolds and microfluidic channels, mechanical cues can be presented by biomaterials and fluid flow, and soluble stimuli can be delivered via perfusion. [35][36][37][38] Top-down approaches include organ-on-a-chip models, which aim to generate key aspects of an organ structure and function in a microfluidic device. Bottom-up approaches rely on the emergent behavior of biological systems to generate complex tissue-and organ-like constructs.…”

Human pluripotent stem cell-derived cardiomyocyte based models for cardiotoxicity and drug discovery

“…Consequently, researchers have begun developing more relevant human model systems for high-throughput in vitro cardiotoxicity testing. As a monolayer or small multicellular aggregates, human pluripotent stem cell-derived CMs (hPSC-CMs) have been used in a wide range of analytical assays to assess the effect of drugs on various cardiobiological parameters: electrophysiology [4], calcium transients [5], contractility [6], cell movement (beating) [7], metabolic activity [8], morphology, and viability [9], alone or in combination [5,[7][8][9].…”