Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development

Abstract

Cardiovascular diseases are prevalent worldwide and are the most frequent causes of death in the United States. Although spending in drug discovery/development has increased, the amount of drug approvals has seen a progressive decline. Particularly, adverse side effects to the heart and general vasculature have become common causes for preclinical project closures, and preclinical models do not fully recapitulate human in vivo dynamics. Recently, organs-on-a-chip technologies have been proposed to mimic the dynamic conditions of the cardiovascular system-in particular, heart and general vasculature. These systems pay particular attention to mimicking structural organization, shear stress, transmural pressure, mechanical stretching, and electrical stimulation. Heart- and vasculature-on-a-chip platforms have been successfully generated to study a variety of physiological phenomena, model diseases, and probe the effects of drugs. Here, we review and discuss recent breakthroughs in the development of cardiovascular organs-on-a-chip platforms, and their current and future applications in the area of drug discovery and development.

Keywords: cardiovascular; drug discovery; heart-on-chip; organ-on-a-chip; vasculature-on-a-chip.

FIG. 1.

Key design parameters required to mimic a heart and general vasculature-on-a-chip model. Color images available online at www.liebertpub.com/aivt

FIG. 2.

(A) Survey on the motivations behind adopting human tissue-based approaches for safety pharmacology studies. (B) AstraZeneca's small-molecule projects from 2005 to 2010. the terminated projects were analyzed to understand the causes for failure and identify potential predictors of success (total of 28 projects). (C) Impact of organs-on-a-chip technologies on the drug development pipeline. [(A) adapted from Holmes et al.; (B) adapted from Cook et al.]. Color images available online at www.liebertpub.com/aivt

FIG. 3.

(A) Schematic of a PDMS-based microfluidic heart-on-a-chip model developed to culture cardiomyocytes. These microfluidic channels were coated by gelatin- and tropoelastin-based hydrogels to induce cellular attachment. (B) The effect of 10% (w/v) tropoelastin and 10% (w/v) gelatin-based hydrogels on the beating pattern (left) and beating frequency (right) of cardiomyocytes (CMs) inside microfluidic microchannels. (C) The schematic of a heart-on-a-chip microdevice designed for pharmacological testing. (D) The effect of isoproterenol on the contractility of CM-seeded muscular thin films, showing an increase in beating rate compared to control. Adapted with permission from Annabi et al. and Agarwal et al. Color images available online at www.liebertpub.com/aivt

FIG. 4.

(A) The effect of transverse mechanical stretch showing a disorganized architecture of cardiomyocytes cultured on muscular thin films (scale bar = 50 μm). (B) Schematic illustration of a microfluidic heart-on-a-chip model that ressembled the native interface of myocardial cells and microcapillaries. Reprinted with permission from Ren et al. (copyright 2013 American Chemical Society). (C) Representation of fluorescence images of cytoskeletal changes in cardiomyocytes under hypoxic conditions, which were induced by the introduction of an oxygen consumption blocker in one of the microfluidic side channels. Reprinted with permission from Ren at al. (copyright 2013 American Chemical Society). (D) Schematic representation of a bi-compartmental co-culture of valvular endothelial (VEC) and valvular interstitial cells (VIC) (top panel). VECs were embedded on a thin and porous membrane on top of a VIC-loaded gelatin methacryloyl (GelMA) (bottom channel). Color images available online at www.liebertpub.com/aivt

FIG. 5.

In vitro microfluidic models to study vascular networks and vascular functions. (A) Microfluidic chip for forming vascular networks and to study angiogenesis. (B, C) Nitric oxide production in static and flow conditions inside the device A (scale bar = 50 μm). (D) Bioprinting methodology to produce vascular networks with agarose sacrificial layers. (E) Bioprinted network (scale bar = 3 mm). (F) Bioprinted vascular network with ECs (green, GFP; blue, DAPI; red, CD31; scale bar = 250 μm). (G) Artery-on-a-chip model where a small mouse artery segment is held in place and perfused through the lumen and outside walls. (H) Microphotograph of artery-on-a-chip model (red, outer side wall; green, inner side wall). (I) Response of the artery-on-a-chip to phenylephrine. [(A–C) adapted with permission from Kim et al.; (D–F) adapted with permission from Bertassoni et al.; (G–I) adapted with permission from Gunther et al..] Color images available online at www.liebertpub.com/aivt

FIG. 6.

Vascular models to study stenosis and thrombosis in vitro. (A) Microfluidic model of stenosis to study the effect of drugs on occlusion. (B) Effect of drug epitifibatide concentration on dissolving clots over time. (C) Microfluidic stenosis model used to test shear-activated microparticle formulation. (D) Photograph of the microfluidic device. (E) Exposure of clots to free or encapsulated t-PA (shear-activated microparticles). (F–H) Time-dependent thrombolysis of clots upon exposure to encapsulated t-PA. (I) Microfluidic device to study thrombosis in vitro containing a flow region (Q1) and a collagen region where pressure gradient is varied (ΔP). (J, K) Thrombus formation on collagen and collagen/TF hydrogels (white arrow indicates flow direction). [(A, B) adapted with permission from Li et al.; (C–H) adapted with permission from Korin et al.; (I–K) adapted with permission from Muthard et al..] Color images available online at www.liebertpub.com/aivt

FIG. 7.

Microfluidic model to study vascular permeability. (A) Photograph of microfluidic dual-channel model to study permeability under shear stress; (B) Schematic of the microfluidic device with the upper channel containing blood endothelial cells (BECs) and the lower channel containing lymphatic endothelial cells (LECs), separated by a porous membrane. (C) Immunostaining for LECs marker podoplanin (green) and DAPI (blue). (D) Immunostaining with endothelial-specific marker claudin-5. (E) Changes in permeability induced by exposure to habu snake venom. Adapted with permission from Sato et al. Color images available online at www.liebertpub.com/aivt