Lab-on-a-chip models of cardiac inflammation

Abstract

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide with numerous inflammatory cell etiologies associated with impaired cardiac function and heart failure. Inflammatory cardiomyopathy, also known as myocarditis, is an acquired cardiomyopathy characterized by inflammatory cell infiltration into the myocardium with a high risk of progression to deteriorated cardiac function. Recently, amidst the ongoing COVID-19 pandemic, the emergence of acute myocarditis as a complication of SARS-CoV-2 has garnered significant concern. Given its mechanisms remain elusive in conjunction with the recent withdrawal of previously FDA-approved antiviral therapeutics and prophylactics due to unexpected cardiotoxicity, there is a pressing need for human-mimetic platforms to investigate disease pathogenesis, model dysfunctional features, and support pre-clinical drug screening. Traditional in vitro models for studying cardiovascular diseases have inherent limitations in recapitulating the complexity of the in vivo microenvironment. Heart-on-a-chip technologies, combining microfabrication, microfluidics, and tissue engineering techniques, have emerged as a promising approach for modeling inflammatory cardiac diseases like myocarditis. This review outlines the established and emerging conditions of inflamed myocardium, identifying key features essential for recapitulating inflamed myocardial structure and functions in heart-on-a-chip models, highlighting recent advancements, including the integration of anisotropic contractile geometry, cardiomyocyte maturity, electromechanical functions, vascularization, circulating immunity, and patient/sex specificity. Finally, we discuss the limitations and future perspectives necessary for the clinical translation of these advanced technologies.

FIG. 1.

Overview of key features of the ideal vascularized microfluidic model of the myocardium for studies of inflammatory conditions. The ideal model should contain four key features: (a) physiologically relevant microenvironment encompassing co-culture of relevant cell types (e.g., cardiomyocytes, endothelial cells, fibroblasts, and vascular cells in a geometrically organized fashion), (b) biomimetic mechanical and physical properties, (c) provision of electrical stimuli for recapitulation of tissue-specific electrophysiological properties, and (d) functional readouts to support disease modeling studies (i.e., vascularization, CM maturation, and patient/sex specificity). CM, cardiomyocyte; EC, endothelial cell; FB, fibroblast; hiPSC, human induced pluripotent stem cell; MΦ, macrophages; MC, monocyte.

FIG. 2.

Examples of microfabricated cardiac systems for disease modeling and drug screening. (a) 3D printed microphysiological device capable of non-invasive measurements of cardiac tissue contractile stress. Reproduced with permission from Lind et al., Nat. Mater. 16, 303–308 (2017). Copyright 2017 Nature. (b) Maturation of iPSC-CMs within a microfluidic cardiac chip. Reproduced with permission from Huebsch et al., Nat. Biomed. Eng. 6(4), 372–388 (2022). Copyright 2022 Nature. (c) Heart-on-a-chip platform with embedded 3D microelectrodes and 3D printed elastomeric microwires. From Wu et al., Biofabrication 15, 035023 (2023). Copyright 2023 Author(s), licensed under a Creative Commons Attribution (CC BY) license. (d) Fabrication of the AngioChip scaffold and cell seeding arrangement with endothelial and parenchymal cells. Reproduced with permission from Zhang et al., Nat. Mater. 15(6), 669–678 (2016). Copyright 2016 Nature. (e) Heart-on-a-chip model for SARS-CoV-2 induced myocarditis. From Luet al., Sci. Adv. 10, eadk0164 (2024). Copyright 2024 Author(s), licensed under a Creative Commons Attribution (CC BY) license. CP, conductive polymer; ECM, extracellular matrix; EVs, extracellular vesicles; HUVECs, human umbilical vein endothelial cells; iPSC-CMs, induced pluripotent stem cell-derived cardiomyocytes; PBMCs, peripheral blood mononuclear cells; PDMS, polydimethylsiloxane; TPE/QD, thermoelastic polymer/quantum dots; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.