Organ-on-a-chip devices have gained attention in the field of in vitro modeling due to their superior ability in recapitulating tissue environments compared to traditional multiwell methods. These constructed growth environments support tissue differentiation and mimic tissue–tissue, tissue–liquid, and tissue–air interfaces in a variety of conditions. By closely simulating the in vivo biochemical and biomechanical environment, it is possible to study human physiology in an organ-specific context and create more accurate models of healthy and diseased tissues, allowing for observations in disease progression and treatment. These chip devices have the ability to help direct, and perhaps in the distant future even replace animal-based drug efficacy and toxicity studies, which have questionable relevance to human physiology. Here, we review recent developments in the in vitro modeling of barrier tissue interfaces with a focus on the use of novel and complex microfluidic device platforms.

The adoption of a new technology into basic research, and industrial and clinical settings requires rigorous testing to build confidence in the reproducibility, reliability, robustness, and relevance of these models. Tissue chips are promising new technology, they have the potential to serve as a valuable tool in biomedical research, as well as pharmaceutical development with regards to testing for efficacy and safety. The principal goals of this study were to validate a previously established proximal tubule tissue chip model in an independent laboratory and to extend its utility to testing of nephrotoxic compounds. Here, we evaluated critical endpoints from the tissue chip developer laboratory, focusing on biological relevance (long-term viability, baseline protein and gene expression, ammoniagenesis, and vitamin D metabolism), and toxicity biomarkers. Tissue chip experiments were conducted in parallel with traditional 2D culture conditions using two different renal proximal tubule epithelial cell sources. The results of these studies were then compared to the findings reported by the tissue chip developers. While the overall transferability of this advanced tissue chip platform was a success, the reproducibility with the original report was greatly dependent on the cell source. This study demonstrates critical importance of developing microphysiological platforms using renewable cell sources.

Renal disease is a global problem with unsustainable health-care costs. There currently exists a lack of accurate human renal disease models that take into account the complex microenvironment of these tissues. Here, we present a reusable microfluidic model of the human proximal tubule and glomerulus, which allows for the growth of renal epithelial cells in a variety of conditions that are representative of renal disease states including altered glomerular filtration rate, hyperglycemia, nephrolithiasis, and drug-induced nephrotoxicity (cisplatin and cyclosporine). Cells were exposed to these conditions under fluid flow or in traditional static cultures to determine the effects of a dynamic microenvironment on the pathogenesis of these renal disease states. The results indicate varying stress-related responses (α-smooth muscle actin (α-SMA) expression, alkaline phosphatase activity, fibronectin, and neutrophil gelatinase-associated lipocalin secretion) to each of these conditions when comparing cells that had been grown in static and dynamic conditions, potentially indicating more realistic and sensitive predictions of human responses and a requirement for a more complex "fit for purpose" model.

We have developed a re-usable multi-layer microfluidic device to model the human kidney that incorporates a porous growth substrate, physiological fluid flow, and the passive filtration of the glomerulus. The target cell line in this project is HK-2, immortalized human kidney proximal tubule cells. Cells were exposed to a shear stress of 0.8 dyne cm À2 within the device and monitored for protein expression, cytoskeletal reorganization, and increased molecular transport. Additionally, an endothelial cell-seeded glomerular filter was added to allow for more realistic "primary urine" within these devices. The results of this research suggest that cells grown within this microfluidic device exhibit more in vivo-like behaviour than those grown using traditional culturing methods, and that the filtration of serum proteins by the glomerulus is necessary for healthy cell function. The addition of this glomerulus-mimic to the device provides the first in vitro model of passive glomerular filtration coupled with the proximal tubule.

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Despite global efforts, it took 7 months between the proclamation of global SARS-CoV-2 pandemic and the first FDA-approved treatment for COVID-19. During this timeframe, clinicians focused their efforts on repurposing drugs, such as hydroxychloroquine (HCQ) or azithromycin (AZM) to treat hospitalized COVID-19 patients. While clinical trials are time-consuming, the exponential increase in hospitalizations compelled the FDA to grant an emergency use authorization for HCQ and AZM as treatment for COVID-19, although there was limited evidence of their combined efficacy and safety. The authorization was revoked 4 months later, giving rise to controversial political and scientific debates illustrating important challenges such as premature authorization of potentially ineffective or unsafe therapeutics, while diverting resources from screening of effective drugs. Here we report on a preclinical drug screening platform, a cardiac microphysiological system (MPS), to rapidly identify clinically relevant cardiac liabilities associated with HCQ and AZM. The cardiac MPS is a microfabricated fluidic system in which cardiomyocytes derived from human induced pluripotent stem cells self-arrange into a uniaxially beating tissue. The drug response was measured using outputs that correlate with clinical measurements such as action potential duration (proxy for clinical QT interval) and drug-biomarker pairing. The cardiac MPS predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities in tissues treated with HCQ. We found no change in QT interval upon acute exposure to AZM, while still observing a significant increase in arrhythmic events. These results suggest that this MPS can not only predict arrhythmias, but it can also identify arrhythmias even when QT prolongation is absent. When exposed to HCQ and AZM polytherapy, this MPS faithfully reflected clinical findings, in that the combination of drugs synergistically increased QT interval when compared to single drug exposure, while not worsening the overall frequency of arrhythmic events. The high content cardiac MPS can rapidly evaluate the cardiac safety of potential therapeutics, ultimately accelerating patients’ access to safe and effective treatments.