JALA Special Issue: Microengineered Cell- and Tissue-Based Assays for Drug Screening and Toxicology Applications

The past two decades have witnessed impressive advances in the integration of microscale engineering with biology. The explosion of genomics and government support for biodefense research in the 1980s led to the inception of a new field now known as biological micro-electro-mechanical systems (bio-MEMS) that focuses on leveraging precision fabrication technologies developed in the microelectronics industry for the study of cells and biomolecules. Remarkable growth accomplished in this field has contributed to numerous conceptual and technological innovations in virtually all areas of life sciences. In particular, researchers have developed a wide variety of microengineered tools that provide unprecedented capabilities to control cultured living cells with high spatiotemporal precision and to present them with physiologically relevant microenvironmental cues. ¹ Recent progress in this microsystems approach for cell biology has also led to microengineered biomimetic models termed tissues- and organs-on-chips that reconstitute complex integrated physiological functions beyond cellular-level responses. ²

With the evolution and maturation of this field, we are now beginning to witness an exciting endeavor directed toward exploring the potential and real-world impact of these microengineered living systems for pharmaceutical and toxicological applications. ³ Fueled by recent escalating interest and support from both regulatory agencies and the pharmaceutical industry, microengineered cell- and tissue-based bioassays are emerging as an area of intense research investigation and technology commercialization. ⁴ This special issue of the Journal of Laboratory Automation offers an extensive survey of some of the most significant advances resulting from this recent trend that we believe are beneficial to a wide range of communities in pharmaceutical and toxicology research.

Of particular interest in this special issue is the development of a combined contractility and electrophysiological assay for high-throughput cardiac safety screening. The inadequacies of current preclinical analysis methods for accurately predicting the arrhythmogenic potential of new drug candidates has garnered considerable attention in recent years. To that end, the current Cardiac In vitro Proarrhythmia Assay (CIPA) initiative has received support from both the U.S. Food and Drug Administration and pharmaceutical companies in the hope that it will lead to the development of more effective analytical methods for predicting the in vivo effects of new drugs.^4,5 Given this interest, platforms such as the one developed by Doerr and colleagues ⁶ are likely to come to the forefront of compound safety screening in the near future. In the presented study, the authors demonstrate how their 96-well plate assay can be used to record both field potential and contraction data, enabling multimodal analysis of cultured cardiomyocytes. Such a system provides more comprehensive information on the functional profiles of the cells, thereby enabling a more complete evaluation of compound action on the engineered cardiac monolayer. The results presented in this work demonstrate how multiple compounds can be assessed simultaneously to achieve higher-throughput analysis of drug action.

Also of interest in this issue is the work of Kimura et al. ⁷ to produce a functional liver-on-a-chip model for analyzing first-pass metabolism in vitro. Despite the current excitement surrounding the potential for organs-on-chips to revolutionize human tissue modeling, the ability to generate microfluidic models connecting multiple organ models perhaps holds even greater promise for driving forward the utility of bioengineered platforms. Platforms capable of effectively modeling tissue-tissue cross-talk may hold the key to accurately modeling compound absorption, distribution, metabolism, and excretion in human systems. ⁸ In the presented study, the authors highlight that their model successfully links small intestine, liver, and lung organ models as a first step toward this goal. The developed system maintains physiological flow velocities to more closely mimic human blood flow and distributions. Importantly, treatment with cyclophosphamide was found to have an effect in the lung tissue only when cells were co-cultured with the liver mimic, indicating the ability for the system to mimic metabolism of the compound as is known to occur in vivo. Further development of systems such as this may lead to the development of complex multiorgan models that accurately model human systems, reducing reliance on animal models for system toxicity screening.

In keeping with the movement toward high-throughput modalities, Kim et al. ⁹ present a novel method for generating spheroid cultures in a 96-well plate interconnected through the use of microfluidic channels. Although less physiologically representative, this system could theoretically be used to generate a multiorgan platform linking 96 tissue compartments for complex intertissue communication analysis. The work of Kim et al. and Kimura et al. represent high-content and high-throughput multiorgan modeling, respectively, but both make use of microfluidic channels to transport medium. Ryu and colleagues ¹⁰ have sought to further improve the biomimicity of microfluidic technologies through the generation of transferrable cell-based blood vessel networks to create links between inlets, outlets, and cell chambers. The use of paracrine-secreting fibroblasts and endothelial cells in these units serves to improve the physiological accuracy of these modular systems and could help drive multiorgan models toward more accurate representations of human systems

In addition to these exciting articles, this issue presents work on the development of an array of new technologies, including methods for achieving automated hanging drop culture production, ¹¹ novel viability assays that enable repeated assessment of a single sample, ¹² techniques for producing high-throughput 3D culture models, ¹³ and simplified methods for attaining reproducible high-throughput assays.^14,15 The collected primary research is supported by in a number of in-depth reviews detailing some of the most important standout technologies for advancing microengineered cell- and tissue-based assays for drug-screening applications.^16–21 We have strived to collect and present a diverse array of articles in order to provide an inclusive overview of the field that emphasizes the importance of these new technologies for valuable real-world applications. We hope you enjoy this special issue from the Journal of Laboratory Automation!

Dan Dongeun Huh, PhDDepartment of BioengineeringUniversity of PennsylvaniaPhiladelphia, PA, USA Deok-Ho Kim, PhDDepartment of BioengineeringUniversity of WashingtonSeattle, WA, USA