Advances in organ-, body-, and disease-on-a-chip systems

In mid-2017 I wrote an editorial in Lab on a Chip requesting articles for a thematic collection of papers for a virtual issue on the emergence and advancement of organ-, body-, and disease-on-a-chip systems (also known as microphysiological systems or MPS). The response has been enthusiastic with 37 papers in the virtual issue available now using the link http://rsc.li/organonachip and additional papers are still being added. This collection provides a rich resource for readers interested in this emerging technology.

The first papers demonstrating the possibility of representing mammalian physiology and response to chemical exposure with a multi organ model combining cell cultures, microfabricated devices and physiologically based pharmacokinetic models appeared in 2004. With initiation of a major funding effort by DARPA and NIH seven years ago the work in this area of technology has exploded as described by Zhang and Radisic (DOI: 10.1039/C6LC01554A) and continues to grow at an accelerating rate. A primary motivation, echoed throughout the collection, is to improve the drug development process. These systems are believed to have potential to reduce or even to replace animals in preclinical testing. Furthermore, authentic representations of human organs, particularly multi-organ systems, have the potential to lead to improved decisions of which compounds to select to enter clinical trials and thereby increase significantly the chances that a drug will successfully exit clinical trials as an approved drug. Society would benefit from more useful drugs and at potentially reduced costs per drug. Additionally, these systems can play a crucial role in improved assessment of potential human toxicological responses to exposure to food ingredients and to industrial chemicals.

This virtual issue contains not only papers in direct response to the original call but selected papers from the first half of 2017. One critical paper is a perspective paper on commercialization efforts (Zhang and Radisic, DOI: 10.1039/C6LC01554A) that reviewed 28 start-up companies in this space. The number of new companies continues to expand and the current number is well beyond 28. Nonetheless, this review provides a useful summary of the commercial entities and their particular strengths and focus.

Other critical review papers and perspectives are included in this collection with each focusing on different attributes required of such systems. These review and perspective papers provide readers with an overview of the critical issues in bringing this technology forward. Cirit and Stokes (DOI: 10.1039/C8LC00039E) focus on the need and potential for microphysiological systems (MPS) to translate in vitro data to predictions of human response. In particular, they make a strong case for the need to obtain quantitative data from MPS systems and to build mathematical models (based on quantitative systems pharmacology) to predict human response. McLean et al. (DOI: 10.1039/C8LC00241J) further elaborate in their review on the critical role microfluidic devices can play in utilizing ex vivo tissues in physiologically relevant environments. Ex vivo tissues, if they can be sustained in physiologically relevant conditions, would be ideal for personalized (or precision) medicine and in general for drug development. Van den Berg et al. (DOI: 10.1039/C8LC00827B) provide a perspective on the development of personalized microphysiological systems and their potential to improve treatment strategies for specific groups or individuals as well as the challenges that need to be addressed. Kieninger et al. (DOI: 10.1039/C7LC00942A) review the incorporation of microsensors in such devices with a discussion of the challenges and benefits of employing monitoring systems designed for 2D systems to applications with 3D and organ-on-a-chip systems. Two review articles address the use of MPS for development of drugs and drug delivery systems for treatment of cancer. Caballero et al. (DOI: 10.1039/C7LC00574A) focus on tumor-vessel-on-a-chip systems to test and understand the potential use of drug nanocarriers in cancer treatment. One question addressed is the rational design of nanoparticles to enhance their efficacy. Hachey and Hughes (DOI: 10.1039/C8LC00330K) review current in vitro tumor-on-a-chip models and discuss the improvement necessary to improve these systems and address the high failure rates in clinical trials, particularly for anti-cancer drugs. Truskey (DOI: 10.1039/C8LC00553B) provides an important critical review of microphysiological systems designed to emulate human skeletal muscle, particularly in a diseased state. He reviews recent technological advances, such as maturation of iPS cells into adult-like skeletal muscle and the need for functional measures of metabolism, that will increase the value of such models. Those reviews will provide the reader with an excellent perspective on the state of the art and possible approaches to realize more effective predictions from preclinical trials.

The other papers address a variety of specific questions and opportunities with these systems. Some focus more on novel applications in basic biology, although many papers are combinations of system development and biological/medical applications.

There is always a trade-off between throughput and physiological accuracy. For earlier preclinical testing high throughout is important while in later stages a more physiologically accurate and complex model that can provide a deeper understanding of the potential effects of a drug on humans is required. These later stage, more detailed systems, often multi-organ systems, can be applied to tens to a hundred compounds while the high throughput studies often based on a single “organ” module may need to address an order of magnitude more compounds. While none of the systems in this collection are truly high throughput there has been progress in developing systems for increased throughput particularly with multicellular or multi-organ components. Incorporation of sensors into these devices can allow real time (or near real time) assessment of cellular functional changes in response to drugs. Any of the papers in this collection focus on integration of such sensors into these devices. Further external pumps are cumbersome, increase the potential for contamination or failure due to formation of gas bubbles that can block flow, and require extended effort to set up. The use of systems without external pumps facilitates the development of self-contained systems as well as the use of online sensors. Ideally microscale systems that can stand alone are ideal for incorporation into drug development and chemical toxicity screens.

Many of these papers focus on the development of complex organ models with multiple cell types to mimic the in vivo organ. Over the last five years there have been major improvements in organ modules. While many of the papers focus on a single organ, some address issues with multiple interacting organs. There is also increased attention being given to vascularized models of tissue which may be essential to understand drug transport or nutrient supply in larger 3D organ or organoid models (>300 micrometers in thickness). These papers address models of single organs (liver, intestine, immune cells, eye, stomach, lung, brain, heart, kidney, vasculature, nasal mucosa, and various tumors) and a gut-liver system.

Other papers include models integrating a model blood vessel network and tissue models, novel systems for control of fluid flow, application of mathematical models to microphysiological systems, and techniques to probe cell heterogeneity.

As the field matures I expect that we will see increased emphasis on multi-organ systems as such integrated systems will be necessary to better understand both a drug's efficacy in terms of a target organ as well as toxicity to other organs. Preclinical tests using multi-organ human systems that can predict both a drug's efficacy and toxicity to other organs would be invaluable to the drug development process. Advances in technologies that can be applied to addressing heterogeneity in human response are likely to increase. With all of these technical and biological advances we can easily anticipate a much improved process for more effective preclinical drug development.

A final note from the Lab on a Chip Editors

This exciting collection of papers and reviews on aspects of organ-, body- and disease-on-a-chip systems highlights the excellent fit of these papers within the Lab on a Chip scope, which aims to publish work at the interface between technological advances and high impact applications. We welcome future submissions on single or multi-organ human systems for drug development and toxicity studies and Lab on a Chip is a perfect home for this work.

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