John P. Wikswo, Frank E. Block III, David E. Cliffel, Cody R. Goodwin, Christina C. Marasco, Dmitry A. Markov, David L. McLean, John A. McLean, Jennifer R. McKenzie, Ronald S. Reiserer, Philip C. Samson, David K. Schaffer, Kevin T. Seale, and Stacy D. Sherrod
Volume: 60, March Special Issue, Publication Year: 2013 (Full Article)
Microfabricated human organs-on-chips (OoCs) and tissue-engineered human organ constructs (HoCs) will complement the cell-culture/animal/human tests comprising the current drug development pipeline. While numerous individual OoCs/HoCs are being developed, only limited reports describe coupled organs in physiologically realistic microHuman (µHu) and milliHuman (mHu) systems that can operate stably for weeks to months. We present a top-down analysis of such microphysiological systems, and identify a series of daunting engineering challenges, which if met should revolutionize drug discovery and systems biology. These include determining the appropriate size for each organ to ensure appropriate relative organ functional activity in the coupled system; vascularizing organs with the surface-to-volume ratios required for physiologically realistic cell densities; developing a universal blood surrogate; miniaturizing pumps and valves for fluidic control; creating size-matched sensors for real-time analytical chemistry and omni-omic workflows for comprehensive molecular characterization in the 5 mL total fluid volume of a mHu and the 5 mL volume of a mHu; creating low-volume microformulators to represent missing organs and adjust blood surrogate in real-time; maintaining and controlling coupled organ systems while allowing physiologically realistic oscillations and damping unnatural ones; characterizing organ health and disease; modeling coupled organ systems; perfecting machine-learning algorithms for automated model inference and integrated electronic control; and minimizing the cost of organs and automated optical microscopy to enable affordable high-content screening. Given the breadth and magnitude of current funding and the caliber of the participating investigators, we anticipate that the engineering and biology community can address these limitations in a timely manner. The OoC/HoC microphysiological systems effort should lead to exciting new advances in organotypic culture; physiologically based pharmacokinetics and pharmacodynamics for drug discovery and assessing toxicity and safety; identification and minimization of the effects of emerging and maliciously engineered pathogens and toxins; and characterization of organ-organ interactions and physiological regulation.