Engineering Challenges for Instrumenting and Controlling Integrated Organ-on-Chip Systems

Abstract

The sophistication and success of recently reported microfabricated organs-on-chips and human organ constructs have made it possible to design scaled and interconnected organ systems that may significantly augment the current drug development pipeline and lead to advances in systems biology. Physiologically realistic live microHuman (µHu) and milliHuman (mHu) systems operating for weeks to months present exciting and important engineering challenges such as determining the appropriate size for each organ to ensure appropriate relative organ functional activity, achieving appropriate cell density, providing the requisite universal perfusion media, sensing the breadth of physiological responses, and maintaining stable control of the entire system, while maintaining fluid scaling that consists of ~5 mL for the mHu and ~5 µL for the µHu. We believe that successful mHu and µHu systems for drug development and systems biology will require low-volume microdevices that support chemical signaling, micro-fabricated pumps, valves and microformulators, automated optical microscopy, electrochemical sensors for rapid metabolic assessment, ion mobility-mass spectrometry for real-time molecular analysis, advanced bioinformatics, and machine learning algorithms for automated model inference and integrated electronic control. Toward this goal, we are building functional prototype components and are working toward top-down system integration.

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

“…These miniaturized human organ models have several advantages over conventional models, such as more accurate prediction of human responses and, in particular, multiorgan interactions when different organ modules are assembled in a single fluid circuit (7,31). Although a majority of focus in the field has been placed on the construction of biomimetic organ models (7,15,(31)(32)(33), it is increasingly recognized that incorporating biosensing would allow for in situ monitoring of the status of these miniaturized organs (9,34). Such a need originates from the fact that many drugs can trigger chronic cellular reactions, whereas others may induce delayed cell responses.…”

A microfluidic optical platform for real-time monitoring of pH and oxygen in microfluidic bioreactors and organ-on-chip devices

“…21 Thus, it is important to monitor the physicochemical parameters within the culture medium. [22][23][24] In addition, proper control of the oxygen tension is a critical task for multi-organon-chip microsystems, 9,25,26 where each organ construct may need a unique microenvironment with special levels of dissolved oxygen. 17 Hence, the development of microfluidic platforms with integrated multi-analyte sensing capabilities for in-line monitoring of physicochemical parameters of organ constructs is needed to fully enable the use of organs-on-chip microsystems for in vitro analysis of cellular functions.…”

“…To facilitate the operation and adaptability of such integrated systems, a sensing device should ideally be equipped with electronic control and automated inference for data acquisition, visualization, and storage. 25 Microfluidic detection methods are highly suited for integration with organ-on-chip devices due to their potential for the analysis of low-volume liquids and high degree of automation. 29 A variety of microfluidic optical and electrochemical techniques have been developed to measure oxygen 22,[30][31][32][33][34][35][36][37][38] and pH 31,34,37,[39][40][41][42][43][44] for cell-based studies.…”

In-plane microvortices micromixer-based AC electrothermal for testing drug induced death of tumor cells

“…5,6 These chip systems are connected by microfluidic channels that are assembled according to the organ networks in the human body to mimic the dynamic in vivo environment. [7][8][9] Laminar flows in these microfluidic channels present a challenge for effective diffusional mixing of the culture medium, metabolites, drugs, or other biological signals from multi-organ chips. 10,11 As a consequence of poor mixing, the cells, tissues, or sensors in organs-on-a-chip systems will present inexact results in drug or vaccine testing.…”