Scaling and systems biology for integrating multiple organs-on-a-chip

Abstract

Coupled systems of in vitro microfabricated organs-on-a-chip containing small populations of human cells are being developed to address the formidable pharmacological and physiological gaps between monolayer cell cultures, animal models, and humans that severely limit the speed and efficiency of drug development. These gaps present challenges not only in tissue and microfluidic engineering, but also in systems biology: how does one model, test, and learn about the communication and control of biological systems with individual organs-on-chips that are one-thousandth or one-millionth of the size of adult organs, or even smaller, i.e., organs for a milliHuman (mHu) or microHuman (μHu)? Allometric scaling that describes inter-species variation of organ size and properties provides some guidance, but given the desire to utilize these systems to extend and validate human pharmacokinetic and pharmacodynamic (PK/PD) models in support of drug discovery and development, it is more appropriate to scale each organ functionally to ensure that it makes the suitable physiological contribution to the coupled system. The desire to recapitulate the complex organorgan interactions that result from factors in the blood and lymph places a severe constraint on the total circulating fluid (~5 mL for a mHu and ~5 μL for a μHu) and hence on the pumps, valves, and analytical instruments required to maintain and study these systems. Scaling arguments also provide guidance on the design of a universal cell-culture medium, typically without red blood cells. This review presents several examples of scaling arguments and discusses steps that should ensure the success of this endeavour.

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

“…Efforts have been initiated toward further compacting and simplifying the platform by adopting LEGO and/or cartridge assemblies as recently reported for the fabrication of organs-on-a-chip models (67)(68)(69)(70)(71). Further efforts on improved scaling of our platform should, in principle, allow for more accurate modeling of the human system and therefore achieve better prediction of drug efficacy/toxicity (33).…”

“…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.…”

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

“…These models may incorporate features such as co-culture of multiple cell types (epithelium, endothelial and pericytes), fluid flow (e.g. microfluidic devices such as 'organon-a-chip') and 3D cell culture system, which have all been suggested to provide more physiologically representative in vitro systems for studying renal drug disposition (30,50,51). Other emerging technologies, including stem cell science and 3D bio-printing, offer further potential for the development of the next-generation in vitro models (52).…”

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.…”