On being the right size: scaling effects in designing a human-on-a-chip

Abstract

Developing a human-on-a-chip by connecting multiple model organ systems would provide an intermediate screen for therapeutic efficacy and toxic side effects of drugs prior to conducting expensive clinical trials. However, correctly designing individual organs and scaling them relative to each other to make a functional microscale human analog is challenging, and a generalized approach has yet to be identified. In this work, we demonstrate the importance of rational design of both the individual organ and its relationship with other organs, using a simple two-compartment system simulating insulin-dependent glucose uptake in adipose tissues. We demonstrate that inter-organ scaling laws depend on both the number of cells, and on the spatial arrangement of those cells within the microfabricated construct. We then propose a simple and novel inter-organ ‘metabolically-supported functional scaling’ approach predicated on maintaining in vivo cellular basal metabolic rates, by limiting resources available to cells on the chip. This approach leverages findings from allometric scaling models in mammals that limited resources in vivo prompts cells to behave differently than in resource-rich in vitro cultures. Although applying scaling laws directly to tissues can result in systems that would be quite challenging to implement, engineering workarounds may be used to circumvent these scaling issues. Specific workarounds discussed include the limited oxygen carrying capacity of cell culture media when used as a blood substitute and the ability to engineer non-physiological structures to augment organ function, to create the transport-accessible, yet resource-limited environment necessary for cells to mimic in vivo functionality. Furthermore, designing the structure of individual tissues in each organ compartment may be a useful strategy to bypass scaling concerns at the inter-organ level.

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

“…Further, as any individual MPS seldom replicates every feature of the organ in vivo , application-driven design of MPS components to capture essential features for the application is crucial to create a relevant physiological and pharmacological environment 1, 2, 19, 21, 24 .…”

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.…”

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.…”