Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism

Abstract

Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell–cell or cell–tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

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

“…Common scaling approaches to date include direct miniaturization and allometric scaling of a variety of in vivo physical characteristics such as organ/tissue mass, blood flowrates, volumes and residence times 1, 11, 19, 20 . The focus of these approaches is to preserve the relative biomass scales of each organ (e.g.…”

Allometric Scaling of physiologically-relevant organoids

“…It has been suggested that allometric behaviour could be considered as a benchmark of physiological relevance 9,25 and a recent study shows that KL can be achieved in high density constructs 12 . The characteristic features of non-luminal organoids, that is high cell densities and their potential to therefore follow physiological metabolic scaling as well as to adopt the structural and functional features of mammalian organs on one hand, and their tendency to develop an oxygen deprived core on the other, appear to be in contrast.…”

Organ‐on‐a‐Chip Technology for Reproducing Multiorgan Physiology

“…There are several methods to solve the scaling issue and develop more physiologically relevant systems, such as allometric scaling and residence time of the blood in each organ . Allometric scaling considers the cell number, cell surface area, and metabolic rate between the body and the organs . Allometric ratios have been used as a scaling factor for the design of multiorgan chips.…”