An in vitro model of glucose and lipid metabolism in a multicompartmental bioreactor

Abstract

The energy balance in vivo is maintained through inter-organ cross-talk involving several different tissues. As a first step towards recapitulating the metabolic circuitry, hepatocytes, endothelial cells and adipose tissue were connected in a multicompartmental modular bioreactor to reproduce salient aspects of glucose and lipid metabolism in vitro. We first examined how the two-way cellular interplay between adipose tissue and endothelial cells affects glucose and lipid metabolism. The hepatocyte cell line HepG2 was then added to the system, creating a three-way connected culture, to determine whether circulating metabolite concentrations were normalized, or whether metabolic shifts, which may arise when endothelial cells and adipose tissue are placed in connection, were corrected. The addition of hepatocytes to the system prevented the drop in the concentrations of glucose, L-alanine and lactate, and the rise in that of free fatty acids. There was no significant change in glycerol levels in either of the connected cultures. The results show that connected cultures recapitulate complex physiological systemic processes, such as glucose and lipid metabolism, and that the HepG2 hepatocytes normalize circulating metabolites in this in vitro environment in the presence of other cell types.

Design Criteria for Generating Physiologically Relevant In Vitro Models in Bioreactors

“…These velocities are consistent with those typically reported for micro-fluidic cell culture devices [42]. For the MCmB model, the v in was set to 3.82 × 10 −3 m/s (corresponding to 180 μL/min inflow), on the basis of previous experiments with this bioreactor [31,[62][63][64][65][66]. Table 4.…”

A pumpless multi‐organ‐on‐a‐chip (MOC) combined with a pharmacokinetic–pharmacodynamic (PK–PD) model

“…Since allometric scaling has been widely used to relate physiological parameters between different organisms, it is natural to extend this concept to determine the relative sizes of organ chambers in MOC. For instance, Ahluwalia reported a modular multi‐compartmental bioreactor (MCmB), which was designed based on allometric scaling laws (Vinci et al, ). However, the authors did not study how their scaling approach affected the physiological observation made from the device.…”

Consensus report on the future of animal-free systemic toxicity testing

“…the results of the feasibility study demonstrated that the vast majority of the predictions made were correct (Schenk et al, 2010). metabolism or certain distribution parameters can provide data for such modeling (Vinci et al, 2012;Gebhardt et al, 2003) but better assays are still required for local specialized metabolism, distribution mediated by transporters, and for excretion processes (e.g., in the kidney). Altogether, this area is far advanced, e.g., for drug development, but its general application for chemicals requires further development (Bessems et al, 2014).…”