Abstract
In vitro screening methods for compound efficacy and toxicity to date mostly include cell or tissue exposure to preset constant compound concentrations over a defined testing period. Such concentration profiles, however, do not represent realistic in vivo situations after substance uptake. Absorption, distribution, metabolism and excretion of administered substances in an organism or human body entail gradually changing pharmacokinetic concentration profiles. As concentration profile dynamics can influence drug effects on the target tissues, it is important to be able to reproduce realistic concentration profiles in in vitro systems. We present a novel design that can be integrated in tubing-free, microfluidic culture chips. These chips are actuated by tilting so that gravity-driven flow and perfusion of culture chambers can be established between reservoirs at both ends of a microfluidic channel. The design enables the realization of in vivo-like substance exposure scenarios. Compound gradients are generated through an asymmetric Y-junction of channels with different hydrodynamic resistances. Six microtissues (MTs) can be cultured and exposed in compartments along the channel. Changes of the chip design or operation parameters enable to alter the dosing profile over a large range. Modulation of, e.g., the tilting angle, changes the slope of the dosing curves, so that concentration curves can be attained that resemble the pharmacokinetic characteristics of common substances in a human body. Human colorectal cancer (HCT 116) MTs were exposed to both, gradually decreasing and constant concentrations of Staurosporine. Measurements of apoptosis induction and viability after 5 h and 24 h showed different short- and long-term responses of the MTs to dynamic and linear dosing regimes
Highlights
In the last decades, microphysiological systems (MPSs) have been proven to better mimic human in vivo physiology in in vitro cell cultures
To produce a gradually changing concentration profile in the main channel, the two reservoirs left of the Y-junction in Figure 2A are filled with two different medium compositions, e.g., plain cell culture medium and medium containing a substance of interest
For example, a substance is added into the reservoir that is connected to the channel featuring the lower flow rate, and plain cell culture medium is applied to the other one, the substance concentration in the main channel is gradually enriched over time (Figure 2B)
Summary
Microphysiological systems (MPSs) have been proven to better mimic human in vivo physiology in in vitro cell cultures. MPSs, often referred to as “organs on chips,” are in vitro platforms designed to model the spatial, chemical, structural, and physiological elements of in vivo cellular environments In most cases, they include a combination of advanced cell culture models. A precise liquid-flow and temperature control, as well as the possibility to very closely mimic in vivo situations make these tools very promising candidates for efficacy and/or toxicity testing of substances for the pharmaceutical industry, in particular as they allow to investigate processes in a more systemic way (Marx et al, 2016; Wang et al, 2018) As those systems become better and better in reproducing in vivo situations in the human body, one of the remaining challenges that has been largely neglected in setting up an efficacy and toxicity screening pipeline is pharmacokinetics (PK)
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