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Dynamic Multiple Organ Plate

Dynamic Multiple Organ Plate

Dynamic Multiorgan Culture Plate developed by IonTox

Dynamic Multiple Organ Plate developed by IonTox

Multiple Organ Plate

Predicting systemic toxicity in vitro requires a platform that incorporates multiple organs interconnected via a fluidics network that simulates blood flow. With the advent of new tissue models for skin, lung, liver, and heart, the opportunity to link these systems together has never been better.

The Dynamic Multiple Organ Plate, or DMOP, is an integrated meso-scale human multiple organ culture plate that can be used for predicting systemic toxicity.

Although several groups are developing sophisticated and complex micro-models that combine bioengineering with functional anatomy of an organ, they are less likely to provide a realistic means of linking drug or chemical biological effects with actual human pharmacokinetics and pharmacodynamics.

One reason for this is the miniature scale, which creates new challenges with regard to assay sensitivity and the balance between tissue mass and fluid volume. Another significant problem is that the fluid that supports cell growth is different for each organ type.

basolateralCurrent models provide for a full fluid exchange between all wells, hence mixing of optimized growth conditions. This reduces the length of time that tissue remain viable and fails to accurately mimic blood and vascular function.

The fluidics system on the DMOP uses a dialysis membrane that is present only in the organ compartment. Wells and tissues are linked by non-permeable tubing. This design keeps each organ isolated from the other organ wells. The only exchange between wells is the movement of small molecules that cross the dialysis membrane. Perfusion fluid is circulated through the fluidic system using a micro syringe pump, thereby maintaining a diffusion gradient until steady-state kinetics are achieved. The administration of a drug or chemical to the apical side of the intestine well (Caco-2) can be followed as it is absorbed into the fluid (blood) compartment.

The analyte then diffuses into the circulating perfusion medium where it is carried to the liver and other organ compartments. In successive compartments, the analyte is delivered to the culture medium until the chamber reaches equilibrium. By collecting medium directly from each organ compartment, the total analyte concentration can be determined. The relationship between analyte concentration and distribution mimics a two-compartment (absorption, distribution, elimination) oral-absorption model.

In 2014, IONTOX, in conjunction with ScitoVation (Formerly The Hamner Institute), conducted an extensive study to evaluate the DMOP using human tissues or cells. The aim of this study was to validate the meso-scale multiple organ plate with a fluid system modeled after the human vascular system. Acetaminophen (APAP) (200 ┬ÁM) was the drug traced through the DMOP in the study. IONTOX validated four critical proof-of-concept elements of the Dynamic Multiple Organ Plate design:

    The incorporation of microdialysis into a multiple-organ tissue culture plate provides a mechanism that allows inter-tissue communication while maintaining the unique culture conditions required for each tissue or cell type.
    The kinetics of APAP could be followed after a single bolus-dose administration to the apical compartment of the Caco-2 intestinal model.
    By monitoring the total amount of APAP in each compartment as well as in the perfusate, a full kinetic picture was possible.
    Delivery of APAP to the liver compartment was via the release of drug through the dialysis membrane. Thus, APAP was picked up in the basolateral chamber of the intestinal model and delivered to the liver chamber.

For further details for the study, see attached.

The DMOP is now available as a service. Please call 269.372.3395 or email info@iontox.com for more information.