Abstract

Combining Organ Equivalents Using the Multi-Organ-Chip Technology

Ilka Maschmeyer, Senior Scientist, TissUse GmbH

The understanding of the bioavailability and metabolism of a chemical, either locally or systemically, is a key aspect in safety assessment. However, present in vitro and animal tests for drug development do not reliable predict the human outcome of tested drugs or substances because they are failing to emulate the organ complexity of the human body, leading to high attrition rates in clinical studies. For example, absorption, distribution, metabolism and excretion (ADME) are key determinants of efficacy and safety for therapeutic candidates. However, these systemic responses of applied substances are ignored in most in vitro tests. Here we present a universal microfluidic chip platform the size of a microscopic slide, consisting of an on-chip micro-pump and capable to interconnect different organ equivalents. The micro-pump ensures stable long-term circulation of media through the tissue culture compartments at variable flow rates, adjustable to physiological mechanical stresses of the respective tissues. In order to emulate the physiological relevant in vivo crosstalk with the ability to perform systemic preclinical substance testing, we have developed a universal 2 Organ-Chip (2-OC) for long-term culture of human organ equivalents interconnected within a common capillary microfluidic network. Several combinations of organs have been performed on this Multi-Organ-Chip platform. For example, we performed a case study with all-trans retinoic acid (ATRA) in an integrated system comprising EpiDermTM skin models and 3D liver organoids. It could be shown, that repeated application results in elevated concentrations of ATRA metabolites and an altered metabolite profile, the latter revealing the potential to induce (and to identify) new detox/metabolic options in the chip. Another combination of liver and intestine modelled the oral treatment and absorption of co-cultures by apical application to the intestinal tissue. Co-cultures of liver and human primary pancreatic islets showed to be able to drop glucose levels from high glucose to physiological values within 24 h. Glucose homeostasis could be maintained for up to 48 h without adding fresh medium to the system. Furthermore, we present a 4-Organ-Chip (4-OC) platform for ADME profiling. In this 4-OC platform, a human primary intestinal model and a skin biopsy have been integrated on standard cell culture inserts. A fluid flow connected these barrier models with a 3D-based liver spheroid. Finally, a barrier segregating the media flow through the organs from fluids excreted by the kidney has been generated by a polymeric membrane covered by a monolayer of human proximal tubule epithelial cells. It could be shown, that our Multi-Organ-Chip is universally applicable to co-culture different organ models over a culture period of up to 28 days. Tissue engineering data and assay performance data for repeated dose substance exposures through topical, apical and systemic administration routes will be presented. 4-OC results showed steady homeostasis during the complete culture period. Hence, a unique Multi-Organ-Chip platform was developed, enabling the testing of effects of substances on a set of miniaturized human organs.