A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture

Abstract

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Current in vitro and animal tests for drug development are failing to emulate the systemic organ complexity of the human body and, therefore, to accurately predict drug toxicity. In this study, we present a multi-organ-chip capable of maintaining 3D tissues derived from cell lines, primary cells and biopsies of various human organs. We designed a multi-organ-chip with co-cultures of human artificial liver microtissues and skin biopsies, each a 1/100 000 of the biomass of their original human organ counterparts, and have successfully proven its long-term performance. The system supports two different culture modes: i) tissue exposed to the fluid flow, or ii) tissue shielded from the underlying fluid flow by standard Transwell® cultures. Crosstalk between the two tissues was observed in 14-day co-cultures exposed to fluid flow. Applying the same culture mode, liver microtissues showed sensitivity at different molecular levels to the toxic substance troglitazone during a 6-day exposure. Finally, an astonishingly stable long-term performance of the Transwell®-based co-cultures could be observed over a 28-day period. This mode facilitates exposure of skin at the air–liquid interface. Thus, we provide here a potential new tool for systemic substance testing.BMBF, 0315569, GO-Bio 3: Multi-Organ-Bioreaktoren für die prädiktive Substanztestung im Chipforma

Integrating biological vasculature into a multi-organ-chip microsystem

“…More importantly, tissue culture inserts, each of a maximum volume of 300 ml, will allow for the exact adjustment of physiological fluid-to-tissue ratios once individual organ equivalents are established in the next development step. While we could already demonstrate the successful co-culture of human skin biopsies and 3D liver spheroids over 28 days in the MOC, 57 the addition of a fully vascularized system to such a co-culture has to be implemented in the future. The fabrication technique is convenient and versatile, and design changes can be implemented in designto-device turnaround times of only 2-3 months.…”

In vitro skin three-dimensional models and their applications

“…In addition, skin-on-a-chip can be expanded to multiple organ chips to test drug metabolism. Accordingly, Maschmeyer et al and Wagner et al engineered two and four organ chips with intestine, liver, skin and kidney [76][77][78]. Furthermore, disease models simulating inflammation and edema exist [79].…”

“…The presence of flow also allows the study of circulating cells, such as circulating breast cancer cells with microvascular endothelium at potential sites of metastasis [83] or immune cells [84]. Using a multi-organ-chip, one can link different organs into a systemic arrangement imitating that of the human organism at a miniaturised scale [76]. Combining the four organ equivalents, skin, intestine, liver, and kidney, this model allows for in vitro microfluidic ADME -absorption, distribution, metabolism and excretion -profiling [78].…”

Multiphase microfluidic synthesis of micro- and nanostructures for pharmaceutical applications

“…Therefore, organs-on-achip models (Table 3) have great potential in mimcking the behavior and efficacy of drugs/nanoparticles more accurately than conventional 2D cell cultures, much faster and less expensive than in vivo animal models. (Berdichevsky et al, 2010;Park et al, 2015) Heart -Heart function (Yazdi et al, 2015) Intestine Anticancer activity Liver, skin Troglitazone Toxicity (Wagner et al, 2013) Lung-on-a-chip was the first trial of the concept of organ-on-a-chip. A layer of human alveolar epithelial cells and a layer of human pulmonary microvascular endothelial cells were co-cultured on the opposite sides of a thin porous elastomeric membrane to simulate the alveolar-capillary interface (Huh et al, 2010).…”