Design and prototyping of a chip-based multi-micro-organoid culture system for substance testing, predictive to human (substance) exposure.

Dynamic miniaturized human multi-micro-organ bioreactor systems are envisaged as a possible solution for the embarrassing gap of predictive substance testing prior to human exposure. A rational approach was applied to simulate and design dynamic long-term cultures of the smallest possible functional human organ units, human "micro-organoids", on a chip the shape of a microscope slide. Each chip contains six identical dynamic micro-bioreactors with three different micro-organoid culture segments each, a feed supply and waste reservoirs. A liver, a brain cortex and a bone marrow micro-organoid segment were designed into each bioreactor. This design was translated into a multi-layer chip prototype and a routine manufacturing procedure was established. The first series of microscopable, chemically resistant and sterilizable chip prototypes was tested for matrix compatibility and primary cell culture suitability. Sterility and long-term human cell survival could be shown. Optimizing the applied design approach and prototyping tools resulted in a time period of only 3 months for a single design and prototyping cycle. This rapid prototyping scheme now allows for fast adjustment or redesign of inaccurate architectures. The designed chip platform is thus ready to be evaluated for the establishment and maintenance of the human liver, brain cortex and bone marrow micro-organoids in a systemic microenvironment.