Microsystems for In vitro Cell Models

In a BMBF-funded collaborative project, we are developing a colon carcinoma organoid-on-chip as an alternative to animal models in the context of preclinical drug development and personalized oncology.

Our cooperation partner CELLphenomics uses patient-derived 3D cell cultures (organoids), including those of colorectal carcinomas, for individual therapy screenings in high-throughput procedures and derives promising therapies from them. In the TumOC project, we are jointly developing an organoid-on-chip (TumOC) system that enables a) long-term physiological cultivation of organoids, b) dynamic treatments, and c) real-time measurements of cellular respiration. This enables us to elucidate the efficacy of anticancer drugs using real-time measurements of cell viability. By simultaneously measuring tumor heterogeneity in combination with repeated-dose experiments using a cascade of different cytostatic drugs, our TumOC system allows the impressive possibility to test and consequently pre-therapeutically predict the mechanism of action for individual combination therapies.

We are developing in vitro test methods for assessing the long-term toxicity of active substances with the aim of replacing animal experiments in the medium term. Maintaining the viability and functional properties of cell systems over sufficiently long times requires continuous monitoring of the cultivation conditions. The concentrations of glucose, oxygen and the pH value of the cell culture medium in the bioreactor are the most important parameters. Continuous measurement of these variables not only allows rigorous quality control, but also provides the input signals for automated operation of the microreactor. A significant part of the activities of the working group is dedicated to the development of sensor technology and its integration into the microreactors. The challenges here arise from miniaturization and, consequently, from the tiny sample volumes available as well as from the requirements for long-term stability.

The focus here is on the development of microsensor particles for real-time monitoring of the state of living cells cultured in artificial environments (in vitro). This approach allows rapid and detailed assessment of the effect of drugs or toxic substances on cell samples in high-throughput physiological environments and is motivated by two important areas: 

Patient-specific therapies: Advances in biomedicine have already made it possible to individually study patient-specific tissue samples to identify appropriate agents, minimize side effects, and adjust dosing for therapies.

Toxicity measurements: In the future, replacement methods for animal testing, i.e., in vitro test systems, will be used to evaluate pharmaceuticals, chemicals, and cosmetics with regard to their toxicity and biocompatibility, and to investigate new therapies in basic research. Besides the ethical motivation, the time and cost factor of animal models is a driving force for the development and establishment of such cell tests.

The measurement system to be developed here will allow real-time optical analysis of the metabolic indicators oxygen, glucose and pH within the cell tissue.

Together with Fraunhofer IAP, we are developing novel reservoirs for the release of active agents and signal molecules in microreactors for the control and manipulation of cell cultures with high temporal and spatial resolution. To accomplish targeted biochemical control of cell behavior, central functional units consisting of externally responsive control elements based on shape memory polymers (FGPs) are integrated into microfluidic environments and combined with real-time measurements of cell viability.