CHIPzophrenia · Feedback-control of the Microenvironment: Modular Organ-on-Chip Technology to elucidate the role of Neurovascular Stress in Schizophrenia

A well-controlled microenvironment is paramount for reproducible biomolecular studies. Organs-on-chips are in-vitro cell culture systems that employ microfluidic and biomaterial engineering towards that goal. They combine the advantages of animal models (physiological environment) with those of plastic-dish culture (human cells), and thereby hold exceptional promise in unraveling the biological processes that underlie health and disease. Yet control over the biochemical environment remains poor.With CHIPzophrenia, I propose to develop a new generation of organ-chip, one that features feedback-enabled control of the biochemical environment. I aim to realize dynamic and well-controlled application of stable therapeutics (via feedback sensors and flow control), and crucially also of highly volatile oxygen/nitrogen stressors by relying on electrochemistry to generate them in situ. My goal is to moreover implement a highly functional modular architecture so that the system can easily be repurposed and sensor/control modules reused – all with negligible dead volumes and displacement (key challenges in current organ-chips towards novel functionalities).I intend to leverage this organ-chip to elucidate how nitrosative stressors disrupt the complex multicellular interactions of the blood-brain barrier, where existing in-vitro models fail to provide the requisite cellular and chemical microenvironment. Yet such disruption is implicated in a wide array of disorders – including schizophrenia, where our biological understanding remains poor and in-vivo models are uniquely challenging. I will specifically test the hypothesis that nitrosative dysregulation of perivascular cells plays a causative role in neuronal dysfunction associated with the disorder. Not only will CHIPzophrenia thus reveal new potential treatment targets, but it will also establish the platform as a transformative tool for dynamic and well-controlled in-vitro research into stress-related disorders and beyond.