Development of a multi-sensor integrated midbrain organoid-on-a-chip platform for studying Parkinson’s disease

Abstract

Due to its ability to recapitulate key pathological processes in vitro, midbrain organoid technology has significantly advanced the modeling of Parkinson's disease over the last few years. However, some limitations such as insufficient tissue differentiation and maturation, deficient nutrient supply, and low analytical accessibility persist, altogether restricting the technology from reaching its full potential. To overcome these drawbacks, we have developed a multi-sensor integrated organ-on-a-chip platform capable of monitoring the electrophysiological, respiratory, and dopaminergic activity of human midbrain organoids. Our study showed that microfluidic cultivation resulted in a marked reduction in necrotic core formation, improved tissue differentiation as well as the recapitulation of key pathological hallmarks. Non-invasive monitoring employing an orthogonal sensing strategy revealed a clear time dependency in the onset of Parkinson's disease-related phenotypes, reflecting the complex progression of the neurodegenerative disorder. Furthermore, drug-mediated rescue effects were observed after treatment with the repurposed compound 2-hydroxypropyl β-cyclodextrin, highlighting the platform's potential in the context of drug screening applications as well as personalized medicine.