A plug-and-play multi-organ-on-chip for studying interaction between central nervous system and peripheral monocytes following neuroinjury from radiation and Parkinson's disease.

Following neuroinjury (e.g., from radiation or Parkinson's disease), peripheral monocytes infiltrate the CNS, promoting neuroinflammation and cognitive decline. However, studying this is challenging due to a lack of suitable in vitro models. Multi-organ-on-a-chips (MOCs) address this gap with interactable in vitro models. We developed a plug-and-play multi-organ-chip (PPMOC) to mimic CNS-monocyte interactions. The PPMOC features two chambers, each with an insert for CNS or monocyte models, interconnected by a channel. A PDMS-based fabrication method using laser cutting of polymethyl methacrylate was developed for its fabrication. Finally, the PPMOC was employed to investigate CNS-monocyte interactions in radiation-induced neuroinjury and Parkinson's disease (PD). Results show that radiation caused neuroinjury, manifesting as decreased viability and morphological damage in nerve cells, and increased permeability of the blood-brain barrier (BBB). Further analysis revealed that radiation-induced neuroinjury inhibits the proliferation of THP-1 cells and promotes their activation and differentiation. Similarly, in PD, increased BBB permeability and activation of THP-1 cells were observed. Analysis of exosomes from the medium revealed upregulation of miR-151a-5p and miR-423-3p. Both models showed upregulated expression of inflammatory proteins and cytokines (e.g., CD14, TLR-2, IL-6, TNF-α, CCL-20), indicating monocyte activation. To sum up, PPMOC, a user-friendly and flexible multi-organ-on-a-chip, will become an important tool for studying CNS-monocyte interactions.