Neurodegenerative diseases pose a significant societal burden both within Europe and on a global scale. However, existing technologies currently hinder the comprehensive exploration and understanding of the molecular and cellular foundations of neurodegeneration. By leveraging the innovative concept of multifunctional neural interfaces within the living mouse brain, COMBO initiative introduces a groundbreaking technology designed for the multifunctional monitoring of brain-on-chip (BOC) systems with exceptional spatio-temporal resolution. Our approach involves combining three-dimensional (3D) bioprinting technologies with multi-electrode arrays (MEA), enhancing electrophysiological recording capabilities, and integrating optical spectroscopic tools in situ. This entails the utilization of tapered optical fibers, proficient in extracting molecular information through Raman spectroscopy. These fiber optic probes will be implemented in vivo across various regions of the mouse brain and subsequently translated in vitro by engineering the optical access channel to the BOC. This pioneering method allows for a unique opportunity to compare molecular spatio-temporal profiles in both in vivo and in vitro models, also exploiting the ability of high resolution two-photon microscopy to monitor functional fluorescence across shallow and deep regions of the 3D construct. It will equip neuroscientists with the capability to engage in long-term multifunctional investigations on brain-inspired in vitro models of neural diseases, also in the perspective of high throughput drug screening experiments. The COMBO initiative thus strives to overcome existing technological limitations, empowering the scientific community to delve deeper into the complexities of neurodegenerative disorders