Perfused brain slice-on-chip platforms: a systematic review of long-term organotypic hippocampal tissue culture

Organ-on-chip (OoC) platforms are increasingly used to replicate structural, functional and molecular features of native tissue within controlled microenvironments. While most current brain-on-chip (BoC) systems rely on 2D cultures or 3D stem cell-derived constructs, the integration of intact brain tissue slices-particularly organotypic explants of the central nervous system-offers distinct advantages by preserving native cytoarchitecture, synaptic connectivity, and regional specificity. This systematic review aimed to identify and critically assess OoC platforms that incorporate ex vivo brain tissue slices maintained under dynamic perfusion for extended periods (≥10 days in vitro). A structured PubMed search conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines identified 2796 records, of which 7 studies met the predefined inclusion criteria. All included studies employed organotypic brain slices derived from early postnatal rodents and integrated them into perfused microfluidic systems. Most platforms combined air-liquid interface culture with low-volume perfusion to support prolonged tissue viability and partial functional maintenance, including electrophysiological activity, preserved structural integrity, and molecular homeostasis. Notably, none of the identified studies reported the successful long-term cultivation of adult rodent or human brain tissue in a comparable perfused OoC configuration, underscoring a major limitation of current approaches. Moreover, assessment of tissue viability and function was heterogeneous and frequently relied on descriptive or insufficiently sensitive readouts, limiting cross-platform comparisons and translational relevance. Future development of BoC technologies should prioritize improved microenvironmental control, the integration of suitable biomaterials, and embedded monitoring strategies capable of assessing metabolic state and circuit-level function. Addressing these challenges will be essential for advancing OoC platforms towards physiologically meaningful and translationally relevant applications in neuroscience.