Biomaterials for neural tissue engineering, cell delivery, and chronic neural interfaces are conventionally characterized through physicochemical descriptors such as stiffness, topography, surface chemistry, and degradation rate. However, their biological effect is mediated by the material–tissue interface, a dynamic layer formed through protein adsorption, extracellular matrix ligand presentation, and progressive cellular remodeling, that determines how these design parameters are translated into neuronal and glial responses. This review synthesizes current evidence on how neurons, astrocytes, and microglia sense the material–tissue interface, how integrin-dependent adhesion complexes, mechanosensitive Piezo1 channels, and downstream FAK/Src, RhoA/ROCK, and YAP/TAZ pathways transduce interfacial cues into intracellular signaling, and how key design variables (mechanical properties, architecture, surface chemistry, electrical conductivity, and degradation) can be tuned to direct these processes in regenerative scaffolds and chronic neural interfaces. Particular attention is given to studies distinguishing direct neuronal effects from glia-mediated modulation, since concurrent changes in neuronal and glial markers are often reported without establishing causal neuron–glia interaction. We further discuss methodological limitations, including model mismatch across 2D, 3D, and in vivo systems and insufficient duration of chronic observation, that constrain current interpretations of biomaterial-induced neuron–glia crosstalk. We argue that functional biomaterial design for neural applications should move from optimizing isolated cellular readouts toward multicellular experimental frameworks capable of resolving neuron–glia–ECM interactions over physiologically relevant timescales.

Biomaterials for neural tissue engineering, cell delivery, and chronic neural interfaces are conventionally characterized through physicochemical descriptors such as stiffness, topography, surface chemistry, and degradation rate. However, their biological effects are mediated by the material–tissue interface, which evolves through protein adsorption, extracellular matrix ligand presentation, and progressive cellular remodeling and determines how these design parameters are translated into neuronal and glial responses. This review synthesizes current evidence on how neurons, astrocytes, and microglia sense the material–tissue interface, how integrin-dependent adhesion complexes, mechanosensitive Piezo1 channels, and downstream FAK/Src, RhoA/ROCK, and YAP/TAZ pathways transduce interfacial cues into intracellular signaling, and how key design variables (mechanical properties, architecture, surface chemistry, electrical conductivity, and degradation) can be tuned to direct these processes in regenerative scaffolds and chronic neural interfaces. Particular attention is given to studies distinguishing direct neuronal effects from glia-mediated modulation, since concurrent changes in neuronal and glial markers are often reported without establishing causal neuron–glia interaction. We further discuss methodological limitations that constrain current interpretations of biomaterial-induced neuron–glia crosstalk, including discrepancies between 2D, 3D, and in vivo models and insufficient durations of chronic observation. We argue that functional biomaterial design for neural applications should move from optimizing isolated cellular readouts toward multicellular experimental frameworks capable of resolving neuron–glia–ECM interactions over physiologically relevant timescales.