- The ability to mimic cell–matrix interactions in a way that closely resembles the natural environment is of a great importance for both basic neuroscience and for fabrication of potent scaffolding materials for nervous tissue engineering. Such scaffolding materials should not only facilitate cell attachment but also create a microenvironment that provides essential developmental and survival cues. We previously found that porous aragonite crystalline matrices of marine origin are an adequate and active biomaterial that promotes neural cell growth and tissue development. Here we studied the mechanism underlying these neural cell–material interactions, focusing on the three-dimensional (3D) surface architecture and matrix activity of these scaffolds. We introduced a new cloning technique of the hydrozoan Millepora dichotoma, through which calcein or 45Ca2+ were incorporated into the organism's growing skeleton and neuronal cells could then be cultured on the labelled matrices. Herein, we describe the role of matrix 3D architecture on neural cell type composition and survival in culture, and report for the first time on the capacity of neurons and astrocytes to exploit calcium ions from the supporting biomatrix. We found that hippocampal cells growing on the prelabelled aragonite lattice took up aragonite-derived Ca2+, and even enhanced this uptake when extracellular calcium ions were chelated by EGTA. When the aragonite-derived Ca2+ uptake was omitted by culturing the cells on coral skeletons coated with gold, cell survival was reduced but not arrested, suggesting a role for matrix architecture in neural survival. In addition, we found that the effects of scaffold architecture and chemistry on cell survival were more profound for neurons than for astrocytes. We submit that translocation of calcium from the biomaterial to the cells activates a variety of membrane-bound signalling molecules and leads to the subsequent cell behaviour. This kind of cell–material interaction possesses great potential for fabricating advanced biomaterials for neural tissue-engineering applications. Copyright © 2008 John Wiley & Sons, Ltd.