Abstract: Functional recovery in penetrating neurological injury is hampered by a lack of clinical regenerative therapies. Biomaterial therapies show promise as medical materials for neural repair through immunomodulation, structural support, and delivery of therapeutic biomolecules. However, a lack of facile and pathology-mimetic models for therapeutic testing is a bottleneck in neural tissue engineering research. We have deployed a two-dimensional, high-density multicellular cortical brain sheet to develop a facile model of injury (macrotransection/ scratch wound) in vitro. The model encompasses the major neural cell types involved in pathological responses post-injury. Critically, we observed hallmark pathological responses in injury foci including cell scarring, immune cell infiltration, precursor cell migration, and shortrange axonal sprouting. Delivering test magnetic particles to evaluate the potential of the model for biomaterial screening shows a high uptake of introduced magnetic particles by injury-activated immune cells, mimicking in vivo findings. Finally, we proved it is feasible to create reproducible traumatic injuries in the brain sheet (in multielectrode array devices in situ) characterized by focal loss of electrical spiking in injury sites, offering the potential for longer term, electrophysiology plus histology assays. To our knowledge, this is the first in vitro simulation of transecting injury in a two-dimensional multicellular cortical brain cell sheet, that allows for combined histological and electrophysiological readouts of damage/repair. The patho-mimicry and adaptability of this simplified model of brain injury could benefit the testing of biomaterial therapeutics in regenerative neurology, with the option for functional electrophysiological readouts.

Key words: in vitro modelling, multielectrode array interfacing, nanoparticles, neuromaterials, scratch assay, transecting injury, traumatic brain injury