Bridging the gap: towards a digital twin to optimize therapeutic cell-seeding strategies in nerve tissue engineering.

Peripheral nerve injuries impose a substantial strain on the lives of millions of people worldwide. Engineered neural tissues provide a promising avenue to improve peripheral nerve repair strategies, potentially allowing the precise seeding of cells and materials that support regenerative processes. Current optimization of cell-seeding strategies relies on testing the impact of relevant parameters in vivo, requiring considerable time and resources. We propose an alternative approach to the design of cellular hydrogels based on a mathematical cell-solute model, informed via in vitro experiment, to identify promising cell-seeding strategies in silico at a limited cost. These designs are manufactured using 3D-printed moulds and validated in vivo. We evaluate the regenerative potential of these designs by focusing on the impact of different cell-seeding strategies on vascular endothelial growth factor secretion and gradient generation, both crucial elements of regenerative angiogenesis in early nerve repair. In this way, we provide a first proof-of-concept of a digital twin for nerve tissue engineering, which uses in silico, in vitro and in vivo repair models.