Engineering cell-derived extracellular matrix for peripheral nerve regeneration

Extracellular matrices (ECMs) play a key role in nerve repair and are recognized as the natural source of biomaterials. In parallel to extensively studied tissue-derived ECMs (ts-ECMs), cell-derived ECMs (cd-ECMs) also have the capability to partially recapitulate the complicated regenerative microenvironment of native nerve tissues. Notably, cd-ECMs can avoid the shortcomings of ts-ECMs. Cd-ECMs can be prepared by culturing various cells or even autologous cells in vitro under pathogen-free conditions. And mild decellularization can achieve efficient removal of immunogenic components in cd-ECMs. Moreover, cd-ECMs are more readily customizable to achieve the desired functional properties. These advantages have garnered significant attention for the potential of cd-ECMs in neuroregenerative medicine. As promising biomaterials, cd-ECMs bring new hope for the effective treatment of peripheral nerve injuries. Herein, this review comprehensively examines current knowledge about the functional characteristics of cd-ECMs and their mechanisms of interaction with cells in nerve regeneration, with a particular focus on the preparation, engineering optimization, and scalability of cd-ECMs. The applications of cd-ECMs from distinct cell sources reported in peripheral nerve tissue engineering are highlighted and summarized. Furthermore, current limitations that should be addressed and outlooks related to clinical translation are put forward as well.