A Novel Superparamagnetic Multifunctional Nerve Scaffold: A Remote Actuation Strategy to Boost In Situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair

Extracellular vesicles (EVs) have inherent advantages over cell-based therapies in regenerative medicine because of their cargos of abundant bioactive cues. Several strategies are proposed to tune EVs production in vitro. However, it remains a challenge for manipulation of EVs production in vivo, which poses significant difficulties for EVs-based therapies that aim to promote tissue regeneration, particularly for long-term treatment of diseases like peripheral neuropathy. Herein, a superparamagnetic nanocomposite scaffold capable of controlling EVs production on-demand is constructed by incorporating polyethyleneglycol/polyethyleneimine modified superparamagnetic nanoparticles into a polyacrylamide/hyaluronic acid double-network hydrogel (Mag-gel). The Mag-gel is highly sensitive to a rotating magnetic field (RMF), and can act as mechano-stimulative platform to exert micro/nanoscale forces on encapsulated Schwann cells (SCs), an essential glial cell in supporting nerve regeneration. By switching the ON/OFF state of the RMF, the Mag-gel can scale up local production of SCs-derived EVs (SCs-EVs) both in vitro and in vivo. Further transcriptome sequencing indicates an enrichment of transcripts favorable in axon growth, angiogenesis, and inflammatory regulation of SCs-EVs in the Mag-gel with RMF, which ultimately results in optimized nerve repair in vivo. Overall, this research provides a noninvasive and remotely time-scheduled method for fine-tuning EVs-based therapies to accelerate tissue regeneration, including that of peripheral nerves. A Mag-gel with applied rotating magnetic field (RMF) serves as a mechano-stimulative platform to exert micro/nanoscale forces to nearby Schwann cells, which can subsequently scale up local extracellular vesicles (EVs) production both in vitro and in vivo. As a non-invasive strategy, application of an RMF to manipulate the local EVs production via the Mag-gel offers a remote time-scheduled approach to optimize the process of peripheral nerve regeneration.image

Automated summary

A superparamagnetic nanocomposite scaffold is developed to control the production of extracellular vesicles (EVs) by applying a rotating magnetic field. This non-invasive and remotely time-scheduled method accelerates tissue regeneration, including that of peripheral nerves.