Ultrasound-activated piezoelectric hydrogel with schwann cell–derived extracellular vesicles enhances neural cell activities: An in vitro study

Peripheral nerve injury (PNI) often leads to incomplete functional recovery because the regulation of the regenerative microenvironment is insufficient. To address this issue, we developed a photopolymerized composite hydrogel (GelMA-SC-EVs-BTO, GSB), which integrates barium titanate (BaTiO₃, BTO) nanoparticles and Schwann cell-derived extracellular vesicles (SC-EVs) into the GelMA matrix, aiming to provide synergistic ultrasound-activated piezoelectric stimulation and continuous EV-mediated biological activity. Physical and chemical property analysis confirmed its porous structure, uniform barium/titanium distribution, stable piezoelectric response (d₃₃ increase, repeatable on/off current output), and continuous release of SC-EVs. In vitro experiments showed that a widely applied neuronal ND cell line (ND7/23) could effectively uptake SC-EVs and exhibit good cell compatibility on the hydrogel under ultrasound stimulation. Functionally, GSB combined with ultrasound could significantly enhance neuronal migration and neurite growth, while upregulating the expression of neurorepair-related markers (MBP, GFAP, GAP-43) and neurotrophic factors (NGF, BDNF). Mechanistically, the pro-regenerative effect is associated with a strong activation of autophagic flux, which is reflected by elevated Atg5/Beclin1/Map1lc3b expression levels, increased LC3B-II formation, decreased p62 levels, and increased punctate aggregation of LC3B. In summary, these findings indicate that ultrasound-activated piezoelectric microcapsule hydrogels establish a microenvironment with bioelectric and biochemical guidance to promote neural cell activities, highlighting its potential as an intelligent biomaterial platform for peripheral nerve regeneration.