Harnessing wireless electrical stimulation and silk-based conductive hydrogels to boost iPSC-derived astrocytes neuroprotection and guide macrophage polarisation in vitro for spinal cord repair.

Spinal cord injury (SCI) remains a major clinical challenge due to its complex pathophysiology and lack of effective treatments. While electrical stimulation (ES) offers therapeutic potential for promoting neural repair, its clinical translation is limited by the invasiveness of conventional systems. Here, we report a non-invasive wireless electrical stimulation (WES) platform based on charge polarisation-induced capacitive coupling, enabled by a conductive silk fibroin/PEDOT:PSS (SF/PEDOT) hydrogel. SF/PEDOT hydrogels exhibit a tuneable mechanical stiffness (2-120 kPa), injectable delivery (<5 N injection force), and electrical conductivity (∼0.3 S/m) closely matching the spinal cord. This hydrogel platform has low charge transfer resistance and enhanced capacitive behaviour, supporting efficient non-invasive capacitive coupling for secondary field transduction at low frequencies (∼10 kHz). Using this WES system, we demonstrated modulation of human blood-derived macrophages (hBDMs) toward a reparative phenotype, while downregulating pro-inflammatory markers even under inflammatory conditions. In parallel, hiPSC derived cortical astrocytes (CTX-ASTRO) encapsulated within SF/PEDOT hydrogels showed enhanced functional maturation under WES, evidenced by upregulated connexin 43 (Cx43) gap junction protein expression. In an in vitro SCI-like model of reactive astrogliosis, WES via SF/PEDOT partially mitigated astrocytic reactivity by reducing CXCL10, GM-CSF, and IL-6 secretion and increasing Cx43 expression. Conditioned media from WES treated CTX-ASTRO further suppressed pro-inflammatory activation of hBDMs. Together, these results provide the first evidence of the dual neuroprotective and immunomodulatory potential of a non-invasive, conductive hydrogel-based WES platform, validated using two human cell types specific to SCI pathophysiology. Thus, this approach offers a minimally invasive, translationally relevant solution for spinal cord repair via non-invasive neuromodulation.