Electrical stimulation and stem cell subdural implantation decrease microglia reactivity after spinal cord injury

Background: Contusive spinal cord injury (SCI) leads to severe and permanent motor, sensory, and autonomic deficits, resulting from both the initial mechanical damage and subsequent secondary pathological cascades. Besides, electrical stimulation (ES) and stem cell therapies have emerged as promising strategies to promote axonal regeneration and neuronal plasticity. Methods: We designed a new implantable device, an Electro Pulsed Biohybrid (EPB) device, to provide local ES and carry stem cells (hMSC and iNSC) for subdural implantation, wired and wireless controlled. We assessed locomotion and sensory outputs, cell migration, neuroinflammation, gliosis, fibrosis, and neuronal survival. Results: The consecutive application of microsecond pulsed electric fields (μsPEFs) into two different configurations during ten days and further continuous current during five days significantly enhanced the migration and engraftment of the implanted hMSC and a significant reduction in the number of microglia injury-dependent reactive cells. The ES did not exacerbate gliosis, fibrosis, neuropathic pain, or neuronal loss after primary trauma, instead, the electrically stimulated animals in comparison with the non-stimulated controls were able to perform better reducing the time during running. Consistent results were obtained with a wireless and wired configuration for the ES supply. Conclusions: The applied sequence of μsPEFs and direct current local stimulation contributed to the early immunomodulation, reducing the acute immunoreactivity involved in further secondary damage, and enhanced implanted hMSC migration, providing a versatile platform for cell therapy and ES combinatorial approach in the SCI treatment.