Newly regenerated axons through a cell-containing biomaterial scaffold promote reorganization of spinal circuitry and restoration of motor functions with epidural electrical stimulation

Abstract

We report the effect of newly regenerated neural fibers via bioengineered scaffold on reorganization of spinal circuitry and restoration of motor functions with electrical epidural stimulation (EES) after spinal transection (ST). Restoration across multiple modalities was evaluated for 7 weeks after ST with implanted scaffold seeded with Schwann cells, producing neurotrophic factors and with rapamycin microspheres. Gradual improvement in EES-facilitated stepping was observed in animals with scaffolds, although, no significant difference in stepping ability was found between groups without EES. Similar number of regenerated axons through the scaffolds was found in rats with and without EES-enabled training. Re-transection through the scaffold at week 6, reduced EES-enabled motor function, remaining higher compared to rats without scaffolds. The combination of scaffolds and EES-enabled training demonstrated synaptic changes below the injury. These findings indicate that sub-functional connectivity with regenerated across injury fibers can reorganize of sub-lesional circuitry, facilitating motor functions recovery with EES.

Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment

“…An intraspinal injection of adenoviral vector carrying cDNA encoding GDNF into the injured spinal cord had a positive effect on functional recovery in rats with SCI [26]. Recently, in our study of Schwann cells producing recombinant GDNF were used in a bioengineered scaffold to promote axons regeneration after a complete SCI [27].…”

New Therapy for Spinal Cord Injury: Autologous Genetically-Enriched Leucoconcentrate Integrated with Epidural Electrical Stimulation

“…For example, for SCI treatment, fibroblasts producing NGF [ 18 ] and NT-3 [ 19 ], Schwann cells producing NT-3 [ 20 ] and NCAM [ 21 ], oligodendrocyte precursor cells producing CNTF [ 22 ], neural progenitor cells producing NT-3 [ 23 ], mesenchymal stem cells producing BDNF [ 24 ], olfactory ensheathing cells producing GDNF [ 25 ], and many other combinations have been developed. The severity and complexity of SCI requires a combination of multiple techniques to cover different mechanisms of injury [ 26 ]. The rationale for the combination of multiple therapies is based on possible synergistic effects of each therapy on a specific target, which altogether results in positive outcomes in post-traumatic spinal cord morpho-functional recovery.…”

The Translesional Spinal Network and Its Reorganization after Spinal Cord Injury

“…Our recent animal data indicate that the supralesional network can influence stepping performance facilitated with EES through the fibers regenerating across the scaffold, while animals with scaffold and with no EES showed only minimal motor recovery (Siddiqui and others 2020). Animals receiving EES in association with hydrogel scaffolds delivering rapamycin and GDNF-secreting Schwann cells, developed newly regenerated fibers through the scaffold, and demonstrated clear improvement in stepping (Chen and others 2018; Hakim and others 2019).…”