Table 1.

Combination strategies regulate eNSPCs to promote endogenous neurogenesis after SCI

Reference	Injure model	Combination strategy	Delivery method	Outcome
Ohori et al., 2006162	T10 spinal cord complete transection rat model	EGF, FGF2, and overexpression of Ngn2	Direct administration to injured tissue	Led to a large number of mature newborn neurons.
Li et al., 2016163	T10 spinal cord complete transection rat model	MAIs inhibitors (EphA4LBD, PlexinB1LBD, NEP1-40), BDNF, and NT-3	Implantation of a LOCS	The full combinatorial therapy exhibited the greatest advantage for reducing the cavitation volumes, facilitating axonal regeneration, neuronal regeneration, revascularization and enhancing locomotion recovery.
		cAMP (Promotes axon regeneration)	Direct administration to uninjured tissue
Fan et al., 2018164	T10 spinal cord complete transection rat model	Cetuximab and PTX	Implantation of a LOCS	Cetuximab inhibited EGFR signaling, which was activated by MAIs, and PTX promoted neuronal differentiation of eNSPCs. The scaffold significantly increased endogenous neurogenesis and reconstructed the neural network in a 4-mm section of excised spinal cord tissue.
Wang et al., 2019126	T10 spinal cord contusion rat model	Polysialic acid (PSA) and minocycline (MC)	Intravenous injection of a PSA nanodrug delivery system	PSA promoted NSPC migration, axon path finding, and synaptic remodeling. Minocycline improved neuroinflammation. The combination promoted the regeneration of neurons and the extension of long axons throughout the glial scar, thereby largely improving the locomotor function of SCI rats.
Ma et al., 2020133	T7-8 spinal cord complete transection mice model	PLX3397 and gelatin hydrogel	Implantation of a gelatin hydrogel	The combination strategy replaced the prolonged, activated microglia/macrophages via cell depletion and repopulation. The improved microenvironment led to the promotion of eNSPC neurogenesis and improvement of functional recovery.
Liu et al., 202030	T9 spinal cord complete transection rat model	Regeneration factor “cocktail” (BDNF, bFGF, NT-3, IGF, GDNF, β-NGF, CNTF, aFGF, EGF, PDGF-AA)	Implantation of a self-assembling peptide (F-SAP) nanofiber hydrogel scaffold	Facilitated eNSPC proliferation, neuronal differentiation, maturation, and myelination, and formed interconnection with severed descending corticospinal tracts.
Chen et al., 202176	T8 spinal cord complete transection rat model	PTX and “middle-to-bilateral” gradient release of SDF1α	Implantation of an aligned collagen-fibrin (Col-FB) fibrous hydrogel	The “middle-to-bilateral” gradient delivery of SDF1α directed eNSPC migration from the stumps of a transected nerve toward the defect site, and PTX promoted neuronal differentiation of eNSPCs.
Zhang et al., 202191	T8 spinal cord complete transection rat model	Exosomes extracted from human umbilical cord-derived mesenchymal stem cells (MExos) and PTX	Implantation of a LOCS	MExos promoted the migration of eNSPCs, LOCS to retain eNSPCs, and PTX directed eNSPC differentiation into more neurons. The multifunctional scaffold showed the ability for promotion of motor functional recovery by enhancing neurogenesis and reducing glial scarring.
Yang et al., 2021165	T8 spinal cord complete transection mice model	LDN193189, SB431542, CHIR99021 and P7C3-A20	Administration of an injectable collagen hydrogel	The combination of small molecules doped with collagen hydrogel promoted migration, induced neurogenesis and inhibited astrogliogenesis of eNSPCs in the injury site, leading to a small recovery of locomotion.
Liu et al., 2021166	T10 spinal cord hemisecting transection rat model	NGF, soft thermosensitive polymer electroactive hydrogel (TPEH), and functional electrical stimulation (ES)	Implantation of a TPEH	NGF, electroactive hydrogel, and ES can all induce endogenous neurogenesis. Their combination provided powerful stimulation for eNSPCs to differentiate into neurons, resulting in effective functional repair.
Zhu et al., 2021144	T8-9 spinal cord complete transection mice model	Mg/Al layered double hydroxide (Mg/Al-LDH) nanoparticles and NT-3	Implant the LDH clay biomaterials	LDH possess a great property to improve inflammatory environment and NT-3 provide the nutritional support for eNSPCs neurogenesis. The combination of them exhibited more new-born neurons in lesion core and better locomotor function recovery than LDH itself.
Fan et al., 2022167	T9-10 spinal cord hemisecting transection mice model	BMSC-Exo and electroconductive hydrogels	Implantation of an electroconductive hydrogel composed of photocrosslinkable gelatin methacrylate hydrogels and PPy hydrogels	BMSC-Exo can reduce inflammation induced by electroconductive hydrogel. In addition, the combination strategy significantly decreased the number of CD68-positive microglia and enhanced eNSPC recruitment and neuronal differentiation, resulting in significant functional recovery.
Xie et al., 2022168	T9 spinal cord hemisecting transection mice model	Purmorphamine (PUR, a SHH signaling agonist), retinoic acid (RA), and magnesium oxide (MgO)/poly(L-lactide-co-ε-caprolactone) (PLCL) scaffold	Implantation of a PLCL scaffold	SHH and RA induced eNSPCs recruitment and neuronal differentiation. PLCL released Mg2+ to promote cell survival by blocking the calcium influx. The combination strategy led to the recovery of locomotor function of SCI mice.