Table 1.

Selected Examples of Neural Scaffolds with Natural Biomaterials for Cell Delivery

Natural Polymers	Structure	Cell Type	Injury Model	Outcomes	Pros/Cons
Acellular Nerve Graft (Jesuraj et al., 2014)	Nerve Graft	SC	Rat 14mm sciatic nerve gap	Histology: SC seeded acellular nerve graft (ANGs) showed comparable fiber numbers to isograft and superior to ANGs alone middle and distal to the graft. Behavior: Muscle force evoked in e xtensor digitorum longus reveal similarly functional recovery between SC seeded ANGs and isograft and superior to ANGs alone.	Pros: Intact endoneurial microstructures can guide regenerating axons. Support equal axonal growth regardless of whether SC source match ANG source. Cons: Nerve fiber width was smaller than isograft, indicating immaturity. May be correlated with the removal of other cues during ANG processing.
Collagen (Ansselin et al., 1997)	Conduit with Kevlar mesh	SC	Rat 18mm sciatic nerve gap	Histology: Number of myelinated fibers was higher in SC seeded collagen guide than un-operated control. Behavior: Nerve conduction velocity in SC seeded collagen guide was approaching un-operated level. SFI showed ~ −70 with cell-seeded guide but compare with autograft or un- operated control. Nerve conduction velocity was 60% of un- operated controls.	Pros: Repaired large in jury gaps with myelinated axons in the distal stump Cons: Survival of transplanted SCs at <5×105 seem to be poor. May be indication of insufficient growth support of collagen and Kevlar fiber mesh. No significant functional recovery was reported.
Collagen (Udina et al., 2004)	Conduit with Matrigel	SC	Mouse 6mm Sciatic nerve gap	Histology: SC-seeded collagen conduits with FK506 treatment showed the highest nerve diameter and number of myelinated a xons in the middle and distal of the guide. Behavior: FK506 treated SC scaffold retained ~70% of pain sensitivity of un-operated animal and 50% of sympathetic sudomotor function estimated by sweating.	Pros: Effective regeneration with allogenic SCs supplemented with immunosuppressant. Cons: Required immunosuppression throughout study. Matrigel filler is not suitable for clinical use.
Collagen (Hatami et al., 2009)	Gel with 25–30 neural- like tubes	hESC- derived neural progenito r cells (NPCs)	Rat thoracic lateral hemisecti on SCI	Histology: Transplanted NPCs showed positive stain for nestin, MAP2, and GFAP 5 weeks post-transplantation. Only about 5% of cells were positive for Ki67. No sign of tumor was observed after 1 year. Behavior: Groups with cell-seeded scaffold showed improved hindlimb locomotor function compared to sham and lesion control, though not very pronounced. Sensory function was also significantly better than other groups.	Pros: Maintained survival and differentiation state of NPCs. Migrations of NPCs out of graft area were observed. No tumor indication after 1 year. Cons: No data were reported on glial scar reduction. Scaffold was not present 5 weeks after implantation, which may be insufficient time for nerve regeneration.
Laminin & Fibronectin (Gonzalez- Perez et al., 2017b)	Tethered to collagen gel in chitosan conduit	SC	Rat 15mm sciatic nerve gap	Histology: Number of myelinated fibers increased in SC seeded laminin - and fibronectin-tethered scaffolds compared to acellular scaffold at midlevel and distal level. Behavior: Muscle action potentials with laminin- and fibronectin-tethered scaffolds were comparable to autograft. Sensitivity recovery was not obvious. Fibronectin modified scaffold seemed to result in better muscle action potential and higher number of myelinated axons than that of laminin.	Pros: Alignment of ECM directed transplanted cell alignment. Cons: Limited sensory improvement. Locomotor function evaluation was not reported.
Fibrin (Johnson et al., 2010a)	Cell embryoid body (EB) encapsulat ed in spherical gel	mESC- derived NPCs	Rat thoracic dorsal hemisec tion SCI	Histology: Neuron maturation marker Neu N was significantly higher in cellular-graft with growth factors and no heparin binding system. This group also showed the highest survival and proliferation 8 weeks post transplantation. Over- proliferations of transplanted cells were observed. Behavior: Grid walk analysis showed graft with cellular-graft with growth factors and no heparin binding system had significantly less missed steps compared to other groups.	Pros: Demonstrated survival and differentiation of NPCs after transplantation. Easily conformed to the lesion shape. Cons: NPCs over-proliferated and formed tumors.
Fibrin (McCreedy et al., 2014)	EBs suspended in gel	mESC- derived progenitor r Motor neurons (pMN)	Rat thoracic dorsal hemisec tion SCI	Histology: Fibrin-based scaffold showed good host-tissue integration with minimal scarring, and migration of transplanted cells into host tissue was frequently observed. Behavior: Not reported.	Pros: Minimal scarring tissue was observed. Highly purified pMN population did not show tumor formation. Cons: pMN might be better suited for ventral injury model. No functional testing was reported.
Fibrin (Kalbermat ten et al., 2008)	Gel in polyhydro xybutyrate (PHB) conduit	SC	Rat 10mm sciatic nerve gap	Histology: Fibrin-based scaffold showed highest axonal outgrowth and SC penetration compared to acellular group and empty conduit. Highest regeneration distance was ~3.5 mm. Behavior: Not reported.	Pros: Fibrin improved cell adhesion to PHB conduit. Cons: Short regeneration distance even with transplanted SCs. This suggests other growth-promoting cues may be needed.
HA (Zhang et al., 2008)	HA- collagen composite in collagen conduit	NSC	Rabbit facial 5mm nerve gap	Histology: Number and area of myelinated fibers in NSC seeded scaffold was comparable to un-operated control. Myelin sheath thickness was also comparable. Behavior: Progressive decrease in current threshold and increase in voltage amplitude of lip muscles in response to a stimulus in treated groups.	Pros: HA provide high surface area and porosity for cell adhesion. Collagen provide mechanical strength needed for PNI regeneration. The clearance rate of the scaffold was primarily in phase with that of regeneration. Cons: Degeneration and swelling of myelin lamellae was evident and is not desirable for recovery.
HA (Mothe et al., 2013)	Hydrogels (HAMC)	NSC with rPDGF	Rat compressio n SCI at level T2 with a 26 g force for 1 min	Histology: NSC transplanted in HAMC-rPDGF showed significantly reduced lesion cavity and increased neuron sparing. NSCs survival was also increased in HAMC- PDGF scaffold. Behavior: BBB locomotor score was not improved compared to cell only control. Number of footfalls decreased in ladder-walk test 7 weeks post-transplant.	Pros: Easy manipulation as HAMC is injectable. Have antioxidant properties that may reduce the flux of free radicals; hence, reduced lesion cavity and increased host cell sparring. Cons: Incorporation of rPDGF did not maintain differentiation profiles of NSC in vivo compared to in vitro.
HA (Thompson et al., 2018)	Hydrogels incorporat ed with astrocyte ECM	ESC- derived V2a interneur on	Rat thoracic dorsal hemisection SCI	Histology: Incorporation of protoplasmic astrocyte-derived ECM increased V2a a xon e xtension within lesion, decreased GFAP+, and ED1+ areas of the surrounding lesion. Behavior: Not reported.	Pros: Decrease in CSPG may be related to HA. Incorporated cell derived ECM and showed improved a xon outgrowth and reduced lesion reactivity. Cons: Did not seem to reduced GFAP levels within lesion.
Alginate (Mosahebi et al., 2003)	Matrix in poly-3- hydroxyb utyrate (PHB) conduit with fibronecti n	SC	Rat 10mm sciatic nerve gap	Histology: Alginate conduit with SC and fibronectin increased axon regeneration distance compared to other groups 3 weeks post-transplantation. By 6 weeks, a xons were able to cross the entire conduit and reach the distal nerve stump. Behavior: Not reported.	Pros: Fibronectin improved SC survival. Cons: Although axons showed good regeneration and reached distal stump, no functional results were reported. Degradation of the scaffold was also not mentioned.
Silk-fibroin (Tang et al., 2014)	Coating PCLA conduit with Immobiliz ed NT-3	NSC	Rat thoracic complete transection SCI	Histology: Addition of NT-3 increased NSC survival to ~75% compared with no-factor control (~27%). An increase in MAP2 and a decrease in GFAP positive cells were observed. Neurofilament positive a xons also increased in Conduit+NT-3+NSCs group. Behavior: BBB locomotor score of Conduit+NT-3+NSCs group was significantly improved compared to cell alone or NT-3 alone conduit group	Pros: Immobilized NT-3 on silk-fibroin had a slow releasing profile. Cons: Implanting PLGA conduit required the complete transection of the spinal cord, which was undesirable as more damage was introduced.