| SCI |
| GelMA hydrogel |
iNSCs |
– |
• functional recovery
promotion |
(67) |
| |
|
|
• cavity area
reduction |
|
| |
|
|
• reduction of inflammation |
|
| |
|
|
• axonal regeneration
promotion |
|
| pHEMA hydrogel |
NSCs |
serotonin |
• acceleration of cellular
differentiation in vitro/in vivo
|
(68) |
| |
|
|
• initial reduction of
tissue atrophy and glial scar formation |
|
| |
|
|
• nonideal long-term support for cellular growth and differentiation |
|
| CSMA hydrogel |
NSCs |
– |
• controlled differentiation
of NSCs in vitro/in vivo
|
(69) |
| |
|
|
• cavity area reduction |
|
| |
|
|
• neurogenesis and functional
recovery promotion |
|
| methacrylamide
scaffold contained in a chitosan channel (nerve conduit) |
NPCs |
interferon-g (IFN-g), platelet
derived growth factor-AA (PDGF-AA), or bone morphogenic protein-2 (BMP-2) growth factor |
• only in vitro results:
NSPC differentiation is maintained at functionally significant
levels for 28 days |
(70) |
| |
|
|
• growth factor immobilization
induced the majority of cells to differentiate into desired cell types
as compared with adsorbed growth factor treatments and controls by
day 28 in vivo
|
|
| collagen and fibrin hydrogels |
MSCs |
– |
• functional recovery
promotion |
(71) |
| |
|
|
• no significant
differences
between collagen and fibrin hydrogels in terms of functional recovery |
|
| Col–HA–Lam hydrogel |
NPCs |
– |
• lesion size reduction |
(72) |
| |
|
|
• functional recovery
promotion |
|
| |
|
|
• longer-term response
examination is needed |
|
| hyaluronan
and methyl cellulose (HAMC) hydrogel |
NSCs/NPCs |
recombinant rPDGF-A |
• functional recovery
promotion |
(73) |
| |
|
|
• cavity area
reduction |
|
| |
|
|
• improvement of graft
survival |
|
| HAMC–RGD peptide hydrogel |
hiPSCs |
PDGF-A |
• early survival and
integration of cell promotion |
(74) |
| |
|
|
• cell differentiation
promotion and attenuation of teratoma formation (when cells were transplanted in the hydrogel) |
|
| |
|
|
• teratoma formation
when cells were transplanted in media |
|
| fibrin hydrogel |
ESCs |
neurotrophin-3 (NT3) and PDGF-AA or NT3 and GDNF |
• improvement of cell
survival with a delayed transplant |
(75) |
| |
|
|
• cellular differentiation
promotion |
|
| |
|
|
• the presence
of growth
factors did not appear to influence survival or proliferation of transplanted
cells |
|
| MC hydrogel |
hiPSCs |
chondroitinase ABC (chABC) |
• lesion cavity
reduction |
(76) |
| |
|
|
• no motor function
improvement |
|
| |
|
|
• chABC favored neuronal
survival and differentiation |
|
| gellan gum (GG)–GRGDS peptide
hydrogel |
adipose stromal stem cells (hASCs) and murine olfactory ensheathing cells (OECs) |
– |
• GG–GRGDS hydrogel
is suitable for cellular culture |
(77) |
| |
|
|
• neurite/axonal outgrowth
promotion in vitro
|
|
| |
|
|
• significant motor and
histological improvements in vivo
|
|
| HA–PPFLMLLKGSTR peptide
hydrogel |
MSCs |
– |
• improved cellular survival
and adhesive growth in vitro
|
(78) |
| |
|
|
• scaffold and MSCs are
found to function in synergy |
|
| |
|
|
• injured spinal cord
tissue restoration and motor functions improvement |
|
| poly(acrylic acid)/agarose/PEG (AC PEG) and AC PEG–RGD peptide hydrogels with 3D ECM deposition |
hMSCs |
– |
• immunomodulation of
the pro-inflammatory environment in
a SCI mouse model promoting a proregenerative environment in situ |
(79) |
| poly(sebacoyl diglyceride) (PSeD)–IKVAVS peptide scaffold |
NSCs |
– |
• reduction of direct
stimulation to spinal cord tissue by PSeD elastomer |
(80) |
| |
|
|
• reduction of immune
response of spinal cord tissue and of scar tissue formation |
|
| |
|
|
• increase of locomotor
recovery |
|
| |
|
|
• IKVAVS peptide creates
a bioactive interface to support NSC growth and differentiation |
|
| alginate-base anisotropic capillaries |
MSCs |
– |
• higher number of axons
expressing BDNF in the hydrogel compared to control cells |
(81) |
| |
|
|
• nonsignificant differences
in the number of regenerating axons increasing the channel diameter |
|
| |
|
|
• the anisotropic structure
can physically guide regenerating axons |
|
| PGA fibers |
NPCs |
– |
• lesion volume reduction |
(82) |
| |
|
|
• survival, engraftment,
and differentiation of grafted cell promotion |
|
| |
|
|
• neovascularization increase |
|
| |
|
|
• glial scar formation
inhibition |
|
| |
|
|
• neurite outgrowth and
axonal extension within the lesion site promotion |
|
| |
|
|
• significant improvement
of motosensory function |
|
| |
|
|
• neuropathic pain attenuation |
|
| PLGA–PEG fibers with
gelatin sponge coating |
iNSCs |
– |
• survival, engraftment,
and differentiation of grafted cell promotion |
(83) |
| |
|
|
• functional recovery
promotion |
|
| Matrigel (nanofibrous scaffold) |
human endometrial-derived stromal
cells (hEnSCs) |
– |
• differentiation of
encapsulated hEnSCs toward neuronlike cells after 14 days posttreatment |
(84) |
| |
|
|
• significantly higher
cellular viability in Matrigel compared with 2D cell culture |
|
| |
|
|
• damaged tissue reconstruction |
|
| |
|
|
• decrease of cavity
size, degree of necrosis, and number of glial and inflammatory cells
around the injury site |
|
| |
|
|
• significant improvement
in motor function of the injured animals |
|
| QL6 peptide scaffold (nanofibrous) |
NPCs |
– |
• QL6 SAP injection into
the SCI site 24 h after trauma, NPC
transplantation 14 days after trauma |
(85, 86) |
| |
|
|
• QL6 scaffold shaped
the hostile posttraumatic microenvironment improving transplant conditions (NPCs surviving) |
|
| |
|
|
• astrogliosis and tissue-scarring reduction |
|
| |
|
|
• significant recovery
of forelimb neural function |
|
| HYDROSAP peptide scaffold (nanofibrous) |
hNSCs |
– |
• formation of an entangled
network of mature and functional neural phenotypes with 3D cell culture
model |
(87) |
| |
|
|
• astrogliosis and immune
response reduction |
|
| |
|
|
• scaffolds with predifferentiated
hNSCs showed higher percentages of neuronal markers, better hNSC engraftment,
and improved behavioral recovery with respect to hNSC-derived progenitors |
|
| CQIK–RADA4 peptide scaffold (nanofibrous) |
hEnSCs |
– |
• CQIK induces hEnSC
transformation to neurallike cell after 10 days postincubation in vitro
|
(88) |
| |
|
|
• significant motor recovery,
neurogenesis, and antiastrogliosis potential |
|
| RADA16 peptide scaffold (nanofibrous) |
human cerebral microvascular endothelial cells (HCMEC/D3) |
– |
• cellular growth, proliferation,
and migration within the scaffold |
(89) |
| |
|
|
• vascularization and
axon growth support |
|
| |
|
|
• glial scar, inflammation,
and immune response minimization |
|
| RADA16–RGD peptide scaffold (nanofibrous) |
MSCs |
– |
• MSC and neuron survival
improvement |
(90) |
| |
|
|
• inflammatory reaction
inhibition |
|
| |
|
|
• functional behaviors
promotion |
|
| NeuroRegen (collagen) scaffold |
MSCs |
– |
• no adverse events observed
during 1 year of follow-up |
(91, 92) |
| |
|
|
• recovery of sensory
and motor functions |
|
| |
|
|
• recovery of interrupted
neural conduction |
|
| TBI |
| sodium alginate (SA) and
HA
hydrogel |
MSCs |
– |
• high cellular viability
and proliferation within the scaffold in vitro
|
(95) |
| |
|
|
• cell protection from
the injury environment |
|
| |
|
|
• cellular survival improvement in vivo
|
|
| |
|
|
• endogenous nerve cell
regeneration |
|
| HA hydrogel |
MSCs |
NGF |
• hydrogel implantation
provides a positive nutrition supply for cell survival and proliferation |
(96) |
| |
|
|
• significant promotion
of functional recovery of motor, learning, and memory abilities |
|
| |
|
|
• acceleration of the
healing process of damaged brain tissues |
|
| |
|
|
• neuroinflammation and
apoptosis suppression |
|
| chitosan/heparin-modified fibronectin
hydrogel |
radial glial cells (RGCs) |
FGF-2 |
• the hydrogel can be
used as a cellular and growth factor delivery vehicle to promote the
regeneration of nervous tissue |
(97) |
| |
|
|
• more detailed in vivo studies are
required to assess cellular survival
and differentiation as well as detailing the extent of anatomical
and functional recovery |
|
| polyurethane
gel |
NSCs |
– |
• favorable proliferation
and differentiation of cells within the scaffold |
(98) |
| |
|
|
• repair of damaged CNS
and functional recovery promotion in vivo
|
|
| PGA fibers |
NPCs |
– |
• lesion volume reduction |
(82) |
| |
|
|
• survival, engraftment,
and differentiation of grafted cell promotion |
|
| |
|
|
• neovascularization increase |
|
| |
|
|
• neurite outgrowth and
axonal extension within the lesion site promotion |
|
| |
|
|
• connection of damaged
neural circuits improvement |
|
| RADA16–IKVAV peptide
scaffold (nanofibrous) |
NSCs |
– |
• NSC proliferation and
differentiation promotion |
(99) |
| |
|
|
• in situ support and bridging of damaged brain wounds |
|
| RADA16–RGIDKRHWNSQ peptide
scaffold (nanofibrous) |
MSCs |
– |
• BDNF-derived peptide (RGIDKRHWNSQ) introduced to promote neurotrophy,
cell proliferation, neuronal differentiation, and neurite outgrowth |
(100) |
| |
|
|
• brain cavity and surrounding
reactive gliosis reduction |
|
| |
|
|
• large cavity repair
is not promoted |
|
| Stroke |
| heparin-modified HA–RGD, YIGSR, IKVAV peptide hydrogel |
iPSCs and NPCs |
BMP-4 and BDNF growth factors |
• in vivo promotion of cell survival and differentiation
after transplantation
into the stroke core |
(105) |
| HA–RGD peptide hydrogel |
iPSCs and NPCs |
– |
• differentiation of
the neural progenitor cells to neuroblasts promotion |
(106) |
| |
|
|
• stem cell viability 1 week posttransplantation nonpromotion |
|
| HAMC hydrogel |
NSCs |
|
• cell survival improvement (due to HA) |
(107) |
| |
|
|
• better cellular depth
of penetration and distribution (due to MC) |
|
| |
|
|
• significant behavioral
recovery in the animal model of stroke |
|
| HAMC hydrogel |
cortically specified neuroepithelial
progenitor cells (cNEPs) |
– |
• greater and faster
functional repair with undifferentiated progenitor cells |
(108) |
| |
|
|
• great tissue damage,
acute cell death during the transplantation process and no functional
repair with late differentiated cell injection |
|
| silk fibroin self-assembling hydrogel |
MSCs |
– |
• longer period cell
engraftment within the scaffold |
(109) |
| |
|
|
• cortical damage reduction
and progressive and significant recovery in stroke mice |
|
| DDIKVAV peptide scaffold (nanofibrous) |
hESCs |
– |
• structural and functional
support of neural grafts in a stroke model |
(110) |
| |
|
|
• cell graft differentiation
and integration promotion |
|
| |
|
|
• host tissue atrophy
reduction resulting in improved motor function over a period of 9 months |
|
| polypyrrole scaffold |
hNPCs |
– |
• functional outcome improvement with NPCs electrically
preconditioning |
(111) |
| PD |
| HA–RGD–heparin hydrogel |
hESC-derived midbrain dopaminergic
neuron |
– |
• cell replacement enhancement |
(116) |
| |
|
|
• alleviation of disease
symptoms |
|
| agarose hydrogel
microcolumns with ECM coating |
dopaminergic neurons with
long axonal tracts |
– |
• dopamine is released
by the transplanted neurons |
(117) |
| |
|
|
• simultaneous replace
of dopaminergic neurons in the substantia nigra and physical reconstruction
of their long axonal tracts to the striatum |
|
| PLLA short nanofibers embedded within a thermoresponsive
xyloglucan
hydrogel |
ventral midbrain (VM) dopamine
progenitors |
GDNF |
• no deleterious impact
on the host immune response in vivo
|
(118) |
| |
|
|
• survival and integration
of grafted neurons enhancement |
|
| |
|
|
• reinnervation of the
striatum |
|
| minimalist N-fluorenylmethyloxycarbonyl (Fmoc)–DIKVAV peptide scaffolds (nanofibrous) |
VM cell grafts |
GDNF |
• DIKVAV introduced to
promote neural differentiation and neurite elongation |
(119) |
| |
|
|
• GDNF introduced to
promote survival and neurite extension of neuron grafts |
|
| |
|
|
• sustained release of
GDNF up to 172 h after gel loading |
|
| |
|
|
• improvement of graft
survival in vivo
|
|
| self-assembling amyloid proteins
hydrogel (nanofibrous) |
hMSCs |
– |
• promotion of MSCs differentiation in vitro/in vivo toward
a neuronal lineage without the addition of growth factors |
(120) |
| |
|
|
• nontoxic hydrogel |
|
| |
|
|
• no excessive immune
response |
|
| |
|
|
• optimal cellular containment
at injury site and improved survival in vivo
|
|
| collagen hydrogel |
NSCs |
collagen-binding LG3 (CLG3) and histidine tagged LP (HLP), an integrin-binding protein complex |
• NSC viability improvement
in the early stage after transplantation into the striatum due to
integrin ligation and microglial infiltration suppression |
(121) |
| AD |
| RADA16–YIGSR peptide
scaffold (nanofibrous) |
NSCs |
– |
• cellular migration,
survival, and neuronal differentiation improvement |
(126) |
| |
|
|
• decrease of the neuronal
apoptosis and synaptic loss |
|
| |
|
|
• the scaffold provided
a trophic support to modulate inflammation and facilitate neuroprotection,
neurogenesis, and antineuroinflammatory |
|
| PNI |
| NeuraGen (collagen) guides filled
with fibrin–agarose hydrogels (FAH) |
MSCs |
– |
• superior clinical,
electrophysiological, and histological results at 12 weeks after repair with hydrogel alone, better outcomes
with hydrogel/MSCs |
(132, 133) |
| |
|
|
• lower percentage of self-amputations |
|
| |
|
|
• partial sensory and
motor function recovery |
|
| |
|
|
• active peripheral nerve
regeneration process with newly formed peripheral nerve fascicles
and remyelination |
|
| |
|
|
• regeneration process
more abundant in autograft group |
|
| |
|
|
• important weight and
volume loss |
|
| |
|
|
• additional donor site
morbidity |
|
| |
|
|
• some signs of atrophy
and fibrosis |
|
| NVR-Gel (hydrogel of
high MW HA and laminin) |
SCs |
GDNF or FGF-2 expressed
by SCs |
• genetic modification
of SCs obtaining a cellular neurotrophic factor delivery system |
(134) |
| |
|
|
• optimal hydrogel matrix in vitro but not in vivo
|
|
| |
|
|
• conversion of the NVR-Gel into a solid state as a forward step |
|
| chitosan conduits filled with cellular collagen type I scaffolds enriched with either fibronectin
or laminin |
MSCs and Schwann cells |
– |
• marked improvement
of regeneration and functional recovery |
(135) |
| |
|
|
• highest values of regenerated
nerves area using SCs (nonsignificant differences among all groups) |
|
| alginate/chitosan hydrogel |
MSCs |
– |
• the hydrogel can provide
a suitable substrate for cell survival in vitro/in vivo
|
(136) |
| |
|
|
• enhance regeneration
compared to control group and hydrogel without cells |
|
| collagen type I and III hydrogel |
extracellular vesicles (EVs) isolated from hMSC cultured media |
– |
• reduction of muscle
atrophy |
(137) |
| |
|
|
• functional recovery
of innervated muscle enhancement |
|
| |
|
|
• EV-induced neuroprotective
mechanisms |
|
| RADA16–RGD–IKVAV peptide scaffold (nanofibrous) |
NPCs and NSCs |
– |
• good survival of NPCs/NSCs when fully
embedded in the 3D environment
of the nanofiber hydrogel |
(138) |
| |
|
|
• NPC differentiation
into neurons and astrocytes without adding extra soluble growth factors
within the scaffold in vitro
|
|
| |
|
|
• more permissive environment
for nerve regeneration with RADA16–RGD–IKVAV with respect to RADA16 alone |
|
| fibrin gel with chitosan nanoparticles (NPs) |
hEnSCs |
insulin (in chitosan NPs) |
• insulin slow release (possible with chitosan NPs) to improve matrix regeneration and neovascularization |
(139) |
| |
|
|
• hEnSC proliferation
promotion within a certain concentration range of insulin in vitro
|
|
| |
|
|
• significant motor function
and sensory recovery improvement while forming regenerative nerve
fibers accompanied by new blood vessels |
|
