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. 2023 Mar 22;20:100614. doi: 10.1016/j.mtbio.2023.100614

Table 2.

Injectable hydrogels for spinal cord tissue engineering.

Hydrogel composition,
Preparation
 Animal profile In vivo model Loaded
With
 Injection profile Results
 Year [ref]
  • 1.

    Type

  • 2.

    Age

  • 3.

    Weight

  • 4.

    Anesthetic

  • 1.

    Type

  • 2.

    Other details

  • 1.

    Site

  • 2.

    Volume

  • 3.

    Needle grade

  • 4.

    Repetition

  • 5.

    Time

  • 6.

    Concentration

  • 7.

    pH

IKVAV-functionalized PA,
Self-assembled
  • 1.

    Rat/Wistar

  • 2.

    Adult

  • 3.

    160–200 ​g

  • 4.

    Ketamine (90 ​mg/kg) and xylazine (10 ​mg/kg)
  • 1.

    Clip compression

2. 134 ​g aneurysm clip/T7-T8		 BDNF
  • 1.

    Into the lesion

  • 2.

    None

  • 3.

    29-gauge needle, Hamilton syringe

  • 4.

    1

  • 5.

    24 h after TSCI

  • 6.

    1%

  • 7.

    7.6

 After 6 weeks:
Minimal inflammation
Appropriate for presenting axons		 Hassanejad-2019 [23]
SF/PDA,
Schiff base reaction;
Self-polymerization
  • 1.

    Rat/Sprague Dawley

  • 2.

    Adult

  • 3.

    220 ​g

  • 4.

    10% chloral hydrate solution (0.3 mL/100 ​g)
  • 1.

    3 ​mm lateral hemisection

  • 2.

    T9-10

 None
  • 1.

    Into the injury site

  • 2.

    None

  • 3.

    21-gauge needle

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    2 ​mg/mL

  • 7.

    8.5

 After 2 weeks:
Enhanced the development of neurons
Possessed a healing impact on spinal cord injury		 Chen-2020 [218]
SHIELD
Michael addition reaction; Thermosensitive; Self-assembled
  • 1.

    Rat/Fischer 344 (F344)

  • 2.

    8–10 weeks

  • 3.

    None

  • 4.

    1–3% isoflurane in oxygen
  • 1.

    Contusion

  • 2.

    75 kDy/C5

 Schwann cell (4.5 ​× ​105 ​cells)
  • 1.

    Into the lesion

  • 2.

    4 ​μL

  • 3.

    33-gauge Hamilton syringe, automated device

  • 4.

    1

  • 5.

    After 2 weeks of recovery

  • 6.

    10 % wt & 6.5 ​mM cell-adhesive peptides

  • 7.

    None

 After 4 weeks:
Decreased neuronal damage, secondary injury, and cystic cavitation
Contributed to cell transplantation outcomes
Improve functional efficiency as a result of increased forelimb strength and coordination		 Marquardt-2020 [219]
Acellular peripheral nerve graft, Thermosensitive
  • 1.

    Rat/Sprague Dawley

  • 2.

    None

  • 3.

    250–300g

  • 4.

    Isoflurane
  • 1.

    Contusion

  • 2.

    200 kDy/C3-4

 None
  • 1.

    Into the lesion

  • 2.

    6 ​μL (flow rate: 1 ​μL/min)

  • 3.

    34-gauge needle

  • 4.

    1

  • 5.

    1 week after injury

  • 6.

    16.5 ​mg/mL

  • 7.

    None

 After 8 weeks:
Less invasive and more efficacious substrate for combined SCI therapy
Enhanced neuronal regeneration and the fraction of distal spinal cord axons covered
After 1 week,
Reduced M1:M2 macrophage ratio in subacute SCI microenvironment		 Cornelison-2018 [220]
PD/GO,
Non-covalent crosslinking
  • 1.

    Rat

  • 2.

    None

  • 3.

    None

  • 4.

    Isoflurane
  • 1.

    Moderate crushing

2. Vascular clip for 1 ​min/30 ​g forces/T9		 Diacerein
  • 1.

    In situ

  • 2.

    500 ​μL

  • 3.

    Microsyringe

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    10 ​mM

  • 7.

    7.4

 After 4 weeks:
Regulated the hyperactivity and inflammation of the brain's astrocytes in vitro and induced the SCI repairing in vivo		 Zhang-2020 [221]
Hydrogel composition, preparation
 Animal profile In vivo model Loaded
With
 Injection profile Results
 Year [ref]
  • 1.

    Type

  • 2.

    Age

  • 3.

    Weight

  • 4.

    Anesthetic

  • 1.

    Type

  • 2.

    Other details

  • 1.

    Site

  • 2.

    Volume

  • 3.

    Needle grade

4. Repetition
5. Time
6. Concentration
7. pH
HA/PEG,
Click chemistry cross-linked
  • 1.

    Rat/Sprague-Dawley

  • 2.

    None

  • 3.

    260–350 ​g

  • 4.

    None
  • 1.

    Moderatel compression

  • 2.

    21 ​g modified aneurysm clip for 1 ​min/T2

 BDNF
PLGA nanoparticles
  • 1.

    Into the intrathecal space

  • 2.

    10 ​μL

  • 3.

    Customized 30G, 22 ​mm long blunt needle, Hamilton syringe

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    10 ​mg of HA-furan with 7 ​mg of (MI)2PEG

  • 7.

    None

 After 4 weeks:
Biocompatible, safe and low-swell
The spinal cord was not harmed as a result of the intrathecal injection		 Furhrman-2015 [152]
HP hydrogel,
Thermosensitive
  • 1.

    Rat/Sprague-Dawley

  • 2.

    Adult

  • 3.

    220–250 ​g

  • 4.

    8% (w/v) chloral hydrate (3.5 ​mL/kg
  • 1.

    Moderate crushing

2. Vascular clip for 1 ​min/30 ​g forces/T9		 aFGF
  • 1.

    Into the lesion

  • 2.

    10 ​μl

  • 3.

    Microsyringe, orthotopically injected

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    2 ​μg/μl

  • 7.

    None

 After 1 week:
Decrease apoptosis of neurons and astrogliosis
After 4 weeks:
Improved neurite growth, axonal rehabilitation, and the healing of SCI		 Wang-2017 [222]
I-5,
Thermosensitive
  • 1.

    Rat/Sprague-Dawley

  • 2.

    Adult

  • 3.

    250–300 ​g

  • 4.

    4% chloral hydrate (10 ​ml/kg, injected intraperitoneally)
  • 1.

    Contusion

  • 2.

    200 kDy was performed with the Infinite Horizon impactor/T10-T11

 Taxol (1 ​μg/μl) or siRNA nanoparticles
  • 1.

    Into the center of the contused area

  • 2.

    10 ​μl

  • 3.

    26 ​G Hamilton syringe, injected manually

  • 4.

    1

  • 5.

    1 week after the contusion injury

  • 6.

    10%

  • 7.

    None

 After 8 weeks of injury (7 weeks after injection):
Improved coordinated locomotion
Induced beneficial extracellular matrix remodeling that can stimulate tissue repair		 Hong-2017 [223]
Alginate, Ion-sensitive crosslinking
  • 1.

    Rat/Wistar

  • 2.

    Adult

  • 3.

    220–280 ​g

  • 4.

    Intraperitoneal injection, ketamine (100 ​mg/kg) and xylazine (10 ​mg/kg)

 1. Lateral hemisection-2. Left of the spinal cord (made with a surgical blade). A gap at the length of 2–4 ​mm alongside the rostral-caudal axis that was extended to the midline/T8-T10 MH (50 ​μg) and paclitaxel (7.168 ​μg)
  • 1.

    Into the lesion

  • 2.

    40 ​μL (flow rate: 4 ​μL/min)

  • 3.

    30G, Hamiltonian syringe

  • 4.

    1

  • 5.

    After 5 ​min from the injury

  • 6.

    2 ​mg/mL

  • 7.

    None

 After 4 weeks:
Dual-drug treatment reduced inflammation and scar tissue.
Increased neuronal regeneration		 Nazemi-2020 [224]
Modified gelatin matrix integrated with shape-memory polymer fibers,
UV-sensitive crosslinking
  • 1.

    Mice/C57

  • 2.

    10 weeks

  • 3.

    20 ​g

  • 4.

    Pentasorbital sodium 0.1%
  • 1.

    Artificially induced SCI

  • 2.

    A small chunk of tissue (2.0 ​× ​1.0 ​× ​1.0 ​mm) from the spinal cord was partially removed (using a stereotactic instrument mounted with a 22G syringe needle/T11-T12

 Motor neurons derived from ESCs (1 ​× ​105 ​cells)
  • 1.

    Into the lesion

  • 2.

    2 ​μL

  • 3.

    None

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    12% gelatin

  • 7.

    7.4

 After 4 weeks:
Increased tissue regeneration and motor function recovery in mice		 Wang-2018 [225]
Hydrogel composition, preparation
 Animal profile In vivo model Loaded
With
 Injection profile Results
 Year [ref]
  • 1.

    Type

  • 2.

    Age

  • 3.

    Weight

  • 4.

    Anesthetic

1. Type
2. Other details
 1. Site
2. Volume
3. Needle grade
4. Repetition
5. Time
6. Concentration
7. pH
CHA gel,
Schiff base reaction
  • 1.

    Rat/Sprague-Dawley

  • 2.

    10 weeks

  • 3.

    210–240 ​g

  • 4.

    Intraperitoneal injection,10 ​mg/kg Rompun & 50 ​mg/kg of Zoletil 50
  • 1.

    Weight-drop impact

  • 2.

    Using a 40-g rod, 2.5 ​mm in diameter, from a height of 30.5 mm/T9

 None
  • 1.

    Into the epicenter of the injured spinal cord

  • 2.

    10 ​μL

  • 3.

    26-gauge microliter syringe, Hamilton

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    2% glycol chitosan and 3% oxidized hyaluronate (ratio: 9:1)

  • 7.

    7.4

 After 1 week:
Leads to neuroinflammatory inhibition		 Han-2020 [226]
HA-PH-RGD/F, Enzymatically cross-linked
  • 1.

    Rat/Wistar

  • 2.

    None

  • 3.

    250 - 300 g

  • 4.

    Pentobarbital anaesthesia (60 mg/kg)
  • 1.

    Hemisection

  • 2.

    Cavity-right half of spinal cord segment (2 mm long)/T8

 hWJ-MSCs
  • 1.

    Into the lesion

  • 2.

    5 ​μL

  • 3.

    Omnican Insulin syringe

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    20 ​mg/ml

  • 7.

    None

 After 8 weeks:
Bridged the lesion cavity, helped vascularization, and enhanced axonal sprouting into the lesion
No locomotor recovery or blood vessel ingrowth and density of glial scar around the lesion		 Zaviskova-2018 [227]
BC/FB,
Thermosensitive
  • 1.

    Rat/Sprague-Dawley

  • 2.

    6–8-week

  • 3.

    170–220 ​g

  • 4.

    Buprenorphine, 5% Isofluorane, maintenance 2% isofluorane
  • 1.

    The dorsal column was crushed bilaterally

  • 2.

    Using watchmaker's forceps/T8

 Decorin
  • 1.

    Into the lesion

  • 2.

    5 ​μL (3.5 ​μL gel ​+ ​1.5 Decorin)

  • 3.

    None

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    3 ​mg/ml BC/4 ​mg/ml FB (BC/FB, 1:3 ratio)

  • 7.

    None

 Functional recovery was assessed at baseline, 2 days, and weekly for 6 weeks.
After 6 weeks:
Cavitation was fully inhibited, and lesion sites became filled with extracellular matrix materials and injury-responsive cells
Up-regulated regeneration-associated genes (RAGs) of dorsal root ganglion neurons (DRGN), increased local axon regeneration/sprouting
Improved electrophysiological, locomotor, and sensory function recovery		 Matthews-2021 [228]
GelMA,
UV-sensitive crosslinking
  • 1.

    Rat/Sprague-Dawley

  • 2.

    Adult

  • 3.

    None

  • 4.

    None
  • 1.

    Weight-drop

  • 2.

    10 ​g impact rod was dropped at the center above T10 from a height of 25 mm/T10

 Bone MSCs-derived exosomes
  • 1.

    Into the lesion

  • 2.

    None

  • 3.

    None

  • 4.

    1

  • 5.

    None

  • 6.

    None

  • 7.

    None

 After 6 weeks:
Led to neurological functional recovery
After 7 days of cell culture:
Induced Tuj-1-positive neurons differentiation, decreased astrocyte scars, and increased axonal elongation		 Cheng-2021 [229]
RADA-16I, Self-assembled
  • 1.

    Rat/Sprague-Dawley

  • 2.

    Adult

  • 3.

    225–250 ​g

  • 4.

    Isoflurane 5%
  • 1.

    Contusion

  • 2.

    150 kDy/C5

 human MSCs
  • 1.

    Into the lesion

  • 2.

    10 ​μL

  • 3.

    None

  • 4.

    1

  • 5.

    2 weeks after the contusion injury

  • 6.

    0.1 ​wt% MP/1 ​mg mL−1 RADA-16I

  • 7.

    7.4

 After 2 weeks:
Led to axon elongation at the location of a spinal cord lesion
Providing topological cues as guidance for axon alignment		 Tran-2022 [230]
Hydrogel composition, preparation
 Animal profile In vivo model Loaded
With
 Injection profile Results
 Year [ref]
  • 1.

    Type

  • 2.

    Age

  • 3.

    Weight

  • 4.

    Anesthetic

  • 1.

    Type

  • 2.

    Other details

  • 1.

    Site

  • 2.

    Volume

  • 3.

    Needle grade

  • 4.

    Repetition

  • 5.

    Time

  • 6.

    Concentration

  • 7.

    pH

AHA/DTP,
Schiff base cross-linked
  • 1.

    Rat

  • 2.

    None

  • 3.

    None

  • 4.

    None
  • 1.

    None

  • 2.

    None

 NSCs
  • 1.

    Into the lesion

  • 2.

    None

  • 3.

    Needle with outer diameter: 600 ​μm

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    10% (w/v) AHA/1.6, 6.5, and 26 ​mg/mL DTP (ratio: 1:1)

  • 7.

    7.4

 After 1 week:
Can help neural stem cells differentiate into neurons
Bridged the lesion cavity, and promoted angiogenesis, remyelination, and neural regeneration
Leads to promote motor functional recovery		 Yu-2023, Li-2022 [231,232]
BOCPG, Schiff base cross-linked and non-covalent crosslinking
  • 1.

    Rat/Sprague-Dawley

  • 2.

    Adult

  • 3.

    280–300 ​g

  • 4.

    Xylazine (5 ​mg/kg)/ketamine (70 ​mg/kg)
  • 1.

    Contusion,

  • 2.

    200 kDy (Infinite Horizon IH-0400 impactor)/T9-T10

 NSCs
  • 1.

    Into the lesion

  • 2.

    5 ​μL

  • 3.

    26-gauge needle

  • 4.

    1

  • 5.

    After 1 week

6. 1%, 3%, and 5% (w/v) BOCP/30% (w/v) Gel
  • 7.

    None

 Enhanced neuronal differentiation, promoted axon outgrowth, and inhibited astrocyte differentiation
After 6 weeks:
Activated endogenous NSCs neurogenesis and induced myelinated axon regeneration into the injury site in vivo
Leads to promote locomotor functional recovery		 Luo-2022 [233]
Ibuprofen-KYIGSRK, Michael addition reaction
  • 1.

    Rat/Sprague-Dawley

  • 2.

    Adult

  • 3.

    200 ​g

  • 4.

    None
  • 1

    Semi-transection

  • 2.

    At left T10 region of the spinal cord/T9-T11

 None
  • 1.

    Into the lesion

  • 2.

    None

  • 3.

    None

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    None

  • 7.

    None

 Enhanced DRG neurons adhesion and neurite extension
After 4 weeks:
Decreased glial scars and increased neurites
Leads to promote motor functional recovery.
Remarkably suppress inflammatory responses and enhance nerve regeneration		 Zhang-2022 [234]
PLEL,
Thermosensitive
  • 1.

    Rat

  • 2.

    Adult

  • 3.

    200 ​g

  • 4.

    Pentobarbital solution (30 ​mg/kg)
  • 1.

    Clip compression

  • 2.

    With arterial clamp for 1 ​min/T9-T10

 EVs
  • 1.

    Into the lesion

  • 2.

    10 ​μL

  • 3.

    None

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    25 ​wt%

  • 7.

    None

 After 4 weeks:
Can reduce the local inflammation and the apoptosis of neural cells
Leads to promote motor functional recovery.
Providing topological cues as guidance for axon alignment		 Zhang-2022 [235]
cfGel,
Thermosensitive
  • 1.

    Rat/Sprague-Dawley

  • 2.

    Adult

  • 3.

    200–250 ​g

  • 4.

    Pentobarbital solution (50 ​mg/kg)
  • 1.

    Transection

  • 2.

    Cut 2 ​mm with microsurgical scissors/T9-T10

 NSCs
Cetuximab FTY720
  • 1.

    Into the lesion

  • 2.

    None

  • 3.

    None

  • 4.

    1

  • 5.

    Immediately injected

  • 6.

    4-arm-PEG-NHNH2 (12 ​mg/mL) and o-Dex (8 ​mg/mL) (ratio: 1:1)

  • 7.

    7.4

 Enhanced neuronal differentiation, and inhibited astrocyte differentiation
After 10 weeks:
Promoted integration and neuronal differentiation of NSCs
Enhanced axonal regeneration and inhibited glial scar formation
Exhibited functional improvement		 Qi-2022 [236]

PA: peptide amphiphile; SCI: spinal cord injury; BDNF: brain-derived neurotrophic factor; SF/PDA: silk fibroin/polydopamine; SHIELD: shear-thinning hydrogel for injectable encapsulation and long-term delivery; Col-I: collagen type I; LN-I: laminin I; HA: hyaluronic acid; GO: graphene oxide; PD/GO hydrogel: GO sheets with 4arm-PEG-diacerein, donated as PD hereafter; 4arm-PEG-diacerein: four-armed polyethylene glycol functionalized with an anti-inflammatory drug, diacerein; PLGA: poly (lactic-co-glycolic acid); HP: heparin-poloxamer; aFGF: acidic fibroblast growth factor; I-5: imidazole-poly(organophosphazenes); MH: minocycline hydrochloride; ESCs: embryonic stem cells; CHA gel: glycol chitosan cross-linked with an oxidized hyaluronate hydrogel; HA-PH-RGD/F: a hydroxyphenyl derivative of hyaluronic acid modified with the integrin-binding peptide RGD and combined with fibrinogen; hWJ-MSCs: human Wharton's jelly-derived mesenchymal stem cells; BC/FB: bovine collagen and fibrinogen; GelMA: gelatin methacrylate; MSCs: mesenchymal stem cells; RADA: arginine (R, Arg), alanine (A, Ala) aspartic acid (D, Asp), alanine (A, Ala); RADA-16I: [Ac-(AcN-ArgAlaAspAla)4-CONH2]; AHA/DTP: aldehyde-modified hyaluronic acid/3, 3′ -dithiobis (propionyl hydrazide); NSCs: neural stem cells; BOCPG: BOC-doped polypyrrole with gelatin; BOC: borax-functionalized oxidized chondroitin sulfate; Gel: gelatin; KYIGSRK: lysine-tyrosine-isoleucine-glycine-serine-arginine-lysine;; DRG: dorsal root ganglion; PLEL: poly (d, l-lactide)-poly (ethylene glycol)-poly(d,l-lactide); EVs: M2 microglia derived extracellular vesicles; cfGel: dual-drug (Cetuximab-FTY720) enhanced hydrogel; Cetuximab: an epidermal growth factor receptor signaling antagonist, FTY720: fingolimod, a first-in-class sphingosine 1-phosphate receptor modulator.