Table 1.

Injectable hydrogels for brain 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
DHC, Self-assembled; Photo-responsive	1.Rat/athymic (CBHrnu) 2.None 3.200–220 ​g 4.Pentobarbital sodium (50 ​mg/kg)	1.TBI injury 2.Created a 5 ​mm diameter bone window (right parietal regions, 4 ​mm lateral to the sagittal suture, 2 ​mm posterior to the coronal suture), by a miniature hand held skull drill, with a 2 ​mm ​× ​2 ​mm brain tissue cylindrical cavity	BME (2 ​mg/mL)	1.Into the lesion 2.100 ​μL 3.None 4.1 5.Immediately injected 6.DHA (5 ​mg/mL), Col (5 ​mg/mL) 7.8	After 4 weeks: Glial scar inhibition Axonal regrowth and remyelination occurred Brain structural remodeling was promoted in the lesions Neurogenesis and angiogenesis were achieved	Liu-2023 [189]
HA-PBA/Gel-Dopa, PH-responsive	1.Mouse/C57BL/6J 2.None 3.None 4.2% Avertin (10 ​mg/mL)	1.TBI injury (severe model), 2.Via a cylindrical rod (speed of 2.5 ​m/s for 0.2 ​s), left parietal skull, 2 ​mm ​× ​2 ​mm brain tissue injury	None	1.Into the lesion 2.100 ​μL 3.None 4.1 5.Immediately injected 6.1.5% (wt/vol) HA-PBA/5% (wt/vol) Gel-Dopa 7.6.5 (for HA-PBA)/4.7 (for Gel-Dopa)	After 3 weeks: Reduced glial scar and closed the lesions Improved neural cell infiltration	Hu-2023 [190]
Alginate/PEDOT, Ion-sensitive crosslinking; Electrostatic interaction; Hydrophobic interaction; Self-assembled	1.Mouse/C57BL/6 2.7–11 weeks 3.22–35 ​g 4.5% isoflurane	1.TBI injury 2.Via dental drill (#60, 0.4572 ​mm, 8177), one hole was drilled (0.8 ​mm anterior, −2.1 ​mm lateral, relative to bregma)	None	1.Into the lesion (4 ​mm below the skull, speed of 0.5 ​mm/s) 2.1.3 ​μL 3.22G needle (3 ​mL syringe) via 3D bioprinter 4.1 5.Immediately injected 6.1%–2% Alginate, 1.1%–1.3% PEDOT Alginate/PEDOT ratio were: 1:1 (A1P1), 1:2 (A1P2), 2:1 (A2P1), 3:1 (A3P1) 7.None	After 3 days: Reduces neuroinflammation in the brain upon injection relative to traditional Pt-based electrodes A suitable blend matches with the brain tissue An appropriate electrical stimulation characteristic The hydrogel is not cytotoxic to neural cells (7 days cytotoxicity test)	Perkucin-2022 [191]
FPGEGa, Schiff base reaction; Electrostatic interaction; Thermosensitive	1.Rat/Wistar 2.Adult 3.220–240 ​g 4.10% chloral hydrate, intraperitoneally	1.TBI injury, Feeney's weight-drop method 2. 20 ​g, 20 ​cm height, target functional area (1 ​mm adjacent to the left side of anterior fontanelle, 2 ​mm diameter was drilled)	SHED-Exo (100 ​μg Exo into100 μL hydrogel)	1.Into the lesion 2.None 3.None 4.1 5.None 6.None 7.None	After 3 weeks: Enhanced neuro-regeneration by restoring motor functions After 2 days: Reduced the formation of intracellular ROS	Li-2022 [192]

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
Chitosan- DF-PEG hydrogel/GelMA-PCL nanofiber, Schiff base reaction	1.Rats/Sprague Dawley 2.7–8 weeks 3.300–320 ​g 4.1% pentobarbital sodium (40 ​mg/kg)	1.Ischemic brain injury, MCAO, via the thread-embolus method of intraluminal vascular occlusion 2.Thread (18 ​mm–22 mm length), blocked the origin of the right MCA. Reperfusion (after 1 ​h of occlusion)	BMSCs (5 ​× ​105 ​cells/10 ​μL)	1.Into the perilesional site 2.10 ​ml 3.26 s-gauge, Hamilton, for 10 ​min 4.1 5.24 h after MCAO 6.1% DF-PEG4000 with 3% GC (1:3), and 5 ​mg/ml nanofibers loaded in the hydrogel 7.None	After 2 weeks: Significant neurogenesis and angiogenesis The reduction of ischemic brain damage, infarct volume, microglial and astrocyte overactivation, and neurological deficits	Pei-2023 [193]
Ncad-mRADA, Self-assembled	1.NSE-DTA mice, Wild-type Institute of Cancer Research mice, C57BL/6J mice, and Dcx-EGFP mice 2.8–16-weeks 3.None 4.1%–3% isoflurane in oxygen	1.Ischemic stroke, MCAO was induced by the intraluminal filament technique 2.10 ​mm silicone-coated 8 filament, 40 ​min later filament was withdrawn	None	1.Into the site 2.2.5 ​μL–3 ​μL 3. Glass capillary needle, slowly stereotaxically injected 4.1 5.13 ​± ​1 day-post MCAO micce and 2 days-post-cryoinjured mice 6.0.5% v/v 7.7.4	Neuroblast migration to the injured site in the striatum Neuronal regeneration Functional recovery improvement in neonates with cortical brain damage	Ohno-2023 [194]
Fmoc-DDIKVAV, Self-assembled	1.Mouse/C57BL/6 2.Adult 3.None 4.2% isoflurane	1.TBI 2.Via stereotaxic frame, craniotomy	Myoglobin (1 ​mg/mL) and/or cortical neural stem cells, (5 ​× ​104/μl cells)	1.Into the striatum 2.2 ​μl 3.microinjection 4.1 5.None 6.15 ​mg/mL 7.None	After 4 weeks: Assist engraftment by supply oxygen and stem cells to the brain simultaneously Established vascular network Significant improvement in neuronal differentiation Greater functional integration of stem cell-derived grafts	Wang-2023 [195]
RADA16; RADA16-SVVYGLR, Self-assembled	1.Zebrafish 2.6 months 3.None 4.200 ​ppm MS222, 5 ​min	1.Optic tectum wound model 2.25G syringe, a needle length of 1.5 ​mm	None	1.Into the lesion 2.500 ​nL 3.None 4.1 5.Immediately injected 6.2% (w/v) 7.3	After 4 weeks: Enhanced the migration and neurogenesis of NPCs Induction of angiogenesis via endothelial and pericyte stimulation Improved functional recovery by enhancing optomotor response	Wang-2017 [196]

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
Fmoc-DDIKVAV, Self-assembled	1.Rat/athymic (CBHrnu) 2.None 3.None 4.General anesthetic, 2% isoflurane	1.Focal ischemia 2.None	hESCs-derived cortical progenitors (1 ​× ​104 ​cells)	1.Into the lesion (above co-ordinates) 2.1 ​μL 3.None 4.2 intracortical injections 5.6 days or 3 weeks after lesioning 6.10 ​mg/mL 7.7.4	After 9 months: Improved the functional recovery and the electrical characteristics of fully developed and integrated neurons Neuronal differentiation at a higher level	Somaa-2017 [197]
Self-healing composite of CS-CNF, Schiff base reaction	1.Zebrafish 2.adult 3.None 4.200 ​ppm tricaine	1.Cerebellum injury model 2.vertically piercing a 26G (260 ​μm inner diameter) syringe needle 1.5 ​mm deep into the skull	NSCs (1 ​× ​104 ​cells)	1.Into the lesion 2.1 ​μL 3.Winged infusion set (27G) 4.1 5.Immediately injected 6.Glycol CS (3%) and DF-PEG (2%) with 0.09 ​wt% CNFs 7.None	After 1 week: Effected on NSC neuronal differentiation Restored neural-impaired zebrafish function	Cheng-2019 [198]
CS-HA, Self-assembled	1.Zebrafish & rat (Sprague-Dawley) 2.Adult 3.250–300 ​g (for rat) 4.200 ​ppm tricaine & isoflurane gaseous (5% induction, 2% maintenance)	1.Zebrafish TBI injury 2.Rat ICH 1.26G syringe, 1.5 ​mm deep into the skull, 2. 23G needle, 1 ​mm anterior and 3.2 ​mm lateral to bregma and 4.5 ​mm back to 4 ​mm ventral to dura mater	None	1.Into the lesion (zebrafish) & into the striatum (rat) 2.2−4 ​μL (zebrafish) & 10 ​μL (rat) 3.23-gauge 4.1 5.Immediately injected 6.3% glycol chitosan and 2% DF-PEG containing 0.1% HA in 1:1 ​vol ratio 7.None	After 1 week: Promoted the healing of CNS damage and the functional recovery Prepared an adaptable environment that allows NSC migration, proliferation, and differentiation Created a microenvironment that encourages axonal development It had a healing impact on the brain-damaged cavity	Liu-2020 [199]
SAP scaffold conjugated with IKVAV sequence, Self-assembled	1.Rat (Sprague-Dawley) 2.12 weeks 3.380–450 ​g 4.Zoletil 50 (55 ​mg/kg)	1.Cerebral neocortex/neopallium loss 2.Created by a biopsy punch, a distance of 2 ​mm to the right of the bregma, with a 2 ​mm ​× ​2 ​mm cavity	NSCs	1.Into the lesion 2.None 3.None 4.1 5.Immediately injected 6.1% (w/v) 7.None	After 6 weeks: Allowed NSCs to differentiate into neurons Supported axon elongation	Cheng-2013 [200]

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
Pluronic-CS/anilinepentamer, Electrically responsive	1.Rat (Wistar) 2.Adult 3.250–300 ​g 4.None	1.Hippocampus ischemic defect 2.None	VEGF (1 ​mg/mL)	1.In the site of ischemia 2.10 ​μL (flow rate: 1 ​μL/min) 3.29-gauge, 25-μL Hamilton syringe 4.1. 5.3 days after hippocampal ischemia 6.None 7.None	After 5 days: simulated the hippocampus' electrical, electrochemical, and mechanical properties Reduced infarction volume Improved the hippocampus-dependent learning and memory performance	Nourbakhsh-2020 [201]
GelMA-imid, light -responsive, Click chemistry cross-linked	1.Rat (Sprague-Dawley) 2.8–11 weeks 3.None 4Intraperitoneal, sodium pentobarbital (30 ​mg/kg)	1.Cryogenic injury 2.None	PDA/SDF1α nanoparticles and hAMSCs	1.Into the center of the damaged area 2.20 ​μL 3.26 ​G syringe 4.1 5.Immediately injected 6.1% 7.None	After 2 weeks: Enhanced hAMSCs homing and neural differentiation Encouraged the growth of endogenous nerve cells Significant potential for TBI physiological recovery	Zheng-2021 [202]
Pol and refrigerated hydrogel incorporated T1AM, Thermosensitive	1.Mouse/Institute of Cancer Research (ICR) 2.5 weeks 3.None 4.None	1.TBI injury, modification of Feeney's weight-drop method 2.40 ​g, height of 7.5 ​cm, a 4 ​mm diameter footplate, a 5 ​mm craniotomy (3 ​mm posterior and 3 ​mm lateral from bregma,on the right parietal)	T1AM (50 ​mg/kg)	1.Into the injured part of the brain 2.50 ​μL 3.None 4.1 5.Immediately injected 6.High poloxamer 407 concentration (25% w/v), low poloxamer 7, None	After 26 days: Enhanced functional TBI recovery Maintained BBB integrity Stopped cell death Decreased brain inflammation and edema Useful for TBI local drug administration and cooling without major adverse effects	Han-2020 [203]
HT, Enzymatically cross-linked	1.Mouse/C57 black 6 (C57BL/6) 2.None 3.22–25 ​g 4.None	1.Moderate TBI, Feeney's weight-drop method 2. 20 ​g, height of 20 ​cm. Open a 3 ​mm hole at midway between Bregma/Lambda (medial edge 1.5 ​mm lateral to midline). Use a craniocerebral percussion device to hit recisely at center of opening	BMSC and NGF	1.Into the lesion 2.20 ​μL 3.Micro-syringe 4.1 5.7 days after TBI 6.0.5 ​wt% 7.None	After 2 weeks: Survival and proliferation of neural cells through the release of neurotrophic factors and the regulation of neuroinflammation	Wang-2022 [204]
HAMC Physically cross-linked (Inverse thermal gelation)	1.Rat/Sprague Dawley 2.None 3.300–350 ​g 4.Isoflurane	1.Stroke (endothelin-1 model of focal ischemia) 2.26G, Hamilton syringe	Cyclosporine and erythropoietin	1.Onto the brain's cortical surface 2.6 ​μL 3.None 4.1 5.4 days after the stroke surgery 6.1.4 ​wt/vol% HA and 3.0 ​wt/vol% MC 7.None	After 6 weeks: Cyclosporine improved plasticity in the striatum Erythropoietin stimulated endogenous NSPCs	Tuladhar-2020 [205]
PNIPAAm-b-PLA-bPEG-b-PLA-b-PNIPAAm pentablock copolymer, Thermosensitive	1.Rat/Sprague-Dawley 2.adult 3.250–270 ​g 4.Intraperitoneal, ketamine−xylazine (100 and 10 ​mg·kg−1)	1.Striatum (the coordinates were determined according to Paxinos and Watson, 2006) 2.6 ​mm for the dorsoventral axis, 3 ​mm for the mediolateral axis, and −0.12 ​mm for the rostrocaudal axis. A craniotomy (2 ​mm)2 ​at the predefined coordinate points using a power drill.	Hydrophobic molecules; riluzole	1.Into the striatum 2.10 ​μL (flow rate: 3.33 ​μL/min) 3.33G 4.1 5.Immediately injected 6.5 ​wt % in PBS 7.7.4	After 1 week: Hydrophobic molecules/drugs can be efficiently loaded into the micelle cores of this cytocompatible hydrogel without any drug burst release	Pertici-2018 [206]
IKVAV-functionalized PA, Self-assembled	1.Mouse/C57BL/6 2.8−11 weeks 3.None 4.2.5% Avertin injected intraperitoneally at a dosage of 10 ​mg/mL	1.The cryogenic focal brain injury model 2.None	None	1.None 2.None 3.None 4.None 5.None 6.None 7.None	After 1 week: Enhanced neurite outgrowth Acted as a non-cytotoxic microtubule stabilizer Increased crucial neural marker expression in mice cortical primary neurons led to significant neuroregeneration and rapid recovery of the sham injured mice brain Significantly led to the neural repair of the damaged brain by increasing reactive astrocytes in the hippocampal dentate gyrus region of the sham injured brain	Pradhan-2018 [207]

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
Gelatin, Enzymatically cross-linked	1.Mouse/C57BL/6 2.6–8 weeks 3.21–23 ​g 4.Intraperitoneal, 10% chloral hydrate (350 ​mg/kg)	1.Moderate TBI, Feeney's weight-drop method 2.20 ​g, height of 20 ​cm. Incision of 1 ​cm in the scalp, right skull exposure, drill (3 ​mm diameter), the right of the midline of the posterior bregma (1.5 ​mm), brain tissue exposure, and no damage.	BMSC (5 ​× ​104 ​cells/ml)	1.Into the lesion 2.10 ​μL 3.Micro-syringe 4.1 5.Seven days after TBI 6.8% wt 7.None	After 5 weeks: Improved neurogenesis and functional reconstruction of TBI mice Significantly increased neural differentiation, cell viability, and neurotrophin secretion	Li-2021 [208]
Gelatin Enzymatically cross-linked	1. Rat/Sprague-Dawley 2. None 3. 250–300 ​g 4. None	1.Intracerebral hemorrhage (via collagenase injection into the striatum) 2.None	EGF (8 ​μg)	1.Brain cavity 2.25 ​μl 3.None 4.1 5.After two weeks 6.8 μg/μL 7.None	After 4 weeks: Enhanced cell migration supplied sustaining release of EGF promoted tissue regeneration	Lim-2020 [209]
TM/PC Self-assembled	1.Mouse/ICR 2.5 weeks 3.None 4.Isoflurane (3.5% induction and 1.5% maintenanc)	1. TBI injury, Feeney's weight-drop method 2.40 ​g, height of 7.5 ​cm, a 4 ​mm diameter footplate, 9needles at the exact location, a 3 ​× ​3 grid with 3 ​mm deep, spaced 1 ​mm in width and 1 ​mm in height	Curcumin	1.Under the endocranium 2.20 ​μL 3.None 4.1 5.None 6.20 ​mg/mL total PPS120 and Cur with a ratio of 8: 2 (w/w) 7.None	After 3 weeks: Decreased reactive astrocytes and activated microglia had a strong anti-inflammatory effect promoted nerve regeneration	Qian-2021 [210]
DCH Self-assembled	1.Immunodeficient mice/C57Bl6 2.8–14 weeks 3.None 4.Isoflurane	1.Intracranial xenograft model of glioblastoma in immunodeficient mice 2.None	Paclitaxel and hGBM (100,000 ​cells)	1. Injected stereotactically into the center of the caudate-putamen nucleus 2. 2 ​μL 3. Pulled glass micropipettes ground to a beveled tip with 150–250 ​μm inner diameter 4. 2 5. None 6. 3 ​wt% 7. None	After 5 weeks: Made local tumor control and enhanced survival. However, tumor cells could escape the area of treatment Produced minimal tissue reactivity Induced less cellular inflammation, reactive astrocytes, and tissue damage than cremaphor-taxol (typical taxol-carrier) or hydrogel alone	Garrett-2020 [211]

DHC: hyaluronan-collagen hydrogel; BME: bone marrow mesenchymal stem cell-derived exosomes; TBI: traumatic brain injury; PEDOT: Poly(3,4-ethylenedioxythiophene); HA-PBA/Gel-Dopa: penylboronic acid modified hyaluronic acid/dopamine modified gelatin, FPGEGa: poly (citrate-gallic acid)-based hybrid hydrogel; SHED-Exo: stem cells from human exfoliated deciduous teeth-derived exosomes; DF-PEG: dibenzaldehydeterminated polyethylene glycol; GelMA: gelatin methacryloyl); PCL: polycaprolactone; MCAO: middle cerebral artery occlusion; Ncad-mRADA: N-cadherin tagged with mRADA; DDIKVAV: aspartate-aspartate-isoleucine-lysine-valine-alanine-valine; Fmoc: Nfluorenylmethyloxycarbonyl; IKVAV: isoleucine-lysine-valine-alanine-valine; RADA: arginine (R, Arg), alanine (A, Ala) aspartic acid (D, Asp), alanine (A, Ala); SVVYGLR: Serin-Valanin-Valanin-Tyrosine-Glycine-Leusin-Arginine; CNS: the central nervous system; NPCs: neural progenitor cells; SAP: self-assembling injectable peptide; hESCs: human embryonic stem cells; CS–CNF: chitosan–cellulose nanofiber; NSCs: neural stem cells; VEGF: vascular endothelial growth factor; CS-HA: chitosan-hyaluronan; GelMA-imid: imidazole groups-modified gelatin methacrylate; PDA: polydopamine; SDF-1α: stromal-cell derived factor-1; hAMSCs: human amniotic mesenchymal stromal cells; ICH: intracerebral hemorrhage; Pol: poloxamer; T1AM: 3-iodothyronamine; BBB: blood-brain barrier; HA: hyaluronic acid; CNS: central nervous system; HT: tyramine-modified hyaluronic acid hydrogels; GalOx: galactose oxidase; HRP: horseradish peroxidase, BMSC: bone mesenchymal stem cells; NGF: nerve growth factors; HAMC: hyaluronan and methylcellulose; PEG: poly (ethylene glycol); CFGO: choline-functionalized injectable graphene oxide; SA: sodium alginate; ChOx: choline oxidase; EGF: epidermal growth factor; DCH: diblock copolypeptide hydrogel, hGBM: human glioblastoma.