Table 4.

Biomedical applications of protein based hybrid hydrogels in biomedical fields, preparation procedures, some properties and their type.

Natural Polymer	Synthetic Polymer	Preparation Procedure	Crosslinker (If Applicable)	Properties/Applications	References
Bone tissue engineering
Gelatin	PEGDA	Polymerization by light curing	No crosslinker	Biodegradable hydrogel for the delivery of small molecules, including a Pyk2-targeted inhibitor, in the treatment of craniofacial and appendicular skeletal defects, promoting osteoblast activity and mineral deposition	[346]
Methacrylated gelatin	PEGDA	UV photo-crosslinking	No crosslinker	Mouse osteoblasts culture on the hydrogel surface showed high viability, adhesion, and proliferation	[347]
Cartilage tissue engineering
Gelatin, alginate	PHEMA	PHEMA-gelatin forms a gel after adding GA and ammonium persulfate (APS)/TEMED (free-radical polymerization initiator), and the reaction between the aldehyde groups of the oxidized alginate and the amino group of the gelatin might be due to a Schiff-base reaction	GA	IPN sodium alginate in HEMA-gelatin scaffolds that promotes the proliferation of chondrocytes	[348]
Gelatin	Pluronic	Graft copolymerization	EDC/NHS as a coupling reagent	Thermosensitive injectable cell-containing scaffold with thermally reversible properties and good biocompatibility	[349]
Methacrylated gelatin	PAAm	Co-polymerization of acrylamide (AAm) and methacrylated gelatin under UV radiation in the presence of a photo-initiator	No crosslinker	Biodegradable hydrogel with sustained growth factors release in articular cartilage defect repair	[350]
Gelatin	Three-block PCL-PEG-PCL and penta block PNIPAAm-PCL-PEG-PCL-PNIPAAm copolymers	TIPS (thermally induced phase separation) method using span-80 as an emulsifier	GA	Biodegradable thermosensitive hydrogel scaffolds	[351]
Fish skin gelatin	Poloxamer 407	FT method	GA	Cryogel used in the regeneration of the nucleus pulposus	[352]
Wound healing
Type I Collagen from bovine skin	PVA	Crosslinking	GA	Biohybrid sponge loaded with indomethacin, a non-steroidal anti-inflammatory drug	[353]
Human-like collagen (HLC)	PVA	Repeated FT where Tween80 was used as pore forming agent	No crosslinker	Soft, translucent, flexible hydrogels with smooth surfaces accelerating wound recovery through upregulating the expression of main growth factors of VEGF and TGF-β	[354]
Soy protein (SP)	Poly (ethylene terephthalate) (PET) AAc	Radical graft polymerization of AAc on the surface of PET fabric, and then the carboxyl groups available in the structure of AAc were activated using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) and then SPI was covalent coated on the surface of PET fabric	EDAC	Gabapentin loaded hydrogel as dressing for highly exudate wounds (diabetic ulcer) with neuropathic pain	[355]
SP	PEG	Condensation reaction between the carbonated moieties of PEG and amino groups of SP forming stable urethane linkages with subsequent release of p-nitrophenol molecules	No crosslinker	Safe and inflammatory inert moist transdermal drug delivery system for wound healing	[356]
Drugs and molecules delivery
Acidic Type I Collagen from calf skin	PVP	γ–irradiation in the absence of oxygen	No crosslinker	Superabsorbent hydrogels	[357]
Hydrolyzed Collagen with low molecular weight	Poly[(acrylic acid)-co-(methacrylic acid)] (poly(AA-co-MAA))	Graft polymerization with APS/TEMED initiator couple	N,N′-methylenebisacrylamide	pH- and thermo sensible hydrogels for oral delivery of insulin and methylene blue	[358]
Porcine Type I Collagen modified with γ-thiobutyrolactone to introduce thiol groups	8-arm PEG-maleimide	Thiol-Michael addition click reaction	No crosslinker	Injectable hydrogels for cell delivery	[359]
Gelatin	poly(3-hydroxybutyrate) (PHB)	Physical gelation (due to the formation of triple helices at low temperatures) or chemical cross-linking (gelatin enzymatically cross-linked with TG), and embedded with drug loaded PHB nanoparticles prepared by the solvent displacement method	Natural enzyme microbial transglutaminase (TG)	Physical or chemical nanocomposite injectable hydrogels for the dual sustained release of naproxen sodium and curcumin	[360]
Methacrylated gelatin	Carboxybetaine methacrylate (CBMA)	Polymerization of vinyl groups of methacrylated gelatin and CBMA initiated by APS and TEMED	No crosslinker	Slow degradable hydrogels for fluorescein isothiocyanate-dextran release	[361]
Gelatin methacrylate	MAA	Gelatin methacrylate copolymerized with MAA by a free polymerization in the presence of KPS and ethylene glycol dimethacrylate (EGDMA)	NHS/EDC zero length crosslinker for GS link to polymeric back bone	pH sensitive hydrogel with controlled delivery of Gentamicin and Ampicillin antibiotics; GS, chemically conjugated to the polymer using amide linkage, leads to the slow release of it and high stability over long period	[362]
Gelatin	PLGA(lactide:glycolide 75:25)	Double water-in-oil-in-water(w/o/w) emulsification-solvent evaporation	No crosslinker	Injectable core/shell microspheres with gel inner phase for controllable release of Losartan potassium	[363]
Feather Keratin (FK)	Poly(methacrylic acid) (PMAA)	After the addition of the monomer (MAA) and crosslinker (BIS), and initiation with APS, the PMAA chains were grafted on the thiol group of the FK chains by grafting copolymerization	N,N-Methylene bisacrylamide (BIS)	pH-sensitive hydrogel for small molecule (rhodamine B) and macromolecule (BSA) release	[364]
SP	Poly(N-isopropylacrylamide-co-sodium acrylate)	Interpenetrating polymer network (IPN) method in the presence of APS/TEMED	GA for soy protein crosslinking and BIS for NIPAAm and AA crosslinking	pH- and temperature-responsive IPN hydrogels for BSA release	[365]
SPI	PAA	Covalent linking by Schiff base reaction of peptides from SPI with PAA (in the presence of GA) or self-assembly by noncovalent hydrophobic interactions (without GA)	With or without GA	Drug sustained release hydrogels for globular proteins (BSA) with excellent pH sensitivity, good water uptake, and high capacity of BSA absorption	[366]
SP	AAc Carbopol MBA AAm	Chemical crosslinking by copolymerization to obtain SPI-carbopol-PAAm hydrogels (in the presence of TEMED/KPS redox initiator)	No crosslinker	Dual (chloroquine diphosphate and curcumin) pH sensitive release hydrogels for antimalaria infection	[367]
Brain injury
Keratin	PNIPAAm	Oxidative crosslinking method via the thiol-ene ‘click’ reaction between thiol group of the keratin and the ethylene bond of the NIPAAm	No crosslinker	Deferoxamine mesylate loaded thermo-sensitive injectable hydrogel for iron-induced brain injury after intracerebral hemorrhage (ICH); they can fill up the complex shapes of lesion cavities easily due to the sol-gel transition, which provided faster iron adsorption speed, and then relieving the iron overload and brain damage after ICH	[368]
Soy protein (SP)	PU	Mixing of PU nanoparticles dispersion (which is stable in water because of the negative charge of dissociated hydrophilic -COOH group) with protein solution in order to shorten the gelation time; the exact interaction between SPI and PU is not specified	No crosslinker	Hybrid thermo-responsive 3D bioprinting ink in neural tissue engineering	[331]
Type I Collagen from rat tail	Block copolymer of polypyrrole (PPy), conducting polymer, and PCL	Bioprinting	No crosslinker	Biodegradable and conductive hydrogel for neural tissue engineering	[369]