Table 3.

Heteropolysaccharide-based hybrid hydrogel systems with biomedical applications.

Hybrid Hydrogel Composite	Obtainment Method	Properties	Application	Reference
Alginate-based hybrid hydrogels
PVA/alginate (Alg)	Physical crosslinking of PVA, followed by chemical crosslinking with alginate	* highly porous, open-cellular pore structures * pore size very 290–190 μm, depending on PVA concentration * scaffolds softer and more elastic than the control alginate, without affecting the mechanical strength * better cell adhesion and faster growth than the control alginate	Scaffolds for cartilage tissue engineering	[196]
PVA/SA hydrogel, containing nitrofurazone	FT method	* increase of SA concentration in PVA hydrogel films increased the swelling ability, elasticity, and thermal stability of PVA/SA hydrogel system * increase of SA content led to significant decreases in gel fraction %, and mechanical properties of PVA/SA hydrogel * low SA content resulted in a decreased protein adsorption, indicating a better blood compatibility	Wound dressing	[197]
Biodegradable PVA/SA-clindamycin-loaded hydrogel film	Physical crosslinking conducted by the FT method	* increasing SA concentration decreased the gelation (%), maximum strength and break elongation, but it resulted in an increase in the swelling ability, elasticity and thermal stability of the hydrogel film * SA content had an insignificant effect on the release profile of clindamycin from the PVA/SA film, whereas PVA/SA-clindamycin improved the healing rate of artificial wound in rats	Wound dressing	[198]
PVA/Alg (1/1 weight ratio) nanofiber hydrogels	In situ crosslinking using citric acid (5 wt%) + curing at 140 °C, for 2 h + conditioning at room temperature	* enhanced thermal stability and insolubility in both water and simulated body fluid (SBF) for 2 days	Tissue engineering	[199]
PVA/calcium alginate nanofiber web	Electrospinning technique	* a maximum calcium alginate content showed the maximum water vapor transmission rate that help in maintaining the local moist environment for accelerating wound healing * apparently new epithelium formation without any harmful reactions, when the wound is covered with the PVA based nanofiber	Wound healing	[200]
PVA/Alg reinforced with cellulose nanocrystals (CNCs)	Acidic hydrolysis	* fibrous porous structure (95.2% porosity) and improved mechanical stability * good properties for in vitro cell attachment	Scaffolds with good proliferation for fibroblast cells	[201,202]
Chondroitin sulfate-based hybrid hydrogels
Chondroitin sulfate (CTS)/PEG	FXIIIa-mediated crosslinking of chondroitin sulfate grafted with PEG	* tuned growth factor binding and release * promoting of stem cell proliferation and osteogenic differentiation	Treatment of osteogenesis	[203]
PVA/HA/CTS hydrogels	Gamma irradiation (5–25 kGy)	* hydrogels with a higher content of HA/CTS exhibited higher enzymatic degradation rates * PVA/HA/CTS hydrogels cultures with human keratinocytes (HaCaT) showed higher cell viability (more than 90%), when compared to the control sample	Potential application in skin tissue engineering	[204]
Glucan-based hybrid hydrogels
PVA/glucan films	Physical blending, followed by drying at 110 °C, without using chemically crosslinking	* no covalent bond between PVA and glucan was found in the formed film; glucan can be released to facilitate wound healing * an increase in glucan content led to a decrease in the tensile strength and an increase of the breaking elongation * a high glucan content with PVA film can hinder the cell mobility and prolong the time of healing * healing time of wound can be shortened by 48%, when glucan content is optimized	Wound dressing	[205]
Chitosan (CS) and chitosan derivatives-based hydrogels
PVA/CS hydrogels	Crosslinking induced by exposure to different doses of γ-radiation	* gel fraction and mechanical properties of the hydrogels increased with increasing PVA concentration and irradiation dose * swelling ability of the hydrogels increased with increasing the CS content	Prevention of microbiological growth, such as bacteria, fungi and microorganisms, with possible use as wound dressing material	[206]
PVA/CS hydrogel membranes	FTcycle, followed by γ-irradiation process	* larger swelling capacity, high mechanical strength, lower water evaporation, and high thermal stability were obtained * good antibacterial activity against Escherichia coli with increasing CS content	Wound dressing	[207]
Addition of glycerol into PVA/CS hydrogels	Irradiation followed by FT	* acceleration of the healing process of wounds in a rat model * nontoxicity toward L929 mouse fibroblast cells * mature epidermal architecture was formed after the 11th day postoperatively	Wound dressing	[208]
Temperature-sensitive CS/PVA hydrogel	Chemical crosslinking, using glutaraldehyde	* the release of paclitaxel (PTX) in PBS (pH 7.4) is sustainable for 13 days * the antitumor activity of the drug-loaded composite hydrogel is 3.7 fold higher than that of Taxol	Intratumoral delivery of PTX	[209]
PVA/CS hydrogel loaded with vitamin B12	Physical blending between different portions of PVA and water soluble CS, followed by treatment with formaldehyde to convert –NH2 group of CS into -N=C group in PVA/CS membranes	* increasing of CS content increases water content, water vapor transmission, and permeability of loaded vitamin B12 through PVA/CS membranes	Potential biomedical applications	[210]
Minocycline loaded PVA/CS hydrogel films	FT method	* high CS concentrations decreased gel fraction, mechanical properties, and thermal stability, and it increased the swelling ability, water vapor transmission, elasticity, and porosity of PVA/CS hydrogel films * faster healing of the wound when compared to the conventional sterile gauze control	Wound dressing	[211]
Nano-insulin loaded CS/PVA hydrogel	Chemical crosslinking, using glutaraldehyde as the cross-linking agent	* miscibility of nano-insulin and hydrogel * porous structure, with good deformability and flexibility * constant release of the insulin * high permeation rate of nano-insulin	Transdermal insulin delivery	[212]
CS / PVA nanofiber mats	Electrospinning, using different CS salts (CS-hydroxybenzotriazole (HOBt), CS-ethylenediaminetetraacetic acid (EDTA), and CS-thiamin pyrophosphate (TPP))	* increase of the swelling degree with increasing CS; concentration, whatever the CS salt * no toxic compounds that reduce the cellular growth of fibroblasts * highest antibacterial activity and better healing activity were obtained for CS-EDTA/PVA fiber	Wound healing system	[213]
PVA/CS/gelatin hydrogel, incorporating polycaprolactone microspheres	Physically incorporation	* improvement of the mechanical properties by PVA * improvement of cell adhesion by gelatin	Delivery of basic fibroblast growth factor (bFGF)	[214]
CS/gelatin/PVA hydrogels	Gamma-irradiation	* increase of the swelling capacity with increasing the CS/gelatin ratio * 3D network structure with a good evaporation rate * about 10–20% water retained in 24 h; * good coagulation effect	Wound dressing	[215]
Gelatin/CS/PVA/ Arabic gum nanofibers	Electrospinning	* steady permeability of large molecules (e.g., BSA) * excellent cell attachment and proliferation	Wound healing	[216]
Gelatin/CS/PVA hydrogels	FT process	* non-toxic for the HT29-MTX-E12 cell line	Potential for tissue engineering applications	[217]
CS/polyethylenimine (PEI) 3D hydrogels	Physical mixture	* stable under cell culture conditions * could support the growth of primary human fetal skeletal cells	Gene transfection agent	[218]
CS-PEG co-polymer (CS-g-PEG)	Chemically grafting of monohydroxy PEG onto the CS backbone, using Schiff base and sodium cyanoborohydride chemistry	* obtainment of an injectable, thermoreversible gel * by optimizing PEG content (45–55 wt.%) and PEG molecular weight, the resultant system underwent a thermoreversible transition from an injectable solution at room temperature to a gel at body temperature	Potential carrier matrices for a wide range of biomedical and pharmaceutical applications	[219]
Thermo-responsive PEG-grafted CS hydrogel	Physical crosslinking	* steady protein release pattern for a period of 70 h after an initial burst release in the first 5 h * by crosslinking with genipin, it was obtained a prolonged quasi-linear release of the protein for up to 40 days; the initial burst release was reduced	Sustained BSA release	[220]
Injectable composite scaffold obtained from collagen-coated polylactide micro carriers/CS hydrogel	Physical crosslinking	* collagen-coated polylactide micro carriers enhanced the mechanical properties * cell metabolic activity increased before 9 days of in vitro chondrocytes growth within the scaffold * after 9–12 days, confluent cell layers were formed	Tissue engineering applications, particularly in orthopedics	[221]
CS/Poly(ε-caprolactone) (PCL)/polypyrrole	Electrospun	enhanced attachment and proliferation of PC12 cells	Neural tissue substrate	[222]
Maleiated CS/thiol-terminated PVA	Solvent casting	fetal porcine hepatocytes survived at least 14 days	Hepatocyte attachment	[223]
PVA/carboxymethyl chitosan (CM)-chitosan hydrogels	Electron beam rosslinking at room temperature	* mechanical properties and swelling degree improved after adding CM-chitosan * considerable antibacterial activity against E. coli for a low CM-chitosan content	Antibacterial activity	[224]
PVA/CM/honey	FT method	* inhibition of the growth of Escherichia coli bacteria * presence of honey leads to faster wound healing	Wound dressing	[225]
Carboxyethyl chitosan (CE)/PVA nanofiber mats	Electrospinning of aqueous CE-chitosan/PVA solution	* CE-chitosan/PVA nanofiber mat was nontoxic to the L929 cells * good in promoting the L929 cell attachment and proliferation	Skin regeneration and healing	[226]
PVA/quaternary chitosan (Q-chitosan mats	Photo-crosslinking electrospinning technique	* efficient inhibition toward growth of Gram-positive and Gram-negative bacteria	Wound dressing applications	[227]
Q-chitosan/polyaniline/ oxidized dextran (DEX)	Lyophilization	High antibacterial activity and enhanced proliferation of C2C12 myoblasts	In situ forming antibacterial and electroactive hydrogels	[228]
Quaternary ammonium chitosan/PVA hydrogels	Gamma irradiation, at different radiation doses and for different polymer ratios	* very good swelling ability (1000–4000%), water evaporation rate and mechanical properties * for doses <40 kGy, the tensile strength increases with increasing the radiation dose * higher crosslinking degree of the hydrogel with increasing the radiation dose * for doses >40 kGy, the hydrogel degraded * inhibition of the growth of Staphylococcus aureus and Escherichia coli	Antimicrobial system	[229]
Poly-4-styrenesulfonic acid/methacrylated glycol CS (MeGC) hydrogel or poly-vinylsulfonic acid/MeGC	Photo-crosslinking	* the initial burst was decreased after adding PSS or PVSA * higher human bone morphogenetic protein-2 (BMP-2)-induced osteogenesis differentiation	Efficient protein delivery	[230]
pH and temperature dual-sensitive hydrogel between glycol chitosan and benzaldehyde-modified Pluronic	Schiff base reaction	in physiological conditions, it was obtained the release of doxorubicin (DOX) and prednisolone from the hydrogels, without any initial burst release	Drug delivery system	[231]
Thermo-responsive Pluronic grafted CS hydrogel	Grafting of Pluronic onto chitosan using EDC/NHS chemistry	* higher mechanical properties than Pluronic hydrogels * in vitro culture of bovine chondrocytes in the hydrogel showed that the cell number and synthesized glycosaminoglycan (GAG) increased spontaneously over a period of 28 days	Cartilage regeneration	[232]
CS-Pluronic nano-hydrogel with targeting peptides	Photo-crosslinking	* high accumulation efficiency in brain tissues	Delivery of β-galactosidase to brain	[233]
CS-Pluronic hydrogels with encapsulated recombinant human epidermal growth factor (rhEGF)	Photo-croslinking	* the release of rhEGF is highly related to the degradation rate of the hydrogels * difference in rhEGF release patterns within 1 day, for different photoirradiation time (2 min–5 min) * epidermal differentiation is highly enhanced * good muco-adhesive property with animal skins	Wound curing	[234]
Semi-interpenetrating polymer network CS/ PEG/acrylamide (AAm) hydrogels	Chemical crosslinking	* increase of the protein half-life * improvement of the CS biocompatibility * increasing PEG content increased the swelling ratio, protein loading capacity, and entrapment efficiency	Closed-loop insulin delivery	[235]
Methacrylate derivative of CS/poly(ethylene oxide diacrylate) (PEODA)	Photo-crosslinking (intensity of UV light ≈ 10 mW/cm2, at a wavelength of 365 nm)	* good mechanical strength * degradation of the gels in the presence of chondroitinase enzyme in a dose-response manner * no degradation in the absence of the enzyme * compatibility with chondrocytes	Cartilage tissue engineering	[236]
Hyaluronic acid-based hybrid hydrogels
Maleiated HA/thiol-terminated PEG	Mould-casting	quick gelation, porous structures, tunable degradation, and cytocompatibility with L929 cells	In situ formed scaffolds for tissue engineering	[237]
HA/PEG-diacrylate coencapsulated with TGF-β-3	Photo-crosslinking	Cartilage differentiation	Cartilage tissue engineering	[238]
Injectable hydrogels of thiolated HA and 4-arm PEG-vinyl sulfone	Michael-type addition reaction	* gelation time decreased with the increase in the molecular weight (45–185 kDa) of HA * degradation time increased (15 days) with the molecular weight of HA and its degree of substitution * degradation in the presence of chondrocytes increased after 14 and 21 days, maybe due to the production of hyaluronidase enzyme by the incorporated chondrocytes	Cartilage tissue engineering	[79]
Methacrylated HA/N-vinyl pyrrolidone, using Alg as a temporal spherical mold	Photo-polymerization (long wavelength UV, 7W/cm2—intensity)	* degradable in the presence of hyaluronidase enzyme	Cartilage tissue engineering	[239]
Hybrid injectable hydrogel, consisting of deferoxamine-loaded poly(lactic-co-glycolic acid) nanoparticles (NPs) incorporated into a HA/CS hydrogel	Physical crosslinking	* angiogenesis was induced by deferoxamine drug release, but also by the presence of HA/CS hydrogel * cytocompatibility and cell proliferation * maximal blood vessels formation * beneficial effect of deferoxamine for neovascularization after 28 days when compared to HA/CS hydrogel	Suitable support for microvascular extension	[240]
Hydrogels of HA with thermosensitive poly(N-isopropyl acrylamide-co-acrylic acid), incorporated with dexamethasone and growth factor TGF β-3	Temperature-induced crosslinking	* enhancement of chondrogenic differentiation and expression of aggregan, collagen type I and type II	Injectable tissue engineering construct for cartilage repair	[241]
Xanthan gum-based hybrid hydrogels
PVA and xanthan gum (XG), in different molar ratios	Crosslinking, using trisodium trimetaphosphate	* for a molar ratio of 4:1 between PVA and XG, mechanical, swelling, and thermal properties superimposed with those of human nucleus pulposus (HNP) tissue * the hydrogels did not show any signs of cytotoxicity towards mouse fibroblasts (NIH3T3)	Good candidate as a potential HNP substitute	[242]
Hybrid (chitosan-g-glycidyl methacrylate) (CS–g–GMA)/xanthan hydrogel	Dissolved CS-g-GMA was mixed with the xanthan solution, under nitrogen gas flow, while keeping the temperature at 50 ± 1 °C under constant magnetic agitation	viability of fibroblasts when cultured onto the synthesized hydrogels	Potential for use in biomedical engineering applications	[243]
Heparin based hybrid hydrogels
Hep/PEG hybrid gels	UV-initiated thiolene reaction between thiolated Hep and diacrylated poly(ethylene) glycol (PEG-DA)	* hepatocyte growth factor (HGF) was retained after 5 days in the hybrid Hep/PEG hydrogel microstructures, but was rapidly released from pure PEG gel microstructures * hepatocytes residing next to Hep/PEG hydrogels were producing ∼4 times more albumin at day 7, compared to cells cultured next to inert PEG hydrogels	* Designing cellular microenvironment in vitro * Vehicles for cell transplantation in vivo	[244]
Hep-based hydrogel system, formed by thiolated heparin and diacrylated PEG	Michael-type addition reaction	* encapsulation by the Hep -based hydrogel did not affect the chondrocyte viability (better than calcium-induced alginate gel) * hydrogel promoted chondrocyte proliferation, while maintaining chondrogenic nature	Promising material for chondrocyte culture, potentially applicable for cartilage regeneration	[245]
Hep/acrylated PEG hydrogel, with rat hepatocytes entrapped	Michael-type addition reaction	* the hydrogel was non-cytotoxic to cells, and promoted the hepatic function * hepatocytes entrapped in the Hep-based hydrogel maintained high levels of albumin and urea synthesis after three weeks in culture * hepatocyte growth factor (HGF) incorporated in the hydrogel was released in a controlled manner (only 40% of GF molecules released after 30 days in culture)	Good characteristics for matrices for in vitro differentiation of hepatocytes or stem cells and as vehicles for transplantation of these cells	[246]
Hep-based hydrogel sheet containing thiolated Hep and diacrylated PEG	Photo polymerization	* in vitro sustained release profile of human epidermal growth factor (hEGF) loaded in the hydrogel * acceleration of the wound healing after application of the hydrogels * advanced granulation tissue formation, capillary formation, and epithelialization in wounds treated by hEGF loaded Hep-based hydrogel	Wound healing	[247]
Hep-poloxamer/decellular spinal cord extracellular matrix (dscECM), used for fibroblast growth factor-2 (FGF2) attachment	EDC/NHS method	* treatment with FGF2-dscECM-HP hydrogel induced the recovery of the neuron functions and tissue morphology in rats that suffered from spinal cord injury (SCI)	Delivery of macromolecular proteins	[248]