Hydrogels based on cellulose and chitin: fabrication, properties, and applications

This review is focused on the fabrication, properties, and applications of hydrogels prepared from two of the most abundant biopolymers on earth, cellulose and chitin. The review emphasizes the latest developments in hydrogel preparation (including solvent systems, cross-linker types, and preparation methods, which determine the “ greenness ” of the process) using these biocompatible and biodegradable biopolymers. The preparation of both physical (without covalent cross-links) and chemical (with covalent cross-links) hydrogels via dissolution/gelation is discussed. Additionally, formation of injectable thermoset and/ or pH sensitive hydrogels from aqueous solutions of derivatives (chitosan, methyl cellulose, and hydroxy-propylmethyl cellulose) with or without a cross-linker are discussed. This review also compares the design parameters for di ﬀ erent applications of various pure and composite hydrogels based on cellulose, chitin, or chitosan, including applications as controlled and targeted drug delivery systems, improved tissue engineering sca ﬀ olds, wound dressings, water puri ﬁ cation sorbents, and others.


Introduction
Hydrogels are physically or chemically cross-linked threedimensional (3D) hydrophilic polymeric networks capable of absorbing large amounts of water (or biological fluids) and swelling. 1 Any (semi-)flexible polymer is able to virtually formulate hydrogels in a variety of physical forms including slabs, membranes, beads, microgels (microspheres), and nanogels (nanoparticles), and once freeze-dried or supercritically dried, hydrogels become cryogels or aerogels, respectively. 2 Hydrogels are held together by either physical interactions (chain entanglements, van der Waals forces, hydrogen bonds, crystallite associations, 3 and/or ionic interactions 4 ) or chemical cross-links (covalent bonding 5 ).
Among the biopolymers, cellulose and chitin are two of the most abundant on earth, thus having great potential in hydrogel preparation. Cellulose consists of a straight chain of β-(1→4)-linked D-glucose units, and chitin, structurally similar to cellulose, is a long-chain co-polymer of β-(1→4)-linked 2-acetamido-2-deoxy-β-D-glucose units, with acetamide groups in the C-2 position. If the degree of acetylation (%DA) of the biopolymer is lower than 50%, it is no longer called chitin, but chitosan. 29 The plentiful hydrophilic functional groups (hydroxyl-and/or amino-) in the backbones of either cellulose or chitin qualify them as promising materials for highly absorbent hydrogel systems.
In this review, we discuss cellulose and chitin hydrogels with emphasis on their fabrication, properties, and applications. Given that chemically modified cellulose and chitin polymers may result in improved processability and/or unique characteristics, hydrogels from several common derivatives of cellulose and chitin are also discussed, including methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC), sodium carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), and chitosan.

Dissolution of native cellulose and chitin
Most hydrogels based on native cellulose or chitin are usually prepared through a two-step process involving dissolution followed by cross-linking (i.e., gelation), although culturing specific bacteria can produce hydrogels directly (discussed in the "physical hydrogels" section below). Specific solvent systems are required to dissolve native cellulose and chitin, which possess poor solubility characteristic due to the numerous inter-and intra-molecular hydrogen bonds between polymeric chains.
To date, only a few solvents have been used for the dissolution of native cellulose or chitin (Table 1). These include some conventional polar solvent systems such as N-methylmorpholine oxide (NMMO), 30 lithium chloride/dimethylacetamide (LiCl/ DMAc), 31,32 paraformaldehyde/dimethylsulfoxide (PF/DMSO), triethylammonium chloride/dimethylsulfoxide (TEAC/DMSO), 33 tetrabutylammonium fluoride/dimethylsulfoxide (TBAF/ DMSO), 34 lithium chloride/N-methyl-2-pyrolidone (LiCl/NMP), 35 a Choline bromide (ChBr); choline chloride (ChCl); dimethylacetamide (DMAc); dimethylsulfoxide (DMSO); freeze/thaw (F/T); microcrystalline cellulose (MCC); methanol (MeOH); N-methylmorpholine-N-oxide (NMMO); N-methyl-2-pyrolidone (NMP); paraformaldehyde (PF); room temperature (RT); supercritical-drying (Sc-dry); tetrabutylammonium fluoride (TBAF); triethylammonium chloride (TEAC). b Cast: cast on a glass or ceramic plate followed by coagulation; bead: drop, 32 inject, 38 extrude, 73 or spray/atomize/nebulizer 65 into the coagulant, spay-drying, 74 or ion exchange; 31 mold: pour in a vial or a specific mold followed by curing and/or coagulation; cure: stand at various temperatures (5-60°C) for a certain time (minutes-weeks). c The "a" and "b" refer to the same dissolution process but different gelation procedures. and calcium chloride dihydrate/methanol (CaCl 2 ·2H 2 O/MeOH). 26 Although the use of these polar solvents has somewhat alleviated the issues with the biopolymer's intractability, the toxicity or corrosivity of these organic components can inhibit batch production and potential applications of the resulting gels. Recent alternatives for cellulose and chitin dissolution and hydrogel production include ionic liquids (ILs), deep eutectic solvents (DESs), and alkali or alkali/(thio)urea aqueous systems developed since the 2000s. Various ILs used for cellulose dissolution consist of an imidazolium, pyridinium, ammonium, or phosphonium cation paired with a strongly basic, hydrogen bond accepting anion (e.g., OAc − , HCOO − , 36 44 Deep eutectic solvents (DESs) are fluids obtained by heating two or three components that are capable of self-association through hydrogen bonding. DESs have almost identical physicochemical properties to those of ILs except that they do not entirely consist of ionic species and may be cheaper. 45,46 The classic examples are the combinations of choline chloride (mp 302°C) with urea (mp 133°C) or thiourea (mp 175°C), forming a DES with a mp of 12°C or 69°C, respectively. 47 Although dissolution of both chitin and cellulose in DESs has been verified, 46 there is only a single report on self-assembly of chitin in such solvents ( producing a soft chitin gel) and no research on cellulose gelation yet to date. 48 Another solvent system for cellulose or chitin dissolution and gelation are the alkali/urea (or thiourea) aqueous systems developed in L. Zhang's group. 49,50 Typically, the dissolution power of alkali/urea solvent systems is in the order NaOH/ thiourea > LiOH/urea > NaOH/urea ≫ KOH/urea aqueous solution. 49,51 In particular, the dissolution process in alkali/ urea systems is very different from that in other solvents mentioned above, i.e., a low temperature treatment (by precooling the solvent 52 or freezing/thawing the mixture 50 ) is needed instead of stirring at room temperature (RT) or high temperatures. This may be because the dissolution of polymers in aqueous systems is an entropy-driven process (i.e., the entropy of the polymers in dissociated state increases significantly compared with that in the crystalline state), whereas in other solvents it is not (e.g., the entropy of the polymer chains after dissolution in IL increases very slightly or even decreases). 52,53 Although the mechanism of the dissolution of cellulose or chitin in all these solvents has not been fully determined, the widely accepted opinion is that hydrogen bond acceptors (N-O, Cl − , OAc − , etc.) and/or donors (-NH 2 in urea or thiourea) of the solvent break up the intra-and inter-molecular hydrogen bonds in the biopolymer chains upon stirring, heating, or low temperature treatment. 36,46,50,54,55 3. Physical hydrogels Physical hydrogels are cross-linked by physical interactions such as chain entanglements, van der Waals forces, hydrogen bonds, hydrophobic or electronic associations. For cellulose and chitin, physical hydrogels have been prepared from four major biopolymer sources: native cellulose or chitin powders (dissolved in specific solvents presented as above), from nanowhiskers (dispersed in water), from biopolymer derivatives (dissolved in water or acid), and from bacterial cellulose (BC; dissolved in specific solvents presented as above; or biosynthesized directly into gels during bacterial culture).

Hydrogel formation from native cellulose or chitin
Cellulose and chitin polymers in solution behave as random coils, semi-flexible (or semi-rigid) chains, or entangled chains, and the degree of entanglement depends on the polymer concentration. [56][57][58][59][60] While polymer solutions of low concentrations are completely isotropic, with increasing polymer concentration, the transition from solution to a liquid crystalline gel takes place followed by gelation into a solid gel that has an anisotropic structure. 31,37 The gel structure becomes more and more organized and stable as biopolymer concentration increases due to the higher degree of entanglements and the more hydrogen bonding interactions that exist. 37 Further, upon curing (i.e., keeping the solution at various temperatures between 5-60°C for minutes or weeks) [61][62][63] or coagulation (i.e., immersion in certain antisolvents such as water, 38 ethanol, 32 methanol, 26 H 2 SO 4 / Na 2 SO 4 , 64 etc.) in various fashions (e.g., beading, molding, or casting; 30,31,34,[65][66][67][68][69][70][71][72][73][74] Table 1), the physicochemical interactions between the polymer chains increases and the stability of the hydrogel enhances.
Usually, physical associations are reversible, leading to a thermo-reversible and "green" (without cross-linkers) sol-gel transition process. 75,76 However, if (a) the reversible gel is coagulated in an anti-solvent, or (b) the NaOH/urea (or thiourea) solvent denatures at high curing temperatures (>60°C, resulting in a yellow color) via reaction and thermal decomposition of the solvent molecules, 54,77 the solvents are washed out (in "a") or destroyed (in "b"), resulting in formation of socalled irreversible gels. Such irreversible physical gels, when vacuum-or supercritically-dried, exhibit lower degrees of crystallinity (reduced by 9-22%) than native cellulose or chitin. 32,43,78 In addition, cellulose I changes to cellulose II and β-chitin changes to α-chitin, respectively, after dissolution and gelation. 26,79 3.1.1. Transparency. The property of "clarity" of hydrogels, or their transparency, is determined as their ability to transmit light, and is measured as light transmittance. Once formed, the transparency of hydrogels differs and depends on the curing temperature or coagulation bath used as a result of the degree of phase separation (so-called spinodal decomposition or spinodal phase separation, where one thermodynamic phase forms two coexisting phases) during the formation of hydrogels. 33,54,64,78 For hydrogels prepared in NaOH/urea aqueous systems, an increase in curing temperature causes a large decrease in transparency (e.g., 85% transmittance at −10°C, 66% transmittance at 20°C, and nontransparent at and above 30°C). This is caused by the increased degree of phase separation and thereby enhanced hydrogel heterogeneities (i.e., the number and size of the resulting polymer aggregates). 54,78 On the other hand, when coagulative regeneration is used, the transmittance can be tuned through control of the degree of phase separation in the sample using a certain amount of coagulant (e.g., water). 34 Incorporation of acetone into water as a coagulation solution increases the transparency of the hydrogels, which may be related with a "specific polymer structure" formed resulting from the balance between swelling of the gel by water and shrinking by acetone. 33 A novel method, deionization of the cellulose/LiCl/DMAc solution with ion exchange resins, has been reported for preparation of gel beads that appear colorless and transparent without a fibrous texture compared with the "water-coagulated gel", probably because the molecular association (crystallite formation) precedes the phase separation during ion exchange. 31 3.1.2. Strength. The strength of hydrogels is yet another well-studied characteristic. In many cases, improved strength comes with higher transparency, and similarly depends on the degree of phase separation discussed above. For example, hydrogels prepared from chitin/NaOH/urea solution through coagulation in acidic or aqueous salt solutions have smoother surfaces, more homogeneous structure, relatively smaller pore sizes, and thus improved tensile strength and transparency compared with those coagulated in water, ethanol, or acetone. 64 Tensile strength is also affected by biopolymer concentration and curing conditions, i.e., higher concentration and curing treatment result in stronger hydrogels owing to the more homogenous and/or more intertwined structure. 63,78 In addition, the mechanical strength of physical hydrogels can be improved by employing a pre-gelation process before performing coagulation as shown in the example of cellulose hydrogel beads from a NaOH/thiourea solution. In this example, hydrated cellulose membranes were packed densely with many nanospheres (200-510 nm according to the pregelation temperature). 61 This could be attributed to the thiourea inclusion complex aggregates (47-160 nm) in which the cellulose chains associated with NaOH hydrates as guests were encaged by NaOH and thiourea. 62,80

Hydrogel formation from cellulose or chitin nanowhiskers
The main process for the isolation of cellulose nanowhiskers (CNWs) and chitin nanowhiskers (ChNWs) from cellulose and chitin fibers, respectively, is based on acid hydrolysis (usually sulfuric acid for CNWs and hydrochloric acid for ChNWs) of the polymer(s). 81,82 The nanoscale size (3-50 nm in width, 0.1-2 µm in length) 83,84 and electrostatic repulsions (negatively charged sulfate groups on CNWs, positively charged amino groups on ChNWs) promote a perfectly uniform dispersion of the whiskers in water. As with native cellulose and chitin, the dispersed whiskers are also able to concentrate and self-organize into nematic or solid gels above a certain concentration. 85,86 Production of stable solid nanowhisker-based gels was achieved through further treatment of the nanowhisker aqueous suspensions, using solvent exchange, 87 ultrasonication, 88,89 dialysis (to concentrate), 90 and, most often, adjustment of pH 91 (Table 2). In ultrasonication-assisted assembly, the sonication bath provides energy with a similar order of magnitude as that of hydrogen bonds (4-50 kJ mol −1 ), 89 allowing for the rearrangement and formation of a 3D-percolated network through hydrogen bonding. The solvent exchange method with a miscible anti-solvent (routinely acetone) results in chain rearrangement and formation of robust macroscopic gels from the nanowhisker suspension. 87 Yet another method is pH adjustment; for instance, when the pH value of the ChNW suspension in acetic acid was adjusted to 10-11, the suspension immediately turned into a freestanding hydrogel even at a concentration as low as 0.5 wt% due to the elimination of repulsive interactions between the ChNW elements under basic conditions. 91 Additionally, cellulose and chitin nanowhiskers are used to reinforce some polymeric matrices, such as cellulose, 92 chitosan, 93 poly(vinyl acetate), 94 and poly(methyl vinyl ether-comaleic acid) and poly(ethylene glycol) 95,96 due to the high Young's modulus (ca. 140 GPa) of the nanowhiskers. 97,98 The nanowhisker density (i.e., content) is generally within 25%, which leads to increased thermal stability, mechanical strength, and overall Young's modulus, but decreased water uptake of the polymeric gels with the increase of whisker content. [93][94][95][96] Functionalization of nanowhiskers with carboxyl or amine groups prior to their incorporation into the polymer networks results in mechanically and hydrophilically adaptive, pH-responsive nanocomposite gels. 99 Once formed, the transparency of nanowhisker-based gels is determined theoretically by the thickness of the gels or the density of the whiskers since a single nanowhisker has a  90 and when used as reinforcement, both cellulose and chitin nanowhiskers can retain the transparency of the polymer matrix (e.g., chitosan, 93 and poly-(acrylic acid) 100 ) to different extents depending on the whisker density.

Hydrogel formation from cellulose or chitin derivatives
The most widely used biocompatible derivatives of cellulose and chitin are hydrophobically modified cellulose (MC and HPMC) and chitosan (deacetylated chitin), respectively. These derivatives are much easier to fabricate into hydrogels because they are water-or acid-soluble. MC and HPMC are water soluble due to the fact that hydrogen bond formation is prevented by the introduction of pendant groups; and chitosan can be dissolved in dilute acid aqueous solutions (e.g., dilute acetic acid). From aqueous solutions of these derivatives, unique hydrogels such as thermoset and pH-sensitive hydrogels can be formed either with or without the addition of a physical cross-linker that can introduce hydrophobic or electrostatic associations. [101][102][103] As an example of such gels, an elastic and thermo-reversible MC gel was formed when heating the MC aqueous solution above a critical temperature, which seemed dependent on MC concentration (63°C at 0.30-2.5 wt%, 104 42.5°C at ca. 4.7 wt%, 101 32°C at 7.0 wt%, and 27°C at 9.0 wt% 105 ). An accepted mechanism of this gelation employs the concept of solvent reorganization on heating of a MC solution, where the solvated cage-like MC structure (originally formed through hydrogen bonds of water along MC chains) gets destroyed and thereby hydrophobic regions of MC are exposed, leading to the formation of hydrophobic aggregates. 104 The mechanism of formation of HPMC gels is thought to be similar, although solutions have slightly higher gelation temperatures (e.g., 70°C at 2 wt%) than MC solutions, indicating that the hydroxypropyl substituents inhibit the gelation. 106-108 These thermo-set hydrogels have much potential as injectable drug or cell carriers in vivo.
Chitosan hydrogels can be obtained by coagulation in alkaline media (such as NaOH 109 and NaOH/Na 2 CO 3 110 aqueous systems) to relieve the electronic repulsion of -NH 3 + groups between polymeric chains. To increase the strength of chitosan hydrogels, physical ionic cross-linkers (Table 3), sodium citrate (SC) 102 and tripolyphosphate (TPP), 103,[111][112][113][114] were employed, which introduced electrostatic interaction between the anion (-COO − or P 3 O10 5 − ) and cation (-NH 3 + ) into the system and led to the formation of pH-sensitive chitosan hydrogels. In such pH-sensitive chitosan hydrogels, the cross-linking density was controlled by adjusting the pH value of the ionic crosslinker solution, e.g., chitosan could be completely ionically cross-linked by P 3 O 10 5− ions in acidic TPP solution ( pH 3), whereas it was slightly ionically cross-linked in the original TPP solution ( pH 8.6). 103 Another hydrophobic cross-linker, β-glycerophosphate (β-GP), was used for formation of thermoset chitosan hydrogels that featured a gelation temperature in the vicinity of 37°C within the pH range of 6.8-7.2 (buffered by the dosage of β-GP). [115][116][117] The addition of β-GP increased pH and ionic strength of the chitosan solution, establishing a favorable environment to form a gel structure by both the screening of electrostatic repulsion and the enhancement of polymerpolymer hydrophobic interactions. 118 The protonation of chitosan, meanwhile, decreased strongly in the neutral chitosan/ β-GP solution, especially at higher temperatures, thus leading to a minor contribution of ionic cross-linking. 118

Hydrogel formation from bacterial cellulose (BC)
The properties of bacterial cellulose (BC) are quite different from those of plant cellulose, especially its high purity, ultrafine network structure, high hydrophilicity, and moldability during hydrogel formation (culturing without any crosslinker). 119 The species of bacteria capable of producing cellulose extracellularly is generally called Acetobacter xylinum (acetic acid bacteria). The culture is carried out normally in a Acetic acid (HOAc); room temperature (RT). b Shape: gelate the chitosan solution in a certain fashion (beading, casting, or molding). c Soak: soak the gel in the cross-linker solution. d Dropping the chitosan solution of high concentrations (e.g., 2% w/v) into the cross-linker solution producing beads with larger diameters, while dropping the cross-linker solution into the chitosan solution of low concentrations (e.g., 0.1% w/v) producing micro or nanogels. static conditions at ca. 28-30°C in the culture medium containing saccharides or natural saps and juices. 120 A white BC gel pellicle generates on the surface, and its thickness increases steadily with time, reaching over 25 mm in four weeks. 120 Such BC gels help the aerobic bacterial cells hold their position close to the oxygen-rich surface and protect themselves from water loss, ultraviolet lights, enemies, heavy metal ions, etc. 121 The as-biosynthesized BC gels show a slightly higher water content and ability to bind water molecules than plant cellulose gels; only 10% of the water molecules in the BC gel behave like free bulk water while the majority are more or less bound to cellulose. 122 BC gels can be easily molded into desired shapes and sizes during synthesis, e.g., tubular BC gels with proper fibril orientation were created by culturing bacteria in oxygen-permeable silicone tubes with inner diameter less than 8 mm, which hold promise for use as microvessels in medical and pharmaceutical applications. 123 BC gels could also be molded into a shape with dimensions similar to cartilage tissues (e.g., meniscus) as a potential implant 124 or a scaffold for chondrocyte proliferation. 125

Chemical cross-linkers
To guarantee the stable structure and effective swelling of cellulose-or chitin-based hydrogels, a covalently bound 3D hydrophilic network is usually required and achieved through the use of chemical cross-linkers during gelation, i.e., small bifunctional or multifunctional molecules such as 1,2,3,4butanetetracarboxylic dianhydride (BTCA), 126,127 succinic anhydride (SA), 128,129 citric acid (CA), 130,131 epichlorohydrin (ECH), 25,132 ethylene glycol diglycidyl ether (EGDE), [133][134][135] and divinyl sulfone (DVS) [136][137][138] (Table 4). Chemical cross-linkers form covalent bonds that link one polymer chain to another. According to the mechanism of cross-linking reactions, chemical cross-linkers for cellulose and chitin can be classified into two types: (a) esterifying agents including carboxylic acids and carboxylic anhydrides; and (b) etherifying agents including organochlorine, epoxide, and vinyl compounds. The first type of cross-linkers results in formation of -COOR bonds and probably a few peptide bonds (-CONH-) in chitin gels, while the second type of cross-linkers results in formation of R-O-R bonds and probably some secondary amine bonds (R-NH-R) for chitin.
Most esterification-type cross-linking reactions of biopolymers with carboxylic anhydrides require effective nucleophilic catalysis, and typically 4-dimethylaminopyridine (DMAP) has been used; examples include using BTCA and SA as crosslinkers. [126][127][128][129] In these reactions, DMAP initially reacts with an acyl group of the anhydride, forming a positive acylpyridinium intermediate and a negative carboxyl counterion. The polysaccharide molecules are deprotonated by the latter, and then attack the acyl group in the former to form an ester (Fig. 1a). 139 There is an alternative for the condensation route between carboxylic acid (e.g., CA) and biopolymer by using watersoluble carbodiimide (e.g., 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide, and N,N′-dicyclohexyl-

136-138
a Dimethylsulfoxide (DMSO); N-methyl-2-pyrolidone (NMP); tetrabutylammonium fluoride (TBAF). b Cellulose derivatives (carboxymethyl cellulose (CMC), hydroxyethylcellulose (HEC), or hydroxypropyl cellulose (HPC)) or chitosan were used. c Nanoparticles with diameters 270-370 nm were obtained and not macrogels, due to the low concentration of the biopolymer in the solution. d Chitosan beads were prepared from the acid chitosan solution through injection into an alkaline coagulant. e Soak: soak the gel in the cross-linker solution. f HPC nanogels were obtained from the 0.1 wt% emulsion with dodecyltrimethylammonium bromide (DTAB) as a surfactant above the critical micelle concentration (cmc) of the surfactant. 137 carbodiimide) as a mediation agent. 131 The mechanism potentially involves formation of a labile acyl-intermediate, capable of reacting with the biopolymer and changing itself into a nontoxic urea derivative (Fig. 1b). When changing the carboxylic acid into CMC, the cross-linking of a CMC/biopolymer composite hydrogel was achievable. 140 For etherifying cross-linkers, i.e., organochlorine, epoxide, and vinyl compounds (e.g., ECH, EGDE, and DVS 25,132-138 ), etherification generally involves reactions in aqueous alkaline conditions (alkali-catalysis) for the deprotonation of hydroxyl groups on the biopolymer, making them highly nucleophilic and reactive with the crosslinker (Fig. 1c). Some chemical cross-linkers are only applicable to deacetylated chitin or chitosan that has amine (-NH 2 ) groups, including glutaraldehyde (GA), 28,141,142 malondialdehyde (MDA), 143 hexamethylene-1,6-di-(aminocarboxysulfonate) (HDS), 93 and genipin (GNP). 74,144 One cross-linker molecule reacts with two amine groups in two chitosan units: GA and MDA cross-link to produce two Schiff bases (-CvN-), HDS results in peptide bonds (-CONH-), and GNP produces both a peptide bond and a tertiary amine (Table 5).
Cross-linking of chitosan gels can be performed either during or after the shaping (molding, casting, or beading) of the gel without the use of catalysts. The Schiff base can be further reduced using the weak reductant, sodium cyanoborohydride (NaBH 3 CN), for the formation of stable secondary amines. 143 Out of all cross-linkers, genipin is naturally obtained from gardenia fruit extract and is the most "green" (10 000 times less cytotoxic than GA 145 ), which endows the resulting gel with better biocompatibility and slower biodegradation rate. 74 4.1.1. Transparency. In general, transparency of chemical hydrogels depends not only on the degree of spinodal phase separation as for physical hydrogels, but also on the extent of cross-linking. Chemical cross-linking contributes to a highly hydrophilic 3D network with a homogeneous structure, although some cross-linkers may imbue the hydrogel with a certain color (e.g., a dark-bluish color for GNP and an amber color for GA). 141,144 According to our own research, 146 the degree of swelling may also have an impact on the transparency of chemical hydrogels, e.g., as-prepared chemical gels from cellulose-rich materials (CRMs; isolated with IL from wood) cross-linked with ECH before swelling in water appeared non-transparent, while after rinsing and swelling in water they became transparent or semi-transparent.
4.1.2. Pore size. The initial pore size of the hydrogels is affected by the preparation process, e.g., hydroxypropylcellulose (HPC) hydrogels synthesized at temperatures above the lower critical solution temperature (LCST) were microporous, whereas those cross-linked in the single-phase regime below the LCST were nonporous since the cross-linking prior to phase separation fixed the average distance of polymer chains. 136,147 However, the measured pore sizes are affected by the drying processes. The pore sizes are generally determined by SEM after lyophilizing (i.e., freeze-drying) the hydrogels, and the resulting cryogels mostly have pore sizes within the average range of 3-8 µm, which decrease with increasing biopolymer concentration or cross-linking degree. 25,132 By controlling ice crystal growth, lyophilization is able to generate various pore sizes (1-250 µm) depending on freezing conditions (temperature, freezing before or after shaping, etc.); 148 however, the gels tend to crack during freeze-drying and the resulting cryogels are highly brittle. 70,78 If supercritical drying is applied as a drying technique, aerogels with pore sizes in the nanoscale (most frequently 2-50 nm (ref. 43)) are obtained since hydrogels shrink substantially during immersion in organic solvents (methanol, ethanol, or acetone) followed by supercritical drying. 68,149 The use of organic solvents to replace the water prior to supercritical drying is generally necessary, as without this step significant foaming (40-160 µm pores) during CO 2 processing is observed. 67,150 However, there is a report stating that the shrinkage of BC gels after immersing in ethanol and supercritical drying was low, and these authors were able to obtain bigger pore diameters up to 100 µm. 151 4.1.3. Strength. The strength of chemical hydrogels is related to the biopolymer type, e.g., chitin hydrogels show higher mechanical strength than chitosan hydrogels (9.5-22 vs. 0.07-1.6 kPa) as a result of the stronger pore walls consisting of stiffer chitin chains. 132,152 The compressive stress of hydrogels increases with increasing biopolymer concentration 132 and cross-linking density. 153 Interestingly, the modulus of chemical cellulose hydrogels rises progressively with swelling after a minimum modulus is reached at a low swelling degree, which may be explained by the high intrinsic chain stiffness (large persistence length) of the cellulose backbone. 138 4.1.4. Water absorbency. There seems to be a debate about the definition of "swelling ratio"; while some reports calculate it as the mass ratio of the freshly prepared hydrogel to the dry sample, more frequently, others refer to the ratio of the "rehydrated" gel to the dry sample. The former value could be at least 2-3 times higher than the latter. In this review, we will use the latter definition. There is little research on the swelling of physical gels due to their weak structure or low swelling, so majority of the literature is related to swelling of chemical hydrogels. There are several factors that influence the water absorbency of hydrogels. First the drying procedure affects the water absorbency capacity of hydrogels. Supercritically-or freeze-dried hydrogels retain the microporosity of the gel systems and thus significantly increase the swelling properties compared with airdried, oven-dried, or vacuum dried hydrogels, whose capillary retention decreases due to the recrystallization of the biopolymers in the gel systems. The former drying methods can produce dry gels with a swelling ratio up to 60 g g −1 , 25 while the latter usually lead to low swelling ratios below 3 g g −1 . 144 Our research shows that the molecular weight (MW) of the biopolymer plays an important role in the water uptake capacity of the resulting aerogel (i.e. supercritically dried hydrogel), e.g., gels from chitin and CRM of higher MWs isolated with IL possessed higher absorbency than corresponding gels from commercial biopolymers of lower MWs. 146 Also, with an increase of polymer concentration, the swelling ratio of the hydrogel decreases significantly as a result of the decrease of pore sizes. 132 The degree of cross-linking also affects swelling properties of hydrogels somewhat, although not significantly. 25,144 The introduction of electronic repulsion forces into the gel strongly increases the swelling capacity, even using common drying (e.g., vacuum drying). It was reported that quaternized cellulose nanofibril nanopaper could swell in water and become a hydrogel with a maximal water absorbency up to 750 g g −1 . 154 Superabsorbent hydrogels with a swelling ratio up to 300-400 g g −1 were prepared by using SA or BTCA as the crosslinker because of the presence of grafted cross-linkers that still had carboxyl groups. [126][127][128][129] Finally, parameters of the aqueous medium, such as ionic strength, 128 pH, 127,131 and temperature, 25 may influence the water uptake of hydrogels (as discussed below).

Irradiative cross-linking
Irradiation is a useful method for the formation of covalent bonding between polymer chains. This method is advantageous because of the high purity of the hydrogel product without use of toxic cross-linkers, thus enlarging the applications in food and pharmaceutical industries. However, only a small fraction (17-30%) of gel aggregates (lumps) could be obtained by γ-ray irradiation at a dose of 20 kGy from 20 wt% biopolymer solutions (such as cellulose/IL/water, CMC and carboxymethyl chitosan (CMCts) aqueous solutions), with the assistance of generated hydroxyl radicals. [155][156][157] Electron beam (EB) irradiation in vacuum seems to be able to increase the gel yield, e.g., after EB irradiation, the gel fraction reached up to 55% at 20 kGy, and increased with the irradiation dose. 158,159 Further, instead of low yield and a liquid product, Petrov et al. obtained opaque spongy materials via UV irradiation from moderately frozen semi-dilute (3 wt%) aqueous polymer (e.g., HPMC, HEC, and MC) solutions with (4-benzoylbenzyl)trimethylammonium chloride (BBTMAC) as a photoinitiator. 160 It was suggested that after freezing, the photoinitiator and water molecules connected to the polymer through hydrogen bonds could form a non-frozen liquid microphase in which the polymer concentration was very high, resulting in a sufficient number of chains in close enough vicinity to bind with each other during irradiation. 160 Additionally, a "radical cross-linker" (usually N,N′-methylenebisacrylamide (MBAAm)) could be added to the solution before irradiation to enhance the gelation efficiency. 161 It has been reported that macroradicals emerge preferentially in weakened 1 and 4 positions of cellulose as a result of the fracture of C-H bonds upon irradiation, 162 while macroradicals of the derivatives are created in the side chains during radical crosslinking as shown in Table 6. 157,163 Degradation of the polymer chains competes with crosslinking during irradiation, especially at high-energy doses and low polymer concentrations (10 wt%), resulting in the destruction of network structure and decrease of tensile strength. 159 Degradation could be decreased by (a) using EB irradiation instead of γ-irradiation because of the much higher radical number created in the system under EB irradiation, or by (b) irradiation in an oxygen-free atmosphere to avoid the generation of oxides and peroxides. 164

Composite hydrogels
There are few concrete and operational applications of pure hydrogels to date, such as injectable thermoset gels (mentioned above), membrane separation, 30 and encapsulation of active species, 39 although much fundamental research on their preparation has been developed. In fact, most of the pure hydrogels may not fit one specific purpose due to the lack of some feature, structure, or property. By mixing with another polymer or inorganics, novel structural materials with advantages of both components can be obtained, which tremendously enhances the appeal of the resulting composite hydrogels in various areas. In this review, we will concentrate on two-component composite hydrogels made from cellulose, chitin, or chitosan as a matrix for various applications.

Natural polymer-based hybrid hydrogels
The preparation processes of composite hydrogels are based on those of pure hydrogels, including dissolution (or dispersion) and cross-linking. Compared to making pure hydrogels, the only extra step during formation of natural polymerbased hybrid hydrogels is the mixing of two biopolymer solutions (usually using the same solvent) before shaping into a gel with or without a cross-linker (identical to those mentioned above). The second biopolymer can also be incorporated by impregnation after obtaining the cellulose or chitin scaffold. 165 When blending with biopolymers such as CMC, sodium alginate and pectin, which have carboxyl groups on the polymer chains, the hydrogel system can be cross-linked particularly with divalent or trivalent ions, e.g., Ca 2 + and Al 3 + , owing to their chelate formation with the carboxyl groups (Fig. 2). 166,167

Biopolymer/synthetic polymer hydrogels
When mixing with synthetic polymers (e.g., polyethylene glycol (PEG) and polyvinyl alcohol (PVA)), the preparation processes are identical to those of natural polymer-based hybrid hydrogels. [168][169][170][171] However, for the grafting, the monomers of the synthetic polymer are often homopolymerized in the cellulose or chitin solution with the assistance of an initiator upon heating, 172,173 irradiation (microwave, 174,175 Electron-Beam, 176,177 UV irradiation 178 ) or both. 179 In some cases, grafting can take place before polymerization, e.g., acrylic acid (AA) was able to link first to the biopolymer via esterification, acting as the active grafting sites on the chains for polymerization. 180 There are a variety of initiators reported in the literature including potassium persulfate (PPS), 181 ammonium persulfate (APS), 182 ceric ammonium sulfate (CAS), 183 cerium ammonium nitrate (CAN), 184 benzoyl peroxide (BPO), 173 2,2′-azobisisobutyronitrile (AIBN), 172 trihexyltetradecylphosphonium persulfate (TETDPPS), 185 and the photoinitiator 2,2-diethoxyacetophenone (DEAP). 178 As an example, sulfate ion radicals (SO 4 −• ) are produced from PPS upon thermal dissociation, which further react with water molecules in the solution to generate hydroxyl radicals (OH • ). Both radicals react with monomers and cellulose   and produce active sites (CvC • of monomers, and -O • on side chains of cellulose) for polymerization and grafting to further produce a branched composite network. Meanwhile, the radical cross-linker, MBAAm, can be applied to chemically cross-link the network.

Biopolymer/inorganic hydrogels
To introduce inorganics into the hydrogel network, several approaches have been adopted: (a) simply mixing the target inorganics with the biopolymer solution followed by shaping into a gel; [186][187][188] (b) transition of the inorganic precursor into target inorganics in the biopolymer solution (or suspension) along with (or followed by) gelation; [189][190][191] (c) in situ transition of the precursor in the hydrated gel or dry scaffold; [192][193][194][195][196][197][198][199] or (d) using BC as a template for the ordered deposition of target inorganics during fermentation. 200 The precursors for various inorganics and the corresponding transition processes are listed in Table 7.
6. Applications 6.1. Drug delivery 6.1.1. Controlled release. Incorporation of a second component into the hydrogel system at different dosages will change the structure and morphology of the network, subsequently controlling their diffusion properties. CMC in the hydrogel system contributes to enhanced pore sizes due to the electronic repulsion of carboxyl groups, leading to a large swelling ratio (in this paper defined as the mass ratio of the original hydrogel to the dried one) of 1000 g g −1 , as well as faster release of protein drugs. 220 Another biopolymer, lignin, also leads to a more homogenous and less dense structure of the resulting composite hydrogel, and an increase in lignin content causes an increase in release rate. 221 On the other hand, the higher density and the homogeneous, smaller pores in the chitin or cellulose nanowhisker nanocomposites, allow not only a reinforcing stucture, 92,93 but also a slow release rate, thus avoiding burst release. 92 Such composite gels with composition-controlled release properties (within hours) are generally applied in vitro in near-neutral pH media such as 19/1 water/ethanol solution, simulated body fluid (SBF), phosphate buffer solution (PBS), or simulated intestinal fluid (SIF) as shown in Table 8. 92,220,221 Drug release from hydrogels can also be controlled by using gel structures that can change reversibly in response to environmental stimuli. Temperature-sensitive hydrogels are probably the most commonly studied class of environmentallysensitive polymer systems in drug delivery research. 222 The common characteristic of temperature-sensitive polymer networks is the presence of hydrophobic groups, such as methyl, ethyl, propyl groups, etc. As temperature increases, interpolymer chain associations through hydrophobic interactions among hydrophobic segments strengthen, resulting in the shrinking of the hydrogel. When grafting N-isopropylacrylamide (NIPAAm) or N-vinylcaprolactam (NVCL) on cellulose or chitosan, negatively thermosensitive drug release hydrogel systems are obtained. 185,[223][224][225] These hydrogels show a decreased swelling ratio with increasing temperature and thereby can be applied as "on-off" release devices, with "on" (swelling) at low temperature and "off" (shrinking) at high temperature.
6.1.2. Targeted release. It would be most desirable if drug release could be administered in a manner that precisely matches the physiological needs at specific sites (site-specific targeting). The most attractive route of targeted release is controlled by pH triggering. The pH gradient in the human gastrointestinal tract ranges from 1 to 7.5 (saliva 5-6, stomach 1-3, intestine 6.6-7.5, and colon 6.4-7.0). 226 Therefore, hydrogel systems exhibiting minimal swelling at acidic pH and maximal swelling around neutral pH can be used as potential oral drug carriers for intestine or colon-specific delivery. While pure chitosan hydrogels (cross-linked or not) usually show a maximal swelling at low pH, 102,103,111,112 multilayer chitosan/alginate composite hydrogel beads cross-linked with Ca 2+ and/or TPP, 227 and single-layer chitosan/alginate beads dually cross-linked with Ca 2+ and SO 4 2− , 228 exhibit a low drug release in simulated gastric fluid (SGF) but sustained release in simulated intestinal and colonic fluids (SIF and SCF), thus achieving intestine or colon-specific delivery. Chitosan/pectin hydrogels are also capable of colon-specific delivery because of their mucoadhesion characteristics and enzyme-dependent degradation. 229,230 In addition, polyacrylic acid (PAAc)-and polyacrylamide (PAAm)-grafted cellulose hydrogels show maximal swelling near neutral pH because of the generation of -COO − groups via the deprotonation of -COOH in PAAc and the hydrolysis of -CONH 2 in PAAm, respectively. 175,176 Thermoset hydrogel systems, such as some pure derivative hydrogels (mentioned above), chitosan/CMC, 231 chitosan/ collagen, 232 and chitosan/PEG, 233 can be injected into the body as a liquid, and form a gel in situ where the body temperature is above their lower critical solution temperature (LCST), offering the potential to serve as targeted drug carriers without the need for invasive surgeries. Moreover, such hydrogels usually significantly prolong the release time up to a few weeks due to the efficient encapsulation of drugs. In addition, magnetic-induced transference is potentially useful for applications in drug targeting delivery, e.g., magnetite/cellulose microspheres loaded with drugs or fluorogen are hypothesized to be able to deliver to and localize in specific locations by using an external magnetic field. 193

Tissue engineering
Tissue engineering is a most recent application of hydrogels, in which they are used as scaffolds to mimic many roles of extracellular matrixes and to engineer new tissues, i.e., these scaffolds provide space and nutrients for new tissue formation, and potentially control the structure and function of the engineered tissue in situ or in vitro. 234 Currently, hydrogel scaffolds are at or near clinical uses in engineering many tissues in the body including cartilage, bone, muscle, skin, fat, artery, ligament, tendon, liver, bladder, and neurons. 12 Hydrogel scaffolds in tissue engineering must meet a number of design criteria to function appropriately and promote new tissue formation, including processability, biodegradability (through hydrolysis 167 or enzymatic cleavage 165,205,[235][236][237], biocompatibility (i.e., excellent cell viability/proliferation, 167,201,238,239 without inflammatory response 240 ), bioactivity (i.e., biomineralization), 238,241 cell adhesion ability, 165,204,205,240 etc. Hybridization of the matrix (cellulose or chitin) with a second component improves one or some of these properties of the scaffolds, e.g., hydroxyapatite (HA) and silica enhance mechanical strength, calcification, as well as accelerate biodegradation, 237,238,242,243 while collagen and gelatin increase strength and cell attachment. 165,236,244 The optimum pore sizes of scaffolds in tissue engineering have been shown to be 5 µm for neovascularization, 245 20-125 µm for regeneration of adult mammalian skin, 246 and 100-350 µm for regeneration of bone. 247 However, it was later suggested that the microarchitecture plays a role in tissue regeneration, e.g., bone can be regenerated in freeze-dried scaffolds with medium pore sizes as low as 16 µm (>90% porosity and concave spherical shape of the pores) via hematoma osteoinduction instead of osteoconduction in big pores. 248 A selection of porous pure and composite scaffolds (dried) based on cellulose, chitin, or chitosan along with their physical properties are given in Table 9. Also, the mechanical properties of human cortical and cancellous bone are listed for comparison. While factors such as drying methods, biopolymer concentration, and cross-linking degree (mentioned above) have impacts on the pore sizes of hydrogels, pore sizes of the scaffolds can also be enhanced either by adding a "porogen"  (e.g., polymethylmethacrylate (PMMA) 201 and NaCl 165 ) or by adding 1% surfactant to the biopolymer solution. 68 It can be seen that the dry porous scaffolds exhibit at least one order of magnitude lower mechanical strength compared to cancellous bone and orders of magnitude lower than cortical bone. In addition, gel swelling (which will occur during cell culture) usually results in a decrease in the mechanical strength. 249 Therefore, hydrogel scaffolds are being widely used in the area of nonload bearing tissue engineering. It has been reported that chitin/HA, chitosan/alginate, and chitosan/silica can be placed into bone defects in a minimally invasive manner to promote bone regeneration. 237,243,244 The scaffolds have also been applied in other tissues, e.g., the chitosan/gelatin scaffold prepared using a novel fabrication process by combining rapid prototyping, microreplication, and freeze-drying techniques possessed well-organized hepatic architectures. 236 Some dense scaffolds (generally air-dried) match cancellous bone properties and are capable of internal fixation of bone fractures, e.g., a chitosan/HA nonporous composite showed a higher bending strength and modulus of 86 MPa and 3.4 GPa, respectively. 250 It is noteworthy, that Li et al. found an injectable thermoset chitosan/HA/Na 2 CO 3 solution, which gelated within 9 min at 37°C, and led to angiogenesis in vivo when loaded with cells. 251

Wound dressing
An ideal wound gel dressing should allow gaseous exchange, maintain the proper moisture level and constant temperature of the wound bed, remove excess exudates, protect the wound against bacteria and contamination, accelerate healing, and alleviate pain. It should also be non-toxic, non-allergenic, nonadherent, and easily removed without trauma. Currently, various forms (such as fibers, membranes, and sponges) of wound dressing products based on BC, chitin, chitosan, and their derivatives are commercially available, 11,265 of which deacetylated chitin or chitosan is a hemostat, and possesses a natural antimicrobial property due to the polycationic nature. 266 Some wound dressing gels and their outstanding features are listed in Table 10.
Since cellulose itself has no antimicrobial activity to prevent wound infection, ZnO or Ag nanoparticles (NPs) can be impregnated into the cellulose gel system to achieve antimicrobial ability. 197,206,207 The mechanisms of the bactericidal effects of ZnO and Ag NPs are different: it is assumed that water molecules can react with incorporated ZnO particles, leading to the generation of reactive oxy-radicals or hydroxylradicals that may cause oxidative injury inside bacterial cells, 197 while Ag NPs may penetrate inside the bacteria or attach to the surface of the bacteria disturbing permeability and respiration functions. 267 Higher concentrations of ZnO or Ag NPs are required for eukaryotes to achieve comparable toxic effects than for bacterial cells, leading to biocompatibility of the materials for human cells. 187,188 Without the antibacterial property, the BC/alginate sponge can be conceived as a temporary wound dressing material due to its appropriate cell attachment and good tear resistance properties. 268 Wet chitin hydrogel membranes show similar water vapor transmission rate (WVTR) to that of intact skin, as well as water uptake ability and flexibility, thus are potentially capable of both transpiring substantial amounts of excess exudate and a Glutaraldehyde (GA); N-acetyl-D-(+)-glucosamine (GlcNAc); hydroxyapatite (HA). b The large difference between the modulus of the same kind of scaffold may be related to the different materials and preparation methods used. c Cellulose was first esterified with glycine.

Green Chemistry Critical Review
This maintaining occlusivity and wound moisture. 269,270 In addition, chitin wound dressings generally show preferred medium or weak adhesion with cells, which is caused by either the globular morphology of proliferative cells or the smaller amount of active free amino groups. 187,271 Incorporating hydrophilic PAAc into the gel system offers two advantages: controlled water sorption and cell attachment of the dressing at the wound site, which is important in the wound healing process. 180 As with cellulose dressings, the antibacterial ability of chitin dressings can be improved by hybridization with ZnO or Ag NPs. 187,188,209 In addition to the hemostatic, antimicrobial, and permeable (for both water vapor (WV) and O 2 ) properties, chitosan dressings are non-irritating and do not cause allergic reactions, especially the ones prepared using lactic acid (LA) as the solvent instead of acetic acid. 110,272 Incorporation of antibiotics in the wound dressings has been developed for further inhibition of wound infection. 109,273 Hybridization with gelatin can improve the healing effect because of the strong bioactivity of gelatin whose main components are collagen, a few protein amylases, and certain organic substances, 274 while hyaluronan helps weaken the water vapor permeability (WVP) and cell adhesion, which are desirable characteristics for wound dressings. 275 The strength of wound dressings is related to the drying method and water content, which is consistent with the tissue scaffolds. In addition, nonporous or porogen-induced porous dressings that are obtained by air-drying are two orders of magnitude stronger than the porous ones obtained by freezedrying. 188,219,268,272,276,277 Almost all hybrid composite gels meet the strength standard for wound dressings, since a low strength of 0.1 MPa is adequate for a wound dressing material. 277

Water purification
Many liquid-and solid-phase extraction techniques have been used for the removal of toxic pollutants from water such as chemical precipitation, flocculation, flotation, coagulation, membrane filtration, ion exchange, adsorption, and electrochemical treatment. 278 Hydrogels have attracted special attention for water purification through adsorption, due to their high absorbency, porous structure, rich functional groups, and relatively low crystallinity. Incorporation of different components into the gel system endows the resulting hybrid hydrogels with abilities to remove various aquatic pollutants such as metal ions (transition or radioactive), dyes (cationic or anionic), and other ions (nitrogenous or phosphorous), etc. (Table 11).
It is known that dissolved pollutant ions or molecules can easily penetrate into cellulose or chitin hydrogels and establish bonds with the amine (-NH 2 ) and/or hydroxyl (-OH) groups at appropriate pH values generally through three different kinds of interactions: (a) complexation (or chelation) between the lone pair electrons of N and/or O and the metal ions; 73,199,279,280 (b) crystallization of the metal ions with the complexed metals as nucleation sites; 73,278 or (c) electrostatic attraction (or ion exchange) between the protonated amino groups and various anions. 281,282 In addition, cross-linking has been found to decrease the adsorption capacity of the gel (although the strength or stability increases) primarily due to the decrease of functional groups, and a decrease in swelling ability of the gel also decreases sorption. 111,134,283 The addition of a second component to the biopolymer can increase the adsorption capacity of the final material. For example, the incorporation of collagen is believed to endow cellulose gels with much better adsorption ability because of the active amino groups of collagen. 284 Zhu et al. used BC beads as adsorbents without removing entrapped dead bacteria cells and found that the adsorption capacity was improved because of the multiple functional groups (such as carboxyl groups, phosphoryl groups, hydroxyl groups, phosphate groups, amino groups, and amide groups) existing in the proteins, polysaccharides, and lipids of the cells, resulting in formation of coordi- nation complexes between N, P, O, or S and metal ions. 200 Also, 0.01 wt% (relative to the chitosan matrix) carbon nanotubes (CNTs) impregnation was useful for enhancing the adsorption capacity of the composite beads due to the large specific surface area and layered hexagonal arrays of carbon atoms in CNTs. [285][286][287] In SiO 2 composite hydrogels, the SiO 2 skeleton has negative charge density (Si-O − ) above pH 3, which can interact with positively charged pollutants. 288 When TiO 2 is added to chitosan, the resulting beads have a net positive charge (TiIV-OH 2 + ) at pH < pH pzc (point of zero charge (pzc)), which can  ). 289 For removal of NH 4 + cations, a hydrogel system grafted with polyacrylic acid (PAAc) is well worth considering due to the ionic interaction between the positively charged NH 4 + and negative adsorption sites (-COO − ) of the adsorbent. 290 Research on selective removal of pollutants from contaminated water using cellulose or chitin hydrogels is scanty. Some research has focused on the adsorption of Cu 2+ , and there is literature suggesting higher adsorption selectivity of adsorbents for Cu 2+ over Cd 2+ . 291 However, in most cases, neither cellulose nor chitin (or chitosan) hydrogels show selectivity for a given pollutant. In order to achieve selective adsorption, two approaches are generally followed: introducing a specific functional group in the system or utilizing ion (or molecular) imprinting techniques. Yan et al. modified the surface of chitosan hydrogel beads with chloroacetic acid to introduce carboxyl groups, producing a product with a higher coordination affinity for Cu 2+ over Mg 2+ and Pb 2+ , 292 while chitosan beads surface grafted with PAAm showed selectivity in adsorbing Hg 2+ over Pb 2+ due to the action of the amide groups. 293  The ion (or molecular) imprinting technique results in ionic (or molecular) recognition cavities (conformational memory) inside the polymeric network using the ion or molecule (generally identical to the one to be selectively adsorbed) as an imprint template during the cross-linking of polymer chains and before elution. [295][296][297] Although scarcely explored, a third strategy is to incorporate enzymes into the biopolymer matrix to selectively modify the target adsorbate before sorption. Phenols were selectively oxidized by the enzyme tyrosinase (immobilized within chitosan gels) into reactive o-quinones, which reacted with nucleophilic amine functional groups present in the chitosan matrix. 298 Adding a second component to the material can also be used to improve the properties and/or functionalities of the resulting composite hydrogels. For example, when incorporating magnetite or other iron oxides into a gel system, the resulting adsorbent can be easily attracted out of the effluent, using a magnetic field. 199,213 Nata et al. prepared an aminated Fe 3 O 4 / cellulose composite which not only could be easily collected but also demonstrated a very high adsorption ability towards metal ions because of the protonation of the introduced NH 2 on Fe 3 O 4 at low pH. 299 To enhance the sorbent's mechanical strength or chemical stability, crucial in batch or column water remediation, fillers of high modulus such as SiO 2 , 288 and CNTs 285-287 can be incorporated; or the biopolymer can be cross-linked with other polymers, such as the self-assembly chitosan/PVA, 213,300 or chitosan/alginate composites. 283 Recycling of the gels and reusing them is of extreme importance for the sustainability of the process. There are several eluents proposed to desorb the ions from gels, including SC, 200 ethylene diamine tetraacetic acid (EDTA), 300 HNO 3 , AlCl 3 , CaCl 2 , NaCl, 213,290 etc., which are chelating or cation exchange agents. In addition, since most of the gels have better adsorption capacity for pollutants when the pH is within 5-7, acid (HCl) 199 or alkali (NaOH) 281,282,294 solutions can be used to strip the ions from the adsorbents. Using these methods, the desorption efficiency can reach 99%, and the gels can be reused at least 4 cycles with sometimes even higher sorption efficacy than the first time. 199,213,290 6.5. Other applications Hydrogels from cellulose, chitin, or chitosan are utilized widely in many other diverse fields. One of their major uses is as the supporting material for functional additives, including (a) membranes containing electrolyte molecules used in a capacitor or battery (e.g., cellulose/chitin containing ILs and H 2 SO 4 , 301,302 and chitosan/PVA containing NH 4 NO 3 and ethylene carbonate (EC) 303 ); (b) porous aerogels containing inorganic catalysts (e.g., Ag, 192,304 TiO 2 , 305,306 and SiO 2 307 ) for heterogeneous catalysis; and (c) hydrogels containing fluorescent quantum dots (QDs) potentially used in fluoroimmunoassays and biological labeling. 186,308 Indeed, chitosan aerogels are potential base catalysts themselves due to the amino groups. 91,309 In addition to their role in catalysis, cellulose/SiO 2 aerogels are able to act as excellent thermal insulators while being flexible and translucent, and having high mechanical stability and processability. 210 Furthermore, pure inorganic nanomaterials, such as TiO 2 , 310 SiO 2 , 210 and Fe 2 O 3 217 with porous networks that are useful in photocatalysis, biosensor, bioseparation, respectively, can be obtained by calcining the corresponding composite hydrogels in various forms as sacrificial templates. There are unique polyelectrolyte hydrogels consisting of polyanionic polymers (e.g., CMC, alginate, and PAAc) and/or polycationic polymers (e.g., chitosan, PAAm, and polyvinylamine (PVAm) 311 ), which can be used as electronic elements. Smitha et al. identified the chitosan/PAAc composite as an ideal proton exchange membrane in the direct methanol fuel cell, as it exhibited high proton conductivity, low methanol permeability, and adequate thermal and mechanical stability. 312 CMC/chitosan and cellulose/alginate hybrid hydrogels are potential electroactive sensors or actuators in electronic devices because they swell or shrink differentially on two electrode sides (anode and cathode) as a consequence of mobile ion transport in an electric field, causing bending towards one electrode. 313,314 To facilitate this, a plasticizer (e.g., glycerol) can be added into the system to weaken the intra-and intermolecular hydrogen bonding in the matrix and thereby improve the flexibility of the product. 314

Conclusions and perspectives
Because of their renewable, biocompatible, and biodegradable characteristics, hydrogels made from cellulose, chitin, and some of their derivatives are attracting and will continue to draw both academic and industrial attention. Considering their other advantages, such as excellent processability, high absorbency, porosity, bioactivity, abundant active groups, etc., it is not surprising that these hydrogels have already found extensive applications in many areas such as drug delivery, tissue engineering, wound dressing, water purification, catalysis, electrical elements, and more. Much fundamental research has been conducted on the preparation of these hydrogels, including the development of solvent systems for native cellulose or chitin, hydrogel formation techniques, physical or chemical cross-linkers, drying methods, etc., however, recent studies have mainly focused on potential applications of the hydrogels in water purification and pharmaceutical and medical systems, and less attention has been paid to other areas such as their use in the electronic and optical fields.
For future studies, more attention should be focused on (1) "green" (safe solvents, none or nontoxic cross-linkers), and/or low-energy processing for hydrogel systems; (2) injectable hydrogels forming safely within the body without the need of surgery for targeting drug release or tissue engineering; (3) pH or enzymatic triggered drug release at targeted sites; (4) hydrogel degradation in a controlled manner in tissue engineering or sustained drug release; (5) development of hydrogel functionalization as an economical way to improve efficacy, selectivity, or recycling during water purification; (6) development of new applications of hydrogel systems (e.g., polyelectrolyte complex hydrogels as electrical elements); (7) development of cellulose and chitin nanowhiskers to prepare novel hydrogels with unique characteristics such as high mechanical strength and photonic properties; and (8) development of novel biopolymer isolation methods (e.g., IL isolation) to produce cellulose and chitin with high molecular weights and thus unique hydrogels. Undoubtedly, hydrogels based on cellulose, chitin, and their derivatives still offer abundant promising opportunities in various industries, although significant challenges will need to be overcome before commercialization, and thus fundamental research into the nature of these systems should also continue.