Strategies in Improving Properties of Cellulose-Based Hydrogels for Smart Applications

  • Farzaneh Sabbagh
  • Ida Idayu MuhamadEmail author
  • Norhayati Pa’e
  • Zanariah Hashim
Living reference work entry
Part of the Polymers and Polymeric Composites: A Reference Series book series (POPOC)


Hydrogels are three-dimensional polymeric networks that are able to absorb and retain large volumes of water. Chemical or physical crosslinks are required to avoid dissolution of the hydrophilic polymer chains into the aqueous phase. Because of their sorption capacity, super absorbing hydrogels have been extensively used as water-retaining devices, mainly in the field of personal hygiene products and in agriculture. Moreover, in recent years, the possibility to modulate their sorption capabilities by changing the external conditions (e.g., pH, ionic strength, temperature) has suggested their innovative application as smart materials, drug delivery devices, actuators, and sensors. The presence of the polyelectrolyte NaCMC in the hydrogel network provides a Donnan equilibrium with the external solution, thus modulating material’s sorption capacity in relation to the external solution ionic strength and pH. An important focus of the research in this field is the material’s biodegradability. This material was obtained by chemical crosslinking of cellulose polyelectrolyte derivatives, carboxymethylcellulose (CMC) and hydroxyethylcellulose (HEC), using small difunctional molecules as crosslinkers (divinyl sulfone, DVS) which covalently bound different polymer molecules in a 3D hydrophilic network. Among the biopolymers, cellulose is of special interest due to its abundance and, hence, easy availability. It is easily derivatized to different cellulosics which can be used to obtain functionalized hydrogel beads for ion exchange and affinity chromatography. Various cellulose derivatives having nitrogen or sulfur-containing groups have been prepared, and their metal ion absorption behavior has been examined. Metal ions are reported to partition between cellulosics and liquid phase. However, the use of cellulose as membrane material is not fully realized due to low stability and poor interactions in water. These drawbacks can be improved by crosslinking, radiation grafting, and surfactant adsorption. In the current chapter, we have focused on the smart applications of cellulose-based hydrogels including drug delivery systems, absorption behavior, and swelling mechanism and their prospects.


Hydrogel Cellulose Super absorption Smart properties Drug delivery 

1 Introduction

Natural cellulosic materials have a wide variety of complex components. Cellulose, hemicellulose, and lignin are important components of natural lignocellulosic materials which comprise the main component of cell walls of plants. Cellulose molecules determine the cell wall framework, and pectin is located between the cellulose microfilaments of the cell wall, while cellulosic materials contain rich cell wall protein, pigment, and ash. In the research and development of cellulose-based hydrogels, it is important to understand the chemical composition and structure of natural lignocellulosic materials and characteristics of each component and also the interrelationships between various components in order to achieve suitable and desirable final characteristics and functional properties.

This chapter discusses properties of cellulose polymers, those that are responsible for preparing cellulose-based hydrogels. The chapter further describes the utility of such cellulose-based hydrogels for various smart applications.

1.1 Physicochemical Properties of Hydrophilic Polymers

Hydrophilic polymers are able to absorb liquids and swell with no dissolving, showing that physical or chemical crosslinks are available inside the macromolecular chains [1]. The network of the polymer resulting from the crosslinks swells in the solvent. The swelling is totally offset by the retractive, elastic force exerted by the crosslinks. The resulting semisolid solution of the water and polymer at equilibrium is called a hydrogel.

The gelling agents for the cosmetic and pharmaceutical applications can be classified into organic and inorganic substances on the basis of the nature of the colloidal phase. One of the examples of inorganic agents is clay that has a lamellar structure and can be highly hydrated. Clays have flat surfaces of particles and are negatively charged, but the edges are positively charged [2]. The content of water in the hydrogel depends on the conditions of the environment, for example, pH, temperature, and ionic strength of the water solution, and also depends on the structure of the network of the polymer. The importance of the swelling ratio of the hydrogel is due to be evaluated for given conditions of the environment because it is effective on the mechanical, optical, surface, diffusive, and acoustic properties of the hydrogel. Hydrogels are theoretically beneficial for the elaboration of smart devices such as artificial muscles, valves, and substrates for controlled drug release. The first invented hydrogel has been based on poly hydroxyethyl methacrylate (PHEMA) that was developed by Otto Wichterle in the 1950s and is used as soft contact lenses [3]. Since then, major improvements have been done through obtaining novel hydrogels, based on natural, synthetic, or hybrid polymers [4]. By association of two polymers, gelation or precipitation can occur. The new generation of hydrogel products has been developed for special applications as a water absorbent such as underwater devices, personal hygiene goods, and water reservoirs for dry soils or for biomedical applications such as lubricating surface coatings, soft contact lenses, phantoms for ultrasound imaging, wound healing dressings, controlled drug release devices, three-dimensional cell culture substrates, cell immobilization islets, bioactive scaffolds for regenerative medicine, and three-dimensional cell culture substrates [5].

1.2 Cellulose as Hydrophilic Polymers

Cellulose is the richest natural biopolymer [6]. There are long chains of anhydro-D-glucopyranose units (AGU) in its structure, and with each molecule of cellulose, there are three groups per AGU with the exception of the terminal ends [7]. Cellulose is not soluble in most of the solvents and especially in the water [6]. The cause of poor solubility is because of the intermolecular hydrogen bonding and strong intramolecular between the individual chains [7]. Despite the poor solubility of cellulose, it is used in a wide range of the applications such as netting, paper, coatings, composites, upholstery, packing, etc. [8]. The morphology of cellulose has a great impact on its reactivity, and the hydroxyl groups located in the amorphous sections react readily and are highly accessible, but those in crystalline sections with strong interchain bonding and close packing can be completely inaccessible. For the cellulose derivatives, different scores can show various characterizations considerably in terms of viscosity, hydration, molecular weight, and solubility; therefore, various scores can be applied to various goals [9].

Cellulose is the most plentiful natural polymer of glucose that is found as the main ingredient of natural fibers and plants such as linen and cotton. Bacterial cellulose (BC) or microbial cellulose is chemically same to plant cellulose (PC), but there are some differences in physical structure and various macromolecular structures. The insolubility in water and the rest of the solvents and the high crystallinity of the cellulose in both PC and BC is due to the units of the glucose that are held together via 1,4-β-glucosidic linkages [10]. This amount is more than 60% for BC and 40%–60% for PC. The nanosized fibers are the result of BC biosynthesis that is smaller than PC fibers around two orders. Therefore, BC cellulose displays an ultrafine and unique fiber network with larger flexible strength and more water holding rather than PC.

Additionally, BC is entirely pure disparate PC that is associated with the rest of the biogenic compounds like pectin and lignin. Hence, whenever BC is applied by bacteria, PC needs more refinement and some reformation. Meanwhile, the further modification of BC could be done using ex situ or in situ approach as shown in Fig. 1 in order to develop desirable form and properties using various types of additives including nanoparticles such as conductive polyaniline [11].
Fig. 1

Modification of bacterial cellulose using (a) ex situ and (b) in situ method

Cellulose and derivatives of cellulose are nature-friendly and can be degraded by various fungi and bacteria available in the water, air, and soil that can synthesize special enzymes such as cellulases [12].

The most important reason for the huge use of cellulose-based devices in biomedical applications is the high biocompatibility of cellulosics, cellulose, and cellulase-mediated. Truly, due to the disability of cells to synthesize cellulose, resorption of cellulose in human and animal tissues does not occur. Martson et al. showed that an implant based on cellulose sponge appears to suffer a slow degradation in the subcutaneous tissue of the rat [13].

1.3 Water-Soluble Cellulose Derivatives

The water-soluble derivatives of cellulose can be reached by etherification of the cellulose that contains the reaction of the organic species like ethyl and methyl units with hydroxyl groups of cellulose [14]. So as to reach soluble derivatives of cellulose, the ordinary number of etherified groups of hydroxyl in a glucose unit or degree of substitution can be controlled to an assured level. Cellulose-based hydrogels can also be created by crosslinking the aqueous solutions of cellulose ethers, for example, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), hydroxyethyl cellulose (HEC), ethyl cellulose (EC), and sodium carboxymethylcellulose (NaCMC). Due to the low cost and nontoxicity of such polymers, all of them have an extended application as emulsifying agents or thickeners in the cosmetics and pharmaceutical industries [15]. NACMC is just the polyelectrolyte that presents sensitivity to ionic strength and pH variations, and so it is a smart cellulose derivative. Actually, using NACMC in a cellulose-based hydrogel makes it a double effect on the swelling property and that is because of electrostatic charges attached to the network [16].

Increasing in the swelling is due to the electrostatic repulsion recognized among charges of the same sign that makes the chains of the polymer force to a more stretched state rather than those found in a neutral network [17]. More than this, due to the Donnan effect, the counterions which exist in the gel induce more water to enter the network by macroscopic electrical neutrality. Making the gel sensitive to different ionic strength or pH is because of different concentrations of mobile counterions among the external solution and gel, which is described by Donnan contribution to the osmotic pressure. The elaboration of superabsorbent hydrogels with a smart behavior is due to the polyelectrolyte nature of NaCMC [18].

2 Application of Cellulose-Based Hydrogels

Extensive employment of hydrogel-based products in a number of industrial and environmental areas of application is considered to be of prime importance. As expected, natural hydrogels are gradually replaced by synthetic types due to their wide varieties of raw chemical resources, higher water absorption capacity, and durability. The responsiveness of some cellulosics to variations of external stimuli, large access, low cost, and biocompatibility of cellulose makes the hydrogel precursor materials. This section lays on some of the applications of cellulose-based hydrogels in the range of the traditional use of hydrogels as water absorbents to more inventive biomedical applications.

2.1 Uses of Cellulose and Cellulose Derivatives

2.1.1 Sodium Carboxymethylcellulose

Figure 2 shows the molecular structure of carboxymethylcellulose which is often used as its sodium salt, sodium carboxymethylcellulose. It is a soluble and cheap polyanionic polysaccharide derivative of cellulose that has been employed as an emulsifying agent in the cosmetic and pharmaceutical industry.
Fig. 2

Molecular structure of carboxymethyl cellulose (R = H or CH2CO2H)

This polymer has many critical properties such as stabilizer, thickener, film-former, and a binder [19]. One of its applications in biomedicine after a surgical procedure is to prevent epidural scar and soft tissue adhesions. Another of its applications includes the therapeutic application of the superoxide dismutase enzyme (SOD), as hydrogels of CMC carrying the enzyme for its controlled release and also as water absorbents in treating edemas [20].

Therapeutic use of SOD enzyme is limited by its fast clearance from the bloodstream and inactivation by its own reaction product, i.e., hydrogen peroxide. To use the NaCMC in preparation of the semi-interpenetrating network of polymer, glutaraldehyde can be used as a crosslinker [21].

2.1.2 Hydroxypropyl Cellulose

Hydroxypropyl cellulose is an ether of cellulose which had been hydroxypropylated using propylene oxide. The hydroxyl groups in the repeating glucose units have been forming –OCH2CH(OH)CH3 groups as shown in Fig. 3. It is a pH insensitive, water soluble, and nonionic cellulose ether. Its application is the film coating, tablet binding, thickening agent, and modified release. To control the release ratio of a water-soluble drug-like oxprenolol hydrochloride, solid dispersions including a polymer blend can be used. Therefore, there is a direct relationship between the release ratio of drug solution and its interaction with the polymer. The graft copolymers can be considered of great interest as direct compression excipients due to their different chemical structure and composition; they showed differences in viscoelastic properties that revealed an interesting range of possibilities for use in drug delivery formulations [22]. The use of this kind of graft copolymer in a formulation could improve the controlled release properties.
Fig. 3

Molecular structure of hydroxypropyl cellulose (R = H or CH2CH(OH)CH3)

Furthermore, non-crosslinked graft copolymers of hydroxypropyl methacrylate on both hydroxypropyl starch and HPC offer interesting characteristics as controlled release matrices. The graft copolymers can stand alone as an effective matrix for tablets designed for drug delivery systems [23].

2.1.3 Oxycellulose

In oxidized cellulose or oxycellulose, some of the groups of the terminal primary alcohol in the glucose have been shifted to groups of carboxyl. Thus, this derivative of CMC is certainly a synthetic polyanhydrocellobiuronide that includes 25% groups of carboxyl that are very weak and have high solubility in the solutions [24]. The products with fewer carboxyl groups are more desirable in the products. Cotton or gauze as an oxidized cellulose is soluble in dilute alkalis but insoluble in acids and water. These products can swell and become gelatinous in the high dilute alkaline solutions. In contact with blood, it swells and become slightly, so forms a dark brown gelatinous product. This capability makes it an appropriate product to use in different surgical procedures [25]. This product also can be used as novel-forming systems because of its dispersion that might be combined with the rest of cosmetic and pharmaceutical adjuvants due to their dispersion in the water. One of the main properties of such products is that basic bioactive compounds liquid (nonvolatile or volatile) acidic, neutral, and a wide variety of solid (amorphous or crystalline) can be loaded into them, so it becomes possible to generate substantive sustained or controlled release formulations in the development of different pharmaceutical, cosmetic, agricultural, and consumer products. Oxidized cellulose dispersion uses in sunscreen spray, anti-acne cream, anti-fungal cream, and anti-acne lotion [26].

2.1.4 Methylcellulose

Methylcellulose is synthetically produced by heating cellulose with caustic and treating it with methyl chloride. The hydroxyl residues are replaced by methoxide (-OCH3 groups) as shown in Fig. 4. Methylcellulose resembles cotton in appearance and is tasteless, neutral, inert, and odorless. It is not soluble in the organic solvents, but it can be swelled in the water and produces a viscous, clear to the opalescent and colloidal solution. Therefore, dilution of aqueous liquids containing methylcellulose can be with ethanol. Their solutions are stable at higher than the range of pH (2–12) without any superficial change in viscosity.
Fig. 4

Molecular structure of methylcellulose (R = H or CH3)

Methylcellulose can be applied as bulk purges, so some of its applications are to treat nose drops, burn preparations ointments, constipation, and in ophthalmic preparations. Using it as a bulk laxative which causes to absorb water completely regularly, tablets of methylcellulose cause intestinal obstruction and fecal impaction [27]. Constructing a bulkier and softer stool, therefore, it can treat the diverticulosis, constipation, irritable bowel syndrome, and hemorrhoids and also absorbs a huge amount of water into the colon. It should be taken with sufficient amounts of fluid to prevent dehydration. The common side effect is nausea and the less common side effects are vomiting and cramp [28]. On the other hand, solid dispersion in which compounds are dispersed into water-soluble carriers has been generally used to improve the dissolution properties and the bioavailability of drugs that are poorly soluble in water. Methylcellulose has the hydroxyl group in its structure and is interactive with the poly (ethylene oxide) (PEO) together with the carboxylic acid of a carboxyvinyl polymer (CP).

2.1.5 Microcrystalline Cellulose

Microcrystalline cellulose has many advantages in the formulation and production of solid dosage forms; however, it has some limitations such as sensitivity to lubricants, moderately low bulk density, loss of compatibility after wet granulation, and moderate flowability [29].

In order to improve the function of the microcrystalline cellulose, silicification is applied. Therefore, some properties such as compressibility, enhanced density, compatibility, low moisture content, larger particle size, flowability, low moisture content, and lubricity will improve. By co-drying a suspension of colloidal silicon dioxide like dried finished product that contains 2% colloidal silicon dioxide and microcrystalline cellulose particles, silicified microcrystalline cellulose (SMCC) is manufactured. The silicon dioxide remains on the surface of microcrystalline cellulose. Rather than the usual kinds of microcrystalline cellulose, silicified microcrystalline cellulose displays higher bulk density [30].

2.1.6 Ethyl Cellulose

Ethyl cellulose is a natural polymer from cellulose derivative where the repeating glucose units are converted into ethyl ether groups (Fig. 5). This polymer is a pH-insensitive cellulose ether, nonionic and soluble in various polar organic solvents but insoluble in water. The functions of this polymer include insoluble factor in matrix or coating methods and a non-swellable polymer [31]. Ethyl cellulose is chosen whenever it is impossible to use water-soluble binders in dosage processing because of water sensitivity of the active ingredient.
Fig. 5

Molecular structure of ethyl cellulose (R = H or CH2CH3)

To avoid the tablets from reacting with another material, this polymer can be applied to coat. To prevent discoloration of simply oxidize materials, for instance, ascorbic acid, and also combination with other polymers, is another application of this polymer. The combination of this polymer with water-soluble polymers is due to prepared sustained release film coating for the coating of tablets, micro-particles, and pellets [32].

2.1.7 Cellulose Ether

In designing the matrix tablets, cellulose ethers are extensively applied. Once they contact with water, the hydrogel layers start to propagate around the dry tablet’s core, due to the cellulose ethers, and start to swell. The hydrogel offers a diffusional barrier for the molecules of water penetrating into the matrix of polymer and thus the molecules of the drug being released [33].

2.1.8 Hydroxypropyl Methylcellulose

Hydroxypropyl methylcellulose (HPMC) or hypromellose is a water-soluble derivative of cellulose ether and is able to apply as a hydrophilic polymer to prepare the controlled release tablets. The water penetrates to the matrix and hydrates the chains of polymer that ultimately separates from the polymer matrix. It is generally recognized that drug release from HPMC matrices follows two mechanisms, drug diffusion through the swelling gel layer and release by matrix erosion of the swollen layer [34]. Therefore, quantifying the percent contribution of diffusion and erosion to the overall drug release is important.

Cellulose derivatives are often used to modify the release of drugs in tablet and capsule formulations and also as tablet binding, thickening, and rheology control agents, for film formation, water retention, and improving adhesive strength and for suspending and emulsifying [35].

2.2 Application of Antimicrobial in Textile Industry

Antimicrobial treatment is increasingly becoming a standard finish for some textile products such as for medical, institutional, and hygienic uses. Recently, it has become popular in sportswear, women’s wear, and aesthetic clothing to impart anti-odor or biostatic properties [36]. Natural textiles such as those made from cellulose and protein fibers are often considered to be more vulnerable to microbial attack than man-made fibers in light of their hydrophilic porous structure and moisture transport characteristics. Thus, the use of antibacterial agents to prevent or retard the growth of bacteria as shown in Fig. 6 is becoming a standard finishing for textile goods [37].
Fig. 6

Antimicrobial action of textiles incorporated with antimicrobial agents

2.3 Solid Dosage Form

Pharmaceutical scientists are increasingly using lipid-based excipients in the development of solid oral dosage forms for taste masking and as sustained release agents. The interest in this class of excipients is growing mainly since they can be applied in a variety of processes and since they are naturally occurring compounds that are predominantly digestible [38]. In dosage forms coated for the purposes of taste masking and immediate release, stability issues can lead to poor taste masking after storage, leading to patient dissatisfaction and poor adhesion to the therapy. A complex solid state of such dosage forms results from the structural hierarchy of the lipid-based excipients. Often, this complexity originates from the excipient’s composition, in which triacylglycerols (TAGs) are combined with diacylglycerols, mono-acylglycerols, free fatty acids, phospholipids, or surfactants [39].

2.4 Tablets

The purpose of design and formulation of fast-release tablets is to make sure that a drug will be absorbed shortly, and also it is focused on fast achieving dissolution. The design and formulation of such tablets are to fully disintegrate within 2.5–10 minutes. Some of the applications of such tablets are to achieve appropriate bioavailability of a poorly soluble drug substance and/or for analgesics [40].

2.5 Superabsorbents for Personal Hygiene Products

In order to absorb fluids in personal care products, the selected hydrogel is acrylated-based superabsorbent hydrogels that are applying significantly. These products hold off the moisture from the surface of the skin that improves the comfort of consumer and health of the skin [41]. Some of the applications of this product include adult incontinence products and in training pants, in personal care stuff and their effectiveness and safety, preventing diaper rash and keeping skin dry and leakage prevention in diapers.

Harmon and Harper invented superabsorbent in 1966, but the application in the diaper industry was introduced in 1982 by Unicharm in Japan and afterward in sanitary napkins [42]. By using superabsorbent materials, high-performance diapers were invented that are thinner, and the diaper rash and leakage has reduced in them. The leakage values reduced to under 2% that shows a success in this product. This is an advantage in the environmental issues due to economic sense through reducing the cost of packaging.

Various efforts have been done to recycle napkins, hospital bed sheets, disposable diapers, and sanitary towels. The main purpose of recycling the diaper is to separate the cellulose that is recyclable and biodegradable [43]. The new generation of NaCMC-based hydrogels crosslinked with DVS has higher swelling capabilities rather than the SAP crosslinked hydrogels. They also have higher water retention under centrifugal loads. By using a phase inversion desiccation in acetone such as a non-solvent for cellulose, such important results will be achieved. This technique is based on a microporous structure that causes to increase the water absorption together with swelling kinetics using the capillary impacts. The most important benefit of cellulose-based hydrogels is their environmentally friendly and their biodegradability type [44].

2.6 Water Reservoirs in Agriculture

There is an increased value in using superabsorbent hydrogels to optimize the water resources and reduce the water consumption in horticulture and agriculture. This technique has novelty for the habits of culture and human toward the water. It is well known that during the swelling process in the hydrogels, the materials shift from glassy to plastic state that has water storing capability as shown in Fig. 7.
Fig. 7

Agricultural application of hydrogel for water storing purpose

In this system, if a descent of humidity among the outside and inside of the material exists, then the swollen hydrogel can start to release the water through a diffusion-driven mechanism slowly [45]. During watering the cultivation, the water is absorbed by the dry hydrogels, and when needed the nutrients and water will be released from the hydrogels to the soil. As shown in Table 1, this method will cause to keep the soil humid for a long time.
Table 1

Water content in the soil as a function of the number of days after watering: effect of different hydrogel contents

Measurement and observation

Hydrogel added into soil

Control 0(%)

0.2 (%)


1.0 (%)

Initial humidity in soil (%)





Plant survival time (days)





Water content at point of germination (%)





Apart from water, other molecules that are loaded in the network of the polymer also can be released by means of diffusion in a sustained and controlled manner. The application of this procedure is to make the cultivation possible in desert and arid regions of the world. In this case, the dry hydrogel in the form of granules or powder will be mixed to the soil around the roots of the plant [46].

The dry hydrogel such as xerogel can be loaded with plant or nutrients pharmaceutical. The advantage of this procedure is to avoid the drainage and evaporation of water, soon after watering, and also can redistribute the water resources in another application. Another benefit of using hydrogels in this method is due to the impact of the swelling on the soil [47]. This positive impact is related to the size of the granules of the hydrogel in the soil before and after the watering. During the watering of the soil, the granules of the hydrogel absorb water and increase their dimensions; thus it will create porosity and pores in the soil which can improve the oxygenation of the roots of the plant. On the other hand, the size of the granules of such hydrogels in the soil is also very important. It is suggested that the large-granule hydrogels are better than the small-granule ones [48]. If they mix properly with the soil, various dimensional shapes for the hydrogel particles and for the soil are possible, based on the interactions between hydrogel and soil hydrogel.

In the effort to develop environmentally friendly alternatives to acrylate-based super absorbent hydrogels, cellulose-based hydrogels prosper perfectly in a present manner. A novelty in the new generation of hydrogels is that they can absorb more than 1 l water for each gram of dry material with no release under the compression. The hydrogel is produced in the form of bulk material or powder material. The soil containing small quantities of the hydrogel can keep the humidity for long times rather than wet soil without hydrogel. This amount of keeping water is around four times more [49].

2.7 Body Water Retainers

The cellulose-based hydrogel has some specific properties that have the capability to appeal for in vivo applications. These properties include versatile and biocompatibility of cellulose. For instance, hydrogels hold potential as devices for the removal of extra water from the body, in the treatment of some pathological conditions, such as diuretic-resistant edemas and renal failure. It is predicted that the hydrogel in the powder form and orally administration absorbs water via its passage in the intestine and pH 6–7, but with no swelling in the acidic environment of the stomach. Because of the requirement to pH-sensitivity, polyelectrolyte cellulose hydrogels based on HEC and NaCMC have been considered for these applications. The hydrogels display enough swelling ratio at pH 7 and the low swelling ratio at acidic pH. The combination of hydrogel and drug for the intestinal pathway is beneficial to remove water from the body [50].

2.8 Stomach Bulking Agents

Superabsorbent hydrogels are interesting in stomach bulking due to not only their modulation through changing the conditions of the environment such as ionic strength, pH, and temperature but also their swelling capacity is designed by controlling the physical and chemical composition and microstructure. The hydrogels are administrated before each meal; this helps to reduce the free space for the food and giving a fullness feeling to the person. The hydrogel is envisaged to pass through the gastrointestinal tract, so it is supposed to confront the various pH of the intestine and stomach environments [51]. Accompanied by super porous acrylate-based hydrogels that swell fast in solutions, the novel cellulose-based hydrogels that are crosslinked by aqueous mixtures of HEC and NaCMC appeal for the production of dietary bulking agents.

These hydrogels have high pH-sensitive water retention capacity and high biocompatibility regarding intestinal tissues. The poly anionic network of NaCMC provides higher swelling potentials at neutral pH rather than acidic pH [52].

2.9 Devices for Controlled Drug Delivery

The cellulose ether on the surface of the tablet such as HPMC forms chain entanglements, starts to swell, and is a physical hydrogel. During the swelling process, the drug dissolves from the swollen surface to the glossy core of the tablet. The drug dissolves in water and diffuses from the network of polymer.

Some of the parameters such as mesh size, water content, and the degree of crosslinking can affect drug release. Dissolution of the chain happens with swelling, and it is related to the structure of the applied cellulose ether [53]. Therefore, drug release occurs from the erosion, complex combination of the swelling and erosion mechanism. The purpose of sophisticated hydrogel-based devices is not only at the sustained release of a bioactive molecule, ranging from hours to weeks, but also at a space-controlled delivery, directly at the site of attention. The reason to encapsulate the bioactive molecules into a hydrogel matrix such as microspheres is related to the short half-life presented by many biomolecules in vivo. During the applying hydrogels to moderate the drug release, the drug loading is achieved during network formation or crosslinking [54]. Additionally, to more modify the release rate, the bioactive molecule can be physically or covalently linked to the network of the polymer.

Smart hydrogels are applicable to control the space and time-release profile of the drug as deswelling-swelling transitions that tune the mesh size of the network of the hydrogel and occur via changes of physiologically relevant variables, for instance, temperature, pH, and ionic strength. Release from cellulose-based polyelectrolyte hydrogels is based on the strong pH variations. The latest advances in the controlled release are according to the protein delivery, gene-specific sites, and growth factors. However, to prevent more surgical removal and foreign body reactions, formulation of hydrogel for transdermal and oral delivery can be nondegradable; the direct protein or drug delivery to different parts of the body needs the biodegradation of hydrogels [55].

2.10 Scaffolds for Regenerative Medicine

Regenerative medicine is an interdisciplinary field that distributes with the stimulated regeneration of organs and tissues in vivo, with a scaffolding template or material that guide and support the cells during the synthesis of new tissues [56]. The high capacity of hydrogels in biocompatibility is due to their high-water content. This character makes them show some rubbery properties in similar condition with soft tissues and let the integration of bioactive molecules and cells during the gelling. Besides, although cells do not readily attach to highly hydrophilic surfaces, the surface or bulk chemistry of hydrogels can be easily modified with domains of the extracellular matrix that promote cell adhesion together with particular cell functions [57]. Consequently, hydrogels are ideal products to design the biomimetic scaffolds for tissue regeneration.

Cellulose and its derivatives have the high biocompatibility and good mechanical properties which is used as the design of tissue engineering scaffolds. Preferably, for finest tissue regeneration, the scaffold should be biodegradable, but practically a slow degradation is often preferred, in order to minimize the risks associated with an impulsive resorption of the scaffold. Despite its biodurability, cellulose is an ideal biomaterial candidate to the design of tissue engineering scaffolds [58]. On the other hand, a very slow degradation can cause unwanted responses such as body reaction in the long period that limits the cellulose applications.

Cellulose and its derivatives, usually in the form of fabrics or sponges, have been applied for the treatment of severe skin burns and in studies on the regeneration of bone tissues, cardiac, vascular, neural, and cartilage. With particular regard to cellulose-based hydrogels, a few independent investigations show that cellulose-based hydrogels are potentially beneficial for inducing the regeneration of neural tissues, bone, and cartilage. In a research, the pretreatment of a cellulose-based scaffold with cellulase before implantation has been planned, in an effort to modify the in vivo degradation cellulose behavior. The benefit of using cellulose rather than other natural or synthetic polymers for tissue engineering purposes is due to the final product of cellulose degradation that is glucose and is a nutrient for cells. Cellulose-based hydrogels are valuable throughout cellulose fabrics and sponges because their bulk chemistry can be easily modified. The biocompatibility of the crosslinking agent used is particularly important, especially in cases where reactive groups of the crosslinker are incorporated into the hydrogel network and might then be released upon degradation.

Hydrogels based on HEC, NaCMC, and (hyaluronic acid) HA have been recently crosslinked with a water-soluble carbodiimide, which is both “zero-length” and nontoxic crosslinker. The carbodiimide, which is washed out from the polymer network after the synthesis, is well-known to induce the formation of ester bonds among polysaccharide molecules without taking part in the linkage [59]. It is worth noting that the ester bonds forming the network have the potential to be digested, in the long term, via hydrolysis, as it normally occurs for synthetic polyesters. Thus, cellulose-based hydrogels crosslinked with carbodiimide show potential for a tunable biodegradation rate, even when not containing HA. Although an investigation on the biodegradation behavior of such hydrogels has not been performed yet, it is reasonable to hypothesize that the degradation rate can be modulated to some extent by controlling the degree of crosslinking.

The mechanical stiffness of the hydrogel is also dependent on the degree of crosslinking and should be designed according to the tissues being addressed. Furthermore, the carbodiimide-mediated crosslinking reaction holds promise for the functionalization of cellulose with several biomolecules, able to promote specific cell functions, due to the ability of the carbodiimide to crosslink various polypeptides. This opens a wide range of possibilities for the design of biomimetic, cellulose-based hydrogel scaffolds for tissue engineering [60].

A final remark regarding the development of regenerative templates concerns the key role played by the scaffold porosity, which enhances the attachment, infiltration, and survival of cells within the scaffold. Due to their nano-sized mesh structure, hydrogels are usually employed to treat small tissue defects while failing in larger implants. Novel manufacturing techniques aiming at the development of several types of porous hydrogels are being investigated and might be of great value in enhancing the regenerative potential of cellulose-based hydrogels as well.

2.11 Wound Dressings

Some process is occurring during the wound healing such as reepithelialization, autolytic debridement, granulation tissue formation, and inflammation. A proper wound dressing is to support healing of the wound from infection. Hydrogels are ideal candidates to develop the wound dressing, as an amorphous or a sheet because the moist in the environment makes the healing fast. The viscosity of amorphous hydrogels during the absorption of fluids decreases due to their physical crosslinking [61]. Hydrogel transparency is an additional advantage as wound healing can be undoubtedly observed. The hydrogels including silver ions in their structures are the most advanced hydrogel dressings.

Figure 8 shows bacterial cellulose (BC) which has been extensively examined for wound healing due to its high-water retention capacity and its purity. NaCMC as gel-forming cellulose derivatives is embraced in the formulation of some hydrogel dressing. Regarding this matter, usually, propylene glycol is in combination with NaCMC that works as a preservative and humectant [62].
Fig. 8

Bacterial cellulose for wound dressing

3 Swelling Controlled Release Systems

Generally, a swelling-controlled release system of a hydrogel shows the swelling ratio increases with time up to 16 h and then continues to increase with time but at a lower rate.

This phenomenon can be explained by the chemical potential difference:
$$ {\mu}_1-{\mu}_{1.0}=\varDelta {\mu}_{\mathrm{mixing}}+{\varDelta \mu}_{\mathrm{ionic}}+\varDelta {\mu}_{\mathrm{elastic}} $$
Here, μ1μ1.0 is the chemical potential difference between solvent and polymer; Δμmixing is the chemical potential difference, defined as interactions between polymer and solvent; Δμionic is the ionic chemical potential difference; and Δμelastic is the chemical potential difference for elastic, always acting against the swelling. Both Δμionic and Δμmixing facilitate the swelling process. At the beginning of the swelling process, Δμionic controls the swelling, but after equilibrating between hydrogel internal and external ions, Δμmixing dominates the swelling process with a value less than Δμionic. As a result, the swelling trend initially increased and then decreased [33, 63]. Figure 9 shows an example of observation among almost all of the blend ratios where after 2 h in acidic medium, the kappa-carrageenan/HEC hydrogels reached equilibrium.
Fig. 9

Swelling of kappa-carrageenan/hydrohyethyl cellulose hydrogels of different concentration in (a) pH 1.2 and (b) pH 12 at room temperature

The protonation of carboxylic groups and the creation of more hydrogen bonds in κC hydroxyl groups results in more compact networks and hence less swelling. Most blend ratios showed more swelling in an alkaline environment than acidic. This phenomenon can be due to electrostatic repulsion of polymer chains as a result of ionization of carboxylic acid groups that breaks the hydrogen bonds. The repulsion force will then push the hydrogel network to expand; thus more water can enter into the network [63].

Esterification of NaCMC with acryloyl chloride also was reported to improve the swelling properties such as the degree of swelling of the esterified product changes as the pH was varied [64]. At pH 9.4 the swelling percentage was quite high compared to that at pH 1.2, so it can be used as a pH-responsive polymer for the various biomedical applications. Since this polymer swells at high pH and collapses at low pH values, this polymer can be used in oral delivery, in which the polymer will retard drug release at low pH values in the stomach while releasing the same at high pH values in the small intestine. Hence this polymer can be used for pH-sensitive drug delivery system like aspirin, indomethacin, diclofenac, etc. in the intestine and also as a wound dressing material [65].

4 Conclusion

Cellulose-based hydrogels are biodegradable and biocompatible materials that indicate promise for a number of industrial uses, particularly in cases where environmental issues are concerned, aside from biomedical applications. Most of the water-soluble cellulose derivatives can be applied, with blending or singularly to make the networks of hydrogel including particular characteristics for the sensitivity to external stimuli and swelling capability. This manner of designing the cellulose hydrogels is for the nontoxic crosslinker agents of the hydrogels or crosslinking treatments in order to increase the safety of manufacturing process and the final product. Some of the cellulose derivatives such as HPMC and NaCMC show smart behavior to physiological variables such as temperature, pH, and ionic strength that make the hydrogels suitable for in vivo applications. Despite the non-bioresorbability of cellulose, the possibility to functionalize cellulose-based hydrogels with biodegradable extracellular matrix domains and bioactive indicates that such hydrogels might be ultimate platforms for the design of scaffolding biomaterials in the field of regenerative medicine and tissue engineering.

5 Future Prospects

Absorbent hydrogels are good candidates for captivating neutral aqueous solutions which are characterized by two main features, equilibrium swelling and swelling rate. Generally, two methods have been practiced to improve the swelling rate of hydrogels: (a) size reduction of the hydrogels and (b) introduction of superporosity into the hydrogels structure. Although synthetic electrolyte and nonelectrolyte hydrogels are being used in a variety of applications, research is moving toward more biocompatible and environment-friendly natural polymer alternatives, such as those based on cellulose.

During the past several decades, cellulose-based hydrogels have already exerted a dramatic impact in biological, biomedical, pharmaceutical, and diagnostic fields. However, there are some intrinsic shortcomings that severely restrict their potential practical applications. Significant efforts have been paid to improve the performance of the cellulose-based hydrogels. The fabrication of cellulosic composite materials by combining two or more components in a single entity can surmount individual shortcomings and give rise to synergistic functions that are absent in the individual components. The incorporation of nanoparticles in three-dimensional cellulosic hydrogel matrix as an innovative means to obtain cellulosic nanocomposite hydrogels with improved properties and multiple functionalities has gained enormous attention in many areas.

Due to their unique swelling features, superabsorbent cellulosic hydrogels could be employed as intelligent materials where the absorbent is required to perform numerous cycles of absorption and desorption. Cellulose-based porous hydrogels as well as thermo-responsive hydrogels have found very specific applications, where properties other than swelling capacity and rate are required. Self-assembled or self-organized hydrogels as well as those based on natural polymers could influence more advanced applications of cellulosic hydrogels.


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Farzaneh Sabbagh
    • 1
  • Ida Idayu Muhamad
    • 1
    • 2
    Email author
  • Norhayati Pa’e
    • 1
  • Zanariah Hashim
    • 1
  1. 1.Food & Biomaterial Engineering Research Group (FoBERG), Bioprocess and Polymer Engineering Department, Faculty of Chemical and Energy EngineeringUniversiti Teknologi MalaysiaJohor BahruMalaysia
  2. 2.Biomaterials Cluster, IJN-UTM Cardiovascular Engineering Centre, Block B, V01Universiti Teknologi MalaysiaJohor BahruMalaysia

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