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Hydrogels are some of the most fascinating soft materials that have been widely explored and employed in the biomedical field due to their distinctive characteristics like high water content, softness, biocompatibility, low cost, and general ability to mimic soft human tissues. The extent of hydrogel research is currently growing rapidly and creating more paths in different fields of advanced biomedical research like drug release systems, tissue engineering/regeneration, wound healing, sensor technologies and pharmacological applications. Although there is much knowledge of hydrogel research in the literature, a compilation and overview of the status of scientific research, which could help to improve the preparation, characterization, and application of hydrogels in these disciplines is considered useful. This chapter thus gives a general overview of hydrogels, their classification, characterization methods, and targeted biomedical fields where they are currently being utilized. Furthermore, it also provides a synopsis of the historical and advanced development in hydrogel technology.

Hydrogels are three-dimensional (3D) structured networks of crosslinked hydrophilic polymer matrices capable of holding a large amount of water (> 10%by definition) and displaying useful characteristics such as softness, toughness, biocompatibility, stretchability, and deformability. The crosslinking among the hydrophilic functionalities facilitates their structural integrity and prevents their immediate dissolution in the aqueous environment. Their ability to entrap and preserve a substantial amount of water or biological solutions, and the unique combination of softness and flexibility are similar to natural soft tissues, and thus make them promising materials to mimic their properties. Additionally, they show exceptional physicochemical properties, including swelling and permeability, as well as distinct mechanical and optical properties, together with biocompatibility, which have made them a flexible tool for applications such as imaging, diagnosis, and treatment.1,2 

Hydrogels can be fabricated into thin films3  or molded into any shape, length, size, or different architectures, depending on the requirement.4  The high water absorption of hydrogels arises due to the presence of hydrophilic functionalities such as –OH, –COOH, –CONH–, –NH2, SO3H, etc. For many advanced applications, these hydrogel networks are designed with diverse polymers of natural or synthetic origin to form a hybrid structure, which is utilized to support, protect or attach new functionalities to the hydrogel structure. Most of the polymers that are used for hydrogel preparation are non-toxic and are considered suitable for many biomedical applications, from skin patches to implants, and they have been successfully implemented in all the sectors.5–8 

Recent advances in the medical field have utilized numerous hydrogel-based products for the treatment of patients. For example, polysaccharide (chitosan, alginate, cellulose, etc.) based hydrogels have been extensively utilized for wound dressing,9–11  poly(2-hydroxyethyl methacrylate) [p(HEMA)] is typically used for contact lenses,12  hyaluronic acid (HA) hydrogels for drug delivery systems,13  and protein (gelatin, collagen, and fibrin)-based hydrogels or scaffolds have been used for tissue engineering.14,15  For the treatment of cancers or tumors, the drugs are incorporated within a hydrogel and injected directly into the tumor site or adjacent areas, restricting the toxicity of the drugs to the localized area where tumor cells persist.16–18  For multidimensional applications, stimuli-responsive hydrogels that can be controlled by altering experimental conditions like temperature, surface charge, pH, and other biological conditions have been developed.19,20 

One of the first mentions of hydrogels appeared during the 19th century for colloidal gels prepared from inorganic salts.21  However, the use of gels was not highlighted until the first synthetic hydrogel on crosslinked poly-2-hydroxyethylmethacrylate (pHEMA) was found by Wichterle and Lim in 1954.22  Since then, the term “hydrogel” was regularly used to describe the three-dimensional network of hydrophilic polymers. During the 1960s, the soft contact lenses developed using the crosslinked macromolecular network of pHEMA were widely distributed around Western Europe. After successful trials, the Food and Drug Administration (FDA) approved the lenses designed using pHEMA in 1971,23  and hydrogels based on pHEMA were further applied to controlled drug delivery applications.24  In 1967, Updike and Hicks used a polyacrylamide (PAM) based hydrogel to entrap enzyme glucose-oxidase to prepare sensors.25 

Figure 1.1 shows the schematic illustration of the significant growth of hydrogels over the years. The chemistry of hydrogels had a significant breakthrough in the sixties when diverse applications of hydrogels were reported for drug delivery, tissue engineering, skincare products, food products, and many other biomedical applications. In the 1970s, new hydrogel concepts were explored and materials such as acrylamides, N-vinylpyrrolidone, and vinyl acetate were applied in order to improve the biocompatibility. During the same period, Tanaka conducted experiments on PAM gels and reported that the gels tend to collapse upon changing the temperature or solvent composition.26  He explained the phenomenon based on mean-field theory and predicted the occurrence of critical endpoints in the phase equilibria.

Figure 1.1

Development of hydrogels over the years.

Figure 1.1

Development of hydrogels over the years.

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In the 1990s, the research was more intensified towards the development of thermo-responsive hydrogels based on different polymers such as polyvinyl alcohol (PVA), poly(N-isopropylacrylamide), polyethylene glycol (PEG), etc.27,28  Furthermore, these hydrogels were utilized to fabricate delivery devices from which on–off release of molecules can occur below the lower critical solution temperature (LCST).29  During the late 90s, injectable hydrogels were widely investigated for biomedical research, and the first application was reported by Elisseeff et al. in 1999 for the targeted delivery of drugs to tissue using cartilage as an exemplary system.30 

The 21st century saw a new wave of physio-chemical methods and structural modifications that took off to improve the mechanical properties of hydrogels by the incorporation of different crosslinkers, changing the physical architectures of polymer networks, utilizing natural–synthetic polymers, incorporating inorganic materials, developing homogenous networks and stereocomplex materials, and so on.31,32  In 2003, Gong et al. employed a free radical polymerization technique to produce the first innovative double-network hydrogels with extremely high mechanical strength (fraction compression stress of 17.2 MPa and strain of 92%).33  The first network was formed using poly(2-acrylamido-2-methylpropanesulfonic acid) and the second network using PAM. The progress in the synthesis of hydrophilic and hydrophobic polymers with varied structural combinations has enabled researchers to develop biocompatible hydrogels for critical biomedical applications, including bone implants, biosensors, contact lenses, tissue engineering, etc. Recently the hydrogel research has advanced swiftly, and more efforts are focused on developing innovative hydrogels like wearable hydrogel patches, conducting hydrogels, injectable hydrogels, self-healing hydrogels, multi-component hydrogels, biodegradable hydrogels, etc.34–36  A PubMed® search for the term “hydrogel” in the title/abstract of peer-reviewed papers demonstrates the exponential increase in the research over the past two decades into the development of these extremely versatile materials in biomedical applications (Figure 1.2).

Figure 1.2

Rapid growth in the number of publications on hydrogels in the past two decades as listed on PubMed®.

Figure 1.2

Rapid growth in the number of publications on hydrogels in the past two decades as listed on PubMed®.

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Hydrogels are categorized into many different groups depending on their origin, structure, preparation method, crosslinking mechanism, charge, responsive nature, physical aspect, and degradation. Figure 1.3 represents a broad classification of hydrogels formulated based on a literature survey.

Figure 1.3

Classification of hydrogels based on different criteria.

Figure 1.3

Classification of hydrogels based on different criteria.

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Basically, hydrogels have been divided into two groups based on their origin, i.e., natural and synthetic hydrogels. Recently, significant development has been achieved in designing hydrogels using natural biomass resources. Typically, natural hydrogels are prepared from polysaccharides like alginate, chitosan, agarose, HA, cellulose, etc. or proteins derived from biological sources (such as collagen, gelatin, elastin, fibrin, etc.). Proteins like collagen and elastin are natural constituents of the extracellular matrix (ECM) and often derived from animal tendons/skin or human sources (e.g. placenta), while polysaccharides for hydrogel preparation are derived from the shells of sea crustaceans, marine algae, and plants. Given the global energy crises and environmental concerns, polysaccharides have been widely investigated in biomedical research because of their non-toxic nature, low cost, biocompatibility and biodegradability. Additionally, they contain ample hydroxyl groups (OH), carboxyl acid groups (COOH), or amine (NH2) groups that provide a convenient platform for anchoring with other groups, hydrogen bonding, functionalization, or chemical modifications that allow crosslinking.

Natural hydrogels are biodegradable materials with good biocompatibility and low toxicity. The molecular structures of natural hydrogels (derived from the ECM) have the inherent properties that can naturally support cell adhesion and proliferation. Other hydrogels produced from plant-based materials are readily available and avoid any kind of viral infections that may have animal origins. However, the undefined structures of these materials allow limited control on the mechanical properties (like rigidity and flexibility), and the difficulty in reproducibility in large-scale production has narrowed their use in many biomedical applications.37 

In contrast, synthetic hydrogels are pre-structured hydrogels with defined chemistry based on the structure of monomers/polymers. The commonly used polymers include PEG, polyvinyl alcohol (PVA), polyethylene oxide (PEO), poly(methacrylic acid), poly(acrylamide) (PAM), poly(N-isopropylacrylamide) (PIPAM), etc. Compared to natural hydrogels, synthetic hydrogels possess the potential for advanced characteristic features such as high water sorption capacity, improved physical and chemical stability, reproducibility, and enhanced gel strength, which are enabled by their chemically crosslinked structure. These features are critical for designing tissue engineering scaffolds, drug release systems, bone implants, biosensors, etc. Despite these advantages, synthetic hydrogels possess different structural chemistries which are not always friendly to the internal cells/tissues and may lead to poor biological activity and compatibility. In order to overcome these limitations, much of the current research activities are focussed on developing biohybrid hydrogels by combining the naturality of natural polymers and the engineerability of synthetic polymers. The hydrogels can be used to treat diseases, support and restore function, and facilitate the growth and remodeling related to a variety of medical issues. In general, the feasibility of using natural, synthetic, or hybrid hydrogels for a specific biomedical application depends on numerous factors, such as biocompatibility, toxicity, biological activity, swelling ratio, mechanical properties, chemical stability, biodegradability, cost, availability, etc.

Hydrogels have been broadly classified as homopolymeric, copolymeric, and interpenetrating polymer network (IPN) hydrogels based on the preparation method.38  Homopolymeric hydrogels represent polymer networks that are created from a single polymer with the same repeating monomers, whereas copolymer hydrogels contain multimonomeric polymer(s) with minimum one hydrophilic polymer, arranged in block, random, or alternating configurations. In contrast, IPN hydrogels are made from two independently crosslinked natural or synthetic polymers confined in the network structure. If one component is crosslinked and the other is not, it is called semi-IPN. Pescosolido et al.39  synthesized an injectable hydrogel from the IPN of two polysaccharides, i.e., calcium alginate and dextran-HEMA. The IPN hydrogels were completely degradable and exhibited favorable characteristics for the delivery of targeted drugs and tissue engineering applications. To expand the scope of these polysaccharides, more efforts were made to enhance the stability of polysaccharides by hybridizing with PVA via semi-IPN.40  More recently, Wang et al. formulated a unique gelatin–alginate IPN hydrogel via physical crosslinking, which exhibited a water content of 79%. The obtained gel exhibited significantly improved mechanical properties compared to pure gelatin hydrogel.41 

There are many ways to crosslink hydrophilic polymer chains to form stable polymer networks of hydrogels. The crosslinking regulates water absorption and helps to uphold the 3D structure of hydrogels in swollen states.42  Among various crosslinking procedures, physical and chemical crosslinking are the most commonly used methods to fabricate hydrogels. Physically crosslinked hydrogels can be fabricated under very mild conditions without the need for crosslinking agents that may cause toxicity to cells or tissues. There are many techniques for producing physically crosslinked hydrogels, such as hydrogen bonding, charge interactions, ionic/electrostatic interactions, stereo-complexing, freezing–thawing, protein interactions, hydrophobic interactions, and crystallization.43  Chemically crosslinked hydrogels consist of a covalently crosslinked network and the bonds are much stronger and often more stable than those of physically crosslinked hydrogels. The chemical crosslinks are produced in a number of ways, such as copolymerization of multifunctional monomers, reactions with crosslinkers, application of high energy radiation, chemical reactions of pendant groups, etc.44,45  The most commonly used strategies include the photo-, redox-, thermal- or radiation-initiated free-radical polymerization,46  enzyme-enabled crosslinking,47  Schiff base crosslinking reactions,48  Diels–Alder click reaction,49  oxime reaction,50  and Michael addition.51 

Hydrogels may be further classified into four groups based on their charge on the crosslinked chain, such as anionic, cationic, neutral, and ampholytic. The charge of the overall network is based on the charge present on the individual polymers that constitute the network structure. Figure 1.4 shows the different crosslinking methods recently adopted for the preparation of hydrogels.

Figure 1.4

Crosslinking approaches adopted for hydrogel preparation. The diagram represents the most commonly used crosslinking methods such as physical crosslinking (ionic crosslinking), chemical crosslinking, LCST/UCST, UV-based crosslinking, dual crosslinking and enzyme crosslinking.

Figure 1.4

Crosslinking approaches adopted for hydrogel preparation. The diagram represents the most commonly used crosslinking methods such as physical crosslinking (ionic crosslinking), chemical crosslinking, LCST/UCST, UV-based crosslinking, dual crosslinking and enzyme crosslinking.

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In general, ionic or electrostatic crosslinking occurs due to the molecular interconnection between the anionic and cationic polyelectrolytes. For example, the positively charged amine groups of chitosan, a natural polymer, and the negatively charged phosphate groups of glycerol phosphate disodium salt can form electrostatic crosslinking to formulate chitosan-based hydrogels.52  Similarly, alginate (an anionic polysaccharide) composed of mannuronic and glucuronic acid monomers was crosslinked with divalent cations like magnesium (Mg2+), calcium (Ca2+), barium (Ba2+), etc.53  The cations tend to specifically crosslink with the guluronate blocks of alginate with an appropriate coordination degree between the divalent ions and form an inter-polymer junction with adjacent blocks, leading to the formation of alginate-based hydrogels. This method is frequently utilized to encapsulate drugs and proteins due to easy crosslinking procedures.54  Recently, Fanghao et al.55  reported an innovative injectable DNA hydrogel formed by an electrostatic interaction between the negatively charged DNA molecule and the positively charged amino group of chitosan. The process of fabricating these biocompatible hydrogels was simple and cost-effective.

Hydrophobic interactions play a crucial role in designing tough hydrogels for large biological systems. The hydrophobic interactions can be formed by incorporating hydrophobic structural units into the hydrophilic polymer chain. Usually, the hydrogel formed by hydrophobic interactions exhibits high toughness due to the flexible movement of junction zones in the hydrogel network, which helps to dissipate energy efficiently and upsurge fraction toughness.56  Hydrophilic interactions have been actively used in associative thickeners like hydrophobically ethoxylated urethanes.57  In these polymers, the hydrophobic groups are able to self-organize into flower-like micelles (in an aqueous medium), connecting hydrophilic groups. Hydrophobic interactions are mainly generated by two methods, i.e., lower critical solution temperature (LCST) or upper critical solution temperature (UCST) and ultrasonic treatment. Perhaps the most common example would be the fabrication of PVA hydrogels by the repeated freezing and thawing cycles. During this process, the crystalline nature of the PVA structure is altered when the temperature goes below a certain critical temperature, and the PVA solution develops into a hydrogel by the intermolecular hydrogen bonding that is created when the temperature drops below the UCST.58  Many parameters, such as the gelation time, swelling degree, and water affinity, are strongly affected by the external temperature change.59  UCST hydrogels mainly possess hydrophilic functionalities, and they undergo excessive swelling (in appropriate solvents) at high temperatures. Examples of UCST hydrogels include natural polymers like gelatin, collagen, agarose, carrageenan, etc.60  Contrary to this, some polysaccharides/macromers, such as chitosan, cellulose derivatives, and poly(N-isopropylacrylamide), develop into hydrogels when the temperature increases above the LCST due to the amicable balance between hydrogen bonding and hydrophobic effects.61  LCST hydrogels contain both hydrophilic and hydrophobic functionalities in their chain and undergo sol-to-gel transitions depending on temperature. Okay et al. performed and reported a series of experiments related to the preparation of high-toughness PAM hydrogels via reversible hydrophobic interactions.62  Fu et al.63  adopted this strategy to design stretchable, conductive hydrogels using acrylate terminated poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone)[Ac(PCEC)]as the hydrophobic unit. These hydrogels were promising for functional devices, like electronic skin, wearable sensors, and intelligent robots.

Enzymatic crosslinking is another technique that is currently gaining much attraction as it provides the opportunity to manipulate the gel formation by regulating the enzyme characteristics. The formation of gels depends on many parameters, like a specific type of enzymes, their structural arrangement, physiological conditions, etc. Compared to physical and chemical crosslinking methods, enzyme-catalyzed hydrogel formation is simple and carried out under mild physiological conditions. For example, no toxic chemicals, no high temperatures, high efficiency, and no harmful radiation are involved in the crosslinking process. The majority of enzymes that are currently employed in the crosslinking process are similar to the enzymes that carry out catalytic reactions in the body. Moreover, other cytotoxic effects and unexpected by-products that arise during chemical or photo-crosslinking methods are avoided as a result of substrate-specific enzyme reactions. The enzyme-catalyzed reactions involve oxidation reactions (such as tyrosinase or peroxidase) that transform substrates into reactive forms that can potentially form covalent bonds. The two most commonly used enzymes are transglutaminase (TG) and horseradish peroxidase (HRP). TG combined with calcium ions promotes the bridging of amide linkages among carboxamide and amine groups.64  HRP can create networks among polymers by effective coupling of hydroxyphenylpropionic acid moieties.65  HRP catalyzes the coupling of aniline,66  phenol,67  and tyramine in the presence of H2O2.68  Recently Jiang et al.69  developed injectable hydrogels using an enzymatically crosslinkable tyramine modified carboxymethyl chitin conjugate for tissue engineering applications. The hydrogels were synthesized using HRP (in the presence of H2O2) under mild physiological conditions. The in vitro and in vivo studies indicated that enzymatically crosslinked hydrogels were favourable for fast gelation and good cell and tissue biocompatibility.

In this process, the crystallites present or that form in the polymer chain serve as building blocks for physical crosslinking in the network, consequently resulting in the formation of a hydrogel. The PVA solution undergoes repeated freezing and thawing cycles to form a hydrogel. The properties of the resultant gel depend on many factors like molecular weight, concentration of solution, freezing time and temperature, number of cycles, etc.70 

Hydrogels have been categorized into biodegradable and non-biodegradable based on their degradation. The hydrogels synthesized from natural polymers such as chitosan, alginate, agarose, fibrin, etc. are completely biodegradable. Degradable gels made from water soluble polymers such as PVA, PEG, PAM, and polyvinylpyrrolidone (PVP) degrade by the breaking of virtual or covalent crosslinks. For many biomedical applications, the biodegradable aspect is the primary criterion for the use of the material inside the body. Recently Heng et al.71  reported the development of a biodegradable hydrogel based on pectin aldehyde and poly(N-isopropylacrylamide-stat-acylhydrazide) as a drug carrier for antitumor therapy. In contrast, non-biodegradable hydrogels are prepared with synthetic polymers. They are not considered environmentally friendly; nevertheless, these hydrogels have been widely explored for developing drug release systems, dental issues, and wound healing.72 

Lately, biodegradable hydrogels have become essential for many biomedical applications. In order to achieve this, labile bonds (i.e., ester, carbonate, amide, carbamate, etc.) are introduced into the polymer backbone or in the crosslinks to fabricate biodegradable hydrogels. These bonds tend to cleave under physiological conditions by chemical or enzymatic methods by hydrolysis.73  Formulations using crosslinkers that are substrates for general and specific MMPs (matrix metalloproteases) are also developed to control degradation and the cell types that grow into the matrices, which also offer the ability to further engineer the degradation rate by using combinations with various amounts of hydrolytically degradable crosslinkers.74 

It is of great interest to control the degradation kinetics of hydrogels for targeted applications as it may help formulate a protocol for the synthesis of the hydrogels. Upon the implantation of a hydrogel, the full understanding of the degradation phenomenon of the hydrogel depends on a wide range of factors due to the complexity of the environment, and the stability and performance of the hydrogel are also based on the biocompatibility and inflammatory nature of the hydrogel and its breakdown products.

Recent advancement in materials chemistry and biomedical science has resulted in the development of a multitude of techniques to characterize hydrogels (Figure 1.5). Important characteristics include the chemical structure, swelling behavior, morphology, rheology, textural, thermal and mechanical properties, biocompatibility, and biodegradability. Each parameter plays a crucial role in building the integral design and function of the hydrogel. Some of the essential characterization methods are discussed below.

Figure 1.5

General techniques used for characterization of hydrogels.

Figure 1.5

General techniques used for characterization of hydrogels.

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The information of different functional groups present in the hydrogel is very crucial as it has a direct influence on the physicochemical properties such as swelling, thermal and mechanical properties, degradation, etc. Moreover, it also helps to design suitable hydrogels for specific applications. Analytical techniques like Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction (XRD) analysis, and ultraviolet-visible (UV-vis) absorption spectroscopy are often employed to analyse and interpret the chemical structure of hydrogels.

Swelling is a fundamental characteristic of hydrogels which occurs due to the diffusion of water molecules or other solutes into the hydrogel network which results in a measurable change in the volume of the hydrogel. Swelling properties are affected by many factors, which include the hydrophilic or hydrophobic polymeric chain, crosslinked polymeric network, type of bonding, surface charge, and surrounding atmosphere such as time, temperature, pH, medium, etc. Determining the swelling properties is essential in order to establish the stability of a hydrogel. Moreover, it also helps to evaluate other features like mechanical properties, degradation, physical stability, crosslinking degree, etc. The swelling capacity is depicted based on the equilibrium swelling ratio,75  which is calculated by the ratio of the weight of swollen hydrogel (Ws) to the weight of dry hydrogel (Wd), as shown below:

Swelling = WsWd/Wd

The hydrogel formed from networks of crosslinked hydrophilic polymers tends to swell more, and this phenomenon is advantageous for many biomedical applications. Similarly, polyelectrolyte-based hydrogels also display high swelling behavior due to the charge repulsion among polymeric chains, which is useful for formulating drug delivery systems.76 

The molecular mass between crosslinks (Mc) is a useful parameter to follow and calculate the crosslinking density and degradation of a hydrogel and can be derived from the Flory–Rehner equation using the swelling characteristics and constants pertaining to the polymer from which the gel is produced.77 

The performance, stability and bioactivity of hydrogels are strongly influenced by their viscoelastic and mechanical properties. Especially for biomedical applications, the knowledge of the mechanical properties of scaffolds or films, or other substrates is very crucial as they have direct contact with the neighbouring tissues, and if appropriate mechanical properties are not maintained, it may lead to damage to surrounding tissues or internal breakdown. Moreover, the mechanical properties have a substantial impact on other in vivo and in vitro behaviors, such as injectability, gelation, cell proliferation, differentiation, drug incorporation, etc. Rheometry and dynamic mechanical analysis (DMA) are the two most common methods regularly used to measure the mechanical properties of hydrogels. Modern rheometers require small sample specimens, can be measured quickly in wide temperature and atmospheric conditions, and can be used, for example, to determine the gelation times of hydrogels and to describe the viscoelastic properties of gels based on their storage and loss moduli. Recent studies have reported that rheological properties are essential to determine the bioactivity of hydrogels like bone tissues, cell adhesion, proliferation and growth, etc.78  Previously, many reviews have presented the rheological properties of hydrogels composed of polysaccharides, biomaterials, proteins, nanoparticles, drugs, etc.79,80  DMA measures the response of a sample as it is mechanically deformed over a range of stress, strain, time and temperature. The advantage of using DMA is that it helps to determine many other characteristics of a hydrogel, such as composition (crystallinity, crosslinking, effect of fillers, etc.), viscoelastic properties (like glass transition, storage and loss moduli, and tan δ), and physical properties (tensile stress–strain, compression, creep testing and stress relaxation). The measurements can be performed using different deformation modes, which include bending, uniaxial tension, torsion, compression, and shear.

In a typical DMA measurement, the hydrogel is attached to the clamps and force is applied at a given temperature and/or frequency, and the response to the force is measured. The stress (σ) is the applied force, and strain (γ) corresponds to the deformation of the sample. The measurement can be performed under dynamic or static conditions using different experimental conditions. The instrument can either apply stress (force) and measure strain (displacement) or vice versa. Figure 1.6 shows the images of hydrogel samples tested using DMA compression and tension modes. Usually, tension clamps are used to measure films and fibers, while compression clamps are used to measure square-shaped, O ring, and tablet type hydrogels.

Figure 1.6

DMA instrument (a); compression test for hydrogels: before (b) and during compression (c); tensile test for films: before (d) and when stress is applied (e).

Figure 1.6

DMA instrument (a); compression test for hydrogels: before (b) and during compression (c); tensile test for films: before (d) and when stress is applied (e).

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Morphological characterization is the most widely used technique to classify the porous microstructures of hydrogels. For biomedical applications, it is necessary to obtain the morphology of hydrogels in the swollen state. Many robust and well-established techniques are available to study swollen hydrogels: scanning electron microscopy (SEM), light microscopy (LM), transmission electron microscopy (TEM), atomic force microscopy (AFM), laser scanning confocal microscopy (LSCM), micro-computed tomography (micro-CT) and scanning tunneling microscopy (STM).81,82  Further, to investigate the nanoscale morphologies of hydrogels, additional measurements like small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS) are performed.83 

Thermal characterization provides a comprehensive understanding of the thermal characteristics of a hydrogel and other thermal transitions that could affect the biocompatibility of the material, such as the glass transition temperature (Tg), initial decomposition temperature (IDT), degree of crystallinity, endothermic or exothermic responses, thermal transitions, melting, etc. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) are frequently used to measure the thermal properties of hydrogels. TGA determines the mass change of a specific hydrogel sample as a function of temperature (or time), while DSC measures the variation in temperature and heat flow related to thermal transitions. Recently, TGA and DSC have been extensively utilized to understand the stability of hydrogel networks that are used for biomedical purposes, like wound healing, drug release, tissue engineering, etc.84,85 

Growth in hydrogel systems has paved the way for new capabilities of hydrogels that are being implemented in specific areas of biomedical research. Applications include delivering drugs or cells, regenerating hard and soft tissues, adhering to wet tissues, preventing bleeding (hemostasis), providing contrast during imaging, protecting tissues or organs during radiotherapy, and improving the biocompatibility of medical implants (Figure 1.7). In this section, we have covered two major areas, tissue engineering/regeneration and drug release systems, where hydrogels are prominently applied.

Figure 1.7

Biomedical applications of hydrogels.

Figure 1.7

Biomedical applications of hydrogels.

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In recent years, numerous hydrogel-based scaffolds have been developed and utilized to repair the injured tissues because of their structural similarity to the extracellular matrix (ECM) and distinctive features, such as hydrophilicity, biodegradability, biocompatibility, porosity, and viscoelasticity. Moreover, hydrogels can encapsulate cells in the porous structure, boost the interactions between cells and the ECM, prompt cell adhesion and provide adequate support for cell growth or regeneration. However, owing to the poor mechanical properties of hydrogels compared to human tissues, they have been utilized for targeted biomedical applications. Currently, many research groups are working towards improving the mechanical properties of these hydrogels by various innovative strategies like the incorporation of nanoparticles, fibrous reinforcing agents, increasing the crosslinking density, formulating strong interpenetrating networks, etc.86,87  Designing a hydrogel-based scaffold for regeneration of bone, cartilage, or other damaged tissues is a challenging task as the scaffold has to withstand and sustain the internal stress–strain of tissues and create an appropriate atmosphere for cell growth. In the case of resorbable scaffolds, after implantation, the aim is for cells to start to grow at the same speed as the degradation of the scaffold happens (Figure 1.8). Too rapid degradation with insufficient cellular ingrowth and ECM deposition could lead to catastrophic failure of the device, while excessive stability may retard and frustrate the remodeling process, leading to undesirable responses such as fibrosis and encapsulation. Polysaccharide-based injectable hydrogels, double-network hydrogels, protein-crosslinked hydrogels, and composite hydrogels have been effectively implemented for bone tissue regeneration.88,89 

Figure 1.8

Schematic representation of hydrogel-based scaffolds for tissue regeneration. Hydrogel-based scaffold implanted in the defective site (A). The material degrades and the cells start to proliferate and deposit their own ECM (B). The material degrades and the defective site is completely surrounded and replaced by viable tissues (C).

Figure 1.8

Schematic representation of hydrogel-based scaffolds for tissue regeneration. Hydrogel-based scaffold implanted in the defective site (A). The material degrades and the cells start to proliferate and deposit their own ECM (B). The material degrades and the defective site is completely surrounded and replaced by viable tissues (C).

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Ideally, the aim of drug delivery systems is to deliver a therapeutic amount of drug to the affected site in the body to promptly achieve, retain and govern the anticipated drug release process. For decades, hydrogels have been conveniently utilized to develop drug delivery systems due to their exceptional properties, such as porous structure, tissue compatibility, easy modifications, and solute permeability. To deliver drugs to the targeted site, the porous structure of the hydrogel provides a matrix for drug loading, and the drug encapsulated within the hydrogel dissolves as soon as the water penetrates into the system. The drug percolates out into the surrounding aqueous medium by means of diffusion.90  Moreover, the targeted drug release in the body at specific sites reduces unwanted systemic side effects and eventually helps to improve the medical treatments. Drug encapsulation, drug release and the release kinetics are the vital factors that are taken into account when fabricating a hydrogel for drug delivery. The easy processability and compatibility of hydrogels allow the encapsulation and release of drugs with various polymeric combinations such as synthetic materials, polysaccharides, proteins,91  nucleic acids,92 etc. and various combinations like alginate/PVA,93  gelatin/PAM,94  PVA/chitosan/gelatin,95 etc.

The biocompatible and biodegradable hydrogel can be obtained by manipulating the chemical and physical structures. To achieve proper control of the prolonged drug release phenomenon, the design of innovative drug delivery systems based on natural or synthetic polymers has been the main emphasis of drug delivery research groups.96,97  Hydrogel drug delivery systems derived from natural polymers include chitosan,98  alginate,99  HA,100  fibrin,101  gelatin,102 etc., while synthetic hydrogels include polymers such as PEG,103  PVA,104  PAM,105 etc. Numerous reports have been documented to display innovative concepts focusing on the development and engineering of specialized hydrogels as sustained drug delivery carriers for inflammatory bowel disease,106  diabetes,107  atopic dermatitis,108  inflammatory arthritis,109  colorectal cancer,110 etc. To specify a particular method for the detection and analysis of drug release from a hydrogel depends on many parameters, like the type of drug, the porosity of the hydrogel, selectivity, cost, the sensitivity of the technique, etc. Typical techniques such as UV/vis spectrophotometry, mass spectroscopy, high-performance liquid chromatography (HPLC), optical spectroscopy, NMR, ELISA (enzyme linked immunosorbent assay), polymerase chain reactions (PCRs), etc. are utilized for drug release studies.

Although hydrogels have many advantageous properties, they still suffer from several limitations. For instance, the high volume of water and large pores of hydrogels tend to weaken the control of the drug packing in the hydrogel network and often lead to fast drug release. Methods of gaining more control over drug release are related to forming stronger associations between the drug and the hydrogel backbone via labile links so that the release is governed not only by diffusion and degradation of the matrix, but also by the cleavage of these bonds. The problem also arises in predicting the appropriate quantity of drugs and maintaining the homogeneity of the drugs in the hydrogel matrix, especially for hydrophobic drugs.

Various mathematical models including the zero order [(Mt(t)/M) = kt], first order (ln(Mt(t)/M) = kt), Peppas power law [(Mt(t)/M) = ktn], Higuchi [(Mt(t)/M) = kt1/2], and Hixon–Crowell equation have been used to mathematically describe the release of drugs from hydrogels. A detailed exposition of the models and their incidence of use can be found in ref. 111. Additionally, the limited mechanical properties of gels may restrict their use for load-bearing applications and could also lead to premature dissolution of the hydrogel prior to the targeted site. Even though these limitations may limit the use of hydrogels for drug release, numerous research groups are currently focused on overcoming these issues and bringing hydrogel-based drug delivery systems to clinical trials.

Usually, physical and chemical methods are adopted to formulate the strong bonding between the hydrogel matrix and the loaded drug, further prolonging the drug release duration, as schematically presented in Figure 1.9a and b. The charged interactions among the ionic hydrogel and the charged drugs have often been utilized to improve the strength and prolong the targeted release of the drugs. For example, carbohydrate-based polymers having both anionic and cationic functionalities can be very effective in prolonging the release of drugs with opposite charges.112  Interestingly, charge interaction is also one of the reasons for using polysaccharides in drug delivery systems. Recently, Li et al.113  formulated innovative carriers of vancomycin (VM) loaded chitosan–polyaniline microgels for the treatment of inflammatory bowel disease. The microgels exhibited unique behavior and displayed a reversible charge after NaCl treatment to form a negatively charged microgel. The negative charge of the microgel demonstrated a high loading efficiency of cationic VM by forming an electrostatic interaction. Similarly, amino functional groups can be used for the controlled release of anionic drugs. For instance, copolymerization of 4-vinylpyridine or N-(3-aminopropyl)methacrylamide improved the loading of nonsteroidal anti-inflammatory drugs into poly(HEMA) hydrogels. The drug release was prolonged for up to 1 week without any decline in the mechanical properties of the hydrogels.114 

Figure 1.9

(a) Physical and (b) chemical methods adopted to enhance the interaction between the hydrogel and the incorporated drug. (c) Plum-pudding composite hydrogel with drug carriers like microparticles, nanoparticles, microgels, liposomes, etc. Strategies of utilizing hydrogels for hydrophobic drugs via (d) random copolymerization, (e) grafting, and (f) incorporation of cyclodextrin.

Figure 1.9

(a) Physical and (b) chemical methods adopted to enhance the interaction between the hydrogel and the incorporated drug. (c) Plum-pudding composite hydrogel with drug carriers like microparticles, nanoparticles, microgels, liposomes, etc. Strategies of utilizing hydrogels for hydrophobic drugs via (d) random copolymerization, (e) grafting, and (f) incorporation of cyclodextrin.

Close modal

Chemical conjugation by covalent bonding is another route to formulate a bond between the drug and polymer matrix. In this case, the release of drug is controlled by the chemical/enzymatic breakdown of the polymer–drug bond, as shown in Figure 1.9b. Many of the research efforts to improve the intrinsic adhesion energy have attempted to introduce covalent bonding with polymer networks via introducing an interlink initiator,115  modification with silane,116 etc. Recently, Basu et al.117  fabricated DNA-based nanocomposite hydrogels crosslinked by oxidized alginate by forming reversible imine bonding. Oxidized alginate attached to the DNA backbone chain formed imine bonds to link the DNA strands. The nanocomposite hydrogels were suitable as drug delivery vehicles for the hydrophobic drug simvastatin and delivered the drug in a controlled manner for approximately five days.

Systematic drug administration frequently faces two major issues, i.e., premature release and non-uniform drug distribution, resulting in lower efficacy and untargeted toxicity. An alternative approach for improving the efficiency of drug delivery involves the incorporation of micro- or nano-gels in the hydrogel matrix to produce composite hydrogels. These composite hydrogels also known as “plum pudding” are formulated by the entrapment of liposomes, microspheres, and other types of particles that have proven to be successful carriers for prolonged and timely drug release, as shown in Figure 1.9c. For example, liposomes incorporated in hydroxyethylcellulose-based hydrogels delivered a controlled release of griseofulvin and calcein.118  Similarly, gelatin microparticles in the oligo-poly(ethylene glycol fumarate) matrix showed prolonged release of TGF-β1 for cartilage repair.119  These systems are interesting as the constraints of microgels and hydrogels in the drug release can be combined and configured into a soft nanocomposite. The bulky hydrogel network averts the migration of microgels from the target site and offers a supplementary diffusive barrier for controlled drug release.120  Recently, Qin et al.121  used a plum-pudding strategy to design injectable hydrogels based on HA and self-assembled triblock micelles to deliver hydrophobic drugs for renal interstitial fibrosis. The approach was proved to show a sustained release of drug in the kidneys for up to 3 weeks in mice.

Classically, hydrogels are utilized as a carrier for the drug delivery of hydrophilic and hydrophobic drugs. However, the incorporation and delivery of hydrophobic drugs are more complicated when compared to hydrophilic drugs due to many reasons, such as drug loading in the hydrogel matrix, effective control inside the hydrogel matrix, and targeted, efficient release of drugs in the aqueous medium. The most common method of producing hydrophobic domains within a hydrogel is by the copolymerization of hydrophobic monomers and infusing hydrophobic sites with three-dimensional polymeric networks. The basic approaches are schematically illustrated in Figure 1.9d–f. This method provides the opportunity to articulate free binding of hydrophobic drugs and reduces the bulk dimensions of the hydrogel, resulting in the shortening of pore size and decelerating the drug release rate. Alternatively, hydrophobic drugs can be rendered water soluble by modification with soluble moieties, e.g. by PEGylation. In such cases, it is important to target a non-active site of the drug, append the solubiliser using chemistry that restores the drug in the original form after cleavage, and/or use a remaining functionality of the solubilising agent to link covalently to the hydrogel polymer backbone linking with a labile tether.122 

Studies suggest that drug delivery systems formulated from a single biopolymeric system suffer from some significant limitations like poor mechanical properties, low swelling rates, hydration hysteresis, etc., which may directly hamper the drug release properties of the hydrogels.123  Many attempts have been made to overcome these limitations by forming a conjugated system with proteins,124  synthetic polymers125  or inorganic solutes,126  or by chemical modifications via grafting,127  crosslinking,128  and forming IPNs,129  Among all, IPN formation emerges as a valuable approach to modify the chemistry of the hydrogel to the desired functional properties and thus the performance of natural or synthetic polymers. Lately, numerous systems based on natural polymers have been used to prepare IPNs as drug carriers.130,131 

The progress of hydrogel chemistry has reached the next level, where different polymer structures, processes, crosslinking methods, characterization techniques, and application areas have come to light, providing new hope and scope for solutions for critical biomedical applications ranging from cancer treatment, bone regeneration and diabetes to the treatment of cardiovascular problems. It remains a challenge to bring these hydrogels from the laboratory scale to the clinical trial and further to the commercial market. It is expected that hydrogel-based biomedical devices or systems will play a major role in future biomedical research due to their biocompatibility, tunability, and biodegradability. Further, there is a scope to develop innovative biopolymer-based hydrogels (such as polysaccharides and proteins), optimize conditions, standardize a protocol for hydrogel production, and utilize them for targeted biomedical applications like drug delivery, tissue engineering, wound healing, and many other biomedical purposes.

The work was supported by the European Regional Development Fund-Project, Application of Modern Technologies in Medicine and Industry (No. CZ.02.1.01/0.0/0.0/17_048/0007280).

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