Introductory Chapter: Hydrogels in Comprehensive Overviews, Recent Trends on Their Broad Applications

1. Introduction

Initial research of hydrogels started in 1894 when the usage of inorganic salts led to a colloidal gel [1]. Once they come into contact with fluids, hydrogels proceed to incorporate and expand to create a three-dimensional (3D) structure considering the presence of hydrophilic groups (amino, hydroxyl, carboxyl, and amide) in their structure [2].

Bemmelen was the first who established the term “hydrogel” to characterize hydrophilic polymeric systems, with high efficiency to absorb huge amounts of water or other fluids (e.g., biological fluids) in their interstitial networks [3]. The first presence on the market for a 3D network is registered in 1949 when a hydrogel based on poly(vinyl alcohol) was crosslinked with formaldehyde, which was retailed with the name Ivalon, utilized as a biomedical implant [4]. The current definition of hydrogel was established on the groundbreaking work of Lim and Wichterle, who used in 1960 gels based on poly (2-hydroxymethyl methacrylate) to create soft contact lenses. This novelty represented the onset of hydrogel investigation for applications in the biological field [1].

2. Classification, source, and structure of hydrogels

The progress of these semisolid systems is characterized by three generations of hydrogels. The first one is represented by chemically crosslinked hydrogels that show excellent swelling and high mechanical stability. The second generation was influenced by Kuhn’s research about the configuration of ionizable polymeric particles [5]. The last generation of hydrogels was encouraged by the stimuli-receptivity of the hydrogel second generation. Hence, smart hydrogels are stimuli-responsive with adjustable mechanical and physicochemical characteristics [6].

The water aspect in a hydrogel can establish the general permeation of nutrients into and biological products out of the hydrogel. When a moistureless hydrogel starts to swallow the water, primary particles of water that penetrate the cellular matrix will hydrate the most hydrophilic groups, which conduces to “primary bound water” [7]. Consequently, the polar parts hydrate, the network absorbs the water, and lets out hydrophobic groups that likewise connect with molecules of water; therefore, the water is hydrophobically bound, which means the “secondary bound water” [8]. Primary and secondary bounds of water usually link, and the resulting combination is named “total bound water.” After the hydrophobic and hydrophilic sites have been connected and linked water molecules, the structure will assimilate supplementary water, due to the osmotic power of the conformation chains to limitless dilution. The new swelling is neutralized by the physical and covalent crosslinks that go to a flexible structure retraction power. Accordingly, the hydrogel will attain an equilibrium swelling level [9]. The supplementary swelling water which is imbibed after the hydrophilic, hydrophobic, and ionic groups turn into saturated with linked water is named “free or bulk water.” This is estimated to saturate the space between the conformation conglomerates and the middle of the longer pores, blank spaces, or macropores [10]. As the hydrogel structure absorbs, if the structure crosslinks or chains are degradable, the hydrogel will start to decompose and dissolve, at a percentage that depends on its distribution. It is very important to mention that a hydrogel, which is used as a scaffold for tissue engineering can never be dehydrated, but the total water in the hydrogel consists of “bound” and “free” water [11].

The exclusive sources of hydrogels consist of two major groups: natural which comprises two principal classes based on polysaccharides and polypeptides (proteins) and the other group is artificial one, which is based on petrochemicals. Natural hydrogels are often manufactured through the addition of a few synthetic units to the natural parts. The synthetic way for the preparation of most synthetic hydrogels is represented by the multifunctional vinyl monomers that are free of radicals. Each monomer has a carbon double linkage where an effective center can disseminate to determine polymer chains [12].

Hydrogels result through chemical or physical crosslinking. Chemically cross-linked systems present durable junctions, whilst physically cross-linked systems present limited junctions [13]. The chemically crosslinking method involves monomers grafting on polymers’ backbone. On the other side, physical crosslinking generates reversible hydrogels [14] and includes the interaction between ions (e.g., hydrophobic association, hydrogen linkages, and polyelectrolyte complexation) [15]. Most of the physical gelation methods rely on the intrinsic features of the component polymers, which diminish the capacity to adjust the qualities of hydrogels, but gelation can be efficiently obtained without the necessity to change the polymer chains. The chemical path can be used to admit for more manageable and specific management of the crosslinking method, possibly in a dynamically and spatially detailed process [16].

Hydrogels can be prepared from each water-soluble polymer; there is a vast and various range of polymers that can be used to fabricate multiple hydrogels with particular properties. Thus, for their formulation, there are natural polymers (hyaluronic acid, chitosan, collagen, dextran, dextran sulfate, gelatin, alginic acid, fibrin, agarose, pectin, chondroitin sulfate, pullulan, carrageenan, polylysine, and carboxymethyl chitin), synthetic polymers (poly(ethylene glycol), poly(lactic acid), poly(lactic-glycolic acid), polycaprolactone, poly(hydroxy butyrate), poly(butylene oxide), poly(acrylic acid), polyacrylamide, and poly(glucosylethylmethacrylate), or any combination of natural and synthetic polymers [17, 18]. Consequently, depending on the polymeric composition, these semisolid systems can be homopolymeric (a single variety of monomer), copolymeric (two or more different monomer varieties), and multipolymer (known as interpenetrating polymer networks, IPNs, which are composed of two separate cross-linked natural or synthetic polymers) hydrogels [19].

3. Properties and applications of hydrogels

Hydrogels exhibit noteworthy physical, chemical, mechanical, and biocompatible properties. Thus, due to their significant water volume, porosity, permeation, biocompatibility, nontoxicity, and soft consistency, hydrogels firmly imitate natural living tissues, greater than any other group of synthetic biomaterials [20]. Besides these attractive features, hydrogels also exhibit other characteristics, such as versatility, low immunogenicity, availability, elastic structure, flexibility, responsiveness to stimuli, tensile strength, conductivity, washability, cooling effect, tolerability, transparency, safety, and excellent adhesion on the skin surface and different mucosa; they are also nonocclusive and nongreasy [21]. Therefore, hydrogels represent an exceptional substrate for utilization in cell culture due to their structural similarity to the extracellular matrix [3].

Regarding the technical properties of these semisolid systems, it can be mentioned the following: maximum stability and adherence in a swelling medium and also during storage; stability at neutral pH, odorless, colorless; suitable absorption rate and particle size; utmost biodegradability without toxic compounds generation; photostability, small soluble volume, re-wetting capacity, and the maximum absorbency under load [22].

Regarding all the outstanding properties that were highlighted above, hydrogels exhibit numerous applications in miscellaneous domains, extending from engineering to biological areas. Presently, the materials based on hydrogels mean a $22.1 billion market, with a substantial expansion to $31.4 billion by 2027. It is anticipated that the market for wearable sensors will reach $2.86 billion in 2025 and for medical sensors, $2.23 billion in 2027 [23]. The main applications of these 3D systems involve biomedical and pharmaceutical fields, bioanalysis, hygienic products, dyes, heavy metal ions elimination, artificial snow, pH sensors, agriculture, food industry, and supercapacitors. Considering the biomedical and pharmaceutical fields, hydrogels can be used for 3D bioprinting, tissue engineering, wound dressings, drug delivery systems, biosensors, regenerative medicine, biomolecules and cells separation, diagnostics, contact lenses, cosmetic medicine, and barrier materials to manage biological adherence [24].

Nowadays, 3D bioprinting has a notable place between other techniques that develop tissue matrices, having considerable uses in the biomedical field (e.g., cancer therapy, tissue engineering, drug screening, or transplantation). Considering the significant interest in this domain, the universal market had a noticeable increase, from $487 million in 2014 to $1.82 billion in 2022 [25]. Hydrogels are “soft biomaterials” utilized for the advancement of cell-laden networks, offering a conducive medium for cellular expansion. These 3D matrices can be created and printed into a range of forms, shapes, and sizes to accomplish the final product specifications [26]. 3D printing based on the nozzle is the most popular method to design hydrogel scaffolds. Viscous liquids are pushed out of the nozzle or syringe and solidified on a construction level. 3D structures are engineered layer by layer by sequential extruding matrices that pursue a predesigned line created by computer modeling [27]. Hydrogels have become principal candidates for several applications due to the current evolution in the 3D bioprinting area. The outstanding feature of hydrogels is that they can be engineered to imitate the extracellular matrix, with large applicability in tissue engineering, immunomodulation, or stem cell therapy for malignant diseases [28]. Hydrogels consist of 3D hydrophilic molecules that assure excellent water absorption; thus, they can encapsulate growth factors and nutrients into their hydrophilic network, mimicking the biological tissue. An adequate bioink for use in 3D bioprinting needs to satisfy certain conditions, such as bioactivity, cytocompatibility, and printability [29]. Regarding the polymers that make up the hydrogel structure, polysaccharides are extensively used to produce bioinks, such as cellulose, hyaluronic acid, alginate, pectin, chitosan, carrageenan, or agarose [30]. 3D bioprinted hydrogels have a large use for tissue bioprinting, including skin, muscles, bones, cartilages, neurons, cardiac fibers, and blood veins [31].

Tissue engineering and regenerative medicine represent recent areas where hydrogels have found their applicability. Due to their biocompatibility, hydrogels can interact directly with biological tissues without causing any disturbance [32]. These scaffolds can consist of large pores that have the role to integrate living tissues, or they can be formulated to deteriorate, discharge growth factors, or generating pores in which human cells can infiltrate and multiply [33]. Hydrogels can be handled as space-filling agents, delivery vectors for bioactive substances, or 3D networks, which can regulate cells and stimuli to assure the expansion of vital tissue. Hydrogels as space-filling agents are used for bulking and to avoid adherence. Hydrogel platforms can be applied in many applications, such as angiogenesis, transplant cells, and organizing various human tissues (bone, cartilage, or muscles) [20].

The applicability of hydrogels in the wound healing domain as wound dressings is due to the excellent combination between their biocompatibility, high water content, and plasticity. Hydrogels can furnish a suitable moisture medium at the lesion site and at the same time allow acceptable gas exchange between the foreign medium and the lesions, promoting wound healing. Hydrogels have the ability to reduce the temperature of the lesion and their high water volume helps to alleviate the injured surface, especially if the wound is dry [34]. Moreover, hydrogels absorb a large amount of lesion exudate and sustain it away from the lesion bed. Due to their non-irritant and non-reactive behavior with human tissues, hydrogels are proper dressings for various types of cutaneous lesions. Hydrogels are flexible and soft semisolid systems, they are easy to apply and remove, being comfortable and soothing the pain for damaged skin tissues; therefore, hydrogel dressings are attractive for patients [35].

Hydrogel scaffolds for drug delivery have firmly developed in their style, increasing further synthetic and covalently crosslinked networks to an extreme group of biomaterials platforms. Hydrogel drug release systems can be utilized for oral, transdermal, ophthalmic [36], vaginal, or rectal applications [21]. Particularly, these models can manage the drug carriers’ design and they can reach the conditions of a specific application, or they can aid researchers to explicate the transport mechanisms, which control the release kinetics from innovative formulations [37]. By regionally drugging target tissues, hydrogel drug transporters furnish imperative safety advantages by diminishing drug exposure in off-target tissue. Exceptionally, cancer therapies rise to benefit remarkably from this type of hugely concentrated drug exposure. As long as hydrogels can narrowly target drug exposure, they can also maintain a constant delivery ratio of drugs over an extended period (from hours to months, according to the formulation) [38]. This prolonged drug delivery is notably favorable for decreasing the doses administrations needed to cure a patient over time which is promising for chronic disease treatment, which requests permanent medication (e.g., diabetes). This prolonged release kinetic offers particular conveniences to augment the efficiency of several therapies like vaccines for infectious diseases. Hydrogels can also integrate properly into soft tissues, performing as possible scaffolds for endogenous cells, which can promote their applicability in the field of regenerative applications [39].

Hydrogels also represent a main part of biosensors development because the necessity for adaptable chemical or biochemical sensors has raised greatly. Moreover, many hydrogel precursors are accessible from the industrial and ecological zones as platforms for sensor geometries. Different sensing mechanisms can be included for sensor progression [40]. A modification in resistance, conductance, and electric charge transmission represents the most commonly utilized procedures and fragile interactions like hydrogen linkage are also effective. Sensor geometries were also soft because the hydrogels were flexible and adjustable. Hydrogels are appealing systems to develop flexible biosensor matrices due to their fundamental properties and structural benefits [41]; thus, they contain elastic materials like polymer, carbohydrates, elastomer, biocompatible molecules, and additives. Hydrogels can also furnish a benign environment for better action of resulting devices. A fast inflow of substance into the hydrogel could be averted essentially. Signal transduction of these semisolid matrices is available through the internal space of them if an adequate sensing medium is favorably imported. Hydrogel biosensors are extensively used in the biomedical field, especially for drug delivery [42].

4. Concluding remarks

Taking into account all the perspectives mentioned above, hydrogels had a significant evolution, from traditional to innovative platforms, with an important impact in biomedical and pharmaceutical fields, including 3D bioprinting, tissue engineering, wound dressings, drug delivery scaffolds, and biosensors. Nevertheless, their huge potential is still being explored, because hydrogel represents versatile systems, with desirable properties, such as viscoelasticity, degradability, biocompatibility, and stimuli-responsiveness, being presently explored for 4D bioprinting of organs and tissues, but the present outcomes are far away from manufacturing an outstanding human-scale tissue construct [43]. The primary challenge distributed by all researchers in this area of tissue engineering and regenerative medicine is ensuring acceptable vascularization because the cell viability of the bioprinted materials in long term is closely related to vascularization. The major test is to incorporate the printed vascular matrix into a living host and to simulate the biological processes and conformational complexity of in vivo graft. The 4D bioprinting can lead to the formulation of vascularized models but expanding them into an entire organ is still a provocation and opened a new paradigm for future explorations [44].