Hydrogel

Hydrogels are among the most amazing soft materials extensively studied and used in the biomedical industry because of their unique properties, such as their high water content, softness, functionality, affordability, and overall capacity to replicate soft human tissues.

The subject of hydrogel research is expanding quickly, opening up new avenues for advanced biomedical research in areas such as drug release systems, wound healing, tissue engineering/regeneration, sensor technologies, and pharmacological applications.

Even though there is a wealth of information about hydrogel research in the literature, it is helpful to put together and summarize the current state of scientific research that could enhance the creation, description, and usage of hydrogels in various fields.

Introduction

Hydrogels are networks of crosslinked hydrophilic polymer matrices that are three-dimensional (3D) and have the ability to hold a significant quantity of water (> 10% by definition). They also exhibit beneficial properties such as deformability, toughness, softness, stretchability, and biocompatibility.

The crosslinking between the hydrophilic functions helps to maintain their structural integrity and stops them from dissolving right away in water. They are promising materials to copy the features of natural soft tissues because of their capacity to trap and retain a significant amount of water or biological solutions, as well as their special blend of softness and flexibility. They also exhibit remarkable physicochemical qualities, including permeability and swelling, unique mechanical and optical characteristics, and biocompatibility, which make them an adaptable instrument for uses in imaging, diagnosis, and therapy.

Depending on the needs, hydrogels can be molded into any size, shape, length, or architecture or created into thin films. The inclusion of hydrophilic functions like -OH, -COOH, -CONH-, -NH2, SO3H, etc., causes hydrogels to absorb a lot of water. These hydrogel networks are made with a variety of natural or synthetic polymers to create a hybrid structure that can be used to support, shield, or add additional functions to the hydrogel structure in a variety of sophisticated applications. The majority of the non-toxic polymers used to make hydrogels are thought to be appropriate for a wide range of biomedical applications, from implants to skin patches, and they have been effectively used in every industry.

Many hydrogel-based products have been used in recent medical advancements to treat patients. For instance, hydrogels based on polysaccharides (chitosan, alginate, cellulose, etc.) have been widely used for wound dressings; hydrogels based on poly(2-hydroxyethyl methacrylate) [p(HEMA)] are commonly used for contact lenses; hydrogels based on hyaluronic acid (HA) are used for drug delivery systems; and hydrogels or structures based on proteins (gelatin, collagen, and fibrin) have been employed for tissue engineering.

The medications used to treat malignancies or tumors are encapsulated in a hydrogel and injected directly into the tumor site or nearby regions, limiting the drugs’ toxicity to the specific location where the tumor cells are still present. Stimuli-responsive hydrogels, which may be adjusted by varying experimental parameters such as temperature, surface charge, pH, and other biological variables, have been produced for multidimensional applications.

History

Hydrogels were initially mentioned concerning colloidal gels made from inorganic salts in the 19th century. However, it wasn’t until Wichterle and Lim discovered the first synthetic hydrogel on crosslinked poly-2-hydroxyethylmethacrylate (pHEMA) in 1954 that the usage of gels was brought to light. Since then, the three-dimensional network of hydrophilic polymers has been frequently referred to as “hydrogel.” Soft contact lenses made with pHEMA’s crosslinked macromolecular network were extensively available in Western Europe in the 1960s. The Food and Drug Administration (FDA) authorized the pHEMA-designed lenses in 1971 following successful trials, and pHEMA-based hydrogels were subsequently used in controlled drug delivery applications.

When numerous uses of hydrogels for medication delivery, tissue engineering, skincare goods, food items, and numerous other biomedical applications were revealed in the 1960s, hydrogel chemistry saw a breakthrough. New hydrogel ideas were investigated in the 1970s, and materials like vinyl acetate, acrylamides, and N-vinylpyrrolidone were used to increase biocompatibility. Tanaka experimented with PAM gels during this time and found that when the solvent composition or temperature is changed, the gels tend to collapse. He suggested the occurrence of critical endpoints in the phase equilibria and used the mean-field theory to explain the phenomenon.

In the 1990s, the research was increasingly pushed towards the development of thermo-responsive hydrogels based on diverse polymers such as polyvinyl alcohol (PVA), poly(N-isopropylacrylamide), polyethylene glycol (PEG), etc. Furthermore, these hydrogels were employed to manufacture delivery devices from which the off-release of molecules can occur below the lower critical solution temperature (LCST). During the late 90s, injectable hydrogels were intensively researched for biomedical research, and the first use was described by Elisseeff et al. in 1999 for the targeted delivery of medicines to tissue utilizing cartilage as an example system.

To improve the mechanical properties of hydrogels, a new wave of physio-chemical techniques and structural changes emerged in the twenty-first century. These techniques included mixing various crosslinkers, altering the physical architectures of polymer networks, using natural and synthetic polymers, adding inorganic materials, creating homogenous networks and stereocomplex materials, and more. The first novel double-network hydrogels with very high mechanical strength (fraction compression stress of 17.2 MPa and strain of 92%) were created in 2003 by Gong et al.. using a free radical polymerization process. Poly(2-acrylamido-2-methylpropanesulfonic acid) was used to create the first network, while PAM was used to create the second.

Researchers have been able to create biocompatible hydrogels for vital biomedical applications, such as tissue engineering, contact lenses, biosensors, bone implants, and more, thanks to advancements in the synthesis of hydrophilic and hydrophobic polymers with a variety of structural combinations. Research on hydrogels has rapidly advanced recently, and more work is being done to create novel hydrogels, such as conductible hydrogels, injectable hydrogels, wearable hydrogel patches, self-healing hydrogels, multi-component hydrogels, biodegradable hydrogels, etc.

Classification of Hydrogels

Depending on their origin, structure, method of manufacture, crosslinking technique, charge, responsiveness, physical aspect, and degradation, hydrogels are divided into different categories.

Origin-Based Hydrogel Classification

In general, hydrogels can be classified as either natural or synthetic, depending on where they come from. Designing hydrogels from natural biomass resources has advanced significantly in recent years. Generally, proteins originating from biological sources (e.g., collagen, gelatin, elastin, fibrin, etc.) or polysaccharides (e.g., alginate, chitosan, agarose, HA, cellulose, etc.) are used to create natural hydrogels.

While polysaccharides for hydrogel manufacture are derived from the shells of sea crustaceans, marine algae, and plants, proteins such as collagen and elastin are naturally occurring components of the extracellular matrix (ECM) and are frequently derived from human or animal sources (such as the placenta or tendons/skin). Due to their non-toxic nature, low cost, biocompatibility, and biodegradability, polysaccharides have been extensively studied in biomedical research in light of the worldwide energy crises and environmental concerns. They also have a lot of hydroxyl (OH), carboxyl acid (COOH), or amine (NH2) groups, which offer a handy platform for hydrogen bonding, functionalization, anchoring with other groups, or chemical changes that enable crosslinking.

Natural hydrogels are low-toxicity, biodegradable substances with good biocompatibility. Natural hydrogels, which are produced from the extracellular matrix, possess molecular architectures that naturally promote cell adhesion and proliferation. Other plant-based hydrogels are readily available and free of viruses originating from animals. However, these materials’ unclear structures make it difficult to manage their mechanical qualities (such as stiffness and flexibility), and their usage in many biomedical applications has been limited due to their challenging repeatability in large-scale manufacturing.

On the other hand, pre-structured hydrogels with specific chemistry derived from the structure of monomers or polymers are known as synthetic hydrogels. PEG, polyvinyl alcohol (PVA), polyethylene oxide (PEO), poly(methacrylic acid), poly(acrylamide) (PAM), poly(N-isopropylacrylamide) (PIPAM), and other polymers are frequently utilized. Because of their chemically crosslinked structure, synthetic hydrogels have the potential to have more advanced characteristics than natural hydrogels, including increased water sorption capacity, greater physical and chemical stability, repeatability, and enhanced gel strength. When creating structures for tissue engineering, drug release systems, bone implants, biosensors, etc., these characteristics are essential. Despite these benefits, synthetic hydrogels have various structural chemistries that might result in poor biological activity and compatibility and are not always kind to the inside cells or tissues.

The majority of current research efforts are concentrated on creating biohybrid hydrogels, which combine the engineerability of synthetic polymers with the naturalness of natural polymers, to get beyond these restrictions. Diseases can be treated, function can be supported and restored, and growth and remodeling associated with various medical conditions can be facilitated by the hydrogels.

Generally speaking, several variables, including biocompatibility, toxicity, biological activity, swelling ratio, mechanical properties, chemical stability, biodegradability, cost, availability, etc., determine whether using natural, synthetic, or hybrid hydrogels for a given biomedical application is feasible.

Classification of Hydrogels Using the Preparation Method

Depending on how they are prepared, hydrogels can be generically categorized as homopolymeric, copolymeric, or interpenetrating polymer network (IPN) hydrogels. While copolymer hydrogels contain multimonomeric polymer(s) with at least one hydrophilic polymer arranged in block, random, or alternating patterns, homopolymeric hydrogels are polymer networks made from a single polymer with the same repeating monomers. IPN hydrogels, on the other hand, are composed of two naturally or artificially crosslinked polymers that are contained within a network structure.

Semi-IPN occurs when one component is crosslinked while the other is not. Created an injectable hydrogel using the IPN of two polysaccharides, namely dextran-HEMA and calcium alginate. The IPN hydrogels showed promising properties for tissue engineering applications and targeted drug administration, and they were fully biodegradable. More attempts were made to improve the stability of polysaccharides by hybridizing with PVA via semi-IPN to broaden the range of these polysaccharides. created a novel gelatin–alginate IPN hydrogel using physical crosslinking more recently, and it had a 79% water content. When compared to pure gelatin hydrogel, the resulting gel showed noticeably better mechanical qualities.

Crosslinking-Based Hydrogel Classification

Hydrophilic polymer chains can be crosslinked in a variety of ways to create stable hydrogel polymer networks. When hydrogels are swelled, the crosslinking helps maintain their three-dimensional structure and controls water absorption. The two most used crosslinking techniques for creating hydrogels are physical and chemical crosslinking.

Without the use of crosslinking chemicals that could be harmful to cells or tissues, physically crosslinked hydrogels can be created in extremely mild circumstances. Hydrogen bonding, charge interactions, ionic/electrostatic interactions, stereo-complexing, freezing/thawing, protein contacts, hydrophobic interactions, and crystallization are some of the methods used to create physically crosslinked hydrogels.

Compared to physically crosslinked hydrogels, chemically crosslinked hydrogels have a positive crosslinked network with bonds that are far stronger and frequently more stable. There are several methods for creating chemical crosslinks, including the copolymerization of multifunctional monomers, crosslinker reactions, high-energy radiation application, pendant group chemical processes, etc. The most often employed techniques are the Michael addition, Diels–Alder click reaction, oxime reaction, enzyme-enabled crosslinking, Schiff base crosslinking reactions, photo-, redox-, thermal-, or radiation-initiated free-radical polymerization, and others.

Based on their charge on the crosslinked chain, hydrogels can be further divided into four groups: ampholytic, cationic, neutral, and anionic. The charge on each of the individual polymers that make up the network structure determines the charge of the entire network.

Crosslinking via ionic or electrostatic interactions

Generally speaking, the molecular bond between the cationic and anionic polyelectrolytes causes ionic or electrostatic crosslinking. To create chitosan-based hydrogels, for instance, the negatively charged phosphate groups of glycerol phosphate disodium salt and the positively charged amine groups of chitosan, a naturally occurring polymer, can electrostatically crosslink.

Similarly, divalent cations such as magnesium (Mg2+), calcium (Ca2+), barium (Ba2+), and others were used to crosslink alginate, an anionic polymer made of mannuronic and glucuronic acid monomers. Alginate-based hydrogels are created when the cations form an inter-polymer connection with neighboring blocks and specifically crosslink with the guluronate blocks of alginate with a suitable coordination degree between the divalent ions.

Because crosslinking processes are simple, this technique is widely used to encapsulate proteins and medications. An inventive injectable DNA hydrogel is created by an electrostatic interaction between the positively charged amino group of chitosan and the negatively charged DNA molecule. These biocompatible hydrogels were easy and reasonably priced to create.

Crosslinking via Hydrophobic Interactions

A key factor in creating strong hydrogels for big biological systems is hydrophobic interactions. By adding hydrophobic structural units to the hydrophilic polymer chain, hydrophobic interactions can be created. Because of the flexible movement of junction zones in the hydrogel network, which helps in energy dissipation and increases fraction toughness, hydrogels generated by hydrophobic contacts typically display high toughness.

Associative thickeners such as hydrophobically ethoxylated urethanes have made extensive use of hydrophilic interactions. In an aqueous medium, the hydrophobic groups in these polymers can self-organize into micelles that resemble flowers, joining hydrophilic groups. Two primary techniques are used to create hydrophobic interactions: ultrasonic treatment and lower critical solution temperature (LCST) or higher critical solution temperature (UCST).

The process of repeatedly freezing and thawing PVA hydrogels is arguably the most widely used example. In this process, the PVA solution turns into a hydrogel due to the intermolecular hydrogen bonding that occurs when the temperature falls below the UCST, and the crystalline character of the PVA structure is changed when the temperature falls below a specific critical temperature. The external temperature change has a significant impact on many characteristics, including gelation time, degree of swelling, and water affinity. The primary functions of UCST hydrogels are hydrophilic, and at high temperatures, they expand excessively (in the right solvents). Natural polymers such as gelatin, collagen, agarose, carrageenan, etc., are examples of UCST hydrogels.

LCST hydrogels experience sol-to-gel transitions based on temperature and have both hydrophilic and hydrophobic functions in their chain. Conducted and published many tests on the creation of PAM hydrogels with high toughness through reversible hydrophobic interactions. Used acrylate terminated poly(ε-caprolactone)–poly(ethylene glycol)–poly(ε-caprolactone)[Ac(PCEC)] as the hydrophobic unit to create flexible, conducting hydrogels. These hydrogels showed promise for wearable sensors, electronic skin, and intelligent robots, among other useful devices.

Crosslinking via Reactions Catalyzed by Enzymes

Another method that is becoming more and more popular right now is enzymatic crosslinking, which allows you to control the properties of the enzyme and hence control the gel formation. Numerous factors, such as a particular enzyme type, their structural arrangement, physiological circumstances, etc., affect how gels develop. Enzyme-catalyzed hydrogel production is straightforward and done in mild physiological circumstances as opposed to physical and chemical crosslinking techniques. For instance, the crosslinking method doesn’t use any hazardous radiation, high temperatures, poisonous chemicals, or great efficiency. Most of the enzymes now used in the crosslinking process are comparable to those involved in catalytic processes within the body.

Furthermore, substrate-specific enzyme reactions prevent other harmful effects and unanticipated byproducts that occur via chemical or photo-crosslinking techniques. Oxidation processes, which are catalyzed by enzymes like tyrosinase or peroxidase, change substrates into reactive forms that may eventually form positive connections. Horseradish peroxidase (HRP) and transglutaminase (TG) are the two most often utilized enzymes.

Carboxamide and amine groups’ amide connections are encouraged to bridge when TG and calcium ions are present. Through the efficient coupling of hydroxyphenylpropionic acid moieties, HRP can form networks among polymers. When H2O2 is present, HRP catalyzes the coupling of tyramine, phenol, and aniline. Injectable hydrogels for tissue engineering applications that use a carboxymethyl chitin conjugate modified by tyramine that is enzymatically crosslinkable. HRP was used to create the hydrogels under mild physiological conditions (with H2O2). Enzymatically crosslinked hydrogels were found to be advantageous for rapid gelation and high cell and tissue biocompatibility in both in vitro and in vivo investigations.

Crosslinking via Crystallization

The crystallites that are already there or that develop in the polymer chain act as building blocks for the network’s physical crosslinking throughout this process, which ultimately leads to the creation of a hydrogel. To create a hydrogel, the PVA solution is repeatedly frozen and thawed. Numerous variables, including molecular weight, solution concentration, freezing temperature and time, number of cycles, etc., affect the final gel’s characteristics.

Hydrogel Classification Based on Degradability.

Based on how they break down, hydrogels have been divided into biodegradable and non-biodegradable categories. The hydrogels made from natural polymers like fibrin, agarose, alginate, chitosan, etc., are entirely biodegradable. Water-soluble polymers like PVA, PEG, PAM, and polyvinylpyrrolidone (PVP) are used to make degradable gels. These gels break down by breaking covalent or virtual crosslinks. The main requirement for using a material inside the body in many biomedical applications is that it be biodegradable.

Biodegradable hydrogels are now necessary for a wide range of biomedical applications. This is accomplished by creating biodegradable hydrogels by introducing labile bonds (such as ester, carbonate, amide, carbamate, etc.) into the crosslinks or the polymer backbone. Under physiological settings, these bonds tend to hydrolyze chemically or enzymatically. To control degradation and the types of cells that grow into the matrices, formulations utilizing crosslinkers that are substrates for both general and specific MMPs (matrix metalloproteases) are also developed. These formulations also provide the ability to further engineer the degradation rate by combining different amounts of hydrolytically degradable crosslinkers.

Controlling the hydrogels’ degradation kinetics for certain uses is quite interesting because it could aid in developing a production protocol. Because of the complexity of the environment, a variety of factors affect the hydrogel’s degradation phenomenon after implantation. The hydrogel’s stability and performance are also dependent on its biocompatibility and inflammatory nature, as well as the breakdown products it produces.

Hydrogel Characterization

Several techniques for characterizing hydrogels have been developed as a result of recent developments in materials chemistry and biomedical research. The chemical structure, swelling behavior, morphology, rheology, textural, mechanical, thermal, and biodegradable qualities are all significant attributes. Every parameter is essential to creating the hydrogel’s overall structure and functionality. Below is a discussion of some of the key characterization techniques.

Characterization of Structure

The details of the many functional groups that are present in the hydrogel are particularly important since they directly affect its physicochemical characteristics, including swelling, mechanical and thermal characteristics, degradation, etc. Additionally, it helps in the design of appropriate hydrogels for certain uses.

The chemical structure of hydrogels is frequently analyzed and interpreted using analytical methods such as Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction (XRD) analysis, and ultraviolet-visible (UV-vis) absorption spectroscopy.

Swelling

One essential property of hydrogels is swelling, which is caused by the diffusion of water molecules or other solutes into the hydrogel network and causes a recognizable shift in the hydrogel’s volume. Numerous parameters, such as the hydrophilic or hydrophobic polymeric chain, crosslinked polymeric network, bonding type, surface charge, and ambient conditions, including time, temperature, pH, medium, etc., all influence swelling capabilities. Establishing a hydrogel’s stability requires knowing its swelling characteristics.

Assessing additional characteristics such as mechanical characteristics, deterioration, physical stability, degree of crosslinking, etc., is also beneficial. The equilibrium swelling ratio, which is determined by dividing the weight of swollen hydrogel (Ws) by the weight of dry hydrogel (Wd), is used to illustrate the swelling capacity. This is demonstrated below:

Swelling = Ws – Wd/Wd.

Many biomedical applications benefit from the tendency of the hydrogel made from networks of crosslinked hydrophilic polymers to swell more. The charge repulsion between polymeric chains also causes polyelectrolyte-based hydrogels to exhibit high swelling behavior, which is advantageous when creating drug delivery systems.

The molecular mass between crosslinks (Mc), which may be obtained using the Flory–Rehner equation using the swelling properties and constants relevant to the polymer from which the gel is made, is a helpful parameter to monitor and compute the crosslinking density and degradation of a hydrogel.

Mechanical Characterization

The mechanical and viscoelastic characteristics of hydrogels have a significant impact on their performance, stability, and bioactivity. Since structures, films, and other substrates come into direct contact with nearby tissues, understanding their mechanical characteristics is especially important for biomedical applications. Failure to maintain proper mechanical properties could result in internal breakdown or damage to the surrounding tissues. Furthermore, various in vivo and in vitro behaviors like injectability, gelation, cell proliferation, differentiation, drug integration, etc., are significantly influenced by the mechanical properties. The two most popular techniques for routinely assessing the mechanical characteristics of hydrogels are rheometry and dynamic mechanical analysis (DMA).

Modern rheometers can measure rapidly across a wide range of temperature and air conditions, require small sample specimens, and can be used, for instance, to define the viscoelastic properties of gels based on their storage and loss moduli and to ascertain the gelation periods of hydrogels. According to recent research, the rheological characteristics of hydrogels—such as bone tissues, cell adhesion, proliferation, and growth—are crucial in determining their bioactivity. The rheological characteristics of hydrogels made of polysaccharides, biomaterials, proteins, nanoparticles, medications, etc., have already been covered in numerous reviews. When a sample is mechanically deformed over a range of stress, strain, time, and temperature, DMA detects how it reacts. A hydrogel’s composition (crystallinity, crosslinking, effect of fillers, etc.), viscoelastic properties (such as glass transition, storage and loss moduli, and tan δ), and physical properties (tensile stress–strain, compression, creep testing, and stress relaxation) can all be ascertained with the aid of DMA. A variety of deformation modes, including bending, uniaxial tension, torsion, compression, and shear, can be used for the measurements.

A standard DMA measurement involves attaching the hydrogel to the clamps, applying force at a specific temperature and/or frequency, and measuring the hydrogel’s reaction to the force. The applied force is represented by the stress (σ), and the sample’s deformation is represented by the strain (γ). Various experimental circumstances can be used to measure in either dynamic or static settings. The device can measure strain (displacement) and apply stress (force), or the other way around.

Morphology

The method most frequently employed to categorize the porous microstructures of hydrogels is morphological characterization. The shape of hydrogels in their swelled condition is required for biomedical applications. 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) are among the numerous reliable and well-established methods available for studying swollen hydrogels. Furthermore, further measurements, such as small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS), are carried out to examine the nanoscale morphologies of hydrogels.

Thermal Analysis

The glass transition temperature (Tg), initial decomposition temperature (IDT), degree of crystallinity, endothermic or exothermic responses, thermal transitions, melting, and other thermal transitions that may impact the material’s biocompatibility can all be thoroughly understood through thermal characterization. The thermal characteristics of hydrogels are commonly measured using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC detects the change in temperature and heat flow associated with thermal transitions, whereas TGA calculates the mass change of a particular hydrogel sample as a function of temperature (or time).

Applications in the Biomedical Field

The development of hydrogel systems has opened the door for novel applications of hydrogels in particular fields of biomedical research. It can be used to carry medications or cells, to regenerate soft and hard tissues, to stick to wet tissues, to stop bleeding (hemostasis), to provide contrast for imaging, to shield organs or tissues from radiation therapy, and to increase the biocompatibility of medical implants.

Tissue Engineering

Since hydrogel-based structures share structural similarities with the extracellular matrix (ECM) and have unique properties like hydrophilicity, biodegradability, biocompatibility, porosity, and viscoelasticity, many of them have been created and used in recent years to repair damaged tissues. Hydrogels can also enclose cells in their porous structure, improve the way cells interact with the extracellular matrix, promote cell adherence, and offer sufficient support for cell growth or regeneration.

However, hydrogels have been used for specific biomedical purposes because of their inferior mechanical qualities when compared to human tissues. Numerous research teams are currently attempting to enhance these hydrogels’ mechanical qualities by a variety of creative techniques, such as adding nanoparticles, fiber reinforcing agents, raising the crosslinking density, creating robust interpenetrating networks, etc.

It is difficult to design a hydrogel-based scaffold for the regeneration of bone, cartilage, or other injured tissues because it must be able to tolerate internal tissue stress and strain and provide the right environment for cell proliferation. The goal with resorbable structures is for cells to begin growing at the same rate that the scaffold degrades following implantation.

The device may fail catastrophically if it degrades too quickly with insufficient cellular ingrowth and ECM deposition, whereas excessive stability may impede and frustrate the remodeling process, resulting in unwanted reactions such as encapsulation and fibrosis. For bone tissue regeneration, injectable hydrogels based on polysaccharides, double-network hydrogels, protein-crosslinked hydrogels, and composite hydrogels have all been successfully used.

Systems for Drug Delivery

To quickly accomplish, maintain, and control the expected drug release process, drug delivery systems should ideally deliver a therapeutic dose of medication to the affected region in the body. Hydrogels have been used for decades to create drug delivery systems because of their remarkable qualities, including solute permeability, tissue compatibility, facile modification, and porous structure. The hydrogel’s porous structure serves as a matrix for drug loading, which transports medications to the intended location. The drug enclosed in the hydrogel dissolves as soon as water enters the system. Through diffusion, the medication seeps into the surrounding aquatic medium.

Additionally, tailored drug release at particular locations inside the body lessens undesirable systemic side effects and ultimately aids in the enhancement of medical treatments. When creating a hydrogel for drug delivery, three crucial elements are considered: drug encapsulation, drug release, and release kinetics. Drugs with a variety of polymeric combinations, including synthetic materials, polysaccharides, proteins, nucleic acids, etc., as well as combinations like alginate/PVA, gelatin/PAM, PVA/chitosan/gelatin, etc., can be encapsulated and released thanks to the hydrogels’ easy processability and compatibility.

The chemical and physical structures can be changed to create a hydrogel that is both biocompatible and biodegradable. Drug delivery research groups have focused mostly on designing novel drug delivery systems based on natural or synthetic polymers to properly control the extended drug release phenomenon. Chitosan, alginate, HA, fibrin, gelatin, and other natural polymers are examples of hydrogel drug delivery methods; synthetic hydrogels are made of polymers, including PEG, PVA, PAM, and others. Several studies have been published that demonstrate novel ideas for the creation and engineering of customized hydrogels as long-term drug delivery vehicles for conditions like diabetes, inflammatory arthritis, atopic dermatitis, colorectal cancer, inflammatory bowel disease, etc.

Despite their many positive attributes, hydrogels nonetheless have several drawbacks. For example, hydrogels’ large pores and high water content tend to make it harder to regulate how drugs are packed in the network, which frequently results in rapid drug release. Techniques for increasing control over drug release involve strengthening the bindings between the drug and the hydrogel backbone through labile linkages so that the release is controlled by the cleavage of these bonds, as well as diffusion and matrix degradation. Predicting the right amount of medication and preserving its homogeneity inside the hydrogel matrix are additional challenges, particularly for hydrophobic medications.

Drug release from hydrogels has been mathematically described using a variety of models, such as 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. The models and their frequency of use are explained in detail in ref. Furthermore, gels’ low mechanical qualities can limit their deployment in load-bearing applications and possibly cause the hydrogel to dissolve before the intended spot. Even though these drawbacks can restrict the application of hydrogels for drug release, many research teams are presently working to resolve these problems and advance hydrogel-based drug delivery systems to clinical trials.

Interactions Between Drugs and Hydrogel

Typically, chemical and physical techniques are used to create a solid link between the medication and the hydrogel matrix. To increase the strength and extend the targeted release of the medications, the charged interactions between the charged drugs and the ionic hydrogel have frequently been used. For instance, polymers based on carbohydrates that possess both cationic and anionic properties can be highly efficient in extending the release of medications with opposing charges. It’s interesting to note that one of the justifications for the use of polysaccharides in drug delivery systems is charge interaction.

After being treated with NaCl, the microgels showed a reversible charge and distinctive behavior, becoming negatively charged. By creating an electrostatic connection, the microgel’s negative charge showed a high loading efficiency of cationic VM. Analogously, amino functional groups can be employed to release anionic medicines in a regulated manner. For example, the loading of nonsteroidal anti-inflammatory medications into poly(HEMA) hydrogels was enhanced by the copolymerization of 4-vinylpyridine or N-(3-aminopropyl)methacrylamide. The hydrogels’ mechanical qualities did not deteriorate even if the drug release was extended for up to a week.

Another method for creating a link between the medication and the polymer matrix is chemical conjugation by covalent bonding. In this instance, the polymer–drug bond’s chemical or enzymatic breakdown regulates the drug’s release. To increase the intrinsic adhesion energy, a lot of research has tried to create covalent bonds with polymer networks by changing the silane, adding an interlink initiator, etc. For about five days, the hydrophobic medication simvastatin was administered in a regulated manner by the nanocomposite hydrogels, which were appropriate as drug delivery vehicles.

Premature release and uneven drug distribution are two common problems with systematic drug administration that lead to decreased efficacy and unintended harm. Adding micro- or nano-gels to the hydrogel matrix to create composite hydrogels is an alternate method for increasing drug delivery efficiency. These composite hydrogels, sometimes referred to as “plum pudding,” are made by trapping liposomes, microspheres, and other particles that are effective delivery systems for rapid and sustained drug release.

Entrapment of hydrophobic sites

Hydrogels have historically been used as a vehicle for the administration of both hydrophilic and hydrophobic medications. For a variety of reasons, including drug loading in the hydrogel matrix, efficient control within the hydrogel matrix, and targeted, effective drug release in the aqueous medium, the incorporation and distribution of hydrophobic medications are more complex than those of hydrophilic drugs. The copolymerization of hydrophobic monomers and the infusion of three-dimensional polymeric networks into hydrophobic locations are the most popular techniques for creating hydrophobic domains inside a hydrogel.

This technique shortens the pore size and slows the pace of drug release by reducing the bulk dimensions of the hydrogel and enabling the free binding of hydrophobic medicines. As an alternative, hydrophobic medications can be made water soluble by adding soluble components, such as PEGylation. In these situations, it’s critical to target a drug’s non-active site, apply the solubilizer using chemistry that cleaves the drug back into its original form, and/or use the solubilizing agent’s remaining functionality to link covalently to the hydrogel polymer backbone using a labile tether.

What is the Use of Hydrogel?

These examples will highlight the most typical uses of hydrogels, which are employed in a wide range of developing medicinal and other scientific applications.

Hygiene Products

Common place items like toothpaste, hair gel, and cosmetics include hydrogels. They are either extremely absorbent or soft and flexible, similar to contact lenses, because they can absorb water up to 99% of their volume.

Disposable diapers and sanitary pads absorb fluids thanks to superabsorbent hydrogels, which are made of acrylate-based polymers. By keeping moisture away from the skin, they improve skin health, make it more comfortable, and stop diaper rash.

These goods have special qualities:

• increased water content
• Low Irritation/Softness
• Adaptability
• compatibility with the majority of cells
• Sensitivity to temperature and chemical behavior

Its composition determines its physical properties, which can be modified based on the intended purpose. It can be made to dissolve, break down, or keep its chemical stability.

Applications in Medicine

Hydrogels are essential components in general medical applications because of their soft softness, porosity, and high water content, which closely resemble natural live bodily tissue.

Because of their high water content, hydrogel wound dressings aid in healing, provide moisture, and reduce pain. When applied on a gauze pad, the hydrogel’s cooling effect helps treat ailments like shingles and chicken pox. It also keeps bandages from adhering to the surface of the wound.

Additional applications include tissue bulking agents, burn bandages, silicone contact lenses, eye patches, nerve guiding conduits, and nucleus replacement technology.

Smart Wound Dressings

Microprocessors, wireless communication radios, microelectronic biosensors, and other components are embedded in the hydrogel of “smart” wound dressings. In addition to protecting the wounds, these dressings have the ability to release medication as needed in response to variations in skin temperature. Additionally, if a prescription is about to expire, they can even light up.

It can be difficult to treat motional wounds, or injuries to movable body components like the joints or neck. Smart wound dressings, on the other hand, adapt to the patient’s body and stay in place when the patient bends their elbow or knee. When there is stress, the dressing’s embedded components or electronics continue to function.

Smart hydrogel dressings have many uses in the treatment of chronic wounds because of their ability to monitor and respond to changes while maintaining their softness and flexibility.

Microfluids

Hydrogels already have complex circuitry and microchannels (from submicron to a few millimeters) built into them if you’re utilizing them to distribute medications or test liquid samples.

High-end converters produce microfluidic devices for use in test strips, organ-on-a-chip technologies, and other applications where the movement or analysis of tiny liquid molecules is necessary. It is feasible to shape feature designs and sizes onto hydrogels since they are generally non-toxic to cells.

Agricultural Production

Hydrogels not only benefit people, but they can also improve plant growth by reducing water loss. By enhancing soil and plant water retention, they can boost agricultural growth by promoting seed germination and enabling crops to thrive in arid environments.

The Advantages of Hydrogel Use

Hydrogel isn’t the best option for everyone because of its special structural characteristics, which can make precise, high-volume manufacturing more difficult. You might not notice this unless you’ve touched it.

Advantages:

• produces a moist atmosphere that promotes the healing of wounds.
• mimics the mechanical characteristics and composition of genuine tissues.
• provides delicate skin with a calming feeling.

Drawbacks:

• It is typically a more costly substance.
• frequently necessitates a more intricate machine configuration to handle potentially difficult applications

Conclusion

With the identification of various polymer structures, processes, crosslinking strategies, characterization techniques, and application areas, hydrogel chemistry has advanced to a new level. This has given rise to new hope and opportunities for solutions for important biomedical applications, such as the treatment of cancer, diabetes, bone regeneration, and cardiovascular issues.

Getting these hydrogels from the lab to the clinical trial and then to the commercial market is still difficult. Future biomedical research is anticipated to rely heavily on hydrogel-based biomedical devices or systems because of their biodegradability, biocompatibility, and tunability. Additionally, there is potential to create novel hydrogels based on biopolymers (like proteins and polysaccharides), standardize a hydrogel production process, optimize conditions, and apply them to specific biomedical applications like wound healing, tissue engineering, drug delivery, and many more.

FAQs

Reference

• Ravi, V. &. (2024, November 4). Hydrogel. Vajiram & Ravi. https://vajiramandravi.com/upsc-daily-current-affairs/prelims-pointers/hydrogel/
• Wikipedia contributors. (2025a, January 1). Hydrogel. Wikipedia. https://en.wikipedia.org/wiki/Hydrogel
• Top 10 applications of hydrogels in biomedical field | Biopharma PEG. (n.d.). https://www.biochempeg.com/article/244.html
• Chambers, S. (n.d.). What is Hydrogel, and How is it Used? Strouse. https://www.strouse.com/blog/6-hydrogel-uses