Int J App Pharm, Vol 13, Issue 1, 2021, 65-76Review Article

HYDROGEL: RESPONSIVE STRUCTURES FOR DRUG DELIVERY

MALLIKARJUN P. N.*, ANUSHA S., SAI NANDINI V., RAMA RAO B., KAMALA KUMARI P. V., SRINIVASA RAO Y.

Department of Pharmaceutics, Vignan Institute of Pharmaceutical Technology, Duvvada, Visakhapatnam 530049, India
Email: mallik6567@gmail.com

Received: 20 Sep 2020, Revised and Accepted: 20 Oct 2020

ABSTRACT

Hydrogels are water-swollen 3D networks made of polymers, proteins, small molecules, or colloids. They are porous in structure and entrap/encapsulate large amounts of therapeutic agents and biopharmaceuticals. Their unique properties like biocompatibility, biodegradability, sensitivity to various stimuli, and the ability to be easily conjugated with hydrophilic and hydrophobic drugs with a controlled-release profile make hydrogels a smart drug delivery system. Smart hydrogel systems with various chemically and structurally responsive moieties exhibit responsiveness to external stimuli including temperature, pH, ionic concentration, light, magnetic fields, electrical fields, and chemical and biological stimuli with selected triggers includes polymers with multiple responsive properties have also been developed elegantly combining two or more stimuli-responsive mechanisms. This article emphasized the types, features, and various stimuli systems that produce responsive delivery of drugs.

Keywords: Stimuli-responsive, Smart hydrogel, Triggers, Environment-sensitive, Biocompatibility, Biodegradability

© 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijap.2021v13i1.39507. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

Hydrogels are water-swollen networks usually formed of a crosslinked polymer having hydrophilic properties. A three-dimensional network of polymers made of natural or synthetic materials possessing a high degree of flexibility due to large water content. Hydrogel molecules or colloidal particles are either chemically or physically cross-linked. While hydrogels are generally prepared based on hydrophilic and hydrophobic monomers under physiological conditions, they can retain a large amount of water or biological fluids [1, 2].

Hydrogels can be classified into two groups depending on the nature of the cross-linking reaction. If the cross-linking reaction involves the formation of covalent bonds, then the hydrogels are termed as a permanent hydrogel. Hydrogels are held together by either physical and chemical interactions cross-links are covalent bonding and physical interactions such as chain entanglements, van der Waals forces, hydrogen bonds, crystallite associations, and ionic interactions. Hydrogel molecule size of the pores affects their deformability and the diffusion of cells, which leads to the release of drugs through diffusion. This can be altered through degradation and swelling of the matrix, either time-dependent or triggered. Specific interactions between the gel matrix and the drug also impact the release of drugs [3, 4].

Hydrogel drug delivery systems include applications in regenerative medicine and cell therapy. Hydrogels present a wide range of design options in terms of the nature of the constitutive molecules, their functionality, and therapy, programmable and controlled release such as attaching ligands, combining them with nanoparticles, attaching drugs, etc.;. For all these reasons, they provide a versatile platform for drug delivery. Hydrogels play a critical role in many tissue engineering scaffolds, biosensors and BioMEMS biomedical (or biological) microelectromechanical system devices, and drug carriers. Among these applications, hydrogel-based drug delivery devices have become a major area of research and commercial products for development [5].

Approaches for the designing and processing of a specific hydrogel for a specific application are required to show maximum mechanical strength, chemical properties, stimuli response, density, biodegradation, and biological and environmental response. Solution polymerization and suspension polymerization are the most common techniques for the production of a variety of hydrogel networks with molecular-scale control over the structure, such as crosslinking density, initiator, emulsifier and reaction conditions and tailored properties like chemical, physical and biological response to stimuli, mechanical strength, biodegradation, and solubility.

Smart hydrogels systems with various chemically and structurally responsive moieties exhibit responsiveness to external stimuli, including physical, chemical, and biological stimuli. The Physical stimuli responses include temperature, light, magnetic fields, electrical fields, and ultrasounds. Chemical stimuli responses pH, ionic concentration sensitive hydrogels and the biological stimuli responses; glucose, antigens, and enzymes sensitive hydrogels. Intelligent polymeric hydrogels change their structural and extent phase transition response to external stimuli resulting in clinical observations and advanced technology [6].

Intelligent network designs have accurate mathematical modeling of drug release profiles. The polymer engineering technology can design and synthesize polymeric networks with a molecular structure that incorporates cross-linking properties, such as biodegradation, mechanical strength, chemical and biological response to stimuli [7].

Hydrogels are required to avoid side-effects for the drug delivery system, such as transdermal drug delivery systems appear as a promising alternative strategy to carry antineoplastic agents, including increased in drug solubility, bioavailability, and stability, prolonged half-life, distribution, and reduction of the total dose required.

Search criteria

The source and range of years used to write this review article are Elsevier, Research scholar, Pubmed, Science direct and 2015-2020 respectively.

Design criteria for hydrogels

Type of Materials, stimuli responses, and process which governs that rate and mode of drug release from hydrogel matrices. These design properties are lead to an increase the efficient drug loading have to be evaluated for drug delivery. The main criteria for designing hydrogel-based drug carriers are drug diffusion, transport which leads to affect the molecular size and characteristics of the drug-polymer network.

The physical and chemical properties are especially modeling molecule release. The physical properties of the hydrogel affect drug release. For example, polymer molecular weights, composition, and polymer/initiator concentrations influence hydrogel swelling and degradation. The stimuli-responses of a hydrogel network can also mediate the amount and rate of drug delivery. The properties of the hydrogel are always critical in designing biocompatible hydrogel formulations for controlled release [8, 9].

Classification

Hydrogels were generally classified into two distinct categories of natural and synthetic based.

Natural hydrogel

The natural polymers which are used to produce natural hydrogels are proteins such as collagen, gelatin, lysozyme, fibrin, dextran, and polysaccharides such as hyaluronic acid and alginate and Chitosan [10].

Synthetic hydrogels

These are prepared by chemical polymerization of monomers and having a wide range of mechanical and chemical properties. They have interpenetrating polymeric network hydrogels such as homopolymeric, copolymeric, and multipolymeric by polymerization techniques. Synthetic Hydrogels are Poly (vinyl alcohol) poly (acrylamide), poly (ethylene glycol), poly (N-isopropyl acrylamide) [11].

Hydrogels can be classified into physical and chemical hydrogels based on their cross-linking mechanism

Physical hydrogels

Physical crosslinks include polymeric chains, hydrogen bonding, hydrophobic interaction, and crystallite formation. While these physical crosslinks may not be permanent junctions, they are sufficient to keep the hydrogel from dissolving in an aqueous media.

Chemical hydrogels

Chemical or covalent crosslinks are permanent junctions formed by covalent bonds. Which creates a covalently crosslinked network is to polymerize end-functionalized macromers [12, 13].

Miscellaneous

Hydrogel networks may include both permanent junctions and semipermanent junctions like chain entanglements. The hydrogel properties, like swelling properties, elastic modulus, and transport of molecules. Hydrogels can further be classified by their ionic charge (neutral, cationic, anionic, and ampholytic), structure (amorphous, semicrystalline, and hydrogen-bond), and preparation methods (homopolymer, copolymer, multi polymer, and interpenetrating polymer network) [14, 15].

The control of the hydrogel network structure allows for the proper design and characterization of the degradation of hydrogel scaffolds, diffusion of bioactive molecules, and migration of cells through the network [16, 17].

Types of stimuli-responsive hydrogels

Hydrogels present a wide range of design options in terms of the nature of the constitutive molecules, functionality, and properties. The design approaches as well as improved activation strategies, are required to provide the control and biological responses required for human translation.

Macromolecular networks present in hydrogels absorb and reversibly release water solutions; these responses depend on specific environmental stimuli. The environment-sensitive hydrogels, also called “smart” hydrogels, smart hydrogels are also known as Stimuli-responsive hydrogels. Modalities and mechanisms associated with externally triggered drug delivery for enhanced drug release of stimuli-responsive gels, with selected triggers [18].

Responsive properties of special hydrogels to the environmental stimuli are especially desirable for clinical applications. In response to internal or external stimuli, hydrogels undergo significant changes in their network structure, swelling behavior, and permeability. External stimuli such as light and electric field have been applied with stimuli generating devices, whereas internal stimuli occur within the native environment of the body [19, 20].

Factors such as the type of monomers, hydrophilic and hydrophobic balance, cross-link density, osmotic pressure, confirmation of chemical groups, etc, which results in changing the stimuli responses of gels.

Physical stimuli

Chemical stimuli

Biological stimuli

Many physical, chemical and biochemical stimuli have been applied to induce various responses to the smart hydrogel systems. The physical stimuli include temperature, electric fields, light, sound, and magnetic fields, while the chemical stimuli include pH, ions, and specific molecular species and biological stimulus involves the responses to enzyme, antigen, and other biochemical agents are represented in fig. 1.

Fig. 1: Stimuli sensitive hydrogels and its mechanism [21]

Physical stimuli hydrogels

Temperature responsive hydrogels

Temperature-sensitive hydrogels are also called as thermo-gels. The temperature is one of the important reaction parameters determining the grafting kinetics. These stimuli sensitive hydrogels show changes in their swelling behavior of the network structure according to the external environments [22, 23].

The characteristic feature of thermoresponsive polymers is the presence of hydrophobic units such as methyl, ethyl, and propyl groups. Critical solution temperature is a key parameter in temperature-sensitive polymers. At a specific temperature, the polymer phase changes according to its composition. If the polymer solution has a lower critical solution temperature (LCST), its solubility in water decreases upon heating. Otherwise, it is called an upper critical solution temperature (UCST). For the case of hydrogels, the solubility decreases, and hydrogels shrink as temperature increases above the LCST [24, 25].

The other category is irreversible hydrogels; the non-covalent cross-linking in the hydrogels tends to undergo sol-gel phase transition instead of swelling and shrinking transitions. Such hydrogels exhibit inverse temperature-dependent sol-gel behavior; they become sol as the temperature increases. At the critical temperature, physically cross-linked thermals undergo a sol-gel transformation, while the chemically cross-linked thermals prominently undergo volume transition. Certain molecular interactions such as hydrogen bonding, Vander Waals forces, molecular entanglements, and hydrophobic interaction assist in the formation of the physical hydrogels [26, 27].

Environmentally sensitive hydrogels exhibit temperature-sensitive swelling behavior due to a change in the polymer or swelling agent, which is compatible over the temperature range. Temperature-sensitive polymers typically exhibit an (LCST), above the temperature, polymers are typically hydrophobic and below which the polymer is soluble. The cross-linked gel swells to significantly higher degrees because of the increased compatibility with water. Examples: poly (n-isopropyl acrylamide) [28].

Thermally-induced gelation is based on hydrophobic and hydrophilic interactions. The thermo-responsive polymer, systems mainly characterized by the presence of hydrophobic groups, such as methyl, ethyl, and propyl groups, which are used in the synthesis of hydrogels. These hydrogels are classified into positive thermosensitive, negative thermosensitive, and thermally irreversible hydrogels [29]. The schematic representation of thermoresponsive hydrogel is as shown in fig. 2.

Fig. 2: The schematic representation of thermoresponsive hydrogel formation loaded with drug-using temperature as a stimulus [30]

Fig. 3: Thermosensitive behaviors of polymers in solution and hydrogels [34]

Positive temperature hydrogels

Hydrogels prepared from upper critical solution temperature (UCST) polymers exhibit shrinking to swelling transition with increasing temperature, and these are referred to as “positive thermosensitive gels”. Shrinking occurs at low temperatures because of a complex structural formation by hydrogen bonding and swells at high temperatures. For example, the hydrogels prepared from polymer networks of poly `1(acrylic acid) (PAA) and polyacrylamide (PAAm) or poly (acrylamide-co-butyl methacrylate) display this positive temperature dependence [31].

Negative temperature hydrogel

Negative thermosensitive gels are characterized by the (LCST) low critical solution temperature of the backbone polymer forming the gel. Rising the temperature above LCST collapses or shrinks the gel, whereas cooling below LCST causes the swelling of the gel. This specific temperature-dependent swelling or shrinking is due to the change in the hydration state of the polymer chains. When the interaction between the polymer chains increases, a sudden and reversible transition in the volume of the network occurs, this is referred to as “volume phase transition (VPT)”. At a critical temperature, these crosslinked hydrogels show this behavior is referred to as “volume phase transition temperature (VPTT)” [32, 33].

Thermo responsive hydrogels include different mechanisms such as inclusive of passive diffusion, erosion, swelling, and dictate the discharge of the drugs. The drug delivery systems based on synthetic thermosensitive polymers such as PNIPAAm, Pluronics are usually non-degradable. Thermoresponsive polymers exhibiting this negative temperature dependence are polyacrylamides, polyvinyl ethers, polyoxazolines, and poly (oligo-ethylene oxide) methacrylates. The schematic representation of the thermosensitive behaviors of polymers is as shown in fig. 3.

Applications

Due to the ability of good biocompatibility and mimic the extracellular matrix environment, hydrogels become the potential candidates for many biomedical applications include soft contact lenses, wound healing, tissue engineering, and sensors.

The porous structure of hydrogels can be adjusted by cross-linked density, thus the release behavior of different bioactive agents like proteins or drugs can be controlled. Temperature-sensitive hydrogels are used for the delivery of drugs, genes, cells, therapeutic agents, and tissue engineering.

Electro responsive hydrogels

Electric field-responsive hydrogels are polymers that swell, shrink, or bend in response is carried out to an applied electric field. They are usually made of polyanions, polycations, or amphoteric polyelectrolytes. The electric-sensitive hydrogels are formed, depending on their composition, such as charge density, nature, hydrophobicity of cross-links, monomers, groups, shape, and position relative to the electrodes. In general, electrically responsive polymers are conducting polymers. For example, polythiophene or sulfonated-polystyrene shows swelling, shrinking or bending in response to an externally applied field [35, 36].

Electrically activated microchips represent another interesting strategy for triggerable pulsatile release of tunable drug combinations with high spatial and temporal precision and integrating a degree of automation that is not easily achievable using other pulsatile delivery strategies [37].

Electro-sensitive hydrogels can be easily controlled the drug release rate in drug delivery by modulating the electric field. Most of the electrolytes are develop drug delivery modules based on electro-sensitive hydrogels under physiological conditions. Hydrogels made poly (2-acrylamide-2-methylpropane sulfonic acid–co-n-butyl methacrylate) were able to release edrophonium chloride and hydrocortisone in a pulsatile manner using an electric current.

Applications

Electro-responsive hydrogels have been used in controlled drug delivery. These hydrogels are used as electroactive sensors or actuators in electronic devices because they swell or shrink differentially on two electrode side anode and cathode [38].

The fast release pattern was also attributed to the electrostatic force, squeezing effect, and electro-osmosis of the gel. Chitosan gels were also used as matrices for electrically modulated drug delivery. Among many electro responsive polymers, electro-responsive hydrogels have become appealing both because of their use for controlled drug delivery as well as their biocompatibility [39].

Magnetic field responsive hydrogels

Magnetic field hydrogels generally consist of a polymer matrix and a magnetic component embedded in the matrix. The properties of magnetic hydrogels contain several factors, including the type of hydrogel used, concentration, size, and distribution of hydrogels. Methods such as the blending method, an in situ precipitation method, and the grafting method have been used to develop to fabricate magnetic hydrogels [40].

Magnetic fields represent another method for external activation of drug release, usually relying on the incorporation of superparamagnetic nanoparticles into the hydrogels, and the use of either static or alternating magnetic fields. The gels are sensitive to magnetic fields and undergo volume change after the application of the external magnetic field.

The polymer network through this combination of solid-like and fluid-like behavior is induced; the influence of the external field on the hydrogels the responsiveness is enhanced. CMC hybrid hydrogels containing CoFe2O4 nanoparticles, chitosan, and CMC-coated Fe3O4 nanoparticles, etc. are used as magnetic field-responsive hydrogels. The Fe3O4 magnetic nanoparticles were used to generate heat through the application of an alternating magnetic field [41]. The schematic representation of magnetic hydrogels design as shown in fig. 4.

Fig. 4: The schematic diagram of the main three routes for the synthesis of the magnetic hydrogels. (A) The blending method. (B) The in situ precipitation method. (C) The grafting-onto method [42]

Applications

These hydrogels have found their applicability in biomedical sectors, such as cell separation, gene and drug delivery, and magnetic intracellular hyperthermia treatment of cancer. These hydrogels are prepared through the precipitation polymerization method for the controlled release of the anti-cancer drug.

Drug release can be magnetically triggered from delivery systems containing superparamagnetic iron oxide nanoparticles SPIONs using either static or alternating magnetic fields. The application of a static magnetic field can be used to mechanically deform or move all or parts of a composite delivery system to induce triggered release [43].

Light responsive hydrogels

Light-responsive hydrogels are composed of a polymeric network possessing light-reactive groups such as photochromic moieties. Novel light-sensitive hydrogels are fabricated by grafting or incorporating photo-sensitive moieties photo chromes into the polymer chain. Light-sensitive polymers are significantly reversible modifications in its chemical and physical properties due to the exposure to light. Such polymers are also known as "photo-sensitive polymers" [44].

Photo-sensitive molecules respond to light via three main mechanisms: isomerization or cyclization, degradation, and dimerization. The physical properties such as mechanical stiffness, shape, swelling/deswelling behavior size, degradation rate, and the chemical properties such as surface hydrophilicity and hydrophobicity ratio of the light-sensitive hydrogels [45].

Visible light-sensitive hydrogels were prepared by introducing a light-sensitive chromophore hydrogel. When hydrogels are exposed to light, the chromophore absorbs light which is then abandoned regionally as heat by using radiationless transitions, which increasing the ‘local temperature of the hydrogel. The temperature increase alters the swelling behavior of hydrogels, which are rate limited by thermal diffuse-sensitive hydrogels. The temperature increase is proportional to the light intensity and chromophore concentration [46].

Applications

Light-sensitive hydrogels can be used in the development of photo-responsive artificial muscles, switches, and memory devices. The hydrogels served as an in situ hydrogel-based drug delivery system for controlled drug release.

Photosensitive hydrogels are the next-generation polymer-based materials for biomedical applications such as photo mediated delivery of therapeutic payloads in a controlled manner and 4-D culture of cells, with an ability to mimic the dynamic and the heterogeneous in vivo microenvironments [47].

Ultrasound responsive hydrogel

Ultrasound refers to the high-frequency waves generated from a piezoelectric material due to the mechanical vibrations when it is subjected to alternating current. Ultrasounds may be classified as low-frequency (<1 MHz), medium-frequency (1–5MHz), and high-frequency (5–10MHz) ultrasounds. The low-frequency ultrasound has a higher penetration depth in tissues.

The ultrasound having a frequency>2MHz possesses a low tissue penetration depth due to increased scattering, which in turn, causes heating and tissue damage. But, the increase in the frequency of the ultrasound is associated with a decrease in the focus point, thereby leading to an increase in the intensity at the focus point [48]. The ultrasound causes thermal and non-thermal effects on tissue fluids. Ultrasonic waves can trigger drug release through either thermal or mechanical effects generated by cavitation or convection forces [49, 50].

Applications

The ultrasounds responsive hydrogel is used for transdermal delivery, thus improving the permeability of the skin such as diclofenac sodium (DS) patches. These strategies are embedded in the hydrogel patch [51].

Based on the properties like mechanical, self-healing, and sensitiveness to ultrasound, the hydrogels can potentially be explored for diverse medical applications such as biomedical implants to smart drug delivery.

High-intensity focused ultrasound (HIFU), having a frequency of 0.8–3.5MHz is getting importance as an exogenous trigger for the treatment of cancer either by direct application or via controlled release of anticancer drugs from nanocarriers [52].

Chemical stimuli sensitive hydrogels

pH-responsive hydrogel

The two main strategies are used for the design of pH-responsive drug delivery systems are (a) the use of polymeric systems with ionizable pendant moieties on their backbone structure and (b) the use of polymers bearing acid-sensitive bonds were breaking of these bonds contribute to the release of drug molecules attached to the polymer backbone. Depending upon the various kinetic model's drug release from the hydrogels are characterized by swelling behavior [53].

pH-sensitive hydrogels consist of gel structure, which varies a change in pH values. The pH-sensitive hydrogels expand or contract depending upon the pH of the solutions. Appropriate pH and ionic strength generate electrostatic repulsive force results in swelling or deswelling of the hydrogel. pH-responsive hydrogels could offer desirable physical and chemical properties at specific pH ranges [54].

Depending on the ionizable pendant group, pH-responsive hydrogels are categorized into two main groups as cationic and anionic hydrogels as shown in fig. 5. As the external pH increases, the hydrogel network undergoes swelling if it contains anionic pendant groups or shrinks if it contains cationic pendant groups in its polymeric backbone [55].

Anionic hydrogel

Anionic hydrogels exhibit swelling behavior when the pH of the swelling buffer is above acid dissociation constant, pKa, due to a simultaneous effect of electrostatic repulsion and water absorption. The structure of these gels remains collapsed at low pH because of the tight physical interactions in the network. Acrylic acid, p-styrene sulphonic acid, itaconic acid, crotonic acid, maleic acid, and methacrylic acid, etc are precedents that are utilized in anionic hydrogels [56].

Cationic hydrogel

In cationic hydrogels, the drug is mostly released at low pH conditions such as the stomach. Cationic hydrogels swell at low pH conditions (pH<pKa) and collapse when exposed to an environment with high pH (pH>pKa). The swelling behavior of pH-responsive anionic or cationic hydrogels is specific in acidic and alkaline buffer solutions [57].

The pH-responsive nature of hydrogels can be applied for biomolecule delivery in neutral or alkaline environments. Polymers such as chitosan, poly (ethylene amine), poly (dimethylamino-ethyl methacrylate), are functional moieties leads to ionized the primary, secondary, and tertiary amines [58].

Most anionic pH-sensitive polymers are based on Carbopol derivatives, which including poly (methacrylic acid) (PMAA), PAA poly(acrylic acid), poly (diethylaminoethyl methacrylate) (PDEAEMA), and phosphoric acid derivatives. These polymers, comprising a large number of ionizable functional groups, are generally referred to as polyelectrolytes. The presence of ionizable groups onto polymer chains results in increased hydrogel swelling compared to nonelectrolyte polymer hydrogels.

pH-responsive hydrogel using poly (lactic acid) (PLA), methoxyl poly (ethylene glycol) (MPEG), and itaconic acid (IA) via heat-initiated free-radical polymerization in the absence of organic solvents. The effect of the pH value on the swelling ratio was determined in buffers with pH ranging from 1.2 to 6.8 [59, 60].

Applications

Both anionic and cationic pH-responsive hydrogels have been investigated for the controlled delivery of therapeutic drugs, genetic agents, and proteins. pH-responsive hydrogels are useful for oral administration of the drug along the digestive tract because of the distinct pH conditions located at special sites, the targeted drug delivery into a tumor site due to alterations in the acidity of tumor tissue [61].

Fig. 5: The pH-responsive swelling of (a) anionic and (b) cationic hydrogels [62]

pH-sensitive hydrogels have been most frequently used as an antibacterial wound dressing. They also have been used in making biosensors and permeation switches. The hydrogels were explored as a carrier for dual model drugs, namely, doxorubicin (DOX) (anti-cancer) and tetracycline (TET) (anti-bacterial). Alginate, dextran, hyaluronic acid, chitosan, and gelatin are some examples of the natural pH-sensitive polymer [63].

Ion-sensitive hydrogels

The polymers having ionizable groups exhibit sensitivity to ionic strength. They can attractive electrostatic force between the oppositely charged species. These polymers become insoluble in deionized water but soluble at a suitable concentration of electrolyte solution. Hence, the polymer properties, like the size of polymer chains and solubility, get al. tered in ion-sensitive polymers as the ionic strength of the solution [64].

The polyelectrolyte gels also demonstrate variation in swelling kinetics in the presence of salts. The introduction of salts results in the growth of the ionic strength of the solution, which ultimately reduces the equilibrium degree of swelling of the polyelectrolyte gels. The hydrogels having high restrained swelling in the presence of ionic solutions having higher ionic valence numbers as compared to low valence numbers.

Applications

The ion-sensitive hydrogels have mainly been applied for the development of delivery systems which are used in applications including nasal and ocular drug delivery.

Ion-sensitive in situ hydrogels that can be used for improved and prolonged ocular pharmacotherapy.

The changes in the properties of the hydrogels due to the alteration in the type or composition of the gelling agent were also analyzed [65].

Biological stimuli sensitive hydrogels

Enzyme-sensitive hydrogels

The most common approach for the design of enzyme-responsive hydrogels involves the incorporation of peptide chains into the gel network as a linker or crosslinker to make the network biodegradable with specific enzymes. These enzymes have been utilized as signals of physiological changes and can be used in site-specific drug delivery [66].

The enzymes used in the organic trigger to induce the biomaterial properties modifications, which can also assist in reaching sustained and controlled release of bioactive molecules upon enzymatic movement [67].

Enzyme-sensitive hydrogels consist of two main functional parts: (i) an enzyme recognizable and accessible substrate, and (ii) a functional component to regulate molecular interactions, which leads to macroscopic transitions in hydrogels. The transitions may be associated with the change in the surface properties, swelling, or shrinking of the gel structures. Molecular interactions that play a significant role in the semacroscopic transitions are VanderWaals forces, hydrogen bonding, electrostatic interactions, hydrophobic interactions, − π π interactions [68].

Applications 

Enzyme-sensitive systems imitate the biological matrices which developed in the potential applications of these hydrogels. The preparation of enzyme sensitive hydrogel microparticles is based on poly (ethylene glycol) for pulmonary drug delivery. 

These prepared enzyme-sensitive hydrogel particles have great potential to be implemented as drug delivery vehicles. The synthesis of pH-sensitive peptide-based hydrogels could efficiently describe the effect of the peptide concentration on the extent of enzymatic degradation of the hydrogels.

Glucose responsive hydrogels 

The strategies for glucose sensing hydrogels are extensively categorized into enzymatic sensing, natural glucose-binding proteins, and artificial molecular recognition. The stimuli-responsive delivery systems using hydrogels that can release insulin are referred to as glucose-sensitive hydrogels. In the controlled drug delivery area includes the development of self-regulated modulates the insulin delivery systems. The swelling of hydrogel triggers the discharge of insulin while the nearby pH of the device reduces when glucose is converted to gluconic acid via glucose oxidase enzymes within the presence of oxygen. Glucose oxidase has been covalently attached to the hydrogel network for controlling the discharge of insulin [69, 70].

These hydrogels are composed of materials that are “bio-clever” the engineered molecular recognition site is related to actuation, inclusive of HEMA and PMA. The nearby pH of the system is decreased when glucose is converted to gluconic acid through glucose oxidase inside the presence of oxygen, which increases the swelling of cationic hydrogels and releases insulin.

Phenylboronic acid (PBA) as glucose sensing groups that Synthesized smart glucose-responsive hydrogels by immobilizing the glucose or galactose binding protein (GBP) within an acrylamide hydrogel network which demonstrated a dynamic response in the presence of glucose.

The hydrogel was conjugated with peptide and was also loaded with insulin, glucose oxidase, and catalase. Designed peptides induce self-assembly of the polymer into a hydrogel at physiological conditions [71].

Antigen responsive hydrogels

Antigen responsive hydrogels are designed by using grafting antigens on hydrophilic polymeric backbones to deliver biomolecules at a specific targeted site. These hydrogels may be combined with antibody grafted crosslinked hydrophilic polymeric backbones. In the absence of a free antigen, the structure of the hydrogel shrinks due to intrachain antigen-antibody binding inside the polymer network. Formulating an antigen sensing tool makes them beneficial biomaterial for biomolecules, protein drug delivery at desired sites, where the exceptional feature is specific molecular recognition of antigen-sensitive hydrogels [72, 73].

An antigen responding hydrogel, which may be prepared by using grafting antigen and the corresponding antibody to the polymer network, the binding between the two introduces crosslinks into the network. The competitive binding of the free antigen triggers which exchange the hydrogel volume, display shape, and pulsatile permeation of protein through the network within the antigen concentration.

Applications

Some biomedical applications, it is highly desirable and useful to develop material or devices, which can respond to specific proteins. Sol-gel phase reversible hydrogels and glucose-sensitive phase reversible hydrogels were prepared based on antigen-antibody interactions.

A semi-interpenetrating network hydrogel was prepared by grafting an antigen and a corresponding antibody to different polymer networks. The gel is formed by crosslinking interactions that occur upon antigen-antibody binding. Hydrogel swelling is triggered in the presence of free antigens that compete with the polymer-bound antigen, leading to a reduction in the crosslinking density [74].

Table 1: Summarized table contains types of stimuli, the material used, and features of hydrogels

Type of stimuli Material used Features References

Physical stimuli

Temperature responsive

 Poly(N-vinyl caprolactam), Poly(N-isopropyl acrylamide), Poloxamers Poly(N-alkylacrylamide), N-trimethyl chitosan chloride, Methoxy poly(ethylene glycol)-poly(pyrrolidone-co-lactide), xyloglucan Chitosan Easy functionalization with drug molecules, Sol-gel transition at 37 ◦C, Unique physical properties similar to the extracellular matrix, Controlled degradation. [83-85]
Electric field responsive

poly lactic-co-glycolic acid and poly(ethyleneglycol) hydrogel

Sulfonated polystyrenes, Poly(thiophene)s,Poly(ethyloxazoline)

poly (2-acrylamide-2-methylpropane sulfonic acid–co-n-butyl methacrylate)

 Undergo shrinking or swelling in the presence of an applied electric field, Biocompatibility, Minimal invasiveness. [86-88]
Magnetic field responsive Hemi cellulose crosslinked with O-acetyl-galactoglucomannan, polyurethane acrylate oligomers bioink, and magnetized platelets Successful absorption and controlled release of drugs, Dispose of anisotropic properties, field strength, field geometry, drug/gene binding capacity. [89-91]
Light responsive Hydroxypropyl methylcellulose and Carbopol hydrogels containing diclofenac-sodium chitosan microspheres, Poly[2-((4,5-dimethoxy-2-nitrobenzyl)oxy)-N-(2-(methacryloyloxy)ethyl)-N, N-dimethyl-2-oxoethan-1-aminium] Reasonable strengthens, Reversible and irreversible, Spatiotemporal control over functional groups, Controlled release, The Light stimulus can be imposed in high accuracy [92-94]
Ultrasound responsive poly(d,l-lactide)(PGA),poly(d,l-glycolide)(PLA),poly(bis(p-carboxyphenoxy))alkane–anhydrides (PCPX), and sebacic acid Mechanical vibrations, cavitation, or convection forces [95, 96]

Chemical stimuli

pH-responsive

 Carboxylated agarose/tannic acid hydrogel scaffolds cross-linked with zinc ions, Poly(acrylamide-co-acrylic acid) poly(AAm-co-AAc) hydrogels, Poly(methacrylicacid), Poly(vinylpyridine), Poly(vinylimidazole)s Sustained release of the incorporated drugs, Biocompatibility, Strong electrostatic interactions, and stability, Increased hydrophilicity and swelling [97-99]
Ionic strength responsive 2-acrylamido-2-methylpropane sulfonic acid cross-linked with N,N’-methylene(bis)acrylamide, Poly(N-isopropyl acrylamide) crosslinked with imidazolium-based dicationic ionic liquid Increased swelling properties, Controllable porous structure, Biodegradability [100-102]
Biological stimuli Enzyme-sensitive hydrogels Poly(allylamine) Hyaluronic acid/tyramine, Dextran/tyramine, Carboxymethylcellulose/tyramine for hydrogel formulation (Elastase, HRP) improve their therapeutic potential, sol-to-gel and gel-to-sol phase transitions leads to change in the surface properties, swelling or shrinking of the gel structures [103]
Glucose responsive hydrogels phenylboronic acid side chains using m-acrylamidophenylboronic acid (AAPBA), N-vinylpyrrolidone, acrylamide, and (N, N-dimethylacrylamide) DMAAm. Increases the swelling of cationic hydrogels and releases insulin. [104, 105]
Antigen responsive hydrogels Vinyl functionalized antigen or antibody with acrylamide or N, N′-methylene bisacrylamide (MBA). Hydrogel swelling is triggered in the presence of free antigens, leading to a reduction in the crosslinking density [106]

Specialized hydrogels

3D printing of hydrogels

3D printing is an emerging technology that allows the fabrication of complex, three-dimensional objects from computer-aided design (CAD). The structure is built layer-by-layer from a series of thin horizontal cross-sections, thus giving a high degree of flexibility in the design. The FDA approved a rapidly dissolving levetiracetam tablet for oral suspension.

Polymer solutions can be used as "bio-inks", provided that they are shear-thinning and that gelation can be triggered either by chemical cross-linking or a physical trigger. This technology has been envisaged in ophthalmic drug delivery, to build drug delivery devices that can deliver to the eye, e. g. with implantable pump systems, or Micro-Electro-Mechanical Systems (MEMS), with drug-infused hydrogels. 3D printing is also being employed for diagnostic and targeted delivery applications.

Using 3D printing from the two-photon polymerization of photocrosslinkable hydrogel gelatin mathacryloyl (GelMA), decorated with magnetically responsive nanoparticles, which can be designed to respond to pathological concentrations of metalloproteinase-2 (MMP-2). Recent examples of hydrogel drug matrices using 3D printing include the printing of lactose-crosslinked gelatin scaffolds for the sustained release of dexamethasone [75, 76].

3D printing and smart hydrogels is a potent combination of bioprinting functional 3D tissues. Hydrogel in bioprinting acts as a matrix that supports and regulates the cells encapsulated inside the matrix. At the current stage, computational models have been set up to assess hydrogel contraction and deformation due to cellular events such as migration, proliferation and traction, cellular concentration, and distribution.

Table 2: The updated research work is done on hydrogels

S. No. Active ingredient Materials Method Result References
1 Ibuprofen Ethyl oleate (EO), propylene glycol (PG), tween 80 Microemulsion technique In vitro permeation data showed that microemulsions increased the permeation rate and increase the topical delivery of ibuprofen [107]
2 Bifonazole Tween 80, isopropyl alcohol (IPA), and HPMC K100M Microemulsion technique The studied micro emulsion-based hydrogel (F5) has a potential for sustained action of drug release and good stability and also to improve its solubility and permeability [108]
3 Montelukast sodium

Chitosan, anhydrous dextrose, sodium tripolyphosphate, glutaraldehyde, microcrystalline

cellulose, magnesium stearate and talc

 Direct compression method

CHGL tablets showed more prolonged drug release

profiles (86 % to 74 %) as compared to CHDX and CHTPP

 [109]
4 Benzydamine Hydrochloride Hydroxypropyl methylcellulose, Poloxamer 407, Poly (lactic-co-glycolic) polymer Emulsion solvent evaporation method.

significantly higher reduction percentage in ulcer surface area compared to those treated with BZN-

PLGA -NPs.

 [110]
5 Poloxamines Triethylamine (TEA), dithiothreitol (DTT), phosphate-buffered saline Reverse thermal gelation Poloxamine-based hydrogels achieved reduced swelling and increased tensile and tissue bonding properties improved stability [111]
6 Chitosan Poly(ethylene) glycol, poly (N-isopropylacrylamide) (PNIPAAm) free-radical polymerization The chitosan/PNIPAAm system improved the level of crystallinity of the films, thermal, mechanical, swelling properties [112]
7 Ranitidine hydrochloride

Sodium Carboxymethyl C

ellulose (NaCMC),

Calcium Carbonate (CaCO3)

 Simple mixing method

0.5% of calcium carbonates with 80:20

ƙC: NaCMC showed the Optimum floating properties, swelling ratio, drug entrapment efficiency, and cumulative drug release.

 [113]
8 Moxifloxacin hydrochloride Polyox and HPMC K4M, Sodium alginate in situ gelation The selected formulations MF4, MF5, and MF9 were shear thinning and an increase in shear stress was observed with an increase in angular velocity [114]
9 1-chloroethyl-3-piperidine-ethyl acrylate acetone, ethanol, dimethylformamide, dimethylsulfoxide Radical polymerization The physical and chemical properties of solutions of the obtained hydrogels, including the kinetics of swelling of gels in aqueous solutions, are studied. [115]
10 Lornoxicam HPMC K15M, Carbopol 934p, Xanthan gum Microemulsion technique They exhibited high flux value, highest release rate, good spreadability and show a significant effect on their physical, rheological, and in vitro drug release characteristics [116]
11 Irbesartan Sodium alginate, Chitosan, and Calcium chloride ionotropic-gelation method The optimized hydrogel microbeads showed controlled release with high % drug entrapment efficiency and swelling index [117]
12 N, N-dimethyl acrylamide Hydroxylamine hydrochloride, hexanoyl chloride, ethyl propionate, dimethyl sulfoxide, triethylamine copolymerization Kinetics of swelling at neutral pH can be controlled [118]
13 Monomethoxy poly(ethylene glycol) (MPEG), 3,6-dimethyl-1,4-dioxane-2,5-dione(D,L-lactide) (DLLA), Ethyl hexanoate, gelatin, toluene, dichloromethane (DCM), diethyl ether, chloroform ring-opening polymerization method To obtain a wide range of molecular weight and hydrophilicity shows rapid gelation [119]
14 Gelatin-polyoxometalate Acrylic acid, sodium hydrogen sulfite, ammonium persulfate, sodium hydroxide self-assembling process Formulation (GP6) shows optimal swelling and maximum release (84%) of the POM at physiological pH 7.4 [120]
15 Doxorubicin Poly(N-isopropylacrylamide)/dextran-maleic acid photo-cross-linking /polymerization A larger and faster release of doxorubicin was found in those hydrogels having a large pore size [121]
16

N-carboxyethyl chitosan

And Dextran

 Sodium periodate, sodium hydroxide, acrylic acid, tert-butyl car bamate (TBC), and trinitrobenzene sulfonic acid (TNBS) gelation method An increase in polymer concentration increased interacting functional groups per finite volume of solution [122]
17 Pluronics F127 and F68 Hydroxypropyl methylcellulose (HPMC) cold method Rheological analyses showed that both elastic and viscous moduli were higher [123]
18 Calcitonin Methacrylic acid (MAA) and methoxy-terminated poly(ethylene glycol) monomethacrylate (PEGMA) free radical solution polymerization The loading efficiency was affected by the amount of solvent used during hydrogel preparation [124]
19 Ciprofloxacin Dextrin, 2-hydroxyethyl methacrylate (HEMA), N, N'-methylene bisacrylamide (MBA) free-radical polymerization technique Good compatibility between the drug and hydrogel matrix, hydrogels shows excellent physical stability [125]
20 Pantoprazole Sodium Acrylamide, Methacrylic Acid, N, N-methylene-bis-acrylamide, Pluronic-F127, Ammonium Persulfate, Tetramethylethylenediamine, Sodium Bicarbonate radical polymerization The swelling properties, mechanical strength, and stability were affected [126]

Applications

3D printing technology is used to manufacture dosage forms. The use of hydrogels with 3D printing is emerging, and the use of microfluidic techniques to generate microgels has been particularly focused on applications in regenerative medicine, for the manufacture of complex tissues and 3D printed gels for drug or gene delivery.

The use of 3D printing in the field of wound healing to design hydrogel-based skin with complex nanostructured layers, which can incorporate growth factors or NSAIDS such as lidocaine.

The use of 3D printing technology for tissue engineering, artificial tissue mimics can indeed be delivered of signaling molecules; 3D printing for cartilage and osteochondral tissue engineering have been recently reviewed [77, 78].

Drug delivery of hydrogels

Hydrogels are widely used in the development of intelligent systems for drug delivery. Smart or intelligent hydrogels have been studied for use in drug delivery systems for the delivery of various drugs ranging from low molecular weight drugs to macromolecular drugs such as peptides, growth factors, and insulin. To develop new drug delivery systems hydrogels can entrap drugs and protect it against hostile environments for slow release via diffusion or erosion depending on the state of hydration.

By utilizing their characteristics, hydrogels can be directed to the desired area, and the drug to which they are attached can be released using the response of the hydrogel to that environment.

They can also control the rate of drug delivery by changing the structure in response to environmental stimuli such as temperature, pH, electrical and magnetic fields, solvent composition, light, ions, etc. Hydrogels are intelligent from this aspect that they can exhibit corresponding physical and chemical behaviors under the influence of various stimuli which result in controlled drug release.

Targeted drug delivery is a way of delivering a drug to a certain area rather than releasing the drug into the entire body so that side effects are reduced and the bioavailability of the cells is increased. Hydrogels are advantageous materials in drug delivery because of their characteristics, such as hydrophilic nature is similar to that of biological tissue. Also, their biocompatibility and the least mechanical irritation to tissues are other advantages in their use as a biomaterial. Moreover, because of the lowest interfacial stress between the hydrogel surface and surrounding fluid, protein adsorption, and cell adhesion onto the gel can be minimized [79].

Smart hydrogels change their properties when in contact with distinct stimuli for controlling drug delivery. At the molecular level, the physical and chemical properties such as permeability, environment-responsive nature, surface functionality, biodegradability, and surface biorecognition sites were optimized in controlled drug delivery applications. Drug incorporation and release of model molecules are the factors that are taken into consideration while fabricating a hydrogel for drug delivery.

Drug incorporation

Ligands which are metabolically cleavable and have a specific affinity for active agents are used to perform drug loading by physical entrapment, with either post-fabrication drug absorption or in-situ encapsulation. Drug loading just before cross-linking helps to maintain its stability as well as its biological potency. Thus, during the fabrication process, this prevents the drug from exposure to rough fabrication conditions or from leaching out.

Release of model molecules

Molecule release occurs by the process of diffusion, as a function of porosity, degradation, or swelling of hydrogels. Physical cross-linking through ultraviolet radiation or thermal and ionic or covalent cross-linking methods can be employed to estimate the permeability and the swelling of hydrogel for the release of the model molecule [80-82].

Table 3: The various routes of administration of hydrogels

S. No. Administration Description Reference[s]
1 Hydrogels in oral drug delivery The drug is incorporated into hydrogels and delivers to the oral cavity for local treatment of diseases of the mouth, such as stomatitis, fungal diseases, periodontal disease, viral infections, and oral cavity cancers. [127]
2 Gi tract drug delivery GI tract drug delivery contains the facility of administration of drugs locally to the specific sites in the GI tract and its large surface area for systemic absorption. For example, stomach-specific antibiotic drug delivery systems for the treatment of Helicobacter pylori infection in peptic ulcer disease. [128]
3 Ocular drug delivery Hydrogels are most widely used in ocular drug delivery system. Most hard and soft contact lenses are formed of polymers in form of hydrogel films. hydrogels are attractive as an ocular drug delivery system because of their facility in dosing as a liquid, and their long-term retention property as a gel after dosing. [129]
4 Rectal delivery Drugs absorbed from the lower part of the rectum drain into the systemic circulation directly. Thus, the rectal route is useful for the drug administration having first-pass metabolism. It is used for local treatment of diseases associated with the rectum, such as hemorrhoids. [130]
5 Topical drug delivery To treat skin infection various hydrogels are used to prepare and apply topically for local action. The active component like Desonide which is a synthetic corticosteroid usually used as an anti-inflammatory. The hydrogels have been formulated for better patient compliance and have moisturizing properties. [131]
6 Subcutaneous delivery Hydrogel formulations for subcutaneous delivery of anticancer drugs are being prepared viz. cross-linked PHEMA was applied to cytarabine. Subcutaneously inserted exogenous materials may more or less evoke potentially undesirable body responses, such as inflammation, carcinogenicity, and immunogenicity. [132]
7 Protein drug delivery Interleukins which are conventionally given as injection are now given as hydrogels. These hydrogels have shown better patient compliance. The hydrogels form in situ polymeric network and release proteins slowly. These are biodegradable and biocompatible. [133]
8 Hydrogels in tissue engineering The micronized hydrogels have been used to deliver macromolecules like phagosomes into the cytoplasm of antigen-presenting cells. The release is because of acidic conditions. Such hydrogels mold themselves to the pattern of membranes of the tissues and have sufficient mechanical strength. This property of hydrogels is also used in cartilage repairing. [134]

CONCLUSION

This review aims to introduce briefly the hydrogels: a class of natural or synthetic polymeric materials that can hold huge amounts of water because of their specific structures and subsequent swelling properties and described recent progress in stimuli-responsive polymers. The various types of stimuli-responsive hydrogels properties and their applications were discussed. An important aspect to be considered while developing these smart hydrogels is controlled biodegradability and biocompatibility. Research into stimuli-responsive polymers as a means of achieving this is steadily gaining momentum, and more novel polymers are being synthesized.

Hydrogels are widely used in the development of intelligent systems for drug delivery. To develop a new drug delivery of stimuli-responsiveness represents a key property in medical applications because it enables a controllable response from biological compartments, such as the release of an encapsulated/entrapped active compound, the triggering of a signaling process, or the detection of a specific biomolecule. The various routes of administration and updated research work done on hydrogels and types, features, and various stimuli systems that produce responsive delivery of drugs were discussed in this article.

ACKNOWLEDGMENT

We express our sincere thanks to Dr. L. Rathaiah, Chairman, Vignan Group of Institutions for providing the necessary facilities to carry out the above review.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All the authors have contributed equally.

CONFLICTS OF INTERESTS

Declare none

REFERENCES

  1. Shivani PS, Ajeet G, Shilpa B, Pankaj G. Hydrogels: introduction, preparation, characterization, and applications. Int J Res Methodol 2015;1:47-71.

  2. Sowjanya P, Boddu VK, Ajay BP. A review article on hydrogels. Int J Res Pharm Nano Sci 2013;2:548-53.

  3. Navarra MA, Dal Bosco C, Serra Moreno J, Vitucci FM. Synthesis and characterization of cellulose-based hydrogels to be used as gel electrolytes. Membranes 2015;5:810-23.

  4. Shen X, Shamshina JL, Berton P, Gurau G, Rogers RD. Hydrogels based on cellulose and chitin: fabrication, properties, and applications. Green Chemical 2016;18:53-75.

  5. Colombo P. Swelling-controlled release in hydrogel matrices for oral route. Adv Drug Delivery Rev 1993;11:37-57.

  6. Ahn S, Kasi RM, Kim SC, Sharma N, Zhou Y. Stimuli-responsive polymer gels. Soft Matter 2008;4:1151-7.

  7. Peppas N, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm 2000;50:27-46.

  8. Sun L, Huang WM, Ding Z, Zhao Y, Wang CC, Purnawali. Stimulus-responsive shape-memory materials. A review. Mater Des 2012;33:577-640.

  9. Lin CC, Metters AT. Hydrogels in controlled release formulations: network design and mathematical modeling. Adv Drug Delivery Rev 2006;58:1379-408.

  10. Zaman M, Siddique W, Waheed S, Muhammad SS. A review: hydrogels, their applications, and polymers used for hydrogels. Int J Biol Pharm Allied Sci 2015;4:6581-603.

  11. Zhu J, Marchant RE. Design properties of hydrogel tissue-engineering scaffolds: expert Rev Med Devices 2011;8:607-26.

  12. Zhu J. Bioactive modification of poly (ethylene glycol) hydrogels for tissue engineering. Biomaterials 2010;31:4639-56.

  13. Chung HK, Park TG. Self-assembled and nanostructured hydrogels for drug delivery and tissue engineering. Nano Today 2009;4:429-37.

  14. Liu SQ, Tay R, Khan M, Ee PLR, Hedrick JL, Yang YY. Synthetic hydrogels for controlled stem cell differentiation. Soft Matter 2010;6:67-81.

  15. Slaughter BV, Khurshid SS, Fisher OZ, Khademhosseini A, Peppas NA. Hydrogels in regenerative medicine. Adv Mater 2009;21:3307-29.

  16. Nguyen TK, West JL. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials 2002;23:4307-14.

  17. Hoffman AS. Hydrogels for biomedical applications. Adv Drug Delivery Rev 2002;43:3-12. 

  18. Kharkar PM, Kiick KL, Kloxin AM. Designing degradable hydrogels for orthogonal control of cell microenvironments. Chem Soc Rev 2013;42:7335-72.

  19. Bajpai AK, SK Shukla, S Bhanu, S Kankane. Responsive polymers in controlled drug delivery. Prog Polym Sci 2008;33:1088-118.

  20. Gupta P, K Vermani, S Garg. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discovery Today 2002;7:569-79.

  21. Anal KA. Stimuli-induced pulsatile or triggered release delivery systems for bioactive compounds. Recent Patents Endocrine Metab Immune Drug Discovery 2007;1:83–90.

  22. Onofrei MD, Filimon A. Cellulose-based hydrogels: designing concepts, properties, and perspectives for biomedical and environmental applications. Material Science; 2016. p. 108-20.

  23. Jarry C, Leroux JC, Haeck J, Chaput C. Irradiating or autoclaving chitosan/polyol solutions: effect on thermogelling chitosan-β-glycerophosphate systems. Chem Pharm Bull 2002;50:1335-40.

  24. Gil ES, SM Hudson. Stimuli-responsive polymers and their bioconjugates. Prog Polym Sci 2004;29:1173–222.

  25. Qiu Y, K Park. Environment-sensitive hydrogels for drug delivery. Adv Drug Delivery Rev 2012;64:49-60.

  26. Chaterji S, IK Kwon, K Park. Smart polymeric gels: redefining the limits of biomedical devices. Prog Polym Sci 2007;32:1083-122.

  27. Cheng X, Y Jin, T Sun, R Qi, B Fan, H Li. Oxidation-and thermo-responsive poly (N-isopropyl acrylamide-co-2-hydroxyethyl acrylate) hydrogels cross-linked via diselenides for controlled drug delivery. RSC Adv 2015;5:4162-70.

  28. Nagam SP, Jyothi AN, Poojitha J, Aruna S, Nadendla RR. A comprehensive review on hydrogels. Int J Curr Pharm Res 2016;8:19-23. 

  29. Z Zhang, J Ni, L Chen, L Yu, J Xu, J Ding. Biodegradable and thermoreversible PCLA–PEG–PCLA hydrogel as a barrier for prevention of postoperative adhesion. Biomaterials 2011;32:4725–36.

  30. Chatterjee, Sudipta, Hui, Patrick. Stimuli-responsive hydrogels. An Interdisciplinary Overview; 2019. p. 7-17.

  31. Serra L, Domenech J, Peppas NA. Drug transport mechanisms and release kinetics from molecularly designed poly (acrylic acid-g-ethylene glycol) hydrogels. Biomaterials 2006;27:5440-51.

  32. N Sood, A Bhardwaj, S Mehta, A Mehta. Stimuli-responsive hydrogels in drug delivery and tissue engineering. Drug Delivery 2016;23:748-70.

  33. J Wiedemair, MJ Serpe, J Kim, JF Masson. In-situ AFM studies of the phase-transition behavior of single thermoresponsive hydrogel particles. Langmuir 2007;23:130-7.

  34. Auge A, Zhao Y. What determines the volume transition temperature of UCST acrylamide–acrylonitrile hydrogels. RSC Adv 2016;6:70616-23. 

  35. Sanna R, Fortunati E, Alzari V, Nuvoli D, Terenzi A. Poly (N-vinyl caprolactam) nanocomposites containing nanocrystalline cellulose. a green approach to thermoresponsive hydrogels. Cellulose 2013;20:2393-402.

  36. Kumar A, Srivastava A, Galaev IY, Mattiasson B. Smart polymers: physical forms and bioengineering applications. Prog Polym Sci 2007;32:1205-37.

  37. Ge J, Neofytou E, Cahill TJ, Beygui R. Drug release from electric-field-responsive nanoparticles. ACS Nano 2012;6:227-33.

  38. Shang J, Shao Z, Chen X. Electrical behavior of a natural polyelectrolyte hydrogel: chitosan/carboxymethylcellulose hydrogel. Biomaterials 2008;9:1208-13.

  39. Kim J, Wang N, Chen Y, Lee SK, Yun GY. The electroactive-paper actuator is made with cellulose/NaOH/urea and sodium alginate. Cellulose 2007;14:217-23.

  40. Zhao W, Odelius K, Edlund U, Zhao C, Albertsson AC. In situ synthesis of magnetic field-responsive hemicellulose hydrogels for drug delivery. Biomacromolecules 2015;16:2522-8.

  41. Hua MY, Liu HL, Yang HW, Chen. The effectiveness of a magnetic nanoparticle-based delivery system for BCNU in the treatment of gliomas. Biomaterials 2011;32:516-27.

  42. Liu, Zhongyang, Liu, Jianheng, Cui, Xiang, Wang. Recent advances on magnetic sensitive hydrogels in tissue engineering. Frontiers Chem 2020;8:124.

  43. Cai K, Luo Z, Hu Y, Chen X, Liao. Magnetically triggered reversible controlled drug delivery from microfabricated polymeric multi-reservoir devices. Adv Materials 2009; 21:4045-9.

  44. Alvarez Lorenzo C, Bromberg L, Concheiro A. Light-sensitive intelligent drug delivery systems. Photochem Photobiol 2009;85:848-60.

  45. Zhao YL, Stoddart JF. Azobenzene-based light-responsive hydrogel system. Langmuir 2009;25:8442-6.

  46. Suzuki T Tanaka. Phase transition in polymer gels induced by visible light. Nature 1990;346:345-7.

  47. Suzuki T Ishii, Y Maruyama. Optical switching in polymer gels. J Appl Phys 1996;80:131-6.

  48. T Manouras, M Vamvakaki. Field responsive materials: photo-, electro-, magnetic-and ultrasound-sensitive polymers. Polym Chem 2017;8:74-96.

  49. Boissenot T, Bordat A, Fattal E, Tsapis N. Ultrasound triggered drug delivery for cancer treatment using drug delivery systems. From theoretical considerations to practical applications. J Controlled Release 2016;241:144-63.

  50. Ahmadi F, McLoughlin IV, Chauhan S. Bioeffects and safety of low-intensity, low-frequency ultrasonic exposure. Prog Biophys Mol Biol 2012;108:119-38.

  51. Huang D, Sun M, Bu Y, Luo F, Lin C, Lin Z, et al. Microcapsule-embedded hydrogel patches for ultrasound responsive and enhanced transdermal delivery of diclofenac sodium. J Mater Chem B 2019;7:2330-7.

  52. Pereira TA, Ramos DN, Lopez RFV. Hydrogel increases localized transport regions and skin permeability during low-frequency ultrasound treatment. Sci Rep 2017;7:1-10.

  53. Taghizadeh B, S Taranejoo, SA Monemian, ZS. Classification of stimuli-responsive polymers as anticancer drug delivery systems. Drug Delivery 2015;22:145-55.

  54. Jianqi F, Lixia G. PVA/PAA thermo-crosslinking hydrogel fiber: preparation and pH-sensitive properties in an electrolyte solution. Eur Polymer J 2002;38:1653-8.

  55. Podual K, FJ Doyle, NA Peppas. Preparation and dynamic response of cationic copolymer hydrogels containing glucose oxidase. Polymer 2000;41:3975-83.

  56. Lalita Devi, Punam Gaba. Hydrogel: an updated primer. J Crit Rev 2019;6:1-10.

  57. Risbud MV, AA Hardikar, SV Bhat. pH-sensitive freeze-dried chitosan-polyvinyl pyrrolidone hydrogels as a controlled release system for antibiotic delivery. J Controlled Release 2000;68:23-30.

  58. Oishi M, Nagasaki Y. Synthesis, characterization, and biomedical applications of core shell-type stimuli-responsive nanogels nanogel composed of poly [2-(N, N-diethylamino) ethyl methacrylate] core and PEG tethered chains. React Function Polymer 2007;67:1311-29.

  59. V Stadler, R Kirmse, M Beyer, F Breitling. PEGMA/MMA copolymer graftings: generation, protein resistance, and a hydrophobic domain. Langmuir 2008;24:8151-7.

  60. L Rivas, SA Pooley, ED Pereira, A Maureira. Water-soluble polyelectrolytes with metal ion removal ability by using the liquid phase based retention technique. Macromolecular. Symp 2006;116:245-6.

  61. Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discovery Today 2002;7:569-79. 

  62. Peppas NA, KM Wood, JO Blanchette. Hydrogels for oral delivery of therapeutic proteins. Expert Opinion Biol Ther 2004;4:881-7.

  63. Cevik O, D Gidon, S Kizilel. Visible-light-induced synthesis of pH-responsive composite hydrogels for controlled delivery of the anticonvulsant drug pregabalin. Acta Biomaterialia 2015;11:151-61.

  64. L Xu, L Qiu, Y Sheng, Y Sun, L Deng, X Li. Biodegradable pH-responsive hydrogels for controlled dual-drug release. J Mater Chem B 2018;6:510–7.

  65. E Cabane, X Zhang, K Langowska, CG Palivan. Stimuli-responsive polymers and their applications in nanomedicine. Biointerphases 2012;7:9.

  66. P Li, S Wang, H Chen, S Zhang, S Yu Y. A novel ion-activated in situ gelling ophthalmic delivery system based on κ-carrageenan for acyclovir. Drug Dev Ind Pharm 2018;44:829-36.

  67. Bawa P, Pillay V, Choonara YE, du Toit LC. Stimuli-responsive polymers and their applications in drug delivery. Biomed Mater 2009;4:022001.

  68. R Chandrawati. Enzyme-responsive polymer hydrogels for therapeutic delivery. Exp Biological Med 2016;241:972-9.

  69. Podual K, Doyle F, Peppas N. Preparation and dynamic response of cationic copolymer hydrogels containing glucose oxidase. Polymer 2000;41:3975–83.

  70. Ehrick JD, Luckett MR, Khatwani S, Wei Y. Glucose responsive hydrogel networks based on protein recognition. Macromolecular Biosci 2009;9:864-8.

  71. Kim JJ, Park K. Modulated insulin delivery from glucose-sensitive hydrogel dosage forms. J Controlled Release 2001;77:39-47.

  72. Traitel T, Cohen Y, Kost J. Characterization of glucose-sensitive insulin release systems in simulated in vivo conditions. Biomaterials 2000;21:1679-87.

  73. T Miyata, N Asami, T Uragami. A reversibly antigen-responsive hydrogel. Nature 1999;399:766-9.

  74. T Miyata, T Uragami, K Nakamae. Biomolecule sensitive hydrogels. Adv Drug Delivery Rev 2002;54:79-98.

  75. Lim SH, Kathuria H, Tan JJY, Kang L. 3D printed drug delivery and testing systems a passing fad or the future. Adv Drug Delivery Rev 2018;132:139-68.

  76. Al-Kinani AA, Zidan G, Elsaid N, Seyfoddin A. Ophthalmic gels: past, present and future. Adv Drug Delivery Rev 2018;126:113-26.

  77. Wang X, Qin XH, Hu C, Terzopoulou A. 3D printed enzymatically biodegradable soft helical microswimmers. Adv Funct Mater 2018;28:1-8.

  78. Daly AC, Freeman FE, Gonzalez Fernandez T. 3D bioprinting for cartilage and osteochondral tissue engineering. Adv Healthcare Mater 2017;6:1-20.

  79. Peppas NA, Lowman AM. Hydrogels: In. Controlled drug delivery. Mathiowitz E. editor. Encyclopedia; 1999. p. 397-418.

  80. Vo TN, Kasper FK, Mikos AG. Strategies for controlled delivery of growth factors and cells for bone regeneration. Adv Drug Delivery Rev 2012;64:1292-309.

  81. Ebara M, Kotsuchibashi Y, Hoffman JM. Smart biomaterials. Berlin: Springer NIMS Monographs; 2014. p. 1-7.

  82. Surojeet Das, Vivek Kumar. Recent advances in hydrogels for biomedical applications. Asian J Pharm Clin Res 2018;11:62-8.

  83. Vihola H, Laukkanen A, Tenhu H, Hirvonen J. Drug release characteristics of physically cross-linked thermosensitive poly (N-vinylcaprolactam) hydrogel particles. J Pharm Sci 2008;97:4783-93.

  84. Tan R, She Z, Wang M, Fang Z, Liu Y. Thermo-sensitive alginate-based injectable hydrogel for tissue engineering. Carbohydr Polym 2012;87:1515-21.

  85. Gong C, Qi T, Wei X, Qu Y. Thermosensitive polymeric hydrogels as drug delivery systems. Curr Med Chem 2013;20:79-94.

  86. Ge J, Neofytou E, Cahill TJ, Beygui RE, Zare RN. Drug release from electric-field-responsive nanoparticles. ACS Nano 2012;6:227-33.

  87. Liu Y, Servant A, Guy OJ, Al-Jamal. An electric-field responsive microsystem for controllable miniaturized drug delivery applications. Procedia Eng 2011;25:984-7.

  88. Anca Onaciu, Raluca. Hydrogels based drug delivery synthesis, characterization and administration. Pharmaceutics 2019; 11:432.

  89. Zhao W, Odelius K, Edlund U, Zhao. In situ synthesis of magnetic field-responsive hemicellulose hydrogels for drug delivery. Biomacromolecules 2015;16:2522-8.

  90. Araujo Custodio S, Gomez Florit M, Toma. Injectable and magnetic responsive hydrogels with bioinspired ordered structures. ACS Biomater Sci Eng 2019;5:1392-404.

  91. Filipcsei G, Csetneki I, Szilagyi. Magnetic field-responsive smart polymer composites in oligomers-polymer composites-molecular imprinting. Springer Berlin/Heidelberg 2007;206:137–89.

  92. El-Leithy ES, Shaker DS, Ghorab MK. Evaluation of mucoadhesive hydrogels loaded with diclofenac sodium-chitosan microspheres for rectal administration. AAPS PharmSciTech 2010;11:1695-702.

  93. Liu Q, Liu L. Novel light-responsive hydrogels with antimicrobial and antifouling capabilities. Langmuir 2019;35:1450-7.

  94. Li L, Scheiger JM, Levkin PA. Design and applications of photoresponsive hydrogels. Adv Mater 2019;1807333:1-17.

  95. Mathiowitz E, Cohen MD. Polyamide microcapsules for controlled release: characterization of the membranes. J Membr Sci 1989;40:1–26.

  96. Mathiowitz E, Cohen MD. Polyamide microcapsules for controlled release: II release characteristics of the micro capsules. J Membr Sci 1989;40:27-41.

  97. Ninan N, Forget A, Shastri VP, Voelcker. Antibacterial and anti-inflammatory pH-responsive tannic acid-carboxylated agarose composite hydrogels for wound healing. ACS Appl Mater Interfaces 2016;8:28511-21.

  98. Nesrinne S, Djamel A. Synthesis, characterization and rheological behavior of pH sensitive poly (acrylamide-co-acrylic acid) hydrogels. Arab J Chem 2017;10:539-47.

  99. Ohmine I, Tanaka T. Salt effects on the phase transition of ionic gels. J Chem Phys 1982;77:5725.

  100. Ozmen MM, Okay O. Superfast responsive ionic hydrogels: effect of the monomer concentration. J Macromol Sci Part A 2006;43:1215-25.

  101. Zhou X, Wang J, Nie J, Du B. Poly (N-isopropylacrylamide)-based ionic hydrogels: synthesis, swelling properties, interfacial adsorption and release of dyes. Polymer J 2016;48:431-8.

  102. Lim Y, Kim SM, Lee Y, Lee W, Yang. Cationic hyperbranched poly (amino ester): a novel class of DNA condensing molecule with cationic surface, biodegradable three-dimensional structure, and tertiary amine groups in the interior. J Am Chem Soc 2001;123:2460-1.

  103. Matsumoto A, Ikeda S, Harada A. Glucose-responsive polymer bearing a novel phenylborate derivative as a glucose-sensing moiety operating at physiological pH conditions. Biomacromolecules 2003;4:1410-6.

  104. Prabaharan M, Mano JF. Stimuli-responsive hydrogels based on polysaccharides incorporated with thermo-responsive polymers as novel biomaterials. Macromol Biosci 2006;6:991-1008.

  105. Miyata T, Asami N, Uragami T. A reversibly antigen-responsive hydrogel. Nature 1999;399:766-9.

  106. Zelzer M, Todd SJ, Hirst. Enzyme responsive materials: design strategies and future developments. Biomater Sci Royal Soc Chem 2013;1:11-39.

  107. Huabing Chen, Xueling Chang. Microemulsion-based hydrogel formulation of ibuprofen for topical delivery. Epub 2006;315:52-8.

  108. Sabale V, Vora S. Formulation and evaluation of microemulsion-based hydrogel for topical delivery. Int J Pharma Investig 2012;2:140-9.

  109. Srinivas Hebbar, Akhilesh Dubey, Ravi G. Studies on cross-linked chitosan hydrogel for matrix tablets of montelukast sodium. Int J Appl Pharm 2017;9:22-9.

  110. Gina S El-feky, Gamal M Zayed. Plga nanoparticles loaded mucoadhesive and thermosensitive hydrogel as a potential platform for the treatment of oral mucositis. Int J Appl Pharm 2019;11:106-12.

  111. Eunhee Cho, Ken Webb. Formulation and characterization of poloxamine-based hydrogels as tissue sealants. Acta Biomaterialia 2012;8:2223-32.

  112. Guoming Sun, Xian Zheng Zhang. Formulation and characterization of chitosan-based hydrogel films having both temperature and pH sensitivity. J Mater Sci Mater Med 2007;18:1563-77.

  113. Suguna Selvakumaran, Ida Idayu Muhamad. Optimization of formulation of floating hydrogels containing gas forming agent using response surface methodology. Int J Pharm Pharm Sci 2013;6:526-30.

  114. Basavaraj K Nanjwade, Rucha V. Formulation and evaluation of micro hydrogel of moxifloxacin hydrochloride. Eur J Drug Metab Pharmacokinet 2012;37:117-23.

  115. Pulatova Nilufar Ubaydullaevna, Maksumova Oytura Sitdikovna. Physico-chemical polymer and hydrogel on the basis of 1-chloro-3-piperidine-2-propyl acrylate. J Crit Rev 2020;7:287-93.

  116. Biswajit Biswal, Nabin Karnal. Formulation and evaluation of microemulsion based topical hydrogel containing lornoxicam. J Appl Pharm Sci 2014;4:77-84.

  117. Devi Lalitha Gatiganti, Madhavi Harika Srimathkandala. Formulation and evaluation of oral natural polysaccharide hydrogel microbeads of Irbesartan. Anal Chem Lett 2016;6:334-44.

  118. Emmanuel O Akala. Novel pH-sensitive hydrogels with adjustable swelling kinetics. Biomaterials 1998;19:1037-47.

  119. Hu Yang, Weiyuan John Kao. Thermoresponsive gelatin/Monomethoxy poly (Ethylene Glycol)–poly (D, L-lactide) hydrogels: formulation, characterization, and antibacterial drug delivery. Pharm Res 2006;23:205-14.

  120. Azizullah, Nisar-ur-Rehman. Novel gelatin-polyoxometalate based self-assembled pH responsive hydrogels. Formulation and in vitro characterization: Des Monomers Polym 2016;19:697-705.

  121. Sun Namkung, Chih Chang Chu. Partially biodegradable temperature and pH-responsive poly (N-isopropyl acrylamide)/dextran-maleic acid hydrogels: formulation and controlled drug delivery of doxorubicin. J Biomater Sci Polymer Edition 2007;18:901-24.

  122. Lihui Weng. Rheological characterization of in situ crosslinkable hydrogels formulated from oxidized dextran and n-carboxyethyl chitosan. Biomacromolecules 2007;8:1109-15.

  123. Aka Any Grah. Formulation of mucoadhesive vaginal hydrogels insensitive to dilution with vaginal fluids. Eur J Pharm Biopharm 2010;76:296-303.

  124. Torres Lugo, Peppas. Molecular design and in vitro studies of novel pH-sensitive hydrogels for the oral delivery of calcitonin. Macromolecules 1999;32:6646-51.

  125. Das S Pal. Dextrin/poly (HEMA): pH responsive porous hydrogel for controlled release of ciprofloxacin. Int J Biol Macromol 2014;72:171-8.

  126. N Vishal Gupta, HG Shivakumar. Preparation and characterization of superporous hydrogels as pH sensitive drug delivery system for pantoprazole sodium. Curr Drug Delivery 2009;6:505-10.

  127. Bindu Sri M, Ashok V, Arkendu Chatterjee. A review on hydrogels as drug delivery in the pharmaceutical field. Int J Pharm Chem Sci 2012;1:642-61.

  128. Kalshetti PP, Rajendra V, Dixit DP, Parekh PP. Hydrogels as a drug delivery system and applications: a review. Int J Pharm Pharm Sci 2012;4:1-7.

  129. Enrica C, Vitaliy VK. Biomedical applications of hydrogels: a review of patents and commercial products. Eur Polymer J 2015;65:252-67.

  130. Xu J, Tam M, Samaei S, Lerouge. Mucoadhesive chitosan hydrogels as rectal drug delivery vessels to treat ulcerative colitis. Acta Biomater 2017;48:247-57.

  131. Syed KHG, Saphwan AA, Glyn OP. Hydrogels: methods of preparation, characterisation, and applications. Prog Mol Environ Bioeng: Anal Model Technol Appl 2011;51:118-20.

  132. Anisha Singh, Pramod Kumar Sharma. A comprehensive review of hydrogels: Int J Pharm Sci Rev Res 2010;4:97-105.

  133. M Amiji, R Tailor, MK Ly J. Gelatin poly (ethylene oxide) semi-interpenetrating polymer network with pH-sensitive swelling and enzyme-degradable properties for oral drug delivery. Drug Dev Ind Pharm 1997;23:575-82.

  134. Liu M, Zeng X, Ma C, Yi H, Ali X. Injectable hydrogels for cartilage and bone tissue engineering. Bone Res 2017;5:1-20.