Introduction

For almost 60 years, hydrogels have been explored in medical and pharmaceutical fields [1]. Their first successful synthesis was performed by Wichterle and Lim, when they developed soft hydrogel contact lenses [2]. Since then, a wide range of applications have emerged in researches worldwide [3].

Back in the 1970s, Nalbandian and coworkers developed a hydrogel made of Pluronic 127 carried with silver nitrate in order to threat thermal burns [4]. In the following decade, hydrogels were applied to encapsulate pancreas islets in alginate membranes [5] and in an association between collagen and shark cartilage for wound dressing [6].

From the 1990s to the present, extensive research brought the most important advances for hydrogels. Copolymers consisting of poly(ethylene oxide) (PEO) and poly(L-lactic acid) (PLLA) were synthesized, designed mainly for delivery of protein, in order to facilitate the loading of hydrophobic drugs [7]. Hyaluronic acid was used to develop a system to release GH and investigate the hydrogel’s potential for drug delivery [8].

The discovered possibility of hydrogels to release hydrophobic drugs opened new possibilities for the delivery of innumerous substances and therapeutics that once found difficulties in reaching the objective needed [9]. Following that, the progress of hydrogel science has led to the increased interest in the so-called smart hydrogels. Basically, they consist in polymeric matrixes with tunable properties and trigger stimuli [10].

Such characteristics point to the advantage of hydrogels in drug delivery, being that they make possible to tune mechanisms such as diffusion and swelling and to program responses to environmental stimuli [11]. In that sense, hydrogels have also shown the ability to carry proteins and peptides [12] and deliver drugs with the need of action improvement or targeting [11].

In the past three decades, it was possible to comprehend the importance of hydrogels in drug delivery: They can facilitate and sustain the release of biologically active agents. Such applicability contributes to the decreasing number of administrations, prevention of damage and successful dosage of drugs [3].

For that matter, it is important to highlight the versatility of hydrogels in different routes of administration [11], especially for transdermal and topical delivery. As pointed by Saha and coworkers, being the skin the largest human organ, with more surface area, drug administration passing through it has drawn much more attention than any other drug delivery system [13]. At the same time, topical and dermatological administration face limitation from the drugs applied, such as poor adherence skin, poor permeability and difficulties in the cooperation by patients [14].

In order to overcome such occurrences and improve treatments and therapies, hydrogels have been used as a viable alternative. Saha and coworkers, for example, were able to enhance the permeability and penetrability of the drugs tested by delivering them transdermally using pluronic lecithin organogels. With this approach, the levels of absorption by the systemic circulation could be enhanced [13].

On the other hand, studies have been performed in the attempt to use films to deliver drugs, both topical and transdermal, in order to improve their action both at the body tissue and systematically [14]. As for disorders occasioned to the skin, such as dermatitis and topical wounds, the use of hydrogels presents as an alternative to overcome problems in the currently used dressings [15].

Wound management is especially difficult since it involves a dynamic and complex process. To reach an ideal healing, treatment of choice must provide maintenance of high humidity at the wound site, removal of excess exudate, protection from infections and contaminants, the ability to be removed without causing further trauma, the allowance of gaseous exchange, comfortability and not frequent dressing change [11]. As pointed by Harrison and Spada, and by Aderibigbe and Buyana [11, 15], hydrogels have shown their importance more recently in wound treatment, mostly due to their fitting to the properties of an ideal dressing. More than that, hydrogels can enhance healing, as they are also able to deliver antibiotics and other needed substances.

Due to the shown properties and unique characteristics, hydrogels can be notably chosen for topical use as they exhibit many benefits over other commonly used drug delivery vehicles, while stepping toward innovative treatments. Recently, some authors have also published reviews considering the need to develop more assertive systems to wound dressing, healing and drug delivery. In the same knowledge field, our review paper aims to discuss commonly used polymers for modified topical delivery.

Hydrogels characteristics

Hydrogels are tridimensional polymeric networks able to absorb a considerable amount of water. Their main characteristic of hydrogels is associated with the presence of hydrophilic and hydrophobic groups in the polymeric chain [16]. The balance between these groups makes water absorption possible at levels from 10 to 99% [17]. At the same time, cross-links have to be present to avoid dissolution in aqueous environment [18].

Cross-links are responsible for connecting the networks, which determine whether the polymeric chain shows viscous-elastic or elastic behavior [18]. The volume of water absorbed by a hydrogel is limited by the elasticity of the polymeric networks, which defines its swelling capacity [19]. When swollen, the hydrogel absorbs such amount of water that the mass of liquid present in its polymeric networks becomes greater than the mass of the polymer that composes it [17].

For clinical use, hydrogels are recommended to be biodegradable, and for that, unstable bonds are frequently introduced into the hydrogel structure. These bonds can either be present in the polymer backbone or in the cross-links used to prepare the hydrogel. The bonds can be broken under physiological conditions, either enzymatically or chemically. A great variety of methods to establish cross-linking have therefore been used in hydrogel preparation [18].

For hydrogels’ synthesis, both physical and chemical methods have been applied. In physically cross-linked hydrogels, dissolution is prevented by physical interactions existing between polymeric chains [18]. Physical cross-links are based on hydrogen bonds, ionic bonds, van der Waals interactions or hydrophobic connections [20]. In chemically cross-linked hydrogels, covalent bonds are present between the polymeric chains [16]. Chemical cross-links require a mediator agent for the reaction to occur, but the formed gels offer higher mechanical stability, since covalent bonds are stronger [17].

The water content of a hydrogel determines its physical and chemical characteristics, which guarantees unique properties to this structure, with the capacity to modify the release profile of loaded drugs [21]. Compared to other classes of biomaterials, hydrogels have the advantages of offering biodegradability, biocompatibility, suitable mechanical strength and porous structure [22]. Hydrogels have also low elastic surface tension with water and other biological fluids, which makes them highly biotolerable [23].

Natural and synthetic hydrogels

Natural hydrogels are composed of biopolymers, polymers that occur in nature and are mainly biodegradable [24]. They are biodegradable and biocompatible and present low or non-toxicity [25]. Associated with that, hydrogels made of natural polymers present more similarities to the living tissue, which makes them more suitable for biomedical application [26].

Though natural hydrogels are supposedly better for medical and pharmaceutical use, most of the hydrogels currently available in the market are synthesized from synthetic polymers. This is especially due to their excellent physical, chemical and mechanical properties, which overcome the natural ones. At the same time, synthetic hydrogels present higher production cost and are not renewable and not environmental friendly [27].

Such duality of behavior presented by the types of hydrogel can point to trammels when it comes to use as the best alternative for innumerous applications. On the other hand, such implication can be exceeded by modifications in the polymeric chains of the hydrogels [23].

Several strategies have been applied to create hydrogels with defined network structures, desirable chemical compositions and tunable mechanical strength, making them suitable for different applications in topical route (Table 1). These hydrogels can be prepared from completely synthetic components and show incredible stability even under stressful environmental conditions [28]. By modifying the polymeric chains with stimuli-responsive functional groups, hydrogels can respond to different stimuli, such as heat, pH, light, chemical agents and magnetic fields [29].

Table 1 Polymers used as delivery systems in topical route
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At the same time, natural and synthetic polymers can have their polymeric chain blended as their important and usable characteristics are coupled. Therefore, an adjustment of the chemical and physical properties of both kinds of polymers can be reached [30].

Materials for hydrogel preparation

Alginate

Alginate is a copolymer produced by brown algae [25] and bacteria, such as Azotobacter and Pseudomonas. Structurally, alginate is composed of two uronic acids: d-mannuronic acid and l-guluronic acid. To form hydrogels of this material, it is necessary that the cross-linking reaction occurs by the substitution of sodium ions by calcium ions, as the following reaction [31]:

$$ 2\text{Na} \, \left( {\text{alginate}} \right) + \text{Ca}^{2 + } \to \, \text{Ca} \, \left( {\text{alginate}} \right)^{2} + 2\text{Na}^{ + } . $$

When the synthesis happens, during gelation, drugs and bioactives (e.g., proteins, cells and DNA) can be retained with full biological activity in the hydrogel matrix. Although loaded in the polymeric network, the bioactive is still free to diffuse within the gel network and be released in the site of action to exhibit its biological effect [31].

Alginate has been suggested for use in wound healing [32] and encapsulation of therapeutic agents [33, 34], especially because of its biocompatibility, biodegradability and facility to be obtained [35]. Hydrogels made of alginate have been considered for the treatment of several kinds of wounds, since their high water content, elasticity, permeability and ability to create a moist environment in the wound bed offer higher patients’ compliance [36].

Calcium alginate hydrogels have also been used to load poorly water-soluble drugs [37], with the aim to increase the solubility of such drugs and modify their release profile [38].

Carboxymethyl cellulose (NaCMC)

Sodium carboxymethyl cellulose (NaCMC) is a water-soluble adhesive polymer that occurs naturally [39]. Hydroxyl and carboxyl groups are present in its structure, which makes it suitable for chemical modifications [40].

NaCMC has been used as a viscosity inducer in ocular formulations, such as in eyes drops and in artificial substitutes for tears. When used alone, NaCMC forms a transparent thin film with low mechanical strength, which compromises its use as ocular biomaterial. To improve the biomechanical properties of NaCMC, the cellulose derivative can be blended with a rigid polymer as polyvinyl alcohol (PVA), while maintaining the biodegradable and bioadhesive properties of NaCMC [39].

The water absorbent properties of NaCMC are another attribute of this polymer, as its excellent skin and mucous membrane compatibility. NaCMC is able to maintain an optimal moist environment in wound region for extracellular matrix formation and re-epithelialization, being proper as a dressing for the treatment of burn wounds [41].

NaCMC can also be used as a hydrophilic polymer and a pH-responsive component to improve the swelling ratio of poly (n-isopropylacrylamide) (PNIPAAM) hydrogels. Such association can produce pH/temperature responsive hydrogels [42] that are suitable for the controlled release of drugs and bioactives [41].

Capanema et al. developed a carboxymethyl cellulose–doxorubicin (CMC-DOX) prodrug hydrogel for topical chemotherapy of melanoma skin cancer. More than analyzing that the degree of substitution of carboxymethyl cellulose in the hydrogels affects its swelling and gel fraction behavior, the study shows that CMC-DOX hydrogel has effective response toward melanoma cancer cells [43].

Chitosan

Chitosan is a semicrystalline, biocompatible and biodegradable amino polysaccharide. It is obtained from the exoskeletons of crustaceans in a process that involves demineralization, deproteinization, deacetylation of chitin, extraction of chitosan and precipitation [44, 45]. Chitosan is also non-toxic and can be used to produce gel membranes, coatings and fibers [46].

Chitosan hydrogels are also versatile, attributed to the presence of several hydroxyl groups that make the polymeric chain to swell rapidly, as it maintains its original shape. These hydrogels exhibit phase transition under environmental stimuli, e.g., pH, temperature or ionic strength [44].

Chitosan is one of the main choices for drug delivery. Its matrix has been used to encapsulate drugs and proteins [47,48,49,50,51,52,53,54], cells and growth factors, among other therapeutic agents [45], as well as to disperse nanoparticles to develop semisolid formulations [55, 56]. Chitosan hydrogels can be used in epidermal and internal implants, since they can keep the drug concentration constant for long periods of time [44].

Hydrogels based on natural polymers are often chosen for controlled release of drugs [57] and, when cross-linked with dialdehydes and dicarboxylic acids, have been described to exhibit less adverse side effects than the synthetic ones. However, there are only few in vivo tests regarding this application. In that sense, chitosan hydrogels have been prepared by cross-linking with glutaraldehyde and glutaric acid, in order to obtain compatible and biodegradable materials for topical use [44]. Synthesis of modified chitosan hydrogels to improve their adhesiveness and evaluate their suitability for topical application has been performed [58, 59].

Hydrogels can knowingly support the wound healing process, since they are able to provide moisture to the wound, preventing fluid loss [60]. Hydrogel dressings can be flexible and helpful in the epidermis repair [61]. In drug delivery, they offer higher flexibility and response to pH and temperature stimuli. Polyvinyl alcohol (PVA) and chitosan have proven excellent mechanical properties, biocompatibility and capacity to increase the collagen synthesis [62, 63].

Silver sulfadiazine (SSD) is considered as a gold standard in the treatment of burns. Commercially, silver sulfadiazine is available in a cream form, which presents many disadvantages. The formation of an adhesive eschar turns difficult to differentiate it from the burn eschar, and such occurrence prevents SSD to penetrate the wound [64]. Increased inflammation is also observed with the use of SSD as well as toxicity toward fibroblasts and keratinocytes [65].

In vitro studies evidenced SSD’s cytotoxicity, which was shown to be minimized by controlling its delivery [66]. Following that direction, an interest has been put in polymeric materials, which often offer valid scope for application in drug delivery. In view of that, chitosan/carbopol hydrogels had SSD incorporated in its matrix, in a way that enhanced burn healing while overcame the disadvantages of the current commercial formulation [65].

Cyclodextrins

Cyclodextrins are oligosaccharides that form tridimensional cyclic structures, exhibiting hydroxyl groups, which makes hydrophobic the inner compartment, while the exterior is hydrophilic. There are three forms of cyclodextrins, namely alpha-, beta- and gamma-cyclodextrins [67, 68].

The structure of cyclodextrins makes them suitable for developing hydrogels and to load drugs in their inner core. The result is the formation of noncovalent complexes with drugs, modifying their solubility, diffusivity and stability [69].

Copolymerization with cyclodextrins offers the possibility to form hydrogels with novel mechanisms of drug uptake and/or retention [70]. The obtained drug–cyclodextrin complex is dispersed within the gel network, being the drug released when in contact with the physiological fluids. However, copolymerization may significantly change physicochemical properties of the hydrogel, especially swelling and viscoelastic properties [71].

Implants based on cyclodextrin hydrogels were tested on rats and rabbits [9, 72]. The formulations were able to reduce the risk of drug loss in the tear fluid, thereby increasing its uptake from the cornea. Hydrogels may therefore be used to overcome the main problems regarding eye delivery, namely drug solubility in tear fluid and permeation through the cornea [73].

Dextran

Dextran is a polysaccharide showing biocompatibility and biodegradability, besides being non-immunogenic and non-antigenic. Such material has been widely used for several biomedical applications, such as drug delivery and tissue engineering. Scaffolds made of dextran are soft and flexible [74], which favors their handling for wound treatment, as well as for tissue re-epithelialization [75].

Dextran is soluble in water and in organic solvents, which makes it feasible for bioapplications. Because dextran can be copolymerized with other polymers, its physical and biological properties can be manipulated according to the required application [75].

Hydrogels made of dextran have been used as a platform to load drug, as well as growth factors for skin regeneration [76]. These hydrogels can also improve drug penetration in the skin and have an enhanced pharmacological effect [77].

Nanogels are hydrogels made in nanoscale. They work with the direct load of drugs, both hydrophilic and hydrophobic. Drug release kinetics can be controlled through degradation rate of cross-links or under stimuli, such as pH and temperature [78].

Nanogels based on N-isopropylacrylamide and 2-hydroxyl methacrylate-lactide-dextran macromer were successfully used for retinal drug delivery [79], being therefore a suitable alternative to eye drops [80].

Poly(ethylene glycol) (PEG)

Poly(ethylene glycol) is a polymer of ethylene oxide and can have a molecular weight lower than 100000. PEGs with molecular weights under 1000 tend to be viscous and colorless, while the ones with higher molecular weights are waxy and white. PEGs are amphiphilic and soluble in aqueous environments, as well as in organic solvents such as ethanol, acetone and chloroform [81].

Drug delivery systems of insoluble networks can be formed with PEG polymer alone; however, to reach stronger cross-links, additional groups must be added to the polymeric chain. Groups such as acrylate, amine and carboxyl can form a biomaterial with high mechanical strength and more resilient networks [82].

PEGs exhibit biocompatibility and non-immunogenicity and are approved by the Food and Drug Administration (FDA) for biomedical use. Examples include their use in tissue engineering and for wound healing [82].

PEG has been used to cover nanoparticle surfaces [83, 84], to enhance both shelf-life in vitro (steric stabilization) and half-life in vivo (stealth properties). In addition, it can provide site-specific drug release, with enhanced therapeutic activity, while limiting adverse side effects [85].

Gabriel et al. developed nanocarriers based on methoxy—poly(ethylene glycol)—hexyl-substituted poly(lactic acid) (mPEGhexPLA) containing tacrolimus (TAC) [86]. TAC is a potent immunosuppressive topic drug, approved for the treatment of dermatitis [87] and recommended for facial psoriasis [88].

Drug dosage could be reduced because of the higher site-specific delivery of TAC in the inflamed skin. The hydrogel formulation containing TAC has successfully been used to improve patients’ compliance and overcome the disadvantages encountered in the currently available formulations [86].

Poly(2-hydroxyethyl methacrylate) (PHEMA)

Poly(hydroxyethyl methacrylate) is one of the first developed synthetic polymers [89] being introduced by Wichterle and Lim in 1960 [2]. Since then, it has been applied in medical and pharmaceutical areas, especially for its non-toxicity and biocompatible properties [89].

PHEMA hydrogels have high water absorbing capacity being widely applied in drug delivery [90]. Their mechanical and swelling properties facilitate the delivery of loaded drugs. Such properties depend on the cross-linking agents used for the synthesis of the hydrogel [91]. The high water content of PHEMA hydrogels enables the uptake of drugs by the simple immersion in concentrated solution. Especially used for the development of contact lenses, PHEMA hydrogels allow the drug diffusion between the lens and the cornea, increasing the drug retention in the ocular tissues significantly, so ocular bioavailability can be enhanced considerably [92].

Wichterle and Lim were the firsts to describe a biocompatible synthetic material for contact lens applications [93, 94]. In their pioneer work, a hydrogel based on poly-2-hydroxyethylmethacrylate (PHEMA) has been developed [2], which later came to be optimized by Bausch and Lomb and then approved by the FDA in 1971 [94].

Contact lenses can be classified as hard or soft. Hard lenses are based on hydrophobic materials such as poly(methyl methacrylate) (PMMA) or poly(hexa-fluoroisopropyl methacrylate) (HFIM). Soft lenses are usually made of hydrogels [94].

Hydrogel contact lenses can be a more convenient way to transport drug through the eye. They exhibit chemical and mechanical stability, reasonable cost, high oxygen permeability and biocompatibility. Hydrogels also have the ability to control drug diffusion, being therefore highly applied for drug delivery [95].

Poly-hydroxyethylmethacrylate (PHEMA) is recognized as an effective biomaterial for the delivery of several ophthalmic drugs [96]. Ciolino, Hoare, Iwata, Behlau, Dohlman, Langer and Kohane [97] developed a prototype contact lenses by coating PLGA (poly[lactic-co-glycolic acid]) films containing test compounds with PHEMA (poly[hydroxyethyl methacrylate]) by ultraviolet light polymerization. In this study, they used fluorescein and ciprofloxacin to perform release studies and the system showed zero-order release kinetics at therapeutically relevant concentrations for 1 month, indicating that the system is suitable for ocular drug delivery. Using the same system changing the compound for econazole, an antifungal, the same group concluded that the econazole-eluting contact lenses could be used to provide extended antifungal activity for fungal ocular infections [98].

Poly(lactic-co-glycolic acid) (PLGA)

Poly(lactic-co-glycolic acid) is one of the most used polymers in biomedical applications. PLGA can be hydrolyzed into lactic acid and glycolic acid, which can be easily metabolized by the human body, via the citric acid cycle, offering a high degree of biodegradability. PLGA is approved by the FDA for use in humans, especially for drug delivery systems, e.g., nanoparticles and microparticles [84, 99,100,101,102,103,104].

The chemical degradation of PLGA is well characterized and is controllable [104, 105]. The drug release from PLGA networks can therefore be modified for site-specific delivery [106].

The physicochemical properties of PLGA are affected by factors that include polymer molecular weight, ratio of lactic to glycolic acid in the copolymers, polymer–drug ratio, preparation process and environmental conditions, such as pH and temperature [107]. These factors also affect the ability of PLGA to form nanoparticles and may control their hydrolysis and degradation. The type of drug is responsible for setting the release rate, as well as the mechanical strength and swelling behavior [108].

PLGA has been studied for controlled releases not just for topical uses but also for cancer treatment [109] and bone tissue regeneration [110]. Poly-(d,l-lactic acid-co-glycolic acid) (PLGA)–polyethylene glycol (PEG)–PLGA triblock copolymer system was used as a sustained-release system for ear drug delivery. Cidofovir was used as model drug for the release studies, showing that the hydrogel can provide sustained release and be controlled by the use of additives [111].

Poly(N-isopropylacrylamide) (PNIPAAm)

Poly(N-isopropylacrylamide) is a synthetic polymer known for its thermo-responsive behavior, since it reacts to temperature stimuli, with a defined lower critical solution temperature (LCST). LCST is a temperature in which the polymer is presented in different structures below and above it [112]. For hydrogels of PNIPAAM, the LCST is around 32°C [113].

PNIPAAm is one of the most extensively studied polymers, since it shows solubility in water at room temperature. Above the LCST, the polymeric solution transforms into an opaque gel, which is caused by hydrophobic interactions [114]. At temperatures below the LCST, hydrogen bonds are formed. When under heating, hydrophobic interactions between the polymeric chains become dominant, if the temperature is higher than the LCST [115].

The uptake and release profiles of drugs from PNIPAAm hydrogels depend on the physicochemical properties of the polymer [116]. In modified-release systems, the swelling of the polymer decreases the release of hydrophobic drugs, whereas the release of hydrophilic drugs is increased. Indeed, the water uptake by the hydrogel contributes to enhance the diffusion of water-soluble drugs within the polymeric network [117].

In attempt to overcome the semisolid limited of effectivity [118] due to short exposition of the area to the product (removal by contact, decrease of viscosity at body temperature, amongst other), in situ hydrogels formulation have gained attention [119]. Thermosensitive hydrogels as polyethylene glycol (PEG)–poly(N-isopropylacrylamide) (PNIPAAm), chitosan/poly(vinyl alcohol), show phase transition in face of temperature alterations. For vaginal administration, for instance, such formulations can be easily applied at room temperature, since they present low viscosity, which allow quickly spreading and flow into the vagina’s mucosa. Besides that, hydrogels can prologue residence of the loaded drug in the vagina [120].

Polyvinyl alcohol (PVA)

Polyvinyl alcohol is synthetic polymer known for its biodegradable and biocompatible properties [121]. Considered one of the oldest materials for hydrogels synthesis, PVA has been used for several biomedical applications, e.g., wound management, drug delivery systems and contact lenses [60].

Despite the wide use of PVA in semisolid formulations, hydrogels based on this polymer have insufficient elasticity and very limited hydrophilic characteristics. As for wound dressing, PVA hydrogels usually have to be blended with other polymers, either natural or synthetic [122], which may change the capacity of the polymer for swelling and its contribution for wound moisture [60]. Chemical modifications, e.g., cross-linking with other polymers, are therefore necessary to develop drug delivery systems with the required biomechanical properties (i.e. flexibility, adhesiveness and permeability) for wound applications [123].

Treatment for severe wounds generally requires drug administration at time intervals for long periods. The use of modified release systems has been proposed as an approach to reduce dosing frequency while keeping the drug released for longer periods of time for a prolonged therapy [124]. The development of a controlled release system by formulating simvastatin in a polyvinyl alcohol (PVA) hydrogel has been useful for wound healing, attributed to the prolonged release of the drug from the hydrogel while reducing dosing frequency [125].

Scleroglucan

Scleroglucan (SCLG) is a natural polysaccharide produced by Sclerotium fungi. Its structure offers interesting properties for the development of topical hydrogels [126]. SCLG is basically composed of a linear backbone of (1,3)-linked d-glucopyranosyl residues bearing a single (1,6)-linked d-glucopyranosyl unit every three sugar residues of the main chain [127]. In aqueous medium, SCLG shows triple helix conformation and pseudo-plastic behavior, which exhibits its transition from sol to gel status [128, 129].

SCLG can be applied in the preparation of modified-release dosage forms for topical drug delivery and may be altered with pH-responsive groups, which have considerable effect on the characteristics of the polymer [130, 131]. For instance, a carboxymethyl derivative of scleroglucan (SCLG-CM) is obtained by the reaction with chloroacetic acid in basic medium, which influences the gel properties. This modification makes SCLG-CM capable of forming hydrogels without the addition of any salt [132].

Paolicelli, Varani, Pacelli, Ogliani, Nardoni, Petralito, Adrover and Casadei [126] recently used three different compounds (fluconazole, diclofenac sodium salt and betamethasone phosphate sodium salt) to perform release studies with the carboxymethyl scleroglucan hydrogel, besides the rheological characterization. Depending on the compound, the mechanical properties slightly changed. Betamethasone made the hydrogel weaker; on the other side, diclofenac made the hydrogel stronger by interacting the carboxylic group with Scl-CM300. This interaction also slowed its release, making this hydrogel useful for a sustained topical release of diclofenac.

Stimuli-responsive hydrogels

Stimuli-responsive hydrogels are polymer networks developed to change in the presence of a stimuli, modifying its form or/and releasing its content. The stimuli for drug release may be physical, chemical or biochemical, causing degradation of the hydrogel itself or the release of the drug by scissile bonds [133]. This stimulus can be both endogenous, inherent to biochemical changes caused by pathology (pH, reactive oxygen species, temperature), and exogenous, from external manipulation (heat, light, ultrasound) [134, 135]. This diversity of stimuli for drug release can be explored and the response of the hydrogels to them can be tuned, leading to a control release and targeted drug delivery, protecting and stabilizing its content until release is triggered [133, 136].

A well-known smart polymer is the Poloxamer 407. P407 is a triblock structure formed by a hydrophobic group, propylene oxide (PO), and a hydrophilic group, ethylene oxide (EO), on the ends EO-PO-EO, and is a reverse thermal gelation polymer. This transition between liquid to gel form is due to the aggregation of copolymer molecules in micelles. When the hydrophobic PO block dehydrates, it forms the core of the micelle leaving the EO as an outer shell, hydrated, to swollen [137]. Yang, Sabharwal, Okonkwo, Shlykova, Tong, Lin, Wang, Guo, Rosowski, Pelton and Kohane [138] developed a hydrogel for otitis media treatment, using P407 due to thermal gelation properties, adding polybutylphosphoester (PBP) to both ends (EO) to maintain the mechanical strength of the hydrogel, forming a pentablock, PBP-EO-PO-EO-PBP. Applying to the tympanic membrane (TM), hydrogel turns into gel by meeting a higher temperature and adhere to TM during required time for disease treatment.

Using alginate and synthetic compounds 2-hydroxyethyl acrylate (HEA) and poly(ethylene glycol) diacrylate (PEGDA), Das, Pham, Lee and Noh [139] synthesized a terpolymeric semi-interpenetrating (semi-IPN) hydrogel using graft polymerization and cross-linking processes by free radical polymerization technique. They tested hydrogels in two different pHs, 2.5 and 7.4, and results show that when the hydrogel is at a lower pH (pH 2.5) it has less void space due to protonation, and the intramolecular H-bonding made the polymer network more rigid.

LeValley, Tibbitt, Noren, Kharkar, Kloxin, Anseth, Toner and Oakey [140] developed a photodegradable functionalized poly(ethylene glycol) to capture and release circulating tumor cells. Linking a photodegradable molecule, o-nitrobenzyl monomer, to PEG’s amino-end, the hydrogel would degrade in the presence of 365 nm light, releasing captured cells in a high-resolution controlled manner.

Future perspectives and conclusions

Programmable hydrogels represent great advance in the area since their development requires control not only when the drug or protein release starts but also when it finishes. For these hydrogels, different from what happens to the stimuli-responsive ones, internal and external factors must be considered (Table 2). Functional structures and properties of the polymers used have to go through alterations in order to develop a programmable hydrogel [141].

Table 2 Advances in hydrogels formulations
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While hydrogels have been extensively study for a long time now, room still exists for novel, chemically modified polymers for a range of new applications in drug delivery. For topical use, many studies are promising, but standard applications and treatments are still preferred. Attributed to their biodegradability, biocompatibility and suitable biomechanical properties, one of the most promising uses of hydrogels is for wounds treatment and management. Chemically different hydrogels can be tailored to exhibit the required physicochemical properties for a set of drugs. Recently, we have modified the functionality of PNIPAAm hydrogels to incorporate and release bromelain, a set of proteolytic enzymes with anti-inflammatory and healing properties [142, 143]. New polymers with innumerous characteristics arise frequently, and for such, new techniques and developments must be performed in order to create new and alternative applications and treatments.