Biomedical applications of hydrogels in drug delivery system: An update

Abstract

Conventional drug delivery system generally deals with the issues involving repeated dosing and systemic toxicities. Since few decades, hydrogels have played a significant role as a carrier in drug delivery to minimize the drawbacks pertaining to conventional drug delivery. They.

have been considered as one of the most reliable groups of biomaterials due to their biocompatibility, physicochemical properties, and designed interaction with living surroundings. The diversity and versatility of hydrogels make them extraordinary not only in the field of targeted drug delivery but also in tissue engineering, fabrication of contact lenses, and wound dressings. Another reason which makes hydrogels a smart carrier in drug delivery is their special characteristic to retain water inside their network. In recent years, hydrogels fabricated from natural, semi-synthetic, and synthetic polymers have gained a lot of attention in targeted drug delivery of therapeutic agents for the management of cancer, gastric ulcers, brain tumors, diabetes, bacterial infections, etc. Also, with their tremendous capability to modify, hydrogels proved to be a promising vehicle for drug delivery in cosmetological and dermatological conditions. The motive behind this review is to highlight the key concept of hydrogels, their fabrication methods, stimuli-responsive polymers used for their fabrication, and their diverse utilization in the delivery system. Further, different completed and ongoing clinical trials of hydrogel-based drugs have also been discussed. Suitable studies are provided from the literature that supports the tremendous utilization of hydrogels in different segments and how they are modified suitably in several ways to achieve desired targeted delivery of therapeutic agents.

Introduction

Hydrogels belong to an important class of biomaterials that are widely utilized in different biomedical segments due to their capability to retain water, mild processing conditions, and outstanding biocompatibility. Their unique characteristics such as controllable swelling behavior and flexibility enhance their broad applicability in bone and cartilage regeneration, targeted delivery of drugs, tissue engineering, electronic and soft robotic component, biosensors, wound injury, and inflammation [1]. They represent three-dimensional structures held together by either supramolecular interaction and covalent linkages with the capability of entrapping large quantities of dissolved solutes [2,3].

The swelling of hydrogels in aqueous solvents is controlled by an association of polymeric networks with functional groups [2,3]. Desired characteristics of hydrogels including biocompatibility, elasticity, mechanical property, permeability, and biodegradability can be achieved by certain changes in the preparation techniques [4]. The water holding capacity and swelling behavior of hydrogels are facilitated by the presence of hydrophilic functional groups such as carboxylic acid, sulfates, amides, and hydroxyl groups [5]. The enormous biocompatibility of hydrogels enables them to mimic like physical, electrical, and chemical functions of biological tissue [3].

Polymers derived from natural, semi-synthetic, and synthetic sources have been widely utilized in the fabrication of hydrogels. Natural polymers such as polysaccharides, guar gum, collagens, proteins, acacia, nucleic acid, etc. Have been considered safe and widely employed in the preparation of hydrogel. These polymers exhibit versatile properties like impressive mechanical stability high biocompatibility, biodegradability and offer target specific drug delivery [6,7]. Owing to high physical strength, desirable flexibility and other key attributes, synthetic polymers viz polyacrylic acid, polyacrylamide, poly (N-vinyl pyrrolidone), poly (hydroxyalkyl methacrylate), acrylic acid, methacrylic acid, N-isopropyl acrylamide, N-vinyl-2-pyrrolidone, etc. Have also been used in hydrogel synthesis [8].

The original hydrogel polymer i.e., a copolymer of 2-hydroxyethyl methacrylate and ethylene dimethacrylate was developed by Wichterle and Lim in 1954. The development of the first soft hydrogel contact lenses by Wichterle in 1961 represented the successful clinical application of hydrogel polymers and remains one of the most important hydrogel-based contact lenses till today [9]. In the past few years, various hydrogel systems such as smart hydrogel, supramolecular hydrogel, shape memory hydrogel, polymer hydrogel scaffolds, injectable hydrogels, actuators, self-healing hydrogels, and injectable hydrogels have been extensively used in tissue engineering, targeted drug delivery, bone regeneration, wound injury, surgical devices, gene therapy, vaccines, immunotherapy, corneal treatment, diagnostic imaging, sensors in cancer therapy and absorbable bone plates, etc. [10,11].

In addition, stimuli-responsive hydrogels have gained the focus of the researchers due to their ability to modify in response to different stimuli including pH, temperature, ultrasound, electric field, enzymes, light, redox, glucose, ions, etc. Such hydrogels can be peptide-based or polymer-based depending on the material used for their fabrication. Also, these hydrogels have shown excellent stimuli-responsive characteristics, biocompatibility, swelling indices, non-toxicity, and biodegradability [8]. Smart hydrogels are controllable over their swelling behavior, mechanical properties towards various stimuli, and network structure [2,12]. They can undergo volume and structural phase transitions in response to external stimuli and thus they have been explored in different fields including life sciences [13]. Different polypeptides or polymers act through dynamic covalent bonding and physical associations between biomaterials used for the fabrication of hydrogels [14].

Hydrogels characterized as multifunctional polymer-based materials have been considered as innovative and promising biomedical systems. Owing to some unique characteristics, they have gained a substantial attention in the field of pharmaceutics, nanomedicine, and biotechnology [15]. Properties like higher water content/hydrophilicity, swellability, tunable particle size, and biocompatibility etc. makes them a promising drug delivery system [16]. In comparison to nanocapsules, micelles, and liposomes, hydrogels exhibit higher drug loading capacity (up to 50% loading efficiency) and offer a controlled drug release [17]. Unlike liposomes, hydrogels have shown phenomenal protection of therapeutic agents from enzymatic degradation and resulted in enhancement of drug stability [15]. Furthermore, hydrogels have been considered as highly stable system owing to the presence of crosslinking structure i.e. multidimensional extension of polymeric chain resulting in close knit like structure. Principally, higher drug loading efficiency of hydrogel is attributed their ability to accommodate macromolecules and bioactive substances in their swollen state that make them superior compared to other nanocarriers [18].

In view of key features of the hydrogel-based system, constant efforts have been made to identify and optimize hydrogel designs to satisfy specific drug delivery purposes. Although a number of articles have been published on hydrogels [[19], [20], [21], [22], [23]], these articles do not cover versatile aspects of the hydrogel-based delivery system. Keeping this fact in mind, the present review is aimed to highlight the key concept of hydrogels, their preparation methods, polymers used in their preparation, and their possible applications in biomedical sciences. Besides, special efforts have been made to highlight various recent researches and progresses made in the field of hydrogel-based delivery systems viz. various types of hydrogel preparations, opted routes of administration in the management of different diseases along with FDA approved hydrogel-based products their indications. In addition, various ongoing and completed clinical trials of hydrogel preparations have also been discussed.

Hydrogel represents 3D (three-dimensional) crosslinked, insoluble, and tissues like polymeric networks that can retain a huge amount of water as well as biological fluids in their swollen phase. Interaction between polymeric hydrogel networks and biological fluids or water occurs through a counter-balanced mechanism resulting in expansion of chain networks via capillary, hydration, and osmotic forces [24]. The equilibrium state of hydrogels can be attained by these forces which determine some essential qualities of hydrogels like mechanical strength, diffusion characteristics, and internal transport [25]. They are composed of a variety of natural and synthetic polymers and their combination in different ratio [15]. Crosslinking of hydrogels can be attained by physical (hydrogen bonding/entanglement) and chemical (covalent) interactions [26]. Their capacity to absorb water is attributed to the presence of hydrophilic functional groups such as –CONH2-, –OH, -SO3H, and –CONH– and macromolecular chains in the polymer structure [15]. Swelling of hydrogel is principally defined by diffusion of water in the hydrogel [27] which is consists of three phases i.e., (a) primary bound water (where water molecules get attached to the hydrophilic group), (b) secondary bound water (interaction between water molecules and existing hydrophobic groups), (c) free water (water is filled into the void spaces at equilibrium swelling) [28]. In general, the swelling rate of hydrogels depends on crosslinking density and concentration of polymers, as the crosslinking density gets high, it results in reduction of swelling ratio which in turn leads to brittleness in hydrogel [29]. The structure of hydrogel is illustrated in Fig. 1.

Hydrogels comprise of several classifications based on biopolymers and polyelectrolytes. They are broadly classified into homopolymeric, copolymeric, and interpenetrating polymeric hydrogels according to their method of preparation. Based on their physical properties, they can be smart and conventional hydrogels. Depending on their source, they can be divided into natural hydrogels, semi-synthetic hydrogels, and synthetic hydrogels [30]. Hydrogels can also be classified based on ionic charges present in them such as nonionic, anionic, cationic, and ampholytic. Based on their biodegradability, they are divided into biodegradable and non-biodegradable hydrogels. Depending on the class of crosslinking agents, they can be classified into physical, biochemical, and chemical hydrogels. Physical hydrogels in response to environmental changes (pH, temperature, mixing of two components, ionic concentration) can undergo a transition from liquid to the gel phase. Chemical hydrogels act through covalent bonding and exhibit degradation resistance and mechanical integrity as compared to other materials. Biochemical hydrogels involve biological substances like amino acids, enzymes, etc. in the gelation process [31]. Fig. 2 represents the classification of hydrogels based on their method of preparation, physical properties, source, ionic charges, biodegradability, and crosslinking.

Hydrogel preparation techniques are generally based on physical crosslinking and chemical crosslinking such as heating or cooling of a polymer, ionic interaction, complex coacervation, H-bonding, maturation, freeze-thawing, chemical grafting, radiation grafting, etc. as discussed below. Different crosslinked networks of natural biopolymers including chitosan, carboxymethylcellulose (CMC), carrageenan, hyaluronan, alginate, and synthetic polymers including polylactic acid (PLA), polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinyl pyrrolidone (PVP), polymethacrylate (PMA), etc. Have been employed in the fabrication of hydrogels [32]. Such types of modifications can enhance the viscoelasticity and mechanical properties of hydrogels for their applications in pharmaceutical and biomedical areas. Different types of physically and chemically crosslinked hydrogels with their applications are enlisted in Table 1.

The physical crosslinking method has gained a lot of interest due to its ease of production and involvement of biopolymers. Physical crosslinkers such as chitosan, carrageenan, hyaluronan, etc. affect the integrity of material i.e., proteins, drugs, etc. to be entrapped. Appropriate selection of type, pH, and concentration of hydrocolloid can provide crucial information for the development of a wide range of physical gel and this area is currently receiving significant attention mainly in the food sector [33]. Different methods to produce physically crosslinked hydrogels are discussed below.

Hot solutions of polymers like carrageenan or gelatin are cooled to form physically crosslinked hydrogels and this formation takes place due to the association of helices which thereby results in helix formation and forming junction zones [34]. In a hot solution, above the melting transition temperature, carrageenan appears as a random coil that slowly transforms to solid helical rods upon cooling. In the presence of salts like Na+, K+, etc., these solid helices further agglomerate to form stable gels due to the repulsion of the sulphonic group as shown in Fig. 3. Physical hydrogels can also be obtained by an alternative method which includes simply warming polymer solution resulting in block copolymerization. Few examples of such types of hydrogels are polyethylene glycol polylactic acid hydrogel [33] and polyethylene oxide polypropylene oxide hydrogel [35].

Ionic interaction involves crosslinking of ionic polymers through the addition of divalent or trivalent counterions. The underlying principle of this technique is based on the gelation of a polyelectrolyte (eg. Na⁺ alginate) solution with multivalent ions having opposite charges (eg. addition of Ca2⁺ and 2Cl^-). Few examples of hydrogels prepared from the ionic interaction method include chitosan-dextran hydrogels [33], chitosan-glycerol phosphate salt [36], and chitosan-poly lysine [37].

The complex coacervation process involves the formation of gels through the mixing of polycations with polyanions. The concept of this technique is based on an aggregation of two polymers having opposite charges to produce soluble and insoluble complexes depending on the pH and concentration of that solution. Some examples include the association of positively charged proteins with anionic hydrocolloids to form complex poly ion hydrogels [38] and coacervation of polycationic chitosan with polyanionic xanthan [39].

Hydrogels from the hydrogen bonding method can be prepared by lowering the pH of aqueous polymeric solutions containing carboxyl groups, for example, hydrogen bound carboxymethylcellulose network is formed by dispersing carboxymethylcellulose in 0.1 M hydrochloric acid solution [40]. The underlying mechanism involves the replacement of sodium with hydrogen in the solution to facilitate hydrogen bonding, thus resulting in decreased solubility of carboxymethylcellulose in water which leads to the formation of an elastic hydrogel. Other examples of hydrogels prepared from the H-bonding method include carboxymethylated chitosan (CM) hydrogels which are formed due to crosslinking of polymers in presence of an acid and polyacrylic acid-polyethylene oxide (PEO-PAA) hydrogels which are produced by lowering pH of respective solution [35]. In addition, Xanthan/Alginate mixed system involves intermolecular hydrogen bonding between xanthan and alginate to form insoluble hydrogel networks.

The formation of hydrogels via heat-induced aggregation of proteinaceous components (eg. Acacia gum) [41] leads to enhanced water holding capacity and mechanical properties of the hydrogel [42]. Three major fractions with different protein content and molecular weight were identified from Acacia gum through hydrophobic interaction chromatography such as AGP (arabinogalactan protein), GP (glycoprotein), and AG (arabinogalactan) [43]. Molecular changes accompanying the heat-induced aggregation process indicate that hydrogels can be formed with precise dimensions of structured molecules. The rate-controlling feature of this technique is that aggregation of proteinaceous compounds takes place only within molecularly dispersed environment present inside the naturally occurring gum. Maturation of gum includes the transfer of lower molecular weight proteins to yield larger concentrations of proteinaceous fraction with higher molecular weight such as arabinogalactan proteins. This technique has also been utilized on other gums i.e., Acacia kerensis and Gum ghatti for the treatment of dental caries [44].

The free thaw cycle is one of the important techniques used for the fabrication of hydrogel with physically crosslinked polymers. The underlying mechanism involves the formation of microcrystals inside the polymeric solution. Few examples of hydrogels prepared from the freeze-thawing method are xanthan hydrogels and polyvinyl alcohol hydrogels [35,45].

The chemical crosslinking process involves the grafting of polymers or linking of two polymeric chains with the use of a crosslinking agent. The phenomena of crosslinking between natural and synthetic polymers can be achieved via the reaction of polymeric functional groups i.e., carboxylic (COOH), hydroxyl (OH), and amide (NH₂) groups with cross-linking agents i.e., adipic acid dihydrazide and glutaraldehyde. Several methods are reported in the literature for the preparation of chemically crosslinked hydrogels. Among them, chemical grafting and radiation grafting method have gained a lot of interest in different biomedical and other segments. Chemically crosslinked hydrogels can also be prepared by hydrophobic interactions which include covalent crosslinking of a polar group incorporated by oxidation or hydrolysis process and IPN (crosslinking of monomer with another polymer to produce interpenetrating network) [33]. Chemical grafting and radiation grafting methods for the preparation of chemically crosslinked hydrogels are discussed below.

Crosslinked networks of several natural and synthetic polymeric hydrogels can be achieved via different crosslinking agents such as epichlorohydrin, glutaraldehyde, etc. Chemical crosslinking mainly involves the incorporation of a new crosslinking agent between polymeric chains to obtain modified cross-linked chains. For example, hydrogel formed by crosslinking of polyvinyl alcohol and corn starch using a crosslinking agent, glutaraldehyde can be utilized as an artificial skin to afford site-specific delivery of medicament. Also, carboxymethylcellulose (CMC) hydrogels prepared by crosslinking of 1,3-diamino propane with CMC chains were used for targeted drug delivery through the skin pores. Another example includes polyvinyl alcohol and xanthan-based hydrogel composites crosslinked with epichlorohydrin. Biodegradable hydrogels for site-specific delivery were prepared by crosslinking acrylic acid and carrageenan with 2-acryl-amido-2-methylpropane sulfonic acid.

[46]. Carrageenan-based hydrogels acted as promising delivery system for enzyme immobilization in different pharmaceutical and biotechnological industries [47]. Sodium hydroxide/Urea based hydrogels have been successfully fabricated using epichlorohydrin as a crosslinking agent [48,49].

Chemically crosslinked hydrogels have gained significant attention in the treatment of chronic bladder diseases [50]. For example, a doxorubicin-loaded poly(N-isopropyl acrylamide) hydrogel significantly caused significant inhibition of T24 cells (human bladder cancer cells) proliferation [51]. Similarly, epirubicin-loaded hydrogel prepared from glutaraldehyde and gelatin exhibited high entrapment efficiency and impressive inhibition of AY-27 cells and tumor load in F344 rats [52].

Grafting may be defined as the polymerization of a monomer with preformed polymer to produce polymeric chains and these chains get activated by either treatment with higher energy radiation or action of any chemical agent. This process involves the branching of functional monomers and further crosslinking with another polymer. In chemical grafting, a chemical agent is required to activate macromolecular backbones, for example, grafting of starch with acrylic acid using N-vinyl-2-pyrrolidone [53]. Chemically grafted hydrogels exhibit outstanding pH-dependent swelling behavior and can be utilized as targeted delivery of vitamins and other drugs into the small intestine.

Radiation grafting involves the formation of hydrogels by higher energy radiations including electron beam and gamma rays. For example, carboxymethylcellulose-based hydrogels were fabricated by Said et al., 2004 [54] in presence of electron beam radiation. Electron beam radiation resulted in free radical polymerization of acrylic acid with carboxymethylcellulose. In presence of radiation, grafting of a monomer with polymer (carboxymethylcellulose) generated free radicals which combine to form hydrogels. They fabricated acrylic acid-based hydrogels to remove heavy metals like cobalt, copper, lead, nickel, and in dressings for temporary skin covers [55]. Another starch-based hydrogel was fabricated employing polyvinyl alcohol grafting. The gel-like solution was prepared by dissolving starch into water and then polyvinyl alcohol solution was added slowly with continuous stirring to produce a homogeneous mixture. The solution was prepared by grafting polyvinyl alcohol with a starch molecule in the presence of radiation. In addition, fabrication of pH and temperature-sensitive hydrogels was carried out by grafting copolymerization of N-isopropyl acrylamide and chitosan [56].