Keywords

1 Introduction

Progress in modern drug delivery and in the area of polymer science has shifted the interest on polymer-based drug delivery systems to obtain spatiotemporal release of the therapeutics. The advent of effective and precise biological therapeutics has accelerated the polymer-based smart delivery systems for both pulsatile dose delivery and implantable reservoir systems. A great number of polymers of both natural and synthetic origin constitutes a vital area of biopharmaceutics in which linear or branched polymer chains have been exploited as polymeric drug carriers.

A through study of underlying mechanisms of transitional behavoiur of polymers under applied stimulus can help design the polymers with well-ordered molecular and structural to give a well-defined reaction to the external conditions. Such stimuli responsive polymers are used for formulating sensitive carriers which deliver drug(s) in response to the varying biological conditions/stimulus present in body. Polymers carrying therapeutics can themselves be bioactive which in addition to drug provide their own therapeutic benefit as well. These polymers are biodegradable and prevent carrier accumulation in the biological system. Pharmaceutical agents can also be conjugated to the polymer through biologically labile bonds to dissociate in particular bioenvironment in response to change like pH, temperature, enzyme or ionic strength etc. The polymer-drug conjugation provides advantages including prolonged circulation half-life and sustained the drug release. Active targeting can be achieved by conjugating the polymeric backbone with the ligand specific to the overexpressed cell surface receptor of the affected tissue. The targeted nanocarriers which are taken up by the receptor mediated endocytosis are taken by the endosome follow an endolysomal pathway where majority of drug molecules are degraded, curtailing the intracellular therapeutic concentration. Hence, new polymeric materials are being explored and undergo endosomal escape preventing entry into the lysosomes and promoting cytoplasmic drug delivery. Therefore, drug delivery research based on polymeric material has produced precognitive systems which allow cytoplasmic delivery of novel therapeutics. The polymeric novel drug delivery carrier systems comprise of microspheres, nanoparticles, nanospheres, nanocapsules, polymeric micelle, polymer-drug conjugates, dendrimers, transdermal patches, and polymeric gels (hydrogel). Hydrogels offer a wide platform for the delivery of various types of therapeutics (small molecules, chemotherapeutics, proteins, antigens, conjugated) owing to their amenability be designed as bioadhesive as well as environment-sensitive systems using various stimuli-sensitive polymers as illustrated in Table 1.

Table 1 Hydrogel used in drug delivery
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Pharmaceutical gels are mainly represented by hydrogel. The hydrogel is a three-dimensional crosslinked network of hydrophilic polymers. These polymers are insoluble in water but are capable of absorbing large volume of water. Hydrogels can be structured as slabs, microparticles (microgel), nanoparticles (nanogel), coatings, and films from polymers of both natural and synthetic origins. Various kinds of material (polymers) used for the fabrication of hydrogels are classified in Table 2, and the properties of ideal material required for the formulation of hydrogel are given in Table 3.

Table 2 Classification of polymers used for hydrogel fabrication
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Table 3 Desired properties of ideal hydrogel material
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1.1 Advantages of Hydrogels

  • Hydrogels are highly flexible and elastic structures which can be tuned and tailored as per need by modifying crosslinking densities.

  • Therapeutic molecules can be easily incorporated by anchoring them covalently to the polymer or entrapping into polymer matrix.

  • Hydrogels offer three-dimensional milieus for molecular-level biological interactions.

  • They possess lower tendency to adsorb biological proteins and adhere to cells because of their inert and hydrophilic surfaces. A hydrogel is a soft and rubbery substance that avoids irritation to the adjoining tissue.

  • Hydrogel undergoes sol–gel transition; the property in particular renders these systems safe for in vivo use. Hydrogels can be manipulated to respond to externally applied factors (stimuli-sensitive), such as temperature, ionic strength, solvent polarity, electric/magnetic field, light, or small biomolecules.

  • Hydrogels offer pharmacokinetic benefits for drug delivery as a depot formulation is created upon administration from which the drug is released slowly in the neighbouring tissue, thereby generating high local concentration of drug over prolonged period of time.

  • Hydrogels can be prepared with properties in between two different materials, e.g. mix a swellable polymer with a temperature- or pH-responsive polymer to obtain the networks with a defined amount of swellability in response to changes in temperature or pH.

  • Hydrogel can also be assembled to form various novel drug nanocarriers in tissue specific dimensions like microspheres, nanoparticles, nanogels, microgels, nanosponges.

  • Hydrogels are highly biocompatible due to presence of high water content and the physiochemical similarity to the native extracellular matrix, both compositionally (particularly in the case of carbohydrate-based hydrogels) and mechanically.

  • Hydrogel are highly flexible and deformable which enable them to acquire the shape of the surface to which they adhere thus rendering them suitable for drug delivery as mucoadhesive or bioadhesive dosage forms.

1.2 Demerits of Hydrogel

  • Hydrogels possess low tensile strength which may lead to their drainage from site of application and limits their use in drug-bearing applications.

  • Lack of homogeneity and low drug loading capacity for hydrophobic drugs.

  • Rapid release of drug because of high water content and large pore size of hydrogel.

  • Lack of ease of application, as many of the hydrogels do not possess sufficient deformability in order to be injectable and hence require surgical procedure for their application.

2 Classification of Hydrogel

2.1 Classification Based on Polymeric Composition

2.1.1 Homopolymeric Hydrogels

Polymer network of these hydrogels comprises of single monomer species that constitutes the basic structural units (Iizawa et al. 2007). Depending upon the properties of monomer and polymerization technique used, homoploymers may form a crosslinked skeletal.

2.1.2 Copolymeric Hydrogel

These hydrogels are made of two types of monomeric units one of which is esssentially hydrophilic in nature. The monomeric units may be organized in a block, random, or alternating configuration alongside the chain of the polymer network (Kubinova et al. 2010).

2.1.3 Multipolymer Interpenetrating Polymeric Hydrogel (IPN)

The polymeric network of these hydrogels is constituted of two independent crosslinked polymers (natural or synthetic). IPN is prepared by intimate blending of two polymers, in which one of the polymers is produced or crosslinked in the immediate presence of the other from which hydrogel matrix is prepared. The resulting hydrogel matrix is generally highly dense, stiff and strong mechanically. Further, they have manageable physical properties, and more proficient drug loading capacity as compared to conventional hydrogels (Mohamadnia et al. 2007).

2.1.4 Semi-inter Penetrating Network (Semi-IPN)

Semi-IPN consists of a combination of a crosslinked polymer and a linear polymer. Semi-IPN is formed when the linear polymer penetrates the crosslinked network of another polymer without formation of any chemical bond.

2.2 Classification Based on Polymeric Composition

Based upon the physical configuration and chemical composition, hydrogels can be classified as.

2.2.1 Amorphous Hydrogels

Hydrogel (non-crystalline) in which chains are randomly arranged.

2.2.2 Semicrystalline Hydrogels

These consist of a complex fusion of amorphous and crystalline phases along with the dense regions of ordered macromolecular arrangement.

2.2.3 Crystalline Hydrogels

The crystalline hydrogels have, chains which are arranged in proper sequence.

2.3 Classification Based on Type of Crosslinking

Based upon the nature of crosslinking connections in the polymeric network, hydrogels are classified into two following categories.

2.3.1 Physically Crosslinked Hydrogels/Reversible Hydrogels

Polymeric network is formed involving temporary interchain junctions arising from polymeric chains entanglements or physical interaction between polymer chains such as ionic interactions, hydrogen bonds, or hydrophobic interactions. Approaches employed for preparing physically crosslinked hydrogels include environmental triggers (pH, temperature, ionic strength) and a variety of physicochemical interactions (hydrophobic interactions, charge condensation, hydrogen bonding, stereocomplexation, or supramolecular chemistry) (Hoare and Kohane 2008).

2.3.2 Chemically Crosslinked Hydrogels/Permanent Hydrogel

These hydrogels are designed through formation of permanent junctions in the polymer network. Chemical crosslinking can be achieved by following methods: using crosslinkers (aldehydes, addition reactions, condensation reaction), grafting, or using radiation.

2.4 Classification According to Network Electrical Charge

Depending on the nature of charge present on the crosslinking chains, hydrogels are classified into four types (Mocanu et al. 2012, Deo et al. 2010 and Percec et al. 2002):

  1. 2.4.1

    Anionic hydrogels (e.g. carboxymethylpullulan hydrogels, alginate);

  2. 2.4.2

    Cationic hydrogels (e.g. N-isopropylacrylamide (NIPAM) and (3-acrylamidopropyl) trimethylammonium chloride (AAPTAC));

  3. 2.4.3

    Neutral hydrogels (miscible composites from water-insoluble polymers like poly(2,4,4-trimethylhexamethylene terephthalamide);

  4. 2.4.4

    Ampholytic hydrogels (e.g. acrylamide-based ampholytic hydrogels).

2.5 Classification on the Basis of Stimuli

These hydrogels are responsive to physical or chemical stimuli and releases drug as a result of the abrupt change in the physical nature of the network in response to the physical or chemical stimuli. Based on this property, hydrogels are classified as follows.

2.5.1 Physically Responsive Hydrogels

The polymeric network of these hydrogels consists if such polymers which undergo structural change alteration in molecular interactions by physical stimuli like temperature, electric or magnetic field.

2.5.2 Chemically Responsive Hydrogel

Drug release from these hydrogels occurs in response to the chemical stimulus like pH, change in ionic strength or presence of certain ions and chemical reagents as a result of molecular changes due to change in interaction between polymer chains and solvent.

3 Methods for Preparation of Hydrogel

3.1 Mechanism of Network Formation

The formation of hydrogel involves the creation of elastic network of polymeric chains through crosslinking. Therefore, any method which can be incorporated to generate a crosslinked polymeric network can be used to create a hydrogel (Ahmed 2015). This process of formation of crosslinked network is known as gelation and can be defined as the linking of macromolecular chains together which initially leads to progressively larger branched yet soluble polymers depending on the structure and conformation of the starting material.

Such hydrogels exhibit sol–gel transition which is most commonly employed for the formation of injectable depot preparations and ophthalmic gels. Sol is defined as the blend of polydispersed branched and soluble polymers. As the linking process proceeds, the size of the branching polymers goes on increasing with decreasing solubility resulting in the formation of gel. The linking can occur through physical (physical gelation) or chemical (chemical gelation) means. This transition of polymer from definite branched polymeric to vast network structure is referred to as as sol–gel transition or gelation. The critical point at which gel appears is known as gel point.

3.2 Physically Crosslinked Hydrogel

Physically crosslinked hydrogel can be formed through following methods.

3.2.1 Heating/Cooling a Polymer Solution

In this approach, the physically crosslinked gel is shaped upon cooling the hot solution of polymers. Upon cooling, the gel is formed as a result of helix formation, formation of junction, and association of helices (Funami et al. 2007). Example of polymer includes: carrageenan and gelatin. Above the melting transition temperature, the carrageenan is present in randomly coiled arrangement, and upon cooling, it transforms into rigid helical rods. In addition, stable aggregates are formed in the presence of positive ions (K+, Na+, etc.) due to screening of repulsive forces between sulphonic groups and increased attractive forces between negative (SO3−) and positive moieties of salt (Na+, K+, etc.). Another simple approach which is used to obtain hydrogel is known as block copolymerization. It involves warming of polymeric solutions, for example hydrogel formed of polyethylene oxide–polypropylene oxide, polyethylene glycol–polylactic acid hydrogel.

3.2.2 Ionic Interaction-/Charge Interaction-Based Hydrogel

In this approach, charge interaction between a polymer and a counter ion or between two polymers of opposite charge leads to in situ formation of polymeric network to form hydrogel (Fig. 1). For example, under physiological conditions, elastin-like polypeptides are crosslinked through electrostatic interaction between the cationic lysine groups and anionic organophosphorus groups (Lim et al. 2007).

Fig. 1
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Hydrogel formation through charge interaction

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Polysaccharide, alginate is one of the most popular examples where crosslinks are fromed through ionic linkage. Gel formation occurs incorporation of calcium ions which crosslink the mannuronic and glucuronic acid residues (Gacesa 1988). The crosslinking can be carried out at room temperature and at physiological pH, that is why alginate is widely used to encapsulate living cells and proteins in its matrix (Goosen et al. 1985).

Another approach for the formation of ionic hydrogel does not necessitate the existence of ions on the polymer chain for the creation of ionic crosslinks. It is based on the ability of the metal ion to accumulate in the polymeric cage because of its small ionic radius, for example the formation of dextran, hydrogel in the presence of potassium ions. Dextran is deficient in ionic binding sites for cations; however, the ionic radius of the potassium ion easily and perfectly occupies the cage formed by six oxygen atoms of glucose entities of three polymer chains, in this manner making a microstructure (Watanabe et al. 1993). However, this dextran/potassium gel is less suitable for drug delivery purposes because it is unstable in water.

In addition, hydrogels can likewise be produced as a result of the formation of complex of polyanions with polycations, for example complex formation between chitosan and polyanions, such as dextran sulphate or polyphosphoric acid that generates ionically crosslinked chitosan hydrogels-based nanoparticles. (Janes et al. 2001). These chitosan hydrogel nanoparticles were loaded with doxorubicin, and reportedly shown a minimum burst release and exhibited good in vitro cytotoxicity due to the released drug.

pH-based ionic interactions can also lead to the formation of hydrogel. pH change promotes the ionization of the functional groups present on the polymer chain to form gel following interaction with the counter ion. Biodegradation of these hydrogels occurs easily by the ionic functionalities present in the extracellular fluid which bind competitively to the gel resulting in the breakdown of the polymeric network. For example, (i) peptides consisting of alternating positively and negatively charged groups can self-assemble through ionic interaction to form hydrogel in situ (Chen 2005) (ii) doxorubicin hydrochloride containing ionically crosslinked hydrogel formed from blend of quaternized chitosan and glycerophosphate which is optically clear and release drug as a function of pH (Wu et al. 2006).

Moreover, charge interactions can be used to crosslink gels to create three-dimensional particulate carriers like microparticle or nanoparticle with promising drug delivery properties. For example, dextran microspheres coated with anionic and cationic polymers reveal impulsive gelation upon mingling owing to ionic complex formation between the oppositely charged microparticles network (Van Tomme et al. 2005).

3.2.3 Crosslinking by Crystallization

3.2.3.1 Crystallization in Homopolymer Systems

Crystallization process involves subjecting the aqueous solution of water-soluble polymer to a series of freeze-thaw cycle resulting in crystallization of the polymer and formation of gel. For example, polyvinyl alcohol, a water-soluble polymer, forms a gel gradually when its aqueous solution is stored at room temperature but with weaker elasticity and strength. Surprisingly, when the solution of PVA was subjected to freeze-thaw process, a gel was formed having greater strength, elasticity, and remained stable for 6 months at 37 °C (Yokoyama et al. 1986; Hassan and Peppas 2000). Mechanism for the formation of stronger gel is attributed to the formation of polymer crystals in the hydrogel network leading to more ordered arrangements of the polymeric chains and stronger anchorages. The properties of hydrogel are dependent on the molecular weight and concentration of PVA, temperature, time duration of freezing, and number of freeze-thaw cycle. This gel is ideal for encapsulation of proteins like BSA as the conformation of protein is retained during the release where the latter follows Fickian diffusion pattern.

The polymer crystals are also formed through hydrogen bonds formation does take place in the concentrated polymeric solution, and the gel gets converted into particulate form on stirring. For example, concentrated solution of dextran spontaneously formed hydrogel when stored at room temperature, and upon stirring, the solution of microspheres was obtained.

3.2.3.2 Crosslinking by Stereocomplex Formation

Polymers consisting of chiral, optically active, monomeric units can form crystallites. Similarly, on mixing the polymer/s with regions of opposite chirality, these regions can associate to form racemic crystalline domains, which are known as stereocomplexes. Thus, stereocomplex hydrogels can be produced by combining enantiomerically enriched polymers of opposite chirality. Instead, they can be formed simply from one polymeric species having regions of opposed chirality. One of the most relevant stereocomplexes is formed by semicrystalline PLLA and PDLA, the homopolymers of l-lactic acid and d-lactic acid, respectively. The strong interaction between polylactide blocks with l- and d-stereochemistry can be utilized for in situ forming hydrogels with high storage moduli (up to 14 kPa) as illustrated schematically in Fig. 2. Star diblock copolymers or multi-arm PEG-PLA dendrimers interact through stereospecific crosslinking to form hydrogel with transition temperatures extending from 10 to 70 °C. The transition temperature is governed by the polymer concentration and length of the PLA block (Hiemstra et al. 2006). These hydrogels have enormous potential to be used in drug delivery. Stereocomplex formation also occurs in mixtures of triblock copolymers, for example PLLA–PEG–PLLA and PDLA–PEG–PDLA, which can be easily transformed into particulate carriers to carry number of drug- and protein-based therapeutics. For example, Lim et al. studied and compared the release of BSA from microspheres formed by these triblock copolymers with the microspheres formulated with single enantiomeric triblock copolymer and with PLLA microspheres (Lim and Park 2000). Natural polymers can also be crosslinked through stereocomplex formation by grafting of enantiomers on their backbone, for example grafting of d- and l-lactic acid oligomers on the dextran backbone (Hennink et al. 2004; Bos et al. 2004). Hydrogel is formed by spontaneous gelation in water without the need of any harsh condition or organic solvent or chemical crosslinkers or the hydrophobic domains thus they are suitable for the delivery of proteins. They have excellent biocompatibility and biodegradability.

Fig. 2
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Hydrogel formation through stereocomplex formation

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Hydrogels based on stereocomplex crosslinking, however suffer from demerit of limited range of polymers available which are capable of forming strong hydrogel. A small change in the composition or stoichiometry during synthesis can disrupt or weaken the stereochemical interaction. The stereocomplex hydrogels are degraded in biological conditions due to the existence of hydrolysable oligomeric lactide side chains and are used for drug delivery applications. They are also degraded in body by means of the degradable structure anchored on the polymer base or by tailoring polymeric backone with degrading groups. For example, hydrogel can be made degradable by involving grafts and linking biosusceptible groups between the polymer chains.

However, many of the seterocomplex hydogels do not contribute as a good candidate for controlled release formulation because the rate of hydrolysis is faster than that required to provide adequate gel strength and to assure drug retention over several weeks or months. Physiologically stable stereocomplex hydrogels capable of releasing drug for several weeks or months are still to be designed, devised and developed.

3.2.4 H-Bonding-Based Hydrogels

Hydrogen bonding-based physically crosslinked gel structure is formed by interaction between polymeric chains consisting of active oxygen and a chain consisting of hydrogen bonding atoms like H, N, or F. These hydrogels are formulated as injectable hydrogels based on sol–gel viscoelastic transition. Such individual polymers remain in solution form which upon blending undergo viscoelastic changes (rheological synergism) due to hydrogen bonding and form the gel. Upon subjecting to shear during injection, hydrogen bonds are cleaved, thereby allowing ease of administration; for example, polyacrylic acid (PAA) and polymethacrylic acid (PMA) make complexes with polyethylene glycol (PEG) as a result of hydrogen bonding interaction between oxygen of PEG and hydrogen from carboxylic group of PAA and PMA (Eagland et al. 1994). The polymeric gel from these polymers can also be prepared by dissolving in ethanol. This gel upon injecting into body diffuses ethanol and converts into gel which degrades gradually as the complex dissociates. Other examples of physically interconnected gel-like structures which are injectable too include combinations of natural polymers such as gelatin-agar (Liu et al. 2005), starch-carboxymethyl cellulose (Bajpai and Shrivastava 2005), and hyaluronic acid-methylcellulose (Gupta et al. 2006).

These hydrogels are formed only upon the protonation of carboxylic acid groups and exhibit pH-dependent swelling behaviour. However, on in vivo administration these hydrogen-bonded networks get diluted and disperse owing to inflow of water, hence constraining their usage to comparatively short-acting drug release systems unless additional crosslinking agent is also used.

Carboxylic group containing polymers can form hydrogel on lowering of pH. For example, sodium CMC forms a hydrogen-bonded hydrogel when dispersed in 0.1 M HCl solution (Takigami et al. 2007). The Na+ ion in CMC is replaced by the hydrogen ion present in the acid solution which results in the hydrogen bond formation followed by a decrease in the solubility of CMC and formation of hydrogel. Based on the similar mechanism, polyacrylic acid and polyethylene oxide (PEO-PAAc) also form a hydrogen-bonded hydrogel as the pH of the aqueous solution decreases (Hoffman 2002). Polymeric blend of xanthan and alginate forms an insoluble hydrogel network due to formation of strong intermolecular bonds.

3.2.5 Supramolecular Complex-Based Hydrogel

Supramolecular hydrogels represent a solid three-dimensional structure shaped involving non-covalent bonds like hydrogen bond, hydrophobic interaction, and cation–π and π–π interactions. While chemical crosslinkers are responsible for stabilizing the hydrogel network of the chemical gels, the non-covalent interactions in supramolecular three-dimensional structure provide strength and stability through the formation of macromolecular polymer and three dimensional gel network.

Supramolecular hydrogels are produced from hydrophilic molecules. Stimuli-responsive supramolecular hydrogel can be made by incorporating some reversible bonds. Furthermore, such reversible supramolecular hydrogels also show self-healing properties and have enormous potential to contribute in drug delivery application.

The most widely used supramolecular complexes include the inclusion complexes formed by the interaction of cyclodextrin and poly(alkylene oxide) polymers like PEO and PPO (Hoare and Kohane 2008). These are capable of forming reversible hydrogels which are easily injectable and therefore utilized to prepare controlled release injectable formulations. Combination of complexation with hydrophobic interaction has resulted in a stronger, denser, and/or more stable hydrogel network. For example, a self assembled supramolecular structure comprising of cyclodextrin and a biodegradable poly(ethylene oxide)–poly[(R)-3-hydroxybutyrate]–poly(ethylene oxide) (PEO–PHB–PEO) triblock copolymer was reported by many researchers. The collaborative outcome of complexation of PEO segments with a-cyclodextrin and the hydrophobic interaction between PHB blocks give rise to the development of the supramolecular hydrogel with a robust macromolecular network (Saboktakin and Tabatabaei 2015). Table 4 summarizes various types of supramolecular hydrogel and their compositions.

Table 4 Types and properties of supramolecular hydrogels for drug delivery
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3.3 Covalently/Chemically Crosslinked Hydrogels

Chemical crosslinking involves the use of a crosslinking agent to link two polymer chains or grafting of monomers on the backbone of the polymers. The functional groups present on the natural or synthetic polymers can react with the crosslinkers (such as glutaraldehyde, adipic acid dihydrazide) resulting in the crosslinking of chains and formation of hydrogel.

There are a number of approaches stated in the literature to form permanent chemical hydrogels. These methods are as illustrated in Fig. 3 and exemplified using chitosan. The major chemical methods employed are use of crosslinkers, grafting and radiation in solid and/or aqueous state. Other chemical crosslinking methods such as IPN (polymerize a monomer contained by additional solid polymer to form interpenetrating network structure) and hydrophobic interactions (including a polar hydrophilic group by hydrolysis or oxidation followed by covalent crosslinking) are also employed to achieve chemically crosslinked permanent hydrogels.

Fig. 3
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Various crosslinking groups and structures in covalently crosslinked chitosan hydrogels

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3.3.1 Crosslinking by Radical Polymerization

Low molecular weight monomers (vinyl and acrylic acid) can be crosslinked in the presence of crosslinking agents. It proceeds through three processes, viz. initiation, propagation, and termination. Initiation of the reaction generates a free radical active site, which attaches monomers in a chain-like manner. Wichterle and Lim (1960) first described hydrogel based on poly(2-hydroxyethyl methacrylate) (pHEMA) polymer, and it is one of the commonly studied hydrogel system. This hydrogel is synthesized by polymerization of hydroxyethyl methacrylate (HEMA) in the presence of crosslinking agent like ethylene glycol dimethacrylate. This approach is used to synthesize pH- or a temperature-sensitive hydrogel by integrating methacrylic acid or N-isopropylacrylamide, respectively, in the vicinity of suitable crosslinking agents. For example, PVA has been crosslinked chemically with monomer (methacrylic acid) in aqueous medium using ethylene glycol dimethacrylate (EGDMA) as crosslinking agent and benzoyl peroxide as a reaction initiator to produce pH-sensitive hydrogel which is a promising delivery system for colonic delivery of 5-fluorouracil in colorectal cancer (Minhas et al. 2013). Various water soluble polymers of synthetic, semi-synthetic, and natural origin have been used for the design of hydrogels using this route. These water-soluble polymers after being derivitized with polymerizable groups can be crosslinked into hydrogels by free radical polymerization, for example dextran, albumin, (hydroxyethyl) starch, poly-aspartamide, poly(vinyl alcohol), and hyaluronic acid. Among these polymers, dextran is most widely exploited for hydrogel preparation and explored for the delivery of drugs, proteins, and imaging agents (Mehvar 2000). In addition, dextran-based hydrogels are under research as a colon delivery system due to the existence of dextranase in the colon. Polymerizable dextran is prepared by reacting aqueous solution of dextran with glyce dylacrylate to produce acryl dextran. Acryl dextran forms a hydrogel following free radical polymerization in the presence of N,N,N′N′-tetramethylene-diamine and ammonium peroxydisulphate as an initiator. Polyacryldextran hydrogel-based microspheres are capable of immobilizing enzyme efficiently with full retention of their activity.

3.3.2 Crosslinking by Complementary Groups Chemical Reaction

Hydrophilic groups, namely NH2, COOH and OH present on the hydrophilic polymers may be used for the hydrogel development. Covalent linkages among polymer chains occurs through the reactions, for example an amine-carboxylic acid or an isocyanate-OH/NH2 reaction or Schiff base formation, which may be used to recognize covalent linkages between polymer chains.

3.3.3 Crosslinking with Aldehydes

–OH groups carrying hydrophilic polymers, e.g. polyvinyl alcohol. may be crosslinked through glutaraldehyde (Zu et al. 2012). Conditions are applied (like low pH, methanol added as a quencher, high temperature) to establish crosslinking are well defined and required to be maintained carefully. However, polymer bearing amine functional group can be crosslinked even under mild conditions through the formation of intermediate Schiff base. This approach is used to form protein -based hydrogels like, gelatin and albumin and the amine containing polysaccharides.

3.3.4 By Addition Reactions

Water soluble polymer can be crosslinked to form hydrogels using bis or higher functional crosslinking agents such as divinylsulfone and 1,6-hexanedibromide through an addition reaction. The properties of hydrogel network can be simply customized to attain the desired characters by changing the concentration of crosslinking agent and the dissolved polymer. In this approach, the crosslinking reactions are performed in organic solvent since water may react with the crosslinking molecules if used. This increases the cost of synthesis and also the toxicity issues thereby, reducing the safety margin for in vivo use. In addition, the crosslinking agents are highly toxic which require the complete removal of unreacted reagent. The drug is loaded after the hydrogel preparation and reagent extraction which results in first-order drug release profile along with the narrow duration of the release and therefore renders such hydrogels unsuitable specifically for sustained and controlled release formulation.

3.3.5 By Condensation Reactions

Condensation reactions among hydroxyl (–OH) groups or amine (–NH2) with carboxyl group (–COOH) result in the formation of polyesters and polyamides, respectively. These reactions are used for the synthesis of hydrogel from water-soluble polymers. One of the most efficient and widely used crosslinking agents to crosslink water-soluble polymers with amide bonds is N,N-(3-imethylaminopropyl)-N-ethyl carbodiimide (EDC). This reaction involves the addition of N-hydroxysuccinimide (NHS) to suppress the side reactions and increase the density and yield of hydrogel (Kuijpers et al. 2000).

These hydrogels have potentials to deliver active pharmaceutical agent as well as protein-based therapeutics over a prolonged period of time. For example, hydrogel loaded with lysozyme could release the enzyme for 2 days both in vitro and in vivo. The loading capacity of the these hydrogels can be increased by incorporating negatively charged agent; for example, addition of negatively charged polysaccharide chondroitin sulphate augmented the loading capability of protein in hydrogel besides retarding the release of the protein from hydrogel due to electrostatic interactions between the cationic protein and anionic polysaccharide.

Another method known as Passerini and Ugi condensation reaction is also used to prepare polysaccharides-based hydrogels (de Nooy et al. 2000). Passerini condensation employs a reaction between carboxylic acid and an aldehyde or ketone with an isocyanide to yield an α-(acryloxy). These hydrogels are degradable at ambient temperature and at pH 9.5 because of the existence of ester bond in the crosslinks. Ugi condensation is extension of Passerini approach, in which amine is added to the above reaction mixture to finally yield α-(acylamino) amide. These are more stable than Passerinin hydrogel under similar conditions due to amide bond in crosslinks. The advantage of these methods is that the reaction can be supported out at room temperature and in water at slightly acidic pH.

3.4 Crosslinking by High Energy Irradiation

Unsaturated substances can be polymerized by employing high energy radiations like gamma and electron beams (Amin 2012). Hydrophilic polymers which are derivatized with vinyl group can be transformed into hydrogels by means of high energy radiation. Alternatively, radiation-induced polymerization can also be used to synthesize hydrogel from a fusion of a monofunctional acrylate (e.g. acryloyl-l-proline methyl ester) and an appropriate crosslinker (Caliceti et al. 2001).

High energy radiation can also induce formation of hydrogel from water-soluble polymer through free radical formation which do not require the presence of vinyl groups. Free radicals are formed from the polymeric chain (e.g. haemolytic fission of C–H bond) when the aqueous polymeric solution is irradiated. Additionally, hydroxyl radicals are also generated by radiolysis of water molecules which can attack polymer chains resulting in the formation of macroradicals (Peppas and Mikos 1986). The macroradicals react with the polymeric chain functionality through covalent bond formation resulting in crosslinked structure. Radiation is usually accomplished in an inert (nitrogen, argon) atmosphere to avoid the generated macroradicals to react with oxygen. Well-acknowledged examples of polymers which can be crosslinked with high energy irradiation are poly(vinyl alcohol), poly(ethylene glycol), and poly(acrylic acid).

The characteristics of the gels, particularly swelling and permeability properties, are reliant on the amount of the polymer used and dose of radiation employed: In general, the crosslinking density rises with the increase in polymer concentration and amount of radiation dose. The major benefit of preparing hydrogel by means of radiation-induced crosslinking is that this synthesis can be used in presence of water under mild conditions (room temperature and physiological pH). In addition, the use of toxic crosslinking agents is not required. Nevertheless, the loading of biologically active compound is to be done after the formation of hydrogel to avoid radiation-induced damage to the pharmaceutically active substance and/or possible interaction between the radical and the therapeutic moiety. The gel formed from PEG and PVA are non-biodegradable due to presence of C–C bonds in the crosslinks.

4 Polymerization Techniques in Hydrogel Synthesis

Hydrogels can be prepared from monomers or polymers of synthetic or natural polymers by using techniques which are capable of crosslinking these units through polymerization. The various synthesis polymerization techniques reported for the synthesis biomedical hydrogels are described in Table 5 (Ahmed 2015; Sahu et al. 2012).

Table 5 Various polymerization techniques employed in hydrogel formation
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5 Characterization of Hydrogel

Mostly, hydrogels are characterized for their various parameters such as morphological characterization, crystalline/thermal behaviour, morphological integrity, rheological, swelling, mechanical and biochemical properties, and in vitro release behaviour. The important features of hydrogels are summarized in Table 6 (Sahu et al. 2012; Chauhan et al. 2012; Rowley et al. 1999; Khare and Peppas 1995).

Table 6 Characterization parameters of hydrogel
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6 Smart Hydrogels

Stimuli-responsive hydrogels are of great potential with a number of applications. Some environmental variations like increased temperature and low pH are found in the body in diseased conditions, and due to this reason, either temperature-responsive and/or pH-responsive hydrogels can be used for site-specific controlled drug delivery. Hydrogels can also respond to specific molecules like antigen and glucose thus find applications in triggered drug delivery and as biosensors (Leda 2015). Apart from temperature and pH, hydrogels may also respond to light, pressure, and electrical variation, thereby giving rise to light-sensitive, pressure-responsive, and electro-sensitive hydrogels, respectively. The disadvantage associated with these stimuli-responsive hydrogels is that they respond very slowly, and to overcome this drawback, nowadays thinner and smaller hydrogels are formulated. Different stimuli-responsive hydrogels with their drug delivery applications are discussed as follows.

6.1 Temperature-Sensitive Hydrogel

Temperature-sensitive hydrogels are most likely and the most frequently studied group of stimuli-responsive hydrogel networks in drug delivery research (Qiu and Park 2012). A number of polymers show temperature-responsive phase transition behaviour. The assemblies of some of those polymers are shown in Fig. 4. The presence of hydrophobic moieties like alkyl group is the most common characteristic of temperature-sensitive polymers. The lower critical solution temperature (LCST) represents that critical temperature below which the all the components of a mixture are miscible at every compositions. LCST is an important factor while selecting polymers for temperature-dependent hydrogels. Generally, polymers with LCST ranging from 28 to 32 °C are considered as good candidate to formulate temperature-sensitive drug delivery systems. Water-soluble polymers shows a proportional relation between solubility and temperature; i.e. as the temperature of the solvent is increased, the solubility of hydrophilic polymers also increases. Conversely, polymers possessing LCST follow inverse relation between temperature and aqueous solubility. Hydrogels comprising of such polymers undergo shrinkage as the temperature rises above LCST. The polymers chains of LCST polymers are linked by temperately hydrophobic groups or contain a mixture of hydrophilic and hydrophobic segments. If the chains are linked with severely hydrophobic groups, then the polymer will lose water solubility. As the temperature is lowered, the aqueous solubility of polymer increases because hydrogen bonding between hydrophilic segments and water molecules dominates the hydrophobic interaction. But, as the temperature increases the hydrophobic interactions among hydrophobic segments become stronger, the overall net effect leads to shrinkage of polymer to form hydrogel through strong hydrophobic interactions between segments of the chain. In general, increase in the hydrophobic constituents of the polymer chain leads to lowering of LCST (Schild 1992).

Fig. 4
figure 4

Structures of some temperature-sensitive polymers

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Different types of block copolymers made of poly (ethylene oxide) (PEO) and poly(propylene oxide) (PPO) also display an opposite temperature-sensitive property. The LCST of these polymers lies close to the physiological temperature, and hence, they are widely employed for the formulation of sol–gel-conversion-based controlled drug delivery systems.

Other temperature-sensitive polymers include poly (N-isopropylacrylamide) (PNIPAM) which is perhaps the most broadly used temperature-responsive polymer. Another example of such polymer which is widely employed as gel-sol system in vivo includes poly(N,N-diethylacrylamide (PDEAM) because of its lower critical solution temperature (LCST) in the range of 25–32 °C, which is close to the body temperature. The LCST of the polymers can be modified by adding other monomers; for example, copolymers of NIPAAm can be prepared using additional monomers, e.g. butylmethacrylate (BMA), to adjust the LCST (Cai and Suo 2011).

6.1.1 Properties of Temperature-Sensitive Hydrogels

Temperature-sensitive hydrogels can experience sol–gel phase transitions, alternative to the typical swelling–shrinking transitions if the polymer chains in hydrogels are non-covalently crosslinked. These thermally reversible gels with inverse temperature dependence are sol at elevated temperatures. Polymers that express this kind of behaviour are block copolymers of PEO and PPO.

Alternatively, the temperature-responsive hydrogels can also be prepared by using such crosslinking agents that possess temperature sensitivity.

Water soluble artificial polymer and a distinct protein-folding motif, the coiled coil were used to form a hybrid hydrogel system (Wang et al. 1999). The hydrogel experienced temperature-induced folding owing to the cooperative conformational shift. Incorporating temperature sensitivity through temperature-sensitive crosslinking agents provides a innovative platform in assembling temperature-sensitive hydrogels-based drug delivery systems.

6.1.2 Negatively Thermosensitive Drug Release Systems

Negatively thermo-responsive hydrogels are those polymers whose volume will decrease tends to increase in the temperature. Negatively responsive hydrogels can liberate encapsulated substances while shrinking with an increase of the temperature.

The examples of such hydrogels include crosslinked P(NIPAAm–co-BMA) hydrogels (Okuyama et al. 1993) and interpenetrating polymer networks (IPNs) of P(NIPAAm) and poly(tetra methylene ether glycol) (PTMEG). The mechanical strength of the NIPAAm gel can be increased by integrating hydrophobic comonomer BMA (Zhang et al. 2009). These hydrogel matrices are used to generate on–off drug release profile with varying temperature conditions; for example, the topically used indomethacin loaded hydrogel showed drug release (on) at low temperature while off at higher temperature. A dense and relatively impermeable layer of gel (designated as skin type barrier) was formed due to sudden temperature change resulting from faster collapse of the surface as compared to the interior part of the gel. This external shrinking was regulated by the length of the methacrylate alkyl side-chain, i.e. the hydrophobicity of the comonomer (Yoshida et al. 1991). The results, moreover, proposed that the drug in the polymeric matrices diffused from the inside to the surface during the off state even when no drug release was observed.

Temperature-sensitive hydrogels can also be positioned within a firm capsule bearing holes or apertures. The on–off release is accomplished by the flexible bulk variation of temperature-sensitive hydrogels (Dinarvand and Emanuele 1995; Gutowska et al. 1997). Such a device is named as a squeezing hydrogel as the drug release is affected by the dimensions and bulk volume of the hydrogel.

Temperature sensitive hydrogels can be strengthened by inserting in them a classified rigid matrix or by grafting them to the surface of rigid membranes. A composite membrane was prepared by dispersing PNIPAAm hydrogel microparticles into a crosslinked gelatin matrix (Chun and Kim 1996). The release of a model drug, 4-acetamidophen, was studied and was found to be dependent on the temperature which determined the swelling status of the PNIPAAm hydrogel microparticles in the microchannels of the membrane. A similar approach was used to develop a reservoir-type microcapsule drug delivery system by encapsulating the drug core with ethylcellulose containing nano-sized PNIPAAm hydrogel particles (Ichikawa and Fukumori 2000). For making stable thermally controlled on–off devices, PNIPAAm hydrogel can be grafted onto the entire surface of a rigid porous polymer membrane.

6.1.3 Positive Thermosensitive Drug Release Systems

Hydrogels formed by IPNs display positive thermosensitive effect which means that they swell at high temperature and shrink on lowering the temperature, for example IPNs of poly (acrylic acid) and polyacrylamide (PAAm) or P(AAm–co-BMA). The swelling behaviour of these hydrogels was reversible depending on the temperature which also resulted in concurrent reversible release of the drug like ketoprofen from that formulated monolithic system.

6.1.4 Thermo-Reversible Gels

Pluronics® and Tetronics® are the most popular form of thermo-reversible gels. Thermo-reversible hydrogels are not ideal for parenteral application since they are non-biodegradable. However, they can be converted to biodegradable form by replacing the PPO segment of PEO–PPO–PEO block copolymers by a biodegradable poly (l-lactic acid) segment (Jeong et al. 1999; Jeong et al. 2000).

The molecular architecture does not remain restricted to the A–B–A-type block copolymer, but can be extended into three-dimensional, hyper-branched structures, such as a star-shaped assembly. Gels with varying LCST values can be achieved by using appropriate combinations of molecular weight and polymer architecture. The hydrogel is formed by introducing the polymer loaded with drug (hydrophilic or hydrophobic) in aqueous solution, and the resulting hydrogel exhibits generally a first-order and S-shaped drug release, respectively.

6.2 pH-Sensitive Hydrogels

pH-sensitive polymers usually comprised of polyelectrolytes that either release or accept protons in response to change in the surrounding pH. They contain a large number of ionizable groups that undergo pH-dependent ionization. Poly (N,N′-diethylaminoethyl methacrylate) (PDEAEM) gets ionized at low pH, while poly (acrylic acid) (PAA) gets ionized at high pH. While the cationic polyelectrolytes, such as PDEAEM, display rapid dissolution and higher swelling when crosslinked at low pH owing to ionization of the polyanions, such as PAA, and undergo dissolution at high pH.

6.2.1 Properties of pH-Sensitive Hydrogels

Hydrogels prepared from crosslinked poly-electrolytes demonstrate vast differences in swelling properties in response to the changing pH of the environment. The pendant acidic or basic groups arranged on the polyelectrolytes undergo ionization parallel to acidic or basic groups of monoacids or monobases. However, the electrostatic forces applied by the neighbouring ionized groups render the ionization of polyelectrolytes difficult.

Polyelectrolyte polymers can show a swelling behaviour far better than the nonelectrolytic polymers because of the existence of ionizable groups arranged along polymer length. The reason behind the swelling of the polyelectrolyte based hydrogels is the presence of electrostatic repulsion between the charges that lie on the polymer chain. The extent of swelling depends on the magnitude of electrostatic repulsion under any condition like pH, ionic strength, and type of counterions present. The pH responsiveness and swelling can be further modified by adding neutral comonomers of different types. These monomers provide varying hydrophobic character to the polymer chain which results in different pH-responsive behaviour. Examples of such monomers include maleic anhydride, 2-hydroxyethyl methacrylate, and methyl methacrylate.

6.2.2 Applications of pH-Sensitive Hydrogels

6.2.2.1 Controlled Drug Delivery

pH-sensitive hydrogels are often used for developing controlled release formulations for oral administration because of varying pH conditions present in the gastrointestinal tract. The varying GIT pH range starting from neutral pH of mouth to acidic pH of the stomach to the alkaline pH of the intestine is exploited to elicit pH-dependent behaviour of polyelectrolyte hydrogels. The polycationic-based hydrogels show minimal swelling at neutral pH, and hence, it is used for the delivery of offensive drugs in the neutral pH of mouth. Semi-IPNs made from polycationic hydrogels are employed for the delivery of drug in the stomach.

For example, semi-IPN of crosslinked chitosan and PEO presented more swelling when exposed to the acidic conditions which is ideal for localized delivery of antibiotics, such as amoxicillin and metronidazole, in the stomach for the management of Helicobacter pylori infection.

Furthermore, hydrogels which are functional at neutral pH are formulated using PAA or PMA. These hydrogels are used for delivering drug at neutral pH (Khare and Peppas 1993). Hydrogels can also be used for preparing enzyme sensitive drug delivery systems by incorporating crosslinkers through such bonds which can be cleaved by biological enzymes. These hydrogels are capable of providing localized or targeted drug delivery owing to the cleavage of bond in the environment (or tissue) where the enzyme responsible for bond cleavage is present. For example, for colon-specific drug delivery, drug loaded hydrogel is prepared by crosslinking polyanion like PAA by using azoaromatic crosslinkers. The drug is released in colon after the cleavage of azoaromatic bond by the azoreductase present in the microbial flora of the intestine (Fig. 5). These hydrogels show slower rate of swelling, and hence, drug release is also slow and minimal.

Fig. 5
figure 5

Swelling of an antigen–antibody-based semi-IPN hydrogel with the amount of free antigen

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Depending upon the need of the therapy and site of drug release, the polymer composition and the type of crosslinker can be changed; for example, terpolymer-based hydrogels comprising of NIPAAm, acrylic acid, and 2-hydroxyethyl methacrylate were synthesized for the pulsatile delivery of streptokinase and heparin based on the progressive pH and temperature variations (Vakkalanka et al. 1996; Brazel and Peppas 1996).

6.3 Specific Ion-Sensitive Hydrogels

Salt concentration can affect the swelling behaviour of a few hydrogels. A nonionic poly (N-isopropylacrylamide) hydrogel showed a strident volume phase transition at a acute concentration of sodium chloride in aqueous solution. Below the LCST, the amount of water present in the hydrogel is dependent on the concentration of sodium chloride. The gel collapses suddenly at a critical concentration of sodium chloride which too is found to be dependent on the temperature. Rise in temperatures results into a equivalent drop in the critical concentration of sodium chloride.

A number of salts are tested, but none of them show such behaviour outside the salting-out region. However, sodium ions form the common part of all the salt taken under investigation, and hence, it is concluded that chloride ions perform a significant role in this phase transition. Although the mechanism of ion sensitivity is unknown, the LCST of the system was found to decrease on increasing the concentration of the chloride ions.

This exclusive phase transition behaviour could be applied for creating chloride ion-sensitive biosensors. The additional salts investigated for phase transition behaviour did not induce network collapse in the studied concentration range, and alternative theory known as ion pair and multiplet (ionomer effect) theory was suggested to clarify these interesting experimental outcomes.

6.4 Specific Antigen-Responsive Hydrogels

For certain biomedical applications, it is essentially required being beneficial to cultivate a material or device, which generates response to particular proteins present in the biological system. One such device based on sol–gel phase-reversible hydrogels was prepared using antigen–antibody interactions which rely on the similar concept as used for glucose-sensitive phase-reversible hydrogels. A semi-interpenetrating network hydrogel was prepared by fixing an antigen and a corresponding antibody to dissimilar polymer grids. The spontaneous crosslinking interaction between antigen and antibody gives rise to a three-dimensional hydrogel network.

Hydrogel swelling is activated in the presence of free antigens that strive with the polymer-bound antigen, resulting in a reduction in the crosslinking density (Fig. 6).

Fig. 6
figure 6

Representation of oral colon-specific drug delivery based on biodegradable and pH-sensitive hydrogels. The azoaromatic groups in the crosslinks are indicated by –N=N–

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7 Conclusion and Future Prospectives

Hydrogel-based drug delivery has emerged as a prospective drug delivery system owing to its distinctive characteristics, and a number of hydrogel-based patents are filed which are in different phase of clinical trials (Table 7). They are relatively biodegradable, elastic, flexible, soft, have minimum tendency to tissue adhesion, and possess high water content which makes them compatible to the living tissue, abolishing irritation to the tissue to which they are administered. However, the high water content of hydrogel results in poor mechanical strength which confers a major disadvantage for their use in drug delivery. Poor mechanical strength presents complexity in fabrication and administration and causes burst release with incomplete release of the active agent. To overcome the issue, hydrogel with improved mechanical strength is prepared through interpenetrating polymer network (IPN), but their synthesis requires the use of chemical crosslinkers which lead to toxicity following their degradation in body.

Table 7 Few patents available on hydrogel
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Therefore, there is a need to form hydrogels with such gelators capable of providing ease of administration and have precise gelation temperature to provide smooth injectability evading gelation in the syringe. Furthermore, strategies are needed to be developed to form covalently crosslinked hydrogel without toxic crosslinkers or with biodegradable crosslinkers which are still to be explored.

There is also a need to develop hydrogels which vary in drug release kinetics. Such hydrogels will expand the area of application based on the release profile desired or required for both drug delivery and tissue application. Hydrogels can also be modulated to follow diverse degradation profile so as to meet the kinetic issues. The stimuli-responsive hydrogel system offers an approach where the rate of drug release can be modulated on off overtime so that hydrogel can be used in conditions where varying doses of drug are required over the time (e.g. delivery of insulin). There is also a need for improvement in hydrogel for the delivery of hydrophobic drugs as well as susceptible molecules like proteins, antibodies, or nucleic acids. The method of synthesis applied for in situ crosslinking the hydrogels (thermal, physically gelling polymers, or the functional group chemistry) may affect the biological properties of entrapped drug molecules. Therefore, an effective method for pre-encasulation or complexation of these bioactive before the in situ gel formation is needed to be developed to solve this issue.

Although a number of interesting physical and chemical methods are presently known, there is certainly a need for other methods. It is expected that principles from the expanding research area of supramolecular chemistry will be applied to design novel type of hydrogels with tailored properties which can preferably be prepared in an aqueous environment. Also, protein engineering might contribute to the development of hydrogel systems with a very precise control over their microstructure and thus their properties. Finally, it can be foreseen that systems in which gel formation is induced by a specific trigger (temperature, pH, or a specific compound) will be developed precisely for application in pharmaceutical and biomedical purposes.