Classifications and Synthesis Parameters

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A Review: Tailor-Made Hydrogel Structures (Classifications and Synthesis Parameters) a

Reena Singhal & Kshitij Gupta a

b

Department of Plastic Technology, Harcourt Butler Technological Institute, Kanpur, India

b

Paint Technology, Kanpur, India Accepted author version posted online: 28 Jul 2015.

Click for updates To cite this article: Reena Singhal & Kshitij Gupta (2015): A Review: Tailor-Made Hydrogel Structures (Classifications and Synthesis Parameters), Polymer-Plastics Technology and Engineering, DOI: 10.1080/03602559.2015.1050520 To link to this article: http://dx.doi.org/10.1080/03602559.2015.1050520

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A Review: Tailor-made Hydrogel Structures (Classifications and Synthesis Parameters) Reena Singhal 1, Kshitij Gupta2 1

Department of Plastic Technology, Harcourt Butler Technological Institute, Kanpur, India, 2 Paint Technology, Kanpur, India

Address correspondence to Reena Singhal, Department of Plastic Technology, Harcourt Butler Technological Institute, Kanpur, UP 208002, India. E-mail: [email protected]

Downloaded by [Reena Singhal] at 23:46 03 August 2015

1. INTRODUCTION Hydrogels are new and promising polymeric biomaterials which have significant role in different areas of health care. Word ‘upcoming’ has been replaced.This is due to their important properties like hydrophilicity, biocompatibility and non-toxicity. They can also be made biodegradable for specific applications. In the past decade, hydrogels have gathered great deal of attention, due to wide variations available in their synthesis, and correspondingly structures. Significant progress has been made in designing and using hydrogel materials for the following applications; e. g. pharmaceutical [1, 2], biomedical [3], drug delivery system [4], agrochemicals [5, 6], food industry [7], etc. Medical and pharmaceutical applications of these hydrogels range from catheter [8], vascular grafts [9], semi-occlusive dressings [10], mammary implants [11], transdermal drug delivery systems [12,13], scaffold for tissue engineering [14] and medicated patches[15] etc. In the 21st century, hydrogel synthesis routes, and correspondingly their applications have been developed tremendously.

Current activities of biomedical device designers,

manufacturers and research physicians indicate that the hydrogels are being increasingly accepted as the biomaterials of choice, in most of the applications requiring compliance

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with soft tissue and cardiovascular tissue [16], tissue engineering [17], controlled release of drugs[18,19] and scaffolds[20] for being non-irritating to the [21] skin for transdermal applications. Novel areas of research include chemical sensors [22]; immobilization of colloidal crystals, artificial skin [23, 24] micro patterned and micro scale hydrogels [25]

The objective of this review is to first categorize hydrogels under various classes and; secondly to describe possible synthesis routes leading to tailoring of its structures suitable


for various applications in the biomedical fields. Hydrogel classification is highly extensive and they can be classified on the basis of their origin, monomer nature and number, charge present, cross-linking and preparation methods, etc. This review also outlines the structure of hydrogels, and narrates how it can be tailored by manipulating important synthesis parameters. Here hydrogel classifications are described with related references along with important methods of crosslinking in table format for easy reference to the readers.

1.1. Components Of Hydrogel Structure Classically, hydrogels can be defined as cross-linked three dimensional hydrophilic polymeric networks that can swell by imbibing large quantities of water. Swelling can range from double to more than thousand times of their weight. Water absorbing nature of hydrogels is mainly due to the presence of hydrophilic groups such as -CONH2, CONH-, -OH, -COOH, -SO3H, etc. which are present in the hydrogel network

The structural framework of hydrogels is formed from three-dimensional networks of

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randomly cross-linked polymeric chains that consist of three different phases. The first phase is a solid polymer network matrix, second phase being interstitial water or biological fluid. The solid portion of the hydrogel is a network of cross-linked polymer chains where their three-dimensional structure is usually described as a mesh, with the interstitial space filled with fluid. The meshes of the networks hold the fluid in place and also impart rubber-like elastic force that can compete with the expansion or contraction of the hydrogels, thus providing the dimensional stability to the hydrogels. For fluid


phase of the hydrogel, it fills up the interstitial pores of the network and makes the hydrogel wet and soft, which is similar to biological tissues in some respects. Regarding the ionic phase of the hydrogels, generally it is composed of ionizable groups bound onto the polymer chains and a number of mobile ions which include counter ions and co-ions due to presence of electrolytic solvent that surrounds the hydrogels.

Figure 1 shows a schematic hydrogel structure, at molecular level, and different types of water present in the hydrogel. Water is present in the hydrogel network in different forms, and water content in hydrogel is an important parameter. Water can be associated to any hydrogel structure in four ways as; (i) easily removable water present in the exterior region is free or bulk water. This can be easily separated from hydrogel under normal conditions; (ii) water present in the interstices of hydrated polymeric network that is trapped physically but not attached to hydrogel network is called interstitial water; (iii)bound water chemically solvates/hydrates the functional moieties (groups or ions) and is directly attached to polymeric chain. This water can be separated out from the hydrogel only under extreme conditions as it stays as integral unit of hydrogel structure;

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(iv)semi-bound water lies in between the two extremes of bound and free water. Water identification and characterization can be easily performed using a DSC thermo gram [26].

1.2. Generic Limitations Of Hydrogels In Biomedical Applications The applications of hydrogels as bio-medical materials are limited due to several reasons. Hydrogels are sometimes impacted by inherent disadvantages of having low mechanical


strength/ mechanical fragility; as well as delayed response time as compared to other implant materials. They offer difficulty in loading as well as handling in certain cases. Biodegradability being an advantage sometimes also poses problem as the environment of loading hydrogel is normally biogenic, thus leading to accelerated degradability. Sterilization of hydrogel is also a significant problem in biomedical systems. Cost of synthesis is relatively high sometimes as compared to other drugs of same utility. The new developments addressed to take care of above problems are also discussed later in section 3.2. 2. CLASSIFICATION Hydrogels can be classified in a number of ways on different basis such as presence of electrical charge, monomer/polymer used in synthesis and pore size. Table 1 gives a comprehensive classification of hydrogels along with all categories and subcategories with relevant references. Various important classifications of hydrogels are discussed in detail in the following section.

2.1 Classification On The Basis Of Electrical Charge Present On Polymer Chain

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Hydrogels can be categorized into three main groups on the basis of presence or absence of electrical charge located in the cross-linked chains [27]. These are neutral/non-ionic hydrogels, ionic hydrogels and ampholytic hydrogels. Figure 2 shows schematic representation of various types of ionic and non-ionic hydrogels. Neutral or non-ionic hydrogels are shown in figure 2(a) and there is no charge on their backbone or side groups. These non-ionic hydrogel swell in aqueous medium solely due to water-polymer interactions. Examples of non-ionic hydrogel include polyacrylamide (PAAm) [28],


polyhydroxyethyl methacrylate (PHEMA) [29], polyvinyl alcohol (PVA) [30], and polyethylene glycol (PEG) [31]. Ionic Hydrogels include cationic (positive charge bearing) hydrogels and anionic (negative charge bearing) hydrogels. Swelling of ionic hydrogel is governed by the pH of the aqueous medium, which determines the degree of dissociation of the ionic chains. Figure 2(b) shows cationic hydrogel which contain positive charge in their backbone. They display superior swelling in acidic media since their chain dissociation is favored at low pH values. Examples of monomers used in synthesis of cationic hydrogels include Vinyl pyridine, aminoethyl methacrylate (AEMA), Diethylaminoethyl methacrylate (DEAEMA), and dimethylaminoethylmethacrylate (DMAEMA) [32-33]. Similarly, anionic hydrogels bear negative charge in their backbone as shown in figure 2(c). These hydrogel dissociate more at higher pH, and thus, display superior swelling in neutral to basic solutions. Examples of monomers of anionic hydrogels include Acrylic acid (AA), p-Styrene sulphonic acid (SSA), Itaconic acid (IA), crotonic acid (CA), maleic acid (MA), and methacrylic acid (MAA) etc. [34]. Figure 2(d) shows ampholytic hydrogels which carry negative as well as positive charges on the same polymer chain. These hydrogel contain

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both acidic and basic groups in each structural repeating unit. These charges are balanced at iso-electric point. A slight change in pH can change the overall ionic properties of these types of hydrogels. N-isopropylacrylamide/[[3(methacryloylamino)propyl]dimethy(3-sulfopropyl)ammonium hydroxide] ( NIPAAm/MPSA) hydrogel is an example of monomer for synthesis of ampholytic hydrogels.


Hydrophobic modified hydrogel belong to a special category of hydrogel, which contain a hydrophilic backbone (can be ionic or non-ionic); with pendent hydrophobic group as shown in figure 2(e). In aqueous solution the balance between the hydrophilic and hydrophobic interaction changes with temperature. Thus, at specific temperature, hydrophobic aggregation occurs resulting in gelation [35].The examples of such hydrogels are physically crosslinked hydrophobically modified chitosan, dextran, pullan and carboxymethyl curdlan. Their important applications include self assembling and insulin loaded hydrogel nanoparticles.

Complex coacervate gel: A special classification involving interaction between oppositely charged polymeric chains is known as complex coacervate gel which is shown in figure 3. In these hydrogels, two polymers of opposite charges (positively and negatively charged) are mixed together [3, 36]. They stick together due to attraction between opposite charges and form soluble and insoluble complexes depending on the concentration and pH of the respective solutions [37]. For example, cationic Chitosan and anionic Xanthan form complex coacervate. Similarly, Proteins are positively charged

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below their isoelectric point and form complex coacervate with anionic hydrocolloids [38]. They are being used in thermo reversible drug delivery [39].

2.2. Classification On The Basis Of Monomer/Polymer Used In Synthesis As hydogels are synthesized using wide variety of monomers for different applications, it is necessary to classify them on various basis. A very important classification of hydogels is shown in Table 1, which is based on the origin of monomers/polymers used


in synthesis [40]. These are natural, synthetic or semi-synthetic, also known as hybrid type hydrogel.

2.2.1. Natural Hydrogels Hydrogels of natural origin [41] are synthesized using natural polymers such as proteins like collagen[42], gelatin[43], fibrin[44], etc. and polysaccharides like hyaluronic acid [45], chitosan [46], dextran [47], alginate[48], etc. Natural hydrogels are biodegradable and support cellular activity [49]. They also offer advantages like high biocompatibility [50], intrinsic cellular interactions [51], and biodegradability [52], and low toxicity byproducts [53]. But they can suffer from some inherent disadvantages of insufficient mechanical strength, immune inflammatory responses [3, 54]. Further disadvantages associated with these natural hydrogels include batch to batch variations [55]; also animal derived materials may pass on viruses or other pathogens [56]. Their applications include scaffoldings for tissue engineering, cartilage regeneration, wound dressing material [57], and controlled drug release [58].

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2.2.2. Synthetic Hydrogels Synthetic hydrogels are prepared by chemical polymerization of man-made monomers. They can be homopolymeric [59], copolymeric [60,61], multipolymeric[ 62-64], polymer blends or inter penetrating polymeric network[IPN] hydrogels [65-66]. These are synthesized by utilizing bulk polymerization [67], solution polymerization [68] or inverse suspension polymerization technique [69]. Hydrogels based on PEG-PLA-PEG [70] and Poly (vinyl alcohol) [71-72] are examples of synthetic hydrogels. Main advantages of


these hydrogels are that they offer precise control during mass production, and can be tailored to give a wide range of properties [73]. Due to low immunogenicity [74], synthetic hydrogels minimize the risk of biological pathogens or contaminants. Disadvantages include low biodegradability and possibility of inclusion of toxic substances from crosslinker and synthesis environment [3, 75].

2.2.3. Hybrid Hydrogels The limitations associated with natural and synthetic hydrogels (as discussed in earlier sections) initiated the requirement to develop such semi-synthetic or hybrid hydrogels that have specifically outlined chemical, physical and biological properties. This was achieved by combining natural polymers with synthetic polymers [76-77]. Figure 4 illustrates few common approaches used to prepare hybrid hydrogels. The first two approaches in the figure 4(a) and figure 4(b) show graft polymers (natural polymer grafted on synthetic polymer and synthetic polymer grafted on natural polymer respectively), which are photopolymerized to form crosslinked hydrogel network. Another approach shown in the figure 4(c) involves crosslinking of a mixture of natural

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and synthetic polymer. These hybrid hydrogels offer the advantage of multiple functionality inclusion in one hydrogel system like adjustable physical properties, crosslinking ability, bio adhesive and proteolytic degradation properties. Wang et. al. [78] reported hybrid hydrogel based on 2-Hydroxypropyl methacrylamide (HPMA) copolymer backbone crosslinked non-covalently by coiled protein.

2.3. Classification On The Basis Of Pore Size Between Polymer Networks Downloaded by [Reena Singhal] at 23:46 03 August 2015

Depending upon the pore size between polymer networks, the network structure of hydrogel can be classified as nonporous, microporous, or superporous [79]. Pores affect the swelling mechanism of hydrogel. In nonporous hydrogel diffusion is the only mechanism for transport of water of swelling in medium. In case of microporous very small pores of the order of few microns to few hundred microns are present in hydrogel which can be studied by using SEM or other microscopy techniques. In microporous hydrogels the swelling mechanism is a combination of diffusion through polymeric substrate as well as leaching through pores; leading to higher diffusion rates. Superporous hydrogels are specially synthesized, and contain very high volume of large sized pores; which are advantageous in obtaining exceptionally high swelling rates in a very short period of time. These types of hydrogels are commercially very promising in varied applications like superabsorbent, responsive biomedical devices, agriculture, etc. Pore size of these is crucial in deciding the diffusing and correspondingly the swelling rates. Highly porous structures exhibit faster and higher swelling [80].

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3. IMPORTANT SYNTHESIS PARAMETERS FOR SYNTHESIZING TAILOR MADE HYDROGEL STRUCTURE A large number of research papers are being published on different kind of hydrogels with different applications, leading to significant enhancements in synthesis routes [8184]. This section describes important synthesis parameter and routes to obtain tailor made hydrogel structures for a particular end use. Table 2 discusses the possible selection of synthesis parameters in obtaining a set of desirable properties in a new hydrogel or


modifying an existing hydrogel. It divides the synthesis parameters in three parts ,that can alter the synthesis as well as final properties of synthesized hydrogel. The important parameters that have been discussed here are nature, number and ratio of monomers, type and concentration of crosslinker and initiator, and polymerization techniques.

3.1. Nature, Number And Ratio Of Monomers These are the basic building blocks of hydrogel and the most important parameter, which decide the following inherent characteristics of resulting hydrogel.

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Biodegradability, Biocompatibility and Toxicity[85]

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Swelling profile by altering network parameters[86]

3.

Incorporation of smart/environment sensitive nature

The selection is to be made based on end use requirements, and the possible selections can be made from three categories of monomers discussed in Table 1.

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In most of the cases it is difficult to obtain desirable properties from one monomer, so a combination of two or more monomers can be used. On the basis of nature, number and ratio of monomer; hydrogels can be divided as homopolymeric, copolymeric, multipolymeric, interpenetrating networks. These hydrogels can be prepared by selecting different combination of monomers, or performing a second polymerization/cross-linking process on the original hydrogel platform. For example by choosing a highly hydrophilic monomer like Acrylamide, a hydrophobic monomer (like


Butyl methacrylate) and an environment sensitive monomer (like Acrylic acid); a proper balance of above three properties can be obtained for use in controlled release of pharmaceuticals[87]

3.1.1. Homopolymer Hydrogels: Homopolymer hydrogels are referred to crosslinked polymer networks obtained from one type of monomeric unit. Figure 5(a) shows a schematic diagram representing homopolymer hydrogel. Structural framework of these homopolymer hydrogels is governed by the polymerization technique, nature of the monomer and crosslinker, etc. For various biomedical applications, single monomer based hydrogel may not completely fulfill the requirements of the proposed applications. For example, good swelling characteristics, and better controlled release properties can be offered by very highswelling hydrogels, but in highly swollen state; their mechanical properties are often poor. Under such conditions, multicomponent hydrogels as well as multiple cross-linking processes can be employed. Examples of homopolymeric hydrogel include poly(N-

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isopropylacrylamide) (PNIPAM) [88-89], polyvinyl alcohol (PVA) [90], Polyacrylamide (PAAm) [91], polyethylene glycol (PEG) [92] etc.

3.1.2. Co-Polymer Hydrogels: Co-polymeric hydrogels are composed of two different monomers [93]; in which at least one monomer is hydrophilic in nature. The hydrophilic monomer is responsible for swelling profile of the hydrogel. Mainly, copolymeric hydrogels structures can be divided


in block, graft, alternating, or random type (based on copolymer structure) [94-97]. These are represented by figure 5(b to e) respectively. The copolymeric hydrogel are generally prepared by chemical crosslinking/polymerization of both monomers using an initiator and multifunctional crosslinker, preferably in the presence of suitable solvent. These hydrogels can also be physically crosslinked by the presence of various interactive forces, like ion-polymer complexations, ionic interactions, chain aggregations, hydrogen bonds, etc. Examples include hydrogels based on poly (ethylene glycol)-poly(Nisopropylacrylamide) (PEG-PNIPAM) [98-99], poly (lactic acid)–poly (ethylene glycol) (PLA-PEG) [100-101], poly(acrylamide-co-acrylic acid) PAAm-AAc [102], poly(vinylpyrrolidone/acrylic acid) (PVP-AAc) [103], etc.

3.1.3. Multipolymer Hydrogels: Hydrogels prepared by polymerization/crosslinking of three or more monomers simultaneously are categorized as multipolymer (or terpolymeric) hydrogels, which are extension of copolymeric hydrogels [104]. One such scheme of preparation of multipolymer hydrogel is illustrated in figure6, where three different monomers are

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copolymerized, and crosslinked to form a multi polymeric hydrogel. Mechanical weakness and fragility of homopolymer/copolymer hydrogel limits their usage in some cases. Overcoming this limitation of these hydrogels have been made possible by preparing multipolymer hydrogels, which offer high mechanical strength, and improved overall hydrogel structure. Examples include hydrogels based on PAAm/gelatin and PAAc-HEMA/gelatin based hydrogels [64,105-106]


3.1.4 Interpenetrating Polymeric Network (IPN) Hydrogels: Interpenetrating polymeric network (IPN) hydrogels generally consist of two intertwined polymer networks, without any chemical linkages in between both polymers. Swelling of first polymeric network is carried out in the monomer of second polymer followed by subsequent crosslinking of second polymeric network [107]. The latter reacts to form second polymeric network that crosslinks within their polymeric network, but without crosslinking to each other to develop an interpenetrating structure as represented in figure 7. Some advantages offered by IPNs are higher order stability, denser hydrogel matrices with improved stiffness and toughness, tunable physical properties, and more efficient drug loading compared to conventional hydrogels [108-109]. In case first polymeric network is linear, and penetrates another cross-linked network (without any other chemical bonds between them), it is called a semi-Interpenetrating Polymer Network (semi- IPN) as shown in figure 8 [110].

3.2. Selection Of Appropriate Crosslinking Method

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One of the most important parameter in deciding the hydrogel network structure is type and amount of crosslinker used in crosslinking. Keeping in view the wide range of performance required corresponding to various applications; very different crosslinking agents are needed. Important cross linkers which can be used to crosslink hydrogels are discussed below by dividing them in two main categories, i.e. physical and chemical crosslinks. These are further subdivided in different subcategories; which are presented


with details and references in table 2.

Hydrogels prepared by synthetic chemical reaction are insoluble due to the presence of chemical crosslinks (covalent bond) or physical cross-links, such as hydrogen bonds, van-der Waal forces, or hydrophobic and ionic interactions. Their swollen state is a consequence of the balance between cohesive forces, and dispersion forces acting on the hydrated chains. Cohesive forces are usually due to covalent cross-linking; but also can be related to electrostatic, hydrophobic, or dipole–dipole forces.

3.2.1. Hydrogels Prepared With Physical Crosslinks Physical hydrogels are characterized by rendering the gels insoluble by noncovalent/chemical crosslinks; and consist of several types of interactions. In contrast to the covalent crosslinking points in chemical networks, physical gels are formed through extended junction zones of several laterally associated polymer chains. A large number of natural polymers form physical networks. Physical hydrogels differ from chemical hydrogels in the type of crosslinks, randomness of the network formation, and the effects of these parameters on the rigidity and elastic moduli of the formed

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networks. Physical hydrogels can be viewed as viscoelastic solids and can be classified according to the method of preparation. Physical cross-linking of polymer chains can also be achieved using a variety of environmental triggers (pH, temperature, ionic strength); and a variety of physicochemical interactions (hydrophobic interactions, charge condensation, hydrogen bonding, stereo complexation, or supramolecular chemistry). Different types of physical gels are discussed below by dividing them in five categories


3.2.1.1. Physical Crosslinking By Hydrogen Bonding Interactions: Hydrogen bonding can be used to synthesize a specific variety of physically crosslinked hydrogels with a kind of reversible crosslinking. As hydrogen bonds are secondary bonds they are formed between H, O and N commonly in favorable conditions; and these bonds cease to exist in harsh conditions, such as an increase in temperature, pH change, etc. These hydrogen bonds are being used in forming injectable hydrogels too [111]. Further sometimes these interactions play an important role in increasing or decreasing swelling of hydrogel in a particular environment. A typical example of such case is very high swelling in acidic medium for copolymer hydrogel based on AAm, AAc, and Butyl Methacrylate [86-87]. Here the swelling was increased upto 100 times due to Hydrogen bonding breaking in acidic medium.

3.2.1.2. Physical Crosslinking By Freeze-Thawing: Physical cross-linking of a polymer to form its hydrogel can also be achieved by using freeze-thaw cycles. The mechanism involves the formation of micro crystals in the

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structure due to freeze-thawing. Examples of this type of gelation are freeze-thawed gels of polyvinyl alcohol and xanthan [112-114].

3.2.1.3. Physical Crosslinking By Thermo-Gelation Add: When a hydrophobic segment is linked with a hydrophilic chain it also prevents hydrogel solubilization due to its hydrophobicity [54]. Thermo-sensitive gelation is triggered by hydrophobic interactions upon a change in temperature. Thermosensitive hydrogels based


on poly (ethylene oxide)-poly (propylene oxide)-poly(ethylene oxide) (PEO–PPO–PEO, known as Pluronics) ,gelatin , polysaccharide and PNIPAM are most commonly used [115-116].

A particularly interesting application for these hydrogels is in injectable hydrogel formulations, which are promising due to easy administration with patient convenience, and correspond to minimally evasive treatment. Thermally or other stimuli sensitive hydrogels, which quickly respond to environmental change under mild conditions are potential candidates for injectable hydrogels category [ 117-120]. The immediate change from a low viscous solution before injection, to quick in-situ formation of strong network after injection occurs due to quick physical crosslinking. This can be achieved by careful selection of appropriate monomer and crosslinker combinations. Options like magnetic, electric and ultrasonic modulations for enhancing release of loaded drug after injection further improves their applicability [121].

3.2.1.4. Physical Crosslinking By Charge Interactions:

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Later in 1990’s some interesting developments have taken place in physical crosslinking, different charge complex formation, micro and nano hydrogels etc. These hydrogels can be synthesized to achieve a specific set of mechanical, thermal and degradation profiles and in certain cases are reversible as well as can be formed in situ [122] Charge interactions have been widely investigated for cross-linking in situ-gelling hydrogels. Charge interactions may occur between a polymer and a small molecule or between two polymers of opposite charge to form a hydrogel and are already described previously in


section 2.1

3.2.1.5 Stereocomplexed Hydrogels: Stereocomplexation is a phenomenon involving interactions between two polymers having same chemical composition but with complementing stereochemistry. Stereocomplexed hydrogels based on PDLA and PLLA, both had same chemistry but opposing chirality, and helicity have been synthesized. It has been suggested that van der Waals interaction between the two polymeric chains is the driving force for hydrogel formation through crosslinking due to stereo complexation. AB type diblock copolymeric hydrogel such as PEG-PLA, ABA type triblock copolymeric hydrogel like PLA-PEGPLA and star shaped block copolymeric hydrogel like PEG-(PLA) and PEG-(PDLA) have been synthesized by utilizing stereo complexation [123]. These stereo complexed copolymeric hydrogels offer improved mechanical strength and faster gelation time.

3.2.1.6 Microgels And Nanogels:

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In case the size of hydrogel is reduced in the micro or nano range i.e. 10 -6 m to 10-9 m, they have tremendous applications in oral drug administration. Ganguly et al [124] recently reviewed the applications of micro and nano hydrogels as suitable nano-carriers for proper cell-mediated immune responses and high drug loading. These can be prepared by different techniques such as spray – drying, ionic gelation, solvent evaporation, salting/ emulsification - diffusion, emulsion/solvent – diffusion, micelle and reverse micelle formation [125]. In this category newly derived self-assembled nano hydrogels


are very promising as they are easy to synthesize, cost-effective and can take significant loading of proteins and peptides etc. The release of pharmaceutics from these micro and nano hydrogels can be desirably triggered by finally tailoring the crosslink density of hydrogel matrix. Recently Jiang et al [126] have highlighted the use of Click chemistry in synthesizing microgels and nanogels with varying dimensions and patterns for encapsulating bioactives including living cells, proteins and drugs. These hydrogel can serve as versatile and viable platforms for sustained protein release, targeted drug delivery and tissue engineering. This is due to their excellent biocompatibility, microporous structure with tunable porosity and pore size, and dimensions spanning to match from human organs, cells to viruses. The distinct advantage of copper-free click chemistry is that it doesn’t interfere with encapsulated bioactives and allows synthesis of micro patterned biomimetic hydrogel hydrogel, functional microgels and nanogels. The potential and novel click chemistry roots include tetrazole-alkene click chemistry, radical mediated thiolene chemistry, Diels-Alder reaction, Oxime reaction and azide-alkyne cycloaddition. [126].

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3.2.2. Hydrogels Prepared With Chemical Crosslinks Chemical hydrogels are very popular class of hydrogels and contain covalent junctions between polymeric hydrogel chains. Unlike physically cross-linked hydrogels, which have the general advantage of forming gels without the need for chemical modification or the addition of cross-linking entities in vivo, chemically crosslinked hydrogels have certain limitations. These hydrogels have chemical residues of crosslinker which maybe objectionable sometimes in biomedical applications. Otherwise these hydrogels are easy


to synthesize, stable and offer wide range in network structures and correspondingly swelling. A wide range of methods are available for introducing covalent linkages in polymeric chains for hydrogel formations; which are divided in five categories and are discussed below.

3.2.2.1 Crosslinking By Radical Polymerization: Chemically crosslinked gels can be obtained by radical polymerization of low molecular weight monomers in the presence of appropriate crosslinking agents. Various hydrogel characteristics such, swelling can be controlled by the amount of crosslinker. Different water-soluble (synthetic, semi-synthetic and natural) polymers have been used for the design of hydrogels via this route. The choice of crosslinker and initiator depends on nature of monomer and solvent generally (e.g. oil soluble or water soluble). Poly (2hydroxyethylmethacrylate) (PHEMA) is a well known and frequently studied hydrogel system. This hydrogel was ﬁrst described by Wichterle and Lim [127] and is obtained by polymerization of HEMA in the presence of a suitable crosslinking agent. Radically

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polymerized hydrogels include various acrylates, vinyl pyrrolidone, p-styrene, sulfonic acid, etc.

3.2.2.2. Crosslinking By Chemical Reaction Of Functional Groups: An interesting route for hydrogel preparation is by reactions between functional groups present in the water-soluble monomers. Examples of reactions are Schiff-base formation [49, 81, 128], Michael-type additions [129], condensation reaction, etc. For example,


water-soluble polymers with hydroxyl groups e.g. poly (vinyl alcohol) can be chemically crosslinked using glutaraldehyde [130].

In order to establish crosslinking, rather drastic conditions have to be applied (low pH, high temperature, methanol added as quencher). In contrast, amine containing polymers can be crosslinked with the same reagent under mild conditions whereby so-called Schiff bases are formed. Hydrophilic polymers can be crosslinked to hydrogels using bis (or higher) crosslinking agent through reactions with their functional groups. Examples of such reactions are the Michael addition reaction between nucleophile (an amine or a thiol group) and an electrophile (vinyl/acrylate/maleimide group) [131]. Various polymers e.g. dextran [132], hyaluronic acid, poly (ethylene glycol) [133], and poly (vinyl alcohol), etc. have been conjugated using such nucleophilic and electrophilic groups to prepare hydrogels via Michael reactions. Hennink et al have discussed different type of reactions needing to crosslinking of degradable and non biodegradable hydrogels. The exa mple of such reaction includes PEG-dithiol with PEG-acrylates leading to degradable hydrogels

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[81]. Similarly, water soluble polymers having amide bonds can be crosslinked by N, N(3-dimethylaminopropyl)-N-ethyl carbodiimide (EDC) [134].

3.2.2.3 Crosslinking By High Energy Irradiation: High energy radiations like gamma radiation or high energy particles like electron beams can induce polymerization/crosslinking in unsaturated organic compounds [135-136]. This is a well known phenomenon and is utilized in different applications due to their


biomedically safe nature. One such application is synthesizing hydrogels from water soluble polymer bearing vinylic and acrylic groups in presence of suitable initiators and crosslinkers [137]. Example of synthetic polymers employed for preparing hydrogels by radiation-induced polymerization include PEG [138], PVA [139], PAAm [100], PVP [140], etc. and their copolymers. Few natural polymers like hyaluronic acid [141], dextran [1142], collagen [143], chitosan [144] etc. are also used for synthesizing natural hydrogels by high energy irradiation.

Mild processing/synthesizing conditions (like room temperature and low acidity) and absence of toxic crosslinking agents are some main advantages of synthesizing hydrogel by radiation induced crosslinking. Such hydrogels are not having harmful chemical residues and therefore are considered safe for biomedical applications [143].

3.2.2.4. Crosslinking Using Enzymes: Enzymes are significantly sensitive as well as specific towards chemical reactions, but in certain cases they can be utilized for crosslinking too [145]. By adjusting the enzymes

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concentration in the reactions; gelation kinetics can be controlled and an increase in the overall crosslinking rate can be observed. For example, Transglutaminase (TG) is one such enzyme that helps to catalyze crosslinking reactions by forming amide linkages between polymers carrying carboxamide and primary amines functionality on them [146]. Similarly, Horseradish peroxidase (HRP) is another enzyme, which in the presence of hydrogen peroxide catalyzes enzymatic crosslinking reaction of polymer such as poly (L-glutamic acid) grafted with tyramine and poly (ethylene glycol). This crosslinking


method resulted in biocompatible in-situ forming hydrogels suitable for injectable hydrogels. [147]

3.2.2.5. Hydrogels With Special Structural Configurations: In order to overcome the problems related to poor mechanical strength of hydrogels in swollen state; several new structures of hydrogels are developed which are reviewed by Johnson et al [148]. Three primary methods were discussed by them which include the following –

a. Slide ring gels Slide ring gels are special structured hydrogels which are similar to linear rotaxane. Their structure is shown in figure 9 and in these hydrogels linear polymer chains bear a number of cyclic molecules. These cyclic molecules are then trapped by bulky molecules placed at both ends of chains.. A small percentage of these cyclic are then fused together to form mobile crosslinks. These crosslinks act similar to pulley for the chains by threading through them and these crosslinks are called slide rings [148].

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These hydrogels exhibit significantly improved mechanical strength in dry as well as swollen state.

b. Double Network hydrogels Double Network gels consist of two independently crosslinked networks one consisting of flexible uncharged polymer, and the other consisting of a rigid polyelectrolyte. Their synthesis is shown in figure 10 by using two different networks. These hydrogel possess best mechanical properties due to high


crosslinking of first polymeric network and lower crosslinking of second polymeric network. Molar composition of the second polymer should be ten times or higher than that of first polymer. The improved mechanical strength of these double network hydrogels is due to high concentration of second component which prevent crack propagation leading to failure [148-149].

c. Nanocomposite hydrogels The area of nanocomposite hydrogels is currently thriving with activities as witnessed by large number of publications published in this area [139141]. Here a nano-filler is incorporated in the hydrogel matrix for a variety of reasons; which are decided mainly by applications [150,151]. The nano-filler may be organic or inorganic and a large variety of mineral clays are being used [152]. In these clay based nano-composite hydrogels the polymer chain ends are adsorbed strongly on the clay surface which leads to significant attachment of chains to different clay particles as shown in figure 11. This leads to development of a strongly connected network between clay particles and polymer chains leading to significantly high toughness. This is a vast science and its detailed discussion is outside the purview of this review.

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3.2.3. Combining Physical And Chemical Crosslinking Physical hydrogels are held together with non-covalent forces, whereas Chemical hydrogels are synthesized by employing chemical crosslinking; both kinds of gels are structurally inhomogeneous. Physical hydrogels have hydrophilic and hydrophobic regions present in the polymeric network. Chemical hydrogels have domains of high crosslink density as compared to conventional hydrogels. Physical hydrogels show lower mechanical properties because of the reversible physical interactions. By increasing the


crosslink density and molecular weight of these hydrogels, mechanical properties can be enhanced, but an increase in the viscosity hinders the handling in injecting applications. The mechanical properties of chemically crosslinked hydrogels are higher than physically crosslinked hydrogels, but inclusion of biologically unfavorable compounds defeats the purpose of hydrogels synthesized for biomedical application. However, biocompatibility can still be achieved by combining both physical and chemical crosslinking in a single hydrogel system [153]. Techniques like thermogelation, photopolymerization, click chemistry, and stereo complexation can be used for the purpose of providing physical as well as chemical crosslinking [154]. Faster gelation tendency, improved biocompatibility and enhanced mechanical and physical properties are the main advantages of combining two mechanisms of crosslinking [155-156].

3.3. Polymerization Techniques For Synthesizing Hydrogels A wide variety of polymerization techniques have been used to synthesize polymeric hydrogels. Few of them which have been generally employed are bulk, solution, suspension, emulsion polymerization and photo-polymerization [157-158]. Suspension

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and Emulsion polymerization can either be general or inverse in nature. The term “inverse” here implied that the aqueous medium has been dispersed in the hydrophobic medium. This is opposite of the conventional emulsions or dispersions and hence the name inverse has been used. Photo-polymerization is radiation induced polymerization which is most effective and efficient and has the advantage of being safe. It can also be used for coatings. This technique is utilized to synthesize chemically crosslinked hydrogels. Changing the synthesis techniques alter the final hydrogel product


significantly in terms of purity, compositional homogeneity, structure, etc. Many newer techniques have been developed in the past decade such as reversible additionfragmentation chain transfer (RAFT) polymerization, mini-emulsion polymerization, atom transfer radical polymerization (ATRP), click chemistry, etc. for synthesis of hydrogels [159-160]. Basically the selection of proper synthesis technique is governed by the nature of monomer/crosslinker combination as well as the desired physical form to suit the end use application. For example, if fine particles of hydrogels are required, one can choose inverse suspension or inverse emulsion polymerization etc. A recent innovation for synthesizing highly superporous polymeric material known as poly HIPES is synthesized by ATRP [160]. 4. CONCLUSION By using an appropriate single monomer or a combination of two or three monomers a desirable tailor-made hydrogel can be synthesized by employing a suitable cross-linking technique. The physical form of synthesized hydrogel is the crucial parameter in finalizing the polymerization technique used. In addition the hydrogel properties can be further modified by incorporation of micro or nano fillers. Special structural

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configurations like slide ring gel or double network gel can be synthesized to enhance mechanical strength of resulting hydrogels. Afterwards a suitable method of polymerization or crosslinking has to be carefully decided for tailoring of hydrogel properties for any desirable application can be achieved. This review covers physical gels in detail because of their promising application in the field of injectable biomedical applications. For incorporation of bioactive substances, physically crosslinked gels are of great interest, especially once the gel formation occurs under mild conditions in the


absence of organic solvents. However chemically crosslinked hydrogels are very stable and are being used in a number of applications like pharmaceutical, agriculture, food industry, cosmetics, etc. Focus needs to be shifted towards the development of new and versatile hybrid chemistries that would offer better properties and suit wider applications in the upcoming years. Innovative methods of synthesis of hydrogels, that may be used in the future, have been investigated and developed in recent years.

REFERENCES [1] Sharpe, L. A.; Daily, A. M.; Horava, S. D.; Peppas, N. A. Therapeutic applications of hydrogels in oral drug delivery. Expert Opinion on Drug Delivery, 2014, 11, 901-915 [2] Peppas, N. A.; Bures, P.; Leobandung, W.; Ichikawa, H. Hydrogels in pharmaceutical formulations. European Journal of Pharmaceutics and Biopharmaceutics, 2000, 50, 2746 [3] Hoffman, A. S. Hydrogels for biomedical applications, Advanced Drug Delivery Reviews, 2012, 64, 18-23

26

[4] Kim, J. K.; Kim, H. J.; Chung, J. Y.; Lee J. H.; Young, S. B.; Kim, Y. H. Natural and synthetic biomaterials for controlled drug delivery Archives of Pharmaceutical Research, 2014,37,60-68 [5] Bajpai, A. K.; Giri, A. Water sorption behaviour of highly swelling (carboxy methylcellulose-g-polyacrylamide) hydrogels and release of potassium nitrate as agrochemical. Carbohydrate Polymers, 2003, 53, 271-279 [6] Teodorescu, M.; Lungu, A.; Stanescu, P. O. Preparation and properties of novel


slow-release NPK agrochemical formulations based on poly (acrylic acid) hydrogels and liquid fertilizers Industrial Engineering Chemistry Research, 2009, 48, 6527-6534 [7] Farris, S.; Schaich, K. M.; Liu, L.; Piergiovanni, L.; Yam, K. L. Development of polyion-complex hydrogels as an alternative approach for the production of bio-based polymers for food packaging applications: a review Trends in Food Science Technology, 2009, 20,316-332 [8] Grover, G. N.; Braden, R. L.; Christman, K. L. Oxime Cross-Linked Injectable Hydrogels for Catheter Delivery Advanced Materials, 2013, 25, 2937-2942 [9] Browning, M. B.; Dempsey, D.; Guiza, V.; Becerra, S.; Rivera, J.; Russel, B.; Höök, M.; Clubb, F.; Miller, M.; Fossum, T.; Dong, J. F.; Bergeron, A. L.; Hahn, M.; CosgriffHernandez, E. Multilayer vascular grafts based on collagen-mimetic proteins Acta Biomaterialia, 2012, 8, 1010–1021 [10] Fonder, M. A.; Mamelak, A. J.; Lazarus, G. S.; Chanmugam, A. Occlusive wound dressings in emergency medicine and acute care. Emergency medicine clinics of North America, 2007, 25, 235-242

27

[11] Arion, H. Carboxy-methyl cellulose hydrogels used to fill breast implants, 15 years of experience European Journal of Plastic Surgery, 2001, 24, 172–175 [12] Prausnit, M. R.; Langer, R. Transdermal drug delivery. Nature biotechnology, 2008, 26, 1261-1268 [13] Hamidi, M.; Azadi, A.; Rafiei, P. Hydrogel nanoparticles in drug delivery. Advanced drug delivery reviews, 2008, 60, 1638-1649 [14] Van Vlierberghe, S.; Dubruel, P. Schacht, E. Biopolymer-based hydrogels as


scaffolds for tissue engineering applications: a review. Biomacromolecules, 2011, 12, 1387-1408 [15] Lee, T. W.; Kim, J. C.; Hwang, S. J. Hydrogel patches containing Triclosan for acne treatment. European journal of pharmaceutics and biopharmaceutics, 2003, 56, 407-412 [16] McCain, M. L.; Agarwal, A.; Nesmith, H. W.; Nesmith, A. P.; Parker, K. K. . Micromolded gelatin hydrogels for extended culture of engineered cardiac tissues. Biomaterials, 2014, 35, 5462-5471 [17] Drury, J. L.; Mooney, D. J. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials, 2003, 24, 4337-4351 [18] Gao, T. T.; Kong, M.; Cheng, X. J.; Xia, G. X.; Gao, Y. Y.; Chen, X. G.; Cha, D. S.; Park, H. J. A thermosensitive chitosan-based hydrogel for controlled release of insulin. Frontiers of Materials Science, 2014, 8, 142-149 [19] Guenther, M.; Wallmersperger, T.; & Gerlach, G. . Piezoresistive Chemical Sensors Based on Functionalized Hydrogels. Chemosensors, 2014, 2, 145-170.

28

[20] Çetin, D.; Kahraman, A. S.; & Gümüşderelioğlu, M. Novel scaffolds based on poly (2-hydroxyethyl methacrylate) superporous hydrogels for bone tissue engineering. Journal of Biomaterials Science, Polymer Edition, 2011, 22, 1157-1178 [21] Hou, C.; Huang, T.; Wang, H.; Yu, H.; Zhang, Q.; & Li, Y. A strong and stretchable self-healing film with self-activated pressure sensitivity for potential artificial skin applications. Scientific reports, 2013, 3. [22] Guenther, M.; Kuckling, D.; Corten, C.; Gerlach, G.; Sorber, J.; Suchaneck, G.;


Arndt, K. F. Chemical sensors based on multiresponsive block copolymer hydrogels. Sensors and Actuators B: Chemical, 2007, 126, 97-106 [23] Sidorenko, A.; Krupenkin, T.; & Aizenberg, J.; Controlled switching of the wetting behavior of biomimetic surfaces with hydrogel-supported nanostructures. Journal of Materials Chemistry, 2008, 18, 3841-3846. [24] Kanai, T.; Sawada, T.; & Yamanaka, J. Fabrication of large-area silica colloidal crystals immobilized in hydrogel film. Journal of the Ceramic Society of Japan, 2010, 118, 370-373. [25] Rivest, C.; Morrison D.; Ni B.; Rubin J.; Yadav, V.; Mahdavi, A.; Karp, J.; Khademhosseini A. Microscale hydrogels for medicine and biology: synthesis, characteristics and applications. Journal of Mechanics of materials and structures 2, 2007, 6,1103-1119 [26] Omidian, H.; Park, K. Introduction to hydrogels. In ‘Biomedical Applications of Hydrogels Handbook’ Eds.: Ottenbrite R. M.; Park K.; Okano T., Springer, New York, 2010, 1-16

29

[27] Kabiri, K.; Omidian, H.; Zohuriaan-Mehr, M. J.; Doroudiani, S. Superabsorbent hydrogel composites and nanocomposites: A review. Polymer Composites, 2011, 32,277–289 [28] Dubrovskii, S. A.; Rakova, G. V. Elastic and osmotic behavior and network imperfections of nonionic and weakly ionized acrylamide-based hydrogels. Macromolecules, 1997, 30, 7478-7486 [29] Refojo, M. F.; Yasuda, H. Hydrogels from 2-hydroxyethyl methacrylate and


propylene glycol monoacrylate. Journal of Applied Polymer Science, 1965, 9, 2425-2435 [30] Bo, J. Study on PVA hydrogel crosslinked by epichlorohydrin. Journal of applied polymer science, 1992, 46, 783-786 [31] Sargeant, T. D.; Desai, A. P.; Banerjee, S.; Agawu, A.; Stopek, J. B. An in situ forming collagen–PEG hydrogel for tissue regeneration. Acta biomaterialia, 2012, 8, 124-132 [32] Gil, E. S.; Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in polymer science, 29, 1173-1222 [33] Ramos, J.; Forcada, J.; Hidalgo-Alvarez, R. Cationic Polymer Nanoparticles and Nanogels: From Synthesis to Biotechnological Applications. Chemical reviews, 2013, 114, 367-428 [34] Karadag, E.; Üzüm, Ö. B.; Saraydin, D. Swelling equilibria and dye adsorption studies of chemically crosslinked superabsorbent acrylamide/maleic acid hydrogels. European Polymer Journal, 2002, 38, 2133-2141 [35] Zhang, Y.; Won, C. Y.; Chu, C. C. Synthesis and characterization of biodegradable network hydrogels having both hydrophobic and hydrophilic components with controlled

30

swelling behavior. Journal of Polymer Science Part A: Polymer Chemistry, 1999, 37, 4554-4569 [36] Choi, S.; Ortony, J.; Krogstad, D.; Spruell, J.; Lynd, N.; Han, S.; Kramer, E. Structure of Block Copolymer Hydrogel Formed by Complex Coacervate Process. in ‘APS Meeting Abstracts’, Vol. 1, 2012, 47012 [37] Qiu, Y.; Park, K. Environment-sensitive hydrogels for drug delivery. Advanced drug delivery reviews, 2001, 53, 321-339


[38] Hamman, J. H. Chitosan based polyelectrolyte complexes as potential carrier materials in drug delivery systems. Marine Drugs, 2010, 8, 1305-1322 [39] Bhattarai, N.; Gunn, J.; Zhang, M. Chitosan-based hydrogels for controlled, localized drug delivery. Advanced drug delivery reviews, 2010, 62, 83-99 [40] Kishida, A.; Ikada, Y. Hydrogels for biomedical and pharmaceutical applications. ch. 6 in ‘Polymeric biomaterials, Second Edition, Revised and Expanded’Eds.: Dumitriu S., Marcel Dekker, New York, 2001 [41] Wray, L. S.; Kaplan, D. L. Biomaterials for Scaffolds: Natural Polymers. in ‘Scaffolds for Tissue Engineering: Biological Design, Materials, and Fabrication’ Eds.: Migliaresi C., Motta A. Pan Stanford Publishing, Singapore, 2014, 301-336 [42] Ma, L.; Gao, C.; Mao, Z.; Zhou, J.; Shen, J.; Hu, X.; Han, C. Collagen/chitosan porous scaffolds with improved biostability for skin tissue engineering. Biomaterials, 2003, 24,4833-4841 [43] Silva, S. S.; Mano, J. F.; Reis, R. L. Potential applications of natural origin polymerbased systems in soft tissue regeneration. Critical reviews in biotechnology, 2010, 30, 200-221

31

[44] Ahmed, T. A.; Hincke, M. T. Strategies for articular cartilage lesion repair and functional restoration. Tissue Engineering Part B: Reviews, 2010, 16, 305-329 [45] Xu, X.; Jha, A. K.; Harrington, D. A.; Farach-Carson, M. C.; Jia, X. Hyaluronic acid-based hydrogels: from a natural polysaccharide to complex networks. Soft Matter, 2012, 8, 3280-3294 [46] Muzzarelli, R. A. Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids. Carbohydrate Polymers, 2009, 77, 1-9


[47] van Dijk-Wolthuis, W. N. E.; Hoogeboom, J. A. M.; Van Steenbergen, M. J.; Tsang, S. K. Y.; Hennink, W. E. Degradation and release behavior of dextran-based hydrogels. Macromolecules, 1997, 30,4639-4645 [48] Rowley, J. A.; Madlambayan, G.; Mooney, D. J. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials, 1999, 20, 45-53 [49] Li, Y.; Rodrigues, J.; Tomas, H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chemical Society Reviews, 2012, 41, 21932221 [50] Tamura, H.; Furuike, T.; Nair, S. V.; Jayakumar, R. Biomedical applications of chitin hydrogel membranes and scaffolds. Carbohydrate Polymers, 2011, 84, 820-824 [51] Zhao, W.; Jin, X.; Cong, Y.; Liu, Y.; Fu, J. Degradable natural polymer hydrogels for articular cartilage tissue engineering. Journal of Chemical Technology and Biotechnology, 2013, 88, 327-339 [52] Mano, J. F.; Silva, G. A.; Azevedo, H. S.; Malafaya, P. B.; Sousa, R. A.; Silva, S. S.; Boesel, L. F.; Oliveira, J. M.; Santos, T. C.; Marques, A. P.; Neves, N. M.; Reis, R. L. Natural origin biodegradable systems in tissue engineering and regenerative medicine:

32

present status and some moving trends. Journal of the Royal Society Interface, 2007 , 4, 999-1030. [53] Weng, L.; Romano, A.; Roone, J.; Chen, W. Non-cytotoxic, in situ gelable hydrogels composed of< i> N-carboxyethyl chitosan and oxidized dextran. Biomaterials, 2008, 29, 3905-3913 [54] Hoare, T. R.; Kohane, D. S.. Hydrogels in drug delivery: progress and challenges. Polymer, 2008, 49, 1993-2007


[55] Klein, T. J.; Rizzi, S. C.; Reichert, J. C.; Georgi, N.; Malda, J.; Schuurman, W.; Crawford, R. W.; Hutmacher, D. W. Strategies for zonal cartilage repair using hydrogels. Macromolecular bioscience, 2009, 9 , 1049-1058 [56] Holmes, T. C. Novel peptide-based biomaterial scaffolds for tissue engineering. TRENDS in Biotechnology, 2002, 20, 16-21 [57] Ribeiro M. P.; Espiga A.; Silva D.; Baptista P.; Henriques J.; Ferreira C.; Silva J. C.; Borges J. P.; Pires E.; Chaves P.; Correia I. J. Development of a new chitosan hydrogel for wound dressing. Wound Repair and Regeneration, 2009, 17, 817-824 [58] Luo Y.; Kirker K. R.; Prestwich G. D. Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery. Journal of Controlled Release, 2000, 69, 169-184 [59] Tian H.; Tang Z.; Zhuang X.; Chen X.; Jing X. Biodegradable synthetic polymers: Preparation, functionalization and biomedical application. Progress in Polymer Science, 2012, 37, 237-280 [60] Awasthi S.; Singhal R. A Study on Interaction and Solubility of Acetaminophen with Poly (AM-co-HEA-co-AA) Hydrogels by DSC: Effect on Drug Diffusion Behavior. Journal of Macromolecular Science, Part A, 2013, 50, 72-89

33

[61] Begam T.; Nagpal A. K.; Singhal R. A study on copolymeric hydrogels based on acrylamide-methacrylate and its modified vinyl-amine-containing derivative. Designed monomers and polymers, 2004, 7, 311-330 [62] Popat K. C.; Desai T. A. B. Alumina. in ‘Biomaterials Science: An Introduction to Materials in Medicine’ Eds.; Ratner B. D.; Hoffman A. S.; Schoen F. J.; Lemons J. E. Elsevier, Oxford, 2013, 162–166 [63] Baroli B. Hydrogels in Tissue Engineering. in ‘Cell and Tissue Engineering’ (ed(s).:


Obradović B.)). Springer-Verlag, Berlin Heidelberg, 2012, 197-216 [64] Singhal R. Hydrogels Multicomponent Anionic: Swelling and Controlled Release ,To be published inTaylor & francis Encyclopedia programTaylor and Francis Encyclopedia Program Encyclopedia of Biomedical Polymers and Polymeric Biomaterials; (CRC Press;accepted manuscript) [65] Banerjee S.; Siddiqui L.; Bhattacharya S. S.; Kaity S.; Ghosh A.; Chattopadhyay P.; Pandey A.; Singh, L. Interpenetrating polymer network (IPN) hydrogel microspheres for oral controlled release application. International Journal of Biological Macromolecules, 2012, 50, 198-206 [66] Fathi A.; Lee S.; Zhong X.; Hon N.; Valtchev P.; Dehghani F. Fabrication of interpenetrating polymer network to enhance the biological activity of synthetic hydrogels. Polymer, 2013, 54, 5534-5542 [67] Shin B. M.; Kim J. H.; Chung D. J. Synthesis of pH-responsive and adhesive superabsorbent hydrogel through bulk polymerization. Macromolecular Research, 2013, 21, 582-587

34

[68] Kabiri K.; Omidian H.; Hashemi S. A.; Zohuriaan-Mehr M. J. Synthesis of fastswelling superabsorbent hydrogels: effect of crosslinker type and concentration on porosity and absorption rate. European Polymer Journal, 2003, 39, 1341-1348 [69] Bajpai S. K.; Bajpai M.; Sharma L. Inverse suspension polymerization of poly (methacrylic acid-co-partially neutralized acrylic acid) superabsorbent hydrogels: synthesis and water uptake behavior. Designed Monomers and Polymers, 2007, 10, 181192


[70] Li F.; Li S.; El Ghzaoui A.; Nouailhas H.; Zhuo R. Synthesis and gelation properties of PEG-PLA-PEG triblock copolymers obtained by coupling monohydroxylated PEGPLA with adipoyl chloride. Langmuir, 2007, 23, 2778-2783 [71] Jiang S.; Liu S.; Feng W. PVA hydrogel properties for biomedical application. Journal of the Mechanical Behavior of Biomedical Materials, 2011, 4, 1228-1233 [72] Schmedlen R. H.; Masters K. S.; West J. L. Photocrosslinkable polyvinyl alcohol hydrogels that can be modified with cell adhesion peptides for use in tissue engineering. Biomaterials, 2002, 23, 4325-4332 [73] Kirschner C. M.; Anseth K. S. Hydrogels in healthcare: From static to dynamic material microenvironments. Acta materialia, 2013, 61, 931-944 [74] Tan H.; Marra K. G. Injectable, biodegradable hydrogels for tissue engineering applications. Materials, 2010, 3, 1746-1767 [75] Langer R. S.; Peppas N. A. Present and future applications of biomaterials in controlled drug delivery systems. Biomaterials, 1981, 2, 201-214

35

[76] Dash M.; Chiellini F.; Ottenbrite R. M.; Chiellini E. Chitosan-A versatile semisynthetic polymer in biomedical applications. Progress in Polymer Science, 2011, 36, 981-1014 [77] Sosnik A.; Sefton M. V. Semi-synthetic collagen/poloxamine matrices for tissue engineering. Biomaterials, 2005, 26, 7425-7435 [78] Wang C.; Stewart R. J.; KopeCek J. Hybrid hydrogels assembled from synthetic polymers and coiled-coil protein domains. Nature, 1999, 397, 417-420


[79] Mastropietro D. J.; Omidian H.; Park K. Drug delivery applications for superporous hydrogels. Expert opinion on Drug Delivery, 2012, 9, 71-89 [80] Ozmen M. M.; Okay O. Superfast responsive ionic hydrogels with controllable pore size. Polymer, 2005, 46, 8119-8127 [81] Hennink W. E.; Van Nostrum C. F. Novel crosslinking methods to design hydrogels. Advanced drug delivery reviews, 2012, 64, 223-236 [82] Hawkins A. M.; Tolbert M. E.; Newton B.; Milbrandt T. A.; Puleo D. A.; Hilt J. Z. Tuning biodegradable hydrogel properties via synthesis procedure. Polymer, 2013, 54, 4422-4426 [83] Ekenseair A. K.; Boere K. W.; Tzouanas S. N.; Vo T. N.; Kasper F. K.; Mikos A. G. Synthesis and characterization of thermally and chemically gelling injectable hydrogels for tissue engineering. Biomacromolecules, 2012, 13, 1908-1915 [84] Park K. M.; Lee Y.; Son J. Y.; Oh D. H.; Lee J. S.; Park K. D. Synthesis and characterizations of in situ cross-linkable gelatin and 4-arm-PPO-PEO hybrid hydrogels via enzymatic reaction for tissue regenerative medicine. Biomacromolecules, 2012, 13, 604-611

36

[85] Suggs L. J.; Shive M. S.; Garcia C. A.; Anderson J. M.; Mikos A. G. In vitro cytotoxicity and in vivo biocompatibility of poly (propylene fumarate-co-ethylene glycol) hydrogels. Journal of Biomedical Materials Research, 1999, 46, 22-32, [86] Tomar R. S.; Gupta I.; Singhal R.; Nagpal A. K. Synthesis of poly (acrylamide-coacrylic acid) based superabsorbent hydrogels: Study of network parameters and swelling behaviour. Polymer-Plastics Technology and Engineering, 2007, 46, 481-488 [87] Singhal R.; Gupta I. A study on the effect of butyl methacrylate content on swelling


and controlled-release behavior of poly (acrylamide-co-butyl-methacrylate-co-acrylic acid) environment-responsive hydrogels. International Journal of Polymeric Materials, 2010, 59, 757-776 [88] De las Heras Alarcón C.; Pennadam S.; Alexander C. Stimuli responsive polymers for biomedical applications. Chemical Society Reviews, 2005, 34, 276-285 [89] Zhang X. Z.; Yang Y. Y.; Wang F. J.; Chung T. S. Thermosensitive poly (Nisopropylacrylamide-co-acrylic acid) hydrogels with expanded network structures and improved oscillating swelling-deswelling properties. Langmuir, 2002, 18, 2013-2018 [90] Onyari J. M.; Huang S. J. Synthesis and properties of novel polyvinyl alcohol–lactic acid gels. Journal of applied polymer science, 2009, 113, 2053-2061 [91] Muniz E. C.; Geuskens G. Compressive elastic modulus of polyacrylamide hydrogels and semi-IPNs with poly (N-isopropylacrylamide). Macromolecules, 2001, 34, 4480-4484 [92] Jeong B.; Kim S. W.; Bae Y. H. Thermosensitive sol–gel reversible hydrogels. Advanced drug delivery reviews, 2002, 54, 37-51

37

[93] Mathur A. M.; Moorjani S. K.; Scranton A. B. Methods for synthesis of hydrogel networks: A review. Journal of Macromolecular Science, Part C: Polymer Reviews, 1996, 36, 405-430 [94] Shim W. S.; Yoo J. S.; Bae Y. H.; Lee D. S. Novel Injectable pH and Temperature Sensitive Block Copolymer Hydrogel. Biomacromolecules, 2005 ,6, 2930–2934 [95] He C.; Kim S. W.; Lee D. S. In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. Journal of controlled release, 2008, 127, 189-207


[96] Chen G.; Hoffman A. S. Graft copolymers that exhibit temperature-induced phase transitions over a wide range of pH. Nature, 1995, 373, 49-52 [97] Overstreet D. J.; Huynh R.; Jarbo K.; McLemore R. Y.; Vernon B. L. In situ forming, resorbable graft copolymer hydrogels providing controlled drug release. Journal of Biomedical Materials Research Part A, 2013, 101, 1437-1446 [98] Brazel C. S.; Peppas N. A. Synthesis and characterization of thermo-and chemomechanically responsive poly (N-isopropylacrylamide-co-methacrylic acid) hydrogels. Macromolecules, 1995, 28, 8016-8020 [99] Kim K. H.; Kim J.; Jo W. H. Preparation of hydrogel nanoparticles by atom transfer radical polymerization of N-isopropylacrylamide in aqueous media using PEG macroinitiator. Polymer, 2005, 46, 2836-2840 [100]Metters A. T.; Anseth K. S.; Bowman C. N. Fundamental studies of a novel, biodegradable PEG-< i> b-PLA hydrogel. Polymer, 2000, 41, 3993-4004 [101] Huh K. M.; Bae Y. H. Synthesis and characterization of poly (ethylene glycol)/poly (L-lactic acid) alternating multiblock copolymers. Polymer, 1999, 40, 6147-6155

38

[102] Singhal R.; Tomar R. S.; Nagpal A. K. Effect of cross-linker and initiator concentration on the swelling behaviour and network parameters of superabsorbent hydrogels based on acrylamide and acrylic acid. International Journal of Plastics Technology, 2009, 13, 22-37 [103] El-Hag Ali A.; Shawky H. A.; Abd El Rehim H. A.; Hegazy E. A. Synthesis and characterization of PVP/AAc copolymer hydrogel and its applications in the removal of heavy metals from aqueous solution. European Polymer Journal, 2003, 39, 2337-2344


[104] Chung H. J.; Lee Y.; Park T. G. Thermo-sensitive and biodegradable hydrogels based on stereocomplexed Pluronic multi-block copolymers for controlled protein delivery. Journal of Controlled Release, 2008, 127, 22-30 [105] Jaiswal M.; Koul V. Assessment of multicomponent hydrogel scaffolds of poly(acrylic acid-2-hydroxy ethyl methacrylate)/gelatin for tissue engineering applications. Journal of Biomaterials Applications, 2013, 27, 848–861 [106] Jia X.; Kiick K. L. Hybrid multicomponent hydrogels for tissue engineering. Macromolecular bioscience, 2009, 9, 140-156 [107] Miyata T. Gels and Interpenetrating Polymer Networks. In ‘Supramolecular Design for Biological Applications’ Ed(s).: Yui N. CRC, Boca Raton, 2002, 95-136 [108] Lee J. W.; Kim S. Y.; Kim S. S.; Lee Y. M.; Lee K. H.; Kim S. J. Synthesis and characteristics of interpenetrating polymer network hydrogel composed of chitosan and poly (acrylic acid). Journal of Applied Polymer Science, 1999, 73, 113-120 [109] Guo Y.; Yuan T.; Xiao Z.; Tang P.; Xiao Y.; Fan Y.; Zhang X. Hydrogels of collagen/chondroitin sulfate/hyaluronan interpenetrating polymer network for cartilage

39

tissue engineering. Journal of Materials Science: Materials in Medicine, 2012, 23, 22672279 [110] Jones D. S.; Andrews G. P.; Caldwell D. L.; Lorimer C.; Gorman S. P.; McCoy C. P. Novel semi-interpenetrating hydrogel networks with enhanced mechanical properties and thermoresponsive engineered drug delivery, designed as bioactive endotracheal tube biomaterials. European Journal of Pharmaceutics and Biopharmaceutics, 2012, 82, 563571


[111] Chenite A.; Chaput C.; Wang D.; Combes C.; Buschmann M. D.; Hoemann C. D.; Leroux J. C.; Atkinson B. L.; Binette F.; Selmani A. Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials, 2000, 21, 2155-2161 [112] Willcox P. J.; Howie D. W.; Schmidt-Rohr K.; Hoagland D. A.; Gido S. P.; Pudjijanto S.; Kleiner L. W.; Venkatraman S. Microstructure of poly (vinyl alcohol) hydrogels produced by freeze/thaw cycling. Journal of Polymer Science Part B: Polymer Physics, 1999, 37, 3438-3454 [113] Giannouli P.; Morris E. R. Cryogelation of xanthan. Food Hydrocolloids, 2003, 17,495-501 [114] Zhang H.; Zhang F.; Wu J. Physically crosslinked hydrogels from polysaccharides prepared by freeze–thaw technique. Reactive and Functional Polymers, 2013, 73, 923928 [115] Moreno E.; Schwartz J.; Larra-eta E.; Nguewa P. A.; Sanmartín C.; Agüeros M.; Sanmartín C.; Agüeros M.; Irache J. M.; Espuelas S. Thermosensitive hydrogels of poly(methyl vinyl ether-co-maleic anhydride) – Pluronic® F127 copolymers for controlled protein release. International Journal of Pharmaceutics, 2014, 459, 1-9

40

[116] Amini A. A.; Nair L. S. Injectable hydrogels for bone and cartilage repair. Biomedical Materials, 2012, 7, 024105 [117] Tous, E.; Purcell, B.; Ifkovits, J. L.; Burdick, J. A. Injectable acellular hydrogels for cardiac repair. Journal of cardiovascular translational research, 2011, 4, 528-542. [118] Bae, K. H.; Wang, L. S.; Kurisawa, M. Injectable biodegradable hydrogels: progress and challenges. Journal of Materials Chemistry B, 2013, 1, 5371-5388. [119] Pakulska, M. M.; Ballios, B. G.; Shoichet, M. S. Injectable hydrogels for central


nervous system therapy. Biomedical materials, 2012, 7, 024101. [120] Parisi-Amon, A., Mulyasasmita, W., Chung, C., & Heilshorn, S. C. ProteinEngineered Injectable Hydrogel to Improve Retention of Transplanted Adipose-Derived Stem Cells. Advanced healthcare materials, 2013, 2, 428-432. [121] Takeuchi Y.; Tsuji moto T.; Uyama H. Thermogelation of amphiphilic poly (asparagine) derivatives. Polymers for Advanced Technologies, 2011, 22, 620-626 [122] Buwalda S. J.; Boere K. W. M.; Dijkstra P. J.; Feijen J.; Vermonden T.; Hennink W. E.: Hydrogels in a historical perspective: From simple networks to smart materials. Journal of Controlled Release , 2014 ,190,254-273 [123] Buwalda S. J.; Calucci L.; Forte C.; Dijkstra P. J.; Feijen J.. Stereocomplexed 8armed poly (ethylene glycol)–poly (lactide) star block copolymer hydrogels: Gelation mechanism, mechanical properties and degradation behavior. Polymer, 2012, 53, 28092817 [124] Ganguly K.; Chaturvedi K.; More U. A.; Nadagouda M. N.; Aminabhavi T. M. Polysaccharide-based micro/nanohydrogels for delivering macromolecular therapeutics. Journal of Controlled Release , 2014 ,71, 199-218

41

[125] Koyamatsu, Y.; Hirano, T.; Kakizawa, Y.; Okano, F.; Takarada, T.; Maeda, M. pHresponsive release of proteins from biocompatible and biodegradable reverse polymer micelles. Journal of Controlled Release, 2014 ,173, 89-95 [126] Jiang Y.; Chen J.; Deng C.; Suuronen E. J.; Zhong Z. Click hydrogels, microgels and nanogels: Emerging platforms for drug delivery and tissue engineering. Biomaterials, 2014, 35,4969-4985 [127] Wichterle O.; Lim, D. Hydrophilic Gels for Biological Use. Nature , 1960 ,185,


117–118. [128] Li Y.; Liu C.; Tan Y.; Xu K.; Lu C.; Wang P. In situ hydrogel constructed by starch-based nanoparticles via a Schiff base reaction. Carbohydrate Polymers, 2014,110, 87-94 [129] Buwalda S. J.; Dijkstra P. J.; Feijen J. In Situ Forming Poly (ethylene glycol)-Poly (L-lactide) Hydrogels via Michael Addition: Mechanical Properties, Degradation, and Protein Release. Macromolecular Chemistry and Physics, 2012 , 213,766-775 [130] Mansur H. S.; Sadahira C. M.; Souza A. N.; Mansur A. A. P. FTIR spectroscopy characterization of poly (vinyl alcohol) hydrogel with different hydrolysis degree and chemically crosslinked with glutaraldehyde. Materials Science and Engineering: C, 2008 , 28,539–548 [131] Chan J. W.; Hoyle C. E.; Lowe A. B.; Bowman M. Nucleophile-initiated thiolmichael reactions: effect of organocatalyst, thiol, and ene. Macromolecules, 2010, 43, 6381-6388

42

[132] Hiemstra C.; van der Aa L. J.; Zhong Z.; Dijkstra P. J.; Feijen J. Rapidly in situforming degradable hydrogels from dextran thiols through Michael addition. Biomacromolecules, 2007, 8, 1548-1556 [133] Jin R.; Moreira Teixeira L. S.; Krouwels A.; Dijkstra P. J.; Van Blitterswijk C. A.; Karperien M.; Feijen J. Synthesis and characterization of hyaluronic acid–poly (ethylene glycol) hydrogels via Michael addition: An injectable biomaterial for cartilage repair. Acta biomaterialia, 2010, 6, 1968-1977


[134] Kuijpers A. J.; Engbers G. H.; Krijgsveld J.; Zaat S. A.; Dankert J.; Feijen J. Crosslinking and characterisation of gelatin matrices for biomedical applications. Journal of Biomaterials Science, Polymer Edition, 2000 , 11, 225-243 [135] Zaldivar M. P.; Fernández N. G.; Peña C. G.; Paneque M. R.; Valentín S. A. Synthesis and characterization of a new semi-interpenetrating polymer network hydrogel obtained by gamma radiations. Journal of Thermal Analysis and Calorimetry, 2011 , 106, 725–730 [136] Yoshii F.; Zhanshan Y.; Isobe K.; Shinozaki K.; Makuuchi K. (1999) Electron beam crosslinked PEO and PEO/PVA hydrogels for wound dressing. Radiation Physics and Chemistry, 55, 133-138 [137] Abd Alla S. G.; Nizam El-Din H. M.; El-Naggar A. W. M. (2007) Structure and swelling-release behaviour of poly (vinyl pyrrolidone)(PVP) and acrylic acid (AAc) copolymer hydrogels prepared by gamma irradiation. European polymer journal, 43, 2987-2998 [138] Peppas N. A.; Keys K. B.; Torres-Lugo M.; Lowman A. M. (1999) Poly (ethylene glycol)-containing hydrogels in drug delivery. Journal of controlled release, 62, 81-87

43

[139] Park S. E.; Nho Y. C.; Lim Y. M.; Kim H. I. Preparation of pH-sensitive poly (vinyl alcohol-g-methacrylic acid) and poly (vinyl alcohol-g-acrylic acid) hydrogels by gamma ray irradiation and their insulin release behavior. Journal of applied polymer science, 2004, 91, 636-643 [140] Singh R.; Singh D. Radiation synthesis of PVP/alginate hydrogel containing nanosilver as wound dressing. Journal of Materials Science: Materials in Medicine, 2012 , 23 , 2649-2658


[141] Lim Y. M.; Gwon H. J.; Park J. S.; Nho Y. C.; Shim J. W.; Kwon I. K.; Kim S. E.; Baik S. H. Synthesis and properties of hyaluronic acid containing copolymers crosslinked by ?-ray irradiation. Macromolecular Research, 2011 , 19,436-441 [142] Yoshii F.; Zhao L.; Wach R. A.; Nagasawa N.; Mitomo H.; Kume T. Hydrogels of polysaccharide derivatives crosslinked with irradiation at paste-like condition. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 2003, 208, 320-324 [143] Hara M. Various Cross-Linking Methods for Collagens: Merit and Demerit of Methods by Radiation. Journal of Oral Tissue Engineering, 2006, 3,118-124 [144] Chmielewski, A. G. Chitosan and radiation chemistry. Radiation Physics and Chemistry, 2010, 79, 272-275 [145] Moreira Teixeira L. S.; Feijen J.; van Blitterswijk C. A.; Dijkstra P. J.; Karperien M. Enzyme-catalyzed crosslinkable hydrogels: emerging strategies for tissue engineering. Biomaterials, 2012, 33, 1281-1290

44

[146] Ren K.; He C.; Cheng Y.; Li G.; Chen X. Injectable Enzymatically-crosslinked Hydrogels Based on Poly (L-glutamic acid) Graft Copolymer. Polymer Chemistry, 2014, 5, 5069-5076 [147] Bae, J. W.; Choi, J. H.; Lee, Y.; Park, K. D. Horseradish peroxidase-catalysed in situ-forming hydrogels for tissue-engineering applications. Journal of tissue engineering and regenerative medicine, 2014 [148] Johnson, J. A.; Turro, N. J.; Koberstein, J. T.; Mark J. E. Some hydrogels having


novel molecular structures. Progress in Polymer Science, 2010, 35, 332-337 [149] Na, Y. H. Double network hydrogels with extremely high toughness and their applications. Korea-Australia Rheology Journal, 2013, 25,185-196 [150] Gaharwar, A. K.; Peppas, N. A.; Khademhosseini, A. Nanocomposite hydrogels for biomedical applications. Biotechnology and bioengineering, 2014, 111 , 441-453 [151] Zhou C.; Wu Q A novel polyacrylamide nanocomposite hydrogel reinforced with natural chitosan nanofibers. Colloids and Surfaces B: Biointerfaces, 2011, 84, 155-162 [152] Yang J.; Deng L. H.; Han C. R.; Duan J. F.; Ma M. G.; Zhang X. M.; Xu F.; Sun R. C. Synthetic and viscoelastic behaviors of silica nanoparticle reinforced poly (acrylamide) core–shell nanocomposite hydrogels. Soft Matter, 2013, 9, 1220-1230 [153] Malda J.; Visser J.; Melchels F. P.; Jüngst T.; Hennink W. E.; Dhert W. J.; Groll J.; Hutmacher D. W. 25th Anniversary Article: Engineering Hydrogels for Biofabrication. Advanced Materials, 2013 , 25, 5011-5028 [154] Hiemstra C.; Zhou W.; Zhong Z.; Wouters M.; Feijen J. Rapidly in situ forming biodegradable robust hydrogels by combining stereocomplexation and photopolymerization. Journal of the American Chemical Society, 2007, 129, 9918-9926

45

[155] Chen C.; Wang L.; Deng L.; Hu R.; Dong A. Performance optimization of injectable chitosan hydrogel by combining physical and chemical triple crosslinking structure. Journal of Biomedical Materials Research Part A, 2013, 101, 684-693 [156] Cui Q.; Wang W.; Gu B.; Liang L. A Combined Physical–Chemical Polymerization Process for Fabrication of Nanoparticle–Hydrogel Sensing Materials. Macromolecules, 2012, 45, 8382-8386 [157] Shin B. M.; Kim J. H.; Chung D. J. Synthesis of pH-responsive and adhesive super-


absorbent hydrogel through bulk polymerization. Macromolecular Research, 2013, 21, 582-587 [158] Rosiak J. M.; Ulanski P. Synthesis of hydrogels by irradiation of polymers in aqueous solution. Radiation Physics and Chemistry, 1999, 55, 139-151 [159] Chaduc I.; Crepet A.; Boyron O.; Charleux B.; D'Agosto F.; Lansalot M. Effect of the pH on the RAFT Polymerization of Acrylic Acid in Water. Application to the Synthesis of Poly (acrylic acid)-Stabilized Polystyrene Particles by RAFT Emulsion Polymerization. Macromolecules, 2013, 46, 6013-6023 [160]Silverstein M. S. PolyHIPEs: Recent advances in emulsion-templated porous polymers. Progress in Polymer Science, 2014, 39, 199-234.

46


Table 1. Classification of Hydrogels Class

Subclass

Reference

Based on Electric Charge

Neutral

[27-31]

present on hydrogel

Cationic

[33-34]

Anionic

[34]

Ampholytic

[34]

Hydrophobic Modified

[35]

Complex Coacervates

[3,26,39]

Based on origin of

Natural

[41-58]

monomer/polymer used in

Synthetic

[59-75]

hydrogel synthesis

Hybrid

[76-78]

Based on pore size of

Non-porous

[79-80]

hydrogel

Micro-porous Super-porous

47


Table 2. Various synthesis parameters for tailor made hydrogel structure Synthesis Parameters

Subclass

Reference

Nature, Number and Ratio of

Homopolymer Hydrogels

[88-92]

Monomers

Copolymer Hydrogels

[94-103]

Multipolymer Hydrogels

[104-106]

Interpenetrating Network (IPN)

[107-110]

Hydrogel Selection of

Physical

Hydrogen Bonding Interaction

[111]

appropriate

Crosslinking

Freeze Thawing

[112-114]

crosslinking

Thermogelation

[115-117]

method

Charge Interactions

[122-123]

Microgels and Nanogels

[124-126]

Chemical

Radical Polymerization

[127]

Crosslinking

Chemical Reaction of Functional

[128-134]

Groups High Energy Irradiation

[135-144]

Crosslinking using enzymes

[145-147]

Special Structural

Slide Ring gels

[148]

Configurations

Double Network

[148-149]

Hydrogels Nano-composite Hydrogels

48

[150-152]


Figure 1.

49


Figure 2.

50


Figure 3.

51


Figure 4.

52


Figure 5.

53


Figure 6.

54


Figure 7.

55


Figure 8.

56


Figure 9.

57


Figure 10.

58


Figure 11.

59

Classifications and Synthesis Parameters

Classifications and Synthesis Parameters

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