Stimuli Responsive Swelling Of Hydrogels Biology Essay

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Hydrogels were the first biomaterial designed for human body. Traditional methods of biomaterial synthesis include cross-linking copolymerization, crosslinking of reactive polymer precursors and crosslinking via polymer-polymer reaction. Tremendous research in field of biomaterials has received a strong revitalization by several novel approaches in hydrogel design. They form the basis of many novel drug delivery systems. Hydrogels can be made to respond to the environment and the extent of the response can be controlled. The environmental conditions to which a hydrogel can be made responsive are pH, temperature, electric field, ionic strength, salt type, solvent, external stress, light or a combination of these (Fig. 1) [2,3].

Figure 1: Stimuli responsive swelling of hydrogels

Potential applications of all types of hydrogels includes: tissue engineering, synthetic extracellular matrix, biosensor, implantable devices, materials controlling the activity of enzymes, phospholipid bilayer destabilizing agents, materials controlling cell reversible attachment, nanoreactors and smart microfluidics. It is because of unique properties that these classes of polymer based systems embrace numerous pharmaceutical and bio medical applications. Hydrogels are water swollen three dimensional structures composed of primarily hydrophilic polymers containing mainly -OH, -CONH, -CONH2, -COOH and -SO3H groups [4]. These are cross linked macro molecular networks that are insoluble but are able to swell rapidly in water or biological fluids.

Biomaterials play a key role in most approaches for engineering tissues as substitutes for functional replacement, for components of devices related to therapy and diagnosis, for drug delivery systems and supportive scaffolds for guided tissue growth. Modern biomaterials could be composed of various components e.g. metals, ceramics, natural tissues, polymers. In this last group, the hydrogels, hydrophilic polymeric gels with requested biocompatibility and designed interaction with living surrounding seem to be one of the most promising groups of biomaterials [5].

Hydrogel is a network of polymer chains that are water-insoluble, sometimes found as a colloidal gel in which water is the dispersion medium. Polymer matrix of hydrogel usually contains at least 20% water and can reach values of 99%. Hydrogels containing more than 95% water are termed superabsorbent and have high biocompatibility due to their large degree of water retention and their physiochemical similarity with the native extracellular matrix both compositionally and mechanically [18,19]. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content [9]. Monomers/polymers commonly used in hydrogel synthesis are shown in figure 2.

Ethylene glycol (EG) Acrylate-PEG-Acrylate (PEGA)

N-(2-hydroxypropyl) meth- Vinyl acetate (VAc) N-vinyl-2-pyrrolidine

acrylamide (HPMA) (NVP)

(a) synthetic

Dextran Chitosan

Collage Alginate


(b) Natural

Figure 2: Monomers/polymers used in hydrogel

2. Classification of Hydrogels

Hydrogels are broadly categorized into two groups on the basis of cross-linking: permanent / chemical gels which are covalently cross-linked (replacing hydrogen bond by stronger and stable covalent bonds) networks. They attain an equilibrium swelling state which depends on the polymer-water interaction parameter and the crosslink density. Reversible / physical gels are the gels when the networks are held together by molecular entanglements, and / or secondary forces including ionic, hydrogen bonding or hydrophobic interactions. In physically cross-linked gels, dissolution is prevented by physical interactions, which exist between different polymer chains. All of these interactions are reversible, and can be disrupted by changes in physical conditions or application of stress [20-22].

2.1 Reversible/physical gels: They are prepared by various methods e.g. Warm a polymer solution to form a gel (e.g., PEO-PPO-PEO copolymers in H2O) [23, 24], Cross-linking of polymer in aqueous solution using freeze-thaw cycles (e.g., freeze-thaw PVA in aqueous solution) [25], Cool a polymer solution to form a gel (e.g., agarose or gelatin in H2O) [26], Lower pH to form an H-bonded gel between two different polymers in the same aqueous solution (e.g., PEO and PAAc) [27], Mix solutions of a polyanion and a polycation to form a complex coacervate gel (e.g., sodium alginate plus polylysine) [28].

2.2 Irreversible/chemical gels: They are also prepared by various methods e.g. crosslink polymers in the solid state or in solution with radiation (e.g., irradiate PEO in H2O) [29], chemical crosslinkers (e.g., treat collagen with glutaraldehyde or a bis-epoxide) [30], multi-functional reactive compounds (e.g., PEG + diisocyanate = PU hydrogel) [31], copolymerize a monomer + crosslinker in solution (e.g., HEMA + EGDMA) [32], copolymerize a monomer + a multifunctional macromer (e.g., bis-methacrylate terminated PLA-PEO-PLA + photosensitizer + visible light radiation), chemically convert a hydrophobic polymer to a hydrogel (e.g., partially hydrolyse PVAc to PVA or PAN to PAN/PAAm/PAAc) [33].

3. Properties of hydrogels:

Hydrogel materials are increasingly studied for applications in biological sensing, drug delivery and tissue regeneration for a number of reasons like hydrogels provides a convenient way of administration, hydrogels three dimensional aqueous structure provide suitable environments for molecular-level biological interactions, many hydrogels provide inert surfaces that prevent nonspecific adsorption of proteins, biological molecules can be covalently incorporated into hydrogel structures which are otherwise hard to do by other processes, hydrogel mechanical properties are highly tunable, for example elasticity can be tailored by modifying cross-linkers, hydrogels can be designed to change properties (e.g. swelling/collapse or solution-to-gel transitions) in response to externally applied triggers, such as temperature, ionic strength, solvent polarity, electric/magnetic field, light, or small (bio) molecules, hydrogels can be designed to act on specific part or parts of body, hydrogels provide magnificent alternative to organ transplant, hydrogels are most importantly very economical and biocompatible compared to other alternatives, hydrogels are biodegradable and do not produce toxic end products.

3.1 Mechanical properties of the hydrogels:

A common method of increasing the mechanical strength is by increasing the crosslinking density, resulting in the formation of stronger gels, but with the increase in crosslinking density there is also a decrease in the % elongation of the hydrogels i.e. the hydrogels become brittle in nature. Hence, depending on the desired properties of the final products an optimum degree of crosslinking should be used. Copolymerization with a co-monomer, which may increase the H-bonding within the hydrogel, has also been utilized by many researchers to achieve desired mechanical properties [38].

3.2 Water Content and Swelling ratio:

The polymer chains of hydrogels interact with the solvent molecules and tend to expand to the fully solvated state. On the other hand cross linked structure works as the reactive force to pull back the polymer chain in size. This reactive force is described by Flory Rubber Elasticity Theory, the counter balance of the expanding and retracting force attains to equilibrium in particular solvent at particular temperature [30].

To describe the swelling behavior of hydrogels, their swelling ratio or water content is currently used in most cases. The water content of hydrogel is expressed in terms of percentage of water by weight.

3.3 Permeability:

The permeability of target molecules is of utmost importance for medical application of hydrogels. For instance, oxygen permeation for contact lens, nutrient and immunological biosubstance transport for immunoisolation and releasing drugs and proteins for drug delivery systems are more characteristic for each applications [39].

4. Preparation of hydrogels

Several techniques have been reported for the synthesis of hydrogels. The first approach involves copolymerization/crosslinking of co-monomers using multifunctional co-monomer, which acts as crosslinking agent. The polymerization reaction is initiated by chemical initiator. The polymerization reaction can be carried out in bulk, in solution, or in suspension. The second method involves crosslinking of linear polymers by irradiation, or by chemical compounds. The monomers used in the preparation of the ionic polymer network contain an ionizable group, a group that can be ionized, or a group that can undergo a substitution reaction after the polymerization is completed. As a result, hydrogels synthesized hydrogels contain weakly acidic groups like carboxylic acids or a weakly basic group like substituted amines, or a strong acidic and basic group like sulfonic acids and quaternary ammonium compounds respectively. Some of the commonly used cross linking agents include N,N-methylenebisacrylamide , divinyl benzene, and ethylene glycol dimethacrylate [40].

The methods for synthesis of hydrogels are discussed here.

4.1 Solution polymerization/crosslinking:

In solution, co-polymerization/crosslinking reactions and ionic or neutral monomers are mixed with the multifunctional crosslinking agent. The polymerization is initiated thermally by UV-light or by redox initiator system. The presence of solvent serves as heat sink and minimizes temperature control problems. The prepared hydrogels need to be washed with distilled water to remove the unreacted monomers, crosslinking agent and the initiator. The best example is preparation of poly (2 hydroxyethyl methacrylate) hydrogels from hydroxyethyl methacrylate, using ethylene glycol dimethacrylate as crosslinking agent. Using the above method, a great variety of hydrogels has been synthesized. The hydrogels can be made pH- sensitive or temperature sensitive, by incorporating methacrylic acid, or N isopropylacrylamide , as monomers [41].

4.2 Suspension polymerization:

This method is employed to prepare spherical hydrogel microparticles with size range of 1 µm to 1mm. In suspension polymerization, the monomer solution is dispersed in the non-solvent forming fine droplets, which are stabilized by the addition of stabilizer.The polymerization is initiated by thermal decomposition of free radicals. The prepared microparticles then washed to remove unreacted monomers, crosslinking agent, and initiator. Hydrogel microparticles of poly(vinyl alcohol) and poly(hydroxy ethyl methacrylate) have been prepared by this method [42].

4.3 Polymerization by irradiation:

High energy radiations like gamma and electron beam have been used to prepare the hydrogels of unsaturated compounds. The irradiation of aqueous polymer solution results in the formation of radicals on the polymer chains. Also, radiolysis of water molecules results in the formation hydroxyl radicals, which also attack the polymer chains, resulting in the formation of macroradicals. Recombination of the macroradicals on different chains results in the formation of covalent bonds, and finally a crosslinked structure is formed. During radiation, polymerization macroradicals can interact with oxygen, and as a result, radiation is performed in an inert atmosphere using nitrogen or argon gas. Examples of polymers crosslinked by radiation method include poly (vinyl alcohol), poly (ethylene glycol), poly (acrylic acid). The major advantage of polymerization by irradiation over chemical initiation is the production of relatively pure, residue-free hydrogels [43-49].

4.4 Chemically crosslinked hydrogels:

Polymers containing functional groups like -OH, -COOH, -NH2, are soluble in water. The presence of these functional groups on the polymer chain, can be used to prepare hydrogels by forming covalent linkages between the polymer chains and complementary reactivity, such as amine-carboxylic acid, isocyanate-OH/NH2 or by Schiff base formation [50].

The crosslinking agents react with the functional groups present on the polymer via addition reaction. These crosslinking agents are highly toxic and hence unreacted agents have to be extracted. Moreover the reaction has to be carried out in organic solvent, as water can react with the crosslinking agent. The drugs have to be loaded after the hydrogels are formed, as a result the release will be typically first order [51, 52].

Crosslinking between polymers through hydrogen bond formation occur as in the case of poly (methacrylic acid) and poly (ethylene glycol). The hydrogen bond formation takes place between the oxygen of poly (ethylene glycol) and carboxylic acid group of poly (methacrylic acid). Carriers consisting of networks of poly (methacrylic acid-ethylene glycol) show pH dependent swelling due to the reversible formation of interpolymer complex, stabilized by hydrogen bonding between the etheric groups of the grafted poly (ethylene glycol), and the carboxylic acid protons of the poly (methacrylic acid) [53].

4.5 Physically crosslinked hydrogels:

Most of the covalent crosslinking agents are known to be toxic, even in small traces. A method to overcome this problem and to avoid a purification step, is to prepare hydrogels by reversible ionic crosslinking . Chitosan , a polycationic polymer can react with positively charged components, either ions or molecules, forming a network through ionic bridges between the polymeric chains. Among anionic molecules, phosphate bearing groups, particularly sodium tripolyphosphate is widely studied.. Ionic crosslinking is a simple and mild procedure. In contrast to covalent crosslinking, no auxiliary molecules such as catalysts are required. Chitosan is also known to form polyelectrolyte complex with poly (acrylic acid). The polyelectrolyte complex undergoes slow erosion, which gives a more biodegradable material than covalently crosslinked hydrogels [54, 55].

5. Application of hydrogels

There are a number of applications associated with hydrogels due to their unique properties discussed earlier. Some of them are highlighted here.

5.1 Agricultural Hydrogels:

The need for improving the physical properties of soils to increase productivity in the agricultural sector was felt in the 1950s. This led to the development of water-soluble polymeric soil conditioners. Other polymers such as polyacrylamide which proved to be more efficient at lower application rates revived interest in the field. These polymers were developed to improve the physical properties of soil in view of: increasing their water-holding capacity, increasing water use efficiency, enhancing soil permeability and infiltration rates, reducing irrigation frequency, reducing compaction tendency, stopping erosion and water run-off increasing plant performance (especially in structure-less soils in areas subject to drought).

Researchers have reported that the use of hydrogels increases the amount of available moisture in the root zone, thus implying longer intervals between irrigations. It must be pointed out that the polymers do not reduce the amount of water used by plants. The water-holding capacity depends on the texture of the soil, the type of hydrogel and particle size (powder or granules), the salinity of the soil solution and the presence of ions. Cross-linked polyacrylamides hold up to 400 times their weight in water and release 95% of the water retained within the granule to growing plants. In general, a high degree of cross-linkage results in the material having a relatively low water-retention capacity. It was suggested that these divalent cations develop strong interactions with the polymer gels and are able to displace water molecules trapped within the polymer [56]. Moreover, the use of hydrogels leads to increased water use efficiency since water that would have otherwise leached beyond the root zone is captured. During hot days, the hair root system of a plant pulls out and depletes most of the water from the area close to the root system, thus causing the plant to go into stress. While increasing the amount of available moisture, hydrogels help reduce water stress of plants resulting in increased growth and plant performance. The performance of the gel on plant growth depends on the method of application as well. It has shown that spraying of the hydrogels as dry granules or mixing them with the entire root zone is not effective. Better results were obtained with layered hydrogels, preferably a few inches below soil surface. Cross-linked polyacrylamide is being considered as a potential carrier for insecticides, fungicides and herbicides [57].

5.2 Liposomal hydrogels and soft contact lenses for the delivery of antibiotics in ophthalmology:

The most common way to improve drug retention on the corneal surface is undoubtedly by using polymers to increase solution viscosity. Currently, two groups of hydrogels are distinguished, namely preformed and in situ forming gels. Preformed hydrogels are simple viscous solutions which do not undergo any modifications after administration [58-60]. In situ forming gels are formulations, applied as solutions, sols, or suspensions, that undergo gelation after instillation due to physico-chemical, changes inherent to the eye. This has been reported that the various factors are used such as temperature, pH, and ion induced, in situ-forming polymeric systems used to achieve prolonged contact time of drugs with the cornea and increase their bioavailability [61].

5.3 Temperature-sensitive hydrogels with molecule-recognition properties:

Temperature-sensitive hydrogels have attracted great interest as smart materials for numerous potential applications [62]. Recently, a new type of temperature-sensitive hydrogels with molecular or ion-recognition property has been developed. These smart hydrogels can change their phase or other properties when recognizing special molecules, so they are considered to be of great potential to be applied in biomedical and pharmaceutical fields, such as drug delivery systems, bioseperations , sensors and actuators, and heavy-metal adsorptions. Cyclodextrins and crown ethers are two kinds of typical host compounds which have remarkable recognition ability towards specific moles through supramolecular "host-guest" complexation. Cyclodextrin is able to selectively associated with guest molecules having the similar size with its cavity and crown ether can capture specific metal ion when the ion diameter fits its cavity size. Incorporating cyclodextrin or crown ether units into temperature-sensitive hydrogel networks can generate novel molecule-recognition hydrogels that respond to both temperature and specific mol. stimuli. Additional, temperature-sensitive hydrogels with glucose-recognition ability can be prepared by introducing special functional moieties (such as glucose oxide, Con A, and phenyl boronic acid) into the hydrogel networks [63].

5.4 Antibacterial activity:

A series of excellent PVA/CM-chitosan blend hydrogels could be prepared by irradiation technique [64]. Comparing to PVA hydrogels, the characteristics of blend hydrogels such as mechanical property and swelling capacity were significantly enhanced by the addition of CM-chitosan. Especially, it can provide satisfying antibacterial activity against E.coli, thus, can be widely used in the field of biomedicine and pharmacy. In addition, it has been reported that there was a grafting reaction between PVA and CM chitosan molecules besides the cross-linking of PVA molecules under irradiation [65].

5.5 Hydrogels as carriers of nutraceutical substances:

The swelling of soy protein filamentous hydrogels and tablets thereof and the release of riboflavin from these drug delivery devices have been investigated under simulated gastrointestinal conditions in the presence or absence of digestive proteases. Microscopic examination showed riboflavin arranged into crystals dispersed randomly throughout the hydrogel and the tablet powder. Swelling experiments showed a comparable behavior of water uptake for hydrogel and tablet at pH 1.2 as well as tablet at pH 7.5, featuring a low swelling rate. [66].

5.6 Hydrogels for protein adsorption:

Polyvinyl alcohol (PVA), crosslinked with glutaraldehyde hydrogels (PVA/GA), PVA with tetraethylorthosilicate (PVA/TEOS) and PVA/GA/TEOS hybrids with recombinant MPB70 protein (rMPB70) incorporated have been chemically characterized by Fourier transform infrared spectroscopy (FTIR). FTIR spectra of PVA hydrogel samples showed the absorption regions of the specific chemical groups associated with poly (vinyl alcohol) and PVA/GA confirming the formation of crosslinked hydrogel (duplet -CH). It was observed C-H broad alkyl stretching band (n = 2850-3000 cm-1) and typical strong hydroxyl bands for free alcohol (non bonded -OH stretching band at n = 3600-3650 cm-1), and hydrogen bonded band (n = 3200-3570 cm-1). The most important vibration bands related to silane alcoxides have been verified on FTIR spectra of PVA/TEOS and PVA/GA/TEOS hybrids (Si-O-Si, n = 1080 and n = 450 cm-1; Si-OH, n = 950 cm-1). FTIR spectra of f PVA hydrogel with rMPB70 incorporated have indicated the specific groups usually found in protein structures. These results have given strong evidence that recombinant protein rMPB70 was successfully adsorbed in the hydrogels and hybrids networks. These PVA based hydrogels and hybrids were further used in immunological assays (Enzyme-Linked Immunosorbent Assay - ELISA). Tests were performed to detect antibodies against rMPB70 protein in serum samples from bovines that were positive in the tuberculin test. Corresponding tests have been carried out without PVA samples in microtiter plates as control [67].

5.7 Hydrogels in proton and methanol transport through membranes:

When hydrogels like crosslinked poly(vinyl alcohol) (PVA) membranes were prepared using sulfosuccinic acid (SSA) at different crosslinking temperatures. The crosslinked PVA membranes were also synthesized by varying the amount of SSA (5-30 % w/v) in order to achieve desirable proton conductive properties for fuel cell applications. The crosslinked PVA membranes were characterized using an FT-IR spectroscopy, a thermogravimetric analysis (TGA), and a differential scanning calorimetry (DSC). Ion exchange capacities (IECs) of the crosslinked PVA membranes were in the range of 0.5-2.24 mmol/g. The water content was in the range of 10-80%, depending on the amount of SSA containing sulfonic acid group. The proton conductivities and the methanol permeabilities through the membranes were investigated in terms of various crosslinking conditions. Especially, it was found that the SSA used in this study played a decisive role in proton conduction (---SO3−H+) and at the same time acted as a barrier for methanol transport. The proton conductivities and the methanol permeabilities of all the membranes were in the range of 10−3 to 10−2 S/cm and 10−7 to 10−6 cm2/s in the temperature range of 25-50 °C, respectively, depending on the crosslinking conditions [68].

5.8 Hydrogels in drug delivery:

Many current drug delivery mechanisms are invasive, painful, or ineffective. Microscale hydrogels may provide an intelligent means of controlled drug delivery that solves these problems. Drug-infused microscale hydrogels can deliver drug therapies in a sustainable and controllable manner. Furthermore, the drug release kinetics may be tailored by manipulating the shape, size, and density distribution of the microgels during the fabrication process. Microgels may also be fabricated from many different hydrogel polymers; this results in a dramatic variability of drug release mechanisms, many of which are environmentally responsive [69, 70]. Hydrogels exhibiting pH sensitivity, temperature sensitivity, and swelling properties have all been exploited for drug release purposes. For example, pH-responsive microgels comprised of ionic networks containing PEG can be used for the oral delivery of medically relevant proteins such as insulin and calcitonin. Additionally, microgels with specific degradation characteristics can be induced to demonstrate pulsatile release responses upon breakdown. For instance, drugs encapsulated within alginate microgels can be released upon depolymerization of the alginate network, which is triggered through removal of divalent cations in the network. Control over drug release systems can be used in the formation of intelligent materials, which may be utilized in targeted drug delivery methods [71].By engineering the material composition, size, and shape of hydrogel drug delivery vehicles, not only can rates of drug diffusion be methodically managed, but release mechanisms can be made responsive to the surrounding environment. For example, smart microgels infused with cancer drugs could delay elution of their payload until they reach cancer cells. Such systems have great potential to increase the safety and effectiveness of future drugs, while decreasing the invasiveness of delivery mechanisms [72, 73].

5.9 Hydrogels in cell-based diagnostics and screening:

In addition to providing a source of viable cells for tissue replacement therapies, the use of microscale hydrogels for close regulation of the cellular microenvironment may also be utilized in high-throughput experimentation and diagnostic tools. Cells in vivo are exposed to various 3D microenvironmental conditions closely monitored by the body. In vitro culturing conditions often differ vastly from those experienced by cells in native organ systems. In traditional cell culture systems, cell-cell, cell-ECM and cell-soluble factor interactions are often too complicated to control, making it difficult to mimic the native spatial and temporal distribution of cell signaling. In addition, culture dishes offer only a 2D environment, as opposed to the 3D environments encountered by cells in the body. Cells cultured in microscale hydrogels come into contact with a microenvironment much more comparable to that experienced by cells in vivo. As a result, this technique may provide a better tool for in vivo studies on cell-environment interactions. The microscale nature of this technique permits combination with high-throughput technologies when studying many microenvironmental factors at once. One particularly promising application for microgels and micropatterned hydrogels is for cellular coculture experiments. By using natural hydrogel polymers such as HA and collagen, it has been demonstrated that effective cell cocultures can be performed using micropatterned hydrogels [74, 75]. In one example, a microwell patterned layer of HA was used as a template to control cell-cell interactions.

5.10 Hydrogels as biosensors:

Hydrogels as integral components of microsensors. The incorporation of hydrogels into biological sensors could also result in a new class of sensing technologies. Hydrogels perfusability enables the embedding of a large number of biological detection factors, such as antibodies, within a gel's 3D structure. When compared to antibody immobilization on a 2D surface, microgels should provide a significant sensing advantage by increasing the density of the receptor molecule. One example is a protein-sensitive, environmentally responsive hydrogel MEMS sensor. In this sensing mechanism, an antibody-laden hydrogel is micropatterned onto a MEMS microcantilever. Then, as the hydrogel absorbs the target protein, the hydrogel swells or contracts, causing the MEMS cantilever to deflect. The degree of deflection is measured using refractive optics.

Micropatterned hydrogel MEMS cantilever sensors have been used for a variety of sensing applications. For example, similar techniques have been demonstrated using pH- or thermally sensitive hydrogels, in which pH or temperature changes (respectively) cause swelling that deflects a microcantilever [76, 77]. Similar work has also demonstrated microcantilever hydrogel sensors capable of accurately sensing.

To develop analyte sensing technologies, several groups have micropatterned hydrogels onto MEMS electrodes using photolithography. By localizing oxidoreductase enzymes onto the microelectrodes, analyte levels can be accurately detected by measuring changes in the conductivity of the micropatterned hydrogel [78-80].

5.11Hydrogels as components of microdevices:

Environmentally responsive hydrogels, whether chemically, thermally, or mechanically activated, have been used in microdevices for a variety of purposes such as controlled microreactors , valves, and pumps [81]. For example, pH-sensitive photocrosslinkable PEG-based hydrogels have served as functional microvalves. As the pH of the microfluidic solution changes, so the geometry of the valve, therefore allowing for effective sealing and opening of the microfluidic pathway [82]. Another method used differential swelling between basic and acidic ionic gels to enable controllable valves [83]. By utilizing a bimetallic strip-like construct, it was possible to force a hydrogel construct to open in a particular direction, depending on the pH of the surrounding medium. Other signaling methods, such as photoactivity and thermal, chemical and electrical stimulation have also been demonstrated [84]. While valves are only one example of environmentally responsive hydrogel structures, the potential implication of microactuated hydrogel constructs could have far reaching applications. For example, chemically actuated hydrogel pumps may one day enable tissue engineering constructs that self perfuse. Micropatterned PEG hydrogels also have applications in microdevices . For example, micropatterned PEG hydrogels embedded within microfluidic channels have been shown to enable control over the location of cells and proteins within the microfluidic channel. The ability to precisely control both cell and protein location can be used to perform cell- or protein-based assays or to create controlled microreactors . It has also been shown that PEG microstructures within microfluidic channels are capable of capturing and localizing cells in regions of low shear stress . Capturing cells from flowing solutions is useful for many applications , such as sensing, cell separation, and cell-based microreactor [85].

5.11Cell encapsulation and immunoisolation:

Hydrogels can also be used to encapsulate cells in microcapsules. This can prevent cell aggregation, which can be useful for stirred bioreactor experiments. Furthermore, cell-laden hydrogels can be coated with various polymers to immunoisolate the encapsulated cells from the surrounding environment. Hydrogel materials express physical characteristics that are similar to the ECM and exhibit high permeability to oxygen, nutrients, and other metabolites, thus providing a favorable environment for cell survival. Typically, the procedures used to encapsulate cells within a hydrogel result in high cell viability, often only requiring that a cell suspension be mixed with the hydrogel precursor prior to crosslinking of the network. When encapsulating cells within hydrogels, it is important to consider the photoinitiator concentration, UV exposure length, macromer concentration, and thermal exposure, since they all affect cell viability. When forming a gel, a balance is needed between the desired mechanical characteristics and long term cell viability. Several studies have demonstrated long-term viability for hydrogel encapsulated cells, especially in microgel structures which encourage effective nutrient and oxygen perfusion. These studies also show that hydrogel cell immunoisolation is useful because it can protect allogenic or xenogeneic cells from the host's immune system within a semipermeable membrane. For example, functional pancreatic cells may be immunoisolated in hydrogel and implanted into an allogenic host [86].

5.12 Diagnostics and microdevices:

Hydrogels can be used as functional components in microdevices and diagnostic tools. Due to the ease of photolithographic and micromolding techniques, it is possible to incorporate hydrogels cheaply into devices and sensors. The wide range of mechanically and chemically responsive smart hydrogels makes this integration particularly appealing. Engineering the chemical or physical makeup of a hydrogel can predetermine their response to environmental stimuli. These so-called smart or environmentally responsive hydrogels can be designed to respond to a wide range of stimuli, such as changes in pH, pI, and temperature.Thermally responsive hydrogels, such as poly(N-isopropyl acrylamide) (PNIAAm) and its derivatives, have a highly reproducible response to temperatures [87].

.Generally, as the temperature of a hydrogel is increased, its volume will increase until it reaches a critical point, called the lower critical solution temperature (LCST). As the temperature of the gel exceeds the LCST, the gel undergoes a volumetric phase change and begins to shrink. This process is reversible; when the temperature is lowered below the LCST, the hydrogel will return to its original volume. PNIPAAm and other thermoresponsive hydrogels are being studied for a wide variety of tissue engineering and drug delivery applications. Another response mechanism is ionic activation [88]. Examples of ionically responsive hydrogels are poly (acrylic acid), poly (methacrylic acid), polyacrylamide (PAam), poly (diethylaminoethyl methacrylate) and poly (dimethylaminoethyl methacrylate). In general, hydrogels with weakly acidic pendent groups will exhibit swelling as the pH of the surrounding medium increases, whereas hydrogels with weakly basic pendent groups will swell as the pH of the surrounding medium decreases. The determining factors for ionic swelling of hydrogels have been widely studied and include ionization equilibrium, ionic content and polymer structure [89].

5.13 Hydrogel implants in articular cartilage:

In a research it has been indicated that the mechanical behavior of the neoformed surfaces was significantly different from that of normal cartilage. Histological analysis of the repaired defects showed that the hydrogel implant filled the defect with no signs of inflammation as it was well anchored to the surrounding tissues, resulting in a newly formed articular surface. In the case of empty control defects, osseous tissue grew inside the defects and fibrous tissue formed on the articular surface of the defects. The repaired surface of the hydrogel implant was more compliant than normal articular cartilage throughout the 16 weeks following the operation, whereas the fibrous tissue that formed postoperatively over the empty defect was stiffer than normal articular cartilage after 5 weeks. This stiffness started to decrease 16 weeks after the operation, probably due to tissue degeneration. Thus, from the biomechanical and histological point of view, the hydrogel implant improved the articular surface repair [90].

5.14 Hydrogels- An Alternative Method for Gene Delivery:

A class of biomaterial that has demonstrated great potential for application in both biomedical and pharmaceutical fields is hydrogels. These three-dimensional hydrophilic polymeric networks (natural or synthetic) are classified on the basis of the type of cross-linking (chemical or physical) present in the network. The chemical gel is characterized by covalent bonds whereas the physical gel is produced via a physical association between polymeric chains or nanoparticles, although there are cases in which both coexist in one hydrogel. Natural hydrogels resemble a variety of living tissues and thus possess a range of biomimetic properties. It has been reported in several researches that modification of hydrogel composition may lead to effective targeting and delivery of nucleic acids to specific cells for gene therapy.

Injectable polymeric environmentally sensitive hydrogels offer several advantages over its implantable cousin. Favorable characteristics include (i) its non-invasive nature, (ii) aqueous preparation of formulations and (iii) it can undergo in situ hydrogel formation negating the need of surgical implantation and/or removal after treatment. With respect to gene delivery, current systems that have been investigated utilize inert encapsulation materials that do not aid in efficient cell transfection by the released DNA. For example nonionic polymers embedded with DNA and compacted with other polycations have several problems including DNA loading efficiency compaction, stability of released DNA in presence of degradation products and released factor(s) aggregation. Novel pentablock cationic copolymers hydrogels based on Pluronic F127 (an FDA approved compound), offer significant promise as non-viral, non-invasive gene delivery devices due to their unique architecture. At present, enhancement of gene transfection rates remains a primary priority in gene therapy treatments. Newly uncovered biomaterials such as hydrogels offer alternatives to the viral vectors with large-scale reductions in adverse side effects allowing scientists to more quickly reach gene therapy goals. The versatility of hydrogels holds tremendous promise in the treatment of many genetic and/or acquired diseases and conditions [91].

5.15 Poly (ethylene glycol)-Containing Hydrogel Surfaces for Antifouling applications in Marine and Freshwater Environments:

The fabrication, characterization and biological evaluation of a thin protein-resistant poly (ethylene glycol) (PEG)-based hydrogel coating have described for its antifouling applications. The coating was fabricated by free-radical polymerization on silanized glass and silicon and on polystyrene-covered silicon and gold. The physicochemical properties of the coating were characterized by infrared spectroscopy, ellipsometry and contact angle measurements. In particular, the chemical stability of the coating in artificial sea water was evaluated over a six-month period. These measurements indicated that the degradation process was slow under the test conditions chosen, with the coating thickness and composition changing only marginally over the period. The settlement behavior of a broad and diverse group of marine and freshwater fouling organisms was evaluated. The tested organisms were barnacle larvae (Balanus amphitrite), algal zoospores (Uiva linza), diatoms (NaVicula perminuta) and three bacteria species (Cobetia marina, Marinobacter hydrocarbonoclasticus, and Pseudomonas fluorescens). The biological results showed that the hydrogel coating exhibited excellent antifouling properties with respect to settlement and removal [92].

5.16 Hydrogel transdermal patch for medical and cosmetic applications:

A hydrogel transdermal drug delivery patch technologies and product designs using highly biocompatible and skin friendly hydrogel materials with high water contents which have benefits of fast skin hydration, soothing and drug delivery effect. The hydrogel matrix with water serves as a reservoir and medium for the slow release of active ingredients. The target markets of the hydrogel transdermal drug delivery patch are medical and cosmetic areas. The hydrogel base can be modified easily to get variable physical properties e.g., softness, stickiness, water content, the diffusion rate of active ingredients etc. according to the specific application area and the medicinal recipe. The new product design can be achieved through simple modification and/or combination of three different types of hydrogels two types of non-cross-linked polymer hydrogels and one network polymer hydrogel. This diversity opens new possibilities of hydrogel application in the areas, where still ointments and pills dominate, but skin hydration and constant dosage of medicine have merits to reduce pains and heal fast e.g. for pain relief, heal crack, lip herpes or atopic neurodermatitis [93]. The hydrogel developed for cooling and soothing contains plenty of water and lowers skin temperature up to 5°C in a few seconds. It can protect the skin from further cell damage in the case of burn. This hydrogel is not sticky and thus allows its application on burned and damaged skin. Especially, it provides highly moist environment immediately and relief from pain, because the exposed nerve endings are cushioned and protected from the moisture. This is designed for burn first aid and after sun burn treatment, but it can be very well applied to cosmetic products, as it provides fast transfer of nutrients through rapid skin hydration and perfect contour ability on the skin [94, 95].

5.17 Post-infarct treatment with an erythropoietin-gelatin Hydrogel for cardiac repair:

Erythropoietin (EPO) exerts its haematopoietic effects by stimulating the proliferation of early erythroid precursors and the differentiation of later precursors of the erythroid lineage. The recombinant form of human EPO is now used frequently in the clinic to treat anaemia associated with end-stage renal disease. Interestingly, recent studies have suggested that EPO also exerts a cardioprotective effect in cases of acute myocardial infarction (MI). With systemic administration, however, the beneficial effects in the context of MI are only observed when large doses of EPO are administered, which are frequently accompanied by polycythaemia and, therefore, the potential for thrombo-embolic complications. Thus, in order to use EPO clinically as a cardioprotective agent, one must find a useful way to avoid dangerous side effects such as polycythaemia. To address that issue, a biodegradable gelatin hydrogel patch incorporated with EPO has been developed which can be administered without inducing polycythemia [96].

5.18 Hydrogels as dental adhesives:

The invention provides new thermoplastic hydrophilic polymers that form hydrogels in water. Specifically, this invention provides a hydrogel based denture adhesive and thermoplastic hydrophilic polymer system that effectively holds dentures in place, allows for easy removal of the denture on demand and effectively provides comfort as a denture cushion. More importantly, this invention provides true hydrogel based daily use products for denture wearers. This invention utilizes the advantages of the hydrogels to prepare disposable denture adhesive/cushion devices (hydrogel based denture adhesive/cushion for daily replacement). This device is able to swell upon the absorbance of water and provide a soft cushion with highly flowable thermoplastic hydrogel that can fit voids and adjust thickness according to the imposed force (bite). A disposal denture adhesive/cushion device prepared from hydrogels in this invention contains 50 to 90 percent of water. The hydrogels of this invention are either a highly flowable gel under pressure or cured in situ to adapt the shapes between oral cavity and denture.

5.19 Hydrogels in wound healing:

The use of hydrogels in the healing of wounds dates back to late seventies or early eighties. As mentioned earlier, hydrogel is a crosslinked polymer matrix which has the ability to absorb and hold water in its network structure [97]. Hydrogels act as a moist wound dressing material and have the ability to absorb and retain the wound exudates along with the foreign bodies, such as bacteria, within its network structure. In addition to this, hydrogels have been found to promote fibroblast proliferation by reducing the fluid loss from the wound surface and protect the wound from external noxae necessary for rapid wound healing. Hydrogels help in maintaining a micro-climate for biosynthetic reactions on the wound surface necessary for cellular activities. Fibroblast proliferation is necessary for complete epithelialisation of the wound, which starts from the edge of the wound [98]. Hydrogel sheets are generally applied over the wound surface with backing of fabric or polymer film and are secured at the wound surface with adhesives or with bandages [99, 100].

5.20 Hydrogels in tissue engineering:

Tissue engineering (TE) is a multidisciplinary approach and involves the expertise of materials science, medical science and biological science for the development of biological substitutes (tissue/ organ) [101]. It is emerging as an important field in regenerative medicine. It has got three basic components namely, cells/tissues, scaffolds and implantation and/or grafting. The principles of TE have been used extensively to restore the function of a traumatized/malfunctioning tissues or organs. In practice, the patient's cells are generally combined with a scaffold for generating new tissue. A scaffold can be made up of either ceramic or polymer, which can be either permanent or resorbable. The pore size of the scaffolds should be >80 μm. This is necessary for the cell migration into the core of the 26 scaffolds, angiogenesis and supply of nutrients to the cells and to take away the metabolic products away from the cells [102-105]. The scaffolds made up of polymers are generally hydrogels. Every year thousands of people are victims of tissue loss and organ failure caused either due to disease or trauma [106].

5.21 Hydrogels for healing diabetic foot ulcers:

Debridement using hydrogel appears to be more effective than standard wound care for healing diabetic foot ulcers [107]. Studies were selected if they were randomised controlled trials (RCTs) that included patients with type 1 or 2 diabetes with active foot ulcers, assessed the effectiveness of treatment with any debridement method compared with no debridement or other debridement methods, and measured complete wound closure or rate of reduction in wound size [108].

5.22 Hydrogels as Gastric retention devices:

Over the last 2 decades there has been a multitude of approaches using well-established principles to prevent the dosage form from exiting the pylorus during gastric emptying [109, 110] reviewed different gastroretentive drug delivery systems and highlighted the use of SPHs as novel orally administerable gastroretentive platforms. Gastric retention devices may be extremely useful for the delivery of many drugs. Such devices would be most beneficial for drugs that act locally in the stomach (e.g., antacids and antibiotics for bacteria-based ulcers), or for those drugs that are primarily absorbed in the stomach [111]. For drugs that have a narrow absorption window (i.e., mainly absorbed from the proximal small intestine), such as riboflavin, levodopa , p-aminobenzoic acid, a controlled release in the stomach would improve bioavailability. For drugs that are absorbed rapidly from the gastrointestinal tract, bioavailability could be improved by a slow release from the stomach. Gastric retention devices can further be used for drugs that are poorly soluble in an alkaline pH medium or for drugs that degrade in the colon (e.g., metoprolol). Prolonged gastric retention, however, is not desirable for all drugs. Gastric retention is not desirable for aspirin and non-steroidal anti-inflammatory drugs, or for drugs that are unstable in acidic pH. In addition, for those drugs that are primarily absorbed in the colon, a longer gastric retention may not be necessary because the time spent in the colon can sustain blood levels for up to 24 h [112].

5.23 Hydrogels in Fast-dissolving tablets:

Fast-dissolving tablets are orally administered without the need for water and swallowing. This feature is especially beneficial to children and the elderly. Freeze-drying, sublimation and direct compression are utilized to make fast-melting tablets. The first two methods make tablets that dissolve in 5-15s, but the technology is rather expensive and tablets are not mechanically strong. One way of making fast-dissolving tablets by the direct compression method is to add fine particles of SPH to the granulation or powder formulation. The SPH microparticles within the tablet core expedite water absorption by an increased wicking mechanism. The disintegration time and tensile strength of the tablet as a function of active concentration, SPH particle size, filler and tableting pressure has been evaluated [113].

5.24 Hydrogels in development of diet aid:

Diet soft drinks, meal replacement shakes, diet drugs and even surgical methods have been used to lose weight .Because of their rapid and extensive swelling, the SPHs can theoretically occupy a significant portion of the stomach space, leaving less space for food, and hence suppressing appetite. This type of system has the potential to facilitate weight loss in obese people. The major challenges to using SPHs as a weight loss aid will be to maintain the integrity and volume of the swollen SPH for a substantial period of time [114].

5.25 Hydrogels for the Controlled Release of Pharmaceutical Proteins:

Hydrogels are versatile delivery systems for protein delivery. Basically, one can choose from a long list of potential sources. One completely synthetic (Polyactive) and one of a hybrid type, both modified dextrans. These examples offer numerous opportunities for achieving prolonged- and delayed-patterns, which makes them excellent candidates for improving the performance of a large number of pharmaceutical proteins that lack proper pharmacokinetic and pharmacodynamic properties [115, 116].

5.26 Chemoembolization and occlusion devices:

Chemoembolization is a combined method of embolization and chemotherapy. Embolization has been used for cancer treatment by restricting the oxygen supply to the growing tumours. This method could be combined with chemotherapeutic agents to achieve local delivery and low systemic toxicity. A chemotherapeutic agent and an anti-angiogenic agent could be loaded into SPHs for chemoembolization therapy. The strong SPHs would likely be better candidates for this application as they fit better in the blood vessels and provide better blocking [117].

SPHs can also be used to develop biomedical devices for treating aneurysms. After determining the size and shape of an aneurysm site, an equivalent SPH is prepared in smaller size. Because of the rapid and extensive swelling properties, the hydrogel will swell at the aneurysm site and clot the blood. Studies have shown that the SPH results in a 95% aneurysm occlusion without parent artery compromise and without inflammatory response. New occlusion devices are also under investigation. One such system, known as Hydrocoil, consists of SPH and platinum coils, and is currently under development [118].