INTRODUCTION:

1.1 Hydrogel:

A three-dimensionalnetwork of polymers made of natural or synthetic materials possessing a high degree of flexibility due to large water content is called hydrogels. Hydrogels with characteristic properties such as desired functionality reversibility, stabilizability, and biocompatibilityto meet both material and biological requirements to treat the tissues and organs to interact with the biological system^1-3. Gelatin and agar were also known and used for various applications in hydrogel as a class of material for biomedical applications.

In 1936 Dupont’sscientists published a paper on recently synthesized methacrylic polymer. In this paper poly [2- hydroxyethyl methacrylic] [poly HEMC] was mentioned⁴. whichterle and lim described the polymerization of HEMA and cross-linking agents by using water and other solvents. Instead of brittle polymers, they get soft, water-swollen, elastic, and clear gel. This transformation led to the modern field of biomedical hydrogels as we studying them today⁴.

Limitations of hydrogel technologiesare less solubility high crystallinity non -biodegradability unfavorable mechanical and thermal properties and also unreacted monomers, use of toxic crosslinkers. Therefore the evaluation of these properties with a combination of natural and synthetic polymers with know characters like biodegradable solubilities crystallinity and biological activities⁵. The pH-sensitive hydrogels are prepared by using based on the combination of different polymers like chitosan and sodium alginate to make a new drug delivery material which delays the drug release property of chitosan at high ph and sodium alginateat low ph. Chitosan could form polyelectrolyte complexation with sodium alginate in simulated gastrointestinal fluid-like chitosan which would extenddrug release ability.The various kinds of crosslinkers (for example Ca²⁺,2n² +, and 2⁺) would be applied to improve the properties of the hydrogel⁶. The chemical and physical crosslinking agents maintain the 3D structure of hydrogel during swelling⁷.

Iwona Gibas et al.⁸ describe that the swelling of hydrogel is a complex process comprising severalsteps, In the first step, the polar hydrophilic group of hydrogel matrix is hydrated by water, which appears in the form of primary bound water. In the second step, the water also interacts with the exposed hydrophobic groups, which appear in the form of secondary bound water. The primary bound water and the secondary bound water both form the total bound water. In the third step, the osmotic driving force of the network towards infinite dilution is resisted by the physical or chemical crosslinks, so additional water is absorbed. The water absorbed into the equilibrium swelling is called the bulk water or the free water, which fills the spaces between the network or chains and the center of the larger pores⁹.

1.2. Brief History of Hydrogels:

The term hydrogel dates back to 1894 when this term was used by Lee etal¹⁰. for colloidal gels of certain inorganic salts. These gels are quite the opposite of the materials which are described by the term hydrogel today¹¹. The first-ever hydrogel reported in 1949 for biomedical implant was poly (vinyl alcohol) cross-linked with formaldehyde and marketed with the trade name Ivalo¹². Later in 1958, Danno prepared poly (vinyl alcohol) hydrogels cross-linked bypassinggamma-irradiation through an aqueous solution¹³. The synthesis of poly (2-hydroxyethyl methacrylate) (pHEMA) gels for contact lens application by Wichterle and Limin 1960 was the revolution for present-day hydrogelS¹⁴.

2. Drug Release Mechanism of pH-Sensitive Hydrogels:

There are different release mechanisms of entrapped/encapsulated drugs in hydrogels such as diffusion-controlled, swelling-controlled, and chemically controlled mechanisms. The diffusion-controlled mechanism is the most acceptable one and its drug release model follows Fick’s law of diffusion. The porosity of the hydrogels is related to the diffusion coefficient of the hydrogels if the molecular dimensions of the drug molecules are much smaller than the pore size of the porous hydrogels. When the pore size in the hydrogels and the size of the drug molecules are comparable, the release of the drug molecules is hindered by the crosslinked polymer chains. As a result, the diffusion coefficient is decreased. If the rate of drug release exceeds the rate of swelling then drug release follows a swelling controlled mechanism¹⁵. This involves absorption of water molecules followed by desorption of the drug. Free interstices between intermolecular chains allow the solvent to penetrate the surface of the hydrogels when they are in contact with water or certain physiological solutions. The solvent moving in develops stress responsible for the increase in distance between the polymer chains (polymer chain relaxation) leading to swelling. This swelling process is accompanied by desorption of the drug and its controlled release^16,17.

If the entrapped molecules in the hydrogels network are smaller such as peptides/proteins, their diffusion is easy and their release takes place by a diffusion-controlled mechanism whereas for larger entrapped molecules like plasmid DNA, diffusion is not easy and their release from the matrix follows a chemically controlled mechanism. Drug release due to the reactions of hydrogels (hydrolytic or enzymatic degradation of polymer chains) is said to follow a chemically controlled mechanism¹⁸. It is further categorized as (i) a kinetically controlled release mechanism (ii) a reaction diffusion-controlled mechanism. In the former case, there is negligible diffusion and the bond cleavage in the polymer chains (polymer degradation) dominates which is the rate-determining step, whereas in the latter case diffusion as well as polymer reactions (polymer degradation) collectively explain the drug release¹⁵.

Figure 1: (a) pH-dependent ionization of specific acidic or basic functional groups on hydrogel chains responsible for swelling, (b) pH-dependent swelling and drug release mechanism¹⁵

3. Structural chemistry of the hydrogel:

The solid portion of the hydrogel is a network of cross-linked polymer chains, a 3D network usually referred to as a mesh as shown in Fig, with the spaces filled up with a fluid, normally water. The meshes hold the fluid and impart an elastic force that can be completed by the expansion and contraction of the hydrogel, and therefore are responsible for the solidity of the hydrogel. The ionic phase of hydrogels usually consists of ionizable groups bound onto the polymer chains and several mobile ions, including counter-ions and co-ions due to the presence of the electrolytic solvent, which surrounds the hydrogel.

Das¹⁹ reported that interpenetrating polymers or networks (IPN) are generally formed of two or more polymer networks through the swelling of the first network in a solvent containing monomers, which then forms the second intermeshing network structure. The double networks of the IPN would either be hydrophobic or hydrophilic with the greater importance being holding the properties of the combination network²⁰.

Figure 2: Structural chemistry of the hydrogel²⁰

4. Unique Properties of Hydrogels:

Hydrogels, when fully swollen, show some unique properties such as being soft and rubbery and having low interfacial tension with water and biological fluids. These properties, especially for the natural hydrogels, make them similar to the extracellular matrix in living tissues^21,22. For hydrogels, there are fewer chances of negative immune response due to low interfacial tension with body fluids which reduces cell adhesion. Many hydrogels have enhanced tissue permeability and drug residence time owing to their mucoadhesive and bioadhesive properties which make them very good vehicles for drug delivery^23,24.

The beauty of natural polymers is that they are non-toxic, biodegradable, biocompatible, abundant, and cheap. However, natural polymer-based hydrogels are poor in mechanical strength. On the other hand, biocompatible synthetic polymer-based hydrogels have good mechanical strength but are expensive, non-biodegradable, and susceptible to shear degradation. To obtain hydrogels with better properties (additive of the two types of polymers), natural polymers (e.g., polysaccharides) have been blended with biocompatible synthetic polymers (e.g., acrylic polymers). This helps to facilitate high drug concentration in the targeted region/tissue and controlled drug release for an extended period. Alternatively, a grafting reaction may be utilized to bind synthetic monomers/polymer onto natural polymer chains to get improved properties ²⁵.

The pores and their sizes in the hydrogel structure play a very important role in deciding their ability to load and release the drug in physiological fluids in vitro and/or in vivo. Porosity, a primary characteristic of hydrogels, can be controlled by tailoring their affinity with water and cross-linking. The affinity of hydrogels for water in turn varies with the number of hydrophilic groups along the polymer chains whereas the cross-linking density is dictated by the concentration of the cross-linker and the time for cross-linking. The release of the loaded drugs may take place by several mechanisms such as swelling control, diffusion control, environmental sensitivity control, and chemically controlled release²⁶.

5. Classification of hydrogels:

Hydrogels are classified based on various factors like biodegradability, type of cross-linking, source, ionic charge, preparation method, physical properties, and the responsive nature of the hydrogels to external stimuli²¹. The complete classification of hydrogels is shown in figure 3.

Table 2: Different stimuli-sensitive hydrogel and their mechanisms.

Nature of stimulus	Stimulus	Mechanism	Example	Ref.
Physical stimuli	Temperature	The shift in temperature changes polymer-polymer and polymer-water interaction responsible for swelling and drug release.	Chitosan-Poly(acrylamide)	40
	Pressure	Swelling under increased pressure and vice versa. This fact is due to an increase in the lower critical solution temperature (LCST) value of hydrogels with pressure. LCST is the temperature below which negative thermoresponsive hydrogels swell.	Poly(N,N-dimethyl acrylamide), Poly(N-isopropyl acrylamide)	41,42
	Light	Exposure to light (UV and visible light) reversibly changes the hydrogel from its flowable form to non-flowable form and vice versa.	Poly(trimethylene iminium trifluorosulfonimide) and 2,6-bis(benzoyl-2-yl)pyridine blend	12,43
	Electric Field	Changes in electrical charge distribution within the hydrogels matrix on the application of electric field cause swelling–deswelling and is consequently responsible for the on-demanding release.	Polythiophene and polypyrrole	41,44
	Magnetic Field	When a magnetic field is applied, it causes pores in the gel to swell leading to drug release.	Magnetite nanoparticles and poly(acrylamide) composite hydrogels	45
	Ultrasound irritation	Exposure to ultrasound temporarily breaks the ionic cross-links in the hydrogels and the drug is released but cross-links are reformed on discontinuation of the ultrasound waves. This facilitates on-demand drug release.	Calcium alginate Poly(lactic acid)	46,47
Chemical stimuli	pH	The shift in pH causes changes in the charge on the polymer chains leading to swelling and drug release. Poly(acrylic acid), Guar gum succinate, Kappa-carrageenan/poly(vinyl alcohol) [35–37] Ionic strength Change in ion concentration also causes swelling and drug release.	Kappa carrageenan-g-poly(acrylic acid) hydrogels	48,49
Chemical stimuli	CO2	In CO2 sensors, a pH-sensitive hydrogel disc comes in contact with a bicarbonate solution. On exposure to CO2, the pH of the solution changes resulting in swelling or deswelling of the hydrogel which causes a change in pressure which is a measure of the partial pressure of CO2.	Poly(2-hydroxyethyl methacrylate)-co- (2-dimethyl aminoethyl methacrylate)	50
	Glucose	Hydrogels show swelling in response to increased glucose concentration. The complex formed between glucose and phenylboronic acid drives the swelling of the hydrogels and consequently insulin release.	Poly(acrylamide)-co-(3-acrylamidophenylboronic acid)	51
	Redox	Disulfide linkages in reduction sensitive hydrogels cleave in the reductive environment (high level of glutathione concentration = 0.5–10 mM) in the intracellular matrix and release bioactive molecules/drugs.	[poly(ethylene glycol) monomethyl ether]-graft-[disulfide linked poly(amido-amine)] and α-cyclodextrin	52
Biological stimuli	Enzyme	Enzymes cause hydrogel degradation and consequently the drug release. This is called a chemically controlled drug release mechanism.	Glycidyl methacrylate dextran-g-poly(acrylic acid)	53
	Antigen	Hydrogels sense the free antigen and undergo swelling followed by drug release.	N-succinimidylacrylate based antigen-antibody entrapment hydrogel	54, 55
	DNA	Grafted hydrogel probes show swelling in the presence of ssDNA.	Single-stranded DNA probe-g-poly(acrylamide) hydrogels	56

8. METHODS:

8.1. Calcium alginate (CA) hydrogel:

Calcium chloride solution of 500mmol and sodium alginate solution of 2% (w/v) were prepared by dissolving the proper amounts of calcium chloride and sodium alginate, respectively, in DDW. The CA beads were prepared by dropwise addition of 10ml of alginate solution into 20ml of calcium chloride solution through a fine stainless steel needle. The distance between the edge of the needle and the surface of the calcium solution was 15cm. The beads were leftin the gelling medium for 15 min, then divided from the solution through a stainless steel grid, and left at room temperature for 15 min before using for further study. In the case of drug-loaded CA beads, the appropriate amount of RF was added to the alginate solution. The mixture was dissolved under magnetic stirring and the formation of the beads was performed by ionic gelation⁵⁷.

8.2. PGMA-g-SA (Glycidyl methacrylate and sodium alginate) hydrogel.

Step -1: For the synthesis of the PGMA-g-SA hydrogels, an emulsion polymerization technique was employed using ammonium peroxy disulfate (APS) as an initiator. The polymerization was carried out in a three-necked flask (100ml) fitted with a condenser and a thermometer. The system also had a nitrogen inlet and was stirred with a magnetic stirrer. SA (1g) and DDW (50ml) were added to the reaction vessel and heated to 65^◦C while flushing nitrogen through the solution. Then the specific amount of GMA and APS (0.15g) was added and the reaction ingredients were stirred vigorously at 65^◦C for 4 h. The prepared stable emulsion was shifted to the Petri dish till gel formation. The PGMA-g-SA hydrogels were cut into pieces with cubic style having dimensions of 5 mm. The PGMA-g-SA hydrogels were rinsed with dichloromethane to eliminatethe residual of the unreacted monomer and PGMA homopolymer. The hydrogels pieces were immersed in ethanol for 7 days for complete removal of unreacted monomer. Finally, the hydrogel pieces were collected and stored at room temperature till further use.

Step-2: Preparation of PGMA-g-SA(Glycidyl methacrylate and sodium alginate) hydrogels loaded with RF drug The same has the above procedure wascarried outexcept adding specific amounts of the drug before finishing the polymerization process. For the formation of drug delivery devices, thehydrogels pieces loaded with RF were left to dry for 2 days by keeping them in desiccators under a vacuum at room temperature⁵⁷.

8.3. Preparation of hydroxyethyl acrylate chitosan by Michael addition reaction:

Step-1: 3g of chitosan is dissolved in 300mL of 1% w/v acetic acid. Then 12g of hydroxyethyl acrylate is added to the solution. The reaction is going to perform at 60°C for 48 h with continuous stirring. After that, the solution was neutralized by adding 10% w/v sodium hydroxide and then precipitated by dropping the solution into acetone. Then that precipitate is washed with plenty of acetone and then followed by drying under vacuum at ambient temperature overnight to obtainhydroxyethyl acrylate chitosan

Step-2: Formulation of pH-sensitive riboflavin hydrogel by using the different ratios of polymer. (Sodium alginate and hydroxyethyl acrylate chitosan)

Hydroxyethyl acrylate and Sodium alginate with the weight ratios of (HC:SA) 75:25, 50:50, 25:75, 0:100 are mixed and dissolved in distilled water under continuous stirring at 70°C.Then solutions are poured into the Petri dish and dried at 40°C to form HC/SA films with a thickness of 100±5µm.The films are then immersed into the solutions containing various divalent cations (0.1 and 0.5M of CaCl2, 0.5M of ZnSO4, 0.5 M of CuSO4) for 30 minutes and dried at 40 °C to obtain HC/SA hydrogel

Step-3: Preparation of drug-loaded HC and SA hydrogel beads

The drug is dispersed in a 10ml solution containing hydroxyethyl acrylate chitosan and sodium alginate. Then the remaining process isthe same as the preparation of blank beads⁶.

9. Evaluation:

9.1. Characterization of the hydrogels:

FT-IR spectra of hydrogels were collected using a Fourier transform infrared spectrophotometer (FT-IR, Perkin Elmer, Spectrum GX, USA). FT-IR spectra were received over a range of 400–4000 cm-1 with a resolution of 4.0 cm-1. The distribution pattern of metal ions within the hydrogels was studied by scanning electron microscope-energy dispersive spectrometer (SEM-EDS, LEO, LEO1455VP, USA)⁶.

9.2. PH is determined by using a sensitive pH meter.

9.3. Swelling behavior:

The degree of swelling was carried out in different fluids (i.e., distilled water for 24 h and SGF for 2 h followed by SIF for 6 h). Dried hydrogels with suitable sizes were weighed and then immersed in 100mL of particular fluids at 37°C. After taking the swollen samples from the fluid, the weights were measured. The degree of swelling was calculated as follows:

Degree of swelling (DS)=M_S-M_I/M_I×100

where Ms and Mi are the weights of the swollen wet hydrogel and the initial dry hydrogel, respectively⁶.

9.4. Degradation behavior of Calcium alginate beads and GMA-g-SA (Glycidyl methacrylate and sodium alginate) hydrogels

To study the degradability ofthe beads and hydrogels, in vitro degradation tests were carried out in phosphate buffer saline (PBS) pH 7.4 at 37^◦C. The degradation procedure was observed by measuring the dry weight loss. Each bead and hydrogel was placed in a vessel comprising 50ml of PBS. At predetermined time intervals, beads and hydrogels were moved from the PBS solution and then dried under vacuum at room temperature to constant weight.

The weight loss ratio (WLR) was calculated by Eq:

WLR (%) = Wo − Wt /Wo × 100

where Wo and Wt are the weights of beads and hydrogels before and after degradation, respectively⁵⁷

9.5. Determination of the drug encapsulation efficiency:

The encapsulation efficiency (EE) was calculated after extracting the drug from the prepared beads and hydrogels. 100mg of drug-loaded beads and hydrogels were isolated in 100 mL PBS (pH 7.4) and stirred for 30 min to confirm the complete extraction of the drug. The mixture was stirred magnetically at 1000rpm for 4 h. The mixture solutions increased to 250mL volumes with PBS (pH 7.4). After centrifuging at 4000 rpm for 30 min, these solutions were diluted and analyzed by a UV–vis spectrophotometer at 445nm. All experiments were done in triplicate in Amber vessels to prevent photodecomposition of RF. The EE of the drug is expressed according to Eq:

Encapsulation efficiency (%) = practical drug loading/ theoretical drug loading × 100⁵⁷.

9.6. In vitro drug release study:

0.15g of paracetamol was filled into the sealed bag formed by HC/SA film. The sealed bags were immersed in 100mL of the SGF for 2 h, then removed and directly immersed in 100mL of the SIF for 6 h (37°C). At particular time intervals, 0.2mL of the fluid was observed and substituted by fresh fluid. The amount of released paracetamol from the sealed bag was determined by the absorbance at 242nm using a UV–vis spectrophotometer. The percentage of released paracetamol was evaluated from standard calibration curves⁶.

9.7. Analysis of in vitro drug release kinetics and mechanism:

The in vitro drug release data were analyzed kinetically using various mathematical models, i.e., zero-order, first-order, Higuchi, and Korsmeyer-Peppas models.

Zero-order model: Q = kt + Q₀

First order model: Q = Q0e^kt

Higuchi model: Q = kt^0.5

Korsmeyer-Peppas model: Q = ktⁿ

where Q denotes the drug released amount in time t, Q₀ is the initial value of Q, k is the rate constant, and n is the release exponent, indicative of the drug release mechanism.

The accuracy of these models was compared by calculation of the squared correlation coefficient (R2 ). In addition, the Korsmeyer-Peppas model is employed to characterize drug release mechanisms: Fickian release (diffusion-controlled release), non-Fickian release (anomalous transport), and case-II transport (relaxation-controlled release). When n is ≤0.5, it is a Fickian release. The n value between 0.5 and 1.0 is defined as a non-Fickian release. When n is ≥1.0, it is case-II transport [6].

9.8. Stability test:

Dried hydrogels of suitable size were weighed, and then placed in different fluids as follows: distilled water for 24 h, SGF for 2 h, and SGF for 2 h followed by SIF for 6 h (temperature was maintained at 37 °C through the immersion). After that, the samples were dried and weighed. The gel content was calculated as follows: Gel content=M_d/M_i×100

where Mi is the initial dry weight of hydrogel and Md is the dry weight of hydrogel after immersing⁶.

10. Application of pH-sensitive hydrogels:

Amongst stimuli-sensitive hydrogels, pH-sensitive hydrogels have been broadly studied and used in biomedical applications, especially in drug delivery applications exploiting the pH variation along the GI tract. pH-sensitive hydrogels find applications in different biosensors (microdevices) like BioMEMS (Biomedical microelectrochemical systems) utilizing pH-sensitive hydrogels consisting of a poly (methacrylic acid) and poly (ethylene glycol) blend⁵⁸. Applications of hydrogels in different biomedical fields are summarized. Aside from the use of pH-sensitive hydrogels in biomedical applications, they are being effectively exploited in the engineering field as microfluidic valves⁵⁹ to control the flow of liquids owing to their swelling and deswelling in response to the pH of the flowing medium. Based on these responses, the pH of the flowing medium opens andcloses the microvalve and consequently controls the flow. The pH-sensitive hydrogels, the kinds of drug-loaded, and their functions^60,61.

Figure 4: Applications of hydrogels in different biomedical fields.

Challenges and Opportunities:

Even thoughpH-sensitive hydrogels have found applications in various fields from drug delivery to tissue engineering applications, there are still challenges to the development of a hydrogel that can behave in the desired manner under acidic and basic conditions. Also, the development of hydrogels that can degrade at the required duration is highly demanded in tissue engineering applications. Similarly, swelling behavior is considered important for hydrogels because fluid uptake is a key factor during tissue regeneration; however, some hydrogels lose their mechanical strength as a result of solution absorption.

There are many fields where pH-sensitive hydrogels have opportunities, for example, in skin tissue regeneration angiogenesis, which is the formation of new blood vessels from existing vessels essential for normal healing. For enhancing angiogenesis, pro-angiogenic agents are very effective whereby pH-sensitive hydrogels would be ideal candidates for their controlled release at the wound site.

CONCLUSIONS:

Biocompatibility, biodegradability, and non-toxicity are the main attributes of any material to be used for biomedical applications. Amongst all the stimuli, pH and temperature exist naturally in the internal environment of the human body. Hence, internal stimuli-responsive hydrogels can be exploited for site-specific drug delivery. The response time of other external stimuli (light, electric field, etc.) responsive hydrogels is very slow. That is the reason why internal stimuli-responsive hydrogels with smaller sizes are usually preferred. The pH-sensitive swelling can be engineered by grafting or copolymerizing certain anionic/acidic monomers (acrylic acid/acrylamide) or cationic groups such as quaternary ammonium groups on polymer chains and can be used for site-specific drug delivery to improve the efficacy ratio. The polymers (e.g., guar gum and dextran) which are susceptible to microbial degradation can be used in modified form with pH-sensitive moieties or blended with pH-sensitive polymers to enhance their acidic pH resistance in the stomach. The drug release mechanism in the intestine simultaneously involves diffusion as well as microbial degradation (chemical release mechanism). In this way, the peptides and proteins can be safely carried through the acidic milieu of the stomach and are released in the less proteolytic environment of the intestine where they can be absorbed easily.

To induce fast responsiveness in hydrogels, the size should be smaller and thinner. Unfortunately, this makes the hydrogels very fragile thus compromising their mechanical strength which is one of the major characteristics required for biomedical applications. To overcome this drawback, researchers are focusing on the synthesis of new polymers by grafting or copolymerization of monomers accompanied by the discovery of novel and non-toxic cross-linkers. These novel syntheses would lead to overall, non-toxic, biocompatible, and biodegradable hydrogels having high drug loading/encapsulation efficiency with a quick response to a stimulus.

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Received on 12.05.2022 Modified on 02.09.2022

Res. J. Pharma. Dosage Forms and Tech. 2023; 15(3):189-197.

DOI: 10.52711/0975-4377.2023.00031

Type	properties	Ref
Alginate	Biocompatible and biodegradable polymer, suitable for in situ injection, crosslinking is under very mild conditions, water-soluble polymer, mechanical weakness, difficulties in handling, storage in solution, and sterilization	27
Chitosan, Chitin	Excellent biocompatibility and good host response, unique biodegradability by lysozyme and other enzymes, high antimicrobial activity, the hydrophilic surface provides easy cell adhesion, proliferation, and differentiation, mechanical weakness, very viscous polymer solution, water-soluble polymer only in acetic medium, high purification cost	28
Starch	Starch Water-soluble polymer, inexpensive, in vivo biodegradable, biocompatible; easy to modify with other polymers, difficulties in crosslinking itself, mechanical weakness, needs modification to enhance cell adhesion	29
Dextran	Water-soluble polymer, in vivo biodegradable by a-amylase, biocompatible, good proliferation and differentiation behavior, expensive polymer, mechanical weakness, needs modification to enhance cell adhesion	28
Glucan	Water-soluble polymer, but yeast-glucan is not soluble in water; biocompatible-biodegradable polymer; has excellent antibacterial and antiviral activities; fast wound healing rate [128]	30
Gelatin	Water-soluble polymer, obtained from various animal by-products forms thermally-revisable and high mechanical hydrogels, widespread in biomedical applications, easily forms films and matrix hydrogels, very viscous polymer solution, very fast biodegradation, lower thermal stability at high temperatures	31
Guare gum	Important properties like biodegradability, nontoxicity,easy availability,and its hydrophilic nature.The most important attribute of guar gum to microbial degradation in the large intestine and it shows swelling at Ph 7.4 in the intestine.	32

Type	Properties	Ref
PNIPAAM	Water-soluble polymer; temperature-responsive polymer; good mechanical properties; biocompatible polymer for tissue engineering and controlled drug delivery; needs chemical crosslinking; needs modification to enhance culture surface for cell delivery; somewhat cytotoxic; significantly lower thermal stability	33
PVP	PVP Water-soluble polymer; excellent wetting properties; swells rapidly; excellent film; non-toxic; biocompatible; wide application in blood plasma expander polymer; high storage stability; mechanical weakness; lower thermal stability	34

Type	Properties	Ref
(MMT)CLAY	Water-soluble polymer; temperature-responsive polymer; good mechanical properties; biocompatible polymer for tissue engineering and controlled drug delivery; needs chemical crosslinking; needs modification to enhance culture surface for cell delivery; somewhat cytotoxic; significantly lower thermal stability	35
ZnO nanoparticle	Inorganic nanoparticles; insoluble in water; have been used for medicine e.g. skin condition powder, and for industrial e.g. portable energy, sensors, wallpapers, and film formation; excellent antibacterial activity at low concentrations; toxic at high concentrations; non-biodegradable	36