INTRODUCTION:

Since the discovery of hydrogel, it has traveled a long way. The pioneer work of developing first synthetic hydrogels by Wichterle in 1954¹ paved the path for establishing hydrogels as versatile candidate for variety of applications ranging from food additives, pharmaceuticals to biomedical implants². In addition, the development of an ever-increasing spectrum of functional monomers and macromers continue to broaden the versatility of hydrogel applications. The prime reasons for using the term versatile for hydrogel is that they can be tailor-made to possess various properties by manipulating the synthetic or processing methods. The physicochemical, mechanical, and biological properties, as well as new functional properties, can be easily modulated. For example, hydrogels can be made to respond to environmental stimuli, such as temperature, pH, light, and specific molecules. Hydrogel had found widespread applications in different technological areas; it has been used as materials for contact lenses and protein separation, as matrices for cell encapsulation, and as devices for the controlled release of drugs and proteins^3,4 (Fig 1). Hydrogels now play a critical role in many tissue engineering scaffolds, biosensor and BioMEMS devices.

Hydrogel is a three-dimensional network of hydrophilic polymer chains held together either by chemical bonds (like covalent bonds) or physical crosslinks (such as entanglements, crystallites)^(3-6) or weak associations

such as van der Waals forces or hydrogen bonds^7,8. The cross-links provide the network structure and physical integrity⁹. Due to the hydrophilic nature of the polymer chains, the network is able to absorb water within its structure and swell without dissolving while maintaining the overall structure⁶.

Cumulative evidence suggests that hydrogels posses such unique properties that make them highly acceptable and sophisticated system for controlled drug delivery. There are numerous advantages responsible for increased popularity of hydrogels among biomaterial scientists.

Fig 1. Cross-linked network in hydrogels

Advantages

· High biocompatibility.

· Interfacial tension- Low interfacial tension with surrounding biological fluid and tissues, which minimizes the driving force for protein adsorption and cell adhesion¹.

· Surface- Low friction surfaces cause no pain and damage to mucous membranes or to the intima of the blood vessel due to soft rubbery nature, and thus no infection and thrombus formation occurs.

· Regulation of release- Regulation of release of the therapeutic agent by controlling water swelling and crosslinking density. It can be applied for both hydrophilic and hydrophobic drugs and charged solutes.

· Relatively easy extraction of polymerization initiators, decomposition products and polymerization solvents prior to in vivo application.

· Hydrogels simulate some hydrodynamic properties of natural biological gels, cells and tissues. Effective in hydrating wound surfaces and liquefying necrotic tissue on the wound surface.

· Non-adherent and can be removed without trauma to the wound bed. "Soothing" effect promotes patient acceptance^2,3,5,7.

Limitations

· Poor mechanical strength and toughness after swelling, but it can be overcome by grafting a hydrogel with good mechanical properties onto the biomaterial.

· Not too absorptive, therefore, hydrogels or hydrogel sheets may not be an appropriate choice for moderate to highly exudating wounds. Require secondary dressings.

· Susceptible to microbial growth due to high moisture content and favourable tissue like structure.

· Natural polymers exhibit chances of evoking immune/inflammatory responses by pathogens.

Hydrogels can be prepared from natural (such as proteins,

polysaccharides, and deoxyribonucleic acids) or synthetic polymers¹⁰(Table 1). Apart from some drawback of natural polymers like insufficient mechanical properties, chances of evoking immune/inflammatory responses by pathogens, they do offer several advantageous properties such as inherent biocompatibility, biodegradability, and biologically recognizable moieties that support cellular activities. Synthetic hydrogels, on the other hand, do not possess these inherent bioactive properties but they usually have well-defined structures that can be modified to yield tailorable degradability and functionality. Natural polymers can be combined with synthetic polymers to obtain combined properties in one hydrogel. For example, the biodegradable property of natural polymers has been combined with several functionalities of synthetic polymers to give new functional hydrogels with biodegradability ¹¹.

CLASSIFICATION:

Hydrogels can be classified in several ways depending on their origin, water content or degree of swelling, method of preparation, types of ionic charges, structural feature of the system, porosity, degradability and cross-linking¹² (Fig 2).

Table 1. List of natural and synthetic polymers used in hydrogel preparation

Natural polymer	Synthetic monomer
Chitosan	Hydroxyethyl methacrylate (HEMA)
Alginate	N-(2-hydroxypropyl) methacrylate (HPMA
Fibrin	N-vinyl-2-pyrrolidone (NVP
Collagen	N-isopropyl acrylamide (NIPAAm)
Gelatin	Vinyl acetate (VAc)
Hyaluronic acid	Acrylic acid (AA)
Dextran	Methacrylic acid (MAA)
	Polyethylene glycol acrylate/methacrylate (PEGA/PEGMA)
	Polyethylene glycol diacrylate/dimethacrylate (PEGDA/PEGDMA)

Properties of Hydrogel

The intermediate nature of hydrogel makes it an ideal material for variety of use. Some of the important properties are discussed below.

Mechanical properties

Mechanical properties of hydrogels are an important consideration during selection of hydrogels for medical (wound dressings), tissue engineering (grafts), Biomedical and pharmaceutical applications. The mechanical strength is very important to assure the integrity of the prepared system. The mechanical strength of the hydrogels can be altered by degree of cross-linking. It is established that increasing the degree of cross-linking the strength of the hydrogel increases but it also lead the hydrogels towards brittleness. Thus, an optimum degree of cross-linking is required to achieve good mechanical properties along with considerable elasticity¹³.

Water carrying properties

The high water content of hydrogels is most important factor which favors its application in biomedicals. In the polymeric network, hydrophilic groups or domains are present that are hydrated in an aqueous environment, thereby creating the hydrogel structure. The crosslinking ratio is one of the most important factors that affect the swelling of hydrogels. The amount of water in a hydrogel and its free vs. bound water ‘character’ determine the diffusion properties of solutes through the hydrogel. Diffusion through hydrogel is best described by Fick’s equation¹⁴. Decrease of the polymer molecular weight lowers swelling and favors dissolution. Drug release depends on the solubility and molecular weight of the drug and is influenced by its concentration inside the gel network.

Bio-compatibility

The soft, smooth, high water carrying capacity and low interfacial free energy (in contact with body fluids) of hydrogels in general makes it biocompatibale. Hydrogels prepared with natural polymer with mild preparation conditions favors bio-compatibility. In vitro cyto-compatibility and hemocompatibilty are important

Fig 2. Classification of hydrogels (hg)

methods to ensure the biocompatibility of the hydrogels. These methods are always preferred over the costly, complicated and invasive in vivo methods. Hemocompatibility studies are also used to ensure the biocompatibility of hydrogels¹⁵. The contact angle is also associated with hydrophilicity, lower will be the contact angle higher will be the hydrophilicity. Hydrophilicity is known to influence the adsorption of blood proteins which in turn regulate a variety of cell behaviors such as cellular attachment¹⁶. Smooth hydrophilic surfaced biomaterials generally possess inherent good blood

compatibility. ASTM provides an in vitro method for the primary evaluation of biomaterials for blood compatibility¹⁷. The method deals with determination of percent hemolysis of citrated goat blood in the presence of biomaterials.

Water vapor transmission rate

Water retention on the surface of hydrogel is an important evaluation parameter for hydrogels used as wound dressing. Water vapor transmission rate (WVTR) is a marker of the moisture retention on the wound surface. It is defined as the quantity of the water vapor under specified temperature and humidity conditions, which passes through unit area of film materials in fixed time and it is measured in grams per square meter (g/m²) over a twenty four hours period according to the US standard ASTM E96–95¹⁸. A wound dressing material having WVTR less than 35 g/m²/hr is defined as moisture retentive. Lower WVTR predicts more rapid healing, re-epithelialization and rapid wound contraction.

METHOD OF PREPARATION:

Hydrogels are prepared by hydrating the cross-linked polymeric/natural materials in water or large water containing biological fluid. Varieties of chemical and physical cross-linking methods are used for designing of biocompatible hydrogels. Chemically cross-linked gels have ionic or covalent bonds between polymer chains. Even though this leads to more mechanical stability, some of the cross-linking agents used can be toxic, and give unwanted reactions, thus rendering the hydrogel unsuitable for biological use. These adverse effects can be removed with the use of physically cross-linked gels. In physically cross-linked gels, dissolution is prevented by physical interactions between different polymer chains. Both of these methods are used today for preparation of synthetic hydrogels.

Chemically Cross-linked Gels

Chemically cross-linked gels constitute major part of conventional hydrogels. The ease, flexibility during preparation and mechanical stability are some common reason for its popularity. Methods under chemical cross-linking include cross-linking of polymers and copolymerization. Cross-linking of polymers utilizes radical polymerization of low molecular weight monomers, or branched homopolymers, or copolymers in the presence of cross-linking agent. This reaction is mostly carried out in solution for biomedical applications. Most hydrophilic polymers have pendant hydroxyl group, thus agents such as aldehydes, maleic and oxalic acid, dimethylurea, diisocyanates etc that condense when organic hydroxyl groups are used as cross-linking agents. Copolymerization reactions are used to produce polymer gels. Many hydrogels are produced by this method for example poly (hydroxyalkyl methylacrylates). Initiators used in these reactions are radical and anionic initiators. Various initiators are used, such as Azobisisobutyronitrile (AIBN), benzoyl peroxide etc. Solvents can be added during the reaction to decrease the viscosity of the solution. The whole cross-linking mechanism consists of four steps: initiation, propagation, cross-linking, and termination. Termination can occur by combination, disproportionation, and chain transfer to monomer. Copolymerization can be induced by high energy radiation such as gamma and electron beam radiation¹⁹ or using enzymes such as transglutaminase²⁰.

Physically Cross-linked Gels

Physically cross-linked gels are now coming into prominence to avoid the toxic effects associated with the use of chemical agents. Several methods have been investigated exploring preparation of physically cross linked gels. These include cross-linking by ionic interactions, crystallization using freeze-thaw process²¹, hydrogen bonds²² and by protein interaction involving genetic engineering²³, These hydrogels can also be used for drug delivery with drug release influenced by concentration, polymer composition, and temperature.

Emerging hydrogels

Multiple factors affect the mass transport of encapsulated molecules including the network crosslinking density, extent of swelling, gel degradation, the size and charge of the encapsulated molecules, and the physical interactions these molecules exhibit themselves and for the polymer matrix. Proper material selection, fabrication process, and surface texture of the device are therefore always critical in designing biocompatible hydrogel formulations for controlled release. Numerous newer hydrogel delivery systems are emerging.

Dynamic hydrogel delivery systems

Dynamic hydrogel delivery systems include degradable hydrogels and stimuli-sensitive hydrogels. Degradable hydrogels eliminate the need for additional surgeries to recover the implanted gels. In addition to hydrolytically degradable hydrogels, synthetic gels incorporating biological moieties that can be degraded enzymatically are also under intensive investigation. One way to fabricate this type of hydrogel is to incorporate peptide substrates for enzymatic hydrogel formation²⁴ and degradation^25,26. Alternatively, polymers that can be naturally degraded by enzymes (e.g. polycaprolactone can be degraded by lipase) can be copolymerized with PEG to form enzymatically degradable gels²⁷. Stimuli-sensitive hydrogels represent another advanced hydrogel system that, under intelligent design, can sense changes in complex in vivo environments and utilize these triggers to modify drug release rates. Ionic or pH-sensitive hydrogels are probably the most studied stimuli-sensitive gels.

Composite hydrogel delivery systems

Two primary types of composite hydrogel delivery systems have been investigated, multi-layer and multi-phase systems. These composite systems have great potential in delivering multiple protein therapeutics for tissue engineering applications where temporal and spatial control over drug delivery is desirable. In multi-layer systems, a basal polymer layer is fabricated, followed by lamination of subsequent layers. Different drugs can be encapsulated into each layer during fabrication and tunable multiple drug release or unique single-drug release profiles are made possible by independently adjusting the cross linking density of each layer²⁸.

In multi-phase hydrogel delivery systems approach, prefabricated microspheres containing one or more proteins are uniformly embedded within a hydrogel containing a second protein^29,
30. The release of the microsphere- encapsulated protein is delayed due to the combined diffusional resistances of the microsphere

Table 2. Applications of hydrogels with different route of administration

S.No	Hydrogels	Site of action	Disease	Remarks	Reference
1.	Cationic hydrogels	GIT	Peptic ulcer	Stomach–specific antibiotic drug delivery	32
2.	Cross-linked copolymers of PMMA with graft chains of polyethylene glycol	Small intestine	Diabetes mellitus	potential devices for colon-specific drug delivery	4
3.	Xyloglucan gels	Rectum	Hemorrhoids	Avoid rectal irritation Avoids variation of availability of drugs that undergo extensive first-pass elimination	33
4.	Alginate with high gluronic acid contents	Eye	Glaucoma	long term retention property	34
5.	Diacrylated ABA block copolymers of lactic acid oligomers (A) & PEG (B)	Skin	Wound healing	Bypass hepatic first-pass metabolism. More comfortable.	23
6.	Cross -linked PHEMA	Subcutaneous	Anticancer effects (cyratabine (Ara-C))	Ideal candidate for implantable materials environment similar to biological tissue	35
7.	Sodium carboxymethylcellulose, pectin and gelatin combination in a polyethylene ±paraffin base, Carbopol 934Pw and neutralized poly(MAA-co-methyl methacrylate (MMA)	Oral	Osteoporosis	Improved availability of 17 β-estradiol (E2) E2 plasma level was maintained to over 300ng/ml per cm³ for 7 h	36
8.	Silicone rubber/hydrogel composite ophthalmic inserts of Poly(acrylic acid) or poly (MAA) IPN was grafted on the surface of the inserts.	Eye	Hormone deficiency	The ocular retention of IPN-grafted inserts was significantly higher with respect to ungraf -ted ones. An in-vivo study using rabbits showed a prolonged release of oxytetracyc-line from the inserts for sustaines release	37
9.	Composite membranes comprising of cross linked PHEMA with a nonwoven polyester support for nitroglycerin.	Transdermal	Antianginal effects	Depending on the preparation conditions, the composite membr-anes can be tailored to give a permeation flux ranging from 4 to 68 mg/cm2 per h	38
10.	Hydrogels involving chemical reticulation of a,b-polyasparthydrazide (PAHy) by glutaraldehyde	Subcutaneous	Placebo	hydrogel was inert when implanted subcutaneously into rats	39
11.	Bioerodible hydrogel based on a semi-IPN structure composed of a poly(1-caprolactone) and PEG macromer terminated with acrylate groups	Subcutaneous	Epilepsy, myoclonic seizures	Long-term constant release over 45 days of clonazepam entrapped in the semi-IPN was achieved in vivo	40

polymer and surrounding gel. These multi-phase dual delivery systems have achieved substantial success. Researchers prepared a composite polymeric scaffold containing PLGA microspheres embedded in porous PLGA matrices with different intrinsic viscosities to simultaneous deliver VEGF and PDGF. The in vitro and in vivo results using this approach have shown promising results in an animal model to enhance the maturation of vasculatures³¹.

Applications of hydrogels

Hydrogels find wide applicability in different fields of medicine due to its versatile nature and biocompatibility. Several reviewers and researchers had published excellent reviews emphasizing on pharmaceutical and biomedical applications of hydrogels⁶. Thus reported applications are briefly summarized in Table 1T-5 while application of hydrogels in wound healing and tissue engineering are discussed in detail. Hydrogels can deliver drugs to various sites including major specific sites; mouth, stomach, small intestine and colon offering versatility in terms of route of administration. By controlling their swelling properties or bioadhesive characteristics in the presence of a biological fluid, hydrogels can be a useful device for releasing drugs in a controlled manner at these desired sites.

Hydrogels in Tissue engineering

When parts or the whole of certain tissues or organs fail, the options for treatment include repair or replacement with a synthetic or natural substitute or regeneration. Synthetic substitute in tissue repair or replacement is limited to the situations where surgical methods and implants have achieved success. Although implants are reasonably successful in the treatment of tissue repair or replacement, tissue engineering is showing a great promise for regeneration of the failed tissue. Extracorporeal treatment is the first option for diseased or injured organs. Extracorporeal devices are basically dependent on passive exchange systems, but currently research is going on the systems which may contain entrapped or encapsulated cells from human or animal sources and are called ‘bioartificial’ organs. Total organ or tissue replacement with a natural substitute requires transplantation of an acceptable, healthy substitute but there is a limited supply of such organs and tissues. This is where the tissue engineering holds out great promise for regeneration of organs. Hydrogels have become increasingly studied as matrices for tissue engineering⁴¹. Hydrogels for use as tissue engineering scaffolds are generally designed to contain pores large enough to accommodate living cells or dissolve/ degrade away, releasing growth factors and thereby creating pores into which living cells may penetrate and proliferate. One significant advantage of hydrogels as tissue engineering matrices than the hydrophobic alternatives such as PLGA is the ease with which one may covalently incorporate cell membrane receptor peptide ligands, in order to stimulate adhesion, spreading and growth of cells within the hydrogel matrix. However, hydrogels possess a significant disadvantage due to their low mechanical properties which results in the significant difficulties in handling⁴². Sterilization issues are also very challenging. It is clear that there are both significant advantages and disadvantages to the use of hydrogels in tissue engineering, and the latter will need to be overcome before hydrogels will become practical and useful in this exciting field.

Hydrogels in wound healing

Hydrogels have been extensively evaluated for varity of purposes in management of wound healing. Moist dressing is one of the most researched areas among them resulting in several marketed hydrogel dressings(Table3).

Hydrogels are effective in promoting natural debridement by hydrating necrotic tissue and loosening and absorbing slough and exudate in a variety of wounds. Hydrogels also encourage autolytic debridement particularly useful on deeper wounds as it can be applied directly into the wound maintaining a moist wound environment, allowing healing to occur from the base of the wound upwards and encouraging rapid granulation and re-epithelialization. They are also capable of absorbing surplus contaminated exudates and safely retain them within the gel structure. The absorption of secretions expands the cross-links in the polymer chains, making room for the inclusion of foreign bodies such as bacteria, detritus and odor molecules that are irreversibly taken up along with the liquid^43-45. Hydrogels save the wound from fluid loss and provide the lesion with additional moisture. It protects the wound from external noxae. Hydrogels have been used successfully in infected wounds and in wounds that have not responded to other debridement and dressing techniques⁴⁶. These are also utilized for the soothing effect, notably on burns, where other dressings are often associated with pain on removal ^{47, 48}. Semi-occlusive hydrogel dressing enhances angiogenesis leading neovesculization. New vessels assure the cells involved in wound repair with oxygen and nutrients from the circulation at maximal pace, thus promoting the formation of granulation tissue. Moreover, the microclimate under the semi-occlusive covering is favorable to cell growth and offers good conditions for proliferation and migration of the epithelial cells at the edges of the wound. Clinical applications suggest an accelerated re-epithelialization under the hydrogel dressing with good cosmetic results. Hydrogels are safe dressings and clinically relevant adverse events, such as patient discomfort or tissue trauma, are rare.

Table 3. List of marketed hydrogel dressings

S.No	Trade Name	Company
1.	Purilon Gel (Hydrogel amorphous )	Coloplast Corp, Marietta, GA, USA
2.	Skintegrity (Hydrogel amorphous)	Hydrogel Medline Industries, Inc, Mundelein,IL, USA
3.	Nu Gel Wound Dressing (Hydrogel wafer)	Johnson & Johnson Wound Management,Somerville, NJ, USA
4.	FlexiGel Hydrogel Sheet Dressing(Hydrogel wafer)	Smith & Nephew, Inc, Largo, FL, USA
5.	Aquaform	Medica, Dusseldorf, Germany
6.	Intrasite Gel	Smith & Nephew, Inc, Largo, Fla. USA
7.	Hydrosorb^(R)	Paul Hartmann, Ltd., UK
8.	Curasol^(TM) (Gel Wound Dressing)	Health-point, Fort Worth, Tex.
9.	Iamin^(R) (Hydrating Gel)	Pro Cyte, Redmond, Wash.
10.	DuoDerm^(R) (Hydroactive Gel)	ConvaTec, A Bristol-Myers Squibb Company, Princeton, NJ
11.	Restore^(TM) (Hydrogel Dressing)	Hollister, Libertyville, Ill
12.	Aquacel AG	Convatec, Skillman, NJ, USA.
13.	Silvasorb	Medline Industries, Inc, Mundelein, IL, USA

Another significant use for hydrogels is loading the dressings with putative therapeutic agents for topical delivery to the wound site^{49, 50}. Recently, dressings that contain and release antimicrobial agents at the wound surface have entered the marketplace. These dressings usually provide a continuous or sustained release of the antiseptic agent at the wound surface to provide a long-lasting antimicrobial action in combination with maintenance of physiologically moist environment for healing. In one approach iodine has been complexed with a polymeric cadexomer starch vehicle to form a topical gel or paste. Silver has also been recently incorporated into a wide variety of semi-occlusive hydrogel dressing, e.g. Silvasorb (Antimicrobial Silver Dressing, Ionic silver Hydrogel sheet or amorphous gel, Medline Industries Inc. Mundelein, IL, USA) and Aquacel AG Ionic silver Hydrogel fiber Convatec, Skillman, NJ, USA.

CONCLUSION:

Wounds are one of the major causes of deformity and death in the world. The extensive research in the area of wound healing has greatly enhanced the knowledge regarding treatment strategies for variety of wounds. It is the major cause of financial burden on the health care system in general and on patients in particular. Researchers have emphasized on the need of moist environment and suitable carrier for co-delivery of multiple bioactives for complete healing. Hydrogels represent suitable alternative to achieve these goals. These developments in therapy has opened new hopes for the patients suffering from complicated wounds, but still there is a sturdy requirement of improved methods of therapy that should involve the principle of minimising harm and augment the basic principles of wound care.

REFERENCES:

1. Wichterle O. Hydrophilic gels for biological use. Nature 1960;185:117-23.

2. Peppas NA, Merrill EW. Differential scanning calorimetry of crystallized PVA hydrogels. J Appl Polym Sci 1976;20:1457–65.

3. Hickey AS, Peppas NA. Mesh size and diffusive characteristics of semicrystalline poly (vinyl alcohol) membranes prepared by freezing/thawing techniques. J Membrane Sci 1995;107:229-37.

4. Peppas NA, Mongia NK. Ultrapure polyvinyl alcohol hydrogels with mucoadhesive drug delivery characteristics. Eur J Pharm Biopharm 1997;43:51–8.

5. Peppas NA, Merrill EW. PVA hydrogels: reinforcement of radiation-crosslinked networks by crystallization. J Polym Sci Polym Chem 1976;14: 441–57.

6. Peppas NA, Mikos AG. Preparation methods and structure of hydrogels, in Hydrogels in Medicine and Pharmacy, CRC Press, Boca Raton 1986;1:1–27.

7. Klier J, Peppas NA. Structure and swelling behavior of polyethylene glycol/ polymethacrylic acid complexes, In Absorbent Polymer Technology, Elsevier, Amsterdam, 1990;147-69.

8. Bell CL, Peppas NA. Biomedical membranes from hydrogels and interpolymer complexes. Adv Polym Sci 1995;122:125–75.

9. Kamath KR, Park K. Biodegradable hydrogels in drug delivery. Adv Drug Deliv Rev 1993;11:59–84.

10. Davis KA, Anseth KS. Controlled release from crosslinked degradable networks. Crit Rev Ther Drug Carr Syst 2002;19:385–23.

11. Torre DL, Torrado S. Interpolymer complexes of poly (acrylic acid) and chitosan: influence of the ionoic hydrogel-forming medium. Biomaterials 2003;24:1459-61.

12. Dolbow JEF. A numerical strategy for investigating the kinetic response of stimulus-responsive hydrogels. Computer Methods in Applied Mechanics and Engineering. 2005;194:4447-80.

13. Gehrke SH, Lee PI. Hydrogels for drug delivery systems. In: Specialized Drug Delivery Systems, Marcel Dekker 1990; 333–92.

14. Flory PJ, Rehner J. Statistical mechanics of cross-linked polymer networks. II. Swelling. J Chem Phys 1943;11:521-26.

15. Hench LL, Ethridge EC. Biomaterials- An interfacial approach. Academic Press. 1990;170-76.

16. Wachem PB, Hogt AH, Beugeling T, Feyen J, Bantjies A, Detmers JP, Aken WG. Adhesion of cultured human endothelial cells onto methacrylate polymers with varying surface wettability and charge. Biomaterials 1987;8:323-28.

17. Roy chowdhury SK, Mishra A, Pradhan B, Saha D. Wear characteristic and biocompatibility of some polymer composite acetabular cups. Wear 2004;256:1026-36.

18. Mi F, Shyu S, Wu Y, Lee S, Shyong J, Huang R. Fabrication and characterization of a sponge-like asymmetric chitosan membrane as a wound dressing Biomaterials 2001;22:165-73.

19. Malcolm B. Huglin, Mat B. Zakaria. Swelling properties of copolymeric hydrogels prepared by gamma irradiation. J Appl Polym Sci 1985;31:2457- 75.

20. Sperinde JJ, Griffith LG. Control and Prediction of Gelation Kinetics in Enzymatically Cross-Linked Poly(ethylene glycol) Hydrogels. Macromolecules 2000;5476-80.

21. Takamura A, Ishii F, Hidaka H. Drug release from poly (vinyl alcohol) gel prepared by freeze-thaw procedure. J Control Rel 1992;20:21-27.

22. Eagland D, Crowther NJ, Butler CJ. Complexation between polyoxyethylene and polymethacrylic acid-the importance of the molar mass of polyoxyethylene. Eur Poly Jour 1994;30:767-73.

23. Hubbell JA. Hydrogel systems for barriers and local drug delivery in the control of wound healing. J Contrl Rel 1996;39:305-13.

24. Hu BH, Messersmith PB. Rational design of transglutaminase substrate peptides for rapid enzymatic formation of hydrogels. J Am Chem Soc 2003;125:14298–99.

25. Lutolf MP, Lauer-Fields JL, Schmoekel, HG, Metters AT, Weber FE, Fields GB, Hubbell JA. Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: engineering cell-invasion characteristics. Proc Natl Acad Sci 2003;100:5413–18.

26. Lutolf MP, Raeber GP, Zisch AH, Tirelli N, Hubbell JA. Cell-responsive synthetic hydrogels. Adv Mater 2003;15:888–92.

27. Rice MA, Sanchez-Adams J, Anseth KS. Exogenously triggered, enzymatic degradation of photopolymerized hydrogels with polycaprolactone subunits: experimental observation and modeling of mass loss behavior. Biomacromolecules 2006;7:1968–75.

28. Streubel A, Siepmann J, Peppas NA, Bodmeier R. Bimodal drug release achieved with multi-layer matrix tablets: transport mechanisms and device design. J Contrl Rel 2000;69:455-68.

29. Jeon O, Kang SW, Lim HW, Chung JH, Kim BS. Long term and zero order release of basic fibroblast growth factor from heparin-conjugated poly (L-lactide-co-glycolide) nanospheres and fibrin gel, Biomaterials 2006;27:1598-07.

30. DeFail AJ, Chu CR, Izzo N, Marra KG. Controlled release of bioactive TGF-beta(1) from microspheres embedded within biodegradable hydrogels. Biomaterials 2006;27:1579–85.

31. Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric system for dual growth factor delivery. Nat Biotechnol 2001;19:1029–34.

32. Patel VR, Amiji MM. Preparation and characterization of freeze dried chitosan poly (ethylene oxide) hydrogels for site-specific antibiotic delivery in the stomach. Pharm. Res 1996;13:588-93.

33. Miyazaki S, Suisha F, Kawasaki N, Shirakawa M, Yamatoya K, Attwood D. Thermally reversible xyloglucan gels as vehicles for rectal drug delivery. J Control Rel 1998;56:75-83.

34. Cohen S, Lobel E, Trevgoda A, Peled T. A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye. J Control. Rel 1997;44:201-08.

35. Teijon JM. Cytarabine trapping in poly (2-hydroxyethyl methacrylate) hydrogels:drug delivery studies. Biomaterials 1997;18:383-88.

36. Kitano M, Mitani Y, Takayama K, Nagai T. Buccal absorption of golden hamster cheek in vitro and in vivo of 17β-estradiol from hydrogels containing three types of absorption enhancers. Int J Pharm 1998;174:19-28.

37. Chetoni P, Colo GD, Grandi M, Morelli M, Saettone MF, Darougar S. Silicone rubber/hydrogel composite ophthalmic inserts: preparation and preliminary in vitro/in vivo evaluation. Eur J Pharm Biopharm 1998;46:125-32.

38. Sun YM, Huang JJ, Lin FC, Lai JY. Composite poly (2-hydroxyethyl methacrylate) membranes as rate-controlling barriers for transdermal applications. Biomaterials 1997;18:527-33.

39. Giammona G, Pitarresi G, Tomarchio V, Spampinato S, Govoni P, Campana T. New hydrogel matrices based on chemical crosslinked a,b-polyasparthydrazide: synthesis, characterization and in vivo biocompatibility studies. Int J Pharm 1996;127:165-75.

40. Cho CS, Han SY, Ha JH, Kim SH, Lim DY. Clonazepam release from bioerodible hydrogels based on semi-interpenetrating polymer networks composed of poly (e-caprolactone) and poly (ethylene glycol) macromer. Int J Pharm 1999;181:235-42.

41. Lee KY, Mooney DJ. Hydrogels for tissue engineering. Chem Revs 2001;101:1869-79.

42. Hutmacher DW. Scaffold design and fabrication technologies for engineering tissues-state of the art and future perspectives. J Biomater Sci Polym 2001;12:107-12.

43. Falanga V. The chronic wound: impaired healing and solutions in the context of wound bed preparation. Blood Cells Dis 2004;32:88-4.

44. Wysocki AB, Staiano-Coico L, Grinnell F. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 1993;101:64-68.

45. Cullen B, Smith R, McCulloch E, Silcock D, Morrison L. Mechanism of action of PROMOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers. Wound Repair Regen 2002;10:16-25.

46. Hollinworth H. Managing a patient with an infected foot ulcer. J Wound Care 1993;2:22-6.

47. Cable B. Hydrogel dressings. J Hum Lact 2001;17:295.

48. Eisenbud D, Hunter H, Kessler L, Zulkowski K. Hydrogel wound dressings: where do we stand in 2003? Ostomy Wound Manage 2003;49:52-7.

49. Vogt PM, Hauser J, Rossbach O. Polyvinyl pyrrolidone-iodine liposome hydrogel improves epithelialization by combining moisture and antisepsis. A new concept in wound therapy. Wound Repair Regen 2001;9:116-22.

50. Masters KS, Leibovich SJ, Belem P. Effects of nitric oxide releasing poly (vinyl alcohol) hydrogel dressings on dermal wound healing in diabetic mice. Wound Repair Regen 2002;10:286-94.

Received on 02.04.2008 Modified on 07.04.2008

Research J. Pharm. and Tech. 1(1): Jan.-Mar. 2008; Page 6-13