Hydrogels for Wound Healing Applications
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This chapter discusses about the hydrogels both natural and synthetic that can be used for wound healing applications. Also it discusses briefly about the various novel techniques that have been developed recently.
Hydrogels; Chitosan, Antimicrobial; Grafting; Blending; Wound dressing; Wound healing; Gene therapy, Stem cell therapy, Skin Engineering, pH and Thermosensitive polymers.
Healthcare is an essential aspect of human survival. So many biopolymers have generated interest in a number of biomedical applications. Wound management is one such area where management of cuts, ulcers, and sores needs dressings which help in promoting rapid wound healing in order to obtain both functional and cosmetic results.  There are different kinds of wound management products: staples or sutures, dressings or bandages, surgical sealants and adhesives, skin substitutes, and other biomaterials. 
Human skin provides an effective barrier to microbial penetration and subsequent infection. However, once the wound has been developed in this barrier, the infection chances increases. In case of chronic wounds, the colonization and infection potential increases as the result of the presence of avascular eschar which provides an environment for the uninhibited growth of microorganisms.  The rate of infection is related to the type of wound, general wound care, and local health of the patient. [88, 90] For avoiding infection, good clinical practices are needed.
The management of chronic wounds is a very costly practice and it also places an enormous drain on healthcare resources; studies have calculated the cost of wounds to the NHS to be about £1bn a year.  So for lowering this cost such wound management products are needed that are more economical and effective.
Out of all the above wound management products, here in this chapter we will discuss more about the wound dressings that will provide an optimal healing environment to the wound. A dressing is an adjunct used by a person for application to a wound in order to promote healing and/or prevent further harm. It is designed to be in direct contact with the wound, so it is different from the bandage in the manner that bandages are normally used to hold dressing in place.
A wound is a break in the epithelial integrity of the skin and may be accompanied by disruption of the structure and function of underlying normal tissue. Wounds can be divided into four categories based on their appearance and stage of healing: Necrotic, sloughing, granulating and epithelializing wounds.  Wounds cause discomfort and are more prone to infection and other troublesome complications.  Some diseases like diabetes, ischaemia and conditions like malnourishment, ageing, local infection, local tissue damage due to burn leads to delay in wound healing. Infection is a major complication of burn injury and is responsible for 50-75% of hospital deaths. 
Human skin has one of the greatest capacities to regenerate itself amongst all of the tissues in our body. It constantly replaces old cells with new cells, enabling it to repair itself when damaged. Wound healing is a complex-physiologic process, which consists of three overlapping phases: inflammatory, proliferative and remodeling phases. The normal healing response begins the moment the tissue is injured. As the blood components spill into the site of injury, the platelets come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers the platelets to release clotting factors as well as essential growth factors. During the inflammation process, neutrophils are the first leukocytes which come at the site of injury to rid it from bacterial contamination. Then, the monocytes and their conversion to macrophages initiate tissue repair by releasing a number of biologically active substances and growth factors that are necessary for the initiation of tissue formation process. In the third process, fibroblasts proliferate and migrate into the wound space and started the deposition of the loose extracellular matrix. Endothelial cells grow into a wound simultaneously with fibroblasts and undergo angiogenesis. Finally, tissue remodeling takes place to reconstruct the basement membrane by the differentiation of keratinocytes as well as the formation of follicle cells. [43, 49, 50] A scar is an essential part of this natural healing process following any type of damage to the skin. This can occur after a surgical incision or the healing of a wound. As your body makes an effort to close an open wound and protect itself from infection, it replaces injured skin tissue with rapidly generated scar tissue. Scarring is slight when the damaged outer layer of skin is healed by rebuilt tissue. When we damage the thick layer of tissue beneath the skin, rebuilding is more complicated. Our bodies lay down collagen fibers (a protein which is naturally produced by the body) and this usually results in a highly obvious scar. A permanent reminder of the injury is left behind. So, a dressing that can induce scarless healing is needed.
Historically, a dressing was usually a piece of material, sometimes cloth, but the use of cobwebs, dung, leaves and honey has also been described. However, modern dressings include gauzes, semipermeable films, low adherent dressings, gels, foams, hydrocolloids, alginates, hydrogels and polysaccharide pastes. Wound dressings are passive, active or interactive. Passive dressings simply provide cover while active or interactive dressings are capable of modifying the physiology of the wound environment. Interactive dressings include hydrocolloids, hydrogels, alginates, foam dressings and antimicrobial dressings. [17, 20, 85]
Traditionally dry wound dressings are considered to be good for healing wounds i.e. the wound should be covered with gauze or left open. But it has been observed by Winter  that when wound is left open to air without any dressing, a scab i.e. a dry covering covers the wound and decreases the rate of epithelialization. On the other hand, if moist dressing is used in place of dry dressings scab will not form and rate of healing increases as moist dressings provide low oxygen tension which helps in wound healing, these dressings not only keep cells viable which enables them to release growth factors while maintaining contact between them and the healing tissues, but may also modulate or stimulate their proliferation, these dressings decrease the pain at rest, during ambulation and during dressing changes also moist environment allows rapid and efficient delivery of any added antimicrobial agent thus prevent the wound from infection. So, the dressings that create and maintain a moist environment, however, are now considered to provide the optimal conditions for wound healing.
2 Requirements of an ideal wound care system
These characteristics should be present in the ideal wound care system (a) it should be capable of maintaining a high humidity at the wound site, (b) it should be non-toxic, (c) non-allergenic, (d) it can be removed without causing trauma to the wound, (e) it should pe impermeable to bacteria, (f) Thermally insulating, (g) it should be soft to touch, (h) it should allow proper gaseous exchange, (i) it should be free from particulate and toxic product, (j) promote tissue reconstruction processes and (k) it should be cost effective. [20, 165, 177]
Out of all the dressings hydrocolloids, alginates and hydrogels each one has its own advantages and limitations but hydrogels are best and have all the characteristics that are needed in an ideal wound dressing. All the above mentioned characteristics can be achieved in hydrogel wound dressings.
3 Hydrogels for Wound Healing Applications
Hydrogels are natural or synthetic cross-linked polymers used in a variety of medical and biomedical applications. Hydrogels consist of a matrix of insoluble polymers with up to 96% water content enabling them to donate water molecules to the wound surface and to maintain a moist environment at the wound bed. They are used in the construction of contact lenses, drug-delivery vehicles, wound dressings and as physiological electrodes or sensors.  Examples of hydrogel include Aquaform, Intrasite, GranuGel, Nu-Gel, Purilon, Sterigel.
These also have the ability to absorb a degree of wound exudate. They transmit moisture vapour and oxygen, but their bacterial and fluid permeability is dependent on the type of secondary dressing used.  Hydrogels swell or shrink in aqueous solutions due to the association, dissociation and binding of various ions to polymer chains. These systems may swell in water until an equilibrium state is reached and retain their original shape. The interactions responsible for water sorption by hydrogels include the process of hydration, which is connected to the presence of such chemical groups as -OH, -COOH, -CONH2, -CONH-, and -SO3H and the existence of capillary areas and differences in osmotic pressure. The forces that make hydrogel dissolution impossible are presence of covalent bonds between individual polymer chains, hydrophobic and electrostatic interactions. 
These are hydrophilic polymer networks which may absorb from 10-20% (an arbitrary lower limit) up to thousands of times their dry weight in water. These may be chemically stable or they may degrade and dissolve. They are called ‘reversible', or ‘physical' gels when the networks are held together by molecular entanglements, and/or secondary forces including ionic, H-bonding or hydrophobic forces. [13, 14, 15] Hydrogels are called ‘permanent' or ‘chemical'gels when they are covalently-crosslinked networks as shown in 1.
Hydrogels can be made by irradiation, freeze-thawing or chemical methods. Out of all the methods, irradiation is considered as a suitable tool for the formation of hydrogels as in this method there is easy control of processing, no need of adding initiators or cross-linkers which are harmful, and have the possibility of formation and sterilization in one step. But as everything has its own advantages and disadvantages this method also has a disadvantage which is hydrogels formed by this method have poor mechanical strength. Nowadays, Freeze thawing technique is generally used to prepare hydrogels having good strength, stability and no crosslinkers and initiators. But the main disadvantage is that the prepared hydrogels have opaque appearance and limited swelling and thermal stability. 
In comparison to the traditional gauze therapy the application of a hydrogel seems to significantly stimulate wound healing.  Various natural and synthetic polymers having good biocompatibility are used to develop hydrogel wound dressing. These polymers include natural polymers such as alginate, chitosan, gelatin and collagen and synthetic polymers such as polyurethane, poly(ethylene glycol), polycaprolactone, poly vinyl pyrrolidone, poly(lactide-co-glycolide), polyacrylonitrile , poly(amino acid), etc. Table 1 below shows different hydrophilic polymers used to synthesize hydrogel matrices.
Table 1 Hydrophilic polymers used to synthesize hydrogel matrices. 
Hydrogels may be classified as homopolymer hydrogels, copolymer hydrogels, multipolymer hydrogels, and interpenetrating polymeric hydrogels. Homopolymer hydrogels are crosslinked networks of one type of hydrophilic monomer unit, whereas copolymer hydrogels are produced by the crosslinking of two comonomer units, one of which must be hydrophilic. Multipolymer hydrogels are produced by the crosslinking of more than three monomers. Finally, interpenetrating polymeric hydrogels are produced by the swelling of a first network in a monomer and the reaction of the latter to form a second intermeshing network structure. [46, 47]
Also, it has been shown that the blending of a natural polymer with a synthetic polymer seems to be a good method for obtaining materials having required mechanical and thermal properties in comparison to pure components. It is also a simple method by which suitable shapes such as films, sponges and hydrogels can be obtained easily to realize a variety of biomedical devices.
2 shows healing is faster with the hydrogel dressing than with the gauze dressing. Wound area covered by hydrogel decreases faster with increasing healing period. On the contrary, the wound covered by gauze dressing reduces by only half a percent even after 14 days. 
3.1 Natural Hydrogels
Natural polymers, such as chitin, chitosan, alginate, collagen, elastin, genipin, gelatin, cellulose etc. have been used for dressing wounds because they play an important role in the healing process. 
Chitosan is a partially deacetylated form of chitin. Chitin as BeschitinÒ, Unitika, is also commercially available as dressing in Japan.  But as far as chitosan is concerned it is biocompatible, biodegradable, haemostatic, fungistatic  and non-toxic and can be successfully used as gels, films, fibres etc. This polymer also show antibacterial properties and possess good wound healing properties. [60, 61, 62] It has many applications as wound dressing, drug delivery device and as scaffold for tissue engineering. [63, 64] Some of the examples of wound dressings are given below which use chitosan as one of the biomaterial.
Asymmetric chitosan membranes have been developed by using immersion-precipitation phase-inversion method. [123, 124, 125] These asymmetric chitosan membranes are homogeneous and have porous structure. This membrane was prepared by preheating casted chitosan solution in oven for different time periods for dry phase separation and then immersed in to coagulant tank for wet phase separation and were subsequently freeze-dried. The skin layer acts as the rate controlling barrier for the release of drug and the porous layer provide mechanical support to the skin layer. The water vapor transmission rate, gas permeability, PBS solution absorption, in-vitro degradation, cell culture, bacterial penetration and wound healing test of this dressing were carried out. These membranes are effective in controlling evaporative water loss, showed excellent oxygen permeability and also antibacterial in nature. These are also found to be an urgent hemostat. In another study, silver sulphadiazine was incorporated as an antimicrobial agent to this asymmetric dressing. The release behaviour of both silver and sulphadiazine ions were studied and found to be significantly different from one another. Silver ions displayed a slow release behavior while sulphadiazine ions exhibited burst effect on first day of the drug release and then slowly tapered off. It is because of the interaction of silver with amino group of chitosan leading to its slow release throughout whereas, as the sulphadiazine ions were free to diffuse through the membrane to reach the wound site thus they showed a burst release. The membranes were further found effective against P. aerugniosa and S. aureus.
In one of the papers, novel wound dressings were formed that composed of chitosan film and Minocycline Hydrochloride (MH) and commercial polyurethane film (Tegaderm) as a backing. It is also a useful formulation for the treatment of severe burn wounds. Water vapor and oxygen can permeate the Tegaderm film but water cannot. The tegaderm film support the polymer membrane. 
In one of the studies, a silver nanocrystalline chitosan (SNC) wound dressing composed of nano-silver and chitosan was constructed by self-assembly and nanotechnology and used for treating deep partial-thickness wounds. In this, sterility and pyrogen testing were performed to ensure biosafety. These dressings promote wound healing and combat infection, and also decrease the risk of silver absorption in comparison with silver sulphadiazine (SSD) dressings. 
There is also one more method of forming wound dressing composed of chitosan i.e. the formation of polyelectrolyte complex of gum kondagogu (GKG) and chitosan. This complex is formed by the electrostatic interaction between carboxyl group of gum and amine group of chitosan. This method is more advantageous as it avoids the use of organic solvents, chemical crosslinking agents and thus reduces the toxicity and undesirable side effects. In this, diclofenac sodium is used as model drug. The diclofenac loaded complex of gum kondagogu/ chitosan shows drug release which changes with change in pH. The drug release was higher at pH 6.8 as compared to pH 1.2, due to higher swelling of complex at higher pH. This holds a great potential as a natural polymer based delivery device for controlled delivery of drugs like diclofenac sodium for two reasons: (i) to reduce dosing frequency and (ii) lower the gastric toxicity. 
Semi-interpenetrating polymer networks (SIPNs) composed of chitosan (CS) and poloxamer were prepared in order to improve the mechanical strength of CS. The WVTR was found to be 2508.2±65.7 gm−2 day−1, i.e. these can maintain a moist environment at wound site which enhance epithelial cell migration. Also, the in vitro assessment of SIPNs showed proper biodegradation and low cytotoxicity and in vivo is carried out on experimental full thickness wounds in a mouse model and found that the wounds covered with these were completely filled with new epithelium without any significant adverse reactions after 3 weeks.
In one of the papers, a kind of surgical wound dressing, the chitosan-gelatin sponge wound dressing (CGSWD) having good antibacterial property is prepared. The in vitro test showed that the antibacterial effect of CGSWD on E. coli K88 is better than that of penicillin, and the effect on S. aureus is also better than that of cefradine. 
One more wound dressing consists of two separate layers were prepared in which the upper layer is a swellable hydrogel material which can absorb exudates and also serve as mechanical and microbial barrier while lower layer is a chitosan acetate foam incorporated with the anti-microbial agent chlorherxidine gluconate.  The antimicrobial activity is checked by the Bauer-Kirby Disk Diffusion Test, inhibition zones can be clearly seen around the discs of chitosan acetate foams incorporated with chlorhexidine gluconate, in culture plates inoculated with either Gram-negative or positive bacteria showing that the dressing is antimicrobial in nature.
Blending is a convenient and effective method to improve physical and mechanical properties of hydrogels. So modification of chitosan is done by blending with other polymers like cellulose.  In this, E. coli and S. aureus were used as the test bacteria to examine the antibacterial properties of chitosan, cellulose and chitosan/cellulose blends. The numbers of colony of these bacteria formed on the test membranes are shown in s 5 and 6. It was noted that the numbers of colony of all test bacteria formed on the chitosan/cellulose blend membranes were decreased with the increase of chitosan concentration. These blends are more effective against E. coli than that of S. aureus, as indicated by the lower colony unit. Thus these dressings are suitable to use as an antimicrobial wound dressing.
Chitosan due to its structural properties has the ability to heal wounds without scar formation.  Since chitosan is composed of D-glucosamine, which is also the component present in the disaccharide subunits of hyaluronic acid, chitosan tries to structurally mimic hyaluronic acid and exerts similar effects.  It has been known that the fetal wound healing takes place without fibrosis or scar formation due to the presence of hyaluronic acid. 
In one of the studies, Chitosan as a semi-permeable biological dressing maintains a moist environment and prevent the wound site from dehydration and contamination. In addition, digital colour separation analysis of donor site scars demonstrated an earlier return to normal skin colour at chitosan-treated areas as shown in 7. 
Collagen is also a biopolymer that is used as a polymer for making wound dressing and drug delivery devices as it is biocompatible and biocompatibility of a material applied to wound tissue is a prerequisite for optimal wound environment and facilitation of the healing processes. A new collagen dressing with gentamycin or amikacin was prepared in one of the research work and these follow the basic requirement of antibacterial bandages. The dressing is composed of two collagen biomaterials—membrane and sponge—both possessing good tissue biocompatibility. These dressing released antibiotics slowly and show the antibacterial treatment in experimentally infected superficial wounds in mice. Thus, it can be used for the treatment of infected wounds in humans. 
As discussed previously that both chitosan and collagen are excellent materials that can be used as wound dressing materials. So it has been seen that if both are used simultaneously then what will be the effect. It is found that the wound dressings composed of chitosan crosslinked collagen sponge (CCCS) enhance the diabetic wound healing. Collagen crosslinked with chitosan showed several advantages required for wound dressing, including the uniform and porous ultrastructure, less water imbibition, small interval porosity, and high resistance to collagenase digestion and slow release of FGF from CCCS/FGF. 
Following moist healing concept, alginates which are able to absorb exudates from wound have become one of the most important materials for wound management. [52, 53, 54, 55, 56] In this particular field, the properties of alginate fibers are unparalleled in many respects. Alginate based products form a gel and effective in removing out of the wound on the contrary to traditional cotton and viscose fibres, which can entrap in the wound developing discomfort during dressing removal.  Also, the alginate fibres are non-toxic, non-carcinogenic, non-allergic, haemostatic, biocompatible, of reasonable strength, capable of being sterilized and easily processable. Sorbsan™ was first commercialized in 1981 and after that there were many dressings launched. The alginate fibers can be converted into wound dressings by using a number of textile processes. Because of its simplicity and also the high absorbency of the product, nonwoven is the main form of alginate wound dressings. 
The antimicrobial action of alginate dressing can be seen as in 8 which shows the antimicrobial action of silver containing alginate fibers against E. Coli. There was 100% reduction in bacteria count within 5 hr after the fibers were placed in contact with solutions containing the bacteria. Sorbsan alginate fibers showed some antimicrobial activity while AquacelTM (made of carboxymethyl cellulose), does not show any antimicrobial effect. 
Gelatin widely found in nature and is the major constituent of skin, bones, and connective tissue. Gelatin can easily be obtained by a controlled hydrolysis of the fibrous insoluble protein, collagen.  This is also used in number of biomedical applications like wound dressings. Hydrogel wound dressing from gelatin, oxidized alginate and borax were prepared and the composite matrix promotes wound healing because of alginate, has haemostatic effect of gelatin and is antiseptic because of borax. The water vapour transmission rate (WVTR) of the hydrogel was calculated and found to be 2686±124 g/m2/day indicating that this hydrogel can maintain a proper fluid balance at the wound site which helps in cell migration. 2 shows the loss of water vapour with time through the hydrogel when placed in a moisture rich environment. 
Genipin has been used to crosslink chitosan membranes to control swelling ratio and mechanical properties. It increased its ultimate tensile strength but significantly reduced its strain-at-fracture and swelling ratio. It had significantly less cytotoxicity for human fibroblasts and slower degradation rate compared to the glutaraldehyde-crosslinked membrane. This genipin - crosslinked chitosan membrane can be successfully used as a wound dressing. 
Bacterial cellulose is a natural polymer consisting of microfibrils containing glucan chains bound together by hydrogen bonds. Bacterial cellulose with chitosan combines properties such as bioactivity, biocompatibility, and biodegradability of the two biopolymers and form an ideal material for dressing wounds. [66, 67] These are antibacterial and scar preventive in nature too.
Since natural polymers have been considered limited in their applications for wound-dressing materials as their low mechanical properties and shortage of processing. So we move towards the synthetic polymers that can be used for wound healing applications.
3.2 Synthetic Hydrogels
Synthetic polymers are also being used successfully in biomedical applications as one of the materials because of their wide range of mechanical properties, suitability for easily forming into a variety of different shapes, and low production costs.
In an ideal dressing both the characteristics i.e. antimicrobial ability and moist healing environment should be present, so in order to prevent the wound from dehydration and bacterial penetration a new dressing composed of polyurethane is designed in such a way that the upper layer of the dressing is microporous (pore size < 0.7 µm) supported by a highly porous lower layer containing micropores (pore size <10 µm) as well as macropores (pore size: 50-100 µm). The pores of both layers are interconnected and form a continuous structure in the membrane. Membranes according to this design were prepared either by means of a two-step or by means of a one-step casting process. Both fabrication methods are based on phase inversion techniques.  These membranes are transparent thus the wound healing can be monitored easily. These dressings are evaluated on the backs of guinea pigs and found that it is occlusive to such an extent that it prevents the wound from dehydration and microbial penetration. The high drainage capacity of both types of polyurethane wound dressings can be explained by the fact that the micropores in the top layers are interconnected. Therefore multiple channels are formed which allow the flow of fluids from the macropores of the sublayer through the micropores in the top layer.Furthermore the wound dressing remained firmly adhered to the wound surface and could be left on the wound until full regeneration of the skin was achieved.
Polyvinyl pyrrolidone (PVP) is one of the most widely used synthetic polymers in medicine because of its solubility in water and its extremely low cytotoxicity. Hydrogels prepared by radiation crosslinking of an aqueous solution of polyvinyl pyrrolidone (PVP) have been used as wound dressing.  These are biocompatible, reduces pain, easily replacable, permeable to oxygen, maintain moist environment at the wound site.
Polyvinyl alcohol (PVA) is a well-known polymer because it is biocompatible and have required mechanical properties and polyethylene oxide (PEO) is a hydrophilic semicrystalline polyether which is biocompatible, non toxic, non polar, non antigenic and non immunogenic and is highly desirable in most biomedical applications requiring contact with physiological fluids.
A hydrogel composed of PEO for wound dressing is prepared and PVA is added to give toughness to the hydrogel by electron beam irradiation and found that these hydrogels showed satisfactory properties for wound dressing that has been evaluated by creating wound on the back of the marmots.  The hydrogel gives a wet environment to wounds which causes faster healing compared with the gauze dressing with a dry environment. The weight of the hydrogel increases quickly at the earlier stages, up to 4 days, due to absorption of effusion produced from the wound as shown in Table 2. After that, the production of effusion from the wound ceases and the weight of the hydrogel decreases due to evaporation of the water in the hydrogel. This means that the healing of wound proceeds smoothly with time. The hydrogel can be peeled off easily from the wound at the time of removal.
Table 2 Absorption of effusion from wound of dressing during healing. 
The toughness of PEO hydrogel is improved by the addition of PVA and tensile strength is measured and found that as shown in 10 and 11, the tensile strength and elongation decrease with increasing dose because of the increase of crosslinking.
Various synthetic polymers as discussed above are used for wound dressing applications. But the major problem with these materials is their biocompatibility characteristics are often unsatisfactory and their interaction with living tissues is a major problem. So a combination of both natural and synthetic polymers is the better option to make a hydrogel having biocompatibility and desired mechanical strength.
3.3 Blended hydrogels
Since both the natural and synthetic polymers have their own advantages and disadvantages so a combination of natural and synthetic polymers can endow the optimal properties necessary for wound repair.  The combination of natural and synthetic polymers is used in the biomedical, bioengineering and biotechnology field nowadays because of their great potential.
A blended hydrogel composed of polyvinyl alcohol/polyvinyl pyrrolidone and charcoal were prepared by single ‘‘freezing and thawing'' or two-step ‘‘freezing and thawing'' and γ-ray irradiation and applied as wound dressing. It is found that the absorption of S. aureus and P. aeruginosa by charcoal/PVA/PVP hydrogels was larger than those by PVA/PVP hydrogels, this is due to the absorption and attachment capability of bacteria by charcoal, this can be shown in 12 given below. 
The most classical way of fabricating a CS based wound dressing has been to design an asymmetric composite structure. In this method, the Cotton fabric was coated with chitosan (CS) and polyethylene glycol (PEG) followed by freeze-drying. The outer dense layer helps in preventing the microbial passage across the dressing and provides a rate controlling barrier for water vapor permeation, while the inner porous layer provides a high surface area for the exudates absorption. For the absorption of wound exudates porosity is the prime requirement in a dressing. It has been found that these dressings have the porosity 54-70% and the pore size was in the range of 75-120µm.  The increase in the PEG content in the blend composition led to an enhanced destabilization of pores, leading to an increase in the pore size with elongated morphology. There seems to be phase separation between the two components which is an important factor for the observed behavior of the porous structure. Cotton fabric has been used as the support layer for the CS-PEG layer and leads to very thin and light weight structures. The structure of the dressing has been designed in such a way that it leads to the high porosity of the bulk structure. The thickness of CS coating plays an important role in the development of the porosity on the surface. The influence of the CS thickness on the surface morphology is presented in 13 given below.
PEG addition to CS makes significant alteration in the surface morphology of this CS-PEG/cotton membrane (freeze-dried), henceforth known as CPC membrane. There is a distinct trend in the loss of inherent elongated porous structure in membranes and formation of the partially collapsed porosity takes place due to the PEG addition. This suggests that a very limited interaction between CS and PEG exists which is reflected in the observed surface morphology. It has been observed that higher the amount of PEG, the higher is the pore destabilization leading to larger pores. This is evident from the morphology of the CPC membrane at 50% PEG-20 content as shown in 14.45
On the above matrix, the addition of PVP and drug followed by coating on the cotton fabric and freeze drying of the coated matrix is also done. It has been found that the drugs undergo fast release with time in phosphate buffer saline (PBS) solution reaching saturation within 2 days. This is the indication that these dressings will be excellent material for wound care management where the dressings need to be replaced every day or every alternative day. Samples with CS do not show zone of inhibition. However, in other samples containing drug, the zone of inhibition has been observed indicating that these dressings will not allow bacterial growth in its surrounding.200 In one of the papers, semi-interpenetrating polymer network (IPN) system is prepared in which CS crosslinking network acts as matrix, linear polymer PEG acts as domain. The formation of the porous structure takes place by extraction with hot water, dispersion phase, PEG had been effectively extracted and then porous network retained.201
In one of the studies, Aloe vera has been added to a mixture of PVA/PVP and these hydrogels are prepared by freezing and thawing, γ-ray irradiation, or a two step method of freezing and thawing and γ-ray irradiation. The swelling degree of hydrogels obtained from the irradiation-only process was much higher than those obtained from freezing and thawing or the two-step method of freezing and thawing and irradiation. The swelling degree increased as the concentration of aloe vera in PVA/ PVP/aloe vera increased and as the radiation dose and repeated cycles of freezing and thawing decreased. The degree of water evaporation increased rapidly up to 5 h, continued to rise steadily up to 15 h, and then leveled off. The PVA/PVP/aloe vera hydrogel had a better curing effect than no dressing and the commercial urethane membrane that can be seen in 15. 
Both natural and synthetic polymers are used for wound healing applications. In one of the studies, a new chitosan-polyvinyl alcohol-alginate film had been developed by the casting/solvent evaporation method. This new type of C-P-A film consists of a chitosan top layer and sodium alginate sublayer separated by an ornidazole-incorporated poly (vinyl alcohol) layer. The schematic explanation of the dressing can be seen in 16 given below. The prepared films had excellent light transmittance, water vapour transmission and fluid drainage ability. The in vitro release studies showed that about 90% of OD was released from the composite films within 60 min, and no significant difference was observed in cumulative release percentage with increases in the drug content and the film at low concentration of OD (1.0 mg/cm2) showed effective antimicrobial activity against S. aureus and E. coli in culture plates. 
Agar is also incorporated into PVP/PEG mixture and the hydrogel is prepared by electron beam irradiation technique. The maximum swelling% decreases with increasing the irradiation dose, but increases with increasing the PEG concentration. Also 17 represents the swelling% of the hydrogel dressings with the time for different irradiation doses. At the first stage of the curves, the swelling rate is very high, and water can penetrate easily into the polymer network. 
A new type of medicated dressing composed of poly(vinyl alcohol)/ poly(N-vinyl pyrrolidone)/ chitosan hydrogels were prepared by a low temperature treatment and subsequent 60Co γ-ray irradiation and then were medicated with ciprofloxacin lactate (an antibiotic) and chitosan oligomer (molecular weight - 3000 g/mol).  The drug and chitosan oligomer release behaviors were studied at 37°C in a modified Franz diffusion cell, which could simulate actual wound conditions. The in vitro drug and chitosan-3000 release behaviors are shown in 18(a, b). The drug release was very quick at the beginning and then became slower and slower. In the first 20 h, about 60% of the drug was released. At the end of the 90 h release experiment, the total amounts of the drug released were 85 and 65% for initial drug contents of 2.0 and 1.0 mg/mL, respectively. As shown in 18(b), chitosan-3000 was released similarly, and the total amount released in 90 h was also dependent on the initial content of the chitosan oligomer. On the other hand, the total percentage of the oligomer released from the hydrogel was lower than that of the drug. This may be because of its stronger interaction with the hydrogel and its higher molecular weight. 
3.4 Modified hydrogels by grafting
Graft copolymerization is an attractive technique of modifying the chemical and physical properties of polymers for widening their practical use. The properties of the resulting graft copolymers are controlled by the characteristics of the side chains, including molecular structure, length, and number. Graft copolymers are the materials which consist of homopolymer backbone and have branches of other types of polymer. It provides an excellent way out to introduce desired functionalities onto the chitosan backbone by covalent bonding with a molecule. This can be achieved by methods such as by chemical, photochemical and γ- initiation. It has been observed that the UV- initiation leads to much lower levels of grafting as compared to the other methods, while the γ- radiation producing very high level of grafting. 
This grafting technique is used to prepare wound dressings using different natural and synthetic polymers. In one of the papers, the wound dressing of acrylic acid-grafted and chitosan/collagen-immobilized polypropylene non-woven fabric (PP-AAg-CCi) were produced. 
Semi-interpenetrating polymer network (semi-IPN) hydrogels were prepared by UV irradiation of water soluble N-carboxylethyl chitosan (CECS) and 2-hydroxyethyl methacrylate (HEMA) aqueous solutions in the presence of D-2959 as photoinitiator. SEM showed that semi-IPN hydrogels displayed porous surface and therefore had high surface area. Cytotoxicity results suggested that semi-IPN hydrogels had good biocompatibility. In this work, a water-soluble N-carboxylethyl chitosan was synthesized by Michael addition reaction, and then CECS/poly (HEMA) hydrogels were prepared by photopolymerization technique The CECS/poly (HEMA) hydrogels could be potentially used as transdermal drug delivery matrix or wound dressing materials. [128,129,130,131]
In one of the studies, a series of environmentally friendly hydrogel films were prepared from dihydroxypropyl chitosan (DHP-chitosan) using irradiation technique without any bifunctional crosslinking compounds. Ionizing radiation usually allows the combination of the synthesis and sterilization of polymeric materials in a single technological step, which reduce cost and production time. The desired elasticity and flexibility of DHP-chitosan hydrogels meet various demands from the applied science of biomedical application, such as wound dressing and tissue engineering. 
3.5 Smart Hydrogels i.e. pH and Temperature Sensitive Hydrogels
Smart polymeric materials respond with a considerable change in their properties to small changes in their environment. Environmental stimuli include temperature, pH, chemicals, and light. These can be natural like alginate, chitosan, and Ä¸-carrageenan or synthetic like poly(N-isopropylacrylamide) and methylmethacrylates polymers. [141,142], or a combination of both like collagen-acrylate and poly(polyethylene glycol co-peptides).  Thermosensitive hydrogels can be classified as positive or negative temperature-sensitive systems. A positive temperature- sensitive hydrogel has an upper critical solution temperature (UCST) i.e. these contract upon cooling below the UCST. Negative temperature-sensitive hydrogels have a lower critical solution temperature (LCST) i.e. these contract upon heating above the LCST. [95, 96, 153] This phenomenon of transition from a solution to a gel is commonly referred to as sol-gel transition.
Yin et al.  synthesized copolymers by a reversible addition fragmentation transfer (RAFT) method, using different NiPAAm and polyacrylic acid (PAA) ratios. They showed that even small changes in pH can have a big effect on the LCST of the hydrogel. This feature can be useful for applications such as drug delivery.  Hydrogels based on poly(N-isopropylacrylamide), PNIPAAm, show a volume phase transition around 32°C. At higher temperatures, these hydrogels shrink and expel water from gel networks. At lower temperatures, the interaction between water and polymer chains becomes favorable, and the hydrogels swell after absorbing water into the gel work. [1, 2, 25] Many researchers reported innovative pH and temperature responsive interpenetrating polymer network (IPN) hydrogels composed of PVA and poly(acrylic acid) (PAAc). [3, 4, 5, 6, 7, 8]
In one of the studies, polypropylene (PP) nonwoven fabric (NWF) was modified by direct current pulsed plasma followed by grafting with acrylic acid (AAc) to improve its surface hydrophilicity and to introduce carboxylic acid group. To incorporate thermosensitive nature, PP-g-collagen NWF was further modified with poly(N-isopropylacrylamide) (PNIPAAm).  During the change of wound dressing where separation of the dressing material from the tissue is required, a low temperature treatment below the LCST of PNIPAAm to the dressing material will make the polymer swell and become hydrophilic by absorbing water. In such case, the NWF dressing could be readily removed from the wound without causing any harm.  One more wound dressing was prepared by immobilizing chitosan on PNIPAAm / polypropylene nonwoven composites surface for wound dressing applications.  Using the thermosensitive nature of PNIPAAm a multilayer membrane wound dressing system was designed. The first layer was a porous polypropylene (PP) nonwoven fabric to provide mechanical support. The second layer was N-isopropyl acrylamide or acrylic acid grafted material to furnish the hydrophilic surface for the adhesion of chitosan and collagen, which was the third layer of the dressing. 
Triblock copolymers poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO), known also as Pluronic® or Poloxamers, are another group of synthetic polymers with a thermoreversible behavior in aqueous solutions. These copolymers have been extensively used in applications such as drug and gene delivery, inhibition of tissue adhesion and burn wound covering [95, 99, 100].
In one of the study, Chitosan was immobilized on PNIPAAm gel/ PP NWF by using cross-linking agent, glutaraldehyde (GA) as shown in 21, and used as wound dressing. The plasma-activation treatment and subsequently UV-light graft polymerization is done. The result showed that CS hydrogels displayed antibacterial ability to E. coli and S. aureus.194
In the above study, the complex structure was characterized by SEM as shown in 22. From this, it is found that the PNIPAAm grafted layer was attached well to the plasma pretreated nonwoven as compared to untreated nonwoven, due to the increase in wettability between hydrogel and substrate.194 Also, 23 shows the freeze dried composite develops porous structure while no pore was observed when CS was dried at room temperature.
However, due to this complicated entangle structure between NWF and CS, the nonwoven was difficult to strip. Consequently, an easy-stripped interface layer was really required for preparing an ideal wound dressing. Therefore, a PNIPAAm hydrogel interface was chosen to solve the entanglement problem due to its temperature sensitivity and high hydrophilic property. This tri-layer wound dressing can be a promising approach for tissue engineering applications whose SEM can be seen in 24.194
3.6 Antimicrobial Dressings
Silver, in ionic or nanocrystalline form, has been used as an antimicrobial agent particularly in the treatment of burns from many years (silver sulfadiazine cream). Iodine also has the ability to lower the microbial activity in chronic wounds in two forms: (a) as povidone-iodine (polyvinylpyrrolidone-iodine complex), an iodophor; and (b) as cadexomer iodine (a 3- dimensional starch lattice containing 0.9% iodine). Some of the examples of antimicrobial dressings are Acticoat, Actisorb Silver 200, Aquacel Ag, Arglaes, Avance, Inadine, Iodoflex, Iodosorb, Metrotop Gel.  Nowadays many medicinal plants and chemicals such as aloe vera and curcumin are incorporated into the dressings to provide antimicrobial nature to the dressing.
Among all the antimicrobial agents, silver has long been known to have strong antimicrobial activities.  Silver impregnated textiles are used as wound dressings for infected wounds also for wounds at high risk of infection.  Antimicrobial yarns  can be produced from cotton, linen, silk, wool, polyester, nylon, and their blends having nanosilver particles and showed effective antimicrobial activity against various bacteria, fungi, etc. It is well known that silver in contact with wound enters it and becomes absorbed by undesirable bacteria and fungi and silver ions kill microbes resulting in treatment of infected wound. It was reported that Ag inactivate microbes as following mechanisms; (1) Ag interacts with enzymes and proteins important for the bacterial respiration and the transport of important substances across the cell membrane and within the cell; (2) Ag interacts with DNA, thereby inhibiting cell division; (3) Ag ions are bound to the cell wall and outer cell, thereby altering the functionality of the cell membrane. [158, 159] Historically, a number of polymer-based materials have been fabricated into e-spun fibers containing nAg like polyacrylonitrile (PAN) [109, 110], cellulose acetate (CA) [112, 113], poly(N-vinylpyrrolidone) (PVP) , and poly(vinyl alcohol) (PVA) [114, 115, 116].
A novel wound dressing material was prepared by electrospinning PVA/AgNO3 aqueous solution into nonwoven webs and then treating the webs by heat or UV radiation. It was found that heat treatment as well as UV radiation reduced the Ag+ ions in the electrospun web into the Ag nanoparticles. Also heat treatment improved the mechanical properties and these electrospun fibre web was a good material as wound dressing.  Some of these nAg-loaded e-spun fiber mats were tested for their antibacterial activity against E. coli, K. pneumoniae, P. aeruginosa and S. aureus. [113, 114, 115, 116].
In one of the studies, mats of gelatin fibers containing nAg were prepared by e-spinning and these are used as wound dressing pads.  Ag+ ions were reduced directly into nAg through a series of steps, including nuclei formation, crystal growth via diffusion mechanism to give primary particles, and spontaneous self-organization of primary particles to form clusters (i.e., secondary particles).  The cumulative release of Ag+ ions from the samples in the acetate buffer and distilled water occurred rather rapidly during the first 60 min after submersion in the releasing medium, and increased gradually afterwards; while those in SBF occurred more gradually over the testing period as shown in 25.
25 Cumulative release profiles of Ag+ ions from 1- and 3 h-cross-linked nAg containing e-spun gelatin (GT) fiber mat specimens reported as the weight of Ag+ ions released (in mg) divided by the actual weight of specimens (in g) in three types of releasing medium, i.e., (a) acetate buffer (pH 5.5), (b) distilled water (pH 6.9), at the skin temperature of 32°C, and (c) simulated body fluid (pH 7.4), at the physiological temperature of 37°C. 
Aloe Vera, a succulent plant having many biologically active ingredients that help in the healing and sealing of wounds thus make it an important product for assistance in the healing of cuts, scrapes and even skin ulcers. Thus it may be concluded that aloe vera leaf gel extract have the ability to be used as a component of wound dressing materials. 
This wound healing ability of aloe vera is because it stimulates fibroblasts directly. Fibroblasts, the skin cells responsible for manufacture of collagen, play an important role in fiber formation of wounds in repair by protein synthesis and associative enzyme activity. [74, 78] Aloe vera also contain mannose-6-phosphate which increases the macropahage activity and promote wound healing.may also promote wound healing in this way. [79, 80, 81, 82] Also, the increased presence of oxygen caused by the aloe vera improve microcirculation which should greatly enhance the wound healing process. [74, 84]
In one of the studies, aloe vera has been added to a mixture of PVA/PVP and had a better curing effect than no dressing and the commercial urethane membrane as discussed above. 
A commercial bandag of Johnson & Johnson having Aloe vera and Vitamin E is in the market and has the following advantages: (a) aloe vera helps soothe, protect and promote natural healing, (b) easy to apply, (c) Antiseptic pad helps to kill germs and side seals help prevent further infection and (d) Hypo - allergenic. There is one more Gentell Hydrogel Aloe Vera Wound Dressing from ActiveForever.com. It is an Aloe Vera-based, hydrating wound gel which protects the wound bed and enhances the moist environment.
Curcumin (diferuloylmethane), a polyphenol, is an active principle of the perennial herb Curcuma longa (commonly known as turmeric). It has many biological functions, including anti-cancer, anti-oxidant and anti-inflammatory activities. The antiseptic activity of an aqueous extract of turmeric was exploited by Johnson and Johnson in Band-Aid®, a turmeric-based bandage (patents), available in the market over the last few years. 
In one of the studies, the feasibility and potential of poly(caprolactone) (PCL) nanofibres as a delivery vehicle of curcumin for wound healing applications is investigated. The fibres showed sustained release of curcumin for 72 h and could be made to deliver a dose much lower than the reported cytotoxic concentration while remaining bioactive. The in vivo wound healing capability of the curcumin loaded PCL nanofibres was demonstrated by an increased rate of wound closure in a streptozotocin-induced diabetic mice model. 
In one of the works, curcumin was incorporated into the chitosan and alginate sponge to deter wound infection. In this, the crosslinked sponges based on chitosan and alginate were successfully prepared at the various conditions of mixing ratios 3 : 1, 2 : 2, 1 : 3. The drug release behavior can be seen in 26. Based on the results of drug release of curcumin, we found that the C2A2 sponges have a sustained release behavior for up to 20 days. This shows that the C2A2 sponge could be a good drug support to be employed for sustained release.
In one of the studies, aqueous PVA solution could be easily cross-linked to form hydrogel and loaded with curcumin. The results show that with increase in the concentration of curcumin, more curcumin gets loaded in the hydrogel. This study is a model for future biological applications of curcumin hydrogel. 29 shows the percentage of curcumin released, on incubation of liposome solutions with curcumin-loaded hydrogel. 
3.7 Texile based Wound Dressings
Biomedical textiles are textile products used for medical and biological applications. They are used for first aid, clinical or hygienic purposes. Some of the examples of their application is in the form of wound dressings, bandages, pressure garments etc. The importance of textiles for wound care applications is determined by their excellent qualities, such as strength, flexibility, air and moisture permeability and 3-dimensional structures.
Nowadays, electrospinning has aroused much interest as an attractive technique for producing polymer fibers with diameter in the range from several micrometers down to tens of nanometers. Because of the presence of high specific area they are used in a wide variety of applications. The nanofibers are usually obtained in non-woven form, which is very suitable for applications such as wound dressings. 
Biopolymers like, chitin, chitosan, alginates along with textile materials have been presented as versatile candidates in the area of wound dressings. These provide all the specifications required for an ideal wound dressing. These are the smart dressings that provide microbial protection, water and air permeability, capability of the covering to adhere well to the wound and to be readily removable without causing any damage to the tissues, prevention of excessive formation of granulation tissue, optimal elasticity etc. Textile based hydrogel dressings are non-toxic and biocompatible too. Non woven Fabric (NWF) serves as an excellent dressing material with its high porosity and larger surface area, which provide an open structure for drainage of exudates and reduces the risk of second infection. The fabric has been used as the support layer for the hydrogel layer and leads to very thin and light weight structures.
Nanofibres are used in the area of wound dressings suitably. Nanofibers containing poly(vinyl pyrrolidone)-iodine complex (PVP-iodine) were obtained by electrospinning in order to prepare materials suitable for wound dressings. The average diameters of the fibers were in the range 150-470 nm. When it comes in contact with skin and mucous membrane, the complex behaves as an iodophor, i.e., it gradually releases active iodine. The broad-spectrum microbicidal activity of PVP-iodine is related to the released non-complexed, freely mobile iodine. The active iodine reacts with enzymes of the respiratory chains and with amino acids from the cell membrane proteins, resulting in destruction of the well-balanced protein tertiary structure and in irreversible damage to the microorganisms. Thus it can be used as a component of nonwoven textile for external antibacterial applications as required in wound dressings. 
Composite nanofibrous membranes (NFM) of type I collagen, chitosan, and polyethylene oxide was fabricated by electrospinning, which could be further crosslinked by glutaraldehyde vapor. NFMs showed no cytotoxicity toward growth of 3T3 fibroblasts and had good in vitro biocompatibility. From animal studies, the NFM was better than gauze and commercial collagen sponge wound dressing in wound healing rate. This novel electrospun matrix will have potential as a wound dressing for skin regeneration. The electrospun membrane is also important for cell attachment and proliferation in wound healing. 
30 shows the changes in wound areas at different healing times using NFM, gauze, and a commercial collagen sponge wound dressing. The wound areas decreased gradually and reached about 5% after 21 d when wound dressings were used. NFM was found to be better than gauze (p < 0.05) and collagen sponge in promoting wound healing.
In one of the research paper, new textile dressings containing dibutyrylchitin (DBCH) or regenerated chitin (RC) were prepared by coating a polypropylene non-woven material with films of DBCH or RC. The sterilized dressings were subjected to biological evaluation. DBCH and RC caused no cytotoxic effects or primary irritation either in vitro or in vivo and both had a positive influence on the wound healing process conducted on 16 albinos and microscopic assessment showed that the wounds covered with the dressing containing DBCH healed fastest.  The photographs of the wounds taken on the 14th day after surgery are shown in 31.
31 Photographs of the wounds taken on the 14th day after surgery. (a) wound treated with DBCH containing dressing material on the 14th day after surgery. (b) wound treated with regenerated chitin containing dressing material on the 14th day after surgery. (c) wound treated with gauze only (control) on the 14th day after surgery.
A microscopic view of the skin lesion on the 14th day after the surgery is shown in 32 given below. In 32 (a) having PP nonwoven material coated with DBCH can see on the left, the layer of epidermis covering the granulated tissue is seen in 32 (b) having PP nonwoven material coated with regenerated chitin, Immature connective tissue covered by epidermis is visible. While in 32 (c) containing gauze only, (control) we can see on the right, immature connective tissue partially covered by squamous epithelium. The microscopic assessment showed that the wounds covered with the dressing containing DBCH healed fastest. 
32 A microscopic view of the skin lesion on the 14th day after the surgery, dressed with the (a) PP nonwoven material coated with DBCH, (b) PP nonwoven material coated with regenerated chitin, (c) gauze only, (control) Dyed by HE. Magnification 120x. 
4 Commercial Dressings
Many commercial dressings like Melolin®, Telfa®, Perfron®, Lotus®, Micropad®, Mesoft®, Regal®, Vernaid® have one unsatisfactory feature i.e. they cause fresh damage to the wound when removed because of their adherence to the wound surface.  So these are hard to peel off from the wound. In order to prevent the harm new hydrogel dressings are required that will provide moist environment at the wound site.
‘Hydron' is a commercial dressing based on poly (2-hydroxyethyl methacrylate) and polyethylene glycol that is formed in situ on the wound by spraying, but this is very costly. [119, 144, 145]. Omiderm (Omikron Scientific Ltd., Rehovot, Israel), a new synthetic transparent wound covering based on hydrophilized polyurethane, was found to be highly permeable to water i.e. its WVTR value is 5000 g/m2/day in comparison to 1400 and 500 g/m2/day for Biobrane (Hall, Woodroof Inc., Santa Ana, CA) and Op site (Smith and Nephew Ltd.), respectively. It is highly permeable to water and prevents fluid accumulation. The topical antimicrobials can be incorporated into these dressings to make it more effective against bacterial growth. 
One more hydrogel dressing is LUOFUCON™ Medical Hydrogel dressing. It is a swelling polymer made from polyethylene oxide and polyvinyl alcohol by moderate crosslinking. It has a three dimensional structure with high hydrophilic groups on the networks thus provide a moist environment to the wound. It can powerfully absorb water and release moisture. it can effectively absorb exudates. The product is semi transparent, so it is convenient to observe the healing conditions of wound. It will not stick to wound, and can be removed easily.
ActicoatTM, a commercial textile dressing with silver nanocrystal shown in 33 is used as wound dressing good for burn patients.
Acticoat possesses effective antimicrobial activity in vitro and in vivo capable of reducing colonization and preventing contamination by micro-organisms. Its release mechanism ensures a continuous distribution of 70 to 100 mg/L of ionized silver over more than 48 hours and rapid start of action (within 30 minutes of application) in optimal moisture conditions. It reduces pain and this benefit can be intensified if dressings are changed only every three days, as recommended by the manufacturer. [187, 188]
Acticoat can be applied to any anatomical location including the face and has proved a successful alternative to traditional silver sulfadiazine preparations in dedicated units with demonstrated less cost than silver sulfadiazine over the same treatment period, reducing the requirements for grafting. [186, 189]
Myskin™ ( 34) is the first product to be launched by CellTran for the active treatment of difficult to heal wounds. It was launched in 2005 and is the first in a range of products specifically developed to treat burns and other skin wounds.  It is comprised of flexible medical-grade silicone coated with a chemically controlled plasma polymer film which supports the growth of skin cells. Once cultured, myskin™ is applied so that cells are in contact with the wound bed. The polymer film is engineered to promote cell growth and subsequent release when triggered by exposure to the wound. In order to obtain autologous cells a small skin biopsy is taken from the patient (usually from the thigh). The cells delivered by myskin have a high proliferative capacity, are able to survive an aggressive wound site and ultimately provide epidermal cover. This promotes the healing of wounds, assisted by the increased expression of natural growth factors which the cultured autologous cells provide.
5 Future Developments
There are few new approaches that are developing nowadays that will help in healing of wound in such a way that it will help in removing the major problem of scarring of burn wounds. There are some novel areas of research and new trials are underway.
(a) Gene Therapy
Gene therapy, aims to help the cell to help itself by providing it with specific genes. Genes once incorporated in the cell affect the cell and its milieu through their products of expression. These in the context of wound healing are growth factors, their receptors, adhesion molecules and inhibitors of proteases.  Introduction of the gene rather than growth factor is cheaper and more efficient for treating chronic wounds. Gene therapy, initially developed for treatment of congenital defects, is a new option for enhancing wound repair. 
(b) Stem Cell Therapy
Another novel method is stem cell therapy. Bone marrow derived stem cells are pleuripotent, being capable of differentiating into a variety of cells. This property can be used in the wound healing environment.  Embryonic and adult stem cells have a prolonged self-renewal capacity with the ability to differentiate into various tissue types. A variety of sources, such as bone marrow, peripheral blood, umbilical cord blood, adipose tissue, skin and hair follicles, have been utilized to isolate stem cells to accelerate the healing response of acute and chronic wounds. 
Nowadays, gene and stem cell therapy both in combination has emerged as a promising approach for treatment of chronic wounds.
(c) Skin Engineering
Skin is an important tissue engineering target for reconstructive surgery of burns victims, but increasingly also to assist in the healing of diabetes related ulcers. The three main developments in tissue engineering of the skin are EpiCel® , Apligraf® and Dermagraft® , Integra®.  The first skin substitutes developed at Sheffield were cultured epithelial autografts can be seen in 35 given below. These are thin sheets of keratinocytes taken by biopsy from a patient and multiplied in the laboratory. These have been used since 1981.
But these sheets of cells were fragile and take 13 days to prepare. So in the late 90's collaboration between clinical scientists and materials scientists at Sheffield made the first big improvement on this technique - the development of flexible synthetic surfaces on which keratinocytes could be easily cultured in vitro. The synthetic support medium allows rapid culture, reducing waste, and makes the tissue very much easier to handle. The cultured keratinocytes plus the synthetic support form a flexible dressing that can be applied directly to the wound bed. Clinical studies have shown that cells migrate from the dressing to the wound and greatly accelerate healing rates, frequently resulting in complete remission for chronic ulcers that had resisted other treatments. The technology has also been successful in treating severe burns patients. 
But the process automation cost is too high so the future developments will depend very much on public and professional support for further research.
The data present an overview which reflects on important developments in advanced wound management materials from fibres to finished products to hydrogels and new techniques. Many natural and synthetic polymers are used as hydrogels for wound healing applications but it is found that both have their own advantages and disadvantages so a combination of both natural and synthetic polymers are generally used for preparing wound dressings that will be ideal and has all the characteristics needed in an ideal wound dressing. Many methods like blending, grafting are used to synthesize the hydrogels having required characteristics. This chapter also describes the use of silver nanoparticles in the biomedical field. These nanoparticles when in
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