Hydrogels for Wound Healing Applications

Hydrogels for Wound Healing Applications Abstract 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. Keywords: Hydrogels; Chitosan, Antimicrobial; Grafting; Blending; Wound dressing; Wound healing; Gene therapy, Stem cell therapy, Skin Engineering, pH and Thermosensitive polymers. 1 Introduction 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. [45] There are different kinds of wound management products: staples or sutures, dressings or bandages, surgical sealants and adhesives, skin substitutes, and other biomaterials. [51] 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. [89] 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. [166] 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. [87] Wounds cause discomfort and are more prone to infection and other troublesome complications. [75] 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. [76] 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 initi ation 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 [191] 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 mois t 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. [17] 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. [20] 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. [46] 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 ‘chemicalgels 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. [120] In comparison to the traditional gauze therapy the application of a hydrogel seems to significantly stimulate wound healing. [11] 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. [13] 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. [192] 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. [47] Chitosan is a partially deacetylated form of chitin. Chitin as BeschitinÃ’, Unitika, is also commercially available as dressing in Japan. [28] But as far as chitosan is concerned it is biocompatible, biodegradable, haemostatic, fungistatic [54] 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 inc orporated 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. [126] 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. [127] 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. [152] 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. [137] 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. [183] 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. [178] 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. [198] 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. [197] It has been known that the fetal wound healing takes place without fibrosis or scar formation due to the presence of hyaluronic acid. [199] 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. [196] 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. [26] 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. [138] 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. [55] Also, the alginate fibres are non-toxic, non-carcinogenic, non-allergic, haemostatic, biocompatible, of reasonable strength, capable of being sterilized and easily processable. Sorbsanâ„ ¢ 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. [19] 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. [18] 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. [195] 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. [119] 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. [132] 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 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. [21] 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. [157] 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. [157] 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. [47] 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 ÃŽ ³-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. [22] 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 75-120 µm. [45] 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. Cot ton 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 drug Hydrogels for Wound Healing Applications Hydrogels for Wound Healing Applications Abstract 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. Keywords: Hydrogels; Chitosan, Antimicrobial; Grafting; Blending; Wound dressing; Wound healing; Gene therapy, Stem cell therapy, Skin Engineering, pH and Thermosensitive polymers. 1 Introduction 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. [45] There are different kinds of wound management products: staples or sutures, dressings or bandages, surgical sealants and adhesives, skin substitutes, and other biomaterials. [51] 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. [89] 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. [166] 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. [87] Wounds cause discomfort and are more prone to infection and other troublesome complications. [75] 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. [76] 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 initi ation 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 [191] 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 mois t 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. [17] 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. [20] 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. [46] 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 ‘chemicalgels 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. [120] In comparison to the traditional gauze therapy the application of a hydrogel seems to significantly stimulate wound healing. [11] 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. [13] 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. [192] 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. [47] Chitosan is a partially deacetylated form of chitin. Chitin as BeschitinÃ’, Unitika, is also commercially available as dressing in Japan. [28] But as far as chitosan is concerned it is biocompatible, biodegradable, haemostatic, fungistatic [54] 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 inc orporated 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. [126] 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. [127] 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. [152] 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. [137] 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. [183] 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. [178] 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. [198] 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. [197] It has been known that the fetal wound healing takes place without fibrosis or scar formation due to the presence of hyaluronic acid. [199] 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. [196] 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. [26] 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. [138] 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. [55] Also, the alginate fibres are non-toxic, non-carcinogenic, non-allergic, haemostatic, biocompatible, of reasonable strength, capable of being sterilized and easily processable. Sorbsanâ„ ¢ 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. [19] 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. [18] 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. [195] 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. [119] 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. [132] 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 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. [21] 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. [157] 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. [157] 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. [47] 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 ÃŽ ³-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. [22] 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 75-120 µm. [45] 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. Cot ton 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 drug

The Well Paid Receptionist

The Well Paid Receptionist Values, Attitudes and Work Behaviour from Johns, G. & Saks, A. M. (2010). Organizational Behaviour. Pearson Education: Toronto. Case Study The Well-Paid Receptionist Harvey Finley did a quick double take when he caught a glimpse of the figure representing Ms. Brannen’s salary on the year-end printout. A hurried call to payroll confirmed it. Yes, his receptionist had been paid $127 614. 21 for her services last year. As he sat in stunned silence, he had the sudden realization that since his firm was doing so well this year, she would earn at least 10 to 15 percent more money during the current fiscal year. This was a shock, indeed. Background Harvey began his career as a service technician for a major manufacturer of copy machines. He received rather extensive technical training, but his duties were limited to performing routine, on-site maintenance and service for customer. After a year’s experience as a service technician, he asked for and received a promotion to sales representative. In this capacity, he established many favourable contacts in the business community of Troupville and the surrounding towns. He began to think seriously about capitalizing on his success by opening his own business. Then, seven years ago, he decided to take the plunge and start his own firm. He was tired of selling for someone else. When he mentioned his plan to his friends, they all expressed serious doubts; Troupville, a city of approximately 35 000 people located in the Deep South, had just begun to recover from a severe recession. The painful memories of the layoffs, bankruptcies, and plummeting real estate values were too recent and vivid to be forgotten. Undeterred by the skeptics, Harvey was optimistic the Troupville’s slow recovery would soon become a boom. Even though his firm would certainly have to be started on a shoestring, Harvey thought his sales experience and technical competence would enable him to survive what was sure to be a difficult beginning. He was nervous but excited when he signed the lease on the first little building. A lifelong dream was either about to be realized or dashed forever. Troupville Business Systems was born. While he has managed to borrow rent, lease, or subcontract for almost everything that was absolutely necessary, he did need one employee immediately. Of course, he hoped the business would expand rapidly and that he would soon have a complete and competent staff. But until he could be sure that some revenue would be generated, he thought he could get by with one person who would be a combination receptionist/secretary and general assistant. The typical salary for such a position in the area was about $30 000 per year; for Harvey, this was a major expense. Nevertheless, he places what he thought was a well-worked ad in the â€Å"Help Wanted† section of the local newspaper. There were five applicants, four of whom just did not seem quite right for the position he envisioned. The fifth applicant, Ms. Cathy Brannen, was absolutely captivating. Ms. Brannen was 27 years old with one child. Her resume showed that she had graduated from a two-year office administration program at a state university. She had worked for only two employers following graduation, one from five years and the most recent for two years. Since returning to her hometown of Troupville two months ago, following her divorce, she had not been able to find suitable employment. From the moment she sat down for the interview, Harvey and Ms. Brannen seemed to be exactly the same wavelength. She was very articulate, obviously quite bright, and most importantly, very enthusiastic about assisting with the start-up of the new venture. She seemed to be exactly the sort of person Harvey had envisioned when he first begun to think seriously about taking the plunge. He resisted the temptation to offer her the job on the spot, but ended the hour-long interview by telling her that he would check her references and contact her again very soon. Telephone calls to her two former employers convinced Harvey that he had actually underestimated Ms. Brannen’s suitability for the position. Each one said without equivocation that she was the best employee he had ever had in any position. Both former employers concluded the conversation by saying they would rehire her in a minute if she were still available. The only bit of disturbing information gleaned from these two calls was the fact that her annual salary had risen to $32 900 in her last job. Although Harvey thought that the cost of living was probably a bit higher in Houston, where she had last worked, he was not sure she would react favourably to the $30 000 offer he was planning to make. However, he was determined that, somehow, Cathy Brannen would be his first employee. Ms. Brannen seemed quite pleased when Harvey telephoned her at home that same evening. She said she would be delighted to meet him at the office the next morning to discuss the position more fully. Cathy Brannen was obviously very enthusiastic about the job as outlined in the morning. She asked all the right questions, responded quickly and articulately to every query posed to her, and seemed ready to accept the position even before the offer was extended. When Harvey finally got around to mentioning the salary, there was a slight change in Cathy’s eager expression. She stiffened. Since Harvey realized that salary might be a problem, he decided to offer Cathy an incentive of sorts in addition to the $30 000 annual salary. He told her that he realized his salary offer was lower than the amount she has earned on her last job. And he told her he understood that a definite disadvantage of working for a new firm was the complete absence of financial security. Although he was extremely reluctant to guarantee a larger salary because of his own uncertainty regarding the future, he offered her a sales override in the amount of two percent of sales. He explained that she would largely determine the success or failure of the firm. She needed to represent the firm in the finest possible manner to potential customers who telephoned and to those who walked in the front door. For this reason, the sales override seemed to be an appropriate addition to her straight salary. It would provide her with incentive to take an active interest in the firm. Cathy accepted the offer immediately. Even though she was expecting a salary offer of $32 500, she hoped the sales override might make up the difference. Who knows,† she thought, â€Å"two percent of sales may amount to big money someday. † It did not, however, seem very likely at the time. Troupville Business Systems began as a very small distributor of copy machines. The original business plan was just to sell copy machines and provide routine, on-site service. More extensive on-site service and repairs requiring that a machine be removed from a customer’s premises were to be provided by a regional distributor located in a major city approximately 100 miles from Troupville. Troupville Business Systems did well from the start. Several important changes were made in the services the firm offered during the first year. Harvey soon found that there was a greater demand for the leasing of copy machines, particularly the large expensive models that he originally planned to sell. He also soon discovered that his customers wanted to be able to contract directly with his firm for all their service needs. Merely guaranteeing that he could get the machines serviced was not sufficient in the eyes of potential customers. In attempting to accommodate the market, he developed a complete service facility and began to offer leasing options on all models. These changes in the business all occurred during the first year. Growth during that year was steady, but not spectacular. While sales continued to grow steadily the second year, it was early in the third year that Harvey made what turned out to be his best decision. He entered the computer business. Harvey had purchased a personal computer soon after Troupville Business Systems was founded. The machine and its capabilities fascinated him, although he knew virtually nothing about computers. He was soon a member of a local users club, was subscribing to all the magazines, and was taking evening computer courses at the local university- in short, he became a computer buff. Harvey recognized the business potential of the rapidly growing personal computer market, but he did not believe that his original business was sufficiently stable to introduce a new product line just yet. During his third year of operations, he decided the time was right to enter the computer business. He added to his product line a number of personal computers popular with a small business in the area. This key decision caused a virtual explosion in the growth of his firm. Several key positions were added, including that of a comptroller. By the fourth year of operations, computers produced by several other manufacturers had been added to Harvey’s product line, and he had developed the capability of providing complete service for all products carried. His computer enterprise was not limited to business customers, because he quickly developed a significant walk-in retail trade. Rapid growth continued unabated. During the first seven years of the company’s existence, Cathy Brannen had proven truly indispensable. Her performance exceeded Harvey’s highest expectations. Although her official position remained that of secretary/receptionist, she took it on herself to learn about each new product or service. During the early years, Harvey often thought that she did a better job than he did whenever a potential customer called in his absence. Even after he acquired a qualified sales staff, Harvey had no concerns when Cathy had to field questions from a potential customer because a regular salesperson was not available. The customer never realized that the professional young lady capably handling all inquiries was â€Å"only† the receptionist. Cathy began performing fewer sales functions because of the increased number of professional salespersons, but her secretarial duties had expanded tremendously. She was still Harvey’s secretary, and she continued to answer virtually every telephone call coming into the business. Since her office was in an open area, she still was the first to greet many visitors. Cathy took a word-processing course at a local business school shortly after joining the firm. As she began working with Harvey’s first personal computer, she, too developed into a computer aficionado and became the best computer operator in the firm. The Current Situation Harvey was shaken by the realization that Cathy Brannen had been paid over $127 000 last year. As he wondered what, if anything, should be done about her earnings, he began to reflect on the previous seven years. Success had come almost overnight. It seemed as though Troupville Business Systems could do nothing wrong. The workforce had grown at a rate of approximately 15 percent per year since the third year of operations. Seventeen people were now employed by the firm. While Harvey’s dad acknowledged that some of this success was due to being in the right place at the right time, he also had reason to be proud of the choices he had made. Time had proven that all his major decisions had been correct. He also could not overestimate Cathy’s contribution to the success of the firm. Yes, certainly, one of the most important days in the life of the firm was the day when Cathy responded to his ad in the newspaper. Success had brought with it the ever-increasing demands on his time. He had never worked so hard, but the rewards were certainly forthcoming. First, there was the new Jaguar, then the new home on Country Club Drive, the vacation home on the coast, the European trips†¦Yes, success was wonderful. During these years Cathy, too, had prospered. Harvey had not thought much about it, but he did remember making a joking comment the first day she drove her new Mercedes to work. He also remembered commenting on her mink coat at the company banquet last December, Cathy had been dazzling. Now that Harvey realized what he was paying Cathy, he was greatly disturbed. She was making almost twice as much money as anyone else in the firm with the exception of himself. The best salesman had earned an amount in the low nineties last year. His top managers were paid salaries ranging from the high sixties to the mid-seventies. The average salary in the area for executive secretaries was no probably between $30 000 and $35 000 per year. A good receptionist could be hired for under $28 000, and yet Cathy had been paid $127 614. 21 last year. The sales override had certainly enabled Cathy o share in the firm’s success. Yes, indeed. As Harvey thought more and more about the situation, he kept returning to the same conclusion. He felt something had to be done about her compensation. It was just too far out of line with other salaries in the firm. Although Harvey was drawing over $200 000 per year in salary and had built an equity in the business of more than $1 million, these facts did not seem relevant as he pondered what to do. It seemed likely that a number of other employees did know about Cathy’s compensation level. Harvey wondered why no one ever mentioned it. Even the comptroller never mentioned Cathy’s compensation. This did seem quite odd to Harvey, as the comptroller, Frank Bain, knew that Harvey did not even attempt to keep up with the financial details. He relied on Frank to bring important matters to his attention. With no idea of how to approach this problem, Harvey decided to begin by making a list of alternatives. He got out a piece of paper and, as he stared at the blank lines, overheard Cathy’s cheerful exchange with a customer in the next room. The Well Paid Receptionist Analysis of â€Å"The Well Paid Receptionist† Harvey Finley is in quite the predicament. He his company’s net profit should be approximately $107, 614. 21 greater than he expected for this year. The problem is that his secretary/receptionist is making six to seven times the amount of an average â€Å"good† secretary/receptionist in the local market and has been for a few years. There’s a few ways this issue can be addressed. One way would be to talk to Ms. Brannen and advice her that there has been an oversight in her salary over the past few years and for the upcoming year the oversight will be corrected and her salary will be adjusted to $25,000 per year with no percent of sales bonus. Another way to address the issue is to fire the manager who should have reported this oversight to Finley and promote Ms Brannen to his position while adjusting her salary to $55,000 per year and explaining the oversight to her as well. One more solution to this issue would be to let things be the way they are since the company has been doing great and growing the way things currently are. The two most important value drivers to consider in establishing the Value Over Time maximization are â€Å"individual employee values† and â€Å"owner values†. Let’s start identifying the specific aspects of the first value driver, the individual employee values. The facts remain that the reason Finley hired Ms. Brannen was mainly based on her individual values and performance at her two previous jobs. She held a two year office administration degree, she was very articulate, bright and most of all she was enthusiastic about assisting in launching this start-up company with Finley. She also had two extremely positive feedbacks from her previous employers that said â€Å"they would rehire her in a minute if she were still available. † The problems lie with her not being satisfied with the initial salary offer for this position. Salary was the only issue with Ms. Brannen other than that she was perfect for this new position at Troupville Business Systems. A few potential problems with Ms. Brannen would be that she only moved from Houston was because she was going through a divorce. What would happen if she were to get back together with her husband? Another potential problem ith her would be the fact that she has a small child. If the child is sick then she will not be able to come into work. This would be an issue since at the moment she would be the only other employee. Also Ms. Brannen has two very good references and if she accepts this position and continues to look for another position elsewhere that may pay better and she can potentially leave Troup ville Business Systems. The potential positive impacts on Value Over Time for Ms. Brannen is that she will continue to shine and prosper as a great striving employee the company will grow. She is the front line and the first person the customer see’s or speaks to when they make the first contact to Troupville Business Systems. She has already proven herself since the launch of this company as being a key player in the success of this start-up company. A few potential negative impacts maybe that Ms. Brannen gets comfortable at the salary she is at and realizes that in her hiring package the terms and agreement were that she was to receive $14,000 salary plus 2% of sales. There was no clause to when this would be removed and she can just put herself on cruise control and still make six figures. I expect her effect to be a positive one over time since this is the person Ms. Brannen is. You can tell a lot by looking at a person’s past performance history and we know she is a person who not only strives to be the best at her job position but also picks up on other job position duties and can perform them just as well if not better than others. We know she is able to handle sales calls if no sales person is available and the client/customer has never noticed. There are ways to turn something negative into something neutral or even better into a positive effect. In the event that Ms. Brannen was offered a better paying position with another firm, Finley would be able to evaluate her for the time that she was working for him to see if she is worth the difference in salary. He would have also had time to make some sales and see how the potential sales market is doing and instead of offering her 2% in sales which obviously we now know was a bad strategy, can offer her more upfront in salary. A person that likes the job they are doing will not leave for one or two thousand dollars more. So Finley can be true to her and make a counter offer in hopes that she would accept and stay. As for the other negative aspect of her getting back together with her husband in Houston and move back there, Finley would either have to offer her a significant more salary or find her husband a position at Troupville Business Systems. The other important value driver to consider in establishing the Value Over Time maximization is â€Å"owner values†. As the owner Finley’s main concern is to keep his business running. Another concern is to make more and more profit each year. Owners need to worry about reputation risk as well and the well being of each of their employees. Some problems Finley is facing with his company, Troupville Business Systems, is that he is paying his secretary more than double what his highest paid manager is making. The problem Finley is facing is not knowing what should be done about this or how to approach the issue. The potential problems that may arise if the current situation is not addressed is that it will cause an up roar with the manager & salesman to find out that a secretary/receptionist is making much more than they are. Managers as well as other employees not knowing her hiring benefits will demand a raise. Another potential problem is that rumors will most likely be started that they are having relations and that’s why a secretary is making six figures. A potential positive impact would be that other employees will see that being a hard worker and sticking through the highs and lows of a business really pays off. This may motivate all other employees to be outstanding or above average performers. The employees have witnessed the value over time with Ms. Brannen and have seen the long-term effects on her salary. A negative impact would be that employees who have already been at Troupville Business Systems and have not seen the value over time in the bonus or benefits will demand a raise or quit. Salary is always a delicate situation to deal with and this is why it is not considered acceptable talk in the office. Another negative impact is over time if the company grows and does not have an increase in sales then Ms. Brannen will still be making more than Finley since he has more overhead to pay for. There are steps that can be taken to negate a potential negative effect. First of all no one should be discussing compensation at all inside or outside the office. Second in case it does get out then there should be a one on one sit down with each employee to discuss their performance, not Ms. Brannen’s. Finley does not need to justify his actions to his employees; he only needs to treat them fairly. Now let’s evaluate the case where the company’s expense gets higher and the sales stay the same and Ms. Brannen is making more than Finley. In this case Finley will have to renegotiate Ms. Brannen’s contract to reflect expenses as well if he does not decided to give her a base salary and no bonus that is. I believe the interactive effect these value drivers will have over time will be positive. During the maturity of Troupville Business Systems we can seen that Finley is a successful leader and Ms. Brannen is an outstanding employee who goes above and beyond her expected duties. These two make a good successful team. Over the years you can see that she has proven herself and should be promoted to a higher ranked position. She deserves the 2% sales bonus because she was with this company from the start and has stuck through the toughest times thus far. The best alternative solution for both effects would be for both Finley and Ms. Brannen sit down and review her contract, salary and bonus and come to an agreement on a fair salary and a possible promotion since she and proven her loyalty and performance to Troupville Business Systems. I’m sure Ms. Brannen realized that this day would come. And as long as the compensation is fair she will not leave since she is so invested in the company. In conclusion I would consider the best course of action would be to offer Ms. Brannen a managerial position within Troupville Business Systems. This will make her happy to get a respectable and long overdue promotion as well as a fair competitive salary of $60,000 a year with no percent bonus in sales. And if she is more motivated by a percent in sales then offer her $50,000 plus 1% of sales with a minimum of $5,000 annual or $20,000 maximum cap. This is fair for both value drivers for Finley as the owner and Ms. Brannen as the Individual employee. If I were Finley the first step would be for me to evaluate her performance and hard work since the start of Troupville Business Systems. I would bring her into my office and have a one on one with her. I would start off by saying how much off an asset she is to the company and how much appreciate her hard work is and has paid off in the success of the company. Then I would proceed by offering her a managerial position within the company. I would advise her that she will need to be trained for managerial duties and will be on an evaluation period as a manager for 3 months. Depending on the decisions made by her and how well she can manage a team she will be offered the permanent position. After she is given the formal offer she will have to decide whether she prefers being a secretary/receptionist or taking on new exciting role as a manager with Troupville Business Systems. Now the difficult part, this is where Finley should bring up the current compensation and offer Ms. Brannen a new compensation package. Advise her that the old compensation will be reduced to an above average rate for a secretary/receptionist and that this new opportunity will be a much better move for her career path. He will need to talk her up a bit like saying that she is management material and how good this is for her career path. Most likely she has been expecting this day to come and will choose to be a manger rather than go with a different company as a secretary. It’s a win/win move on parts of both parties.

Internet Tracking Devices Essay - 1306 Words

Internet Tracking Devices Cookies are small text files stored on Internet browsers that assign unique numbers to individual users. These cookies are usually placed on Internet users computers by web-sites without their knowledge. Every time that a user returns to the site that placed a cookie on their browser, the cookie is sent back from the user to the original web-site, providing a way to remember over time particular individuals. Furthermore, cookies are often simultaneously placed by third parties. The most common third-party cookies are placed by the various companies that serve banner ads that appear across many web-sites. Top companies in this business category include DoubleClick and Engage. Third-party cookie placement†¦show more content†¦Microsoft said it made its decision to offer the software after its own research showed that the use of third-party cookies, even though anonymous, was a matter of great consumer concern. Microsofts feature goes the extra step of explaining, in each cookie-blocking dialog with the user, how the cookies placement enables the third party to recognize them as they browse among different sites. Web bugs A Web bug is a graphic on a Web page or in an Email message that is designed to monitor who is reading the Web page or Email message. Web bugs are often invisible because they are typically only 1-by-1 pixel in size. They are often represented as HTML/IMG tags. Ad networks can use Web bugs to add information to a personal profile of what sites a person is visiting. The personal profile is identified by the browser cookie of an ad network. At some later time, this personal profile which is stored in a data base server belonging to the ad network, determines what banner ad one is shown. 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A Free And Equal Health Care System - 2238 Words

When we look at our health care in Canada, we see a free and equal health care system. To a Canadian who was born and raised here, lives in a stable middle class and is surrounded by a good environment, it is mostly true. For those people who do not relate to those aspects of living it is a much different experience dealing with the health care system. When we look at groups of people such as the low income groups, the aboriginals, and the immigrants, we will see how inequalities to accessing health care are there. What does health inequalities mean? We have a choice if we want to live a healthy life, but those choices differ from the way we live. Economic, environmental and racial inequality affect the way you can live a healthy life.†¦show more content†¦Looking into these factors we will see the effects they have on inequality in relation to health care. Social Status There is a major difference in your health based on your social status. Your social class has a great impact on your physical health, how you will receive medical care, and your life expectancy. It is a known fact that all around the world, as well as Canada, those people with low income commonly have the worst health. They experience a much lower form of care, even though they have a high rate of health issues. In a report done by the Toronto Public Health called Unequal City: Income and Health Inequalities in Toronto, they reported that â€Å"Low income groups in Toronto often have worse health. For the most recent years of data analyzed, 20 of the 34 health status indicators assessed for this report showed significant health inequities where low income groups had worse health† (Ingen, Khandor, Fleiszer). The average of 20 out of 34 just shows us how much of low income people take up of poor health. This is happening because they are constantly dealing with daily struggles . Having to overcome so many barriers leads to chronic stress. Research done by showed that â€Å"chronic and uncontrolled stress and strain can weaken people’s immune systems, making them more vulnerable to disease and illness.† This stress usually leads to overeating, alcohol, and many more. Jobs are a significant aspect of health inequality faced