Single-Element Biologic Systems
Wound coverage with amniotic membraneHuman amniotic membranes obtained from the placenta after delivery have been used for decades to cover burn wounds. These membranes are readily available in large supply in major hospitals and can be prepared relatively inexpensively. They possess most of the characteristics of an ideal skin substitute: excellent adherence to the wound, very low immunogenicity, decrease of pain, bacterial control, and stimulation of healing. Moreover, a great advantage of the amniotic membrane is its translucency, allowing inspection of the wound.
Amniotic membranes can be applied on superficial second-degree burns, donor sites, and deep second-degree burns after early debridement. They are also useful to cover 1:3 meshed autografts, and they have been reported to be extremely effective in sterilizing contaminated wounds and cleaning burns of bacteria within 3-5 days. Nevertheless, amniotic membranes have to be changed daily and need to be covered with gauze to prevent desiccation because they display less efficacy in preventing water loss compared with homograft or xenograft. In addition, they do not allow long-term coverage and could be dissolved early by the wound. Amniotic membranes can be kept refrigerated for 6 weeks, or they can be frozen for longer storage and banking purposes.
Acellular human dermis
Acellular human dermis substitute (eg, AlloDerm; LifeCell Corporation, Branchburg, NJ) is essentially healthy human dermis with all the cellular material removed. It is then virus-screened and preserved by freeze-drying. Different, mostly nonrandomized control studies or case presentations using AlloDerm showed a variation in results relating to dressing technique. Thinner grafts overlying the AlloDerm exhibited better take, which was deemed advantageous in terms of the donor site. Its use has now been described in various applications with some degree of success.
Acellular human dermis is prepared from cadaver skin by extensive washing and purification followed by high-dose x-ray radiation and either deep freezing or glycerol preservation. Because of the limited donor population and the extensive and both time-consuming and money-consuming security tests, allogenic human skin cannot cover all needs and is very expensive.
Wound coverage with xenogenic grafts
The ideal xenogenic material used for dermal substitution should have the following clinical properties:
- Be hemostatic and possess good adherence to any wound bed (including cartilage and bone surfaces); fully cover the wound surface without any dead spaces
- Adhere immediately to the wound borders
- Cover the whole wound area and protect it against infectious agents and the loss of water and tissue fluids
- Cover the wound area, reducing or eliminating pain
- Lack any specific inflammation-stimulatory agents and not produce any foreign body reaction, granuloma formation, or acute or chronic immunologic rejection
- Serve as a natural matrix for host granulation tissue formation and coordinate fibroblast proliferation and angiogenesis with early tubular formation and capillary development
- Serve as a natural surface, promoting host epithelial cell proliferation, reepithelization, and basal membrane structure development, and create a stable connection between the new, developed connective tissue and the new, proliferated epidermis
- Promote a normal epidermal differentiation and enhance the maturation of epidermis, which covers the healing wound (natural collagen matrix)
- Because of 1-7, protect against both the contracture of wound borders and typical scar formation
- Be fully transparent and allow excellent clinical observation of the wound area and the healing process
Porcine skin is the most common source of xenograft because of its high similarity to human skin. Sterility is an essential concern with xenogeneic tissues transplanted on wounds. Ionizing radiation appears to be the most suitable method for a guarantee of this sterility and for application in mass production. In addition, irradiation coupled with freeze-drying seems to decrease the antigenic properties of the pigskin graft and to increase its potential to inhibit bacterial growth. Thus, pigskin is a well-suited temporary dressing for the coverage of second-degree burns, especially after early excision. It usually promotes scar-free healing, with an average healing period of about 10 days.
In addition, pigskin provides a suitable overlay to cover widely meshed (1:8 to 1:12) autografts. Because freeze-drying and irradiation are expensive, a low-cost alternative preservation technique was successfully developed by using 98% glycerin as the antiseptic followed by storage at room temperature for 20-300 days.
To cover wounds with a dermal matrix to favor graft take of cultured epidermal sheets and to prevent rejection of xenogeneic tissues, efforts have been made to develop nonimmunogenic artificial dermal matrices. Such dermal components must promote the prompt coverage of the largest excised full-thickness wounds, control fluid loss, and prevent infections. Recent advances in the technology of in vitro tissue reconstruction have made it possible to approach these requirements.
Acellular Matrices and Combination Products
The engineering of skin tissue and the development of a skin substitute have been studied from a variety of approaches. The acellular collagen-chondroitin sulfate material proposed by Yannas et al[6] represented one of the first attempts at engineering a dermal component to substitute the volume of missing tissue. Bello and coworkers[7] proposed a bilayered model of skin by using contracted collagen lattices containing living dermal fibroblasts covered in a 2-step procedure with in vitro–reconstructed epidermal sheets.
Native collagen and native collagen–containing products have been proposed for covering superficial wounds, for tissue augmentation, or for hemostatics in visceral surgery. The practical use of soluble collagen for wound healing is limited because of problems with storage stability and the time required to prepare enriched collagen solutions. Traditional collagen pads or Vlieses manufactured out of solubilized collagen material are not suitable for these purposes because of their high compression after application onto the wound surface and their lack of transparency. This last phenomenon is of great importance because of the possibility of permanent visual control of the wound during each healing phase.
Ruszczak et al[8] proposed a treatment strategy for superficial and deep wounds and for tissue substitution in the form of a composite graft, a 2-step procedure based on xenogenous collagen implantation for dermis substitution and reconstructed keratinocyte allografts for surface covering. Transplanted basal keratinocytes supplied keratinocyte-derived signaling molecules and growth factors, which actively helped to restore a dermoepidermal exchange pathway and to stimulate healing. The collagen material (CollatampFascia; INNOCOLL Inc, US) was a ready-to-use, mechanically stable, in vivo noncontractible, primarily free of any nonbiologic and synthetic components, nonpyrogenic, biologically and immunologically neutral, and long-term preservable membrane. This material could be used both as a wound dressing and as an implant for healing chronic, acute, and surgical superficial or partial- or full-thickness wounds.
A novel collagen spongy matrix containing oxidized regenerated cellulose (ORC) named Promogran (Johnson & Johnson Wound management, NJ) has been introduced to both US and EU markets. Promogran has been designed to treat exuding wounds, including diabetic, venous and pressure ulcers. The matrix is composed of 45% ORC and 55% collagen. The ORC/collagen matrix binds to metalloproteases in chronic wound exudate without altering the activity of essential tissue growth factors, and it creates a milieu for moist wound healing.
Because metalloprotease levels may be elevated in chronic wounds and contribute to degradation of important extracellular matrix proteins and inactivate growth factors, their binding into the ORC/collagen matrix may have a positive effect on the physiological wound healing process. Promogran has been found to significantly increase the healing ratio of diabetic foot ulcers compared with a traditional moistened gauze procedure, especially in ulcers of less than 6 months' duration.
Both products described above are a single layer construct and may require additional moisture control barrier to complete the dressing.
An original method of Burke and Yannas' artificial skin is now called the Integra Dermal Regeneration Template and is commercialized. Burke and Yannas' artificial skin is a bilayer membrane composed of a dermal portion that consists of a porous lattice of fibers of a cross-linked bovine collagen and glycosaminoglycan (GAG) composite and an epidermal layer of synthetic polysiloxane polymer (silicone). The GAG that is used is chondroitin-6-sulfate; the degradation rate of the collagen-GAG sponge is controlled by glutaraldehyde-induced cross-links. The collagen-GAG dermal layer functions as a biodegradable template that induces organized regeneration of dermal tissue (neodermis) by the body and the infiltration of fibroblasts, macrophages, lymphocytes, and endothelial cells that form a neovascular network. As healing progresses, native collagen is deposited by the fibroblasts, and the collagen portion of artificial skin is biodegraded over approximately 30 days.
Serial biopsy samples, ranging from 7 days to 2 years after the application of the artificial skin, demonstrated that an intact dermis was achieved with regrowth of apparently normal papillary and reticular dermis. No scar formation appeared in the biopsy samples of patients examined. The superficial silicone layer of the Integra Dermal Regeneration Template is imbedded with monofilament nylon sutures to easily distinguish it from the collagen dermal layer. This pseudo epidermal layer must eventually be removed by the surgeon and is usually replaced by thin epidermal autografts during the 2-step transplantation. At present, the Integra Dermal Regeneration Template is approved in the United States only for the postexcisional treatment of life-threatening, full-thickness or deep partial-thickness thermal injury where sufficient autograft is not available at the time of excision or not desirable because of the physiological condition of the patient.
Another bilayer skin substitute used mostly for severe burns is Biobrane (Bertek Pharmaceuticals Inc, Morgantown, WVa). Biobrane is a biosynthetic wound dressing constructed of a silicon film with a nylon fabric partially imbedded into the film. The fabric presents to the wound bed a complex 3-dimensional (3-D) structure of trifilament thread to which collagen has been chemically bound and cross-linked. Blood/sera clot in the nylon matrix, thereby firmly adhering the dressing to the wound until epithelialization occurs.
Biobrane was introduced in 1979 for commercial use in the treatment of burn wounds and donor sites and has several advantages, including adherence, safety, control of evaporative water loss, flexibility, durability, bacterial barrier, ease of application and removal, availability, hemostatic properties, and cost-effectiveness. In comparison with pigskin and skin allografts, Biobrane showed superior wound adherence. The product has been found to significantly reduce local wound pain, to speed up the healing process, and to significantly prevent bacterial colonization of the wound surface.
Synthetic or semisynthetic dressings
SiliconesSilicone dressings consist of chemically and biologically inert, usually transparent, silicon sheets or gels. Some of the silicone membranes are porous to allow gas and moisture exchange between the wound surface and the environment. Other silicone membranes are nonpermeable to ensure a fully occlusive wound environment.
Silicone dressings not only work as antiadhesives but also may reduce hypertrophic and keloid scarring. Silicone has been found to be useful in flattening of scarring tissue; increasing elasticity; and reducing discoloration, making the scars more cosmetically acceptable. Additionally, silicone or siliconized membranes have been found useful in covering split-skin donor sites or fresh meshgrafts. Moreover, silicone membranes work as an epidermislike portion in combination engineered skin substitutes (as previously mentioned).
Barrier films
Barrier films are protective polymers dissolved in a fast-drying carrier solvent, which, ideally, should be noncytotoxic, be pain reducing on application to broken skin, protect skin from loosing moisture or from exogenic fluids, protect from skin stripping, and be compatible with clothing. Such dressings may be applied as fluids, which quickly polymerize on the wound surface or as industrially prepared membranes made mostly from polyurethane or polylactate.
Foams
Foams mostly consist of polyurethane porous sponges or polyurethane foam films with or without adhesive borders. Most of them are suitable for use on light-to-medium exuding wounds. Many types of foams may be left on the wound surface for up to 7 days, depending on exudate volume. Foams are not recommended for any kind of dry wounds. Besides the usual range of sizes, anatomically shaped dressings are available for specific wound locations (eg, sacral region, heel).
Tissue adhesives
Tissue adhesives have been developed to exchange suturing in some, mostly small and not-too-deep wounds that can heal by primary intention. Moreover, such products may be used in the form of surface covering liquid bandages. Currently used tissue adhesives contain cyanoacrylate components, including bucrylate, enbucrilate, and mecrylate, which polymerize in an exothermic reaction on contact with either a fluid or a basic substance. Such a process leads to the forming of a strong, flexible, waterproof band.
Tissue adhesives are used for simple lacerations, which otherwise might require the use of fine sutures, staples, or skin strips, producing cosmetic results similar or better than traditional suturing. This is a needless and mostly painless method of wound repair that does not require follow-up visits for suture removal.
Tissue adhesives provide the strength of healed tissue seen at 7 days. Special attention is necessary to ensure that wound edges are appropriately adapted and that no adhesive passes between wound borders.
Hyaluronic acid
Vapor-permeable films (also known as semipermeable films), made of materials that can be found in some tissues, are now becoming popular wound dressings. Most of them are made of industrially manufactured and purified hyaluronic acid. Hyalograft 3D and Laserskin (HYAFF-11) are indicated for use on diabetic foot ulcers and venous leg ulcers. Entirely composed of a benzyl ester derivative of hyaluronic acid, they may be used as membranes for direct wound dressing or as scaffolds for the cultivation of fibroblasts and keratinocytes for further transplantation.
Hydrogels
Hydrogel dressings contain a large portion of water, often more than 70-90%. They have some important characteristics of an ideal dressing. Hydrogels can cool the surface of the wound, resulting in marked pain reduction. Moreover, hydrogels maintain the moist wound environment and are mostly suitable for use on dry or necrotic wounds or on lightly exuding wounds. They are suitable for use at all stages of wound healing except for infected or heavily exuding wounds. Hydrogels are a good alternative for classic wet dressings. In some cases, however, hydrogels may macerate the healthy skin (mostly wound border areas), decreasing the keratinocyte reepithelialization ratio or leading to overwetting of split-skin donor sites. Hydrogels are available as sheet dressings or gels.
Hydrocolloids
Hydrocolloid dressings are much more complicated than hydrogels because they contain a variety of constituents, such as methylcellulose, pectin, gelatin, and polyisobutylene. Some of them also contain alginate. After contact with the wound surface, hydrocolloids slowly absorb fluids, leading to a change in the physical state of the dressing and to the formation of gel covering the wound. Thus, they are called interactive dressings.
Hydrocolloids ensure the moist wound environment, promote the formation of granulation tissue, and provide pain relief by covering nerve endings with both gel and exudate. These dressings are marketed with or without adhesive borders. Depending on the choice of product, hydrocolloids are suitable for the dressing of both acute wounds and chronic wounds, for desloughing, and for different stages of light-to-heavily exuding wounds.
Initially, hydrocolloid wound dressings need to be changed daily (depending of the exudate level), but, once the exudate has diminished, dressings may be left on the wound surface for up to 7 days. With a few exceptions, hydrocolloids require a secondary dressing to be fixed in place. Hydrocolloids should not be used on infected wounds.
Calcium alginates
Alginates are highly absorbable biodegradable dressings derived from seaweed (eg, Kaltostat, Tegagen, SorbSan, SeaSorb, Algisite M, Algosteril). They contain the building blocks of mannuronic acid (M) and glucuronic acid (G). The high M alginates are soft and gel-like, whereas the high G alginates are more stable and ribbon- or rope-like.
Large quantities of alginates are used each year to treat exudating wounds, such as leg ulcers, pressure sores, and infected surgical wounds. In addition to controlling exudate by ion exchange, alginates are believed to exert a bioactive effect by activating macrophages within the chronic wound bed to generate proinflammatory signals (eg, tumor necrosis factor-alpha [TNF-alpha], interleukin 1, interleukin 6 [IL-6], interleukin 12). This may then initiate a resolving inflammatory response characteristic of healing wounds. Chronic wounds are now well known to be characterized by macrophage-rich inflammation, and any putative macrophage defects probably relate to the functional status of the macrophages present at the wound site.
In vitro studies have demonstrated that some dressings containing alginates can activate macrophages, as evidenced by their increased production of TNF-alpha. Research is currently underway to modulate alginate dressings to enhance these effects and to incorporate antimicrobial silver into alginate preparations (eg, Acticoat Absorbent). In addition, new preparations (eg, AGA-100) that have a reduced cytotoxicity to cells, such as fibroblasts, compared with both Kaltostat and Sorbsan, are being developed.
Alginates are not the dressing of choice for infected wounds and should not be applied to dry or drying wounds. Most alginates require a secondary dressing.
Dressings containing an antimicrobial agent
An important consideration in the design of new dressings is their ability to combat microbial infection. Many dressings now exploit bioactive properties to promote healing and to control infection. These dressings include the now well-known sustained-release iodine and silver dressings (eg, Iodosorb, Actisorb Silver 220). Silver metal and its salts have been used for several generations under many different formulations (eg, ointments, pulvers, foams, films). Possible reasons for the antimicrobial effect of silver include (1) interference with bacterial electron and ion transport; (2) binding to bacterial DNA, which may impair cell replication; (3) interaction with cell membrane, which may damage its structural and receptor function; and (4) formation of insoluble and metabolically ineffective compounds.
The ideal silver dressing will contain a concentration of silver to exert an effective antibacterial effect without or with only limited systemic absorption. However, locally applied silver compounds may react with wound fluid and form black silver sulphide, giving the skin a gray discoloration. The use of silver nitrate solution is more likely to cause this phenomenon than modern silver dressings.
One of the widely used silver dressings is Actisorb Plus, an activated charcoal cloth impregnated with silver. It is reported to absorb bacteria, which are then inactivated by the silver. Now marketed as Actisorb Silver 220, it is intended for use over partial- or full-thickness wounds, such as pressure ulcers, venous ulcers, diabetic ulcers, and acute and chronic wounds, and it is claimed to be the only dressing currently available in the United States that "combines broad-spectrum antimicrobial action, bacterial toxin management and odor control."[9]
Another new generation product, Acticoat, the silver antimicrobial barrier dressing, consists of a rayon/polyester nonwoven core laminated (by sonic welds) between an upper and lower layer of silver-coated, high-density polyethylene mesh (HDPE). The laminations are held in place with ultrasound welds. The silver-coated HDPE layers are designed to be barriers against microbial infection of a wound.
Acticoat is now available as both a nonabsorbable form and an absorbent antimicrobial barrier dressing effective to bacterial penetration. In its absorbable form, Acticoat is a calcium alginate dressing using novel silver-coating technologies in a dressing designed to prevent wound adhesion, to control bacterial growth, and to facilitate burn wound care. The barrier functions of the dressing may help reduce infection in moderately-to-heavily exuding partial- and full-thickness wounds, including decubitus ulcers, venous stasis ulcers, surgical wounds, first- and second-degree burns, grafts, and donor sites. The sustained-release of broad-spectrum ionic silver activity protects the dressing from bacterial contamination, whereas the alginate absorbs excess wound fluid to form a gel that maintains a moist environment for optimal wound healing.
In a new multilayer Acticoat (Acticoat-7), the silver antimicrobial barrier dressing consists of 2 rayon/polyester nonwoven inner cores laminated (by sonic welds) between 3 layers of silver-coated HDPE. The laminations are held in place with ultrasound welds. The silver-coated HDPE layers are designed to be barriers against microbial infection of a wound. Such products can provide an effective antimicrobial barrier for up to 5-7 days against 150 pathogens, including both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). See Smith & Nephew; Acticoat 7.
A number of controlled clinical studies have been performed to evaluate the safety and the efficacy of Acticoat. In a matched-pair, randomized, prospective clinical study for the treatment of burns, Acticoat was assessed for its ease of use, patient comfort, and antimicrobial effectiveness compared with standard care in the same institution. In general, the results were promising, with patients reporting less pain on removal with Acticoat and nurses reporting no significant difference in ease of application. The frequency of burn wound sepsis and the occurrence of secondary bacteriemia were both reduced.
A comprehensive laboratory study of the antimicrobial activity of Acticoat has also been reported. In a number of tests, Acticoat demonstrated improved antimicrobial performance over existing silver-based products. In addition to killing bacteria more rapidly, it had the lowest minimum inhibitory concentration and minimum bactericidal concentration. In a controlled study on donor site wounds, Allevyn showed significantly better results than Acticoat with respect to time to healing and extent of reepithelialization. No significant differences were seen in the incidence of bacterial cultures, and, while scarring appeared initially worse with Acticoat, this resolved by 3 months. Overall, the findings did not support the use of Acticoat for this application, although they did support its continued use for burn sites.
A comparison was made of home-care costs of local wound care in surgical patients.[10] Seventy-six patients were randomized between occlusive and gauze dressings. Patient groups were similar with regard to age, wound size, and etiology. Dressing-change frequency in the occlusive group (median: 0.6/d) was significantly (P = .008) lower than in the gauze group (1.1/d). Mean daily material costs of modern dressings were Euro 5.31 vs. Euro 0.71 in the gauze group (mean difference, Euro 4.60; 95% confidence interval, Euro 2.68-6.83). Daily total (material plus nursing) costs showed no difference between the groups (mean difference, Euro 2.86; 95% confidence interval, Euro 6.50-10.25). Wound healing in the gauze-treated group tended to be quicker than in the occlusive dressing group (medians: 30 vs 48 d, respectively; log-rank P = .060).
At least in this study, the use of occlusive dressings did not lead to a reduction in costs and wound healing time compared with gauze dressings for surgical patients receiving wound care at home.
Local collagen-based drug delivery systems
Collagen-based dermal matrices (sponges or transparent, semipermeable membranes) containing gentamicin have been successfully used for the treatment of infected burn wounds and for the prevention of wound infection in large-surface wounds, including severe burns. Such matrices (Sulmycin-Implant, Collatamp-G, INNOCOLL Inc, US) are commercially available and are distributed by Schering-Plough, United States, in many countries
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