You are in: eMedicine Specialties > Dermatology > SURGICAL Surgical DressingsArticle Last Updated: Jun 7, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School Robert A Schwartz is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi Coauthor(s): Zbigniew Ruszczak, MD, PhD, Clinical Dermatologist, Clinical Allergist, Consultant in Wound Healing and On Site Drug Delivery Systems, Consultant in Dermatopathology, Consultant in Pharmaceutical Industry in Europe and the United States; Ewa Joss-Wichman, MD, Senior Registrar, Lecturer, Department of Dermatology and Venereology, Dermatological Hospital, Medical University of Lodz, Poland; Rafal Wichman, MD, Medical Faculty, Medical University of Lodz, Poland; Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland Editors: Désirée Ratner, MD, Director of Dermatologic Surgery, George Henry Fox Assistant Clinical Professor, Department of Dermatology, Columbia Presbyterian Medical Center, New York Presbyterian Hospital; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; John G Albertini, MD, Dermatologic Surgery, The Skin Surgery Center; Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center Author and Editor Disclosure Synonyms and related keywords: wound dressings, skin substitutes, skin reconstruction, dermis replacement, skin replacement, artificial skin, skin equivalent, wound repair, permanent coverings, conventional autografts, autografts, temporary coverings, allografts, de-epidermized cadaver skin, in vitro reconstructed epidermal sheets, xenografts, conserved pig skin, synthetic dressings, acellular dressings INTRODUCTIONSection 2 of 10
  Rapid covering and healing of both acute skin defects and chronic skin defects are important objectives for wound healing. The best way to heal a wound is to close it according to surgical standards as quickly as possible after injury. However, this procedure is limited to those wounds and those anatomical regions that allow both excision and adaptation of wound borders to close the wound by primary intention or per primam (Latin term meaning to close the wound by suturing [or equivalent method] and restructuring of the skin continuity). In large-surface and deep wounds in which the primary wound closure is not possible or not practicable, the most important issue is to dress the wound with appropriate materials to allow the following: (1) to keep the wound free of infection, (2) to reduce or eliminate pain, (3) to reduce or eliminate all potential factors inhibiting natural healing (eg, dead tissue in burns, superficial fibrosis, necrotic tissue), and (4) to replace or substitute the missing tissue as much as possible. Wound repair Wound repair involves the timed and balanced activity of inflammatory, vascular, connective tissue, and epithelial cells. All of these components need an extracellular matrix to balance the healing process. Skin wounds heal by the formation of epithelialized scars of different contraction ability rather than by the regeneration of a true full-thickness tissue. To minimize scar formation and to accelerate healing time, different wound dressings and different techniques of skin substitution have been introduced in the last decades. Autologous skin grafting in the form of split- or full-thickness skin is still a criterion standard. However, in many patients, this technique may not be practicable for a variety of reasons, and the wound must be allowed to heal by second intention. Moreover, in cases in which skin grafts are used, a new wound is created on the donor side. Thus, eliminating a new wound to close the old one and to close as many tissue defects as possible without the risk of large area infection, necrosis, tissue hypertrophy, and contraction, as well as deformation of wound borders, is a necessity. The next important problem is to reduce or eliminate scar formation, particularly in the field of large-surface wounds. Traditional management of large-surface or deep wounds involves open and closed methods. In the open method, the wounds are left in a warm, dry environment to crust over, whereas, in the closed method, wounds are covered with different kinds of temporary dressings and topical treatment, including antibiotics, until healing by secondary intention. The early removal of the dead tissue (eg, in burns) reduced pain, the number of surgical procedures, and the length of the hospital stay. The surgical intervention (ie, tangential excision of partial- or full-thickness wound) followed by wound closure with autografts or temporary dressings is one of the currently used methods. In large-surface, full-thickness wounds, the wound can be excised down to the fat or the fascia, particularly if infection is present. Excision to the fat induces the removal of the subdermal plexus of blood vessels and decreases the take of autografts because this tissue is less vascularized. Excision down to the fascia induces better take of the autografts but has aesthetic disadvantages. Wound debridement can also be achieved by enzyme digestion of the dead tissues. Proteolytic enzymes (eg, collagenases used topically) allow a more specific destruction of necrotic tissues, while preserving viable dermis and avoiding blood loss, but the treatment can be painful and can increase the risk of local infection. In addition, it takes a long time to achieve a clean wound bed. Wound coverings Currently available wound coverings can be divided into 2 categories: (1) permanent coverings, such as autografts, and (2) temporary coverings, such as allografts (including de-epidermized cadaver skin and in vitro reconstructed epidermal sheets), xenografts (ie, conserved pig skin), and synthetic dressings. Conventional autograft (epidermis and a significant amount of dermis) obtained from healthy skin areas is considered the optimum wound cover in that its viability yields immediate take (incorporation into the wound bed) and resistance to wound infection. However, harvesting of autograft creates a second wound in the healthy tissue, a donor wound. This open wound increases the risk of infection and fluid/electrolyte imbalance. Repeated conventional harvests of autograft from a donor wound site can result in contour defects or scarring. Optimizing the healing of both main wounds and donor wounds becomes a later goal of patient management and the development of different surgical dressings, which can be used based on the principle of phase-adapted wound healing. Most recently, developed wound dressings are in use only as temporary dressings because of their synthetic or chemical components, limited persistence on the wound surface, and foreign body character. Primary closure versus second-intention treatment of skin punch biopsy sites was evaluated in a randomized trial.1 Punch biopsy sites healed by second intention appear at least as good as biopsy sites closed primarily with sutures. Volunteers preferred suturing for 8-mm biopsy sites and had no preference for 4-mm sites. Elimination of suturing of punch biopsy wounds results in personnel efficiency and economic savings for both patients and medical institutions. The wounds had been dressed with petroleum jelly under an occlusive dressing that consisted of gauze covered by a transparent dressing (Tegaderm; 3M, St Paul, Minn) and were left in place for 3 days. After that time, the gel foam was removed from the second-intention site and both biopsy sites were cleansed with water to remove any exudate. Then, an occlusive transparent dressing was reapplied to both sites. After this initial dressing change, dressings were changed weekly or more often at the volunteers' discretion until the biopsy sites were completely healed or reepithelialized. Efficient wound dressings can be important for both small and large wounds. Some of the currently available surgical dressings used in dermatologic and dermatosurgical practice are discussed. CLASSIFICATION OF WOUNDSSection 3 of 10
Wounds encountered in surgical and dermatosurgical practice can be classified according to their thickness, the involvement of skin or other structures, the time elapsing from the trauma (breaking of skin continuity), and their morphology. Additional classifications include factors that determine how to close the wound, classification of how the wound heals, and classification of the wound by bacterial contamination. Thickness of the wound
Involvement of other structures
Time elapsing from the trauma
Morphology
Factors that determine how to close the wound
Classification of how the wound heals
Classification of wound by bacterial contamination The 4 types of surgical wounds are as follows: clean, clean contaminated, contaminated, and dirty.
In the daily praxis, the main objective for dermatologists, dermatosurgeons, and surgeons is to transfer the wound from a spontaneous stage to a surgical stage and to heal the wound by primary intention. However, this is not always possible or practicable. In such cases, wounds heal mostly by secondary intention, and the injured tissue becomes healthy again; appropriate wound dressings are necessary to give the wound an optimal environment to heal. WOUND BED PREPARATIONSection 4 of 10
Before any kind of wound dressing is applied, the wound should be appropriately prepared to enhance both the effectiveness of the dressing and the self-healing ability of the wound. To achieve optimal healing, wounds must not be infected, they should contain as much vascularized wound bed as possible, and they should be free of exudate. Wound bed preparation in both acute wounds and chronic wounds is currently a part of the overall wound healing cascade, including (1) local blood coagulation, (2) vascular supply, (3) inflammation, (4) granulation tissue formation and revascularization, (5) epithelialization, (6) wound contraction, and (7) scar formation. However, the way of wound bed preparation in acute wounds differs from that of chronic wounds. For example, in acute wounds, debridement is an effective way to remove both damaged tissue and potential bacteria. Once performed, the acute wound should be clean and prepared to heal easily by primary intention. However, in the case of chronic wounds, debridement is usually an ongoing process. Unlike acute wounds, chronic wounds have what is termed necrotic burden consisting of nonviable tissue and exudate. This is usually a result of many, mostly long-standing local or systemic abnormalities, such as diabetes, arterial or venous insufficiency, and local tissue compression, leading pathogenetically to chronic wounds. Drs Falanga2, Sibbald, and Harding introduced the concept of wound bed preparation in the late 1990s. Wound bed preparation is defined as the global management of the wound to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures, including wound debridement, bacterial balance, and moisture balance. This concept leads to more effective strategies to address the reasons why chronic wounds fail to heal. Wound bed preparation as a strategy allows physicians to break into individual components in various aspects of wound care, while maintaining a global view of what they wish to achieve. Chronic wounds have always been overshadowed by acute wounds. Scientific breakthroughs and therapeutic measures would generally be developed or envisioned first for wounds caused by trauma, scalpel, or other types of acute injury. For instance, stimulation of reepithelialization by dressings providing moist conditions was first observed experimentally in acute wounds. The acceleration of healing by peptide growth factors was first formally demonstrated in experimental acute wounds in animals. These observations provided proof of principle for the effectiveness of topically applied growth factors, and they led to testing and commercialization of these agents in chronic wounds. Many other examples exist, but the point is that knowledge accumulated about acute injury has been the anchor on which one has relied for developing a therapeutic strategy for chronic wounds. The common error is to view wound bed preparation as the same as wound debridement. In acute wounds, wound debridement is a good way to remove necrotic tissue and bacteria. This is not the case for chronic wounds, where much more than debridement needs to be addressed for optimal results. Chronic wounds can be intensely inflammatory (eg, venous ulcers) and, thus, produce substantial amounts of exudate that interfere with healing or with the effectiveness of therapeutic products, such as dressings, growth factors, and bioengineered skin substitutes. Therefore, in the context of wound bed preparation, the concerns are not only the removal of actual eschars and frankly nonviable tissue but also the removal of the exudative component. Another important aspect of chronic wounds, which make them different from acute wounds in the context of wound bed preparation, is the possible need for a maintenance debridement phase. Debridement, whether it is performed by surgical, enzymatic, or autolytic means, is usually considered a procedure or a therapeutic step with defined time frames. This may be true of acute wounds that have become colonized and necrotic and, thus, need to be revitalized. However, with chronic wounds, debridement is generally unable to fully remove the underlying pathogenic abnormalities; necrotic material, nonviable tissue, and exudate (ie, necrotic burden) continue to accumulate. Within the context of wound bed preparation, the notion of an initial debridement phase followed by a maintenance debridement phase may be adopted. For example, after the initial debridement of chronic wounds, a temporary positive outcome on wound closure may be observed. However, often, a healing arrest occurs, with a return to a poor wound bed. One explanation may be that, because of the underlying and uncorrected pathogenic abnormalities, necrotic tissue and exudate, which now cause the healing arrest, continue to accumulate. Rather than always starting from the beginning, with periodic debridement and exudate control, one might consider a steady state removal of the necrotic burden that should continue throughout the life of the wound. In the concept of wound bed preparation, the biologic microenvironment of chronic wounds has to be clearly understood. For example, after an appropriate dressing is used, optimal compression therapy for edema control in venous ulcers decreases the amount of exudate and, thus, clears the macromolecules that may be trapping growth factors. Similarly, correction of the bacterial burden decreases the possibility of infection, but it also diminishes the ongoing inflammation that often characterizes many chronic wounds. Some chronic wounds may be "stuck" in one of the phases of the normal healing process, such as the inflammatory or proliferative phase. Eliminating the bacterial burden by the use of debridement, some antibacterial products, or adequate dressings can help this situation. As another example, appropriate debridement removes tissue and, therefore, cells that have accumulated and are no longer responsive to signals required for optimal wound healing. In this respect, fibroblasts from chronic wounds, including venous and diabetic ulcers, have been shown to become senescent and are unresponsive to certain growth factors. The term cellular burden has been created to describe this phenomenon. When a wound is debrided, this cellular burden is removed and wound responsiveness is restored. In the future, some specially developed chemical or biologic agents will probably help for normalizing such cells rather than removing them. In aiming at a well-vascularized wound bed, much can be achieved by removing necrotic or fibrinous tissue, by controlling edema, by decreasing bacterial burden, by performing compression therapy (especially for venous ulcers), and by off-loading (in the setting of pressure-induced ulcers). Further improvements in the vascularization of the wound bed can also be achieved by applying growth factors (eg, platelet-derived growth factor [PDGF]), by applying bioengineered skin, or even by using occlusive dressings. Indeed, one of the most important effects of occlusive dressings in chronic wounds, in addition to pain relief and absorption of exudate, may be stimulation of granulation tissue formation. Some growth factors, not yet available commercially, have the potential to greatly stimulate angiogenesis. These agents include fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF). Bioengineered skin and autologous or allogeneic skin can stimulate the formation of granulation tissue and, perhaps indirectly, the process of reepithelialization. Particularly noteworthy is the so-called edge effect (migration of the wound's edge toward the wound's center) after the application of bioengineered skin to previously unresponsive chronic wounds. These clinical effects have been observed with bioengineered skin and with simple keratinocyte sheets. It has been hypothesized that these stimulatory effects are due to the synthesis and the release of certain cytokines by the donor cells. However, the situation is probably highly complex, with cross-talk developing between the donor cells and the recipient resident wound cells. This cross-talk leads not only to the release of cytokines but also to the recruitment of other cell types from surrounding tissue and the circulation, to the formation of new blood vessels, and to the laying down of a more ideal extracellular matrix. The concept of wound bed preparation can help to recognize that chronic wounds have a complex life of their own and that they are not simply an aberration of the normal healing process. This concept allows examination of the different components that need to be addressed in chronic wounds and development of long-term strategies for the more complex issues that lead to failure to heal. The authors recommend the daily use of the concept of wound bed preparation, which, together with an appropriately chosen wound dressing or tissue substitute, will lead to more effective treatment of acute and chronic difficult-to-treat wounds. Moreover, this area of wound care is also critical to the assessment and evaluation of any new advanced wound healing technologies. AUTOLOGOUS AND ALLOGENIC SKIN REPLACEMENTSection 5 of 10
Skin replacement using autologous grafts The best way to cover large surface wounds is the transplantation of the patient's own skin (ie, split-thickness skin grafts) from an adjacent undamaged area that matches closely in terms of texture, color, and thickness. This surgical procedure inflicts an injury on the donor site analogous to a superficial second-degree burn, allowing spontaneous healing in 2-3 weeks, usually without scarring. Autograft is the method of choice to achieve definitive coverage of burned skin with good quality of healed skin. This technique has been improved by expanding the surface of the skin graft with a mesh apparatus, depending on the needs of the patient. Recently, as much as 25-30 times expansion has been described. However, excessive meshing usually results in healed skin that is more susceptible to infections and has a basketlike pattern, a major drawback for aesthetic appearance. An alternative is the Meek island graft or sandwich graft. This method allows easier handling of widely expanded autografts than meshed skin. In addition, because the autograft islands are not mutually connected, failure of a few of them does not affect the overall graft take. The Meek technique has been reported to be superior to the mesh procedure for expansion ratios of more than 1:6. In large surface burns, early closure of burn wounds with autologous skin grafts is limited by the lack of adequate donor sites. A delay of 2-3 weeks is necessary to wait for healing of donor sites before harvesting them again. The split-skin graft from the initial donor site can usually be reharvested 2-3 times and healed autografted wounds. This coverage process is time consuming and, thus, induces high risks of morbidity and mortality, mainly due to bacterial invasion. Cuono and coworkers3 proposed a 2-step procedure using composite autologous-allogenic skin replacement (de-epidermized skin allografts for dermis substitution and autologous, in vitro–reconstructed epidermis for surface covering) in burns. Compton et al4, as well as Hefton and coworkers5, preferred the use of both autologous, in vitro–reconstructed and allogenic, in vitro–reconstructed epidermal grafts for large-surface wounds. Although the use of epidermal autografts has markedly advanced the management of extensive burns and saved lives, this technique has major limitations, as follows: (1) at least 3 weeks is needed for growth of cultured epidermal sheets in the laboratory, thus delaying the coverage of wounds; (2) epidermal sheets need to be grafted on a clean wound bed because they are highly sensible to bacterial infection and toxicity of residual antiseptics; (3) the success of the treatment strongly depends on the dexterity of the laboratory and surgical teams, from the production of the sheets to their graft and care after grafting because this material is very fragile; (4) the regeneration of the dermal compartment underneath the epidermis is a lengthy process, and skin remains fragile for at least 3 years and usually blisters; and (5) the aesthetic aspect of the healed skin is less acceptable than the one obtained with a split-thickness graft. It was recognized early that any successful artificial skin or skinlike material must replace all of the functions of skin and, therefore, consist of a dermal portion and an epidermal portion. It was clinically apparent that a deep burn or other deep and/or large-surface wounds could not be completely closed promptly after injury by using the patient's available autograft donor sites. Moreover, in certain clinical situations (eg, elderly and young individuals), the donor sites themselves (if taken at standard thickness) create new wounds that often take a long time to heal and create additional metabolic stress, infection risk, and scarring. Wound coverage with allogenic skin One of the main differences between the cultured epidermal sheet and a split-thickness autograft is the lack of the dermal structure from the cultured autograftable sheets. The absence of dermis is perceived as the major cause for a lower percentage of graft takes and higher fragility and blistering after epidermal sheet transplantation compared to split-thickness autograft. A dermal component protects the basal layer of the epidermis and has a significant impact on the postgrafting biologic responses of the epithelial cells to the differentiation and wound-healing processes. After early debridement of deep and extensive burns, temporary closure of the wound is usually achieved with cadaver allograft before autografting with cultured epidermal sheets. Instead of completely removing cadaver skin before sheet transplantation, an excision of allogeneic epidermis can be performed with a dermatome to only maintain the allogeneic dermis on the wound. Because nonliving dermis alone may not be rejected, autologous cultured epidermal sheets can be grafted onto it, thus greatly enhancing healing. Indeed, cultured epidermal sheets grafted onto homograft dermis display early rete ridge development and anchoring fibril regeneration, in addition to a graft take of 95%. Knowing that devitalization of allografts reduces their antigenicity, the use of allogeneic cadaver skin as a biologic dressing is now widely accepted and is usually preferred to synthetic dressings. The preservation of allografts can be performed by different techniques, such as freeze-drying, glutaraldehyde fixation, or glycerolization. Cryopreservation of homografts with glycerol is the most popular method of cadaver skin processing because freeze-drying is too expensive and glutaraldehyde fixation has proven less efficient. Moreover, skin preservation can reduce the risk of virus transmission from skin grafting, providing time to rid the donor skin of pathogens. Indeed, incubation of cadaver skin for several hours at 37°C in glycerol displays a significant virucidal and bactericidal effect. To provide sufficient cadaver skin instantly accessible for the patient with a burn, skin banks, such as the Euro Skin Bank in Beverwijk, The Netherlands, have been well developed through the years. However, allogenic skin banking has a significantly higher cost compared with xenogeneic skin banking and biologic dressings. TYPES OF DRESSINGSSection 6 of 10
Until the early 1980s, only a few wound care products were available apart from traditional dressings (eg, gauze-based products) and paste (eg, zinc paste) bandages. The first modern wound dressings introduced during the mid 1980s usually combined 2 main characteristics: moisture keeping and absorbing (eg, polyurethane foams, hydrocolloids) or moisture keeping and antibacterial (eg, iod-containing gels). During the mid 1990s, the group of surgical dressings expanded into the well-recognized groups of products, such as vapor-permeable adhesive films, hydrogels, hydrocolloids, alginates, and synthetic foam dressings. Additionally, new groups of products, such as antiadhesive, mostly silicone meshes; tissue adhesives; barrier films; and silver- or collagen-containing dressings, were introduced. Finally, in the second half of the 1990s, combination products and engineered skin substitutes were developed. Until the end of 2002, many different dressings had been marketed (see the Table below). Currently, the global tendency demonstrates decreasing numbers of product categories approved both in Europe and in the United States, making the wound dressing market more transparent. The ideal wound dressing should have the following characteristics:
Classic dressings (not all categories are discussed in this article) include dry dressings and moisture-keeping dressings. Dry dressings include gauze and bandages, nonadhesive meshes, membranes and foils, foams, and tissue adhesives. Moisture-keeping dressings include pastes, creams and ointments, nonpermeable or semipermeable membranes or foils, hydrocolloids, hydrogels, and combination products. Bioactive dressings include antimicrobial dressings, interactive dressings, single-component biologic dressings, and combination products. Skin substitutes include epidermal substitutes (autologous or allogenic), acellular skin (dermis) substitutes (allogenic or xenogenic), autologous and allogenic skin, and skin substitutes containing living cells. Different types of wounds require different dressings or combinations of dressings. Dressing Categories Currently Marketed in the United States
ACELLULAR DRESSINGS AND SKIN SUBSTITUTESSection 7 of 10
Single-element biologic systemsWound coverage with amniotic membrane Human 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:
Tissues of animal origin have been used for thousands of years to cover extensive wounds. Although it has become evident in this century that xenograft achieves only temporary wound coverage, its unlimited availability under well-controlled conditions still makes animal skin a favorable wound covering. 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 20-300days. 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 productsThe 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 al6 represented one of the first attempts at engineering a dermal component to substitute the volume of missing tissue. Bello and coworkers7 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 al8 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. Recently, 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 Silicones Silicone 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. Local collagen-based drug delivery systems Recently, 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 worldwide. ENGINEERED SKIN DRESSINGS AND SUBSTITUTESSection 8 of 10
Wound coverage with allogenic cultured epidermal sheets One of the drawbacks in the use of autologous cultured epithelial sheets for the coverage of deep and extensive wounds is the time required for the growth of cells in vitro. In fact, recent clinical and experimental work demonstrated that allogeneic cultured epithelial sheet grafts do not survive. Even when the allograft was depleted of Langerhans cell, the rejection occurred in mice after 14-16 days. Readily available cultured allografts transplanted on deep partial-thickness skin burns induce faster healing of the wound promoted by the residual resident keratinocytes. Thus, the allograft may favor the proliferation and the differentiation of spontaneously regenerating epithelium. Allogenic cultured epithelial sheets can also be frozen for storage and easier transportation without impairing their graft efficiency. Matrices containing living skin-derived cells The living cell–containing bilayered product designed to speed up healing of both partial-thickness wounds and full-thickness wounds, including diabetic leg ulcers, has recently been approved both in the United States and in Europe. TransCyte (Smith & Nephew, Largo, Fla) was the first human-based, bioengineered, temporary skin substitute for the treatment of excised full- and partial-thickness burns approved by the US Food and Drug Administration (FDA) in 1997. TransCyte consists of a polymer membrane and newborn human keratinocyte cells cultured under aseptic conditions in vitro on a nylon mesh. Prior to cell growth, this nylon mesh is coated with porcine dermal collagen and bonded to a polymer membrane (silicone). This membrane provides a transparent synthetic epidermis when the product is applied to the burn. As fibroblasts proliferate within the nylon mesh during the manufacturing process, they secrete human dermal collagen, matrix proteins, and growth factors. Following freezing, no cellular metabolic activity remains; however, the tissue matrix and bound growth factors are left intact. The human fibroblast-derived temporary skin substitute provides a temporary protective barrier. TransCyte is transparent and allows direct visual monitoring of the wound bed. TransCyte is indicated for use as a temporary wound covering for surgically excised full-thickness and deep partial-thickness thermal burn wounds in patients who require such a covering prior to autograft placement. This product is also indicated for the treatment of mid dermal to indeterminate depth burn wounds that typically require debridement and that may be expected to heal without autografting. TransCyte contains essential human structural and provisional matrix proteins, GAGs, and growth factors known to facilitate wound healing. The outer layer is a synthetic epidermal layer that is biocompatible and protects the wound surface from environmental insults. It is semipermeable to allow fluid and gas exchange. The inner layer is a bioengineered human dermal matrix that adheres quickly to the wound surface. It contains essential structural proteins (type I, III, and V collagen), provisional matrix proteins (fibronectin, tenascin, SPARC), GAGs (versican, decorin), and growth factors (transforming growth factor-beta1 [TGF-beta1], keratinocytes growth factor [KGF], VEGF, insulinlike growth factor 1 [IGF-1]). In partial-thickness wounds, the patient's epithelial cells can proliferate and migrate across the wound, resulting in rapid wound healing. TransCyte must be stored and frozen between -70°C and -20°C, and it is defrosted directly before use. Recently, a novel bilayer skin substitute, OrCel, developed by Ortec (Ortec International Inc, New York, NY), containing living allogenic human cells has been approved in the United States. OrCel is a bilayered cellular matrix in which human allogeneic epidermal keratinocytes and dermal fibroblasts have been cultured in 2 separate layers into a type I bovine collagen sponge. Donor dermal fibroblasts are cultured on and within the porous sponge side of the collagen matrix, while keratinocytes, from the same donor, are cultured on the coated, nonporous side of the collagen matrix. OrCel serves as an absorbable biocompatible matrix that provides a favorable environment for host cell migration and has been shown to contain the following cell-expressed cytokines and growth factors: FGF-1 (bFGF), nerve growth factor (NGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1alpha (IL-1alpha), interleukin 1beta (IL-1beta), IL-6, human growth factor (HGF), KGF-1 (FGF-7), macrophage colony-stimulating factor (M-CSF), platelet-derived growth factor alpha/beta (PDGF-AB), transforming growth factor-alpha(TGF-alpha), TGF-beta, transforming growth factor-beta2, (TGF-beta2), and VEGF. OrCel is not intended to be a human skin replacement, and it does not contain Langerhans cells, melanocytes, macrophages, lymphocytes, blood vessels, or hair follicles. DNA analysis performed on 2 OrCel-treated donor site patient tissue samples showed no trace of allogeneic cell DNA after 2-3 weeks. Another advanced bioengineered skin equivalent based on xenogenic collagen type I (of bovine origin) was Organogenesis' main product, Apligraf. It is a commercialized form of living skin equivalent, an original idea proposed by Bello and coworkers.7 This preparation, also known earlier as Graftskin, is made by separating out the cells (keratinocytes and fibroblasts) from normally discarded infant human foreskin. The lower layer (dermis) consists of a collagen matrix formed by purified bovine type I collagen mixed with a suspension of dermal fibroblasts when the collagen matrix is believed to be condensed. This reduction of the volume of collagen approximately 30-fold within days and the formation of dense collagen lattices serve later as the dermal component. In the second step, human dermal keratinocytes are seeded on such a collagen matrix, forming an epidermislike structure. Apligraf obtained the Premarket Approval Application (PMA) from the FDA for use in the treatment of chronic venous leg ulcers and diabetic foot ulcers. In what was said to be the first controlled study of tissue therapy in acute wounds, 20 patients with acute split-thickness donor site wounds were evaluated; this product took clinically and proved to be a safe, pain-free, and effective form of tissue therapy. Because it behaves similar to an autograft, its use can avoid the creation of a donor site wound. A 3-inch (about 76.2 mm) diameter disc and a 4 X 8-inch (about 101.6 X 203.2 mm) sheet have been available recently. Non-collagen–based products that enhance dermal regeneration At the end of this review, some interesting and in part commercially available products manufactured without a collagen matrix are discussed. This kind of development can be seen as an answer to some, partially nonscientific, discussions about the safety of animal-derived collagen products. During the 1990s, intensive development had been made on biocompatible materials delivering living cells into the wound bed to stimulate host wound environment and to enhance the healing ratio. Smith & Nephew proposed Dermagraft, a product containing cryopreserved human fibroblast-derived dermal substitute composed of fibroblasts, extracellular matrix, and a bioabsorbable scaffold. Although this product does not contain collagen, it has been approved as a dermal substitute. Dermagraft is manufactured from human fibroblast cells derived from newborn foreskin. During the manufacturing process, the human fibroblasts are seeded onto a bioabsorbable polyglactin mesh scaffold. The fibroblasts proliferate to fill the interstices of this scaffold and secrete human dermal collagen, matrix proteins, growth factors, and cytokines to create a 3-D human dermal substitute containing metabolically active, living cells. Dermagraft does not contain macrophages, lymphocytes, blood vessels, or hair follicles. The product is indicated for use in the treatment of full-thickness diabetic foot ulcers greater than 6 weeks' duration, which extend through the dermis, but without tendon, muscle, joint capsule, or bone exposure. Dermagraft should be used in conjunction with standard wound care regimens and in patients who have adequate blood supply to the involved foot. Clinical study demonstrated that patients treated with Dermagraft were 1.7 times more likely to heal than the control group (conventional therapy included sharp debridement, sodium chloride–moistened gauze, and pressure-reducing footwear) at any given time during the study. Chronic diabetic foot ulcers treated with Dermagraft closed significantly faster than ulcers treated with conventional therapy alone. Another possibility was to use hyaluronic acid manufactured in the form of nonporous and porous membranes. Such membranes have been used alone or as a carrier for living cells. In this case, the patient's own cells have been cultivated in vitro and seeded on the membrane prior to clinical application. Laserskin autograft is an epidermal substitute consisting of autologous keratinocytes on a laser-microperforated membrane of hyaluronic acid (HYAFF; Fidia, Anato Terme, Italy). 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 scaffolds for the cultivation of fibroblasts and keratinocytes. Results of an animal study and preliminary clinical data on Laserskin have shown durability, good take rates, and low infection rates when cultured with autologous keratinocytes and autologous/allogeneic fibroblast feeder cells. Recently, this product has been described in the treatment of diabetic foot ulcers using a 2-step technique. Following wound debridement, the fibroblast grafts were applied and covered with paraffin gauze. Keratinocyte grafts were then applied after approximately 7 days and covered with gauze for an additional 7 days prior to inspection. Complete healing with no complications was achieved in 53 (91%) of 58 patients in an average time of 72 ± 48.18 days. Subsequent histologic examination showed good integration of the grafts into newly formed granulation tissue. Although these preliminary results are promising, the authors acknowledged that they should be followed up with a randomized, controlled clinical trial. Recently, products designed to enhance the healing of difficult-to-treat dermal and mucosal wounds have been designed by using fibrin glue as a carrier for living cells. These products are based on a 2-component fibrin glue technology (Baxter International Inc, US), in which autologous keratinocytes have been incorporated prior to the application. BioTissue AG (Freiburg, Germany) originally developed the products BioSeed-S and BioSeed-M. BioSeed-S is an autologous skin graft for treating poorly healing wounds. For BioSeed-S treatment, a small piece of the patient's own skin has to be removed. The skin cells are isolated and grown in the BioTissue laboratories. After about 2-3 weeks, the cells in fibrin adhesive (biological tissue glue) are applied to the patient's wound. The fibrin adhesive fixes the cells to the wound and allows better ingrowth. BioSeed-S is also very simple for the doctor to handle; the gel-like skin graft is applied to the wound by using a syringe. The special feature of BioSeed-S is that the cells are still capable of dividing, which means they continue to increase in number after grafting and, thus, close up the wound. BioSeed-M is an autologous oral mucosa replacement, which is used in oral surgery and for dental treatment. PERSPECTIVESSection 9 of 10
Many different materials are available to dress both acute wounds and chronic wounds. Most of them were developed to comply with phase-adapted wound healing principles. However, typical surgical dressings (eg, gauzes, bandages, membranes, foils, polymer sponges, hydrogels, hydrocolloids) cannot replace missing tissue, especially missing dermis. Currently, the use of an appropriate biologically active matrix to speed up the healing of missing tissue becomes a standard in wound dressing and skin reconstruction. However, what are the sources of new cell population in the healing wound? Many cells derive from adjacent tissue (local preexisting cell population), but increasing evidence suggests that both circulating (marrow-derived) stem cells and preexisting (organ-specific) stem cells can evolve tissue regeneration. These cells have surface markers of progenitor cells and a board differentiation capacity. Transfer studies demonstrated that mesenchymal precursors can populate several tissues and that vasculogenesis can arise from circulating endothelial progenitor cells. The availability of such cell types may be rate-limiting for dermal wound healing. Moreover, stem cells are important targets for the local application of growth factors and for gene therapy, and they participate in the natural healing processes occurring during wound organization and remodeling. The CD34-positive cell population and its subpopulations (ie, fibrocytes) have been demonstrated to participate in rapid new vessel and matrix formation. They secrete chemokines, hematopoietic growth factors, and fibrogenic cytokines. Moreover, these progenitor cells have been found to express each of the surface components that are required for antigen presentation, including class II major histocompatibility complex (MHC) antigens, costimulatory signaling molecules, and different adhesion molecules. The application of autologous (or allogenic) stem cells alone or together with some specific growth factors used in an appropriate 3-D matrix may help to initiate; to control; and, if necessary, also to terminate the de novo reconstruction of missing skin. Because of technical, ethical, and legislation difficulties connected with the use of stem cells and natural or recombinant growth factors and the complexity of the biological signaling cascade, the main interest has been focused on the development of an in vitro reconstructed skin, which can be transplanted directly to the wound bed and permanently replace the missing tissue. Neither the commercially available products nor the products currently described in experimental studies are able to fully substitute the natural living skin. However, a big effort has been achieved in the substitution of the main component of each wound, the missing connective tissue matrix creating human dermis. Once the dermis is reconstructed, the covering of the wound surface with both in vitro expanded epidermis and autologous split-skin transplants is significantly easier and has a much better chance to succeed. The handling of such dermal-replacement products is relatively easy. However, Integra Dermal Regeneration Template must be extensively washed before use, Apligraf must be defrosted and prewarmed, and CollatampFascia needs to be rehydrated. Both allogenic dermis or xenogenic acellular dermis need to be washed out (to remove chemical preservatives) or defrosted. Products containing living cells (eg, TransCyte, OrCel, Dermagraft) require only a few simple preparation steps, mostly washing or defrosting. Biobrane is principally ready to use as packed and may be obtained in 2 forms having either a standard adhesion or a low adhesion. SkinTemp can be easily applied on superficial and partial-thickness wounds and is also easily removed. This product is approved in the United States as a temporal wound dressing; it has to be removed from the wound within 7 days. Clinically, all products can be applied on all types of skin wounds (including burns and split-skin donor sites.) Additionally, collagen membranes used as a single agent can be used on mucous membranes. Collagen sponges and membranes used as a single agent or in combination with other implantable agents can be applied for deep tissue substitution and dead space filling as well as for coverage of nerves, tendons, ligaments, and vessels without or, if necessary, with additional fixation (ie, by a tissue sealant). Comparison of the effect of a collagen membrane versus a polyurethane membrane on the healing of split-thickness graft donor sites showed that the use of collagen significantly improved wound healing time and quality. A further advantage of collagen products is the possibility to combine them with both patient-derived (autologous) and recombinant growth factors, cytokines, living cells, and other stimulatory or antimicrobial agents to speed up the formation of granulation tissue, scar-free healing, and reepithelization. Currently, commercially manufactured collagen sponges containing immobilized antibiotic (eg, gentamicin, Collatemp-G [INNOCOLL, Germany], Sulmycin-Implant [Schering-Plough, US]) that are approved in many countries worldwide are successfully used to treat chronic wounds (eg, leg ulcers, decubital wounds) and to treat and prevent wound infection in burns serving both as dermis substitutes and as a controlled drug delivery system. With the exception of isolated groups in Europe, much of the research and commercial development of modern surgical dressings or tissue-engineered skin replacements is based in the United States. Although several important issues concerning wound pretreatment, choice of matrix support (for cell growth), and use of allogenic cells remain to be fully resolved, little doubt exists that tissue-engineered approaches to wound repair will present significant therapeutic benefits when compared with existing treatments. Such benefits may include the following:
The socioeconomic benefits of such treatments are apparent from the list presented above. As a consequence, both industry and health care would profit from concerted efforts (possibly through increased collaboration) to develop novel and more effective wound dressings and skin substitute devices. REFERENCESSection 10 of 10
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