Skin Substitutes for Treating Chronic Wounds

Заменители кожи для лечения хронических ран (Продолжение).

Technology Assessment Report

David L Snyder, PhD, Nancy Sullivan, BA, and Karen M Schoelles, MD, SM, FACP.

ECRI Institute EPC

Rockville (MD):Agency for Healthcare Research and Quality (US);2012Dec18.



Wounds – раны

Healing – заживление

Maturation – созревание

temporary shield – временныйщит

clot – сгусток

dosages – дозировки

toensure - обеспечить

Substitutes – заменители

Presumably – предположительно

Inadequate – недостаточность

Dressings – перевязочный материал

dry gauze – сухаямарля

ointment – мазь

frequently – часто

wet-to-moist – мокрый и влажный

SkinGrafts – кожные трансплантаты

Nonadherent – неадгезивные

Seaweed – морскиеводоросли

Moisture – влажность



Phases of Normal Wound Healing

Skin wounds heal in three distinct phases: the hemostatic or inflammation phase, the proliferative phase, and the maturation or remodeling phase. The inflammatory phase begins with tissue damage that often results in the release of blood and the formation of a fibrin clot. Platelets release cytokines and growth factors that attract inflammatory cells (neutrophils, eosinophils, and monocytes) and initiate the inflammatory response. The inflammatory phase also initiates cellular and vascular responses that clear dead tissue, bacteria, and foreign material from the wound. Vasodilation and increased capillary permeability around the wound allow serum proteins and leukocytes to infiltrate the area and begin the healing process. Macrophages appear within 48 hours and aggressively remove dead tissue and bacteria. Activated macrophages secrete cytokines that attract fibroblasts to the wound. The clot forms a temporary shield over the wound and provides a structure through which inflammatory cells, fibroblasts, and vascular endothelial cells move to form granulation tissue. The inflammatory phase lasts about 2–5 days.

Fibroblasts appear in the wound within 2–3 days and mark the beginning of the fibroblast proliferation phase. This phase may last up to three weeks. Fibroblasts produce and extrude collagen, which then forms into fibers that provide tensile strength to the wound. Fibroblasts also secrete a variety of growth factors that guide the formation of the new extracellular matrix. New blood vessels advance into the wound along with the fibroblasts to satisfy the metabolic needs of collagen formation. The new blood vessels, collagen, and proteoglycan ground substance form the granulation tissue. Granulation tissue fills a deep wound during the early phases of the healing process. Its formation is a key part of wound healing. Myofibroblasts within the granulation tissue contract, pull the wound edges together, and reduce the size of the wound. Re-epithelialization occurs during the fibroblast proliferative phase as epithelial cells (keratinocytes) proliferate and migrate over the granulation tissue. The new epithelial cells provide a barrier to bacteria and prevent fluid loss. In wounds with a large surface, epithelialization is enhanced by a moist environment. Dry wounds with a large dry eschar (commonly referred to as a “scab”) impede epithelial cell migration.

Growth factors and cytokines released into a wound play various roles in orchestrating the chain of events that results in restoration of the skin's barrier function and mechanical integrity. Growth factors are polypeptides that interact with cell receptorsto signal migration, proliferation, differentiation, and secretion of proteins such as collagen or additional growth factors. Platelet-derived growth factors (PDGFs) begin the healing process and start the interaction between cells and the extracellular matrix in the wound. Platelets also release transforming growth factor (TGF)-α and TGF-β, which increase cell proliferation. Activatedmonocytes and macrophages produce additional growth factors that activate angiogenesis. PDGF stimulates fibroblast proliferation and along with TGF-β stimulates fibroblasts to produce collagen, hyaluronic acid, matrix metalloproteinases, and additional proteins that build the extracellular matrix. Growth factors present in the newly formed granulation tissue stimulate the proliferation of keratinocytes at the wound margins. While PDGF and TGF are important elements in the healing process they represent only a small portion of all of the factors involved in wound healing. Vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor, connective tissue growth factor, and other factors have roles in different stages of wound healing. Understanding of the interaction between these growth factors, cells, and the extracellular matrix in chronic wounds is far from complete. Currently, the use of growth factors to promote wound healing has a limited role. Successful use of growth factors will depend on a better understanding of when each growth factor or combination of factors should be used, how to deliver the growth factors to the wound, and what dosages will ensure proper wound healing.

By three weeks after injury, collagen synthesis and degradation are in homeostasis, and wound remodeling begins. Maturation of the wound takes place with increasing levels of type I collagen, compared with type III collagen, and thickening of the collagen fibers. The new tissue formed in the wound progressively increases in tensile strength. This process may continue for up to two years.

The wound healing process should result in the restoration of skin structure and function. Lazarus et al.has proposed that healedwounds be placed in one of three categories: ideally healed, acceptably healed, and minimally healed. An ideally healed wound has returned to “normal anatomic structure, function, and appearance that includes a fully differentiated and organized dermis andepidermis with intact barrier function.” An acceptably healed wound has “epithelialization capable of sustaining functional integrity during activities of daily living.” A minimally healed wound has achieved “restoration of epithelial coverage that does not establish a sustained functional result and may recur.”


Skin Substitutes

Skin substitutes were developed as an alternative to skin grafts, especially for burn patients. Autologous tissue grafting is an invasive and painful procedure, and often the extent of damaged skin is too large to be covered by autologous tissue graft alone. Tissue engineered skin substitutes and cultured skin cells were developed during the 1980s. Skin substitutes are now primarily used in treating chronic wounds rather than for burns, in part because chronic wounds are far more common than burn wounds.

A true “skin substitute” would act like an autologous skin graft in adhering to the wound bed while providing the physiological and mechanical functions of normal skin.The skin substitutes included in this report contain various combinations of cellular and acellular components intended to stimulate the host to regenerate lost tissue and replace the wound with functional skin. Presumably, successful healing during management with these products would also require maintenance of a moist wound environment and other procedures thought to promote healing. These include removal of exudate and necrotic tissue, infectioncontrol, nutritional support, pressure avoidance (e.g., off-loading for diabetic foot ulcers and pressure ulcers) and edema control (e.g., compression for venous leg ulcers).

Dieckmann et al. have suggested that skin substitutes can be divided into two broad categories: biomaterial and cellular.Biomaterial skin substitutes do not contain cells (acellular) and are derived from natural or synthetic sources. Natural sources include human cadaveric skin processed to remove the cellular components and retain the structural proteins of the dermis andcollagen matrix obtained from bovine and porcine sources. Synthetic sources include degradable polymers such as polylactide and polyglycolide. Whether natural or synthetic, the biomaterial provides an extracellular matrix that allows for infiltration of surrounding cells. Cellular skin substitutes are distinguished by their origin: xenogeneic (from nonhuman species), autologous (from the patient), and allogenic (from another human). Keratinocytes and fibroblasts obtained from these sources are cultured in vitro to produce the cellular material used to make the substitute. However, the classification of skin substitutes into either biomaterial or cellular is not completely accurate since the two are combined into several wound care products.


Usual Care for Chronic Wounds

Several requirements are necessary for proper and rapid healing of an open wound. During healing, either the edges of the wound seal back together (healing by “primary intention”) or granulation tissue must form to fill the wound bed (healing by “secondary intention”). Most importantly, the wound must remain moist because new epidermal cells will only travel across moist surfaces.Bacterial infection must be controlled and any fluids should be removed from the wound site while appropriate moisture is maintained. Additionally, contributing factors to wound occurrence should be eliminated or minimized if elimination is not possible. Bedridden patients may need special support surfaces and protein-calorie malnutrition and vitamin deficiencies should be corrected. Inadequate blood flow to the site of the wound should be corrected if possible, and drugs known to impede wound healing should be adjusted.


Usual care for established chronic wounds incorporates common principles mentioned above that apply to managing all wound types. Clinicians remove necrotic tissue through débridement (achieved through sharp débridement using forceps and scissors, autolytic débridement by endogenous enzymes present in the wound, or application of exogenous enzymes in commercially available wound care products), maintain moisture balance by selecting the proper wound dressing to control exudate, and take measures to prevent or treat wound infections and to correct ischemia in the wound area. For venous leg ulcers, some form of compression is part of usual care. For diabetic foot ulcers, some form of off-loading is part of usual care. However, the methods for achieving each of these wound management principles varies among clinical practice guidelines and clinical studies.

Wound dressings used as usual care show considerable variability among clinical studies. A systematic review commissioned by the AHRQ Technology Assessment Program found that among 43 RCTs examining the treatment of diabetic foot ulcers, 51 percent used saline wet-to-dry dressing as the control while 14 percent used a hydrocolloid dressing. The number of dressing changes per day also varied. Among 66 RCTs of venous leg ulcers, saline wet-to-dry was the control dressing in only 3 studies while an occlusive dressing such as hydrocolloid was used in 25 studies. Other control dressings used in the venous leg ulcers studies included the Unna boot, dry gauze, Vaseline gauze, or ointment. Venous ulcer dressings were changed less frequently than diabetic foot dressings, most often once or twice weekly.

Chronic wounds are often treated with saline-moistened cotton gauze (wet-to-moist). Gauze dressings are moderately absorptive, easily available, and inexpensive. Saline-moistened gauze dressings can maintain a moist wound environment provided they are kept continuously moist until the dressing is removed. Therefore, wet-to-moist gauze dressings require close maintenance and added nursing time. The removal of a wet-to-moist dressing that has been allowed to dry may reinjure the wound by removing granulation tissue and lead to delayed wound healing. The removal of dried gauze dressings also causes the patient considerable pain, impedes healing, and increases the risk of infection. While gauze dressings are much less expensive per dressing than modern synthetic dressings, the increase in labor costs and ancillary supplies such as gloves and biohazardous waste disposal increase the total cost of care. The drawbacks of saline-moistened gauze dressings have been reviewed elsewhere.

The phrase “standard of care” was commonly used in the studies included in this report in reference to the wound care used in the control group or the base wound care to which a skin substitute was added (see Appendix C for descriptions of control group wound care). However, as described above, “usual care” or “standard of care” does not describe an agreed-upon set of procedures to be used when treating chronic wounds. In the evidence tables describing the wound care received in each study in this report, we have separated the description into three parts: the skin substitute, the control dressing, and the ancillary wound treatment. The Ancillary Wound Treatment column describes the usual care or standard care received by all patients.

Skin Grafts

Skin grafts are used in treating venous leg ulcers, diabetic foot ulcers, and burn wounds. Skin grafts are believed to assist wound healing by providing dermal collagen, growth factors, and biological occlusion and protection of the wound. Skin grafts are usually taken from a portion of intact skin of the same individual (autograft), but may be obtained by human skin donors (allograft). Skin grafts may be used in later stages of wound healing after the wound has established sufficient granulation tissue to support the graft. A recent Cochrane Review points out that insufficient evidence from RCTs was available to indicate whether skin grafting increased venous ulcer healing.

Wound Dressings

Dressings are selected based on the characteristics of the wound at any given point during the healing process. Wounds that produce exudate need an absorptive dressing (hydrocolloid, foam, alginate, hydrofiber) and dry wounds need a dressing that provides hydration (hydrogel). The type of dressing used will change as the wound goes through the phases of healing. Wound dressings that inhibit the loss of water vapor from the wound, thereby creating a moist environment, promote wound healing. Moist wound environments promote epithelialization and healing. Besides creating a moist wound environment, ideal dressings perform the following functions: remove excess exudates and toxic components, allow gaseous exchange, provide thermal insulation, and protect against secondary infection. A wide variety of wound dressings is available. Some of the unique features of each are described below.

The following dressings may be used on chronic or acute wounds depending on the nature of the wound.

  • Low or nonadherent dressings are inexpensive and allow wound exudate to pass through into a secondary dressing while helping to maintain a moist wound environment. These dressings are specially designed to reduce adherence to the wound bed. Nonadherent dressings are made from open weave cloth soaked in paraffin, textiles, or multilayered or perforated plastic films. This type of dressing is suitable for flat, shallow wounds with low exudate such as a venous leg ulcer.
  • Hydrocolloid dressings are composed of adhesive, absorbent, and elastomeric components. Carboxymethylcellulose is the most common absorptive ingredient. They are permeable to moisture vapor, but not to water. Additionally, they facilitate autolytic débridement, are self-adhesive, mold well, provide light-to-moderate exudate absorption, and can be left in place for several days, minimizing skin trauma and disruption of the healing process. They are intended for use on light-to-moderate exuding, acute or chronic partial- or full-thickness wounds but are not intended for use on infected wounds. Upon sustained contact with wound fluid, the hydrocolloid forms a gel.
  • Foam dressings vary widely in composition and construction. They consist of a polymer, often polyurethane, with small, open cells that are able to hold fluids. Some varieties of foam dressings have a waterproof film covering the top surface and may or may not have an adhesive coating on the wound contact side or border. Foams are permeable to water and gas, and are able to absorb light to heavy exudate. This type of dressing is frequently used under compression stockings in patients with venous leg ulcers.
  • Film dressings consist of a single, thin transparent sheet of polyurethane coated on one side with an adhesive. The sheet is permeable to gases and water vapor but impermeable to wound fluids. Film dressings retain moisture, are impermeable to bacteria and other contaminants, allow wound observation, and do not require a secondary dressing. Excessive fluid buildup may break the adhesive seal and allow leakage. Film dressings are intended for superficial wounds with little exudate and are commonly used as a secondary dressing to attach a primary absorbent dressing. The dressing may remain in place for up to seven days if excessive fluid does not accumulate. Film dressings have been used extensively to treat split-thickness graft donor sites.
  • Alginate dressings are made from calcium or calcium-sodium salts of natural polysaccharides derived from brown seaweed. When the alginate material comes into contact with sodium-rich wound exudates, an ion exchange takes place and produces a hydrophilic gel. This hydrophilic gel is capable of absorbing up to 20 times its weight and does not adhere to the wound. This dressing can remain in place for about seven days if enough exudate is present to prevent drying. This category of dressing is best suited for moist, moderate-to-heavy exuding wounds. Alginate dressings require a secondary dressing, such as a film dressing, to hold them in place and to prevent the alginate from drying out.
  • Hydrofiber dressing is composed of sodium carboxymethylcellulose fibers. The fibers maintain a moist wound environment by absorbing large amounts of exudate and forming a gel. This dressing is not intended for lightly exudingwounds. A secondary dressing is required.
  • Hydrogel sheets are three-dimensional networks of cross-linked hydrophilic polymers. Their high water content provides moisture to the wound, but these dressings can absorb small-to-large amounts of fluid, depending on their composition. Depending on wound exudate levels, hydrogels may require more frequent dressing changes, every 1–3 days, compared with other synthetic dressings. Hydrogel sheets can be used on most wound types but may not be effective on heavily exuding wounds. The gel may also contain additional ingredients such as collagens, alginate, or complex carbohydrates. Amorphous hydrogels can donate moisture to a dry wound with eschar and facilitate autolytic débridement in necrotic wounds. A second dressing may be used to retain the gel in shallow wounds.

Growth Factors

Growth factors have the potential to be important options when treating wounds. Becaplermin (Regranex gel, Ortho-McNeil Pharmaceutical, Inc., Titusville, NJ, USA) contains human recombinant PDGF and has been approved by FDA for treating diabetic neuropathic ulcers with adequate peripheral circulation. Four randomized controlled trials have demonstrated that becaplermin is more effective than placebo in promoting diabetic foot ulcer healing. In these studies becaplermin had a complete healing rate of 50 percent with a mean of 14 weeks to healing compared with 36 percent at 20 weeks for placebo. However, becaplermin's clinical experience outside these RCTs has not been as positive. In everyday clinical situations the healing rates have been reported to be closer to 33 percent for becaplermin and 26 percent for controls. The high cost of the drug coupled with the less-than-expected healing rates may explain why becaplermin has not been more widely used.