The Edge Effect: Current Therapeutic Options to Advance the Wound Edge

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The Edge Effect: Current Therapeutic Options to Advance the Wound Edge
Advances in Skin & Wound Care, February 2007

Clinical Topic: Skin/wound care

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The Edge Effect: Current Therapeutic Options to Advance the Wound Edge

Kevin Woo MSc, RN, ACNP GNC(C)
Elizabeth A. Ayello PhD, RN, APRN,BC, CWOCN, FAPWCA, FAAN
R. Gary Sibbald BSc, MD, FRCPC (Med) (Derm), FAPWCA, MEd

Advances in Skin & Wound Care: The Journal for Prevention and Healing
February 2007
Volume 20 Number 2
Pages 99 - 117


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Abstract

PURPOSE: To provide practitioners with information about advanced treatment options related to the edge effect of chronic wounds.

TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in wound care.

OBJECTIVES: After reading the article and taking the test, the reader should be able to:

1. Describe the DIME model and the normal wound healing process.

2. Identify differences in the physiologic responses of chronic wounds from acute wounds.

3. Discuss advanced treatment modalities for healing chronic wounds.

ADV SKIN WOUND CARE 2007;20:99-117; quiz 118-9.

Wound healing may be stalled for many reasons. One such reason is the "edge effect," which refers to epithelium that is failing to migrate across a firm and level granulation base. The epidermal edge may have a steep cliff-like appearance, rather than the desired tapered edge of advancing purple-pink epithelium that slopes into the mature granulation base (Figure 1).

Figure 1 - Click to enlarge in new window

Figure 1. EPITHELIUM FAILING TO MIGRATEIn this wound, the epithelium is failing to migrate across a firm and level wound base. The epidermal edge has a steep, cliff-like appearance.

This article focuses on the edge effect, and it is the fourth in a 4-part series that addresses the wound bed preparation model of DIME-Debridement, Inflammation or infection, Moisture balance, and Edge effect for the introduction of advanced therapies in wounds not healing at the expected rate.

Following the wound bed preparation paradigm 1 (Figure 2), the cause of the wound must be identified and appropriately treated and patient-centered concerns must be addressed before focusing on local wound care strategies. The approach to preparing the wound bed for ulcers with the ability to heal involves debridement of nonviable tissue, control of inflammation or infection, and moisture balance. If the wound is not 30% smaller at week 4, despite optimal local wound care, then it is unlikely to heal by week 12 and advanced therapies should be considered.2

Figure 2 - Click to enlarge in new window

Figure 2. WOUND BED PREPARATIONTreat the whole patient and optimize local wound care before using advanced therapies to correct the edge effect.

In this article, the evidence that substantiates the use of various active therapies to manage the edge effect will be examined. The highest level of available evidence, including results from meta-analyses and randomized control trials, has been selected for this review. Clinicians are reminded that if a wound does not have the ability to heal (for example, due to inadequate vasculature or coexisting illness), advanced therapies are seldom indicated and their chance of success is minimal.

ACUTE VS. CHRONIC WOUND HEALING

Normal acute wound healing follows an orderly sequential trajectory that integrates the complex physiologic and molecular events of coagulation, inflammation (cell recruitment and migration), and connective tissue proliferation followed by remodeling and maturation.3 After initial injury to the dermal tissue, hemostasis is established by platelet aggregation and fibrin clot formation that is followed by the activation of intrinsic and extrinsic coagulation pathways. Subsequently, the local ingress of neutrophils and macrophages to the injured area marks the beginning of the acute inflammatory phase. A myriad of growth factors are then produced by both platelets and neutrophils to accelerate wound healing. During the proliferative phase, the soft-tissue defect is replaced with new granulation tissue and matrix materials composed of fibronectin, hyaluronic acid, and collagen.

As wound healing progresses, the majority of the type III collagen that is produced by the fibroblasts is converted to type I collagen to enhance the tensile strength and integrity of the tissue. Reorganization and remodeling of the tissue will proceed even after epithelialization has taken place. Clinically, the wound is closed; however its reduced tensile strength makes it more vulnerable to breakdown at this stage.

In a chronic nonhealing wound, a prolongation of the inflammatory stage often interferes with normal wound healing; the new matrix is broken down by inflammatory products as quickly as it is constructed with the proliferative response. The granulation tissue that is produced may be defective for several reasons. For example, an increased bacterial burden triggers the release of excess vascular endothelial growth factor (VEGF), producing excessive but abnormally weak vascular endothelial buds. The subsequent granulation tissue can easily be digested by metalloproteinases and appears beefy red and friable (Figure 3).

Figure 3 - Click to enlarge in new window

Figure 3. RED FRIABLE WOUND

FUNCTION OF KERATINOCYTES

Keratinocytes are the primary cells in the epidermis. They play an important role in wound healing and in restoring the epithelium as a protective barrier after injury (Table 1). Shortly after the skin barrier is compromised, the keratinocytes are signaled by the proinflammatory lymphocytic cells to produce interleukin 1 (IL-1). Activated keratinocytes produce a number of growth factors, including heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor-[alpha]; integrin receptors; antimicrobial peptides (AMPs); and signaling molecules. Histoimmunochemical studies have demonstrated that the AMP level is low in chronic diabetic and venous leg ulcers.4,5 Morasso and Tomic-Canic6 demonstrated abnormal keratinocytes in chronic wounds that were capable of proliferation but with incomplete differentiation. Epidermal cells can be stalled with the lack of migration necessary for reepithelialization.7 This phenomenon produces the sharp cliff edge that may be seen clinically as a buildup of abnormal cells on the skin that results in thick, rolled edges.

Table 1 - Click to enlarge in new window

Table 1. MAJOR ROLES OF KERATINOCYTES DURING HEALING PROCESS

The exact mechanism to explain impaired reepithelialization is not known; however it may be related to the activation of [beta]-catenin transcriptional pathway and oncogene c-myc.8 These abnormal keratinocytes no longer respond to the signaling that stimulates them to perform their reepithelialization role in closing the wound.

Therapies for chronic wounds must be aimed at the keratinocyte abnormalities: removing abnormal keratinocytes, stimulating quiescent keratinocytes, or providing exogenous keratinocytes that are capable of stimulating a stalled wound.

APPROACHES TO CHRONIC, NONHEALING WOUNDS

Increasing scientific evidence suggests that cells in stalled chronic wounds are altered phenotypically, with an increase in senescent cells that are less responsive to cellular signaling, decreased growth factors,9,10 and other diminished cellular responses. Impaired cell migration and insufficient angiogenesis to support complete closure may also occur, with an imbalance of matrix metalloproteases (MMPs) and their inhibitors favoring tissue destruction.11-13 Wound healing may be improved by the local addition of deficient components, including growth factors and tissue matrix components. Cellular therapies include autologous epidermis, allografts, and living skin equivalents. Another approach could include complementary therapies, such as hyperbaric oxygen, negative pressure therapy, electrical stimulation, and ultrasound.

Commonly used therapies to advance the wound edges are summarized in Table 2 and discussed in more detail below.

Table 2 - Click to enlarge in new window

Table 2. SUMMARY OF ADVANCED THERAPY OPTIONS

ACELLULAR PREPARATIONS

Based on the current understanding of the pathophysiology of chronic wounds, the idea of using growth factors to stimulate healing has some appeal. Growth factors are subgroups of cytokines that are biologically active polypeptides, recognized for their contribution to the cell activation during wound healing (Table 3). In general, they can modulate and affect cellular behaviors (eg, mitosis) after binding to specific cell surface receptors that trigger the induction of a complex cascade of signal transduction pathways.

Table 3 - Click to enlarge in new window

Table 3. GROWTH FACTORS USED IN WOUND HEALING

Growth factors may act on adjacent cells as paracrine factors, on the cell itself as autocrine factors, or on remote cells via the bloodstream as endocrine factors. Chronic wounds are deficient in growth factors because of numerous mechanisms, including reduced growth factor expression, limited release from senescent cells, disproportionate degradation by MMPs, and possibly trapping or sequestration within perivascular cuffs.28,29 The ability to synthesize and concentrate adequate quantities of growth factors has led to clinical trials evaluating their use. Examples of growth factors and clinical studies relevant to wound healing are presented in Table 3.

The only growth factor that is approved by the US Food and Drug Administration is platelet-derived growth factor (PDGF). Platelet-derived growth factor is a dimeric protein composed of 2 disulfide linked polypeptide chains. There are 3 different isoforms: heterodimer PDGF-AB, 2 homodimers PDGF-AA, and PDGF-BB. Becaplermin (REGRANEX Gel, Johnson & Johnson, New Brunswick, NJ) is a topical rhPDGF-BB produced by inserting the gene for the B chain of PDGF into the yeast pathogen of Saccharomyces cerevisias using recombinant DNA technology. Platelet-derived growth factor is a potent chemoattractant and mitogen for fibroblasts.30 It stimulates the production of fibronectin and hyaluronic acid and is seminal to matrix formation and modulation of other growth factor activities in the wound. Platelet-derived growth factor is more active (catalyst) in acute wounds (or after sharp debridement) than in a chronic wound, where it is only one of many growth factors.

A meta-analysis of 4 randomized trials, including a total number of 874 patients with diabetes and neurotrophic foot ulcers, compared the effect of topical rhPDGF-BB or becaplermin gel at a dose of either 30 or 100 [mu]g/g with placebo gel, good ulcer care, or a combination of both.14 The primary focus of the studies was complete wound healing, although time to achieve complete healing was often captured as the secondary efficacy criterion. The growth factor was successful only in conjunction with adequate wound bed preparation (sufficient blood supply, infection control, pressure offloading, and active surgical debridement). Healing occured in up to 83% of patients treated with active surgical debridement and topical PDGF. Active surgical debridement in a person with sufficient blood supply to heal involves regular removal of defective surface granulation associated with increased bacterial burden to reach a bleeding but firm vascular base, as well as hyperkeratotic callus around the wound margin. It is contended that active debridement can stimulate healing by creating an acute wound within a chronic wound environment. Where surgical debridement was deemed inadequate (removal of peripheral callus), only 20% of patients achieved healing with the treatment of PDGF.

The results strongly suggest that "wound debridement is a vital adjunct in the care of patients with chronic diabetic foot ulcers."32 Combining all the data, patients with a median ulcer area of 1.5 cm² or less demonstrated greater healing in the treatment versus control group (50% vs 36%; P = .007).14 The efficacy of becaplermin for pressure ulcer treatment has not yet been established. Using a pressure ulcer model (n = 124), Rees et al33 did not demonstrate a dose response curve for the becaplermin gel and healing.

In another pressure ulcer trial, Mustoe et al 34 were unable to show a significant benefit of 3 concentrations of becaplermin gel over placebo. Pierce et al35 explored how rPDGF-BB may induce chronic wounds to heal. Biopsies were taken from the pressure ulcers of a cohort of 20 patients. Overall, fibroblast content was significantly higher for the rPDGF-BB-treated ulcers than the placebo-treated ulcers (P = .03). Increased collagen fibrillogenesis by fibroblasts, as assessed by intracellular procollagen type I immunostaining and electron microscopy, was associated with healing in rPDGF-BB-treated wounds.

Although textbooks in the 1990s predicted that growth factors would revolutionize wound care, most of the original promise has been unfulfilled. Similar attempts to improve wound healing have been unsuccessful as illustrated with the following examples.

If a single growth factor is not the most effective means of stimulating healing in a chronic wound, perhaps a combination of growth factors is required to affect wound healing. Platelet gels or releasates are prepared from platelet-rich plasma obtained by differential centrifugation of whole blood. Cryoprecipitate may be added in the process to achieve a firmer consistency of the gel (platelet-rich plasma, PRP).36,37 By adding gluconate calcium, thrombin, or batroxobine in platelet gels, the thrombocyte [alpha]-granules are activated to release a plethora of growth factors, including PDGF, transforming growth factor-beta, epidermal growth factor, insulin-like growth factor (IGF-1 and [beta]-estradiol [E2]), and vascular endothelial growth factor.38 Platelet-derived growth factors will, in turn, activate signal transduction enzymatic pathways that upregulate the tissue-regeneration cascade.
In a pilot study, Mazzucco et al 39 demonstrated that patients with dehisced sternal wounds (n = 22) achieved complete wound closure in 3.5 weeks using platelet gel, compared with 6 weeks in the control group (P < .0002). Is there similar evidence to support the use of platelet gel in chronic wounds? Driver and the Autologel Diabetic Foot Ulcer Study Group40 reported that more patients with diabetic foot ulcers who were being treated with a platelet-rich plasma gel achieved healing than those being treated with a saline gel (81.3% vs 41.1%; P = .02). The authors removed large and small wound size outliers from the analysis, which may have biased the reported result.
Other studies have not seen beneficial results. In separate randomized, placebo-controlled studies, Senet et al 41 and Stacey et al42 reached the same conclusion that topical autologous platelets have no significant impact on the healing of chronic venous leg ulcers. Senet et al41 failed to demonstrate any modulation of growth factor levels by platelet gel.
Fibrin glue (Tissel, Tissucol, Fibrin Sealant FS, Tachosil) has been used extensively as a biologic tissue adhesive during thoracic, cardiovascular, and general surgical procedures in the past. Fibrin glue is composed of 2 separate solutions of fibrinogen and thrombin. When mixed together, thrombin in the presence of calcium converts fibrinogen into fibrin monomers. Fibrin monomers are spontaneously polymerized and crosslinked into fibrin scaffolding under the influence of endogenous factor XIII catalyses, creating a stable mechanical structure on which fibroblasts can migrate into the wound.25 The glue produces a fibrin matrix for the initiation of the proliferative stage of wound healing. As a therapeutic agent, the fibrin glue may also exert antibacterial properties in wounds by improving phagocyte motility and inactivating bacterial proteolytic enzymes.43
Lapante et al 44 demonstrated that the reepithelialization rate can be significantly accelerated by the application of fibrin and PRP in vivo (P < .05). Fibrin and platelet gels may be a viable delivery vehicle for cultured keratinocytes, fibroblasts, and exogenous growth factors. This material has been referred to as a "smart matrix."
Fibroblasts are responsible for the production of substances such as glycosaminoglycans (GAG), which constitute the major component of early granulation tissue for the deposition and aggregation of collagen fibers. The 4 primary GAGs include hyaluronic acid, chondroitin-4-sulfate, dermatan sulfate, and heparin sulfate. Hyaluronic acid, or hyaluronan, is a ubiquitous carbohydrate polymer that is part of the extracellular matrix. It is a linear polysaccharide composed of repeated disaccharide units of glucuronic acid and N-acetyl-glucosamine. Hyaluronan may help to restore vascular integrity and replace damaged tissue due to its ability to increase vascular endothelial cell migration and motility.45
Hyalofill-F (ConvaTec, Skillman, NJ) is a partial benzyl ester derivative of hyaluronan. A case series has demonstrated healing of 24 of 32 (75%) of diabetic neurotrophic foot ulcers at 20 week.46 Colletta et al47 followed 20 patients whose venous leg ulcers were treated with Hyalofill-F plus compression therapy. After 8 weeks, the wound area decreased by 63%. Significant differences were noticed in both ulcer area (P < .01 ) and ulcer depth (P = .03) during the study. In a comparative study, Hyalofill-F plus compression performed significantly better in the treatment of chronic venous ulcers versus compression with nonadherent gauze.48 Ulcer area decreased by 8.1 cm² in the hyaluronan derivative group but by only 0.4 cm² in the gauze control group (P = .0019) at 8 weeks. The hyaluronan derivative has some promising results in initiating the healing process; however, there are no comparative studies showing increased healing rates.
Matrix metalloproteinases are a family of structurally related zinc-dependent neutral endopeptidases that are capable of degrading collagen and other components of the extracellular matrix (ECM), such as fibronectin, vitronectin, elastin, and proteoglycan core proteins. Matrix metalloproteinases are an important part of the inflammatory stage of wound healing, but they become destructive to the wound matrix when a prolonged inflammatory stage predominates a stalled chronic wound. There are approximately 24 human members of the MMP gene family, and they are classified based on their structure and substrate specificity.
Matrix metalloproteinases are produced by various cells including keratinocytes, fibroblasts, endothelial cells, neutrophils, and macrophages. The proteolytic property of the MMP is important during wound healing to remove debris and facilitate cell migration.10 Excessive accumulation and activation of MMPs can suppress cell proliferation and angiogenesis due to destruction of growth factors and matrix proteins that provide necessary substrates for cell migration and integrity of the tissue.49,50
Wound fluids from chronic ulcers have been shown to be proteolytic, from an over expression and activation of MMPs and from a deficient level of the tissue inhibitors of MMPs (TIMPs).51-53 Matrix metalloproteinases are also produced by bacteria present in chronic wounds, and these MMPs may be responsible for the damage from critical colonization and infection. To substantiate the proteolytic theory, the levels of MMP-2 and MMP-9 in chronic wound fluid are 5 to 10 times higher than in acute wound fluid.54
Promogran (Johnson & Johnson, New Brunswick, NJ) is prepared from bovine collagen impregnated in oxidized regenerated cellulose/collagen (ORC/collagen). This product restores the balance at the microenvironment level through binding and inactivation of proteases, while protecting the biologic activity of endogenous growth factors. Inactivation of proteases may also reduce the generation of reactive oxygen species (ROS) and harmful free radicals.55 Cullen et al56 examined 24-hour wound fluid with spectrofluorimetry. Neutrophil-derived elastase activity was 7% in the presence of ORC/collagen versus 75% elastase activity in the control samples.
Vin et al 57 reported a study of 73 patients with venous leg ulcers. Thirty-seven patients were randomly allocated to receive ORC/collagen (Promogran), while 36 received petrolatum gauze (Adaptic, ETHICON, Inc, division of Johnson & Johnson). Surface area reduction was greater in the Promogran group than in the Adaptic group (median decrease 82.4% vs 44.6%; P < .001). Wollina et al58 found that both venous leg ulcers and wound microcirculation could be improved with the use of Promogran. The authors conducted a prospective trial that involved 40 patients with chronic venous leg ulcers (mean age, 74 years). Wound microcirculation was evaluated using a technique based on noncontact remission spectroscopy. The mean reduction of ulcer area was statistically significant in patients treated with Promogran between the initial and final measurements (P < .05).
The results of using Promogran in patients with diabetic plantar ulcers are somewhat equivocal. In 1 study, of 276 patients with diabetic foot ulcers, no significant difference was found in the frequency of complete wound healing between Promogran and moistened gauze (37.0% vs 28.3%) after 12 weeks of treatment.59
An additional antibacterial benefit may be seen when Promogran is combined with 1% ionized silver (Prisma, Johnson & Johnson).
CELLULAR THERAPY
Tissue engineering is a burgeoning technology that strives to develop biologic substitutes or synthetic skin equivalents that emulate certain normal skin functions to accelerate wound healing.27 Ideally, a biosynthetic skin substitute should have the ability to develop rapid and sustained adherence to the wound surface, allow water vapor transmission, resist friction and shear stresses, prevent proliferation of bacteria, contain low antigenicity, and be free of local and systemic toxicity. The mechanisms by which bioengineered skin devices aid wound repair are multifaceted, including potential restoration of a biochemical balance and moist wound milieu, structural support for tissue regeneration, and the provision of cytokines and growth factors in physiologic concentrations. In general, skin substitutes are constituted by epidermal cells, dermal cells, or composites (by combining both dermal and epidermal cells).
Different techniques are used to obtain a graft. Heterografts are tissue derived from one source and applied to another (eg, bovine skin or cadaver skin used as a temporary covering). Autografting involves having a patient's own skin removed from one area of the body and applied to another, which creates a donor site wound in addition to the recipient site wound. Autografts can be full or partial thickness.
Autologous cells can be removed from the patient by skin biopsy from a different part of the body. The cells are then separated and cultured for expansion and placed on the wounds. Because autografts are cultivated from the patient's own skin cells, they will not be rejected by the patient's immune system. Examples of autologous keratinocytes sheets expanded through culture techniques in vitro include Epicel, EpiDex, TransCell, and Laserskin (Table 4).
Table 4. HUMAN SKIN EQUIVALENTS
Also known as cultured epidermal autograft (CEA), Epicel(Genzyme Biosurgery, Cambridge, MA) was first introduced in 1987. This product is a sheet of proliferating autologous keratinocytes attached to supportive petrolatum gauze. Epicel is cocultured with irradiated murine cells in a medium containing vancomycin, amikacin, and bovine serum. Epicel is contraindicated in patients with a known history of allergy to these agents. McAree et al 60 described the successful application of Epicel on 7 pediatric burn patients. They reported 69% initial take and 80% final graft take. In a retrospective review of 30 adult patients over a 5-year period, Carsin et al61 also examined the use of Epicel to cover wounds from extensive burn injury. Epicel provided permanent coverage to an average of 26 +/- 15% of total body surface area, similar to results from conventional grafts. Up to 69 +/- 23% of the Epicel-grafted areas did not require regrafting at the time of discharge or if the patient died for other reasons, indicating a high success rate. No controlled studies comparing Epicel with conventional grafting are currently available.
In a prospective controlled trial, Munster 62 evaluated the mortality rate associated with the use of Epicel: 14% in the 22 patients who were treated with Epicel and 48% in the 42 patients treated with standard wound dressings (P < .007). Confounding variables were not matched in their comparison, leading to potential measurement errors. Although case reports describe the application of Epicel to cover areas following congenital nevi excision,63 Epicel use has not been reported in the treatment of chronic wounds.
EpiDex (Modex Therapeutics, Lausanne, Switzerland [not FDA-approved]) is produced from autologous outer root sheath epidermal cells of the hair follicles in the anagen stage (during the active growth phase). These keratinocytes have a long life span and high proliferative capacity. A study of patients (n = 77) with venous leg ulcers showed no significant difference in the frequency of complete wound closure at week 12 between subjects who were randomized to EpiDex and those randomized to regular mesh graft (32.6% vs 41.2%; P = .4).64 However, the number of patients able to achieve complete wound closure was small, with only 14 patients in each group. Limat and Hunziker65 treated 50 chronic leg ulcers with EpiDex. Forty-five percent of the ulcers were healed and 40% more had reduced size at 8 weeks postgrafting.
TransCell (CellTran Limited, Sheffield, UK [not FDA-approved]) contains keratinocytes in a plasma coating with 20% carboxylic acid that allows them to attach and proliferate. In a small study of patients with full-thickness diabetic neuropathic foot ulcer of at least 4 weeks' duration, 6 out of 9 subjects achieved complete healing using TransCell dressing.66 During the 6-month assessment period, between 6 and 24 applications of TransCell were required. Considering the implication of cost, large randomized control trials should be implemented to evaluate the efficacy of this biologic agent.
To enhance cellular vitality and graft handling, keratinocytes can be cultured on woven scaffold composed of benzyl ester of hyaluronic acid derivative (Hyalograft 3D, Laserskin autograft, Fidia Advanced Biopolymers, srl, Abano Terme, Italy; not FDA-approved).67,68 Microperforations are made on the surface of the dressing by laser to allow for migration of keratinocytes onto the wound bed and passage of wound fluid. In an observational study, Lobmann et al68 reported a 79% wound closure rate in patients with type 2 diabetes (n = 14) 64 days after Laserskin was applied. These ulcers were difficult to heal, with an average duration of more than 6 months. A comparative study of Hyalograft with nonadherent paraffin gauze (Jelonet, Smith & Nephew, Hull, UK) in persons with diabetic neurotrophic foot ulcers (n = 79) demonstrated no statistically significant difference.69 Sixty-five percent of patients who were randomly assigned to Hyalograft healed completely, compared with 50% patients in the paraffin gauze group (P = .191). Considering the location of the ulcers, the authors performed an analysis comparing plantar versus dorsal foot ulcers. The number of healed dorsal area ulcers in the treatment protocol was significantly higher than in the control group (66.7% vs 32.25%; P = .049). No difference was found in the plantar ulcer subgroup.
Perhaps plantar ulcers are more difficult to heal than dorsal foot ulcers, regardless of the type of dressing used topically, due to a higher degree of shear and friction with mobility. As a reminder, healing of diabetic foot ulcers should always start with adequate offloading and regular sharp debridement before dressing selection.
Autologous keratinocytes have also been propagated in a fibrin sealant to yield BioSeed-S (BioTissue Technologies, Freiburg, Germany [not FDA-approved]). Johnsen et al 70 found that Bioseed-S could enhance epithelialization, with 55.8% of the leg ulcers (n = 52) healed in 6 weeks. The mean epithelialization increased from 23% to 62.5% between the 8th and 42nd day after grafting. The study was limited by the lack of a control population and randomization.
A number of drawbacks exist with respect to the use of autologous keratinocytes. First, a biopsy must be performed on patients to harvest keratinocytes. Second, there is a time delay of 3 to 4 weeks while the keratinocytes are cultivated. Third, the culture lifetime of keratinocytes and mitogen responsiveness tend to decline with an individual's age. Lastly, adult keratinocytes do not stimulate the growth of other keratinocytes.71 To circumvent problems associated with autografts, allogeneic grafts sheets are procured from a donor other than the patient who requires treatment. They are discussed next.
EPIDERMAL, DERMAL, AND COMPOSITE PRODUCTS
Freezing of skin through lypholization will kill cells but preserve growth factors, cytokines, and other epidermal and dermal signaling molecules that may promote wound healing.
LyphoDerm (XCELLentis, Gent, Belgium [not FDA-approved]) is a freeze-dried lysate from cultured allogeneic epidermis keratinocytes isolated from neonatal foreskin tissue. It is formulated into a hydrophilic gel that makes this product easier to apply. Harding et al 72 demonstrated that LyphoDerm might be efficacious in the treatment of venous leg ulcers. Analysis was based on how patients were actually being treated: 38% of the patients in the group were treated with compression therapy, a hydrocolloid dressing, and LyphoDerm, and they demonstrated complete ulcer healing within 24 weeks, compared with 27% in the group that received compression therapy, a hydrocolloid dressing, and a vehicle control. However, the reported findings did not reach statistically significant levels (P = .144).
Depending on whether viable cells (eg, fibroblasts or keratinocytes) are seeded, dermal grafts are classified as a cellular (nonseeded) or cellular (seeded). AlloDerm (LifeCell Inc, Branchburg, NJ) is an acellular human cadaveric dermal construct. Although epidermal components and dermal cells are removed by detergent followed by a process of freezing and drying, a structural matrix is preserved in AlloDerm that resembles human dermis. The potential advantage of having a dermal template is that it minimizes problems associated with fragility of the material and prevents premature wound contracture and graft failure. Sheridan et al 73 grafted 10 sites on 6 children with burns involving 47% to 85% of total body surface area. All subjects received AlloDerm to a randomly assigned study area that was compared with an adjacent area where a conventional autograft was applied. Selected endpoints were initial engraftment as judged by a blinded, experienced observer and Vancouver scar scores. Successful initial epithelialization was noted at 7 days postburn for 83% +/- 3.4% (range 60% to 95%) at the AlloDerm treated sites and 83.3% +/- 4.3% (range 60% to 98%) at the control sites. The result was not significant (P = .96).
In a similar study, Munster et al 74 observed no significant difference in successful graft take (P value not reported) between a standard split-thickness control graft and AlloDerm; the grafts were stapled side by side on adult burn victims (n = 17).
The use of AlloDerm has now been expanded for repair of soft-tissue defects and as a fascial substitute after abdominal wall reconstruction.75-79 One of the disadvantages of this material involves the risk of disease transmission. Its role in chronic wound care remains unclear.
Biobrane (Bertek Pharmaceuticals, Inc, Morgantown, WV) is an example of a xenograft that incorporates skin from another species in the device. It contains collagen-derived peptides from a porcine dermal template bonded to a nylon mesh and semipermeable silicone membrane. Biobrane-L contains less complex fabric than the original Biobrane, and it is indicated for use when less aggressive adherence is indicated.
Lang et al 80 systematically reviewed 84 cases of children with burn (n = 7) and scald injuries (n = 77) who were treated with Biobrane. Of those patients, 71 had wounds that healed using Biobrane without adverse events. Lal et al81 randomly assigned 41 pediatric patients to receive active treatment with Biobrane and 48 patients to receive conservative treatment with topical antimicrobials and dressing changes. At the end of the study, they concluded that within 48 hours of a superficial burn the application of Biobrane shortened the duration of hospitalization and healing times in children of all ages without an increased risk of infection. Another randomized control trial indicated that treatment with Biobrane was not superior to an occlusive hydrocolloid dressing (DuoDerm, ConvaTec, Skillman, NJ) in a study of children (n = 72) with intermediate-thickness burns.82 The mean time to complete reepithelialization was 11.21 days in the DuoDerm group compared with 12.24 days in the Biobrane group (P = .47). Animal studies have shown that Biobrane is rapidly digested by tissue hyaluronidase once placed on wound and disintegrated within 3 weeks.83 Several other comparison studies indicated that Biobrane may be less effective than other skin substitutes (OrCel, Ortec International, New York, NY; TransCyte, Advanced Biohealing, New York, NY).84 In addition to burn-related wounds, use of Biobrane has been reported in case studies in the management of toxic epidermal necrolysis.85
OASIS (HEALTHPOINT, Ltd, Fort Worth, TX) is composed of porcine-derived acellular small intestine submucosa. It consists of a collagen-based ECM or scaffold that includes glycosaminoglycans, fibronectin, and growth factors to support and accommodate cell proliferation. In a prospective randomized, multicenter, comparative trial (n = 73), 46% of patients with diabetic neurotrophic foot ulcers were healed with OASIS; only 28% (P = .055) were healed with PDGF therapy at the end of 12 weeks.86 The overall healing rates between groups did not reach statistical significance. In an analysis of only plantar ulcers only, 52% healed with OASIS versus 14% with PDGF (P = .014).86 Mostow et al87 compared the effectiveness of OASIS wound matrix and compression with compression alone in chronic leg ulcers. Of the 120 patients who were recruited into the study, 55% of the wounds in the OASIS group were healed at 12 weeks, compared with 34% in the standard care group (P = .02). None of the patients treated with OASIS experienced wound recurrence at the 6-month follow-up.
Integra (Integra LifeSciences Corporation, Plainsboro, NJ) is a bilaminar dermal regeneration template comprising of a porous matrix of crosslinked bovine tendon collagen and shark glycosaminoglycan copolymer (chondroitin-6-sulfate) and an epidermal substitute made of a synthetic silicone polymer. Integra has been used extensively in the treatment of burns 88 and reconstructive surgery.89 Muangman et al90 performed a retrospective review of patients with complex wounds treated with Integra at their burn center. Integra was used in the management of a variety of wounds, including necrotizing fasciitis, extremity degloving injury, meningococcemia, squamous cell carcinoma (Marjolin ulcer), postburn lip reconstruction, and full-thickness burns with exposed bone or tendon. They found that engraftment rates of Integra and autograft were similar: 98% +/- 4% and 97% +/- 4%, respectively.
Moiemen et al 91 described the use of Integra for reconstructive surgery. Patients reported a 72% increase in range of motion, 62% improvement in softness, and 59% improvement in appearance compared with the preoperative site. Although the successful use of Integra in the treatment of complex wounds has been reported in other case studies,92-99 rigorous clinical trials are lacking.
E-Z Derm (Brennen Medical, Inc, St. Paul, MN) is a porcine heterograft collagen matrix.100 A prospective, randomized trial of 32 patients with partial-thickness burns was reported comparing E-Z Derm with Jelonet as a burn dressing.101 No statistically significant differences were found between the 2 groups in terms of time for spontaneous healing. In a second study, Vanstraelen102 indicated that time to healing was longer with E-Z Derm (11.3 days) than with an alginate dressing (8.1 days) (P < .001). Hypertrophic scarring was not observed under the alginate dressings but occurred in 25% of xenograft-dressed sites (P < .01). The investigators also reported allergic reactions to the porcine xenograft in their sample.
GraftJacket matrix (Wright Medical Technology, Inc, Arlington, TN) is obtained from human skin that undergoes an elaborate process to remove the epidermis and dermal cells. A dermal construct that serves as a 3-dimensional scaffold for tissue regeneration is preserved. The GraftJacket has been studied in the treatment of deep diabetic foot ulcers to determine its efficacy in wound repair. Martin et al 103 studied 17 patients with diabetic foot ulcers that were appropriately offloaded and surgically debrided before GraftJacket was applied. Eighty-two percent of wounds healed in 20 weeks.
Comparing GraftJacket with standard ulcer care, Brigido et al 104 reported that ulcer area reduced by 73% versus 34% and ulcer depth decreased by 89% versus 25% in favor of GraftJacket. Only 1 application of GraftJacket was required in the above studies.
TransCyte (Advanced Biohealing, New York, NY) is recognized by an outer layer of nonporous silicone that resembles epidermis and an inner membrane of dermal analog derived from neonatal human fibroblasts. Viable cells are removed from the manufacturing process. Because the silicone component of the graft is not biodegradable, this product can be used only as a temporary wound cover. When used in partial-thickness burn wounds in children, TransCyte promotes faster reepithelialization than Biobrane and silver sulfadiazine cream.105 Of the 33 patients with a total of 58 wound sites, the mean time to reepithelialization was 7.5 days for TransCyte, 9.5 days for Biobrane, and 11.2 days for silver sulfadiazine (P < .001). Similar results were reported by Noordenbos et al.106 In their study of paired wound sites on 14 patients, they confirmed that wounds treated with TransCyte healed more quickly than those treated with silver sulfadiazine (mean 11.14 days to 90% epithelialization vs 18.14 days, respectively; P = .002). Children with burn injury covered by TransCyte had a shorter length of hospital stay than those received conventional therapy: 5.9 +/- 0.9 days vs 13.8 +/- 2.2 days (P = .002).107
Dermagraft (Advanced Biohealing, New York, NY) is the first single-layer product that consists of metabolically active dermal structure. It is engineered from cultured neonatal fibroblasts embedded in polyglactin or polyglycolic acid bioabsorbable mesh. Neonatal foreskin is a common and convenient tissue source of putative keratinocyte stem cells that are characterized by rapid mitogenic and metabolic activities and minimal antigenicity. As the fibroblasts proliferate, they produce collagen, glycosaminoglycans, fibronectin, ECM proteins, and growth factors. In fact, it was demonstrated that even local blood flow could be augmented by approximately 70% (5 out of the 7 ulcers studied) in diabetic foot ulcers that were treated with Dermagraft.108 Potential allograft rejection is also reduced because Dermagraft does not carry epidermal cells that contain surface antigens (HLA-DR).
Hanft et al 109 randomly assigned 28 patients with diabetic foot ulcers to receive Dermagraft or saline-soaked gauze. All subjects received shoes with custom-molded inserts and a clinical evaluation weekly. At the last follow-up visit at week 12, more ulcers healed in the Dermagraft group than in the saline gauze group (71.4% vs 14.3%; P = .003). The safety profile of the product is supported by the finding that fewer patients experienced an infection in the treatment group than in the control group. In a larger trial that included 314 patients with diabetic foot ulcers, Marston et al110 reported that 30% of the Dermagraft patients healed by week 12 compared with 18.3% of the control patients. No evidence of immune response leading to graft rejection was seen.
In another controlled, randomized, prospective study, patients were allocated to receive 1 piece of Dermagraft weekly, 2 pieces of Dermagraft every 2 weeks, 1 piece of Dermagraft every 2 weeks, or saline-moistened gauze.111 Sharp debridement, moist wound healing, and pressure relief were part of standard care provided to the recruited patients with diabetic foot ulcers (n = 50). By week 12, 50% of the subjects healed with weekly Dermagraft application, followed by 21.4% with 2 applications biweekly, 18.2% with single application biweekly, and 7.7% with standard care alone. Dermagraft was more effective than control treatment (P = .03). Weekly application of Dermagraft was more effective than biweekly treatment (despite the same quantities of dressing used), implicating a dose effect.
Based on previous clinical trial results, cost-effectiveness analysis using a Markov-based simulation model indicated that Dermagraft may be more cost effective than conventional treatment in the management of diabetic foot ulcers.112 Using regression analysis, the authors estimated that the healing rate was 6.7% with Dermagraft and 2.8% with conventional therapy during a 10-week trial period.
In a study of venous leg ulcers, 18 patients were randomized to either Dermagraft under 4-layer compression bandaging or compression alone, the difference in the number of wounds healed was not significant (5 used Dermagraft and 1 used compression alone; P = .15).113 However, reduction of the size of the ulcer was significant with the mean total ulcer area rate of healing being 0.82 cm²/week in the Dermagraft group and 0.15 cm²/week for the control group (P = .001). The mean percentage reduction was 84% for the Dermagraft-treated patients and 16% for the control group.
Sibbald et al 114 reported a case series of 6 patients (aged 8 to 23 years) with recessive dystrophic epidermolysis bullosa who were treated with Dermagraft. Each patient received between 7 and 32 skin substitute applications to between 6 and 19 sites; patients were followed for at least 8 weeks. At weeks 1 to 2, epidermal coverage ranged from 80% to 100%.
Apligraf (Organogenesis, Inc, Canton, MA), which is also called Graftskin, is derived from neonatal foreskin. It is a bilayered, living-skin construct composed of cornified differentiated keratinocytes that constitute an epidermis and a lattice of type 1 bovine collagen containing viable fibroblasts that constitute a dermal matrix. Apligraf is a live construct that must be applied clinically within 5 days of delivery. The epidermal layer provides a natural barrier to mechanical injury, while the ECM promotes the in growth of cells, such as fibroblasts, that act as a delivery system of growth factors to stimulate wound healing.115
In a pivotal multicenter, prospective, randomized controlled trial of patients with diabetic foot ulcers,116 regular debridement and appropriate offloading measures were provided to all participants. Local wound treatment of Apligraf applied weekly was compared with the use of a saline-moistened woven polyamide net (n = 208). At the final visit, 63 (56%) of patients in the Apligraf group healed, compared with only 36 (38%) in the control group. The odds ratio for complete healing for an Apligraf-treated ulcer as compared with a control-treated ulcer was 2.14 (95%CI 1.23-3.74). Similar results were replicated and reported by Sams et al.117
Apilgraf has also been used to treat lower-extremity ulcers after patients had undergone revascularization procedures.118 Healing of a substantial proportion of these patients was complicated by diabetes and renal failure (n = 31). At 4, 8, and 12 weeks, 21%, 62%, and 86% of the Apligraf-treated group had closed wounds. The difference in wound closure was significant at all time points between the Apligraf-treated and moist-saline gauze groups (P < .01).
According to the analysis by Redekop et al,119 treatment with Apligraf plus good wound care can lead to a 12% reduction in cost over the first year of treatment in comparison with good wound care alone. The cost-effectiveness model considered the incremental cost per ulcer per month gained and the incremental cost per amputation avoided. Apligraf use increased the amount of ulcer-free time by 1.53 months and reduced the risk of amputation by 10.8%. In a randomized controlled trial, up to 63% of venous leg ulcers patients treated with Apligraf and appropriate compression therapy achieved complete wound closure in 6 months compared with 49% in the control group.120 Following a subgroup analysis of patients having ulcers for more than 1 year, the calculated odds ratio of 2.01 implied that patients treated with Apligraf were twice as likely to reach complete wound healing as patients in the control.121
Sibbald et al 122 examined the cost effectiveness of combining Apligraf with compression to treat venous ulcers versus using compression alone. The model results indicate that over 3 months, the use of the skin substitute provided a benefit of 22 ulcer days averted per patient at an incremental cost of $304 (societal).
OrCel (Ortec International, Inc, New York, NY) is another example of tissue-engineered skin with a bilayered cellular matrix in which normal human allogeneic skin cells (epidermal keratinocytes and dermal fibroblasts) are seeded and cultured in 2 separate layers into a type I bovine collagen sponge. It is different from Apligraf in that the epidermal layer of OrCel is thicker and less differentiated than Apligraf.
Application of OrCel has been investigated in a randomized trial of split-thickness donor sites in burn patients.84 Each patient had 2 designated donor sites of equivalent surface area and depth. Sites were randomized to receive a single treatment of either OrCel or Biobrane-L. Based on planimetry assessments, the mean time to achieve 100% wound closure was 13.7 days using OrCel, as compared with 19.3 days using Biobrane (P = .0001).
OrCel has been used in the treatment of chronic conditions, such as epidermolysis bullosa and venous leg ulcers,123,124 with favorable results. Recessive dystrophic epidermolysis bullosa is characterized by frequent blistering and shearing of the skin and progressive hand syndactyly and flexion contractures. Skin grafting and surgical interventions are often required. Eisenberg and Llewellyn123 treated 7 children with recessive dystrophic epidermolysis bullosa. Although quantitative data were not obtained, the experience of using OrCel was positive in general.
Brown-Etris 124 describes a study of 36 patients with hard-to-heal venous ulcers. In the OrCel group, 71% healed completely at 6 months compared with 37% in the control group. Overall, bilayered skin substitutes are efficacious, especially in the venous leg ulcer population. Pooling the results from the 2 studies of venous leg ulcers conducted by Falanga119 and Brown-Etris,124 a fixed effect model yields a relative risk of healing with the skin substitute comparedwith a simple dressing of 1.51 (95% CI 1.22 to 1.88) anda number needed totreat of 1/0.2. For example, 5 patients would need to be treated with a skin substitute rather than a simple dressing for 1 additional ulcer to heal at 6 months.125
Another recent meta-analysis reviewed the clinical efficacy of artificial skin graft in chronic wound care. Ho et al 126 reported that a higher number of patients with diabetic neurotrophic foot ulcers using artificial grafts achieved complete wound healing than those in the control group after 11 to 12 weeks (RR = 1.44; 95% CI = 1.22, 1.71) but not at 6 to 8 weeks. Thirteen trials, including data from 1475 patients, were reviewed; 5 trials used Apligraf, 6 used Dermagraft, 1 used Hyalograft 3D plus Laserskin, and 1 used Biobrane. The investigators were unable to demonstrate an overall similar effect on the use of artificial skin grafts plus compression in venous disease.
GammaGraft (Promethean Life Sciences, Inc, Pittsburgh, PA) is a gamma-irradiated cadaveric allograft that is kept in a penicillin/gentamycin solution. It is a composite graft that contains both epidermal and dermal components. Unlike other skin substitutes that require cold storage and timely use once received from the manufacturer, GammaGraft can be stored for as long as 24 months at room temperature. Case reports are available to substantiate the use of GammaGraft on wounds in the lower extremity.127
COMPLEMENTARY THERAPIES
Hyperbaric oxygen therapy (HBOT) is defined as the administration of 100% oxygen to patients within an airtight vessel at pressures greater than 1 atmosphere absolute (ATA) (usually 1.5 to 3.0 ATA). Adequate tissue oxygen tension is essential to wound healing. Oxygen is involved in the hydroxylation of praline and lysine, the polymerization and cross-linking of procollagen strands, collagen transport, fibroblast and endothelial cell replication, effective leukocyte killing, angiogenesis, and other biologic processes integral to wound healing. Diminished circulation and hypoxia increase lactate production secondary to anaerobic metabolism and is deleterious to wound healing. The key question is whether there is any merit in hyperoxygenation.
Systemic HBOT sessions usually entail approximately 45-120 minutes in the chamber once or twice daily for 20-30 sessions. In vivo studies have shown that elevated arterial oxygen tensions can up-regulate growth factors, down-regulate inflammatory cytokines, promote angiogenesis, and exert antibacterial effects in wounds.
Pooled data from 6 randomized controlled trials on diabetic ulcers suggest a significant reduction in the risk of major amputation with HBOT.128 Wound size reduction and the number of healed wounds did not increase. Only 2 trials were reported in the literature that evaluated the efficacy of HBOT in the management of venous ulcers and pressure ulcers. Patients with venous ulcers who were treated with HBOT achieved a more significant reduction in wound areas than did those managed by sham treatment.129 Rosenthal and Shurman130 reported that although none of the pressure ulcers healed in the control group, 58% in the treatment group healed by HBOT.
Due to the paucity of research, there is insufficient evidence to determine whether HBOT is effective for the treatment of venous or pressure ulcers.131 It should be noted that oxygen in high doses is toxic, particularly to the brain and lungs. Other potential drawbacks of HBOT include damage to the ears and sinuses, time and direct cost associated with daily travel to and from the treatment center, and the psychological effect of confinement.
Electrotherapy, including electrical stimulation (ES), is defined as the application of an electrical current to transfer energy through a wound or on skin in close proximity to the wound. The central tenet of electrotherapy rests on the fact that a transepithelial potential is generated by inward (apical-basal) transport of sodium ions through the membrane sodium-potassium pump. When integrity of the skin is compromised, the electrical current follows the low-resistance pathway and flows toward the center of the wound laterally from the adjacent region.132 This current of injury will continue until the skin defect is totally repaired. The use of electrical current may influence wound healing by attracting the cells of repair or galvanotaxis, changing cell membrane permeability and transport, stimulating DNA synthesis, enhancing cellular secretion, increasing adenosine triphosphate production, and reorganizing the collagen matrix.133
Zhao et al 134 has shown that ES induces significant angiogenesis secondary to VEGF activation. It is thought that the healing process will be interrupted if the current ceased to function. A rationale for using electrotherapy is that it mimics the natural current of injury, accelerating the wound healing process. Akai et al135 reviewed 29 randomized controlled trials of 63 patients to examine the role of electrotherapy in musculoskeletal repair process. The investigators reported a small but significant finding in favor of electrotherapy (pooled difference of 0.42; 95% CI = 0.31-0.53). Although studies of wound care were included in the meta-analysis, inclusion of other studies of soft-tissue and musculoskeletal injuries may have diluted the treatment effect.
Peters et al 136 reported wound healing in 65% of the diabetic patients treated with ES, compared with 35% of patients treated with placebo. The finding did not quite reach the significance level (P = .058). Houghton et al137 found that when electrotherapy was applied to chronic leg ulcers, wound surfaces reduced by almost half (44.3%) of the initial wound size over 4 weeks, compared with 16% using a sham unit. Evidence suggests that ES may also have bactericidal effects on microorganisms.138 Electrical stimulation is contraindicated in the presence of malignancy, osteomyelitis, implanted electrical devices, or topical substances containing metallic ions (eg, providone-iodine, zinc, silver) or over the heart.
Electromagnetic therapy differs from electrotherapy in that it exerts a field effect that travels in space without the need of apropagation medium; it does not exert a direct electrical effect. There is no evidence to suggest that this form of therapy is beneficial to the treatment of pressure ulcers or venous leg ulcers.139,140
Low-energy laser therapy delivers treatment energies of less than 10 J/cm² at powers of 50mW or less. There are various types of lasers, including crystalline, semiconductor, liquid, and gas lasers. In laboratory and animal studies, wound cells were exposed to the photon energy produced by low-level laser therapy.141 The results indicated that laser might stimulate protein synthesis and the proliferation of fibroblasts and macrophages.
Does low-level laser therapy stimulate healing? Flemming and Cullum 142 conducted a systematic review of laser therapy for venous leg ulcers. They concluded that there was no evidence of a benefit of low-level laser therapy in the treatment of these chronic wounds.
Therapeutic ultrasound typically delivers sound waves in the form of a mechanical vibration emitted at frequencies of 1 and 3 MHz; the higher the frequency, the deeper the depth that the sound wave can penetrate. Vibration of ultrasound generates micron-sized bubbles within the coupling medium and tissue fluids, referred to as cavitation. The gas bubbles begin to migrate soon after they are compressed and condensed. The movement and compression of the bubbles provide a unidirectional and steady mechanical force that is known as streaming. These effects of ultrasound are capable of altering cellular activities and signal-transduction pathways of the tissues. Leukocyte adhesion, growth factor production, collagen production, increased angiogenesis, increased macrophage responsiveness, increased fibrinolysis, and increased nitric oxide are some of the examples of ultrasound-induced cellular effects.
Despite sound theoretical underpinning, Baba-Akbari Sari et al 143 concluded in their Cochrane systematic review that there is no evidence of benefit associated with the use of ultrasound in the treatment of pressure ulcers. Similarly, Flemming and Cullen144 state that none of the trials reported a difference in healing rates between ultrasound therapy and sham ultrasound or standard treatment in the care of venous ulcers; however, a trend toward faster healing in favor of ultrasound was observed. A recent randomized, double-blinded, sham-controlled, multicenter study investigated the effect of ultrasound on diabetic foot ulcers.145 After 12 weeks of care, the proportion of wounds healed in the active ultrasound therapy device group was significantly higher than that in the sham control group (40.7% vs 14.3%, P = .0366). Kaplan Meier survival analysis results found a mean time to healing of 9.12 weeks (SD = 0.58) and a median of 11 weeks (SD = 0) for the ultrasound compared with a mean of 11.74 weeks (SD = 0.22) and a median of 12 weeks (SD 0.82) for sham treatment (log rank P < .0144).
Ultraviolet light (UVL) contains type A, B, and C wavelengths. Ultraviolet light may increase epithelial cell turnover and has been used to remove slough, stimulate granulation and epidermal growth, and destroy bacteria in wounds. Wills et al 146 demonstrated that UVL (predominantly A and B) helped in the healing of pressure ulcers. The mean percentage of change in pressure ulcer size from baseline to complete healing was 53.3% in the ultrasound and UVL group; and 23.7% and 32.4% in the laser and control groups, respectively.147 Unfortunately, the effectiveness of using UVL alone was not evaluated in the study.
Despite promising results, ultraviolet radiation can be mutagenic, causing skin cancers. A vasoconstrictor reflex resulting in a marked decrease in skin oxygenation had also been demonstrated after UVL treatment. Such worrisome adverse effects could be detected even 2 weeks after therapy.148 In summary, UVL therapy for chronic wounds should be considered investigational.
Negative pressure wound therapy (NPWT) is the delivery of intermittent or continuous subatmospheric pressure to the wound bed. All the existing NPWT systems have regulated suction and tubing, but differ in the type of dressings used and the amount of suction delivered.
In 1 particular system, an open-celled sponge or foam, composed of either polyurethane or polyvinyl alcohol foam, is cut and placed onto the surface of the wound. The foam is then sealed over with a transparent drape to create a closed, airtight system, maintaining a negative pressure environment through a regulated vacuum pump. Contraction of the foam dressing exerts a centripetal effect at the wound edges and a mechanical force at the interface of the foam and wound. The suction effect and mechanical stress are transmitted to cellular and cytoskeletal levels, causing deformation of ECM and cells that is postulated to promote cellular proliferation.
Other potential advantages of NPWT include the removal of excess interstitial fluid to reduce the intercellular diffusion distance, improved blood flow, reduction of bacterial colonization, sequestration of excess MMPs and wound exudation, and augmentation of local functional blood perfusion.149
Armstrong et al 150 conducted a multicenter randomized controlled trial (n = 162) to examine the effect of NPWT in complex wounds after partial foot amputation to the transmetatarsal level in patients with diabetes. Fifty-six percent of the patients healed in the NPWT group compared with 39% of the control group (P = .04). Although investigations pertaining to the management of acute postsurgical wounds using NPWT also demonstrated positive results,151-154 no randomized controlled trial is available for this review.
Evans and Land 155 conducted a systematic review on NPWT for treating chronic wounds and only 2 randomized controlled trials were qualified for analysis. In the first study, Joseph et al156 reported a greater reduction in chronic wound volume coupled with granulation formation in the NPWT group compared with saline gauze dressing group (78% vs 30%; P = .038). In the second study, McCallon et al157 indicated that diabetic neurotrophic foot wounds treated with NPWT healed faster than wounds treated with saline-moistened gauze dressings (23 vs 43 days). Although pooled analysis of these 2 small trials is in favor of NPWT, this conclusion must be interpreted with caution given the small sample size (n = 34) and methodologic flaws.158
CONCLUSIONS
Over the years, we have made tremendous strides in our understanding of stalled chronic wounds and the associated edge effect. The crucial role of keratinocytes in wound closure has been apparent. State-of-the art advanced therapies have been developed to promote wound healing. A critical review of studies for advanced therapies will help clinicians determine the appropriate treatment options for evidence-based practice.
In the future, well-designed randomized controlled trials will be the key to inform us of the efficacy of these therapies. These trials need to be combined with expert opinion and patient preference for appropriate product selection. As new evidence continues to emerge, our approach to wound care management will evolve and improve the healing of stalled chronic wounds.
REFERENCES
1. Sibbald RG, Orsted HL, Coutts PM, Keast DH. Best practice recommendations for preparing the wound bed: update 2006. Wound Care Canada 2006;4:15-29. [Context Link]
2. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. The accuracy of venous leg ulcer prognostic models in a wound care system. Wound Repair Regen 2004;12: 163-8. [Context Link]
3. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005;366:1736-43. [Context Link]
4. Galkowska H, Olszewski WL, Wojewodzka U. Expression of natural antimicrobial peptide beta-defensin-2 and Langerhans cell accumulation in epidermis from human non-healing leg ulcers. Folia Histochem Cytobiol 2005;43:133-6. [Context Link]
5. Heilborn JD, Nilsson MF, Jimenez CI, et al. Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int J Cancer 2005;114:713-9. [Context Link]
6. Morasso MI, Tomic-Canic M. Epidermal stem cells: the cradle of epidermal determination, differentiation, and wound healing. Biol Cell 2005;97:173-83. [Context Link]
7. Brandner JM, McIntyre M, Kief S, Wladykowski E, Moll I. Expression and localization of tight junction-associated proteins in human hair follicles. Arch Dermatol Res 2003;295:211-21. [Context Link]
8. Stojadinovic O, Brem H, Vouthounis C, et al. Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol 2005;167:59-69. [Context Link]
9. Bergan JJ, Schmid-Schonbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. N Engl J Med 2006;355:488-98. [Context Link]
10. Medina A, Scott PG, Ghahary A, Tredget EE. Pathophysiology of chronic nonhealing wounds. J Burn Care Rehabil 2005;26:306-19. [Context Link]
11. Bullen EC, Longaker MT, Updike DL, et al. Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. J Invest Dermatol 1995;104:236-40. [Context Link]
12. Impola U, Jeskanen L, Ravanti L, et al. Expression of matrix metalloproteinase (MMP)-7 and MMP-13 and loss of MMP-19 and p16 are associated with malignant progression in chronic wounds. Br J Dermatol 2005;152:720-6. [Context Link]
13. Grinnell F, Zhu M. Fibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulin. J Invest Dermatol 1996;106:335-41. [Context Link]
14. Smiell JM, Wieman TJ, Steed DL, Perry BH, Sampson AR, Schwab BH. Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Reg 1999;7:335-46. [Context Link]
15. Robson MC, Phillips LG, Lawrence WT, et al. The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores. Ann Surg 1992;216:401-8.
16. Asai J, Takenaka H, Ichihashi K, Ueda E, Katoh N, Kishimoto S. Successful treatment of diabetic gangrene with topical application of a mixture of peripheral blood mononuclear cells and basic fibroblast growth factor. J Dermatol 2006;33:349-52.
17. Robson MC, Phillips TJ, Falanga V, et al. Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers. Wound Repair Reg 2001;9:347-52.
18. Hong JP, Jung HD, Kim YW. Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers. Ann Plast Surg 2006;56:394-8.
19. Tsang MW, Wong WK, Hung CS, et al. Human epidermal growth factor enhances healing of diabetic foot ulcers. Diabetes Care 2003;26:1856-61.
20. Hirshberg J, Coleman J, Marchant B, Rees, R. TGF-beta 3 in the treatment of pressure ulcers: a preliminary report. Adv Skin Wound Care 2001;14:91-5.
21. Landi F, Aloe L, Russo A, et al. Topical treatment of pressure ulcers with nerve growth factor: a randomized clinical trial. Ann Intern Med 2003;139:635-41.
22. Nayeri F, Stromberg T, Larsson M, Brudin L, Soderstrom C, Forsberg P. Hepatocyte growth factor may accelerate healing in chronic leg ulcers: a pilot study. J Dermtolog Treat 2002;13:81-6.
23. Yonem A, Cakir B, Guler S, Azal OO, Corakci A. Effects of granulocyte-colony stimulating factor in the treatment of diabetic foot infection. Diabetes Obes Metab 2001;3:332-7.
24. deLalla F, Pellizzer G, Strazzabosco M, et al. Randomized prospective controlled trial of recombinant granulocyte colony-stimulating factor as adjunctive therapy for limb-threatening diabetic foot infection. Antimicrob Agents Chemother 2001;45:1094-8.
25. Stadelmann WK, Digenis AG, Tobin GR. Physiology and healing dynamics of chronic cutaneous wounds. Am J Surg 1998;176(2A Suppl):26S-38S. [Context Link]
26. Bennett SP, Griffiths GD, Schor AM, Leese GP, Schor SL. Growth factors in the treatment of diabetic foot ulcers. Br J Surg 2003;90:133-46. [Context Link]
27. Enoch S, Grey JE, Harding KG. Recent advances and emerging treatments. Br Med J 2006;332:962-5. [Context Link]
28. Cooper DM, Yu EZ, Hennessey P, Ko F, Robson MC. Determination of endogenous cytokines in chronic wounds. Ann Surg 1994;219:688-92. [Context Link]
29. Greenhalgh DG. Wound healing and diabetes mellitus. Clin Plast Surg 2003;30:37-45. [Context Link]
30. Shen JT, Falanga V. Innovative therapies in wound healing. J Cutan Med Surg 2003;7:217-24. [Context Link]
31. Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers. Plast Reconstr Surg 2006;117(7 Suppl):143S-151S.
32. Steed DL, Donohue, D, Webster MW, Lindsley L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. J Am Coll Surg 1996;183:61-4. [Context Link]
33. Rees RS, Robson MC, Smiell JM, Perry BH. Becaplermin gel in the treatment of pressure ulcers: a phase II randomized, double-blind, placebo-controlled study. Wound Repair Reg 1999;7:141-7. [Context Link]
34. Mustoe TA, Cutler NR, Allman RM, et al. A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers. Arch Surg 1994;129:213-9. [Context Link]
35. Pierce GF, Tarpley JE, Allman RM, et al. Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB. Am J Pathol 1994;145:1399-410. [Context Link]
36. Borzini P, Mazzucco L. Platelet gels and releasates. Curr Opin Hematol 2005;12:473-9. [Context Link]
37. McAleer JP, Sharma S, Kaplan EM, Persich G. Use of autologous platelet concentrate in a nonhealing lower extremity wound. Adv Skin Wound Care 2006;19:354-63. [Context Link]
38. Crovetti G, Martinelli G, Issi M, et al. Platelet gel for healing cutaneous chronic wounds. Transfus Apher Sci 2004;30:145-51. [Context Link]
39. Mazzucco L, Medici D, Serra M, et al. The use of autologous platelet gel to treat difficult to heal wounds: a pilot study. Transfusion 2004;44:1013-8. [Context Link]
40. Driver VR, Hanft J, Fylling CP, Beriou JM, Autogel Diabetic Foot Ulcer Study Group. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage 2006;52: 68-70,72,74. [Context Link]
41. Senet P, Bon FX, Benbunan M, et al. Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers. J Vasc Surg 2003;38:1342-8. [Context Link]
42. Stacey MC, Mata SD, Trengove NJ, Mather CA. Randomized double-blind placebo-controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg 2000;20:296-301. [Context Link]
43. Currie LJ, Sharpe JR, Martin R. The use of fibrin glue in skin grafts and tissue-engineered skin replacements: a review. Plast Reconstr Surg 2001;108:1713-26. [Context Link]
44. Laplante AF, Germain L, Auger FA, Moulin V. Mechanisms of wound epithelialization: hints from a tissue-engineered reconstructed skin to long-standing questions. FASEB J 2001;15:2377-89. [Context Link]
45. Martin BR, Sangalang M, Wu S, Armstrong DG. Outcomes of allogenic acellular matrix therapy in treatment of diabetic foot wounds: an initial experience. Int Wound J 2005;2:161-5. [Context Link]
46. Vazquez JR, Short B, Findlow AH, Nixon BP, Boulton AJ, Armstrong DG. Outcomes of hyaluronan therapy in diabetic foot wounds. Diabetes Res Clin Pract 2003;59:123-7. [Context Link]
47. Colletta V, Dioguardi D, DiLonardo A, Maggio G, Torasso F. A trial to assess the efficacy and tolerability of Hyalofill-F in nonhealing venous leg ulcers. J Wound Care 2003;12:357-60. [Context Link]
48. Taddeucci P, Pianigiani E, Colletta V, Torasso F, Andreassi L, Andreassi A. An evaluation of Hyalofill-F plus compression bandaging in the treatment of chronic venous ulcers. J Wound Care 2004;13:202-4. [Context Link]
49. Lobmann R, Ambrosch A, Schultz G, Waldmann K, Schiweck S, Lehnert H. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and nondiabetic patients. Diabetologia 2002;45:1011-6. [Context Link]
50. Yager DR, Zhang LY, Liang HX, Diegelmann RF, Cohen IK. Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids. J Invest Dermatol 1996;107:743-8. [Context Link]
51. Drinkwater SL, Smith A, Burnand KG. What can wound fluids tell us about the venous ulcer microenvironment? Int J Low Extrem Wounds 2002;1:184-90. [Context Link]
52. Mwaura B, Mahendran B, Hynes N, et al. The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2, and PDGF-AA on the chronicity of venous leg ulcers. Eur J Vasc Endovasc Surg 2006;31:306-10. [Context Link]
53. Parks WC. Matrix metalloproteinases in repair. Wound Repair Reg 1999;7:423-32. [Context Link]
54. Wysocki AB, Staiano-Coico L, Grinnell F. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 1993;101:64-8. [Context Link]
55. Cullen B, Watt PW, Lundqvist C, et al. The role of oxidized regenerated cellulose/collagen in chronic wound repair and its potential mechanism of action. Int J Biochem Cell Biol 2002;34:1544-56. [Context Link]
56. Cullen B, Smith R, McCulloch E, Silcock D, Morrison L. Mechanism of action of PROMOGRAN, a protease modulating matrix for the treatment of diabetic foot ulcers. Wound Repair Reg 2002;10:16-25. [Context Link]
57. Vin F, Teot L, Meaume S. The healing properties of Promogran in venous leg ulcers. J Wound Care 2002;11:335-41. [Context Link]
58. Wollina U, Schmidt WD, Kronert C, Nelskamp C, Scheibe A, Fassler D. Some effects of a topical collagen-based matrix on the microcirculation and wound healing in patients with chronic venous leg ulcers: preliminary observations. Int J Low Extrem Wounds 2005;4:214-24. [Context Link]
59. Veves A, Sheehan P, Pham HT. A randomized controlled trial of Promogran (a collagen/oxidized regenerated cellulose dressing) vs standard treatment in the management of diabetic foot ulcers. Arch Surg 2002;137:822-7. [Context Link]
60. McAree KG, Klein RL, Boeckman CR. The use of cultured epithelial autografts in the wound care of severely burned patients. J Pediatr Surg 1993;28:166-8. [Context Link]
61. Carsin H, Ainaud P, Bever HL, et al. Cultured epithelial autografts in extensive burn coverage of severely traumatized patients: a five-year single-center experience with 30 patients. Burns 2000;26:379-87. [Context Link]
62. Munster AM. Cultured skin for massive burns. A prospective, controlled trial. Ann Surg 1996;224:372-7. [Context Link]
63. Compton CC, Nadire KB, Regauer S, et al. Cultured human sole-derived keratinocyte grafts re-express site-specific differentiation after transplantation. Differentiation 1998;64:45-53. [Context Link]
64. Tausche A, Skaria M, Lorenz B, et al. An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers. Wound Repair Reg 2003;11:248-52. [Context Link]
65. Limat A, Hunziker T. Use of epidermal equivalents generated from follicular outer root sheath cells in vitro and for autologous grafting of chronic wounds. Cells Tissues Organs 2002;172:79-85. [Context Link]
66. Moustafa M, Simpson C, Glover M, et al. A new autologous keratinocyte dressing treatment for nonhealing diabetic neuropathic foot ulcers. Diabet Med 2004;21:786-9. [Context Link]
67. Hollander D, Stein M, Bernd A, Windolf J, Pannike A. Autologous keratinocytes cultured on benzyl ester hyaluronic acid membranes in the treatment of chronic full-thickness ulcers. J Wound Care 1999;8:351-5. [Context Link]
68. Lobmann R, Pittasch D, Muhlen I, Lehnert H. Autologous human keratinocytes cultured on membranes composed of benzyl ester of hyaluronic acid for grafting in nonhealing diabetic foot lesions: a pilot study. J Diabetes Complications 2003;17:199-204. [Context Link]
69. Caravaggi C, De Giglio R, Pritelli C, et al. HYAFF11-based autologous dermal and epidermal grafts in the treatment of noninfected diabetic plantar and dorsal foot ulcers. Diabet Care 2003;26:2853-9. [Context Link]
70. Johnsen S, Ermuth T, Tanczos E, et al. Treatment of therapy-refractive ulcera cruris of various origins with autologous keratinocytes in fibrin sealant. Vasa 2005;34:25-9. [Context Link]
71. Nelson EA, Cullum N, Jones J. Venous leg ulcers. Clin Evid 2006 Jun;(15):2607-26. [Context Link]
72. Harding KG, Krieg T, Eming SA, et al. Efficacy and safety of the freeze-dried cultured human keratinocyte lysate, LyphoDerm 0.9%, in the treatment of hard-to-heal venous leg ulcers. Wound Repair Reg 2005;13:138-47. [Context Link]
73. Sheridan R, Choucair R, Donelan M, Lydon M, Petras L, Tompkins R. Acellular allodermis in burns surgery: 1-year results of a pilot trial. J Burn Care Rehabil 1998;19:528-30. [Context Link]
74. Munster AM, Smith-Meek M, Shalom A. Acellular allograft dermal matrix: immediate or delayed epidermal coverage? Burns 2001;27:150-3. [Context Link]
75. Andre RF, Lohuis PJ, Vuyk HD. Nasal septum perforation repair using differently designed, bilateral intranasal flaps, with nonopposing suture lines. J Plast Reconstr Aesthe Surg 2006;59:829-34. [Context Link]
76. Glasberg SB, D'Amico RA. Use of regenerative human acellular tissue (AlloDerm) to reconstruct the abdominal wall following pedicle TRAM flap breast reconstruction surgery. Plast Reconstr Surg 2006;118:8-15. [Context Link]
77. Kapfer SA, Keshen TH. The use of human acellular dermis in the operative management of giant omphalocele. J Pediatr Surg 2006;41:216-20. [Context Link]
78. Kish KJ, Buinewicz BR, Morris JB. Acellular dermal matrix (AlloDerm): new material in the repair of stoma site hernias. Am Surgeon 2005;71:1047-50. [Context Link]
79. Scott BG, Welsh FJ, Pham HQ, et al. Early aggressive closure of the open abdomen. J Trauma 2006;60:17-22. [Context Link]
80. Lang EM, Eiberg CA, Brandis M, Stark GB. Biobrane in the treatment of burn and scald injuries in children. Ann Plast Surg 2005;55:485-9. [Context Link]
81. Lal S, Barrow RE, Wolf SE, et al. Biobrane improves wound healing in burned children without increased risk of infection. Shock 2000;14:314-9. [Context Link]
82. Cassidy C, St. Peter SD, Lacey S, et al. Biobrane versus DuoDERM for the treatment of intermediate thickness burns in children: a prospective, randomized trial. Burns 2005;31:890-3. [Context Link]
83. Wang HJ, Chou TD, Tsou TL, et al. The application of new biosynthetic artificial skin for long-term temporary wound coverage. Burns 2005;31:991-7. [Context Link]
84. Still J, Glat P, Silverstein P, Griswold J, Mozingo D. The use of a collagen sponge/living cell composite material to treat donor sites in burn patients. Burns 2003;29:837-41. [Context Link]
85. Arevalo JM, Lorente JA. Skin coverage with Biobrane biomaterial for the treatment of patients with toxic epidermal necrolysis. J Burn Care Rehab 1999;20:406-10. [Context Link]
86. Niezgoda JA, Van Gils CC, Frykberg RG, Hodde JP. Randomized clinical trial comparing OASIS Wound Matrix to Regranex Gel for diabetic ulcers. Adv Skin Wound Care 2005;18(5 Pt 1):258-66. [Context Link]
87. Mostow EN, Haraway GD, Dalsing M, Hodde JP, King D; OASIS Venous Ulcer Study Group. Effectiveness of an extracellular matrix graft (OASIS wound matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. J Vasc Surg 2005;41:837-43. [Context Link]
88. Fette A. Integra artificial skin in use for full-thickness burn surgery: benefits or harms on patient outcome. Technol Health Care 2005;13:463-8. [Context Link]
89. Dantzer E, Braye FM. Reconstructive surgery using an artificial dermis (Integra): results with 39 grafts. Br J Plast Surg 2001;54:659-64. [Context Link]
90. Muangman P, Engrav LH, Heimbach DM, et al. Complex wound management utilizing an artificial dermal matrix. Ann Plast Surg 2006;57:199-202. [Context Link]
91. Moiemen NS, Vlachou E, Staino JJ, Thawy Y, Frame JD. Reconstructive surgery with Integra dermal regeneration template: histologic study, clinical evaluation, and current practice. Plast Reconstr Surg 2006;117(7 Suppl):160S-174S. [Context Link]
92. Ahmed S, Hussein SS, Philp B, Healy C. Use of biologic dressing as a temporary wound dressing in reconstruction of a significant forehead Mohs defect. Dermatol Surg 2006;32:765-7. [Context Link]
93. Akhtar S, Hasham S, Abela C, Phipps AR. The use of Integra in necrotizing fasciitis. Burns 2006;32:251-4. [Context Link]
94. Campitiello E, Della Corte A, Fattopace A, D'Acunzi D, Canonico S. The use of artificial dermis in the treatment of chronic and acute wounds: regeneration of dermis and wound healing. Acta Biomedica Ateneo Parmense 2005;76(Suppl 1):69-71. [Context Link]
95. Clayman MA, Clayman SM, Mozingo DW. The use of collagen-glycosaminoglycan copolymer (Integra) for the repair of hypertrophic scars and keloids. J Burn Care Res 2006;27:404-9. [Context Link]
96. Dagregorio G, Guillet G. Artificial skin as a valuable adjunct to surgical treatment of a large squamous cell carcinoma in a patient with epidermolysis bullosa. Dermatol Surg 2005;31:474-6. [Context Link]
97. Frame JD, Frame JE. Modifying integra as a regeneration template in deep tissue planes. J Plast Reconstr Aesthet Surg 2006;59:460-4. [Context Link]
98. Poucke SV, Jorens PG, Peeters R, et al. Pyoderma gangrenosum: a challenging complication of bilateral mastopexy. Int Wound J 2004;1:207-13. [Context Link]
99. Yeong EK, Huang HF, Chen YB, Chen MT. The use of artificial dermis for reconstruction of full thickness scalp burn involving the calvaria. Burns 2006;32:375-9. [Context Link]
100. Lawin PB, Silverstein P, Still JM. E-Z Derm: a porcine heterograft material. Am J Clin Dermatol 2001;3:507-8. [Context Link]
101. Healy CM, Boorman JG. Comparison of E-Z Derm and Jelonet dressings for partial skin thickness burns. Burns Incl Therm Inj 1989;15:52-4. [Context Link]
102. Vanstraelen P. Comparison of calcium sodium alginate (KALTOSTAT) and porcine xenograft (E-Z DERM) in the healing of split-thickness skin graft donor sites. Burns 1992;18:145-8. [Context Link]
103. Martin BR, Sangalang M, Wu S, Armstrong DG. Outcomes of allogenic acellular matrix therapy in treatment of diabetic foot wounds: an initial experience. Int Wound J 2005;2:161-5. [Context Link]
104. Brigido SA. The use of an acellular dermal regenerative tissue matrix in the treatment of lower extremity wounds: a prospective 16-week pilot study. Int Wound J 2006;3:181-7. [Context Link]
105. Kumar RJ, Kimble RM, Boots R, Pegg SP. Treatment of partial-thickness burns: a prospective, randomized trial using Transcyte. ANZ J Surg 2004;74:622-6. [Context Link]
106. Noordenbos J, Dore C, Hansbrough JF. Safety and efficacy of TransCyte for the treatment of partial-thickness burns. J Burn Care Rehabil 1999;20:275-81. [Context Link]
107. Lukish JR, Eichelberger MR, et al. The use of a bioactive skin substitute decreases length of stay for pediatric burn patients. J Pediatr Surg 2001;36:1118-21. [Context Link]
108. Newton DJ, Khan F, Belch JJ, Mitchell MR, Leese GP. Blood flow changes in diabetic foot ulcers treated with dermal replacement therapy. J Foot Ankle Surg 2002;41:233-7. [Context Link]
109. Hanft JR, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis. J Foot Ankle Surg 2002;41:291-9. [Context Link]
110. Marston WA, Hanft J, Norwood P, Pollak R; Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomised trial. Diabetes Care 2003;26:1701-5. [Context Link]
111. Gentzkow GD, Iwasaki SD, Hershon KS, et al. Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care 1996;19:350-4. [Context Link]
112. Allenet B, Paree F, Lebrun T, et al. Cost-effectiveness modeling of Dermagraft for the treatment of diabetic foot ulcers in the french context. Diabetes Metab 2000;26:125-32. [Context Link]
113. Omar AA, Mavor AI, Jones AM, Homer-Vanniasinkam S. Treatment of venous leg ulcers with Dermagraft. Eur J Vasc Endovasc Surg 2004;27:666-72. [Context Link]
114. Sibbald RG, Zuker R, Coutts P, Coelho S, Williamson D, Queen D. Using a dermal skin substitute in the treatment of chronic wounds secondary to recessive dystrophic epidermolysis bullosa: a case series. Ostomy Wound Manage 2005;51(11):22-46. [Context Link]
115. Dinh TL, Veves A. The efficacy of Apligraf in the treatment of diabetic foot ulcers. Plast Reconstr Surg 2006;117(7 Suppl):152S-149S. [Context Link]
116. Veves A, Falanga V, Armstrong DG, Sabolinski ML; Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care 2001;24:290-5. [Context Link]
117. Sams HH, Chen J, King LE. Graftskin treatment of difficult to heal diabetic foot ulcers: one center's experience. Dermatol Surg 2002;28:698-703. [Context Link]
118. Chang DW, Sanchez LA, Veith FJ, Wain RA, Okhi T, Suggs WD. Can a tissue-engineered skin graft improve healing of lower extremity foot wounds after revascularization? Ann Vasc Surg 2000;14:44-9. [Context Link]
119. Redekop WK, Stolk EA, Kok E, Lovas K, Kalo Z, Busschbach JJ. Diabetic foot ulcers and amputations: estimates of health utility for use in cost-effectiveness analyses of new treatments. Diabetes Metab 2004;30:549-56. [Context Link]
120. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol 1998;134:293-300. [Context Link]
121. Falanga V, Saboliniski M. A bilayered living construct (APLIGRAF) accelerates complete closure of hard-to heal venous ulcers. Wound Repair Reg 1999;7:201-7. [Context Link]
122. Sibbald RG, Torrance GW, Walker V, Attard C, MacNeil P. Cost-effectiveness of Apligraf in the treatment of venous leg ulcers. Ostomy Wound Manage 2001;47(8):36-46. [Context Link]
123. Eisenberg M, Llewelyn D. Surgical management of hands in children with recessive dystrophic epidermolysis bullosa: use of allogeneic composite cultured skin grafts. Br J Plast Surg 1998;51:608-13. [Context Link]
124. Brown-Etris M, Shields DK, Galluzzi KE, et al. Preliminary clinical outcomes on the use of composite cultured skin for the healing of venous ulcers. The 13th Annual Symposium on Advanced Wound Care & 10th Annual Medical Research Forum on Wound Repair, 2000. [Context Link]
125. Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev 2005;1:CD001737. [Context Link]
126. Ho C, Tran K, Hux M, Sibbald, G, Campbell K. Artificial skin grafts in chronic wound care: a meta-analysis of clinical efficacy and a review of cost-effectiveness. Technology Report 52. Canadian Coordinating Office for Health Technology Assessment, 2005. [Context Link]
127. Rosales MA, Bruntz M, Armstrong DG. Gamma-irradiated human skin allograft: a potential treatment modality for lower extremity ulcers. Int Wound J 2004;1:201-6. [Context Link]
128. Roeckl-Wiedmann I, Bennett M, Kranke P. Systematic review of hyperbaric oxygen in the management of chronic wounds. Br J Surg 2005;92:24-32. [Context Link]
129. Hammarlund C, Sundberg T. Hyperbaric oxygen reduced size of chronic leg ulcers: a randomized double-blind study. Plast Reconstr Surg 1994;93:829-34. [Context Link]
130. Rosenthal AM, Schurman A. Hyperbaric treatment of pressure sores. Arch Physical Med Rehab 52:413-5. [Context Link]
131. Gray M, Ratliff CR. Is hyperbaric oxygen therapy effective for the management of chronic wounds? J Wound Ostomy Continence Nurs 2006;33:21-5. [Context Link]
132. Ojingwa JC, Isseroff RR. Electrical stimulation of wound healing. J Invest Dermatol 2002;36:1-11. [Context Link]
133. Kloth LC. Electrical stimulation for wound healing: a review of evidence from in vitro studies, animal experiments, and clinical trials. Int J Lower Extrem Wounds 2005;4:23-44. [Context Link]
134. Zhao M, Bai H, Wang E, Forrester JV, McCaig CD. Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors. J Cell Sci 2004;117(Pt 3):397-405. [Context Link]
135. Akai M, Kawashima N, Kimura T, Hayashi K. Electrical stimulation as an adjunct to spinal fusion: a meta-analysis of controlled clinical trials. Bioelectromagnetics 2002;23:496-504. [Context Link]
136. Peters EJ, Lavery LA, Armstrong DG, Fleischli JG. Electric stimulation as an adjunct to heal diabetic foot ulcers: a randomized clinical trial. Arch Phys Med Rehabil 2001;82:721-5. [Context Link]
137. Houghton PE, Kincaid CB, Lovell M, et al. Effect of electrical stimulation on chronic leg ulcer size and appearance. Phys Ther 2003;83:17-28. [Context Link]
138. Gentzkow GD. Electrical stimulation to heal dermal wounds. J Dermatol Surg Oncol 1993;19:753-80. [Context Link]
139. Cullum N, Nelson EA, Flemming K, Sheldon T. Systematic reviews of wound care management: beds, compression, laser therapy, therapeutic ultrasound, electrotherapy, and electromagnetic therapy. Health Technol Assess 2001;5(9):1-221. [Context Link]
140. Ravaghi H, Flemming K, Cullum N, Olyaee Manesh A. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database Syst Rev 2006;2:CD002933. [Context Link]
141. Basford J. Laser therapy: scientific basis and clinical role. Orthopedics 1993;16:541-7. [Context Link]
142. Flemming K, Cullum N. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev 2000;4:CD00180. [Context Link]
143. Baba-Akbari Sari A, Flemming K, Cullum NA, Wollina U. Therapeutic ultrasound for pressure ulcers. Cochrane Database Syst Rev 2006;3:CD001275. [Context Link]
144. Flemming K, Cullum N. Therapeutic ultrasound for pressure sores. Cochrane Database Syst Rev. 2000;4:CD001275. [Context Link]
145. Ennis WJ, Foremann P, Mozen N, Massey J, Conner-Kerr T, Meneses P. Ultrasound therapy for recalcitrant diabetic foot ulcers: results of a randomized, double-blind, controlled, multicenter study. Ostomy Wound Manage 2005;51:24-39. [Context Link]
146. Wills EE, Anderson TW, Beattie BL, Scott A. A randomized placebo-controlled trial of ultraviolet light in the treatment of superficial pressure sores. J Am Geriatr Soc 1983;31:131-3. [Context Link]
147. Nussbaum EL, Biemann I, Mustard B. Comparison of ultrasound/ultraviolet-C and laser for treatment of pressure ulcers in patients with spinal cord injury. Phys Ther 1994;74:812-25. [Context Link]
148. Dodd HJ, Sarkany I, Gaylarde PM. The short-term benefit and long-term failure of ultraviolet light in the treatment of venous leg ulcers. Br J Dermatol 1989;120:809-18. [Context Link]
149. Banwell P, Teot L. Topical negative pressure (TNP): the evolution of a novel wound therapy. J Tissue Viability 2006;16:16-24. [Context Link]
150. Armstrong DG, Lavery LA. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomized controlled trial. Lancet 2005;366:1704-10. [Context Link]
151. Chaouat M, Bonnet F, Seroussi D, Smarrito S, Mimoun M. Topical negative pressure for the treatment of complex cavity wounds associated with osteitis. J Wound Care 2006;15:292-4. [Context Link]
152. Luckraz H, Murphy F, Bryant S, Charman SC, Ritchie AJ. Vacuum-assisted closure as a treatment modality for infections after cardiac surgery. J Thorac Cardiovasc Surg 2003;125:301-5. [Context Link]
153. Miller MS, McDaniel C. Treating wound dehiscence with an alternative system of delivering topical negative pressure. J Wound Care 2006;15:321-4. [Context Link]
154. Song DH, Wu LC, Lohman RF, Gottlieb LJ, Franczyk M. Vacuum-assisted closure for the treatment of sternal wounds: the bridge between debridement and definitive closure. Plast Reconstr Surg 2003;111:92-7. [Context Link]
155. Evans D, Land L. Topical negative pressure for treating chronic wounds: a systematic review. Br J Plast Surg 2001;54:238-42. [Context Link]
156. Joseph E, Hamori CA, Bergman S, Roaf E, Swann NF, Anastasi GW. A prospective randomised trial of vacuum assisted closure versus standard therapy of chronic nonhealing wounds. Wounds 2000;12:60-7. [Context Link]
157. McCallon SK, Knight CA, Valiulus JP, Cunningham MW, McCulloch JM, Farinas LP. Vacuum-assisted closure vs saline-moistened gauze in the healing of postoperative diabetic foot wounds. Ostomy Wound Manage 2000;46(8):28-32,34. [Context Link]
158. Gray M, Peirce B. Is negative pressure wound therapy effective for the management of chronic wounds? J Wound Ostomy Continence Nurs 2004;31:101-5. [Context Link]
159. d'Hemecourt PA, Smiell JM, Karim MR. Sodium carboxymethylcellulose aqueous-based gel vs becaplermin gel in patients with nonhealing lower extremity diabetic ulcers. Wounds 1998;10:69-75.
160. Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. The Diabetic Ulcer Study Group. J Vasc Surg 1995;21:71-81.
161. Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers: a phase III, randomized, placebo-controlled, double-blind study. Diabetes Care 1998;21:822-7.
162. Wieman TJ. Clinical efficacy of becaplermin (rhPDGF-BB) gel. Becaplermin Gel Studies Group. Am J Surg 1998;176(2A Suppl.):74S-9S.

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