The role of surgical debridement in healing of diabetic foot ulcers

A critical question in the treatment of chronic wounds is whether and when debridement is needed. The three most common chronic wounds are the diabetic foot ulcer (DFU), the venous leg ulcer, and the pressure or decubitus ulcer. Surgical debridement, aimed at removing necrotic, devitalized wound bed and wound edge tissue that inhibits healing, is a longstanding standard of care for the treatment of chronic, nonhealing wounds. Debridement encourages healing by converting a chronic nonhealing wound environment into a more responsive acute healing environment. While the rationale for debridement seems logical, the evidence to support its use in enhancing healing is scarce. Currently, there is more evidence in the literature for debridement for DFUs than for venous ulcers and pressure ulcers; however, the studies on which clinicians have based their rationale for debridement in DFUs possess methodologic flaws, small sample sizes, and bias. Thus, further studies are needed to develop clinical evidence for its inclusion in treatment protocols for chronic wounds. Here, the authors review the scientific evidence for debridement of DFUs, the rationale for debridement of DFUs, and the insufficient data supporting debridement for venous ulcers and pressure ulcers.     

Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers

The cause of impaired healing in chronic leg ulcers is not known. However, recent attempts to modify the healing process have focused on adding growth factors to stimulate healing and have failed to produce dramatic improvements in healing. This study used a unique model of chronic wound healing in humans to obtain wound fluid samples from chronic venous leg ulcers that had changed from a nonhealing to a healing phase. These samples were used to assess cytokine and growth factor levels, and mitogenic activity in these nonhealing and healing chronic wounds. The pro-inflammatory cytokines interleukin-1, interleukin-6 and tumor necrosis factor-alphawere found to be present in significantly higher concentrations in wound fluid from nonhealing compared to healing leg ulcers. There were detectable levels but, no significant change in the levels of platelet derived growth factor, epidermal growth factor, basic fibroblast growth factor or transforming growth factor-betaas ulcers healed. Wound fluid was added to fibroblasts in vitro to assess mitogenic activity. There was a significantly greater proliferative response to healing wound fluid samples compared to nonhealing samples. These results suggest that healing may be impaired by inflammatory mediators rather than inhibited by a deficiency of growth factors in these chronic wounds.     

Ability of chronic wound fluids to degrade peptide growth factors is associated with increased levels of elastase activity and diminished levels of proteinase inhibitors

The stability of peptide growth factors exposed to fluids from healing surgical wounds and from nonhealing chronic wounds was examined in vitro. (125)I-Labeled transforming growth factor-beta1 or platelet-derived growth factor-BB was incubated with fluids from healing surgical wounds and fluids from venous stasis or pressure ulcers. Fluids from healing surgical wounds had no appreciable effect on the level of (125)I corresponding to intact growth factor. In contrast, incubation with fluids from several venous stasis or pressure ulcers resulted in significant degradation of these growth factors. Degradation was blocked by broad-spectrum serine proteinase inhibitors and by specific inhibitors of neutrophil elastase. Levels of elastase activity in wound fluids correlated with the ability to degrade peptide growth factors. Further comparisons showed qualitative and quantitative differences in the endogenous proteinase inhibitors, alpha2-macroglobulin and alpha1-antiproteinase. These results could explain, in part, the variable growth factor levels which have been found in chronic wounds. More importantly, the ability of some chronic nonhealing wounds to rapidly degrade exogenously added growth factors has important implications with regard to past and future clinical attempts to use peptide growth factors to treat these types of problem wounds.     

Infrared thermography to prognose the venous leg ulcer healing process—preliminary results of a 12‐week,prospective observational study

Venous leg ulcers are complex, and their multifactorial etiology make successful treatment a difficult and long process. Nonhealing ulcers are the greatest challenge because they are resistant to standard therapies. In this study, we analyzed whether monitoring the temperature of the ulcered limb wound area could benefit the diagnosis of the wound's tendency to heal (estimating the presence of a healing or nonhealing wound) in patients with two‐sided venous leg ulcers. This prospective, 12‐week observational study included 57 adult individuals with chronic venous leg ulcers. The dynamics of wound healing was assessed by planimetry and infrared thermography every two weeks. We analyzed temperatures measured at three marked areas—the wound, the periwound skin, and the reference area. An initial wound area larger than 1 cm² was associated with a temperature increase of 0.027 °C in the periwound skin. A 1‐cm² decrease in the wound area was associated with a 0.04 °C decrease in the temperature difference between the periwound skin and wound. A strong positive relationship was identified for both the bacteriology variables (the presence of bacteria: temperature increase in the periwound skin of 0.4 °C, p < 0.001; the number of bacterial species in a wound, temperature increase of 0.95 °C, p < 0.001). The temperature in the reference area was significantly correlated with the failure of the superficial and perforating veins (temperature increase of 0.69 °C, p = 0.04). This study reports that the assessment of the temperature a limb may be beneficial in predicting whether an ulcer is a healing or a nonhealing ulcer. The decrease in the temperature differences between the areas referred to as healing wounds was the only beneficial prognostic marker. Other temperature differences in the periwound skin were caused by disorders, such as multibacterial wound infections and superficial venous inflammation.     

The specialized wound care center: a 7-year experience at a tertiary care hospital

Multidisciplinary wound care centers have proliferated as a result of an increasing need for care of nonhealing wounds. Information regarding types of wounds treated, length of treatment, compliance with treatment, and rates of healing was collected from a tertiary care hospital-based wound center over a 7-year period. Venous stasis ulcers were the most common type of wound treated (21%) and were also the most likely to heal. Pressure ulcers (20%), diabetic neuropathic ulcers (14%), ischemic ulcers (6%), and postsurgical wounds (6%) comprised the remainder of wounds treated. The success of treating wounds varied greatly with the wound's etiology. Despite the chronic nature of these wounds, most patients did not become long-term patients of the wound center. This study provides baseline outcome measures, which can serve as the basis for the comparison of treatment protocols and the development of prospective clinical trials.     

Classification and treatment of chronic nonhealing wounds. Successful treatment with autologous platelet-derived wound healing factors (PDWHF)

Previous animal data showed that platelets contain growth factors that stimulate capillary endothelial migration (angiogenesis), fibroblast proliferation and migration, and collagen synthesis. This study utilized autologous platelet-derived wound healing factors (PDWHF) to treat 49 patients with chronic nonhealing cutaneous ulcers. Patients were classified on the basis of 20 clinical and wound status parameters to generate a wound severity index. Forty-nine patients--58% diabetic (20% with renal transplants); 16% with trauma, vasculitis, etc.; 14% with decubitus ulcers; and 6% each with venous stasis or arterial insufficiency--with a total of 95 wounds had received conventional wound care for an average of 198 weeks (range: 1-1820 weeks). After informed consent was obtained, patients received autologous PDWHF. Mean 100% healing time for all patients was 10.6 weeks. There was no abnormal tissue formation, keloid, or hypertrophic scarring. A multivariant analysis showed a direct correlation to 100% healing with initial wound size and the initiation of PDWHF therapy. This is the first clinical demonstration that locally acting growth factors promote healing of chronic cutaneous ulcers.     

Evaluation of wound fluid biomarkers to determine healing in adults with venous leg ulcers: A prospective study

Clinical practice guidelines recommend using repeated wound surface area measurements to determine if a chronic ulcer is healing. This results in delays in determining the healing status. This study aimed to evaluate whether any of a panel of biomarkers can determine the healing status of chronic venous leg ulcers. Forty‐two patients with chronic venous leg ulcers had their wound measured and wound fluid collected at weekly time points for 13 weeks. Wound fluid was analyzed using multiplex enzyme‐linked immunosorbent assay to determine the concentration of biomarkers in the wound fluid at each weekly time point. Healing status was determined by examining the change in wound size at the previous and subsequent weeks. Predictive accuracy with 95% confidence intervals (CI) is reported. Of 42 patients, 105 evaluable weekly time points were obtained, with 32 classified as healing, 27 as nonhealing, and 46 as indeterminate. Thirteen biomarkers significantly differed between healing and nonhealing wounds (p < 0.1) and were included in a multivariate logistic regression model. Granulocyte macrophage‐colony stimulating factor (p < 0.001) and matrix metalloprotease‐13 (p = 0.004) were the best predictors of wound healing. Receiver operating characteristic curves indicated 92% accuracy (95% CI: 85%,100%) for granulocyte macrophage‐colony stimulating factor, and 78% accuracy (95% CI: 65%,90%) for matrix metalloprotease‐13 in discriminating between healing and nonhealing wounds. This study found that two biomarkers from wound fluid can predict healing status in chronic venous leg ulcers. These findings may lead to the ability to determine the future trajectory of a wound and the ability to modify treatment accordingly.     

Early healing rates and wound area measurements are reliable predictors of later complete wound closure

This study was undertaken to determine if healing rates are reliable early predictors of ultimate complete wound closure in venous leg ulcers and diabetic foot wounds. We conducted a retrospective analysis of 306 venous leg ulcers and 241 diabetic foot ulcers enrolled in two large controlled, prospective, randomized pivotal trials to compare topical wound treatments, to determine whether certain early markers of healing could be correlated with later total wound closure. Two-sided tests at 95% confidence demonstrated that wound margin advance, initial healing rate, percent wound surface area reduction, and wound healing trajectories (all p <0.001) were powerful predictors of complete wound healing at 12 weeks. Wounds with poor healing progress by these criteria at 4 weeks were highly likely to remain unhealed after 8 additional weeks of treatment. Analysis of the diabetic foot ulcers and venous leg ulcers subgroups separately demonstrated consistent statistical test results with high significance; similarly, the results remained valid independent of the topical treatment used. The early prediction of eventual wound healing or nonhealing using early healing rates may enable more efficient triage of patients to advanced healing technologies. We believe that these surrogate markers are robust predictors of healing regardless of wound etiology and that they merit wider use in clinical trials and routine patient care.     

An open multicenter comparative randomized clinical study on chitosan

Chitosan, a natural polysaccharide derivate from chitin, offers a promising alternative biomaterial for use in wound dressings. In this work, the safety and efficacy of a next‐generation KA01 chitosan wound dressing in facilitating the healing of nonhealing chronic wounds was studied. This open multicenter comparative prospective randomized clinical study was conducted at three medical centers in China. A total of 90 patients (45 in test group and 45 in control group) with unhealed chronic wounds including pressure ulcers, vascular ulcers, diabetic foot ulcers, and wounds with minor infections, or at risk of infection, were treated with the next generation chitosan wound dressing as the test article or traditional vaseline gauze as a control. Baseline assessments were undertaken with the primary end point being wound area reduction. The secondary end points included pain reduction (using the NRS11 pain scale) at dressing change, wound exudate levels, wound depth and duration of the treatment. After 4 weeks treatment, the wound area reduction was significantly greater in the test group (65.97 ± 4.48%) than the control group (39.95 ± 4.48%). The average pain level in the test group was 1.12 ± 0.23 and 2.30 ± 0.23 in the control group. The wound depth was also lower in the test group 0.30 ± 0.48 cm than the control group 0.54 ± 0.86 cm. The level of exudate fell and the dressing could be removed integrally in both the test and control groups. The mean duration of the test group was 27.31 ± 5.37 days and control group 27.09 ± 6.44 days. No adverse events were reported in either group. In conclusion this open multicenter comparative prospective randomized clinical study has provided compelling evidence that the next generation chitosan wound dressing can enhance wound progression towards healing by facilitating wound reepithelialization and reducing the patients pain level. Furthermore the dressing was shown to be clinically safe and effective in the management of chronic wounds.     

Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors

To assess the differences in proteolytic activity of acute and chronic wound environments, wound fluids were collected from acute surgical wounds (22 samples) and chronic wounds (25 samples) of various etiologies, including mixed vessel disease ulcers, decubiti and diabetic foot ulcers. Matrix metalloproteinase (MMP) activity measured using the Azocoll assay was significantly elevated by 30 fold in chronic wounds (median 22.8 microg MMP Eq/ml) compared to acute wounds (median 0.76 microg MMP Eq/ml) (p < 0.001). The addition of the matrix metalloproteinase inhibitor Illomostat decreased the matrix metalloproteinase activity by approximately 90% in all samples, confirming that the majority of the activity measured was due to matrix metalloproteinases. Gelatin zymograms indicated predominantly elevated matrix metalloproteinase-9 with smaller elevations of matrix metalloproteinase-2. In addition tissue inhibitor of metalloproteinase-1 levels were analyzed in a small subset of acute and chronic wounds. When tissue inhibitor of metalloproteinase-1 levels were compared to protease levels there was an inverse correlation (p = 0.02, r = - 0.78). In vitro degradation of epidermal growth factor was measured by addition of 125I labelled epidermal growth factor to acute and chronic wound fluid samples. There was significantly higher degradation of epidermal growth factor in chronic wound fluid samples (mean 28.1%) compared to acute samples (mean 0.6%). This also correlated to the epidermal growth factor activity of these wound fluid samples (p < 0. 001, r = 0.64). Additionally, the levels of proteases were assayed in wound fluid collected from 15 venous leg ulcers during a nonhealing and healing phase using a unique model of chronic wound healing in humans. Patients with nonhealing venous leg ulcers were admitted to the hospital for bed rest and wound fluid samples were collected on admission (nonhealing phase) and after 2 weeks (healing phase) when the ulcers had begun to heal as evidenced by a reduction in size (median 12%). These data showed that the elevated levels of matrix metalloproteinase activity decreased significantly as healing occurs in chronic leg ulcers (p < 0.01). This parallels the processes observed in normally healing acute wounds. This data also supports the case for the addition of protease inhibitors in chronic wounds in conjunction with any treatments using growth factors.     

Wound outcomes in patients with advanced illness

A prospective case series was studied to assess the potential for complete healing of wounds among patients with advanced illness referred to a regional palliative care program in Toronto, Canada. Two hundred and eighty‐two patients, of which 148 were primarily diagnosed with cancer and 134 with non cancer advanced illness, were assessed and followed until their deaths. On the baseline initial referral date, 823 wounds were documented. The wound classes assessed included pressure ulcers, malignant wounds, skin tears, venous leg ulcers, diabetic foot ulcers and arterial leg/foot ulcers. Proportions of patients showing complete healing of at least one wound were calculated, stratified by patient's survival time post‐baseline (1 week, 1 month, 3 months and 6 months). Proportions of patients showing complete healing of at least one wound increased the longer patients lived and ranged between 12·9% and 43·5% for stage I pressure ulcers, 0% and 60% for stage II pressure ulcers, 2·4% and 100% for skin tears, 10% and 100% for venous leg ulcers and 0% and 50% for diabetic foot ulcers. Only one person showed complete healing of a stage III pressure ulcer and no complete healing was observed with stage IV pressure ulcers, unstageable pressure ulcers, malignant wounds and arterial leg/foot ulcers.     

The molecular biology in wound healing & non-healing wound

The development of molecular biology and other new biotechnologies helps us to recognize the wound healing and non-healing wound of skin in the past 30 years. This review mainly focuses on the molecular biology of many cytokines (including growth factors) and other molecular factors such as extracellular matrix (ECM) on wound healing. The molecular biology in cell movement such as epidermal cells in wound healing was also discussed. Moreover many common chronic wounds such as pressure ulcers, leg ulcers, diabetic foot wounds, venous stasis ulcers, etc. usually deteriorate into non-healing wounds. Therefore the molecular biology such as advanced glycation end products (AGEs) and other molecular factors in diabetes non-healing wounds were also reviewed.     

A prospective,randomised, controlled,multi‐centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft,bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers

A prospective, randomised, controlled, parallel group, multi‐centre clinical trial was conducted at three sites to compare the healing effectiveness of treatment of chronic lower extremity diabetic ulcers with either weekly applications of Apligraf^® (Organogenesis, Inc., Canton, MA), EpiFix^® (MiMedx Group, Inc., Marietta, GA), or standard wound care with collagen‐alginate dressing. The primary study outcome was the percent change in complete wound healing after 4 and 6 weeks of treatment. Secondary outcomes included percent change in wound area per week, velocity of wound closure and a calculation of the amount and cost of Apligraf or EpiFix used. A total of 65 subjects entered the 2‐week run‐in period and 60 were randomised (20 per group). The proportion of patients in the EpiFix group achieving complete wound closure within 4 and 6 weeks was 85% and 95%, significantly higher (all adjusted P‐values ≤ 0·003) than for patients receiving Apligraf (35% and 45%), or standard care (30% and 35%). After 1 week, wounds treated with EpiFix had reduced in area by 83·5% compared with 53·1% for wounds treated with Apligraf. Median time to healing was significantly faster (all adjusted P‐values ≤0·001) with EpiFix (13 days) compared to Apligraf (49 days) or standard care (49 days). The mean number of grafts used and the graft cost per patient were lower in the EpiFix group campared to the Apligraf group, at 2·15 grafts at a cost of $1669 versus 6·2 grafts at a cost of $9216, respectively. The results of this study demonstrate the clinical and resource utilisation superiority of EpiFix compared to Apligraf or standard of care, for the treatment of diabetic ulcers of the lower extremities.     

Erbium: Yttrium Aluminum Garnet Laser Accelerates Healing in Indolent Diabetic Foot Ulcers

The objective of the study was to evaluate the effect of the erbium:yttrium aluminum garnet (YAG) laser on diabetic foot ulcers (DFUs) that had not responded to standard care. We retrospectively evaluated 22 nonhealing DFUs that received at least 4 weeks of standard wound care, demonstrated poor healing response, and subsequently were treated with an erbium:YAG laser. We measured the percent wound area reduction (PWAR) for the 4 weeks before initiating laser therapy and the PWAR for 4 weeks after the initiation of laser therapy. Erbium:YAG laser treatment consisted of 2 components: debridement and resurfacing. The laser settings were the same for all treatments. We used the paired t test to compare pretreatment with posttreatment wound area reduction. During the 4-week period before the initiation of laser therapy, the average PWAR was –33.6%. Four weeks after initiating treatment with the erbium:YAG laser, the average PWAR was 63.4% (p = .002) and 72.7% of wounds had ≥50% PWAR. By 12 weeks, 50% of wounds had healed. Erbium:YAG laser therapy accelerated DFU healing in a cohort of patients with ulcers that had been unresponsive to standard of care therapy.     

Effectiveness of an acellular synthetic matrix in the treatment of hard‐to‐heal leg ulcers

Hard‐to‐heal leg ulcers are a major cause of morbidity in the elderly population. Despite improvements in wound care, some wounds will not heal and they present a significant challenge for patients and health care providers. A multi‐centre cohort study was conducted to evaluate the effectiveness and safety of a synthetic, extracellular matrix protein as an adjunct to standard care in the treatment of hard‐to‐heal venous or mixed leg ulcers. Primary effectiveness criteria were (i) reduction in wound size evaluated by percentage change in wound area and (ii) healing assessed by number of patients healed by end of the 12 week study. Pain reduction was assessed as a secondary effectiveness criteria using VAS. A total of 45 patients completed the study and no difference was observed between cohorts for treatment frequency. Healing was achieved in 35·6% and wound size decreased in 93·3% of patients. Median wound area percentage reduction was 70·8%. Over 50% of patients reported pain on first visit and 87·0% of these reported no pain at the end of the study. Median time to first reporting of no pain was 14 days after treatment initiation. The authors consider the extracellular synthetic matrix protein an effective and safe adjunct to standard care in the treatment of hard‐to‐heal leg ulcers.     

The impact of Manuka honey dressings on the surface pH of chronic wounds

Chronic non healing wounds have an elevated alkaline environment. The acidic pH of Manuka honey makes it a potential treatment for lowering wound pH, but the duration of effect is unknown. Lowering wound pH can potentially reduce protease activity, increase fibroblast activity and increase oxygen release consequently aiding wound healing. The aim of this study was to analyse the changes in surface pH and size of non healing ulcers following application of Manuka honey dressing after 2 weeks. The study was an open label, non randomised prospective study. Patients presenting consecutively with non healing chronic superficial ulcers, determined by aetiology and no reduction in wound size in previous 3 weeks. Single pH measurements recorded using Blueline 27 glass surface electrode and R 315 pH meter set (Reagecon/Alkem, Co. Clare Ireland). Area determined using Visitrak (Smith & Nephew, Mull, UK) digital planimetry. Apinate (Manuka honey) (Comvita, Slough, UK) applied to wounds for 2 weeks after which wounds re-evaluated. Eight males and nine females with 20 ulcers (3 bilateral) were included: venous, 50% (n = 10); mixed aetiology, 35% (n = 7); arterial, 10% (n = 2) and pressure ulcer, 5% (n = 1). Reduction in wound pH after 2 weeks was statistically significant (P < 0.001). Wounds with pH >or= 8.0 did not decrease in size and wounds with pH 相似文献   

Oxidative stress in chronic venous leg ulcers

Venous leg ulcers are common and cause considerable morbidity in the population. As healing may be slow or may never be achieved, ulcers create persistent and substantial demands on clinical resources. Great efforts have been made to accelerate tissue repair in chronic venous leg ulcers with limited success. This may at least be partly due to the limited knowledge on the microenvironment of chronic wounds. In fact, the tremendous impact of the microenvironmental conditions on the outcome of wound healing has increasingly become apparent. Oxidative stress as a consequence of an imbalance in the prooxidant-antioxidant homeostasis in chronic wounds is thought to drive a deleterious sequence of events finally resulting in the nonhealing state. The majority of reactive oxygen species are most likely released by neutrophils and macrophages and to an unknown extent from resident fibroblasts and endothelial cells. As the inflammatory phase does not resolve in chronic wounds, the load of reactive oxygen species persists over a long period of time with subsequent continuous damage and perpetuation of the inflammation. In this article, we will critically discuss recent findings that support the role of oxidative stress in the pathophysiology of nonhealing chronic venous leg ulcers.     

Use of homologous platelet factors in achieving total healing of recalcitrant skin ulcers

We used homologous platelet-derived wound healing factors (HPDWHF) to achieve complete healing of recalcitrant ulcers of diverse cause. Twenty-three patients with 27 skin ulcers who had been receiving conventional wound care with no evidence of healing for an average period of 25 weeks (range, 12 to 156 weeks) were studied. The patients were first subjected to controlled wound care for 3 months, with saline solution and silver sulfadiazine dressings used in all cases. At the end of this period, persistent nonhealing ulcers were treated by topical use of HPDWHF and silver sulfadiazine. Ulcer parameters were recorded on the first day and every week during therapy until complete epithelization was achieved in either group. Each ulcer acted as its own control. In the controlled wound care group, only three ulcers in three patients achieved complete healing; the remaining 24 ulcers in 20 patients failed to achieve even 50% healing in the stipulated 3-month period. However, when subjected to HPDWHF applications, these ulcers healed completely, 100% healing occurring in 9.67 +/- 4.9 weeks (range, 3 to 19 weeks), which is highly significant (p less than 0.01). The healing response to HPDWHF applications was of uniform progression over the weeks. Only the basic cause of the ulcer determined the healing rates in this group. The shortest and the longest time to achieve 100% healing occurred in patients with diabetes (6.88 +/- 2.97 weeks) and in the venous stasis group (14.00 +/- 7.07 weeks). Age, sex, location of ulcer, ulcer duration, and ulcer measurements had no influence on the HPDWHF-stimulated healing rates. This is the earliest report of HPDWHF-stimulated repair in chronic nonhealing skin ulcers.     

Topical application of prostaglandin E1 ointment to cutaneous wounds in ischemic rabbit ears

The effects of an ointment containing prostaglandin E1 ·α-cyclodextrin clathrate compound (PGE1 · CD ointment) on wound healing were evaluated in an ischemic rabbit ear model. The PGE1 · CD ointment (30 μg/g, ca. 50 mg) was applied to surgical ulcers 6 mm in diameter on ischemic ears in Japanese-White rabbits for 2 weeks. The rate of reduction in wound size was 15.0 mm²/week in the PGE1 treated group and 5.3 mm²/week in the control group during the first week. During the following week, the rate was 9.6 mm²/week in the PGE1 treated group and 13.5 mm²/week in the control group. Much more granulation tissue was found in wounds in the PGE1-treated group than in the control group. These findings showed that topical application of PGE1 · CD ointment improved wound healing under ischemic conditions during the first week of treatment. They also indicate that PGE1 · CD ointment may be clinically useful as a topical agent for treatment of ischemic skin ulcers during the early stages of inflammation. Received: 13 July 1998 / Accepted: 11 February 1999