Wound repair

Telemedicine allows experts to assess patients in remote locations, enabling quality convenient, cost-effective care. To help assess foot wounds remotely, we investigated the reliability of a novel optical imaging system employing a threedimensional camera and disposable optical marker. We first examined inter-and intraoperator measurement variability (correlation coefficient) of five clinicians examining three different wounds. Then, to assess of the system's ability to identify key clinically relevant features, we had two clinicians evaluate 20 different wounds at two centers, recording observations on a standardized form. Three other clinicians recorded their observations using only the corresponding threedimensional images. Using the in-person assessment as the criterion standard, we assessed concordance of the remote with in-person assessments. Measurement variation of area was 3.3% for intraoperator and 11.9% for interoperator; difference in clinician opinion about wound boundary location was significant. Overall agreement for remote vs. in-person assessments was good, but was lowest on the subjective clinical assessments, e.g., value of debridement to improve healing. Limitations of imaging included inability to show certain characteristics, e.g., moistness or exudation. Clinicians gave positive feedback on visual fidelity. This pilot study showed that a clinician viewing only the three-dimensional images could accurately measure and assess a diabetic foot wound remotely.

Significant damage to tissue surrounding burn injuries occurs after the removal of the thermal source. This damage is caused by a combination of both necrotic and apoptotic cell death in the zone of stasis. Preserving the zone of stasis can reduce the wound size and thereby improve wound healing. We tested whether a peptide previously identified to inhibit necrotic and apoptotic cell death in neurons through c-Jun inhibition could enhance wound healing. We first tested the effects of this peptide on a keratinocyte and fibroblast cell line in culture. The peptide promoted proliferation of keratinocytes but had no effect on fibroblast proliferation, while the peptide also inhibited ultraviolet-induced apoptosis of keratinocytes. We finally tested the peptide in vivo, using a mouse model of burn injury. Wounds that were treated with the peptide reepithelialized faster than controls, while cell death surrounding the wound site was markedly reduced 24 hours postinjury, suggesting that the prevention of apoptosis as well as the proliferative effects of this peptide contribute to the wound healing process. Our data implicate c-Jun in multiple processes during wound repair and demonstrate that treatment of burn injuries using inhibitors of c-Jun dimerization at the time of injury can promote wound healing.

The present paper presents a hypothesis aimed at explaining why venous leg ulcers, pressure ulcers, and diabetic foot ulcers develop into a chronic state. We propose that the lack of proper wound healing is at least in part caused by inefficient eradication of infecting, opportunistic pathogens, a situation reminiscent of chronic Pseudomonas aeruginosa infections found in patients suffering from cystic fibrosis (CF). We have analyzed sections from chronic wounds by fluorescence in situ hybridization and found distinct microcolonies-the basal structures of bacterial biofilms. Several researchers have previously reported that another important hallmark of biofilm formation is development of increased tolerance to various antimicrobial measures and treatments. Furthermore, the immune response to infecting bacteria in the cystic fibrosis lung is dominated by polymorphonuclear neutrophils (PMNs), and we have recently shown that in vitro biofilms of P. aeruginosa produce a shielding mechanism that offers protection from the phagocytic activity of PMNs. 1,2 We hypothesize that the presence of P. aeruginosa in biofilms, and the lack of concomitant elimination by attended PMNs, are the main causes of inefficient eradication by antibiotic treatment and antimicrobial activity of the innate immune system, respectively. The epidemic increase in obese humans worldwide is followed by a similar increase in diabetes and cardiovascular diseases. Such patients are particularly prone to the development of chronic wounds, which become colonized by a number of bacterial species. Gjdsbl et al. 3 investigated the bacterial profile of chronic venous leg ulcers and found Staphylococcus aureus (in 93.5% of the investigated ulcers), Enterococcus faecalis (71.7%), Pseudomonas aeruginosa (52.2%), coagulase-negative staphylococci (45.7%), Proteus species (41.3%), and anaerobic bacteria (39.1%). In Denmark and in the USA, it has been estimated that 1-2% of the populations, respectively, are experiencing a nonhealing wound. 4 Consequently, this has become a burden to the health care systems and the patients experience suffering, lost employment, and reduced quality of life. Bacterial infections are generally considered to be treatable by administration of antibiotics; however, this is not always true. Contributing to the lack of successful antibiotic treatment is the ability of colonizing bacteria to establish themselves and proliferate in a biofilm. Current estimates Why chronic wounds will not heal Bjarnsholt et al.

Wound healing is a complex process involving an integrated response by many different cell types and growth factors in order to achieve rapid restoration of skin architecture and function. The present study evaluated the applicability of a chitosan hydrogel (CH) as a wound dressing. Scanning electron microscopy analysis was used to characterize CH morphology. Fibroblast cells isolated from rat skin were used to assess the cytotoxicity of the hydrogel. CH was able to promote cell adhesion and proliferation. Cell viability studies showed that the hydrogel and its degradation by-products are noncytotoxic. The evaluation of the applicability of CH in the treatment of dermal burns in Wistar rats was performed by induction of full-thickness transcutaneous dermal wounds. Wound healing was monitored through macroscopic and histological analysis. From macroscopic analysis, the wound beds of the animals treated with CH were considerably smaller than those of the controls. Histological analysis revealed lack of a reactive or a granulomatous inflammatory reaction in skin lesions with CH and the absence of pathological abnormalities in the organs obtained by necropsy, which supported the local and systemic histocompatibility of the biomaterial. The present results suggest that this biomaterial may aid the re-establishment of skin architecture.

Six out of 10 patients with chronic wounds suffer from persistent wound pain. A multinational and multicenter randomized double-blind clinical investigation of 122 patients compared two moist wound healing dressings: a nonadhesive foam dressing with ibuprofen (62 patients randomized to Biatain Ibu Nonadhesive Coloplast A/S) and a nonadhesive foam without ibuprofen (60 patients to Biatain Non-Adhesive-comparator). Patients were recruited from September 2005 to April 2006. The ibuprofen foam was considered successful if the pain relief on a five-point Verbal Rating Scale was higher than the comparator without compromising safety including appropriate healing rate. Additional endpoints were change in persistent wound pain between dressing changes and pain at dressing change on days 1-5 (double blind) and days 43-47 (single blind). The primary response variable, persistent pain relief, was significantly higher in the ibuprofenfoam group, as compared with the comparator on day 1-5, with a quick onset of action (p < 0.05). Wound pain intensity was significantly reduced with the ibuprofen foam during day 1-5 with 40% from baseline, compared with 30% with the comparator (p < 0.001). At day 43-47, the patients in the ibuprofen-foam group had a significant (p < 0.05) reemergence of persistent pain and pain at dressing change (p < 0.05) when the active dressing was changed to the comparator. Wound healing was similar in the ibuprofen foam and comparator group. No difference in adverse events between the comparator and the ibuprofen foam with local sustained release of low-dose ibuprofen was observed in this study. It was generally found that women reported less pain intensity than men, and pain intensity decreased with increasing age. In addition, pain intensity increased with initial pain intensity and increasing wound size. This study has demonstrated that the ibuprofen-foam dressing provided pain relief and reduced pain intensity without compromising healing or other safety parameters.

A multicenter prospective randomized clinical trial was undertaken to compare two foam dressings (Allevyn Hydrocellular, Smith & Nephew and Mepilex, Molnlycke Health Care AB) in the management of chronic venous leg ulceration. Patients were also randomized to two compression bandage systems (4-layer vs. cohesive short stretch) as a factorial design. Those with causes of ulceration other than venous disease were excluded. In all, 156 patients met the entry criteria and were randomized from the 12 clinical centers with a median (range) ulcer size of 4.33 (0.33-123.10) cm 2 . After 24 weeks a total of 100 (64.1%) patients had complete ulcer closure, 46 (29.5%) had withdrawn from the trial, nine (5.8%) remained unhealed and one patient died. Of the patients randomized to Mepilex, 50/75 (66.7%) had complete ulcer healing compared with 50/81 (61.7%) on Allevyn. The hazard ratio for healing after adjustment for bandage type and trial center was 1.48 (95% C.I. 0.87-2.54, p50.15), which only marginally changed following adjustment for baseline variables, neither of which achieved statistical significance (p50.16). Withdrawal rates were similar between groups (23, 30.7% Mepilex vs. 23, 28.4% Allevyn). Pain improved following treatment with both dressings (p < 0.001), but with no difference between dressings.

Vacuum-assisted closure has become a new technique in the challenging management of contaminated, acute, and chronic wounds. Although promising clinical results have been described, scientific proof to substantiate the mechanism of action of this therapy is scarce. In the present study, we examined whether the positive effect on wound healing found in vacuum-assisted closure-treated wounds could be explained by an effect on the bacterial load. Fifty-four patients who needed open wound management before surgical closure were included in this study. Wounds were randomized to either vacuum-assisted closure therapy (n= 29) or treatment by conventional moist gauze therapy (n= 25). Healing was characterized by development of a clean granulating wound bed (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;ready for surgical therapy&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;) and reduction of wound surface area. To quantify bacterial load, biopsies were collected. No significant difference was found in time needed to reach &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;ready for surgical therapy&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; comparing both therapies. Wound surface area reduction was significantly larger in vacuum-assisted closure-treated wounds: 3.8 +/- 0.5 percent/day (mean +/- SEM) compared to conventional-treated wounds (1.7 +/- 0.6 percent/day; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). The total quantitative bacterial load was generally stable in both therapies. However, nonfermentative gram negative bacilli showed a significant decrease in vacuum-assisted closure-treated wounds (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), whereas Staphylococcus aureus showed a significant increase in vacuum-assisted closure-treated wounds (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). In conclusion, this study shows a positive effect of vacuum-assisted closure therapy on wound healing, expressed as a significant reduction of wound surface area. However, this could not be explained by a significant quantitative reduction of the bacterial load.

Scar formation is a common, unwanted result of wound healing in skin, but the mechanisms that regulate it are still largely unknown. Interestingly, wound healing in the oral mucosa proceeds faster than in skin and clinical observations have suggested that mucosal wounds rarely scar. To test this concept, we created identical experimental wounds in the oral mucosa and skin in red Duroc pigs and compared wound healing and scar development over time. We also compared the pig oral mucosal wound healing to similar experimental wounds created in human subjects. The findings showed significantly reduced scar formation at both clinical and histological level in the pig oral mucosa as compared with skin 49 days after wounding. Additionally, the skin scars contained a significantly increased number of type I procollagen immunopositive cells and an increased fibronectin content, while the oral mucosal wounds demonstrated a prolonged accumulation of tenascin-C. Furthermore, the pig oral mucosal wounds showed similar molecular composition and clinical and histological scar scores to human oral mucosal wounds. Thus, the reduced scar formation in the pig oral mucosa provides a model to study the biological processes that regulate scarless wound healing to find novel approaches to prevent scar formation in skin.

The effective management of nonhealing wounds is based on a complete patient history, a detailed initial assessment of the wound, and an analysis of probable causative factors. This information is used to individualize a management strategy to the underlying pathophysiology preventing healing and to implement appropriate wound interventions. Regular reassessment of progress toward healing and appropriate modification of the intervention are also necessary. Accurate and clinically relevant wound assessment is an important clinical tool, but this process remains a substantial challenge. Wound assessment terminology is nonuniform, many questions surrounding wound assessment remain unanswered, agreement has yet to be reached on the key wound parameters to measure in clinical practice, and the accuracy and reliability of available wound assessment techniques vary. This article, which resulted from a meeting of wound healing experts in June 2003, reviews clinically useful wound measurement approaches, provides an overview of the principles and practice of chronic wound assessment geared to a clinical audience, and introduces a simple mnemonic, MEASURE. MEASURE encapsulates key wound parameters that should be addressed in the assessment and management of chronic wounds: Measure (length, width, depth, and area), Exudate (quantity and quality), Appearance (wound bed, including tissue type and amount), Suffering (pain type and level), Undermining (presence or absence), Reevaluate (monitoring of all parameters regularly), and Edge (condition of edge and surrounding skin). This article also provides some preliminary recommendations targeted to developing best practice guidelines for wound assessment. (WOUND REP REG 2004;12:S1-S17)

This investigation was conducted to determine if a correlation exists between wound healing outcomes and serial debridement in chronic venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs). We retrospectively analyzed the results from two controlled, prospective, randomized pivotal trials of topical wound treatments on 366 VLUs and 310 DFUs over 12 weeks. Weekly wound surface area changes following debridement and 12-week wound closure rates between centers and patients were evaluated. VLUs had a significantly higher median wound surface area reduction following clinical visits with surgical debridement as compared with clinical visits with no surgical debridement (34%, p50.019). Centers where patients were debrided more frequently were associated with higher rates of wound closure in both clinical studies (p50.007 VLU, p50.015 DFU). Debridement frequency per patient was not statistically correlated to higher rates of wound closure; however, there was some minor evidence of a positive benefit of serial debridement in DFUs (odds ratio-2.35, p50.069). Our results suggest that frequent debridement of DFUs and VLUs may increase wound healing rates and rates of closure, though there is not enough evidence to definitively conclude a significant effect. Future clinical research in wound care should focus on the relationship between serial surgical wound debridement and improved wound healing outcomes as demonstrated in this study.

The mechanism of hypertrophic scar reduction using silicone gel sheeting remains elusive. We hypothesize that the decrease in scar formation is due to occlusion and homeostasis of the barrier layer. Using an established model of hypertrophic scarring, rabbits were divided into four groups and scars were tape-stripped or occluded with Kelocote, Cavilon, or Indermil, with each rabbit serving as its own internal control. All wounds were harvested on day 28 and examined histologically to measure the scar elevation index (SEI), epithelial thickness, and cellularity. Immunohistochemistry fluorescence was used to quantify inflammation in the dermis. Transepidermal water loss (TEWL) was measured for each occlusive agent and tape stripping. Ultrastructural analysis was performed by electron microscopy. Kelocote, Cavilon, and Indermil all significantly decreased SEI when compared with controls.

Doing the right thing'' in wound care is not an easy task. Studies suggest that 3 factors determine compliance with performing basic wound care from an evidence-based medicine perspective: complexity, cognitive effort, and the compensation system. Two models were explored to investigate compliance with basic wound care at hospital based wound centers: offloading of diabetic foot ulcers (DFUs) and compression bandaging for venous leg ulcers. Using a very large wound-care registry it was determined that only 6% of DFU patients received the gold standard of care for offloading, i.e., total contact casting (TCC), but among those patients who received it, the average cost of treatment was half the cost of those who did not. Although inexpensive to administer, TCC is a relatively time-consuming procedure which is poorly reimbursed. Other DFU treatments such as bilaminate skin, are more costly but are reimbursed much more generously. Thus, the reimbursement system favors the use of more expensive therapies over more economical ones. In the case of venous leg ulcers (VLUs), only 17% of patients received adequate compression. Provision of adequate compression among VLU patients has been similarly hindered by inadequate reimbursement policy. Lack of familiarity with clinical practice guidelines increases the cognitive effort for clinicians. Improving the economic model to favor the provision of effective basic care, creating easier-to-use products, and making clinical practice guidelines available at the point of service may make it easier to ''do the right thing(s)'' in wound care.

Zinc is an essential trace element in the human body and its importance in health and disease is appreciated. It serves as a cofactor in numerous transcription factors and enzyme systems including zinc-dependent matrix metalloproteinases that augment autodebridement and keratinocyte migration during wound repair. Zinc confers resistance to epithelial apoptosis through cytoprotection against reactive oxygen species and bacterial toxins possibly through antioxidant activity of the cysteine-rich metallothioneins. Zinc deficiency of hereditary or dietary cause can lead to pathological changes and delayed wound healing. Oral zinc supplementation may be beneficial in treating zinc-deficient leg ulcer patients, but its therapeutic place in surgical patients needs further clarification. Topical administration of zinc appears to be superior to oral therapy due to its action in reducing superinfections and necrotic material via enhanced local defense systems and collagenolytic activity, and the sustained release of zinc ions that stimulates epithelialization of wounds in normozincemic individuals. Zinc oxide in paste bandages (Unna boot) protects and soothes inflamed peri-ulcer skin. Zinc is transported through the skin from these formulations, although the systemic effects seem insignificant. We present here the first comprehensive account of zinc in wound management in relation to current concepts of wound bed preparation and the wound-healing cascade. This review article suggests that topical zinc therapy is underappreciated even though clinical evidence emphasizes its importance in autodebridement, anti-infective action, and promotion of epithelialization.

ABSTRACT In the United States, chronic wounds affect 6.5 million patients. An estimated excess of US$25 billion is spent annually on treatment of chronic wounds and the burden is rapidly growing due to increasing health care costs, an aging population and a sharp rise in the incidence of diabetes and obesity worldwide. The annual wound care products market is projected to reach $15.3 billion by 2010. Chronic wounds are rarely seen in individuals who are otherwise healthy. In fact, chronic wound patients frequently suffer from &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;highly branded&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; diseases such as diabetes and obesity. This seems to have overshadowed the significance of wounds per se as a major health problem. For example, NIH&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Research Portfolio Online Reporting Tool (RePORT; http://report.nih.gov/), directed at providing access to estimates of funding for various disease conditions does list several rare diseases but does not list wounds. Forty million inpatient surgical procedures were performed in the United States in 2000, followed closely by 31.5 million outpatient surgeries. The need for post-surgical wound care is sharply on the rise. Emergency wound care in an acute setting has major significance not only in a war setting but also in homeland preparedness against natural disasters as well as against terrorism attacks. An additional burden of wound healing is the problem of skin scarring, a $12 billion annual market. The immense economic and social impact of wounds in our society calls for allocation of a higher level of attention and resources to understand biological mechanisms underlying cutaneous wound complications.

Hypertrophic scars result from excessive collagen deposition at sights of healing dermal wounds and can be functionally and cosmetically problematic. Pharmacological regulation of collagen synthesis and deposition is a direct approach to the control of scar tissue formation. We tested the ability of the phenanthrolinone derivative FG-1648 (in 0.5% Carbopol 971 PNF gel, pH 6.5), a prolyl 4-hydroxylase inhibitor, to reduce hypertrophic scar formation in a rabbit ear hypertrophic scar model. New Zealand White rabbits were divided into two treatment groups (n ¼ 12 wounds per group with an equal number of controls): low-dose group: 0.5% FG-1648; high-dose group: 1% FG-1648. Left ears were used for treatment and right ear for control. Four 7-mm dermal ulcer wounds were made on each ear. The inhibitor was topically applied to the wound at the time of wounding and once daily up to postoperative day 7. Wounds were harvested at postoperative day 28 and scar hypertrophy quantified by measurement of the scar elevation index. All wounds showed complete healing. Treatment of wounds with 1% prolyl 4-hydroxylase inhibitor decreased the scar elevation index by 26% compared to control wounds (p < 0.01). Wounds treated with 0.5% FG-1648 inhibitor showed no difference in scar elevation compared to control wounds. These results suggest that inhibition of prolyl 4-hydroxylase may be a suitable agent for topical treatment for the prevention of hypertrophic scar tissue. (WOUND REP REG 2003;11:368-372) Excess formation of scar at sites of tissue injury occurs from the deposition of collagen beyond that required for normal healing. This excess deposition results from excessive collagen synthesis, possibly combined with a reduction in collagen degradation that is a component of normal scar maturation. 1-3 Various stages of the synthetic and degradative pathways of collagen are the focus of research aimed at preventing the formation of excessive scar for the purpose of improving both aesthetic and functional outcomes.

Background:
Evaluating outcomes such as health-related quality of life is particularly important and relevant in skin conditions such as pressure ulcers where the condition and associated interventions pose substantial burden to patients. Measures to evaluate such outcomes need to be developed by utilising patient-perspective to ensure that content and conceptualisation is relevant to patients.

Objectives
Our aim was to develop a conceptual framework of health-related quality of life in pressure ulcers, based on patients’ views about the impact of pressure ulcers and interventions on health-related quality of life to inform the development of a new patient-reported outcome measure.

Setting, participants and methods
We developed a working conceptual framework based on a previous review of the literature, then used semi-structured qualitative interviews with 30 adults with pressure ulcers (22–94 years) purposively sampled from hospital, community and rehabilitation care settings in England and Northern Ireland to obtain patients’ views, and thematic content analysis and review by a multidisciplinary expert group to develop the final conceptual framework.

Findings
Our conceptual model includes four health-related quality of life domains (symptoms, physical functioning, psychological well-being, social functioning), divided into 13 sub-domains and defined by specific descriptive components.

Conclusions
We have identified health-related quality of life outcomes that are important to people with pressure ulcers and developed a conceptual framework using robust and systematic methods, which provides the basis for the development of a new pressure ulcer-specific measure of health-related quality of life.

A human study was conducted in which the efficacy of in vivo diffuse near-infrared (NIR) spectroscopy was demonstrated in predicting wound healing in diabetic foot ulcers. Sixteen chronic diabetic wounds were followed and assessed for subsurface oxy-hemoglobin concentration using the NIR device. Weekly measurements were conducted until there was wound closure, limb amputation, or 20 completed visits without healing. Digital photography measured wound size, and the degree of wound contraction was compared with the NIR results. In the 16 patients followed, seven wounds healed, six limbs were amputated, and three wounds remained opened after 20 visits. The initial values in subsurface hemoglobin concentration in all wounds were higher than the nonwound control sites. Healed wounds showed a consistent reduction of hemoglobin concentration several weeks before closure that approached control site values. In wounds that did not heal or resulted in amputation of the limb, the hemoglobin concentration remained elevated. In some cases, these nonhealing wounds appeared to be improving clinically. A negative slope for the rate of change of hemoglobin concentration was indicative of healing across all wounds. In conclusion, evaluation of wounds using NIR may provide an effective measurement of wound healing. NIR spectroscopy can determine wound healing earlier than that visibly assessed by current clinical approaches.

The quality of skin wound healing can be improved by the application of scaffolds as skin replacement materials. Although the clinical requirements for the function of such materials are defined, the translation of these requirements into physical and mechanobiological properties of scaffolds is difficult. Natural as well as constructed biological materials and synthetic substitutes are discussed. Furthermore, new techniques such as electrospinning and solid freeform fabrication as well as new types of materials such as self-assembling peptides are reviewed with regard to their potential role in the production of skin substitute materials.

Four off-loading devices used for the treatment of diabetic forefoot ulcers were compared: a custom-molded insole shoe, a cast MABAL shoe, a prefabricated pneumatic walking brace, and a bivalved total contact cast (BTCC). It was anticipated that all devices would significantly reduce forefoot plantar pressure compared with a control shoe. Sixteen healthy volunteers participated. Plantar pressures were evaluated using the Pedar system, while walking speed was determined using an optoelectric timer. Peak pressure (PP) of ten plantar areas and pressure-time integral for the first metatarsal area were analyzed statistically using a repeated measures analysis of variance. Forefoot pressures were significantly reduced compared with the control shoe for all devices (po0.001). PP was most reduced (by 65.8%) for the BTCC, and pressure-time integral was most reduced for the BTCC and cast MABAL shoe. Small but significant differences between devices in walking speed (po0.05) could not explain the substantial PP differences between the different devices. Although all off-loading devices resulted in a significant reduction of forefoot plantar pressure, devices differed significantly in the magnitude of pressure reduction. Further research will have to reveal the level of off-loading sufficient for effective treatment of diabetic ulcers. (WOUND REP REG 2005;13:537-542) 537

Chronic wounds expose the dermal matrix and underlying tissue to a diversity of microbes from the body and surrounding environment. We determined the microbial diversity of 19 chronic wounds using both molecular methods (sequence analysis of rRNA genes) and routine clinical culturing methods using swab samples. We identified 93 phylotypes in 2,653 rRNA clone sequences and found that compared with other environments, the microbial diversity of chronic wounds is relatively well characterized, i.e., 95% of sequences have ≥97% identity with known human commensals. In total, 75% of sequences belonged to four well-known wound-associated phylotypes: Staphylococcus (25%), Corynebacterium (20%), Clostridiales (18%), and Pseudomonas (12%). Approximately 0.5% of sequences (seven phylotypes) belonged to potentially new species. Individual wound samples contained four to 22 phylotypes, but in all wounds only a few (one to three) phylotypes were dominant. In more than half the wound specimens, polymerase chain reaction and culturing methods gave different diversity and dominance information about the microbes present. This exploratory study suggests that combining molecular and culturing methods provides a more complete characterization of the microbial diversity of chronic wounds, and can thereby expand our understanding of how microbiology impacts chronic wound pathology and healing.

Aim: Scarring is a physiological process in adult wound repair. Although keratinocytes and fibroblasts are the main cell types of the skin, they differ in migration behaviour and inflammatory responses depending on their location in the body. The aim of this article is to describe wound repair in genital skin and to depict differences with regard to skin anatomy and cellular responses to inflammatory stimuli in acute and chronic wound healing. Methods: This report reviews data from patients undergoing reconstructive and aesthetic plastic surgery as well as published studies on genital wound repair. Genital surgery comprised plastic reconstructive surgery after urological interventions of biological men and women, tissue from trans-males and trans-females undergoing gender reassignment surgery and tissue from patients undergoing aesthetic genital surgery. The cohort comprised a total of 68 patients (32.9 ± 11.3 years), of which 31 were male (mean 30.4 ± 9.3 years) and 37 were female ...

For many years, lactate has been known to accelerate collagen deposition in cultured fibroblasts and, without detailed explanation, has been presumed to stimulate angiogenesis. Similarly, hypoxia has been linked to angiogenic effects and collagen deposition from cultured cells. Paradoxically, however, wound angiogenesis and collagen deposition are increased by breathing oxygen and decreased by hypoxia. Lactate accumulates to 4-12 mM in wounds for several reasons, only one of which is the result of hypoxia. Oxygen in wounds is usually low but can be increased by breathing oxygen (without change in lactate). We have reported that lactate elicits vascular endothelial growth factor (VECF) from macrophages, as well as collagen, some heat shock proteins, and VECF from endothelial cells, and collagen from fibroblasts, even in the presence of normal amounts of oxygen. Hypoxia exerts many of these same effects in cultured cells. In this study, we elevated extracellular lactate in wounds by implanting purified solid-state, hydrolysable polyglycolide. A steady-state 2-3 mM additional elevation of lactate resulted. With it, there was a significant short-term elevation of interleukin-1b, a long-term elevation of VECF (2·) and transforming growth factor-b1 (2-3·), a 50% elevation in collagen deposition, and a large reduction of insulin-like growth factor-1 () 90%). We propose that lactate induces a biochemical ''perception'' of hypoxia and instigates several signals that activate growth factor/cytokine signals while the continued presence of molecular oxygen allows endothelial cells and fibroblasts to reproduce and deposit collagen. The data are consistent with ADP-ribosylation effects and oxidant signaling. (WOUND REP REG 2003;11:504-509)

Venous ulcers are chronic wounds affecting up to 1% of adults in developed countries. Considering that noncontact normothermic therapy has been shown to modify the wound healing process, we conducted a prospective comparative clinical trial aimed at evaluating 980 nm diode laser in laser-assisted venous ulcer healing. Thirty-four Caucasian patients with venous leg ulcers were included in the study and separated into two homogenous groups based on age, sex ratio, size, and etiologies of the ulcers. In the laser group, 980 nm InGasAs diode laser (power 15 W, spot size 8 mm, time 3 seconds, fluence 90 J/cm 2) was applied weekly for 9 weeks to the ulcers in a homogenous standardized manner, resulting in a local temperature of 45-50 1C, which was controlled with a thermal infrared camera. Complete healing, reduction in size, and pain during and between each procedure were evaluated each time. Of the 18 patients in the laser group, three (16.7%) were completely healed during laser treatment. In the control group (16 patients), the healing was complete for four patients (25%). This difference was not significant (p50.62). At the ninth follow-up visit, in the control group, the ulcers had decreased on an average to 94.3% of the original area of the ulcers. In the laser group, the decrease was to 74.2% of the original area of the ulcers. Again, this difference was not significant (p50.60). The mean VAS score between each treatment was 2.7 (0.5-4.4) in the laser group compared with 3.8 (2.3-5.0) in the control group (0.13 < p < 0.86). During the treatment, the mean VAS score was 1.8 (0.2-3.8) in the laser group compared with 3.8 (2.1-6.0) in the control group (0.08 < p < 0.67). 980 nm diode laser-assisted venous ulcer healing was easy to perform and very well tolerated. However, there were no statistically significant differences in reduction of ulcer size between the two groups, suggesting that this particular laser regimen does not promote wound healing. Additional studies involving larger patient populations and an increased frequency of treatment should be performed to confirm our initial conclusions.

Hairless rats were topically treated with a combination of 10% curcumin and 3% ginger extract (or with each agent alone) for a 21-day period. Following this, the rats were treated topically with Temovate (corticosteroid) for an additional 15 days. At the end of the treatment period, superficial abrasion wounds were induced in the treated skin. Abrasion wounds healed more slowly in the skin of Temovate-treated rats than in skin of control animals. Healing was more rapid in skin of rats that had been pretreated with either curcumin or ginger extract alone or with the combination of curcumin-ginger extract (along with Temovate) than in the skin of rats treated with Temovate and vehicle alone. Skin samples were obtained at the time of wound closure. Collagen production was increased and matrix metalloproteinase-9 production was decreased in the recently healed skin from rats treated with the botanical preparation relative to rats treated with Temovate plus vehicle. In none of the rats was there any indication of skin irritation during the treatment phase or during wounding and repair. Taken together, these data suggest that a combination of curcumin and ginger extract might provide a novel approach to improving structure and function in skin and, concomitantly, reducing formation of nonhealing wounds in ''at-risk'' skin.

The Wound Healing Society (WHS) is a professional society of physicians, nurses, physical therapists, podiatrists, and other wound care specialists, basic scientists, clinical researchers, and industrial researchers dedicated to assuring that every patient receives optimal wound care. Its mission is to advance the science and practice of wound healing. To that end, the following comprehensive, evidence-and consensus-based guidelines were developed to address The Prevention of Diabetic Ulcers. The guidelines are presented in generic terms; the details of specific tests, therapies, and procedures are at the discretion of an interdisciplinary team of health care professionals who establish, implement, and evaluate policies and procedures directed at prevention of diabetic ulcers.

A multicenter prospective randomized clinical trial was undertaken to compare a generic four-layer bandage system with a cohesive short-stretch system (Actico, Activa Healthcare) in the management of venous leg ulceration. Both systems are designed to produce sufficient pressure to counteract venous hypertension. Patients in leg ulcer services with leg ulceration were screened for inclusion in this trial. Patients with arterial disease (ankle brachial pressure index < 0.8) and causes of ulceration other than venous disease were excluded. For patients with bilateral ulceration, the limb with the larger area of ulceration was studied. Patients were randomized to receive either type of compression bandage and simultaneously randomized to one of two foam dressings that were changed weekly unless more frequent changes were clinically required. In all, 156 patients met entry criteria and were randomized from the 12 clinical centers with median (range) ulcer size of 4.33 (0.33-123.10) cm 2 . Analysis revealed that after 24 weeks a total of 111 (71%) of patients had complete ulcer closure, 32 (21%) had withdrawn from the trial, 12 (8%) remained with open ulceration, and one patient had died. Of the 74 patients randomized to the four-layer bandage, 51(69%) had ulcer closure on treatment compared with 60/82 (73%) on the cohesive short-stretch system. Intention-to-treat analysis produced a hazard ratio for healing of 1.08 (95 percent CI 0.63-1.85, p ¼ 0.79). Withdrawal rates were similar between groups (15, 20% four-layer bandage; 17, 21% cohesive short-stretch system). Ulcer closure rates for patients treated with the cohesive short-stretch system were similar to those for patients managed by the four-layer bandage system in this trial. (WOUND REP REG 2004;12:157-162) 157

Hypertrophic scars and keloids are two forms of excessive cutaneous scarring. Considering the importance of extracellular matrix elements in tissue repair, a morphological and quantitative analysis of the elastic system components (fibrillin-1 and elastin) was performed in normal skin, normal scars, hypertrophic scars, and keloids. In superficial and deep dermis, fibrillin-1 volume density was significantly higher in normal skin compared with normal scars, hypertrophic scars, and keloids. The fibrillin-1 volume density did not show differences between hypertrophic scars and keloids in superficial or deep dermis. In superficial dermis, elastin volume density was higher in normal skin compared with normal scars, hypertrophic scars, and keloids. In deep dermis, the elastin volume density was higher in keloids compared with normal skins, normal scars, and hypertrophic scars. We showed that the distribution of fibrillin-1 and elastin is disrupted in all kinds of scars analyzed, but there are two patterns: one for normal scars and another for excessive scars.

Keloid formation has been linked to aberrant fibroblast activity, exacerbated by growth factors and inflammatory mediators. Prostaglandin E2 (PGE2), synthesized from arachidonic acid by cyclooxygenases (COX) and synthases (PGES), acts as both an inflammatory mediator and fibroblast modulator. Although PGE2 has known antifibrotic effects in the lower airway, its role in dermal fibrosis in general, and keloid formation in particular, remains unclear. This study focused on: (1) the effects of PGE2 on keloid fibroblast migration, contraction, and collagen synthesis and (2) endogenous PGE2 synthesis in response interleukin-1b. PGE2 decreased keloid fibroblast migration and contraction via an EP2/ EP4-cAMP mechanism that disrupted actin cytoskeletal dynamics and reversed transforming growth factor-b1-induced collagen I and III synthesis. Impaired fibroblast PGE2 production has been linked to lower airway fibrosis and recently to keloid formation. Here, we showed that interleukin-1b stimulation leads to nuclear factor-kB translocation to the nucleus, resulting in up-regulation of COX-2 and microsomal PGE2 synthase 1. Up-regulation of COX-2 in, and secretion of PGE2 by keloid fibroblasts are diminished compared with their normal fibroblast counterparts. We suggest that the antifibrotic effects of PGE2 during keloid formation are potentially diminished due to aberrant paracrine fibroblast signaling. Exogenous PGE2 may supplement decreased endogenous levels and inhibit keloid formation or progression. Wound Rep Reg (2007) 15 122-133 c 2007 by the Wound Healing Society

The mechanism for the clearance of excess healing fibroblasts at the end of tendon healing has not been reported despite the importance of maintaining tissue homeostasis. This study investigated the role of apoptosis in cell turnover in a rat central 1/3 patellar tendon donor site injury model. At days 4, 7, 14, 28, months 2 and 6, the rats were killed. Patellar tendons without injury served as control. Apoptotic cells were determined by an in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay and anti-active caspase-3 antibodies, while proliferating cells were determined by anti-proliferating cell nuclear antigen antibodies. The total fibroblast-like cell density in the center of the wound increased from day 4 and thereafter steadily returned to normal. In situ TUNEL assay showed few positive staining cells in the wound at days 4 and 7. The percentages of TUNEL-positive fibroblast-like cells showing morphological characteristics of apoptosis increased sharply and reached the maximum on day 28 (median %: 31.38%). No fibroblast-like cell was stained at month 6 and the healed tissue was similar to that in a normal uninjured tendon. A similar trend was observed with active caspase-3 immunohistochemistry. In conclusion, an increase in apoptosis at the end of tendon healing coincided with a decrease in cellularity.

The quality of skin wound healing can be improved by the application of scaffolds as skin replacement materials. Although the clinical requirements for the function of such materials are defined, the translation of these requirements into physical and mechanobiological properties of scaffolds is difficult. Natural as well as constructed biological materials and synthetic substitutes are discussed. Furthermore, new techniques such as electrospinning and solid freeform fabrication as well as new types of materials such as self-assembling peptides are reviewed with regard to their potential role in the production of skin substitute materials.