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Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and would healing end points. The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.

Wound dressings containing silver as antimicrobial agents are available in various forms and formulations; however, little is understood concerning their comparative efficacy as antimicrobial agents. Eight commercially available silver-containing dressings, Acticoat((R)) 7, Acticoat((R)) Moisture Control, Acticoat((R)) Absorbent, Silverceltrade mark, Aquacel((R)) Ag, Contreet((R)) F, Urgotol((R)) SSD and Actisorb((R)), were tested to determine their comparative antimicrobial effectiveness in vitro and compared against three commercially available topical antimicrobial creams, a non treatment control, and a topical silver-containing antimicrobial gel, Silvasorb((R)). Zone of inhibition and quantitative testing was performed by standard methods using Escherichia coli, Pseudomonas aeruginosa, Streptococcus faecalis and Staphylococcus aureus. Results showed all silver dressings and topical antimicrobials displayed antimicrobial activity. Silver-containing dressings with the highest concentrations of silver exhibited the strongest bacterial inhibitive properties. Concreet((R)) F and the Acticoat((R)) dressings tended to have greater antimicrobial activity than did the others. Topical antimicrobial creams, including silver sulfadiazine, Sulfamylon and gentamicin sulfate, and the topical antimicrobial gel Silvasorb((R)) exhibited superior bacterial inhibition and bactericidal properties, essentially eliminating all bacterial growth at 24 hours. Silver-containing dressings are likely to provide a barrier to and treatment for infection; however, their bactericidal and bacteriostatic properties are inferior to commonly used topical antimicrobial agents. [ABSTRACT FROM AUTHOR]

Background: Platelet-derived growth factor (PDGF) has been demonstrated in pre-clinical studies to promote granulation tissue and stimulate cutaneous ulcer healing. Becaplermin gel 100 microg/g is the commercial preparation of the PDGF-BB homodimer and has been Materials and Methods:A Phase IV (Postmarketing) investigator-blinded, randomized, parallel group, multicenter trial was performed comparing once daily application of Regranex Gel 0.01% plus standardized wound therapy to standardized therapy alone. Metaanalyses were performed on the results of the Phase IV trial integrated into the pooled results of 4 previous trials using becaplermin gel evaluating incidence of complete healing, time to healing, and relative ulcer size at endpoint. Results: In the Phase IV trial, 42% of the Regranex Gel treatment group healed versus 35% for the standardized therapy alone (P = 0.316). Of the subjects who achieved complete healing, there was evidence for preferential healing of ulcers with baseline areas less than 1.46 cm2 for Regranex Gel treatment (P = 0.0286).The integrated analysis showed that becaplermin 100 µg/g was superior to vehicle gel (P = 0.015) and standardized care (P = 0.002) in achieving complete healing. In the ulcers less than or equal to 10 cm2 in area, the becaplermin gel 100 µg/g was also superior to vehicle gel (P = 0.011) and standardized care (P = 0.006). Significant differences were seen among treatment groups (P = 0.010; Cox's Proportional Hazards Analysis).The Kaplan-Meier estimate of the 35th percentile for the time to complete healing was 99 days for becaplermin gel 100 microg/g versus 141 days for the vehicle. Conclusion: The results of the pooled integrated analyses are consistent with those reported from the 4 preapproval studies showing that Regranex Gel 0.01% significantly increases the incidence of complete healing and reduces the time to complete closure of diabetic neuropathic ulcers. These results reinforce the position that Regranex Gel 0.01% is a useful adjunct for the treatment of diabetic foot ulcers. [ABSTRACT FROM AUTHOR]

Background: It is estimated that 2.5 million people in the United States have chronic venous ulcers. Standard care for these ulcers includes compression, debridement of necrotic tissue, treatment of edema, and control of infection. There has been a search for additional therapeutic compounds and/or devices to enhance ulcer healing beyond that provided by standard care. A previous phase 2a clinical trial suggested repifermin (KGF-2) might enhance ulcer healing. Materials and Methods: A randomized, double-blinded, parallel group, multi-center clinical trial was conducted to evaluate the safety and efficacy of topical repifermin treatment, for up to 26 weeks, in the healing of chronic venous ulcers in 352 patients.Results: The percent of ulcers achieving 100% closure by 20 weeks was not significantly different in ulcers treated with 60 microg/cm2 or 120 microg/cm[2] of repifermin compared with placebo treatment. Similarly, there was no difference in total healing among the 3 treatment groups at 26 weeks or at 16 weeks. Time to closure was also statistically identical for the 3 treatment groups. Safety analyses showed that topical repifermin is well-tolerated.Conclusion: Healing of chronic venous ulcers is not enhanced by the addition of topical repifermin (KGF-2) to standardized care. [ABSTRACT FROM AUTHOR]

ObjectiveTo compare the proportion of patients with Stage III pressure ulcers with complete wound closure at Week 24, when treated with conventional therapy or conventional therapy plus a human fibroblast-derived dermal replacement.MethodsA prospective, multi-center, randomized, single-masked, controlled exploratory study was conducted comparing Dermagraft with conventional therapy alone. The primary measure was wound closure at 24 weeks. Secondary measures were wound closure at Week 12 and the percentage reduction in wound area and volume.ResultsThere were no significant differences found between the treatment groups with respect to the proportions of patients healing by Week 24. Two (11%) Dermagraft and 2 control (13%) patients had healed by Week 24. There were no significant differences found between the treatment groups with respect to the percentage reduction in ulcer area or the percentage reduction in ulcer volume by Week 12 (last observations carried forward). The reduction in wound volume was 41.2% for the Dermagraft arm and 17.4% for the control arm at study end.ConclusionsThe primary study endpoint (proportion of patients with complete wound closure) was observed in a small number of patients. The positive trend in reduction of wound volume achieved in the treatment arm of the study may be significant in facilitating other treatment modalities, such as surgical closure. Further clinical studies are needed to establish the place of dermal replacement therapy in the management of chronic pressure ulcers. [ABSTRACT FROM AUTHOR]

Oxygen is a necessary component of normal wound healing and is required for multiple cell functions, including the killing of bacteria by leukocytes. A new oxygen-generating dressing has been developed that provides intermittent periods of hyperoxia interspersed with periods in which the wound oxygen tension is allowed to autoregulate. Materials and Methods: The effects of an oxygen-generating dressing on healing of infected wounds were examined in 2 experiments using a rodent model of a chronically infected (>10[5] bacteria/g of tissue) granulating wound. Serial wound area measurements were compared among animals treated with the oxygen-generating dressing, the growth factor KGF-2, a vehicle control, a negative dressing control, and a positive dressing control. Serial biopsies of the wound for quantitative bacteriology were performed throughout both experiments. Results In both experiments, infected wounds healed fastest when topically treated with an oxygen-generating dressing (P< 0.05). Although KGF-2 treated wounds healed faster than the vehicle control wounds in experiment 1, the oxygen-generating dressing was statistically better than KGF-2 (P<0.05). The oxygengenerating dressing decreased the bacterial burden in the granulating wounds 100-fold greater than did all other treatments. Conclusions: The oxygen-generating dressing used in these experiments decreased the number of tissue bacteria in these infected wounds to less than 10[5] colony forming units (CFU) per gram of tissue. This, plus the stimulatory effect of oxygen on numerous healing processes, facilitated more rapid healing of the infected granulating wounds. [ABSTRACT FROM AUTHOR]

There is a continual need for new products for wound care, as well as a desire by scientists and clinicians to translate information into wound healing improvements for patients. Pharmaceutical and biotechnology companies devote immense resources to fulfilling these needs and desires. However, there are many impediments to drug development that are poorly understood by caregivers, patients, and the public at large. Among these impediments are the tremendous costs involved, the short patent protection time, and regulatory issues. In addition, there is a marked attrition of potential drugs as they progress through the various stages of development. When the costs, time, regulatory issues, and attrition impediments are overcome, the problems with reimbursement become an impediment. This is especially true in the elderly population in which most chronic wound healing problems occur. Finally, academic societies such as the Wound Healing Society and its members pose an impediment to drug development. There is a need to interact with various governmental agencies and industry to facilitate translating science to patient care. This has not been done with a strong, uniform voice. These are but a few of the impediments that prevent scientific advances from resulting in new products available at the bedside to improve the quality of life of our patients. [ABSTRACT FROM AUTHOR]

Introduction: Cytokine growth factors have been ineffective in infected wounds (>105 bacteria/g of tissue) for several reasons. Bacteria degrade the polypeptides themselves, and this effect is accentuated in the presence of tissue cells when excessive matrix metalloproteinases are produced. Also, the growth factor receptors for several cytokines have been shown to have decreased expression in chronic wounds.Materials and Methods: The effects of genomics-based KGF-2 (repifermin) on healing of infected wounds were examined in 3 experiments using a rodent model of a chronically infected (>105 bacteria/g of tissue) granulating wound. Serial wound area measurements were compared among animals treated with vehicle, 2 doses of KGF-2, and KGF-2 in combination with GM-CSF. Binding of biotinylated KGF-2 was compared with binding of a biotinylated irrelevant protein control in sections of both noninfected and infected granulation tissue. Serial biopsies of the wounds for quantitative bacteriology confirmed the wounds were infected throughout the experiments.Results: In all 3 experiments, infected wounds healed faster when topically treated with KGF-2 (P <0.05). The effect was seen most dramatically toward the end of the wound closure curve when the wounds were 75% to 90% closed. Using GM-CSF in combination or in sequence with KGF-2 did not enhance the activity of KGF-2 alone. There was no clear decrease in KGF-2 binding in infected versus noninfected wounds. In contrast, sections incubated with the control-irrelevant protein were uniformly negative. Bacterial counts confirmed the wounds remained at a bacterial tissue level of >105 organisms/g.Conclusion: Repifermin (genomics-based KGF-2) appears more robust than other reported growth factors in the presence of high levels of bacteria. This appears to be the result of its lesser degree of degradation in the presence of bacteria and tissue fibroblasts and the ability of its receptors to remain functional in infected tissue. [ABSTRACT FROM AUTHOR]

During the past 5 years, progress in the treatment of pressure ulcers appears to have reached a plateau. Several factors in the design of recent clinical studies may have contributed to this situation. These factors include the criteria chosen for patient selection, small sample size, and lack of a concisely defined final clinical outcome. Hunt noted that wound stratification according to a patient's physiological characteristics may be a key to quantifying differences among clinical treatments.To address this issue, we examined the expression of cyclin D/cdk4 in pressure ulcer fibroblasts taken from tissues during a recent clinical trial. The treatment groups included patients treated with the following regimens: placebo, granulocyte macrophage-colony stimulating factor alone, basic fibroblast growth factor alone, or granulocyte macrophage-colony stimulating factor and basic fibroblast growth factor given in sequence. Immunocytochemical colocalization of cyclin D and cdk4 showed that, before the initial treatment began, patients were distributed disproportionately among treatment subgroups in regards to the initial expression of these markers. For example, we found that compared with other subgroups, ulcer fibroblasts in the basic fibroblast growth factor treatment group showed a much lower expression of cyclin D/cdk4 at day 0. However, this group exhibited higher levels of expression of this complex after 35 days of treatment. This study shows that measurement of cyclin D/cdk4 expression permits more accurate stratification of patients within treatment subgroups, measurement of a cell's ability to detect the presence of functional cytokines, identification of area(s) of failure within the G1 of the cell cycle, and a basis for critical evaluation of various treatments. [ABSTRACT FROM AUTHOR]

Previous analyses of fluids collected from chronic, nonhealing wounds found elevated levels of inflammatory cytokines, elevated levels of proteinases, and low levels of growth factor activity compared with fluids collected from acute, healing wounds. This led to the general hypothesis that chronic inflammation in acute wounds produces elevated levels of proteinases that destroy essential growth factors, receptors, and extracellular matrix proteins, which ultimately prevent wounds from healing. To test this hypothesis further, pro- and activated matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and the ratios of MMPs/TIMPs were assayed in fluids and biopsies collected from 56 patients with chronic pressure ulcers. Specimens included ulcers treated for 0, 10, and 36 days with conventional therapy or with exogenous cytokine therapies. Quantitative assay data were correlated with the amount of healing. The average MMP-9/TIMP-1 ratio in fluids from 56 ulcers decreased significantly as the chronic pressure ulcers healed. Furthermore, the average MMP-9/TIMP-1 ratio was significantly lower for fluids collected on day 0 from wounds that ultimately healed well (> or =85% reduction in initial wound volume) compared with wounds that healed poorly (< 50% wound volume reduction). These data show that the ratio of MMP-9/TIMP-1 levels is a predictor of healing in pressure ulcers and they provide additional support for the hypothesis that high levels of MMP activity and low levels of MMP inhibitor impair wound healing in chronic pressure ulcers. [ABSTRACT FROM AUTHOR]

Utilizing specific cell cycle markers of gene activity, temporal changes in the equilibrium of proliferating and non proliferating fibroblasts were shown in pressure ulcers after 36 days of quality care. Average cell counts from multiple tissue sections showed that fibroblast nuclei were stained in decreasing order by antibodies to p21, p21/proliferating cell nuclear antigen (PCNA) and PCNA. P21 labeling suggested that the majority of ulcer fibroblasts were senescent. Fibroblast nuclei showing PCNA staining identified those fibroblasts that were capable of synthesizing DNA and contributing to pressure ulcer repair. Increased rates of wound closure were correlated with a decreasing number of p21 positive cells and an increasing portion of PCNA labeled cells. While the proportion of antigens appeared to correlate with the status of wound closure after 36 days of quality care, they did not always appear to reflect the final outcome of the pressure ulcer. No significant differences were observed in ulcer fibroblasts labeled with p21 at 0 and 10 days, however, the differences were significant after 36 days of quality care (p = 0.05, analysis of variance, post hoc Tukey test). The cellular contribution to pressure ulcer repair appeared to occur from ulcer fibroblasts that were capable of division, of emerging from quiescence, and that were successful in repairing their DNA. [ABSTRACT FROM AUTHOR]

Accurate and clinically practical methods for measuring the progress of acute wound healing is necessary before interventions designed to optimize and even accelerate acute wound healing can be applied. Complete wound closure rates and operative wound closure severity are irrelevant to most acute wounds since most are closed at the time of primary tissue repair and remain closed throughout healing. Analogous to chronic wound closure, the rate of increase of incision tensile strength progressively decreases as time passes and 100% unwounded tissue strength is never achieved making the endpoint definition of 'healed' vague. Conceptualizing acute wound healing in terms of its design elements with reintegration into a final outcome lends itself to the description of acute wound healing as a mathematical trajectory. Frequently such an equation is a rate expressing the change in an acute healing parameter, most often tensile strength, over time. Such an approach also normalizes misinterpretations in analysis or errors in theory developed by measuring healing parameters at fixed points in time. Distributions of fractional strength gain times (e.g., 85% normal strength) can be determined using statistical methodology similar that used for failure time of survival analysis. Preclinical studies show that acute wound healing trajectories can be shifted to the left from a 'normal' or 'impaired' curve to an accelerated or more 'ideal' curve. A useful method for measuring acute wound healing outcomes is therefore required before the basic science of acute wound healing is inevitably applied to the problem of acute surgical wounds. [ABSTRACT FROM AUTHOR]

In chronic wounds, the healing process is prolonged and incomplete, proceeding in an uncoordinated manner, and resulting in poor anatomical and functional outcome. There have been numerous attempts to discover models that mimic human wound healing processes. The fibroblast populated collagen lattice is one such model that has been proposed. This study evaluated whether the fibroblast populated collagen lattice can be a model of chronic wound healing using the pressure ulcer as a paradigm. Fibroblast cultures of wound biopsies and wound volume measurements were obtained serially during a four arm blinded, placebo-controlled sequential cytokine clinical trial of pressure ulcers. Fibroblasts obtained from study patients were added to collagen lattices and contraction was determined daily for 10 days. Collagen gel-area measurements were converted to reflect percentage of gel contraction. These data of both edge and base wound biopsies on days 0, 10, and 36 were categorized into treatment groups and one-way analysis of variance showed no significant differences in contraction among these groups. When considering all fibroblast populated collagen lattices, there was significantly greater contraction at days 10 and 36 for cells from both edge and base biopsies compared to day 0 (p < 0.05). The Spearman Rank Correlation test comparing all patients with fibroblast populated collagen lattice results from fibroblasts obtained at the edge or base of the wound at days 0, 10, and 36 and clinical pressure ulcer healing on day 36 showed no correlation. This lack of correlation not only persisted for each of the four treatment arms but also for responder status based on decrease in wound volume over the 35 day trial period. In conclusion, chronic wound healing is a complex process that is not modeled by in vitro fibroblast populated collagen lattices. [ABSTRACT FROM AUTHOR]

New treatments for chronic wounds require carefully performed clinical trials with significant endpoints. Total wound closure is the only endpoint currently accepted by the Food and Drug Administration. This study describes a scale that measures ease of wound closure and applies it to a four-arm prospectively randomized, blinded pressure ulcer trial of recombinant human platelet-derived growth factor-BB. Following validation of interrater reliability, 83 evaluable subjects' photographs were given a weekly ease of closure score by four raters blinded to treatment. The change of ease of closure score was correlated with the change of wound area and volume. Each ease of closure score was given a procedural cost. Results showed ease of closure did not directly correlate with either wound area or volume, suggesting that it was measuring additional information. The mean change in ease of closure score was 6 for subjects treated with 100 microg recombinant human platelet-derived growth factor-BB daily; 5 for those treated with 300 microg growth factor daily or 100 microg recombinant human platelet-derived growth factor-BB bid; and 4 for those treated with placebo. The cost savings ranged from $7200 for the group receiving 100 microg recombinant human platelet-derived growth factor-BB daily to $6300 for the controls. Outcomes in all 4 groups were significantly improved from their starting evaluation (p < 0.001). Based on this study, ease of closure is a verifiable endpoint that can be related to cost efficiency and may be a measure of efficacy. [ABSTRACT FROM AUTHOR]

Pressure ulcers are associated with significant rates of morbidity and mortality, particularly in the geriatric and spinal cord-injured populations. Newer pharmacologically active therapies include the use of topically applied recombinant human platelet-derived growth factor-BB (becaplermin), the active ingredient in REGRANEX) (becaplermin) Gel 0.01%, which has been approved in the United States for treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. In this study, the efficacy of becaplermin gel in the treatment of chronic full thickness pressure ulcers was compared with that of placebo gel. A total of 124 adults (>/= 18 years of age) with pressure ulcers were assigned randomly to receive topical treatment with becaplermin gel 100 microg/g (n = 31) or 300 microg/g (n = 32) once daily alternated with placebo gel every 12 hours, becaplermin gel 100 microg/g twice daily (n = 30), or placebo (sodium carboxymethylcellulose) gel (n = 31) twice daily until complete healing was achieved or for 16 weeks. All treatment groups received a standardized regimen of good wound care throughout the study period. Study endpoints were the incidence of complete healing, the incidence of >/= 90% healing, and the relative ulcer volume at endpoint (endpoint/baseline). Once-daily treatment of chronic pressure ulcers with becaplermin gel 100 microg/g or 300 microg/g significantly increased the incidences of complete and >/= 90% healing and significantly reduced the median relative ulcer volume at endpoint compared with that of placebo gel (p < 0.025 for all comparisons). Becaplermin gel 300 microg/g did not result in a significantly greater incidence of healing than that observed with 100 microg/g. Treatment with becaplermin gel was generally well tolerated and the incidence of adverse events was similar among treatment groups. In conclusion, once-daily application of becaplermin gel is efficacious in the treatment of chronic full thickness pressure ulcers. [ABSTRACT FROM AUTHOR]