Serial surgical debridement: A retrospective study on clinical outcomes in chronic lower extremity wounds

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%, p =0.019). Centers where patients were debrided more frequently were associated with higher rates of wound closure in both clinical studies ( p =0.007 VLU, p =0.015 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, p =0.069). 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.     

A single arm prospective feasibility study evaluating wound closure with a unique wearable device that provides intermittent plantar compression and offloading in the treatment of non-healing diabetic foot ulcers

The incidence and economic burden of diabetic foot ulcers continues to rise throughout the world. In this prospective study, a unique device designed to offload the wound, enhance circulation and monitor patient compliance was evaluated for safety and efficacy. The device provides offloading and intermittent plantar compression to improve the pedal flow of oxygenated blood and support wound healing while recording patient use. Ten patients with non-healing diabetic foot ulcers UTgrade 1A/Wagner grade 1 were treated weekly for up to 12 weeks. The primary endpoint was complete wound closure at 12 weeks, and secondary endpoints included healing time, percent area reduction and changes in pain using the visual analogue pain scale. Eight out of ten wounds healed within 12 weeks(80%), and the mean healing time was 41 days(95% CI:24.3–58.3). The percent area reduction was 75(SD:53.9). The baseline visual analogue pain scale was 4.5(2.9) as compared with 3.3(3.4) at end of study. No device-related or serious adverse events were reported. This unique intermediate plantar compression and offloading device may be considered as an alternative for safe and effective for treatment of non-healing diabetic foot ulcers. During treatment, wound healing was significantly accelerated, and pain was improved. Larger randomised controlled trials are underway to validate these early findings.     

Evaluation of the use of prognostic information for the care of individuals with venous leg ulcers or diabetic neuropathic foot ulcers

This is a randomized factorial design clinical trial that investigates the efficacy and feasibility of providing prognostic information on wound healing. Prognostic information was provided based on baseline or 4-week wound characteristics. Healing rates were then determined at 24 weeks for venous leg ulcers and 20 weeks for diabetic neuropathic foot ulcers. Centers that had access to baseline information for venous leg ulcer prognosis had an odds ratio (OR) of healing of 1.42 (95% confidence interval [CI]: 1.03, 1.95) while centers that had access to information at 4 weeks had an OR of healing of 1.43 (95% CI: 1.05, 1.95) compared with controls. Diabetic neuropathic foot ulcer patients treated in centers that had been randomized to receive only 4-week prognostic information were more likely to heal than individuals seen in centers randomized to receive no intervention (OR 1.50, 95% CI: 1.05, 2.14). Our study found that it is feasible and efficacious to provide prognostic information on venous leg ulcers and diabetic neuropathic foot ulcers in a wound care setting using an existing administrative database. This intervention was easy to administer and likely had low associated costs. This method of dispersing prognostic information to healthcare providers should be expanded to include recently published treatment algorithms.     

A single arm prospective feasibility study evaluating wound closure with a unique wearable device that provides intermittent plantar compression and offloading in the treatment of non‐healing diabetic foot ulcers

The incidence and economic burden of diabetic foot ulcers continues to rise throughout the world. In this prospective study, a unique device designed to offload the wound, enhance circulation and monitor patient compliance was evaluated for safety and efficacy. The device provides offloading and intermittent plantar compression to improve the pedal flow of oxygenated blood and support wound healing while recording patient use. Ten patients with non‐healing diabetic foot ulcers UTgrade 1A/Wagner grade 1 were treated weekly for up to 12 weeks. The primary endpoint was complete wound closure at 12 weeks, and secondary endpoints included healing time, percent area reduction and changes in pain using the visual analogue pain scale. Eight out of ten wounds healed within 12 weeks(80%), and the mean healing time was 41 days(95% CI:24.3–58.3). The percent area reduction was 75(SD:53.9). The baseline visual analogue pain scale was 4.5(2.9) as compared with 3.3(3.4) at end of study. No device‐related or serious adverse events were reported. This unique intermediate plantar compression and offloading device may be considered as an alternative for safe and effective for treatment of non‐healing diabetic foot ulcers. During treatment, wound healing was significantly accelerated, and pain was improved. Larger randomised controlled trials are underway to validate these early findings.     

Clinical Classification of Bioengineered Skin Use and Its Correlation with Healing of Diabetic and Venous Ulcers

BACKGROUND: Chronic wounds are being treated with bioengineering skin constructs. Yet, there is no standard way of assessing these wounds. We developed a classification system to evaluate wounds after construct application. The classification system evaluates the early clinical effect of bioengineered skin and early construct appearance giving a total score named the skin substitute score. OBJECTIVE: Apply classification system to both venous and diabetic foot ulcers and determine whether classification system has validity and predictability for healing. METHODS: Evaluated serial photographs in 83 and 78 patients with diabetic foot ulcers and in 84 and 83 patients with venous ulcer on Days 7 and 14, respectively, treated with a bilayered bioengineered skin construct. Applied the classification system and determined the percentages of healed patients. RESULTS: There was a significant correlation between better skin substitute score and complete wound closure for both venous ulcers p=0.002 on Day 7 and p=0.01 on Day 14) and diabetic foot ulcers p=0.0005 on Day 7 and p<0.0001 on Day 14). CONCLUSION: Optimal clinical effect was associated with complete wound closure. As the clinical effect becomes less than optimal continued clinical persistence of the construct becomes important. This classification system seems to have validity in predicting complete wound closure in wounds treated with a bilayered bioengineered skin construct.     

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.     

Retrospective observational analysis of the use of an architecturally unique dermal regeneration template (Derma Pure®) for the treatment of hard‐to‐heal wounds

The purpose of this analysis was to evaluate the use of DermaPure, a decellularised human skin allograft, in the treatment of a variety of challenging wounds. This retrospective observational analysis reviewed a total of 37 patients from 29 different wound clinics across the USA. Each patient received one application of DermaPure which was followed until complete closure. A statistical analysis was performed with the end point being complete healing. All wounds on average, had a duration of 56 weeks and healed in an average time of 10·58 weeks. Individual wound categories included diabetic foot ulcers, which healed in 8·21 weeks; venous leg ulcers, which healed in 11·29 weeks; and surgical/traumatic wounds, which healed in 11·8 weeks.     

Human pilot studies reveal the potential of a vitronectin: growth factor complex as a treatment for chronic wounds

Several different advanced treatments have been used to improve healing in chronic wounds, but none have shown sustained success. The application of topical growth factors (GFs) has displayed some potential, but the varying results, high doses and high costs have limited their widespread adoption. Many treatments have ignored the evidence that wound healing is driven by interactions between extracellular matrix proteins and GFs, not just GFs alone. We report herein that a clinical Good Manufacturing Practice-grade vitronectin:growth factor (cVN:GF) complex is able to stimulate functions relevant to wound repair in vitro, such as enhanced cellular proliferation and migration. Furthermore, we assessed this complex as a topical wound healing agent in a single-arm pilot study using venous leg ulcers, as well as several 'difficult to heal' case studies. The cVN:GF complex was safe and re-epithelialisation was observed in all but 1 of the 30 patients in the pilot study. In addition, the case studies show that this complex may be applied to several ulcer aetiologies, such as venous leg ulcers, diabetic foot ulcers and pressure ulcers. These findings suggest that further evaluation is warranted to determine whether the cVN:GF complex may be an effective topical treatment for chronic wounds.     

Wound healing trajectories as predictors of effectiveness of therapeutic agents

BACKGROUND: One goal of wound healing research is to discover agents to accelerate healing. Regulatory agencies have suggested stringent criteria to determine efficacy, that of 100% wound closure. Data analysis at a single point such as 100% closure does not provide detailed information about agent effectiveness over the entire span of healing. HYPOTHESIS: Wound healing trajectories can provide such information and can be used to demonstrate utility as alternative end points for wound healing trials. DESIGN: Data from 160 patients in 11 clinical trials of diabetic foot ulcers conducted at 2 centers were evaluated. Wound healing trajectories were constructed for patients whose wounds healed (100% closure) and those whose did not (<100% closure) over a 20-week period. The percentage of patients achieving total healing vs time of treatment was plotted and divided into patients receiving a test agent or placebo. RESULTS: The healing trajectories were almost identical for patients achieving complete healing at the 2 centers, as were the trajectories for patients with less than 100% closure. However, the trajectories of patients achieving total healing were significantly different from those not achieving 100% closure. Fifty-two percent of all patients achieved 100% healing by 20 weeks; 61% of patients receiving an experimental agent had total healing compared with 39% of placebo-treated patients. Linear regression suggested that all patients would achieve total healing by 37 weeks. CONCLUSIONS: Since wound healing trajectories for diabetic foot ulcers treated at 2 centers so closely mimic one another, trajectories might be useful efficacy end points, and used to compare significant points along a continuum rather than a single static end point. Shifting of the wound healing trajectory from an impaired to a more ideal course may be considered when determining efficacy of new wound treatments.     

Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers

About 600,000 people in the United States are estimated to be affected by venous ulcers. The cornerstone of care of chronic venous ulcers involves the application of compression bandages. Other therapies include treatment of associated infection, treatment for edema and inflammation, and debridement when necessary. Repifermin, a recombinant human KGF-2 (fibroblast growth factor-10), exerts a proliferative effect on epithelial cells, in vitro and in vivo, and has been shown to accelerate wound healing in several experimental animal models. A randomized, double-blind, parallel-group, placebo-controlled, multicenter study was conducted to evaluate the safety and efficacy of topical repifermin treatment, for 12 weeks, in the healing of chronic venous ulcers in 94 patients. Repifermin was shown to accelerate wound healing, with significantly more patients achieving 75% wound closure with repifermin than with placebo. The treatment effect appeared more marked for a subgroup of patients with initial wound areas < or = 15 cm2 and wound ages of < or = 18 months. A longer duration of treatment (e.g., 26 weeks) may allow better differentiation of the benefit of repifermin compared with placebo, particularly with respect to complete wound closure. The safety assessment showed that repifermin was well tolerated.     

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.     

The efficacy of low-frequency ultrasound as an added treatment for chronic wounds: A meta-analysis

We performed a meta-analysis to evaluate the effect of low-frequency ultrasound as an added treatment for chronic wounds. A systematic literature search up to May 2022 was performed and 838 subjects with chronic wounds at the baseline of the studies; 412 of them were using the low-frequency ultrasound (225 low-frequency high-intensity contact ultrasound for diabetic foot wound ulcers, and 187 low-frequency low-intensity non-contact ultrasound for a venous leg wound ulcers), and 426 were using standard care (233 sharp debridements for diabetic foot wound ulcers and 193 sham treatments for venous leg wound ulcers). Odds ratio (OR), and mean difference (MD) with 95% confidence intervals (CIs) were calculated to assess the effect of low-frequency ultrasound as an added treatment for chronic wounds using the dichotomous, and contentious methods with a random or fixed-effect model. The low-frequency high-intensity contact ultrasound for diabetic foot wound ulcers had significantly lower non-healed diabetic foot wound ulcers at ≥3 months (OR, 0.37; 95% CI, 0.24-0.56, P < .001), a higher percentage of diabetic foot wound ulcers area reduction (MD, 17.18; 95% CI, 6.62-27.85, P = .002) compared with sharp debridement for diabetic foot wound ulcers. The low-frequency low-intensity non-contact ultrasound for a venous leg wound ulcers had a significantly lower non-healed venous leg wound ulcers at ≥3 months (OR, 0.31; 95% CI, 0.15-0.62, P = .001), and higher percentage venous leg wound ulcers area reduction (MD, 18.96; 95% CI, 2.36-35.57, P = .03) compared with sham treatments for a venous leg wound ulcers. The low-frequency ultrasound as an added treatment for diabetic foot wound ulcers and venous leg wound ulcers had significantly lower non-healed chronic wound ulcers at ≥3 months, a higher percentage of chronic wound ulcers area reduction compared with standard care. The analysis of outcomes should be with caution because of the low sample size of all the 17 studies in the meta-analysis and a low number of studies in certain comparisons.     

Low-frequency ultrasound (20-40 kHz) as an adjunctive therapy for chronic wound healing: a systematic review of the literature and meta-analysis of eight randomized controlled trials

Ultrasound as a therapeutic agent in chronic wound healing has been studied extensively. This systematic review and meta-analysis specifically examines low-frequency (20-30 kHz) ultrasound delivered at either low or high intensity. The objective of this review was to determine whether low-frequency ultrasound used as an adjunctive therapy improves the outcomes of complete healing and reduction of size of chronic lower limb wounds. PubMed, Cochrane/CENTRAL, technical assessment, relevant wound-related journals, and clinical guidelines were searched along with contacting manufacturers and authors of relevant randomized controlled trials were completed. Searches focused on the use of low-frequency ultrasound in randomized controlled trials. Data were collected via a data collection form and was adjudicated independently via coauthors. Meta-analyses and heterogeneity checks were performed using Mantel-Haenszel and inverse variance (fixed and random effects) statistical methods on studies with similar outcomes (complete healing and percent wound area reduction) over similar time periods. Single study results were reported via the statistical methods used in the study. Eight randomized controlled trials were identified. Results demonstrated that early healing (at ≤5 months) in patients with venous stasis and diabetic foot ulcers was favorably influenced by both high- and low-intensity ultrasound delivered at a low frequency-either via contact or noncontact techniques. However, the quality of the data may be suspect, especially for low-frequency low-intensity noncontact ultrasound because of significant biases. In patients presenting with either venous stasis or diabetic foot ulcers (Wagner classification 1-3), early healing appears to be facilitated by either low-frequency low-intensity noncontact ultrasound or low-frequency high-intensity contact ultrasound.     

Wound-healing trajectories as outcome measures of venous stasis ulcer treatment

Outcome measures of venous ulcer healing are not uniformly accepted. Stringent criteria of 100% closure fail to provide information of healing over the entire span of repair. Wound-healing trajectories (plot of percentage of wound closure versus time of wound treatment) were constructed for 232 patients treated in eight clinical trials at two independent wound care/research centres. Trajectories were constructed for ulcers that totally healed (100% closure) and those that did not (<100% closure) over a 20-week period. Kaplan-Meier survival plots determined the percentage of patients achieving total healing versus time of treatment. The wound-healing trajectories were almost identical for patients achieving complete ulcer healing, as were the trajectories for patients with less than 100% closure. The trajectories for the ulcers healing completely were significantly different from those with <100% closure. Only 60% of all patients achieved 100% closure by 20 weeks. Using linear regression, it was predicted that it would take 31 weeks for all patients to achieve total healing. Total healing is an inadequate outcome measure for healing of venous stasis ulcers. Clinical trials using this measure would require excessive time periods. As wound-healing trajectories for patients treated at two centres mimic one another, shifting the wound-healing trajectory from one of impaired healing to one of a more ideal healing course may be considered a better outcome measure for determining healing of venous stasis ulcers.     

Wound shape geometry measurements correlate to eventual wound healing

Wound geometry measurements have long been associated with wound-healing outcomes but there is little published evidence to support this. We studied serial wound tracings of 338 venous leg ulcers (VLUs) that had been followed during a controlled, prospective, randomized pivotal trial of two topical wound treatments, to determine whether the relationship between wound surface area and wound perimeter planimetry measurements, as well as the qualitative assessment of wound shape, could be correlated to wound-healing outcomes. VLUs that transitioned to a more convex wound shape, and maintained a linear relationship between their wound margin size and wound surface area size, had faster healing rates and were more likely to completely heal by 12 weeks (odds ratio=4.84, p =0.001). VLUs that initially presented with isolated areas of epithelium within the wound margins, large concavities, or were segmented into multiple ulcers typically had a poorer linear correlation between their margins and their surface area. Only 18 out of 134 (13%) VLUs with a linear r ²<0.80 eventually reached full wound closure, vs. 43% (102 of 270) of the remaining wounds with an r ²≥0.80 (Fisher's exact p <0.001). We believe our results show that the proportional relationship between one-dimensional perimeter and area measurements accurately correlates to the healing progress of the wound. Wounds that do not correlate to this linear relationship (concave geometries or multiple islands of healing) may be physiologically different than wounds that have good linear correlation, which we concluded through the analysis of wound acetate tracings.     

Healing of diabetic foot ulcers and pressure ulcers with human skin equivalent: a new paradigm in wound healing

HYPOTHESIS: In patients with diabetic foot and pressure ulcers, early intervention with biological therapy will either halt progression or result in rapid healing of these chronic wounds. DESIGN: In a prospective nonrandomized case series, 23 consecutive patients were treated with human skin equivalent (HSE) after excisional debridement of their wounds. SETTING: A single university teaching hospital and tertiary care center. PATIENTS AND METHODS: Twenty-three consecutive patients with a total of 41 wounds (1.0-7.5 cm in diameter) were treated with placement of HSE after sharp excisional debridement. All patients with pressure ulcers received alternating air therapy with zero-pressure alternating air mattresses. MAIN OUTCOME MEASURE: Time to 100% healing, as defined by full epithelialization of the wound and by no drainage from the site. RESULTS: Seven of 10 patients with diabetic foot ulcers had complete healing of all wounds. In these patients 17 of 20 wounds healed in an average of 42 days. Seven of 13 patients with pressure ulcers had complete healing of all wounds. In patients with pressure ulcers, 13 of 21 wounds healed in an average of 29 days. All wounds that did not heal in this series occurred in patients who had an additional stage IV ulcer or a wound with exposed bone. Twenty-nine of 30 wounds that healed did so after a single application of the HSE. CONCLUSIONS: In diabetic ulcers and pressure ulcers of various durations, the application of HSE with the surgical principles used in a traditional skin graft is successful in producing healing. The high success rate with complete closure in these various types of wounds suggests that HSE may function as a reservoir of growth factors that also stimulate wound contraction and epithelialization. If a wound has not fully healed after 6 weeks, a second application of HSE should be used. If the wound is not healing, an occult infection is the likely cause. All nonischemic diabetic foot and pressure ulcers that are identified and treated early with aggressive therapy (including antibiotics, off-loading of pressure, and biological therapy) will not progress.     

Thrombin peptide Chrysalin® stimulates healing of diabetic foot ulcers in a placebo-controlled phase I/II study

Thrombin and thrombin peptides play a role in initiating tissue repair. The potential safety and efficacy of TP508 (Chrysalin) treatment of diabetic foot ulcers was evaluated in a 60-subject, prospective, randomized, double-blind, placebo-controlled phase I/II clinical trial. Chrysalin in saline or saline alone was applied topically, twice weekly, to diabetic ulcers with standardized care and offloading. A dose-dependent effect was seen in the per-protocol population where 1 and 10 mug Chrysalin treatment resulted in 45 and 72% more subjects with complete healing than placebo treatment. Chrysalin treatment of foot ulcers more than doubled the incidence of complete healing (p<0.05), increased mean closure rate approximately 80% (p<0.05), and decreased the median time to 100% closure by approximately 40% (p<0.05). Chrysalin treatment of heel ulcers within this population resulted in mean closure rates 165% higher than placebos (p<0.02) and complete healing in 86% (6/7) of ulcers compared with 0% (0/5) of placebo ulcers (p<0.03). Local wound reactions and adverse events (AEs) were equal between groups with no reported drug-related changes in laboratory tests or serious AEs. These results indicate the potential safety and efficacy of Chrysalin for treatment of diabetic foot ulcers.     

Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers

OBJECTIVES: Platelet products have been proposed as adjuvant therapy for wound healing. We undertook this study to determine the healing effect of topically applied frozen autologous platelets (FAP) on chronic venous ulcers, compared with effect of placebo, and whether use of topical FAP modifies local expression of vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), interleukin 8 (IL-8), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in wound fluid. METHODS: This randomized, placebo-controlled, double-blind trial was carried out in institutional practice, with ambulatory patients with proved chronic venous leg ulcers. In all patients, whole venous blood was drawn for preparation of FAP. FAP or normal saline solution was applied three times per week for up to 12 weeks, together with hydrocolloids and standardized compression bandages. Leg ulcer surface was assessed with numerical pictures. IL-8, VEGF, KGF, and TIMP-1 levels were determined (enzyme-linked immunosorbent assay) in wound fluid after each 4 weeks of treatment. RESULTS: Fifteen patients were randomized into two groups with comparable leg ulcer characteristics. Mean percent reduction in ulcer area was 26.2% in the FAP group versus 15.2% in the placebo group (P =.94). One ulcer in each group was completely healed at study end. Levels of TIMP-1 increased significantly during FAP treatment. IL-8 concentration was significantly lower in wound fluid of healing ulcers than in the fluid of nonhealing ulcers, in both FAP and placebo groups. Growth factor levels were not modified with FAP treatment. CONCLUSION: Topical autologous platelets have no significant adjuvant effect on healing of chronic venous leg ulcers and increased wound fluid TIMP-1 concentration. Ulcer healing is associated with a decrease in wound fluid IL-8.     

Effect of systemic insulin treatment on diabetic wound healing

This study investigates if different diabetic treatment regimens affect diabetic foot ulcer healing. From January 2013 to December 2014, 107 diabetic foot ulcers in 85 patients were followed until wound healing, amputation or development of a nonhealing ulcer at the last follow‐up visit. Demographic data, diabetic treatment regimens, presence of peripheral vascular disease, wound characteristics, and outcome were collected. Nonhealing wound was defined as major or minor amputation or those who did not have complete healing until the last observation. Median age was 60.0 years (range: 31.1–90.1 years) and 58 cases (68.2%) were males. Twenty‐four cases reached a complete healing (healing rate: 22.4%). The median follow‐up period in subjects with classified as having chronic wounds was 6.0 months (range: 0.7–21.8 months). Insulin treatment was a part of diabetes management in 52 (61.2%) cases. Insulin therapy significantly increased the wound healing rate (30.3% [20/66 ulcers] vs. 9.8% [4/41 ulcers]) (p = 0.013). In multivariate random‐effect logistic regression model, adjusting for age, gender, smoking status, type of diabetes, hypertension, chronic kidney disease, peripheral arterial disease, oral hypoglycemic use, wound infection, involved side, presence of Charcot's deformity, gangrene, osteomyelitis on x‐ray, and serum hemoglobin A1C levels, insulin treatment was associated with a higher chance of complete healing (beta ± SE: 15.2 ± 6.1, p = 0.013). Systemic insulin treatment can improve wound healing in diabetic ulcers after adjusting for multiple confounding covariates.     

Heparin-like inhibitory activity to fibroblast growth factor-2 in wound fluids of patients with chronic skin ulcers and its modulation during wound healing

Fibroblast growth factors are potent mitogens and angiogenic factors which play a critical role in wound healing. Fibroblast growth factors require heparan sulfates as cofactors in order to activate their cognate receptors and exert their cellular and biological effects. Heparan sulfates were extracted from wound fluids of 5 patients with chronic diabetic foot ulcers or chronic venous stasis ulcers and tested for their capacity to modulate fibroblast growth factor-receptor binding, during the course of the ulcers' resolution, until complete healing (3-8 months). Total heparan sulfates concentration measured as iduronic acid equivalents, decreased in wound fluids from 1.1 +/-0.3 microg/ml to 0.26 +/-0.1 microg/ml as wound healing progressed. These heparan sulfates exhibited a predominant inhibitory effect on fibroblast growth factor-2 binding to fibroblast growth factor receptor-1, when tested in cells deficient in cell surface heparan sulfates. During wound healing, there was a marked decrease in the relative inhibitory activity of the extracted heparan sulfates on fibroblast growth factor-2-receptor binding. Heparan sulfates extracted from chronic skin ulcers of different etiologies such as diabetic foot or chronic venous stasis ulcers showed the same pattern of alternating balance in heparan sulfates mediated activity. The presence of fibroblast growth factor inhibitory factors which possess heparin-like activity in fluids of chronic skin ulcers and their ability to modulate fibroblast growth factor-receptor activity throughout the process of wound healing, may significantly contribute to the mechanism of chronicity. Treatments to counter this inhibition may offer new possibilities for healing chronic wounds.