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

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

Topically applied rhGM-CSF for the wound healing: a systematic review

The process of wound healing involves a complex interplay of cells, mediators, growth factors and cytokines. GM-CSF has been shown to be involved in a number of processes essential in this event. Topically applied rhGM-CSF has been reported to successfully treat wounds with diverse etiology, including burns, chronic venous leg ulcers, pressure ulcers, and leprosy ulcers, both in animal experiments and clinical studies. To evaluate the effect of the rhGM-CSF on wound healing, 8 RCT studies and 23 clinical studies and case reports are collected for analysis of the evidence. The overall effects of rhGM-CSF on the healing of wound are diverse. Topically applied rhGM-CSF is beneficial for deep partial-thickness burn wounds, chronic leg ulcers, and leprosy ulcers. rhGM-CSF may have a positive effect on other type of chronic ulcers such as pressure ulcers and cancer related ulcers, but the evidence is not sufficient for generalised use at present. rhGM-CSF is suggested have no accelerating effect on the healing of healthy wounds or surgical incisions.     

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

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

Clinical efficacy of a silver‐releasing foam dressing in venous leg ulcer healing: a randomised controlled trial

Biatain and Biatain‐Ag are two identical wound dressings except the fact that Biatain‐Ag releases silver. In the present multinational double‐blinded randomised controlled trial the effect of the two dressings were compared for treatment of venous leg ulcers. A total of 181 patients were treated for 6 weeks with either Biatain or Biatain‐Ag followed by 4 weeks treatment with Biatain. Biatain‐Ag showed superior performance in relative wound area reduction after 6 weeks treatment and the estimated treatment difference increased after 10 weeks indicating that the effect of silver continues at least for 4 weeks after treatment. A subgroup of the patients differed significantly from the others with respect to parameters associated with a poor healing prognosis; patients were older, had significant history of venous thrombosis, larger ulcers with longer duration and more often recurrent. For this subgroup of patients Biatain‐Ag showed significant (P < 0·05) better performance in terms of relative ulcer area reduction and healing rate. In conclusion, this study suggests the superior performance of Biatain‐Ag compared with the non silver‐releasing dressing Biatain in particular for patients having ulcers associated with a poor healing prognosis.     

Prognostic factors for delayed healing of complex wounds in adults: A scoping review

Complex or hard-to-heal wounds continue to be a challenge because of the negative impact they have on patients, caregivers, and all the associated costs. This study aimed to identify prognostic factors for the delayed healing of complex wounds. Five databases and grey literature were the sources used to research adults with pressure ulcers/injuries, venous leg ulcers, critical limb-threatening ischaemia, or diabetic foot ulcers and report the prognostic factors for delayed healing in all care settings. In the last 5 years, a total of 42 original peer-reviewed articles were deemed eligible for this scoping review that followed the JBI recommendations and checklist PRISMA-ScR. The most frequent prognostic factors found with statistical significance coinciding with various wound aetiologies were: gender (male), renal disease, diabetes, peripheral arterial disease, the decline in activities of daily life, wound duration, wound area, wound location, high-stage WIfI classification, gangrene, infection, previous ulcers, and low ankle brachial index. It will be essential to apply critical appraisal tools and assessment risk of bias to the included studies, making it possible to make recommendations for clinical practice and build prognostic models. Future studies are recommended because the potential for healing through identification of prognostic factors can be determined, thus allowing an appropriate therapeutic plan to be developed.     

The role of surgical debridement in healing of diabetic foot ulcers

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

Initial healing rates as predictive factors of venous ulcer healing: The use of a laser-based three-dimensional ulcer measurement

There is a need for practical methods to predict the healing time of venous leg ulcers. In a prospective cohort study of 81 patients with venous leg ulcers, we used a recently described laser-based three-dimensional measurement of the ulcers at days 0 and 28 to estimate the predictive power of horizontal (HIHR) and vertical initial healing rates (VIHR) for wound healing by week 24. The rates were calculated by Gilman's equation [( A ₁− A ₂)/(( p ₁+ p ₂)/2)_(0–4)] and by its modification [( V ₁− V ₂)/(( A ₁+ A ₂)/2)_(0–4)], respectively. The influence of risk factors on both the initial healing rates was also studied. The HIHR and VIHR are important predictors of healing at 24 weeks. They are not influenced by age, ulcer duration, initial ulcer area, and insufficient sapheno-femoral junction, and/or calf perforating veins. Together with ulcer duration, they are independent predictors of the 24-week healing (the area under ROC curve equals to 0.9). VIHR gives us additional information and significantly improves the prediction of 24-week healing.     

Potential prognostic factors for delayed healing of common,non‐traumatic skin ulcers: A scoping review

Healing of non‐traumatic skin ulcers is often suboptimal. Prognostic tools that identify people at high risk of delayed healing within the context of routine ulcer assessments may improve this, but robust evidence on which factors to include is lacking. Therefore, we scoped the literature to identify which potentially prognostic factors may warrant future systematic reviews and meta‐analyses. We conducted electronic searches in MEDLINE and Embase to identify studies in English published between 1997 and 2017 that tested the association between healing of the three most common non‐traumatic skin ulcers encountered by health care professionals (venous leg, diabetic foot, and pressure ulcers) and patient characteristics, ulcer characteristics, and results from clinical investigations. We included 42 studies that investigated factors which may be associated with the healing of venous leg ulcers (n = 17), diabetic foot ulcers (n = 15), and pressure ulcers (n = 10). Across ulcer types, ulcer characteristics were most commonly reported as potential prognostic factors for healing (n = 37), including the size of the ulcer area (n = 29) and ulcer duration at first assessment (n = 16). A total of 35 studies investigated the prognostic value of patient characteristics (n = 35), including age (n = 31), gender (n = 30), diabetes (n = 22), smoking status (n = 15), and history of deep vein thrombosis (DVT) (n = 13). Of these studies, 23 reported results from clinical investigations as potential prognostic factors, with the majority regarding vessel quality. Age, gender, diabetes, smoking status, history of DVT, ulcer area, and ulcer duration at time of first assessment warrant a systematic review and meta‐analysis to quantify their prognostic value for delayed ulcer healing.     

Advances in the management of leg ulcers--the potential role of growth factors

Venous ulcers are a major health problem because of the increased costs of the treatment and the refractory nature of the ulcers. The treatment cost is estimated to be around 1 billion dollars per year in the United States (US), and the average cost for one patient over a lifetime exceeds dollars 400,000. There has been an increasing trend in the use of growth factors in their management. Genetic engineering has revolutionised the research of wound healing, as the majority of recombinant growth factors are now available for in vitro and in vivo studies. Online searches of Medline, Pub Medical and Embase were carried out using the terms venous ulcers, leg ulcers, growth factors and growth hormone. The literature regarding the potential role of growth factors in the management of leg ulcers is reviewed. The important clinical studies are critically analysed with a view to appreciate the emerging therapies and the further research possibilities in the management of venous leg ulcers. Clinical results with the use of growth factors in non-healing wounds are encouraging. However, small sample sizes and inconsistent end points in different clinical studies have been the main hurdle in reaching a definite conclusion. Further research is needed to provide the definite evidence. Future developments may include different delivery methods for the growth factors, use of different combinations of growth factors administered simultaneously or, sequentially, bioengineered skin grafts and chemical induction of angiogenesis with the use of gene transfer techniques.     

The molecular biology in wound healing & non-healing wound

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

A prospective study on the wound healing and quality of life outcomes of patients with venous leg ulcers in Singapore—Interim analysis at 6 month follow up

Venous leg ulceration results in significant morbidity. However, the majority of studies conducted are on Western populations. This study aims to evaluate the wound healing and quality of life for patients with venous leg ulcers (VLUs) in a Southeast Asian population. This is a multi-centre prospective cohort study from Nov 2019 to Nov 2021. All patients were started on 2- or 4-layer compression bandage and were reviewed weekly or fortnightly. Our outcomes were wound healing, factors predictive of wound healing and the EuroQol 5-dimensional 5-level (EQ-5D-5L) health states. Within our cohort, there were 255 patients with VLU. Mean age was 65.2 ± 11.6 years. Incidence of diabetes mellitus was 42.0%. Median duration of ulcer at baseline was 0.30 years (interquartile range 0.136–0.834). Overall, the median time to wound healing was 4.5 months (95% confidence interval [CI]: 3.77–5.43). The incidence of complete wound healing at 3- and 6-month was 47.0% and 60.9%, respectively. The duration of the wound at baseline was independently associated with worse wound healing (Hazard ratio 0.94, 95% CI: 0.89–0.99, P = .014). Patients with healed VLU had a significantly higher incidence of perfect EQ-5D-5L health states at 6 months (57.8% vs 13.8%, P < .001). We intend to present longer term results in subsequent publications.     

The effect of ankle range of motion on venous ulcer healing rates

Limitation of ankle movement may contribute to calf muscle pump failure, which is thought to contribute to venous leg ulcer formation, which affects nearly 1 million Americans. We therefore wished to study ankle movement in patients with venous leg ulcers and its effect on healing. Using goniometry, we measured baseline ankle range of motion in venous leg ulcer patients from a Phase 2 dose‐finding study of an allogeneic living cell bioformulation. Two hundred twenty‐seven patients were enrolled in four active treatment groups and one standard‐care control group, all receiving compression therapy. Goniometry data from a control group of 49 patients without venous disease, from a previous study, was used for comparison. We found patients with active venous leg ulcers had significantly reduced ankle range of motion compared with the control group (p = 0.001). After 12 weeks of therapy, baseline ankle range of motion was not associated with healing, as there was no significant difference between healed and nonhealed groups, suggesting that ankle range of motion is not important in venous leg ulcer healing or, more likely, is overcome by compression. However, patients with venous ulcers located on the leg (as opposed to the ankle) had significantly higher ankle range of motion for plantar flexion and inversion (p = 0.021 and p = 0.034, respectively) and improved healing with both cell bioformulation and standard care (p = 0.011), suggesting that wound location is an important variable for ankle range of motion as well as for healing outcomes.     

Relationship between edema and the healing rate of stasis ulcers of the leg

Leg volumes and ulcer size were measured in patients who underwent four consecutive different treatment regimens for stasis ulcers. Most ulcers enlarged on simple wound care. Any regimen which included external support led to healing, but there was no correlation between the healing rate and the amount of swelling in the leg. Our evidence suggests that both the ulcer and the edema are due to the same cause, probably venous stasis, and any therapy which does not improve venous drainage is probably doomed to failure.     

The use of proteases as prognostic markers for the healing of venous leg ulcers

Abnormally high levels of some proteases are associated with pathological changes in the wound bed of venous leg ulcers. This study involved two experiments which measured proteases in wound fluid harvested from leg ulcers in order to predict healing. In the first experiment, neutrophil elastase, a protease, was harvested from wound fluid extracted from the bandages of seven patients with leg ulcers. This was undertaken once a week over a period of up to six weeks. The amount of elastase recovered from the bandages showed wide variation between patients and there was no consistent correlation between the activity of elastase and healing of the ulcers, as determined nine months after sampling for the enzyme. The second experiment determined the stability of neutrophil elastase that was added to bandages for one week. The stability was found to vary from approximately 50% to 100%, depending on the type of bandage used. In addition to the possibility of using protease measurements to predict healing, the procedure was found to be simple, non-invasive and relatively inexpensive, and could be performed routinely in the clinic.     

Factors that influence healing in chronic venous ulcers treated with cryopreserved human epidermal cultures.

BACKGROUND: Cryopreserved epidermal cultures (CEC) offer an "off the shelf" treatment for chronic wounds. These cultures are derived from neonatal foreskin and grow rapidly in vitro to form epidermal sheets. They do not require a biopsy from the patient, an advantage compared to autografts. They seem to act as a biological dressing, stimulating epithelialization from the wound edges and adnexae, probably through growth factor release. OBJECTIVE: To summarize our recent experience with the use of CEC in chronic venous leg ulcers and to determine the factors that influence healing in chronic venous ulcers treated with CEC. PATIENTS AND METHODS: A single arm, open label study including a total of 11 patients with documented venous ulcers was performed. The study involved the application of cryopreserved epidermal cultures every other week to nonhealing leg ulcers for a total of 12 weeks or until complete healing of the ulcer. RESULTS: A total of 11 patients with one or more leg ulcers were treated. The average age was similar in healed and unhealed groups. Seven patients completely healed after an average of 4.14 CEC applications. Four patients did not heal after a total of 12 CEC applications. CONCLUSION: Predictors for failure to heal after CEC application in our patients were long wound duration, wound size, presence of lipodermatosclerosis, and history of failed prior split-thickness skin grafts.     

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

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

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

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

A systematic review of Calendula officinalis extract for wound healing

Use of complementary and alternative medicine for wound healing is influencing mainstream medical practice. This systematic review evaluates the role of Calendula officinalis flower extract as monotherapy compared to control for wound healing in vivo. Searches were conducted in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, and Scopus (up to April 2018) with 14 studies meeting the inclusion criteria, comprising 7 animal experiments and 7 clinical trials. Findings from the review on acute wound healing showed faster resolution of the inflammation phase with increased production of granulation tissue in the test groups treated with extract. These findings were consistent in five animal studies and one randomized clinical trial. Chronic wound healing studies were varied. Two clinical control studies on venous ulcers demonstrated decreased ulcer surface area compared to controls. Another randomized clinical trial demonstrated no improvement for the calendula group in diabetic leg ulcer healing. Burn healing similarly showed mixed results. Two animal studies demonstrated a prophylactic effect for the administration of calendula extract prior to burn injury. A randomized clinical trial of patients suffering from partial to full thickness burns demonstrated no benefit for topical application of calendula extract compared to controls. Two randomized clinical trials assessed the potential for extract to prevent acute post radiation dermatitis, with one study showing improvements compared to trolamine, while the other found no improvement compared to aqua gel cream. Animal studies provide moderate evidence for improved recovery from the inflammation phase and increased production of granulation tissue in calendula extract treatment groups. This review identified some evidence for the beneficial effects of C. officinalis extract for wound healing, consistent with its role in traditional medicine. There is a need for larger, well‐designed randomized control trials to assess the effect of calendula on wound healing including complications.     

Healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency.

OBJECTIVE: Although newer techniques to promote the healing of leg ulcers associated with chronic venous insufficiency are promising, improved healing rates and cost effectiveness are unproven. We prospectively followed a series of patients who underwent treatment with outpatient compression for venous stasis ulcers without adjuvant techniques to determine healing rates and costs of treatment. METHODS: Two hundred fifty-two patients with clinical or duplex scan evidence of chronic venous insufficiency and active leg ulcers underwent treatment with ambulatory compression techniques. The patients were prospectively followed with wound measurements at 1-week to 2-week intervals, and the factors that were associated with delayed healing were determined. RESULTS: Of all the ulcers, 57% were healed at 10 weeks of treatment and 75% were healed at 16 weeks. Ultimately, 96% of the ulcers healed, and only 1 major amputation was necessitated (0.4%). Initial ulcer size and moderate arterial insufficiency (ankle brachial index, 0.5 to 0.8; n = 34) were factors that were independently associated with delayed healing (P <.01). Patient age, ulcer duration before treatment, and morbid obesity did not significantly affect healing times. The cost of 10 weeks of outpatient treatment with compression techniques ranged from $1444 to $2711. CONCLUSION: The treatment of venous stasis ulcers with compression techniques results in reliable, cost-effective healing in most patients. Current adjuvant techniques may prove to be useful but are likely to be cost effective only in a minority of cases, particularly in patients with large initial ulcer size or arterial insufficiency.