Topical oxygen therapy results in complete wound healing in diabetic foot ulcers

Diabetic foot ulcers (DFUs) are a significant problem in an aging population. Fifteen percent of diabetics develop a DFU over their lifetime, which can lead to potential amputation. The 5‐year survival rate after amputation is 31%, which is greater than the lifetime risk of mortality from cancer. Topical oxygen is a promising technique for the adjunctive therapy of chronic wounds including DFUs, but few controlled studies exist to support its clinical adoption. The aim of this study was to compare a portable topical oxygen delivery system in patients with nonhealing DFUs to standard best practice. Twenty patients were randomized into a topical oxygen group (n = 10), and a nonplacebo control group with regular dressings and standard care (n = 10), and attended the diabetic foot clinic once weekly for 8 weeks. Ulcer surface area over time was analyzed using standardized digital imaging software. DFUs were present without healing for a mean duration of 76 weeks prior to the study. They found a significant difference in healing rate between patients receiving topical oxygen and those receiving standard care. Topical oxygen, therefore, represents a potentially exciting new technology to shorten healing time in patients with nonhealing DFUs. More prospective randomized and powered studies are needed to determine the benefits of topical oxygen, but our current results are very promising.     

Prediction of wound healing in human diabetic foot ulcers by diffuse near‐infrared spectroscopy: A pilot study

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.     

Evidence of differential microbiomes in healing versus non‐healing diabetic foot ulcers prior to and following foot salvage therapy

Diabetic foot ulcers (DFU) contribute to 80% of lower extremity amputations. Although physicians currently rely on clinical signs along with non‐specific biomarkers of infection, such as erythrocyte sedimentation rate and C‐reactive protein, to diagnose and monitor DFU, there is no specific and sensitive measure available to monitor or prognosticate the success of foot salvage therapy (FST). To address this we performed a prospective, observational microbiome analysis to test the hypotheses that: (i) the initial microbiomes of healed versus non‐healed DFU are distinct; (ii) the microbial load, diversity and presence of pathogenic organism of the DFU change in response to antibiotics treatment; and (iii) the changes in the DFU microbiome during treatment are prognostic of clinical outcome. To test this, microbiome analyses were performed on 23 DFU patients undergoing FST, in which wound samples were collected at zero, four, and eight weeks following wound debridement and antibiotics treatment. Bacterial abundance was determined using quantitative polymerase chain reaction (qPCR). Eleven patients healed their DFU, while FDT failed to heal DFU in the other 12 patients. Microbiome results demonstrated that healing DFUs had a larger abundance Actinomycetales and Staphylococcaceae (p < 0.05), while DFUs that did not heal had a higher abundance of Bacteroidales and Streptococcaceae (p < 0.05). FST marked increases Actinomycetales in DFU, and this increase is significantly greater in patients that healed (p < 0.05). Future studies to confirm the differential microbiomes, and that increasing Actinomycetales is prognostic of successful FST are warranted. Statement of Clinical Significance: Tracking changes in the prevalence of pathogens in diabetic foot ulcers may be a clinical tool for monitoring treatment response to foot salvage therapy and prognosticating the need for further surgical intervention. The initial wound sample microbiome may provide important prognostic information on the eventual clinical outcome of foot salvage therapy. It may serve as an important clinical tool for patient counseling and making surgical decision of pursuing foot salvage versus amputation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1596–1603, 2019.     

Relationship between maceration and wound healing on diabetic foot ulcers in Indonesia: a prospective study

The aim of this study was to clarify the relationship between maceration and wound healing. A prospective longitudinal design was used in this study. The wound condition determined the type of dressings used and the dressing change frequency. A total of 62 participants with diabetic foot ulcers (70 wounds) were divided into two groups: non‐macerated (n = 52) and macerated wounds (n = 18). Each group was evaluated weekly using the Bates–Jensen Wound Assessment Tool, with follow‐ups until week 4. The Mann–Whitney U test showed that the changes in the wound area in week 1 were faster in the non‐macerated group than the macerated group (P = 0·02). The Pearson correlation analysis showed a moderate correlation between maceration and wound healing from enrolment until week 4 (P = 0·002). After week 4, the Kaplan–Meier analysis showed that the non‐macerated wounds healed significantly faster than the macerated wounds (log‐rank test = 19·378, P = 0·000). The Cox regression analysis confirmed that maceration was a significant and independent predictor of wound healing in this study (adjusted hazard ratio, 0·324; 95% CI, 0·131–0·799; P = 0·014). The results of this study demonstrated that there is a relationship between maceration and wound healing. Changes in the wound area can help predict the healing of wounds with maceration in clinical settings.     

Association of time in range with postoperative wound healing in patients with diabetic foot ulcers

Time in range (TIR) is a novel indicator of glycaemic control that has been reported to have an association with diabetic complications. The objective of the study was to explore the association of TIR with postoperative wound healing in patients with diabetic foot ulcers (DFUs). We retrospectively analysed the data of DFU patients who had undergone surgical treatment from 2015 to 2019. A 1:1 ratio in propensity score matching (PSM) was adopted to compare patients with TIR ≥50% with those <50%. Data were summarised using chi‐squared, Fisher''s exact, and Mann‐Whitney U tests. Patients with TIR <50% underwent a higher rate of secondary surgery within a month (P = .032) and had a longer hospital stay (P = .045) with greater hospital charges (P < .001) than the TIR ≥50% group. Multivariate analysis revealed that TIR (P = .034), Wagner score (P = .009), diabetes treatment (P = .006), and type of surgery (P = .013) were independent risk factors for secondary surgery. Additionally, patient subgroups with TIR <50% and baseline HbA1c < 7.5% (P = .025), albumin level ≥ 30 g/L (P = .039), HDL < 1.16 (P = .021), or Wagner score ≥ 3 (P = .048) also experienced a higher incidence of secondary surgery. TIR was correlated with postoperative wound healing in patients with DFUs. Strict glycaemic targets should be established for surgical patients.     

A cost‐effectiveness analysis of optimal care for diabetic foot ulcers in Australia

In addition to affecting quality of life, diabetic foot ulcers (DFUs) impose an economic burden on both patients and the health system. This study developed a Markov model to analyse the cost‐effectiveness of implementing optimal care in comparison with the continuation of usual care for diabetic patients at high risk of DFUs in the Australian setting. The model results demonstrated overall 5‐year cost savings (AUD 9100·11 for those aged 35–54, $9391·60 for those aged 55–74 and $12 394·97 for those aged 75 or older) and improved health benefits measured in quality‐adjusted life years (QALYs) (0·13 QALYs, 0·13 QALYs and 0·16 QALYs, respectively) for high‐risk patients receiving optimal care for DFUs compared with usual care. Total cost savings for Australia were estimated at AUD 2·7 billion over 5 years. Probabilistic sensitivity analysis showed that optimal care always had a higher probability of costing less and generating more health benefits. This study provides important evidence to inform Australian policy decisions on the efficient use of health resources and supports the implementation of evidence‐based optimal care in Australia. Furthermore, this information is of great importance for comparable developed countries that could reap similar benefits from investing in these well‐known evidence‐based strategies.     

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.     

Effect of total contact cast in non‐healing diabetic foot ulcers in Lebanese patients

The aim of this study was to evaluate the effectiveness of total contact casting (TCC) in treating non‐healing diabetic foot ulcers in Lebanese diabetic patients. Twenty‐three diabetic patients were treated with TCC, and relevant data were collected retrospectively. Sixteen patients were analysed; the average duration of casting was 6 weeks, and 75% of the patients achieved complete ulcer closure without recurrence during one year of follow‐up and without any complications. TCC appears to be an effective treatment of diabetic foot ulcers.     

Severity of albuminuria as an early indicator for wound healing in type 2 diabetic foot ulcers

This study aimed to investigate the relationship between the severity of albuminuria and wound healing in type 2 diabetic foot ulcers. A total of 121 patients with diabetic foot ulcers were recruited from January 2015 to June 2017 and divided into nonproliferation and proliferation groups according to their healing status. Univariate and multivariate logistic regression were performed to assess the risk factors of wound proliferation. Skin biopsies were also taken from normal tissue near the wound in 54 participants. The microvessel density as well as the relationships among the microvessel density, albuminuria and wound proliferation were evaluated. Results showed that in a multiple linear regression model, factors including body‐mass index, microalbuminuria, and macroalbuminuria showed independently significant association with wound healing in patients. The receiver operating characteristic curve analysis indicated albuminuria as a predicator for wound healing with a cutoff value of 32 mg/g. Meanwhile, normoalbuminuric patients showed significantly higher level of skin microvessels density than microalbuminuria and macroalbuminuria patients, while microalbuminuria patients also had statistically more microvessels that macroalbuminuria patients. The microvessel density were statistically significantly higher in the proliferation group than that in the nonproliferation group. In summary, this study suggested that albuminuria can be used as an independent indicator for the healing of type 2 diabetic foot ulcers.     

Angiosome‐targeted revascularisation in diabetic foot ulcers

Peripheral vascular disease is a common complication of type 2 diabetes and is often more severe and diffuse than in non‐diabetic individuals with a higher risk of major amputations in the lower limbs. Diabetic foot revascularisation using both traditional bypass surgery and endovascular therapy are often burdened by the failure and the inevitable subsequent massive amputation. In this study, we examined the clinical response of diabetic patients with critical limb ischaemia and extended ischaemic wounds, treated with a new angiosome‐based revascularisation technique. In a 3‐year period, nine diabetic patients with imminent amputation threatening and foot ulcers with no feasible arterial revascularisation options were treated by the angiosome‐based surgical technique by means of deep vein arterialisation. The postoperative tcPO2 evaluation showed a mean increase in the cutaneous oxygen tension in all patients treated. The overall survival rates were 88·88%, 88·88% and 77·77% at 12, 24 and 36 months, respectively. Limb salvage was 100% at 1 year and steady at 88·88% thereafter. Surgical deep venous arterialisation might be considered as an extreme alternative to attempt tissue preservation in limbs unfit for conventional arterial revascularisations. This technique would give advantages to the patients in terms of better compliance to the minor amputations and thus avoiding major limb amputations.     

Formulated collagen gel accelerates healing rate immediately after application in patients with diabetic neuropathic foot ulcers

We assessed the safety and efficacy of Formulated Collagen Gel (FCG) alone and with Ad5PDGF‐B (GAM501) compared with Standard of Care (SOC) in patients with 1.5–10.0 cm² chronic diabetic neuropathic foot ulcers that healed <30% during Run‐in. Wound size was assessed by planimetry of acetate tracings and photographs in 124 patients. Comparison of data sets revealed that acetate tracings frequently overestimated areas at some sites. For per‐protocol analysis, 113 patients qualified using acetate tracings but only 82 qualified using photographs. Prior animal studies suggested that collagen alone would have little effect on healing and would serve as a negative control. Surprisingly trends for increased incidence of complete closure were observed for both GAM501 (41%) and FCG (45%) vs. Standard of Care (31%). By photographic data, Standard of Care had no significant effect on change in wound radius (mm/week) from during Run‐in to Week 1 (?0.06±0.32 to 0.78±1.53, p=ns) but both FCG (?0.08±0.61 to 1.97±1.77, p<0.002) and GAM501 (?0.02±0.58 to 1.46±1.37, p<0.002) significantly increased healing rates that gradually declined over subsequent weeks. Both GAM501 and FCG appeared to be safe and well tolerated, and alternate dosing schedules hold promise to improve overall complete wound closure in adequately powered trials.     

High‐dose folic acid and its effect on early stage diabetic foot ulcer wound healing

High‐dose folic acid (HDFA; vitamin B9)—5 mg, given daily, has not been evaluated as a treatment to improve early stage‐diabetic foot ulcer (ES‐DFU) wound healing. However, HDFA has been demonstrated to correct: (a) endothelial dysfunction and decreased nitric oxide (NO) bioavailability, associated with type‐2 diabetes mellitus (T2DM); and (b) hyperhomocysteinemia (HHcy) that may promote impaired DFU‐wound healing. Measures of wound area (cm²) reduction (wound closure; WC), over a 4‐week period (4 W‐WC), greater than 50% of the wound area, have been reported as a robust indicator of the potential for DFU‐wound healing. By using this model, we examined the effectiveness of a wound treatment in promoting progressive healing and complete wound closure for the chronic, nonhealing DFU‐wound. To investigate this possible relationship between HDFA and ES‐DFU wound healing, a retrospective cohort study of medical records, between November 2018 and April 2019, was performed for Veterans with T2DM and ES‐DFUs following treatment with HDFA. During the study period 29 (n = 29) Veterans with ES‐DFU wounds who received HDFA treatment were identified. Medical record reviews of this retrospective cohort of ES‐DFU Veterans receiving HDFA report 90% (26/29) experiencing complete DFU‐wound closure during the study period. Of the 29 Veterans with ES‐DFUs receiving HDFA, the medical records of nine (30%), with healed wounds, provided documentation suitable for 4 W‐WC, pre‐ and post‐HDFA treatment study comparisons. This study documents significant (P < .05) improvements comparing 4 W‐WC values for standard treatment for Veterans with poorly progressing, worsening or stagnating ES‐DFU‐wounds to those for the same subjects following HDFA treatment. These observations suggest that chronic ES‐DFUs treated with HDFA may experience significantly improved wound closure and complete healing (re‐epithelialization) when compared with standard treatments without HDFA. With validation from RCTs, HDFA may be established as an effective treatment to promote wound healing and closure for nonhealing ES‐DFUs.     

Validity of DMIST for monitoring healing of diabetic foot ulcers

A new diabetic foot evaluation scale was proposed, using the seven domains of depth, maceration, inflammation/infection, size, tissue type of the wound bed, type of wound edge, and tunneling/undermining. This scale was named “DMIST” as an acronym from the initials of the domains. The purpose of this study was to evaluate the validity of DMIST. Secondary analysis was conducted in three investigations performed using the diabetic foot ulcer assessment scale (DFUAS) in Japan and Indonesia. Secondary analysis was assessed using DMIST, PUSH, and DESIGN for 4 weeks based on DFUAS score and photographs of diabetic foot ulcers by researchers. Concurrent validity was determined from the correlation of total DMIST scores with PUSH and DESIGN scores. Construct validity was determined by comparisons between total DMIST score and grade of the Wagner classification. Predictive validity was determined by receiver operating characteristic curve analysis for wound non‐healing 4 weeks later. Subjects comprised 35 Japanese patients and 118 Indonesian patients. Correlations of total DMIST score with PUSH and DESIGN scores were 0.831 and 0.822, respectively. Comparison of total DMIST scores with grade of the Wagner classification (Grade I vs. Grade II/III vs. Grade IV/V) was p < 0.001. Based on an area under the curve of 0.872, a DMIST score of 9 was selected as a cut‐off, offering sensitivity of 0.855 and specificity of 0.786 for wound non‐healing 4 weeks later. Our findings suggest that DMIST offers high validity.     

Neurogenic factors in the impaired healing of diabetic foot ulcers

BACKGROUND: We hypothesize that the reduced innervation of skin can be observed both in clinically neuropathic and non-neuropathic diabetic foot ulcers and can contribute to low inflammatory cell infiltration. MATERIALS AND METHODS: Twenty patients with type 2 diabetes and active foot ulcers, without clinical evidence of peripheral sensory neuropathy (n = 12) and with sensory neuropathy (n = 8) were involved in this study. Biopsies from ulcer margin were examined immunohistochemically. RESULTS: Studies revealed presence of protein gene product 9.5 (PGP9.5)+ nerve endings only in reticular dermis in 3 of 12 non-neuropathic subjects, however, regenerating GAP-43+ endings were seen in dermis of almost all specimens. Lack of substance P+ nerve endings was characteristic for both groups. The reduced distribution of calcitonin gene-related peptide+ nerves in epidermis and dermis was seen mainly in neuropathic group. In neo-epidermis lack of nerve growth factor expression was observed in both groups, whereas neurotrophin 3 immunostaining was characteristic for neuropathic specimens (P < 0.03). Expression of trkA and trkC receptors did not differ significantly between groups. Low inflammatory cell infiltration and moderate presence of fibroblasts was characteristic for all studied specimens. CONCLUSIONS: The observed reduction of foot skin innervation and neurogenic factors expression can be correlated with low inflammatory cell accumulation and subsequently leads to the observed chronicity of diabetic foot ulcer healing process in both neuropathic and non-neuropathic patients.     

不同部位糖尿病足溃疡愈合情况分析

目的了解不同部位糖尿病足溃疡愈合情况。方法采用前瞻性研究方法,对142例Wagner分级2~4级的糖尿病足溃疡患者采取多学科协作的综合治疗方法,收集入院首次临床检查资料,留取入院每次清创后足溃疡照片,比较治疗30d内不同部位的足溃疡创面缩小率。结果发生在足背、足踝、足弓、足趾、足前掌及足跟的Wagner分级为2级的溃疡创面缩小率比较,差异有统计学意义(P0.01),发生在足趾的糖尿病足溃疡创面缩小率最小,足踝部及足背部溃疡创面缩小率较大。Wagner分级为2、3级的非受压组溃疡创面缩小率显著大于受压组(均P0.01)。结论不同部位糖尿病足溃疡愈合存在差异,治疗糖尿病足过程中采取适当的减压措施有利于糖尿病足溃疡的愈合。     

Autologous wound margin point columnar full-thickness skin grafting combined with negative pressure wound therapy improves wound healing in refractory diabetic foot ulcers

Diabetic lower extremity ulcers (DLEUs) are a severe complication of diabetes mellitus (DM) and are difficult to heal. This study aimed to explore the efficacy of autologous point columnar full-thickness skin graft taken from the ulcer wound margin combined with negative pressure wound therapy (NPWT) in refractory DLEUs. This is a prospective cohort study. A total of 40 inpatients with refractory DLEUs were recruited in the Diabetes Foot Center of Guangxi Zhuang Autonomous Region People's Hospital from October 2019 to November 2021. According to the doctors' professional suggestions and the patients' personal wishes, these enrolled patients were divided into two groups based on different topical wound management: the graft group (n = 18) and the conventional wound therapeutic (CWT) group (n = 22). The efficacy evaluations included the time to complete re-epithelialization of the wound and healing speed within 14 days of graft treatment or after 14 days of graft treatment in the two groups. Before the treatment, the graft group had a significantly larger ulcer area than the CWT group [27.22 (15.28, 46.59) versus 10.92 (7.00, 24.93) cm², P < .01]. However, the time to complete wound re-epithelialization in the graft group was shorter than in the CWT group [58.22 ± 30.60 versus 86.09 ± 49.54 d, P < .05]. Meanwhile, the healing speed in graft group was markedly faster than in CWT group, whether within 14 days [0.60 (0.40, 0.92) versus 0.16 (0.07, 0.34) cm²/d, P < .01] or after 14 days of graft treatment [0.57 (0.45, 0.91) versus 0.13 (0.08, 0.27) cm²/d, P < .01]. However, the total treatment cost in the graft group was lower than in the CWT group [419.59 ± 137.20 versus 663.97 ± 497.02 $, P < .05]. The novel treatment modality of autologous full-thickness skin graft taken from the ulcer wound margin combined with NPWT has hereby proposed for the first time, and is a safe, effective, and reliable method with a good performance-to-cost ratio to promote wound healing and shorten the healing time for DLEUs.     

Cost‐effectiveness of treating vascular leg ulcers with UrgoStart® and UrgoCell® Contact

Although chronic wounds have a high socio‐economic impact, data on comparative effectiveness of treatments are rare. UrgoStart^® is a hydroactive dressing containing a nano‐oligosaccharide factor (NOSF). This study aimed at evaluating the cost‐effectiveness of this NOSF‐containing wound dressing in vascular leg ulcers compared with a similar neutral foam dressing (UrgoCell^® Contact) without NOSF. Cost‐effectiveness analysis from the perspective of the German statutory health care system was performed using a decision tree model for a period of 8 weeks. Cost and outcome data were derived from the clinical study ‘Challenge’ suggesting a response rate (≥40% wound size reduction) of UrgoStart^® of 65·6% versus 39·4% for the comparator. In the treatment model, effect‐adjusted costs of €849·86 were generated after 8 weeks for treatment with UrgoStart^® versus €1335·51 for the comparator resulting in an effect‐adjusted cost advantage of €485·64 for UrgoStart^®. In linear sensitivity analyses, the outcomes were stable for varying assumptions on prices and response rates. In an 8‐week period of treatment for vascular leg ulcers, UrgoStart^® shows superior cost‐effectiveness when compared with the similar neutral foam dressing without any active component (NOSF). As demonstrated within a randomised, double‐blind clinical trial, UrgoStart^® is also more effective in wound area reduction than the neutral foam dressing. Wound healing was not addressed in this clinical trial. Follow‐up data of 12 months to allow for reulceration assessment were not generated.