Healing Of Chronic Foot Ulcers Research Articles

Topical Application of Autologous Plasma-Derived Plasminogen Accelerates Healing of Chronic Foot Ulcers in Type 2 Diabetes Patients.

Plasminogen (Pg) is currently considered a master regulator of wound healing, but the molecular mechanisms of its efficacy in improving impaired closure of chronic skin ulcers in type 2 diabetes patients remain unclear. Here, we investigated wound healing effects of autologous plasma-derived Pg in diabetes patients with chronic foot ulcers and evaluated Pg-induced changes in levels of key protein markers related to wound repair. Type 2 diabetes patients with chronic wounds of lower extremities were included in the study and received topical applications of Pg in a dose of 1.0 mg/mL every 2 days during 20 days, in addition to the standard wound management treatment. Patients treated only according to conventional protocol served as a control. Wound closure rates were monitored by digital planimetry of wound areas. Plasminogen supplementary treatment significantly accelerated relative wound closure as compared with diabetes patients from the control group (24 ± 4 days vs 120 ± 17 days, respectively, P < .01). As shown by Western blot, Pg application reduced expression of protein regulators of hypoxia events, angiogenesis, and autophagy such as hypoxia-inducible factor-1α (by 6.3-folds, P < .01), angiostatins (by 2.5-folds, P < .05), and autophagy marker LC3-II/LC3-I (by 8.6-folds, P < .05), while increasing vascular endothelial growth factor level by 1.9-folds (P < .05). Gelatin zymography showed that Pg-supplemented therapy decreased activity of matrix metalloproteinase-9 (MMP-9) by 3.5-folds at the end of treatment period (P < .01). We report here for the first time that topically applied plasma-derived Pg has a pronounced beneficial effect in promoting foot ulcer healing in patients with type 2 diabetes through preventing hypoxia-induced signaling, reducing autophagy flux, diminishing excessive MMP activity, and enhancing angiogenesis.

Tibial transverse transport induces mobilization of endothelial progenitor cells to accelerate angiogenesis and ulcer wound healing through the VEGFA/CXCL12 pathway

BackgroundTibial transverse transport (TTT) can promote the healing of chronic foot ulcers, but the specific cellular and molecular mechanisms by which TTT promotes wound healing remain unclear. MethodsNew Zealand White rabbits were selected to induce foot ulcer models. The treatment included unilateral TTT surgery and bilateral TTT surgery. Observation of tissue neovascularization structure by HE staining and CD31 immunofluorescence detection. Collagen fiber formation was detected through the Masson staining. The mobilization of endothelial progenitor cell (EPCs) were analyzed by VEGFR2 immunofluorescence detection and flow cytometry detection of the number of VEGFR2/Tie-2-positive cells in peripheral blood. ELISA and qPCR assay were performed to detect VEGFA and CXCL12 levels. ResultsThe complete healing time of ulcer surfaces in sham, unilateral and bilateral TTT groups was about 22 days, 17 days and 13 days, respectively. TTT treatment significantly increased the deposition of granulation tissue and epithelialization of wounds. It also led to an increase in collagen fiber content and the level of the microvascular marker CD31. Furthermore, TTT treatment upregulated the levels of VEGFA and CXCL12 in peripheral blood and wound tissues, as well as increased the expression of VEGFR2 in wound tissues and the proportion of VEGFR2/Tie-2 in peripheral blood. Moreover, these effects of TTT treatment in the bilateral group was more significant than that in the unilateral group. ConclusionsTTT may facilitate wound fibroblasts to release VEGFA and CXCL12, causing EPC mobilization, thus promoting angiogenesis and ulcer wound healing.

Randomized controlled clinical trial evaluating the efficacy of hyperbaric oxygen therapy in facilitating the healing of chronic foot ulcers in diabetic patients: the study protocol

BackgroundDiabetic limb ulcers are highly prevalent and contribute to a significant increase in cost for the treatment of these patients in health services. However, healing of these wounds is a major health problem and may even lead to amputation. The primary aim of the current study is to evaluate the efficacy of hyperbaric oxygen therapy (HBOT) in facilitating the healing of diabetic foot ulcers, in addition to secondarily evaluating whether it reduces the number of amputations and improves the quality of life in these patients.MethodsA non-blind randomized clinical study will be conducted in the city of Imperatriz, Maranhão state, Brazil, from 2019 to 2020, in diabetic patients with chronic foot ulcers (classified as Wagner grades 2, 3 and 4, persisting for more than 1 month). The outpatient follow-up for diabetic foot patients will be done at the Unified Health System, with a sample size of 120 patients (the randomization allocation will be 1:1, being 60 patients for each arm). Half of the patients will receive standard treatment, i.e. dressings, debridement, antibiotics and load relief, along with HBOT (HBOT group), and the other half will receive only standard treatment (control group). The patients of the HBOT group will be evaluated upon admission, after 10, 20, 30 and 35 HBOT sessions, and after 6 months and 1 year. The patients of the control group will also be evaluated at equivalent periods (upon admission, after 2, 4, 6 and 7 weeks, 6 months and 1 year). The SF-36 quality of life questionnaire will be filled upon admission and after 3 months of follow-up in both groups. The primary and secondary endpoints will be assessed with 1 year of follow-up.DiscussionDiabetic foot ulcers are a highly prevalent complication of diabetes with serious consequences. A study to assess the efficacy of HBOT in healing the ulcers and reducing the rate of amputations in diabetic patients is justified, which will eventually aid in the development of guidelines for treating these ulcers.Trial registrationRegistration number RBR-7bd3xy. Registered on 17 July 2019—Retrospectively registered.

Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update).

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. In conjunction with advice from internal and external reviewers and expert consultants in the field, this update is based on a systematic review of the literature centred on the following: the Population (P), Intervention (I), Comparator (C) and Outcomes (O) framework; the use of the SIGN guideline/Cochrane review system; and the 21 point scoring system advocated by IWGDF/EWMA. This has resulted in 13 recommendations. The recommendation on sharp debridement and the selection of dressings remain unchanged from the last recommendations published in 2016. The recommendation to consider negative pressure wound therapy in post-surgical wounds and the judicious use of hyperbaric oxygen therapy in certain non-healing ischaemic ulcers also remains unchanged. Recommendations against the use of growth factors, autologous platelet gels, bioengineered skin products, ozone, topical carbon dioxide, nitric oxide or interventions reporting improvement of ulcer healing through an alteration of the physical environment or through other systemic medical or nutritional means also remain. New recommendations include consideration of the use of sucrose-octasulfate impregnated dressings in difficult to heal neuro-ischaemic ulcers and consideration of the use of autologous combined leucocyte, platelet and fibrin patch in ulcers that are difficult to heal, in both cases when used in addition to best standard of care. A further new recommendation is the consideration of topical placental derived products when used in addition to best standard of care.

Effectiveness of interventions to enhance healing of chronic foot ulcers in diabetes: a systematic review.

The management of diabetic foot ulcers (DFU) remains a challenge, and there is continuing uncertainty concerning optimal approaches to wound healing. The International Working Group of the Diabetic Foot (IWGDF) working group on wound healing has previously published systematic reviews of the evidence in 2008, 2012 and 2016 to inform protocols for routine care and to highlight areas which should be considered for further study. The working group has now updated this review by considering papers on the interventions to improve the healing of DFU's published between June 2014 and August 2018. Methodological quality of selected studies was independently assessed by a minimum of two reviewers using the recently published 21-point questionnaire as recommended by IWGDF/European Wound Management Association, as well as the previously incorporated Scottish Intercollegiate Guidelines Network criteria. Of the 2275 papers identified, 97 were finally selected for grading following full text review. Overall, there has been an improvement in study design and a significant rise in the number of published studies. While previous systematic reviews did not find any evidence to justify the use of newer therapies, except for negative pressure wound therapy in post-surgical wounds, in this review we found additional evidence to support some interventions including a sucrose-octasulfate dressing, the combined leucocyte, fibrin and platelet patch as well as topical application of some placental membrane products, all when used in addition to usual best care. Nonetheless, the assessment and comparison of published trials remains difficult with marked clinical heterogeneity between studies: in patient selection, study duration, standard of usual care provision and the timing and description of the clinical endpoints.

Role of hyperbaric oxygen therapy in the treatment of chronic ulcers of the foot in patients with type II diabetes mellitus

Background: The aim of this study is to evaluate the effect of hyperbaric oxygen therapy (HBOT) in healing of chronic foot ulcers in patients with type II diabetes mellitus.Methods: A case control study included 40 type II diabetic patients with chronic foot ulcers not healing for more than 4 weeks. It has been conducted at Naser Institute for Research and Treatment and Menoufia University Hospital during the period between April 2017 and September 2018. Patients with non-healing diabetic foot ulcers were referred by physicians and were also identified through a number of wound care clinics in various hospitals.Results: Most ulcers were observed in the sole and heel in both groups A and B (n=14 and 9 respectively), while the rest of ulcers were distributed in other areas of the foot, namely the medial and lateral malleoli, dorsum and toes. On comparing the wound related complications developing during the treatment period, no statistically significant difference was found between both groups (p=0.147). As regards Wagner's grade, 7 patients (17.5%) had grade 4 ulcers, 18 patients (45%) had grade 3 ulcers and 15 patients (37.5%) had grade 2 ulcers, showing no statistically significant difference between both groups before treatment (p=0.259).Conclusions: HBOT is a useful adjunct in the treatment of non-healing diabetic foot ulcers, and that the cost of HBOT itself will be reduced as it becomes more widely available in the clinical setting, and as further knowledge of its other advantages, such as limited side effects and relative safety, become more widely appreciated.

The Proteolytic Fraction from Latex of Vasconcellea cundinamarcensis (P1G10) Enhances Wound Healing of Diabetic Foot Ulcers: A Double-Blind Randomized Pilot Study.

The aim of the study was to investigate the role of the proteolytic fraction from Vasconcellea cundinamarcensis, designated as P1G10, on the healing of chronic foot ulcers in neuropathic patients with diabetes 2. Fifty patients were enrolled in a prospective, randomized, double-blind trial, to verify the efficacy and safety of a topical dressing formulated with 0.1% P1G10, intended for wound healing, versus a hydrogel (control) protocol. Upon completion of the intervention, the outcome evaluated the number of patients attaining full epithelization (100%), or at least 80% healing. Statistical analysis compared the data on each group for the significance of the differences. Collection of data was finished in week 16, and the results were analyzed by intention to treat. The results showed that, in the control group, 5 patients attained 100% ulcer healing, 3 patients ≥ 80% healing and 11 experienced ulcer changes ≤ 80%, and the remainder showed no changes or their wounds became worse. Meanwhile, in the P1G10 group, 11 patients experienced full healing, 4 had healing ≥ 80% and 5 had ulcer changes ≤ lower than 80%, and the remainder showed no changes or their wounds became worse. The healing incidence for the first endpoint (100% healing) showed that the P1G10 group was 2.95-fold more efficacious than the control group (CI 95%) and 2.52-fold (CI, 95%) higher than its control for the second endpoint (80% healing). These data support the hypothesis that topical application of the proteolytic fraction identified as P1G10 significantly enhances foot ulcer healing compared to hydrogel treatment.

The role of chloramines in treatment of diabetic foot ulcers: an exploratory multicentre randomised controlled trial.

BackgroundChronic foot ulcers in diabetes are serious, costly and frequently difficult to heal. Recent guidelines conclude that new dressings and treatments generally fail to show superiority compared with standard of care. Several mechanisms are probably responsible for impaired healing of chronic foot ulcers, including inflammation and infection. Chloramines have presumed antiseptic and antibacterial properties, and have shown to be a useful treatment in odontology.MethodsIn an explorative open randomised controlled multi-centre study, we compared chloramine-based treatment with current standard of care for 12 weeks and follow-up for 24 weeks. Seventeen patients in each group, mean age about 70, duration of diabetes > 20 years and foot ulcers about 1.5 years, completed the 12 weeks study.ResultsAfter 5 weeks, the difference between the groups in relative reduction in ulcer area was statistically significant (p=0.016). Absolute change in ulcer area was first statistically significant within the chloraminetreated group after 2 weeks (p=0.026), after 8 weeks in the control group (p=0.0023), with significant difference between groups after 5 weeks (p=0.024). The approximate relative decrease per week was 19.4% (95%CI 12.2, 26.0; p<0.0001) in the chloramine-treated group and 11.7% (95%CI 6.4, 16.7; p<0.0001; between-group difference p=0.083). After 9 weeks 7 patients had healed in the chloraminetreated group, but only one in the control group (p=0.039). There were no statistically significant differences in wound healing at 12 or 24 weeks, and no marked differences in signs of infection, pain, quality of life (EQ-5D), or incidence of adverse events.ConclusionsChloramine-based treatment seems to be efficacious, particularly in the early phase of the care of infected diabetic foot ulcers. It is safe and easy to use, and could prove to be a valuable addition in the treatment arsenal, providing non-surgical debridement. Future studies will evaluate its role in wound care.

A review of the clinical experience with recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in orthopaedic bone repair and regeneration

Recombinant human PDGF BB homodimer (rhPDGF-BB) is a potent chemotactic and mitogenic factor for cells crucial to musculoskeletal tissue repair, including mesenchymal stem cells (MSCs), osteogenic cells, and tenocytes. Furthermore, rhPDGF-BB promotes angiogenesis by upregulation of vascular endothelial growth factor (VEGF). These properties allow rhPDGF-BB to initiate the tissue repair and regeneration cascade, a mechanism of action that has been demonstrated through preclinical and clinical studies. The established mechanism of action and preclinical safety profile of rhPDGF-BB support clinical investigation of this molecule in diverse conditions that require osseous repair. Furthermore, the safety and efficacy profiles of rhPDGF-BB observed in the healing of chronic foot ulcers in diabetic patients along with previously reported preclinical data in orthopaedic models provide additional rationale to assess the application of rhPDGF-BB containing scaffolds in bone applications, including periodontal disease and end-stage ankle arthritis. Additional combinations of rhPDGF-BB with tissue-specific matrices are being studied in additional clinical musculoskeletal indications, such as rotator cuff repair involving tendon and bone integration. This paper reviews the clinical experience with rhPDGF-BB in bone repair.

The Role of Recombinant Human Platelet-derived Growth Factor-BB (rhPDGF-BB) in Orthopaedic Bone Repair and Regeneration

Recombinant human PDGF BB homodimer (rhPDGF-BB) is a potent recruiter of, and strong mitogenic factor for, cells crucial to musculoskeletal tissue repair, including mesenchymal stem cells (MSCs), osteogenic cells and tenocytes. rhPDGF-BB also upregulates angiogenesis. These properties allow rhPDGF-BB to trigger the cascade of bone and adjoining soft tissue repair and regeneration. This mechanism of action has been established in numerous preclinical and clinical studies. Demonstration of the safety and efficacy of rhPDGF-BB in the healing of chronic foot ulcers in diabetic patients and regeneration of alveolar (jaw) bone lost due to chronic infection from periodontal disease has resulted in two FDA-approved products based on this molecule. A third product is in late stages of clinical development, with pilot and pivotal clinical studies of rhPDGF-BB mixed with an osteoconductive bone matrix (Augment(®) Bone Graft) in foot and ankle fusions demonstrating that this product is at least as effective as bone autograft, and has an improved safety profile. Additional combinations of rhPDGF-BB with tissue-specific matrices are also being studied clinically in additional musculoskeletal indications.

Foot Care

Foot Care

Why Critical Limb Ischemia Criteria are Not Applicable to Diabetic Foot and What the Consequences are

Neuropathy, peripheral arterial occlusive disease and microvascular disturbances are important factors contributing to foot problems in diabetic patients. In the diabetic foot with ischemia, the alterations in skin microvascular function are pronounced including severely reduced capillary circulation and abolished hyperaemic responses. These microvascular disturbances, which are superimposed on the already existing structural diabetic microangiopathy, are compatible with a state of "chronic capillary ischemia" and an increased shunting of blood through arteriovenous channels. This maldistribution of blood in skin microcirculation is not detected by measurement of peripheral blood pressure (systolic ankle blood pressure, systolic toe blood pressure). As indicated in several studies toe blood pressure is a poor predictor of local tissue perfusion, tissue survival and healing of chronic foot ulcers. Consequently, the disturbances in peripheral tissue perfusion of the diabetic foot may be underestimated leading to delayed vascular interventions and/or medical treatment. Thus, measurements of peripheral blood pressure, e.g. toe blood pressure, should be combined with investigations of local tissue perfusion in order to get an adequate estimation of peripheral tissue perfusion in diabetic patients. For this purpose local skin microcirculation can be investigated by transcutaneous oxygen tension of the forefoot. Also, due to these reasons, the threshold for revascularization should be lower in diabetic patients with foot ulcer.

Dipeptidyl Peptidase 4 Inhibition May Facilitate Healing of Chronic Foot Ulcers in Patients with Type 2 Diabetes

The pathophysiology of chronic diabetic ulcers is complex and still incompletely understood, both micro- and macroangiopathy strongly contribute to the development and delayed healing of diabetic wounds, through an impaired tissue feeding and response to ischemia. With adequate treatment, some ulcers may last only weeks; however, many ulcers are difficult to treat and may last months, in certain cases years; 19–35% of ulcers are reported as nonhealing. As no efficient therapy is available, it is a high priority to develop new strategies for treatment of this devastating complication. Because experimental and pathological studies suggest that incretin hormone glucagon-like peptide-1 may improves VEGF generation and promote the upregulation of HIF-1α through a reduction of oxidative stress, the study evaluated the effect of the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase-4, such as vildagliptin, on angiogenesis process and wound healing in diabetic chronic ulcers. Although elucidation of the pathophysiologic importance of these aspects awaits further confirmations, the present study evidences an additional aspect of how DPP-4 inhibition might contribute to improved ulcer outcome.

Hyperbaric Oxygen Therapy Facilitates Healing of Chronic Foot Ulcers in Patients With Diabetes

OBJECTIVEChronic diabetic foot ulcers are a source of major concern for both patients and health care systems. The aim of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) in the management of chronic diabetic foot ulcers.RESEARCH DESIGN AND METHODSThe Hyperbaric Oxygen Therapy in Diabetics with Chronic Foot Ulcers (HODFU) study was a randomized, single-center, double-blinded, placebo-controlled clinical trial. The outcomes for the group receiving HBOT were compared with those of the group receiving treatment with hyperbaric air. Treatments were given in a multi-place hyperbaric chamber for 85-min daily (session duration 95 min), five days a week for eight weeks (40 treatment sessions). The study was performed in an ambulatory setting.RESULTSNinety-four patients with Wagner grade 2, 3, or 4 ulcers, which had been present for >3 months, were studied. In the intention-to-treat analysis, complete healing of the index ulcer was achieved in 37 patients at 1-year of follow-up: 25/48 (52%) in the HBOT group and 12/42 (29%) in the placebo group (P = 0.03). In a sub-analysis of those patients completing >35 HBOT sessions, healing of the index ulcer occurred in 23/38 (61%) in the HBOT group and 10/37 (27%) in the placebo group (P = 0.009). The frequency of adverse events was low.CONCLUSIONSThe HODFU study showed that adjunctive treatment with HBOT facilitates healing of chronic foot ulcers in selected patients with diabetes.

Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis

A prospective, multicenter, randomized, controlled 12-week study was undertaken to evaluate the effectiveness of a human fibroblast-derived dermis for treating foot ulcers in the diabetic patient. This report summarizes the findings from one center. Following a 2-week screening period, patients were randomized to either human fibroblast-derived dermis (HFDD) (Dermagraft) plus saline-moistened gauze or to the control group (CT) of saline-moistened gauze alone. Effectiveness end points were: 1) wound closure by week 12, 2) time to wound closure, and 3) percent wound closure by week 12. Safety was assessed by review of adverse events and laboratory findings. Patients randomized to HFDD received an application at day 0 and up to seven additional treatments. All patients in each group received shoes with custom-molded inserts and were seen weekly. The study population was comprised of 28 patients (14 HFDD/14 CT) with chronic ulcers (>6 weeks' duration at time of screening). By week 12, significantly more chronic ulcers healed in the HFDD group than in the CT group (71.4% versus 14.3%, p = .003). Healed HFDD patients achieved wound closure significantly faster than CT patients (p = .004). Patients treated with HFDD showed a statistically significant higher percent of wound closure by week 12 than did CT patients (p = .002). The percent of patients who experienced an infection involving their study wound was less in the HFDD group than in the CT group. It was concluded that HFDD is a safe and effective treatment for chronic foot ulcers in diabetic patients.

Healing of Chronic Foot Ulcers in Diabetic Patients Treated with a Human Fibroblast-Derived Dermis

A prospective, multicenter, randomized, controlled 12-week study was undertaken to evaluate the effectiveness of a human fibroblast-derived dermis for treating foot ulcers in the diabetic patient. This report summarizes the findings from one center. Following a 2-week screening period, patients were randomized to either human fibroblast-derived dermis (HFDD) (Dermagraft) plus saline-moistened gauze or to the control group (CT) of saline-moistened gauze alone. Effectiveness end points were: 1) wound closure by week 12, 2) time to wound closure, and 3) percent wound closure by week 12. Safety was assessed by review of adverse events and laboratory findings. Patients randomized to HFDD received an application at day 0 and up to seven additional treatments. All patients in each group received shoes with custom-molded inserts and were seen weekly. The study population was comprised of 28 patients (14 HFDD/14 CT) with chronic ulcers (>6 weeks' duration at time of screening). By week 12, significantly more chronic ulcers healed in the HFDD group than in the CT group (71.4% versus 14.3%, p = .003). Healed HFDD patients achieved wound closure significantly faster than CT patients (p = .004). Patients treated with HFDD showed a statistically significant higher percent of wound closure by week 12 than did CT patients (p = .002). The percent of patients who experienced an infection involving their study wound was less in the HFDD group than in the CT group. It was concluded that HFDD is a safe and effective treatment for chronic foot ulcers in diabetic patients.