epidermal-growth-factor and Diabetic-Foot

Epidermal growth factor (EGF) has been used in wound management and regenerative medicine since the late 1980s. It has been widely utilized for a long time and still is because of its excellent tolerability and efficacy. EGF has many applications in tissue engineering, cancer therapy, lung diseases, gastric ulcers, and wound healing. Nevertheless, its in vivo and during storage stability is a primary concern. This review focuses on the topical use of EGF, especially in chronic wound healing, the emerging use of biomaterials to deliver it, and future research possibilities. To successfully deliver EGF to wounds, a delivery system that is proteolytically resistant and stable over the long term is required. Biomaterials are an area of interest for the development of such systems. These systems may be used in non-healing wounds such as diabetic foot ulcers, pressure ulcers, and burns. In these pathologies, EGF can reduce the risk of amputation of the lower extremities, as it accelerates the wound healing process. Furthermore, appropriate delivery system would also stabilize and control the EGF release profile in a wound. Several in vitro and in vivo studies have already proven the efficacy of such systems in the above-mentioned types of wounds. Moreover, several formulations such as ointments and intralesional injections are already available on the market. However, these products are still problematic in terms of inadequate diffusion of EGF, low bioavailability storage conditions, and shelf-life. This review discusses the nano formulations comprising biomaterials infused with EGF which could be a promising delivery system for chronic wound healing in the future.

Topics: Diabetic Foot; Drug Delivery Systems; Epidermal Growth Factor; Humans; Veterans; Wound Healing

Topics: Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Randomized Controlled Trials as Topic; Wound Healing

To evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) in treating diabetic foot ulcers (DFUs), we conducted both database searches (PubMed, MEDLINE, EMBASE, CENTRAL, and Web of Science) and reference searches for randomised controlled trials from the inception of databases to 30 January 2020. Two reviewers independently scrutinised the trials, extracted data, and assessed the quality of trials. The primary outcome was the proportion of complete healing. The secondary outcomes were mean time to complete healing and adverse events. A subgroup analysis was performed by different administration routes. Statistical analyses were performed in RevMan 5.3. The time to complete healing Kaplan-Meier curves was pooled in the R software. Of the 156 citations, 9 trials (720 participants) met eligibility criteria and were included. The rhEGF achieved a higher complete healing rate than placebo (OR: 2.79, [95% CI: 1.99, 3.99]). The rhEGF also significantly shorten complete healing time (MD: -14.10 days, [95% CI: -18.03, -10.16]). Subgroup analysis showed that topical application was superior to intralesional injection, but that may be because of different ulcer severity they included. No significant difference was shown in adverse events. Results were coherent with sensitivity analyses. Therefore, rhEGF is an effective and safe treatment for DFUs.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Injections, Intralesional; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; Wound Healing

Diabetic foot ulcers (DFUs) are one the common complications of diabetes mellitus. Many trials were performed to evaluate the effect of recombinant human epidermal growth factor (rhEGF) in healing DFUs. This meta-analysis was performed to synthesize the evidence of rhEGF treatment in DFUs in comparison to placebo. Databases included for the search were PubMed, EMBASE, the Cochrane Library, Web of Science, EBSCOhost, ScienceDirect, and Scopus (up to January 2019). The outcome of interest was the complete healing rate of DFUs. We performed random effects meta-analysis stratified by the types of administration route (intralesional injection and topical apply) by calculating the odds ratios (OR) and 95% confidence interval (95% CI). A total of six studies involving 530 patients were eligible for analysis. The combined OR (intralesional injection and topical apply) was 4.005 (95% CI: (2.248; 7.135),

Topics: Diabetic Foot; Epidermal Growth Factor; Humans; Odds Ratio; Randomized Controlled Trials as Topic; Recombinant Proteins; Wound Healing

Foot ulcers affect 15% of patients with diabetes, resulting in a great health burden. The occurrence and development of diabetic foot ulcers is associated with neuropathy, peripheral arterial disease, and infection. Several growth factors are involved in these processes, including epidermal growth factor, vascular endothelial growth factor, transforming growth factor-beta, fibroblast growth factor, and erythropoietin, which could promote wound healing of patients with diabetes. Thus, this review discusses the role of these growth factors in the pathogenesis of diabetic foot ulcers, aiming to achieve novel insights into the management of diabetic foot ulcers.

Topics: Diabetic Foot; Diabetic Nephropathies; Epidermal Growth Factor; Erythropoietin; Humans; Intercellular Signaling Peptides and Proteins; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

Topical growth factors accelerate wound healing in patients with diabetic foot ulcers (DFU). Due to the absence of head-to-head comparisons, we carried out Bayesian network meta-analysis to compare the efficacy and safety of growth factors.. Using an appropriate search strategy, randomized controlled trials on topical growth factors compared with standard of care in patients with DFU, were included. Proportion of patients with complete healing was the primary outcome. Odds ratio (95% confidence interval) was used as the effect estimate and random effects model was used for both direct and indirect comparisons. Markov Chain Monte Carlo simulation was used to obtain pooled estimates. Rankogram was generated based on surface under the cumulative ranking curve (SUCRA).. A total of 26 studies with 2088 participants and 1018 events were included. The pooled estimates for recombinant epidermal growth factor (rhEGF), autologous platelet rich plasma (PRP), recombinant human platelet-derived growth factor (rhPDGF) were 5.72 [3.34, 10.37], 2.65 [1.60, 4.54] and 1.97 [1.54, 2.55] respectively. SUCRA for rhEGF was 0.95. Sensitivity analyses did not reveal significant changes from the pooled estimates and rankogram. No differences were observed in the overall risk of adverse events between the growth factors. However, the growth factors were observed to lower the risk of lower limb amputation compared to standard of care.. To conclude, rhEGF, rhPDGF and autologous PRP significantly improved the healing rate when used as adjuvants to standard of care, of which rhEGF may perform better than other growth factors. The strength of most of the outcomes assessed was low and the findings may not be applicable for DFU with infection or osteomyelitis. The findings of this study needs to be considered with caution as the results might change with findings from head-to-head studies.

Topics: Amputation, Surgical; Animals; Bayes Theorem; Diabetic Foot; Epidermal Growth Factor; Humans; Markov Chains; Monte Carlo Method; Platelet-Derived Growth Factor; Platelet-Rich Plasma; Randomized Controlled Trials as Topic; Recombinant Proteins; Wound Healing

Soon after epidermal growth factor (EGF) discovery, some

Topics: Administration, Topical; Cellular Microenvironment; Diabetic Foot; Epidermal Growth Factor; Humans; Receptor Protein-Tyrosine Kinases; Wound Healing

Diabetic foot ulceration is a major complication of diabetes mellitus. Recombinant human epidermal growth factor (rhEGF) is used topically in the treatment of diabetic foot ulcers. This meta-analysis was designed to evaluate if rhEGF increased the complete healing rate of diabetic foot compared with controls. We searched the MEDLINE, Cochrane Library, EMBASE, and Web of Knowledge databases (up to December 22, 2015). Studies were identified and selected, and data were extracted by 2 independent reviewers. A total of 4 randomized controlled trials including 294 patients were identified. The studies evaluated the rate of healing of diabetic foot that were treated with rhEGF or controls. On account of study heterogeneity, a random-effects model was performed, and the combined odds ratio (OR) indicated a significantly greater complete healing rate in patients treated with rhEGF compared to placebo. The ORs ranged from 1.66 to 14.64, with a combined OR of 4.36 (95% confidence interval = 1.48-12.81, P = .007). These results indicate that rhEGF is efficacious in the treatment of diabetic foot ulcers by increasing the rate of wound healing. These findings support the use of rhEGF in treating diabetic foot.

Topics: Administration, Topical; Anti-Ulcer Agents; Diabetic Foot; Epidermal Growth Factor; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome; Wound Healing

Because the chronic ulcer of the foot in diabetes is often unresponsive to standard care, there has been considerable interest in the potential benefit of so-called "advanced wound therapies"--many of which have a biological basis. This article summarizes the findings of earlier systematic reviews, together with the findings of more recent publications. The available evidence suggests that while some biological therapies offer promise, more work is needed to substantiate their role in clinical practice. This conclusion needs to be placed in the context of very strong observational data demonstrating the major improvements that can accompany changes to the way in which wound care is delivered with, in particular, the introduction of multidisciplinary team work and more rapid referral for expert assessment.

Topics: Becaplermin; Bioengineering; Cells, Cultured; Coculture Techniques; Collagen; Diabetic Foot; Epidermal Growth Factor; Fibroblast Growth Factor 2; Fibroblasts; Humans; Keratinocytes; Proto-Oncogene Proteins c-sis; Stem Cells; Tissue Expansion Devices

The diabetic population is increasing worldwide at a staggering rate. Diabetic foot ulcers are a major contributor to nontraumatic lower limb amputations and peripheral arterial disease is one of main contributing pathophysiologic causes of diabetic ulcers. The dire need to reduce complication and wound healing recovery period of the chronic ischemic diabetic foot (CIDF) is indispensable to limb salvage and improvement of quality of life of patients with CIDF. This article discusses newer modalities that have been proposed to improve CIDF efficiently, safely, and effectively either alone or as adjuvants to conventional therapy.

Topics: Cell- and Tissue-Based Therapy; Diabetic Foot; Epidermal Growth Factor; Fibrinolytic Agents; Granulocyte Colony-Stimulating Factor; Humans; Prostaglandins

Management of diabetic foot ulcers remains a rather challenging task. Epidermal growth factor (EGF) plays a central role in wound healing. It acts on epithelial cells and fibroblasts promoting restoration of damaged epithelium. However, its bioavailability is impaired in chronic diabetic foot ulcers. Current evidence suggests that application of human recombinant EGF in addition to standard treatment is able to achieve both partial and complete healing and to prevent foot amputations. Its efficacy has been tested at various concentrations and by various administration routes (topical application and intralesional injection). Intralesional injection has better availability on the deep wound layers, but pain at the injection site is a common complaint. Generally, adverse events have been minor to mild. Finally, numerous issues need to be further clarified before widespread use of EGF becomes possible in everyday practice. Such issues include optimal dosage and administration route, characteristics of the ulcers most likely to heal (severity and ischemic/neuropathic or both), and cost-effectiveness.

Topics: Adult; Aged; Diabetic Foot; Drug Administration Routes; Epidermal Growth Factor; Evidence-Based Medicine; Humans; Middle Aged; Recombinant Proteins; Risk Assessment; Time Factors; Treatment Outcome; Wound Healing; Young Adult

Assessment of the safety, efficacy and effectiveness of growth factors alone or in combination with other technologies in the treatment of DFU including medical, economical, social, ethical and juridical aspects.. We systematically searched relevant data bases limited to English and German language and publications since 1990. Review and assessment of the quality of publications followed methods conforming to widely accepted standards for evidence-based medicine and health economics.. We identified 25 studies comparing becaplermin, rhEGF, bFGF and the metabolically active skin grafts Dermagraft and Apligraf with standard wound care (SWC) alone or extracellular wound matrix. Study duration ranged from 12 to 20 weeks and the study population comprised between 17 and 382 patients. Treatment with becaplermin, rhEGF, Dermagraft and Apligraf resulted in a higher incidence of complete wound closure and shorter time to complete wound healing with statistically significant differences. Regarding the proportion of adverse events there was no difference between treatment groups. The methodological quality of the studies was affected by significant deficiencies. Economic evaluations showed becaplermin being cost-effective.. Add-on therapy with growth factors and active skin substitutes for treating uncomplicated DFU could be an alternative to SWC alone. For explicit recommendations further studies with stronger evidence are necessary.

Topics: Combined Modality Therapy; Diabetic Foot; Epidermal Growth Factor; Evidence-Based Medicine; Fibroblast Growth Factors; Humans; Platelet-Derived Growth Factor; Recombinant Proteins; Skin, Artificial; Technology Assessment, Biomedical

Repair machinery and local infection control failure contribute to wound chronicity and lower extremity amputation in diabetic patients. In these wounds, inflammation is a proximal condition which disrupts wound matrix turnover and the local redox balance. Contemporary therapeutic interventions are relatively broad including drugs, devices and surgical procedures. However, clinical efficacy remains modest and recurrences are frequent. Recombinant growth factors advent was followed by their premature and empiric introduction in the clinical practice. Its topical administration is still challenged by local kinetic and pharmacodynamic limitations related to the hostile microenvironment of chronic wounds. The rationale of infiltrating epidermal growth factor (EGF) down inside complex diabetic wounds as an alternative treatment modality is described here. The concept emerged from two experimental evidences: (a) locally infiltrated EGF prevented trophic ulcers and limb necrosis upon denervation, (b) acute, controlled experimental wounds' exudate exhibited proteolytic activity. Depositing EGF in deep cells' responsive strata allows for two main pharmacological actions indispensable for chronic wounds healing: cyto-protection and proliferation of fibroblasts and endothelial cells, thus inducing progressive granulation. Ten years of clinical experience have validated laboratory and theoretical concepts, while most importantly have improved quality-of-life to thousands of diabetic patients.

Topics: Administration, Topical; Animals; Diabetic Foot; Epidermal Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Treatment Outcome; Wound Healing

Chronic foot ulceration is a major source of morbidity in diabetic patients. Despite traditional comprehensive wound management, including vascular reconstruction, there remains a cohort of patients with non-responding wounds, often resulting in amputation. These wounds may benefit from molecular manipulation of growth factors to enhance the microcirculation.. A review of the current literature was performed using Pubmed, with secondary references obtained from key articles.. There has been a generally disappointing clinical outcome from growth factor trials, although topical platelet-derived growth factor has shown significant benefit and should be considered in non-healing, well perfused ulcers after failure of conventional wound care. The modulatory role of the extracellular matrix in the cellular response to growth factors and data from regenerative-type fetal wound healing are further areas of interest. The chemical induction of microvessel formation may become a future therapeutic option.

Topics: Diabetic Foot; Endothelial Growth Factors; Epidermal Growth Factor; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Granulocyte Colony-Stimulating Factor; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Lymphokines; Platelet-Derived Growth Factor; Risk Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Wound Healing

BACKGROUND The aim of this study was to analyze the clinical application of cortex phellodendri compound fluid (CPCF) in the treatment of diabetic foot ulcers. MATERIAL AND METHODS From January 2012 to December 2015, a total of 720 cases of diabetic foot ulcers (DFU) were randomly assigned into an experimental group (n=540) that was treated by CPCF and a control group (n=180) that was treated by a Kangfuxin solution (KFS). After 4 weeks of treatment, their ulcer area, serum growth factor, clinical total effective rate, and incidence of adverse events were assessed. RESULTS There were 720 patients who completed the trial. The experimental group was superior to the control group in reducing ulcer area, increasing growth factor content, and total effective rate (P<0.05). There was no significant difference in the adverse events rates between the 2 groups. CONCLUSIONS CPCF external treatment of diabetic foot ulcer can promote ulcer healing and increase the concentration of growth factors, and it is safe and reliable.

Topics: Administration, Cutaneous; Aged; Diabetic Foot; Drugs, Chinese Herbal; Epidermal Growth Factor; Female; Fibroblast Growth Factors; Humans; Male; Materia Medica; Middle Aged; Phellodendron; Phytotherapy; Treatment Outcome; Vascular Endothelial Growth Factor A; Wound Healing

This study was conducted to evaluate the efficacy and safety of a novel spray-applied growth factor therapy containing recombinant human epidermal growth factor (rhEGF) for the treatment of chronic diabetic foot ulcers (DFU).. This study was a phase III double-blind, randomized, placebo-controlled trial. 167 adult patients at six medical centers were randomized to receive routine wound care plus either topical spray treatment with 0.005% rhEGF (n = 82) or an equivalent volume of saline spray (n = 85) twice a day until ulcer healing or for up to 12 weeks.. Demographics, medical status, and wound characteristics were comparable between rhEGF and placebo groups. More patients in the rhEGF group significantly had complete wound healing compared to placebo (73.2% versus 50.6%, respectively; P = .001). Wound healing velocity was faster in the rhEGF group (P = .029) regardless of HbA1c levels. The rhEGF group had a shorter median time to 50% ulcer size reduction (21 versus 35 days; hazard ratio = 3.13, P < .001) and shorter time to complete ulcer healing (56 versus 84 days; hazard ratio = 2.13, P < .001).. This study confirms that application of spray-applied rhEGF in DFU patients results in faster healing velocity and higher complete healing rate regardless of HbA1c levels.

Topics: Administration, Topical; Adult; Aged; Diabetic Foot; Double-Blind Method; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Prospective Studies; Treatment Outcome; Ulcer; Wound Healing

Lipoic acid (LA) and hyperbaric oxygenation therapy (HBOT) improve chronic wound healing.. We compared the effects of LA or its enantiomer R-(+)-lipoic acid (RLA) on wound healing.. Groups LA + HBOT (L), RLA + HBOT (R) and placebo + HBOT (P). Lesion areas measured before treatment and on 20th and 40th day. The biopsies and plasma were harvested before treatment and on 7th and 14th (measurements of VEGF, vascular endothelial growth factor; EGF, epidermal growth factor, TNF-α and IL-6).. Ulcers improved more on RLA. In both L and R groups, EGF and VEFG increased in time. RLA decreased IL-6 on T7 and T14, which did not happen with LA. TNF-α levels decreased on T14 in both LA and RLA.. The improved wound healing is associated with increased EGF and VEGF and reduced plasma TNF-α and IL-6.. RLA may be more effective than LA in improving chronic wound healing in patients undergoing HBO therapy.

Topics: Aged; Aged, 80 and over; Antioxidants; Chronic Disease; Combined Modality Therapy; Diabetic Foot; Double-Blind Method; Epidermal Growth Factor; Female; Humans; Hyperbaric Oxygenation; Interleukin-6; Male; Middle Aged; Stereoisomerism; Thioctic Acid; Tumor Necrosis Factor-alpha; Wound Healing

To determine if partial wound closure surrogate markers proposed for neuropathic, small diabetic foot ulcers (DFUs) can be extended to advanced lesions and if the development of granulation tissue can be used to predict complete healing.. Data from two multicenter, double-blind, randomized clinical trials (one of them placebo controlled) that used intralesional recombinant human epidermal growth factor (rhEGF) to promote granulation and healing were used. For confirmation in a larger sample from common clinical practice, the results of an active postmarketing surveillance of rhEGF treatment of DFUs in 60 healthcare units was included. The surrogates evaluated were percent area change, log healing rate, ratio of log areas, and percent of granulation tissue covering the wound area. The tests used were surrogate final end point correlation, receiver operating characteristic curves to discriminate healers from nonhealers, validation tests using logistic regression models, and the proportion-mediated estimation.. Two weeks >50% granulation, end of treatment >75% granulation, and 16.1% area change showed significant predictive value (>70% correct classification) for final wound closure. The granulation-based variables fulfilled the criterion that the effect of rhEGF treatment on wound closure was mediated by the surrogate.. This work provides the first evidence for the use of granulation tissue development as a predictor of wound healing in advanced DFUs. These results can be useful for clinical trial design, particularly during the exploratory phase of new products.

Topics: Aged; Diabetic Foot; Double-Blind Method; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Treatment Outcome; Wound Healing

This study investigated the molecular changes of extracorporeal shockwave therapy (ESWT) and hyperbaric oxygen therapy (HBOT) in chronic diabetic foot ulcers.. A cohort study consisted of 39 patients (44 ulcers) in the ESWT group and 38 patients (40 ulcers) in the HBOT group with similar demographic characteristics. The ESWT group received shockwave therapy twice per week for total six treatments. The HBOT group received hyperbaric oxygen therapy daily for total 20 treatments. Biopsy was performed from the periphery of the ulcer before and after treatment. The specimens were immuno-stained, and the positive immuno-activities of vWF, VEGF, eNOS, PCNA, EGF and TUNEL expressions were examined and quantified microscopically.. Significant increases in vWF, VEGF, eNOS, PCNA and EGF expressions and a decrease in TUNEL expression were noted after ESWT (P<0.05), whereas the changes after HBOT were statistically not significant (P>0.05). The differences of vWF, VEGF, eNOS, PCNA, EGF and TUNEL expressions between the two groups were comparable before treatment (P>0.05), however, the differences became statistically significant after treatment (P<0.05) favoring the ESWT group.. ESWT showed significant increases in angiogenesis and tissue regeneration over HBOT in diabetic foot ulcers.

Topics: Diabetic Foot; Epidermal Growth Factor; Female; Humans; Hyperbaric Oxygenation; Immunohistochemistry; Male; Proliferating Cell Nuclear Antigen; Vascular Endothelial Growth Factor A; von Willebrand Factor

Previous studies have shown that an epidermal growth factor-based formulation (Heberprot-P) can enhance granulation of high-grade diabetic foot ulcers (DFU). The aim of this study was to explore the clinical effects of this administration up to complete wound closure. A pilot study in 20 diabetic patients with full-thickness lower extremity ulcers of more than 4 weeks of evolution was performed. Mean ulcer size was 16.3 +/- 21.3 cm(2). Intralesional injections of 75 microg of Heberprot-P three times per week were given up to complete wound healing. Full granulation response was achieved in all 20 patients in 23.6 +/- 3.8 days. Complete wound closure was obtained in 17 (85%) cases in 44.3 +/- 8.9 days. Amputation was not necessary in any case and only one relapse was notified. The most frequent adverse events were tremors, chills, pain and odour at site of administration and local infection. The therapeutic scheme of intralesional Heberprot-P administration up to complete closure can be safe and suitable to improve the therapeutic goal in terms of healing of chronic DFU.

Topics: Aged; Diabetic Foot; Dosage Forms; Drug Administration Schedule; Epidermal Growth Factor; Female; Follow-Up Studies; Humans; Injections, Intralesional; Male; Middle Aged; Pilot Projects; Treatment Outcome; Wound Healing

To evaluate the efficacy and safety of recombinant human epidermal growth factor (rh-EGF) in healing foot ulcers in diabetic patients.. A total of 28 subjects with foot ulcers were recruited into the pilot study. Patients who had obvious peripheral arterial disease, trans-tibial amputation, plastic surgery or skin flap, and skin graft were excluded. The properly debrided wounds and the non closure wounds after toe amputation were included. When the wounds became clean or uninfected, they received twice-a-day treatment with 0.005% Easyef and hydrocolloid dressing. The size and severity of the wounds were evaluated. Others such as blood sugar, renal and hepatic function, serum albumin, vascular condition, foot infection or osteomyelitis were assessed.. All of 28 patients had positive response of granulation (100%). Complete healing was noted in 13 out of 23 subjects and finished 8-week follow-up (56.5%). The rates of wound closure were 43.3%, 59.9%, 68.7%, and 84.8% in week 2, 4, 6 and 8, respectively, regardless of the severity. Being dropped out, three patients needed further interventions. No skin allergic reaction. Over-granulation was observed in one female patient (3.7%), but as minor.. Easyef has positive effects on healing of moderate-to-severe foot ulcers and demonstrated being safe to diabetic patients. The drug had high tolerability and compliance.

Topics: Administration, Topical; Aged; Debridement; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Pilot Projects; Recombinant Proteins; Wound Healing

A multicenter, double-blind, placebo-controlled trial was carried out to evaluate the intra-lesional infiltration of recombinant epidermal growth factor (EGF) in Wagner's grade 3 or 4 diabetic foot ulcers (DFUs). Subjects (149) were randomised to receive EGF (75 or 25 microg) or placebo, three times per week for 8 weeks and standard good wound care. The main endpoint was granulation tissue covering > or = 50% of the ulcer at 2 weeks. It was achieved by 19/48 controls versus 44/53 in the 75 microg group [odds ratio (OR): 7.5; 95% confidence interval (CI): 2.9-18.9] and 34/48 in the 25 microg group (OR: 3.7; 1.6-8.7). Secondary outcome variables such as end-of-treatment complete granulation response (28/48 controls, 46/53 with 75 microg and 34/48 with 25 microg EGF), time-to-complete response (controls: 5 weeks; both EGF dose groups: 3 weeks), and wound closure after follow-up (25/48 controls, 40/53 with 75 microg and 25/48 with 25 microg EGF) were also treatment dependent. Multivariate analyses yielded that they were significantly enhanced by 75 microg EGF treatment and neuropathic versus ischemic ulcers. Most adverse events were mild and no drug-related severe adverse reactions were reported. It was concluded that recombinant human EGF (rhEGF) local injections offer a favourable risk-benefit balance in patients with advanced DFU.

Topics: Aged; Diabetic Foot; Dose-Response Relationship, Drug; Double-Blind Method; Epidermal Growth Factor; Female; Follow-Up Studies; Granulation Tissue; Humans; Injections, Intralesional; Male; Middle Aged; Recombinant Proteins; Treatment Outcome; Wound Healing

To investigate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) in advanced diabetic foot ulcers (DFU) A double-blind trial was carried out to test two rhEGF dose levels in type 1 or 2 diabetes patients with Wagner's grade 3 or 4 ulcers, with high risk of amputation. Subjects were randomised to receive 75 (group I) or 25 mug (group II) rhEGF through intralesional injections, three times per week for 5-8 weeks together with standardised good wound care. Endpoints were granulation tissue formation, complete healing and need of amputation. Safety was assessed by clinical adverse events (AEs) and laboratory evaluations. Forty-one patients were included. After 5-8 weeks of treatment, 83% patients in the higher dose group and 61% in group II achieved useful granulation tissue covering more than 98% of the wound area. At long-term assessment, 13 (56.5%) patients healed in group I and 9 (50%) in group II. The mean time to complete healing in group I was 20.6 weeks (95% CI: 17.0-24.2) and 19.5 weeks (16.3-22.7) in group II. After 1-year follow-up, only one patient relapsed. Amputation was not necessary in 65% and 66.7% of groups I and II, respectively. The AEs rates were similar. The most frequent were sepsis (33%), burning sensation (29%), tremors, chills and local pain (25% each). rhEGF local injection enhances advanced DFU healing and reduces the risk of major amputation. No dose dependency was observed.

Topics: Adult; Aged; Amputation, Surgical; Analysis of Variance; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Foot; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epidermal Growth Factor; Female; Follow-Up Studies; Granulation Tissue; Humans; Injections, Intralesional; Male; Middle Aged; Probability; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Treatment Outcome; Wound Healing

This paper studies the healing effect of recombinant human epidermal growth factor (EGF) on chronic diabetic foot ulcers. A total of 89 patients (65 male and 24 female) aged from 36 to 82 years (average of 54) enrolled for the prospective, open-label trial, crossover study. Predetermined criteria were used for diagnosis and classification of ulcer. The average duration of ulcer was 6 months (range from 3 to 27 months) prior to study. Upon study, the ulcers were debrided and treated with hydrocolloid or composite dressing depending on the condition of the wound. If treatment effect was minimal using advanced dressing for 3 weeks, patients were crossed over to twice-a-day treatment with 0.005% EGF and advanced dressing. Among the patients, 21 patients showed improvement using hydrocolloid or composite dressing alone and 68 patients were crossed over to treatment with EGF and advanced dressing. In the EGF-treated patients, complete healing was noted in 52 patients within an average of 46 days (range from 2 to 14 weeks). Recurrence was not noted during the 6-month observation. But 5 patients showed new lesions different from the prior site. Sixteen patients required further interventions. This paper suggests that topical treatment with EGF combined with advanced dressing may have positive effects in promoting healing of chronic diabetic foot wounds.

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Cross-Over Studies; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Prospective Studies; Wound Healing

To study the healing effect of recombinant human epidermal growth factor (hEGF) on diabetic foot ulcers.. A total of 127 consecutive patients were screened and 61 diabetic subjects were recruited into this double-blind randomized controlled study. Predetermined criteria were used for diagnosis and classification of the diabetic wound. The patients were randomized into three groups. All patients attended our Diabetes Ambulatory Care Center every other week for joint consultation with the diabetologist and the podiatrist. Group 1 (control) was treated with Actovegin 5% cream (Actovegin), group 2 with Actovegin plus 0.02% (wt/wt) hEGF, and group 3 with Actovegin plus 0.04% (wt/wt) hEGF. The study end point was the complete closure of the wound. Failure to heal was arbitrarily defined as incomplete healing after 12 weeks.. Final data were obtained from 61 patients randomly assigned into three groups. The mean ages of the patients, wound sizes, wound duration, metabolic measurements, and comorbidities were comparable within groups, except that group 3 had more female patients. Mean follow-up for the patients was 24 weeks. Data were cutoff at 12 weeks, and results were analyzed by intention to treat. After 12 weeks, in group 1 (control) eight patients had complete healing, two patients underwent toe amputation, and nine had nonhealing ulcers. In group 2 (0.02% [wt/wt] hEGF) 12 patients experienced wound healing, 2 had toe amputations, and 7 had nonhealing ulcers. Some 20 of 21 patients in group 3 (0.04% [wt/wt] hEGF) showed complete wound healing. Healing rates were 42.10, 57.14, and 95% for the control, 0.02% (wt/wt) hEGF, and 0.04% (wt/wt) hEGF groups, respectively. Kaplan-Meier survival analysis suggested that application of cream with 0.04% (wt/wt) hEGF caused more ulcers to heal by 12 weeks and increased the rate of healing compared with the other treatments (log-rank test, P = 0.0003).. Our data support the contention that application of hEGF-containing cream, in addition to good foot care from a multidisciplinary team, significantly enhances diabetic foot ulcer wound healing and reduces the healing time.

Topics: Age of Onset; Aged; Diabetic Foot; Double-Blind Method; Epidermal Growth Factor; Female; Foot Ulcer; Humans; Male; Middle Aged; Placebos; Recombinant Proteins; Time Factors; Wound Healing

Advanced modalities are used for wounds where conventional treatment is insufficient in diabetic foot patients. In this study, we investigated the effects of using Epidermal growth factor (EGF) and NPWTmodalities alone or in combination on the frequency and level of amputation. In the retrospective study, which included 286 patients in total, 76 patients were referred with the decision of amputation or amputation was planned during hospitalization. After the treatments, amputation and distalization of amputation were found 73.3% and 33.3% in the conventional treatment patients. While 86.4% amp and 18.2% amp distalization were found in negative pressure wound therapy (NPWT) only patients, this rate was 52.4% and 90.5% in EGF + NPWT patients, 50% and 83.3% in EGF only patients. While amp and distalization rates were found to be significantly better in those receiving only EGF or EGF + NPWT (

Topics: Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Negative-Pressure Wound Therapy; Retrospective Studies; Wound Healing

The aim of this study is to analyze the application effect of traditional Chinese medicine (TCM) comprehensive nursing in diabetic foot patients.. 230 patients with diabetic foot admitted to Third people's Hospital of Haikou from January 2019 to April 2022 were classified as two groups, which consisted of a control group (n = 95) and an experimental group (n = 135). The control group took routine nursing intervention, while the experimental group took TCM comprehensive nursing intervention. The effect of intervention was compared by inflammatory factors (B-FGF, EGF, VEGF, and PDGF), wound area, self-rated anxiety scale (SAS), and self-rated depression scale (SDS).. After nursing, the levels of B-FGF, EGF, VEGF, and PDGF were higher in the experimental group (all p < 0.05). The total effective rate of diabetic foot recovery in the experimental group was 94.87% (74/78), higher than 87.67% (64/73) in the control group (p = 0.026). After nursing, the scores of SAS and SDS in the experimental group were lower than those in the control group (all p < 0.05).. The application of TCM comprehensive nursing in diabetic foot patients can greatly change the levels of B-FGF, EGF, VEGF, and PDGF in wound tissue, promote the healing of ulcer surface, improve patients' anxiety and depression, and enhance the quality of life of patients.

Topics: Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Medicine, Chinese Traditional; Quality of Life; Vascular Endothelial Growth Factor A

Diabetic foot ulcers (DFUs) cause high morbidity and mortality despite best treatment. Thus, new products are urgently needed to treat DFUs. Intralesional epidermal growth factor (EGF) (Heberprot-p) is considered to be an adjuvant therapy to standard of care (SOC) in DFUs. In the present study, the effect of Heberprot-p treatment on wound healing is compared to standard treatment.. The data of patients with DFUs were retrospectively analysed. The patients who had had DFUs of at least four weeks' duration and who had been treated in the wound clinic between January 2014 and 2017 were included in the study. The patients were divided into study and control groups. The study group consisted of patients in whom intralesional recombinant human EGF, Heberprot-p 75μg, was applied; the control group consisted of the remaining patients in whom EGF was not applied. The efficacy of Heberprot-p treatment in Wagner 2 and 3 DFUs were retrospectively investigated.. The study group (n=29 patients) who received Heberprot-p treatment was found to have shorter treatment times and higher rates of wound healing than the control group (n=22 patients). Although the amputation rate in the study group was less than the control group, the difference was not statistically significant.. Heberprot-p therapy is a promising treatment in DFUs, which can be routinely used as an adjunct to standard care.

Topics: Amputation, Surgical; Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Retrospective Studies; Treatment Outcome; Wound Healing

Diabetic foot ulcers (DFU) are a common complication of Type 2 Diabetes Mellitus (T2DM). Development of bioactive wound healing covers is an important task in medicine. The use of autologous platelet-rich plasma (PRP) consisting of growth factors, cytokines and components of extracellular matrix is a perspective approach for DFU treatment, but we previously found that some T2DM PRP samples have a toxic effect on mesenchymal stem cells (MSCs) in vitro. Here, we covalently immobilized T2DM PRP proteins on polycaprolactone (PCL) nanofibers, and the growth of endothelial cells on the PCL-COOH-PRP was investigated. Additionally, the level of NO reflecting the cytotoxic effects of PRP, angiogenin, and VEGF levels were measured in T2DM PRP samples. The results showed that the application of PCL-COOH-PRP nanofibers allows to remove the cytotoxicity of T2DM PRP and to improve endothelial cell adhesion and proliferative activity. We showed that the origin of T2DM PRP (the level of PRP toxicity or presence/absence of DFU) does not influence the efficiency of cell growth on PCL-COOH-PRP, and on the level of angiogenin, vascular epidermal growth factor (VEGF) in PRP itself.

Topics: Cell Proliferation; Diabetes Mellitus, Type 2; Diabetic Foot; Endothelial Cells; Epidermal Growth Factor; Humans; Nanofibers; Platelet-Rich Plasma; Vascular Endothelial Growth Factor A

Diabetic foot ulcer (DFU) is a common diabetic complication associated with disability and reduced quality of life. Available therapeutics are not sufficient to combat the spread of DFU. Here we aim to investigate the impact of alagebrium, an advanced glycation end product (AGE)-crosslink breaker, on the healing of DFU.. Diabetes was induced in Wistar rats by STZ, and after four weeks, wound was induced on the foot. Alagebrium (10 mg/kg) was administered orally for 14 days, and wound size was measured every 3 days. Behavioral tests i.e., hot plate and footprint tests, were performed to assess sensory function and gait. Blood was collected to assess HbA1c, serum AGEs, MDA and NOX1. Tissue was collected to assess histological changes and expression of NF-κB, iNOS, TNF-α, VEGF and EGF. In a subsequent set of experiments with similar design, alagebrium was applied topically as a film-forming gel.. Systemic alagebrium treatment accelerated the healing of diabetic wound, improved sensory functions and gait, and ameliorated histological changes. It also reduced serum levels of AGEs, MDA and NOX1, and the tissue expression of NF-κB, iNOS, TNF-α, and increased VEGF and EGF in diabetic rats. Topical alagebrium led to similar beneficial effects i.e., accelerated diabetic wound healing, improved wound histological changes, reduced expression of NF-κB and iNOS and increased VEGF.. Our findings suggest repurposing of alagebrium for the management of DFU to accelerate the healing process and improve the clinical outcomes in diabetic patients.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Foot; Epidermal Growth Factor; Glycation End Products, Advanced; Humans; NADPH Oxidase 1; NF-kappa B; Quality of Life; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Wound Healing

To determine the role of the intralesional recombinant epidermal growth factor (rEGF) in the healing and prevention of extremity amputation in advanced diabetic foot ulcer patients.. Observational study.. Department of Cardiovascular Surgery, Duzce State Hospital, Duzce, Turkey, between November 2018 and September 2019.. A total of 58 patients with diabetic foot ulcers that were treated at the study place were enrolled. The lesions were graded with Wagner Classification System. EGF (75 microg of Heberprot-P) vials were stored at +4°C and cold-chain requirements were followed. EGF 5 mL was dissolved with 0.09% saline solution; and 0.5-1 ml of the solution was injected into the tissues and edge of the lesions regularly. The data was evaluated at the end of two years of the treatment period. The primary objective was wound healing, formation of granulation tissue; and the secondary objective was the prevention of lower extremity amputation.. Diabetic foot ulcers wound healing was achieved in 93.1% (n=54) of patients with the formation of granulation tissue. The complete recovery was observed in 94.1% (n=32) of the patients who had Grade III and IV lesions. Lower extremity amputation was performed in two (3.4%) subjects. The lesions of two patients required flap surgery. The most common adverse events were tremor and syncope.. Recombinant epidermal growth factor is highly effective for the treatment of diabetic foot ulcers and prevention of extremity amputation. Intralesional rEGf provides efficient and safe wound healing/closure in patients with diabetic foot ulcers. Key Words: Amputation, Epidermal growth factor, Diabetic foot, Wound healing.

Topics: Amputation, Surgical; Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Turkey; Wound Healing

Treatment of diabetic foot ulcer (DFU) is of great challenge as it is shown to be infected by multidrug resistant bacteria (MDR bacteria). Sixty four bacterial isolates were isolated from DFU cases; antibiotic susceptibility tests were carried out for all of them. One bacterial isolate (number 11) was shown to resist the action of 8 out of 12 antibiotics used and was identified by both a Vitek-2 system and 16S rRNA fingerprints as belonging to

Topics: Animals; Anti-Bacterial Agents; Bacteria; bcl-2-Associated X Protein; Diabetes Mellitus, Experimental; Diabetic Foot; Drug Resistance, Bacterial; Epidermal Growth Factor; Plant Extracts; Rats; Rats, Sprague-Dawley; RNA, Ribosomal, 16S; Streptozocin; Syzygium; Wound Healing

To investigate the effect of transverse tibial bone transport on the treatment of Wagner Stage 4 diabetic foot.. From January 2017 to October 2019, a total of 19 patients with Wagner Stage 4 diabetic foot ulcers were recruited. All patients were treated with transverse tibial bone transport. A detailed follow-up was carried out at 1 week, 1 month, 3 months, 6 months, and 1 year after surgery. The wound healing rate and the limb salvage rate at 1 year after the surgery were evaluated. Preoperative and 3-month postoperative digital subtraction angiography (DSA) were obtained. The level of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) before surgery and on 1st, 4th, 11th, 18th, 28. The wound healing rate and the limb salvage rate were both 94.74% in the patients at 1 year after the surgery. DSA showed the thickening of the calf and foot arteries, clear visualization, and a rich vascular network. The levels of VEGF, bFGF, and PDGF on the 11th, 18th, 28. Transverse tibial bone transport can improve the blood circulation of the affected limbs, promote the healing of diabetic foot wounds, and reduce the amputation rate of the affected limbs. Transverse tibial bone transport can promote the healing of Wagner Stage 4 diabetic foot.

Topics: Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Fibroblast Growth Factor 2; Humans; Osteogenesis, Distraction; Platelet-Derived Growth Factor; Treatment Outcome; Vascular Endothelial Growth Factor A

Diabetic foot ulcer (DFU) is a serious health problem. Major amputation increases the risk of mortality in patients with DFU; therefore, treatment methods other than major amputation come to the fore for these patients. Graft applications create an appropriate environment for the reproduction of epithelial cells. Similarly, epidermal growth factor (EGF) also stimulates epithelization and increases epidermis formation. In this study, we aimed to compare patients with DFU treated with EGF and those treated with a split-thickness skin graft.. Patients who were treated for DFU in the general surgery clinic were included in the study. The patients were evaluated retrospectively according to their demographic characteristics, wound characteristics, duration of treatment, and treatment modalities.. There were 26 patients in the EGF group and 21 patients in the graft group. The mean duration of treatment was 7 weeks (4-8 weeks) in the EGF group and 5.3 weeks (4-8 weeks) in the graft group (P < .05). In the EGF group, wound healing could not be achieved in one patient during the study period. In the graft group, no recovery was achieved in three patients (14.2%) in the donor site. Graft loss was detected in four patients (19%), and partial graft loss was observed in three patients (14.2%). The DFU of these patients were on the soles (85.7%). These patients have multiple comorbidities.. EGF application may be preferred to avoid graft complications in the graft area and the donor site, especially in elderly patients with multiple comorbidities and wounds on the soles.

Topics: Aged; Amputation, Surgical; Diabetes Mellitus; Diabetic Foot; Epidermal Growth Factor; Humans; Retrospective Studies; Skin Transplantation

Lower-extremity diabetic ulcers are responsible for 80% of annual worldwide nontraumatic amputations. Epidermal growth factor (EGF) reduction is one of the molecular pillars of diabetic ulcer chronicity, thus EGF administration may be considered a type of replacement therapy. Topical EGF ad-ministration to improve and speed wound healing began in 1989 on burn patients as part of an acute-healing therapy. Further clinical studies based on topically administering EGF to different chronic wounds resulted in disappointing out-comes. An analysis of the literature on unsuccessful clinical trials identifi ed a lack of knowledge concerning: (I) molecular and cellular foundations of wound chronicity and (II) the phar-macodynamic requisites governing EGF interaction with its receptor to promote cell response. Yet, EGF intra- and perile-sional infi ltration were shown to circumvent the pharmacody-namic limitations of topical application. Since the fi rst studies, the following decades of basic and clinical research on EGF therapy for problem wounds have shed light on potential uses of growth factors in regenerative medicine. EGF's molecular and biochemical effects at both local and systemic levels are diverse: (1) downregulation of genes encoding infl ammation mediators and increased expression of genes involved in cell proliferation, angiogenesis and matrix secretion; (2) EGF in-tervention positively impacts both mesenchymal and epithelial cells, reducing infl ammation and stimulating the recruitment of precursor circulating cells that promote the formation of new blood vessels; (3) at the subcellular level, upregulation of the EGF receptor with subsequent intracellular traffi cking, includ-ing mitochondrial allocation along with restored morphology of multiple organelles; and (4) local EGF infi ltration resulting in a systemic, organismal repercussion, thus contributing to attenuation of circulating infl ammatory and catabolic reac-tants, restored reduction-oxidation balance, and decreased toxic glycation products and soluble apoptogenic effectors. It is likely that EGF treatment may rearrange critical epigenetic drivers of diabetic metabolic memory. KEYWORDS Epidermal Growth Factor, diabetes, diabetes complications, wound healing, diabetic foot, amputation, ulcer, Cuba.

Topics: Biomarkers; Cuba; Diabetic Foot; Epidermal Growth Factor; Gene Expression; Humans; Wound Healing

Diabetic foot ulcer is one of the most frightened diabetic complications leading to amputation disability and early mortality. Diabetic wounds exhibit a complex networking of inflammatory cytokines, local proteases, and reactive oxygen and nitrogen species as a pathogenic polymicrobial biofilm, overall contributing to wound chronification and host homeostasis imbalance. Intralesional infiltration of epidermal growth factor (EGF) has emerged as a therapeutic alternative to diabetic wound healing, reaching responsive cells while avoiding the deleterious effect of proteases and the biofilm on the wound's surface. The present study shows that intralesional therapy with EGF is associated with the systemic attenuation of pro-inflammatory markers along with redox balance recovery. A total of 11 diabetic patients with neuropathic foot ulcers were studied before and 3 weeks after starting EGF treatment. Evaluations comprised plasma levels of pro-inflammatory, redox balance, and glycation markers. Pro-inflammatory markers such as erythrosedimentation rate, C-reactive protein, interleukin-6, soluble FAS, and macrophage inflammatory protein 1-alpha were significantly reduced by EGF therapy. Oxidative capacity, nitrite/nitrate ratio, and pentosidine were also reduced, while soluble receptor for advanced glycation end-products significantly increased. Overall, our results indicate that the local intralesional infiltration of EGF translates in systemic anti-inflammatory and antioxidant effects, as in attenuation of the glycation products' negative effects.

Topics: Aged; Arginine; Biomarkers; Blood Sedimentation; C-Reactive Protein; Chemokine CCL3; Cytokines; Diabetic Foot; Epidermal Growth Factor; fas Receptor; Female; Humans; Injections, Intralesional; Lysine; Male; Middle Aged; Nitrates; Nitrites; Receptor for Advanced Glycation End Products; Recombinant Proteins; Wound Healing

Epidermal growth factor is used as an adjuvant to close the wound in addition to standard care in diabetic foot ulcers. This study aimed to investigate the long-term outcomes after intralesional epidermal growth factor injections in the treatment of diabetic foot ulcers. Thirty-six feet of 34 patients (n = 34) with diabetic foot ulcers were included. Patient demographics, Wagner classifications, recurrence and amputation rates, Foot Function Index, Short Form 36, and American Academy of Orthopedic Surgeons Foot and Ankle Module scores were evaluated at the final follow-up examination. The mean age was 61.000 ± 13.743 years. The mean duration of wounds was 240.200 ± 146.385 days. A mean of 18.125 ± 4.494 (range 9 to 24) doses were applied. Wound closure was achieved in 33 of the 36 (91.7%) lesions. A complete response (granulation tissue >75% or wound closure) was observed in 29 (87.9%) lesions. The mean time to wound closure was 52.08 ± 10.65 (range 25 to 72) days. At the 5-year follow-up, 4 patients were lost to follow-up because of exitus owing to diabetic complications. Of the remaining 29 patients, 27 were ulcer free. In 2 patients (2 lesions, 6.9%) toe amputation was performed due to ischemic necrosis. The mean Foot Function Index, American Academy of Orthopedic Surgeons Foot and Ankle Core Scale, and AAOS Shoe Comfort Scale scores were 55.40 ± 12.15, 65.92 ± 17.56, and 56.42 ± 11.98, respectively. Complete wound healing and a low recurrence and amputation rates could be obtained with intralesional epidermal growth factor added to the standard treatment protocol.

Topics: Aged; Cohort Studies; Diabetic Foot; Epidermal Growth Factor; Female; Follow-Up Studies; Humans; Injections, Intralesional; Male; Middle Aged; Quality of Life; Retrospective Studies; Severity of Illness Index; Skin Transplantation; Time Factors; Treatment Outcome; Wound Healing

Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic foot ulcer (DFU) treatment due to its antimicrobial effect, increased angiogenesis and enhanced collagen synthesis. The molecular mechanism underlying HBO therapy particularly the involvement of Nrf2 in the wound healing process was investigated in the present study. In addition, we have studied the levels of angiogenic markers in ulcer tissues and their correlation with Nrf2 during HBO therapy compared with standard therapy (Non-HBO) for DFU. A total of 32 Patients were recruited and randomized to standard wound care procedure alone (n = 17) or HBO therapy in combination with standard wound care procedure (n = 15) for 20 days. Our results showed that the tissue levels of Nrf2 along with its downstream targets were significantly increased in patients who underwent HBO therapy when compared to Non-HBO therapy. Further, HBO therapy induced angiogenesis as assessed by increased levels of angiogenesis markers such as EGF, VEGF, PDGF, FGF-2 and CXCL10 in the tissue samples. The expressions of eNOS and nitrite concentrations were also significantly increased in HBO therapy when compared to Non-HBO therapy subjects. Moreover, HBO therapy sensitises the macrophages to release FGF-2 and EGF thereby promotes angiogenesis. Further, it increased the levels of neutrophil attractant CXCL-8 thereby promotes the release of chemokine CCL2, a well-known mediator of neovascularization. The Pearson correlation showed that Nrf2 has a positive correlation with EGF, VEGF and PDGF. In conclusion, the findings of the present study suggest that HBO therapy promotes wound healing by increasing oxygen supply and distribution to damaged tissues, stimulating angiogenesis, decreasing inflammation, and increasing the nitrite levels. Increased levels of Nrf2 transiently regulate the expression of angiogenic genes in wound biopsies, which may result in accelerated healing of chronic wounds.

Topics: Aged; Biomarkers; Chemokine CCL2; Chemokine CXCL10; Diabetic Foot; Epidermal Growth Factor; Female; Fibroblast Growth Factor 2; Gene Expression Regulation; Humans; Hyperbaric Oxygenation; Interleukin-8; Macrophages; Male; Middle Aged; Neovascularization, Physiologic; NF-E2-Related Factor 2; Nitric Oxide Synthase Type III; Nitrites; Organ Specificity; Oxygen; Platelet-Derived Growth Factor; Vascular Endothelial Growth Factor A; Wound Healing

The proteolytic microenvironment in the wound area reduces the stability and the half-life of growth factors in vivo, making difficult the topical delivery of growth factors. Here, epidermal growth factor (EGF) was conjugated to hyaluronate (HA) to improve the long-term stability against enzymatic degradation and the therapeutic effect by enhancing the biological interaction with HA receptors on skin cells. After the synthesis of HA-EGF conjugates, they were incorporated into a patch-type formulation for the facile topical application and sustained release of EGF. According to ELISA, the HA-EGF conjugates showed a long-term stability compared with native EGF. Furthermore, HA-EGF conjugates appeared to interact with skin cells through two types of HA and EGF receptors, resulting in a synergistically improved healing effect. Taken together, we could confirm the feasibility of HA-EGF conjugates for the transdermal treatment of chronic wounds.

Topics: Administration, Topical; Animals; Cell Line; Diabetes Mellitus, Experimental; Diabetic Foot; Drug Liberation; Drug Synergism; Epidermal Growth Factor; Humans; Hyaluronic Acid; Rats; Skin; Transdermal Patch; Wound Healing

NTRODUCTION Diabetic foot ulcers are a chronic complication in patients with diabetes mellitus. They appear as a result of the combination of diabetic polyneuropathy and angiopathy, and in many cases require amputation of the affected extremity. Clinical trials have demonstrated that repeated local infiltration with Heberprot-P can improve healing of chronic diabetic foot ulcers. Although there is evidence of its effects as a granulation stimulator and on cell migration and proliferation, genetic control mechanisms explaining its anti-inflammatory and oxidative stress reduction properties are not yet thoroughly understood. OBJECTIVE Analyze changes in expression of genes involved in healing after treatment of diabetic foot ulcers with Heberprot-P. METHODS Biopsies were collected from diabetic foot ulcers of 10 responding patients before and after 2 weeks' treatment with Heberprot-P (75-μg applied intralesionally 3 times per week). Total RNA was obtained and quantitative PCR used to determine expression of 26 genes related to inflammation, oxidative stress, cell proliferation, ngiogenesis and extracellular matrix formation. Genetic expression was quantified before and after treatment using REST 2009 v2.0.13. RESULTS After treatment, there was a statistically significant increase in expression of genes related to cell proliferation, angiogenesis and formation of extracellular matrix (PDGFB, CDK4, P21, TP53, ANGPT1, COL1A1, MMP2 and TIMP2). A significant decrease was observed in gene expression related to inflammatory processes and oxidative stress (NFKB1, TNFA and IL-1A). CONCLUSIONS Our findings suggest that Heberprot-P's healing action on diabetic foot ulcers is mediated through changes in genetic expression that reduce hypoxia, inflammation and oxidative stress, and at the same time increase cell proliferation, collagen synthesis and extracellular matrix remodeling. The kinetics of expression of two genes related to extracellular matrix formation needs further exploration. KEYWORDS Epidermal growth factor, EGF, diabetic foot ulcer, wound healing, quantitative real-time PCR, gene expression, Cuba.

Topics: Biopsy; Diabetic Foot; Epidermal Growth Factor; Gene Expression; Humans; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Transcriptome; Wound Healing

Diabetic foot ulcers (DFUs) are a constant threat to diabetic patients and can lead to amputations and even death. Intralesional administration of propranolol in diabetic wounds has not been reported previously. This study aimed to investigate the efficacy of propranolol cream in diabetic wounds. Fifty-six spontaneously diabetic mice were divided into the propranolol group and the control group. After preparing full-thickness wounds on the back of the mice, 1% propranolol cream was topically applied to wounds in the experimental group and 0% propranolol cream in controls. The wound sizes were measured and calculated against the original area. The wounds were analyzed up to 21 days after injury. At all evaluation time-points, the wound size (%) in the propranolol group was significantly smaller than in the controls. Epidermal growth factor (EGF) protein expression increased in the experimental vs.. Vascular endothelial growth factor (VEGF) expression was significantly lower in the experimental vs. control group whereas NG2 proteoglycan was increased throughout the study. However, matrix metallopeptidase (MMP)-9 expression was at first significantly higher in the experimental vs. control group then the MMP-9 protein level in the control group increased and surpassed that in the experimental group. In conclusion, intralesional administration of 1% propranolol cream promotes reepithelialization and regulates abnormal angiogenesis in diabetic wounds. Propranolol cream may become a new drug for the treatment of DFUs.

Topics: Administration, Topical; Adrenergic beta-Antagonists; Animals; Antigens; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Foot; Disease Models, Animal; Epidermal Growth Factor; Female; Immunohistochemistry; Mice; Propranolol; Proteoglycans; Skin Cream; Vascular Endothelial Growth Factor A; Wound Healing

Selecting empirical therapy for a diabetic foot infection (DFI) requires knowing how likely infection with Pseudomonas aeruginosa is in a particular patient. We designed this study to define the risk factors associated with P aeruginosa in DFI.. We performed a preplanned microbiological subanalysis of data from a study assessing the effects of treatment with intralesional epidermal growth factor for diabetic foot wounds in patients in Turkey between January 1, 2012, and December 31, 2013. Patients were screened for risk factors, and the data of enrolled individuals were recorded in custom-designed patient data forms. Factors affecting P aeruginosa isolation were evaluated by univariate and multivariate logistic regression analyses, with statistical significance set at P < .05.. There were 174 patients enrolled in the main study. Statistical analysis was performed in 90 evaluable patients for whom we had microbiological assessments. Cultures were sterile in 19 patients, and 89 bacterial isolates were found in the other 71. The most frequently isolated bacteria were P aeruginosa (n = 23, 25.8%) and Staphylococcus aureus (n = 12, 13.5%). Previous lower-extremity amputation and a history of using active wound dressings were the only statistically significant independent risk factors for the isolation of P aeruginosa in these DFIs.. This retrospective study provides some information on risk factors for infection with this difficult pathogen in patients with DFI. We need prospective studies in various parts of the world to better define this issue.

Topics: Aged; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Risk Factors; Turkey; Wound Infection

The diabetic foot ulcer (DFU) is the leading cause of lower extremity amputation worldwide and is directly associated with comorbidity, disability and mortality. Oxidative stress mechanisms have been implicated in the pathogenesis of these wounds. Intra-lesional infiltration of epidermal growth factor has emerged as a potential therapeutic alternative to allow for physiological benefit while avoiding the proteolytic environment at the centre of the wound. The aim of this study was to characterise the response of patients with DFUs to epidermal growth factor treatment in terms of redox status markers. Experimental groups included patients with DFUs before and 3-4 weeks after starting treatment with epidermal growth factor; compensated and non-compensated diabetic patients without ulcers; and age-matched non-diabetic subjects. Evaluations comprised serum levels of oxidative stress and antioxidant reserve markers. Patients with DFUs exhibited the most disheveled biochemical profile, with elevated oxidative stress and low antioxidant reserves, with respect to non-ulcerated diabetic patients and to non-diabetic subjects. Epidermal growth factor intra-lesional administration was associated with a significant recovery of oxidative stress and antioxidant reserve markers. Altogether, our results indicate that epidermal growth factor intra-ulcer therapy contributes to restore systemic redox balance in patients with DFUs.

Topics: Adult; Aged; Aged, 80 and over; Cuba; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Oxidative Stress; Wound Healing

Intralesional epidermal growth factor (EGF) has been available as a medication in Turkey since 2012. We present the results of our experience using intralesional EGF in Turkey for patients with diabetic foot wounds.. A total of 174 patients from 25 Turkish medical centers were evaluated for this retrospective study. We recorded the data on enrolled individuals on custom-designed patient follow-up forms. Patients received intralesional injections of 75 μg of EGF three times per week and were monitored daily for adverse reactions to treatment. Patients were followed up for varying periods after termination of EGF treatments.. Median treatment duration was 4 weeks, and median frequency of EGF administration was 12 doses. Complete response (granulation tissue >75% or wound closure) was observed in 116 patients (66.7%). Wounds closed with only EGF administration in 81 patients (46.6%) and in conjunction with various surgical interventions after EGF administration in 65 patients (37.3%). Overall, 146 of the wounds (83.9%) were closed at the end of therapy. Five patients (2.9%) required major amputation. Adverse effects were reported in 97 patients (55.7%).. In patients with diabetic foot ulcer who received standard care, additional intralesional EGF application after infection control provided high healing rates with low amputation rates.

Topics: Aged; Amputation, Surgical; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Injections, Intralesional; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Turkey

Topics: Amputation, Surgical; Cuba; Diabetic Foot; Epidermal Growth Factor; Humans; Politics; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Personnel; United States; Wound Healing

Currently, there is increasing the number of diabetic foot patients with tissues defects. The local treatment of this pathology against the backdrop of diabetic angiopathy and polyneuropathy is a topical issue.. Treatment of wound defects in patients with neuroischemic form of diabetic foot syndrome; study of the effectiveness of collagen implants and gene-therapy technologies in wound closure.. The comparative study was conducted for analyzing clinical effects of "Heberprot-P" and bioplastic material "Collost" on wound healing process in patients with verified diagnosis "diabetic foot syndrome" on the base of City Clinical Hospital №81(Moscow) and "Diabetic Foot" center (Kazan).. The article shows the availability, methodology, results of combination treatment of wound defects of lower limbs in DFS patients with gen-therapy methods and bioplastic materials based on native type I collagen.. The use of bioplastic materials based on native type I collagen for treatment of tissue defects in patients with diabetic foot is preferably than the use of epidermal growth factor.. Актуальность. В настоящее время отмечается увеличение количества больных с синдромом диабетической стопы с дефектами кожи и мягких тканей. Остро стоит вопрос о местном лечении данной патологии на фоне диабетической ангиопатии и полинейропатии. Цель работы - повысить качество лечения раневых дефектов у больных нейроишемической формой синдрома диабетической стопы, изучить эффективность коллагеновых имплантатов и генотерапевтических технологий в закрытии раневых дефектов кожи и мягких тканей. Материал и методы. На базе Городской клинической больницы # 81 Департамента здравоохранения г. Москвы и центра 'Диабетическая стопа' г. Казани проведено сравнительное исследование, по изучению воздействия препарата эберпрот-п и биопластического материала коллост на течение раневых процессов у больных с верифицированным диагнозом 'синдром диабетической стопы'. Результаты. В статье рассматривается доступность методики, результаты комбинированного лечения раневых дефектов кожных покровов и мягких тканей нижних конечностей у пациентов с синдромом диабетической стопы с применением генотерапевтических методов и биопластических материалов на основе нативного коллагена I типа. Выводы. Применение пластических биоматериалов на основе нативного коллагена I типа в лечении дефектов тканей у больных с синдромом диабетической стопы предпочтительнее эпидермального фактора роста.

Topics: Coated Materials, Biocompatible; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Treatment Outcome; Wound Closure Techniques; Wound Healing

The intralesional injection of recombinant human epidermal growth factor (EGF-IL), a new therapy, has been claimed to prevent major amputations in advanced diabetic foot lesions. In this study, the efficacy of EGF-IL on advanced diabetic foot ulcers (DFU) was reviewed.. Intralesional 75 µg EGF application (Heberprot-P® 75, Heber Biotec, Havana, Cuba) to 12 diabetic foot lesions in 11 patients (8 males, 3 females; mean age: 62.2±10.6 years) was evaluated. Most of the patients had undergone revascularization and received hyperbaric oxygen therapy (HBOT) and negative pressure wound therapy (NPWT), along with standard care, but failed to heal. After amputation was offered as the final option, EGF-IL was applied to evaluate its effects.. Two patients underwent amputation, while 10 lesions of the remaining 9 patients healed completely.. Our results prove that intralesional application of EGF can prevent amputations in advanced diabetic foot cases with an ischemic component. However, evidence in the literature supporting its use remains lacking, and its high cost presents an additional problem. Thus, we believe that intralesional application of EGF should be an option for ischemic wounds only after vascular evaluation (and intervention when possible), HBOT, NPWT, and standard care have proven insufficient.

Topics: Aged; Amputation, Surgical; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Hyperbaric Oxygenation; Injections, Intralesional; Male; Middle Aged; Negative-Pressure Wound Therapy; Recombinant Proteins; Turkey; Wound Healing

The aim of this study was to explore the clinical effects of intralesional administration of an epidermal growth factor (EGF) up to complete wound closure.. Seventeen diabetic patients with full-thickness lower extremity ulcers of more than 4 weeks of evolution were enrolled in the study. Mean ulcer size was 15.5 +/- 7.5 cm(2). Intralesional injections of 75 µg of Heberprot-P three times per week for 5-8 weeks were given up to complete wound healing.. Full granulation response was achieved in all patients in 32.4 +/- 6.6 days. Complete wound closure was obtained in 16 (94.1%) cases in 53.1 +/- 4.7 days. The most frequent adverse events were burning sensation, tremors, chills and pain at the site of administration. After 1-year follow-up, only one patient relapsed.. Intralesional EGF administration up to complete closure can be safe, effective and suitable to improve healing of chronic diabetic foot ulcer (DFU).

Topics: Aged; Diabetic Foot; Epidermal Growth Factor; Female; Follow-Up Studies; Humans; Injections, Intralesional; Male; Middle Aged; Recombinant Proteins; Risk Factors; Time Factors; Treatment Outcome; Wound Healing

Topics: Cuba; Diabetic Foot; Epidermal Growth Factor; Philately

Topics: Cuba; Diabetic Foot; Epidermal Growth Factor; Humans; Philately

Human epidermal growth factor (hEGF) gene therapy was achieved with an electrospun nanofibrous mesh with matrix metalloproteinase (MMP) responsiveness to control release of plasmid human epidermal growth factor (phEGF) in diabetic ulcers. For MMP responsiveness, linear poly(ethyleneimine) (LPEI) was immobilized on the surface of the nanofiber via an MMP-cleavable linker. phEGF was electrostatically incorporated into LPEI-immobilized nanofibrous meshes with various charge ratios and phEGF incorporation efficiency was increased with increasing charge ratios. The release of both phEGF and LPEI was significantly increased in the presence of MMP-2 due to the enzymatic digestion of the MMP-cleavable linkage between the matrix and LPEI. Human dermal fibroblasts with the released fraction showed a higher expression level of hEGF compared to naked phEGF or phEGF/LPEI complexes. Diabetic wounds treated with phEGF-incorporated nanofibrous meshes showed high hEGF expression level and accelerated wound recovery rates without wound contractions for 14days. Neocollagen and cytokeratin accumulation were significantly increased as well as the expression of the keratinocyte-specific markers at the re-epithelized tissue treated with phEGF nanofibrous meshes, which clearly indicates that EGF gene was transfected to dermal cells and this consequently assisted wound recovery without phenotypic changes of the re-epithelized tissues. Thus, phEGF-incorporated nanofibrous mesh is expected to accelerate the wound-healing process as well as reduce wound contraction during recovery from diabetic ulcers.

Topics: Administration, Topical; Angiogenesis Inducing Agents; Animals; Bandages; Combined Modality Therapy; Diabetic Foot; Electrochemistry; Epidermal Growth Factor; Equipment Design; Equipment Failure Analysis; Female; Genetic Therapy; Materials Testing; Mice; Mice, Inbred C57BL; Nanofibers; Particle Size; Plasmids; Rotation; Treatment Outcome; Wound Healing

After several exploratory and confirmatory clinical trials, the intralesional administration of human recombinant epidermal growth factor (hrEGF) has been approved for the treatment of advanced diabetic foot ulcers (DFU). The aim of this work was to evaluate the effectiveness and safety of this procedure in medical practice.. A prospective, post-marketing active pharmacosurveillance was conducted in 41 hospitals and 19 primary care polyclinics. Patients with DFU received hrEGF, 25 or 75 μg, intralesionally 3 times per week until complete granulation of the ulcer or 8 weeks maximum, adjuvant to standard wound care. Outcomes measured were complete granulation, amputations, and adverse events (AE) during treatment; complete lesion re-epithelization and relapses in follow-up (median: 1.2; maximum 4.2 years).. The study included 1788 patients with 1835 DFU (81% Wagner's grades 3 or 4; 43% ischemic) treated from May 2007 to April 2010. Complete granulation was observed in 76% of the ulcers in 5 weeks (median). Ulcer non-ischemic etiology (OR: 3.6; 95% CI: 2.8-4.7) and age (1.02; 1.01-1.03, for each younger year) were the main variables with influence on this outcome. During treatment, 220 (12%) amputations (171 major) were required in 214 patients, mostly in ischemic or Wagner's grade 3 to 5 ulcers. Re-epithelization was documented in 61% of the 1659 followed-up cases; 5% relapsed per year. AE (4171) were reported in 47% of the subjects. Mild or moderate local pain and burning sensation, shivering and chills, were 87% of the events. Serious events, not related to treatment, occurred in 1.7% of the patients.. The favorable benefit/risk balance, confirms the beneficial clinical profile of intralesional hrEGF in the treatment of DFUs.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Diabetic Foot; Dose-Response Relationship, Drug; Epidermal Growth Factor; Female; Granulation Tissue; Humans; Injections, Intralesional; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Treatment Outcome; Wound Healing; Young Adult

Diabetic foot ulcer is a principal diabetic complication. It has been shown that diabetic patients have decreased growth factor concentrations in their tissues, particularly epidermal growth factor. Growth factor shortage impairs wound healing, which leads to chronic nonhealing wounds and sometimes eventual amputation. Ischemic diabetic foot ulcer is the most difficult to treat and confers the highest amputation risk. Injecting epidermal growth factor deep into the wound bottom and contours encourages a more effective pharmacodynamic response in terms of granulation tissue growth and wound closure. Epidermal growth factor injected into the ulcer matrix may also result in association with extracellular matrix proteins, thus enhancing cell proliferation and migration. Heberprot-P is an innovative Cuban product containing recombinant human epidermal growth factor for peri- and intra-lesional infiltration; evidence reveals it accelerates healing of deep and complex ulcers, both ischemic and neuropathic, and reduces diabetes-related amputations. Clinical trials of Heberprot-P in patients with diabetic foot ulcers have shown that repeated local infiltration of this product can enhance healing of chronic wounds safely and efficaciously. As a result, Heberprot-P was registered in Cuba in 2006, and in 2007 was included in the National Basic Medications List and approved for marketing. It has been registered in 15 other countries, enabling treatment of more than 100,000 patients. Heberprot-P is a unique therapy for the most complicated and recalcitrant chronic wounds usually associated with high amputation risk. Local injection in complex diabetic wounds has demonstrated a favorable risk-benefit ratio by speeding healing, reducing recurrences and attenuating amputation risk. Further testing and deployment worldwide of Heberprot-P would provide an opportunity to assess the product's potential to address an important unmet medical need.

Topics: Amputation, Surgical; Clinical Trials as Topic; Cuba; Diabetic Foot; Epidermal Growth Factor; Humans; Recombinant Proteins; Severity of Illness Index; Wound Healing

To investigate the underlying mechanism for the therapeutic effect of a traditional Chinese medicinal recipe, Antidotal and Myogenic Ointment (AMO), on the foot ulcer in diabetic rat using cDNA microarray technology.. 45 rats were made diabetic by i. p. injection of streptozocin. The treated animals were then fed for 6 months,and subjected to the dissection of distal popliteal artery after ligation of the vessels. Another month later, grade II burn injury was produced on the bottom of their foot as a model of diabetic foot ulcer. The rats were then randomly divided into three groups (15 each) to receive AMO, epidermal growth factor (EGF) and saline for 30 days, with dressing change in every 2 days. The area of ulcer wound and their healing rate were recorded before and after the treatment. Total RNA was extracted from the tissue samples collected near the wound, and the expression profile of cytokine genes demonstrated using the microarry for rats.. In comparison with the saline group, difference in the level of expression was found in 25 genes (23 of them were up-regulated and 2 down-regulated) in EGF group, and 30 genes in AMO groups (29 of them up-regulated and 1 down-regulated ). In comparison with EGF group, difference in level of expression was found in 16 genes in AMO group, with 11 up-regulated and 5 down-regulated. Neurotrophic factors and chemotactic factors, etc were among the genes involved.. In comparison with EGF, AMO is more effective in the treatment of foot ulcer in diabetic rats. It is possible that AMO produces such effects through the regulation of balance in cytokine expression.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Foot; Epidermal Growth Factor; Male; Ointments; Oligonucleotide Array Sequence Analysis; Phytotherapy; Rats; Rats, Wistar; Treatment Outcome; Wound Healing

To compare the platelet enrichment ratio of platelet-rich plasma (PRP) prepared by different centrifuge methods and to compare the concentration of growth factors released from autologous platelet-rich gel (APG) with the whole blood.. Thirteen diabetic patients with refractory skin lesions were enrolled in APG treatment. (1) Three kinds of centrifuge methods were selected for PRP by 11 diabetic patients: A (n = 6): 529 x g for 4 minutes in the first centrifuge and 854 x g for 6 minutes in the second centrifuge; B (n = 5): 313 x g for 4 minutes in the first centrifuge and 1,252 x g for 6 minutes in the second centrifuge; C (n = 5): 176 x g for 5 minutes in the first centrifuge and 1,252 x g for 5 minutes in the second centrifuge. Platelet counted on the whole blood and PRP was determined. The APG, produced by combining the PRP with thrombin and calcium gluconate (10:1) was used by patients. (2) PDGF-BB, TGF-beta1, VEGF, EGF, and IGF-1 were measured in the APG and the whole blood using the enzyme-linked immunosorbent assay method.. (1) The average platelet concentration was higher in group B [(1,363.80 +/- 919.74) x 10(9)/L] than in groups A [(779.67 +/- 352.39) x 10(9)/L)] and C [(765.00 +/- 278.78) x 10(9)/L] and the platelet recovery rate was 75.2% +/- 21.0% in group B. (2) The concentration of growth factors all increased with the increasing platelet number. On average, for the whole blood as compared with APG, the PDGF-BB concentration increased from (145.94 +/- 133.24) pg/mL to (503.81 +/- 197.86) pg/mL (P < 0.05); TGF-beta1 concentration increased from (3.31 +/- 2.27) ng/mL to (5.67 +/- 4.80) ng/mL (P < 0.05); IGF-1 concentration increased from (14.54 +/- 35.34) ng/mL to (110.56 +/- 84.36) ng/mL (P < 0.05); and EGF concentration increased from (160.73 +/- 71.10) pg/mL to (265.95 +/- 138.43) pg/mL (P < 0.05). No increase was found for VEGF (P > 0.05). (3) There was positive correlation between the platelet concentration and PDGF-BB and TGF-beta1 (r = 0.627, r = 0.437, P < 0.05). (4) Thirteen diabetic repractory dermal ulcers received APG treatment for 18 times, 9 ulcers (69.2%) and 10 sinuses (88.3%) were cured at the end of 12-week treatment.. The method of group B is the best centrifuge method. A variety of growth factors are detected and released from the platelets at significant levels in APG. There is positive correlation between the platelet concentration and PDGF-BB and TGF-beta1.

Topics: Adult; Aged; Diabetes Complications; Diabetic Foot; Epidermal Growth Factor; Female; Gels; Growth Substances; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Platelet Count; Platelet-Derived Growth Factor; Platelet-Rich Plasma; Plateletpheresis; Skin Ulcer; Treatment Outcome; Vascular Endothelial Growth Factor A; Wound Healing

In this study the w/o/w extraction-evaporation technique was adopted to prepare poly(lactic-co-glycolic acid) (PLGA) microspheres loading recombinant human epidermal growth factor (rhEGF). The microspheres were characterized for morphology by transmission electron microscopy (TEM) and particle size distribution. The release performances, the proliferation effects and therapeutic effects of rhEGF-loaded PLGA microspheres were all studied. The results showed that these spherical microspheres had a narrow size distribution and a high drug encapsulation efficiency (85.6%). RhEGF-loaded microspheres enhanced the growth rate of fibroblasts and wound healing more efficiently than pure rhEGF. The number of the proliferating cell nuclear antigen (PCNA) in the epidermis layer with the microsphere treatment was significantly larger than those of the control groups. Overall locally sustained delivery of rhEGF from biodegradable PLGA microspheres may serve as a novel therapeutic strategy for diabetic ulcer repair.

Topics: Animals; Biocompatible Materials; Cell Line; Cell Proliferation; Delayed-Action Preparations; Diabetes Mellitus, Experimental; Diabetic Foot; Epidermal Growth Factor; Fibroblasts; Lactic Acid; Male; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Recombinant human epidermal growth factor (REGEN-D 150), which was cloned and over expressed in E. coli, has shown enhanced healing of chronic diabetic foot ulcers (DFU) by significantly reducing the duration of healing in addition to providing excellent quality of wound healing and reepithelization. Post-marketing surveillance (PMS) study of REGEN-D 150 in 135 patients of DFU in India was compared with Phase III clinical trial data of REGEN-D 150 in India. Statistical analysis of study data determined that the empirical survival probability distribution, in terms of non-healing of ulcers, was lowest in the case of PMS study, better than that for Phase III; more DFU patients were healed in PMS study. Percentage of patients cured in any given week (e.g., in week 10) is above 90% in PMS study, as compared to 69% in Phase III clinical trial; this percentage was around 18% for the control group with placebo in the Phase III trial. The average wound healing time was significantly lower in PMS study, 4.8 weeks, while it was 9 weeks in Phase III clinical trials while the average wound healing with REGEN-D 150 was found to be 86% in this study. REGEN-D 150 has been found to result in healthy granulation and stimulate epithelization, thus leading to final wound closure. The PMS study has established the efficacy of REGEN-D 150 in faster healing of diabetic foot ulcers.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Clinical Trials, Phase II as Topic; Diabetic Foot; Epidermal Growth Factor; Female; Follow-Up Studies; Humans; Male; Middle Aged; Patient Selection; Recombinant Proteins; Retrospective Studies; Wound Healing

This study examined if a series of epidermal growth factor (EGF) local infiltrations can enhance the healing process of complicated diabetic wounds. Twenty-nine in-hospital patients with diabetic neuropathic or ischaemic lesions with high risk of amputation were treated in a non controlled pilot study conducted at the National Institute of Angiology, Havana. Lesions, classified as Wagner's grade 3 or 4, included ulcers > or = 20 cm2 for > or = 25 days or amputation residual bases > or = 30 cm2 for > or = 15 days, healing refractory despite comprehensive wound care. EGF (25 microg) intralesional infiltrations (approximately 250 microl of a 25 microg/ml solution/injection point) were performed thrice weekly up to the eighth week. Wound closure was monitored during the treatment and recurrence examined for a year following discharge from hospital. Eighty-six per cent of the patients treated showed a productive granulation at infiltration session 8. Histological examination at this point indicated a substantial wound matrix transformation, granulation tissue cell repopulation and angiogenesis. Of the 29 patients treated, amputation was prevented in 17 (58.6%) of them who completed 24 infiltration sessions. They averaged 71.1 +/- 18.3% of reepithelisation during a mean in-hospital period of 66.5 +/- 4.9 days. Wound recurrence after 1 year of follow-up appeared in only one patient. Preliminary evidences suggest that EGF intralesional infiltrations may be effective in reducing diabetic lower limb amputation.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Debridement; Diabetic Foot; Epidermal Growth Factor; Female; Granulation Tissue; Humans; Male; Middle Aged; Pilot Projects; Wound Healing

Patients with diabetes mellitus experience impaired wound healing, often resulting in chronic foot ulcers. Healing can be accelerated by application of growth factors like platelet-derived growth factor (PDGF). We investigated the mitogenic responses, measured by 3[H]thymidine incorporation, of fibroblasts cultured from diabetic ulcers, non-diabetic ulcers, and non-lesional diabetic and age-matched controls, to recombinant human PDGF-AB, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor (IGF-I). We determined the optimal concentration of these factors and investigated which single factor, or combination of factors, added simultaneously or sequentially, induced the highest mitogenic response. For single growth factor additions, in all fibroblast populations significant differences in mitogenic response to different growth factors were observed, with PDGF-AB consistently inducing the highest response and IGF-I the lowest (p < 0.043). IGF-I produced only a 1.7-fold stimulation over control in diabetic ulcer fibroblasts, versus 2.95-fold for chronic ulcer, 3.2-fold for non-lesional (p = 0.007) and 5-fold for age-matched fibroblasts (p = 0.007). The highest mitogenic response induced by EGF was significantly less for chronic ulcer fibroblasts compared with age-matched and nonlesional controls (p < 0.03), chronic ulcer fibroblasts also needed significantly more EGF to reach this optimal stimulus (p < 0.02 versus age-matched and non-lesional controls). The simultaneous addition of FGF-IGF-I, PDGF-IGF-I and FGF-PDGF to diabetic ulcer fibroblasts always produced a higher stimulatory response than sequential additions (p < or = 0.05). Also the addition of bFGF, PDGF-AB and EGF prior to IGF-I induced a higher 3[H]thymidine uptake in all fibroblasts compared to the combination of each in reverse order. Significant differences were observed when comparing the combinations of growth factors with the highest stimulatory responses (PDGF-IGF-I, FGF-PDGF and EGF-PDGF added simultaneously) to a double dose of PDGF, with the highest mean rank for the combination PDGF-IGF-I (p = 0.018). In conclusion, combinations such as PDGF-AB and IGF-I may be more useful than PDGF-AB alone for application in chronic diabetic wounds.

Topics: Cell Division; Cells, Cultured; Diabetic Foot; Drug Synergism; Epidermal Growth Factor; Fibroblast Growth Factor 2; Fibroblasts; Humans; Insulin-Like Growth Factor I; Microtubules; Platelet-Derived Growth Factor; Recombinant Proteins

To investigate clinical effects and possible mechanisms of various growth factors on impaired healing ulcers of patients with diabetic disease.. Seventy-eight patients were divided into three groups; saline control, epidermal growth factor(EGF) experimental group, and platelet-derived wound healing factor (PDWHF) experimental group. General healing conditions, wound closing index, healing rates and histological changes of the patient's ulcer wound were observed during 1-8 weeks after treatment.. The wound closing index and healing rate of ulcers were significantly increased in the EGF and PDWHF experimental groups compared with the control group, while the angiogenesis, fibroblast hyperplasia, and collagen deposit were more obvious in EGF and PDWHF experimental groups than that of control group. The promoting effects on wound healing in PDWHF experimental group were better than in EGF group.. It suggests that local application of certain growth factor alone or various growth factors together is an effective method to improve the condition of impaired healing of diabetic ulcers.

Topics: Aged; Diabetic Foot; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Platelet-Derived Growth Factor; Wound Healing