Stimulation of healing of chronic wounds by epidermal growth factor.

We evaluated the effect of topical epidermal growth factor treatment on healing of chronic wounds in a prospective, open-label, crossover trial. Five males and four females who ranged in age from 40 to 72 years (average 57 +/- 9 years) were enrolled. Four patients had adult-onset diabetes mellitus, two had rheumatoid arthritis, two had old burn scars, and one had a failed abdominal incision. The average duration of the ulcers prior to treatment with epidermal growth factor was 12 +/- 5 months (range 1 to 48 months). Following failure of the wounds to heal with conventional therapies, including debridement, skin graphs, and vascular reconstruction, wounds were treated twice daily with Silvadene alone for periods ranging from 3 weeks to 6 months. No evidence of healing was observed in any of the patients' wounds during Silvadene treatment, and patients were crossed over to twice a day treatment with Silvadene containing 10 micrograms epidermal growth factor per gram. Wounds of eight patients healed completely with epidermal growth factor-Silvadene treatment in an average of 34 +/- 26 days (mean +/- SD, range 12 to 92 days) and did not reoccur for periods ranging from 1 to 4 years. One patient failed therapy. These results suggest that topical treatment of chronic wounds with epidermal growth factor may stimulate healing.     

Becaplermin gel (PDGF-BB) as topical wound therapy. Plastic Surgery Educational Foundation DATA Committee

Becaplermin gel is the first topical growth factor to demonstrate therapeutic efficacy in the healing of diabetic wounds. For diabetic patients who have poorly healing ulcers despite good perfusion and a reasonable trial of wound care, this product may be of considerable benefit. It should be tried for a 2-week time period and the results objectively assessed before continuation of therapy.     

Differential diagnosis of Charcot arthropathy and osteomyelitis

Foot problems are common causes of morbidity in patients with diabetes mellitus. Foot ulcers are the leading cause of hospitalization in diabetic patients. Bones may be involved in two different clinical conditions: osteomyelitis and Charcot osteoarthropathy. Osteomyelitis usually develops by spreading from contiguous soft tissue to underlying bone. Charcot foot is deformation of foot as a result of muscle athrophy, bone and joint structure changes in a joint as a secondary complication of neuropathy. To distinguish bone infection from non-infectious bone disorders as in Charcot joint may be difficult, especially if there is no skin ulceration. So, the mere absence of skin ulcers does not exclude the diagnosis of osteomyelitis.     

间充质干细胞治疗糖尿病皮肤损伤的研究进展

糖尿病患者的皮肤组织易受内源性及外源性的各种损伤,且创面具有愈合慢、易感染等特点,这种特点在下肢皮肤创伤中表现尤为突出,常伴有高截肢风险,故糖尿病皮肤损伤可严重影响患者的生活质量。间充质干细胞（MSCs）是一类多能干细胞,其具有易分离、易培养、多向分化和免疫源性低等特征,目前已被广泛应用于创伤修复、组织再生等研究。对于糖尿病皮肤损伤,MSCs的临床移植治疗已成为继药物、手术之后的又一种治疗新技术。本文结合MSCs的生物学特性,对其应用在糖尿病皮肤损伤方面的研究进展做一综述。     

Clinical application of fresh fibroblast allografts for the treatment of diabetic foot ulcers: a pilot study

Diabetic foot ulcers often pose a difficult problem for health care professionals because of the defects associated with fibroblast functioning. Although there has been much interest recently in the use of topical growth factors for the treatment of diabetic foot ulcers, the effects are generally not very dramatic. Cryopreserved fibroblast implants, which are able to adjust to a wound's environment and provide the desired growth factors and other substances that may be lacking in a chronic wound, represent an exciting development and a major advance. These products may well provide growth factors in the right concentration and in the right sequence, something that has proved difficult to achieve with the topical application of recombinant growth factors. However, cell activities are impaired by cryopreservation. The purpose of this study was to assess the effects of fresh human allogeneic fibroblast grafting for the treatment of diabetic foot ulcers. Eight patients with diabetic foot ulcers ranging from 6 to 17 weeks in duration were treated. The size of the wounds ranged from 2.0 to 6.0 cm2, with three patients exhibiting exposed bones. A history of diabetic foot ulcers was present in five patients. Human dermal fibroblasts from healthy teenagers were cultured in Dulbecco's modified Eagle medium/Ham's F-12 supplemented with 10% autologous serum. The cultured cells were applied over the wounds immediately after debridement; fibrin was used as a cell carrier. A dressing was then applied with Tegaderm and kept moist until healing was complete. The progress and time for complete wound closure and patient satisfaction were assessed, with follow-up time ranging from 6 to 18 months. Complete wound healing occurred in all patients. Eleven to 21 days were needed for complete reepithelization of the wound, and no clinical or laboratory abnormalities were noted. Patient satisfaction was also very positive. In this study, the use of fresh human fibroblast allografts was found to be a safe and effective treatment for diabetic foot ulcers.     

The effect of the boron-based gel on the treatment of diabetic foot ulcers: A prospective,randomized controlled trial

BackgroundChronic ulcers represent impaired healing capacity with high mortality in the elderly or patients with systemic disorders such as diabetes. Boron is an effective agent in wound healing by promoting cell migration and proliferation and reducing inflammation in the wound area. This study aimed to evaluate the therapeutic effect of a sodium pentaborate-based topical formulation compared to control on the treatment of diabetic foot ulcers.MethodsA prospective, double-blind, randomized controlled trial was conducted to apply randomly the topical sodium pentaborate 3% gel or topical conventional remedy (control) by patients diagnosed with diabetic foot ulcers. The 171 eligible participants aged 18–75 years received the allocated medicines twice a day for a month with an allocation ratio of 3:1. Twenty-five days and two months after the end of the trial, participants were reinvestigated for their ulcer condition and any recurrence. Wagner’s classification of diabetic foot ulcers was applied to this purpose (0−5).Results161 participants (57 females, 104 males; mean age: 59.37) completed this study. After the intervention, most participants in the intervention group had a lower ulcer grade than the control group (adjusted mean difference (95% CI): − 0.91 (−1.1 to −0.73); p < 0.001). Moreover, most participants in the intervention group (n = 109 (90.8%)) were treated at a higher rate than the control group (n = 5 (12.2%)) after intervention (adjusted odds ratio (95% CI): 0.008 (0.002–0.029); p < 0.001). There was no case of recurrence in the intervention group while its rate was (n = 2 (40%)) in the control group (p < 0.001).ConclusionThe present study suggests that topical sodium pentaborate gel may help treat and decrease the grade of diabetic foot ulcers and prevent the recurrence of diabetic foot ulcers.     

Role of platelet-derived growth factor as an adjunct to surgery in the management of pressure ulcers

Management options for pressure ulcers include local wound care, surgical repair, and, more recently, topical application of platelet-derived growth factor (PDGF). PDGF is a glycoprotein that is mitogenic for mesenchymal cells and has been studied extensively for applicability in promoting the healing of chronic human wounds. Using data obtained from a multicenter clinical trial for the treatment of full-thickness pressure ulcers, a subset analysis was performed to investigate the outcome of salvage surgery for pressure ulcers, after incomplete closure occurred with the topical use of either recombinant human PDGF-BB (rhPDGF-BB) or placebo gel. At the University of Michigan Wound Care Center, subset data from a randomized, double-blind, placebo-controlled, parallel group clinical trial were reviewed to compare the effects of three concentrations of rhPDGF-BB on full-thickness pressure ulcers of the trunk with those of the placebo. Twenty-eight patients were enrolled and 27 completed the trial. An intent-to-treat analysis was used to evaluate data. If the ulcer did not heal by the end of the 16-week trial period, the surgeon, still blinded to the treatment group, offered salvage surgical repair of the pressure ulcer. Eleven patients underwent salvage surgical repair using myocutaneous flaps, primary closure, or skin grafts. Of three patients who received placebo followed by surgery, none progressed to full healing within 1 year. Of 12 patients in the treatment group who received rhPDGF-BB and salvage surgery, 11 (92 percent) ultimately healed the ulcers within 1 year after the start of the clinical trial. These findings suggest that treatment with rhPDGF-BB before surgery enhances the ability to achieve a closed wound over surgery alone. It must yet be determined to what degree rhPDGF-BB contributed to the excellent results seen in the rhPDGF-BB/surgery group. It is possible that rhPDGF-BB "primes" the local wound milieu to make it more responsive to complete closure following surgical treatment.     

Biopolymer gel matrix as acellular scaffold for enhanced dermal tissue regeneration

Biological grafts have drawbacks such as donor scarcity, disease transmission, tissue infection, while the scaffolds of either collagen or chitosan fabrics fail to become part of the tissue at the wound site, though they favor the formation of connective tissue matrix. This study developed a novel composite consisting of the combination of atelocollagen and chitosan in order to provide a biodegradable molecular matrix in gel form as a biomimetic surface for cell attachment, to promote the wound healing in excision wounds. We found that the topical application of biopolymer composite on the wound promoted cell proliferation, migration and collagen deposition overtime. The enhanced cellular activity in the collagen-chitosan treated wound tissue was also assed by increased levels of Platelet derived growth factor (PDGF) and Nerve growth factor (NGF) associated with elevated levels of antioxidants and decreased level of lipid peroxidation. The acellular matrix-like topical application material is designed to guide the eventual re-establishment of an anatomically normal skin. The results of this study demonstrate the feasibility of multi-cell regeneration on a molecular system that mimics tissue engineering in vivo.     

Antimycotic ciclopirox olamine in the diabetic environment promotes angiogenesis and enhances wound healing

Diabetic wounds remain a major medical challenge with often disappointing outcomes despite the best available care. An impaired response to tissue hypoxia and insufficient angiogenesis are major factors responsible for poor healing in diabetic wounds. Here we show that the antimycotic drug ciclopirox olamine (CPX) can induce therapeutic angiogenesis in diabetic wounds. Treatment with CPX in vitro led to upregulation of multiple angiogenic genes and increased availability of HIF-1α. Using an excisional wound splinting model in diabetic mice, we showed that serial topical treatment with CPX enhanced wound healing compared to vehicle control treatment, with significantly accelerated wound closure, increased angiogenesis, and increased dermal cellularity. These findings offer a promising new topical pharmacologic therapy for the treatment of diabetic wounds.     

Curcumin as a wound healing agent

Turmeric (Curcuma longa) is a popular Indian spice that has been used for centuries in herbal medicines for the treatment of a variety of ailments such as rheumatism, diabetic ulcers, anorexia, cough and sinusitis. Curcumin (diferuloylmethane) is the main curcuminoid present in turmeric and responsible for its yellow color. Curcumin has been shown to possess significant anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-mutagenic, anti-coagulant and anti-infective effects. Curcumin has also been shown to have significant wound healing properties. It acts on various stages of the natural wound healing process to hasten healing. This review summarizes and discusses recently published papers on the effects of curcumin on skin wound healing. The highlighted studies in the review provide evidence of the ability of curcumin to reduce the body's natural response to cutaneous wounds such as inflammation and oxidation. The recent literature on the wound healing properties of curcumin also provides evidence for its ability to enhance granulation tissue formation, collagen deposition, tissue remodeling and wound contraction. It has become evident that optimizing the topical application of curcumin through altering its formulation is essential to ensure the maximum therapeutical effects of curcumin on skin wounds.     

In vitro glycation of a tissue-engineered wound healing model to mimic diabetic ulcers

Diabetic foot ulcers are a major complication of diabetes that occurs following minor trauma. Diabetes-induced hyperglycemia is a leading factor inducing ulcer formation and manifests notably through the accumulation of advanced glycation end-products (AGEs) such as N-carboxymethyl-lysin. AGEs have a negative impact on angiogenesis, innervation, and reepithelialization causing minor wounds to evolve into chronic ulcers which increases the risks of lower limb amputation. However, the impact of AGEs on wound healing is difficult to model (both in vitro on cells, and in vivo in animals) because it involves a long-term toxic effect. We have developed a tissue-engineered wound healing model made of human keratinocytes, fibroblasts, and endothelial cells cultured in a collagen sponge biomaterial. To mimic the deleterious effects induced by glycation on skin wound healing, the model was treated with 300 µM of glyoxal for 15 days to promote AGEs formation. Glyoxal treatment induced carboxymethyl-lysin accumulation and delayed wound closure in the skin mimicking diabetic ulcers. Moreover, this effect was reversed by the addition of aminoguanidine, an inhibitor of AGEs formation. This in vitro diabetic wound healing model could be a great tool for the screening of new molecules to improve the treatment of diabetic ulcers by preventing glycation.     

Application of platelet derived growth factor-BB and diabetic wound healing: the relationship with oxidative events

The reasons that cause delay in wound healing in diabetes are a decrease in the level of growth factors secretion, an increase in the destruction of growth factors and in oxidative stress. Platelet derived growth factor (PDGF) is one of the important growth factors that play a role in all phases of wound healing. This study investigates time-dependent effects of topically PDGF-BB administration on oxidative events on the healing of dorsolateral-excisional wounds in diabetic rats. Forty-two female Wistar-albino rats with streptozotocin-induced diabetes were divided into four groups: control group, untreated group, chitosan-treated group, chitosan?+?PDGF-BB-treated group. Two identical full-thickness excisional skin wounds were made under anaesthesia in all rats except for the control group. In the PDGF-BB-treated and chitosan-treated groups, the wounds were treated topically PDGF-BB (7?ng/mL, single daily dose) and blank chitosan gel (equal amount) after wounding, respectively. After these administrations, on day 3 and day 7 of wound healing, rats were sacrificed. Thiobarbituric acid reactive substances, glutathione, nitric oxide, ascorbic acid levels, and superoxide dismutase activity in wound tissues were spectrophotometrically measured. PDGF-BB administration significantly increased TBARS levels and non-enzymatic antioxidant levels in early phase of diabetic wound healing. PDGF-BB dramatically reduced NO_x levels on day 3 and sharply increased NO_x levels on day 7 of wound healing. Consequently, PDGF-BB administration can be effective on oxidative balance in the early phase of diabetic wound healing.     

GLUT4 and UBC9 protein expression is reduced in muscle from type 2 diabetic patients with severe insulin resistance

Aims

Subgroups of patients with type 2 diabetes mellitus demand large insulin doses to maintain euglycemia. These patients are characterized by severe skeletal muscle insulin resistance and the underlying pathology remains unclear. The purpose of this study was to examine protein expression of the principal glucose transporter, GLUT4, and associated proteins in skeletal muscle from type 2 diabetic patients characterized by severe insulin resistance.

Methods

Seven type 2 diabetic patients with severe insulin resistance (mean insulin dose 195 IU/day) were compared with seven age matched type 2 diabetic patients who did not require insulin treatment, and with an age matched healthy control group. Protein expression of GLUT4 and associated proteins was assessed in muscle and fat biopsies using standard western blotting techniques.

Results

GLUT4 protein expression was significantly reduced by ∼30 pct in skeletal muscle tissue from severely insulin resistant type 2 diabetic subjects, compared with both healthy controls and type 2 diabetic subjects that did not require insulin treatment. In fat tissue, GLUT4 protein expression was reduced in both diabetic groups. In skeletal muscle, the reduced GLUT4 expression in severe insulin resistance was associated with decreased ubiquitin-conjugating enzyme 9 (UBC9) expression while expression of GLUT1, TBC1D1 and AS160 was not significantly different among type 2 diabetic patients and matched controls.

Conclusions

Type 2 diabetic patients with severe insulin resistance have reduced expression of GLUT4 in skeletal muscle compared to patients treated with oral antidiabetic drugs alone. GLUT4 protein levels may therefore play a role in the pathology behind type 2 diabetes mellitus among subgroups of patients, and this may explain the heterogeneous response to insulin treatment. This new finding contributes to the understanding of the underlying mechanisms for the development of extreme insulin resistance.     

中医病证相符的糖尿病慢性皮肤溃疡大鼠造模方法初探

目的观察不同造模方法致糖尿病大鼠慢性皮肤溃疡创面形态及愈合时间的影响。方法 50只SD大鼠随机分为5组:皮肤缺损组(QS组:剪皮),糖尿病组(DM组:STZ+剪皮),糖尿病加金黄色葡萄球菌组(DMJJ组:STZ+剪皮+金葡菌),糖尿病加激素组(DMJS组:STZ+剪皮+激素注射),糖尿病加激素加异物组(DMYW组:STZ+剪皮+激素注射+异物埋置)。糖尿病模型稳定后每周测量血糖1次,每日称量体重、观察疮面情况、测量创面面积。12 d后处死,石蜡包埋肉芽组织观察其组织病理形态。结果 DMJJ组前5d愈合速度快于其余组(P0.01);DMYW组的愈合时间延长,DMYW组愈合率显著偏低,与其余组比较有统计学意义(P0.01)。造模12 d其余组愈合率无统计学差异,DMYW组愈合率显著低于其余组(P0.01)。结论注射激素大鼠表现出中医"阴证"证型特点,糖尿病加激素注射加异物埋置复合因素造模法能使大鼠创面表现出与临床相似的"阴证"证型特点。     

Normal tissue plasminogen activator and plasminogen activator inhibitor activity in plasma from patients with type 1 diabetes mellitus.

The fibrinolytic system was investigated in 38 patients (21 males and 17 females) affected by type 1 diabetes mellitus (18 free from complications, 10 with retinopathy, and 10 with autonomic neuropathy) and in 8 healthy controls. Two separate fibrinolysis-stimulating tests were done: standardized venous occlusion and 1-desamino-8-D-arginine vasopressin infusion. Plasma tissue plasminogen activator antigen and activity and plasma plasminogen activator inhibitor activity were measured. All the patients were in good metabolic control (mean HbA1c 7.4%, range 6.1-8.0%). No significant differences were observed either between the diabetic patients and the control subjects, nor among the subgroups of diabetic patients. The fibrinolytic system is probably not involved in type 1 diabetes mellitus.     

Optimization and Characterization of Thymoquinone-Loaded Liposomes with Enhanced Topical Anti-inflammatory Activity

Thymoquinone, the major constituent of Nigella sativa oil has been found to have a promising topical anti-inflammatory activity; however, exaggerated heat and photo-sensitivity and lipophilicity prevent the best use of this promising product. The present work aimed to formulate an ideal thymoquinone liposomal system for topical delivery. Different liposomal systems were developed using thin film hydration method by applying different cholesterol molar concentrations, different total lipid molar concentrations, and different drug-to-lipid ratios. Morphological characterization of the prepared formulae was performed using polarized light, scanning electron microscope, and transmission electron microscope. The optimized formula (F12) was selected on the basis of enhanced permeation through the skin and was incorporated into chitosan gel for topical application. The gel formulation was clear with suitable skin permeation and exhibited acceptable rheological properties. Using carrageenan-induced paw edema in rats, the developed chitosan gel (F12) showed significant superior in vivo anti-inflammatory activity over the chitosan gel of the TQ (p?<?0.05) and comparable effect to the marketed indomethacin gel. As a conclusion, results revealed the potential of formulating thymoquinone as liposomal formulation in enhancing the anti-inflammatory effect compared to the TQ solution.     

Hyperbaric Oxygen Therapy to Treat Diabetes Impaired Wound Healing in Rats

Wound healing in diabetes is frequently impaired and its treatment remains a challenge. Hyperbaric oxygen therapy (HBOT) receives a wide attendance and is often used as a last resort treatment option, however, its effectiveness for many conditions is unproven. We tested the effect of HBOT on healing of diabetic ulcers in an animal experimental setting. Experimental diabetes was induced by intraperitoneal injection of streptozotocin. Four weeks after diabetes induction, rats were ulcerated by clamping a pair of magnet disks on the dorsal skin for 16 h. After magnet removal, the animals received HBOT, daily on weekdays, for 4 weeks. To examine the effect of HBOT on diabetes impaired wound healing, the degree of wound tissue perfusion, inflammation, angiogenesis, and tissue breaking strength were evaluated. HBOT effects on the degree of inflammation and number of blood vessels could not be observed. HBOT improved the tissue breaking strength of the wound, however, this did not reach statistical significance. Twenty hours after ending the HBOT, a significantly improved oxygen saturation of the hemoglobin at the venous end of the capillaries and the quantity of hemoglobin in the micro-blood vessels was measured.     

Increased type-III/type-I collagen ratios in diabetic human conjunctival biopsies

The ratio of type-III to type-I collagen is measured in human conjunctival biopsies from control and diabetic subjects. The tissue is digested by CNBr and the resulting peptides are quantified by SDS polyacrylamide gel electrophoresis. The peptides used are alpha 1-(I)CB7 and alpha 1-(III)CB8. In control population, of type-III collagen slightly increases with age. In two diabetic populations, (juvenile onset diabetes and maturity onset diabetes), the percentage of type-III collagen is significantly higher than in age-matched control groups. These data plus those previously obtained on genetically diabetic mice indicate that diabetes mellitus affects the expression of interstitial collagen phenotype. Preliminary results on prediabetic subjects suggest the role of genetic factors in such alterations.     

The efficacy of a topical gel with triester glycerol oxide in denture-related mucosal injuries

doi: 10.1111/j.1741‐2358.2011.00549.x
The efficacy of a topical gel with triester glycerol oxide in denture‐related mucosal injuries Objective: The efficacy of a topical gel with triester glycerol oxide for treating ulcerations related to new complete dentures was studied and compared with a placebo gel. Materials and methods: Fifty edentulous patients were enrolled in this double‐blind clinical study. All subjects received new maxillary and mandibular complete dentures and were recalled 1, 3 and 7 days after denture placement. Twenty‐five subjects received topical gel with triester glycerol oxide (TGO), and 25 subjects received topical gel without TGO. At each visit, pain and discomfort with the new dentures was assessed, and at the last visit, healing of ulcerations was also graded by a clinician. Subjects also graded the gel’s taste, smell and ease of use. Results: Specifically, there was no statistically significant difference in ulcer healing (p > 0.05), ratings of smell, taste and ease of use (p > 0.05) or pain and discomfort scores (p > 0.05). However, within‐group differences were observed in pain and discomfort scores between follow‐up sessions (p = 0.01 for all comparisons). Conclusion: Clinically, TGO gel is not effective in the treatment of mucosal injuries occurring following placement of complete dentures.     

Wound healing potential of chitosan and N-sulfosuccinoyl chitosan derivatives

Comparative study of chitosan wound healing properties and its synthesized derivatives in MC-100 gel was carried out using the model of experimental full thickness skin wounds. It was determined that N-sulfosuccinoyl chitosan derivatives added into the gel in a concentration of 0.05% possess the higher wound healing activity in comparison with other chitosan derivatives and decrease the half-healing period of wounds 2–3 times in comparison with the control.