Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers

OBJECTIVE—We studied the relationships of diabetic ulcer wound fluid matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and transforming growth factor-ß1 (TGF-ß1) with wound healing rate.RESEARCH DESIGN AND METHODS—The ulcers were cleansed to remove exudates, and wound fluids were collected for analysis of MMP-2 and -9, TIMP-1, and TGF-ß1.RESULTS—At presentation, MMP-9 and the MMP-9–to–TIMP-1 ratio correlated inversely with the wound healing rate at 28 days (P < 0.001). MMP-9 and the MMP-9–to–TIMP-1 ratio were lower in the 23 patients who achieved complete healing at 12 weeks versus the 39 who did not. The pro–MMP-9 concentration was predictive of healing within 12 weeks. Addition of cutoffs for TIMP-1 (>480 pg/ml) and TGF-ß (>115 pg/ml) further improved its predictive power (area under the curve 0.94).CONCLUSIONS—These findings suggest that a milieu with high MMP-9 may be indicative of inflammation and poor wound healing. Measurements of MMP-9, TIMP-1, and TGF-ß in wound fluid may help to identify ulcers at risk of poor healing.Diabetic foot ulcers often fail to heal, and the mechanism is not well explained (1). In previous studies of wounds, delayed healing is characterized by an increase in matrix metalloproteinases (MMPs), a decrease in the tissue inhibitors of metalloproteinases (TIMPs), and a reduction in some growth factors, in particular, transforming growth factor-β (TGF-β) (2–9). Both MMPs and TIMPs are secreted by cells involved in wound healing, and their concentrations vary according to the phase of healing (4,6).Studies of diabetic foot ulcer wounds in humans are limited as a result of the difficulty of obtaining tissue samples. Wound fluid can be obtained noninvasively and could potentially overcome this problem. The clinical relevance of studying wound fluid is supported by our previous report that high bacterial count in diabetic wound fluid has a negative impact on wound healing (10). Therefore, the aim of this study was to measure MMP-9, MMP-2, TIMP-1, and TGF-β1 in wound fluid obtained from diabetic foot ulcers and to examine their relationships with wound healing.     

The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial

OBJECTIVE: To determine if a human fibroblast-derived dermal substitute could promote the healing of diabetic foot ulcers. RESEARCH DESIGN AND METHODS: A randomized, controlled, multicenter study was undertaken at 35 centers throughout the U.S. and enrolled 314 patients to evaluate complete wound closure by 12 weeks. Patients were randomized to either the Dermagraft treatment group or control (conventional therapy). Except for the application of Dermagraft, treatment of study ulcers was identical for patients in both groups. All patients received pressure-reducing footwear and were allowed to be ambulatory during the study. RESULTS: The results demonstrated that patients with chronic diabetic foot ulcers of >6 weeks duration experienced a significant clinical benefit when treated with Dermagraft versus patients treated with conventional therapy alone. With regard to complete wound closure by week 12, 30.0% (39 of 130) of Dermagraft patients healed compared with 18.3% (21 of 115) of control patients (P = 0.023). The overall incidence of adverse events was similar for both the Dermagraft and control groups, but the Dermagraft group experienced significantly fewer ulcer-related adverse events. CONCLUSIONS: The data from this study show that Dermagraft is a safe and effective treatment for chronic diabetic foot ulcers.     

Optimization of photo-biomodulation therapy for wound healing of diabetic foot ulcers in vitro and in vivo

Unclear optical parameters make photo-biomodulation (PBM) difficult to implement in diabetic foot ulcer (DFU) clinically. Here, 12 wavelengths (400–900 nm) were used to conduct PBM to heal DFU wounds in vitro and in vivo. PBM at 10 mW/cm² and 0.5–4 J/cm² with all 12 wavelengths promoted proliferation of diabetic wound cells. In a mimic DFU (mDFU) rat model, PBM (425, 630, 730, and 850 nm, and a combination light strategy) promoted mDFU healing. The positive cell proliferation, re-epithelialization, angiogenesis, collagen synthesis, and inflammation were possible mechanisms. The combination strategy had the best effect, which can be applied clinically.     

复方多黏菌素B软膏在老年非手术糖尿病足溃疡创面修复中的应用

目的探讨复方多黏菌素B软膏在老年糖尿病足溃疡创面非手术修复中的应用。方法 128例老年糖尿病足患者根据创面使用药物不同随机分为试验组(复方多黏菌素B组)及对照组(磺胺嘧啶银组),每组64例。分别在开始治疗后1、2、3、4周观察比较两组患者创面组织细菌定量、创面愈合率及表皮生长因子的表达。结果 (1)在开始治疗后3周时试验组患者创面组织细菌定量均值小于对照组(P<0.05),第4周后明显小于对照组(P<0.01);(2)两组患者创面愈合率在治疗1、2、3周后无统计学差异,4周后试验组创面愈合率明显高于对照组(P<0.01);(3)治疗3周后两组患者创面的表皮生长因子比较有统计学差异(P<0.05),第4周差异更明显(P<0.01)。结论复方多黏菌素B软膏适用于全身感染已被控制但局部感染较重、高龄、基础病变多、难以承受多次麻醉手术清创后植皮封闭创面的老年患者,对治疗修复糖尿病足溃疡创面是一种安全、有效、简易的外用药物。     

Effects of vacuum-compression therapy on healing of diabetic foot ulcers: randomized controlled trial

A single-blind, randomized controlled trial was conducted to evaluate vacuum-compression therapy (VCT) for the healing of diabetic foot ulcers. Eighteen diabetic patients with foot ulcers were recruited through simple nonprobability sampling. Subjects were randomly assigned to either an experimental or a control group. Before and after intervention, the foot ulcer surface area was estimated stereologically, based on Cavalieri's principle. The experimental group was treated with VCT in addition to conventional therapy for 10 sessions. The control group received only conventional therapy, including debridement, blood glucose control agents, systemic antibiotics, wound cleaning with normal saline, offloading (pressure relief), and daily wound dressings. The mean foot ulcer surface area decreased from 46.88 +/- 9.28 mm(2) to 35.09 +/- 4.09 mm(2) in the experimental group (p = 0.006) and from 46.62 +/- 10.03 mm(2) to 42.89 +/- 8.1 mm(2) in the control group (p = 0.01). After treatment, the experimental group significantly improved in measures of foot ulcer surface area compared with the control group (p = 0.024). VCT enhances diabetic foot ulcer healing when combined with appropriate wound care.     

Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study

OBJECTIVE: To study the effect of systemic hyperbaric oxygenation (HBO) therapy on the healing course of nonischemic chronic diabetic foot ulcers. RESEARCH DESIGN AND METHODS: From 1999 to 2000, 28 patients (average age 60.2 +/- 9.7 years, diabetes duration 18.2 +/- 6.6 years), of whom 87% had type 2 diabetes, demonstrating chronic Wagner grades I-III foot ulcers without clinical symptoms of arteriopathy, were studied. They were randomized to undergo HBO because their ulcers did not improve over 3 months of full standard treatment. All the patients demonstrated signs of neuropathy. HBO was applied twice a day, 5 days a week for 2 weeks; each session lasted 90 min at 2.5 ATA (absolute temperature air). The main parameter studied was the size of the foot ulcer measured on tracing graphs with a computer. It was evaluated before HBO and at day 15 and 30 after the baseline. RESULTS: HBO was well tolerated in all but one patient (barotraumatic otitis). The transcutaneous oxygen pressure (TcPO(2)) measured on the dorsum of the feet of the patients was 45.6 +/- 18.1 mmHg (room air). During HBO, the TcPO(2) measured around the ulcer increased significantly from 21.9 +/- 12.1 to 454.2 +/- 128.1 mmHg (P < 0.001). At day 15 (i.e., after completion of HBO), the size of ulcers decreased significantly in the HBO group (41.8 +/- 25.5 vs. 21.7 +/- 16.9% in the control group [P = 0.037]). Such a difference could no longer be observed at day 30 (48.1 +/- 30.3 vs. 41.7 +/- 27.3%). Four weeks later, complete healing was observed in two patients having undergone HBO and none in the control group. CONCLUSIONS: In addition to standard multidisciplinary management, HBO doubles the mean healing rate of nonischemic chronic foot ulcers in selected diabetic patients. The time dependence of the effect of HBO warrants further investigations.     

Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo.

OBJECTIVE--To assess the efficacy of topically applied CT-102 APST for treating diabetic neurotrophic foot ulcers. RESEARCH DESIGN AND METHODS--Thirteen patients entered a randomized, double-blind trial of topically applied CT-102 APST vs. placebo (normal saline) gauze dressings for the treatment of nonhealing diabetic neurotrophic foot ulcers. CT-102 APST (Curative Technologies, Setauket, NY) was prepared from homologous platelets and contained multiple growth factors including PDGF, PDAF, EGF, PF-4, TGF-beta, aFGF, and bFGF. Inclusion criteria for subjects included diabetes, ulcer of > 8 wk duration, peri-wound transcutaneous oxygen tension > 30 mmHg, platelet count > 100,000/mm3, and no wound infection. Wounds were excised before entry and were > 700 mm3 but < 50,000 mm3 in volume, < 100 cm2 in area, and involved subcutaneous tissue. RESULTS--In the CT-102 group, 5 of 7 ulcers were healed (100% epithelialized) by 15 wk, but only 1 of 6 ulcers was healed by 20 wk with placebo (P < 0.05). Average percent reduction in ulcer area at 20 wk was 94% for CT-102 vs. 73% for placebo. Daily reduction in ulcer volume was 73.8 +/- 42.4 mm3/day (mean +/- SE) for CT-102 vs. 21.8 +/- 8.1 mm3/day for placebo (P < 0.05). Daily reduction in ulcer area was 6.2 +/- 1.8 mm2/day for CT-102 vs. 1.8 +/- 0.4 mm2/day for placebo (P < 0.05). CONCLUSIONS--CT-102 significantly accelerated wound closure in diabetic leg ulcers when administered as part of a comprehensive program for the healing of chronic ulcers.     

Evaluation of wound healing in diabetic foot ulcer using platelet-rich plasma gel: A single-arm clinical trial

The aim of the present study was to evaluate the effectiveness of using autologous platelet-rich plasma (PRP) gel for treatment of diabetic foot ulcer (DFU) during the first 4 weeks of the treatment. In this longitudinal and single-arm trial, 100 patients were randomly selected after meeting certain inclusion and exclusion criteria; of these 100 patients, 70 (70%) were enrolled in the trial. After the primary care actions such as wound debridement, the area of each wound was calculated and recorded. The PRP therapy (2 mL/cm² of ulcers) was performed weekly until the healing time for each patient. We used one sample T-test for healing wounds and Bootstrap resampling approach for reporting confidence interval with 1000 Bootstrap samples. The p-value < 0.05 were considered statistically significant. The mean (SD) of DFU duration was 19.71 weeks (4.94) for units sampling. The ratio of subjects who withdrew from the study was calculated to be 2 (2.8%). Average area of 71 ulcers in the mentioned number of cases was calculated to be 6.11 cm² (SD: 4.37). Also, the mean, median (SD) of healing time was 8.7, 8 weeks (SD: 3.93) except for 2 mentioned cases. According to one sample T-test, wound area (cm²), on average, significantly decreased to 51.9% (CI: 46.7–57.1) through the first four weeks of therapy. Furthermore, significant correlation (0.22) was not found between area of ulcers and healing duration (p-value > 0.5). According to the results, PRP could be considered as a candidate treatment for non-healing DFUs as it may prevent future complications such as amputation or death in this pathological phenomenon.     

Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial

OBJECTIVE: We assessed in a randomized prospective trial the effectiveness of Graftskin, a living skin equivalent, in treating noninfected nonischemic chronic plantar diabetic foot ulcers. RESEARCH DESIGN AND METHODS: In 24 centers in the U.S., 208 patients were randomly assigned to ulcer treatment either with Graftskin (112 patients) or saline-moistened gauze (96 patients, control group). Standard state-of-the-art adjunctive therapy, which included extensive surgical debridement and adequate foot off-loading, was provided in both groups. Graftskin was applied at the beginning of the study and weekly thereafter for a maximum of 4 weeks (maximum of five applications) or earlier if complete healing occurred. The major outcome of complete wound healing was assessed by intention to treat at the 12-week follow-up visit. RESULTS: At the 12-week follow-up visit, 63 (56%) Graftskin-treated patients achieved complete wound healing compared with 36 (38%) in the control group (P = 0.0042). The Kaplan-Meier median time to complete closure was 65 days for Graftskin, significantly lower than the 90 days observed in the control group (P = 0.0026). The odds ratio for complete healing for a Graftskin-treated ulcer compared with a control-treated ulcer was 2.14 (95% CI 1.23-3.74). The rate of adverse reactions was similar between the two groups with the exception of osteomyelitis and lower-limb amputations, both of which were less frequent in the Graftskin group. CONCLUSIONS: Application of Graftskin for a maximum of 4 weeks results in a higher healing rate when compared with state-of-the-art currently available treatment and is not associated with any significant side effects. Graftskin may be a very useful adjunct for the management of diabetic foot ulcers that are resistant to the currently available standard of care.     

湿性愈合疗法联合高压氧治疗糖尿病足溃疡的效果

目的 探讨湿性愈合疗法联合高压氧治疗糖尿病足溃疡的应用.方法 通过在临床实践中以传统换药为基础,再使用湿性愈合疗法联合高压氧治疗糖尿病足溃疡,评价患者对该疗法的满意度、切口愈合率、愈合时间、换药次数,并与单独使用传统换药相比较,进行两者之间的差异分析.结果 实验组显效18例（85.7％）,有效3例（14.3％）,对照组显效10例（47.6％）,有效6例（28.6％）,无效5例（23.8％）,两组比较差异有统计学意义（x2=5.68,P＜0.05）;愈合时间实验组需要（27.8±3.75）d,对照组需要（38.6±3.81）d,两组比较差异有统计学意义（t=9.2,P＜0.05）;换药次数实验组需要（15.6±3.45）次,对照组需要（24.8±3.62）次,两组比较差异有统计学意义（t=8.4,P＜0.05）;患者满意度实验组为95.4％优于对照组的68.9％,两组比较差异有统计学意义（t=5.15,P＜0.05）.结论 采用以传统换药为基础,再使用湿性愈合疗法联合高压氧治疗糖尿病足溃疡能明显提高创面愈合率,减少换药次数,减轻护士工作量,其结果可为合理应用该疗法促进糖尿病足溃疡愈合又可减少患者的痛苦提供临床依据.     

Obesity in pregnancy is a predictor of persistent subclinical myocardial dysfunction over postpartum period

The International Journal of Cardiovascular Imaging - No previous study provided a complete functional evaluation of all cardiac chambers in pregnant women with obesity. Moreover, the impact of...     

Effect of dalteparin on healing of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective,randomized, double-blind,placebo-controlled study

OBJECTIVE: Chronic foot ulcers are a common, severe, and expensive complication threatening life and limb in patients with diabetes. The aim of the present study was to investigate the effect of dalteparin on ulcer outcome in patients with diabetes, peripheral arterial occlusive disease, and chronic foot ulcers. RESEARCH DESIGN AND METHODS: A total of 87 patients were investigated in a prospective, randomized, double-blind, placebo-controlled trial. Participants were randomized to treatment with subcutaneous injection of 5000 units dalteparin (Fragmin, Pharmacia Corporation; n = 44) or an equivalent volume of physiological saline (n = 43) once daily until ulcer healing or for a maximum of 6 months. Ulcer outcome was investigated by evaluating the number of patients 1). who healed with intact skin; 2). in whom the study ulcer was improved, unchanged, or impaired; or 3). who were amputated above or below the ankle level, as compared with control subjects. RESULTS: Two patients, one on dalteparin and one on placebo, dropped out of the study. Ulcer outcome was significantly better (P = 0.042, two-sided chi(2) test for trend) in the dalteparin group (n = 43) compared with the placebo group (n = 42). A total of 29 patients healed with intact skin (n = 14) or decreased the ulcer area >or=50% (n = 15) in the dalteparin group compared with 20 (n = 9 and 11, respectively) in the placebo group. Five patients in each group showed impaired ulcer healing, i.e., the ulcer area increased >or=50%. Two patients in the dalteparin group were amputated compared with eight in the placebo group. Time to healing with intact skin was 17 +/- 8 weeks in the dalteparin group compared with 16 +/- 7 weeks in placebo group (NS). CONCLUSIONS: The results of the present study indicate that dalteparin improves the outcome of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease.     

The role of foot self-care behavior on developing foot ulcers in diabetic patients with peripheral neuropathy: A prospective study

BackgroundAlthough foot self-care behavior is viewed as beneficial for the prevention of diabetic foot ulceration, the effect of foot self-care behavior on the development of diabetic foot ulcer has received little empirical investigation.ObjectiveTo explore the relationship between foot self-care practice and the development of diabetic foot ulcers among diabetic neuropathy patients in northern Taiwan.MethodsA longitudinal study was conducted at one medical center and one teaching hospital in northern Taiwan.ParticipantsA total of 295 diabetic patients who lacked sensitivity to a monofilament were recruited. Five subjects did not provide follow-up data; thus, only the data of 290 subjects were analyzed. The mean age was 67.0 years, and 72.1% had six or fewer years of education.MethodsData were collected by a modified version of the physical assessment portion of the Michigan Neuropathy Screening Instrument and the Diabetes Foot Self-Care Behavior Scale. Cox regression was used to analyze the predictive power of foot self-care behaviors.ResultsA total of 29.3% (n = 85) of diabetic neuropathy patients developed a diabetic foot ulcer by the one-year follow-up. The total score on the Diabetes Foot Self-Care Behavior Scale was significantly associated with the risk of developing foot ulcers (HR = 1.04, 95% CI = 1.01–1.07, p = 0.004). After controlling for the demographic variables and the number of diabetic foot ulcer hospitalizations, however, the effect was non-significant (HR = 1.03, 95% CI = 1.00–1.06, p = 0.061). Among the foot self-care behaviors, lotion-applying behavior was the only variable that significantly predicted the occurrence of diabetic foot ulcer, even after controlling for demographic variables and diabetic foot ulcer predictors (neuropathy severity, number of diabetic foot ulcer hospitalizations, insulin treatment, and peripheral vascular disease; HR = 1.19, 95% CI = 1.04–1.36, p = 0.012).ConclusionsAmong patients with diabetic neuropathy, foot self-care practice may be insufficient to prevent the occurrence of diabetic foot ulcer. Instead, lotion-applying behavior predicted the occurrence of diabetic foot ulcers in diabetic patients with neuropathy. Further studies are needed to explore the mechanism of lotion-applying behavior as it relates to the occurrence of diabetic foot ulcer.