Neurogenic factors in the impaired healing of diabetic foot ulcers

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

The role of surgical debridement in healing of diabetic foot ulcers

An estimated 15% of patients with diabetes mellitus will develop a foot ulcer during their lifetime. Debridement is included in multiple guidelines and algorithms for the care of patients with diabetic neuropathic foot ulcers, and it has long been considered an essential step in the protocol for treating diabetic foot ulcers. In addition to altering the environment of the chronic wound, debridement is a technique aimed at removing nonviable and necrotic tissue, thought to be detrimental to healing. This is accomplished by removing abnormal wound bed and wound edge tissue, such as hyperkeratotic epidermis (callus) and necrotic dermal tissue, foreign debris, and bacteria elements known to have an inhibitory effect on wound healing. While the rationale for surgical debridement seems logical, the evidence for its role in enhancing healing is deficient. In this paper, we systematically review five published clinical trials, which met the criteria and investigated surgical debridement of diabetic foot ulcers to enhance healing. Most existing studies are not randomized clinical trials optimized to test the relationship between debridement of diabetic foot ulcers and wound healing. Therefore, a focused, well‐designed study is needed to elucidate the effect of surgical debridement on the healing status of chronic wounds.     

Validity of DMIST for monitoring healing of diabetic foot ulcers

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

不同部位糖尿病足溃疡愈合情况分析

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

The role of surgical debridement in healing of diabetic foot ulcers

A critical question in the treatment of chronic wounds is whether and when debridement is needed. The three most common chronic wounds are the diabetic foot ulcer (DFU), the venous leg ulcer, and the pressure or decubitus ulcer. Surgical debridement, aimed at removing necrotic, devitalized wound bed and wound edge tissue that inhibits healing, is a longstanding standard of care for the treatment of chronic, nonhealing wounds. Debridement encourages healing by converting a chronic nonhealing wound environment into a more responsive acute healing environment. While the rationale for debridement seems logical, the evidence to support its use in enhancing healing is scarce. Currently, there is more evidence in the literature for debridement for DFUs than for venous ulcers and pressure ulcers; however, the studies on which clinicians have based their rationale for debridement in DFUs possess methodologic flaws, small sample sizes, and bias. Thus, further studies are needed to develop clinical evidence for its inclusion in treatment protocols for chronic wounds. Here, the authors review the scientific evidence for debridement of DFUs, the rationale for debridement of DFUs, and the insufficient data supporting debridement for venous ulcers and pressure ulcers.     

Growth factors in the treatment of diabetic foot ulcers

BACKGROUND: 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. METHODS: A review of the current literature was performed using Pubmed, with secondary references obtained from key articles. RESULTS AND CONCLUSION: 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.     

Antibiotic treatment of infected diabetic foot ulcers

Antimicrobial treatment can be effective in diabetic foot ulcers. However, choosing the appropriate regimen depends on the clinical and microbial presentation. This review describes the factors practitioners need to consider.     

Fibronectin in hyperglycaemia and its potential use in the treatment of diabetic foot ulcers: A review

Metabolism of fibronectin, the protein that plays a key role in the healing of wounds, is changed in the patients with diabetes mellitus. Fibronectin can interact with other proteins and proteoglycans and organise them to form the extracellular matrix, the basis of the granulation tissue in healing wounds. However, diabetic foot ulcers (DFUs) suffer from inadequate deposition of this protein. Degradation prevails over fibronectin synthesis in the proteolytic inflammatory environment in the ulcers. Because of the lack of fibronectin in the wound bed, the assembly of the extracellular matrix and the deposition of the granulation tissue cannot be started. A number of methods have been designed that prevents fibronectin degradation, replace lacking fibronectin or support its formation in non-healing wounds in animal models of diabetes. The aim of this article is to review the metabolism of fibronectin in DFUs and to emphasise that it would be useful to pay more attention to fibronectin matrix assembly in the ulcers when laboratory methods are translated to clinical practice.     

Relationship between items of DMIST and healing of diabetic foot ulcers

A monitoring tool for the wound-healing process of diabetic foot ulcers (DFUs) was developed. It comprises seven domains, namely, depth, maceration, inflammation/infection, size, tissue type of the wound bed, type of wound edge, and tunnelling/undermining. It was named “DMIST” based on the initials of its domains. Although DMIST is useful for assessing wound-healing processes, the monitoring items related to wound healing remain unclear, thereby making the selection of optimal care based on the assessment difficult. We identified the relationship between the DMIST items and wound healing. This study was a secondary analysis of five previous investigations and was conducted using DMIST based on the diabetic foot ulcer assessment scale score and DFU images. Multivariate logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) after simultaneously controlling for potential confounders. The examined DFU healing status revealed that some DFUs healed at 4 weeks from baseline, whereas some DFUs did not. Variables considered in the models were the scores of each DMIST domain. The study population comprised 146 Indonesian patients and 33 Japanese patients. Depth, maceration, and size were associated with DFU healing at 4 weeks from baseline [depth: OR = 0.317 (95% CI: 0.145-0.693, P = 0.004); maceration: OR = 0.445 (95% CI: 0.221-0.896, P = 0.023); size: OR = 0.623 (95% CI: 0.451-0.862, P = 0.004)]. Our findings suggest that appropriate management of maceration promotes DFU healing.     

Nonsurgical strategies for healing and preventing recurrence of diabetic foot ulcers

We have outlined an approach to the nonsurgical treatment of diabetic foot ulcers based on an understanding of their etiology. We have emphasized the importance of off-loading as the crucial element to success in healing foot ulcers and preventing their recurrence in those with diabetes. Computerized design of custom insoles can allow the unloading of elevated plantar pressure while incorporating the shape of the foot, which was formerly the major criterion used insole design.     

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

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

Biomechanical concepts in the treatment of ulcers in the diabetic foot

The diabetic patient and the associated pedal abnormalities pose a particularly challenging problem for the doctor from both a management and a prevention standpoint. The sequellae of diabetes mellitus have both neurologic and vascular origins. Neurologically, the diabetic is predisposed to peripheral and autonomic neuropathy, while vascular aberrations may manifest anywhere in the arterial network. Secondary breakdown of cutaneous and osseous structures are the direct result of a chronic insensitivity to pain and a faulty healing mechanism. Healing is, at best, delayed due to this inborn error of glucose metabolism. Ulceration in the diabetic patient remains one of the most troublesome complications of diabetes mellitus. The most diligent and expeditious treatment will fall short nonetheless, if the patient has not been completely educated concerning his affliction. The association of patient education and the response to therapy cannot be overstressed. The diabetic should be educated concerning proper foot care and should be made aware of the serious complications that may result from improper hygiene and pedal neglect. The patient should not assume a passive role in the treatment, but rather, actively participate in his recuperation and rehabilitation. Frankly, it is the patient's understanding of the disease process as it affects the foot and his willingness to accept part of the responsibility for his foot care that will determine the ultimate success of the treatment. The biomechanical considerations that follow the primary management of the acute presentation of diabetic lesions, are aimed at preventing further breakdown and lesion formation by minimizing the adverse effects of gait or ambulation. Biomechanical methods of treating or preventing neuropathic diabetic ulcers have been examined. The conventional medical management of neuropathic and angiopathic ulcers includes antibiosis, local debridement, and bed rest. Due to today's lifestyle, complete bed rest is not always convenient for the patient and even cooperative patients may neglect to use crutches or minimize the problem of their ulcer due to the absence of pain. The methods discussed afford the patient a more normal lifestyle; however, proper patient compliance is required. Patients who use the total contact cast must be willing to keep their weekly appointments zealously and report any problems pertaining to their treatment. After the ulcer has been closed, the patient and doctor must realize that the battle is only half over. Steps must be taken in order to deter one of the most frequent complications, reoccurrence of the ulcer.(ABSTRACT TRUNCATED AT 400 WORDS)     

Healing of diabetic foot ulcers and pressure ulcers with human skin equivalent: a new paradigm in wound healing

HYPOTHESIS: In patients with diabetic foot and pressure ulcers, early intervention with biological therapy will either halt progression or result in rapid healing of these chronic wounds. DESIGN: In a prospective nonrandomized case series, 23 consecutive patients were treated with human skin equivalent (HSE) after excisional debridement of their wounds. SETTING: A single university teaching hospital and tertiary care center. PATIENTS AND METHODS: Twenty-three consecutive patients with a total of 41 wounds (1.0-7.5 cm in diameter) were treated with placement of HSE after sharp excisional debridement. All patients with pressure ulcers received alternating air therapy with zero-pressure alternating air mattresses. MAIN OUTCOME MEASURE: Time to 100% healing, as defined by full epithelialization of the wound and by no drainage from the site. RESULTS: Seven of 10 patients with diabetic foot ulcers had complete healing of all wounds. In these patients 17 of 20 wounds healed in an average of 42 days. Seven of 13 patients with pressure ulcers had complete healing of all wounds. In patients with pressure ulcers, 13 of 21 wounds healed in an average of 29 days. All wounds that did not heal in this series occurred in patients who had an additional stage IV ulcer or a wound with exposed bone. Twenty-nine of 30 wounds that healed did so after a single application of the HSE. CONCLUSIONS: In diabetic ulcers and pressure ulcers of various durations, the application of HSE with the surgical principles used in a traditional skin graft is successful in producing healing. The high success rate with complete closure in these various types of wounds suggests that HSE may function as a reservoir of growth factors that also stimulate wound contraction and epithelialization. If a wound has not fully healed after 6 weeks, a second application of HSE should be used. If the wound is not healing, an occult infection is the likely cause. All nonischemic diabetic foot and pressure ulcers that are identified and treated early with aggressive therapy (including antibiotics, off-loading of pressure, and biological therapy) will not progress.     

糖尿病足部溃疡外科保肢治疗进展

糖尿病足部溃疡是糖尿病的一个严重并发症,占非创伤性截肢的第1位。糖尿病足发病涉及足踝外科、血管外科、内分泌科.、感染控制,治疗方案需多学科联合诊治。清创术是治疗糖尿病足部溃疡的基础,清创过程中须注意维持足部正常解剖结构;负压封闭引流技术以及抗生素骨水泥在外科感染控制、溃烂创面愈合方面优势明显,疗效满意;肌腱延长术可缓解足底部应力集中导致的溃疡发生、进展等,其适应证广泛,优势在于既可预防足部溃疡形成也可治疗溃疡;皮瓣移植虽可以解决创口愈合问题,但是需要考虑移植皮瓣能否承担与足底组织相同的功能;胫骨骨搬运是一项较新的技术,具体机制还不清楚,但从临床疗效看具有一定的应用前景。     

The beneficial effect of motorised ankle dorsiflexion on the healing of diabetic foot ulcers

Many people with diabetes develop foot ulcers which, in extreme cases, lead to digit amputation. A small trial of a new device that induces ankle dorsiflexion improved peripheral circulation and resulted in the complete healing of all ulcers.     

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

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