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Preventing foot ulceration in diabetes: systematic review and meta-analyses of RCT data

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• Published: 27 November 2019
• Volume 63 , pages 49–64, ( 2020 )

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• Fay Crawford   ORCID: orcid.org/0000-0002-0473-9959 1 , 2 ,
• Donald J. Nicolson 1 ,
• Aparna E. Amanna 1 ,
• Angela Martin 1 ,
• Saket Gupta 1 ,
• Graham P. Leese 3 ,
• Robert Heggie 4 ,
• Francesca M. Chappell 5 &
• Heather H. McIntosh 6  

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Aims/hypothesis

Foot ulceration is a serious complication for people with diabetes that results in high levels of morbidity for individuals and significant costs for health and social care systems. Nineteen systematic reviews of preventative interventions have been published, but none provides a reliable numerical summary of treatment effects. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to make the best possible use of the currently available data.

We conducted a systematic review and meta-analysis of RCTs of preventative interventions for foot ulceration. OVID MEDLINE and EMBASE were searched to February 2019 and the Cochrane Central Register of Controlled Trials to October 2018. RCTs of interventions to prevent foot ulcers in people with diabetes who were free from foot ulceration at trial entry were included. Two independent reviewers read the full-text articles and extracted data. The quality of trial reporting was assessed using the Cochrane Risk of Bias tool. The primary outcome of foot ulceration was summarised using pooled relative risks in meta-analyses.

Twenty-two RCTs of eight interventions were eligible for analysis. One trial of digital silicone devices (RR 0.07 [95% CI 0.01, 0.55]) and meta-analyses of dermal infrared thermometry (RR 0.41 [95% CI 0.19, 0.86]), complex interventions (RR 0.59 [95% CI 0.38, 0.90], and custom-made footwear and offloading insoles (RR 0.53 [95% CI 0.33, 0.85]) showed beneficial effects for these interventions.

Conclusions/interpretation

Four interventions were identified as being effective in preventing foot ulcers in people with diabetes, but uncertainty remains about what works and who is most likely to benefit.

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Introduction

Foot ulceration is a serious complication of diabetes that can result in high levels of morbidity for individuals and burdens health and social care systems with huge costs [ 1 , 2 ]. Predicting those people most likely to develop a foot ulcer has been the subject of much research and the independent risk factors have been established [ 3 , 4 ]. However, the value of prediction models to inform treatment decisions depends on the availability of effective interventions to modify risk [ 5 ].

As part of a wider research project to create a cost-effective, evidence-based pathway for assessing and managing the foot in diabetes, we conducted an overview of existing systematic reviews to synthesise the available evidence on treatment effects (PROSPERO registration: CRD42016052324). Although the overview identified 19 published reviews [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], it failed to provide reliable numerical summaries of effects because of limitations of the reviews in scope, overlap and quality [ 25 ]. A comprehensive review of RCTs was required to enable us to make the best possible use of the data currently available and re-explore the possibility of performing meta-analyses.

Our aim was to systematically review data from RCTs of interventions used to prevent foot ulcerations in diabetes, and to conduct meta-analyses to obtain pooled estimates of their effects. We included data from RCTs only, as this is the only method of clinical evaluation that controls for known, unknown and unmeasured confounding.

The protocol can be viewed at www.journalslibrary.nihr.ac.uk/programmes/hta/1517101 .

Eligibility criteria

Trials were permitted to include people of any age with a diagnosis of type 1 or type 2 diabetes, with or without a history of ulceration, but free from foot ulceration at trial entry.

Simple interventions (e.g. education aimed at individuals with diabetes or physicians, or the provision of footwear) and complex interventions (where several interventions were provided together) were eligible for inclusion. Standard care or active treatment were eligible as comparators.

Primary outcomes

We were primarily interested in foot ulcers (incident, primary and recurrent) reported as binary outcomes (present/absent). These could be defined, for example, as ‘a full-thickness skin defect that requires more than 14 days to heal’ [ 26 ] or according to a system of ulcer classification [ 27 ]. Primary outcomes were the absolute numbers of incident primary ulcers and of incident recurrent ulcers.

Secondary outcomes

In reports where foot ulceration was the primary outcome we also sought data on amputation (minor: involving the foot [intrinsic to the foot]; or major: involving the foot and leg); mortality; gangrene; infection; adverse events; harms; time to ulceration; quality of life (measured using the EuroQol five-dimensions questionnaire or the six- or 12-item Short Forms); timing of screening; self-care; hospital admissions; psychological (knowledge/behaviour); and adherence to therapy.

We searched OVID MEDLINE (see electronic supplementary material [ESM] Table 1 ) and OVID EMBASE (from inception to February 2019) and the Cochrane Central Register of Controlled Trials (to October 2018) for eligible RCTs, without language restrictions. ClinicalTrials.gov was searched for ongoing clinical trials (search date: 21 February 2019).

Trial selection and data extraction

One reviewer screened all titles and abstracts and a 10% random sample was checked by a second reviewer. Two reviewers working independently screened full-text articles and extracted data (D. J. Nicholson, and either F. Crawford or A. E. Amanna) about the included populations, including the risk classification, interventions, comparators and outcomes. For each trial we extracted absolute numbers on an intention-to-treat basis, where the numbers randomised to each group were available, and calculated RRs and 95% CIs. Where reports lacked information or clarity, we contacted the trial authors. Non-English language reports were translated.

Risk of bias (quality) assessment

We assessed the quality of trial reporting using the Cochrane Risk of Bias tool [ 28 ]. The five domains we assessed were: random sequence generation, allocation concealment, blinding of assessors to the outcome, incomplete outcome data and selective reporting [ 28 ]. We also noted whether an a priori sample size calculation was reported [ 29 ].

Data analysis

Absolute numbers were extracted and RRs and 95% CIs were calculated. Where it made clinical and statistical sense to pool the data, we undertook meta-analyses with trial data weighted according to the inverse variance method and assessed heterogeneity using the I 2 statistic [ 28 ]. Analyses were conducted using R version 3.4.2 ( https://cran.r-project.org ).

From 10,488 studies, 22 RCTs met our eligibility criteria [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. A flow diagram showing the flow of information throughout the process of screening and selecting studies for inclusion in the review is presented in Fig. 1 and the characteristics of the included trials are described in Table 1 . Table 1 also incorporates the results from the risk of bias assessment; only five of the 22 trials [ 36 , 39 , 42 , 46 , 50 ] were judged to be at low risk of bias.

Flow diagram of study selection

Overall, the included trials assessed eight different types of interventions to prevent foot ulceration, which we grouped as follows: (1) education alone (three trials) [ 34 , 35 , 36 ]; (2) dermal infrared thermometry (four trials) [ 37 , 38 , 39 , 40 ]; (3) complex interventions (five trials) [ 41 , 42 , 43 , 44 , 45 ]; (4) custom-made footwear and offloading insoles (six trials) [ 46 , 47 , 48 , 49 , 50 , 51 ]; (5) digital silicone device (one trial) [ 32 ]; (6) antifungal treatment (one trial) [ 30 ]; (7) elastic compression stockings (one trial) [ 31 ]; and (8) podiatric care (one trial) [ 33 ].

Education alone

Three RCTs evaluated single-session education interventions of varying length and content for people at high risk of foot ulceration [ 34 , 35 , 36 ].

• Meta-analysis

( n  = 423) (Fig. 2a ) showed no statistically significant difference in the incidence of foot ulceration at 6 months compared with standard care and advice (RR 1.04 [95% CI 0.54, 1.97]) [ 34 , 35 , 36 ]. The quality of the included trials was variable, with only one trial [ 36 ] judged to be at low risk of bias across all domains. Other sources of potential bias arose from one trial [ 34 ] being stopped early and another [ 35 ] reporting an interim analysis before target recruitment was reached [ 52 ].

Forest plots of foot ulcers in people receiving standard care vs ( a ) education alone, ( b ) dermal infrared thermometry, ( c ) complex interventions and ( d ) custom-made footwear and offloading

Two trials of education interventions reported data on amputation [ 34 , 36 ], mortality [ 34 ], knowledge [ 34 ], behaviour [ 36 ] and/or quality of life [ 36 ]. No amputations were recorded for participants in either arm at 6 months’ follow-up in one trial [ 34 ]. The other trial reported 3/85 amputations in the intervention arm vs 0/85 in the control arm at 6 months, and no difference ( n  = 9 in both arms) at 12 months [ 36 ].

One trial [ 34 ] reported that two participants, one in each arm, had died by 6 months. In the same trial, a statistically significant difference in knowledge (as measured by the Patient Interpretation of Neuropathy knowledge score) was observed in the intervention arm [ 34 ].

One trial [ 36 ] reported on quality of life and found no differences between the two arms on the Diabetic Foot Scale, but higher scores for those in the education arm on the Nottingham Assessment of Functional Footcare questionnaire, which assesses behaviour, compared with the control group.

Dermal infrared thermometry

Four RCTs involving 468 participants with diabetes were identified [ 37 , 38 , 39 , 40 ]. In one trial [ 37 ], the numbers of participants randomised to either dermal infrared thermometry or standard care were not known, and so an RR and 95% CI could not be calculated.

A pooled analysis of data from three RCTs ( n  = 243) [ 38 , 39 , 40 ] found that dermal infrared thermometry reduced the number of foot ulcers in people with a history of foot ulceration (RR 0.41 [95% CI 0.19, 0.86]) (Fig. 2b ). Outcomes were collected between 6 and 15 months. The quality of these trials was variable, with only one trial [ 39 ] judged to be at low risk of bias across all domains.

Trials of dermal thermometry variously reported on amputation following infection [ 37 ], quality of life (36-item Short Form [SF-36]) [ 37 ], adherence to therapy [ 38 , 39 ] and time to ulceration [ 39 , 40 ].

In one trial, amputations following infections occurred in 0/41 participants in the intervention group vs 2/44 in the comparator group [ 38 ]. In the same trial there was no statistically significant difference in quality of life measured using SF-36 in any category or in the overall score [ 38 ].

Two trials [ 39 , 40 ] found no statistically significant difference between the dermal thermometry group and the comparator group in the time that prescribed footwear and insoles were worn, as measured using a self-report questionnaire containing an ordinal scale of <4 to >12 h/day. The time to ulceration was statistically significantly longer in the dermal thermometry treatment group compared with standard care in one trial [ 39 ] but not in another [ 40 ].

Complex interventions

Five RCTs evaluated the effects of complex interventions (i.e. integrated combinations of patient- or physician-level interventions and structural interventions) on the development of a foot ulcer [ 41 , 42 , 43 , 44 , 45 ].

A pooled analysis of data from five RCTs ( n  = 2587) showed that complex interventions statistically significantly reduced the number of foot ulcers (RR 0.59 [95% CI 0.38, 0.90]) at 1 or 2 year follow-up (Fig. 2c ), with little evidence of statistical heterogeneity ( I 2  = 10%; Fig. 2c ) despite the variety of interventions tested. However, with the exception of one trial [ 42 ], all had a high risk of bias and the validity of these data may be compromised. One trial gave no information about the participants’ risk category [ 44 ], while three included people with no history of foot ulceration [ 41 , 43 ]. One trial included people who were at low/moderate or high risk of developing a foot ulcer, found that 75% of ulcers occurred in people with higher levels of risk; for the highest risk category (category 4), 2/6 individuals in the intervention group and 2/3 individuals in the comparator group developed foot ulcers [ 41 ].

None of the individual trial results reached statistical significance and only one [ 42 ] reported an a priori sample size calculation; however, one trial [ 45 ] recruited everyone attending the foot care service.

Amputation [ 43 , 45 ], time to ulceration [ 41 ] and/or knowledge [ 43 ] were reported in three trials. In one trial [ 43 ] amputations occurred only in the control arm (2/31 vs 0/31 in the intervention arm), and in a second trial [ 45 ] there were fewer amputations in the intervention group (one major and six minor amputations) compared with the control group (12 major and 13 minor) [ 45 ]. The time to ulceration was shorter in the control group vs the intervention group in one trial, but this did not reach statistical significance [ 41 ].

In one trial participants’ knowledge about foot care, as measured using a diabetes knowledge questionnaire, was statistically significantly better in the intervention group compared with the control group [ 43 ].

Custom-made footwear and offloading insoles

Six RCTs evaluated custom-made footwear and offloading insoles [ 46 , 47 , 48 , 49 , 50 , 51 ].

A pooled estimate of data from six trials showed a beneficial association for custom-made footwear and offloading insoles on reducing the development of foot ulcers (pooled RR 0.53 [95% CI 0.33, 0.85]; Fig. 2d ) for outcomes collected at 12–24 months in 1387 people, of whom 464 had no history of foot ulceration. There was evidence of considerable statistical heterogeneity ( I 2  = 78%), which we explored using baseline risk of ulceration in a subgroup analysis (Fig. 3 ). This pooled analysis of four trials [ 46 , 47 , 50 , 51 ], all of which excluded people with no history of foot ulceration, failed to detect a statistically significant difference (RR 0.71 [95% CI 0.47, 1.06]). The six trials were of variable quality, with only two [ 46 , 50 ] having a low risk of bias across all five domains.

Subgroup analysis. Forest plot of foot ulcers in people with a history of foot ulceration receiving custom-made footwear and offloading vs standard care

Adherence [ 46 , 48 , 49 ] and/or cost [ 48 ] data were reported in four trials. One trial measured adherence using a temperature-based monitor placed inside the shoe, and found that 35/85 participants in the intervention group and 42/86 in the control group adhered to wearing their allocated footwear [ 46 ]. The trial authors conducted a subgroup analysis in participants who wore their allocated footwear, which showed a statistically greater reduction in ulcer recurrence in the intervention group; however, the analysis using data from the entire trial population failed to detect a beneficial association. A second trial of custom-made footwear and offloading insoles measured adherence using a self-reported physical activity questionnaire, and found that footwear and insole use was high in the groups who received cork inserts (83%) and prefabricated insoles (86%) [ 47 ]. A third trial measured participant compliance with footwear using self-reports of the number of hours per day that the shoes were worn. There were no statistically significant differences between each group in the number of people who wore the shoes for less than 4 h per day (23/149 vs 16/150), 4–8 h (77/149 vs 83/150), 8–12 h (38/149 vs 46/150) and 12–16 h (10/149 vs 6/150) [ 49 ].

Cost data collected in one trial published in 2012 found the cost of supplying footwear and insoles to be €675 per person per year [ 48 ].

Digital silicone devices

In one RCT of digital silicone devices [ 32 ], 167 participants with peripheral neuropathy, as defined by a vibration perception threshold of >25 V measured using a biothesiometer, and toe deformities (clawed toes, hallux valgus, interdigital lesions) were randomised to receive a bespoke silicone digital orthotic ( n  = 89) or standard care ( n  = 78). The number of ulcers was statistically significantly lower in the intervention group (RR 0.07 [95% CI 0.01, 0.55]) at 3 month follow-up. This trial had a low risk of bias in all domains except for allocation concealment, which was unclear.

Antifungal treatment

In a trial of antifungal nail lacquer, participants in the intervention group ( n =  34) received advice to inspect their feet daily and apply ciclopirox 8% to their toenails [ 30 ]. The control group ( n  = 36) received advice about daily foot inspections. A history of foot ulcers was reported by 57% of participants. After 12 months there were two ulcerations in each group (RR 1.06 [95% CI 0.19, 5.76]). The risk of bias was unclear in two domains: allocation concealment and blinding of the outcome assessor.

Elastic compression stockings

An RCT of elastic stockings randomly allocated 160 people with no history of foot ulceration to either knee-length elastic stockings worn for 6 h/day or standard care [ 31 ]. There were three ulcers in the intervention group and ten in the control group, a difference that was not statistically significant (RR 0.37 [95% CI 0.11, 1.02]). The trial had a high or unclear risk of bias in the domains of sequence generation, allocation concealment and assessor blinding.

Thirteen limbs were reported as lost during the 48 month trial; 3/74 in the intervention arm and 10/75 in the control arm.

Podiatric care

One trial compared free chiropody care ( n  = 47) with no chiropody care ( n  = 44) for people all at high risk of foot ulceration [ 33 ]. Those receiving free chiropody were recommended to seek care at least once per month. The control group could seek chiropody if they were willing to pay for it, and their standard care included advice on the possible benefits of regular chiropody. There was no statistically significant difference in the number of ulcerations in the two groups (RR 0.67 [95% CI 0.43, 1.05]). This trial had a low risk of bias in all domains except assessor blinding to outcome data, which was unclear.

There were 2/47 amputations in the intervention arm vs 1/44 in the control arm. Deaths were recorded as 2/47 in the intervention arm vs 4/44 in the control arm [ 33 ].

Data for other secondary outcomes of interest, such as gangrene, self-care, hospital admissions, timing of screening and adverse events or harms, were absent from the trial reports.

Ongoing trials

The search for ongoing trials of foot ulcer prevention in diabetes from the ClinicalTrials.gov website found 24 studies being conducted worldwide. The stated interventions in these studies are: physiotherapy ( n  = 1), skin temperature ( n  = 6), hygiene ( n  = 1), offloading insoles ( n  = 10), risk stratification ( n  = 2), PET-CT ( n  = 1), amniotic tissue ( n  = 1) and unclear ( n  = 2). The list of these studies can be obtained from the corresponding author.

The purpose of this systematic review was to evaluate the evidence base and obtain summary statistics for preventative interventions for foot ulceration in diabetes to create a cost-effective, evidence-based care pathway. The meta-analyses of dermal infrared thermometry, complex interventions and therapeutic footwear with offloading insoles suggest that these interventions can help prevent foot ulceration in people with diabetes.

The meta-analysis of data from RCTs of dermal infrared thermometry in people with a history of foot ulceration and a moderate to high risk of ulceration indicates that this is a promising intervention deserving of further evaluation in randomised trials with larger participant samples, and we note from our search of the ClinicalTrials.gov trial registry that new trials are currently underway. If foot ulcer prevention can be confirmed in large, well-conducted trials, this form of self-monitoring could relieve pressure on healthcare systems. However, advising individuals to abstain from all weight-bearing activities when foot temperatures rise by more than 4°C may prove challenging, and poor adherence might diminish any benefit in a real-world context outside of a trial setting.

Specialist foot care, of the type evaluated in the included trials of complex interventions, is considered a marker of good-quality diabetes service delivery and it is intuitively correct to suppose it leads to improved outcomes. While a statistically significant reduction in foot ulcers was apparent in our meta-analysis, such an effect was not evident in any single trial. This does support the suggestion of others that very large sample sizes may be needed for trials of this nature [ 53 ]. Surprisingly, there was a low level of statistical heterogeneity in the pooled data, despite quite marked differences in the clinical care provided in the intervention arms of the trials and the participation of people with three different levels of ulcer risk.

Our review did not identify any trials of complex interventions that reflect the composition of multidisciplinary foot services as recommended in clinical guidelines [ 54 , 55 , 56 ]. These influential documents advise the involvement of diabetologists, podiatrists, vascular surgeons, diabetes specialist nurses and orthotists as the core team in a diabetes foot care service, but patient outcomes from such healthcare service arrangements have not been evaluated in RCTs. An evaluation of outcomes from people at different levels of ulceration risk who receive care in specialist foot care settings would be worthwhile.

The true value of therapeutic footwear and offloading insoles in preventing foot ulcers has been obscured by contradictory trial results and poor interpretation of data in systematic reviews; two larger trials involving only those with a history of foot ulcers both failed to detect evidence of effectiveness [ 46 , 47 ], and visual inspection of our analyses of pooled data from all six trials shows greatest beneficial effect in those where the majority of participants were considered to be at high or moderate risk but had not experienced a foot ulcer [ 48 , 49 ], albeit only one reached statistical significance [ 48 ]. Our subgroup analysis of data from four trials of participants with a history of foot ulceration found no statistically significant difference in the number of recurrent ulcers between the custom footwear and control groups.

This observation calls into question the conclusions of other systematic reviews evaluating footwear and insoles in the prevention of foot ulcers [ 6 , 17 , 24 ]. The most recent included randomised and non-randomised data and adopted a consensus approach to the analysis. The reviewers concluded that: ‘The evidence base to support the use of specific self-management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong, but…is practically non-existent for the prevention of a first foot ulcer and non-plantar foot ulcer’ [ 24 ]. An individual participant data analysis using data from these six trials together with data from the ten ongoing studies of offloading insoles identified by our search of the ClinicalTrials.gov database could permit subgroup analyses to explore the value of footwear and offloading insoles in people with different baseline risks, and potentially resolve these ongoing uncertainties.

The marked reduction in ulcerations reported with the use of a dermal silicone device by individuals at high risk of ulceration is encouraging [ 32 ]. These devices are simple to make at the chair-side and easy for wearers to keep clean. Although they are a type of offloading intervention, we did not include these data in the meta-analysis of footwear and offloading insoles because they differ substantially in that they are only worn around the toes.

Three separate small trials [ 30 , 31 , 33 ] evaluating, respectively, the effects of a daily application of a fungal nail lacquer (ciclopirox 8%) with daily foot inspections, the use of elastic compression stockings and podiatry all failed to show a reduction in foot ulcers, possibly as a result of small sample sizes.

Strengths and limitations of this review

We have comprehensively reviewed a body of evidence from RCTs and made the fullest use of the data currently available to derive best estimates of treatment effects to inform a wider piece of work. In so doing we have highlighted uncertainties, gaps and limitations in the existing evidence base to inform practice, generated new research hypotheses and added value to this area of research.

The weaknesses of this review arise from the potential biases identified in many of the trial reports, especially for complex interventions, which may have produced unreliable results. Previous authors of systematic reviews have cited a lack of similarity between studies [ 13 ], lack of standardisation in terminology, prescription, manufacture and material properties of interventions [ 16 ], heterogeneity in study designs, methodology and participant populations [ 18 ], and differences in participant demographics [ 22 ] as reasons for not conducting meta-analyses, and we are aware of the potential limitations in the pooled analyses that we present here, both in the number and quality of trials. We have tried to produce conservative, less biased summary measures by adopting an intention-to-treat approach and a random-effects model. We acknowledge criticisms about the use of the latter [ 57 ], but believe the insights gleaned and the generation of new research hypotheses justifies our decision to pool data [ 58 ].

Conclusions

Our analyses found evidence of beneficial effects for four types of interventions used to prevent foot ulcers in people with diabetes, but considerable uncertainty remains about what works and who is most likely to benefit. Attention should be given to recommendations for the conduct of trials of interventions for the foot in diabetes, and researchers conducting future trials should endeavour to complete the trial to target recruitment as informed by an a priori sample size calculation [ 29 , 59 ].

Data availability

A copy of the extracted dataset can be obtained from the corresponding author.

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Acknowledgements

We thank M. Smith (NHS Fife librarian) and our public partner W. Morrison (Dunfermline, UK) for their help and enthusiasm during the project. We also thank the following for their kind replies to our requests for clarification and additional information about their trials: D. G. Armstrong (University of Southern California, Los Angeles, CA, USA), L. Cisernos (Universidad Federal de Minas Gerais, Brazil), C. Chan (University of Alberta, Edmonton, AB, Canada), J. Everett (University of Calgary, AB, Canada), M. Gershater (Malmö University, Sweden), T. Kelechi (Medical University of South Carolina, Charleston, SC, USA), L. Lavery (University of Texas, Austin, TX, USA), D. Litzelman (Indiana University, Bloomington, IN, USA), S. Morgan (University of Washington, Seattle, WA, USA) and A. Piaggesi (University of Pisa, Italy). We appreciate the help received from two anonymous journal referees for their insightful comments and suggestions for improving our manuscript.

Members of the wider project team who were not directly involved in this research were: K. Gray (R&D Department, NHS Fife), D. Weller (Department of General Practice, University of Edinburgh), J. Brittenden (Institute of Cardiovascular and Medical Sciences, University of Glasgow), J. Lewsey and N. Hawkins (both Health Economics and Health Technology Assessment [HEHTA], Institute of Health and Wellbeing, University of Glasgow).

This systematic review was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (HTA project: 15/171/01) as part of a wider project. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.

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Crawford, F., Nicolson, D.J., Amanna, A.E. et al. Preventing foot ulceration in diabetes: systematic review and meta-analyses of RCT data. Diabetologia 63 , 49–64 (2020). https://doi.org/10.1007/s00125-019-05020-7

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What Are Diabetic Foot Ulcers?

• 1 JAMA Contributing Writer
• Review A Review of Common Painful Foot and Ankle Conditions Minton Truitt Cooper, MD JAMA

Diabetic foot ulcers are wounds on the feet that develop in patients with type 1 or type 2 diabetes.

About one-third of people with diabetes develop a foot ulcer during their lifetime. Diabetic foot ulcers affect about 18.6 million people worldwide and 1.6 million in the US annually. Approximately half of diabetic foot ulcers become infected, and about 20% of these infections result in amputation of part of the foot or the whole foot.

How Do Diabetic Foot Ulcers Develop?

People with diabetes often develop damage to their peripheral nerves (neuropathy). Sensory neuropathy leads to decreased sensation of pain and pressure, which may cause people with diabetes not to feel a sharp object in their shoe that can puncture the skin and cause a foot ulcer. Foot deformities and dry skin, which often occur with diabetic neuropathy, can lead to formation of a callus on the foot. Repetitive stress from walking or minor cuts and scrapes on the foot can cause a callus to develop into an ulcer.

About 50% of people with a diabetic foot ulcer have peripheral artery disease, a condition that reduces blood flow to the legs. Individuals with diabetic foot ulcers and peripheral artery disease are at increased risk of developing infected ulcers and undergoing foot amputation.

How Are Diabetic Foot Ulcers Evaluated?

Clinicians should examine the size and depth of a diabetic foot ulcer and look for signs of infection. Ultrasound imaging should be performed to evaluate blood flow in the legs. For some patients with a diabetic foot ulcer, laboratory testing for elevated blood inflammatory markers and imaging studies (x-rays followed by magnetic resonance imaging [MRI] if needed) are performed to determine if a bone in the foot has become infected.

How Are Diabetic Foot Ulcers Treated?

Diabetic foot ulcers should be treated with wound care, surgical removal of any dead or infected tissue, and appropriate wound dressings. Patients with infected diabetic foot ulcers need treatment with antibiotics. A knee-high cast or prefabricated boot can help healing by reducing pressure on the ulcer. The risk of amputation is decreased when patients are cared for by a multidisciplinary care team, which typically includes a podiatrist, infectious disease specialist, vascular surgeon, and primary care clinician.

Patients with a diabetic foot ulcer and peripheral artery disease may undergo leg bypass surgery to restore blood flow to the foot, which can decrease the risk of amputation. Minimally invasive vascular surgical procedures (endovascular therapy) may also be used for patients with a diabetic foot ulcer and peripheral artery disease. Amputation of part or all of the foot may be required for patients with diabetic foot ulcers and infected bone.

Diabetic Foot Ulcer Treatment Outcomes

After 3 months of treatment, 30% to 40% of diabetic foot ulcers heal, but about one-quarter persist after 1 year of treatment. Diabetic foot ulcers recur after treatment in approximately 40% of patients at 1 year and 65% at 5 years.

How to Decrease Recurrent Foot Ulcers

People with a healed diabetic foot ulcer should be evaluated by a foot care professional every 1 to 3 months, receive instructions about how to properly monitor their feet, and be advised about footwear that fits well and reduces pressure on the feet.

For More Information

American Diabetes Association diabetes.org/diabetes/foot-complications

Published Online: November 17, 2023. doi:10.1001/jama.2023.17291

Conflict of Interest Disclosures: None reported.

Source: Armstrong DG, Tan TW, Boulton AJM, et al. Diabetic foot ulcers: a review. JAMA . 2023;330(1):62-75. doi:10.1001/jama.2023.10578

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Voelker R. What Are Diabetic Foot Ulcers? JAMA. 2023;330(23):2314. doi:10.1001/jama.2023.17291

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• Open access
• Published: 06 August 2022

A qualitative study of barriers to care-seeking for diabetic foot ulceration across multiple levels of the healthcare system

• Tze-Woei Tan   ORCID: orcid.org/0000-0002-6658-9482 1 , 2 ,
• Rebecca M. Crocker 3 ,
• Kelly N. B. Palmer 3 ,
• Chris Gomez 4 ,
• David G. Armstrong 1 , 2 &
• David G. Marrero 3  

Journal of Foot and Ankle Research volume  15 , Article number:  56 ( 2022 ) Cite this article

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Introduction

The mechanisms for the observed disparities in diabetes-related amputation are poorly understood and could be related to access for diabetic foot ulceration (DFU) care. This qualitative study aimed to understand patients’ personal experiences navigating the healthcare system and the barriers they faced.

Fifteen semi-structured interviews were conducted over the phone between June 2020 to February 2021. Participants with DFUs were recruited from a tertiary referral center in Southern Arizona. The interviews were audio-recorded and analyzed according to the NIMHD Research Framework, focusing on the health care system domain.

Among the 15 participants included in the study, the mean age was 52.4 years (66.7% male), 66.7% was from minority racial groups, and 73.3% was Medicaid or Indian Health Service beneficiaries. Participants frequently reported barriers at various levels of the healthcare system.

On the individual level, themes that arose included health literacy and inadequate insurance coverage resulting in financial strain. On the interpersonal level, participants complained of fragmented relationships with providers and experienced challenges in making follow-up appointments. On the community level, participants reported struggles with medical equipment.

On the societal level, participants also noted insufficient preventative foot care and education before DFU onset, and many respondents experienced initial misdiagnoses and delays in receiving care.

Conclusions

Patients with DFUs face significant barriers in accessing medical care at many levels in the healthcare system and beyond. These data highlight opportunities to address the effects of diabetic foot complications and the inequitable burden of inadequately managed diabetic foot care.

Peer Review reports

Diabetic foot ulceration (DFU) is a common and often catastrophic complication for people with diabetes. In the United States, people with diabetes have an up to 34% lifetime risk of developing a foot ulcer [ 1 , 2 ], a medical complication that increases their five-year mortality rate by 2.5 times [ 3 , 4 ]. Moreover, foot ulceration is a causal factor for up to 85% of diabetic patients who subsequently undergo lower extremity amputation [ 1 , 5 ]. As compared to the overall United States population, people with diabetes are more likely to undergo lower extremity amputation and repeat amputations [ 1 , 6 ]. The annual medical cost associated with DFU care in the United States is an additional $9–13 billion on top of other costs associated with diabetes [ 7 ].

Moreover, DFUs and subsequent amputations are unevenly patterned along lines of racial and ethnic minority status, low socio-economic status, low insurance coverage rates, and geographic isolation. African American, Hispanic, and Native American adults with diabetes have higher prevalence of DFUs and amputation than their White counterparts [ 8 , 9 , 10 ]. Across the board, patients in the lowest income quartiles experience higher odds of amputation and death due to peripheral artery disease [ 11 , 12 ]. In addition, those with suboptimal or no medical insurance are at an elevated risk of major amputation [ 13 ]. This illuminates a glaring and yet unabated public health problem, especially among minority and low-income populations [ 8 , 9 , 12 , 13 , 14 , 15 , 16 ].

The mechanisms of these observed disparities in DFU incidence and progression are poorly understood [ 9 , 11 , 17 , 18 ]. There is evidence, however, indicating that access to affordable and quality medical care, preventive services, and limb salvage care is an important contributing factor to disparities in amputation rates [ 19 , 20 , 21 ]. This qualitative study aimed to understand patients’ personal experiences with DFUs in a safety net health system, including their processes of navigating the healthcare system and the barriers they faced. The themes elicited in the study concerning multiple barriers at varying levels of the healthcare system will help to improve health care delivery in a population experiencing elevated risks of diabetes-related ulceration and amputation.

This qualitative study was designed to better understand the various challenges faced by patients with a history of DFUs and lower extremity amputations as they managed their conditions and sought medical care. Semi-structured interviews were conducted between June 2020 to February 2021 and the results were analyzed according to the “Health Care System” domain of the National Institute on Minority Health and Health Disparities Research Framework [ 22 ]. The University of Arizona Institutional Review Board approved the study in July 2019 (Protocol Number 1906749805).

Participants

Patients were selected from the Southwestern Academic Limb Salvage Alliance (SALSA), a multidisciplinary limb salvage care team located in Tucson, Arizona, to participate in semi-structured interviews. SALSA treats over 5,000 patient visits annually for diabetic foot problems, of which 40% are from racial and ethnic minority groups. It is the primary referral center for limb salvage and care for minorities and patients with low socioeconomic status in suburban and rural Arizona. Participants were identified and approached for participation during scheduled clinic appointments or by follow-up phone calls by our research team. We purposely sampled participants, using criterion sampling, to reflect the diverse range of race/ethnicity, gender, history of DFU, foot infection, minor amputation (below the ankle), and major amputation (ankle or above) treated by SALSA [ 23 ].

Interview guide and data collection

The research team jointly developed a semi-structured interview guide to encourage patient perspectives regarding their living experiences with foot ulceration and how they sought care for DFUs. Interviews were conducted in the patients’ preferred language (English or Spanish). Three research team members experienced in qualitative interviews (R.M.C., K.N.B.P., and D.G.M.) completed 15 interviews over the phone, lasting 40–60 min each. Interviews were recorded with consent using the “Tape A Call” mobile application ( www.tapeacall.com ) or via the University of Arizona Health Sciences Zoom Platform. The interviews were conducted in phases to allow for simultaneous analysis and redirection of subsequent data collection.

The research team used the Dedoose software version 9.0.17 (SocioCultural Research Consultants, LLC, Los Angeles, CA) to assist in data storage, coding, and data analysis. Audio files of the interviews were transcribed into the language spoken. After a quality assurance check, the transcriptions were uploaded into the software. The transcripts were independently reviewed and coded by three members of the research team (R.M.C., K.N.B.P., and T-W.T.). Data for this article were analyzed according to the NIMHD Research Framework (2017) that includes a multilevel approach including individual, interpersonal, community, and societal-level factors. While this model includes several domains, for the purposes of this paper we are focusing only on the Health Care System domain. This framework has been used in health disparities research to conceptualize and evaluate a wide array of determinants that promote or worsen health disparities [ 24 ]. Team members met regularly to compare coding results and resolve discrepancies by discussion and consensus.

The study sample included 15 participants (Table 1 ). The mean age was 54.2 years. Eleven participants (73.3%) were Medicaid or Indian Health Program beneficiaries and 80% of participants were either unemployed or had retired. All participants had history of at least one DFU, 12 had a history of foot infection, eight underwent minor amputations, and one had a major amputation. Four patients underwent at least one open surgery or endovascular procedure due to peripheral artery disease. During the interviews, participants frequently reported barriers at various levels of the health care system (Table 2 , Fig.  1 ).

Patient reported barriers at all levels influence of the health care system domain

Individual Level of Influence

Health literacy.

While most participants were aware of the risks of foot infection and amputation, there were significant gaps in their health literacy that compromised their ability to make informed decisions about when and how to seek medical care. Most notably, although all participants had a history of DFUs, many were unfamiliar with the term “ulcer” and expressed confusion when interviewers asked questions using that term. This finding, which reflects poor communication by providers and medical staff, resulted in most participants using alternate terms such as “blister,” “callous,” “cut,” “infection,” and “injury” to describe their foot abnormalities. This confusion in terminology was critical, as many patients described not initially seeking medical care because they interpreted their foot abnormality to be a common, everyday problem rather than one warranting medical attention. As one participant described: “Nobody ever really said what I’m looking for just anything that is not normal, I guess. But like I said, I have never heard of a diabetic foot ulcer.” (57-year-old Hispanic male, history of DFU).

In addition, participants described gaps in their health literacy related to the specifics of foot ulcer progression and the appropriate management strategies to prevent amputation. Most participants did not have a solid understanding of warning signs for when medical care should be secured for foot problems or what type of medical care should be sought. One frustrated participant stated: “If I had gotten better, like a different type of information that they could’ve given me, that might’ve helped me improve this ulcer to be going away. From what I have been given, you know, it’s just hard. I don’t know if it’s my foot itself or if it’s the medication. I don’t know. I don’t know if I am a unique case, I know there are people out there that have one foot. And they are able to get, probably, their ulcer better” (29-year-old Native female, history of DFU and recurrent foot infection).

Insurance coverage

While all participants had medical care coverage under Medicaid, Medicare, Indian Health Services or commercial insurance, the majority described significant medical expenses and financial strain related to their diabetes care in general, and in many cases to DFU care in particular. Most of the participants reported multiple recurring expenses such as medications (particularly insulin), co-payments for specialist visits and procedures, and the need for extensive travel, a financial strain that was frequently exacerbated by temporary or permanent loss of employment and under-employment. One participant said that following his second toe amputation: “I was in the hospital for 15 days, 13 days. They are charging me a copay, but I don’t have money to pay it. I am currently not working. I have social security and they don’t give me very much and it’s not enough to cover the copay.” (67-year-old Hispanic male, commercial insurance). In addition, many described substantial out-of-pocket payments for ancillary supplies, such as diabetic footwear and wound dressings due to inadequate insurance coverage, which often resulted in participants being unable to secure the supplies and care they needed for optimal DFU management. For example, a participant explained: “They want me to get diabetic shoes and the orthotic but at the time I didn’t have Medicaid … and with the deductible, they wanted $1,000 for the pair of shoes and the orthotic and I couldn’t afford it.” (45-year-old White female, Medicaid).

Interpersonal Level of Influence

Patient–clinician relationships.

Participants reported a wide array of levels of satisfaction with their medical providers, from long-standing personal and medically supportive relationships to negative experiences of not being listened to or being bounced from provider to provider. A predominant theme involved fragmented relationships with healthcare providers due to multiple factors including patients’ changes in residence, transitions in insurance status, providers leaving the area or switching practices, providers’ medical and holiday leave, and the COVID-19 pandemic. Given the complexity of managing their diabetes and related complications, these interruptions to patient-clinician relationships posed considerable barriers to effective disease management.

In addition, participants mentioned challenges in making timely appointments, and in getting time with their primary care physicians after major clinical events such as hospitalizations. One patient explained: “I had a lot of problems getting in contact with that doctor (primary care doctor). And after, I think it was the first four months after the amputation, and I just kept on trying to contact her… and I would try to call her, and she never returned my calls.” (47-year-old Hispanic male, history of multiple DFUs, foot infection, and toe amputation).

Similar challenges existed around establishing trusting relationships with the nurses that conducted home wound care following DFUs and amputations. This was due in large part to turnover in nursing staff or the rotation of nurses who conducted their home visits. A participant explained: “They [the companies] make a big deal about bringing the nurse in and have them trained on me and then two weeks later, I get a new nurse and redo it.” (45-year-old White female, underwent more than 20 procedures for DFUs).

Lastly, participants reported that the COVID-19 pandemic further intensified this lack of provider continuity due to limited in-person visits. For example, one participant described his struggles to connect with a new endocrinologist during the pandemic, stating: “I see him once and a current situation came up, so I haven’t been able to see him since then. [Due to the pandemic] it has been phone interviews, so, I haven’t really developed any significant rapport with my current endocrinologist.” (41-year-old White male, history of recurrent DFUs and toe amputations).

Community Level of Influence

Availability of services.

Participants commonly reported struggles with getting the medical equipment needed to prevent and manage their DFUs in a timely fashion, including offloading braces, dressing supplies, and therapeutic shoes and insoles. A few noted that the wound supplies provided by the hospital, clinic, or home healthcare companies ran out before their wounds had healed. One participant described maintaining medical supplies as his biggest challenge, saying: “The nurses themselves have been wonderful but their companies have been mainly touch-and-go with maintaining the supplies being delivered at an appropriate time” (41-year-old White male, Medicaid). Despite having prescriptions from physicians and insurance coverage, many participants also faced long waits for securing specialized diabetic shoes from medical supply companies, resulting in delayed or interrupted care. One participant described: "The insoles that I went in for, that they prescribed for me, it took me a long time to get them. Probably like three months after … and then when I got them, they, they were very flimsy, they didn’t last. It took me awhile to get another pair, a better design of the ones that they had” (47-year-old Hispanic male, self-employed, commercial health insurance).

Participants living in rural areas outside of Tucson cited additional challenges in managing their DFUs due to the time, expense, and distance involved in securing the elaborate routines of specialist appointments, routines, medications, and wound care necessary to effectively manage their DFUs. One participant described: “It was a difficulty because I am on the reservation and sometimes the medical things that I would need, like I said, insulin, the IV antibiotics, they wouldn't be able to come out here and do it. If I had lived in a city, then the people would come and get it done.” (38-year-old Native male, Medicare, rural Arizona).

Societal Level of Influence

Quality of care.

Many participants noted insufficient preventative foot care and education prior to DFU onset. Some reported that they did not learn about ulcer prevention until they developed DFUs. For example, one participant stated: “I don’t really remember (doctors) saying anything on ways to prevent other ulcers.” (38-year-old Native male, Medicaid and Indian Health Services). Some participants similarly reported that they did not receive routine foot examinations prior to developing their first DFU, even though they had regularly scheduled primary care appointments. One explained: “Well, early on they didn’t look at my feet. Before I got the ulcer, they didn’t look at them. They would just instruct me to check my blood sugar. But then after the ulcer and when they cut off my toe, that’s when they started to check my feet.” (67-year-old Hispanic male, commercial insurance).

Other barriers presented themselves while seeking adequate medical care for their new ulcers. Participants initially sought care from a variety of different venues— primary care doctors, podiatrists, specialists, emergency rooms, and urgent care clinics— as determined by how serious they interpreted their foot problems and insurance status and access issues. Some participants had the experience of being sent to multiple facilities in search of appropriate care, and those living in rural areas faced travel to different cities or towns. For example, a participant recalled that: “I went to the ER down here in XXX (a community hospital) and that was Friday (was discharged home) and then I saw my doctor on Monday and he sent me to XXX (a tertiary hospital) in Tucson.” (41-year-old White male, history of multiple DFUs and two toe amputations).

Many respondents experienced initial misdiagnoses and delays in receiving care. This included a few participants who presented for diabetic foot complications to acute care facilities, such as urgent care clincs and emergency rooms, and were sent home without an appropriate diagnosis, treatment, and follow-up. One woman recalled her frustrating journey that led to amputation:

‘I called my doctor…. She told me I want you to see an infectious disease doctor and have them put you on an IV antibiotic …. So, I get to the infectious disease doctor, and he says, ‘I’m not going to put you on antibiotic, it isn’t infected.’ So, that’s how I ended up with an amputation because he did not put me on any antibiotic. So, I went into the hospital, and they assigned me an infectious disease doctor and she came in, I’ll never forget this, and she started talking to me like I was stupid, and she goes, ‘You know you’re diabetic, you should’ve gone to a doctor right away ...’ And I said, ‘… hold on a second here, I am a very intelligent person and yes, I did, I went to my own doctor who made an appointment for me to see an infectious disease doctor.” (71-year-old White female, history of multiple DFUs and toe amputations)

Over the past two decades, substantial advances in diabetes therapy have greatly extended health and reduced morbidity. However, as evidenced in this article, significant obstacles to effective DFU treatment and management remain at multiple levels of the healthcare system. Some of these obstacles can be mitigated with more thoughtful education and alignment of access points to receive adequate health care. In this context we offer observations from our study to help address these deficits, particularly as they relate to decreasing notable health disparities.

An important individual level barrier is deficits in health literacy surrounding appropriate terminology to describe diabetic foot complications and how to make informed medical decisions about when to seek medical intervention [ 25 ]. Our findings suggest that a more aggressive and tailored education approach that guides patients to act quickly in seeking medical care and for rapid wound examination is warranted. Part of this education needs to emphasize that diabetes increases the infection and amputation risks of these seemingly “minor” foot injuries. Burdensome expenses related to DFU care posed a second individual level barrier, suggesting the need for continued advocacy for full coverage of DFU care among safety net insurance providers [ 26 , 27 ].

On the interpersonal level, our data illustrate that disruptions to the patient-clinician relationship damages rapport with patients and hinders optimal DFU care. Study participants frequently reported difficulties in accessing appropriate health care providers and disruptions to the patient-physician relationship due to the turnover of providers, changes to region and insurance status, and other factors. This gap calls for developing solutions to address medical provider shortages and to “fill in” health care assessment in a timely manner. One potential approach is to expand the use of trained community health workers who can help triage persons with differing levels of foot ulcers to available health care providers who work outside of the patient’s known environment [ 28 , 29 ].

On the community level, despite having appropriate prescriptions and insurance coverage, participants described significant challenges receiving medical equipment, which was often perceived to be due to shortcomings at the medical supply companies. Since most persons with diabetes see their pharmacist more frequently than any other member of their health care team, developing collaborations between pharmacies, providers, or healthcare system in which pharmacists take on the role of providing medical equipment such as wound care supplies or diabetic shoes, may be an effective approach. Pharmacist supported diabetes care has been shown to be well received by minority patients and to result in improved diabetes outcomes [ 30 , 31 ].

Finally, on the societal level, there is a need to improve preventive care for DFUs on the primary care physician level, a crucial strategy for limb salvage. The American Diabetes Association recommends that all patients with diabetes have their feet inspected at each doctor visit and have a comprehensive foot evaluation at least annually to identify risk factors for DFUs [ 32 ]. Greater focus needs to be placed on educating medical providers and patients, and on the importance of preventive foot care including self-foot inspection, foot examination by a medical professional, and the use of appropriate footwear. In addition, given that sample participants commonly reported receiving misdiagnoses and delays after seeking medical care for DFUs, a standardized protocol and care pathway for when, where, and how patients should seek initial DFU care and how the DFUs should be treated are imperative. Because delays occur both before and after seeking care, a focus must be made to educate both patients and providers about the standard protocol [ 33 ].

There are limitations to this study which should be considered when interpreting the results. Given the relatively modest sample size, we were not able to analyze the data for gender or age effects or by duration of diabetes. Nonetheless, this hard to reach patient sample representing a diverse population did offer very similar stories about the experiences and health disparities they faced in dealing with DFUs.

Diabetic foot ulceration remains a common and life-altering disease complication and one that disproportionately burdens people of racial and ethnic minority status, low socio-economic status, low insurance coverage, and those residing in rural areas. Our study examined the lived experience of a sample of persons with diabetes that face significant barriers at all levels of the healthcare system. Their stories highlight the importance of selecting multiple points of entry to make significant improvements in peoples’ health literacy, relationships with providers, and access to quality and effective medical care, services, and medical supplies. Moreover, this approach should creatively incorporate multiple possible modes of service delivery, including the integration of community health workers and pharmacists. While there are considerable challenges to achieving this goal, concerted efforts are needed to reduce DFUs’ devastating effects on mortality and morbidity and the inequitable burden of poorly managed diabetes foot care among highly affected populations.

Availability of data and materials

The de-identified qualitative data that support the findings of this study are available from corresponding author upon reasonable request.

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Acknowledgements

Our team acknowledge the participants of the study.

The project is supported by a National Institute of Diabetes and Kidney Disease K23 Mentored Patient-Oriented Research Career Development Award (1K23DK122126) and a Society of Vascular Surgery Foundation Mentored Research Career Development Award Program (T-W.T) and a National Institute of Diabetes and Kidney Disease R01 (1R01124789) Award (D.G.A).

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Tze-Woei Tan: Conceptualization, Methology, Validation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing, Supervision, Project Administration, Funding Acquisition. Rebecca M. Crocker: Conceptualization, Methology, Validation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing. Kelly N.B. Palmer: Conceptualization, Methology, Validation, Formal Analysis, Writing – Review & Editing. Chris Gomez: Methology, Validation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing. David G. Armstrong: Conceptualization, Methology, Writing – Review & Editing. David G. Marrero: Conceptualization, Methology, Validation, Formal Analysis, Writing – Original Draft, Writing – Review & Editing. The author(s) read and approved the final manuscript.

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Tan, TW., Crocker, R.M., Palmer, K.N.B. et al. A qualitative study of barriers to care-seeking for diabetic foot ulceration across multiple levels of the healthcare system. J Foot Ankle Res 15 , 56 (2022). https://doi.org/10.1186/s13047-022-00561-4

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• Published: 19 June 2024

The risk factors in diabetic foot ulcers and predictive value of prognosis of wound tissue vascular endothelium growth factor

• Jing Xu 1   na1 ,
• Jian Gao 2   na1 ,
• Hui Li 3   na1 ,
• Zhoujun Zhu 2 ,
• Junliang Liu 4 &
• Chong Gao 5  

Scientific Reports volume  14 , Article number:  14120 ( 2024 ) Cite this article

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• Endocrine system and metabolic diseases

Diabetic foot ulcer (DFU) is a leading cause of high-level amputation in DM patients, with a low wound healing rate and a high incidence of infection. Vascular endothelial growth factor (VEGF) plays an important role in diabetes mellitus (DM) related complications. This study aims to explore the VEGF expression and its predictive value for prognosis in DFU, in order to provide basis for the prevention of DFU related adverse events. We analyzed 502 patients, with 328 in healing group and 174 in non-healing/recurrent group. The general clinical data and laboratory indicators of patients were compared through Spearman correlation analysis, ROC analysis and logistic regression analysis. Finally, the independent risk factors for adverse prognosis in DFU patients were confirmed. Spearman analysis reveals a positive correlation between the DFU healing rate and ABI, VEGF in wound tissue, and positive rate of VEGF expression, and a negative correlation with DM duration, FPG, HbA1c, TC, Scr, BUN, and serum VEGF. Further logistic regression analysis finds that the DM duration, FPG, HbA1c, ABI, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression are the independent risk factors for adverse prognosis in DFU ( p  < 0.05). DM duration, FPG, HbA1c, ABI, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression are the independent risk factors for prognosis in DFU patients. Patients with these risk factors should be screened in time, which is of great significance to prevent DFU related adverse events and improve outcomes.

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Introduction.

Diabetic foot (DF) is a common complication of diabetes mellitus (DM) patients, which is clinically manifested as foot infection, ulcer or deep tissue destruction, with an alarming incidence rate of 20%. It is long term incurable, and even leads to amputation 1 . Epidemiological data show that the amputation rate of DF patients is 19.03%, while the annual mortality rate is as high as 16.26%, which seriously threatens the life quality and safety of patients 2 . Peripheral vascular disease is the main cause of diabetic foot ulcer (DFU). When the blood vessels are ischemic, it is necessary for lower extremity to establish the collateral circulation through arteriogenesis and angiogenesis. During this period, the role of vascular growth factor is particularly important 3 . As the main angiogenesis factor, vascular endothelial growth factor (VEGF) is involved in cancer, infection and other vascular dependent diseases. Current studies have confirmed that the level of serum VEGF in DM patients is associated with DM related complications, especially the increase in the severity of lower extremity vascular disease. There are various isoforms of VEGF. VEGF-A promotes early events of angiogenesis, including endothelial cell migration and proliferation. VEGF-A can improve the re-epithelization of diabetes wounds, and can be applied to the treatment of chronic wounds such as DFU, venous stasis ulcer and pressure ulcer with local skin ischemia. VEGF-C accelerates diabetic wound healing by enhancing angiogenesis as well as lymphangiogenesis in the granulation tissue. Generation of new lymphatic vessels in the wound should facilitate the exit of excess fluid and leukocytes and concomitantly decrease the edema associated with the inflammatory response. Also VEGF-A possesses lymphangiogenic effects but these effects were not as pronounced as with VEGF-C 4 , 5 , 6 . However, there are few clinical studies on the correlation between expression of VEGF in serum/tissue and wound healing in DFU patients with chronic refractory wounds 7 .

Therefore, analyzing the expression of VEGF in wound tissue has important clinical significance for the prevention and treatment of DFU. This study aims to explore the VEGF expression and its predictive value for prognosis in different degrees of DFU, in order to provide basis for clinicians to prevent DFU related adverse events.

Patient case selection

We obtained ethical approval exemption from the Second People’s Hospital of Lianyungang Ethics Committee to perform this study since we did not have direct contact with the participants. Informed consent was obtained from all participants and/or their legal guardians. We confirm that all methods were performed in accordance with the relevant guidelines and regulations. Patients treated for Type 2 DM combined with DFU in database records of our hospital were retrospectively analyzed from Jan 1, 2017, to Mar 31, 2023 (updated medical record system was used since Jan 1, 2017). Those who had complete medical records and met the 1999 WHO diabetes diagnostic criteria 8 were selected. The exclusion criteria including: (1) patients diagnosed as Type 1 or gestational DM; (2) patients with acute complications such as diabetic ketoacidosis and hyperosmolar coma; (3) patients with primary liver and kidney function impairment, and/or blood and immune system diseases; and (4) patients receiving glucocorticoid, Immunosuppressive drug or chemotherapy drugs. The healing of DFU was defined as: (1) complete wound healing within one year of treatment, with no new ulcers; (2) wound not healed within one year of treatment; (3) original ulcer healed within one year of treatment, new ulcer at the healed ulcer site; and (4) original ulcer healed within one year of treatment, new ulcer in other areas or on the other foot. According to Wagner’s grading, there were 35 cases of level 1, 247 cases of level 2, 139 cases of level 3, 61 cases of level 4 and 20 cases of level 5.

Based on whether the wound healed after treatment, all patients were divided into a healing group and an non-healing/recurrent group.

Observation indicators

The general clinical data were collected respectively, including age, sex, DM duration and ankle brachial index (ABI, the ratio of systolic pressure between ankle artery and brachial artery). Meanwhile, the laboratory indicators of patients were compared, including fasting plasma glucose (FPG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), blood urea nitrogen (BUN), C-reactive protein (CRP), serum creatinine (Scr), serum uric acid (SUA), glycosylated hemoglobin (HbA1c). All the above indicators were derived from the patient database.

In addition, the expression of VEGF was measured by the authors using ELISA (in serum) and Western Blot (in wound tissue). The peripheral venous blood (1.5 ml) was collected and then centrifuged at 3000 r for 10 min to separate red blood cells. Blood anticoagulant was added and the blood was centrifuged again at 3000 r for 10 min. 100 μl of supernatant was taken for testing. The absorbance of the sample was tested at a wavelength of 450 nm by ELISA reader. The wound tissues from both groups were collected and placed in 1.5 ml tubes. Protein was extracted by adding lysis solution, and VEGF was determined after electrophoresis, electroporation, elution, blocking, overnight incubation with mouse-anti human VEGF antibody, elution, secondary antibody, and then re-elution. The remaining tissue was fixed with 4% 0.01 mol/L (pH = 7.4) polyformaldehyde, dehydrated with ethanol, made transparent with xylene, and embedded in paraffin for section. Rabbit-anti human monoclonal VEGF antibody was added (1:100), incubated in water bath for 1 h, and then secondary antibody for 30 min. After immunohistochemical staining, the uniformly stained area was observed under a high-power microscope.

Statistical analysis

Statistical analysis was conducted using Statistical Packages of Social Sciences (SPSS) software (version 26.0). Quantitative data following a normal distribution were represented as \(\overline{x} \pm s\) , and comparisons between two groups were made using the t -test. Meanwhile, nonnormally distributed variables was compared through non parametric tests. Categorical data were represented as n (%), and analyzed using the chi-square test. The correlation between DFU and various indicators was analyzed using Spearman correlation analysis. The factors which had close correlation with poor healing of DFU were further analyzed using logistic regression analysis. We used the receiver operating characteristic (ROC) curve to evaluate the non-healing risk of wounds in DFU which was predicted by VEGF expression. Statistical significance was set at p  < 0.01 or p  < 0.05.

Ethics approval and consent to participate

The study was reviewed by the Second People’s Hospital of Lianyungang Ethics Committee. We obtained ethical approval exemption since we did not have direct contact with the participants.

A total of 502 consecutive cases are involved in the current study, including 235 males and 267 females with a mean age of 65.71 ± 9.43 years (ranges from 38 to 79 years). There are 328 cases in the healing group and 174 cases in the non-healing/recurrent group. The detailed patient information is shown in Table 1 .

Comparative analysis of general data and laboratory indicators

In the non-healing/recurrent group, the DM duration, FPG, TC, HbA1c, CRP, BUN, Scr, and serum VEGF are significantly higher than those in the healing group ( p  < 0.001, p  = 0.035, p  < 0.001, p  = 0.017, p  < 0.001, p  = 0.009, p  = 0.012, p  = 0.026, respectively). Conversely, ABI, LDL-C, HDL-C, SUA, VEGF in wound tissue, and positive rate of VEGF expression are significantly lower than those in the healing group ( p  < 0.001, p  = 0.019, p  = 0.030, p  = 0.013, p  = 0.024, p  = 0.008, respectively) (Table 1 ).

Spearman correlation analysis between DFU and various indicators

The Spearman correlation analysis shows a positive correlation between the healing rate of DFU and ABI, HDL-C, LDL-C, VEGF in wound tissue, and positive rate of VEGF expression ( p  = 0.008, p  = 0.018, p  = 0.032, p  < 0.001, p  < 0.001, respectively). A negative correlation is observed with the DM duration, FPG, HbA1c, TC, Scr, BUN, and serum VEGF ( p  < 0.001, p  = 0.020, p  = 0.019, p  = 0.017, p  = 0.025, p  = 0.015, p  < 0.001, respectively), as shown in Table 2 .

ROC analysis of VEGF and its predictive value for prognosis

The area under the ROC curve (AUC) for serum VEGF is 0.728 ( p  < 0.001), with a cut-off point of 1.77 μg/L, a sensitivity of 89.50%, and a specificity of 57.30%. The AUC for VEGF in wound tissue is 0.790 ( p  < 0.001), with a cut-off point of 1.24 μg/L, a sensitivity of 93.00%, and a specificity of 65.10%. The AUC for positive rate of VEGF expression in wound tissue is 0.759 ( p  < 0.001), with a sensitivity of 89.10%, and a specificity of 74.30%. These results suggest that the level of VEGF and its expression in the local ulcer wounds have predictive value for the long-term prognosis of patients (Fig.  1 ).

ROC curve for predicting wound healing in patients with DFU.

Logistic regression analysis of risk factors for DFU

The logistic regression analysis is conducted with DFU as the dependent variable and DM duration, ABI, FPG, HbA1c, TC, Scr, BUN, HDL-C, LDL-C, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression as the independent variables. The analysis shows that DM duration, ABI, FPG, HbA1c, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression are significant risk factors for non-healing/recurrent DFU ( p  < 0.001, p  = 0.013, p  < 0.001, p  = 0.020, p  < 0.001, p  < 0.001, p  < 0.001, respectively) (Table 3 ).

Model discrimination and consistency validation

The discriminatory ability of the model is assessed using the concordance index (C-index), yielding a calculated C-index of 0.896 (95% CI 0.782–0.997, p  < 0.01). This result indicates a strong discriminatory power of the model in predicting the risk of poor wound healing in DFU patients. The goodness-of-fit test for the predictive model revealed no significant discrepancy between the predicted and actual values ( p  > 0.05), suggesting that the model is robust and aligns well with the actual probability of risk occurrence, thereby demonstrating high calibration and reliability.

Studies have indicated that a hyperglycemic environment predisposes to distal limb neuropathy, vascular disease, and peripheral circulatory disorders 9 , 10 . This results in a lack of normal neuroprotective mechanisms in the foot, reduced blood supply, inadequate nutrient provision, and ultimately, local ulceration or even total foot necrosis. DFU is a leading cause of high-level amputation in DM patients, with a low wound healing rate and a high incidence of infection. The 5-year postoperative survival rate is less than 60%, significantly impacting patients' physical and mental health and quality of life 11 .

In this study, the Spearman analysis reveals a positive correlation between the DFU healing rate and ABI, VEGF in wound tissue, and positive rate of VEGF expression, and a negative correlation with DM duration, FPG, HbA1c, TC, Scr, BUN, and serum VEGF. However, after further multivariate logistic regression analysis, it is found that the DM duration, FPG, HbA1c, ABI, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression are the independent risk factors for adverse prognosis in DFU patients.

Long-term increase in blood glucose level can inhibit cell growth, promote vascular endothelial apoptosis, and induce arteriosclerosis, which is detrimental to the healing of the wound 12 . The content of HbA1c depends on the concentration of blood glucose and the duration of contact between blood glucose and hemoglobin. It is not affected by such factors as the time of blood collection, fasting and insulin use. Compared with blood glucose measurement, it has fewer influencing factors and can better reflect the long-term control of blood glucose level 13 . In addition, a longer DM duration usually brings more pain to patients, making them less compliant to the treatment, which means that it is more difficult for patients to control the blood glucose level 14 . This study suggests that when the DM duration, FPG and HbA1c are higher, non-healing or recurrence is more likely to occur. However, the meta-analysis of Huang et al. 15 shows that there is no significant relationship between the DM duration and the recurrence of DFU. The regional and ethnic differences may be the reason for the contrary.

ABI is a screening and diagnostic tool for peripheral artery disease recommended by the American Diabetes Association. The decrease of blood flow is an important reason for the recurrence of DFU, and ABI is an important indicator used to evaluate vascular status. Previous studies have also shown that ABI is closely related to the Wagner grading of DF 16 , 17 . The abnormal ABI indicates arterial ischemia or calcification which leads to vascular endothelial cell damage and variation, peripheral neuropathy, and even extremity gangrene 18 . The result of this study suggests that DFU are more prone to adverse prognosis when ABI is lower, which is consistent with most studies 12 , 19 .

VEGF is a key regulator of vascular function, with vascular endothelial cells serving as both the target and source of VEGF 20 . In the context of injury, VEGF stimulates endothelial cell mitosis, enhances vascular permeability, and protects neurons, thereby promoting angiogenesis. Microcirculatory disturbance is one of the important pathophysiological bases of DM associated peripheral neuropathy. Poor blood glucose control in DM patients can lead to vascular structural changes such as thickening of microvascular basement membrane, swelling and proliferation of endothelial cells, and increased vascular permeability. These changes in microcirculation can cause the occurrence and development of DM associated peripheral neuropathy by causing energy metabolism disorder, sorbitol accumulation and inositol depletion, and abnormal increase of oxidative stress. At this time, the level of VEGF increases to promote angiogenesis and neural repair. Our results indicate that DFU patients in non-healing/recurrent group show higher serum VEGF. Therefore, higher serum VEGF is associated with DM associated peripheral neuropathy which is a precursor for DFU. The expression of VEGF in wound tissue is influenced by local oxygen concentration and hormone levels, and it synergizes with other cytokines and growth factors to facilitate wound repair 21 . Meanwhile, VEGF can also indirectly increase collateral circulation flow and restore blood supply. Studies have found that it can promote the repair of skin wound in DFU rats by regulating the increase of VEGF level, and the VEGF expression level in skeletal muscle of DFU patients is significantly lower than that of non-DM patients with lower extremity atherosclerosis and occlusion 22 , 23 . At all time points after injury, the VEGF expression level on wound surface of DM rats is lower than that of normal rats. Moreover, the decrease in VEGF expression level in ischemic extremities will lead to a significant reduction in collateral circulation around the occluded vessels 24 . Finally, the low VEGF expression level causes insufficient collateral compensation and progression of refractory persistent ischemic ulcers. Our result indicates that the VEGF expression has important clinical significance in judging prognosis of DFU. In view of this, VEGF may be a therapeutic target for DFU. Given the escalating incidence of DM, understanding the role of VEGF expression in DFU wound tissue is crucial for patient prognosis, wound healing, prevention of secondary infections, and effective management of DFU recurrence.

The present study, to our knowledge, is the first study evaluating related risk factors and simultaneously exploring VEGF expression in wound tissues and its predictive value of prognosis in DFU. However, there are still several limitations in the current study, Firstly, the relatively small sample size (because of our newly updated medical record system). Expanding our sample population will better eliminate data bias and reduce errors as much as possible, or even obtain a definite subversive result. Secondly, microvascular complications (diabetic retinopathy, diabetic nephropathy, etc.) were not included in our analysis as potential risk factors because of limited evaluable data. Gazzaruso et al. 25 showed that the absence of diabetic retinopathy and nephropathy were independently associated with DFU healing, and retinopathy was a predictor both of minor amputation and mortality. Moreover, a 7-year follow-up cohort study by Olesen et al. 26 indicated that microvascular disease was independently associated with a threefold increase of amputation risk. These findings imply that microvascular complications of DM may be used as potential markers of worse outcomes in DF. Thirdly, this study did not include TcPO2 as an evaluating indicator of DM peripheral vascular disease. We should note that ABI may lose its diagnostic power when artery calcifications presents. Literature has showed that TcPO2 is a potential predictor of major adverse cardiovascular events among patients with uncomplicated type 2 DM and that its predictive value seems to be greater than that of ABI 27 . Finally, the subjects included in this study all belong to single center, which relatively limiting the research region. Therefore, high-quality, large sample, and multicenter clinical and basic mechanism studies should be performed in our future clinical work to provide physicians with the best evidence-based information.

In conclusion, DM duration, FPG, HbA1c, ABI, serum VEGF, VEGF in wound tissue, and positive rate of VEGF expression are the independent risk factors for prognosis in DFU patients. Patients with these risk factors should be screened in time, which is of great significance to prevent DFU related adverse events and improve outcomes. In addition, these risk factors may be considered as predictors for adverse prognosis of DFU, providing evidence for the prevention and treatment of severe complication such as gangrene requiring amputation in future works.

Data availability

All supporting data can be provided upon request to the authors. Jing Xu should be contacted if someone wants to request the data.

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This study was funded by: Natural Science Foundation of Xinjiang Uygur Autonomous Region, No.: 2022D01C583; Natural Science Foundation of Bengbu Medical College, No.: 2020byzd338.

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These authors contributed equally: Jing Xu, Jian Gao and Hui Li.

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Department of Oncology, The Second People’s Hospital of Lianyungang, No. 41 Hailiandong Road, Haizhou District, Lianyungang, 222006, China

Department of Orthopedics, The Sixth Affiliated Hospital of Xinjiang Medical University, No. 39 Wuxingnan Road, Tian Shan District, Urumqi, 830002, China

Jian Gao & Zhoujun Zhu

Department of Internal Medicine, Urumqi Maternal and Child Health Care Hospital, No. 3838, Convention and Exhibition Avenue, Midong District, Urumqi, 831400, China

Department of Orthopedics, Weihai Stomatological Hospital, No. 268, Tongyi South Road, Huancui District, Weihai, 264299, China

Junliang Liu

Department of Orthopedics, The Second People’s Hospital of Lianyungang, No. 41 Hailiandong Road, Haizhou District, Lianyungang, 222006, China

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XJ, GJ and LH are co-first authors of this manuscript. XJ and GJ designed the study and collected the data. ZZJ and LJL did the data analysis. LH wrote the manuscript. GC revised the manuscript and decided to submit the manuscript for publication. All authors read and approved the final manuscript.

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Xu, J., Gao, J., Li, H. et al. The risk factors in diabetic foot ulcers and predictive value of prognosis of wound tissue vascular endothelium growth factor. Sci Rep 14 , 14120 (2024). https://doi.org/10.1038/s41598-024-64009-4

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Diabetic Leg Ulcers: Reflective Account Essay

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Introduction

Factors that lead to skin lesions in diabetes, fungi and protozoa, physiological effects of ozones, use of ozone as an external therapy in diabetic skin lesions, advantages associated with topical ozone therapy in diabetic patients.

Diabetes is one of the disorders associated with metabolism and circulation. Skin is one of the organs affected by chronic metabolic problems that lead to nerve damage and poor circulation. Chronic leg ulcers associated with diabetes are conditions that occur over a long duration mostly in elderly people between the age of 65 to 80, with the peak occurrence at the age of 80. Venous insufficiency is commonly reported within the range of suggested aetiologies. Pain is commonly reported to affect over 89% of patients suffering from venous leg ulceration, Caballero. E and Frykberg, R.G. (1998).

Leg ulceration is one of the chronic disabling conditions. 1-2% of the developed world population is believed to be affected. Its median duration of occurrence is 6-9 months with a range of 4 weeks to 72 years. Although healing can be accelerated, more than 40% of the patients will experience open ulceration for more than one year. Even in cases where healing is achieved, 26-69% 12-month recurrence rate has been reported. Thus some patients may suffer from leg ulceration symptoms for a lifetime, Albrant, D.H. (2000).

Peripheral nerve malfunction is common in uncontrolled diabetes. The mechanisms that result in neurons damage in diabetes are not well understood. Oxidative stress in the neurons due to a high level of blood glucose could be a factor. Diabetic neuropathy may involve the sensory, motor, and autonomic nervous systems. Malfunction of the sensory neurons leads to loss of feeling, problem sensing limb position, reflex loss, pain, and tingling (paresthesias). Local circulation is altered by autonomic neuropathy as motor impairment results in muscle weakness, Michelle, B and Kate, F. (2007).

Circulatory impairment

Arteries, as well as arterioles, are prone to have plaque buildup in cases of chronic diabetes. The exact reason for this is not clear but Type II non-insulin-dependent diabetic patients usually suffer from diabetic dyslipidemia (abnormal blood lipid). The low-density lipoproteins particles adhere to the blood vessel walls causing vascular occlusion and the resulting lowered nutrient and oxygen supplies stress tissue resistance as well as impair the process of tissue recovery from injury.

Mechanical stress

Tissue perfusion is inhibited by repeated chronic pressure upon the skin that compresses dermal arterioles. Ulceration results from this tissue weakness that further exposes it to pathogenic microorganisms. Osteomyelitis may be initiated if the ulceration does reach the underlying bone.

A common inhabitant of chronic diabetic wounds. Examples include Aspergillus and Candida where Aspergillus, Candida, Actinomycoses, Histoplasma, and Cryptococcus are neutralized by the drug Ozone. Several protozoan organisms are usually found in diabetic chronic wounds. Cryptosporidium, Giardia, and free-living amoebas such as Hartmonella, Acanthamoeba, and Naegleria are among the protozoan species sensitive to ozone, Michelle, B and Kate, F. (2007).

The oxygen that is under pressure increases local circulation and stops anaerobic bacteria proliferation when it is applied to the affected tissue. Its main two effects include;

• Arteriole vasodilation promotes tissues oxygenation and delivery of immunological factors and nutrients. Removal of toxins and venous outflow is increased by vasodilation of the veins.
• Its antipathogenic action covers a broad range of microorganisms.

The benefits of ozone are felt in diabetic leg ulcers. Diabetic ulcers treatment would include a multidisciplinary approach that may include topical, surgical as well as systemic interventions. Topical antibiotics have the disadvantage of not penetrating deep into the wound and may cause allergy and secondary dermatitis, Dyas. A., et al. (1983). Only a portion of the microorganism are prone to the effect of certain antibiotics and bacterial resistance is also common (e.g., β-lactam antibiotic resistance observed in staphylococcus resistant to methicillin. Examples of bacteria found in diabetic leg ulcers include Klebsiella, E. coli, Proteus, Pseudomonas, Enterobacter, Bacteroides, Clostridium per fringe, peptostreptococcus, and prevotella.

In diabetic ulcers, an ozone application stimulates circulation and provides broad-spectrum topical coverage. With a higher dose and increasing number of applications, it penetrates into deeper tissues attacking anaerobic bacteria.

An individual assessment must be made in relation to the skin lesion to be treated. This evaluation includes size (Lesion diameter and depth), involvement of ligaments, dermal tissues, bone, and muscle. The circulatory competence of adjacent tissue, its relative health, and the presence of necrosis and or purulence are other factors to be considered. Thus due to variations in the clinical observations, ozone therapy is individualized. Its concentration frequencies and length are adjusted in the course of treatment. In case of burns and wet ulcers, initial ozone concentrations should be low so as to avoid excessive systemic absorption but on gradual epithelization, there is a need to adjust concentrations of ozone applied Cavanagh, P.R., et al,. (2005).

• It’s easy to administer therapy. On mastering the principles of ozone therapy which includes dosage adjustment and the treatment protocols, a clinician can safely administer topical ozone therapy to a wide range of afflictions related to diabetes.
• It has a broad spectrum of action. It inactivates facultative, anaerobic, and aerobic bacterial organisms, a wide range of viruses as well as a wide range of protozoans and fungal pathogens. If systemic antibiotics were to be used to treat these ulcerative conditions, a large assortment of them would have to be used which is not possible in normal medical practice.
• Its both preventive, chronic care, and acute care therapeutic agent. When its application is timely, it may thus deviate from the need to have a systemic therapy hence saving the patient organ stress and drugs side effect.
• It enhances tissue oxygen and blood perfusion to surface tissues that have a low blood supply.
• With its oxidizing potential, it destroys bacterial toxins that destroy tissues and that enhance a colonizing advantage for the bacteria.
• It doesn’t suffer the risk of resistance due to mutations from the microorganisms. Conventional antibiotics used should be constantly upgraded to avoid pathogen resistance.
• Topically applied oxygen/ozone mixtures are completely compatible with antibiotics systemically applied and with debridement as well as the other procedures of wound care.

Oxygen/Ozone mixtures are however not without disadvantages. They are not transportable and thus they have to be made at the time and within the site of administration. Since their administration needs to be serial in diabetic wounds, this usually translates in most cases to the daily application that has to go on until the ulcer resolves. Topical applications have limited penetrability. Although they have a panpathogenic potential on the ulcer surfaces, they cannot act at greater depths, Dyas. A., et al. (1983)

Leg ulceration has been one of the chronic conditions known to have a detrimental and significant effect upon the patients’ life. In various research findings some of the physical effects pointed out to be associated with leg ulceration include Odor, pain, itch, infection, and leakage. Pain is a common factor that most patients will complain about. A devastating effect is experienced by the patient when wound exudate is unsuccessfully managed. Although most nurses consider wound healing as the most important desirable outcome, alleviation of the disturbing symptoms is of more importance than wound closure, Albrant D.H, (2000).

Epidemiological studies that have been conducted suggest that up to 70% healing rates can be achieved in case of venous ulceration by use of compression bandaging while for arterial disease, healing rates are much lower. From these estimates thus, up to 30% of diabetic patients with leg ulcers cannot quickly and easily achieve healing. Thus in this kind of group, promotion of patients’ self-care and management of the symptoms should form the top priority.

There is no real sense of not following up and managing symptoms of a patient who has been cured since, after the first instance of leg ulcers, the patient has to put on compression hosiery. There would also be a need for a follow-up assessment in order to avoid recurrence, Caballero. E and Frykberg, R.G. (1998).

Previous studies have shown that, within a five-year follow-up period with patients who got specialist care, there was a 26-51 percent recurrence rate. Even with wound healing with no recurrence, patients who had healed ulcers could still complain of functional limitations and pain. Thus the process of patient care route would be more encouraged than just a specialized healing system, Briggs, M. and Closs, S. J. (2003). There is a need for a change of focus that emphasizes how to manage and live with the condition among healthcare workers and the patients. Reduction of pain and improvement of mobility may have a generally positive effect on the rate of wound healing.

This change of emphasis to symptom management rather than just healing has the potential of improving care for the patients that live with chronic leg ulcer conditions and may also improve the rate of healing, Charles, H. (1995).

Diabetic leg ulcer has been shown to have a serious impact on the patients’ life. Pain is the main problem associated with a diabetic leg ulcer but there are reported differences in its severity and prevalence. Other problems associated with diabetic leg ulcers include immobility, lack of energy, sleep disturbance, limitations in leisure and work activities, lack of self-esteem, frustrations and worries, Jeffcoate, W.J and Harding, K.G. (2003).

Problems that are related to the type of treatment administered have also been reported. This may include contradictory and unclear advice given by professionals that the patient cannot follow. Thus its of most importance that nursing practice scope be expanded so as to include patients problems beyond what is commonly considered-compression therapy and wound dressings. Meaningful interventions need to be developed as well as evaluated. Guidelines on diabetic leg ulcers need to be thus adjusted to fit in the expanded scope and focus more on the problems that the patient could be experiencing.

Albrant D.H. (2000). Management of foot ulcers in patients with diabetes. J Am Pharm Assoc; 40(4): 467-474.

Briggs, M. and Closs, S. J. (2003). The prevalence of leg ulceration; a review of the literature. European Wound Management Association Journal 3(2), 14–20.

Charles, H. (1995). The impact of leg ulcers on a patient’s quality of life. Professional Nurse 10(9), 571–572, 574.

Caballero. E and Frykberg R.G. (1998). Diabetic foot infections. J Foot Ankle Surg; 37:248-255.

Cavanagh, P.R., Lipsky, B.A and Bradbury, A.W. (2005). Treatment of diabetic foot ulcers. The Lancet: 366(9498): 1725-1735.

Dyas. A., Boughton, B. and Das B. (1983). Ozone killing action against bacterial and fungal species. Journal of Clinical Pathology; 36(10): 1102-1104.

Jeffcoate, W.J and Harding, K.G. (2003). Diabetic foot ulcers. The Lancet; 361 (9368): 1545-1551.

Michelle, B and Kate, F. (2007). Living with leg ulceration: a synthesis of qualitative research Journal of Advanced Nursing 59 (4), 319–328.

• Kendall Regional Medical Center: Prevention of Pressure Ulcer
• The Reduction of Hospital-Acquired Pressure Ulcer
• Wound Care Management in Clinical Environment
• Diabetes Type 2 in Children: Causes and Effects
• Health, Culture, and Identity as Diabetes Treatment Factors
• Type 2 Diabetes: Nursing Change Project
• Second Pregnancy Aggravated by Multiple Risk Factors
• Type 2 Diabetes in Geriatric Patients
• Chicago (A-D)
• Chicago (N-B)

IvyPanda. (2021, September 8). Diabetic Leg Ulcers: Reflective Account. https://ivypanda.com/essays/diabetic-leg-ulcers-reflective-account/

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IvyPanda . 2021. "Diabetic Leg Ulcers: Reflective Account." September 8, 2021. https://ivypanda.com/essays/diabetic-leg-ulcers-reflective-account/.

1. IvyPanda . "Diabetic Leg Ulcers: Reflective Account." September 8, 2021. https://ivypanda.com/essays/diabetic-leg-ulcers-reflective-account/.

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IvyPanda . "Diabetic Leg Ulcers: Reflective Account." September 8, 2021. https://ivypanda.com/essays/diabetic-leg-ulcers-reflective-account/.

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Clinical case: complicated diabetic foot ulcer

Caso clínico: pie diabético complicado, mm martínez delgado.

Centro Penitenciario de Soria, Centro Penitenciario de Soria, Spain

Description of a clinical case of a long-standing diabetic patient, who on admission to prison presents ulcerations on both feet, of ten years of evolution. Until his admission to the Penitentiary Center he has suffered repeated hospital admissions, repeatedly proposing amputation, which the patient refused.

The objective of this work is to demonstrate the importance of performing an etiological diagnosis of the lesion, taking into account all the factors that are present in a diabetic foot lesion.

Descripción del caso clínico de un paciente diabético de larga evolución, que al ingreso en prisión presentaba ulceraciones en ambos pies, de diez años de evolución. Cuando entró en el centro penitenciario, había tenido repetidos ingresos hospitalarios, y le propusieron en varias ocasiones la amputación, que el paciente rechazó.

El objetivo de la presentación de este caso clínico es demostrar la importancia de realizar un diagnóstico etiológico, teniendo en cuenta todos los factores presentes en una lesión de pie diabético.

Introduction

Diabetes mellitus is a major healthcare concern, as evidenced by its high prevalence rate in the general population (8.3%). With age the proportion of patients affected increases and it reaches 11% in the population over 65 years old. These figures are only indicative since it is considered that there is a similar proportion of undiagnosed patients, leading to a six-fold increase of the number of diabetic patients in the last forty years 1 .

Approximately between 15 and 25% of diabetic patients will present with foot ulcers throughout their life, this being the main cause of non-traumatic amputation worldwide. The overall prevalence rate of this complication is between 1.3 and 4.8%. These are developed by the convergence of several predisposing, triggering and aggravating factors.

• - The following are considered predisposing factors: peripheral neuropathy, leading to a lack of sensitivity and motor neuropathy causing an imbalance between flexion and extension muscles which give rise to arthropathy; and the autonomic neuropathy which entails hyperkeratosis and dry skin.
• - Triggers: any friction or injury
• - Aggravating factors: infection and ischemia which determine the future of the limb and the patient.

Diabetic foot ulcers can be neuropathic or neuro-ischemic, a fact which will strongly determine their management. A delayed etiological diagnosis can lead to chronic healing with a potential risk for both the limb and the patient 2 .

The main objective of presenting this clinical case is to show the importance of etiological diagnosis and taking into account all factors within a diabetic foot ulcer.

Clinical case

61 year-old male patient diagnosed with type-2 diabetes mellitus (DM2) fourteen years ago. This diagnosis was initially accompanied by sensitive and motor peripheral neuropathy, metatarsophalangeal arthropathy with no signs of osteomyelitis and diabetic arthropathy.

The patient had presented ulcers in both his feet for ten years now, in the metatarsophalangeal area. These had never completely healed in this period. He did not present partial nor total amputations. He had needed several admissions in hospital due to recurrent infections and had needed debridement and IV antibiotics in multiple occasions. Amputation had been suggested before, but he had always refused it.

Currently and according to the patient himself, although he is aware of the main considerations in managing diabetic foot ulcers his compliance has not been as constant as it should have been, especially regarding pressure relief and offloading the area. He does not smoke and has never smoked and reports no further toxic habits. He has an appropriate metabolic control of his disease with 7.4% glycated hemoglobin values.

Medical treatment at the time of hospital admission:

• - Lantus ® insulin 28 units: once a day in the morning
• - Apidra ® insulin: if hyperglycemia
• - Atorvastatin ® 10mg: once a day
• - Adiro ® 100mg: once a day
• - Hidroxil B1-B6-B12 ® : once a day
• - Currently he is under no treatment for pain although previously he had been on Pregabalin ® and Tramadol ® but has discontinued this treatment due to secondary effects.
• - Treatment for the ulcer until admission:
• - Cures with therapeutic honey and cleaning with soft soap.
• - Offload with 1cm-thick pads as a foot sole. He uses a stick to avoid weight bearing.
• - Hyperoxygenated fatty acid compounds (HFAC): three times a day in both legs.
• - Dressing to support the pad.

Physical exam upon admission

The patient presents sole ulcers on both feet: 2x3 cm wide on the right foot and 4x3 cm wide on his left foot, this being more severe ( Figures 1 and ​ and2). 2 ). They present a large amount of hyperkeratosis, swollen borders with exudation and bad smell. The areas between the fingers are also moist, soft and also smell bad. Dorsal pedal and posterior tibial pulses in the right foot are very weak. Onychomycosis is present in all nails.

The patients reports cramps in both feet although more frequently in the left one, intermittent claudication of less than 150 meters and itching of the malleolar and anterior tibial regions, mostly in the left foot. He presents nighttime pain that subsides with the decline position. In the left leg he has an ocher pigmentation of the skin in the malleolar region with two areas of blisters with no further ulceration and no-pitting edema in the tibial region. He presents dermatitis in the base of the toes with no external signs of varicose veins. He has moderate Charcot arthropathy in his left foot. The patient is independent for activities of daily living ( Figures 1 and ​ and2). 2 ).

• - The probing to bone test is performed to determine the degree of communication between the surface of the ulcer and the joint, and it is negative.
• - DopplerUS shows calcified laminar atherosclerotic plaques mainly in distal territories. He presents a biphasic flow due to impaired vascular elasticity, in the posterior retro-malleolar territories of the pedal and tibial arteries. This is compatible with moderate chronic arterial ischemia.
• - The ankle-brachial index (ABI) is determined with a result of 1.2 in the right foot and 1.3 in the left one.
• - Leriche-Fontaine classification: stage IV.
• - Pain visual analogue scale (VAS): 6 of nighttime predominance, forcing him to wake up and move his legs.
• - Blood pressure (BP): 102/63
• - Weight: 75.900 kg
• - Height: 1.76cm
• - Body mass index (BMI): 24.
• - Culture of wound: colonization by Staphilococcus aureus

The care plan was established based on the etiological diagnosis. In this case the patient presents a neuropathic ulcer with a moderate ischemic component and venous insufficiency of the most affected limb which impairs treatment.

Therefore, this is a patient with a chronic ulcer of mixed neuropathic and ischemic origin and venous hypertension in his left leg. Neuro-ischemic ulcers are treated as ischemic until revascularization is achieved. The main basis of treatment is control of exudation since this favors infection and significantly increases the risk of amputation.

Venous hypertension should be treated with compression by means of a low-elasticity multilayer bandage with the necessary precautions in view of his chronic moderate arterial ischemia 3 . The care plan is developed according to the DOMINATE management system to encourage wound healing 4 .

The DOMINATE acronym wound care management system:

• - Debridement: removal of nonviable tissue that impedes healing by means of mechanical and cleaning techniques.
• - Offloading: it eliminates wound stress and trauma which interfere with healing with a 1.5cm thick pad and walking devices. Appropriate shoes with anterior offload should be used.
• - Moisture, malignant, medications, mental health: control of chronic exudates by proper absorbent dressing (calcium alginate). Education of patients on the need of their cooperation for the care plan. Continuous supervision of instructions. Verification of medications that may interfere with wound healing. Control of stress and its effects on tissue inhibitors of metalloproteases (TIMPs).
• - Infection, inflammation: control of infection, identification of infection signs, antimicrobial therapy such as polyhexanide-betaine solution (Prontosan ® ), cadexomer iodine (Iodosorb ® ). Wound culture and systemic antibiotics under medical prescription 5 .
• - Nutrition: identification of malnutrition, correction of deficits and early referral no dieticians (endocrinology). Glycated hemoglobin levels should be kept under 7.
• - Arterial insufficiency: weak pedal and posterior tibial pulses in the right foot and absent in the left foot. Non-significant ankle-brachial index in view of calcification shown on the US. Referral to specialist (vascular surgeon) to assess potential revascularization.
• - Technical advances: moist control with daily cures and moist-free products.
• - Edema: control of edema. The patient will exercise his lower limbs while avoiding weight bearing (cycling, strengthening lower limb muscles), low-elasticity multi-layer bandage in his left leg.
• - Education: on his disease.
• - Empowerment: He is notified that without his cooperation good results are difficult to achieve.

Diabetic foot ulcers, which associate neuropathy, ischemia and venous hypertension need specialized care. An appropriate knowledge of the lesion etiopathology provides the key to understand the diagnosis and approach its treatment reducing the risks associated to delayed diagnosis or inappropriate treatments. The scientific evidence supports the use of compressive therapies as an efficient and safe alternative for ulcers of mixed origin. Compression significantly improves edema and reduced exudates 3 .

The selection of products for debridement was based on available evidence after performing a bibliographical search. Calcium alginate dressings control moist as well as cadexomer iodine which provides quick cleaning of the wound and nonviable tissue with a significant antimicrobial activity without excessive moist 5 .

Generally speaking, chronic wounds do not heal with dressings but epithelize when the cause is solved. According to some publications between 49 and 85% of all diabetic foot complications are evitable. This can be achieved by a combination of appropriate care, interdisciplinary strategies and specific health education for diabetic patients 2 .

Education for patients, caregivers and healthcare providers is an essential aspect of efficient treatment strategies. Therefore, we need efficient systems and structures ensuring appropriate evaluation and compliance by the patient by providing appropriate care. Patients’ involvement and that of their environment improve results.

In this case, imprisonment lead to the reduction of complications and presumably to avoiding amputation, at least temporarily since he was able to focus on his disease. During the process the patient became aware of the importance of taking care of himself 6 7 . After one year of treatment the right foot has completely healed and the left one has gone through several stages although complete healing has not been achieved ( Figures 3 and ​ and4 4 ).

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Molecular pathology and therapeutics of the diabetic foot ulcer; comprehensive reviews

Affiliations.

• 1 Ramanbhai Patel College of Pharmacy, CHARUSAT, Changa, Gujarat, India.
• 2 Vedmultispeciality Hospitals, Khatraj, Gujarat, India.
• PMID: 37294861
• DOI: 10.1080/13813455.2023.2219863

Diabetes mellitus (DM) is a chronic metabolic condition linked to high blood sugar levels. Diabetes causes complications like neuropathy, nephropathy, and retinopathy. Diabetes foot ulcer (DFU) is a significant and serious wound healing issue resulting from uncontrolled DM. The main causes of the development of the DFU are oxidative stress brought on by the NO moiety, release of pro-inflammatory cytokines like tumour necrosis factor (TNF)-α and interleukin (IL-1), cellular dysfunction, and pathogenic microorganisms including staphylococcus and streptococcus species . The two main types of wounds that are prevalent in DFU patients are neuropathic and neuroischemic. If this wound is not properly treated or cared for, a lower limb may have to be amputated. There are several therapy options for DFU, including antibiotics, debridement, dressings, nano formulations, and growth factor preparations like PDGF-BB, to help the wound heal and prevent amputation. Other novel approaches involved the use of nerve taps, microneedle patches, nanotechnology-based formulations and stem cell applications to promote healing. There are possibilities of drug repurposing for the DFU treatment based on targeting specific enzymes. This article summarises the current pathophysiological aspects of DFU and its probable future targets.

Keywords: Diabetes; cytokines; drug repurposing; foot ulcer; matrix metalloproteinases; neuroischemic; staphylococcus; streptococcus species.

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Type 2 Diabetes: Case Study Of A 65 Year Old Male Suffers From Long Term Type 2 Diabetes Mellitus

Published 20 Jun 2024

My patient, a 65-year-old male suffers from long term Type 2 diabetes mellitus. He currently has no symptoms and no recent triggering events suggesting that his diabetes are controlled for now. The patient explained how certain food types containing high levels of sugar increases his blood glucose and causes hyperglycaemia.

Upon triggering hyperglycaemia, the patient generates many symptoms such as:

• Thirst - Nocturia
• Tiredness - Polyuria

The patient was first diagnosed with Type 2 Diabetes Mellitus at the age of 40. Diagnosis was first made after a blood glucose test was done while fasting the night before. The patient experienced many symptoms before his diagnosis such as dizzy spells, polyuria and felt very lethargic. Due to this long term illness, the patient now suffers from many complications such as:

• poor wound healing,
• nephropathy
• retinopathy

The patient’s development of chronic kidney disease and loss of sight was previously due to poorly controlled diabetes. Recently the patient also was referred to hospital as he suffered from a diabetic foot ulcer and had a cast for many months due to impaired wound healing. This had a major impact as the patient struggled to walk.

Drug History:

At first when the patient was diagnosed, he was initially prescribed Metformin.

• Metformin: The first line of medication given to Type 2 diabetes patients. It decreases blood sugar levels by increasing peripheral usage of glucose to help the body handle insulin better. The patient was advised to take 500mg once daily of this medication preferably with breakfast.1

Metformin was no longer suitable for the patient as other complications arose form this. He is now prescribed Gliclazide and Linigliptin.

• Gliclazide: It is a sulfonylurea2 drug that increases the amount of insulin that your body makes.3 It is mainly effective when only residual pancreatic beta cell activity present2. Gliclazide occasionally causes hypoglycaemia so it is always advised for the patient to carry some sugar related products with them3. The patient takes one tablet once daily after breakfast.
• Linigliptin: This drug is usually taken if metformin is inappropriate to take for the patient. It inhibits dipeptidylpeptidase-4 to increase insulin secretion and lower glucagon secretion. The patient takes this once daily (5mg).4

Read also: Struggling with your assignments? Get expert case study help and ace your projects effortlessly.

Social History:

The patient has never smoked and stopped drinking alcohol many years ago.

Family History:

Many of the patient’s family members had a history of diabetes mellitus. The patients mother and father and wife suffered from Type 2 Diabetes mellitus.

Main Complaint:

Type 2 diabetes is a chronic metabolic condition caused by insulin resistance. This occurs when the body fails to use insulin effectively and pancreatic insulin production becomes deficient. There are many risk factors associated with Type 2 diabetes such as obesity, high blood pressure, lack of exercise and disturbance in blood lipid levels.5 Due to these factors the risk of cardiovascular conditions can also increase. There are many cardinal signs associated with Type 2 diabetes mellitus. These symptoms are polyuria (particularly at night), excessive thirst, very lethargic, poor wound healing when there are cuts and wound on skin and blurred vision. 6

Diagnosis and Testing:

Diagnosis is based on thorough history taking by an experienced clinician. This should include assessing glycemic control, patient’s recent blood glucose and levels of frequency hypoglycaemic episodes. The patient should also be asked about their medications type, dosage and times of administration.10 There are many investigations that can be done for diabetes diagnosis such as blood glucose test and refer the patient to the GP to check their urine.7

Management of Type 2 Diabetes Mellitus:

NICE guidelines states the type of responsibility and support that should be provided for an adult with Type 2 diabetes at the age of 18 years onwards. These are,8

• Ensure that an individually care plan is set up for all adults with Type 2 diabetes
• Offer a structured group education programme e.g. DESMOND (Diabetes Education for Self- Management for Ongoing and Newly Diagnosed)
• Ensure that the person or members of the family know how to contact the diabetes team
• Provide information on government disability benefits (if needed)
• Manage lifestyle issues such as diet and exercise
• Screen for complications such as retinopathy to minimise the risks
• Provide up-to-date information on diabetes support groups

Dental Management: Dental clinicians need to consider certain factors before initiating dental treatment to prevent the risk of a medical emergency. One of the medical emergencies that can happen with Type 2 diabetes is hypoglycaemia (low blood sugar). Hypoglycaemia is treated in many ways:11

• Treat with a sugary snack and test your blood sugar after 10-15 mins if patient is conscious
• Put patient in recovery position and don’t put anything in their mouth. Give a glucagon injection middle third off the thigh if patient is unconscious or very drowsy

Patients undergoing major surgical treatment may require an adjustment to their insulin dosage or medications. 1

Oral Manifestations: Diabetic dental patients can be at threat for dental disease. High blood glucose levels can have an impact on periodontal health as it is a risk factor for periodontitis. There are many oral complications associated with poorly controlled diabetes mellitus. These are:9

• Burning sensation
• Gingivitis periodontitis
• Dental caries
• Bacterial, viral And fungal infections
• Periapical Abscess

It is very important to regularly monitor blood glucose levels to prevent these risks.

• NICE Guidelines (2018 ) Metformin Hydrochloride - Indication and Dose, Available at: https://bnf.nice.org.uk/drug/metformin-hydrochloride.html (Accessed: 12th February 2019)
• NICE Guidelines (2018 ) Gliclazide , Available at: https://bnf.nice.org.uk/drug/gliclazide.html (Accessed: 12th February 2019 ).
• NHS (2016) Gliclazide , Available at: https://beta.nhs.uk/medicines/gliclazide/(Accessed: 10th February 2019 ).
• NICE Guidelines (2018) Lingliptin - Indication and Dose , Available at: https://bnf.nice.org.uk/drug/linagliptin.html (Accessed: 13th February 2019 ).
• NICE Guidelines (May 2017 ) Type 2 diabetes in adults: management, Available at: https://www.nice.org.uk/guidance/ng28/chapter/Introduction (Accessed: 13th February 2019 ).
• NHS (2016) Type 2 Diabetes - Symptoms , Available at: https://www.nhs.uk/conditions/type-2-diabetes/symptoms/ (Accessed: 13th February 2019 ).
• NHS (2016) Type 2 Diabetes - Getting Diagnosed , Available at: https://www.nhs.uk/conditions/type-2-diabetes/getting-diagnosed/ (Accessed: 13th February 2019 ).
• NICE Guidelines, CKS (2017) Diabetes - Type 2 Scenario: Managment - adults , Available at: https://cks.nice.org.uk/diabetes-type-2#!scenario (Accessed: 13th February 2019 ).
• Marwat M., Begum S. () Dental Managment of a Diabetic Patient , Available at: https://www.slideshare.net/mobile/mamoonkhan3/dental-management-of-a-diabetic-patient (Accessed: 14th February 2019 ).
• Rajesh V., Lalla, Joseph A., D’Ambrosio. (October 2001 ) 'Dentistry & Medicine ', Dental managment considerations for the patient with diabetes mellitus , 132(), pp. 1425-1431 [Online]. Available at: https://www.ugr.es/~jagil/lalla_diabetes.pdf(Accessed: 14th February 2019 ).
• NHS (2016 ) Low blood sugar (hypoglycaemia) , Available at: https://www.nhs.uk/conditions/low-blood-sugar-hypoglycaemia/ (Accessed: 14th February 2019 ).

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Pressure-reducing design of 3d-printed diabetic shoe midsole utilizing auxetic lattice structure.

1. Introduction

2. research methods, 2.1. midsole design based on re-entrant hexagonal lattice structure, 2.2. foot model construction and gait measurement, 2.3. mechanical characterization and fe modeling, 2.4. wear trial of proposed midsoles, 3.1. tensile and compression tests, 3.2. comparison of results between fe simulation and experimental measurements, 3.3. plantar pressure distribution, 3.4. midsole deformation and plantar contact area, 4. discussion, 4.1. effects of auxetic structural design on plantar pressure distribution, 4.2. effects of auxetic structural design on midsole deformation and plantar contact area, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Share and Cite

Zhang, J.; Lu, S.; Lin, Y.; Wang, Y.; Yi, X.; Fang, W. Pressure-Reducing Design of 3D-Printed Diabetic Shoe Midsole Utilizing Auxetic Lattice Structure. Appl. Sci. 2024 , 14 , 5291. https://doi.org/10.3390/app14125291

Zhang J, Lu S, Lin Y, Wang Y, Yi X, Fang W. Pressure-Reducing Design of 3D-Printed Diabetic Shoe Midsole Utilizing Auxetic Lattice Structure. Applied Sciences . 2024; 14(12):5291. https://doi.org/10.3390/app14125291

Zhang, Jifa, Shizhu Lu, Yinyin Lin, Yang Wang, Xiaolie Yi, and Wencheng Fang. 2024. "Pressure-Reducing Design of 3D-Printed Diabetic Shoe Midsole Utilizing Auxetic Lattice Structure" Applied Sciences 14, no. 12: 5291. https://doi.org/10.3390/app14125291

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