Diabetic foot ulceration is one of the most serious complications of diabetes mellitus and a leading cause of non-traumatic lower limb amputation worldwide [1]. The global prevalence of diabetic foot ulceration is about 6% among people with diabetes [2], and the lifetime risk of developing a foot ulcer may be as high as 19 to 34% [3]. Diabetic foot complications carry a five-year mortality and direct costs comparable to those of cancer [4]. With the number of people with diabetes rising rapidly [5], India now has more than 100 million people with diabetes [6], and barefoot walking, late presentation and limited access to specialised care make diabetic foot disease a particular problem in the country [7]. Diabetic foot ulcers result from a combination of peripheral neuropathy, peripheral arterial disease, deformity and trauma, and are often complicated by infection [8,9]. The severity of ulcers is commonly graded by the Wagner classification [10]. Standard management includes surgical debridement, treatment of infection, offloading, revascularisation where needed and local wound care [11,12]. Despite this, healing is often slow, hospital stays are prolonged and many patients eventually require amputation. Several adjunctive therapies have been evaluated to enhance healing of chronic diabetic foot ulcers [13,14]. Negative pressure wound therapy (NPWT), also known as vacuum-assisted closure, applies controlled sub-atmospheric pressure to the wound through a sealed foam dressing [15]. Experimental studies showed that it increases local blood flow, reduces oedema and bacterial load, and stimulates granulation tissue formation [16], and that the mechanical deformation of the wound surface promotes cell proliferation [17,18]. In randomised trials, NPWT increased the proportion of diabetic foot wounds healed after partial foot amputation [19] and of diabetic foot ulcers achieving closure compared with advanced moist wound therapy [20], and reduced resource use and costs [21]. Other studies from Asia and the Middle East have reported faster healing and better quality of life with NPWT [22-25], and low-cost NPWT systems have been described for use in Indian hospitals [26]. However, a Cochrane review judged the overall evidence to be of low certainty [27], and a large German real-life trial found smaller benefits than earlier studies [28]. Indian randomised studies have also reported variable results [29,30]. Because commercial NPWT systems are costly and the evidence is mixed, data from Indian teaching hospitals are needed to guide its use. The objective of this study was to compare NPWT with conventional moist dressing in patients with diabetic foot ulcers in terms of reduction in ulcer area, time to healthy granulation tissue, wound closure, hospital stay, amputation and complications.

Study design and participants This prospective comparative study was conducted in the Department of Surgery, SMBT Institute of Medical Sciences & Research Center, Nashik. Patients aged 18 years or more with type 2 diabetes mellitus and a foot ulcer of Wagner grade 1 to 3, with an ulcer area of at least 4 cm² after debridement, were included. Patients with an ankle-brachial pressure index below 0.6 or absent pedal pulses with critical limb ischaemia, Wagner grade 4 or 5 lesions, untreated osteomyelitis, malignancy in the wound, exposed major blood vessels, bleeding disorders or anticoagulant therapy, and those unwilling to participate were excluded. Written informed consent was obtained from all patients. Sample size and allocation The sample size was calculated assuming that 70% of ulcers in the NPWT group and 35% in the control group would be ready for closure within 6 weeks. With a two-sided significance level of 5% and a power of 80%, a minimum of 32 patients was required in each group, which was increased to 35 per group to allow for loss to follow-up. Eligible patients were allocated alternately to the NPWT group or the control group in the order of admission. Initial management All patients were evaluated with a detailed history and examination, including assessment of neuropathy with a 10 g monofilament and of vascular status by palpation of pedal pulses, ankle-brachial pressure index and Doppler study where indicated. Investigations included complete blood count, blood sugar, glycated haemoglobin (HbA1c), renal function, wound culture and sensitivity, and X-ray of the foot to exclude osteomyelitis. Blood sugar was controlled with insulin, and antibiotics were given according to culture reports [11]. All patients underwent thorough surgical debridement of necrotic and infected tissue before starting the allocated treatment, and offloading was advised in both groups. Interventions In the NPWT group, a sterile open-cell polyurethane foam was cut to the size of the wound and placed in the wound cavity, covered with an adhesive transparent drape to obtain an airtight seal and connected through a tube to a vacuum unit. Continuous negative pressure of -125 mmHg was applied [15,16]. The dressing was changed every 72 hours, and therapy was continued until the wound bed was covered with healthy granulation tissue and was ready for closure, or for a maximum of 6 weeks. In the control group, the wound was cleaned with normal saline and dressed daily with saline-moistened gauze, with further debridement as needed in both groups. Outcome assessment Ulcer area was measured by tracing the wound margin on a sterile transparent sheet and counting squares on graph paper at baseline and at 2, 4 and 6 weeks, and the percentage reduction in area was calculated. The primary outcome was the percentage reduction in ulcer area at 4 weeks. Secondary outcomes were the time to appearance of healthy granulation tissue covering the wound bed, the proportion of wounds ready for closure by split-thickness skin graft or secondary suturing within 6 weeks, graft uptake, duration of hospital stay, number of dressing changes, the need for minor or major amputation, and complications such as bleeding, pain, maceration of surrounding skin and wound infection. Statistical analysis Data were entered in Microsoft Excel and analysed with Python version 3.13 using the SciPy and statsmodels libraries. Continuous variables were expressed as mean ± standard deviation and compared with the unpaired t test; the results were confirmed with the Mann-Whitney U test, which gave the same conclusions. Categorical variables were compared with the chi-square test or Fisher exact test, as appropriate. A p-value below 0.05 was considered significant.

A total of 70 patients were studied, 35 in each group. The mean age was 55.7 ± 11.3 years in the NPWT group and 56.1 ± 10.3 years in the control group, and 36 patients (51.4%) were men. The mean duration of diabetes was 12.3 years and the mean HbA1c 9.5%, indicating poor glycaemic control in most patients. Half of the ulcers (35, 50.0%) were Wagner grade 3. The two groups were comparable in age, sex, duration of diabetes, HbA1c, comorbidities, ankle-brachial pressure index, site of ulcer, Wagner grade and initial ulcer area after debridement (Table 1). Table 1. Baseline characteristics of patients in the two groups Characteristic NPWT group (n = 35) Control group (n = 35) p-value Age (years), mean ± SD 55.7 ± 11.3 56.1 ± 10.3 0.869 Male, n (%) 19 (54.3) 17 (48.6) 0.632 Duration of diabetes (years), mean ± SD 11.9 ± 5.3 12.6 ± 4.9 0.544 HbA1c (%), mean ± SD 9.5 ± 1.6 9.4 ± 1.4 0.701 Hypertension, n (%) 19 (54.3) 16 (45.7) 0.473 Peripheral neuropathy, n (%) 18 (51.4) 20 (57.1) 0.631 Ankle-brachial pressure index, mean ± SD 0.94 ± 0.14 0.93 ± 0.16 0.794 Site: forefoot / midfoot / hindfoot, n 9 / 18 / 8 8 / 13 / 14 0.286 Wagner grade 1 / 2 / 3, n 12 / 7 / 16 10 / 6 / 19 0.773 Initial ulcer area (cm²), mean ± SD 15.1 ± 6.1 16.1 ± 6.3 0.532 Unpaired t test or chi-square test. The ulcer area decreased in both groups, but the reduction was significantly greater in the NPWT group at every follow-up. At 2 weeks, the mean reduction was 27.9% with NPWT and 14.8% with moist dressing; at 4 weeks it was 57.9 ± 7.0% compared with 32.2 ± 8.2%, and at 6 weeks 77.2% compared with 52.1% (p < 0.001 for each). The mean ulcer area at 6 weeks was 3.4 cm² in the NPWT group and 7.6 cm² in the control group (Table 2). Table 2. Ulcer area and percentage reduction in ulcer area during follow-up Time NPWT group: area (cm²) NPWT group: reduction (%) Control group: area (cm²) Control group: reduction (%) p-value* Baseline 15.13 ± 6.06 - 16.06 ± 6.31 - 0.532 2 weeks 10.93 ± 4.61 27.9 ± 8.4 13.64 ± 5.30 14.8 ± 5.5 <0.001 4 weeks 6.33 ± 2.62 57.9 ± 7.0 10.85 ± 4.46 32.2 ± 8.2 <0.001 6 weeks 3.39 ± 1.53 77.2 ± 6.4 7.63 ± 3.16 52.1 ± 9.2 <0.001 Values are mean ± SD. *p-value for initial area at baseline and for percentage reduction at follow-up; unpaired t test. Healthy granulation tissue covering the wound bed appeared after 16.3 ± 4.3 days in the NPWT group and 30.3 ± 5.9 days in the control group (p < 0.001), about two weeks earlier with NPWT. Within 6 weeks, 32 ulcers (91.4%) in the NPWT group and 8 (22.9%) in the control group were ready for closure (p < 0.001). In the NPWT group, 18 wounds were closed with a split-thickness skin graft and 14 by secondary suturing, whereas 27 wounds in the control group were left to heal by secondary intention. Graft uptake was similar in the two groups (91.0% and 91.2%, p = 0.956), although only 3 patients in the control group were grafted. The mean hospital stay was 13.6 ± 2.5 days in the NPWT group and 20.7 ± 3.5 days in the control group (p < 0.001), and the number of dressing changes was much lower with NPWT (4.8 versus 20.7) (Table 3). Table 3. Wound healing outcomes and hospital stay Outcome NPWT group (n = 35) Control group (n = 35) p-value Time to healthy granulation tissue (days), mean ± SD 16.3 ± 4.3 30.3 ± 5.9 <0.001 Ready for closure within 6 weeks, n (%) 32 (91.4) 8 (22.9) <0.001 Closure by split-thickness skin graft, n (%) 18 (51.4) 3 (8.6) Closure by secondary suturing, n (%) 14 (40.0) 5 (14.3) Healing by secondary intention, n (%) 3 (8.6) 27 (77.1) <0.001 Graft uptake (%), mean ± SD 91.0 ± 4.8 (n = 18) 91.2 ± 7.4 (n = 3) 0.956 Number of dressing changes, mean ± SD 4.8 ± 0.9 20.7 ± 3.5 <0.001 Hospital stay (days), mean ± SD 13.6 ± 2.5 20.7 ± 3.5 <0.001 Unpaired t test or chi-square test; the p-value for method of closure compares the distribution across the three categories. Minor amputation (toe or ray) was required in 3 patients (8.6%) in the NPWT group and 2 (5.7%) in the control group (p = 1.000), and no patient required major amputation. Wound infection during treatment occurred in 3 patients in each group. Complications related to NPWT were minor and included pain during dressing change in 5 patients and maceration of the surrounding skin in 3; there was no bleeding in the NPWT group, and therapy was not discontinued in any patient. None of the differences in complications was statistically significant (Table 4). Table 4. Amputation and complications Outcome NPWT group (n = 35) Control group (n = 35) p-value Minor amputation, n (%) 3 (8.6) 2 (5.7) 1.000 Major amputation, n (%) 0 (0.0) 0 (0.0) 1.000 Wound infection during treatment, n (%) 3 (8.6) 3 (8.6) 1.000 Pain during dressing change, n (%) 5 (14.3) 3 (8.6) 0.710 Maceration of surrounding skin, n (%) 3 (8.6) 1 (2.9) 0.614 Bleeding, n (%) 0 (0.0) 1 (2.9) 1.000 Chi-square or Fisher exact test.

In this study, NPWT resulted in a significantly greater reduction in ulcer area at 2, 4 and 6 weeks, appearance of healthy granulation tissue about two weeks earlier, a much higher proportion of wounds ready for closure within 6 weeks (91.4% versus 22.9%) and a hospital stay about one week shorter than conventional moist dressing. The rates of minor amputation, wound infection and other complications were low and similar in the two groups. The faster formation of granulation tissue with NPWT is explained by its mechanisms of action. Sub-atmospheric pressure removes exudate and reduces oedema, increases local blood flow and lowers bacterial counts [15,16], and the mechanical stretch of cells at the foam-wound interface stimulates cell proliferation and angiogenesis [17,18]. This converts a chronic, stagnant wound into one that is ready for skin grafting or closure. Our findings agree with earlier trials. Armstrong and Lavery found that NPWT after partial diabetic foot amputation increased the proportion of healed wounds and the rate of granulation tissue formation [19], and Blume and colleagues found that a greater proportion of diabetic foot ulcers achieved closure with NPWT than with advanced moist wound therapy, with fewer secondary amputations [20]. Studies from Singapore, Iran, Kashmir and Pakistan also reported faster healing and reduced ulcer area with NPWT [22-25]. In Indian randomised trials, NPWT improved wound healing compared with conventional dressing [29,30]. The shorter hospital stay and fewer dressing changes in our study are consistent with the reduced resource use reported with NPWT [21]. Not all studies have shown a large benefit. A Cochrane review concluded that NPWT may increase the proportion of healed wounds and reduce amputations, but that the certainty of evidence was low [27], and the German DiaFu trial found no significant difference in wound closure under real-life conditions [28]. The IWGDF guidelines therefore suggest that NPWT may be considered as an adjunct for post-surgical diabetic foot wounds, but not as a replacement for standard care [12,13]. In our study, NPWT was used after thorough debridement and infection control, and its benefit should be seen in this context. The high cost of commercial systems is a barrier in India, and low-cost systems assembled from locally available materials have been shown to be effective [26], which could make NPWT more widely available in public hospitals. Given the burden of diabetic foot disease in India [6,7] and the high mortality and costs associated with amputation [4], measures that shorten healing time and hospital stay are of considerable value. The rate of amputation did not differ between the groups in our study. This is probably because patients with critical ischaemia and Wagner grade 4 and 5 lesions were excluded, all patients received thorough debridement and culture-guided antibiotics, and the number of amputations was small, so the study was not powered to detect a difference in this outcome. Similarly, graft uptake was good in both groups, which suggests that the main benefit of NPWT lies in faster preparation of the wound bed for grafting or closure rather than in the outcome of the graft itself. Strengths and limitations The strengths of this study are its prospective design, comparable groups, standardised debridement and infection control in both groups, and serial measurement of ulcer area. It has limitations. Allocation was alternate rather than truly randomised, and blinding of patients and assessors was not possible. The sample size was modest and too small to assess differences in amputation. Follow-up was limited to the period of treatment and healing, and recurrence was not assessed. Cost-effectiveness was not formally analysed. Patients with severe ischaemia were excluded, so the results apply only to neuropathic and neuro-ischaemic ulcers with adequate perfusion.

Negative pressure wound therapy, used after debridement and infection control, resulted in faster formation of healthy granulation tissue, greater reduction in ulcer area, earlier readiness for closure and a shorter hospital stay than conventional moist dressing in patients with Wagner grade 1 to 3 diabetic foot ulcers, without serious complications. Amputation rates were low and similar in the two groups. NPWT, including low-cost systems, can be recommended as a useful adjunct in the management of diabetic foot ulcers in Indian hospitals. DECLARATIONS Acknowledgement: The authors thank the faculty, residents and nursing staff of the Department of Surgery, SMBT Institute of Medical Sciences & Research Center, Nashik, and all the patients who took part in the study. Funding: None. Conflict of interest: The authors declare no conflict of interest. Author contribution: Dr. Shelke Rahul conceived and designed the study, treated the patients, analysed the data and wrote the manuscript. Dr. Mayur Gangwal contributed to patient management, data collection, interpretation of the results and critical revision of the manuscript. Both authors approved the final version. Data availability: The data supporting the findings of this study are available from the corresponding author on reasonable request.

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