• View in gallery

    Image showing no recovery in the donor site.

  • View in gallery

    A, Wagner grade 3 diabetic foot ulcer (DFU). Infection and necrosis are seen. B, The DFU after debridement. C, Application of negative pressure wound therapy. D, The DFU after negative pressure wound therapy. No infection or necrosis is seen. E, The DFU after the intralesional epidermal growth factor injections.

  • View in gallery

    A, Wagner grade 3 diabetic foot ulcer (DFU). Infection and necrosis are seen. B and C, The DFU after debridement and wound side revision. D, Application of negative pressure wound therapy. E, The DFU after the intralesional epidermal growth factor injections.

  • View in gallery

    Image showing poor recovery of a graft in the plantar side of the diabetic foot ulcer.

  • View in gallery

    A, The no recovery graft in the phalanx of the diabetic foot ulcer. B and C, The wound treated with intralesional epidermal growth factor.

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Can Intralesional Epidermal Growth Factor Reduce Skin Graft Applications in Patients with Diabetic Foot Ulcer?

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Background

Diabetic foot ulcer (DFU) is a serious health problem. Major amputation increases the risk of mortality in patients with DFU; therefore, treatment methods other than major amputation come to the fore for these patients. Graft applications create an appropriate environment for the reproduction of epithelial cells. Similarly, epidermal growth factor (EGF) also stimulates epithelization and increases epidermis formation. In this study, we aimed to compare patients with DFU treated with EGF and those treated with a split-thickness skin graft.

Methods

Patients who were treated for DFU in the general surgery clinic were included in the study. The patients were evaluated retrospectively according to their demographic characteristics, wound characteristics, duration of treatment, and treatment modalities.

Results

There were 26 patients in the EGF group and 21 patients in the graft group. The mean duration of treatment was 7 weeks (4-8 weeks) in the EGF group and 5.3 weeks (4-8 weeks) in the graft group (P < .05). In the EGF group, wound healing could not be achieved in one patient during the study period. In the graft group, no recovery was achieved in three patients (14.2%) in the donor site. Graft loss was detected in four patients (19%), and partial graft loss was observed in three patients (14.2%). The DFU of these patients were on the soles (85.7%). These patients have multiple comorbidities.

Conclusions

EGF application may be preferred to avoid graft complications in the graft area and the donor site, especially in elderly patients with multiple comorbidities and wounds on the soles.

Background

Diabetic foot ulcer (DFU) is a serious health problem. Major amputation increases the risk of mortality in patients with DFU; therefore, treatment methods other than major amputation come to the fore for these patients. Graft applications create an appropriate environment for the reproduction of epithelial cells. Similarly, epidermal growth factor (EGF) also stimulates epithelization and increases epidermis formation. In this study, we aimed to compare patients with DFU treated with EGF and those treated with a split-thickness skin graft.

Methods

Patients who were treated for DFU in the general surgery clinic were included in the study. The patients were evaluated retrospectively according to their demographic characteristics, wound characteristics, duration of treatment, and treatment modalities.

Results

There were 26 patients in the EGF group and 21 patients in the graft group. The mean duration of treatment was 7 weeks (4-8 weeks) in the EGF group and 5.3 weeks (4-8 weeks) in the graft group (P < .05). In the EGF group, wound healing could not be achieved in one patient during the study period. In the graft group, no recovery was achieved in three patients (14.2%) in the donor site. Graft loss was detected in four patients (19%), and partial graft loss was observed in three patients (14.2%). The DFU of these patients were on the soles (85.7%). These patients have multiple comorbidities.

Conclusions

EGF application may be preferred to avoid graft complications in the graft area and the donor site, especially in elderly patients with multiple comorbidities and wounds on the soles.

Diabetic foot ulcer (DFU) is a serious health problem experienced by 15% of patients with diabetes mellitus in their lifetime.1 It is an important complication that can lead to major limb amputations, composing 40% to 60% of nontraumatic amputations.2 The rate of reamputation in 5 years is 28% to 51% after the first amputation in patients with DFU.3,4 The 5-year mortality in these reamputated patients is approximately 40% to 66%.3,4 Therefore, other treatment methods come to the fore in DFU treatment instead of major amputations. Major limb amputations are attempted to be reduced with the help of appropriate debridement and tissue transfers.5

Epidermal growth factor (EGF) is a molecule from the growth factor family that regulates cell proliferation, migration, and differentiation.6 Isolated for the first time from the submandibular salivary glands of mice, EGF is mitogenic for many mesodermal and ectodermal origin cells.7 It has been used in intralesional or topical forms in various studies. Epidermal growth factor stimulates epithelization and increases epidermis formation as a result of its characteristics.8 Similarly, graft applications create an appropriate environment for the reproduction of epithelial cells starting from the center of the graft site.

In this study, we aimed to compare patients with DFU treated with intralesional EGF and those treated with a split-thickness skin graft (STSG).

Participants and Methods

Patients who were treated for DFU in the general surgery clinic of Selcuk University were included in the study. The patients were evaluated retrospectively according to their demographic characteristics, wound characteristics, duration of treatment, and treatment modalities. Selcuk University Non-Interventional Ethics Board (Konya, Turkey) approved this study.

Inclusion Criteria

Patients older than 18 years who developed a DFU; patients with Wagner grades 2, 3, and 4; patients who accepted treatment; patients who completed the treatment process; and patients with adequate documents and findings were included in the study. Patients who have not peripheral arterial occlusion decisions (An ankle-brachial index range was 1.00–1.40, the detection nonocclusion with a Doppler ultrasound examination and a nonmonophasic flow in the peripheral vessels, there was nonobstruction on magnetic resonance angiography, there were no failure to detect arteria dorsalis pedis and arteria tibialis posterior pulsations in physical examination). Patients who have not detected any peripheral arterial occlusion and patients with normal peripheral blood flow after revascularization were also included in the study.

Exclusion Criteria

Patients who developed foot ulcer due to nondiabetic reasons (eg, venous, arterial, traumatic, etc); patients without diabetes; patients with Wagner grade 0 (excluded because of the absence of open wounds), 1 (excluded because of success with classical treatment methods), or 5 (excluded because of a major amputation requirement as the essential treatment modality); patients who did not accept treatment; patients without adequate clinical information; and patients who had not completed their treatment were not included in the study. In addition, patients with severe vascular insufficiency and circulatory disorders (failure to detect arteria dorsalis pedis and arteria tibialis posterior pulsations on physical examination and absence of flow or biphasic flow on hand Doppler, detection of occlusion with Doppler ultrasound examination, an ankle-brachial index of <0.90, failure to see the flow and detection of an obstruction on magnetic resonance angiography) and patients who could not be revascularized by interventional radiology were not included in the study because of their low graft success rate. Patients who underwent major amputation were excluded from the study. Patients receiving immunosuppressive therapy and those taking corticosteroids were also excluded.

Study Groups

The intralesional EGF group consists of patients who accepted the EGF treatment and have no malignancy or history of malignancy. Those who did not accept tissue sampling from any part of their body for grafting were also included in this group. The graft group consists of patients treated with graft without intralesional EGF.

Grades of DFU

The Wagner-Meggitt classification was used9: grade 0, intact skin; grade 1, superficial ulcer without spread to deep tissues; grade 2, ulcer with tendon, bone, ligament, or joint involvement; and grade 3, deep ulcer with abscess or osteomyelitis.

Evaluation of Vascular Circulation

Clinically, peripheral artery disease (PAD) was evaluated according to the Fontaine classification8: stage 1, asymptomatic (PAD present, not completely blocked); stage 2, claudication pain (stage 2A, symptoms after >200 m of free walking; stage 2B, symptoms with <200 m of walking); stage 3, rest pain; and stage 4, foot necrosis and gangrene.

Failure to detect arteria dorsalis pedis and arteria tibialis posterior pulsations on physical examination and absence of flow or biphasic flow seen on hand Doppler were evaluated as PAD.4 Detection of occlusion with Doppler ultrasound examination and monophasic flow in the peripheral vessels was evaluated as PAD. An ankle-brachial index less than 0.90 was assessed as PAD5; 1.00 to 1.40 was considered normal.10 Failure to see the flow and detection of an obstruction on magnetic resonance angiography was assessed as the presence of PAD.

Evaluation of Osteomyelitis

Radiography was performed to evaluate osteomyelitis first. The presence of cortical erosion in the bones around the ulcer and demineralization of the bone and new periosteal bone formation were evaluated as osteomyelitis. Magnetic resonance imaging was performed when deemed necessary for the diagnosis of osteomyelitis. Patients with osteomyelitis were included in the groups after the osteomyelitis condition was treated. Patients with continuing osteomyelitis were not included in the groups.

Evaluation of Infection Symptoms and Treatment

Infection symptoms were evaluated clinically. Purulent discharge at the base of the wound was evaluated in terms of the presence of hyperemia around the wound, abscess, temperature increase, induration, and infection symptoms. According to the Infectious Diseases Society of America (IDSA) guidelines, infection is present if there is purulent drainage or two or more signs of inflammation (erythema, pain, tenderness, warmth, or induration).11 In addition, growth in the cultured wounds was considered an infection. Broad-spectrum antibiotics were started for all of the inpatients with infection symptoms for 7 to 10 days. Patients' antibiotics were changed according to their culture results. The antibiotic treatments of patients with osteomyelitis lasted for at least 14 days. Patients with infection were included in the groups after the infection was treated. Patients whose infection could not be controlled were not included in the groups.

The local and systemic infection findings of the patients were evaluated according to the IDSA classification11: grade 1 (no infection), no findings of systemic or local infection; grade 2 (mild infection), infection limited to only the skin and subcutaneous tissues, less than 2 cm2 of erythema around the wound, no findings of systemic infection; grade 3 (moderate infection), infection in the skin and deep subcutaneous tissues (bone, tendon, joint), greater than 2 cm2 of erythema around the wound, no findings of systemic infection; and grade 4 (severe infection), the presence of systemic infection findings in addition to infection findings in the foot (body temperature >38°C or <36°C, pulse >90/min, respiratory rate >20/min or PaCO2 <32 mm Hg, plasma leukocyte count >12,000 or <4,000 K/UI).

Evaluation of Neuropathy

A monofilament test was performed to detect diabetic peripheral neuropathy. Semmes-Weinstein 5.07/10 g was used for the monofilament test. It was applied to eight different zones on each sole. The test was considered positive if the patient did not feel anything despite application of the filament until it bends.

Evaluation of Treatment Success

Successful treatment and complete recovery were defined as full coverage with granulation tissue on the wound and coverage of this wound with graft (not only that the graft was applied to the wound but that the graft was viable during the controls and that the skin was closed by providing new skin formation) or the entire wound covered with skin after the EGF injections.

Termination of Treatment

Complete response to treatment, the need for major amputation, failure to continue regular treatment, and the development of complications related to treatment led to termination of the study for those patients.

Surgical Debridement Procedure

Surgical debridements were performed under sterile operating room conditions. Debridement was continued until the infected tissues were completely removed. During the debridement, minor amputations and bone debridements were also performed when necessary. Debridement was performed again in some of the patients when necessary. No other treatment method was applied for debridement except surgical debridement.

Termination of Debridement Treatment

Debridement continued until the wound was completely free of necrotic and infected tissue. The debridement procedure was terminated for wounds that did not show signs of infection, were cleared from necrotic tissues, or had no growth in the tissue culture.

Application of Negative Pressure Wound Therapy

After debridement, all of the patients underwent negative pressure wound therapy (NPWT) (Confort C300; Confort Private Health Services Medical Materials Industry and Trade Co Ltd, Eskisehir, Turkey), which continued until the formation of granulation tissue on the wound base. Negative pressure wound therapy without instillation was used. The pressure was set in an intermittent mode, with a maximum of 125 mm Hg and a minimum of 75 mm Hg. The wounds that were closed with NPWT for 3 days were opened at the end of the third day. This process continued until granulation tissue was formed on the wound bed. Surgical debridement was continued between NPWT applications when needed. This application was performed on all of the patients.

Assessment of Wound Recovery

Complete coverage of the wound base with granulation tissue, reduced infection parameters of the patients, absence of signs of infection in the clinical and physical examination, absence of growth in the culture results, removal of necrotic tissues completely from the wound, and absence of new necrotic and infected tissues were evaluated as recovery. Debridement and NPWT were terminated, and other treatment modalities were used to close the wound.

Application of Intralesional EGF

Intralesional EGF (75 μg of Heberprot-P; HAS Biotech, Vitoria, Spain) was applied intralesionally three times a week on the wound site of the patients who had no need for debridement, had granulation tissue on the base, and had only dermis and epidermis defects.

Graft Application

All of the patients underwent STSG. The grafts were taken with the help of cordless dermatomes, with a 0.3- to 0.45-mm thickness from the front of the thigh of the leg with the wound. The grafts, taken under sterile conditions, were placed on the wound in the same session. Small incisions were made on the graft to drain the seroma and hematoma that accumulated beneath. After a tie-over, the wound was kept closed for 3 days. After 3 days, the dressing was opened for evaluation. Grafts that adhered to the granulation tissue, that were vital, and that had no ischemic color change were evaluated as successful. The donor site was closed using a paraffin tulle dressing coated with chlorhexidine (Bactigras; Smith & Nephew Healthcare Ltd, Hull, England). The donor site was opened postoperatively and observed daily. The Bactigras on it was never changed, and it remained until it dried and fell off.

Statistical Analysis

Data collection was performed using Microsoft Excel 2007 (Microsoft Corp, Redmond, Washington), and patient data were evaluated using a statistical software program (IBM SPSS Statistics for Windows, Version 20.0; IBM Corp, Armonk, New York). For the continuous variables, descriptive statistics were calculated and are expressed as mean ± SD. The categorical variables are presented as numbers and percentages. Analysis of the χ2 test or the Fisher test was conducted to compare the variables among the groups. A P < .05 was considered statistically significant.

Results

There were 47 patients with DFU. Three patients had been excluded due to irregularly administered treatment, and three due to missing records. There were 26 patients in the EGF group. The mean ± SD age was 55.5 ± 8.2 years, with 20 men (77%) and six women (23%). There were 21 patients in the graft group. The mean ± SD age was 57.3 ± 10.1 years, with 17 men (81%) and four women (19%). The demographic and clinical data of the patients are presented in Table 1.

Table 1.

Demographic and Clinical Features of the Epidermal Growth Factor (EGF) and Graft Groups

Table 1.

Infection was detected in 24 patients (92.3%) in the EGF group and in 19 (90.5%) in the graft group. Broad-spectrum antibiotics were started for 7 to 10 days for all of the patients with infection symptoms. Patients' antibiotics were changed according to their culture results. Ampicillin/sulbactam and amoxicillin/clavulanate were given to all of the patients with signs of infection as broad-spectrum antibiotics. Anti-anaerobic therapy was added for patients with gangrenous and foul-smelling wounds. Vancomycin or daptomycin was also added for patients with suspected methicillin-resistant Staphylococcus aureus. The most common microorganism in tissue cultures in both groups was S aureus—81% and 76% in the EGF and graft groups, respectively.

The mean hemoglobin A1c (HbA1c) level measured at the first admission of the patients in the EGF group was 9.18% (range, 7.4%–12%), and it was 9.31% (range, 7.8%–12%) in the graft group. The mean HbA1c values of the patients 1 month later were 5.6% in the EGF group and 5.5% in the graft group. The mean ± SD number of NPWT applications was 4.56 ± 2.24 in the EGF group and 5.42 ± 1.96 in the graft group.

In the EGF group, 15 patients (57.7%) had hypertension and three (11.5%) had chronic obstructive pulmonary disease. In the graft group, ten patients (47.6%) had hypertension and three (14.3%) had chronic obstructive pulmonary disease. Eighteen patients (69.2%) in the EGF group and 15 (71.4%) in the graft group were treated with insulin. The mean duration of diabetic disease was 23 years (range, 17–30 years) in the EGF group and 22.1 years (range, 15–30 years) in the graft group. The median duration of DFU diagnosis was 2.5 months (range, 1–9 months) in the EGF group and 2.6 months (range, 1–8 months) in the graft group. Five patients (19.2%) in the EGF group and four (19.0%) in the graft group had previously undergone minor amputation. Of the patients in the EGF group, seven (26.9%) had Wagner grade 2 DFU, 15 (57.7%) had grade 3 DFU, and four (15.4%) had grade 4 DFU. In the graft group, these percentages were 28.6%, 57.1%, and 14.3%, respectively. Revascularization was performed in four of these patients by interventional radiology. In these four patients, revascularization was performed before the planned treatment (debridement, EGF injection, grafting, NPWT, etc) The mean size of the wound in the EGF group was 9.7 cm (range, 4–16 cm) and in the graft group was 9.0 cm (3–18 cm). The mean ankle-brachial index of the patients was 0.98 in the EGF group and 1.10 in the graft group. The mean (25th–75th percentile) duration of treatment was 7.0 weeks (4–8 weeks) in the EGF group and 5.3 weeks (4–8 weeks) in the graft group (P < .05). Off-loading was performed in all of the patients with DFU, especially at the sole, heel, and foot lateral. Off-loading was not required for patients with a wound on the dorsal foot and a wound on the toes. Approximately half of the patients undergoing off-loading were able to adapt to the off-loading practice until the end of treatment (EGF group: eight patients (57.1%); graft group: six patients [46.1%]). The mean duration of treatment of patients who could adapt to off-loading was 5.5 weeks (range, 4–6 weeks) in the EGF group and 4.3 weeks (range, 4–5 weeks) in the graft group. This rate was 7.3 weeks (7–8 weeks) and 6 weeks (4–8 weeks) in patients who could not adapt and those who refused the off-loading application, respectively.

In the EGF group, wound healing could not be achieved in one patient during the study, but recovery was successful after 4 months. In the graft group, no recovery was achieved in three patients (14.3%) in the donor site, but recovery was achieved later through long-term treatment (Fig. 1). Graft loss was detected in four patients (19.0%), and partial graft loss was observed in three patients (14.3%) (Table 2). There were no complications in the EGF group excluding minor complications (vomiting, hypotension, nausea, dizziness, pain, etc) (Table 3 and Figs. 2 and 3). There was no graft healing and partial graft healing in four patients (80%) who had DFU in the plantar foot (Fig. 4), in two patients (100%) who had DFU in the heel, and in one patient (20%) who had DFU in a phalanx (Fig. 5). Differences detected between groups are shown Table 4.

Figure 1.
Figure 1.

Image showing no recovery in the donor site.

Citation: Journal of the American Podiatric Medical Association 111, 5; 10.7547/19-027

Table 2.

Complications in the Graft Group (n = 21)

Table 2.
Table 3.

Complications in the EGF and Graft Groups

Table 3.
Figure 2.
Figure 2.

A, Wagner grade 3 diabetic foot ulcer (DFU). Infection and necrosis are seen. B, The DFU after debridement. C, Application of negative pressure wound therapy. D, The DFU after negative pressure wound therapy. No infection or necrosis is seen. E, The DFU after the intralesional epidermal growth factor injections.

Citation: Journal of the American Podiatric Medical Association 111, 5; 10.7547/19-027

Figure 3.
Figure 3.

A, Wagner grade 3 diabetic foot ulcer (DFU). Infection and necrosis are seen. B and C, The DFU after debridement and wound side revision. D, Application of negative pressure wound therapy. E, The DFU after the intralesional epidermal growth factor injections.

Citation: Journal of the American Podiatric Medical Association 111, 5; 10.7547/19-027

Figure 4.
Figure 4.

Image showing poor recovery of a graft in the plantar side of the diabetic foot ulcer.

Citation: Journal of the American Podiatric Medical Association 111, 5; 10.7547/19-027

Figure 5.
Figure 5.

A, The no recovery graft in the phalanx of the diabetic foot ulcer. B and C, The wound treated with intralesional epidermal growth factor.

Citation: Journal of the American Podiatric Medical Association 111, 5; 10.7547/19-027

Table 4.

Clinical and Treatment Features of the EGF and Graft Groups After the Treatment

Table 4.

Discussion

Epidermal growth factor is a necessary factor for wound healing, stimulating cell growth, proliferation, and differentiation.12 It can be administered topically and intralesionally. Recombinant human EGF is produced by recombinant DNA technology.13 It binds to the EGF receptors on the surface of cells, stimulating DNA synthesis and cell proliferation.13 In the present study, EGF was used. It is a protein that coordinates intracellular and intercellular signals and plays a mitogenic role in wound healing, facilitating the migration of cells responsible for wound closure to the site of DFU, formation of the granulation tissue, contraction of the wound borders by myofibroblasts, angiogenesis, proliferation of epithelial cells, and their migration to the place of ulceration.14 Although we carry keratinocytes to the chronic wound surface with graft application, we stimulate growth of the keratinocytes, proliferation of the keratinocytes, and new vessel formation of the wound with the use of EGF. This makes EGF one step ahead of the other wound closure methods.

In diabetic wounds, direct closure methods are suitable for small wounds, whereas graft closure methods are preferred for large but shallow wounds.15 Free flaps can be used in large wounds, but problems may be encountered because of the failure of recovery of the donor site and PADs in patients with diabetes.16,17 Depending on the size of the defect, a propeller flap can be applied; with this application, a tension-free and primary closure can be provided on the donor site.15 Nevertheless, caution should be exercised when selecting patients for these flaps. The reason is that the success rate of these flaps, especially in elderly patients, is low because of peripheral vascular diseases.18 Most patients were treated with grafts to avoid donor site complications, except the patients selected in our clinic.

More than 50% of patients with DFU showed clinical signs of infection.19 In a large prospective study, the presence of infection increased the minor amputation rate by 50% compared with patients with noninfected DFU.20 Therefore, control of infection is of paramount importance in the treatment of patients with DFU. With sweat and oil gland dysfunctions, the diabetic foot becomes dry and keratinized, cracking and fissuring more easily and becoming a portal of entry for infections.21 In the present study, infections were detected in more than half of the patients in accordance with the literature. Definitive therapy for patients with DFU with infection should be based on the results of culture and sensitivity analysis. The antibiotic treatment should always involve an agent active against gram-positive cocci, with special attention for methicillin-resistant S aureus in high-risk patients.22 The IDSA has formulated guidelines and important recommendations for the treatment of infections, declaring that empirical antibiotic treatment should be performed primarily on the basis of infection severity and possible pathologic agents.11 McKinnon et al23 confirmed that treatment with ampicillin/sulbactam was equally effective but significantly less expensive than imipenem/cilastin for moderate DFU with infection. The most common isolated organisms were S aureus, Staphylococcus epidermidis, and Streptococcus species. Among anaerobic microorganisms, Peptostreptococcus magnus and Bacteroides fragilis were noted.24 In another study, S aureus, group B streptococci, Enterococcus, and facultative gram-negative bacilli were identified in the cultures of DFU infections.25 In both groups, we treated the wound infections of the patients primarily because the EGF and graft applications to the infected tissues are contraindicated. The EGF and graft applications were planned after the infection was eliminated.

Surgical management (surgical debridement, minor amputation) of patients with DFU infection is frequently required and involves an aggressive incision, drainage, and debridement of nonviable soft tissue and bone.11 Multiple debridements are often important to provide sufficient drainage and control of infection.11 In a study that retrospectively assessed two groups of patients treated for DFU, patients in group 1 were treated only with intravenous antibiotic treatment, and patients in group 2 were treated with intravenous antibiotic therapy in addition to surgical methods within the first 3 days of hospital admission. It was determined in the study that the patients in group 2 needed fewer high ankle amputations and a 6-day shorter hospitalization than those in group 1.26 In the present study, repeated daily debridements were performed until the wound was removed from dead tissues, the smelly discharge was removed, and the signs of infection regressed.

Chronic hyperglycemia is known to disrupt wound healing in patients with DFU.27 Glycemic control is an accepted method of basic prevention of microvascular complications and has been shown to reduce amputation rates.28 A systematic review showed that absolute glycemic control was associated with only a 35% decrease in amputation risk in patients with DFU.29 Studies have shown different outcomes regarding the impact of glycemic control on wound healing, time to wound healing, and amputation rate. A clinical study reported HbA1c as a notable determinant of DFU healing in patients with diabetes. The healing time for foot ulcers in patients with lower HbA1c values was shorter than that for patients with higher values. Although foot ulcer healing has also been reported in patients with higher HbA1c values, the healing time was significantly longer.30 In the American Diabetes Association data, the HbA1c test was accepted as a defined risk marker for the complications of diabetes.31 A recent study has shown that patients with baseline HbA1c values less than 7.5% are more likely to heal during treatment.30 Therefore, HbA1c levels were measured for all of the patients on the first day of hospitalization, and treatment was provided for glycemic control. The decrease in HbA1c levels was observed with healing of the wound in the control group. We were able to quickly control the HbA1c levels of our patients because patients' wound infections were quickly treated with aggressive debridements and appropriate antibiotics. In addition, the blood glucose monitoring, diabetic treatments, and diets of the patients were completely under our control during the hospital stay.

Negative pressure wound therapy is a novel, noninvasive adjunctive treatment method. A vacuum-assisted closure device to check subatmospheric pressure aids wound healing by removing infected or noninfected fluid from open wounds, preparing the wound bed for closing, reducing edema, and raising formation and perfusion of granulation tissue.32 The therapy is applied to the stump after amputation or after controlling the infection in patients with DFUs. It is known to help wound healing and to accelerate granulation on the wound base.33 In the present study, NPWT was applied to accelerate granulation on the wound base. Armstrong et al34 showed that the time during which 76% to 100% of granulation tissue developed in the NPWT group was shorter than that in the moist dressings group. In the present study, NPWT was continued until the granulation tissue was formed. Using NPWT has helped us shorten the treatment time and reach tissue granulation faster because EGF and graft applications started after granulation tissue formation was completed. Wound bed preparation and granulation tissue formation are essential prerequisites for wound healing. Some articles assessed granulation tissue growth (90% or >90% of granulation tissue formation), preparation of reepithelialization, and skin grafting as end points.35-37 In the present study, the formation of granulation tissue, beginning epithelialization of the wound, or the placement of the graft was not accepted as completion of the treatment. Wound healing means that the graft was alive and epithelialized, or that the wound was completely covered with epithelial tissue.

There is accumulating evidence that the effective range of negative pressure is between –50 mm Hg and –150 mm Hg.36 Strengths as low as –40 mm Hg may be applied for the treatment of sensitive, poorly perfused tissue.37 According to the same study, levels of negative pressure higher than –80 mm Hg are rarely needed.37 However, according to other research on porcine peripheral wounds, a suction pressure of –125 mm Hg was suggested for the removal of exudate from the wound. There is little information on the optimum level of negative pressure for clinical use, and it has been thought that the level of negative pressure may be set in a variety of patients.37 In summary, –75 mm Hg to –125 mm Hg has been recommended, but unusual problems have to be taken into account when dealing with the treatment of sensitive, badly perfused tissue and wounds with high levels of exudate.38

An STSG was prepared and applied to the patients. These grafts are skin grafts from which the epidermis and a portion of the dermis are taken. These grafts can be applied quickly and easily in the closure of skin defects. In addition, STSGs are the most commonly used types of graft for the closure of wider defects.39 Skin grafts are tissues with a limited blood supply that causes bleeding only on the applied surface because they do not have their own blood vessels. Split-thickness skin grafts have less metabolic requirements than full-thickness skin grafts because they are thinner. For this reason, STSGs are considered an ideal material to close wound surfaces.39 They have poor aesthetic results, but aesthetics is not a priority in patients with DFU.

The cells of the epidermis are called keratinocytes, originating from the stratum basale. Melanocytes, Langerhans cells, and Merkel cells are also present in the epidermal layer of the skin.40 As a result of the closure of the wound surface with skin graft, the surface of the wound is covered with keratinocytes in a short time.41 During the grafting process, healthy keratinocytes, melanocytes, Langerhans cells, and Merkel cells are carried into the tissue. Epidermal growth factor is involved in cell proliferation, growth, and differentiation.42 Both methods enable the epidermis cells to grow and replicate, helping with wound closure. Thus, these two methods were compared in the study.

In some studies, STSG was reported to be successful in burns and plastic surgery as well as in patients with DFU.43 Although there are many wound care covers and synthetic grafts, STSG is considered the gold standard and can be accepted as the primary treatment method for DFUs.44 Moreover, microcirculation and macrocirculation disorders, peripheral neuropathy, endothelial dysfunction, and poor glycemic control in patients with diabetes impair wound healing.45,46 These conditions also affect the healing of skin grafts and donor sites in patients. Impaired vascular flow in patients with diabetes has been reported to cause graft failure.47 When the complication rate of STSG was compared between diabetic and nondiabetic patients, it was found to be 5.15 times higher in patients with diabetes.48 These complications included graft retention, infection, and the need for regrafting.48 In one study, the complication rate in the graft site after STSG in patients with diabetes was 35%.49 In the present study, the complication rate in the graft site was 33% in the STSG group. When the complications were evaluated, they were found to be more common in patients with high comorbidity, a low ankle-brachial index, and grafting on the plantar side of the foot. In a study by Ramanujam et al,47 comorbidities such as cardiovascular diseases and peripheral vascular diseases were found to be more effective than diabetes itself in graft complications. In the present study, wound closure could not be achieved in one patient in the EGF group.

Diabetic foot ulceration on the plantar side of the foot is predominantly caused by a loss of preventive sensation along with a combination of excessive or continued compressive, shear, and frictional forces leading to tissue failure.50 The two major reasons for DFU that are generally reported and accepted are protective sensory loss and “heavy or extreme pressure.”51 It is well-recognized and accepted that off-loading—the elimination of abnormal pressure points to promote healing—is a cornerstone of successful DFU control and prevention.52 In the present study, 40.4% of the patients had neuropathy, and nearly all of these patients had a wound on the plantar face and heel of the foot. In the present study, off-loading was performed in all of the patients with DFU, especially at the sole, heel, and foot lateral. Patients in the EGF group received off-loading as soon as the EGF injection was completed. The graft group underwent off-loading after the graft was alive and epithelial formation was observed. There is a long-standing clinical tradition of using various off-loading accessories such as footwear, surgery, and other off-loading interventions to heal DFUs.53 All of these noted that nonremovable off-loading methods result in significantly improved healing outcomes for neuropathic plantar forefoot ulcers compared with removable devices.54 Total-contact casts were applied as an off-loading method to all of the patients with wounds on the sole of the foot and heel in the present study. Contraindications for the use of nonremovable knee-high off-loading devices include both light infection and light ischemia, moderate-to-heavy infection, moderate-to-heavy ischemia, or heavy-discharge ulcers.54 Therefore, before off-loading, it was ensured that the patients did not have an infection or that the flow of discharge was hindered. Several noncontrolled studies have shown that 70% to 96% of plantar foot ulcers can be healed in a reasonable time frame (mean of 34–79 days) with ankle-high removable off-loading devices, provided that they are used regularly.55 The larger systematic review published an overall healing rate of 97% with a mean off-loading period of 29.5 days.56 In the present study, the patients underwent an average of 28.4 days of off-loading. Nonremovable, knee-high off-loading equipment was used for the first 7 days (the need to control the wound or graft), followed by ankle-high removable off-loading for the balance period. When we compare patients who adapt and do not adapt to the off-loading application, we found that the duration of treatment is shorter in patients who can adapt to the off-loading application compared with other patients.

Pain in the graft donor site of patients reconstructed due to tissue defect is observed as the first concern of patients in the postoperative period.57 The partial-thickness skin graft donor site is generally more painful than the recipient site.58 The superficial wounds of the donor area, including the epidermis and dermis, heal under the right conditions, depending on the patient's age and general condition, in 8 to 14 days.59 Donor site complications increase especially in patients with diabetes and in those who are elderly.60,61 In one study, researchers noted that no meaningful associations were recognized for graft location, age, HbA1c level, and graft size.52 In the present study, the complication rate in the donor site was 14.3%. When these patients were evaluated, the mean age was 61 years, and the comorbid patients accounted for 66%. Intralesional EGF was used on nonrecovered wounds in the donor site. It was observed in this study that the use of EGF protected patients against donor site complications.

In a study of 83 patients, the mean recovery time of patients who underwent STSG due to DFU was found to be 6.9 weeks for patients with no complications.52 Mahmoud et al62 reported recovery in 8 weeks in 62% of patients with diabetes treated with STSG. In another study, the mean recovery time was 12 weeks in patients who developed complications and 4.9 weeks in patients without any complications.47 In the present study, the mean recovery period for the STSG group was 5.4 weeks in patients with no complications and 7 weeks in patients with complications. In comparison, the mean recovery period in the EGF group was 7 weeks. Therefore, the recovery time for the EGF group can be considered to be too long (P < .05).

This study has several limitations, namely, the retrospective nature of the study, the low number of patients, and the fact that some patients came from other health institutions after undergoing STSG.

Conclusions

Both STSG and EGF applications are reliable methods for patients with DFU. Application of EGF is a safe method because of its low risk of complications, applicability in areas with a low graft success rate (eg, soles of the feet), and no need for hospitalization. Intralesional EGF application may be preferred to avoid complications in both the donor and recipient sites, especially in elderly patients with multiple comorbidities and wounds on the soles, thereby ensuring that patients can be protected from complications in the graft area as well as the donor site.

Financial Disclosure: None reported.

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Department of General Surgery, Faculty of Medicine, Selcuk University, Konya, Turkey.

Corresponding author: Serdar Yormaz, MD, Department of Surgery, Selcuk University Medicine Faculty, Konya, 42075 Turkey. (E-mail: serdaryormaz@gmail.com)

Conflict of Interest: None reported.