Extended Extracorporeal Shockwave Therapy for Chronic Diabetic Foot Ulcers: A Case Series

Introduction. It is hypothesized that cumulative extended application of extracorporeal shockwave therapy (ESWT) can be beneficial to sustain the effect of ESWT and improve the long-term outcome in chronic diabetic foot ulcers (DFUs). Objective. The purpose of this study is to investigate the effectiveness of multiple extended booster ESWT to maintain the effects of ESWT on the outcomes of chronic DFUs. Materials and Methods. Four patients with a DFU were treated with ESWT, including 1 patient with 12 treatments and 3 patients with 6 treatments. Evaluations included clinical assessment, blood flow perfusion, and biopsy of the ulcers. Results. At 48 weeks, the results showed completely healed ulcers in 2 patients and improved ulcers in the other 2 patients. In the DFU Scale Short-Form, the score decreased in 1 patient and remained unchanged in 3 at 48 weeks. Blood perfusion increased in 1 patient but remained unchanged in 3. In immunohistochemical analysis, the angiogenic, anti-inflammatory, proliferative, and tissue repair biomarkers were elevated in 1 patient and decreased in 3. Conclusions. The effects of ESWT appear to maintain certain levels for an extended period of time at 1 year but start to show deterioration on tissue viability. Therefore, it is speculated that intermittent booster ESWT may maintain the effects of ESWT and sustain the tissue viability and repairing. The use of ESWT appeared to be effective for DFU treatment, and extended ESWT showed a tendency of sustaining ESWT effects when multiple booster treatments are utilized in patients with a DFU.

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Chronic diabetic foot ulcers (DFUs) are defined as nonhealing ulcers of the foot lasting more than 3 months’ duration in patients with diabetes.^1-6 The etiologies of chronic DFUs are multifactorial. Diabetic ulcers are caused by angiopathy with small vessel occlusion associated with poor skin sensation due to peripheral neuropathy and secondary infection.^7,8 Moulik et al⁹ reported 45% neuropathic, 16% ischemic, and 24% neuroischemic DFUs in 185 patients. The 5-year amputation rates were 11%, 29%, and 25% and the 5-year mortality rates were 45%, 55%, and 18% for neuropathic, ischemic, and neuroischemic DFUs, respectively.⁹ The overall amputation rate in DFUs was 21.5% to 28.4% in the reported series.¹⁰ Significant risk factors for amputation include peripheral vascular disease, elevated neutrophils in white blood cells, C-reactive protein, triglyceride, Wagner grade, age of patient, and age of wound.^10-12

Management of chronic DFUs requires a multifaceted approach, including dressings, glucose control, shoe wear, infection control, wound care, vascular and nutritional consultation, and surgery in select cases. The results of surgical and nonsurgical treatments are inconsistent, and most studies reported unsatisfactory results.^13-15 Therefore, many adjunctive therapies are designed to improve the care of chronic DFUs (eg, hyperbaric oxygen therapy [HBOT], recombinant human platelet-derived growth factor BB, negative pressure wound therapy, and acellular matrices). Some achieved limited success, but none showed universal results.^16-23

Extracorporeal shockwave therapy (ESWT) has been shown to induce neovascularization and increase angiogenic and osteogenic growth factors that lead to improvement in blood flow perfusion and tissue regeneration in animal experiments.^24,25 Molecular changes support that ESWT acts as mechanotransduction that produces the therapeutic benefits through complex biological pathways for neoangiogenesis and tissue regeneration in chronic DFUs.^1,26,27 A study from 2007 reported²⁸ positive effects of ESWT in the treatment of acute and chronic wounds. Prior studies showed ESWT is more effective than HBOT in the treatment of DFUs in short-term follow-up.^2,5,6 Other studies^3-5 also demonstrated the effectiveness of ESWT in chronic DFUs and nondiabetic foot ulcers. In addition, ESWT was shown to improve skin flap survival, burn wound healing, and blood flow perfusion.^29-31

Several studies^1,2,5,26,27 found ESWT is an effective treatment for chronic DFUs with significant improvement in the numbers of completely healed and > 50% improved foot ulcers as well as decreased mortality and morbidity, including the rate of amputation and local blood flow perfusion. The effectiveness of ESWT in chronic DFUs is most noticeable within 1 year following treatment. However, the effects of ESWT began to decline and the clinical outcome and blood flow perfusion showed deterioration in follow-up from 1 year to 5 years post treatment. The Spearman rank correlation analysis showed clinical outcomes correlated significantly with the changes in blood flow perfusion at 1 year and 5 years.⁶ There are multiple reasons to explain the changes, including that the natural course of the disease may predispose to further disease progression with time. Further, the authors speculate the effects of ESWT may gradually disappear with time without additional treatment or stimulation to sustain the effects of ESWT. Thus, the nonlasting effects of ESWT in chronic DFUs beyond 1 year have raised the question of the long-term effect of ESWT in chronic DFUs. 

The purpose of this case series is to assess the effectiveness of multiple extended booster ESWT to maintain the effects of ESWT and improve the outcome in chronic DFUs. The authors hypothesized that cumulative extended application of ESWT at certain time intervals can be beneficial to sustain the effects of ESWT and improve the long-term outcomes of ESWT in the treatment of chronic DFUs.

This study was conducted at Kaohsiung Chang Gung Memorial Hospital (Kaohsiung, Taiwan). The inclusion criteria consisted of patients with nonhealing, Wagner³² grade II or less DFUs of > 3 months’ duration and hemoglobin A_1C < 12%. The exclusion criteria included patients with cardiac arrhythmia or a pacemaker, malignancy, joint sepsis, nondiabetic ulcers, multiple ulcers, or a fistula; pregnant women; history of poor compliance; obesity (body mass index > 40 kg/m²); patients on dialysis; and patients involved in another clinical trial.

In addition to ESWT, patients received multidisciplinary wound care including dressings, offloading, and glucose control. The evaluations included clinical assessment of ulcer severity status, local blood flow perfusion, and biopsy for histopathological examination and immunohistochemical analysis. 

Shockwave application
The shockwave source used was dermaPACE (SANUWAVE, Suwanee, GA). The treatment dosage was dependent on the ulcer size; the number of impulses equaled the treatment area in cm² x 8, but at least 500 shocks at E2 at 4Hz (equivalent to 0.11 mJ/mm² energy flux density) were delivered twice weekly for a total of 6 treatments. During ESWT, the treatment head of the device was gently glided over the entire surface of the wound extending 1 cm from the wound perimeter in every direction. The treatment area was calculated as the actual size of the ulcer extending 1 cm in each direction. The dosage of the booster ESWT was the same as the initial course of treatment. In cases with completely healed ulcers, ESWT was applied to the same area, including the perimeter between the ulcer and normal skin. 

Blood flow perfusion scan
Tissue viability was evaluated by local blood flow perfusion scan pre- and post-ESWT. Local blood flow perfusion was measured using Doppler Flowmetry (Perivasculary; Moor Instruments Ltd., Devon, UK). To perform this analysis, the DFU was placed on a light-absorbing background material such as a black or a dark green cloth. The distance between the scanner head and the object was 15 cm. The minimum and maximum values are set at 0 and 5 volts, respectively. The perfusion scan image color scale displayed the lowest value in dark blue and the highest value in dark red. The minimal value, the maximal value, and the mean and standard deviation were computer analyzed.

During the course of study, a total of 21 patients were screened; only 4 patients fulfilled the criteria and 17 were excluded. All 4 patients received ESWT to the foot with the DFU. Three patients received 6 treatments of ESWT, and 1 patient received 12 treatments of ESWT. The analyses of this study were based on a small case series with a cohort of 4 patients. All patients were labeled according to the methods of treatment (Table). 

Patients 2 and 4 had completely healed DFUs at 24 weeks post ESWT and had no recurrence at 48 weeks. Patient 1 showed 86% reduction of ulcer size at 48 weeks post ESWT, and patient 2 showed 40% reduction in ulcer size. The clinical results of a representative case is shown in Figure 1. It appears ESWT effectively healed the DFUs, and the regenerative process appears to be continuous for 48 weeks or longer after ESWT. When DFUs were assessed using the Diabetic Foot Ulcer Scale Short-Form,³³ the score decreased in patient 4 and remained unchanged in patients 1–3. From immediate post ESWT to 48 weeks post treatment, patient 3 showed a worse score. Therefore, the effects of ESWT on DFU scores are sustainable for up to 48 weeks after the initial treatment before deterioration may take place if no additional treatment was rendered. 

Blood flow perfusion
The blood flow perfusion rate increased in patient 3 and remained unchanged in patients 1, 2, and 4. From immediate post ESWT to 48 weeks, the blood flow perfusion rate was improved in patients 1 and 2 and decreased in patient 3. The skin perfusion pressure seemed to decrease after ESWT. Likewise, blood flow perfusion rate showed a tendency to increase in only patient 3 shortly after ESWT and patients 1 and 2 in immediate post ESWT to 48 weeks post treatment.

Immunohistochemical analyses
The angiogenesis biomarker, platelet-derived growth factor, was elevated in patients 1, 2, and 4 and decreased in patient 3 after ESWT. The neovascularization biomarkers, nitrate oxide synthase, vessel endothelial growth factor, were elevated in patients 1, 2, and 4 and decreased in patient 3 after ESWT; the von Willebrend factor increased in patients 1–3 and decreased in patient 4. The proliferating biomarkers, proliferating cell nuclear antigen and epidermal growth factor, were up in patients 1, 2, and 4 and down in patient 3 following ESWT. Anti-inflammatory cytokines, transforming growth factor beta 1, increased in patients 1, 2, and 4 and decreased in patient 3 after ESWT. In addition, for tissue repair biomarkers, metalloproteinase 13 increased in patients 1, 2, and 4 and decreased in patient 3; beta-catenin increased in patients 2–4 and decreased in patient 1, and fibronectin showed decreases in all patients post ESWT. The microphotographs of the different molecular changes are shown in Figure 2.

Complications
All patients tolerated ESWT treatment well. Mild local redness or swelling was treated with observation and ice pack application. There were no systemic or neurovascular complications or device-related problems.

The authors’ prior studies reported the effectiveness of ESWT on DFUs.^2,5,6,26,31 Despite a small case number, the results showed ESWT may be effective to heal or improve DFUs. The effects of ESWT appear to maintain certain levels for an extended period of time of 1 year before starting to show deterioration on the tissue viability. Therefore, it is speculated that intermittent booster ESWT may maintain the effects of ESWT and sustain tissue viability and repairing. The results of this series showed a tendency of tissue regeneration when intermittent booster ESWT is used in DFUs.

The mechanism of ESWT is not fully understood. Extracorporeal shockwave therapy was shown to induce neovascularization and increase angiogenic and osteogenic growth factors that lead to improvement in blood flow perfusion and tissue regeneration.^24,25 The molecular changes support that ESWT acts as mechanotransduction that produces the therapeutic benefits through complex biological pathways for neoangiogenesis and tissue regeneration in chronic DFUs.

The limitations of this study included the small number of patients and relatively short follow-up time. Additional study is needed to confirm these results on extended ESWT for chronic DFUs.

Extracorporeal shockwave therapy appears effective for the treatment of DFUs. The observational results in this case series showed a tendency of increased ESWT effects when multiple courses of booster treatment are utilized. Additional randomized controlled studies with a larger patient population are needed to further confirm the efficacy of ESWT in DFUs.

Authors: Wen-Yi Chou, MD^1,2; Ching-Jen Wang, MD^1,2; Jai-Hong Cheng, PhD¹; Jen-Hong Chen, MD^1,2; Chien-Chang Chen, MD¹; and Yur-Ren Kuo, MD^3,4

Affiliations: ¹Center for Shockwave Medicine and Tissue Engineering; ²Division of Sports Medicine, Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan; ³Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; and ⁴Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Correspondence: Ching-Jen Wang, MD, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan, Orthopedic Surgery, 123, Ta Pei Road, Niao Sung District, Kaohsiung 83301 Taiwan; cjwang1211@gmail.com

Disclosure: A grant was received in total or in partial support of this study from Chang Gung Research Fund (CMRPG8D0321, CMRPG8D0322, CLRPG8E0131). Dr. Wang serves as a member of the Advisory Committee of SANUWAVE (Suwanee, GA); the remaining authors disclose no financial or other conflicts of interest.