Diabetic Ulcer Research O/V

This interactive presentation gives an overview of published research on the treatments for Diabetic Foot Ulcers. RESEARCH OVERVIEW TREATMENT MODALITIES FOR DIABETIC FOOT ULCERS (DFU)

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Make your choice

WALKERS

NMES

SHOCKWAVE THERAPY

HIGH-INTENSITY LASER

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WALKERS

Clinical effectiveness

Piaggesi, 2016

Caravaggi 2007

Khalifa 2023

RCTs

Reviews

Lazzarini, 2020

Morona, 2013

Majid, 2017

Guidelines

Bus, 2023

Cost-effectiveness

HQO, 2017

Wearable technology (smart walker)

Finco, 2023

SHOCKWAVE THERAPY

Working principles

Mittemayr, 2012

Clinical effectiveness

Clinical trials

Galiano, 2019

Jeppesen, 2016

Wang, 2011

Snyder, 2020

Hitchman, 2023

Jeong, 2023

Systematic Reviews

Hitchman, 2023

HIGH-INTENSITY LASER

Working principles

Review

Houreld, 2014

Wound healing effectiveness

Clinical trials

Basalameh, 2013

Maltese, 2015

Neuropathic pain management

Pilot Study.

Chatterjee, 2019

NEUROMUSCULAR STIMULATION (NMES)

Working mechanisms

Kloth, 2013

Kloth, 2005

Clinical effectiveness

Microcurrent

Wirsing, 2015

Kurz, 2022

Polak, 2014

HVPC

Peters, 2001

Girgis, 2023

Reviews

Chen, 2020

Melotto, 2022

Caravaggi et al. 2007

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Caravaggi C, Sganzaroli A, Fabbi M, Cavaiani P, Pogliaghi I, Ferraresi R, Capello F, Morabito A. Nonwindowed nonremovable fiberglass off-loading cast versus removable pneumatic cast (AircastXP Diabetic Walker) in the treatment of neuropathic noninfected plantar ulcers: a randomized prospective trial. Diabetes Care. 2007 Oct;30(10):2577-8.

Design: Controlled, Randomized, Prospective Trial Subjects: 60 consecutive diabetic patients with neuropathic plantar ulcers Methods: subjects were randomly assigned into 2 groups: • group A : using an Aircast Pneumatic Walker • group B : using the fiberglass off-loading cast Outcomes: Healing time, Healing rate at 90-days, Side effects Results: • Healing time was significantly lower in the fiberglass cast group (average 48 days) compared to the Aircast Walker group (average 71 days) • Healing rate at 90-days follow up was 82.7% in the cast group and 79.3% in the Aircast walker group, with no statistical difference. • Concerning side effects there were no statistical differences between the two groups.

Key message: From the good rate of healing and low risk of complications shown, the Aircast Pneumatic Walker is a valid alternative for treatment of neuropathic plantar ulcers.

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Morona et al. 2013

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Morona JK, Buckley ES, Jones S, Reddin EA, Merlin TL. Comparison of the clinical effectiveness of different off-loading devices for the treatment of neuropathic foot ulcers in patients with diabetes: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2013 Mar;29(3):183-93.

Design: Systematic Review & Meta-Analysis Methods: Literature was searched up until May 2012. The papers needed to describe the use of various orthotic devices in the treatment of chronic neuropathic ulcers. Outcomes: Adverse events, ulcers healed, time to healing, ulcer size change, amputations required. Results: • 13 studies included. • No differences found between devices for complete healing of ulcers. • Non-removable devices and walkers rendered irremovable were found to be equally effective for time to healing. • When encompassing all removable devices (inc. therapeutic shoes, walkers) and non-removable off-loading devices (total contact casts and walkers rendered irremovable), non-removable off-loading devices were found, to be more effective at promoting the healing of diabetic foot ulcers (p = 0.001).

Key message: Non-removable off-loading devices (cast or walker rendered irremovable) are more likely to result in ulcer healing than removable off-loading devices (due to compliance). However, no differences were found in terms of the 'complete healing of ulcers' with removable cast walkers from five studies.

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Piaggesi et al. 2016

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Piaggesi A, Goretti C, Iacopi E, Clerici G, Romagnoli F, Toscanella F, Vermigli C. Comparison of Removable and Irremovable Walking Boot to Total Contact Casting in Offloading the Neuropathic Diabetic Foot Ulceration. Foot Ankle Int. 2016 Aug;37(8):855-61.

Design: Randomised Comparative Study Subjects: 60 patients with DFUs, Methods: Subjects were randomly assigned to 3 different offloading modalities: 1.Total contact casting (TCC) (group A), 2.Walking boot rendered irremovable (i-RWD; group B), 3.Removable walking boot (RWD; group C). The i-RWD and RWD were the same brace, just left removable in group C. Patients were followed up weekly for 90 days or up to complete re-epithelization. Outcomes: Ulcer survival, Healing time, Ulcer size reduction, adverse events, patients' acceptance and costs Results: • Mean healing time in the 3 groups did not differ (P = .5579). • Ulcer size reduction from baseline to the end of follow-up was significant (P < .01) in all groups without differences between the groups. • Seven patients in group A (35%), 2 in group B (10%), and 1 in group C (5%) (Fisher exact test P = .0436 group A vs group C) reported non-severe adverse events. • Patients' acceptance and costs were significantly better in group C (P < .05).

Key message: Walking boot was as effective as Total Contact Casting (TCC) on offloading the neuropathic Diabetic Foot Ulcers. Non-severe adverse events, patient acceptance and patient costs were significantly better with the removable brace compared to TCC.

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Majid et al. 2017

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Majid U, Argáez C. Off-Loading Devices for People with Diabetic Neuropathic Foot Ulcers: A Rapid Qualitative Review [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Jun 17. PMID: 33296155.

Design: Rapid Qualitative Review Methods: • The main search concepts were the use of offloading devices for diabetic foot ulcers in community or care institutions (hospital, care home, retirement home etc.) Outcomes included: • People’s (and their care providers’) understandings and experiences of living with offloading devices for diabetic foot ulcers (inclusive of how these devices are accessed); Results: • 12 studies were included. • Patients across studies believed that offloading devices were integral to successfully treating their ulcers, as well as preventing future foot-related complications. • The cost of offloading devices was an important determinant for patients in device decision-making and everyday use. • In general, patients preferred removable offloading devices ( specifically the AirCast ) because it enabled them to continue their everyday lives. • Removable cast walkers were perceived as easier to apply and remove and did not require regular appointments with healthcare professionals for removal. • However, patients expressed challenged interacting with certain device mechanics and some perceived that walkers were ineffective because they did not fully immobilise the feet.

Key message: There are many barriers to offloading device adherence for diabetic foot ulcers, including the effectiveness of footwear, the cost of the device and how it fits with patients’ everyday activities. Some preference was stated towards Aircast walkers as it enabled participants to continue their everyday lives.

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Lazzarini et al. 2020

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Lazzarini PA, Jarl G, Gooday C, Viswanathan V, Caravaggi CF, Armstrong DG, Bus SA. Effectiveness of offloading interventions to heal foot ulcers in persons with diabetes: a systematic review. Diabetes Metab Res Rev. 2020 Mar;36 Suppl1(Suppl1):e3275.

Design: Systematic Review Methods: PubMed, EMBASE, and Cochrane databases were searched (July 2014-August 2018) relating to four offloading intervention categories in populations with diabetic foot ulcers: (a) offloading devices, (b) footwear, (c) other offloading techniques, and (d) surgical offloading techniques. Outcomes included: Ulcer healing, plantar pressure, adherence, adverse events, cost-effectiveness etc. Results:

41 studies were included.

•

Key message: Cast and knee-high walkers rendered irremovable are equally effective and the first-choice off-loading intervention for diabetic ulcers.

• High-quality evidence was found for non-removable knee-high offloading devices being more effective than removable offloading devices and therapeutic footwear for healing plantar forefoot and midfoot ulcers. • Total contact casts (TCCs) and non-removable knee-high walkers were shown to be equally effective. • Moderate-quality evidence exists for removable knee-high and ankle-high offloading devices being equally effective in healing, but knee-high devices have a larger effect on reducing plantar pressure and ambulatory activity.

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Khalifa et al. 2023

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Khalifa WA, Argoon SA, AbdEllah-Alawi MH. Determinants of healing of diabetic foot ulcer comparing two offloading modalities: A randomized prospective study. Foot (Edinb). 2023 Mar 17;56:102016.

Design: Randomised Control Trial Subjects: 87 patients with active diabetic foot ulcers Methods: Participants were randomly assigned to either a removable walker (W-arm) or a cast-shoe (C-arm) at 3:2 ratio. Both groups received the routine ulcer care and were followed-up for 24 weeks. Outcomes included: SINBAD score, Adherence, Ulcer healing, Ulcer area and adverse events. Results: • The 24-week healing rate was 81% for the walker group and 62 % for the cast-shoe group. • The mean adherence was 55 % ± 26 % and 46 % ± 29 for the walker and cast shoe groups respectively. • Ulcer healing was significantly positively associated with: better adherence, device type (walker), less SINBAD score (2 or less), absence of ischemia, absence of infection, smaller ulcer area, superficial ulcer, better 4-week area reduction, and better blood glucose control. • The most important predictors were adherence, total SINBAD score and 4-week area reduction.

Key message: Knee-high walker had a better efficacy for healing compared to a cast-shoe for diabetic foot ulcers (81% vs 62% at 24 weeks). Adherence was also greater for the knee-high walker compared to the cast-shoe.

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Walker resulted in less adverse events, less cases of non-healing and better overall healing at 24 weeks.

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Health Quality Ontario. 2017

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Health Quality Ontario. Fibreglass Total Contact Casting, Removable Cast Walkers, and Irremovable Cast Walkers to Treat Diabetic Neuropathic Foot Ulcers: A Health Technology Assessment. Ont Health Technol Assess Ser. 2017 Sep 21;17(12):1-124.

Design: Health Technology Assessment Methods: Searches to identify randomized controlled trials that compared fibreglass total contact casting, removable cast walkers, and irremovable cast walkers with other treatments (offloading or non-offloading) in patients with diabetic neuropathic foot ulcers. Outcomes included: Cost-effectiveness, 5-year budget impact analysis, qualitative interviews on treatment choices. Results: • 13 RCTs were included in the analysis. • Compared to removable cast walkers, ulcer healing was improved with total contact casting (moderate quality evidence) and irremovable cast walkers (low quality evidence). • No difference in ulcer healing between total contact casting and irremovable cast walkers • The economic analysis showed that total contact casting and irremovable cast walkers were less expensive and led to more health outcome gains than removable cast walkers. • Irremovable cast walkers were as effective as total contact casting and were associated with lower costs. • Patients felt that total contact casting was more effective but removable cast walkers were more convenient and came with a lower cost burden.

Key message: Total contact casting and irremovable cast walkers had higher rates of ulcer healing than removable cast walkers. Offloading devices could result in cost- savings in the future.

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Bus et al. 2023

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Bus SA, Armstrong DG, Crews RT, Gooday C, Jarl G, Kirketerp-Moller K, Viswanathan V, Lazzarini PA. Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2023 update). Diabetes Metab Res Rev. 2023 May 25:e3647.

Design: Evidence-based Guidelines Methods: A multidisciplinary working group of independent international experts in offloading DFU were invited to develop this guideline. A series of clinical questions was devised, and a systematic review and meta-analysis of studies was performed to develop summaries and recommendations for each question. This encompassed factors such as certainty of evidence, cost- effectiveness, patient values, desirable/undesirable effects, feasibility etc. Results: Recommendations included: • For plantar forefoot or midfoot ulcer healing, use a non-removable knee-high offloading device (including total contact casts and removable knee-high walkers rendered non-removable) as the first-choice offloading intervention. • For patient intolerance or contraindications, use a removable knee-high walker as second-choice. • For non-plantar ulcers, use a removable offloading device, footwear modifications, toe spacers, orthoses or digital flexor tenotomy depending on the type and location of the foot ulcer. • For infected ulcers, primarily deal with the infection and then use a removable offloading intervention.

Key message: Offloading interventions are arguably one of the, if not the, most important interventions with the highest 'certainty of evidence' available for healing neuropathic DFUs and reducing the global burden of these ulcers.

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Finco et al. 2023

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Finco MG, Cay G, Lee M, Garcia J, Salazar E, Tan TW, Armstrong DG, Najafi B. Taking a Load Off: User Perceptions of Smart Offloading Walkers for Diabetic Foot Ulcers Using the Technology Acceptance Model. Sensors (Basel). 2023 Mar 2;23(5):2768.

Design: Randomised Control Trial Subjects: 21 adults with DFUs (age 61.5 ± 11.8 years; 85.7% male). Methods: Participants were randomized to wear either: • Irremovable cast walker (Reference group) (n=11) • Removable cast walker (Control group) (n=8) • Smart removable walkers (smart boot) that provided feedback on adherence, walking steps and walking cadence (Intervention group) (n=9). Results: • Smart boot users reported that learning how to use the boot was easy (ρ =- 0.82, p≤ 0.001). • Participants who had lower cadence (ρ = 0.74, p < 0.001) or deeper ulcers (ρ = −0.55, p < 0.001) reported that the smart boot helped them follow physician orders. • Non-fallers, compared to fallers, reported the design of the smart boot made them want to wear it longer (p = 0.04) and it was easy to take on and off (p = 0.04) and would like to use it more in the future (ρ = 0.55) (all p < 0.001).

Key message: Smart offloading devices with a remote patient monitoring solution may help promote adherence among older adults to wear offloading boots prescribed for Diabetic Foot Ulcers.

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Mittermayr et al. 2012

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Mittermayr R, Antonic V, Hartinger J, Kaufmann H, Redl H, Téot L, Stojadinovic A, Schaden W. Extracorporeal shock wave therapy (ESWT) for wound healing: technology, mechanisms, and clinical efficacy. Wound Repair Regen. 2012 Jul-Aug;20(4):456-65.

• Shock waves used in treating problematic wounds were not determined to be destructive, rather they have been shown to induce/normalize biological responses, which stimulate and support tissue repair and regeneration. • Although the mechanism of action is still under investigation, it was shown that the physical properties of shock waves are translated to complex biological responses including release of factors, cytokine, and chemokines involved in enhanced tissue perfusion and angiogenesis, both essential for the wound healing cascade. • Increase in platelet-cell adhesion molecule 1 (PECAM-1) expression – critically involved in trans- endothelial migration processes at inflammatory sites, endothelial cell migration and the formation of new blood vessels. • Single ESWT treatment turned on/augmented, for a prolonged period, 25 – 30 key pro-angiogenic genes that were previously silent in both a diabetic model and in normal healing wound • Chronic inflammation and bacterial burden also negatively affect wound healing and, therefore, the suppression of pro-inflammatory status as well as the antimicrobial effect of shock waves could further lead to improved wound healing: • In vivo studies have displayed enhanced early local inflammatory responses (high levels of macrophage-derived inflammatory protein [MIP]-1a and MIP-1b) in sham-treated animals when compared with ESWT-treated grafts. • Shockwaves significantly reduced leukocyte and macrophage infiltration into the isograft; these are pivotal cells in the inflammatory response. • A study showed that the bacterial burden in wounds was statistically reduced in a patient population receiving ESWT treatment. • The application of shock waves to wounds is technically easy to perform, allows treatment in an outpatient setting (well tolerated without the need for analgesia), saves time, and does not require anaesthetics.

Key message: Potential mechanisms by which shock wave treatment exerts its therapeutic effects include initial neovascularization with ensuing durable and functional angiogenesis. Furthermore, recruitment of mesenchymal stem cells, stimulated cell proliferation and differentiation, and anti-inflammatory and antimicrobial effects as well as suppression of nociception are considered important facets of the biological responses to therapeutic shock waves.

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Wang et al. 2011

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Wang CJ, Wu RW, Yang YJ. Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy. Diabetes Res Clin Pract. 2011 May;92(2):187-93.

Design: Randomised Control Trial Subjects: 77 patients (84 feet) with diabetic foot ulcers were included in final analysis. Methods: Participants were randomised into two groups: 1. ESWT group: Focused shockwave therapy 2x / week for total 6 treatments (n=39 patients, n=44 feet), 2. HBOT group: Hyperbaric oxygen therapy daily for total 20 treatments (n=38 patients, n=40 feet). Outcomes included: Ulcer healing, complete healing, blood flow perfusion rates and histopathological examination. Results: • The overall clinical results showed significant differences in:

Key message: Extracorporeal shockwave therapy (ESWT) showed significant improvement in blood flow perfusion rate and cell activity leading to better healing of the ulcers in comparison to hyperbaric oxygen therapy in chronic diabetic foot ulcers.

• completely healed ulcers in ESWT (57%) and HBOT (25%) (P = 0.003); • ≥ 50% improved ulcers in ESWT (32%) and HBOT (15%) (P = 0.071); • unchanged ulcers in ESWT (11%) and HBOT (60%) (P < 0.001) • None worsened for the ESWT and the HBOT group respectively.

19 • Histopathological examination revealed considerable increases in cell proliferation and decreases in cell apoptosis in the ESWT group as compared to the HBOT group. • Blood flow perfusion rates were comparable between the two groups before treatment (P = 0.245); however, significant differences were noted after treatment favoring the ESWT group (P = 0.002).

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Jeppesen et al. 2016

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Jeppesen SM, Yderstraede KB, Rasmussen BS, Hanna M, Lund L. Extracorporeal shockwave therapy in the treatment of chronic diabetic foot ulcers: a prospective randomised trial. J Wound Care. 2016 Nov 2;25(11):641-649.

Design: Prospective Randomised Trial Subjects: 23 patients with chronic diabetic foot ulcers (DFUs) classified as Wagner ulcer groups 1 and 2. Methods: Patients with chronic DFUs were randomised (1:1) to receive either: 1.A series of six focused ESWT treatments over 3 weeks in combination with standard care (n=11) 2.Standard care alone (n=12) Outcomes included: : Ulcer size, transcutaneous oxygen tension (TcPO2) and pain score at baseline, 3 weeks, 5 weeks and 7 weeks. Results: • Transcutaneous oxygen tension was significantly increased in the ESWT group compared with those receiving standard care alone at 3 weeks (p=0.044). • Ulcer area reduction was 34.5% in the intervention group versus 5.6% in the control group at 7 weeks (p=0.387). • Within-group analysis revealed a significant reduction of ulcer area in the intervention group (p<0.01), while healing was not demonstrated in the control group (p>0.05). • No significant decrease in pain scores comparing the intervention and control group was detected at weeks 3, 5 and 7.

Key message: Extracorporeal shockwave therapy resulted in significantly increased tissue oxygenation at 3 weeks and significantly reduced ulcer area across 7 weeks compared to standard care alone.

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Galiano et al. 2019

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Galiano R, Snyder R, Mayer P, Rogers LC, Alvarez O; Sanuwave Trial Investigators. Focused shockwave therapy in diabetic foot ulcers: secondary endpoints of two multicentre randomised controlled trials. J Wound Care. 2019 Jun 2;28(6):383-395.

Design: Two Multicentre Randomised Control Trials Subjects: 336 subjects with Diabetic foot ulcers (DFUs) that did not reduce in volume by at least 50% over two weeks standard treatment were included. Methods: Patients with DFUs in both studies were randomised and managed with: 1. Standard care and focused ESWT active therapy (n=172) 2. Standard care and sham treatment (n=164) Treatment was delivered 4 times over a two-week treatment phase in study 1 and up to 8 times over 12 weeks in study 2. Outcomes included: Change in target ulcer area, time to wound closure, rate of wound closure, mean wound area reduction, recurrence and amputation. Results: • At 12-weeks, wound area reduction (48.6% versus 10.7%, p=0.015) and perimeter reduction (46.4% versus 25.0%, p=0.022) were significantly greater in the active therapy group compared with the sham-treated group, respectively. • The difference in time to wound closure was significantly in favour of the active therapy group compared to the sham group (84 days versus 112 days for 25% of subjects to reach wound closure respectively; p=0.0346). • Wound area reduction from baseline at week 12 of ≥90% was significantly higher in the active therapy group. • Amputation was insignificantly higher in the sham-treated group and recurrence did not differ.

Key message: Extracorporeal shockwave therapy (ESWT) used adjunctively with standard care leads to more effective closure of wounds than standard care alone. The ESWT device was found to be reliable for treatment of Diabetic foot ulcers.

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Snyder et al. 2020

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Snyder R, Galiano R, Mayer P, Rogers LC, Alvarez O; Sanuwave Trial Investigators. Diabetic foot ulcer treatment with focused shockwave therapy: two multicentre, prospective, controlled, double-blinded, randomised phase III clinical trials. J Wound Care. 2018 Dec 2;27(12):822-836.

Design: Two Multicentre Randomised Control Trials Subjects: 336 subjects with Diabetic foot ulcers (DFUs) that did not reduce in volume by at least 50% over two weeks' standard treatment were included. Methods: Patients with DFUs in both studies were randomised and managed with: 1. Standard care and focused ESWT active therapy (n=172) 2. Standard care and sham treatment (n=164) Treatment was delivered four times over a two-week treatment phase in study 1 and up to eight times over 12 weeks in study 2. Outcomes included: Complete wound closure within 12, 20 and 24 weeks, adverse events at 24 weeks and wound area reduction. Results: • Statistically significantly more DFU healed at 20 (35.5% versus 24.4%; p=0.027) and 24 weeks (37.8% versus 26.2%; p=0.023) in the active treatment arm compared with the sham-controlled arm. • Regarding adverse events, the subjects who used active therapy 18% experienced increased wound size compared with 31.1% in the sham cohort at 12 weeks. • In the pooled dataset, wound area reduction was statistically significantly different in favour of active therapy from week 6 to week 24.

Key message: Extracorporeal shockwave therapy is an effective therapeutic modality in combination with standard care for neuropathic DFU that do not respond to standard care alone.

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Hitchman et al. 2023

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Hitchman LH, Totty JP, Cai P, Smith GE, Carradice D, Chetter IC. Extracorporeal shockwave therapy for diabetic foot ulcers: a feasibility study. J Wound Care. 2023 Mar 2;32(3):182-192.

Design: Single-Centre, Mixed Methods Feasibility Study. Subjects: 22 patients with a Diabetic Foot Ulcers (DFU)

Methods: Patients who met the eligibility criteria underwent standard wound care, and additional ESWT three times over a seven-day period. Focused shockwaves were given at 120shocks/cm2 at 0.1mJ/mm2 Semi-structured interviews were conducted after 4 weeks from treatment allocation to explore participants' experience of undergoing ESWT. Outcomes included: Wound size, DFUs healed at 12 weeks, Quality of life. Results: • The mean attendance at clinic was 90.9% and 65.1% for follow-up. • The mean score for acceptability and tolerability was 9.86±0.48 (95% confidence interval (CI): 9.62-10.01) and 9.15±2.57 (95% CI: 7.87-10.42), respectively. • There were no serious adverse events or side-effects. • Of the DFUs, 45.5% healed during follow-up and QoL scores improved until eight weeks. • Key themes identified from the qualitative interviews were: desire for fast healing; improved QoL; flexibility of new treatments; and accessibility of transport.

Key message: It is possible to recruit and retain patients with DFUs into a trial investigating extracorporeal shockwave therapy (ESWT) and was acceptable and tolerable for patients. Wound healing and quality of life scores increased until 8 weeks with ESWT.

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Jeong et al. 2023

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Jeong D, Lee JH, Lee GB, Shin KH, Hwang J, Jang SY, Yoo J, Jang WY. Application of extracorporeal shockwave therapy to improve microcirculation in diabetic foot ulcers: A prospective study. Medicine (Baltimore). 2023 Mar 17;102(11):e33310..

Design: Prospective Study Subjects: 25 patients (50 feet) with Wagner grade I to II DFU in this study. Methods: The affected feet of patients were used as the ESWT group (n=32) and the unaffected contralateral feet were used as the control group (n=18). ESWT was performed in 3 sessions per week for a total of 3 weeks. Each patient received 9 sessions over the course of 3 weeks. Each foot received 1500 impulses at an energy flux density of 0.2 mJ/mm2 with a frequency of 4 Hz. Outcomes included: Transcutaneous partial oxygen pressure (TcPO2) tissue microcirculation in the feet before and after ESWT. Based on a previous study, the optimal cutoff level of TcPO2 was set to 43 mmHg, and the odds ratio was 4.4. Results: • The TcPO2 level in the ESWT group was recovered by the 2nd week of treatment (>43 mmHg) (P < .05 compared to baseline). • In the control group, no significant differences from baseline were found (P>.05) • In subgroup comparisons (Wagner grade I vs. Wagner grade II), no significantly differences were found for serial changes in TcPO2 levels across the 3 weeks. • A period of ESWT application of at least 2 weeks or more than 6 sessions may be considered for the treatment of DFU with Wagner grades I and II.

Key message: ESWT significantly increased microcirculation in DFU and could be beneficial for the treatment of DFU if applied for at least 2 weeks or more than 6 sessions.

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Hitchman et al. 2023

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Hitchman L, Totty J, Smith GE, Carradice D, Twiddy M, Iglesias C, Russell D, Chetter IC. Extracorporeal shockwave therapy compared with standard care for diabetic foot ulcer healing: An updated systematic review. 2023 Aug;20(6):2303-2320.

Design: Systematic Review Methods: Databases were searched for trials comparing ESWT plus standard care to standard care alone or sham ESWT in participants with DFUs. The Cochrane Risk of Bias 2 tool and GRADE approach was used to assess bias and certainty. All trials must have reported an objective measure of ulcer healing to be eligible for inclusion. Results: • 6 trials consisting of 471 participants were included. • Time to ulcer healing, proportion of healed ulcers and reduction in ulcer size was most likely improved in patients treated with ESWT compared with standard ulcer care alone (GRADE: low certainty). • Patients treated with ESWT were more likely to heal at 20 weeks post- ESWT compared with those treated with standard ulcer care alone (GRADE: low certainty). • Adverse events did not differ between ESWT and standard care alone (GRADE: low certainty) • No trials assessed the quality of life or cost effectiveness of the ESWT compared to standard care alone.

Key message: ESWT remains a promising new treatment but the translation into routine clinical practice is still limited by the low certainty of evidence surrounding its effectiveness, case selection and optimum dose.

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Houreld 2014

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Houreld NN. Shedding light on a new treatment for diabetic wound healing: a review on phototherapy. ScientificWorldJournal. 2014 Jan 6;2014:398412.

• Impaired diabetic wound healing has been associated with impaired cellular function, and decreases in cellular migration, proliferation, nitric oxide (NO) synthesis, growth factors, and collagen synthesis. • There is also an increase in proteinases that degrade the extracellular matrix and collagen (MMPs) and cells appear to be stuck in the inflammatory phase of wound healing. • Photobiomodulation (laser therapy) involves the application of light (often laser light of a specific wavelength or a light emitting diode, LED) to stimulate cellular processes. • Laser irradiation in vitro (dish/test tube) has shown that these cells respond in a favourable fashion, even irradiation of diabetic cells. • There is an increase in factors associated with wound healing : cellular migration, proliferation, viability, collagen production, ATP, mitochondria concentration, cytochrome c oxidase activity, NO, growth factors, and gene regulation. • There is also a decrease in MMPs, apoptosis and proinflammatory cytokines . • The effects of laser irradiation are highly dependent on the laser parameters such as wavelength, power density, and fluence. • Higher fluencies can have a negative effect on cells, while too low fluences have no effect.

Key message By studying the effects of laser irradiation in vitro, the underlying mechanisms are being identified. Phototherapy can be an important tool in speeding up the healing process as well as alleviating pain and inflammation in diabetic wounds.

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Basalameh et al. 2013

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Basalamah, Mohammed & Ebid, Anwar & Thabet, Ali & El-Kafy, Ehab. (2013). Effect of Pulsed High Intensity Laser in treatment of Diabetic Foot Ulcer:a Randomized Controlled Study. Jokull. 63.

Design: Randomised Controlled Trial Subjects: 43 patients (ages 40 to 60 years) with grade II diabetic foot ulcers took part in the study. Methods: Participants were randomly assigned to either: • High Intensity Laser Therapy (HILT) group (n=22): YAG 3 sessions/week for 8 weeks plus standard medical treatment • Placebo laser group (n=21): Sham laser treatments plus standard medical treatment. Outcomes included: Wound surface area (WSA) at baseline, after 4 weeks (midpoint) and after 8 weeks. Results: • No significant difference in WSA was observed between both groups at baseline (p>0.001). • The decrease in WSA post treatment was significantly greater in the laser group (4 weeks: 4.40±0.61 cm2, 8 weeks: 0.89±0.58 cm2) as compared to the placebo group (4 weeks: 6.02±0.83 cm2, 8 weeks: 4.21±0.46 cm2) (P<0.01 for 4 and 8 weeks). • The percentage % decrease in WSA after 4 and 8 weeks for laser group was: • Laser group: 4 weeks: 31%, 8 weeks: 79%, • Placebo group: 4 weeks: 0.72%, 8 weeks: 30%.

Key message: High Intensity Laser Therapy proved to be an effective and safe therapy for treatment of chronic grade II diabetic foot ulcers patients.

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Wound surface area decreased significantly in the laser group at 4 and 8 weeks .

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Maltese et al. 2015

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Maltese G, Karalliedde J, Rapley H, Amor T, Lakhani A, Gnudi L. A pilot study to evaluate the efficacy of class IV lasers on nonhealing neuroischemic diabetic foot ulcers in patients with type 2 diabetes. Diabetes Care. 2015 Oct;38(10):e152-3.

Design: Pilot Study Subjects: 11 patients with type 2 diabetes who were nonresponsive to conventional treatment for at least 12 weeks Methods: Participants were allocated to two groups: • Laser treatment was delivered once a week prior to standard care and dressing (laser) (n=5), • Standard treatment group (control) (n=6). Standard care for DFUs included antibiotic treatment, dressing, and off- loading, was similar in both groups. Outcomes included: Complete healing of Ulcer. Results: • Both groups had similar ulcer size and duration, renal function and age. • Within the 12-week follow-up, four of five laser-treated patients (80%) had a complete ulcer resolution (most ulcers healed after 4.6 weeks). • In the control group, no ulcer healing occurred by week 12 (zero out of six patients). • Levels of renal function and peripheral arterial disease were maintained in the laser group.

Key message: High power laser therapy along with standard care resulted in complete ulcer healing of neuroischemic DFUs in 80% of participants.

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Chatterjee et al. 2019

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Chatterjee P, Srivastava AK, Kumar DA, Chakrawarty A, Khan MA, Ambashtha AK, Kumar V, De Taboada L, Dey AB. Effect of deep tissue laser therapy treatment on peripheral neuropathic pain in older adults with type 2 diabetes: a pilot randomized clinical trial. BMC Geriatr. 2019 Aug 12;19(1):218.

Design: Randomized, double-masked, sham-controlled, interventional trial. Subjects: 40 patients with type 2 diabetes with painful diabetic peripheral neuropathy. Methods: patients were randomised to receive either: • Deep Tissue Laser Treatment (DTLT) (n=20) with LightForce HPL or • Sham laser treatment (SLT) (n=20). SLT treatment was identical to DTLT treatment, except in that in SLT, the laser emission was disabled. All patients were treated 2x/week for 4 weeks and then 1x/week for 8 weeks (12 weeks in total). All subjects received standard-of-care also. Results: • After the 12-week intervention period, pain levels significantly decreased in both groups and were significantly lower in the DTLT group than in the SLT group. • The Timed Up and Go test times (assessing functionality) were significantly improved in both groups and were 16% shorter in the DTLT group than in the SLT group. • Patients' quality of life improved significantly in the DTLT group but not in the SLT group. • No adverse events were reported.

Key message: Deep tissue laser therapy significantly reduced pain and improved the quality of life of older patients with painful diabetic peripheral neuropathy.

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Kloth 2005, 2014

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Kloth LC. Electrical stimulation for wound healing: a review of evidence from in vitro studies, animal experiments, and clinical trials. Int J Low Extrem Wounds. 2005 Mar;4(1):23-44.

31 • Protein synthesis: ES triggers the opening of voltage sensitive calcium channels within the fibroblast plasma membrane. This results in the upregulation of insulin and TGF- β receptors on the cell surface that may cause increased rates of collagen and DNA synthesis. • Cell migration: cells involved in wound healing migrate toward the anode or cathode of an electric field delivered into the cell cultures (through ES). • Numerous in vitro and in vivo studies have demonstrated that microampere levels of DC either kill or inhibit proliferation of common wound pathogens • The dosage range of 250 – 500 µC/s (= µA) represents a small window of electrical energy that has been shown to produce very favorable wound-healing results in studies. • The strength of the endogenous wound electrical fields measured in animals and humans that have been observed to direct cell migration (electrotaxis) after wounding have been measured between 10 and 100 µA/cm². • In recalcitrant wounds, it seems likely that the endogenous electrical fields are askew or absent, in which case the wounds often do not respond to standard wound care. How Exogenous Electrical Currents enhance wound healing Endogenous Bioelectric Currents • The human body has internal bioelectric systems that produce electrochemical signals, evident by the action potentials recorded from various organs/muscles during electrophysiological evaluation procedures (e.g.electrocardiogram). Cutaneous Bioelectric Currents: the Skin Battery • Measurable currents that reportedly contribute to wound healing are also found in the intact and wounded skin of humans, mammals, and amphibians. • When a wound occurs in the skin, an electrical leak is produced that short- circuits the “skin battery” at that point, allowing current to flow out of the moist wound, and is shut off when a wound dries out.

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Kloth LC. Electrical Stimulation Technologies for Wound Healing. Adv Wound Care (New Rochelle). 2014 Feb 1;3(2):81-90.

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Wirsing et al. 2015

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Wirsing PG, Habrom AD, Zehnder TM, Friedli S, Blatti M. Wireless micro current stimulation--an innovative electrical stimulation method for the treatment of patients with leg and diabetic foot ulcers. Int Wound J. 2015 Dec;12(6):693-8.

Design: Case reports Subjects: 47 patients with hard-to-heal wounds. Patients with venous, arterial and mixed leg ulcers were predominant; other aetiologies such as diabetic foot lesions (n=6), pressure ulcers, vasculitis and pyoderma were also included. Methods: WMCS treatment protocol specified treatment twice or thrice per week, for 45-60 minutes per session, with 1·5 μA current intensity. Standard wound care was applied to all patients, including compression bandages, if necessary. Results: • Clear progress of wound healing, even after 2 weeks, was observed in all cases. • The mean reduction of the wound surface after WMCS treatment was 95% in 8 weeks. • Complete healing was achieved within 3 months for the majority of the cases. • No clinical side effects were observed.

Key message: Wireless Micro Current Stimulation technology significantly accelerated wound healing for patients with hard-to-heal wounds of different aetiologies, including diabetic foot ulcers.

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Kurz et al. 2022

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Kurz P, Danner G, Lembelembe JP, Nair HKR, Martin R. Activation of healing and reduction of pain by single-use automated microcurrent electrical stimulation therapy in patients with hard-to-heal wounds. Int Wound J. 2023Aug;20(6):2053-2061.

Design: Observational Study Subjects: Forty wounds (39 patients: 18 female - 21 male), mean age 68.9 years comprised of: 7 post-surgical, 3 trauma, 12 diabetic foot (DFU), 10 venous, 4 pressure injuries, 4 mixed venous or arterial ulcers. Methods: All participants received automated microcurrent EST for 12 days. The current was low voltage biphasic and monophasic pulsed current (LVBMPC); 50- 500µA for the biphasic components and 40µA for the monophasic component. The LVBMPC program, which lasts for approximately 30 min, is automatically applied every 2 hours in the first 24h and every 4h during the next 24h. Patients received 12 days therapy. Outcomes included: Clinical responses scored on a 0-5 scale (5-excellent-0-no response). Pain assessed at 48 h, 7 days, and 14 days on a 0-10 visual analogue scale (VAS). Results: • Overall, 78% of wounds showed a marked positive clinical response: scores of 5 (excellent) and 4 (good). • 68 % of wounds were painful with a mean VAS score of 5.5. • Almost every patient (96%) with pain experienced reduction within 48 h. • All patients with painful wounds experienced pain reduction after 7 days: 2.50 VAS (45% reduction) and further pain reduction after 14 days: 1.83 VAS (33%).

Key message: Low voltage microcurrent therapy produced very positive clinical response and rapid pain reduction; it offers patients with a wide range of hard-to-heal wounds (including Diabetic foot ulcers) to benefit from activation of healing and rapid reduction of pain.

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Peters et al. 2001

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Peters EJ, Lavery LA, Armstrong DG, Fleischli JG. Electric stimulation as an adjunct to heal diabetic foot ulcers: a randomized clinical trial. Arch Phys Med Rehabil. 2001 Jun;82(6):721-5.

Design: Randomized, double-blind, placebo-controlled pilot trial Subjects: 40 patients with diabetic foot ulcers, consecutively sampled. Methods: 40 DFU patients randomly assigned to: 1. Treatment group (n=20): HVPC electrical stimulation every night for 8 hours. • A dose of 50V with 80 twin peak monophasic pulses per second (80Hz) was delivered for 10 minutes. This was followed by 10 minutes of 8 pulses per second (8Hz) of current. Pulse width was 100µs. 2. Placebo groups (n=20): used identical functioning units that delivered no current. Additional wound care in both groups consisted of weekly debridements, topical hydrogel, and off-loading with removable cast walkers. Patients were followed for 12 weeks or until healing, whichever occurred first. Outcomes included: Proportion of wounds that healed during the study period. Compliance rate of wound healing, and time until healing. Results: • 65% of the patients healed in the group treated with stimulation, whereas 35% healed with placebo. • After stratification by compliance, a significant difference was identified among compliant patients in the treatment group (71% healed), noncompliant patients in the treatment group (50% healed), compliant patients in the placebo group (39% healed), and noncompliant patients in the placebo group (29% healed, linear-by-linear association, p = .037). • There was no significant difference in compliance between the 2 groups.

Key message: High-voltage, pulsed galvanic electric stimulation enhances diabetic foot ulcer wound healing when used with local wound care and appropriate pressure and shear reduction.

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Polak et al. 2014

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Polak A, Franek A, Taradaj J. High-Voltage Pulsed Current Electrical Stimulation in Wound Treatment. Adv Wound Care (New Rochelle). 2014 Feb 1;3(2):104-117.

Design: Review Inclusion criteria for the studies: • Treatment groups using HVPC and control groups that received standard wound care (SWC) alone or SWC plus sham HVPC. • Conservatively treated patients with pressure ulcers (PUs), chronic leg and diabetic foot ulcers (DFUs), and in some patients with surgically treated venous insufficiency/venous leg ulcer (VLUs). Results: • 10 RCTs and one casuistic case study were discussed in the review. 6 studies in this review were of high-quality and 4 were of low quality. • 3 of the high-quality studies concerned PUs. PUs were treated for at least 6 weeks and the healed area exceeded 70% in relation compared with their pretreatment sizes. • These results are promising indications of the efficacy of HVPC ES as a PU treatment modality. • The authors of the two other high-quality studies treated DFUs and VLUs, achieving healing rates of, respectively, 86% after 12 weeks and of 59% after 6 weeks. • These results too show that HVPC can be effectively used for treating these types of wounds.

Key message: High-voltage pulsed current electrical stimulation is a promising therapy. It is relatively inexpensive, noninvasive, painless and safe from measurable side effects, and suitable for application in the clinical treatment of chronic wounds, including diabetic foot ulcer.

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Girgis et al. 2023

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Girgis B, Carvalho D, Duarte JA. The effect of high-voltage monophasic pulsed current on diabetic ulcers and their potential pathophysiologic factors: A systematic review and meta-analysis. Wound Repair Regen. 2023 Mar;31(2):171-186.

Design: Systematic Review and Meta-Analysis • including RCTs focusing on HVMPC application for the treatment of diabetic ulcers, neuropathic ulcers, ischemic ulcers, pressure ulcers and acute wounds. The definitions of pressure ulcers (PrUs) and DFUs might overlap, since any pressure ulcer on the foot of a patient with diabetes is defined as a diabetic foot ulcer. Results: • 32 studies matched the eligibility criteria, including 1061 patients with 1103 skin lesions; 12 RCTS were included in the quantitative meta-analysis. • HVMPC plus standard wound care (SWC) likely increased the probability of complete wound healing of pressure ulcers (PrUs) compared with sham/no stimulation plus SWC; relative risk (RR) 2.08; 95% CI: [1.42, 3.04], p = 0.0002; I2 = 0%, p = 0.61; eight studies, 358 ulcers. • Nonetheless, several aspects remain to be clarified for safe and effective application of electrical stimulation for wound healing. • Minor adverse events: some studies documented minor and rare reactions such as red, raised, itchy skin beneath the dispersive electrode that was attributed to contact dermatitis. These were usually resolved in 1-2weeks. • Serious adverse events did occur in one study, though unlikely that any were related to the HVMPC intervention.

Key message: The present review found direct evidence, with moderate certainty, for the efficacy of HVMPC to treat pressure ulcers albeit its safety needs to be confirmed. Moreover, the positive observations on many of the skin lesions with pathophysiologic factors potentially contributing to diabetic ulcers might indirectly suggest that its efficacy may not be limited to pressure ulcers.

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Chen et al. 2020

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Chen Z, Chen ZY, Liu WH, Li GS. Electric Stimulation as an Effective Adjunctive Therapy for Diabetic Foot Ulcer: A Meta-analysis of Randomized Controlled Trials. Adv Skin Wound Care. 2020 Nov;33(11):608-612.

Design: Systematic review and meta-analysis • including randomized clinical trials published through March 2019 that compared the efficacy of ES and standard wound care (SWC) versus SWC alone for DFU treatment. Outcomes included: Percentage decrease in ulcer area at 4 weeks (4w- PDUA) as assessed by image-recording; Healing rate at 12 weeks. Results: • Of the 145 randomized clinical trials initially identified, 7 studies (with a total of 274 patients) met the inclusion criteria. • The studies used BP pulsed current, HVPC, low intensity direct current • The percentage decrease in ulcer area at 4 weeks was significantly greater in patients treated with ES and SWC than SWC alone (standardized mean difference = 1.09 (95% CI, 0.62 – 1.57; P < .001; I2 = 67%) • The ulcer healing rate at 12 weeks was also significantly faster in the ES group (risk difference = 0.19 (95% CI, 0.06 – 0.32; P = 0.005; I2 = 0%)

Key message: This meta-analysis demonstrates that ES may accelerate DFU healing and be an effective adjunctive therapy for these complex wounds.

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