Electromechanical therapy in diabetic foot ulcers patients: A systematic review and meta-analysis

Purpose Diabetic foot ulcer (DFU) is one of the most devastating and troublesome consequences of diabetes. The current therapies are not always effective because of the complicated aetiology and interactions of local and systemic components in DFU. However, adjunctive therapy (electromechanical therapy) has become the latest modality in recent years, although there is a lack of significant research to support its utilization as a treatment standard. The purpose of this systematic research was to review the literature on the application of electromechanical therapies in the healing of DFUs. Methods For this systematic review, we searched PubMed, Medline, EmBase, the Cochrane library, and Google Scholar for the most current research (1990–2022) on electromechanical therapies for DFUs. We used the PICO method (where P is population, I is intervention, C is comparator/control, and O is outcome for our study) to establish research question with the terms [Electromechanical therapy OR Laser therapy OR photo therapy OR Ultrasound therapy OR Shockwave therapy] AND [diabetic foot ulcers OR diabetes] were used as search criteria. Searches were restricted to English language articles only. Whereas, Cochrane handbook of “Systematic Reviews of Interventions” with critical appraisal for medical and health sciences checklist for systematic review was used for risk of bias assessment. There were 39 publications in this study that were deemed to be acceptable. All the suitably selected studies include 1779 patients. Results The meta-analysis of 15 included research articles showed the overall effect was significant (P = 0.0002) thus supporting experimental groups have improvement in the DFUs healing in comparison to the control group. Conclusion This systematic review and meta-analysis revealed electromechanical treatments are significantly viable options for patients with DFUs. Electromechanical therapy can considerably reduce treatment ineffectiveness, accelerate healing, and minimize the time it takes for complete ulcer healing. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-023-01240-2.


Introduction
Diabetes is an emerging epidemic with rising incidence, morbidity, and death [1].Diabetic Foot Ulcer (DFU) is one of the most devastating and troublesome consequences of diabetes and the most significant predictor for lower-extremity amputations [2].DFU is frequently linked to infection, peripheral neuropathy, and peripheral vascular disease.Nearly 80% of nontraumatic amputations are caused by DFUs, which account for around 35% of the patients in diabetes clinics [2].Approximately 6% of people worldwide have DFU, and the disease can have up to a 77% five-year mortality rate [2,3].According to the International Diabetes Federation, the number of persons with diabetes has constantly increased; currently, there are 643 million cases worldwide, and by 2045, there will be 783 million cases [4].
It is crucial to research techniques and therapies to lessen the burden of the disease in a productive and economical manner since managing DFU continues to be a significant therapeutic problem on a global scale.Due to poor leukocyte chemotaxis and phagocytosis, diminished macrophage activity in the wound matrix, decreased collagen synthesis and deposition, and reduced growth factor release, wound recovery in diabetes patients is often slower than in healthy persons [5,6].Diabetes patients have a poor capacity to heal wounds, which makes managing the illness more challenging.Therefore, the development of a treatment for DFUs should take into account a multidisciplinary approach that includes glycaemic management, daily local care, antimicrobials, antiseptics, surgical revascularization, and engineered biological tissues [6,7].
Surgery debridement, dressings, pressure offloading, vascular assessment, infection treatment, glycaemic control, and patient education make up the standard of care for DFUs [8,9].These treatments are not always successful because of the complex aetiology and interaction of local and systemic factors.As a result, it requires a variety of time and cost periods to support the healing process [10].An optimal adjuvant therapy has yet to be established, which is urgently needed for DFU healing [11].According to a number of earlier research, nonpharmacological treatments such electrical stimulation [12], low-level laser therapy (LLLT), hyperbaric oxygen therapy [13], and foot off-loading may also be helpful in the healing of DFUs.Additionally, it has been proposed that the use of ultrasound, light therapy, and electrical stimulation will hasten the healing of DFUs by promoting the migration of different cell types and improving wound perfusion [14,15].However, an ideal adjuvant therapy has not yet been identified, which is urgently required for the wound healing of DFUs [11].Due to the dearth of highquality data that provides solid evidence to support their clinical use, there is a clear need for evidence to substantiate the use of electromechanical therapies (laser therapy, phototherapy, ultrasound therapy, and shockwave therapy) in the management of DFUs [16].
In the current study, we set out to comprehensively review the literature on the application of electromechanical therapies in the healing of DFUs, synthesise the results using meta-analysis of randomised controlled trials (RCTs), and provide clinical guidelines and evidence-based recommendations for the treatment of DFUs in the future.

Material and methods
For this systematic review in November 2022, we searched PubMed, Medline, EmBase, the Cochrane library, and Google Scholar for the most current research (1990-2022) on electromechanical treatments for DFUs.PICO format was followed to design the research question as it is the recommended method by Cochrane and PRISMA guidelines.The terms [Electromechanical therapy OR Laser therapy OR photo therapy OR Ultrasound therapy OR Shockwave therapy] AND [diabetic foot ulcers OR diabetes] were used as search criteria.Searches were restricted to English language articles only.The relevancy of the titles, abstracts, and keywords was checked by two independent reviewers.Publications having titles or abstracts that complied with the requirements for this systematic review were chosen for a more thorough examination.To discover whether there were any other studies that were pertinent, we also went through the reference tracking of bibliographies and manual searches during the first search.The titles and abstracts were evaluated for inclusion by the writers independently.Only studies that satisfied the inclusion criteria were deemed eligible after being located utilising the PRISMA technique and critical appraisal tools (https:// jbi.global/ criti cal-appra isal-tools) (Table 1).The risk of bias of included studies was assessed by using an assessment tool of the "Cochrane Handbook for Systematic Reviews of Interventions version" with critical appraisal for medical and health sciences checklist for systematic review.The data of patients, their age, sex, type of therapy/intervention, duration was extracted.Depending upon the availability of data in the studies we used Standardized Mean Difference (SMD).The statistical analysis (meta-analysis) was performed using Review Manager 5.4 and a 95% confidence interval.Based on the heterogeneity between the studies we selected random or fixed-effect model for metaanalysis.To determine the entire cumulative impact, forest plots were curated.

Quality assessment
The assessment tool covers 7 domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases.Bias was assessed as "low risk," "high risk," or "unclear risk."

Results
Following the PRISMA guidelines and critical appraisal tools to ensure the quality and consistency of the identified articles, several criteria were used for article eligibility as described in Table 1.After the initial search, 8200 duplicate articles from all researched databases were deleted.Further, 3651 papers were removed from the research after their titles and abstracts were examined.The remaining 449 articles were reviewed and selected by the principal author and co-author based on the set inclusion and exclusion criteria.This study comprised 39 papers that were determined to be eligible (Fig. 1).
Fig. 1 The PRISMA flow chart of the literature selection for the meta-analysis.After eliminating any obviously irrelevant information, the authors separately reviewed the research abstracts and full texts to choose which publications to include based on the inclusion and exclusion criteria (Table 1).Any issues or disagreements were discussed by all writers and were resolved The selected studies include 1779 patients with DFUs.Most of the selected studies have been published in USA (n = 8), followed by Brazil (n = 5) and Egypt (n = 4) as presented in Table 2.While 11 studies reported the use of laser therapy for the treatment of DFUs, 10 studies reported shockwave therapy, 8 studies reported stimulation therapy, 7 reported ultrasound therapy and 3 reported light/phototherapy (Table 2).The mean difference (15.68) for these studies also showed significant difference among experimental and control groups (95% CI, 7.49, 23.87).The overall effect was significant (P = 0.0002) that indicates experimental groups have improvement in the DFUs healing compared to control group.Fifteen studies in the forest plot compared the electromechanical therapies vs placebo/control groups that showed significant difference (P < 0.00001) in heterogeneity among the groups with 98% I 2 value (Fig. 2).
Similarly, data from fourteen studies compared the number of healed wounds among experimental and control groups.The overall effect was non-significant (P = 0.12) with odds raio (1.31; 95% CI, 0.93, 1.84) for these studies showing better healing among experimental groups compared to control group.There was also a moderate degree of heterogeneity among these studies (I 2 = 68%, P = 0.00001) (Fig. 3).

Discussion
In the current study, we looked at novel therapies used to treat DFUs.After a thorough review, extracorporeal shockwave treatment (ESWT) has been shown through experimental research to accelerate the production of angiogenesis-related growth and proliferation factors, shorten the inflammatory phase, and reduce the risk of wound infection [17][18][19][20][21][22].Furthermore, by modifying substance P and calcitonin gene-related peptides, ESWT significantly lessens pain in the vicinity of the wound [23].In 282 patients with chronic wounds who had previously failed conventional treatments, Wolff, Wibmer [18] used ESWT and reported a full cure rate of 74.03% without recrudescence.ESWT was also proven to be effective and well tolerated for treating complex, non-healing, acute, and chronic soft tissue wounds Schaden, Thiele [19].Thus, ESWT has emerged as a viable first-line treatment for DFU.
In this review, we combined the studies and created a forest plot to compare electromechanical treatments with the placebo/control group.The mean difference for these studies revealed a significant difference between the experimental and control groups, although, the analysis revealed heterogeneity across the groups with a 98% I 2 value.Overall, there was a significant difference between the experimental and control groups in how quickly DFUs healed.Our findings support those of earlier research by Butterworth, Walsh [24], Dymarek, Halski [25] and Omar, Gwada [26], which prove the effectiveness of ESWT on chronic wounds.
In a randomised clinical trial by Kaviani, Djavid [27], it was shown that low-level laser treatment (685 nm) cured 8 of 13 (66.6%)ulcers in the experimental group compared to 3 of 9 (33.3%) in the control group receiving sham radiation.However, this finding was not statistically significant.In a Level I investigation, Minatel, Frade [28] reported that healing rates for a group of 7 patients with 10 ulcers treated with combined 660-and 890-nm light were considerably greater at 15-day interval than for a group of 7 patients with 13 ulcers treated with placebo radiation.In a recent RCT (Level II evidence), Petrofsky, Lawson [29] found that electrical stimulation and local dry heat resulted in a statistically significant improvement in DFU healing rates and enhanced blood flow to the surrounding area.ESWT resulted in a substantial reduction in wound size and ulcer healing time when compared to normal therapyOmar, Alghadir [30].
Low-level laser therapy (LLLT), one of the adjuvant treatments, has been identified as a viable mechanism of treatment to hasten the healing of ulcers [31].The findings of several studies looking into the impact of LLLT on DFU are encouraging.Studies have demonstrated a considerable decrease in the size of the ulcer using LLLT with wavelengths of 632 nm (5 J/cm 2 ; 20 mW)/904 nm (6 J/cm 2 ; 20 mW) and 658 nm (4 J/cm 2 ; 30 mW) [30,76].In addition to decrease in DFU pains, considerably higher reductions in ulcer size and the percentage of healing compared to controls have been recorded [32][33][34][35].However, its therapeutic advantages rely on a number of factors, making it crucial to identify the best parameterization for the efficient treatment of DFU [36].Additionally, there is a dearth of reliable data that would support the therapeutic use of LLLT in DFU.The benefits of LLLT on DF have been reported in earlier systematic studies [37,38], however the current review includes significant updates to its clinical effectiveness and improves parameterization for clinical decision-making.
A prior study [38] suggested the LLLT settings of 660 and 890 nm wavelengths, 50 mW/cm 2 power density, 2 J/cm 2 fluence, 30 s of exposure period, and a distance of 1 cm from the wound.The LLLT parameters used in our study were based on the RCTs showing wavelength: 400-904 nm, power density: 30-180 mW/cm 2 , and fluence: 2-10 J/cm 2 .Most of these variables complied with the suggested LLLT settings.
The impacts of LLLT on numerous cellular processes and molecular pathways, such as promoting expression of regulators for cell proliferation, migration, survival, and granulation, were part of the mechanism of LLLT in hastening the healing process of chronic DFU [39].Additionally, it was discovered that the LLLT group's ulcers had more granulation tissue than the control group [28,32].LLLT can increase the expression of essential fibroblast growth factors and induce collagen production in damaged fibroblasts of diabetic mice [40][41][42][43].Transforming growth factor beta [44], interleukin-1 and interleukin-8 [45], platelet-derived growth factor (PDGF)increased macrophage phagocytic activity [46][47][48][49][50].The synthesis of collagen and extracellular matrix may be increased, the above-mentioned key cytokines and growth factors may be attracted, and the migration, proliferation, and differentiation of various cell types may all be encouraged by LLLT.All these factors may collectively play significant roles in the healing of DFUs.During LLLT therapy, the epithelium and conjunctive tissues displayed unique and quickly expanding cellular renovation, aiding in the process of tissue healing [51].According to research by Zhou and colleagues, LLLT can increase the expression of heat shock proteins 70 and 1 in injured tissues, which can then increase the synthesis of growth factors like transforming growth factor-beta and aid in wound healing [52].
Regarding the aspect of potential mechanism, it remains unclear.However, the outcomes of the histopathologic analysis show that ESWT can have both a direct and indirect impact.ESWT might encourage collagen production [19], fibroblastic growth, and angiogenesis by increasing cellular ATP production, which then activates purinergic receptors and Erk1/2 signalling [19,22,53].EWST is therefore believed to have the ability to accelerate the healing process.ESWT, on the other hand, may act as a stimulant of microenvironment metabolism and a promoter of dermal cell development, both of which are necessary for ulcer healing.Additionally, ESWT might promote the production of growth factors, such as fibroblast growth factor, transforming growth factor, insulin-like growth factor-1, platelet-derived growth factor, and vascular endothelial growth factor, which are crucial for DFU wound healing [19,54].This would then encourage neovascularization of the tissue and enhance blood perfusion.
In terms of safety, electromechanical therapies are acceptable as non-invasive adjuvant treatments.Electromechanical treatments can have adverse effects during treatment, including temporary skin reddening, mild discomfort, and tiny hematomas.Rarely are serious adverse effects and consequences such as bleeding, thrombosis, muscle injury, and wound infections.These show how superior, safety and tolerance of electromechanical treatments are, as well as their potential to be a workable adjuvant therapy for patients with DFU.Haze, Gavish [55] in a study reported that no device-related adverse events were observed in patients with DFU, and percent closure was significantly greater in the active group compared to sham-treated controls.

Strengths and limitations
The thorough search for evidence, the criteria-based selection of pertinent material, the rigorous assessment of validity, the objective or quantitative summary, and the evidencebased judgments are only a few of this systematic literature review's qualities.The study has several restrictions.The results may only be applicable to people with diabetes and foot ulcers as this meta-analysis only included patients with DFU.Cost-effectiveness was not investigated based on the data available.The included studies' differences in demographic data, baseline ulcer features, and follow-up or treatment periods might possibly have contributed to the heterogeneity observed in the meta-analysis.

Conclusion
According to the findings of the systematic review and metaanalysis, electromechanical treatments are viable and secure choices for individuals with DFUs.Electromechanical therapy can considerably reduce treatment ineffectiveness, speed up healing, and minimize the time it takes for DFUs to heal.

Fig. 2 Fig. 3
Fig. 2 Forest plot showing improvement in the mean effects for experimental (electromechanical therapies) compared to control/placebo groups of diabetic foot ulcer patients

Table 1
Inclusion and exclusion criteria for studies

Table 2
Demographic characteristics of selected studies