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Introduction
Wound healing is a complex process involving inflammation, proliferation, and tissue remodeling, which ultimately restores the integrity of damaged tissue. While most wounds close within weeks, disruption of the healing process can lead to chronic wounds or ulcers, characterized by incomplete or prolonged healing with a high risk of recurrence. Various factors, including local causes like infection and tissue hypoxia, systemic diseases like diabetes mellitus, and certain medications, contribute to the development of chronic wounds such as diabetic ulcers, venous leg ulcers, or pressure ulcers (1-3).

Managing chronic wounds requires addressing the primary cause, such as controlling blood sugar levels in diabetics or vascular surgery for patients with venous or ischemic vascular disease. Additionally, treatments involve removing necrotic or infected tissue, maintaining a moist wound environment, wound cleansing, and proper diet. Compression therapy is particularly relevant for venous leg ulcers as it improves venous return. Despite these measures, many chronic wounds fail to heal or recur, prompting the search for new effective treatment options (4).

Among the strategies for chronic wound treatment, extracorporeal shock wave therapy (ESWT) has shown promise. Initially used for treating renal and ureteral calculi (5,6), ESWTs success in urology prompted exploration in other areas, including wound healing (7-9). Its primary mechanism of action is believed to be improving tissue circulation by stimulating the production of energy-rich nitric oxide (NO), leading to reduced muscle rigidity and improved biomechanical functioning, enhancing mobility and self-perception. ESWT can also activate key factors involved in connective tissue repair, such as fibroblasts that increase proliferation and expression of essential factors like TGF-beta-1 and collagen types I and III (10-14).

Recent trials using ESWT for wound healing after Fourniers gangrene suggest its potential to stimulate local stem cells (15). As researchers focused on harnessing ESWTs capabilities, we aim to summarize the current state of art in ESWT for wound management based on personal experience and a review of the literature. By understanding ESWTs efficacy and theoretical basis, we hope to shed light on its potential as an advanced wound healing therapy. This article provides valuable insights into how ESWT can complement existing wound management approaches, offering new hope for patients with chronic wounds or ulcers. 
Material and Methods
Literature search, selection of relevant publication, data extraction, assessment of methodological quality and appraisal has been performed according to the search strategy and predefined criteria according to International Organization for Standardization and Biological evaluation of medical devices (16). After screening and appraisal of 184 new data sources identified in the literature search for the update period (1990-2022), 14 new primary clinical data studies and 5 state-of-the-art data publications were included as relevant, and thus 165 studies excluded. The 19 relevant publications comprised 1 guidance document, 4 systematic reviews/meta-analyses, 11 clinical studies applying focused ESWT, as well as 3 publications reporting on the use radial ESWT. The latter three publications represent off-label use and were included for assessment of related implication. At our four centers, we had different personal experiences using focused ESWT for different types of wound healing problems, such as diabetic and venous ulcers, and Fournier`s gangrene (9,11,15). This allowed us to illustrate the results of the literature review with relevant images.
Results
TECHNICAL BACKGROUND FOCUSED SHOCK WAVES
Shock waves are mechanical, acoustic waves that are characterized by high pressure amplitudes and a steep increase in pressure. Unlike usual ultrasound that consists of periodic oscillations with limited bandwidth, shock waves are represented by a single, mainly positive pressure pulse that is followed by comparatively small tensile wave components. The duration of the positive pressure pulse is only about 0.3-0.5 μs, the duration of the total pulse is about 3x the amount, thus about 1- 2 μs. Such a pulse contains frequencies ranging from a few kHz to over 10 MHz (16).

Focused shock waves can be generated by means of electrohydraulic, piezoelectric or electromagnetic shock wave generators. The method of electromagnetic shock wave generation is based on the physical principle of electromagnetic induction. Electromagnetic devices may use a cylindrical coil, focusing the shock waves by means of a rotation paraboloid. The method of electrohydraulic shock wave generation is based on a spark that is initiated due to high voltage applied between two electrode tips placed at the focal point of a parabolic reflector. The spark generates a spherical shock wave by rapid vaporization of the water between the tips. Due to the comparatively large aperture of the shock wave sources relative to the focus size, the shock wave energy can be introduced into the body over a large coupling area. Most of the shock wave energy is only released in the relatively small focal zone inside the body.

RADIAL SHOCK WAVES
The method of action of a ballistic pressure wave system is based exactly on the linear impulse- momentum principle deduced from Newton’s law. Pressure waves have wavelengths of between 0.15 and 1.5 m. First of all, a projectile is accelerated with compressed air (similarly to an air gun), to a speed of several meters per second (approx. 5 to 25 m/s, far below the sound velocity in water of about 1500 m/s) and then abruptly slowed down by hitting an impact body (transmitter). When the projectile strikes the impact body, some of its kinetic energy is transmitted to the impact body. The impact body then performs a translational movement over a short distance (typically < 1 mm) at slower speed (typically < 1 m/s) until the coupled tissue or the handpiece decelerates the impact body movement. The motion of the impact body is transmitted to the tissue at the point of contact, from where it propagates divergently in the form of a “radial” pressure wave. Typical peak pressures of radial pressure waves are about 0.1 to 1 MPa (17).
MECHANISM OF ACTION OF ESWT
Based on early studies of Haupt et al. in 1992 (8), several animal studies have been performed to evaluate the potential of ESWT for the treatment of wounds. In mouse and rat burn wound models, ESWT was found to induce angiogenesis and to enhance the percentage of wound closure, the re-epithelialization rates, blood flow, and the number of rolling and sticking leukocytes, suggesting improved metabolism (18). It was further reported that repeated ESWT application accelerates angiogenesis in burn wounds significantly more than a single application (19). The angiogenic effects of ESWT were confirmed in a murine skin graft model, also showing increased expression of VEGF-A and other cytokines involved in angiogenesis (20). In diabetic wound models, it could be demonstrated that ESWT reduces wound size and inflammatory reaction, while increasing the wound breaking strength and the number of fibroblasts and collagen fibers at the wound site (21,22). Finally, ESWT has been found to have potential in the rescue of ischemic skin flaps, as it reduced the necrotic area and the number of apoptotic cells in a rat skin flap model. ESWT also substantially increased the modulation of oxygen radicals, attenuation of leukocyte infiltration, decrease in tissue apoptosis, and recruitment of skin fibroblasts (23). Recent trials using ESWT for improvement of wound healing after Fournier`s gangrene indicate also a stimulation of local stem cells (15).

Performance data identified from systematic review literature
TREATMENT PARAMETERS
The reviews reported on the use of ESWT in the treatment of the indications of acute and chronic wounds, including burns, post-burn scars, venous ulcers, pressure ulcers, decubitus ulcers, diabetic foot ulcers, and gangrene, primarily affecting the limbs and extremities. most treatments with ESWT involved multiple treatment sessions and there was a range of values applied for the technical parameters of the ESWT devices (Table 1). 

Table 1: Parameter ranges for Extracorporeal Shock Wave Therapy of wounds identified from the reviewed literature

CLINICAL OUTCOME
Performance data reported in all eleven systematic reviews supported an additional positive clinical effect of the ESWT intervention when used in conjunction with standard wound care (Table 2). Outcomes were assessed for healing of wounds, proportion of completely healed wounds, healing time, healing rate, reduction wound area/healed wound area, as well as number of unresponsive wounds, recurring wounds and infection rates. Outcomes for the treatment of burn scars included assessment of specific performance, such as pain, pruritis, scare appearance score (VSS), scar thickness, scar elasticity and trans-epidermal water loss (24,25). 

Table 1: Overview of relevant systematic reviews and meta-analyses of Extracorporeal Shock Wave Therapy for wound healing

a)    Burns (picture)

b)    Diabetic foot ulcers    (picture)

c)    Different types of wounds      (picture)

DETAILED EFFECTS OF ESWT ON WOUND HEALING
Based on these criteria, positive clinical performance was reported for diabetic foot ulcers (Fig.1), pressure ulcers, venous ulcers, decubitus ulcers, chronic wounds, acute burn wounds, post- burn scars and post-burn heterotopic ossification. A summary of identified key clinical performance outcomes identified from the systematic reviews is provided for treatment of post-burn scars (Table 3a), mixed wound studies (Table 3b), mixed ulcer studies and diabetic ulcers (Table 3c).

Fig. 1:    82-year old female with diabetic foot syndrome. Complete healing after three treatments with Low-intensity extracorporeal shock wave therapy (Li-ESWT) using an electrohydraulic focal shock wave generator (2300 impulses at 4Hz).
a) Initial finding with a large ulcus resistant to classical wound dressing.
b) Good healing of the wound 7 weeks after the first ESWT-treatment
c) Complete healing of the wound with minimal scar formation

For a number of studies these sub-groups indications were not specifically assessed and data for acute burn wound treatment and post-burn heterotopic ossification were limited to a small number of studies or lower quality data assessing re- epithelialization, pain and heterotopic ossification. The systematic reviews only reported on one alternative    treatment    options,    Hyperbaric oxygenation therapy (HBO), used specifically in the treatment of diabetic foot ulcers (27,28,33). ESWT demonstrated mostly better performance than HBO in the assessed performance outcomes; complete healing, unresponsive wounds and healing rate (Table 3d). Moreover, a recent study on the use of ESWT in postoperative wound management of Fournier`s gangrene (15) showed complete restoration of the filling skin defect with adequate local skin tissue (ie. penile vs. scrotal) without any side-effects for the patients (Fig. 2,3) 

Table 3: Performance data of Extracorporeal Shock Wave Therapy from identified from systematic reviews
a)    Post burn wounds     (picture)

b)    mixed wounds              (picture)

c)    Diabetic foot ulcers      (picture) 

d)    Diabetic foot ulcers treated with ESWT compared to hyperbaric oxygen therapy (HBO)     (picture)

Fig. 2: Technique of LI-ESWT for postoperative wound healing after radical excision in patient with Fournier´s gangrene
a. Application of 3000 Shock Waves on the rim of the wound using the Handpiece of the electromagnetic device Duolith SD (Storz-Medical, Taegerwilen, Switzerland) with 0.25 mJ/mm2 at 3 Hz.
b. Significant improvement of the wound healing after three weeks following 4 treatments of ESWT.
c. Complete healing of the scrotal wound after 6 treatments with Li-ESWT following 6 months after the first treatment. Basically, no scar formation. No surgery required.

Fig. 3: Low-intensity extracorporeal shock wave therapy (Li-ESWT) using an electromagnetic device as single management of wound healing following radical excision of infected tissue after Fournier`s gangrene.
a) Radical excision of the involved tissue
b) Complete restoration of the wound by scrotal and penile tissue after 12 weeks. No surgery required at all.
c) Final cosmetic result after 3 months with minimal scar formation

EXPERIENCE WITH RADIAL SHOCK WAVE THERAPY
We identified four studies were identified that reported on the use of radial ESWT for the treatment of wounds (35-38). Treatment of burns was performed with radial ESWT and water- filtered infrared-A irradiation and compared to water-filtered infrared-A irradiation alone (36). Statistically significant improvement in the group receiving treatment with radial ESWT was reported for pain measured by VAS, and healing, specifically wound healing rate, time (including related duration of hospital stay), scar scores, and blood perfusion. No report of pruritis or assessment of pruritis was performed. No adverse events were reported. However, water-filtered infrared-A irradiation does not represent a standardized approach in wound-healing. Therefore, it cannot really be taken as a control group to radial ESWT.

Treatment of a variety of chronic wounds (> 3months) diagnosed as ulcers full thickness or subcutaneous damage with necrosis were treated with radial ESWT and standard wounds care and compared to treatment with standard wound care alone. Pain and pruritis were not reported or subject to specifically assessed. Extensive assessment of wound healing and related wound characteristics was performed and statistically significant improvements in the rESWT group was seen for change in wound area (and related length and width), wound bed score, and Bates-Jensen wound assessment tool score length. However, they did report that there were two unusual adverse events observed in the wound area; local bleeding episodes (vascular background) and uncontrolled hyper-granulation tissue (inflammatory background). Neither were indicated to be serious nor prevented ongoing treatment (37).

Overall, the clinical data detailing off-label use of radial ESWT in the treatment of wounds demonstrated some positive outcomes. Nevertheless, based on these early and incomplete data, the DIGEST-guidelines recommend radial extracorporeal shock wave therapy only treatment of scars following burns and not for open wounds (39).

Side effects of ESWT
The most serious adverse events were infection and amputation. Infection was reported to occur in up to 36.8% of patients being treated for ulcers and up to 9% of patients being treated with ESWT for burns. In all studies reporting infection, the incidence in the ESWT was similar of less than the comparator standard care alone group. Similarly for amputation that was reported in one study, the incidence in the ESWT ground was lower than in the control group. The most common reported safety events were transient and mild events such as reddening, bruising, swelling, small hematomas, petechiae, and oedema of the skin, as well as mild pain or discomfort at the treatment site during treatment (Table 4).

Table 4: Overview the Guidelines of DIGEST (German Speaking Society of Shock Wave Therapy) – also applied by the International Society of Medical Shock Wave Therapy (ISMST)

Table 5: Identified safety events reported in systematic reviews of Extracorporeal Shock Wave Therapy for wound healing

The systematic reviews only reported on one alternative treatment option, which was HBO. While the localized safety events reported for ESWT treatment were not reported with HBO, this treatment option was associated with unique adverse events, including middle ear barotraumas and sinus pain. Overall. the systematic reviews reported that ESWT was well-tolerated, and did not display a causal association with any serious adverse events.

RECOMMENDATION OF ESWT IN GUIDELINES
A single relevant guideline was identified from screening of expert associations and their repositories. This was a DIGEST guideline (39) supporting the use of ESWT (both fESWT and rESWT) for wounds, principally for treatment of burn wounds and scars (Table 5).

Discussion
After positive effects on still existing wounds were repeatedly observed in the treatment of pseudarthroses, especially on the lower leg, 208 patients with a wide variety of wound healing disorders were treated with shock waves in a pilot trial (9). The essential aspect of this anecdotal case collection was to demonstrate that the patients obviously benefited from ESWT and that it could be applied with practically no side effects. Now the challenge was to prove the effect of shockwaves on wound healing in a clean clinical trial. The main problem was to treat standardized wounds in order to assess the influence of ESWT. For this purpose, the harvest sites for skin grafts (Mehscraft plasty) on the thigh were chosen. These standardized wounds could be brought to complete epithelialization significantly faster with ESWT compared to the placebo group (40).

Extensive assessment post-market experience data for the devices, and data extracted from identified relevant literature in this clinical evaluation, have shown only single minor safety events, with the majority of potential risks identified (24-34). This provides a validation of the effectiveness of the implemented risk control measures; both during development and in the technical design of the different devices, as well as through the adequate communication of risk information and appropriate safe use instructions in the accompanying device materials. This underlines, that ESWT is a very safe treatment option for the patients Off-label use of radial ESWT in the treatment of wounds, was identified and assessed in this clinical evaluation. These few studies demonstrated some positive outcomes, with statistically significant improvements in pain, and wound healing for a number of wound types. No serious adverse events were reported (35-37). Thus, Off-label use might be justified by the treating physician based on their assessment of the positive benefit that an 41off- label intervention will provide in the treatment of their patients` specific condition (38). However, it has to be emphasized, that at the moment there are only sparse data available (39). This might be an issue for further studies (i.e. comparing the efficacy of radial versus focal ESWT).

Even, if still only based on case studies, the healing effect of ESWT following extensive tissue resection due to Fourniers gangrene shows a complete restoration of the pre-existing local skin, such as perineal, penile or scrotal (Fig. 2,3). The underlying mechanism for this should be related to a stimulation of stem cells, which has been already shown experimentally in animal models of trauma of the pelvic floor or of erectile dysfunction (41,42). The skin offers the unique opportunity to watch the progress of healing and tissue restauration as a model for regenerative medicine. In conclusion, ESWT offers a safe and non-invasive treatment option for a variety of wound healing problems, from improving the healing of ulcers to complete restauration of the skin after extensive surgery in the management of Fournier`s gangrene.

Funding
No funding 
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