Abstract
Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150–500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.
Highlights
Chronic non-healing wounds of the skin, such as venous or diabetic foot ulcers, are globally a major cause of morbidity and burden to health services, the incidence of which is rising due to the increase in co-morbidities such as diabetes and vascular diseases [1]
We show for the first time that low intensity shockwave treatment is an important physical stimulus that regulates macrophage functions in vivo and in vitro and this is conducive to wound healing
The greater effect was the significantly enhanced uptake of apoptotic cells by macrophages following shockwave treatment, an effect potentially mediated, in part, through mechanotransduction via ERK activation. These shockwave-induced biological processes have potential as a non-invasive process to reengage macrophages in the progression of healing in chronic wounds
Summary
Chronic non-healing wounds of the skin, such as venous or diabetic foot ulcers, are globally a major cause of morbidity and burden to health services, the incidence of which is rising due to the increase in co-morbidities such as diabetes and vascular diseases [1] They have a complex etiology and closure continues to be challenging with current guideline treatments that include compression or pressure offloading, debridement, infection control, and local ulcer care with various multilayer wound dressings [2,3]. Extracorporeal shockwave therapy (ESWT), has been used clinically for several conditions including urological lithotripsy [4], scars, tendonitis, non-union fractures, plantar fasciitis and osteonecrosis, with few side effects [5,6,7,8] Potential for such a therapy, using comparatively low shockwave intensities, has been recognized clinically for diabetic and venous ulcer management and is a feasible non-invasive method for improving chronic wound healing [9,10]. It has been suggested that ESWT dampens the release of pro-inflammatory mediators to improve healing in experimental models [13]; the full molecular and cellular effects have not been characterized
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