Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds

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.

Implications of considering peri‐implant bone loss a disease, a narrative review

“…In addition, a recent study demonstrated that there is a synergy between cellular mechano‐transduction and biochemical signals in the regulation of macrophages which would be related to CD11b and Piezo1 crosstalk 85 . In this context it has been proposed that shockwave‐induced immunomodulation has potential as a non‐invasive physical therapy to regulate macrophage functions linked with wound healing 86 and osseointegration 78,79,87 . This could be a biological mechanism behind the re‐fixation of orthopedic implants 88,89 …”

Use of the Shock Wave Therapy in Basic Research and Clinical Applications—From Bench to Bedsite

“…Among all the clinical applications of the shock wave in dermatology, the ability to enhance tissues regeneration is most often applied. Several studies have assessed the effectiveness and safety of shockwave therapy in the treatment of patients with chronic leg ulcers [63][64][65][66][67]. Chronic foot ulcers are defined as non-healing ulcers with a duration time of at least 3months.…”

“…Although, no severe complications of the SWT appliances have been described so far, the safety concerns are not unfounded. On one hand, it has been proven that SWT can modulate the proliferation [90] and destruction of cells as well as modulate the immune response [64]. On the other hand, SWT is commonly used as a part of the rehabilitation and a recovery process in patients with malignancies [91].…”

The Emerging Role of Immune Cells and Targeted Therapeutic Strategies in Diabetic Wounds Healing

“… 92 Different electrical stimulations also promote wound healing by regulating different immune cells. 133 Holsapple JS 134 et al recruited patients with treatment-resistant venous ulceration for two weeks of extracorporeal shockwave therapy (ESWT), and the results showed that ESWT significantly increased the uptake of apoptotic cells, healing-associated cytokine and growth factor gene expression and modulated the macrophage morphology to one suggestive of macrophage activation, all of which contributed to wound resolution. Moreover, ESWT decreased the number of total and degranulated MCs and alleviated pelvic pain in a rat model of prostatitis.…”