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  Previous laboratory studies and initial clinical trials have demonstrated that ESWT may be useful and effective through its stimulation of numerous endogenous growth factors in animal models,^18–21 its enhanced recruitment of endothelial progenitor cells,²² and induction of angiogenesis.^23,24 Nitric oxide (NO), a potent vasodilatation mediator, was greatly increased after the ESWT treatment leading to improved tissue perfusion. One of the mechanisms for long-term improvement of tissue perfusion after ESWT has been shown in an ischemic flap using a rat model.^25,26 Shockwave enhances NO production through increased expression of NO synthase. The most potent endogenous pro-angiogenic and vasculogenic factor, vascular endothelial growth factor (VEGF), is acutely induced²⁷ after the shockwave, and VEGF receptors are more highly expressed in targeted tissue.^28–30

  In animal models, ESWT has been shown to produce favorable molecular microenvironment in the wound tissue, suppress early pro-inflammatory cytokines and chemokines, and enhance expression of several wound healing relevant genes^19,31: ELR-positive CXC chemokines, CC chemokines, and cytokines. They were also able to demonstrate enhanced early local inflammatory responses (high levels of macrophage-derived inflammatory protein [MIP-1α, MIP-1β]) in the sham treated animals compared to ESWT-treated grafts indicating an anti-inflammatory mechanism of shockwaves. Furthermore, shockwaves significantly reduced infiltration of leukocytes and macrophages into the isograft. Studies have demonstrated attenuated early local inflammatory responses (low levels of macrophage-derived inflammatory protein [MIP-1a, MIP-1b]) in grafts in ESWT treated animals indicating an anti-inflammatory mechanism of shockwaves.^18,32

  ESWT enhances cell proliferation, stimulates extracellular matrix metabolism, decreases apoptosis^22,33,34 at the local wound tissue level, and down-regulates oxygen-regulated burst of leukocytes and leukocyte infiltration into the isograft.

Extracorporeal Shockwave Therapy

  Extracorporeal shockwave therapy has been in use since the 1980s primarily as a treatment for urinary stones (lithotripsy). Shockwaves are defined as a sonic pulse characterized by a high peak pressure (500 bar), short lifecycle (10 ms), fast pressure rise (< 10 ns), a broad frequency spectrum (16 Hz–20 MHz), and the generation of high stress forces upon interfaces (Figure 1a). The physical energy of shockwaves is mechanotransduced into favorable biological effect on structures such as bones and soft tissue with undetermined mechanisms. Shockwave energy, frequency of the generated waves, number of pulses, and the number and interval of re-treatments are crucial characteristics of treatment description, and are imperative for comparing the different ESWT studies and standardizing shockwave treatment for various indications. The acoustic pressure wave can be generated by a variety of physical principles that impact these treatment parameters (Table 1). Figure 1b represents the spectrum of energy generated by ESWT according to clinical indication—soft tissue, bone, and kidney stones. As the energy increases the biological effects switch from regeneration to destruction. Energy flux density for soft tissue indications is typically in the range of 0.08–0.25 mJ/mm².