PACE® treatment leads to an increase in blood perfusion. As the PACE® shockwaves penetrate the microcirculatory system, there is an immediate change in local blood flow in the treated area. Li et al. determined that local blood perfusion increased from two to eight hours after treatment due to the vasodilation (increasing diameter) of preexisting vessels.1 Research performed at the Cleveland Clinic using Doppler readings to measure blood flow in treated tissue showed an increase in blood perfusion and vessel density 24 hours after treatment.2 This increase in perfusion is important since ischemia is often associated with impaired healing.3

Antibiotic-resistant bacterial colonies often produce biofilms. A biofilm is a defense mechanism that creates a physical protective barrier against antibiotic treatment. Wanner et al. concluded that shockwave treatment can break up physical biofilm barriers and allow antibiotics access to entrenched bacteria so bacterial colonies may be eradicated.4 SANUWAVE® conducted bench testing to assess the effect of shockwaves on Staphylococcus aureus (Gram-positive bacterium) and Pseudomonas aeruginosa (Gram-negative bacterium) biofilms, which showed that shockwaves removed completely the viable bacterial biofilms from the shockwave exposed surfaces.

An immediate inflammatory response is apparent after PACE® treatment. Researchers at the Cleveland Clinic reported a decrease in rolling and sticking leukocytes (white blood cells) and an increase in transmigrating leukocytes moving through the vessel wall and into the treatment area.5 Increasing leukocyte activation assists in the inflammatory phase of wound healing by triggering the release of pro-angiogenic factors. After shockwave treatment, wounds move much faster through the inflammatory phase6 when compared to the normal inflammatory process.7

Studies show that the early pro-angiogenic and pro-inflammatory responses to PACE® treatment are accompanied by significantly increased expression of both CD31 and angiogenesis pathway-specific genes, including ELR-CXC chemokines (CXCL1, CXCL2, CXCL5), CC chemokines (CCL2, CCL3, CCL4), cytokines (IL-1B, IL-6, G-CSF, VEGF-A), matrix metalloproteinases (MMP3, MMP9, MMP13), hypoxia-inducible factors (HIF-1a), and vascular remodeling kinase (Mst1) as early as six hours and up to seven days post-treatment.2,6,7 This may be evidence of an immediate and long-term angiogenic effect and of a jump start of inflammatory healing response that moves chronic wounds to a normal healing cascade of events. Further, PACE® treatment significantly decreased neutrophil and macrophage (white blood cell) infiltration into the wound, attenuating both CC- and CXC-chemokines at the wound margin.6 This may indicate a change from a chronic, nonhealing wound to a natural healing state. Shockwave treatment was found to decrease the rate of apoptosis (programmed cell death) to normal levels. Wang et al. reported a statistically significant decrease in TUNEL (indicator of apoptosis) after PACE treatment.8

At a cellular level, PACE® treatment applies mechanical forces to individual cells in the treated tissue. The cells respond to these mechanical forces through cellular expression: Pro-angiogenic and cellular proliferation factors such as endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), proliferating cell nuclear antigen (PCNA), epidermal growth factors (EGF), and others are upregulated. These factors start a cascade of cellular activities that cause an increase in cellular proliferation and tissue regeneration and have been shown to persist for up to 12 weeks.9

The pro-angiogenic factors released in response to PACE® treatment lead to new blood vessel formation resulting in the creation of new capillary networks in the treated tissue. Vascular endothelial growth factor (VEGF) is related to the growth of new blood vessels that allow prefusion improvement in a wound and periwound region. Wang et al. reported an increase in VEGF after PACE® treatment.8 Davis et al. reported that by Day 7, shockwave treatment created a greater number of blood vessels versus untreated controls.7 Another series of studies compared the effects of shockwave treatment with a direct gene therapy and VEGF application in ischemic tissue.10-12 The shockwave treatment actually outperformed direct topical VEGF application in these studies.

Cellular proliferation is one of the most noticeable stages of wound healing: Cells divide and cover the wound surface to close the wound. This process begins with a granulation tissue phase that builds vascularized tissue in the wound defect. Proliferating cell nuclear antigen (PCNA) is a factor related to cellular replication and repair machinery indicating that this stage of wound healing is progressing. Wang et al. reported a statistically significant increase in average PCNA levels after PACE treatment.8 This finding indicates that PACE treatment may accelerate wound granulation. Stojadinovic et al. reported marked granulation tissue development on post-treatment Day 4.7 Saggini et al. reported that the percent of granulation tissue increased significantly in the wounds of patients after being treated with shockwaves. 13

Results of a recent Phase III clinical trial strongly suggest that the dermaPACE® System has an effect in the stabilization, size reduction and, with time, complete re-epithelialization of chronic wounds, specifically diabetic foot ulcers. Clinically significant re-epithelialization of greater than 90% was demonstrated to have statistical significance at 12 weeks in favor of PACE®-treated wounds (51/107, 47.7%) compared with sham-control wounds (31/99, 31%) (p=0.016). Furthermore, of the wounds that achieved at least 90% wound area reduction at 12 weeks, the median reduction in area exceeded 99%. Overall, PACE-treated wounds were twice as likely to achieve 90% to 100% wound closure compared with sham-control subjects within 12 weeks of the initial PACE procedure. Further, by 12 weeks, the reduction in target ulcer area in PACE subjects was on average 48.6% compared with an average of only 10.7% in subjects randomized to sham-control (p=0.015).14