Shockwave Therapy Surpasses Standard of Care in First-Line Diabetic Wound and Pressure Ulcer Treatment

Pulsed Acoustic Cellular Expression (PACE®) is a proprietary form of extracorporeal shockwave technology (ESWT) that utilizes high-energy, nonthermal acoustic pressure waves generated via an electric discharge inside a fluid, which is known as electrohydraulic method. Specially modulated shockwaves are delivered directly into the wound bed and periwound that penetrate deep inside the tissue to promote wound healing and wound closure.

PACE therapy is more likely to achieve wound closure than standard first-line wound care treatments. Its unique mechanism of action (MOA) helps explain why PACE-treated wounds heal better and faster.

This proven solution helps expedite the healing process at the cellular level, resulting in less time and resources spent on costly treatments that are not as effective. SANUWAVE’s dermaPACE System* offers a better, simpler, and cost-effective alternative to the traditional standard of care or other advanced wound therapies, for improved patient outcomes and enhanced quality of life.

How PACE Technology Works

PACE-treated wounds were twice as likely to achieve 90% to 100% wound closure compared with sham-treated control subjects within 12 weeks of the initial treatment.

Wound Healing Benefits of PACE Therapy

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

*The dermaPACE System is the first shockwave system to be FDA-cleared for the treatment of diabetic foot ulcers (DFU) in the United States. It is CE-marked in Europe for application in acute and chronic defects of the skin and subcutaneous tissues. These include:

  • Post-operative wound healing defects
  • Post-traumatic wounds
  • Deep, partial-thickness burns
  • Decubitus ulcers (pressure ulcers)
  • Diabetic ulcers
  • Arterial ulcers
  • Venous ulcers
References
  1. Li et al. Improvement of Blood Flow, Expression of Nitric Oxide, and Vascular Endothelial Growth Factor by Low-Energy Shockwave Therapy in Random-Pattern Skin Flap Model. Annals of Plastic Surgery. 2008 Dec;61(6):646-53.
  2. Krokowicz et al. Microcirculatory response to shockwave therapy in acute model – preliminary report. Presented during the International Society for Musculoskeletal Shockwave Therapy, Toronto, Canada, June 2007.
  3. Sanctis et al. Effects of Shock Waves on the Microcirculation in Critical Limb Ischemia (CLI) (8-Week Study). Angiology. 2000 Aug;51(8:2): S69-78.
  4. Wanner et al. Low-energy shock waves enhance the susceptibility of staphylococcal biofilms to antimicrobial agents in vitro. J Bone Joint Surg Br. 2011 Jun;93(6):824-7.
  5. Siemionow et al. Pulsed Acoustic Cellular Therapy Supports Pro-angiogenic Factors Expression in Ischemic Muscles. Poster presentation at the Diabetic Foot Conference 2008.
  6. Davis et al. Extracorporeal Shock Wave Therapy Suppresses the Early Pro-Inflammatory Immune Response to a Severe Cutaneous Burn Injury. International Wound Journal. Vol 6, No 1. 2008.
  7. Stojadinovic et al. Angiogenic response to Extracorporeal Shock Wave Treatment in Murine Skin Isografts. Angiogenesis. 2009 2008;11(4):369-80
  8. Wang et al. Molecular Changes in Diabetic Foot Ulcers. Diabetes Research and Clinical Practice. 2011.
  9. Wang CJ et al. Biological Mechanism of Musculoskeletal Shockwaves. International Society for Musculoskeletal Shockwave Therapy Newsletter, Volume 1, Issue 1, 2004.
  10. Meier R, Brunner A, Deibl M, Oehlbauer M, Piza-Katzer H, Kamelger FS, Shock wave therapy reduces necrotic flap zones and induces VEGF expression in animal epigastric skin flap model. J Reconstr Microsurg. 2007 May; 23(4):231-6.
  11. Meier R, Heumer GM, Oehlbauer M, Wanner S, Piza-Katzer H, Kamelger FS, Comparison of the effectiveness of gene therapy with vascular endothelial growth factor or shockwave therapy to reduce ischemic necrosis in an epigastric skin flap model in rats. J Plast Reconstr Aesthet Surg. 2007;60(3):266-71.
  12. Kamelger et al. Comparison of the Effectiveness of Gene Therapy with Vascular Endothelial Growth Factor or Shock Wave Therapy to Reduce Ischaemic Necrosis in an Epigastric Skin Flap Model in Rats. 2007; 60:266-271.
  13. Saggini et al. Extracorporeal shock wave therapy for management of chronic ulcers in the lower extremities. Ultrasound Med Biol. 2008 Aug;34(8):1261-71.
  14. Phase III Pivotal Trial Results of dermaPACE for the Treatment of Diabetic Foot Ulcers. Data on file with SANUWAVE Health, Inc.