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Using a Non-Invasive Pulsed Acoustic Cellular Expression System to Promote Angiogenesis in Chronic Wounds

Non-invasive pulsed acoustic cellular expression (PACE) can improve microcirculation and oxygenated hemoglobin, which can help regenerate tissue and heal chronic wounds. These authors provide a guide to PACE technology using a case study.

The incidence of chronic wounds continues to rise worldwide and constitutes an extraordinary burden not only on patients’ quality of life but also on healthcare costs.1 Chronic wounds are defined as wounds that, after 3 months, have not proceeded through the orderly and timely phase of tissue repair that leads to reconstituted anatomic and functional integrity.2

Diabetes mellitus is a metabolic disease characterized by impaired glucose metabolism resulting in higher than normal glucose levels in the body. This condition occurs due either to cells failing to produce insulin, failing to respond to insulin, or both. Diabetes affects 29.1 million Americans and this number is on the rise. Patients with diabetes have a 25% lifetime incidence of foot ulcers with a 28–51% five-year recurrence rate.3  
The neuropathy, microcirculatory and cellular dysfunction seen in patients with diabetes delays the wound healing process. Neuropathy results when increased blood glucose levels damage neurons, leading to a decrease in the ability of nerve fibers to transmit adequate signals.4 High glucose levels can weaken the walls of small blood vessels, impairing their ability to deliver essential components such as oxygen and nutrients to distal tissues, resulting in small vessel disease. Bone marrow releases endothelial progenitor cells (EPCs) to the circulatory system in response to ischemia. EPCs play an active role in angiogenesis and are essential in wound healing.5 This release process, as well as other cellular and metabolic macromolecular processes, is impaired in patients with diabetes.

The etiology of diabetic foot ulcers (DFUs) is usually multifactorial.6–8 The vast majority of DFUs can be directly attributed to the debilitating triad of peripheral neuropathy, vascular compromise, and increased plantar pressures due to structural deformities. Although infection is not commonly an etiology for DFUs, it is not uncommon to see infected DFUs because these wounds typically contain areas of necrosis and increased bioburden, and are prone to bacterial contamination due to the immunocompromised state of the patient.6–8 These same risk factors for foot ulcers also predispose patients to amputations, 85% of which are a direct result of diabetic foot ulcers.3 Interventions that can help increase wound closure in this patient population have the potential not only to be cost effective but also to prevent potential long-term sequelae and maintain patients’ quality of life.  

Current standard therapies for DFUs have limited success rates and may fall short in addressing the associated microvascular pathology, thus presenting significant challenges to effective wound management. The clinical standard of care for DFUs includes adequate wound bed preparation with appropriate debridement, application of specialized dressings to provide the wound with a moist environment, and sufficient offloading to avoid pressure necrosis. Additionally, there are many adjunctive therapies designed for the care of chronic wounds such as negative pressure wound therapy, ultrasound, and hyperbaric oxygen therapy (HBOT).

A Closer Look at an Innovative DFU Treatment

An innovative treatment modality for use as an adjunctive therapy for DFUs is a non-invasive pulsed acoustic cellular expression (PACE) system (dermaPACE, Sanuwave, Suwanee, GA). This new modality is based on extracorporeal shockwave technology (ESWT), which has been in use for over 30 years in lithotripsy and has compelling research that shows healing effects in bone and soft tissue.9 The PACE system, unlike ESWT, uses the electrohydraulic shockwave principle to produce biphasic, high-energy acoustic waves.  

The PACE system functions by emitting a high-voltage spark in a fluid medium, which results in the formation and collapse of a vapor bubble. This action releases acoustic waves with high peak pressures that rapidly decline as the shockwave propagates over distance.9,10 These high-energy pressure waves cause compressive and tensile stresses on cells and tissue in the treatment area as they absorb the produced energy. These stresses promote expression of angiogenic growth factors and positive inflammatory responses.   

PACE therapy dosage is based on a unique protocol in which the number of shocks per treatment is dependent on the wound’s surface area (cm2). The energy the acoustic wave generates is focused on the target tissue site. The mechanical stimulation of the subcutaneous tissues promotes neovascularization and leads to improved healing in chronic, recalcitrant ulcerations.

Case Series on PACE for Skin Perfusion and Wound Healing

The remainder of this article details the results of a prospective, single site, single-arm pilot case series. This case series aimed to evaluate the effects of weekly PACE therapy on localized skin perfusion and wound healing in diabetic patients with normal ABIs but decreased wound oxygenation. A near-infrared imaging spectroscopy (NIRS) camera (SnapshotNIR, Kent Imaging, Calgary, AB, Canada) was used to determine the tissue oxygen saturation (StO2).

NIRS is a non-invasive tool used to assess and monitor tissue oxygenation in a wide range of clinical scenarios. NIRS camera technology is based on measuring the absorption of light in the near infrared spectrum from 700–1,000 nm.11 Distinct biological molecules change their optical properties when bound to oxygen; at these wavelengths, oxygenated and deoxygenated hemoglobin are the primary light absorbers. Other endogenous chromophores such as melanin and water have low values for light absorption relative to hemoglobin in this spectrum.11

The differences in absorption coefficients between oxygenated and deoxygenated hemoglobin allow the NIRS camera to calculate the oxygen saturation of the wound tissue and to give the clinician a visual idea of the functional blood flow in and around the wound tissues. Due to the differences in light absorption patterns between oxygenated and de-oxygenated hemoglobin, oxygenated blood appears red, whereas de-oxygenated blood appears blue to black in the resulting image. With the NIRS camera used in this case series, the operator touches the imaging screen in the area of interest on the wound and the system calculates and displays the corresponding StO2.

The patient population in this single-arm case series was comprised of 5 patients with a history of diabetes and an open wound of the lower extremity that had failed at least one previous advanced wound care therapy. All patients were over 18 years of age and had an ankle-brachial index (ABI) within the normal limits. Patients signed an informed consent form and a photo-release prior to any treatments. No compensation was provided for participation.

All 5 patients were treated with the PACE system with dosage in accordance with the system’s wound-size based dosage protocol. Manual measurements of wounds were taken at baseline and prior to every weekly PACE treatment. The NIRS camera was used to capture a baseline standard image, baseline NIRS image, and to take a standard and NIRS image prior to each weekly PACE treatment. Patients were seen for 5 visits and had a total of 4 PACE treatments each. Changes in both wound size and percentage of oxygenated hemoglobin in the wound from baseline to treatment completion were reviewed.

Table 1 exhibits the change in wound measurements and StO2 levels from baseline to final treatment for the 5 patients who received PACE therapy. All patients displayed a reduction in wound size, and an increase in oxygenated hemoglobin from baseline levels. Additionally, throughout the PACE treatment period the investigator noted that all 5 patients displayed clinical signs of increased granulation tissue within the wound bed and that the weekly wound measurements moved in a greater positive trajectory than she otherwise would have expected.  

Case Example

A 56-year-old patient with type 1 diabetes, neuropathy, calciphylaxis, renal dysfunction, degenerative joint disease, hypertension and an ABI of 1.02 has had a chronic wound on her left lower leg and foot for 16 months. The patient had tried and failed multiple advanced wound care therapies.

The initial wound measurement was 9.5 cm x 9.8 cm x 0.1 cm. The baseline tissue oxygenation at the wound site was 49%. The patient received weekly PACE therapy treatments with dosage according to wound size. After 4 PACE therapy treatments the wound measurements had reduced to 8.7 cm x 9.5 cm x 0.1cm and the tissue oxygenation had increased to 60%. This translates into an overall decrease in wound size of -1.05 cm3, and an improvement in oxygenated hemoglobin of 11%. Clinically, the wound bed exhibited development of more granulation tissue than would have been expected without PACE treatment. Three weeks after the patient’s last PACE treatment, she underwent a successful split thickness skin graft to close the wound. The plastic surgeon consented to do the procedure based on the increased StO2 measurement at treatment’s end.


Diabetes is a complicated disease with many serious sequelae. It is very common for patients with diabetes to develop foot ulcers. These ulcers can deteriorate quickly due to the multiple comorbidities found within this patient population. While prompt and aggressive wound care with rigorous and proven protocols is the key to successful treatment of diabetic foot wounds and remains the cornerstone of therapy, adjunctive therapies are valuable for “jump-starting” the healing cascade and shortening wound healing time.  

In the authors’ opinion, PACE therapy, as a non-invasive adjunctive to standard of care that may initiate the healing cascade and shorten wound healing, provides a novel therapeutic modality for these difficult to treat chronic wounds. By improving microcirculation and oxygenated hemoglobin, PACE therapy encourages the regeneration of granulation tissue and skin in chronic wounds.  

It is not uncommon for patients with diabetes to have uncompromised large vessel blood flow (structural flow), but compromised functional flow in and around their wounds due to persistent micro-vessel abnormalities. Immunomodulatory mechanisms of shockwave therapy promote expression of macromolecules in wound healing, including vascular endothelial growth factor (VEGF), spurring new blood vessel formation and increased oxygenation to the wound tissues.

The NIRS camera proved to be a very user-friendly point of care imaging device to track weekly wound progress. It provided an objective means of evaluating wound response to PACE therapy. The increase in tissue oxygenation that the NIRS system showed, matched the visual improvement seen in the wound bed and correlated to an overall decrease in wound size.  

Patient comfort and improved quality of life, combined with an increase of healthcare expenditures for treatment, make chronic wounds the subject of extensive research. Alternative effective treatment options such as PACE therapy are highly desirable to reduce both the suffering that chronic wounds cause patients, as well as their costs to society.

Windy Cole is Adjunct Professor and Director of Wound Care at Kent State University College of Podiatric Medicine in Independence, Ohio.

Stacey Coe is a Clinical Research Coordinator at Kent State University College of Podiatric Medicine.


Windy Cole, DPM; Stacey Coe, BA, CCRP

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