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Noncontact, Low-Frequency Ultrasound Therapy Enhances Neovascularization and Wound Healing in Diabetic Mice

Maan, Zeshaan N. M.B.B.S., M.S.; Januszyk, Michael M.D.; Rennert, Robert C. B.A.; Duscher, Dominik M.D.; Rodrigues, Melanie Ph.D.; Fujiwara, Toshihiro M.D., Ph.D.; Ho, Natalie; Whitmore, Arnetha B.A.; Hu, Michael S. M.D., M.P.H., M.S.; Longaker, Michael T. M.D., M.B.A.; Gurtner, Geoffrey C. M.D.

Plastic and Reconstructive Surgery: September 2014 - Volume 134 - Issue 3 - p 402e–411e
doi: 10.1097/PRS.0000000000000467
Experimental: Original Articles

Background: Chronic wounds are a major source of morbidity for patients and represent a significant health burden. Implementing noninvasive techniques that accelerate healing of these wounds would provide great benefit. Ultrasound appears to be an effective modality for the treatment of chronic wounds in humans. MIST Therapy is a noncontact, low-frequency ultrasound treatment delivered through a saline mist. A variety of mechanisms have been proposed to explain the efficacy of ultrasound therapy, but the underlying molecular and cellular pathways impacted by this technique remain unclear. The in vivo effect of noncontact, low-frequency ultrasound was therefore examined in a humanized excisional wound model.

Methods: The treatment group received noncontact, low-frequency ultrasound therapy three times per week, whereas the control group received a standard dressing change. Wounds were photographed at regular intervals to calculate healing kinetics. Wound tissue was harvested and processed for histology, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay.

Results: The MIST group demonstrated significantly accelerated wound healing, with 17.3 days to wound closure compared with 24 days in the controls (p < 0.05). This improvement became evident by day 9, with healing evidenced by significantly decreased mean wound area relative to original size (68 percent versus 80 percent; p < 0.01). Expression of markers of neovascularization (stromal cell-derived factor 1, vascular endothelial growth factor, and CD31) was also increased in the wound beds of noncontact, low-frequency ultrasound–treated mice compared with controls.

Conclusion: Noncontact, low-frequency ultrasound treatment improves neovascularization and wound closure rates in excisional wounds for diabetic mice, likely because of the stimulated release of angiogenic factors.

Supplemental Digital Content is available in the text.

Stanford, Calif.

From the Department of Surgery, Stanford University School of Medicine.

Received for publication November 21, 2013; accepted February 4, 2014.

Presented at the 99th Annual Clinical Congress of the American College of Surgeons, in Washington, D.C., October 6 through 10, 2013.

Disclosure: The manufacturer of the noncontact, low-frequency ultrasound device provided an unrestricted gift to the authors’ group, including funds and equipment to support this study. The authors have no financial interest in any of the products or devices mentioned in this article.

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Geoffrey C. Gurtner, M.D., Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, 257 Campus Drive West, Hagey Building GK-201, Stanford, Calif. 94305-5148,

©2014American Society of Plastic Surgeons