Temple University School of Podiatric Medicine Journal Review Club
Editor's note: This post is part of the Temple University School of Podiatric Medicine (TUSPM) journal review club blog series. In each blog post, a TUSPM student will review a journal article relevant to wound management and related topics and provide their evaluation of the clinical research therein.

Article Title: Wound Healing and Anti-inflammatory Effects of Topical Hyaluronic Acid Injection in Experimental Staphylococcal Surgical Site Infections
Authors: Jin Hyung Park, MD, PhD, Eon Ju Park, MD, Hyung Suk Yi, MD.
Journal Name and Issue: The International Journal of Lower Extremity Wounds, 2017 Volume: 16 issue: 3, page(s): 202-207
Reviewed by: Christine Vareed, Class of 2019, Temple University School of Podiatric Medicine

Introduction

Staphylococcus aureus is a primary cause of post-operative surgical site infection. S. aureus produces hyaluronidase, which degrades hyaluronic acid (HA). HA is important in wound healing because it prevents bacterial proliferation and provides anti-inflammatory properties. Although early bactericidal antibiotic treatment is important for wound infection, systemic antibiotics often do not prove to be entirely beneficial for wound penetration. Therefore, newer treatment methods that are not at risk of antibiotic resistance are necessary. S. aureus is the most common cause of wound infection because of its virulence factor, the exoenzyme hyaluronidase. This exoezyme breaks down the HA of the host and prevents moisture balance, cell proliferation, and immune coordination. HA is essential for host immune maintenance and prevention of bacterial proliferation. The aim of this study was specifically to target the wound healing effect of HA on wound infection by using HA along with systemic antibiotic treatment.

Methods

The properties and effects of HA were evaluated by combining HA with systemic antibiotics in prevention and treatment of surgical site infections induced with S. aureus-inoculated thread. Open wounds were created in 40 rats (20 for the test group and 20 for the control group), and the wound bed was sutured with S. aureus-inoculated thread. A rectangular wound (20 × 10 mm2) was created at 3 cm distal to the lower scapula and parallel to the skin axis at the center of the dorsum, with S. aureus-contaminated sutures used in the wound. The control group received injections of saline, whereas the test group was injected with HA. Specifically, the HA group received 5 µL of 2 mL of Hyruan Plus (sodium hyaluronate 20.0 mg, sodium chloride 8.5 mg, sodium phosphate buffer). Cefazolin was injected in all groups, and sutures were removed two days following the procedure. The clinical appearance of the wound was observed at days two, four, six, and eight after the procedure and was photographed. Wound histology, bacterial count, and gross pathology were assessed in incremental days following the procedure.

Results

The HA group rats showed significantly greater wound healing than the control group in terms of abscess assessment, neutrophilic infiltrate, and necrosis. The HA group had a smaller amount of discharge, less purulence, and less foul odor comparatively. Although both groups showed gradual decreases in wound parameter over time, the HA area decreased in greater significance. At day two, wound area of the HA group was 79.68% +/− 4.66%, compared with 89.63% +/− 5.03% for the control group. The wound area at day four was 71.05% +/− 6.49% in the HA group, which was less than that of the control group, at 82.66% +/− 5.31%. The wound area at day six was 52.07% +/− 7.63% in the HA group, whereas the area in the control group it was 70.34% +/− 5.60%. Finally, the wound area of the HA group at day eight was less than that of the control group, with statistical significance (26.54% +/− 6.12% versus 50.59% +/− 5.50%). Overall, immediate local injection of HA in wounds significantly reduced surgical site infection occurrence and duration in an animal model.

Conclusion

Approximately 31% of wound infections are caused by S. aureus, which is only becoming more difficult to treat because of methicillin-resistant strains. S. aureus works in complex fashion to promote disease, most significantly by producing the bacterial exoenzyme hyaluronidase that acts during the early stages of subcutaneous infection. Hyaluronidase cleaves the β-1,4-glycosidic bond of HA in the extracellular membrane, thus promoting penetration of S. aureus. It has been hypothesized in earlier literature that HA infection may allow bacterial hyaluronidase to degrade extra HA instead of the host’s HA to maintain the extracellular matrix. This would then prevent dissemination of S. aureus, in turn promoting wound healing. Although it has been observed that the exact mechanism of the S. aureus virulence factor mechanism is unclear, this is the first study of its kind to prove HA effective when it is used with subsequent systemic antibiotics in treatment and prevention of S. aureus infection. This study, along with further research studies done on HA in wound healing, may represent viable treatment options for wound patients in the future.

About the Authors:
Christine J. Vareed is a third year podiatric medical student at Temple University School of Podiatric Medicine (TUSPM) in Philadelphia, Pennsylvania. She graduated from University of Connecticut in 2012 with a Bachelor of Science in Physiology & Neurobiology, and completed her Master of Biomedical Science degree at Geisinger Commonwealth School of Medicine in 2013.

Dr. James McGuire is the director of the Leonard S. Abrams Center for Advanced Wound Healing and an associate professor of the Department of Podiatric Medicine and Orthopedics at the Temple University School of Podiatric Medicine in Philadelphia.