A Novel Oxidative Stress Chronic Wound Mouse Model to Test Wound Healing Therapeutics

Ryoko Hamaguchi, BS
Department of Surgery
Division of Plastic Surgery
Poster Overview

As clinician-scientists, we aim to create animal models that mimic human diseases and allow us to develop, test and deliver treatments to the patients we serve. Historically, creating animal models of chronic, poorly healing wounds has proven difficult, as the treatments to interfere with healing can cause animal death. In our study, we designed a regimen of drugs that prolong the inflammation process (antioxidant inhibitors), then administered these at a low dose to genetically modified “diabetic” mice. Using these animals as a platform to test treatments for wound healing, we created small wounds on the mice’s backs and treated them with fat grafting (F, implanting small amounts of mouse fat into the wound), a dressing made of amniotic membrane (A), or a dressing made from fetal cow tissue (P). None of the mice died, and while all treatment groups scored higher on markers of wound healing than the untreated mice, the mice with fat grafting appeared to close their wounds fastest. This model provides us with a powerful addition to our toolkit for testing large numbers of wound treatments in the lab, including ointments and special dressings, to develop the most effective treatments for human patients.

Scientific Abstract

Reliable chronic wound models have been difficult to achieve, often limited by high animal mortality. We treated 11-week-old db/db mice with tempered doses of antioxidant enzyme inhibitors, creating a low-mortality, chronic wound environment that could be employed for testing therapeutics. 1×1 cm2 full-thickness dorsal skin wounds were created in 10 animals, which were treated with catalase (ATZ; intraperitoneal 0.5 g/kg) and glutathione peroxidase (MSA; topical 300 mg/kg) inhibitors, then either fat grafting (F), amniotic membrane scaffold (A), fetal bovine dermis scaffold (P) or no treatment. All animals were sacrificed on Post-operative Day 14 and wound tissue was harvested for analysis. There were no animal deaths, and wound healing rates were slower for A and P, and faster for F, compared to untreated control. The three treated groups exhibited higher granulation tissue formation, collagen deposition and keratinocyte proliferation than control. Leucocyte infiltration was lowest in F. Arresting the wounds in the inflammatory stage of healing, this model provides a low-mortality murine model of chronic diabetic wounds for the development, testing and toxicity screening of novel therapeutics. Here, fat grafting showed the most potential, identifying it as a potential candidate for larger studies to investigate its clinical utility in patients.

Clinical Implications
This model will be instrumental for the expedited development and optimization of wound healing therapeutics for the most challenging tissue defects that bridge multiple medical specialties, including diabetic wounds and traumatic injuries in patients with multiple comorbidities that preclude healing.
Research Areas
Authors
Ryoko Hamaguchi, B.S., Adriana C. Panayi, M.D., Mengfan Wu, M.D., Ph.D., Qinxin Liu, M.D., Ph.D., Mehran Karvar, M.D., Chenhao Ma, M.D., Yori Endo, M.D., Dennis P. Orgill, M.D., Ph.D.
Principal Investigator
Dr. Dennis P. Orgill, M.D., Ph.D.

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