Limitations of the db/db mouse in translational wound healing research: Is the NONcNZO10 polygenic mouse model superior? Robert C. Fang, MD; Zol B. Kryger, MD; Donald W. Buck II, MD; Mauricio De La Garza, MD; Robert D. Galiano, MD; Thomas A. Mustoe, MD Laboratory for Wound Repair and Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois Reprint requests: Thomas A. Mustoe, MD, Department of Surgery, Division of Plastic Surgery, Northwestern Feinberg School of Medicine, Galter 19-250, 675 North Saint Clair, Chicago, IL 60611, USA. Tel: 11 312-695-6022; Fax: 11 312-695-5672; Email: tmustoe@nmh.org Manuscript received: November 28, 2009 Accepted in final form: August 5, 2010 DOI:10.1111/j.1524-475X.2010.00634.x ABSTRACT Murine models have provided valuable insights into the pathogenesis of both di- abetes and chronic wounds. However, only a few published reports to date have investigated wound healing differences among the differing diabetic mouse mod- els. The goal of the present study was to further define the wound healing defi- ciency phenotypes of streptozotocin-induced (STZ-induced), Akita, and db/db diabetic mice in comparison with a promising new polygenic strain of Type 2 diabetes (NONcNZO10) by using three specific wound models that targeted different critical processes in the pathogenesis of chronic wounds. Incisional, excisional, and ischemia/reperfusion wound models were established on mice of each strain. Wound healing parameters including tensile strength, epithelial gap, and wound necrosis were evaluated. In contrast to the other diabetic mice, the NONcNZO10 strain was found to have significant wound healing impairments in all wound healing models. Not only do the NONcNZO10 mice appear to better model human Type 2 diabetes, these provocative findings suggest that the mice may show more clinically relevant wound healing deficiencies than previous di- abetic mouse models. Diabetes mellitus and its complications are one of the ma- jor health care burdens of the United States. The number of people with obesity and the Type 2 diabetes has in- creased at an alarming rate in the last two decades. The prevalence of diabetes was estimated to be > 7% of the US population, affecting more than 23 million people in 2007. This number has been projected to almost double to over 44 million in the next 25 years. Over 90% of these cases can be classified as the ‘‘garden-variety’’ Type 2 form of diabetes. 1,2 Impaired wound healing, chronic wounds, and amputations are a significant source of morbidity and mortality for this particular patient population. Many questions regarding the specific pathophysiology of dia- betic wounds have yet to be elucidated. Efforts to study this difficult problem and develop targeted therapeutics continue to intensify. The pathogenesis of impaired tissue repair in chronic wounds in diabetes mellitus is complex, and the contribu- tions of factors on the cellular and molecular levels have remained active areas of investigation. Diabetes mellitus is associated with both macrovascular and microvascular disease, both of which may lead to local tissue hypoxia. Peripheral neuropathy is critical to continued cutaneous injury. In the local wound milieu, an altered immunity al- lows for increased bacterial colonization and biofilms to develop, while the events of ischemia/reperfusion (I/R) can cause repetitive tissue injury and eventual tissue necrosis. Renal disease is also common in this population, and the adverse effects of uremia on wound healing are still being elucidated. These factors are deleterious to the compo- nents of wound healing such as epithelialization, deposi- tion of granulation tissue, development of tensile strength, and response to ischemia or other kinds of stress. 1,3,4 Murine models have provided valuable insights into the pathogenesis of both diabetes and chronic wounds. How- ever, the selection of a diabetic mouse for use in wound healing studies is not straightforward. Most published studies of diabetic wound healing have focused mainly on either monogenic models of obesity and diabetes or those that replicate the Type 1 form alone. In particular, the db/db strain (a monogenic leptin receptor deficient model of obesity and Type 2 diabetes) has long been established to have impaired healing in an excisional model and has achieved widespread acceptance in many wound healing studies. 5–7 Although this model has been useful, an impor- tant weakness has been the inflated role that leptin plays in appetite control in mice as compared with humans. One concern has been the possibility that the overall deficiency of the leptin axis in mice has a wider range of phenotypic changes than just the clinically apparent diabetes. A recent report showed that the impaired wound healing phenotype in db/db mice is not related to the level of hyperglycemia, raising the implication that impaired wound healing in db/ db mice is complex, and may not be fully translatable to the wound healing deficits observed in humans with Type 2 diabetes. 8 Furthermore, Type 2 diabetes in humans is a polygenic disease, unlike the monogenic basis of db/db mice. The development of new polygenic diabetic mice in the recent years has provided an opportunity to investigate promising models of diabetic wound healing that may be Wound Rep Reg (2010) 18 605–613 c  2010 by the Wound Healing Society 605 Wound Repair and Regeneration