Wound Healing Kinetics of the Genetically Diabetic Mouse

Author(s): 
Sandra Saja Scherer, MD;1 Giorgio Pietramaggiori, MD;1,2 Jasmine C. Mathews;1 Rodney Chan, MD;1 Paolo Fiorina, MD, PhD;3 Dennis P. Orgill MD, PhD1

With diabetes mellitus and obesity on the rise,1,2 and the increased prevalence of complex wounds and impaired healing,1,2 there is a crucial need to develop reliable wound repair models to identify effective therapeutic approaches.3,4

To be clinically relevant, an experimental model should appropriately reproduce the clinical situation physiologically and pathogenically.4 Experimental models can be either in vitro or in vivo.

In-vitro models are necessary in wound healing because of the orchestral fashion in which different cell types and the vascular and immune systems interact. In-vitro models are necessary in wound healing to study specific conditions, mechanisms of action, and the direct influence of therapeutics on individual cell types. Numerous in-vitro studies explore individual function and response to miscellaneous factors of cells such as keratinocytes,5,6,7–9 endothelial cells,10–12 fibrocytes,13–16 or molecules such as collagen,17 and many other components involved in wound healing. Additionally, in-vitro studies are often faster, cheaper, simpler, and more specific than in-vivo studies. In-vitro studies can also limit complications and variability.4

All findings derived from in-vitro studies have helped to elucidate important aspects of wound healing at the molecular level.

However, in-vitro studies often fail to reproduce the complexity of an organism and pathologic condition, making the in-vivo model a crucial tool for discoveries with clinical relevance to wound healing.

Researchers have studied in-vivo wound healing in a variety of species including pigs,18,19 rabbits,20–23 rats,24,25 and mice.2,4,26–32 The present review focuses on the mouse model, which has been instrumental throughout the development of the wound care field. Mice are appealing candidates for wound healing research because of their availability, low cost, and the ability to test a large number of animals in small facilities with highly reproducible results. In addition, the wide variety of knockouts and diseased mice available are important tools for the comprehension of wound healing mechanisms.

Wound repair kinetics vary among species. Mice, for example, heal mainly by contraction2,26,27,33 due to the presence of the panniculus carnosus muscle in the subcutaneous tissue. Humans lack this muscle and thus heal less through contraction and more through re-epithelialization—except in some areas where substantial wound contraction can occur, such as the joints.29

To generate a model that resembles human wound healing, researchers have developed ingenious models using wild-type mice and mice of various phenotypes including several diabetic mice, and have shown different levels of wound healing impairment. A phenotype similar to diabetes type 1 can be induced in mice by administering the cytotoxin streptozocin, which targets and inhibits proper pancreatic beta cell function.29 It has been reported that these mice have high variability in glucose levels,34 lower collagen synthesis resulting in reduced wound strength,35,36 less granulation tissue formation,37 altered T-cell function, and decreased macrophage phagocytosis.36

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