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Control under pressure

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Science Translational Medicine  21 Jan 2015:
Vol. 7, Issue 271, pp. 271ec11
DOI: 10.1126/scitranslmed.aaa6671

The high costs and mortality associated with chronic ulcers, including foot ulcers and pressure ulcers, accentuate the clinical and economic challenges of the diabetes epidemic. Although hundreds of products exist on the market to treat existing chronic ulcers, relatively little attention has been paid to the prevention of ulcer formation. This void has resulted in vicious cycles of wound opening, treatment, healing, and reopening. Now, Duscher et al. describe the use of an iron-chelating agent to begin to address this clinical need.

High glucose concentrations and oxidative stress in diabetic patients lead to dysregulation of a tissue’s response to hypoxia, which in healthy people would stimulate the formation of new blood vessels but in diabetic patients leads to tissue necrosis. Previous studies have suggested that deferoxamine (DFO), an iron-capturing agent that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of elevated iron concentrations in blood, can reduce iron-catalyzed oxidative stress and thus restore a more normal tissue response to hypoxia. However, in order for DFO to effectively prevent ulcer formation, it would need to be delivered into the skin, which is protected by an outer layer that is impermeable to relatively large and hydrophilic molecules like DFO.

To address these challenges, the authors formulated DFO into a complex with nonionic surfactants, causing formation of a reverse-micelle structure with a hydrophilic core of DFO and a hydrophobic shell that can easily shuttle across the outer layer of skin. When packaged into a release-controlling polymer matrix, the micelles gradually diffused from the patch and through the stratum corneum, where they dispersed in the relatively hydrophilic tissue beneath to cause the release of DFO. When this drug delivery system was applied every other day to a pressure ulcer model in diabetic mice, healing was accelerated from 39 to 27 days. The quality of the healed tissue was enhanced in terms of vascularization and thickness, and the tissues showed increased levels of vascular endothelial growth factor, which is typical of a healthy response to hypoxia. Most importantly, pre-treatment of the skin effectively prevented formation of new pressure ulcers, with decreased levels of both oxidative stress and cell death in response to hypoxia.

Both diabetic foot ulcers and pressure ulcers occur in predictable locations on the skin, so a strategy to prevent ulcer formation in these areas would be valuable. However, longer-term studies need to be conducted because in this study, ulcer prevention was tracked only over 3 days after injury. In addition, although DFO is FDA-approved, the surfactants used to deliver it through the skin are not. Nonetheless, this study represents a new and innovative strategy to prevent ulcer formation in “at risk” patients.

D. Duscher et al., Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proc. Natl. Acad. Sci.U.S.A. 112, 94–99 (2015). [Abstract]

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