Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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A Transdermal Drug Delivery System for Deferoxamine for the Prevention and Treatment of Diabetic Wounds
Dominik Duscher, MD1,2, Zeshaan N. Maan, MBBS, MS1, Alexander J. Whittam, BS1, Mohammed Inayatullah, PhD1, Janos Barrera, BS1, Arnetha J. Whitmore, BA1, Jayakumar Rajadas, PhD1, Geoffrey C. Gurtner, MD, FACS1.
1Stanford University, Stanford, CA, USA, 2Johannes Keppler University, Division of Plastic Surgery, Linz, Austria.

PURPOSE:
The primary reason for compromised diabetic wound healing is impaired neovascularization in response to tissue ischemia. Hypoxia inducible factor-1 alpha (HIF-1α) is the governing transcriptional factor in the response to hypoxia and its function has been shown to be impaired in diabetes. We examined whether upregulation of HIF-1α expression and activity via a transdermal drug delivery system (TDDS) for deferoxamine (DFO) could effectively improve diabetic wound healing and if DFO preconditioning could prevent diabetic ulcer formation.
METHODS:
A TDDS containing the FDA approved small molecule DFO, known to enhance HIF-1α transactivity by preventing iron-catalyzed reactive oxygen stress, was developed. The TDDS was assessed for its physico-chemical characteristics, drug release profile and its effects on diabetic wound healing. DFO TDDS application was compared to DFO polymer spray as well as 1mM and 100mM drip-on application. Upon closure, tensile strength testing of the wound was performed and histological samples were collected.
RESULTS:
The TDDS displayed satisfactory physico-chemical characteristics and a sustained drug release profile. DFO TDDS application resulted in significantly accelerated diabetic wound closure (12 days) compared to DFO application via polymer spray (14.7 days) as well as 1mM (15.25 days), 100mM drip-on (15.6 days), and vehicle control patch (19.4 days) (*P < 0.05). No significant differences were observed between the polymer spray application and the aqueous solutions. Histological examination revealed an increase in dermal thickness, collagen density, and vascularity in the DFO patch group (*P < 0.05). Uniaxial skin tensile testing demonstrated increased wound strength in the treatment group according to Young’s modulus (*P < 0.01) and ultimate tensile strength (*P < 0.05). Most interestingly, prophylactic application of the DFO TDDS prevented ulcer formation in a chronic diabetic ulcer model (*P < 0.01).
CONCLUSION:
At present, there are no effective therapies to prevent diabetic ulcer formation and only modestly effective technologies to help heal ulcers once they have formed. We have developed a DFO TDDS application that outperforms DFO delivery via polymer spray and aqueous solution in diabetic wound healing with faster closure and improved wound quality. Additionally, the local sustained delivery of DFO via a TDDS represents the first prophylactic pharmacological approach to prevent ulcer formation. As this method involves repurposing a previously FDA approved molecule, it can be rapidly translated into the clinic and ultimately transform the care and prevention of diabetic complications.

Figure 1. A transdermal drug delivery system for DFO. DFO is aggregated with polymers and surfactants. By controlled release from a polymer matrix DFO is delivered in a targeted and sustained fashion.


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