Iron Chelation with Transdermal Deferoxamine Accelerates Healing of Murine Sickle Cell Ulcers

Melanie Rodrigues, Clark A. Bonham, Caterina P. Minniti, Kalpna Gupta, Michael T. Longaker, Geoffrey C. Gurtner

Research output: Contribution to journalArticle

Abstract

Objective: Sickle cell ulcers (SCUs) are a devastating comorbidity affecting patients with sickle cell disease (SCD). SCUs form over the medial or lateral malleoli of the lower extremity, are slow to heal, and prone to recidivism. Some SCUs may never heal, leading to chronic pain and foot deformities. There is no specific and effective therapy for SCUs. Systemic deferoxamine (DFO) has been demonstrated to prevent some of the sequelae of SCD by chelating iron. In this study, we tested the ability of DFO delivered via a transdermal delivery system (DFO-TDDS) to accelerate healing in a murine model of SCU. Approach: Excisional wounds were created in a transgenic murine model of SCD expressing >99% human sickle hemoglobin, and healing rates were compared with wounds in wild-type mice. Next, excisional wounds in SCD mice were treated with DFO-TDDS, DFO injection, or left untreated. Wound closure rates, histology, and iron in the healed wounds were analyzed. Results: Wounds in SCD mice healed significantly slower than wild-type mice (∗∗∗p < 0.001). DFO-TDDS-treated wounds demonstrated significantly accelerated time to closure, reduced size, and improved wound remodeling compared with untreated wounds (∗∗∗p < 0.001) and DFO injection treatment (∗p < 0.05). DFO released from the TDDS into wounds resulted in chelation of excessive dermal-free iron. Innovation: DFO-TDDS is a novel therapeutic that is effective in healing wounds in sickle cell mice. Conclusion: DFO-TDDS significantly accelerates healing of murine SCUs by chelation of excessive free iron and is currently manufactured in an FDA-compliant facility to be translated for treating human SCUs.

Original languageEnglish (US)
Pages (from-to)323-332
Number of pages10
JournalAdvances in Wound Care
Volume7
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Deferoxamine
Ulcer
Iron
Wounds and Injuries
Sickle Cell Anemia
Foot Deformities
Sickle Hemoglobin
Injections
Cell- and Tissue-Based Therapy
Chronic Pain
Wound Healing
Comorbidity
Lower Extremity
Histology
Skin

Keywords

  • deferoxamine
  • iron chelator
  • sickle cell disease
  • sickle cell ulcers
  • wound healing

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Iron Chelation with Transdermal Deferoxamine Accelerates Healing of Murine Sickle Cell Ulcers. / Rodrigues, Melanie; Bonham, Clark A.; Minniti, Caterina P.; Gupta, Kalpna; Longaker, Michael T.; Gurtner, Geoffrey C.

In: Advances in Wound Care, Vol. 7, No. 10, 01.10.2018, p. 323-332.

Research output: Contribution to journalArticle

Rodrigues, Melanie ; Bonham, Clark A. ; Minniti, Caterina P. ; Gupta, Kalpna ; Longaker, Michael T. ; Gurtner, Geoffrey C. / Iron Chelation with Transdermal Deferoxamine Accelerates Healing of Murine Sickle Cell Ulcers. In: Advances in Wound Care. 2018 ; Vol. 7, No. 10. pp. 323-332.
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AU - Longaker, Michael T.

AU - Gurtner, Geoffrey C.

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AB - Objective: Sickle cell ulcers (SCUs) are a devastating comorbidity affecting patients with sickle cell disease (SCD). SCUs form over the medial or lateral malleoli of the lower extremity, are slow to heal, and prone to recidivism. Some SCUs may never heal, leading to chronic pain and foot deformities. There is no specific and effective therapy for SCUs. Systemic deferoxamine (DFO) has been demonstrated to prevent some of the sequelae of SCD by chelating iron. In this study, we tested the ability of DFO delivered via a transdermal delivery system (DFO-TDDS) to accelerate healing in a murine model of SCU. Approach: Excisional wounds were created in a transgenic murine model of SCD expressing >99% human sickle hemoglobin, and healing rates were compared with wounds in wild-type mice. Next, excisional wounds in SCD mice were treated with DFO-TDDS, DFO injection, or left untreated. Wound closure rates, histology, and iron in the healed wounds were analyzed. Results: Wounds in SCD mice healed significantly slower than wild-type mice (∗∗∗p < 0.001). DFO-TDDS-treated wounds demonstrated significantly accelerated time to closure, reduced size, and improved wound remodeling compared with untreated wounds (∗∗∗p < 0.001) and DFO injection treatment (∗p < 0.05). DFO released from the TDDS into wounds resulted in chelation of excessive dermal-free iron. Innovation: DFO-TDDS is a novel therapeutic that is effective in healing wounds in sickle cell mice. Conclusion: DFO-TDDS significantly accelerates healing of murine SCUs by chelation of excessive free iron and is currently manufactured in an FDA-compliant facility to be translated for treating human SCUs.

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