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Deferoxamine Improves Wound Healing In A Mouse Model Of Delayed Healing From Pressure Injury
Lisa Tucker-Kellogg1, N. Jannah M. Nasir1, Johannes A. Heemskerk1, Ralph Bunte1, Paul Matsudaira2, Peter T.C. So3.
1Duke-NUS Medical School, Singapore, Singapore, 2National University of Singapore, Singapore, Singapore, 3MIT, Cambridge, MA, USA.

BACKGROUND: Animal wounds often heal rapidly, unlike human pressure ulcers. Pressure ulcer research requires animal models of impaired regeneration (without diabetes), in order to seek treatments to restore regeneration. In this work, we develop a mouse model of delayed muscle regeneration after gradual pressure-induced injury, and we investigate the therapeutic effect of the drug deferoxamine on muscle regeneration. Deferoxamine is an FDA-approved drug that has been found to accelerate regeneration of skin, but its effect on muscle regeneration is unknown.
METHODS: Pressure injuries were created in C57BL6 mice by applying a pair of 12mm magnets to the dorsal skinfold and panniculus carnosus muscle in two 12-hour intervals. Deferoxamine (or saline control) was injected subcutaneously for 16 days (n=7). To compare against acute wound healing, acute-control mice had the same muscles injured via cardiotoxin.
RESULTS: In acute-control mice, muscle underwent phagocytosis within 3 days, exhibited substantial regeneration at 8 days, and completed regeneration by 16 days. In mice with pressure injuries, dead muscle showed minimal immune infiltrate or phagocytosis at 3 days. Pressure injuries exhibited lasting tissue compaction, which raises the question of whether delayed infiltration may arise from physical compaction (decreased penetrability) and/or poor immunogenicity. At 10 days, infiltration was significant and dead muscle was phagocytosed. At 40 days, muscle tissue was still actively regenerating, as evidenced by myoblast-like cells and immature myofibers. Deferoxamine treatment of pressure-injured muscles caused increased infiltration of macrophages with M2 (pro-regenerative) protein marker at 3 and 10 days, followed by greater muscle regeneration at 40 days, compared with saline control.
CONCLUSIONS: We claim a successful animal model of delayed regeneration after pressure injury, associated with delayed immune cell infiltration. Furthermore, we find that deferoxamine treatment improves muscle regeneration, associated with increased macrophage infiltration.


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