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Toll-Like Receptor Agonism with Synthetic Thymosin Alpha 1 Enhanced Revascularization and Speeds Healing in Murine Chronic Diabetic Wounds
Phoebe Lee, BS, Shawn Jeffrey Loder, MD, Fuat David Guerrero, BS, Baris Bengur, MD, Wayne Vincent Nerone, BS, Rachel Ricketts, Lauren Kokai, PhD.
University of Pittsburgh Department of Plastic Surgery
2022-01-15
Presenter: Phoebe Lee
Affidavit:
Certified
Director Name: Kacey Marra
Author Category: Medical Student
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
Background/Purpose: In diabetic wounds microvascular injury and dysregulation of periwound vascularity engenders hypoxia and allows for a milieu of inflammatory markers and cells to accumulate and delay wound closure. Thymalfasin is an FDA approved synthetic analog of the Toll-like Receptor (TLR) -2/4/9 agonist Thymosin alpha-1 which can promote endothelial migration and acute wound closure. Given this we hypothesized that Thymalfasin could be used to enhance resolution.
Methods: Male obese diabetic (B6.Cg-Lepob) mice underwent bilateral wounding with inverted skin-edge flaps, which were allowed to granulate for 4-weeks followed daily intraperitoneal Thymalfasin (250ug/kg) or vehicle for 1-week. Photographs were taken before and after treatment. A second cohort was generated and periwound was collected for flow cytometry against CD31/VEGFR/CD34/CD45.
Results: Prior to treatment, there was no statistical difference in chronic wound area between treatment and control (0.41+/-0.32 vs. 0.42+/-0.26 cm After 1-week treatment, chronic wounds demonstrated a post-treatment area of 0.06+/-0.13 cm2 with only 40% of wounds remaining open. Time-matched vehicle-treated wounds demonstrated area of 0.32+/-0.19 cm2 in area and no closure post-injury week 5. This was a statistically significant decree in the Thymalfasin-treated group (91.58+/-16.48 % [Treatment] vs. 8.19 +/- 23.41% [Control]; p=0.0002). Periwound tissues were significantly enriched for mature endothelial (CD31+VEGFR2+CD34-CD45-) cells in the Thymalfasin-treated group (p<0.0001).
Discussion/Conclusion: In stable murine chronic diabetic wounds, Thymalfasin was sufficient to stimulate rapid closure, significantly decrease wound area, and enrich mature endothelium suggesting the potential for TLR agonism to treatment of diabetic chronic wounds.
