Electrospun 11β-HSD1 Inhibitor-Loaded Scaffolds for Accelerating Diabetic Ulcer Healing.

Abstract

Diabetic ulcers (DUs) are a common and severe complication of diabetes, characterized by impaired wound healing due to a complex pathophysiological mechanism. Elevated levels of 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) in wounds have been demonstrated to modulate glucocorticoid activity, leading to delayed skin cell proliferation and restricted angiogenesis, ultimately hindering wound healing. In this study, we propose an electrospun poly(ε-caprolactone) (PCL) nanofiber scaffold doped with the 11β-HSD1 inhibitor BVT2733 (BPs) to prevent 11β-HSD1 activity during the diabetic wound healing process. The electrospun scaffold loaded with BVT2733 is designed to achieve localized inhibition of 11β-HSD1 in DUs. This scaffold exhibited a porous morphology and desirable drug-loading capacity, meeting the requirements for wound coverage and effective delivery of BVT2733 BPs. In vitro studies demonstrated that the sustained release of BVT2733 from the scaffold promoted skin cell proliferation and migration while stimulating angiogenesis by upregulating HIF1-α/VEGF expression. The therapeutic effect of the scaffold was further confirmed in a full-thickness wound model using diabetic mice. The mice treated with the scaffolds exhibited an accelerated wound healing rate, increased neovascularization, enhanced collagen deposition, and regeneration of skin appendages within 2 weeks postinjury. The findings here provide evidence for the use of 11β-HSD1 inhibitor-integrated biomaterials in treating DUs and represent a novel biological platform for modulating dysregulated mechanisms in DUs.