Bilayer PCL/GelMA microneedle patch codelivers deferoxamine and primed mesenchymal stem cell secretome for enhanced diabetic wound repair.

Abstract

Chronic diabetic wounds remain refractory to healing due to persistent inflammation, impaired re-epithelialization, extracellular matrix dysregulation, and microvascular dysfunction. Here, we report a mechanically robust and biologically integrated microneedle (MN) platform composed of a poly(ε-caprolactone) (PCL) core and a gelatin methacryloyl (GelMA) coating, engineered for the localized compartmentalized co-delivery of deferoxamine (DFO) and mesenchymal stem cell-derived conditioned medium (CM). By leveraging a dual-reservoir architecture-incorporating fresh liquid CM within the GelMA shell and lyophilized CM within the structural PCL core-the platform achieves complementary biphasic release kinetics while preserving the biological integrity of labile growth factors. In a diabetic wound model using Wistar rats, treatment with a bioactive MN platform significantly accelerated re-epithelialization, resolved chronic inflammation, and increased collagen deposition by approximately 40% compared to untreated and blank MN controls. Furthermore, vascular assessment on day 14 revealed a qualitative increase in CD31-positive vascular structures within the treated wounds. Notably, microneedles co-loaded with DFO and CM markedly improved key healing parameters compared with untreated diabetic wounds, with several parameters approaching those observed in non-diabetic control tissues at the 14-day endpoint. Mechanistically, these findings are consistent with a hierarchical healing process in which restoration of immune homeostasis promotes epithelialization and extracellular matrix remodeling, followed by enhanced vascularization. Collectively, these results indicate that spatially compartmentalized MN-mediated co-delivery of DFO and CM may represent a promising strategy for activating endogenous regenerative pathways and enhancing tissue repair in diabetic wounds. This approach may also provide a scalable therapeutic platform for improving the impaired healing capacity associated with diabetes.