Spatiotemporal controlled release of YCM/Cu²⁺ hydrogel microneedle system synergistically accelerates chronic wound...

The healing of diabetic wounds is critically impaired by a hostile microenvironment featuring barrier disruption, microvascular dysfunction, and immune dysregulation, which perpetuates infection and stalls tissue regeneration. Current clinical strategies lack the capacity for coordinated multiphasic intervention. To address this, we designed and fabricated a spatiotemporally orchestrated partitioned microneedle patch. The needle segment is fabricated from methacrylated hyaluronic acid (HAMA) hydrogels loaded with copper ions (Cu²⁺), while the backing matrix consists of aldehyde and methacrylate dual-modified hyaluronic acid (AHAMA) hydrogels encapsulating the young 3D spheroid mesenchymal stem cell-derived conditioned medium (YCM). Upon this patch application, the quick-dissolving tips release Cu²⁺ to exert immediate, potent antibacterial activity and initiate pro-angiogenic signaling. Subsequently, the sustained release of a multifaceted repertoire of bioactive factors from the YCM orchestrates key regenerative processes, including macrophage polarization to an anti-inflammatory, pro-regenerative (M2) phenotype, restoration of mitochondrial function, and mitigation of oxidative stress, thereby resolving chronic inflammation. Collectively, in vitro and in vivo validation demonstrates that this integrated platform effectively eliminates infections, stimulates neovascularization, resolves pathological inflammation and oxidative damage, and facilitates functional extracellular matrix remodeling. Our work establishes a potent and translatable acellular strategy that synergistically combines antimicrobial action with active immunomodulation to disrupt the vicious cycle of non-healing wounds, offering a promising paradigm for the treatment of refractory diabetic wounds and advancing the frontier of regenerative medicine.