Bilayer tri-dermal-network hydrogel for sequential delivery of PD-168077 in multimodal diabetic wound regeneration

Diabetic chronic wounds (DCWs) present a complex pathophysiology. Therapeutic development is hindered by two key challenges: flawed drug discovery comparisons (e.g., normal vs. DCW skin) that include systemic factors, and advanced dressings that rely on complex, difficult-to-translate designs. This study first introduces a precise Cmap screening strategy, comparing human self-healing versus non-healing DCW patient skin, to identify the dopamine D4 receptor (DRD4) agonist PD-168077 (PD) as a novel therapeutic. To overcome delivery challenges, a biomimetic dermal hydrogel (PCHMA) was fabricated from natural skin components (hyaluronic acid and collagen I/III). This system utilizes a notably facile "single formulation, dual concentrations, dual curing" matrix photopolymerization to create a bilayer-structure hydrogel with triple-crosslinking network. The resulting matrix possesses intrinsic therapeutic capabilities and provides programmed drug release via a "fast-release" layer for immediate anti-inflammation and a "slow-release" layer for sustained regeneration. In vitro, PCHMA effectively suppressed inflammation and oxidative stress, promoted a pro-repair M2 macrophage phenotype by downregulating the IL-1β/IL-6 axis, and enhanced cell proliferation, migration, and endothelial tube formation. In vivo, PCHMA markedly accelerated wound closure in db/db mice, while simultaneously improving angiogenesis and extracellular matrix remodeling. This integrated platform, combining a precisely-screened drug with a translational, bioactive delivery system, offers a promising, multimodal strategy for DCW management.