Redox-Responsive GHK-Conjugated Sponge Spicules for Sustained Dermal Delivery and Enhanced Collagen Synthesis

Sponge spicules have emerged as promising biomaterial scaffolds due to their biocompatibility and unique structural properties; however, achieving stable and bioactive functionalization remains a key challenge. The tripeptide GHK is known to promote collagen synthesis and wound repair, yet its therapeutic efficacy is often limited by rapid diffusion and instability. Here, we report ALTUM, a thiol-functionalized sponge spicule composite in which GHK is covalently conjugated via disulfide linkage to enable controlled and redox-responsive peptide delivery. ALTUM exhibited sustained GHK retention under physiological and storage conditions, while exposure to reduced glutathione (GSH) selectively accelerated peptide release through disulfide bond cleavage. This dual release behavior-long-term stability combined with reduction-triggered activation-distinguishes ALTUM from conventional delivery systems. The composite also demonstrated structural stability under thermal, cyclic, and photostability conditions. In an artificial human skin model, ALTUM enhanced dermal penetration of GHK and significantly increased collagen deposition in the dermal layer, demonstrating its capacity to promote collagen production within deeper skin tissue, compared to simple spicule-peptide mixtures. ALTUM was fabricated at an optimized spicule-to-peptide ratio of 3% (w/w), preserving the needle-shaped spicule morphology after surface modification. In vitro, ALTUM exhibited a sustained release profile, with GHK release markedly accelerated in the presence of 10 mM glutathione (GSH) compared with non-reductive conditions, reaching approximately 60% cumulative release over 35 days. In the bioprinted artificial human skin model, ALTUM delivered 9.72 ng/cm² of GHK, more than five-fold higher than the physical mixture of spicules and free GHK (1.9 ng/cm²), and significantly increased type I collagen expression in human dermal fibroblasts. Mechanistically, ALTUM-mediated delivery was associated with increased TGF-β expression and engagement of the SMAD signaling pathway, as indicated by increased phosphorylation of SMAD2/3, consistent with involvement of the TGF-β-SMAD axis in the observed collagen induction. Collectively, these findings establish ALTUM as a structurally stable, redox-responsive dermal delivery platform that enhances collagen synthesis and skin regeneration.