Nanostructured Polyurethane‐Collagen Hydrogels: Bioactive Crosslinked Networks for Enhanced Wound Healing

Nanostructured polyurethanes (nPUs) are promising materials for biomedical applications due to their mechanical strength, controlled degradation, and bioactivity. In this study, collagen-based hydrogels were developed using nPUs synthesized from ethoxylated glycerol and either hexamethylene diisocyanate (HDI) or isophorone diisocyanate (IPDI), functionalized with L-tyrosine (T). These nPUs were incorporated at 15% and 30% by weight into porcine dermis collagen. The HDI-based nPUs (HDI-T), with particle sizes between 6 and 58 nm, achieved high crosslinking densities (> 90%) and superabsorbent capacities (> 6000%), which accelerated gelation under physiological conditions. The resulting hydrogels showed enhanced elasticity and resistance to deformation-critical for wound healing. Structural analysis revealed semi-crystalline and rough surfaces. Hydrogels crosslinked with HDI-T (P(HDI-T)) exhibited excellent hydrolytic stability at pH 8.5 and in simulated body fluids (SBF), as well as reduced enzymatic degradation. These systems allowed for sustained release of methylene blue at both physiological and acidic pH, while ketorolac release was more pronounced in acidic conditions. Biologically, the hydrogels were non-hemolytic and biocompatible, promoting monocyte and fibroblast metabolic activity. Notably, P(HDI-T30) hydrogels stimulated the release of Interleukin-10 (IL-10), contributing to inflammation modulation. In addition, they exhibited potent antibacterial activity, inhibiting Escherichia coli (E. coli) growth by up to 150% and Staphylococcus aureus (S. aureus) by 60% compared to controls. In vivo, complete wound closure was observed by Day 17, with regenerated tissue rich in collagen. These findings demonstrate the potential of nPU-collagen hydrogels as multifunctional biomaterials for advanced wound healing, combining mechanical integrity, controlled drug release, antibacterial efficacy, and immune modulation.