Customized pH-responsive poly(urethane)-based formulations treating chronic skin wound inflammation and promoting tissue regeneration.

Severe inflammation and infections are major contributors to wound chronicity. Although various wound dressings have been engineered to deliver therapeutics locally, the lack of patient personalization is still a limiting factor. In this endeavor, this work aims to establish an adaptable therapeutic strategy by combining stimuli-responsive materials and 3D bioprinting for the prospective fabrication of shape-personalized patches capable of tuning payload release in response to the alkalinity of infected wound exudates. First, a -COOH-bearing amphiphilic poly(ether urethane) was synthesized and used to formulate thermo-/alkaline-pH-responsive hydrogels, while human recombinant lactoferrin (hrLF) was selected for its naturally derived therapeutic properties. Then, the hrLF-loaded hydrogel thermo-responsiveness was rheologically assessed, while the hrLF suitability for the biologically aggressive environment of chronic wounds was evaluated through UV/Vis spectroscopy and a colorimetric assay. Moreover, a finely tuned drug release was observed in response to pH via a non-Fickian diffusion mechanism. Furthermore, in in vitro studies on simplified inflamed wounds, hrLF promoted human dermal fibroblast proliferation (increased DNA content), exerted anti-inflammatory effects (reduced expression of TNF-α, IL-1β and IL-6), and exhibited bacteriostatic activity against Staphylococcus aureus. Finally, the hrLF-loaded hydrogel showed promising processability as a biomaterial ink. Overall, the engineered system showed strong adaptation to the dynamic wound environment.