Custom-design of intrinsically antimicrobial polyurethane hydrogels as multifunctional injectable delivery systems for mini-invasive wound treatment

Effective management of hard-to-close skin wounds is a challenging issue due to several co-morbidities in affected patients. Particularly, infections represent a major obstacle in wound healing. The design of efficient wound treatments thus represents an urgent need. Injectable drug delivery hydrogels with intrinsic antimicrobial and antifungal properties were herein designed for perspective application in the mini-invasive treatment of hard-to-close wounds. First, an amphiphilic polyurethane was synthesized from Poloxamer® 407 macrodiol and N-Boc diethanolamine chain extender (DHP407, Mw =33 kDa). Chain-extension reaction step was optimized to maximize the formation of -NH groups along the polymer chains (4.5 × 10^20±1.8 × 10^19 –NH groups/gpolymer), after Boc-caging group removal (D-DHP407). DHP407 and D-DHP407 water-based solutions were thermosensitive with slightly different Critical Micellar Concentration (17.5 μg/mL vs. 19.7 μg/mL) and cluster hydrodynamic diameter (235.6 ± 19.9 nm vs. 260.1 ± 20.5 nm), and similar Critical Micellar Temperature (22.5 °C vs. 23.1 °C). A polyurethane solution concentration (15% w/V) was selected by tube-inverting test and rheological analysis showing injectability, as evidenced by sol-to-gel transition at 27.7 ± 0.6 °C for DHP407 and 29.7 ± 0.6 °C for D-DHP407, within few minutes, at similar gelation kinetics. DHP407 and D-DHP407 hydrogels showed controlled release of Bovine Serum Albumin (BSA) model protein (1 mg/mL), with no burst phenomena. BSA released from DHP407 and D-DHP407 hydrogels at 24 h was 33.7 ± 5.0% and 24.6 ± 1.2%, respectively. D-DHP407 hydrogel was biocompatible and able to support NIH-3T3 cell proliferation. Furthermore, D-DHP407 hydrogel showed intrinsic antifungal and antibacterial activity against C. albicans and Gram-positive S. aureus and Gram-negative E. coli bacteria, injectability and capability to retain shape post-injection, making it promising for future use in the management of hard-to-close skin wounds.