Optimized polymeric film-based nitric oxide delivery inhibits bacterial growth in a mouse burn wound model

Abstract

Nitric oxide (NO) has many biological roles (e.g., antimicrobial agent, promoter of angiogenesis, prevention of platelet activation, etc.) that make NO releasing materials desirable for a variety of biomedical applications. Localized NO release can be achieved from biomedical grade polymers doped with diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) and poly(lactic-co-glycolic acid) (PLGA). In this study, the optimization of this chemistry to create film/patches that can be used to decrease microbial infection at wound sites is examined. Two polyurethanes with different water uptakes (Tecoflex SG-80A (6.2 ± 0.7 wt %) and Tecophillic SP-60D-20 (22.5 ± 1.1 wt%)) were doped with 25 wt% DBHD/N2O2 and 10 wt% of PLGA with various hydrolysis rates. Films prepared with the polymer that has the higher water uptake (SP-60D-20) were found to have higher NO release and for a longer duration than the polyurethane with lower water uptake (SG-80A). The more hydrophilic polymer enhances the hydrolysis rate of the PLGA additive, thereby providing a more acidic environment that increases the rate of NO release from the NO donor. The optimal NO releasing and control SG-80A patches were then applied to scald burn wounds that were infected with Acinetobacter baumannii. The NO released from these patches applied to the wounds is shown to significantly reduce the A. baumannii infection after 24 h (~4 log reduction). The NO release patches are also able to reduce the TGF-β levels, in comparison to controls, which can enhance reepithelialization, decrease scarring, and reduce migration of bacteria. The combined DBHD/N2O2 and PLGA-doped polymer patches, which could be replaced periodically throughout the wound healing process, demonstrate the potential to reduce risk of bacterial infection and promote the overall wound healing process.

Attenuation of thrombosis and bacterial infection using dual function nitric oxide releasing central venous catheters in a 9 day rabbit model

“…The NO-releasing layer consisted of E2As with 25 weight% DBHD/NONO and 5, 10, or 25 weight% PLGA additives. Twenty-five weight% DBHD/NONO has been found to be optimum in terms of providing sufficient NO for extended release lifetimes [39, 40, 44]. The E2As top coat is used to prevent/reduce leaching of DBHD/NONO, neutralize the surface charge, and yield a smoother finish to the surface [40].…”

“…B.) [40, 41, 44]. The specific properties (i.e., acid or ester end groups) of the PLGA additives were previously studied in terms of their initial NO burst release effects, where PLGAs with acid end groups were found to produce an unwanted burst release from DBHD/NONO [40, 41].…”

Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO)

“…Nitric oxide releasing polymers have also provided a potential strategy for use as active wound healing dressings, capable of reducing bacterial infections at wound sites and accelerating the wound healing process for incisional and excisional wounds, 179,219,221 burn wounds, 290 and diabetic wounds. 232 While normal fibroblasts do not synthesize NO, it has been demonstrated that fibroblasts isolated from the regular wound can release NO.…”

“…120,221 Brisbois et al tested the antibacterial efficacy of DBHD/N 2 O 2 and PLGA (5050DLG1A) doped biomedical grade PU films as a dressing for burn wounds (10 cm 2 and partial thickness) in a mouse model. 290 Burn wounds are quite common, but difficult to treat and often lead to infections. 111 The burn wounds in mice were inoculated by A. baumannii for 24 h prior to application of the NO and control wound dressings.…”

Enhanced antibacterial efficacy of nitric oxide releasing thermoplastic polyurethanes with antifouling hydrophilic topcoats

“…35–37 While silver has been found to be an effective antimicrobial agent, it has also demonstrated concerns for cytotoxicity. 38, 39 Antimicrobial peptides are also being studied in great detail but due to the complexity of their interactions, 40 they are not a popular class of practically useful antimicrobial agents.…”