Synthesis and Evaluation of Functionalized Polyurethanes for pH-Responsive Delivery of Compounds in Chronic Wounds

Abstract

Chronic wounds, depending on the bacteria that caused the infection, can be associated with an extreme acidic or basic pH. Therefore, the application of pH-responsive hydrogels has been instigated for the delivery of therapeutics to chronic wounds. Herein, with the aim of developing a flexible pH-responsive hydrogel, we functionalized hydrophilic polyurethanes with either cationic (polyethylene imine) or anionic (succinic anhydride) moieties. A comprehensive physicochemical characterization of corresponding polymers was carried out. Particularly, when tested in aqueous buffers, the surface charge of hydrogel films was closely correlated with the pH of the buffers. The loading of the cationic and anionic hydrogel films with various compound models (bromophenol blue; negatively charged or Pyronin Y; positively charged) showed that the electrostatic forces between the polymeric backbone and the compound model will determine the ultimate release rate at any given pH. The potential application of these films for chronic wound drug delivery was assessed by loading them with an antibiotic (ciprofloxacin). In vitro bacterial culturing was performed using Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Results showed that at the same drug dosage, different release profiles achievable from cationic and anionic polyurethanes can yield different degrees of an antibacterial effect. Overall, our results suggest the potential application of cationic and anionic hydrophilic polyurethanes as flexible pH-responsive materials for the delivery of therapeutics to chronic wounds.

Keywords: chronic wound dressing; controlled drug release; pH responsive hydrogels; polyurethane-based hydrogels.

Figure 1

Graphic showing acidic or alkaline pH of an infected wound, and the design of pH-sensitive films for responsive release of drugs in these wounds.

Figure 2

Schematics showing (A) synthesis of PU−PEI, (B) synthesis of PU−CA.

Figure 3

(A) FTIR spectra of PU, PU−PEI, and PU−CA; (B) deconvolution of FTIR spectra of PU, PU−PEI, and PU−CA in the region between 1640 and 1740 cm⁻¹.

Figure 4

(A) SEC of PU, PU−PEI, and PU−CA; (B) TGA and DTGA of PU, PU−PEI, and PU−CA.

Figure 5

(A) Schematic of the majority of groups found in PU−PEI and PU−CA hydrogels; (B) surface zeta potential measurements of PU−PEI and PU−CA hydrogel films; (C) schematic of the primary charges of amino acid and carboxylic acid groups across the pH scale.

Figure 6

(A) Stress–strain behaviour of PU, PU−PEI, and PU−CA hydrogel films; (B) stress at break of PU, PU−PEI, and PU−CA hydrogel films; (C) Young’s moduli of PU, PU−PEI, and PU−CA hydrogel films.

Figure 7

(A) The release profile of PU−PEI hydrogel film with bromophenol blue; (B) surface zeta potential measurements of PU−PEI hydrogel films and bromophenol blue; (C) the release profile of PU−CA hydrogel film with bromophenol blue; (D) surface zeta potential measurements of PU−CA hydrogel films and bromophenol blue. The p-value was used to determine the level of significance for data comparisons, with significance levels represented by asterisks (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 8

(A) The release profile of PU–PEI hydrogel film with Pyronin Y; (B) surface zeta potential measurements of PU–PEI hydrogel films and Pyronin Y; (C) the profile of PU−CA hydrogel film with Pyronin Y; (D) surface zeta potential measurements of PU−CA hydrogel films and Pyronin Y. The p-value was used to determine the level of significance for data comparisons, with significance levels represented by asterisks (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 9

(A) The step pH release profile of PU–PEI hydrogel film with bromophenol blue; (B) the step pH release profile of PU–CA hydrogel film with Pyronin Y. The p-value was used to determine the level of significance for data comparisons, with significance levels represented by asterisks (* p < 0.05, ** p < 0.01, **** p < 0.0001, and ns; not significant).

Figure 10

(A) The release profile of PU−PEI hydrogel film with ciprofloxacin; (B) surface zeta potential measurements of PU−PEI hydrogel films and ciprofloxacin; (C) the profile of PU−CA hydrogel film with ciprofloxacin; (D) surface zeta potential measurements of PU-CA hydrogel films and ciprofloxacin. The p-value was used to determine the level of significance for data comparisons, with significance levels represented by asterisks (* p < 0.05, ** p < 0.01).

Figure 11

Assessing the viability of (A) E. coli and (B) S. aureus that was challenged with membranes loaded with ciprofloxacin compared to empty membranes. One-way ANOVA with Tukey’s multiple comparisons test was applied. Data represent mean ± Std error of mean (SEM), * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns; not significant; n = 3 biological replicates, with 2 technical replicates each.