Polymicrobial musculoskeletal wound infections are troublesome complications and can be difficult to treat when caused by invasive fungi or bacteria. However, few local antifungal delivery systems have been studied. Chitosan and polyethylene glycol (PEG) sponge local antifungal delivery systems have been developed for adjunctive therapy to reduce musculoskeletal wound contamination. This study evaluated the effects of blending PEG, at 6,000 or 8,000 g/mol, with chitosan in sponge form on in vitro amphotericin B and vancomycin elution, eluate activity, cytocompatibility, and in vivo prevention of a bacterial biofilm. Blended chitosan sponges released both amphotericin B and vancomycin in vitro. All tested amphotericin B eluates remained active against Candida albicans, and vancomycin eluates from blended sponges maintained activity against Staphylococcus aureus. Amphotericin B eluates obtained after 1 h from blended sponges elicited 62-95% losses in fibroblast viability, but 3 h eluates only caused 22-60% decreases in viability. In a Staphylococcus aureus infected mouse catheter biofilm prevention model, vancomycin loaded chitosan/PEG 6000 sponge cleared bacteria from 100% of the catheters, with reduced clearance rate observed in other sponges. These results indicate that the chitosan/PEG blended sponges have potential for local antifungal and/or antibiotic combination delivery as an adjunctive therapy to prevent wound infections.
Local versus systemic antibiotic delivery may be an effective strategy for treating musculoskeletal infections, especially when antibiotic-resistant bacteria are present. Lyophilized uncrosslinked, genipin crosslinked, and genipin crosslinked with poly(N-isopropylacrylamide) (PNIPAM) chitosan sponges were analyzed for their in vitro degradation rate, chemical crosslinking, antibiotic uptake, elution, biologic activity, and cytotoxicity. These evaluations were pursued to determine if crosslinking with genipin could be used to create a tailorable point of care loaded sponge for local infection control. Crosslinking the chitosan sponges decreased degradation in phosphate-buffered saline from 4.48 ± 2.28 wt % remaining of the uncrosslinked sponges to 78.82 ± 1.15 and 73.87 ± 1.27 wt % remaining at week 1 for the genipin and PNIPAM/genipin crosslinked sponges, respectively. The PNIPAM/genipin crosslinked sponges exhibited the most sustained release of biologically active antibiotics, with an average antibiotic release 63% higher than uncrosslinked and 37% higher than genipin crosslinked sponges, after 96 h. No significant cytotoxic effects from sponges or eluates were exhibited with NIH 3T3 fibroblasts. These preliminary results indicate that genipin crosslinked chitosan sponges, with or without PNIPAM, have potential as local delivery systems for adjunctive therapy for infection control, especially when longer degradation periods and higher antibiotic elutions are desired.
This research investigated the combination of polyethylene glycol with chitosan in point-of-care loaded sponges made by one or two lyophilizations for adjunctive local antifungal delivery in musculoskeletal wounds. Blended and control chitosan sponges were evaluated in vitro for antifungal release and activity, degradation, cytocompatibility, and characterized for spectroscopic, crystallinity, thermal, and morphologic material properties. In vivo biocompatibility and degradation of sponges were also evaluated in a rat intramuscular pouch model 4 and 10 days after implantation. Blended sponges released amphotericin B active against Candida albicans (>0.25 µg/mL) over 72 h and did not elicit cytotoxicity response of fibroblasts. Blended sponges exhibited decreases in surface roughness, decreased thermal decomposition temperatures, as well as small Fourier transform infrared spectroscopy and crystallinity differences, compared with chitosan-only sponges. Three of the four blended sponge formulations exhibited 31%-94% increases in in vitro degradation from the chitosan sponges after 10 days, but did not demonstrate the same increase in in vivo degradation. Low inflammatory in vivo tissue response to blended and chitosan-only sponges was similar over 10 days. These results demonstrated that adding polyethylene glycol to chitosan sponges does improve local antifungal release, cytocompatibility, and in vitro degradation, but does not increase in vivo degradation.
Background Local drug delivery has substantial potential to prevent infections compared with systemic delivery. Although calcium sulfate (CaSO 4 ) has been studied for local drug delivery and two types are commercially available, it is unknown whether they differentially release antibiotics. Questions/purposes We determined the differences between two sources of CaSO 4 and the K 2 SO 4 catalyst's presence on the degradation, daptomycin elution, and activity against Staphylococcus aureus. Methods We formed pellets from synthetic and naturally sourced (from gypsum) CaSO 4 and loaded with 5% daptomycin and 3% or 0% K 2 SO 4 . We used in vitro experiments to determine the daptomycin concentration and degradation profiles over 10 days. Turbidity assays were used to evaluate the activity of the daptomycin eluates against S. aureus.
Background The rate of release of an antibiotic from an antibiotic-loaded polymethylmethacrylate (PMMA) bone cement is low. This may be increased by adding a particulate poragen (eg, xylitol) to the cement powder. However, the appropriate poragen amount is unclear.Questions/purposes We explored the appropriate amount of xylitol to use in a PMMA bone cement loaded with daptomycin and xylitol. Methods We prepared four groups of cement, each comprising the same amount of daptomycin in the powder (1.36 g/40 g dry powder) but different amounts of xylitol (0, 0.7, 1.4, and 2.7 g); the xylitol mass ratio (X) (mass divided by mass of the final dry cement-daptomycin-xylitol mixture) ranged from 0 to 6.13 wt/wt%. Eight mechanical, antibiotic release, and bacterial inhibitory properties were determined using three to 22 specimens or replicates per test. We then used an optimization method to determine an appropriate value of X by (1) identifying the best-fit relationship between the value of each property and X, (2) defining a master objective function incorporating all of the best fits; and (3) determining the value of X at the maximum master objective function.
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