Characterization of trimethyl chitosan/polyethylene glycol derivatized chitosan blend as an injectable and degradable antimicrobial delivery system.

Advanced local delivery systems are needed as adjunctive treatments for severe injuries with high infection rates, such as open fractures. Chitosan systems have been investigated as antimicrobial local delivery systems for orthopaedic infection but possess mismatches between elution and degradation properties. Derivatives of chitosan were chosen that have enhanced swelling ratios or tailorable degradation properties. A combination of trimethyl chitosan and poly(ethylene glycol) diacrylate chitosan was developed as an injectable local delivery system. Research objectives were elution of antimicrobials for 7 days, degradation as open fractures heal, and cytocompatibility. The derivative combination eluted increased active concentrations of vancomycin and amikacin compared to the non-derivatized chitosan paste, 6 vs. 5 days and 5 vs. 4 days, respectively. The derivative combination degraded slower than non-derivatized paste in an enzymatic degradation study, 14 vs. 3 days, which increased antimicrobial delivery duration. Cytocompatibility of the combination with fibroblast and pre-osteoblast cells exceeds the cell viability standard set in ISO 10993-5. Combination paste requires an increased ejection force of 9.40 N (vs. 0.64 N), but this force was within an acceptable injection force threshold, 80 N. These preliminary results indicate combination paste should be further developed into a clinically useful adjunctive local delivery system for infection prevention.

Development and Evaluation of an Injectable Chitosan/ß-Glycerophosphate Paste as a Local Antibiotic Delivery System for Trauma Care.

Complex open musculoskeletal wounds are a leading cause of morbidity worldwide, partially due to a high risk of bacterial contamination. Local delivery systems may be used as adjunctive therapies to prevent infection, but they may be nondegradable, possess inadequate wound coverage, or migrate from the wound site. To address this issue, a thermo-responsive, injectable chitosan paste was fabricated by incorporating beta-glycerophosphate. The efficacy of thermo-paste as an adjunctive infection prevention tool was evaluated in terms of cytocompatibility, degradation, antibacterial, injectability, and inflammation properties. In vitro studies demonstrated thermo-paste may be loaded with amikacin and vancomycin and release inhibitory levels for at least 3 days. Further, approximately 60% of thermo-paste was enzymatically degraded within 7 days in vitro. The viability of cells exposed to thermo-paste exceeded ISO 10993-5 standards with approximately 73% relative viability of a control chitosan sponge. The ejection force of thermo-paste, approximately 20 N, was lower than previously studied paste formulations and within relevant clinical ejection force ranges. An in vivo murine biocompatibility study demonstrated that thermo-paste induced minimal inflammation after implantation for 7 days, similar to previously developed chitosan pastes. Results from these preliminary preclinical studies indicate that thermo-paste shows promise for further development as an antibiotic delivery system for infection prevention.

Local Delivery of Amikacin and Vancomycin from Chitosan Sponges Prevent Polymicrobial Implant-Associated Biofilm.

Military personnel have high risk for infection, particularly those with combat-related extremity trauma. Administration of multiple or broad-spectrum antibiotics provides clinicians with a strategy for preventing biofilm-based medical device infections. Selection of effective antibiotic combinations based on common pathogens may be used to improve chitosan wound dressing sponge-based local antibiotic delivery systems. In vitro assays in this study demonstrate that vancomycin and amikacin have a synergistic relationship against a strain of osteomyelitis-producing Gram-positive Staphylococcus aureus, although an indifferent relationship was observed against Gram-negative Pseudomonas aeruginosa. In an in vivo model of orthopedic hardware-associated polymicrobial (S. aureus and Escherichia coli) biofilm, chitosan sponges loaded with a combination of vancomycin and amikacin at 5 mg/mL each showed a greater percentage of complete clearance, 50%, than either antibiotic alone, 8.33%. Doubling the loading concentration of the combination achieved a complete clearance rate of 100%, a four log-fold reduction of S. aureus on the wire and a six log-fold reduction in bone. E. coli was detected in bone of untreated animals but did not form biofilm on wires. Results demonstrate the clinical potential of chitosan sponges to prevent infection and illustrates antibiotic selection and loading concentrations necessary for effective biofilm prevention.