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

Abstract

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.

Characterization and Antibiofilm Activity of Mannitol–Chitosan-Blended Paste for Local Antibiotic Delivery System

“…The extended degradation and elution of antibiotics from mannitol blends may be due to the potential formation of a polyelectrolyte complex through hydrogen-bonding interactions between mannitol hydroxyl groups and the hydroxyl groups present on chitosan, a hypothesis supported by previous studies [42,43]. The most commonly reported polyelectrolyte complex between chitosan and polyols is the thermogelling combination of beta-glycerophosphate and chitosan [36,44,45]. One beta-glycerophosphate/chitosan local delivery system reported by Boles et al only eluted amikacin and vancomycin until Day 5, with antimicrobial activity against S. aureus for only three days [36].…”

“…The most commonly reported polyelectrolyte complex between chitosan and polyols is the thermogelling combination of beta-glycerophosphate and chitosan [36,44,45]. One beta-glycerophosphate/chitosan local delivery system reported by Boles et al only eluted amikacin and vancomycin until Day 5, with antimicrobial activity against S. aureus for only three days [36]. The increased duration of elution for the mannitol blend could be attributed to differences in the amount of aqueous solution used for hydration as well as the antibiotic loading; less water within the system could lead to stronger intermolecular interactions between chitosan, extending the delivery even when the total amount of antibiotic loaded is lower [35,36].…”

“…One beta-glycerophosphate/chitosan local delivery system reported by Boles et al only eluted amikacin and vancomycin until Day 5, with antimicrobial activity against S. aureus for only three days [36]. The increased duration of elution for the mannitol blend could be attributed to differences in the amount of aqueous solution used for hydration as well as the antibiotic loading; less water within the system could lead to stronger intermolecular interactions between chitosan, extending the delivery even when the total amount of antibiotic loaded is lower [35,36]. In chitosan pastes with PEG only, both the elution of antibiotics and antimicrobial activity were only previously reported for 72 h [34,35].…”

“…The acidic dissolution of chitosan and ensuing inflammation could be higher in the form of a hydrated paste, which may explain the increased inflammation seen in vivo compared to neutralized chitosan sponges [61]. This would cause a greater inflammatory response than previously reported beta-glycerophosphate chitosan paste, which was attributed to the neutralizing effect of beta-gylcerophosphate [36]. Another possible explanation for the inflammatory response seen with the ChMPEG paste is the potential for mannitol to act as an osmotic diuretic.…”

“…Chitosan, an abundant natural biopolymer derived from the exoskeletons of crustaceans, has been developed into a variety of therapeutic delivery systems due to its beneficial characteristics including: biocompatibility, ability to degrade in vivo, mucoadhesivity, and intrinsic antimicrobial properties [32,33]. Injectable chitosan pastes have been previously evaluated as local antibiotic delivery systems, offering advantages of conforming to complex wound bed geometries [34,35,36,37]. Chitosan pastes and sponges have been shown to deliver aminoglycoside and glycopeptide antibiotics at concentrations high enough to eradicate biofilm locally to the wound bed [38,39,40,41], but remaining persister cells could lead to recurrent infection.…”