Antibiotic-Loaded Drug Delivery Platforms: Theory, Structural Evolution, and Elution Characteristics
Mensah, Lydia
2021
Abstract
The occurrence of periprosthetic joint infections (PPJI), a major complication of joint arthroplasty, is rising. Current treatment involves the use of antibiotic-loaded bone cement (ALBC) intraoperatively and postoperative intravenous drug delivery. Amphiphilic block copolymers can be a localized drug delivery system for prophylactic and supplementary treatment of PPJI when loaded with antibiotics to overcome the limitations of ALBC and systemic drug delivery. In this thesis, current PPJI treatments were evaluated, and the structural evolution and bacterial growth inhibition characteristics of antibiotic-loaded Polyoxyethylene- polyoxypropylene-polyoxyethylene (PEO-PPO-PEO) triblock copolymers were investigated. A number of clinical studies were examined to identify those in which controlled drug release or mechanical behavioral assessments were conducted on ALBC. Anecdotal evidence suggests that ALBC can help eradicate or delay the onset of infections, but quantifying the response functionality is challenging. The ALBC study focused on vancomycin (VAN)—which is more commonly proscribed for staphylococcal osteomyelitis—in part due to its higher potency relative to gentamycin. The studies indicate that large fractions (>99%) of loaded VAN are sequestered in the bulk matrix of cement and are not labile once the cement has set due to high molecular weight (1449.3 g/mole) and glassy behavior. VAN fluence measurements ranged from 1 to 283 μg/cm2hr. The initial strength of the samples ranged from 52 to 96 MPa. Efforts to raise the elution rate by increasing drug loading reduced cement strength. Smaller drug molecules and more gel-like immobilization matrices with lower glass transition temperatures offered higher potential for larger and more comprehensive drug elution. Differential scanning calorimetry was used to probe the thermophysical properties of 25% F127 gels loaded with ciprofloxacin (CIPRO) (0.05-0.2%), VAN (0.8-5%), gentamicin (GM) (0.2-0.8%), and cefepime (CEFE) (2-10%). CEFE had the greatest effect on Tmicelle with a range of ~3-8 ºC with respect to decreasing concentration. GM showed the smallest effect with a range of 8.5-10.5 ºC. CIPRO had an invariant effect over the concentrations tested, but decreased Tmicelle by ~2.5 ºC. CIPRO also showed an invariant effect on the endotherm energy between concentrations after the initial decrease to 3.4 J*mol-1. CEFE showed an athermal micellization process as the concentration of CEFE increased. Additionally, GM and VAN showed an invariant effect on the endotherm energy. Dynamic mechanical analysis of 25% F127 loaded with CIPRO were investigated to probe the kinetics of the gel transition, which occurred up to 7 ºC lower than the neat sample. Cell culture assays were used to probe whether antibiotic-loaded amphiphilic gels act as a functional antimicrobial. Additionally, modification of the traditional bacterial plate culture assay by introducing a void within the agar allowed insight on the properties of an injectable plug. Zone of inhibition (ZoI) and bacterial growth inhibition were used as qualitative and quantitative assessments. VAN and GM loaded amphiphilic gels had a range of 3.00-3.90 cm and 3.50-5.70 cm, respectively. Bacterial growth inhibition curves showed that VAN decreased maximum optical density (OD) by 70-80%. Gompertz growth model was used to summarize the OD curves and determine the growth rates and lag times for 0-5% VAN. This dissertation yielded a characterization of the changes in thermophysical properties and insight on elution and antimicrobial activity of antibiotic-loaded F127 gels. A greater understanding of the interactions between amphiphilic copolymer solutions and dissolved solutes was achieved to probe their use as a localize drug delivery vehicle.Deep Blue DOI
Subjects
Amphiphilic copolymer osteomyelitis drug delivery antibiotic loaded hydrogels bone cement drug elution
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