(49) Feasibility of thermo-sensetive chitosan mixtures as a delivery vector for treatment of perio-implant diseases

Introduction: Peri-implantitis is a disease attributed to bacterial growth, which causes inflammation and bone resorption around the implant and may result in implant failure. While peri-implantitis is a significant clinical problem, no specific treatment protocol has been established for in situ disinfection of implant surfaces or the sockets surrounding implants. Chitosan hydrogel is an FDA-approved biocompatible and antimicrobial material that has potential to be used as a treatment option for this disease. Consequently, this study aimed to examine the feasibility of creating thermosensitive formulations of chitosan for delivery of antibiotics or growth factors into implant defects

Methods: High-molecular weight chitosan powder (
Sigma) was dissolved in 0.75% acetic acid with stirring overnight to a concentration of 3%. Chitosan solution was then dialyzed against 25x volume of Millipore-purified water for 16 hours and the final concentration adjusted to 1.5 %. Chitosan solution was centrifuged for 30 minutes at 4000 rpm to remove particulates, and the clarified solution stored at 4 °C. For synthesis of thermosensitive mixtures, 50% beta-glycerol phosphate (BGP) was added at concentrations between 1-7 mM, and the storage and loss modulus, G’ and G”, were measured during temperature sweep from 20 °C to 50 °C on a Discovery HR 10 rheometer (Waters). Adjustments to chitosan pH were made with bicarbonate solution, as needed to adjust the liquid-soft solid transition to between 35-37 °C. Optimized formulations were identified for addition of ampicillin, metronidazole, ampicillin-metronidazole, doxycycline, clindamycin, and extract of amniotic membrane growth factor (Amino)

Results: Testing an range of BGP concentrations, we were able to induce liquid-gel transition in the chitosan solution at temperatures ranging from 20-50 °C. To induce the transition to gel within a physiological temperature range of 35-37 °C, the final concentration of BGP was 2.3mM, with 1.1 mM Bicarbonate to reach a pH value of 6.8. We found that addition of 1 mg/ml Clindamycin was compatible with this formula. Addition of metronidazole or ampicillin-metronidazole required 3.0 mM BGP with 4.4 mM Bicarbonate to maintain a physiological gelling temperature. Ampicillin or doxycycline alone required 4.0 mM BGP, and growth factor required 4.1 mM BGP.

Conclusions: The ability of chitosan gel to form thermosensitive mixtures with antimicrobial agents or growth factor was evaluated. Results showed that this material is feasible as a delivery vector in situ for a variety of medicaments, while maintaining the ability to transition from a liquid to a gel at human body temperature. Future study will determine the adhesive property of these formulas to titanium surfaces, and the antimicrobial effects on titanium surface biofilms.
Key words: Peri-implantitis, chitosan, thermo-sensitive, antimicrobial agents

Lead Author's Contributions to the Research Project. : The Lead Author brought up the idea of this research and she constantly followed up all steps with co-authors .