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Jake Armstrong, Richard Zhang, Cindy M L Hutnik; Development of an injectable, space-filling thermosensitive hydrogel as a subconjunctival bleb scaffold and sustained release drug depot. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3150.
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© ARVO (1962-2015); The Authors (2016-present)
The subconjunctival injection of anti-metabolites prior to glaucoma microstent insertion has become a popular surgical technique. Currently, aqueous preparations of Mitomycin C are used. However, aqueous solvents cause rapid dispersion of drugs and provide no lasting physical support. Thermosensitive chitosan hydrogels transform from an injectable liquid state, into a semi-solid gel at temperatures approximating body temperature. The purpose of this study was to engineer a thermosensitive hydrogel for injection into the subconjunctival space to serve as a depot for sustained drug delivery after glaucoma surgery.
High molecular weight chitosan was solubilized in 1% acetic acid, which was subsequently removed through dialysis. Beta-glycerophosphate (β-GP) was added dropwise, on ice, to attain samples of pH 7, 7.1 and 7.2. Tube inversion test within a heated water bath was used to assess gelation time vs temperature. Acetylsalicylic acid (ASA) was loaded into gels as a test compound. A perfusion system was used to perfuse PBS through ASA-loaded chitosan gels at the rate of aqueous humor production (2.6ul/min) in order to estimate the release of ASA over time under physiological conditions. Human Tenon’s capsule fibroblasts (HTCFs) were cultured on chitosan gels at 37°C to assess cytotoxicity, as well as in collagen matrices to evaluate cell-mediated collagen contraction as a measure of in vitro scarring activity.
Tube inversion tests revealed that time to gelation and the temperature of gelation were determined by pH. Samples with pH 7.2 underwent gelation the quickest, in under two minutes at temperatures ranging from 34 to 40°C. ASA was successfully loaded into the chitosan gels and exhibited a delayed release profile upon perfusion. Minimal cytotoxicity was noted when cultured with HTCFs and ASA loaded gels inhibited cell-mediated collagen contraction compared to vehicle control.
Chitosan and beta-glycerophosphate hydrogels possess thermosensitive characteristics and can deliver small molecule therapeutics such as ASA in a delayed release manner. These properties would make chitosan-based drug delivery systems highly desirable for glaucoma surgery, specifically for bleb formation and stabilization.
This is a 2020 ARVO Annual Meeting abstract.
Figure 1 – The prepared samples were assessed at various temperatures for time to gelation (N=3).
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