Eye conditions like allergic conjunctivitis are difficult to treat because, although there are highly effective drugs available on the market, delivery is very difficult. Widely used conventional eyedrops, for example, are cleared naturally by the eye before they can work. Instead, researchers from McMaster University led by Heather Sheardown have created an easy-to-apply alternative to eyedrops based on chitosan thermo-gels [Ross et al., Acta Biomaterialia 141 (2022) 151-163, https://doi.org/10.1016/j.actbio.2022.01.043].
“We wanted to create a system, which can be applied as a normal eyedrop to the inferior fornix, that gels [as a result of] the heat of the eye, allowing for prolonged drug release,” says first author of the work, Mitchell Ross.
The new delivery system consists of a poly(N-isopropylacrylamide) thermo-gel crosslinked with chitosan that, although ultimately degradable, can deliver drug treatments for allergy symptoms over a prolonged period. The drug-containing polymer solution is applied to the inferior fornix – lower internal part of the eye – where it forms a gel at body temperature that gradually degrades and releases its cargo.
“By crosslinking chitosan with our synthesized thermo-gelling polymer, we were able to produce stiff gels with a tunable transition temperature,” explains Ross.
The researchers used a short chain chitosan with a low degree of deacetylation to render the material degradable by the natural enzyme lysozyme, which is found in tears. Simultaneously, the incorporation of methyl methacrylate, along with n-isopropylacrylamide and acrylic acid, enables control of the temperature at which the solution gels. By tuning the chitosan crosslinking, either through physical interaction or covalent bonding, the gel can be designed to degrade over the course of one to four days. Meanwhile, the gels can release an anti-allergy drug into the eye.
“By transitioning from a solution to a gel [in response to] the heat of the eye, the stiff hydrogel is able to prolong the release of the loaded drug by increasing the diffusion time,” points out Ross. “Compared with conventional topical formulations, the thermo-gel can prolong drug release, improving drug efficacy. The prolonged release can also mitigate the amount of drug which becomes systemically absorbed compared to conventional eyedrops.”
The ability to crosslink chitosan by different methods enables the creation of gels with tunable degradation time and varied mechanical properties. The material only requires body temperature to gel, so could be used to treat other conditions where it could be applied topically such as the nose or mouth or even injected. However, the effect of lysozyme was less than expected, so the team are now working on improving enzymatic degradation and increasing the natural adhesive properties of chitosan to mucus membranes, as well as exploring the delivery of other drugs.
Schematic of the chitosan thermo-gel for treatment of eye conditions.
Photograph of chitosan thermo-gel in the interior fornix of a rabbit’s eye.