Development of a biodegradable contact lens system for ocular drug delivery

Abstract

Purpose: The aim of this thesis was to develop a biodegradable ocular drug delivery system (comprising contact lenses and conjunctival inserts), with the ability of controlled release of PVA using a physical cross linking method.

Methods: In the first experimental chapter (Chapter 3), a commercially available 3D printer was modified and the 3D printing process with a gelatin methacrylate (GelMA) biomaterial ink was optimized. GelMA biomaterial ink was selected as a base material owing to its biocompatibility and demonstrated high levels of controllability. In the second experimental chapter (Chapter 4), the shape fidelity of the 3D printed contact lenses loaded with polyvinyl alcohol (PVA) as a therapeutic agent was evaluated. In the third experimental chapter (Chapter 5), a physical crosslinking strategy was evaluated as a potential modification to prolong the release of PVA from the GelMA network. In the final experimental chapter (Chapter 6), the degradation mechanism of GelMA-based conjunctival inserts in the presence of a matrix metallo proteinase enzyme (MMP9) is described, along with its correlation with the release of PVA.

Results The results demonstrate that by tuning the printing conditions and ink parameters, soft biomaterials from a GelMA ink of higher shape fidelity and accuracy can be efficiently printed even on low-cost 3D printers. Moreover, a fine interplay between the dye concentration (CDye) and exposure time is key to effective polymerization and resolution, ensuring successful printing of the hydrogel biomaterials with higher structural integrity. It is further possible to add PVA to these lenses and the PVA release curves showed that about 1300 µg of PVA was released over the study duration of 24 hrs. PVA can act as a viscosity enhancer and protect corneal cells against dry eye related desiccation stress. These results were confirmed with the help of non-invasive keratograph break-up time measurements on a 3D printed eyeball model, where 1.4% (w/v) PVA solution displayed significantly higher tear break-up time compared to a control (p < 0.05). The release rate of PVA from these biomaterials can be controlled by applying short freeze thaw cycles, which induces formation of crystalline domains in the interpenetrating network. The appearance of endothermic peaks at 48 °C and 60 °C in differential scanning calorimetry (DSC) thermograms and 20°–2θ peaks in X-ray diffraction (XRD) patterns suggest the formation of these crystalline domains. The release profiles of the PVA containing hydrogels prove that crystalline domain formation could support sustained PVA release and control its initial burst release. The release profiles displayed highest linearity with the Korsmeyer–Peppas model (0.9944 < R² < 0.9952), indicating that these systems follow non-Fickian or anomalous transport. The results from this thesis highlight the versatility of 3D printing to fabricate GelMA-based conjunctival inserts. There are different factors that influence the MMP-mediated degradation of GelMA hydrogels, and that the degradation rate is a function of MMP9 enzyme concentration. The 3D printed GelMA/PVA inserts formed a semi-interpenetrating network. The results from the biodegradation study show that about 59.6% and 83.3% of the P-Gel-5% hydrogel was degraded at the end of 8 hrs and 12 hrs in the presence of 50 µg/ml MMP9 enzyme solution. Similarly, about 47.0%, 50.2% and 81.7% of the P-Gel-5% hydrogel was degraded at the end of 8 hrs, 12 hrs, and 24 hrs, respectively, in the presence of 25 µg/ml MMP9 enzyme solution. However, no degradation was observed in the control group incubated with PBS at the end of the study duration of 24 hrs. The PVA release graphs demonstrate that 222.7 ± 20.3 µg, 265.5 ± 27.1 µg and 242.7 ± 30.4 µg of PVA was released at 25 µg/ml, 50 µg/ml and 100 µg/ml MMP9 enzyme concentrations after 24 hrs. These results suggest that degradation rate of GelMA is a function of MMP9 enzyme concentration and the PVA release profiles of these inserts in the presence of different concentrations of MMP9 showed highest linearity with the Korsmeyer–Peppas model.

Conclusions This thesis has investigated 3D printed CLs and conjunctival inserts for controlled ocular drug delivery. Several important findings have been reported, and the shortcomings have been discussed in this thesis. With the advancements in 3D printing, personalized ophthalmic devices fabricated from 3D printing could be a commercially viable option, but the cost and transparency need to be considered.