(315c) Wireless Iontophoresis Lens Mediated Ocular Drug Delivery

Age related macular degeneration (AMD) is the most common cause of vision loss in the elderly population (65 years or older).^1,2 The number of AMD cases is anticipated to reach over 288 million worldwide.^1,2 Neovascular AMD, leading to severe visual loss due to choroidal neovascularization, comprises 10% of all AMD cases.^3,4 The current clinical treatment for neovascular AMD treatment relies on inhibiting the vascular endothelial growth factor (VEGF) pathway by using intravitreal injection of anti-VEGF drugs (i.e., Bevacizumab: 1.25 mg/injection or Aflibercept: 2.0 mg/injection) every 4-6 weeks.^3,4 However, intravitreal injection-based approach (1) is invasive, (2) is not practical for self-administration, (3) requires frequent office visits for injections, (4) suffers from short drug half-life, and (5) causes complications due to repeated injections (i.e., endophthalmitis, retinal detachment, retinal hemorrhage, globe perforation cataract formation, and secondary glaucoma).^5–7 Therefore, there is a critical need for alternative, safe and non-invasive approaches enabling efficient, precise, and accurate drug delivery into the posterior segment of the eye for AMD treatment.

In this study, we develop a non-invasive self-administered wireless iontophoresis device in the form of a single-use contact lens for efficient delivery of anti-VEGF drugs, Bevacizumab and Aflibercept, into the posterior segment of the eye for AMD. For this purpose, the site-specific and local drug reservoirs are integrated with wireless antenna/coil design in a single lens platform. The wireless iontophoresis lens is fabricated using our previously patented, simple polymer casting and microfluidics-based flexible electronics fabrication method.^8–10 Briefly, predetermined locations of drug reservoirs and microchannels for wireless antenna coils are created on molds using computerized numerical control. The microchannels on the mold are filled with conductive graphene nanoplatelet solution (prepared by ethanol thermal reaction) using syringe pump controlled microfluidic approach. Following graphene circuit formation, the drug suspension at initial dose (Bevacizumab: 1.25 mg or Aflibercept: 2.0 mg, based on applied doses in clinic) is used to fill the site-specific drug reservoirs. After drying, PMMA solution (10 wt% in chloroform) is cast on the mold with wireless graphene antenna and drug. Upon drying and film formation, the film is peeled off to transfer the drug and graphene antenna.^8–10

The integrity of wireless antennas and drug reservoirs are validated using scanning electron microscopy (SEM). The conductivity/sheet resistance of the graphene antennas are evaluated via 4-point probe measurement. The functionality of the antenna is tested using a light-emitting diode electrically connected to the wireless array as a visual indicator in PBS (pH 7.4 at 37 °C) mimicking cell culture using a waveform/function generator, oscilloscope, and network analyzer. The frequency characteristics of the wireless antenna are assessed via network analyzer. The drug loading efficiency and release profiles are evaluated by collecting release samples at predetermined time points under different wireless electrical stimulation (WES) parameters in PBS (pH 7.4 at 37 °C) using drug specific ELISA kits. Visual release tests on agarose gels (2 wt% in PBS, pH 7.4), mimicking the eye tissue, are also conducted using fluorescence dye attached drug loaded lens.

The in vitro biocompatibility therapeutic efficacy of the drug loaded lens is assessed against VEGF expressing in vitro AMD model using retinal pigment epithelium cells (ARPE-19 from ATCC) by detecting the changes in VEGF expression using ELISA and PCR tests. We also tested the efficient penetration of the drugs to the posterior segments using fluorescence dye attached drug loaded lens on ex vivo pig eyes using fluorescence imaging of the pig eye tissue sections.

Our results demonstrated the successful fabrication of the wireless iontophoresis lens with high resolution and small feature size using the patented method.^8–10 The initial prototypes for iontophoresis application demonstrated controlled release of model drugs under different electrical stimulation conditions without changing the temperature and pH of the environment. The same platform showed efficient drug penetration into the agarose gel, mimicking the eye tissue. We also demonstrated that retinal pigment epithelium cells (RPE) can attach, grow, and proliferate on these platforms without any biocompatibility issues. Our ex vivo tests on pig eyes clearly showed that the drugs can be pushed to the retina without causing any visual damage to the cornea and the lens.

In conclusion, this wireless iontophoresis lens technology enables non-invasive WES directed on-demand ocular drug delivery, self-administered by the patient, preventing frequent office visits, and reducing treatment burden for AMD. The local drug reservoir technology also provides therapeutic stability enabling prolonged shelf-life and precise dose control, minimizing dose related side effects. The successful development of this technology will change the paradigm in traditional iontophoresis concept and clinical practice by introducing a wireless and self-administered contact lens platform not only for AMD but also for the potential treatment of other ocular conditions addressing the economic and societal needs of patients.

References:

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