Development of a 3D Printed Refillable Drug Delivery Device for Sustained Release to the Retina
Authors: Ito Yuya , Raut Bibek , Nagai Nobuhiro , Abe Toshiaki , Kaji Hirokazu 
Published: December 2020

Retinal degenerative diseases (RDD) such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP) cause progressive loss of vision, affecting millions of people worldwide. Drug delivery system (DDS) such as vitreous injection and intraocular implant has been widely investigated to treat RDD. However, they are invasive and can risk infection of the eye. Thus, we have been working on the development of transscleral DDS, which are less invasive and can achieve more localized release of drug than the conventional methods [1]. We have previously reported capsule-type and sheet-type DDS devices that can be implanted on the transscleral (periocular) region of the eye [2] [3]. However, such devices need to be replaced once drug run out. Herein, we report a 3D printed refillable DDS device for long term delivery of drugs to the retina.
The refillable device consisted of 3 sections: -polyvinyl alcohol gel chamber with openings to regulate drug release, the drug chamber as a reservoir for a test drug, and polydimethylsiloxane (PDMS) chamber with port holes to allow reinjection of the drug (Fig. 1a). The device was designed in SolidWorks 2018 (Dassault Systèmes, France) and 3D printed (Qidi Shadow 5.5S, QidiTech) using polyethylene glycol diacrylate (PEGDA) mixed with 1% photoinitiator (Irgacure819, w/w), and 1% photosensitizer (2-isopropylthioxanthone, w/w). PDMS and PVA hydrogel were manually introduced into the drug injection chamber and the drug release chamber, respectively. PDMS was cured by thermal curing and PVA was gelled by freeze-thawing. After introducing a model drug, Albumin-fluorescein isothiocyanate conjugate (FITC-Albumin), into the device, it was immersed in 5 mL of Dulbecco’s phosphate buffered saline(DPBS) and incubated at 37℃ inside a humidified incubator. The fluorescence intensities of DPBS solutions were measured by spectrofluorimetry to quantify diffusion of drugs from the capsule into the DPBS solution. The DPBS solutions were replaced at each measurement. In addition, drug reinjection and quantification of the released drug were performed. Quantification of the released drug was done by above-mentioned process.
The refillable capsule-type DDS device was fabricated with a curved geometry such that it can fit the outer circumference of the eyeball (Fig. 1b). Specifically, the dimensions of the device were 20 mm inside diameter, 22 mm curvature diameter, 2 mm thickness and 4.4 mm width. By 3D printing, it was possible to fabricate a complex 3D shape that is not possible using conventional mold technique. Because the drug is impermeable to PEGDA, unidirectional release of the drug from the release ports was possible (Fig. 1c). The unidirectional release is important because it can reduce drug elimination by conjunctival clearance and increase efficiency of drug delivery. In vitro release tests of the device were performed with varying concentrations of PVA gel. The result showed that as the PVA concentration was increased, the drug release rate decreased. At 5 wt% PVA concentration, an extreme initial burst and complete release of FITC-Albumin in 7 days was observed whereas at 10 wt% PVA concentration, over 90% drug release in 30 days and complete release in 50 days were observed, and at 20 wt% PVA concentration, drug release over 100 days was observed. Similar drug release trends were observed when the drug was repeatedly injected into the same devices for 3 times. Also, no leakage of the drug from the PDMS port was confirmed during repeated injection.
These in vitro experiment results show the potential of the device for future transscleral implants. As the next step, we are planning to implant the downsized device on rabbit’s eye and investigate biocompatibility and efficacy for treatment of RDD.
References
[1] H. Kaji et al., “Drug delivery devices for retinal diseases”, Adv. Drug Deliv. Rev., 128, 148-157 (2018).
[2] N. Nagai et al., “A platform for controlled dual-drug delivery to the retina:protective effects against light-induced retinal damage in rats”, Adv. Healthcare Mater., 3, 1555-1560 (2014).
[3] Y. Sato et al., “A multilayered sheet-type device capable of sustained drug release and deployment control”, Biomed. microdevices., 21, 60 (2019).

Figure 1