Evaluation of a Novel Encapsulated Cell Technology Device Designed for Intraocular Delivery of CNTF

Abstract

Abstract: : Purpose: Intraocular implantation of CNTF secreting NT–501 polymer devices (11 mm x 1.1 mm) has been shown to arrest photoreceptor degeneration in an animal model of retinitis pigmentosa. However, smaller sized devices would be more desirable for ocular applications. The current study investigated the impact of a smaller device design on device performance and safety profile. The new device configuration consists of a reduced device size (6 mm x 0.62 mm) while maintaining efficacious levels of CNTF delivery by using the high CNTF secreting NTC–201–6A cells. Methods:Compared to NT–501, the new device volume and encapsulated cell number was reduced 10–fold by decreasing the length and diameter of the implant by approx. 50%. In addition to the geometry changes, the membrane porosity of the new device was increased to provide greater molecular flux as determined by passive diffusion of a 70 kDa FITC dextran. CNTF output of devices in vitro over the course of 3 months was evaluated. Devices were implanted into the rabbit vitreous and explanted at 3–days, 1–month and 3–month periods. Device CNTF output, vitreous CNTF levels and encapsulated cell viability were assessed at each time–point. The CNTF levels were determined by ELISA. Encapsulated cell viability was characterized by a metabolic assay and histomorphology. Indirect ophthalmoscopic and fundus examinations were conducted to assess any potential ocular irritation associated with the presence of device and wound healing. Results: The smaller devices were successfully implanted using a 0.8 mm diameter sclerotomy followed by closure with a single suture. In contrast, implantation of the NT–501 devices requires a 2.1 mm implant incision and multiple interrupted sutures to ensure closure. No adverse post–operative complications were reported in either group following ophthalmic examination of the animals. Cell density in the explanted small devices was closer to the pre–implant density compared to the NT–501 devices and is hypothesized to be a result of the increased nutrient flux to the device and nutrient to cell number ratio available to the smaller device. Preliminary in vivo results show that CNTF release and accumulation in the vitreous is comparable (P > 0.05) to historical efficacious levels protecting photoreceptor degeneration. Conclusions: This study has demonstrated that reducing the size and increasing the flux characteristics of a cell encapsulation device can create surgical benefits and maintain efficacious levels of CNTF and, therefore, be considered as a potential improvement to encapsulation cell technology.

Keywords: retina • age–related macular degeneration • photoreceptors