Investigation of a High Permselectivity Membrane and Its Effect on Encapsulated Cell Viability and Therapeutic Protein Release Over a 1-Year Implantation Period in Rabbits

Abstract

Purpose: : Neurotech’s encapsulation technology to date has incorporated a capsule of hollow fiber membrane (PES14) with immunoprotection properties shown in multiple clinical trials to provide sustained, multi-year drug delivery in humans. This study evaluated the effect of a new encapsulation membrane (MNPS1000) with protein permselectivity characteristics 1000-fold greater than the PES14 membrane on encapsulated cell viability and drug secretion levels over a 1-year implant period in New Zealand White rabbits.

Methods: : Molecular diffusion, molecular weight cut-off, hydraulic permeabilitiy and pore size distribution tests were performed to characterize the membranes. Membranes were further evaluated to determine extent of protein binding comparing pre and post-serum fouling diffusion as well as using a fibroblast adhesion assay. Following membrane manufacture and characterization, CNTF producing cells were encapsulated in devices utilizing both membrane types. Devices were held in vitro and then implanted into the vitreous of New Zealand White rabbits for 1, 3, 6 and 12 month periods. Upon explant, device CNTF release and vitreal CNTF levels were quantified by ELISA. Encapsulated cell viability was evaluated using a metabolic activity assay and cell number was semi-quantified by histological cell counting of sectioned devices. Indirect ophthalmoscopic and fundus examination were conducted during this study by a board certified veterinarian ophthalmologist to assess implant safety and tolerability.

Results: : Device groups using either the PES14 or the MNPS1000 performed well over the 1-year implant in rabbits. Devices manufactured using the higher permselectivity MNPS1000 membrane, however, resulted in improved encapsulated cell viability (P < 0.05) and increased CNTF secretion levels over 1-year implantation. Protein binding to the MNPS1000 membrane was virtually zero compared to a 40% protein binding increase in the PES 14 membrane group (P < 0.05). Implants from both groups were safe and well tolerated over the 1-year study period.

Conclusions: : Encapsulation cell technology membranes with high permselectivity and lower protein binding properties appear to improve transplant cell viability and increase long-term protein secretion. Encapsulated cell technology implant with MNPS1000 will be evaluated in future clinical trials.

Keywords: retinal degenerations: hereditary