Design of Hollow Hyaluronic Acid Cylinders for Sustained Intravitreal Protein Delivery

Abstract

A hollow cylinder intravitreal implant was developed to achieve sustained release of protein to the retina for the treatment of retinal diseases. Hollow cylinders were fabricated by molding and cross-linking hyaluronic acid, the major component of the vitreous humor. Hollow cylinders were filled with a concentrated protein solution, and the properties of the cylinder walls were tested. Cross-linked hyaluronic acid hydrogels with swelling degrees as low as 2.7 were achieved as a means to extend the release of protein. Hollow cylinders were capable of releasing an antigen-binding fragment for over 4 months at a maximum release rate of 4 μg per day. Protein release from hollow cylinders was modeled using COMSOL Multiphysics® software, and diffusion coefficients between 1.0 × 10−11 and 3.0 × 10−11 cm2/s yielded therapeutically effective levels of protein. Cylinders with a 1 mm outer radius were capable of loading >1 mg of protein while releasing at least 2.5 μg a day for over 4.5 months. Although smaller cylinders facilitate intravitreal placement, decreasing the cylinder radius severely limited drug loading. Design of hollow cylinder intravitreal implants must balance high drug loading to reduce device size with control of the diffusion coefficient to sustain protein release.