Development, implantation, in vivo elution, and retrieval of a biocompatible, sustained release subretinal drug delivery system

Abstract

A biocompatible, sustained-release subretinal drug-delivery platform was developed to overcome the therapeutic accessibility limitations of current retinal disease treatments. The prototype implants were fabricated by coating nitinol, poly(methyl methacrylate) or chromic gut core filaments, with a drug-eluting polymer matrix. The polymer coatings are manufactured and coated by SurModics. The coating is a mixture of poly(butyl methacrylate) and poly(ethylene-co-vinyl acetate). The drug is either triamcinolone acetonide or sirolimus. The rods were successfully implanted into the subretinal space of 20/24 rabbits. Four rabbits were lost to early surgery from a dysfunctional infusion line and hemorrhage. No serious complications were observed during the 4-week follow-up period. Slight conjunctival redness was reported in all rabbits by 1-day follow-up, but the redness had subsided by the following week. Intraocular lens touch occurred in six rabbits during the implantations; of these, four had a lensectomy at the time of surgery, and the remaining two developed cataract. Corneal edema developed in three rabbits by 1-week follow-up, but subsided within 2 weeks. Initial observations of the implantation and elution characteristics revealed that the implants are well tolerated by the retinal tissue and that the implant can elute triamcinolone acetonide for a period of at least 4 weeks without eliciting an inflammatory response or complications. There were adverse clinical indications with the sirolimus-loaded implants at the delivered dose. Device retrieval required an uncomplicated surgical procedure, and revealed no associated or adherent tissue. Implant drug content analysis and opacity changes to the polymer matrix coating following retrieval demonstrated the sustained elution of the drug.

Biocompatibility and Biodegradation Studies of Subconjunctival Implants in Rabbit Eyes

“…Topical application is the mainstay of most ocular therapy, but ocular bioavailability is poor due to the efficient protective barriers [1], [2], [3]. The recognition of this limitation in efficient ocular drug delivery has led to a range of systems that vary in mode of administration, implantation site, composition and vehicles [4], [5], [6], [7], [8], [9], [10], [11], [12], which all aim to circumvent the problems of drug bioavailability, sustainability and feasibility of administration [13].…”

“…PLGA has been used extensively in studies to deliver a wide variety of drugs using various forms such as microparticles, emulsions, implants and hydrogels [11], [12], [18], [19], [20]. The ability to tailor the polymer degradation time by altering the ratio of the monomers used during synthesis has made PLGA a common choice in the production of a variety of biomedical devices such as grafts, sutures, implants, root-canal fillings and prosthetic devices [5].…”

Biomedical Imaging in Implantable Drug Delivery Systems

“…In addition to measuring tissue response, OCT has also been used for other purposes such as visualizing the microstructure of the implant matrix [85, 86], quantifying the diffusion of drug in the eye [87] and guiding the placement of implants [88]. In one study, Patterson et al used 3D OCT to characterize the in situ degradation of PLGA microspheres contained within a hyaluronic acid hydrogel gel after implantation into a rat skull defect model.…”

Drug delivery to the posterior segment of the eye for pharmacologic therapy

“…Beeley et al performed a study of a sustained-release, subretinal TA implant in rabbits [49]. A rod-shaped implant consisting of a 3.5-mm long filament with an outer drug-loaded polymer coating was used in this study.…”