Biocompatibility and Biodegradation Studies of Subconjunctival Implants in Rabbit Eyes

Abstract

Sustained ocular drug delivery is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Biodegradable subconjunctival implants with controlled drug release may circumvent these two problems. In our study, two microfilms (poly [d,l-lactide-co-glycolide] PLGA and poly[d,l-lactide-co-caprolactone] PLC were developed and evaluated for their degradation behavior in vitro and in vivo. We also evaluated the biocompatibility of both microfilms. Eighteen eyes (9 rabbits) were surgically implanted with one type of microfilm in each eye. Serial anterior-segment optical coherence tomography (AS-OCT) scans together with serial slit-lamp microscopy allowed us to measure thickness and cross-sectional area of the microfilms. In vitro studies revealed bulk degradation kinetics for both microfilms, while in vivo studies demonstrated surface erosion kinetics. Serial slit-lamp microscopy revealed no significant inflammation or vascularization in both types of implants (mean increase in vascularity grade PLGA50/50 12±0.5% vs. PLC70/30 15±0.6%; P = 0.91) over a period of 6 months. Histology, immunohistochemistry and immuno-fluorescence also revealed no significant inflammatory reaction from either of the microfilms, which confirmed that both microfilms are biocompatible. The duration of the drug delivery can be tailored by selecting the materials, which have different degradation kinetics, to suit the desired clinical therapeutic application.

Optimization of Subconjunctival Biodegradable Microfilms for Sustained Drug Delivery to the Anterior Segment in a Small Animal Model

“…30 We also found that PA-loaded microfilm group had significantly less collagen encapsulation at 2 weeks, and less CD11c infiltration around the microfilms at 2 and 4 weeks in comparison with the blank microfilm group. It is well known that corticosteroids possess antifibrotic and anti-inflammatory actions.…”

“…In the surface erosion mode, also called heterogeneous degradation mode, there is a continuous decrease in volume or size as polymers degrade at the surface first, followed by dissolution of the surface layer. 30 In our study, the microfilms exhibited bulk degradation because the M w and M n decreased gradually throughout the study period, but no changes in the microfilm dimension or thickness (as seen in the histologic study) were observed during the initial 4 weeks. Furthermore, we also have examined the effect of PA loading onto microfilms, and we noted that blank and PA-loaded microfilms demonstrated quite similar degradation profiles ( Supplementary Fig.…”

“…PLGA is an amorphous copolymer and is easier to be degraded than a PLC copolymer, which has semicrystalline structure. Our previous studies have confirmed that PLC microfilms degrade slower than PLGA microfilms in vitro and in vivo, 30 which enables PLC to be a better candidate for a sustained ocular drug delivery system. Furthermore, PLGA copolymers have a higher glass transition temperature than PLC copolymers, which makes PLGA copolymers physically hard, while PLC copoly- mers appear to be soft and elastic.…”

Safety evaluation of poly(lactic-co-glycolic acid)/poly(lactic-acid) microspheres through intravitreal injection in rabbits

“…16 The microspheres possessed a spherical shape, smooth surface, and diameter of 40-100 μm, with an in vitro release profile of more than 60 days, as analyzed in the previous studies. 6,15 PLGA-and/or PLA-sustained drug release systems applied in the eye have shown prolonged release of drugs 21,22 and have facilitated effective treatments for chronic ocular disorders such as proliferative vitreoretinopathy, retinal diseases, glaucoma, and neovascularization. The present researchers' previous studies have revealed that a single intravitreal injection of EPO-dextran PLGA/PLA microspheres could significantly protect retinas damaged from optic nerve crush in rats.…”

A Biodegradable, Sustained-Released, Tacrolimus Microfilm Drug Delivery System for the Management of Allergic Conjunctivitis in a Mouse Model

“…These characteristics allow PLC to have a slower hydrolysis rate, and therefore achieve a longer release. 28 Moreover, PLC copolymers are softer and more elastic, as it has a lower glass transition temperature than PLGA. 29 A softer material can minimize the surgical trauma during the implantation procedure as well as the risk of erosion or extrusion of the implant following the insertion.…”