Evaluation of an injectable thermosensitive hydrogel as drug delivery implant for ocular glaucoma surgery.

Lei Xi,Tao Wang,Xiaoning Li,Jian Ge,Jing Luo,Qiongjuan Zheng,Daping Quan,Ji Liu,Feng Zhao,Benedetta Bussolati

doi:10.1371/journal.pone.0100632

Abstract

In this study, a biodegradable thermo-sensitive hydrogel from poly(trimethylene carbonate)15-F127-poly(trimethylene carbonate)15 (PTMC15-F127-PTMC15) was designed and evaluated as an injectable implant during ocular glaucoma filtration surgery in vivo and in vitro. Mitomycin C (MMC) was loaded into this hydrogel for controlled released to prolong the efficacy and to reduce the long-term toxicity. The properties of the hydrogel were confirmed using 1H NMR and gel permeation chromatography (GPC). Compared to the Pluronic F127 hydrogel, the PTMC15-F127-PTMC15 hydrogel showed a good solution-gel transition temperature at 37°C, a lower work concentration of 5% w/v and a longer mass loss time of more than 2 weeks. The in vitro study showed that the drug could be released from PTMC15-F127-PTMC15 (5% w/v) hydrogel for up to 16 days with only 57% of drug released in the first day. Moreover, the cell toxicity, which was tested via LDH and ANNEXIN V/PI, decreased within 72 h in human tenon's fibroblast cells (HTFs). The in vivo behavior in a rabbit glaucoma filtration surgery model indicated that this hydrogel loaded with 0.1 mg/ml MMC led to a better functional bleb with a prolonged mean bleb survival time (25.5±2.9 days). The scar tissue formation, new collagen deposition and myofibroblast generation appeared to be reduced upon histological and immunohistochemistry examinations, with no obvious side effects and inflammatory reactions. The in vitro and in vivo results demonstrated that this novel hydrogel is a safe and effective drug delivery candidate in ocular glaucoma surgery.

Highlights

Glaucoma filtration surgery [1], a classical surgery that creates a fistula to allow the aqueous humor to drain into the filtering bleb, has proven to be an effective method in the treatment of glaucoma, a leading cause of irreversible blindness worldwide [2]
Characteristic of PTMC15-F127-PTMC15 block copolymer The ring-opening polymerization of TMC was initiated by F127 and catalyzed by TMEDA at 55uC for 48 h
The gel permeation chromatography (GPC) curve (Figure 1A) of F127 disappeared, and the elution curve appeared in a short time at approximately 1.36104 g/mol in a monomodal manner (PDI = 1.27), suggesting that the polymerization of TMC was successful

Summary

Introduction

Glaucoma filtration surgery [1], a classical surgery that creates a fistula to allow the aqueous humor to drain into the filtering bleb, has proven to be an effective method in the treatment of glaucoma, a leading cause of irreversible blindness worldwide [2]. The FDA approved this hydrogel due to its enhancement of protein stability [28], lack of inherent myotoxicity [29] and excellent biocompatibility [30]. It has been extensively used for the treatment of burns [31], where it acts as a depot for the in situ controlled release of many drugs with subcutaneous injection [30,32,33,34,35,36,37,38]. The relatively high critical gelling concentration (CGC) (16%) in aqueous solution and the fast degradation rate of a few hours have limited its application

Methods

Results

Discussion

Conclusion