Evaluation of an Injectable Thermosensitive Hydrogel As Drug Delivery Implant for Ocular Glaucoma Surgery

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.

Effects of Gelatin Hydrogel Loading Mitomycin C on Conjunctival Scarring in a Canine Filtration Surgery Model

“…In another report, a biodegradable thermo-sensitive hydrogel loaded with MMC for glaucoma surgery was evaluated both in vitro and in vivo. 11 The in vitro study showed that MMC was released from this DDS for up to 16 days, with 57% of the MMC being released in the first day. The in vivo study (using rabbits) indicated that this hydrogel loaded with 0.1 mg/mL MMC led to a functional bleb with prolonged bleb survival.…”

“…There have been several studies focused on subconjunctivally implanted drug delivery systems (DDSs) to provide a sustained release of antiproliferative drugs during an extended period after glaucoma surgery. [4][5][6][7][8][9][10][11] The findings of most of those studies have indicated that these DDSs maintained IOP reduction and prolonged bleb persistence in a manner similar to the conventional application of antimetabolites, such as 5-fluorouracil and MMC, while significantly reducing their toxicity. However, those DDSs have yet to produce clinically satisfactory results.…”

Sustained intravitreal delivery of dexamethasone using an injectable and biodegradable thermogel

“…Another thermosensitive hydrogel composed of poly(trimethylene carbonate) 15 -Pluronic F127-poly(trimethylene carbonate) 15 copolymer was prepared and then the mitomycin C-loaded hydrogel was injected into the subconjunctival space to inhibit postoperative fibrosis in a rabbit glaucoma filtration surgery model. However, this formulation exhibited a significant burst release in vitro and approximately 57% of the incorporated drug was released within the first day [52]. Also, Hwang and Hsiue [53] proposed a thermoreversible hydrogel composed of an amphiphilic copolymer containing poly(2-ethyl-2-oxazoline) and poly(e-caprolactone) blocks as a sustained carrier for intraocular delivery of bevacizumab.…”

Poly(trimethylene carbonate)-based polymers engineered for biodegradable functional biomaterials

“…A PTMC-containing triblock copolymer with a clinically used thermoresponsive hydrophilic polymer Pluronic F127® (PTMC-F127-PTMC, Figure 1I), showing a sol-gel transition at 37°C, locally accumulated at the injected position, presenting a stable drug release profile over 25 days and no adverse reactions during the in vivo test using a rabbit glaucoma model. 201 Kim et al first reported the thermoresponsive hydrogel system based on the PEG-tagged PTMC derivatives derived from bisMPA, displaying a lower critical solution temperature (LCST) around the body temperature, which is tuned by copolymerization of the TMC analogues with a long alkyl pendant. 202 Ajiro et al also reported that a TMA-derived PTMC derivative ( Figure 3B) bearing a methoxy terminated triethylene glycol unit at the side chain showed an LCST around the body temperature at a particular molecular weight range.…”