A Drug-Eluting Biomaterial Device for Reducing Post-Surgical Inflammation and Fibrosis in Glaucoma Patients

Abstract

Purpose : Drainage tube or trabeculectomy surgeries in late-stage glaucoma remains beset by unacceptably high 1-year failure rates due to post-operative inflammation and fibrosis. Fibrosis is known to follow a two-stage process with inflammation over the first 1-7 days followed by collagen deposition. Current approaches to remedy this rely on administration of anti-metabolites (mitomycin C) and an intensive course of patient-administered corticosteroid drops. These present their own issues, particularly adverse side-effects and poor patient compliance.
Therefore, we describe a proteoglycan (PG)-modified hyaluronic acid (HyA) drug-device that aims to address post-surgical inflammation and remove patient compliance issues.

Methods : PG-Hyaluronic acid hydrogels were chemically crosslinked and assessed for percentage crosslinking, swelling, degradation and ease of insertion into cadaveric rabbit eyes. The innate ability of the modified gels to reduce collagen deposition in the absence of drugs was tested using primary human conjunctival fibroblasts stimulated with Transforming Growth Factor-Beta (TGF-β). The device was further enhanced using prednisolone drug loading with release assessed over 28 days in PBS and efficacy evaluated in a chick embryo model.

Results : It was found that HyA hydrogels were capable of rapid swelling in <30 min, stability up to 4 weeks minimum and enzymatic degradation related to cross-linking efficacy. The device was easily implanted using standard surgical tools (Figure 1A). In vitro analysis using drug-free, PG-HyA gels in TGF-β stimulated conjunctival fibroblasts demonstrated a reduction to normal collagen levels at 24 hours (Figure 1 B+C).
Release of prednisolone from gel composites were found to exhibit a biphasic release with an initial burst release over 72 hours and a more gradual release for up to 28 days. Furthermore, this was found to effectively inhibit angiogenesis up to 5 days ex-vivo.

Conclusions : This work demonstrates a strong proof of concept validation for a straightforward solution to a long running issue in glaucoma surgery. Future work now focuses on an in-depth pre-clinical study.

This is a 2021 ARVO Annual Meeting abstract.

 

Figure 1. A) Mock device insertion in rabbit eye. B) Proteoglycan (PG) mediated modulation of collagen deposition (red stain) in human conjunctival fibroblasts following TGF-β stimulation. C) Collagen was reduced to baseline levels for all doses (n=3 ±SEM,1-way ANOVA).