Sequential Therapy with Saratin, Bevacizumab and Ilomastat to Prolong Bleb Function following Glaucoma Filtration Surgery in a Rabbit Model

Currently available anti-scarring treatments for glaucoma filtration surgery (GFS) have potentially blinding complications, so there is a need for alternative and safer agents. The effects of the intrableb administration of a new combination of the anti-VEGF bevacizumab, sodium hyaluronate and a collagen matrix implant were investigated in a rabbit model of GFS, with the purpose of modulating inflammation, angiogenesis, fibroblast migration and fibrogenesis in the wound healing process. A comparative-effectiveness study was performed with twenty-four rabbits, randomly assigned to the following treatments: (a) biodegradable collagen matrix implant (Olo), (b) bevacizumab-loaded collagen matrix implant (Olo-BVZ), (c) bevacizumab-loaded collagen matrix implant combined with sodium hyaluronate (Olo-BVZ-H5) and (d) sham-operated animals (control). Rabbits underwent a conventional trabeculectomy and were studied over 30 days in terms of intraocular pressure and bleb characterization (height, area and vascularity in central, peripheral and non-bleb zones). Histologic differences among groups were further evaluated at day 30 (inflammation, total cellularity and degree of fibrosis in the area of surgery). Local delivery of bevacizumab (Olo-BVZ and Olo-BVZ-H5) increased the survival of the filtering bleb by 21% and 31%, respectively, and generated a significant decrease in inflammation and cell infiltration histologically 30 days after surgery, without exhibiting any local toxic effects. Olo-BVZ-H5 showed less lymphocyte infiltration and inflammation than the rest of the treatments. Intraoperative intrableb implantation of bevacizumab, sodium hyaluronate and a collagen matrix may provide an improved trabeculectomy outcome in this model of intense wound healing. This study showed an effective procedure with few surgical complications and a novel combination of active compounds that offer new possibilities to improve the efficacy of filtration surgery.

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Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery

Scientific Reports ◽

10.1038/s41598-020-80542-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yong Yao Chun ◽

Zhu Li Yap ◽

Li Fong Seet ◽

Hiok Hong Chan ◽

Li Zhen Toh ◽

...

Keyword(s):

Positive Charge ◽

Sirna Delivery ◽

Rabbit Model ◽

Epigenetic Silencing ◽

Filtration Surgery ◽

Glaucoma Filtration Surgery ◽

Gelatin Hydrogel ◽

Cellular Environment ◽

Effective Delivery ◽

Delivery Platform

AbstractSmall interfering RNA (siRNA) therapy is a promising epigenetic silencing strategy. However, its widespread adoption has been severely impeded by its ineffective delivery into the cellular environment. Here, a biocompatible injectable gelatin-based hydrogel with positive-charge tuned surface charge is presented as an effective platform for siRNA protection and delivery. We demonstrate a two-step synthesis of a gelatin-tyramine (Gtn-Tyr) hydrogel with simultaneous charge tunability and crosslinking ability. We discuss how different physiochemical properties of the hydrogel interact with siSPARC (siRNA for secreted protein, acidic and rich in cysteine), and study the positive-charge tuned gelatin hydrogel as an effective delivery platform for siSPARC in anti-fibrotic treatment. Through in vitro studies using mouse tenon fibroblasts, the positive-charge tuned Gtn-Tyr hydrogel shows sustained siSPARC cellular internalization and effective SPARC silencing with excellent biocompatibility. Similarly, the same hydrogel platform delivering siSPARC in an in vivo assessment employing a rabbit model shows an effective reduction in subconjunctival scarring in post glaucoma filtration surgery, and is non-cytotoxic compared to a commonly used anti-scarring agent, mitomycin-C. Overall, the current siRNA delivery strategy involving the positive-charge tuned gelatin hydrogel shows effective delivery of gene silencing siSPARC for anti-fibrotic treatment. The current charge tunable hydrogel delivery system is simple to fabricate and highly scalable. We believe this delivery platform has strong translational potential for effective siRNA delivery and epigenetic silencing therapy.

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Effect of SMILE-derived decellularized lenticules as an adhesion barrier in a rabbit model of glaucoma filtration surgery

BMC Ophthalmology ◽

10.1186/s12886-021-02090-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Houfa Yin ◽

Xinyi Chen ◽

Xiaogang Hong ◽

Jian Ma ◽

Fang Wu ◽

...

Keyword(s):

Rabbit Model ◽

Adjunctive Treatment ◽

Control Group ◽

Small Incision Lenticule Extraction ◽

Filtration Surgery ◽

Glaucoma Filtration Surgery ◽

Adhesion Barrier ◽

Adverse Side Effects ◽

Subconjunctival Space ◽

Lenticule Extraction

Abstract Background To investigate the effects of small incision lenticule extraction (SMILE)-derived decellularized lenticules on intraocular pressure (IOP) and conjunctival scarring in a rabbit model of glaucoma filtration surgery. Methods Trabeculectomy was performed on both eyes of New Zealand rabbits. A decellularized lenticule was placed in the subconjunctival space in one eye of the rabbits (the decellularized lenticule group), and no adjunctive treatment was performed in the fellow eye (the control group). The filtering bleb features and IOP were evaluated 0, 3, 7, 14, 21, and 28 days after surgery, and histopathologic examination was performed 28 days after surgery. Results Decellularized lenticules significantly increased bleb survival and decreased IOP postoperatively in the rabbit model with no adverse side effects. The histopathologic results showed a larger subconjunctival space and less subconjunctival fibrosis in the decellularized lenticule group. Conclusions Decellularized lenticules can prevent postoperative conjunctiva-sclera adhesion and fibrosis, and they may represent a novel antifibrotic agent for trabeculectomy.

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Expression of Connective Tissue Growth Factor after Glaucoma Filtration Surgery in a Rabbit Model

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.03-0485 ◽

2004 ◽

Vol 45 (2) ◽

pp. 485 ◽

Cited By ~ 34

Author(s):

Douglas W. Esson ◽

Arvind Neelakantan ◽

Sandhya A. Iyer ◽

Timothy D. Blalock ◽

Lakshmi Balasubramanian ◽

...

Keyword(s):

Growth Factor ◽

Connective Tissue ◽

Connective Tissue Growth Factor ◽

Rabbit Model ◽

Tissue Growth ◽

Filtration Surgery ◽

Glaucoma Filtration Surgery

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Pluripotent epigenetic regulator OBP-801 maintains filtering blebs in glaucoma filtration surgery model

Scientific Reports ◽

10.1038/s41598-020-77811-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yuji Yamamoto ◽

Atsushi Mukai ◽

Toru Ikushima ◽

Yasuo Urata ◽

Shigeru Kinoshita ◽

...

Keyword(s):

Wound Healing ◽

Rabbit Model ◽

Vehicle Control ◽

Control Group ◽

Eye Drops ◽

Subconjunctival Injection ◽

Filtration Surgery ◽

Glaucoma Filtration Surgery ◽

Vehicle Control Group ◽

Epigenetic Regulator

AbstractInhibition of fibrosis is indispensable for maintaining filtering blebs after glaucoma filtration surgery (GFS). The purpose of this study was to investigate the ability of a pluripotent epigenetic regulator OBP-801 (OBP) to ameliorate extracellular matrix formation in a rabbit model of GFS. Rabbits that underwent GFS were treated with OBP. The gene expression profiles and intraocular pressure (IOP) were monitored until 30 postoperative days. The bleb tissues were evaluated for tissue fibrosis at 30 postoperative days. In in vitro models, OBP interfered the functions of diverse genes during the wound-healing process. In in vivo GFS models, the expressions of TGF-β3, MMP-2, TIMP-2 and 3, LOX, COL1A and SERPINH1 were significantly inhibited at 30 postoperative days in the OBP group compared with those in the vehicle control group. OBP treatment involving subconjunctival injection or eye drops showed no adverse effects, and reduced levels of α-SMA and collagen deposition at the surgical wound site. OBP maintained the long-lived bleb without scar formation, and IOP was lower at 30 postoperative days compared with the vehicle control group. These findings suggest that OBP is an effective and useful candidate low-molecular-weight agent for improving wound healing and surgical outcomes in a rabbit model of GFS.

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