Success Of Glaucoma Filtration Surgery Research Articles

Novel Therapies for the Prevention of Fibrosis in Glaucoma Filtration Surgery

Conjunctival fibrosis remains the major impediment to the success of glaucoma filtration surgery. Anti-metabolites remain the gold standard for mitigating post-surgical fibrosis, but they are associated with high complication rates and surgical failure rates. Establishing a more targeted approach to attenuate conjunctival fibrosis may revolutionize the surgical approach to glaucoma. A new strategy is needed to prevent progressive tissue remodeling and formation of a fibrotic scar, subsequently increasing surgical success and reducing the prevalence of glaucoma-related vision loss. Advancements in our understanding of molecular signaling and biomechanical cues in the conjunctival tissue architecture are broadening the horizon for new therapies and biomaterials for the mitigation of fibrosis. This review aims to highlight the strategies and current state of promising future approaches for targeting fibrosis in glaucoma filtration surgery.

Discrimination and quantification of scar tissue by Mueller matrix imaging with machine learning

Scarring is one of the biggest areas of unmet need in the long-term success of glaucoma filtration surgery. Quantitative evaluation of the scar tissue and the post-operative structure with micron scale resolution facilitates development of anti-fibrosis techniques. However, the distinguishment of conjunctiva, sclera and the scar tissue in the surgical area still relies on pathologists’ experience. Since polarized light imaging is sensitive to anisotropic properties of the media, it is ideal for discrimination of scar in the subconjunctival and episcleral area by characterizing small differences between proportion, organization and the orientation of the fibers. In this paper, we defined the conjunctiva, sclera, and the scar tissue as three target tissues after glaucoma filtration surgery and obtained their polarization characteristics from the tissue sections by a Mueller matrix microscope. Discrimination score based on parameters derived from Mueller matrix and machine learning was calculated and tested as a diagnostic index. As a result, the discrimination score of three target tissues showed significant difference between each other ([Formula: see text]). The visualization of the discrimination results showed significant contrast between target tissues. This study proved that Mueller matrix imaging is effective in ocular scar discrimination and paves the way for its application on other forms of ocular fibrosis as a substitute or supplementary for clinical practice.

Subconjunctival bevacizumab versus mitomycin c as adjuvant treatment to subscleral trabeculectomy

Aim To compare the clinical outcome of adjuvant subconjunctival bevacizumab (BVZ) injection versus mitomycin C (MMC) during subscleral trabeculectomy. Patients and methods In this study, 20 patients who were divided into two groups: group A included 10 (20 eyes) patients who underwent subscleral trabeculectomy with subconjunctival injection of 1.25 mg/0.1 ml BVZ, and group B included 10 (20 eyes) patients who underwent subscleral trabeculectomy with adjuvant intraoperative use of 0.2 mg/ml MMC for 2 min. This prospective nonrandomized clinical comparative study was conducted in Nour-El-Hayaha Eye Center (Cairo). Patients were diagnosed for primary open angle glaucoma with uncontrolled intraocular tension by maximum tolerable antiglaucoma therapy. The study excluded patients with neovascular glaucoma, congenital and juvenile glaucoma, history of ocular pathology, or surgery as retinal surgeries and uveitis. Results Twenty patients were considered for the study, nine (45%) patients (18 eyes) were males and 11 (55%) patients (22 eyes) were females. The patients’ ages ranged from 35 to 65 years (mean age 55.2±8.3). Mild hyphema, in one eye in group A (8.33%), wound leak in one (8.33%) eye in each group, and shallow anterior chamber in two (16.7%) cases in each group. It was the most common encountered complication in our study. One (8.33%) case of shallow anterior chamber in group A led to choroidal effusion. One (8.33%) case in group B developed late bleb-related endophthalmitis after 3 months, which ended in phthisis bulbi. Conclusion The success of glaucoma filtration surgery is heralded by a wound healing response mainly mediated by fibroblast proliferation, migration, and contraction that leads to postoperative subconjunctival scar. The effect of subconjunctival BVZ and MMC-augmented trabeculectomy in cases of primary open angle glaucoma was beneficial in improving the success rate with better intraocular pressure control and prolonging the trabeculectomy survival with no significant difference between the two groups.

5-Flurouracil microencapsulation and impregnation in hyaluronic acid hydrogel as composite drug delivery system for ocular fibrosis

AbstractEffective and sustained release formulations of antimetabolite 5-Flurouracil (5Fu) for ocular fibrosis are highly desirable for success of glaucoma filtration surgery (GFS). However, burst release and rapid clearance of carriers and/or drug still exist as major limitations. Here, we report the feasibility of encapsulating 5Fu in sustained release carrier of poly (d,l-lactide-co-glycolide) (PLGA) microspheres (MPs) and impregnating in a hyaluronic acid (HA) hydrogel as unit dose formulation. In order to optimize the encapsulation process by solid-in-oil-in-water emulsion technique, the effects of PLGA end groups, PLGA concentration, and 5Fu loading were studied systematically. The MPs were extensively characterized for surface morphology, particle size distribution, thermal properties, crystallinity, residual solvent, syringeability, and in vitro release. The optimized formulation of MPs was ~94 μm in size and released 5Fu in a sustained manner for up to two weeks. In our concept, MPs are dispersed...

Regulation of Tenon's Capsule Fibroblast Cell Proliferation by the Opioid Growth Factor and the Opioid Growth Factor Receptor Axis

Glaucoma filtration surgery often fails because of the fibrotic reaction from Tenon's capsule fibroblasts (TCFs). This study examined whether the interaction of the opioid growth factor (OGF) [Met(5)]-enkephalin with its receptor (OGFr) is a regulator of TCF proliferation. The presence of OGF and its receptor (OGFr) was determined in rabbit TCFs (RTCFs) by immunocytochemistry. The kinetics of OGFr were established in receptor binding assays. The ability of OGF to inhibit RTCF proliferation was assessed with dose-response, receptor mediation, and reversibility studies. Dependence on OGF and OGFr was ascertained by antibody neutralization and siRNA studies, respectively. The mechanism of action of the OGF-OGFr axis on survival (apoptosis, necrosis) and DNA synthesis of RTCFs was elucidated. OGF and OGFr were detected in RTCF cells, and specific and saturable binding to OGFr was recorded. Exogenous OGF had a dose-dependent, reversible, and receptor-mediated inhibitory effect on cell proliferation. Endogenous OGF was found to be constitutively produced and tonically active in cell replication, with neutralization of this peptide causing acceleration of cell proliferation. The silencing of OGFr by using siRNA technology stimulated cell replication, validating OGFr's integral role. The mechanism of OGF-OGFr action was not related to cell survival, but rather to DNA synthesis-specifically, the cyclin-dependent kinase inhibitory pathway. Knockdown of p16 or p21 eliminated OGF's inhibitory effect on growth. The OGF-OGFr system is a native biological regulator of cell proliferation in RTCFs and may offer a means of improving the success of glaucoma filtration surgery in a safe and nontoxic manner.

SPARC Deficiency Results in Improved Surgical Survival in a Novel Mouse Model of Glaucoma Filtration Surgery

Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC-null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC-null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery.

Subconjunctival sustained release 5-fluorouracil for glaucoma filtration surgery1

To determine the release characteristics of a 5-fluorouracil-loaded poly (lactic acid) disc (5-FU-PLA-DS) and the effect of sustained drug delivery on the success of glaucoma filtration surgery in rabbit eyes. A method of microspheres accumulated by excessive carriers was used in the preparation of the 5-FU-PLA-DS. The disc was characterized for drug loading, entrapment efficiency, in vitro release, and external morphology. It was then implanted subconjunctivally into rabbit eyes with trabeculectomy. Intraocular pressure, ocular inflammatory reaction, filtration bleb appearance, and persistence were evaluated up to postoperative d 90. A quantitative analysis of 5-fluorouracil (5-FU) was performed in the aqueous humor. Ultrasound biomicroscopy was used to assess the appearance of the filtering fistula. The 5-FU-PLA-DS was produced with the drug-loading of 3.07+/-0.08 mg (mean+/-SD). 5-FU was released for 91 d with suppressive concentrations. The decrease in intraocular pressure from baseline was significantly more marked in the 5-FU-PLA-DSimplanted eyes during postoperative d 3-90, and the persistence of bleb and filtration fistula was longer than the control eyes (P<0.05). Corneal toxicity and hyperemia triggered by 5-FU was lower in the 5-FU-PLA-DS-implanted eyes than those exposed to 5-FU intraoperatively. The 5-FU concentration in the aqueous humor was insufficient for corneal endothelial damage. No evidence of toxic reaction was found in the conjunctival biopsy. 5-FU-PLADS displaying sustained intraocular release of 5-FU, reduced intraocular pressure, and prolonged bleb persistence, while significantly reducing 5-FU toxicity.

Review Basic Science and Clinical Aspects of Wound Healing in Glaucoma Filtering Surgery

Success of glaucoma filtration surgery is influenced by the wound healing response. Attention has been focused on pharmacological agents to control a process that leads to excessive scarring and eventual failure of glaucoma filtration surgery. Several agents, including 5-fluorouracil and mitomycin C, as well as other antiproliferative drugs will be discussed. Newer antifibrotic agents and novel drug delivery systems are under development in tissue culture and animal models in an effort to improve efficacy and safety. This article summarizes current treatment modalities and future prospects to prevent excessive wound healing and improve the success of glaucoma filtration surgery.

The Use of Bioerodible Polymers and Daunorubicin in Glaucoma Filtration Surgery

Purpose: Glaucoma filtering surgery usually fails from postoperative fibroblast proliferation, collagen deposition, and subsequent sclerostomy or bleb scarring. Daunorubicin inhibits fibroblast proliferation in vivo and in vitro. The authors studied the effect of a sustained subconjunctival release of daunorubicin by way of a bioerodible polymer on the success of glaucoma filtration surgery in a rabbit model.Methods: Daunorubicin was incorporated into the copolymer by compression molding. The resultant implant measured 3.0 mm in diameter, 1.0 mm in thickness, and 8.0 mg in weight. A posterior lip sclerectomy was performed in both eyes of 23 rabbits by the same surgeon. One eye was randomized to receive the disc with daunorubicin, whereas the fellow eye received a blank disk as a control. The appropriate polymer disk then was placed on the scleral surface immediately posterior to the sclerostomy site and the conjunctiva was closed. Intraocular pressures and slit-lamp biomicroscopy were recorded preoperatively, then every other day after surgery for 31 days. Intraocular pressure, bleb survival, and complications were evaluated.Results: The decrease in intraocular pressure from baseline was significantly greater in the daunorubicin eyes than in the control eyes during postoperative days 5 through 25. Bleb survival was significantly longer in the daunorubicin eyes than in the control eyes (bleb failure in 91% of control eyes versus 22% of treatment eyes by day 13). There were no statistically significant differences between the daunorubicin-treated and control eyes regarding corneal clouding, lens clarity, cataract formation, or conjunctival injection. However, conjunctival erosions occurred in four daunorubicin-treated eyes. Histopathologic examination was performed 2 weeks after surgery on the eyes of three randomly selected rabbits.Conclusion: Daunorubicin in a bioerodible delivery system may potentially be a useful adjunct to glaucoma filtering surgery and requires further evaluation.

Enhancement of filtration surgery with cytosine arabinoside and reversal of toxicity with 2'-deoxycytidine.

Antifibrosis agents have improved the success of glaucoma filtration surgery, although undesired side effects are not readily reversible and may present a major limitation in the use of these agents. Our purpose was to study the efficacy of cytosine arabinoside (Ara-C) as an adjunctive antimetabolite in glaucoma surgery in the rabbit, and reversal of toxicity due to this agent with the competitive inhibitor 2'-deoxycytidine. Posterior lip sclerectomy was performed in rabbit eyes treated with 15 mg subconjunctival Ara-C daily for 7 d then every other day for 7 d. Mean intraocular pressure was lower in eyes treated with Ara-C compared with controls at all time points following filtration surgery. On the 10th postoperative day, the mean intraocular pressure of control eyes (25.0 +/- 1.9 mm Hg) had returned to baseline levels, whereas the intraocular pressure of eyes treated with Ara-C was significantly lower (16.0 +/- 1.7 mm Hg) (P < 0.001). Bleb survival was also prolonged in the Ara-C-treated eyes. The major ocular side effect of Ara-C was corneal toxicity, with epithelial defects in 40% of eyes after 8 daily injections of 15 mg Ara-C. Reversal of toxicity was enhanced with 2'-deoxycytidine, with complete resolution of epithelial toxicity after 6.5 +/- 1.7 d following daily topical 10% 2'-deoxycytidine compared with 12.7 +/- 0.58 for control (P < 0.002). These results demonstrate that postoperative subconjunctival injection of Ara-C results in improved bleb function after filtration surgery in the rabbit. Recovery from corneal epithelial toxicity due to Ara-C is markedly enhanced with the competitive inhibitor 2'-deoxycytidine.

In Vitro Evaluation of Antiproliferative Potential of Topical Cyclo-oxygenase Inhibitors in Human Tenon's Fibroblasts

Pharmacologic agents which inhibit fibroblast proliferation and scar formation may improve the success of glaucoma filtration surgery. To evaluate the potential use of nonsteroidal anti-inflammatory drugs as an antifibrotic treatment following glaucoma filtration surgery, the time and dose-related effects of four commonly used topical cyclo-oxygenase inhibitors—diclofenac, flurbiprofen, piroxicam, and suprofen—on human Tenon's fibroblast attachment and proliferation were studied. Fibroblasts were incubated with different concentrations of a drug and analysed for dose response 1, 3, and 8 days following drug addition. The cell density was quantified by Coulter counting, hexosaminidase assay, and [3H]thymidine uptake into the DNA. All four drugs inhibited fibroblast attachment at the highest concentrations. Diclofenac was the most effective agent in inhibiting fibroblast proliferation, with inhibition occurring at a range of concentrations above 10-3-10-4 mmol I-1. Flurbiprofen, piroxicam, and suprofen were comparable to each other in their antiproliferative activities, with inhibition occurring at a range of concentrations above 10-1-10-2 mmol I-1. These results suggest a potential role for the commonly used topical nonsteroidal anti-inflammatory drugs in preventing excessive fibroblast proliferation following GFS, but further clinical studies are indicated to assess their activity as anti-inflammatory and antiproliferative agents in preventing bleb failure.

Effect of Brief Exposure to Mitomycin C on Viability and Proliferation of Cultured Human Tenon's Capsule Fibroblasts

The purpose of this study is to determine why a single intraoperative dose of mitomycin C (MMC) appears to promote the success of glaucoma filtration surgery. Human Tenon's capsule fibroblasts were exposed to MMC and 5-fluorouracil (5-FU) in vitro at the concentrations and durations of exposure used clinically. Cell proliferation was assessed by quantification of 3H-thymidine uptake. Cell viability was studied using a sulfarhodamine B cell protein stain and by trypan blue exclusion. Neither MMC (0.4 mg/ml) nor 5-FU (40 mg/ml) were cytocidal. Both 1- and 5-minute exposures to MMC were antiproliferative. A 1-minute exposure to 0.4 mg/ml inhibited 3H-thymidine uptake by 77%. For the 5-minute exposure, 3H-thymidine uptake was inhibited by 50% at 0.06 mg/ml and by 90% at 0.4 mg/ml. For 5-FU, 3H-thymidine uptake was inhibited by 50% at 10 mg/ml and by 64% at 40 mg/ml. Mitomycin C probably does not improve the success of filtration surgery by killing fibroblasts. The ability of a brief exposure to MMC to improve filtration surgery may be due to an almost complete inhibition of proliferation. Alternatively, it may be due to sustained tissue binding, effects on other components of wound healing, such as cell migration and extracellular matrix production, or effects on the vasculature. A 1-minute exposure may be as effective as a 5-minute exposure.

The effects of transferrin receptor antibody, transferrin receptor antibody bound to Pseudomonas exotoxin and transforming growth factor-alpha bound to Pseudomonas exotoxin on human tenon's capsule fibroblast proliferation.

Pharmacological agents which modulate the wound healing process by the inhibition of proliferation of fibroblasts may improve the success of glaucoma filtration surgery. Since cell proliferation is essential to the wound healing process, we targeted the surface receptors that are associated with proliferating cells. We present the effects of three such agents-purified mouse anti-human transferrin receptor monoclonal antibody 42/6 (anti-TfR-42/6), anti-transferrin monoclonal antibody bound to a Pseudomonas exotoxin (anti-TfR-PE40) and transforming growth factor-alpha Pseudomonas exotoxin (TGF-alpha-PE40)--on human fibroblasts from Tenon's capsule. The inhibition of human subconjunctival fibroblast proliferation by anti-TfR-42/6 (with a concentration up to 25 micrograms/ml) and by anti-TfR-PE40 and TGF-alpha-PE40 (both with a concentration range of 5000-0.00001 micrograms/ml) was determined by colorimetric (OD), and cell counting (CC) assays over a 9-day period. Neither anti-TfR-42/6 nor anti-TfR-PE40 had an antiproliferative effect on the fibroblasts. TGF-alpha-PE40 demonstrated an antiproliferative effect in a dose response manner. The mean 50% inhibitory dose (ID50) by OD was 32.91 micrograms/ml, while the ID50 by CC was 27.88 micrograms/ml. EGF was used as a negative control for TGF-alpha-PE40 toxin. The inhibitory effect of the toxin conjugate was completely blocked by the addition of 1000 micrograms/ml of EGF. These in vitro studies show that TGF-alpha-PE40 may be useful in modulating the proliferation of human ocular fibroblasts; they also give some indication of drug dosages for future in vivo testing.

Llse of Bioerodible Polymers Impregnated with Mitomycin in Glaucoma Filtration Surgery in Rabbits

A prospective, randomized, double-masked, and placebo-controlled study was performed to evaluate the effects of a localized and sustained release of mitomycin on the success of glaucoma filtration surgery in rabbits. A bioerodible polymer was used as the drug carrier. Full-thickness filtration surgeries were performed and data from 22 rabbits were collected. One eye received a polymer impregnated with mitomycin (0.02 mg or 0.06 mg), while the fellow eye received a drug-free polymer. Intraocular pressure, bleb survival, and postoperative complications were investigated. Intraocular pressures remained lower for a longer period of time (P < 0.004) and filtration blebs lasted longer (P < 0.05) in experimental eyes than in control eyes. Conjunctivitis and sectoral corneal haze occurred more frequently in eyes treated with the higher dosage mitomycin compared with control eyes. The use of mitomycin-C in a polymer delivery system appeared to promote the success of glaucoma filtration surgery in rabbits. With the lower dosage of mitomycin, clinically significant ocular toxicity was not noted.

Glaucoma Filtration Surgery in Rabbits Using Bioerodible Polymers and 5-Fluorouracil

A prospective, randomized, double-masked, and placebo-controlled study was performed to examine the effect of a localized and sustained delivery of 5-fluorouracil (5-FU) on the success of glaucoma filtration surgery in 18 rabbits. A bioerodible polyanhydride composed of bis (p-carboxyphenoxy) hexane (PCPH) and sebacic acid (SA) was used as the drug carrier. The polymer and 5-FU (10% by weight) were molded into 4-mm long cylinders by a 15-gauge needle. These implants, with and without the therapeutic agent, were placed at the site of filtration surgery intraoperatively. The results showed that intraocular pressures (IOPs) were lower in the experimental eyes during the second postoperative week, but eventually both experimental and control eyes returned to preoperative levels. Filtration blebs lasted longer in experimental eyes and bleb failure occurred before IOP failure in both experimental and control eyes. Implant disappearance occurred after IOP and bleb failure. Experimental eyes had more postoperative complications than control eyes. Eventually, the filtration surgery failed in both the experimental and control rabbit eyes.