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Project
Role of vascular endothelial growth factor (VEGF) -isoforms in pathological retinal angiogenesis and neurogenesis.
Glaucoma is a chronic progressive disease characterised by specific structural abnormalities of the optic nerve head and patterns of visual field loss. Currently, lowering intraocular pressure (IOP) is themain pillar in the treatment of glaucoma and filtering surgery is the most efficient approach for doing so. However, in 30% of the cases, the constructed channel closes due to excessive scar formation, resulting in surgical failure. Therefore, a need for refinement of the surgical technique and for adjunctive therapeutic strategies to improve surgical outcome and to prevent filtration failure, remains.
The first project of this doctoral thesis focuses on the improvement of the surgical technique and the development of adjunctive anti-fibrotic strategies to fight postoperative fibrosis and surgical failure in an attempt to optimise the surgical technique and thus improve the surgical outcome. This project consists of the following three studies which will be discussed below.
In the first study, two different trabeculectomy techniques were compared in a prospective, randomised, single-centre study. One eye of each patient was randomly assigned to a trabeculectomy with an anterior chamber maintainer and a combination of 2 adjustable and 2 releasable flap sutures (technique 1), while the other eyeunderwent a trabeculectomy with a viscoelastic and 2 releasable flap sutures (technique 2). The remainder of the operation was similar in both eyes. There was no significant difference in IOP reduction, in frequency of postoperative complications and interventions, nor in the reduction of medications between the two techniques. In conclusion, using an anterior chamber maintainer might add safety when operating eyes at risk, while in most cases the classic technique 2, which is less sophisticated and faster, guaranteed excellent results if it was performed meticulously by an experienced surgeon. Therefore, technique 2 was used for the subsequent studies.
In the second study, microplasmin, a truncated form of the human plasmin, was tested as an anti-scarring agent in arabbit model for filtration surgery. The pilot experiments revealed promising data that the anterior chamber injections alone showed a trend toincrease bleb area during the first week, but the combination of anterior chamber injection and 4 times daily topical eye drops were needed to improve bleb survival and increase bleb area in a rabbit model for filtration surgery. Therefore, in an attempt to extended ocular delivery, microplasmin was added to poloxamer and hydroxypropylmethylcellulose (HPMC)gels. The gel formulations developed were not able to improve the outcome after trabeculectomy, despite the fact that the activity of microplasmin lasted at least 24 hours. Strikingly, poloxamer 17% (w/w) gel alone could increase bleb area and prolong bleb survival, probably due to a mechanical effect. Further optimisation of the delivery method to achieve a longer release of active microplasmin over several weeks is necessary and could prove to be beneficial.
In the last part of the surgical project, translational research was conducted based on the favourable effects of bevacizumab in the prevention of fibrosis in vitro and in vivo which we demonstrated previously. In a prospective, randomized, double-masked and placebo-controlled study, the effect ofa single, preoperative, intracameral administration of bevacizumab (1.25mg/ml; Avastin®) in terms of clinical outcome following trabeculectomy in patients with either primary open-angle glaucoma (POAG) or normal tension glaucoma (NTG) was investigated. Interestingly, a single intracameral administration of bevacizumab at the end of trabeculectomy was associated with increased absolute success rates, reduced need for postoperative interventions in order to reach the target IOP, and more diffuse blebs with a lower degree of vascularity.
Despite a successful IOP reduction, glaucoma continues to progress in some patients. Indeed, besides a raised IOP, other risk factors related to ocular ischemiahave been associated with the pathogenesis of glaucoma. Currently, verylittle is known about the metabolic alterations in the retina of glaucoma patients, as only surrogate measurements of metabolism were availableuntil recently. The second component of this doctoral thesis focuses on the change of oxygen metabolism in the glaucomatous retina measured by non-invasive retinal oximetry and to gain more insights into the vascular aspects of this disease.
During the first phase of this project, the protocol and the analysis were fine-tuned in accordancewith the group of Professor Stefánsson (Reykjavik, Iceland). The quality of the retinal vessel oximetry images were improved by the addition of topical phenylephrine 5% after tropicamide 0.5% for dilation, without influencing the retinal oxygen saturation values or the retinal vessel diameter in glaucoma patients.
In the second phase, retinal vessel oximetry measurements were compared between glaucoma patients and healthy subjects, and between different types of glaucoma groups. Oxygen saturation values were similar in POAG and NTG patients. Healthy subjects had a greater oxygen consumption compared to glaucoma patients, which could be related to tissue atrophy in glaucoma.
In the third phase, the association between retinal vessel oxygen saturation in glaucoma patients with structural optic discand retinal nerve fiber layer (RNFL) changes and visual field defects was determined. Severe glaucoma damage was associated with increased oxygen saturation in venules and decreased arteriovenous difference in retinal oxygen saturation. These data confirm that in eyes with severe glaucomatous damage, oxygen consumption was decreased due to tissue loss.
In conclusion, two different surgical techniques were compared and the technique with viscoelastics and 2 releasable flap sutures was chosen for further use. Two anti-fibrotic strategies were evaluated. Microplasmin looked promising in pilot experiments but the developing for extended ocular drug delivery needed further optimisation. Furthermore, a single intracameral administration of bevacizumab at the end of trabeculectomy proved to be beneficial for the outcome after trabeculectomy. In addition, retinal oximetry was different between healthy subjects and glaucoma patients and our data suggested that oxygen consumption was decreased in glaucoma patients due to tissue loss.
The first project of this doctoral thesis focuses on the improvement of the surgical technique and the development of adjunctive anti-fibrotic strategies to fight postoperative fibrosis and surgical failure in an attempt to optimise the surgical technique and thus improve the surgical outcome. This project consists of the following three studies which will be discussed below.
In the first study, two different trabeculectomy techniques were compared in a prospective, randomised, single-centre study. One eye of each patient was randomly assigned to a trabeculectomy with an anterior chamber maintainer and a combination of 2 adjustable and 2 releasable flap sutures (technique 1), while the other eyeunderwent a trabeculectomy with a viscoelastic and 2 releasable flap sutures (technique 2). The remainder of the operation was similar in both eyes. There was no significant difference in IOP reduction, in frequency of postoperative complications and interventions, nor in the reduction of medications between the two techniques. In conclusion, using an anterior chamber maintainer might add safety when operating eyes at risk, while in most cases the classic technique 2, which is less sophisticated and faster, guaranteed excellent results if it was performed meticulously by an experienced surgeon. Therefore, technique 2 was used for the subsequent studies.
In the second study, microplasmin, a truncated form of the human plasmin, was tested as an anti-scarring agent in arabbit model for filtration surgery. The pilot experiments revealed promising data that the anterior chamber injections alone showed a trend toincrease bleb area during the first week, but the combination of anterior chamber injection and 4 times daily topical eye drops were needed to improve bleb survival and increase bleb area in a rabbit model for filtration surgery. Therefore, in an attempt to extended ocular delivery, microplasmin was added to poloxamer and hydroxypropylmethylcellulose (HPMC)gels. The gel formulations developed were not able to improve the outcome after trabeculectomy, despite the fact that the activity of microplasmin lasted at least 24 hours. Strikingly, poloxamer 17% (w/w) gel alone could increase bleb area and prolong bleb survival, probably due to a mechanical effect. Further optimisation of the delivery method to achieve a longer release of active microplasmin over several weeks is necessary and could prove to be beneficial.
In the last part of the surgical project, translational research was conducted based on the favourable effects of bevacizumab in the prevention of fibrosis in vitro and in vivo which we demonstrated previously. In a prospective, randomized, double-masked and placebo-controlled study, the effect ofa single, preoperative, intracameral administration of bevacizumab (1.25mg/ml; Avastin®) in terms of clinical outcome following trabeculectomy in patients with either primary open-angle glaucoma (POAG) or normal tension glaucoma (NTG) was investigated. Interestingly, a single intracameral administration of bevacizumab at the end of trabeculectomy was associated with increased absolute success rates, reduced need for postoperative interventions in order to reach the target IOP, and more diffuse blebs with a lower degree of vascularity.
Despite a successful IOP reduction, glaucoma continues to progress in some patients. Indeed, besides a raised IOP, other risk factors related to ocular ischemiahave been associated with the pathogenesis of glaucoma. Currently, verylittle is known about the metabolic alterations in the retina of glaucoma patients, as only surrogate measurements of metabolism were availableuntil recently. The second component of this doctoral thesis focuses on the change of oxygen metabolism in the glaucomatous retina measured by non-invasive retinal oximetry and to gain more insights into the vascular aspects of this disease.
During the first phase of this project, the protocol and the analysis were fine-tuned in accordancewith the group of Professor Stefánsson (Reykjavik, Iceland). The quality of the retinal vessel oximetry images were improved by the addition of topical phenylephrine 5% after tropicamide 0.5% for dilation, without influencing the retinal oxygen saturation values or the retinal vessel diameter in glaucoma patients.
In the second phase, retinal vessel oximetry measurements were compared between glaucoma patients and healthy subjects, and between different types of glaucoma groups. Oxygen saturation values were similar in POAG and NTG patients. Healthy subjects had a greater oxygen consumption compared to glaucoma patients, which could be related to tissue atrophy in glaucoma.
In the third phase, the association between retinal vessel oxygen saturation in glaucoma patients with structural optic discand retinal nerve fiber layer (RNFL) changes and visual field defects was determined. Severe glaucoma damage was associated with increased oxygen saturation in venules and decreased arteriovenous difference in retinal oxygen saturation. These data confirm that in eyes with severe glaucomatous damage, oxygen consumption was decreased due to tissue loss.
In conclusion, two different surgical techniques were compared and the technique with viscoelastics and 2 releasable flap sutures was chosen for further use. Two anti-fibrotic strategies were evaluated. Microplasmin looked promising in pilot experiments but the developing for extended ocular drug delivery needed further optimisation. Furthermore, a single intracameral administration of bevacizumab at the end of trabeculectomy proved to be beneficial for the outcome after trabeculectomy. In addition, retinal oximetry was different between healthy subjects and glaucoma patients and our data suggested that oxygen consumption was decreased in glaucoma patients due to tissue loss.
Date:1 Oct 2008 → 30 Sep 2012
Keywords:Angiogenese, Neurogenese
Disciplines:Ophthalmology and optometry
Project type:PhD project