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Title: Modulation of wound healing after glaucoma surgery
Author: Sharma, G. U.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Glaucoma is the leading cause of irreversible blindness worldwide. Glaucoma is a progressive eye disorder characterised by atrophy of the optic nerve. In some cases, poor aqueous drainage may cause raised intraocular pressure, which causes damage to the optic nerve, leading to blindness. One of the approaches to lower intraocular pressure is to surgically create a drainage channel for the outflow of aqueous humour. Impaired wound healing and continued scarring response at the site of surgery can lead to suboptimal intraocular pressure control and eventual failure of surgery in many patients. Current treatments in the form of cytotoxic agents (e.g., mitomycin C, 5-Fluorouracil) are associated with severe side effects. The anti-Vascular Endothelial Growth Factor (VEGF) monoclonal antibody bevacizumab, (Avastin) has shown potential to decrease scarring after glaucoma surgery. However, bevacizumab clears rapidly from the subconjunctival space when injected. To overcome rapid clearance, a slow release dosage form of bevacizumab was developed. The slow release implantable dosage form is preferable for two reasons – first, it can provide local delivery of the drug to the tissue and, secondly, the desired effect of the drug can persist for a longer duration of time. The bevacizumab slow release tablet was formulated and characterised, and its anti-angiogenic efficacy was tested in an in vivo rabbit corneal angiogenesis model. The bevacizumab implantable tablet was formulated successfully without any signs of protein aggregation and was able to inhibit VEGF induced corneal angiogenesis for up to 30 days in a rabbit model. Wound healing is a complex process that involves the different overlapping phases of haemeostasis, inflammation, angiogenesis and remodeling of the extracellular matrix. The current in vitro models study each aspect of wound healing in isolation. The most commonly used in vitro model for studying conjunctival contraction is fibroblast populated collagen gels. However, it does not take into consideration an important aspect of wound healing, that is, inflammation. A novel co-culture in vitro model was developed using human Tenon’s fibroblasts and U937 cell line-derived macrophages seeded in a collagen matrix. The presence of macrophages significantly increased fibroblast-mediated contraction; correlating with the clinical observation that inflammation significantly increases conjunctival contraction and may increase the chances of failure of surgery. In this model, it was found that the presence of macrophages was able to overcome the effect of high doses of mitomycin C on fibroblasts, similar to the clinical situation where the use of mitomycin C does not necessarily guarantee the success of the surgery, especially in cases where the eye is highly inflamed. The co-culture model will be useful in investigating new drugs that could potentially act on both inflammatory cells and fibroblasts. It is challenging to develop anti-scarring drugs because the mechanisms for scarring are varied and there is continuous cross talk between the different mediators of scarring. Due to the involvement of multiple pathways, when one pathway is inhibited, another pathway can still initiate scarring. Hence, we sought a prophylactic treatment to deal with fibrosis caused after glaucoma surgery. A novel approach of increasing the stiffness of the tissue by cross-linking collagen was investigated as a potential prophylactic treatment to inhibit tissue contraction after glaucoma surgery. Collagen gels were cross-linked using riboflavin and ultraviolet radiation, using a similar dose that is used clinically in the treatment of keratoconus. It was found that cross-linking increased the stiffness of the collagen gels and was able to inhibit fibroblast-mediated tissue contraction in the presence of macrophages and in a porcine ex vivo model. It is envisaged that cross-linking the tissue during glaucoma surgery could potentially dampen the scarring response, especially in high-risk patients. Overall, this thesis focused on trying to better understand ways to treat the multifactorial condition of fibrosis. It is not only important to have an efficacious drug molecule but it is also important to strategise the delivery of the anti-scarring drugs. We also showed, with the help of an in vitro model, that the presence of inflammatory cells can nullify the effect of anti-scarring drugs. While modulating the complicated process of wound healing with the help of drugs is challenging, there is a possibility that the prophylactic treatment of cross-linking could better protect patients and reduce the need for medication. Finally, apart from molecules and cells, modulating the extracellular matrix could offer an additional approach to reducing scarring.
Supervisor: Khaw, P. T. ; Brocchini, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available