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Title: The modulation of wound healing for glaucoma filtration surgery
Author: Lockwood, A. J.
ISNI:       0000 0004 8497 6173
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Glaucoma is a leading cause of blindness worldwide. Surgical lowering of intraocular pressure (IOP) is frequently necessary, although scarring causes failure. Chemotherapeutics applied locally increase success but may have blinding complications, including hypotony and infections. Modifications in technique reduce risk, though intense monitoring is required postoperatively. Matrix metalloproteinase inhibitors (MMPis) may be a less toxic anti-scarring alternative. Because the inhibition is reversible multiple injections are needed in experiments to maintain efficacy. Injections are uncomfortable, painful and costly however. The pharmacokinetic profile also shows concentration spikes and rapid drug clearance. A sustained release preparation is therefore desirable. Here we show in chambers modeling aqueous flow that single pure ilomastat MMPi implants maintained a therapeutic concentration between 10 and 23 days. In the in vivo model, bleb survival appeared to be significantly prolonged, however a foreign body reaction existed to undissolved implants, with significant collagen deposition in the conjunctiva. To improve efficacy and reduce the proscarring nature of undissolved drug, implants of the more soluble MMPi marimastat and combination implants of ilomastat together with hyaluronic acid were formulated. These dissolved faster, but failed earlier. A combined implant of the anti-inflammatory dexamethasone and ilomastat appeared to prolong survival with less, but still considerable reaction. Coating ilomastat implants with a biocompatible polymer caused less reaction, but inflammatory foci existed around presumed polymer defects. A more hydrophilic polymer caused less reaction, though with macrophage infiltration. During these experiments it became apparent that bleb appearance when using implants did not necessarily correlate with survival. Thus the notion of 'bleb survival' as an outcome was questioned and other outcomes tested. Dye to trace aqueous movement was too slow. Inducing ocular hypertension in the rabbit caused only a temporary, unpredictable pressure rise, and buphthalmos. Pooling IOP data from larger numbers after standard surgery appeared to be most accurate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available