Proliferative vitreoretinopathy, a potentially blinding condition, involves excessive proliferation of retinal pigment epithelium (RPE) cells and is the main complication following retinal detachment (RD). Complicated cases of RD are treated with silicone oil (SiO) tamponades which can potentially be used as drug reservoirs. The aim of this study was to investigate different methodologies to develop a sustained and controlled drug release of anti-proliferative and anti inflammatory drugs from SiO tamponades using all-trans retinoic acid (atRA) and ibuprofen (Ibu). In detailed studies of atRA and Ibu, including atRA degradation behaviour, the drugs were found to be non-toxic to an adult RPE cell line (ARPE 19) below 10-5 M. The solubility of both drugs in SiO was assessed using radioisotope techniques. Prodrugs of atRA and Ibu were synthesised via conjugation to polyethylene oxide (PEO), and cleavage of the resulting ester bond, toxicity towards RPE cells, solubility in SiO and release into media were assessed. Prodrug cleavage was successful in vitro for Ibu but not achieved in the case of atRA due to its highly conjugated nature. Cytotoxicity assays showed PEO attachment had no effect on cytotoxicity and PEO prodrug solubility in SiO followed the expected trend of decreasing solubility with increased PEO chain length. Overall the saturation concentration of drug in SiO achieved through the use of PEO-prodrugs was too low for an effective therapy. Lipophilic prodrugs with a poly(dimethylsiloxane) (PDMS) pro-moiety were synthesised and investigated. Their cleavage was problematic due to PDMS being highly hydrophobic and cleavage could only be achieved in vitro when a small hydrophilic spacer was added between PDMS and the drug. The effects of PDMS prodrugs as additives in SiO were investigated and the presence of PDMS-atRA in SiO was shown to have a positive effect on both atRA solubility and longevity of release. The clinically-relevant release period (6-8 weeks) was independent of atRA starting concentration but dependant on the PDMS-atRA concentration within the blend. This has potential for further development into tamponade drug reservoirs for future patient benefits. A series of linear and branched amphiphilic copolymer architectures were also evaluated as additives for SiO. Monomer selection included oligoethylene oxide methacrylate (OEGMA), 2-hydroxyethyl methacrylate, PDMS-methacrylate (PDMSMA) and the brancher PDMS-dimethacrylate (PDMSDMA). SiO solubility of p(OEGMA-co-PDMSDMA) was investigated and copolymers which contained the smallest hydrophilic and largest lipophilic components only achieved small solubility (0.1 % v/v). To overcome these solubility issues, hydrophobic PDMSMA monomer was utilised. Both linear p(PDMSMA-co-OEGMA) and branched p(PDMSMA-co-OEGMA-co-PDMSDMA) were successfully synthesised and displayed high solubility within SiO, up to 40-50 % v/v. The potential for SiO tamponades as long-acting drug reservoirs has been demonstrated after inclusion of a novel end-modified PDMS additive leading to long term release of atRA. The formation of novel polymer architectures that show considerable miscibility with SiO also shows the scope of the opportunity for further additive development to tailor release profiles.

Age-related macular degeneration (AMD) is the largest cause of blindness for those over 65 in the developed world. There is currently no treatment for the retinal cellular loss associated with the disease. One potential therapy is to implant retinal stem cells into the eye using a biodegradable polymer scaffold. Blends of the biodegradable polymers, poly(L-lactic acid) (PLLA) and poly(D,L-lactic-co-glycolic acid) (PLGA) have been formulated into microspheres. The influence of changing processing parameters on the size and morphology of the microspheres has been studied. A human retinal pigment epithelial (APRE-19) cell line was shown to adhere, survive and proliferate on the surface of the microspheres in vitro. Assays have demonstrated that the nature of the blend influenced cell behaviour. Transplantation of retinal pigment epithelial (RPE) cells on a supportive matrix has also been investigated as a therapy for AMD. In view of AMD related pathology of the native RPE support, Bruch’s membrane (BM), transplanted RPE cells require a scaffold to reside on. Copolymers based on methyl methacrylate (MMA) and poly(ethylene glycol) methacrylate (PEGM) have been synthesised and chemically modified at the PEG terminus. These polymers were subsequently manufactured into a fibrous scaffold using an electrospinning technique and investigated as an artificial BM. RPE cells were shown to attach and proliferate successfully on the surface of the fibrous scaffold in vitro. Cell adhesion was significantly enhanced on scaffolds with the PEG chain terminus modification. Significantly less apoptotic cell death was also observed on these surfaces. The diffusion properties of these artificial membranes have also been investigated. In addition, the novel gelation of the produced copolymers under certain conditions has been studied

The degradation of eyesight is a frightening experience for individuals and unfortunately gradual loss of vision with old age is commonplace. One of the most common forms of eye disease which effects vision is Age-Related Macular Degeneration (AMD). AMD is the leading cause of blindness in the developed world and there is currently no cure for the disease. One treatment option available for the neovascular form of AMD is the injection of Bevacizumab [an anti-vascular endothelial growth factor (VEGF) drug] into the eye on a monthly basis. Investigation into the biodegradable polymers poly(L-lactic acid) (PLLA) and poly(D,L-lactic-co-glycolic acid) (PLGA) as a possible drug delivery system with highly uniform and reproducible microspheres was developed. Under optimised parameters Bevacizumab-encapsulated PLLA:PLGA microspheres were successfully prepared with a steady release of Bevacizumab being obtained. Additionally, fibrous scaffolds of methyl methacrylate (MMA) and poly(ethylene glycol) methacrylate (PEGM) were prepared by an electrospinning process. These MMA:PEGM co-polymers were investigated as a possible Bruchs membrane replacement and as the support for retinal pigment epithelium (RPE) transplantation. The MMA:PEGM co-polymers were functionalised with N-succinimidyl which resulted in the fibres forming a gel in vitro. Gel formation was examined further and successful RPE cell attachment and growth onto these gels was observed. Further work on surface active agents was undertaken to improve the cell adhesion, proliferation and growth of RPE cells onto these methacrylate based frameworks. An arginine-glycine-aspartic acid (RGD) peptidomimetic was prepared and reacted onto the surface of the MMA:PEGM co-polymers, however, the peptidomimetic-attached MMA:PEGM fibres offered little improvement in cell growth in comparison with N-succinimidyl–activated MMA:PEGM co-polymer fibres. Additional attachment of the natural proteins laminin, collagen and fibronectin onto the microspheres was achieved. Attachment of these proteins prolonged the release of the dye from the microspheres and showed no cytotoxic effects when examined in-vitro.