Themed Issue on Mobile HCI @ iHCI

In the UK, 20% of people aged 75 years and over are living with sight loss and age-related macular degeneration (AMD) is the most common cause of sight loss in the UK, impacting nearly 10% of those over 80; regrettably, these figures are expected to increase in coming decades as the population ages (RNIB, 2012). This paper reports on the authors' design activities conducted for the purpose of informing the development of an assistive self-monitoring, ability-reactive technology (SMART) for older adults with AMD. The authors reflect on their experience of adopting and adapting the PICTIVE (Plastic Interface for Collaborative Technology Initiatives through Video Exploration) participatory design approach (Muller, 1992) to support effective design with and for their special needs user group, reflect on participants' views of being part of the process, and discuss the design themes identified via their PD activities.

Impact in contact lenses and the anterior eye:challenges prevailing in 2015

As we settle into a new year, this second issue of Contact Lens and Anterior Eye allows us to reflect on how new research in this field impacts our understanding, but more importantly, how we use this evidence basis to enhance our day to day practice, to educate the next generation of students and to construct the research studies to deepen our knowledge still further. The end of 2014 saw the publication of the UK governments Research Exercise Framework (REF) which ranks Universities in terms of their outputs (which includes their paper, publications and research income), environment (infrastructure and staff support) and for the first time impact (defined as “any effect on, change or benefit to the economy, society, culture, public policy or services, health, the environment or quality of life, beyond academia” [8]). The REF is a process of expert review, carried out in 36 subject-based units of assessment, of which our field is typically submitted to the Allied Health, Dentistry, Nursing and Pharmacy panel. Universities that offer Optometry did very well with Cardiff, Manchester and Aston in the top 10% out of the 94 Universities that submitted to this panel (Grade point Average ranked order). While the format of the new exercise (probably in 2010) to allocate the more than £2 billion of UK government research funds is yet to be determined, it is already rumoured that impact will contribute an even larger proportion to the weighting. Hence it is even more important to reflect on the impact of our research. In this issue, Elisseef and colleagues [5] examine the intriguing potential of modifying a lens surface to allow it to bind to known wetting agents (in this case hyaluronic acid) to enhance water retention. Such a technique has the capacity to reduced friction between the lens surface and the eyelids/ocular surface, presumably leading to higher comfort and less reason for patients to discontinue with lens wear. Several papers in this issue report on the validity of new high precision, fast scanning imaging and quantification equipment, utilising techniques such as Scheimpflug, partial coherence interferometry, aberrometry and video allowing detailed assessment of anterior chamber biometry, corneal topography, corneal biomechanics, peripheral refraction, ocular aberrations and lens fit. The challenge is how to use this advanced instrumentation which is becoming increasingly available to create real impact. Many challenges in contact lenses and the anterior eye still prevail in 2015 such as: -While contact lens and refractive surgery complications are relatively rare, they are still too often devastating to the individual and their quality of life (such as the impact and prognosis of patients with Acanthmoeba Keratitis reported by Jhanji and colleagues in this issue [7]). How can we detect those patients who are going to be affected and what modifications do we need to make to contact lenses and patient management prevent this occurring? -Drop out from contact lenses still occurs at a rapid rate and symptoms of dry eye seem to be the leading cause driving this discontinuation of wear [1] and [2]. What design, coating, material and lubricant release mechanism will make a step change in end of day comfort in particular? -Presbyopia is a major challenge to hassle free quality vision and is one of the first signs of ageing noticed by many people. As an emmetrope approaching presbyopia, I have a vested interest in new medical devices that will give me high quality vision at all distances when my arms won’t stretch any further. Perhaps a new definition of presbyopia could be when you start to orientate your smartphone in the landscape direction to gain the small increase in print size needed to read! Effective accommodating intraocular lenses that truly mimic the pre-presbyopic crystalline lenses are still a way off [3] and hence simultaneous images achieved through contact lenses, intraocular lenses or refractive surgery still have a secure future. However, splitting light reaching the retina and requiring the brain to supress blurred images will always be a compromise on contrast sensitivity and is liable to cause dysphotopsia; so how will new designs account for differences in a patient's task demands and own optical aberrations to allow focused patient selection, optimising satisfaction? -Drug delivery from contact lenses offers much in terms of compliance and quality of life for patients with chronic ocular conditions such as glaucoma, dry eye and perhaps in the future, dry age-related macular degeneration; but scientific proof-of-concept publications (see EIShaer et al. [6]) have not yet led to commercial products. Part of this is presumably the regulatory complexity of combining a medical device (the contact lens) and a pharmaceutical agent. Will 2015 be the year when this innovation finally becomes a reality for patients, bringing them an enhanced quality of life through their eye care practitioners and allowing researchers to further validate the use of pharmaceutical contact lenses and propose enhancements as the technology matures? -Last, but no means least is the field of myopia control, the topic of the first day of the BCLA's Conference in Liverpool, June 6–9th 2015. The epidemic of myopia is a blight, particularly in Asia, with significant concerns over sight threatening pathology resulting from the elongated eye. This is a field where real impact is already being realised through new soft contact lens optics, orthokeratology and low dose pharmaceuticals [4], but we still need to be able to better predict which technique will work best for an individual and to develop new techniques to retard myopia progression in those who don’t respond to current treatments, without increasing their risk of complications or the treatment impacting their quality of life So what will your New Year's resolution be to make 2015 a year of real impact, whether by advancing science or applying the findings published in journals such as Contact Lens and Anterior Eye to make a real difference to your patients’ lives?

Defining response to anti-VEGF therapies in neovascular AMD

The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient’s age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as ‘responder status’ after treatment for n-AMD, ‘tachyphylaxis’ and ‘recalcitrant’ n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.

Variation in carotenoid content of kale and other vegetables:a review of pre- and post-harvest effects

Lutein and zeaxanthin are carotenoids that are selectively taken up into the macula of the eye, where they are thought to protect against the development of age-related macular degeneration. They are obtained from dietary sources, with the highest concentrations found in dark green leafy vegetables, such as kale and spinach. In this Review, compositional variations due to variety/cultivar, stage of maturity, climate or season, farming practice, storage, and processing effects are highlighted. Only data from studies which report on lutein and zeaxanthin content in foods are reported. The main focus is kale; however, other predominantly xanthophyll containing vegetables such as spinach and broccoli are included. A small amount of data about exotic fruits is also referenced for comparison. The qualitative and quantitative composition of carotenoids in fruits and vegetables is known to vary with multiple factors. In kale, lutein and zeaxanthin levels are affected by pre-harvest effects such as maturity, climate, and farming practice. Further research is needed to determine the post-harvest processing and storage effects of lutein and zeaxanthin in kale; this will enable precise suggestions for increasing retinal levels of these nutrients.

Participatory design:how to engage older adults in participatory design activities

Ongoing advances in mobile technologies have the potential to improve independence and quality of life of older adults by supporting the delivery of personalised and ubiquitous healthcare solutions. The authors are actively engaged in participatory, user-focused research to create a mobile assistive healthcare-related intervention for persons with age-related macular degeneration (AMD): the authors report here on our participatory research in which participatory design (PD) has been positively adopted and adapted for the design of our mobile assistive technology. The authors discuss their work as a case study in order to outline the practicalities and highlight the benefits of participatory research for the design of technology for (and importantly with) older adults. The authors argue it is largely impossible to achieve informed and effective design and development of healthcare-related technologies without employing participatory approaches, and outline recommendations for engaging in participatory design with older adults (with impairments) based on practical experience.

Changes in intraocular pressure in study and fellow eyes in the IVAN trial

PURPOSE: To describe changes in intraocular pressure (IOP) in the 'alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)' trial (registered as ISRCTN92166560). DESIGN: Randomised controlled clinical trial with factorial design. PARTICIPANTS: Patients (n=610) with treatment naïve neovascular age-related macular degeneration were enrolled and randomly assigned to receive either ranibizumab or bevacizumab and to two regimens, namely monthly (continuous) or as needed (discontinuous) treatment. METHODS: At monthly visits, IOP was measured preinjection in both eyes, and postinjection in the study eye. OUTCOME MEASURES: The effects of 10 prespecified covariates on preinjection IOP, change in IOP (postinjection minus preinjection) and the difference in preinjection IOP between the two eyes were examined. RESULTS: For every month in trial, there was a statistically significant rise in both the preinjection IOP and the change in IOP postinjection during the time in the trial (estimate 0.02 mm Hg, 95% CI 0.01 to 0.03, p<0.001 and 0.03 mm Hg, 95% CI 0.01 to 0.04, p=0.002, respectively). There was also a small but significant increase during the time in trial in the difference in IOP between the two eyes (estimate 0.01 mm Hg, 95% CI 0.005 to 0.02, p<0.001). There were no differences between bevacizumab and ranibizumab for any of the three outcomes (p=0.93, p=0.22 and p=0.87, respectively). CONCLUSIONS: Anti-vascular endothelial growth factor agents induce increases in IOP of small and uncertain clinical significance.

An update on the characteristics of patients attending the Kooyong Low Vision Clinic

BACKGROUND: Since 1972, the Australian College of Optometry has worked in partnership with Vision Australia to provide multidisciplinary low-vision care at the Kooyong Low Vision Clinic. In 1999, Wolffsohn and Cochrane reported on the demographic characteristics of patients attending Kooyong. Sixteen years on, the aim of this study is to review the demographics of the Kooyong patient cohort and prescribing patterns. METHODS: Records of all new patients (n = 155) attending the Kooyong Low Vision Clinic for optometry services between April and September 2012 were retrospectively reviewed. RESULTS: Median age was 84.3 years (range 7.7 to 98.1 years) with 59 per cent female. The majority of patients presented with late-onset degenerative pathology, 49 per cent with a primary diagnosis of age-related macular degeneration. Many (47.1 per cent) lived with their families. Mean distance visual acuity was 0.57 ± 0.47 logMAR or approximately 6/24. The median spectacle-corrected near visual acuity was N8 (range N3 to worse than N80). Fifty patients (32.3 per cent) were prescribed new spectacles, 51 (32.9 per cent) low vision aids and five (8.3 per cent) were prescribed electronic magnification devices. Almost two-thirds (63.9 per cent) were referred for occupational therapy management and 12.3 per cent for orientation and mobility services. CONCLUSIONS: The profile of patients presenting for low-vision services at Kooyong is broadly similar to that identified in 1999. Outcomes appear to be similar, aside from an expected increase in electronic devices and technological solutions; however, the nature of services is changing, as treatments for ocular diseases advance and assistive technology develops and becomes more accessible. Alongside the aging population and age-related ocular disease being the predominant cause of low vision in Australia, the health-funding landscape is becoming more restrictive. The challenge for the future will be to provide timely, high-quality care in an economically efficient model.

Distribution of light in the human retina under natural viewing conditions

Age-related macular degeneration (AMD) is the leading cause of blindness inAmerica. The fact that AMD wreaks most of the damage in the center of the retina raises the question of whether light, integrated over long periods, is more concentrated in the macula. A method, based on eye-tracking, was developed to measure the distribution of light in the retina under natural viewing conditions. The hypothesis was that integrated over time, retinal illumination peaked in the macula. Additionally a possible relationship between age and retinal illumination was investigated. The eye tracker superimposed the subject's gaze position on a video recorded by a scene camera. Five informed subjects were employed in feasibility tests, and 58 naïve subjects participated in 5 phases. In phase 1 the subjects viewed a gray-scale image. In phase 2, they observed a sequence of photographic images. In phase 3 they viewed a video. In phase 4, they worked on a computer; in phase 5, the subjects walked around freely. The informed subjects were instructed to gaze at bright objects in the field of view and then at dark objects. Naïve subjects were allowed to gaze freely for all phases. Using the subject's gaze coordinates, and the video provided by the scene camera, the cumulative light distribution on the retina was calculated for ∼15° around the fovea. As expected for control subjects, cumulative retinal light distributions peaked and dipped in the fovea when they gazed at bright or dark objects respectively. The light distribution maps obtained from the naïve subjects presented a tendency to peak in the macula for phases 1, 2, and 3, a consistent tendency in phase 4 and a variable tendency in phase 5. The feasibility of using an eye-tracker system to measure the distribution of light in the retina was demonstrated, thus helping to understand the role played by light exposure in the etiology of AMD. Results showed that a tendency for light to peak in the macula is a characteristic of some individuals and of certain tasks. In these situations, risk of AMD could be increased. No significant difference was observed based on age.

The Regulation of AMD Pathobiology by Complement Factor H

Complement factor H (CFH) is a major susceptibility gene for age-related macular degeneration (AMD); however, its impact on AMD pathobiology is unresolved. Here, the role of CFH in the development of AMD pathology in vivo was interrogated by analyzing aged Cfh+/- and Cfh-/- mice fed a high fat, cholesterol-enriched diet. Strikingly, decreased levels of CFH led to increased sub-retinal pigmented epithelium (RPE) deposit formation, specifically basal laminar deposits, following high fat diet. Mechanistically, our data show that deposits are due to CFH competition for lipoprotein binding sites in Bruch’s membrane. Interestingly and despite sub-RPE deposit formation occurring in both Cfh+/- and Cfh-/- mice, RPE damage accompanied by loss of vision occurred only in old Cfh+/- mice. We demonstrate that such pathology is a function of excess complement activation and C5a production, associated with monocyte recruitment, in Cfh+/- mice versus complement deficiency in Cfh-/- animals. Due to the CFH dependent increase in sub-RPE deposit height we interrogated the potential of CFH as a novel regulator of Bruch’s membrane lipoprotein binding and show, using human Bruch’s membrane explants, that CFH removes endogenous human lipoproteins in aged donors. Interestingly, although the CFH H402 variant shows altered binding to BrM, this does not affect its ability to remove endogenous lipoproteins. This new understanding of the complicated interactions of CFH in AMD-like pathology provides an improved foundation for the development of targeted therapies for AMD.

Development of Multi-modal and Super-resolved Retinal Imaging Systems

Advancements in retinal imaging technologies have drastically improved the quality of eye care in the past couple decades. Scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) are two examples of critical imaging modalities for the diagnosis of retinal pathologies. However current-generation SLO and OCT systems have limitations in diagnostic capability due to the following factors: the use of bulky tabletop systems, monochromatic imaging, and resolution degradation due to ocular aberrations and diffraction.

Bulky tabletop SLO and OCT systems are incapable of imaging patients that are supine, under anesthesia, or otherwise unable to maintain the required posture and fixation. Monochromatic SLO and OCT imaging prevents the identification of various color-specific diagnostic markers visible with color fundus photography like those of neovascular age-related macular degeneration. Resolution degradation due to ocular aberrations and diffraction has prevented the imaging of photoreceptors close to the fovea without the use of adaptive optics (AO), which require bulky and expensive components that limit the potential for widespread clinical use.

In this dissertation, techniques for extending the diagnostic capability of SLO and OCT systems are developed. These techniques include design strategies for miniaturizing and combining SLO and OCT to permit multi-modal, lightweight handheld probes to extend high quality retinal imaging to pediatric eye care. In addition, a method for extending true color retinal imaging to SLO to enable high-contrast, depth-resolved, high-fidelity color fundus imaging is demonstrated using a supercontinuum light source. Finally, the development and combination of SLO with a super-resolution confocal microscopy technique known as optical photon reassignment (OPRA) is demonstrated to enable high-resolution imaging of retinal photoreceptors without the use of adaptive optics.

RETINAL ANGIOMATOUS PROLIFERATION: A Quantitative Analysis of the Fundoscopic Features of the Fellow Eye

PURPOSE: To quantitatively analyze and compare the fundoscopic features between fellow eyes of retinal angiomatous proliferation and typical exudative age-related macular degeneration and to identify possible predictors of neovascularization. METHODS: Retrospective case-control study. Seventy-nine fellow eyes of unilateral retinal angiomatous proliferation (n = 40) and typical exudative age-related macular degeneration (n = 39) were included. Fundoscopic features of the fellow eyes were assessed using digital color fundus photographs taken at the time of diagnosis of neovascularization in the first affected eye. Grading was performed by two independent graders using RetmarkerAMD, a computer-assisted grading software based on the International Classification and Grading System for age-related macular degeneration. RESULTS: Baseline total number and area (square micrometers) of drusen in the central 1,000, 3,000, and 6,000 μm were considerably inferior in the fellow eyes of retinal angiomatous proliferation, with statistically significant differences (P < 0.05) observed in virtually every location (1,000, 3,000, and 6,000 μm). A soft drusen (≥125 μm) area >510,196 μm2 in the central 6,000 μm was associated with an increased risk of neovascularization (hazard ratio, 4.35; 95% confidence interval [1.56-12.15]; P = 0.005). CONCLUSION: Baseline fundoscopic features of the fellow eye differ significantly between retinal angiomatous proliferation and typical exudative age-related macular degeneration. A large area (>510,196 μm2) of soft drusen in the central 6,000 μm confers a significantly higher risk of neovascularization and should be considered as a phenotypic risk factor.

RETINAL ANGIOMATOUS PROLIFERATION: A Quantitative Analysis of the Fundoscopic Features of the Fellow Eye

PURPOSE: To quantitatively analyze and compare the fundoscopic features between fellow eyes of retinal angiomatous proliferation and typical exudative age-related macular degeneration and to identify possible predictors of neovascularization. METHODS: Retrospective case-control study. Seventy-nine fellow eyes of unilateral retinal angiomatous proliferation (n = 40) and typical exudative age-related macular degeneration (n = 39) were included. Fundoscopic features of the fellow eyes were assessed using digital color fundus photographs taken at the time of diagnosis of neovascularization in the first affected eye. Grading was performed by two independent graders using RetmarkerAMD, a computer-assisted grading software based on the International Classification and Grading System for age-related macular degeneration. RESULTS: Baseline total number and area (square micrometers) of drusen in the central 1,000, 3,000, and 6,000 μm were considerably inferior in the fellow eyes of retinal angiomatous proliferation, with statistically significant differences (P < 0.05) observed in virtually every location (1,000, 3,000, and 6,000 μm). A soft drusen (≥125 μm) area >510,196 μm2 in the central 6,000 μm was associated with an increased risk of neovascularization (hazard ratio, 4.35; 95% confidence interval [1.56-12.15]; P = 0.005). CONCLUSION: Baseline fundoscopic features of the fellow eye differ significantly between retinal angiomatous proliferation and typical exudative age-related macular degeneration. A large area (>510,196 μm2) of soft drusen in the central 6,000 μm confers a significantly higher risk of neovascularization and should be considered as a phenotypic risk factor.

Distribution of Light in the Human Retina under Natural Viewing Conditions

Age-related macular degeneration (AMD) is the leading cause of blindness inAmerica. The fact that AMD wreaks most of the damage in the center of the retina raises the question of whether light, integrated over long periods, is more concentrated in the macula. A method, based on eye-tracking, was developed to measure the distribution of light in the retina under natural viewing conditions. The hypothesis was that integrated over time, retinal illumination peaked in the macula. Additionally a possible relationship between age and retinal illumination was investigated. The eye tracker superimposed the subject’s gaze position on a video recorded by a scene camera. Five informed subjects were employed in feasibility tests, and 58 naïve subjects participated in 5 phases. In phase 1 the subjects viewed a gray-scale image. In phase 2, they observed a sequence of photographic images. In phase 3 they viewed a video. In phase 4, they worked on a computer; in phase 5, the subjects walked around freely. The informed subjects were instructed to gaze at bright objects in the field of view and then at dark objects. Naïve subjects were allowed to gaze freely for all phases. Using the subject’s gaze coordinates, and the video provided by the scene camera, the cumulative light distribution on the retina was calculated for ~15° around the fovea. As expected for control subjects, cumulative retinal light distributions peaked and dipped in the fovea when they gazed at bright or dark objects respectively. The light distribution maps obtained from the naïve subjects presented a tendency to peak in the macula for phases 1, 2, and 3, a consistent tendency in phase 4 and a variable tendency in phase 5. The feasibility of using an eye-tracker system to measure the distribution of light in the retina was demonstrated, thus helping to understand the role played by light exposure in the etiology of AMD. Results showed that a tendency for light to peak in the macula is a characteristic of some individuals and of certain tasks. In these situations, risk of AMD could be increased. No significant difference was observed based on age.

Retinal Macroglial Responses in Health and Disease

Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes andM¨uller cells (retinal macroglia) provide physical support to neurons and supplement them with several metabolites and growth factors.Macroglia are involved in maintaining the homeostasis of extracellular ions and neurotransmitters, are essential for information processing in neural circuits, participate in retinal glucose metabolism and in removing metabolic waste products, regulate local blood flow, induce the blood-retinal barrier (BRB), play fundamental roles in local immune response, and protect neurons from oxidative damage. In response to polyetiological insults, glia cells react with a process called reactive gliosis, seeking to maintain retinal homeostasis. When malfunctioning, macroglial cells can become primary pathogenic elements. A reactive gliosis has been described in different retinal pathologies, including age-related macular degeneration (AMD), diabetes, glaucoma, retinal detachment, or retinitis pigmentosa. A better understanding of the dual, neuroprotective, or cytotoxic effect of macroglial involvement in retinal pathologies would help in treating the physiopathology of these diseases.The extensive participation of the macroglia in retinal diseases points to these cells as innovative targets for new drug therapies.

PROTEIN-TRIGGERED SUSTAINED DRUG RELEASE CONTROLLED BY APTAMERS BOUND TO OLIGOMER-CROSSLINKED ALGINATE

Sustained drug release systems provide many advantages over traditional delivery methods such as extending the time in which the drug is found to be within an effective concentration within the therapeutic window, which decreases the frequency of administration of the drug, and increases patient compliance. Research using polyacrylamide crosslinked by oligomers containing an aptamer sequence, has demonstrated a pulsatile release over 50 minutes triggered by a 2 mM target adenosine concentration. This thesis aims to build off this concept by designing a system that delivers in a sustained manner when triggered by micromolar target concentrations reflective of disease in vivo, using macromolecular targets. For example, the disease wet age related macular degeneration (wet AMD) is associated with increased concentrations of the protein vascular endothelial growth factor (VEGF-A) – a macromolecule. Patients with wet AMD would benefit from the implantation of devices or microspheres that release drugs in a sustained manner in response to local VEGF concentrations. In this thesis, we hypothesize that the protein lysozyme, used to demonstrate proof-of-concept, could trigger the increased release of drugs from oligomer-crosslinked alginate. The objectives are to (i) demonstrate sustained release from alginate, (ii) design oligomer crosslinked alginate that degrades in response to lysozyme, and then (iii) use these systems to control the release of FITC-dextran with and without lysozyme. A series of control experiments and analyses were used to optimize the crosslinking of alginate by annealed oligomers. The cumulative release of FITC-dextran (MW 20,000) from oligomer crosslinked alginate increased by 3.4 μg when lysozyme (3 μM) was introduced at 48 hours, as opposed to controls which released only 0.2 μg. FITC-loaded alginate microspheres coated by oligomer-crosslinked alginate released 15% more FITC-dextran over 120 hours when placed into 3 μM of lysozyme than without lysozyme. Controls of alginate crosslinked with PEG or control oligomers (without a lysozyme aptamer sequence) had no changes in release with lysozyme. The incorporation of a lysozyme aptamer onto oligomers used to crosslink alginate disks or alginate coatings on microspheres resulted in different diffusion and release of FITC-dextran into PBS with or without lysozyme. This approach could be adapted for the delivery of drugs to diseases with specific protein profiles such as wet AMD.