PROJECTS
| Retinal Metabolism |
Laser Surgery |
| Ocular Blood Flow |
Ultramicrosurgery |
| Vascular Regulation |
Microfistula |
| Disease Models |
Funding |
| Laser Therapy |
Training and Career Development |
Retinal Metabolism
Oxygen is the most vital nutrient required to support retinal function. Using microelectrodes with tip diameters of one thousandth of a millimeter, we are identifying which layers of the retina require the most oxygen. This then indicated which retinal components are most susceptible to insufficient oxygen supply. Perhaps the most important finding to date has been that there are specific layers within the inner retina that dominate inner retinal oxygen consumption. These layers, the plexiform layers, contain cells that perform much of the signal processing required in the inner retina. They are also the sites of much of the retinal pathology seen in ischemic diseases such as diabetic retinopathy. This observation has opened up a new avenue of research aimed at suppressing the oxygen requirements of these cells, thereby making the retina more resistant to the effects of reduced oxygen supply.
Schematic illustration of the oxygen distribution across the retina (black line) and the sources and sinks for oxygen within the different retinal layers. The retina has a highly organized structure in which different cell classes or components are organized in specific layers. This allows studies of the metabolic properties of different cell types to be achieved. The oxygen distribution reflects the presence of oxygen sources (the vascular beds) and the key oxygen consuming layers. We have developed a range of mathematical models to allow us to quantify retinal oxygen consumption in specific layers.
Actual data from a laboratory rat showing an excellent agreement between the theoretical prediction and the experiment data. This experiment illustrates the increased oxygen consumption of the photoreceptor inner segments (300 µm track depth) in the outer retina. Even simple physiological changes such as dark adaptation can affect retinal oxygen levels. Changes to the oxygen supply to the retina in various retinal diseases can result in insufficient oxygenation of critical cell layers.
Ocular Blood Flow
Nutrient supply to the eye and the efficient removal of waste products is achieved by blood flowing through the network of vasculature within the eye. Retinal ischemia (inadequate blood flow) ia a major component in many retinal diseases. We have a number of techniques for measuring ocular blood flow, and we are looking into the effects of different types of retinal disease on the proper regulation of blood flow. Because the retina needs to be largely transparent, the retinal circulation has evolved to have rather special properties. Because the retina must be largely transparent ( to allow light to pass through and reach the photoreceptors), the vascular network is relatively sparse. However, the retinal vessels have a powerful ability to locally regulate blood flow in response to changing demands or supply conditions. This powerful autoregulatory ability appears to be compromised in many disease states. Understanding the mechanisms responsible for these effects will ultimately tell us how to target therapeutic strategies to overcome the problem or ameliorate its effects.
Vascular Regulation
We have a range of in vitro preparations for studying the anatomy, physiology and pharmacology of different components of the ocular circulation. At the smallest end of the scale we are able to study the vasoactive properties of individual retinal vessels. Tiny tubes are inserted into either end of the vessel and test solutions are passed through the vessel in much the same way that blood normally flows. This is technically very demanding since the vessels are typically only 100 microns in diameter. Potentially vasoactive drugs can be added into the perfusing solution and the effects on the diameter of the vessel determined.
Schematic illustration of the isolated perfused vessel system.
Digital “frame grabbed” image of a human retinal artery in the perfusion apparatus
We have also established experimental systems for studying larger vessel (myograph technique) or the entire vascular tree of the eye by using an isolated perfused eye preparation. Our belief is that it is only by understanding the behaviour of the individual components of the vascular system can an accurate picture of the performance of the entire system be developed. This is an essential step if pharmacological agents are to be developed to manipulate ocular blood flow to reduce the effects of specific eye diseases.
Disease Models
Many naturally occurring or induced models of retinal disease can be studied in the laboratory. In this way we can begin to understand the dominant mechanisms responsible for the human diseases such as diabetic retinopathy, retinal degeneration, and ischemic diseases of the retina following blockage of retinal vessels. Through a process of national and international collaborations we have been using our unique technologies to measure blood flow and oxygen metabolism in the eyes of laboratory rats with diseases of greatest relevance to clinical ophthalmology.
Laser Therapy
We are investigating new techniques for using laser therapy in the prevention of the sight threatening consequences of diabetic retinopathy and retinal ischemia. Our approach is to use better targetted therapy and the minimum level of laser treatment required to produce the therapeutic benefit. This involves research into the interaction between different wavelength lasers and the retinal tissue, as well as the use of energy modulation of the laser to confine the laser therapy to specific cell types.
Laser Surgery
New methods of surgical cutting are being investigated. The combination of highly localized laser energy and the robotically controlled manipulation of the cutting instruments are being combined to allow microsurgery within the eye at a resolution not previously attainable in ophthalmology. This may open up a new range of surgical approaches to cutting troublesome membranes or vessel compressing tissues in a host of retinal diseases.
Ultramicrosurgery
A range of robotically driven instruments are being developed. These instruments are able to be manipulated inside the eye with a precision of a few microns. The elimination of the natural hand tremor of the surgeon allows procedures to be performed on a microscopic scale not previously attainable. These patented instruments are now under further development to bring them to the stage where a clinical trial can be undertaken. Negotiations with commercial partners to assist with the design, manufacture, and marketing of these instruments are underway.
Microfistula
A new type of glaucoma drainage surgery is under development. Microscopic drainage tubes “microfistulas” are implanted in the eye to increase the outflow of fluid from the eye to restore normal pressure within the eye. High pressure within the eye is a major risk factor in glaucoma, a common sight threatening disease currently requiring life long medication to lower the pressure within the eye. The novel aspect of our surgical approach is that the implantation is achieved without disruption of the overlying tissue at the drainage site, and the biocompatible implant dissolves with time leaving a clear drainage pathway.
Funding
The major source of funding for our work is obtained from competitive grants awarded by the National Health and Medical Research Council of Australia (NH&MRC). We have managed to secure continuous NHMRC funding for almost 20 years. Current funding includes a collaborative component of a major New Program Grant ($5.7M over five years, 2002-2006), and a Development Grant ($437,000 over three years, 2002-2004). Supplementary funding for specific projects when required has been obtained from International funding agencies such as JDFI, National agencies such as Retina
Training and Career Development
The Physiology and Pharmacology Centre offers a very dynamic environment for the training of young scientists, clinicians, and engineers. The world-class facilities of the Lions Eye Institute, and the presence of many internationally competitive researchers offers many opportunities for post graduate and post doctoral studies.
Postgraduate Positions Available (2004 –2007):
- Retinal Mitochondrion Physiology
- Laser Interaction with Tissue
- Drainage Pathways following Filtration Surgery
- Spectroscopic Monitoring of Retinal Metabolism
- Tissue Pressure within the Optic Nerve
- The Physiology of Central Vein Occlusion
- New Techniques for Treatment of Branch Vein Occlusion
For further information contact Professor Dao-Yi Yu dyyu@cyllene.uwa.edu.au
