Physical and theoretical models of anatomical and physiological systems are being used in our laboratory to study a variety of phenomena such as the transport of drugs into the eye and the thermal ablation of tumors. The following three projects are reported for this year: (1) Magnetic Resonance Imaging (MRI) of Drug Movement in the Eye: A number of inflammatory and neoplastic diseases of the eye are currently treated by repeated intravitreal drug injection. We are developing sustained drug release devices for both intravitreal and subconjunctival implantation that could release drugs for periods as long as months. These devices would eliminate the need for frequent invasive intervention. A number of different drugs and device configurations are being evaluated in vitro and in vivo. Understanding the mechanism of drug transport within the eye is crucial to optimal delivery of agents with the implant devices. In one project, we are using MRI as a non-invasive means to track the movement of several MRI-enhancers, such as Gd-DPTA and dendrimers of various sizes and charge. The delivery of these agents is by slow continuous infusion or by specially designed long-term release implant devices. In conjunction with these experiments, we are modifying our previous 3-D finite element model to include the three main layers of the posterior segment of the eye: retina, choroid/rpe, and sclera. The finite element mathematical model incorporates the geometry and physical properties of the implant device, the physico-chemical properties of the drug, and the physiology of the eye. These models are useful in guiding the design of the drug release devices for optimal therapy. (2) To aid in the assessment of the various physiological mechanisms that control the movement of drug delivered in the eye, we are using florescence imaging to map and to quantitate the concentration of marker agents, like Alexaflor dye, from microtomed rabbit eye tissue sections. Rabbits are injected with the dye and sacrificed at serial time points for tissue sampling. Image processing tools are employed to quantitate image intensity with marker concentration. (3) Delivery of Therapeutic Proteins to the Eye: An angiostatic protein, PEDF, (photoreceptor epithelial derived factor) has been shown to restrict the growth of new blood vessels in the choroids, which could inhibit the evolution of macular degeneration. PEDF is a large molecular weight protein (50 kD) and presents unique delivery problems to the eye compared to smaller molecular weight drugs modelled by the previous study with Gd-DPTA. We have studied the movement of this protein across the sclera, choroid, and retinal pigment epithelial cells (rpe) following subconjunctival delivery of PEDF from a drug implant. We are currently developing novel implant devices that can release the protein for many days or even weeks. Studies have been conducted in mice and rats using fluorescent-labelled proteins and the concentration-time history of the protein within eye tissues has been measured. Also, a series of in vitro experiments have been conducted with rpe monolayer cell cultures and excised segments of bovine sclera to study the transport of ovalbumin and PEDF in these model eye systems. (4) Radio-frequency Ablation of Solid Tumors: We have developed an in vitro method of simulating thermal ablation of tumor tissue using chicken egg whites whose protein coagulates at approximately 60 degrees C. Our initial experiments used video recording of the egg protein coagulation and demonstrated the temporal and spatial pattern of tissue 'death' which coincides with the protein coagulation. Several clinical thermal ablation probes were studied. These experimental ablation patterns have been corroborated by heat transfer mathematical models. We have extended these studies by using polyacrylimide gels as tissue simulants and we have measured temperature profiles during RF ablation by means of thermocouples and infra-red thermography. Our experiments help us to gain a better understanding of the effect of cooling by adjacent blood vessels on the thermal burn patterns and to predict temperature profiles from a variety of commercially available thermal probes.
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