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. 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 an MRI-enhancer, drug surrogate, Gd-DPTA, that is delivered to the rabbit eye from a polymer implant. In conjunction with these experiments, we have developed a 3-D finite element model that predicts the concentration of the delivered Gd-DPTA in the eye. We have correlated the theoretical predictions with experimental MRI data to better understand the drug transport processes. The finite element mathematical models incorporate the geometry and physical properties of the device, the physico-chemical properties of the drug, and the physiology of the eye. The models are useful in guiding the design of the drug release devices for optimal therapy. (2) 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 modeled by the previous study with Gd-DPTA. We are studying the movement of this protein across the sclera, choroid, and retinal epithelial cells following subconjunctival delivery of PEDF from a drug implant. We are developing novel implant devices that can release the protein for many days or even weeks. Studies are being conducted in mice and rats using fluorescent-labelled proteins and the concentration-time history of the protein within eye tissues is being measured. (3) 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 are extending these studies by using polyacrylimide gels as tissue simulants and we are measuring temperature profiles during RF ablation by means of thermocouples and infra-red thermography. Our experiments are designed 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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