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, the distribution of anti-HIV drugs, hemodynamic phenomona in vascular systems, and the thermal ablation of tumors. The following three projects are reported for this year: (1) 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 would eliminate the need for frequent invasive intervention. A number of different drugs and device configurations are being evaluated in vitro. Implant devices have been preliminarily tested in rats for the delivery of an angiostatic protein (photoreceptor epethial derived factor, PEDF) and these devices have resulted in delivery of PEDF through sclera, choroid, and retina of the rat eye. Finite element mathematical models that incorporate the geometry and physical properties of the device, the physico-chemical properties of the drug, and the physiology of the eye have been developed to assist in design of the devices. We are also using non-invasive methods with MRI to study transport of drug surrogates in the eye compartments using MRI tracers. (2) We have developed a preliminary physiologic pharmacokinetic model of the distribution of a pro-drug, FddA, for treating HIV infection in the central nervous system of AIDS patients. The initial model is based on data from mice experiments. The model can be extended to other species, including monkey and humans. Such models are useful in guiding the design of more effective drugs that will be better absorbed in the gastrointestinal tract after oral doses, and also will penetrate adequately into the brain and cerebral spinal fluid (3) We are investigating the use of magnetic resonance angiography (MRA) for making hemodynamic measurements in vascular systems, such as carotid and renal arteries. We have fabricated plastic and glass flow models of normal and stenosed human carotid and renal arteries and are characterizing the flow patterns and velocity fields in these """"""""phantoms"""""""" by means of particle image velocimetry (PIV) techniques. With the well-characterized flow models, we can validate the flow measurements made by MRA in these in vitro phantoms at identical flow conditions. MRA is being studied as a non-invasive means of making hydrodynamic measurements in patients for detecting vascular pathologies such as stenosis. We are also making measurements of pressure drops between the thoracic aorta and the renal artery just distal to a renal stenosis in our in vitro models in both steady and pulsatile flow. Finite element models of the carotid and renal flow systems are be used to corroborate the experimental results. (4) 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 experiments use video recording of the egg protein coagulation and have 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 plan to extend these studies using polyacrylimide gels as tissue simulants and to measure temperature profiles during RF ablation using infra-red thermography.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Intramural Research (Z01)
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Robinson, Michael R; Lee, Susan S; Kim, Hyuncheol et al. (2006) A rabbit model for assessing the ocular barriers to the transscleral delivery of triamcinolone acetonide. Exp Eye Res 82:479-87
Kim, Hyuncheol; Csaky, Karl G; Gravlin, Luisa et al. (2006) Safety and pharmacokinetics of a preservative-free triamcinolone acetonide formulation for intravitreal administration. Retina 26:523-30
Kim, Hyuncheol; Csaky, Karl G; Chan, Chi-Chao et al. (2006) The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res 82:760-6
Park, Juyoung; Bungay, Peter M; Lutz, Robert J et al. (2005) Evaluation of coupled convective-diffusive transport of drugs administered by intravitreal injection and controlled release implant. J Control Release 105:279-95
Kim, Hyuncheol; Csaky, Karl G; Gilger, Brian C et al. (2005) Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease. Invest Ophthalmol Vis Sci 46:655-62
Kim, Hyuncheol; Lizak, Martin J; Tansey, Ginger et al. (2005) Study of ocular transport of drugs released from an intravitreal implant using magnetic resonance imaging. Ann Biomed Eng 33:150-64
Amaral, Juan; Fariss, Robert N; Campos, Maria M et al. (2005) Transscleral-RPE permeability of PEDF and ovalbumin proteins: implications for subconjunctival protein delivery. Invest Ophthalmol Vis Sci 46:4383-92
Kim, Hyuncheol; Robinson, Michael R; Lizak, Martin J et al. (2004) Controlled drug release from an ocular implant: an evaluation using dynamic three-dimensional magnetic resonance imaging. Invest Ophthalmol Vis Sci 45:2722-31
Yim, Peter J; Cebral, Juan R; Weaver, Ashley et al. (2004) Estimation of the differential pressure at renal artery stenoses. Magn Reson Med 51:969-77
Lutz, Robert J; Warren, Kathy; Balis, Frank et al. (2002) Mixing during intravertebral arterial infusions in an in vitro model. J Neurooncol 58:95-106

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