| Summary: | Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. === Includes bibliographical references. === Drug-eluting stents (DES) virtually eradicate the clinical phenomena of vessel restenosis; yet, they also increase the short and long term risks for stent thrombosis. To improve their safety and efficacy, it is critical to examine factors that alter local biologic outcome. The central hypothesis of this thesis is that local efficacy and toxicity are in part determined by the duration of drug exposure and local arterial drug concentrations. This thesis investigates how factors both intrinsic and extrinsic to the device impact local intravascular drug delivery. Computational models of local fluid mechanics and drug transport were formulated to study how arterial drug uptake is modulated by local blood flow, stent placement, administered drug dose and release kinetics, and the evolving local vascular response to the device. Lumenally flowing blood around stent struts was capable of transporting drug to the arterial wall in the presence of both single and multiple configurations of drug eluting stent struts. The extent of blood flow mediated arterial drug delivery depended upon the rate of drug release and administered dose. Slow drug release led to sustained, low magnitude drug uptake; exceedingly fast release resulted in transient and minimal tissue absorption due to rapid drug depletion. === (cont.) Drug release over several minutes maximized peak arterial drug concentrations, though arterial drug levels were not sustained. Mural thrombus did not alter the rate of drug release from a stent; however, clots increased local drug availability and reduced the extent of drug washout. Subsequently, variability in mural thrombi formation caused fluctuations in arterial drug levels. Computational modeling revealed that free diffusion of hydrophobic drugs was slower than experimental arterial drug absorption. Subsequently, a novel mechanism for arterial drug transport has been proposed in which drug diffuses faster through the arterial wall due to its association with carrier proteins. Within this thesis, we have elucidated that device, patient, and physician-dependent device implantation are among the factors governing arterial drug deposition; these subsequently dictate local efficacy and toxicity. Thus, rational design of improved local therapeutics requires consideration of how multiple interrelated factors intrinsic and extrinsic to the device determine local efficacy and toxicity. === by Brinda Balakrishnan. === Ph.D.
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