Intravascular Delivery From Drug-Eluting Stents: Effect of Anisotropic Diffusivity and Drug Loading On Arterial Drug Distribution

Stents are widely used in coronary angioplasty procedures to prevent vessel remodeling.  However, patients implanted with bare-metal stents very often experience a high risk of in-stent restenosis (ISR) due to the inflammatory response to vascular injury and the low effect of systemic drug in-take.^[1,2]  Promising results in ISR reduction has been achieved by using polymer-coated drug-eluting stents as a local drug delivery device.^[1,2] The device is able to ensure a continuous release of drug at the diseased vascular site, maintain a high local drug level while keeping the systemic drug level negligible.^[3]  Moreover, recent study found that ISR is more likely to happen in stented coronary arteries with non-uniformly distributed struts, with the maximum thickness of neointimal hyperplasia occurring at the site with maximum inter-strut angle.^[4,5]

In this work we present a two-dimensional mathematical model which describes the intravascular delivery of a hydrophobic drug from a drug-eluting stent with bio-durable polymeric coating.  The model takes into account the stent geometry and incorporates the coupled drug diffusion and reversible binding in the vascular wall.  The finite volume method is used in solving the model.  Drug release profiles in the coating, spatially-averaged bound- and free-drug concentrations in the arterial wall, and spatiotemporal drug distributions in the arterial wall are simulated.  Two types of drug-loadings are investigated: (i) drug loading less than or equal to the solubility, and (ii) high drug loading much larger than the solubility.

Release profiles in the stent-coating are observed to depend not only on the coating diffusivity but also on the properties of the surrounding tissue.  The spatially-averaged drug concentrations at quasi-steady state are more profoundly affected by the vascular diffusivity than that of the coating.  Anisotropic drug diffusivities results in similar average drug levels in the vascular tissue but very different spatial distributions.  Lack of drug in some areas of the superficial arterial wall is observed and explains the reported experimental finding of thickest ISR occurrence at maximum inter-strut angle.  Higher circumferential diffusivity reduces the drug gradient in the circumferential direction and produces more uniform drug loading in the superficial vascular wall, which can reduce the thickness of in-stent restenosis.  Moreover, higher free-drug concentration than that of bound-drug can occur at local sites and an analytical expression for the critical condition of occurrence is derived.

Reference

[1] Simon DI, Costa MA. Molecular basis of restenosis and drug-eluting stents. Circulation. 2005; 111(17):2257-2273.

[2] Colombo P, Bruschi G, Santin M. Interfacial biology of in-stent restenosis. Expert Review of Medical Devices. 2005; 2(4):429-443.

[3] Sohier J, De Scheerder I, Van Den Mooter G, Deconinck E. Pharmaceutical aspects of drug eluting stents. J. Pharm. Sci. 2008; 97(12):5047-       5060.

[4] Hiro T, Fujii T, Yasumoto K, Murashige A, Kohno M, Murata T. Impact of the cross-sectional geometry of the post-deployment coronary stent       on in-stent neointimal hyperplasia - An intravascular ultrasound study. Circulation J. 2002; 66(5):489-493.

[5] Mintz GS, Carlier SG, Kobayashi Y, Fujii K, Yasuda T, Takebayashi H. Nonuniform strut distribution correlates with more neointimal       hyperplasia after sirolimus-eluting stent implantation. Circulation. 2004; 110(22):3430-3434.