(639f) 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.