Thrombus causes fluctuations in arterial drug delivery from intravascular stents

Abstract

Arterial drug concentrations determine local toxicity. As such the emergent safety concerns surrounding drug-eluting stents mandate an investigation of the factors contributing to fluctuations in arterial drug uptake. Drug-eluting stents were implanted into porcine coronary arteries, arterial drug uptake was followed and modeled using 2-dimensional computational drug transport. Arterial drug uptake in vivo occurred faster than predicted by free drug diffusion, thus an alternate, mechanism for rapid transport has been proposed involving carrier-mediated transport. Though there was minimal variation in vivo in release kinetics from stent to stent, arterial drug deposition varied by up to 114% two weeks after stent implantation. The extent of adherent mural thrombus also fluctuated by 113% within 3 days after implantation. The computational drug transport model predicted that focal and diffuse thrombi elevate arterial drug deposition in proportion to the thrombus size by reducing drug washout subsequently increasing local drug availability. Fluctuations in arterial drug uptake are commonly reported. We now explain that variable peristrut thrombus can explain such observations even in the face of a narrow range of drug release from the stent. The mural thrombus effects on arterial drug deposition may be circumvented by forcing slow, rate limiting arterial transport that cannot be further hindered by mural thrombus. Keywords stents; drug delivery; restenosis; thrombus II. IntroductionThere is increasing concern for the risk of thrombosis in drug-eluting stents late after implantation. It was reported that drug-eluting stents clot at 0.6% each year after implantation for up to 3 years 1 and remain an issue even years after implantation 2,3 . Documentation of delayed healing and re-endothelialization suggest that the unhealed tissue state might provide a nidus for thrombosis [4][5][6] . Drug-eluting stents may delay recovery of endothelial function *Corresponding author. Phone: 617 253 1569 Fax: 617 253 2514 innga@mit.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript compared to their bare metal counterparts even 6 months after implantation 7,8 . Heightened local arterial drug levels may be responsible for these observations and may be an especially potent problem given the narrow therapeutic window for paclitaxel and sirolimus and their selective effects on smooth muscle and endothelial cells 9,10 . Complete appreciation of the role and limitations of drug eluting stents requ...

Arterial Mass Transport Behaviour of Drugs from Drug Eluting Stents

“…The presence of clot alters the local environment of the stent strut and the physiological transport forces that regulate arterial uptake and retention. Balakrishnan et al(2008) reported that drug eluting stents clot at a rate of 0.6% each year after implantation for up to 3 years. Strut position within a clot also has a major influence on the arterial uptake.…”

“…Often with biological modelling it is necessary to make assumptions when applying boundary conditions. For example treating the artery wall as rigid (Mongrain et al, 2007;Devereux, 2005;Kaazempur-Mofrad and Ethier, 2001) or assuming that mass transport within the wall is modulated solely by diffusion (Balakrishnan et al, 2008(Balakrishnan et al, , 2007(Balakrishnan et al, , 2005Mongrain et al, 2007Mongrain et al, , 2005 are two examples of ways commonly employed to simplify what is in reality a very complex problem. However, as previously mentioned the fundamental in vivo issues should be taken into account as much as possible when applying such simplifications.…”

“…Coupled with the complex geometry of the coronary arteries, the pulsating blood velocity profile is an integral part in the mass transport behaviour of blood borne species. However, when considering the transport of drugs from a DES a common assumption to make is the presence of a steady fully developed flow profile within the lumen (Balakrishnan et al, 2008(Balakrishnan et al, , 2007(Balakrishnan et al, , 2005Mongrain et al, 2007Mongrain et al, , 2005. When modelling BSMT it may be necessary to incorporate the time-dependent pulsatile nature of blood flow.…”

“…The application of such a boundary condition is prevalent in mass transport studies of this nature (Kolachalama et al, 2009;Balakrishnan et al, 2008Balakrishnan et al, , 2007Balakrishnan et al, , 2005Rajamohan et al, 2006).…”

“…Therefore it can be assumed that the luminal inlet concentration has a constant value equal to zero. This boundary condition has been used extensively in mass transport studies on DES (Balakrishnan et al, 2008(Balakrishnan et al, , 2007(Balakrishnan et al, , 2005Mongrain et al, 2007Mongrain et al, , 2005.…”