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Optimization of Drug Delivery by Drug-Eluting Stents.

Bozsak F, Gonzalez-Rodriguez D, Sternberger Z, Belitz P, Bewley T, Chomaz JM, Barakat AI - PLoS ONE (2015)

Bottom Line: However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation.We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance.The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire d'Hydrodynamique (LadHyX), École Polytechnique-CNRS, Palaiseau cedex, France.

ABSTRACT
Drug-eluting stents (DES), which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours) or very slowly (over periods of several months up to one year) at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.

No MeSH data available.


Related in: MedlinePlus

The computational model used in the simulations considers the endothelium to be denuded upstream and downstream of the stent, over a distance that is one half of the inter-strut spacing measured from the stent strut centers.The subendothelial space and the media are modeled as distinct layers of the arterial wall.
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pone.0130182.g001: The computational model used in the simulations considers the endothelium to be denuded upstream and downstream of the stent, over a distance that is one half of the inter-strut spacing measured from the stent strut centers.The subendothelial space and the media are modeled as distinct layers of the arterial wall.

Mentions: As depicted in Fig 1, the model considers a straight and axisymmetric arterial segment. The arterial wall is assumed rigid and is modeled as a two-layered structure with the subendothelial space (SES) of the intima and the media represented as distinct porous layers. The endothelium and internal elastic lamina (IEL) are considered as interfacial matching conditions, while the adventitia is modeled as a boundary condition of the media. The model uses a recently developed reversible second-order reaction model [33] to account for the interaction of the drug with the cells of the arterial wall. The DES is assumed to consist of three circular cross-section struts spaced at intervals of 0.7 mm. Each strut has a diameter of 100 μm and is covered with a 10 μm-thick polymer coating, reflecting approximate dimensions of typical second-generation DES [34]. We assume that as a result of stent deployment, the endothelium is completely denuded within the stented portion of the vessel as well as up to a distance equal to half of the inter-strut spacing (0.35 mm) both upstream and downstream of the stent but is intact otherwise. We define the therapeutic domain as the volume of the arterial wall containing the stent and extending by two-thirds of the stent length both upstream and downstream of the stent (Fig 1). The flow in the arterial lumen is governed by the Navier-Stokes equations, while flow in the arterial wall is assumed to be governed by Darcy’s Law. The entire flow field is treated as steady. Time-dependent drug transport occurs as follows: 1) in the lumen the drug is transported via convection and diffusion; 2) in the polymer coating of the stent drug transport is assumed to be purely diffusive; 3) in the SES and media drug transport is via convection and diffusion with both specific binding and unbinding of the drug to cells of the arterial wall (ECs and SMCs) and non-specific binding to the extracellular matrix.


Optimization of Drug Delivery by Drug-Eluting Stents.

Bozsak F, Gonzalez-Rodriguez D, Sternberger Z, Belitz P, Bewley T, Chomaz JM, Barakat AI - PLoS ONE (2015)

The computational model used in the simulations considers the endothelium to be denuded upstream and downstream of the stent, over a distance that is one half of the inter-strut spacing measured from the stent strut centers.The subendothelial space and the media are modeled as distinct layers of the arterial wall.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470631&req=5

pone.0130182.g001: The computational model used in the simulations considers the endothelium to be denuded upstream and downstream of the stent, over a distance that is one half of the inter-strut spacing measured from the stent strut centers.The subendothelial space and the media are modeled as distinct layers of the arterial wall.
Mentions: As depicted in Fig 1, the model considers a straight and axisymmetric arterial segment. The arterial wall is assumed rigid and is modeled as a two-layered structure with the subendothelial space (SES) of the intima and the media represented as distinct porous layers. The endothelium and internal elastic lamina (IEL) are considered as interfacial matching conditions, while the adventitia is modeled as a boundary condition of the media. The model uses a recently developed reversible second-order reaction model [33] to account for the interaction of the drug with the cells of the arterial wall. The DES is assumed to consist of three circular cross-section struts spaced at intervals of 0.7 mm. Each strut has a diameter of 100 μm and is covered with a 10 μm-thick polymer coating, reflecting approximate dimensions of typical second-generation DES [34]. We assume that as a result of stent deployment, the endothelium is completely denuded within the stented portion of the vessel as well as up to a distance equal to half of the inter-strut spacing (0.35 mm) both upstream and downstream of the stent but is intact otherwise. We define the therapeutic domain as the volume of the arterial wall containing the stent and extending by two-thirds of the stent length both upstream and downstream of the stent (Fig 1). The flow in the arterial lumen is governed by the Navier-Stokes equations, while flow in the arterial wall is assumed to be governed by Darcy’s Law. The entire flow field is treated as steady. Time-dependent drug transport occurs as follows: 1) in the lumen the drug is transported via convection and diffusion; 2) in the polymer coating of the stent drug transport is assumed to be purely diffusive; 3) in the SES and media drug transport is via convection and diffusion with both specific binding and unbinding of the drug to cells of the arterial wall (ECs and SMCs) and non-specific binding to the extracellular matrix.

Bottom Line: However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation.We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance.The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire d'Hydrodynamique (LadHyX), École Polytechnique-CNRS, Palaiseau cedex, France.

ABSTRACT
Drug-eluting stents (DES), which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours) or very slowly (over periods of several months up to one year) at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.

No MeSH data available.


Related in: MedlinePlus