Mathematical Modeling of Intravascular Drug Delivery In Drug-Eluting Stents with Biodegradable Coating

Drug-eluting stents (DES) are commonly used in the coronary angioplasty procedure for preventing vessel remodeling and reducing in-stent restenosis. Typical DES consists of a metallic mesh coated with a polymeric thin film, within which the drug is embedded and released for a prolonged time at the implanted coronary artery site. While both biodurable and biodegradable polymers can be used for the stent coating, biodurable coatings exclusively produce very slow release after a fast initial burst [1]. In contrast, a coating of biodegradable polymer such as poly(D,L-lactic-co-glycolic acid) (PLGA) exhibits multiphase drug release characteristics due to polymer degradation and erosion [2], and is more versatile in the design and control of drug release profiles.

This work presents a mathematical model that describes the coupled process of polymer degradation, erosion, and drug transport in a PLGA-coated DES. The delivery of a hydrophobic drug (sirolimus) is considered. A combined mechanism of bulk random-chain scission and catalyzed end-chain scission was used for the degradation model [3], which was able to capture the polymer molecular weight change and erosion rates. The drug transport is modeled by an evolving effective diffusivity that is dependent on the current porosity, diffusivity in the bulk polymer, and partitioning between the polymer and liquid phase (in the pores).

The model is first simulated for an in vitro drug release study and compared with experimental data in the literature [4]. The model correctly predicts the in vitro release of sirolimus from the PLGA-coated DES. Following that, the model is extended to study in vivo drug delivery from the DES implanted in a coronary artery [5]. Drug in the arterial wall is assumed to undergo a first-order reversible binding and an internalization mechanism [6]. Different configurations of the stent strut in the arterial wall (contacting, half-embedment, and full-embedment) were studied. The full-embedment configuration is observed to have the longest duration of release as well as the highest drug concentration profiles in the arterial wall. The porous structure generated by degradation and erosion facilitates a significant amount of drug dissipation into the lumen for the half-embedment (or contacting) configuration, resulting in shorter release time and lower arterial drug concentration. This finding potentially distinguishes biodegradable coating greatly from biodurable coating in terms of in vivo DES performance.

Reference

[1] G. Acharya, K. Park, Mechanisms of controlled drug release from drug-eluting stents, Adv Drug Deliver Rev, 58 (2006) 387-401.

[2] A. Finkelstein, D. McClean, S. Kar, K. Takizawa, K. Varghese, N. Baek, K. Park, M.C. Fishbein, R. Makkar, F. Litvack, N.L. Eigler, Local drug delivery via a coronary stent with programmable release pharmacokinetics, Circulation, 107 (2003) 777-784.

[3] R.P. Batycky, J. Hanes, R. Langer, D.A. Edwards, A theoretical model of erosion and macromolecular drug release from biodegrading microspheres, Journal of Pharmaceutical Sciences, 86 (1997) 1464-1477.

[4] X.T. Wang, S.S. Venkatraman, F.Y.C. Boey, J.S.C. Loo, L.P. Tan, Controlled release of sirolimus from a multilayered PLGA stent matrix, Biomaterials, 27 (2006) 5588-5595.

[5] X. Zhu, D.W. Pack, R.D. Braatz, Modeling intravascular delivery from drug-eluting stents: effect of anisotropic vascular diffusivity and drug loading on arterial drug distribution (submitted).

[6] M.A. Lovick, E.R. Edelman, Computational simulations of local vascular heparin deposition and distribution, Am J Physiol-Heart C, 40 (1996) H2014-H2024.