Transient subject-specific drug delivery in stented arteries: physics-based simulation of controlled release and retention
Presenting Author: Farhad Rikhtegar Nezami 1
1 Institute for Medical Engineering and Science, Massachusetts Institutes of Technology, USA
Additional Authors: Abraham R. Tzafriri2, and Elazer R. Edelman1,3
2 CBSET Inc., Lexington, MA, USA
3 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, USA
BACKGROUND/PURPOSE: Drug-eluting stents are the mainstay therapy for obstructive arterial disease, yet further innovation is hampered by cost and lack of experimental techniques. In silico models, akin to what developed here, offer flexible and readily available tools to address these issues, enabling determination of the spatio-temporal variation of bound/unbound drug concentration in the arterial wall not achievable through animal models or human trials.
METHOD: We developed and verified a drug-delivery module to study pharmacokinetics and pharmacodynamics in emerging endovascular implants (Figure 1). To extend the realism, we here consider controlled transient release of drug from the coating (including the burst phase), flow-mediated convection of drug, realistic diffusion inside the porous tissue, and binding process. Sirolimus was assumed to be loaded on abluminal face of emerging bioresorbable scaffolds and released in a porous artery via plasma infiltration and diffusion. Binding/unbinding to extracellular matrix cells and specific receptors were also included. An innovative reduced-order model of pharmacokinetics was developed to approximate the realistic release profile and validated by experimental measurements conducted by device manufacturers. We confined the costly simulation of months of drug release via an innovative combination of transient and quasi-steady settings with negligible accuracy compensation.
RESULTS: Our simulation outcomes demonstrate that strut apposition considerably rises the free drug concentration in vascular tissue. However, drug retention and receptor saturation quickly plateau the concentration of bound drug in the entire volume of the vasculature at the intervention segment. Hemodynamic disruption by struts and drug pooling at the site of blood recirculation impose an asymmetric pattern of drug delivery increasing the mural concentration distal to stagnation sites. This, as well, saturates the drug receptors well beyond the site of intervention highlighting the importance of biological flows in drug transport.
CONCLUSION: Physico-chemical characteristics of depleted drug play a critical role in drug dynamics. Our developed module is an invaluable tool to design and develop emerging devices and contribute to regulatory oversight and evaluation of clinical performance.
Acknowledgement: European Union’s Horizon 2020 program (grant agreement no 777119) and NIH R01 909.