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Margination of Microcapsules in Small Arteries

Periodic Reporting for period 1 - MSMART (Margination of Microcapsules in Small Arteries)

Reporting period: 2015-09-03 to 2017-09-02

Vascular-targeted drug delivery using micro/nano-particles as drug carriers have been exploited in recent years in therapeutic interventions of cancer, cardiovascular, pulmonary and inflammatory diseases and so on. This approach has numerous advantages over conventional delivery (e.g. lower drug dosage and thus reduced side effects, sustained release), however, a major challenge is to improve cell selectivity and wall-adhesion efficiency by functionalizing the drug carriers. Extensive research has focused on identifying disease-associated biomolecules on the endothelium, or suitable antibody/peptides targeting these molecules, however, much less attention has been paid to a crucial haemodynamic aspect: will the drug carriers be able to migrate from the midstream of the blood to the RBC-free layer close to the vessel wall, under complex interactions with blood cells? This is particularly important in small arteries, where many diseases (e.g. arteriolosclerosis) develop but surgical operations become difficult. The aim of the present project is therefore to conduct a systematic study of the effects of system parameters, such as the blood flow condition, the particle shape, size etc on the cross-stream migration and margination of microparticles in blood flows in small arteries.
Specific research objectives are: 1, to develop experimental and computational platform to study the cross-stream migration and margination of microcapsules in blood flow in small arteries; 2, to investigate the effects of system parameters, such as the shape and size of the capsule, the flow inertia and shear rates, vessel geometry etc. on margination of microcapsules in blood flows; 3, to develop practical principles for engineering microcapsules with optimum margination in blood flow in small arteries. All three research objectives have been largely achieved during the fellowship period.
During the project, the fellow has developed a new experimental platform and a simulation tool, and employed those to systematically consider the effects of wall shear rate, inertia, particle size and shape, channel geometries on particle migration and margination in blood flow in simulated arterioles. The experiment results suggested that microparticles with an equivalent diameter of about 3μm tend to have the best accumulation near the wall. However, the degree of accumulation varied with the wall shear rate, particle size, and shape. The margination propensity of the particles is increased when the wall shear rate is reduced. The microparticles (regardless of shape) with a smaller size of 2μm exhibit higher margination propensity than that of a larger one (i.e. 4μm). It is also found that the oblate particles have better margination when compared with the spherical particles with the same volume, indicating that the margination of microparticles increases with decreasing the aspect ratio.
The fellow has attended a number of conferences to disseminate the research results. Notably, she participated in the conference of Flow 17 held in UPMC in Paris on July 3-5, 2017, which is an important meeting in the field of fluid dynamics with applications on medical diagnostics, drug development and delivery, ink-jet printing and so on. The work presented received wide attention from the international peers at the meeting. The fellow is in the process of writing two manuscripts to disseminate the results.
The project addressed a fundamental issue in microparticle-based intravascular drug delivery, which is a promising approach for targeted therapeutic or diagnostic procedures in cancer and cardiovascular diseases. It provides the first experimental evidence that microparticles with proper size can marginate in blood flow and shows that the effect of aspherity can promote margination. Those results will potentially contribute to the design of microparticles with better margination property and therefore higher chance of adhesion to arterial endothelium. The project will also pave the way for novel designs of injectable medicines or imaging-contrast agents with enhanced vascular targeting efficiency. Those will benefit EU patients, pharmaceutical companies, and strengthen the economic competitiveness of the EU.
Intravascular delivery of drugs using microparticles