Numerous studies evaluate pharmacokinetic properties of nano-objects, but very few established correlations between
physico-chemical design, toxicity and therapeutic efficiency of nanoparticles (NPs) in human1. Indeed, when injected in
the body, NPs face rapid covering by various proteins (so-called protein corona, PC)2, which modify NPs surface
properties (energy, chemistry, size), and biological responses (cell uptake, toxicity). This can either completely contradict
or enhance NPs therapeutic efficiency demonstrated either in 2D or 3D in-vitro models3. This discrepancy results from the
huge influence of dynamic flow imposed by human bloodstream, tuning the PC formation compared to static conditions.
The dynamic flow creates shear stress (tangential force of the flowing blood), which stimulates the endothelial surface of
blood vessels and provides a continual source of biomolecules4. To establish new outcomes about the role of PC on the
biodistribution and circulation, dynamic studies considering blood composition and blood dynamic constraints (shear,
circumferential, longitudinal stresses…) applied to NP and the vessel wall must be conducted. To the best of our knowledge,
only two studies were conducted in dynamic media those last two years5,6, but were restricted to coated PDMS-based
microfluidic systems with one fixed shear stress. Those systems are of course interesting, but the crucial influences of the
bio-fluid dynamic depending on blood vessel type as well as the interaction with the vessel wall are missing. Indeed, the
interaction between the shear stress imposed by blood flow to the vessel wall, NPs and the endothelial layer in direct contact
with the flow cannot be monitored. On the other hand, different attempts were developed very recently for the
characterization of PC covering NPs such as NIR-FCS7, asymmetrical flow field-flow fractionation (AF4)8, cryo-TEM9 to
establish PC fingerprint and to link this signature to the behavior of cells in contact with NPs. Those crucial and recent
technological developments can be transposed within the project to the study of functional NPs injected in biomimetic
vessels. Indeed, all those current studies referred to NPs in a static environment whereas by using a biomimetic
system, where the shear stress can be tuned by controlling the fluid dynamic, this project will be able to provide new
insight on PC formation in a model of capillaries, which represent the smallest vessels from which NPs are
distributed to tissues.
To the best of our knowledge, nothing is known about PC formation under dynamic condition, which has a major
influence on NP pharmacokinetics and pharmacodynamics. This PhD project aims to develop a vessel-on-chip model
in order to determine parameters (NP surface, biofluid flow velocity, composition…) influencing PC formation
around NPs under physiological condition of dynamic flow. To achieve this aim, a microfluidic system composed of
channels covered by a layer of endothelial cells mimicking capillaries will be developed. This microfluidic system
models the arrival of nanomedicines to the targeted tissue to highlight the influence of dynamic shear stress on NPs covering
by proteins. To consider shear stress influence, NPs will be tested and deeply characterized after their injection in the vesselon-
chip model. The PhD project will then enable the study of NP surface interaction at the nanoscale in robust vessel models
by combining the know-how, i.e. vessel mechanic and physiology, and material sciences of CITHEFOR and IJL,
respectively.

1) Shi, J.; et al. Cancer Nanomedicine: Progress, Challenges and Opportunities. Nat Rev Cancer 2017, 17 (1),
20–37.
(2) Mahmoudi, M.; et al. Protein−Nanoparticle Interactions: Opportunities and Challenges. Chem. Rev. 2011,
111 (9), 5610–5637.
(3) Ke, P. C. et al. A Decade of the Protein Corona. ACS Nano 2017, 11 (12), 11773–11776.
(4) Caracciolo, G. et al. Identity of Nanoparticles In Vivo : Clinical Implications of the Protein Corona. Trends
in Biotechnology 2017, 35 (3), 257–264.
(5) Ho, Y. T. et al. Quantifying Vascular Distribution and Adhesion of Nanoparticles with Protein Corona in
Microflow. Langmuir 2018, 34 (12), 3731–3741.
(6) Lee, T.-R. et al. On the Near-Wall Accumulation of Injectable Particles in the Microcirculation: Smaller Is
Not Better. Sci Rep 2013, 3 (1), 2079.
(7) Negwer, I. et al. Monitoring Drug Nanocarriers in Human Blood by Near-Infrared Fluorescence Correlation
Spectroscopy. Nat Commun 2018, 9 (1), 5306.
(8) Alberg, I. et al. Polymeric Nanoparticles with Neglectable Protein Corona. Small 2020, 16 (18), 1907574.
(9) Sheibani, S. et al. Nanoscale Characterization of the Biomolecular Corona by Cryo-Electron Microscopy,
Cryo-Electron Tomography, and Image Simulation. Nat Commun 2021, 12 (1), 573.

Keywords: vessel; vessel on chip; protein-corona