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Artificial arteries to improve the study of disease

Abdul Barakat
Abdul Barakat
CNRS Research Director and AXA Professor of Mechanics and Biology at École Polytechnique (IP Paris)
Key takeaways
  • The development of artificial arteries and vessels can help to better understand the fluid mechanics in arteries in order to better treat medical problems.
  • This system is being deployed in collaboration with Lille University Hospital (CHU Lille) to measure the “Willebrand factor”, involved in thrombosis formation, which can result in blockage of blood vessels.
  • Another artery model is used to represent microvascular diseases such as hypertension or Alzheimer's disease.
  • These models make it possible to study this issue by representing a vessel in its complexity, with the different types of cells that make it up or that are associated with it in the brain.

Small wind­ing paths or blood high­ways, ves­sels are essen­tial ele­ments of biol­o­gy. Long con­sid­ered as sim­ple porous pipes by phys­i­ol­o­gy, they turn out to be involved in com­plex phys­i­cal and bio­chem­i­cal mech­a­nisms that Abdul Barakat’s team is study­ing in the Hydro­dy­nam­ics Lab­o­ra­to­ry (Lad­HyX).

We are devel­op­ing arti­fi­cial arter­ies and ves­sels to study the for­ma­tion of bio­log­i­cal phe­nom­e­na, such as dis­eases, on dif­fer­ent scales. The aim is to take into account a fac­tor often neglect­ed by mod­ern biol­o­gy: the flu­id mechan­ics in arter­ies. We have thus devised two mod­els, which can be adapt­ed and applied to mul­ti­ple med­ical questions.

From coronary artery disease…

The first is formed from a col­la­gen hydro­gel base form­ing a tube of 3 mil­lime­tres inter­nal diam­e­ter and 4.5 mil­lime­tres exter­nal diam­e­ter. Smooth mus­cle cells and endothe­lial cells, which form nat­ur­al arter­ies, are intro­duced into the tube. The result is an arti­fi­cial ves­sel that close­ly resem­bles a coro­nary artery, which sup­plies the heart with oxy­gen. This mod­el rep­re­sents a very high-pres­sure flow regime with shear. It is intend­ed to study coro­nary artery dis­ease, also known as atherosclerosis. 

In order to char­ac­terise the cel­lu­lar response to the induced mechan­i­cal fac­tors, it is pos­si­ble to make use of high-res­o­lu­tion imag­ing sys­tems, such as con­fo­cal flu­o­res­cence microscopy, as well as imped­ance sen­sors. By plac­ing these sen­sors on the wall of our arti­fi­cial arter­ies, we pro­duce a true spa­tial­i­sa­tion that accounts for the cel­lu­lar dynam­ics involved. This approach makes it pos­si­ble to account for the dynam­ics of cel­lu­lar respons­es or inter­ac­tions between the dif­fer­ent types of cells in the vas­cu­lar wall. 

This sys­tem is, for exam­ple, deployed in col­lab­o­ra­tion with the Uni­ver­si­ty Hos­pi­tal of Lille in order to mea­sure the pro­duc­tion and dis­tri­b­u­tion of the Wille­brand fac­tor involved in the for­ma­tion of throm­bo­sis, which can clog blood ves­sels. It also enables the Uni­ver­si­ty of New South Wales in Syd­ney to study the effect of tur­bu­lence on arte­r­i­al walls and the EFS in Stras­bourg to study the for­ma­tion of platelets in the blood.

At Lad­hyx, this mod­el is help­ing us to under­stand the heal­ing of a ves­sel dur­ing the inser­tion of a stent, the small springs used to cor­rect a vas­cu­lar nar­row­ing. The pro­ce­dure can dam­age the endothe­lial cells that line the ves­sel lumen, cre­at­ing a risk of “steno­sis”, a col­lapse of the vas­cu­lar walls. By antic­i­pat­ing the heal­ing char­ac­ter­is­tics of each type of stent, we hope to avoid this phe­nom­e­non1.

 … to microvascular disease

The sec­ond type of mod­el, still based on col­la­gen hydro­gel, has diam­e­ters of 120 to 150 µm2 and allows the rep­re­sen­ta­tion of microvas­cu­lar dis­eases such as hyper­ten­sion or Alzheimer’s dis­ease. In the case of Alzheimer’s dis­ease, this brain pathol­o­gy is often con­sid­ered as a dis­ease caused by the abnor­mal behav­iour of pep­tides (tau or β‑amyloid). How­ev­er, this rep­re­sen­ta­tion has not led to real clin­i­cal advances despite sig­nif­i­cant invest­ment over the last few decades. Now, the idea is emerg­ing that Alzheimer’s dis­ease may result from a microvas­cu­lar dis­or­der. Lab­o­ra­to­ries have shown a cor­re­la­tion between this dis­ease and cere­bral hypop­er­fu­sion, i.e. abnor­mal blood flow in the brain.

In some ani­mal mod­els, it is pos­si­ble to manip­u­late per­fu­sion of the brain. In this way, it is pos­si­ble to observe degen­er­a­tion of neu­rons and an accu­mu­la­tion of the pep­tides asso­ci­at­ed with Alzheimer’s dis­ease. We there­fore sus­pect that an anom­aly in mechan­i­cal fac­tors par­tic­i­pates in the devel­op­ment of the dis­ease or may even ini­ti­ate it. Our mod­els make it pos­si­ble to study this ques­tion by rep­re­sent­ing a ves­sel in all its com­plex­i­ty, with the dif­fer­ent types of cells that make it up or are shared with it in the brain. We can even vary the cell com­po­si­tion to rep­re­sent dif­fer­ent bio­log­i­cal situations.

In gen­er­al, our mod­els open up the study of the bio­log­i­cal effects of mechan­i­cal forces. It is known that such fac­tors can mod­i­fy the expres­sion of pro­teins. There is there­fore a dimen­sion of mechan­i­cal-bio­chem­i­cal inter­ac­tions that we are seek­ing to explore.

From mod­el to clinic

Advances in math­e­mat­i­cal mod­el­ling, bio­engi­neer­ing and in sil­i­co med­i­cine are lead­ing to the devel­op­ment of increas­ing­ly effi­cient mod­els of human patholo­gies. In an edi­to­r­i­al for the lat­est Vir­tu­al Phys­i­o­log­i­cal Human con­fer­ence 3, spe­cial­ists showed that these lat­est gen­er­a­tions of mod­els have reached the clin­ic at sev­er­al levels. 

They can shed light on pre­vi­ous­ly unknown aspects of phys­iopathol­o­gy and thus open up new avenues of treat­ment. This is the case of the obstruc­tive sleep apnoea mod­el pro­posed by the team of Vir­ginie Le Rolle and Alfre­do Hernán­dez at the Uni­ver­si­ty of Rennes, which analy­ses the cou­pling between res­pi­ra­tion, metab­o­lism and pul­monary mechanics. 

Some of them allow indi­vid­u­alised cal­cu­la­tions accord­ing to a patient’s data and there­fore improve the per­son­al­i­sa­tion of man­age­ment. The car­diac elec­tro­phys­i­ol­o­gy mod­el com­bin­ing MRI and ECG data devel­oped under the direc­tion of Ger­not Plank, from the Med­ical Uni­ver­si­ty of Graz in Aus­tria, is part of this approach.

More­over, oth­ers have helped to antic­i­pate and man­age treat­ment regimes, such as the post-Cae­sare­an sec­tion heal­ing mod­el pro­posed by Fer­nan­da Fidal­go from the Uni­ver­si­ty of Por­to. These are all exam­ples how mod­els and clin­i­cal prac­tice converge.

Interview by Agnès Vernet
1E.E. Antoine et al. (2016), J R Soc Inter­face, 13 (125) : 20 160 834. doi : 10,109 8/rsif.2016.0834
2C.A. Dessalles et al. (2021), Bio­fab­ri­ca­tion 14 (1), 015003. doi : 10,108 8/1758–5090/ac2baa
3I. E Vignon-Clementel et al., Ann Bio­med Eng (2022) 50(5):483–484. doi: 10.1007/s10439-022–02943‑y

Contributors

Abdul Barakat

Abdul Barakat

CNRS Research Director and AXA Professor of Mechanics and Biology at École Polytechnique (IP Paris)

Abdul Barakat is also adjunct professor of Mechanical and Manufacturing Engineering at the University of New South Wales in Sydney, Australia. A graduate of Biofluid Mechanics from MIT, Abdul Barakat co-founded the startup Sensome, which develops advanced sensor technologies for medical devices. His research interests include vascular biomechanics and bioengineering, cellular mechanobiology and endovascular devices. He has published more than 250 journal and conference papers and is the recipient of the Pfizer-Parke Davis Atorvastatin Research Award (2001), an AXA Research Fund Permanent Chair (2010), and the Eugenio Beltrami Senior Scientist Prize from the International Research Center for Mathematics and Mechanics of Complex Systems (2020). He is also an elected member of the American Institute for Medical and Biological Engineering.