Artificial arteries to improve the study of disease

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.

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.

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.

Interview by Agnès Vernet