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