Organ-on-chip: a mini biotechnology with big ambitions

Minia­tur­is­ing the com­plex­i­ty of a func­tion­al organ in a small sys­tem the size of a domi­no is no longer impos­si­ble. Thanks to a com­bi­na­tion of research in micro-flu­idics, cell biol­o­gy and bio­engi­neer­ing, the sci­en­tif­ic com­mu­ni­ty has suc­ceed­ed in cre­at­ing organs-on-a-chip.

These devices repro­duce the func­tion­al­i­ty, physi­co-chem­i­cal envi­ron­ment and phys­i­o­log­i­cal process­es of human organs and tis­sues on a micro­scop­ic scale. They are man­u­fac­tured on plas­tic or glass sur­faces, engraved with dif­fer­ent chan­nels and com­part­ments, with­in which dif­fer­ent cell types are cul­tured and inter­act. The archi­tec­ture of these chips makes it pos­si­ble to imi­tate the bio­log­i­cal process­es at work with­in an organ, such as blood pres­sure, cell inter­ac­tions or the speed of flu­id cir­cu­la­tion in inter­face tis­sues (lungs, intestines, kidneys).

The use of human cells also makes it pos­si­ble to recre­ate inter­est­ing exper­i­men­tal con­di­tions and observe the direct effects – on large organs – of cer­tain mechan­i­cal stress­es or expo­sure to ther­a­peu­tic molecules.

Cédric Bouzigue is a lec­tur­er in biol­o­gy at École Poly­tech­nique (IP Paris) and a researcher at the Optics and Bio­sciences Lab­o­ra­to­ry. He is devel­op­ing organ-on-chip for appli­ca­tions involv­ing severe kid­ney dis­ease. “My job is to do plumb­ing on a scale of a few microme­tres”, he smiles. The micro-flu­idic sys­tems he designs make it pos­si­ble to “con­trol sig­nals and cir­cu­la­tion, by recon­sti­tut­ing three-dimen­sion­al geome­tries that approx­i­mate what hap­pens in a real organ”. As explained below, he is work­ing on a mod­el that repro­duces the inter­faces between blood and urine in the kidney.

The biol­o­gist describes organ-on-a-chip as a the­o­ret­i­cal­ly ide­al device, as it “makes it pos­si­ble to rec­on­cile the rel­e­vance of a func­tion­al sys­tem that repro­duces the func­tion of an organ, with obser­va­tion and mea­sure­ment tech­niques that are inac­ces­si­ble in vivo.” As a result, the sci­en­tif­ic com­mu­ni­ty can mul­ti­ply the num­ber of analy­sis and quan­tifi­ca­tion tech­niques on a sin­gle medi­um, accu­rate­ly mon­i­tor cell sig­nalling and test the effi­ca­cy of dif­fer­ent active sub­stances “while vary­ing and con­trol­ling the con­di­tions of use and exper­i­men­ta­tion.” In short, these devices aim to “do bet­ter with less,” accord­ing to the title of one of the chap­ters in the book Éton­nante chimie (CNRS édi­tions, 2021).

Organs-on chips are still a devel­op­ing tech­nol­o­gy. They have not yet tak­en over the bench­es of biol­o­gy lab­o­ra­to­ries, where exper­i­ments are still main­ly con­duct­ed using cell cul­tures in Petri dish­es or ani­mal mod­els. “Organs-on-chips are not yet suf­fi­cient­ly devel­oped and com­plex to replace ani­mal mod­els through­out the research process,” points out Cédric Bouzigues.

Nev­er­the­less, the pre­clin­i­cal tri­als cur­rent­ly con­duct­ed to test the effi­ca­cy and tox­i­c­i­ty of new drugs do not reflect all aspects of human tis­sue func­tion. What’s more, in a recent report, the US Food and Drug Admin­is­tra­tion point­ed out that nine out of ten drugs fail at the human clin­i­cal tri­al stage, despite hav­ing passed the ani­mal test­ing stage. While no health safe­ty process can – for the time being – match the one cur­rent­ly in place, a tech­nol­o­gy such as organ-on-a-chip could help to speed up and facil­i­tate the trans­la­tion of new ther­a­pies from the lab­o­ra­to­ry to humans. For Cédric Bouzigues, “we could val­i­date cer­tain hypothe­ses on chips ini­tial­ly, before con­firm­ing them on liv­ing models.”

Before this tech­nol­o­gy becomes wide­spread, biol­o­gists from the Optics and Bio­sciences Lab­o­ra­to­ry are work­ing with a team from the Paris Car­dio­vas­cu­lar Research Cen­ter to devel­op and test mod­els of the renal glomeru­lus (the kidney’s fil­tra­tion unit) on microchips. “Glomeru­lonephri­tis and seg­men­tal or focal hyali­nosis are rare kid­ney inflam­ma­tions. With­out trans­plan­ta­tion, these patholo­gies are fatal”, explains Cédric Bouzigues.

The sci­en­tists have there­fore designed a glomeru­lus-on-a-chip sys­tem that repro­duces the crit­i­cal mech­a­nisms favour­ing the onset and pro­gres­sion of the pathol­o­gy. “Our sys­tem-on-a-chip con­sists of two cham­bers – uri­nary and vas­cu­lar – sep­a­rat­ed by a mem­brane made up of glomeru­lar pari­etal cells.” These cells form the cap­sule in which the urine is formed. Thanks to an opti­cal imag­ing device, the sci­en­tists can observe what is hap­pen­ing in the chip, at both mol­e­c­u­lar and cel­lu­lar lev­el, par­tic­u­lar­ly when it is exposed to active mol­e­cules poten­tial­ly involved in the devel­op­ment of pathologies.

Organ-on-chip offers promis­ing pos­si­bil­i­ties. Ulti­mate­ly, it could be pos­si­ble to cre­ate per­son­alised devices for each patient, depend­ing on their pathol­o­gy and genet­ic char­ac­ter­is­tics. Organ-on-a-chip paves the way for per­son­alised med­i­cine, mak­ing it pos­si­ble to test a patient’s response to a ther­a­py and offer them the pos­si­bil­i­ty of a treat­ment tai­lored to their profile.

At the same time, oth­er research teams are work­ing on dif­fer­ent types of organ-on-chips, such as vas­cu­lar sys­tems to study hyper­ten­sion, or intestine‑, kid­ney- and lung-on-chip. The mate­ri­als used to man­u­fac­ture these devices are gen­er­al­ly poly­mers such as PDMS. They offer high pre­ci­sion and excel­lent bio­com­pat­i­bil­i­ty. How­ev­er, the dura­bil­i­ty of organ-on-chip remains a chal­lenge, as it is cur­rent­ly dif­fi­cult to envis­age using them to study patholo­gies that devel­op over the long term.

Chal­lenges remain, but organ-on-chips are unde­ni­ably mak­ing their way into the lab­o­ra­to­ry. The begin­nings of a rev­o­lu­tion in our under­stand­ing of com­plex bio­log­i­cal process­es are being felt at both fun­da­men­tal and clin­i­cal levels.

Samuel Belaud