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