Microphysiological Systems Los Recapitulate Lub plab-Kidney Axis
Mar 18, 2022
Laura Giordano: 3 Lab tus kiv cua tos koj rau Webtalk!1,3Silvia Maria Mihaila,1,3Hossein Eslami Amirabadi,1,2thiab Rosalinde Masereeuw
NtevraumKab mob (CKD) feem ntau tshwm sim nrog rau lwm yam comorbidities, qhia txog qhov nyuaj pathophysiology uas xav tias yuav tsum tau hloov kho los ntawm lub plab bidirectional -raumcrosstalk. Los ntawm kev sib txuas cov kev txhim kho hauv cov ntaub so ntswg engineering, fabrication, micro fluidics, thiab biosensors, micro physiological systems (MPSs) tau tshwm sim los ua kev cog lus rau kev ua raws li kev sib txuas hauv vitro ntawm ntau lub cev, thaum hais txog cov kev txwv ntawm cov qauv tsiaj. Mimicking lub (patho) lub cev lub cev ntawm lub plab-mob axis hauv vitro yuav tsum muaj MPS uas tuaj yeem sim tsis tau tsuas yog qhov kev sib tham ncaj nraim no xwb tab sis kuj muaj kev koom tes ntawm lwm cov neeg koom nrog lub cev xws li lub siab thiab lub cev tiv thaiv kab mob. Peb tham txog kev txhim kho tsis ntev los no hauv thaj chaw uas tuaj yeem ua rau hauv vitro qauv ntawm lub plab-mob axis hauv CKD.
Hu rau:joanna.jia@wecistanche.com
Cistanche tubulosa tiv thaiv kab mob raum, nyem qhov no kom tau txais cov qauv
Mob raum mob ntev: Ib qho Metabolic Disorder nrog cuam tshuam Inter-Organ thiab Inter-organismal Signaling
NtevraumKab mob (CKD) yog qhov dav tshaj plawsraumkab mob thiab yog tus cwj pwm los ntawm kev maj mam poob ntawm lub cev ua haujlwm dhau sijhawm, uas cuam tshuam lub peev xwm los lim cov khoom pov tseg hauv cov ntshav los ntawm cov ntshav (Lub thawv 1). Lub raum muaj ntau lub luag haujlwm tshwj xeeb, xws li ntshav pom thiab ua kom lub cev muaj zog rau kev tshem tawm cov khoom pov tseg hauv metabolic, rov ua kom cov khoom noj muaj txiaj ntsig zoo, kev saib xyuas cov ntshav ntim thiab electrolyte homeostasis, thiab kev ua haujlwm hauv metabolic thiab endocrine [1].
Lub complex thiab enigmatic pathophysiology ntawm CKD yog xav kom hloov los ntawmraumcrosstalk nrog ntau lub cev thiab cov tshuab, tshwj xeeb tshaj yog los ntawm kev sib txuas lus ntawm ob sab hauv nruab nrog cev nrog rau txoj hnyuv, hu ua lub plab- raum axis[2]. Tib neeg lub plab ua rau muaj kev sib koom ua ke ntawm cov kab mob microbes uas nyob hauv kev sib raug zoo nrog lawv tus tswv [3] thiab muab kev koom tes tseem ceeb thiab tshwj xeeb rau tib neeg metabolome (saib Glossary). Nyob rau hauv symbiosis, txoj hnyuv nqus tau ua kom cov khoom noj muaj txiaj ntsig microbial, thaum lub raum tswj hwm homeostasis los ntawm kev tso tawm cov khoom noj uas muaj cov tshuaj lom metabolic kawg. Conversely, lub raum tsis ua hauj lwm ua rau tsub zuj zuj ntawm plab microbiota-derived metabolites (ie, uremic toxins) ua rau kev loj hlob ntawm uremic syndrome. Qhov teeb meem no ua rau lub plab dysbiosis uas cuam tshuam rau cov kab mob inflammatory, endocrine, thiab neurological pathways koom nrog CKD pib thiab kev loj hlob (Lub thawv 2 thiab daim duab 1)[4]. Zuag qhia tag nrho, CKD tuaj yeem pom tau tias yog ib qho teeb meem metabolic uas cuam tshuam cuam tshuam rau kev cuam tshuam hauv nruab nrog cev thiab cov kab mob sib kis ntawm cov metabolites thiab cov cim qhia cov molecules nrog rau kev ua haujlwm ntawm lub cev tiv thaiv kab mob (Daim duab 2). Raws li, lub luag haujlwm tseem ceeb ntawm lub plab-mob raum chaw taws teeb qhia los ntawm uremic toxins [5] nce qhov yuav tsum tau ua ntxiv rau lub plab metabolome hauv CKD.
Kev lig kev cai,raumKev tshawb nrhiav kab mob tau vam khom ntau rau kev kho mob [6] thiab kev tshawb fawb tsiaj [7] uas muaj kev txwv tsis pub muaj kev sim thiab muaj kev sib txawv ntawm cov tsiaj sib txawv. Raws li qhov tsis muaj qhov tsim nyog hauv vitro kev sim ua qauv, tam sim no muaj qhov yuav tsum tau muaj rau cov kab lis kev cai ntawm tes uas tuaj yeem ntes qhov sib txawv ntawm hauv vivo lub cev ua haujlwm los ntawm kev siv cov kab lis kev cai tshwj xeeb thiab tshwj xeeb microenvironments, suav nrog 3D scaffolds thiab microfluidics [8 ]. Muab qhov kev nce qib hauv kev coj noj coj ua thiab biomanufacturing, kev sib koom ua ke ntawm kev saib xyuas lub sijhawm tiag tiag, thiab kev tswj hwm ywj pheej ntawm kev sim ntsuas, kev ntes qhov nyuaj ntawm tib neeg lub cev hauv vitro yog qhov pom tseeb. Peb muab cov ntsiab lus dav dav ntawm cov cim zoo tshaj plaws thiab kev nce qib tsis ntev los no hauv thaj tsam ntawm 3D hauv vitro qauv thiab qhia txog lawv qhov cuam tshuam rau kev txhim kho 3D bidirectional plab-mob raum axis. Peb kuj sib tham txog cov teeb meem loj uas cov no muaj, yuav ua li cas kov yeej lawv, thiab muab kev nkag siab tshiab rau cov kev taw qhia tam sim no ntawm daim teb no hauv cov ntsiab lus ntawm CKD.
Microphysiological qauv rau Unravel Complex Organ Interconnections
Kev tshwm sim ntawm micrography sociological systems (MPSs), tseem hu ua organ-on-chips (OOCs), tau tsim muaj peev xwm tshiab los kawm txog cov txheej txheem physiological koom nrog hauv tib neeg lub cev thiab kev sib cuam tshuam hauv nruab nrog cev. Ntau qhov sib txawv ntawm MPSs yog qhov tshwm sim uas txhawb nqa 'physiome-on-a-chip' txoj hauv kev rau simulating cov haujlwm ua haujlwm ntawm lub cev, nrog rau kev sib tham ntawm lawv, es tsis txhob tsom mus tsim cov khoom ua kom tiav. Los ntawm txoj kev pom, MPSs feem ntau muaj ib los yog ntau lub micro-channels uas muaj qhov sib txawv ntawm ntau pua micrometers uas cov ntim me me (nanoliters rau microliters) yog (rov) ncig. Los ntawm kev ua kom muaj kev sib raug zoo ntawm cov hlwb, cov ntim no tso cai rau kev sib cuam tshuam ntawm tes-cell interplay kom raug ntes thaum kom ntseeg tau tias tsawg kawg reagent noj thiab compound dilution [9,10]. Ntxiv laminar ntws tuaj yeem muab cov hlwb txuas ntxiv nrog cov khoom noj tshiab thiab cov pa oxygen thaum tib lub sijhawm tshem tawm cov khoom pov tseg, thiab tuaj yeem tsim cov tshuaj spatiotemporal thiab mechanical gradients hauv lawv thaj tsam [11]. Kev rho tawm lub cev ntawm cov ntaub so ntswg sib txawv yog ua tiav los ntawm kev sib xyaw ua ke rau hauv microchannels sib cais los ntawm nyias nyias nyias los yog txheej ntawm extracellular matrix (ECM) [12].
Kev tsim lub ntsws-on-a-chip platform, nyob rau hauv uas cov neeg kho tshuab strain thiab ntau hom ntawm tes tau ua ke los ua kev ua pa ntawm lub ntsws, pioneered txoj kev loj hlob ntawm biologically inspired MPSs [13]. Txij thaum ntawd los, kev nce qib hauv microfluidic tuav tau ua rau nws tuaj yeem txuas cov qauv sib txawv hauv nruab nrog cev thiab tswj lawv cov lus sib tham hauv ib lossis ntau yam khoom siv [14,15]. Cov kev txhim kho tshiab kawg hauv thaj teb no ua rau peb sib tham txog cov kev nce qib no hauv kev cuam tshuam rau kev ua qauv lub plab-raumaxis hauv CKD thiab tshawb nrhiav cov kev cai ntawm MPSs rau kev txhawb nqa kev sib txuas lus hauv nruab nrog cev, tseem xav txog kev sib koom ua ke ntawm kev sib koom ua ke hauv cov qauv silico.
Txoj hauv kev rau Replicating lub plab- raum axis siv MPSs
Ntau lub plab-on-a-chip tshuab tau tsim los ntawm kev sib xyaw microfluidics, cov ntaub so ntswg engineering, thiab microelectromechanical systems. Ntawm cov neeg sawv cev tshaj plaws, lub plab-on-a-chip los ntawm Wyss lub koom haum (USA) tau ua tiav kev ua haujlwm ntawm tib neeg txoj hnyuv microenvironment los ntawm kev siv cov kua dej ntawm lub cev thiab cov peristalsis-zoo li cov neeg kho tshuab, thiab cov kev txhawb nqa ntawm tes sib txawv rau hauv villus. - thiab crypt-zoo li cov qauv, tsim kom muaj ib tug tuab epithelial monolayer, thiab txhim kho cellular muaj nuj nqi (Daim duab 3A) [16–19]. Tsis ntev los no, cov yam ntxwv topological tau tshwm sim los ua qhov tseem ceeb hauv kev ua haujlwm ntawm tes, tab sis tsuas yog qee qhov kev tshawb fawb tau sim ua kom rov ua dua lub crypt-villus architecture hauv microfluidic systems uas tam sim no tau yooj yim tau los ntawm 3D high-resolution stereolithography [20], photolithography [21] ], thiab micro-molding ntawm crosslinked hydrogels [22]. Tam sim no, ua raws li cov kab mob hauv plab hnyuv zoo li cov qauv tau hais los ntawm kev tsim cov kab mob plab hnyuv ntawm sab apical ntawm ib qho fusible hollow-fiber membrane system [23,24] lossis hauv lumen ntawm microchannels [25]. Qhov sib ntxiv ntawm ECM txheej thiab unidirectional apical khub ua rau lub plab hnyuv loj phenotype nrog cov qauv zoo li villus. Kev cuam tshuam rau Clostridium difficile secreted toxin A, lub plab hauv plab uas muaj kab mob hauv lub cev thiab lub plab zom mov cuam tshuam hauv dysbiosis, lossis rau lub plab microbiota-derived metabolite, p-cresol, ua rau muaj kev cuam tshuam zoo permeability [23,24]. Concomitantly, p-cresol tau hloov mus rau p-cresyl sulfate thiab p-cresyl glucuronide, qhov kawg-metabolites uas sib sau hauv cov ntshav thaum lub sij hawm CKD kev loj hlob, zoo li ntawm cytochrome P450-kho cov metabolism hauv qab los ntawm conjugation, yog li qhia txog kev koom tes ntawm txoj hnyuv mus rau biotransformation ntawm plab microbiota-derived metabolites rau hauv uremic toxins [23].
Qhov nyuaj thiab ntau haiv neeg ntawm txoj hnyuv epithelium tuaj yeem txhim kho tau los ntawm kev siv 3D tib neeg cov ntaub so ntswg organoids [26,27]. Txawm li cas los xij, lawv txoj kev siv tau ua pov thawj nyuaj vim tias lawv kaw, sab nraud-hauv kev teeb tsa hampers thauj cov kev tshawb fawb thiab raug rau cov kab mob commensal thiab pathogenic. Txawm li cas los xij, Thorne thiab cov neeg ua hauj lwm tau pom tias, los ntawm kev sib cais ntawm cov organoids enzymatic, cov kab mob hauv plab hnyuv tau tuaj yeem ua tus kheej thiab de novo cais mus rau hauv thaj chaw tsis sib txawv lossis txawv, tsim cov niche-zoo li compartments [28]. Los ntawm kev sib koom ua ke ib qho kev cais microvascular endothelium kab lis kev cai nyob rau hauv kev ywj pheej cov phooj ywg thiab cyclic deformation, cov khoom nqus ntawm cov hlwb raug soj ntsuam [29,30]. Tsis ntev los no, kev suav nrog crypt-villus domains nyob rau hauv lub raj-zoo li lub epithelium nrog ib fusible lumen tau pom los txhawb nqa stereotypical cell patterning nta nrog tus kheej-regenerative peev xwm [31].
Txoj kev tshawb fawb hauv vitro ntawm tus tswv tsev-microbiota kev sib cuam tshuam tau cuam tshuam los ntawm qhov tsis muaj peev xwm ntawm cov qauv ua qauv los txhawb nqa lub zog microbiota rau ob peb hnub. Txawm hais tias qhov kev koom tes ntawm cov hnoos qeev rau tus tswv-microbiome kev sib cuam tshuam feem ntau tau saib tsis pom, nws tsis ntev los no tau pom tias kev sib koom ua ke ntawm cov mucus tuab - ua raws li kev tiv thaiv lub cev ntawm cov kab mob thiab cov hnyuv epithelium - tuaj yeem ncua kev puas tsuaj thiab paracellular permeability. [32, 33]. Raws li, tus qauv tsim microfluidic, HuMiX, tau ua kom ncaj qha coculture ntawm cov kab mob anaerobic thiab cov kab mob hauv plab los ntawm kev koom ua ke ntawm cov qog ua haujlwm ua haujlwm nrog rau cov phooj ywg pulsatile thiab cov neeg kho tshuab stimulation (Daim duab 3B) [34].
Feem ntau ntawm cov plab hnyuv microbiota yog obligate anaerobes uas xav tau<0.5% o2="" growth="" conditions="" that="" are="" difficult="" to="" represent="" in="" vitro="" [19,35].="" this="" limitation="" was="" overcome="" by="" engineering="" mpss="" that="" incorporate="" physiologic="" oxygen="" gradients="" and="" support="" the="" dynamic="" interaction="" between="" intestinal="" and="" vascular="" endothelial="" layers.="" the="" chip="" consisted="" of="" an="" upper="" anaerobic="" epithelial="" chamber="" and="" a="" lower="" aerobic="" endothelial="" chamber,="" separated="" by="" a="" polydimethylsiloxane="" (pdms)="" membrane.="" through="" a="" radial="" oxygen="" gradient="" generated="" by="" the="" system,="" intestinal="" cells="" were="" oxygenated="" whereas="" anaerobic="" conditions="" allowed="" microbiota="" growth,="" as="" assessed="" by="" real-time="" monitoring="" via="" integrated="" noninvasive="" oxygen="" sensors="" [19,36].="" similar="" physiological="" hypoxia="" conditions="" were="" achieved="" by="" zhang="" and="" coworkers="" who="" cocultured="" oxygen="" super-sensitive="" bacterial="" species="" using="" a="" differently="" designed="" mps,="" the="" gumi="" (figure="" 3c)="" [37].="" this="" platform="" induced="" a="" steep="" oxygen="" gradient="" through="" the="" addition="" of="" a="" long-term="" continuous="" fellow="" of="" anoxic="" apical="" medium="" and="" aerobic="" basal="" media.="" the="" use="" of="" polysulfone,="" which="" unlike="" pdms="" is="" an="" oxygen-impermeable="" material,="" prevented="" any="" oxygen="">
Kev loj hlob ntawmraum-on-a-chip systems kuj tau nyuaj vim qhov tsis muaj cov hlwb ua haujlwm kom rov ua dua hauv vitro cov qauv ntawm ntau lub cell thiab kev ua haujlwm nyuaj hauv nephron. Raws li, txheeb ze rau lub plab-on-a-chip ntaus ntawv, kev loj hlob ntawmraum-on-a-chip systems yog rau qee qhov lagging qab. Txog rau tam sim no, cov qauv ntawm glomerular, proximal tubule, thiab distal tubule physiology tau tsim, tab sis kev koom ua ke ntawm tag nrho cov Cheebtsam rau hauv ib qho tiav nephron-on-a-chip tseem yuav ua tiav [38]. Txhawm rau ua kom lub cev muaj feem cuam tshuam, ntxiv rau cellular complexity, biomimeticraum-on-a-chip yuav tsum integrate (i) cell-cell kev sib cuam tshuam xws li cov nyob nruab nrab ntawm podocytes los yog proximal tubule epithelial hlwb thiab cov (micro) vascular endothelium, (ii) transcellular electrochemical thiab osmotic siab gradients uas tsav cov kua thiab metabolites thoob plaws lub interstitial chaw, (iii) cov kua dej ua ke, thiab (iv) cov txheej txheem ntawm lub raum tubules, nrog rau (v) cellular metabolic thiab endocrine functions [38].
Cov tubule proximal plays lub luag haujlwm tseem ceeb hauv metabolic pov tseg tawm thiab biomolecule reabsorption thiab yog li ntawd yog qhov tseem ceeb ntawm kev txaus siab rau kev loj hlob hauv vitro.raum-on-a-chip systems uas recapitulate hauv vivoraumntaub so ntswg. Kev loj hlob ntawm kev ua haujlwmraumtubules siv cov cell tubule nrog biofunctionalized hollow fibers enabled Jansen thiab cov neeg ua hauj lwm los kawm txog secretory clearance ntawm plab microbiota-derived metabolites. Cov txheej txheem no tau ua rau cov kws tshawb fawb pom tau tias yuav ua li cas, los ntawm kev paub txog tej thaj chaw deb thiab kev taw qhia, cov kab mob sib thooj ntawm cov tubules paub txog qib siab ntawm indoxyl sulfate thiab ua raws li cov kev qhia ntawm cov neeg thauj khoom lub luag hauj lwm rau lawv cov excretion nyob rau hauv ib qho kev sim kom ruaj khov metabolite theem thiab homeostasis [39].
Endothelium-interstitial space-epithelium kev sib cuam tshuam tswj kev sib pauv txuas ntxiv ntawm cov kua nruab nrab ntawm cov hlab ntsha thiab cov zis. Lin thiab cov neeg ua hauj lwm ua tiav tau tsim ib qho perfusable 3D vascularized proximal tubule uas muaj peev xwm simulate, ntawm tubule-vasculature pauv ntawm cov kua, lub zog reabsorption muaj nuj nqi ntawm lubraum[40]. Cov qauv no tso cai rau kom muaj nuj nqis rau kev lees paub ntawm lub raum albumin uptake thiab qabzib reabsorption nyob rau lub sijhawm, muab cov cuab yeej cog lus rau kev soj ntsuam rau lub raum (patho) lub cev ua haujlwm thiab tshuaj tshuaj. Lwm yam tshaj li kev sib pauv hloov pauv, lubrauminterstitial qhov chaw kuj suav hais tias yog lub hauv paus rau txoj kev loj hlob ntawmraumfifibrosis, ib qho cim ntawm CKD. Qhov no yog xav tias yog tshwm sim los ntawm caws pliav ntawm lub tubule interstitial qhov chaw raws li qhov tshwm sim ntawm interstitial myofibroblast activation thiab tom qab ECM deposition. Txawm li cas los xij, tsuas yog qee qhov kev tshawb fawb tau tshaj tawm nws kev koom ua ke rau hauv 3D hauv vitro systems. Qhov kev lees paub ntawm qhov yooj yim thiab muaj txiaj ntsig zoo 3D tubule / interstitium microenvironment qauv rau kev kawm ntawm lub raum fifibrosis hauv lub cev muaj feem cuam tshuam hauv vitro tau tshaj tawm los ntawm Moll thiab cov neeg ua haujlwm [41]. Txoj kev tshawb no tau siv cisplatin kom ua tiav kev raug mob ntawm tubular. Kev rov ua dua tshiab hauv vitro ntawm lub raum tubule / interstitium microenvironment tau ua tiav los ntawm kev siv tib neeg dermal fibroblasts es tsis siv lub raum fibroblasts vim hais tias yav dhau los qhia txog qib qis ntawm cov cim fibrotic nyob rau hauv cov xwm txheej basal. Txawm li cas los xij, txawm tias qhov kev txwv no, lub kaw lus tau pom tias cov hlwb epithelial ua lub luag haujlwm tseem ceeb hauv kev ua kom muaj zog thiab sib txawv ntawm myofifibroblasts. Moll thiab cov neeg ua haujlwm tau sim rov ua qhov kev tshawb fawb no siv thawj lub raum fibroblasts tab sis ntsib qhov sib txawv ntawm qhov tshwm sim. Muab qhov tseem ceeb ntawm qhov chaw interstitial hauv CKD, kev tshawb fawb 3D hauv vitro ntxiv yuav tsim nyog los piav qhia nws lub luag haujlwm hauv kab mob pib thiab kev loj hlob.
Covlub raumkuj tseem qhib 25 (OH) vitamin D los ntawm hydroxylation ntawm 1 txoj hauj lwm, ua rau 1,25 (OH) 2vitamin D, ib qho tseem ceeb cov tshuaj hormones uas feem ntau tsis txaus ntawm cov neeg mob CKD thiab uas tuaj yeem cuam tshuam rau plab microbiota muaj pes tsawg leeg thiab teeb meem kev ncaj ncees. Tsis ntev los no, on-chip sawv cev ntawm hepatic metabolism thiabraumKev ua kom cov vitamin D yog tsim los ntawm perfusing vitamin D-muaj nruab nrab rau hauv microfluidic nti, qhia tias complex inter-organ metabolic kev sib cuam tshuam yog heev attainable siv MPS technologies [42].
Hauv CKD, qhov txo qis hauv cov saw hlau luv fatty acid (SCFA) ntau lawm, ua tiav los ntawm kev nce ib txhij ntawm cov tshuaj uremic toxin ntau lawm thiab lawv cov kab ke sib xyaw ua ke [4], yog xav tias yuav tsav cov kab mob ua rau mob ntev uas yog CKD [4,43] ]. Tseeb tiag, SCFAs, tshwj xeeb tshaj yog butyrate, muaj ob qho tib si nephroprotective thiab plab hnyuv tiv thaiv teebmeem [4,44], thiab qib siab ntawm butyrate tau cuam tshuam nrog lub plab thaiv kev ncaj ncees thiab kev txhim kho plab hnyuv vim nws cov khoom tiv thaiv kab mob [45]. Txawm li cas los xij, qhov no tsis ntev los no tau tawm tsam los ntawm Trapecar thiab cov neeg ua haujlwm sib koom ua ke uas, hauv kev xav txog kev xav, pom tau tias SCFAs tuaj yeem ua rau muaj qhov mob hnyav heev hauv cov qauv plab-siab. Los ntawm kev sib txuas ob daim hlau pneumatic cais sawv cev rau lub plab thiab daim siab, CD4 ntxiv rau T hlwb thiab inflammatory hom 17 T pab (Th17) hlwb tuaj yeem ncig hauv thiab nruab nrab ntawm ob qhov chaw. Qhov cuam tshuam tawm tsam ntawm SCFAs tuaj yeem cuam tshuam nrog cov qib ntawm qhov mob, nrog rau qhov ua rau mob hnyav ua rau muaj kev cuam tshuam ntau dua [46].
Rau peb txoj kev paub, tam sim no tsis muaj MPS uas hais txog qhov cuam tshuam ntawm lub plab-derived metabolites ntawm plab,raum, lossis lwm yam kabmob, nrog rau kev taug qab ntawm lawv cov biotransformation, nyob rau hauv cov ntsiab lus ntawm CKD. Tuning lub nti rau kev ncaj ncees recapitulate bidirectionality ntawm ntau lawm thiab tshem tawm fluxes ntawm metabolites yuav yog ib qho nyuaj. Kev sib xyaw microbiota muab tau los ntawm cov quav kuaj ntawm cov neeg mob CKD rau hauv lub plab hnyuv microfluidic yuav ua rau peb kawm txog kev hloov pauv hauv cov metabolism hauv microbial thiab txheeb xyuas lawv (hauv) cov teebmeem ncaj qha rau cov kab mob hauv thaj chaw deb, ib qho uas tsis tuaj yeem ua tiav los ntawm kev sim vivo.
Technological Advances Enhancing the In Vivo Translational Value of MPSs Tsim MPS yog qhov nyuaj thiab yuav tsum muaj ntau txoj hauv kev. Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias tsis muaj MPS ib leeg tuaj yeem ua tau txhua yam, thiab, nyob ntawm daim ntawv thov, cov tshuab sib txawv yuav xav tau. Qhov zoo thiab kev txwv ntawm cov txheej txheem muaj rau tackling lub plab-raumaxis tau muab sau tseg nyob rau hauv Table 1. Ib qho ntawm cov kev sib tw tshaj plaws nyob rau hauv lub tshav pob yog tsim kom muaj ib tug system uas yog biologically complex thiab txaus technically yooj yim los tsim nyob rau hauv cell culture laboratories.
Pab pawg Ingber (Wyss Institute, USA) tau tsim cov txheej txheem ua kom zoo rau kev cog qoob loo ntawm tes, txuas cov khoom siv microfluidic rau cov nti, thiab ua piv txwv [16–18,47]. Txawm hais tias kev siv thev naus laus zis, lawv cov microfluidic system yuav tsum muaj kev cob qhia tseem ceeb ntawm cov neeg ua haujlwm tsis siv neeg, txawm tias tsis siv neeg microfluidic kuaj [47]. Pumpless multiorgan chips, pioneered los ntawm Shuler laboratory (Cornell University, USA), raws li zoo raws li los ntawm cov tuam txhab xws li Hesperos Inc. (Daim duab 3E) thiab InSphero, ua rau kom cov throughput ntawm tus nqi ntawm kev txwv txwv rau cov khub thiab cov cuab yeej complexity [48] (https://hesperosinc.com/). Txawm hais tias txwv tsis pub siv cov ntaub ntawv biophysical, MPS tsim los ntawm Griffith lub chaw kuaj mob (Massachusetts Institute of Technology, USA) ua rau siv cov txheej txheem ntau dua, piv txwv li, los ntawm kev ua kom ncaj qha mus rau cov ntaub so ntswg analog thiab los ntawm kev siv cov qauv hloov pauv Transwell® inserts (Daim duab 3C, D) [37,49] ib.
Cov tuam txhab tsim kho tshiab tau zoo ib yam tsim ntau lub platforms, xws li TissUse®.Lawv cov twj tso kua mis txuas rau hauv nruab nrog cev thiab ua rau lub kaw lus tsis tshua muaj npuas ntxiab thiab to. Txawm li cas los xij, cov khoom siv no muaj kev txwv microfluidic routing, piv txwv li, tus khub apical nyob rau hauv lub plab qauv yog tsis muaj, thiab customization ntawm cov ntaub so ntswg qauv yog nyuaj.
Lwm qhov kev sib tw loj yog cov khoom siv chip. PDMS yog ib qho ntawm cov khoom siv feem ntau vim nws cov pa permeability zoo heev, kho qhov muag pom tseeb, thiab cov khoom siv prototyping. Txawm li cas los xij, oxygen permeability yog ib qho downside thaum coculturing obligate anaerobe microbiome nrog cov hnyuv hlwb [20,37]. Hauv kev sim hydrophobic compounds, piv txwv li, hauv tshuaj toxicity lossis kev tshawb fawb txog kev ua tau zoo, PDMS tsis pom zoo vim nws nqus cov tshuaj hydrophobic me me. Li no, MPSs uas muaj cov ntaub ntawv inert ntau dua, uas tiv thaiv kev sib txuas ntawm cov khoom sib txuas, yog qhov kev ntseeg siab tshaj plaws. Piv txwv li, Edington thiab cov neeg ua haujlwm ua haujlwm tau tsim cov polystyrene-raws li microfluidic platform ntawm interconnected MPSs nyob rau hauv ib qho kev sim los tsim ib tug physiome-on-a-chip uas muaj peev xwm tsim complex molecular tis profiles rau advanced tshuaj nrhiav tau daim ntawv thov [50].
Txoj kev loj hlob ntawm cov platforms nrog kev sib xyaw sensors (oxygen, urea, lactate, los yog qabzib), thiab / los yog optical transparency, tau ua kom yooj yim rau lub sijhawm tiag tiag ntawm cov xov tooj ntawm tes tsis muaj kev tshuaj ntsuam (Box 3) [51,52]. Ib lub platform nrog kev sib xyaw ua ke ntawm kev sib xyaw ua ke tsis ntev los no tau tsim. Qhov no ua haujlwm MPS cov chav nyob ua ntu zus, muaj zog, thiab tsis siv neeg, thiab suav nrog lub cev ntsuas lub cev los saib xyuas cov kab mob microenvironment, biochemical sensors los ntsuas cov dej soluble biomarkers, me me microscopes los ntes cov kev hloov pauv morphological, thiab microfluidic-routing breadboard rau cov kua dej hauv lub sijhawm. txoj kev [53].
Kev txheeb xyuas kev suav kuj tseem tsim nyog los tsim kom pom seb MPS cov ntaub ntawv los ntawm kev sim tuaj yeem raug ntxiv rau hauv vivo kev ua tau zoo [54]. Yog li, kev koom ua ke ntawm kev kawm tshuab algorithms (hauv silico qauv) yuav tsum dhau los ua ib qho kev sib tw ntawm MPSs [55]. Cov qauv kev suav tuaj yeem hloov kho los pab daws cov kev txwv ntawm kev sim sib txuas MPSs thiab nqa cov ntaub ntawv nyob rau hauv ntau yam ntawm kev tshawb fawb tsiaj thiab cov txheej txheem extrapolation [54]. Cov kev kwv yees tau los ntawm cov kev tshawb fawb silico tuaj yeem muab cov lus qhia ntxiv los txhim kho MPS qauv [55]. Piv txwv li, hauv kev tshawb fawb silico tuaj yeem ua haujlwm los ua qauv kev tiv thaiv kab mob hauv lub cev tom qab kev puas tsuaj ntawm plab hnyuv thiab kwv yees tus cwj pwm ntawm tes thaum raug rau qee qhov tshwj xeeb lossis biomolecules [56-59].
Xaus cov lus thiab cov kev xav yav tom ntej
Nyob rau hauv lub xyoo tom ntej, qhov kev nthuav dav ntawm CKD tau kwv yees tias yuav nce siab thoob ntiaj teb, ua rau muaj kev nyuaj siab nyiaj txiag thiab kev sib raug zoo. Txawm hais tias lub teb chaws twg los xij, kev kho mob txhua xyoo thiab kev siv nyiaj hauv zej zog tau pom tias nce ntxiv nrog rau kev loj hlob ntawm CKD [60], qhia txog qhov xav tau ceev rau tus qauv kab mob uas yuav kawm CKD pathophysiology thiab txheeb xyuas cov hom phiaj kho mob.
Txawm li cas los xij, ntau qhov teeb meem tseem yuav raug daws, thiab ntau qhov teeb meem yuav tsum tau daws ua ntej MPSs tuaj yeem tsim tau tus qauv CKD kom raug (saib Cov Lus Nug Zoo). Piv txwv li, cov xwm txheej thawj zaug uas tsav qhov pib ntawm CKD tseem tsis tau paub, ua rau tus qauv ntawm CKD pib hauv MPS nyuaj.Lub raumKev raug mob uas ua rau muaj kev loj hlob ntawm CKD muaj ntau haiv neeg thiab feem ntau koom nrog cov kab mob plawv, ua rau lawv cov sawv cev nyuaj dua. Tsis tas li ntawd, muaj pes tsawg leeg ntawm lub plab microbiome yog complex thiab nyuaj rau cov me nyuam; Txawm li cas los xij, nws yog ib qho tseem ceeb uas yuav tsum muaj rau tus qauv kab mob CKD. Qhov kev vam meej tshiab tshaj plaws ntawm MPSs uas koom ua ke cov kab mob anaerobic tau ua tiav los ntawm kev sib koom ua ke ntawm biosensors rau oxygen sensing, nrog rau kev suav nrog cov tswj ntws thiab cov mucus txheej uas txo cov kab mob overgrowth thiab txwv txoj hnyuv cell puas (Table 1). Txawm li cas los xij, cov kab mob anaerobic dav dav hauv cov kab ke tseem yuav ua tiav, txawm hais tias qhov no yuav tsim nyog rau kev sawv cev ntawm lub plab microbiome. Cov teeb meem nrog cov ntaub ntawv nqus thiab huab cua-permeable kuj sawv cev rau qhov teeb meem loj hauv kev ua haujlwm, nyuaj rau kev tsim nyog ntawm cov kab ke rau kev loj hlob ntawm cov kab mob anaerobic lossis rau kev kuaj lipophilic compounds. Qhov cuam tshuam ntawm kev sib txuas hauv nruab nrog cev tau qhia meej meej hauv qhov kev tshuaj xyuas no; Yog li ntawd nws yog ib qho tseem ceeb ntawm qhov tseem ceeb rau kev sib koom ua ke ntawm cov hlab ntshav thiab lub cev tiv thaiv kab mob hauv MPSs, tab sis cov no tau muab tso rau hauv ob peb tus qauv xwb.
Los ntawm kev txhim kho kev sib koom tes, kev sib koom ua ke ntawm bioprinting, biomaterials, thiab biosensors rau kev saib xyuas lub sijhawm ntawm microenvironment tuaj yeem hais txog cov yam ntxwv ntawm anatomical thiab biochemical, nrog rau qhov nyuaj, ntawm cov tshuab uas tsim nyog los ua kom lawv lub cev muaj feem cuam tshuam. Raws li MPS thev naus laus zis tau nce zuj zus, nrog rau cov qauv tam sim no rau kev txhim kho ntau yam kev qhuab qhia, cov lus nug uas tsis tau teb yuav raug hais thaum kawg.
Kev lees paub
Txoj haujlwm no tau txais nyiaj los ntawm EU Horizon 2020 kev tshawb fawb thiab kev tsim kho tshiab raws li Marie Skłodowska Curie daim ntawv cog lus pub dawb STRATEGY-CKD H2020-2019-ETN (860329), nrog rau WIDESPREAD-05-2018-TWINNING hu REMODEL (857491). Txoj haujlwm no tau txhawb nqa ntxiv los ntawm DutchLub raumFoundation (DKF, 17OI13). RM yog ib tug tswv cuab ntawm ESAO/ERA-EDTA-kev pom zoo ua haujlwm pab pawg EUTox.
Cov ntaub ntawv
1. Himmelfab, J. et al. (2020) Qhov chaw tam sim no thiab yav tom ntej ntawm kev lim ntshav. Nat. Rev. Nephrol. 16, 573–585 : kuv
2. Yeepoel, P. et al. (2017) Lub cev -raumaxis. Pediatr. Nephrol. 32, 2005–2014
3. De Sordi, L. et al. (2017) Lub plab microbiota pab txhawb kev sib txawv ntawm cov caj ces thiab kev kis kab mob ntawm cov kab mob. Cell Host Microbe 22, 801–808
4. Rukavina Mikusic, NL et al. (2020) Lub plab microbiota, thiab mob ntevraumkab mob: pov thawj thiab cov txheej txheem uas kho qhov tshiab
kev sib txuas lus hauv plab hnyuv- raum axis. Pflugers Arch. 472, 303–320 : kuv
5. Nigam, SK and Bush, KT (2019) Uraemic syndrome of chronicraumkab mob: hloov tej thaj chaw deb sensing thiab signaling. Nat. Rev. Nephrol. 15, 301–316
6. Okada, H. et al. (2020) Cov ntsiab lus tseem ceeb los ntawm Cov Ntaub Ntawv Pov Thawj-raws li Cov Kev Cai Kho Mob rau Kev Kho MobLub raumKab mob 2018. Clin. Exp. Nephrol. 23, 1–15 : kuv
7. Becker, GJ thiab Hewitson, TD (2013) Tsiaj qauv ntawm cov mob ntevraumkab mob: pab tau tab sis tsis zoo tag nrho. Nephrol. Hu rau. Hloov. 28, 2432–2438, ib
8. Faria, J. et al. (2019)Lub raum-raws li nyob rau hauv vitro qauv rau kev tshuaj ntsuam toxicity. Arch. Toxicol. 93, 3397–3418
9. Bee IB, DJ et al. (2002) Physics thiab kev siv ntawm microfluidics hauv biology. Annu. Rev. Biomed. Eng. 4, 261–286
10. Zhang B., et al. (2018) Kev nce qib hauv organ-on-a-chip engineering. Nat. Rev. Mater. 3, 257–278 : kuv
11. Lin, B. and Levchenko, A. (2015) Spatial manipulation with microfluidics. Pem hauv ntej. Bioeng. Biotechnol. 3, 39 ib
12. Yim, K. et al. (2014) Lub cev muaj feem cuam tshuam rau lub cev ntawm daim tawv nqaij. Biotechnol. J. 9, 16–27
13. Huh, D. et al. (2010) Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668
14. Lee, SH and Sung, JH (2018) Organ-on-a-chip technology for reproducing multiorgan physiology. Adv. Healthc. Mater. 7, 1700419, ib
15. Sung, JH et al. (2019) Tsis ntev los no kev nce qib hauv lub cev-on-a-chip systems. Qhov quav. Chem. 91, 330–351 : kuv
16. Kim, HJ et al. (2012) Tib neeg lub plab-on-a-chip nyob los ntawm microbial flora uas tau ntsib txoj hnyuv peristalsis zoo li cov lus tsa suab thiab ntws. Lab Chip 12, 2165–2174
17. Kim, HJ and Ingber, DE (2013) Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. Tus lej. Biol. (Cab) 5, 1130–1140
18. Kim, HJ et al. (2016) Kev koom tes ntawm microbiome thiab mechanical deformation rau plab hnyuv kab mob overgrowth thiab o nyob rau hauv tib neeg plab-on-a-chip. Proc. Natl. Acad. Sci. USA 113, E7–E15
19. Jalili-Firoozinezhad, S. et al. (2019) Ib tug complex tib neeg lub plab microbiome kab lis kev cai nyob rau hauv ib tug anaerobic txoj hnyuv-on-a-chip. Nat. Biomed. Eng. 3, 520–531 : kuv
20. Creff, J. et al. (2019) Fabrication of 3D scaffolds reproducing intestinal epithelium topography by high-resolution 3D stereolithography. Biomaterials 221, 119404
