Human organs-on-chips for disease modelling, drug development and personalized medicine

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(8), P. 467 - 491

Published: March 25, 2022

The failure of animal models to predict therapeutic responses in humans is a major problem that also brings into question their use for basic research. Organ-on-a-chip (organ chip) microfluidic devices lined with living cells cultured under fluid flow can recapitulate organ-level physiology and pathophysiology high fidelity. Here, I review how single multiple human organ chip systems have been used model complex diseases rare genetic disorders, study host–microbiome interactions, whole-body inter-organ reproduce clinical drugs, radiation, toxins infectious pathogens. address the challenges must be overcome chips accepted by pharmaceutical industry regulatory agencies, as well discuss recent advances field. It evident instead drug development avatars personalized medicine ever closer realization. This Review discusses types organ-on-a-chip diverse applications disease modelling, medicine, reach full potential.

Language: Английский

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Tumor-Derived Extracellular Vesicles Breach the Intact Blood–Brain Barrier via Transcytosis

ACS Nano, Journal Year: 2019, Volume and Issue: 13(12), P. 13853 - 13865

Published: Sept. 3, 2019

The restrictive nature of the blood-brain barrier (BBB) creates a major challenge for brain drug delivery with current nanomedicines lacking ability to cross BBB. Extracellular vesicles (EVs) have been shown contribute progression variety diseases including metastatic cancer and suggested as promising therapeutics vehicles. However, native tumor-derived EVs breach BBB mechanism(s) involved in this process remain unknown. Here, we demonstrate that can intact vivo, by using state-of-the-art vitro vivo models BBB, identified transcytosis mechanism underlying process. Moreover, high spatiotemporal resolution microscopy demonstrated endothelial recycling endocytic pathway is transcellular transport. We further identify characterize which circumvent low physiologic rate decreasing expression rab7 increasing efficiency their These findings previously unknown mechanisms an during course metastasis be leveraged guide inform development approaches deliver therapeutic cargoes across treatment including, but not limited to, malignancies.

Language: Английский

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Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips

Nature Biomedical Engineering, Journal Year: 2020, Volume and Issue: 4(4), P. 421 - 436

Published: Jan. 27, 2020

Language: Английский

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Neuronal regulation of the blood–brain barrier and neurovascular coupling

Nature reviews. Neuroscience, Journal Year: 2020, Volume and Issue: 21(8), P. 416 - 432

Published: July 7, 2020

Language: Английский

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Multiorgan-on-a-Chip: A Systemic Approach To Model and Decipher Inter-Organ Communication

Trends in biotechnology, Journal Year: 2021, Volume and Issue: 39(8), P. 788 - 810

Published: Feb. 2, 2021

Multiorgan-on-a-chip (multi-OoC) devices, by supporting cross-organ communication, allow the study of multiorgan processes and modeling systemic diseases.Multi-OoC approaches provide new insights that would be lost using single-OoC models.Various coupling configurations have been proposed for building multi-OoC platforms, these present different levels user-friendliness.Multi-OoC platforms potential to transform medical research opening avenues understanding diseases developing personalized treatments.To further emulate complexity human system in vivo, key elements immune, nervous, vascular systems are being integrated into models.The next generation multi-OoCs will incorporate multimodal real-time readouts form on-chip chemical, physical, molecular sensors, as well online multiomic analysis. great redefine way which health is conducted. After briefly reviewing need comprehensive models with a dimension, we highlight scenarios advantageous. We overview existing including body-on-a-chip devices modular involving interconnected organ-specific modules. how can unique information not accessible models. Finally, discuss remaining challenges realization their worldwide adoption. anticipate technology metamorphose biology medicine providing holistic treating multisystem diseases. Interactions between multiple organs essential ensure proper physiological functioning body. Although physically separated communication mediated via blood lymph circulation various signals (soluble factors, exosomes, cells, etc.) maintain overall viability homeostasis. For example, journey orally ingested substances (nutrients, chemicals, drugs, orchestrated involves through specific sequence each organ has function: small intestine absorbs (digested) substances, liver metabolizes them, they then delivered target circulation, kidney excretes corresponding waste products. This complex process absorption/distribution/metabolism/excretion/toxicity (ADMET; see Glossary) affects fate, distribution, efficacy (if applicable), possible toxicity exogenous (e.g., food, additives, environmental pollutants) [1.Cheng F. et al.AdmetSAR: source free tool assessment chemical ADMET properties.J. Chem. Inf. Model. 2012; 52: 3099-3105Crossref PubMed Scopus (725) Google Scholar] unwanted side-effects secondary tissues. In addition, many functions body depend on regulatory pathways hormonal feedback loops involve endocrine system. The reproductive system, comprises tissues, relies control peripheral Similarly, Langerhans islets pancreas secrete insulin promotes glucose uptake liver. Together, this deciphering emulating temporal involved functions. As direct consequence, such sepsis, osteoarthritis, gout, infertility, neurodegenerative organs, must therefore pursued accurately model them. identifying biomarkers fluids diagnostic purposes. instance, tumor tissues release molecules (miRNA, circulating DNA, peptides, etc.), tumor-derived extracellular vesicles (tdEVs), cells (CTCs) play central role cancer metastasis patient management [2.Rikkert L.G. al.Cancer-ID: toward identification blood.Front. Oncol. 2020; 10: 608Crossref (1) Scholar,3.Heitzer E. al.Current future perspectives liquid biopsies genomics-driven oncology.Nat. Rev. Genet. 2019; 20: 71-88Crossref (304) Scholar]. All examples illustrate it include depicted Figure 1, most commonly achieved animal Nevertheless, vivo suffer from numerous limitations: high experimental costs, limited throughput, ethical concerns, differences genetic background. More importantly, exhibit large terms drug effects and/or disease phenotypes compared humans, explains frequent failure clinical trials [4.Low L.A. al.Organs-on-chips: decade.Nat. Drug Discov. (Published September 10, 2020. https://doi.org/10.1038/s41573-020-0079-3)Crossref (9) Overall, animals do analysis inter-organ crosstalk, determination quantitative pharmacokinetics (PK), or prediction parameters, recently highlighted [5.Ingber D.E. Is time reviewer 3 request chip experiments instead validation studies?.Adv. Sci. 72002030Crossref (22) Therefore, advanced vitro incorporating dimension developed faithfully pathophysiology. Previous efforts employed either conditioned medium cocultures Transwell platforms. However, use volumes liquid, slow low-concentration signaling factors diluted, altogether hampers studying cellular communication. Furthermore, culture entirely static, precludes emulation dynamic application controlled cell biochemical physical stimuli. Using microfluidic format solve some issues offering sub-milliliter volumes, culture, exquisite spatiotemporal over parameters cell/tissue vicinity. cell–cell studied microdevices under continuous flow chambers porous membranes [6.Chung H.H. al.Use tissue barrier co-culture models.Lab Chip. 2018; 18: 1671-1689Crossref Scholar], pillar arrays [7.Lembong J. al.A fluidic platform spatially patterned growth, differentiation, cocultures.Tissue Eng. Part A. 24: 1715-1732Crossref (12) channels [8.Zhou Q. al.Liver injury-on-a-chip: co-cultures biosensors monitoring during injury.Lab 2015; 15: 4467-4478Crossref Building cultures, organ-on-a-chip (OoC) aim mimic architecture function an combining 3D bioengineered constructs cell-laden hydrogels [9.Patrício S.G. al.Freeform printing viscoelastic matrix.Biofabrication. 12035017Crossref (2) differentiated epithelium [10.van den Broek L.J. al.Progress prospectives skin-on-chip development emphasis types technical challenges.Stem Cell Rep. 2017; 13: 418-429Crossref (38) Scholar,11.Schimek K. al.Bioengineering full-thickness skin equivalent 96-well insert substance permeation studies applications.Bioengineering (Basel). 5: 43Crossref (11) multicellular spheroids [12.Nashimoto Y. al.Integrating perfusable networks three-dimensional device.Integr. Biol. (Camb.). 9: 506-518Crossref organoids [13.Rajan S.A.P. al.Probing prodrug metabolism reciprocal humanized multi-tissue platform.Acta Biomater. 106: 124-135Crossref (8) Scholar, 14.Achberger al.Merging organoid generate multi-layer retina-on-a-chip platform.Elife. 8Crossref (7) 15.Picollet-D'hahan N. al.Deciphering cell-intrinsic properties: issue robust production.Trends Biotechnol. 35: 1035-1048Abstract Full Text PDF (0) Scholar]), ex explants) [16.Schwerdtfeger Tobet S.A. From organotypic body-on-a-chip: A neuroendocrine perspective.J. Neuroendocrinol. 31e12650Crossref (3) 17.McLean I.C. al.Powering systems.Lab 1399-1410Crossref 18.Shim S. al.Two-way chip: tumor–lymph node interaction.Lab 19: 1013-1026Crossref recellularized scaffolds [19.Wang microengineered collagen scaffold generating polarized crypt-villus intestinal epithelium.Biomaterials. 128: 44-55Crossref (116) bioprinted [20.Yu Choudhury D. Microfluidic bioprinting models.Drug Today. 1248-1257Crossref (35) microfabricated structures [21.Hinman S.S. al.Microphysiological design: simplicity elegance.Curr. Opin. Biomed. 94-102Crossref possibly active stimulation (electrical, biochemical, mechanical) [22.Kaarj Yoon J.-Y. Methods delivering mechanical stimuli organ-on-a-chip.Micromachines 700Crossref 23.Gaio al.Cytostretch, organ-on-chip platform.Micromachines 2016; 7: 120Crossref (16) 24.Visone R. microscale biomimetic electro-mechanical cardiac microtissues.APL Bioeng. 2046102Crossref OoC field blossoming decade, virtually all barriers Scholar,25.Mastrangeli M. al.Building blocks European roadmap.ALTEX. 36: 481-492Crossref (4) Scholar,26.Mastrangeli al.Organ-on-chip development: towards roadmap organs-on-chip.ALTEX. 650-668Crossref These revolutionizing experimentation hold promise reducing testing. based single type tissue, lack both major recent breakthrough, modeled device (Figure 2). detailed Box two realize platforms: units integration one plate (multi-OoC plates).Box 1Multi-OoC Typology ApplicationsMulti-OoC classified main distinct types, typology referring engineering approach used realization, namely connection plate.First, connected capillary tubing motherboard reproduce interactions more IA). allows reconfiguration supports individual vascularized microvasculature endothelial cells. modules first established matured before other. By contrast, IB) integrate single-plate at locations, where act vascular-like support second much akin human-on-a-chip paradigm IC). Multi-OoC plates compact user-friendly, require manual cumbersome connection, limit risks leakage, and, cases, actuation They also advantageous minimizing total recirculation volume (see section 'Circulation Medium' text). vascularization less trivial, following (section .Organ Models. text) may challenging.These arguably better suited former 'Lego-like' likely preferred fundamental academic setting. offer only low-to-moderate ideal preclinical, toxicity, tests. turnkey plate-based higher hence appropriate therapeutic targets, selection optimization candidates.Figure ISchematic Representation Two Main Approaches Developing Systems.Show full caption(A) Through organ, (B); (C) integrating plate, line philosophy.View Large Image ViewerDownload Hi-res image Download (PPT) plate. First, challenging. candidates. review combinations best particular applications. Specific areas brings superior set considered provided approach. Selected past 5 years summarized Table 1 (Key Table).Table 1Key Table. Overview Recently Reported PlatformsaAbbreviations: A549, non-small lung cells; AA, amino acid; ALI, air–liquid Interface; AMSCs, airway stromal mesenchymal (donor derived); APCs, antigen-presenting BCA, bicinchoninic BF, bovine fetuin; BSA, serum albumin; Caco-2, heterogeneous epithelial colorectal adenocarcinoma ECM, matrix; FBS, fetal serum; Fob1.19, osteoblast hA, astrocytes; HA, hyaluronic HA-1800, astrocyte 16HBE, bronchial HBMECs, brain microvascular HBVPs, pericytes; HCT-116, colon HepaRG, hepatic stem HEPES, (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer; HepG2/C3a, hepatocellular carcinoma hHSteC, stellate HL60, leukemia hLSMECs, sinusoidal HM, microglial; HMVEC-L, HNC, neural hPCF, primary fibroblasts; hRPTECs, renal proximal tubule HUVECs, umbilical vein Hw36, hepatocytes; Kupffer macrophages; IFN, interferon; IL, interleukin; L-02, hepatocyte LC, chromatography; LDH, lactate dehydrogenase; MBA-MD-231, breast MCF-7, MDCK, Madin–Darby canine MEA, measurements neurons Maestro™ MEA (Multi Electrode Arrays) system; NHBE, normal bronchial/tracheal NPCs, progenitor NTera2/cl.D1, pluripotent testicular embryonal PEEK, polyetheretherketone; PEGDA, poly(ethyleneglycol) diacrylate; PET, polyethylene terephthalate; PI, propidium iodide; PSF, polysulfone; RPTECs, RPTEC/TERT-1, immortalized SSCs, spermatogonial THP-1, monocyte TIG-121, diploid fibroblast Treg, T cell; UC, ulcerative colitis. lines preceded (GFP) (RFP) indicate engineered express GFP/RFP.,bReferences [13,18,27–35,37,39,40,43–47,50,51,53,54,88,93,94] found reference list end paper.a Abbreviations: GFP/RFP.b References Scholar,18.Shim Scholar,27.Bovard lung/liver-on-a-chip acute chronic studies.Lab 3814-3829Crossref 28.Kimura H. al.An intestine–liver pharmacokinetic studies.J. Lab. Autom. 265-273Crossref (62) 29.Oleaga C. al.Investigation effect off-target cardiotoxicity multi-organ system.Biomaterials. 182: 176-190Crossref 30.Materne E.-M. neurospheres equivalents long-term testing.J. 205: 36-46Crossref (97) 31.Hübner al.Simultaneous evaluation anti-EGFR-induced tumour adverse model.Sci. 8: 15010Crossref 32.Kim al.96-well format-based parallel interconnection spheroids.J. 274-282Crossref (47) 33.Ong L.J.Y. al.Self-aligning Tetris-like (TILE) mimicking interactions.Lab 2178-2191Crossref 34.Satoh T. multi-throughput multi-organ-on-a-chip formatted pneumatic pressure-driven platform.Lab 115-125Crossref 35.Theobald al.In metabolic activation vitamin D3 multi-compartment liver–kidney platform.Sci. 4616Crossref Scholar,37.Chong L.H. liver-immune coculture array predicting drug-induced sensitization.Lab 3239-3250Crossref Scholar,39.Edington C.D. al.Interconnected microphysiological pharmacology studies.Sci. 4530Crossref (165) Scholar,40.Herland al.Quantitative responses drugs fluidically coupled chips.Nat. 4: 421-436Crossref (64) Scholar,43.Loskill P. al.μOrgano: Lego®-like plug & multi-organ-chips.PLoS One. 10e0139587Crossref (18) 44.Esch M.B. al.Modular, pumpless GI tract tissue.Lab 16: 2719-2729Crossref 45.Maschmeyer I. four-organ-chip intestine, liver, equivalents.Lab 2688-2699Crossref 46.Ramme A.P. al.Autologous induced cell-derived four-organ-chip.Future OA. 5FSO413Crossref (20) 47.Trapecar al.Gut–liver physiomimetics reveal paradoxical modulation IBD-related Inflammation short-chain fatty acids.Cell Syst. 10 (e9): 223-239Abstract (27) Scholar,50.Bauer al.Functional pancreatic on-a-chip: novel 2 diabetes 14620Crossref Scholar,51.Xiao 28-day menstrual cycle.Nat. Commun. 814584Crossref (175) Scholar,53.Kong cells.Oncotarget. 78421-78432Crossref Scholar,54.Xu Z. al.Design construction microenvironment metastasis.ACS Appl. Mater. Interfaces. 25840-25847Crossref Scholar,88.Aleman Skardal multi-site metastasis-on-a-chip assessing metastatic preference cells.Biotechnol. 116: 936-944Crossref (33) Scholar,93.Skardal reductionist progression screening.Biotechnol. 113: 2020-2032Crossref (90) Scholar,94.Skardal al.Multi-tissue three-tissue 8837Crossref (189) paper. Toxicity closely linked purposes least other (target) organ. examine inhaled aerosols combined [27.Bovard 2C). pharmacological typically added minimal liver–target absorption [28.Kimura Alternatively, when undesired treatment evaluated, expected, (nephrotoxicity), heart (cardiotoxicity) [29.Oleaga (neurotoxicity) [30.Materne long-ter

Language: Английский

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Multi-lineage Human iPSC-Derived Platforms for Disease Modeling and Drug Discovery

Cell stem cell, Journal Year: 2020, Volume and Issue: 26(3), P. 309 - 329

Published: March 1, 2020

Language: Английский

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Is it Time for Reviewer 3 to Request Human Organ Chip Experiments Instead of Animal Validation Studies?

Advanced Science, Journal Year: 2020, Volume and Issue: 7(22)

Published: Oct. 12, 2020

For the past century, experimental data obtained from animal studies have been required by reviewers of scientific articles and grant applications to validate physiological relevance in vitro results. At same time, pharmaceutical researchers regulatory agencies recognize that results preclinical models frequently fail predict drug responses humans. This Progress Report reviews recent advances human organ-on-a-chip (Organ Chip) microfluidic culture technology, both with single Organ Chips fluidically coupled "Body-on-Chips" platforms, which demonstrate their ability recapitulate physiology disease states, as well patient clinically relevant pharmacokinetic exposures, higher fidelity than other or studies. These findings raise question whether continuing require testing for publication funding still makes ethical sense, if more physiologically Chip might better serve this purpose. issue is addressed article context history field, advantages disadvantages approaches versus are discussed should be considered wider research community.

Language: Английский

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In Vitro Models of the Blood-Brain Barrier

Handbook of experimental pharmacology, Journal Year: 2020, Volume and Issue: unknown, P. 75 - 110

Published: Jan. 1, 2020

Language: Английский

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Mechanisms of Blood–Brain Barrier Dysfunction in Traumatic Brain Injury

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(9), P. 3344 - 3344

Published: May 8, 2020

Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in United States with roughly two million TBIs occurring annually. Due to spectrum severity and heterogeneity TBIs, investigation into secondary injury is necessary order formulate an effective treatment. A mechanical consequence trauma involves dysregulation blood–brain barrier (BBB) which contributes exposure peripheral components parenchyma. Recent studies have shed light on mechanisms BBB breakdown TBI including novel intracellular signaling cell–cell interactions within niche. The current review provides overview BBB, detection methods disruption, cellular molecular implicated regulating its stability following TBI.

Language: Английский

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Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(8)

Published: Feb. 4, 2021

Significance Human PSC-derived iBMECs have been generated to study disease mechanisms and drug development for neurological disorders. However, their full transcriptomic characterization is unclear, which could result in inaccurate physiological studies of treatments with ineffective clinical outcomes. Utilizing a comprehensive metaanalysis validated by studies, we find that many current protocols used generate produce homogenous epithelial cell population. Overexpression ETS transcription factors reprogram these cells into phenotypic endothelial (rECs) recapitulate certain vascular functions, albeit lacking expression some organotypic transporter genes high electrical resistance vitro. Nevertheless, they represent crucial step toward the generation an vitro model suitable pharmaceutical blood–brain barrier.

Language: Английский

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