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

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. 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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. 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