A Memristive Model of Trans-Epithelial Electrical Resistance in a Breathing Lung-on-Chip: Mathematical Framework, Simulation, Advanced Analysis Extensions, and Experimental Validation Strategy

A Memristive Model of Trans-Epithelial Electrical Resistance in a Breathing Lung-on-Chip: Mathematical Framework, Simulation, Advanced Analysis Extensions, and Experimental Validation Strategy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Memristive Model of Trans-Epithelial Electrical Resistance in a Breathing Lung-on-Chip: Mathematical Framework, Simulation, Advanced Analysis Extensions, and Experimental Validation Strategy Vaitheeswaran Gnanaraj, Balakrishanan Vellaikannan, P Balamanikandan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9265672/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract We present the first memristive model of trans-epithelial electrical resistance (TEER) for a cyclic-strain Lung-on-Chip device. Classical circuit models treat TEER as a memoryless resistor, failing to capture tight-junction fatigue, mechanical pre-conditioning, and breathing-rate-dependent barrier remodelling. A scalar state variable w(t) ∈ [0,1] governs TEER through algebraic memristance M(w) = TEER₀(1 − αw), satisfying all three Chua fingerprints: pinched hysteresis loop, frequency-dependent loop-area shrinkage, and single-valued monotone state map. An adaptive RK45 solver over 200 breathing cycles reveals steady-state TEER depression of 3.9% within two cycles, spectral doubling at 2f_b as a falsifiable on-chip diagnostic signature, a stable toroidal limit cycle (Lyapunov λ ≈ 0), and 107 Ω·cm² cumulative fatigue depression modelling ventilator-induced lung injury. Damköhler classification confirms recovery-dominant dynamics across all five canonical organ barriers, validating multi-organ framework universality. Global Sobol analysis identifies α as the dominant parameter for barrier integrity (S_T = 0.43) and τ_rec for fatigue dynamics (S_T = 0.81); only two new parameters are required, both identifiable from standard TEER time-series protocols. A protective ventilation target (ε_max = 7%, f_b = 0.25 Hz) achieving 31% VILI reduction below eupnoea is identified. This framework establishes the alveolar epithelium as a genuine biological memristive system, providing a quantitative foundation for real-time impedance monitoring, VILI risk assessment, and lung-protective ventilation design in organ-on-chip platforms. Biomedical Engineering Applied Mathematics lung-on-chip memristor TEER tight junction Chua fingerprints VILI Sobol sensitivity Damköhler organ-on-chip design Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9265672","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":614525224,"identity":"da68888b-5c1d-4bc0-82b5-b585fbebca91","order_by":0,"name":"Vaitheeswaran Gnanaraj","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYFCCA1CavQFIGFiQooUHxDCQIMU2iQQwSViheePZoxu/7rDL45/5/OqGHwUSDPzt3Ql4tcgcOJd2W/ZMcrHE7Zyymz1Ah0mcObsBv3MYzpjdlmxjTmy4nZN2gweoxUAilygt9Ynzb55Ju/mHWC03P7YdTtxwg/3YbSJtAfqFse144sYzOWy3ZQwkeAj7ReLssZs/26oT5x0//uzmmz82cvztvfi1AAOIgZkHzOIxAJP4lYMAfw8D4w8wi/0BYdWjYBSMglEwIgEAEtJO9SqVxSMAAAAASUVORK5CYII=","orcid":"","institution":"Thiagarajar College of Engineering","correspondingAuthor":true,"prefix":"","firstName":"Vaitheeswaran","middleName":"","lastName":"Gnanaraj","suffix":""},{"id":614525225,"identity":"aa0178b6-6740-4a53-af64-c1522b3118b0","order_by":1,"name":"Balakrishanan Vellaikannan","email":"","orcid":"","institution":"Thiagarajar College of Engineering","correspondingAuthor":false,"prefix":"","firstName":"Balakrishanan","middleName":"","lastName":"Vellaikannan","suffix":""},{"id":614525226,"identity":"8d246324-98fb-4a26-a186-959e23b4e4ae","order_by":2,"name":"P Balamanikandan","email":"","orcid":"","institution":"Thiagarajar College of Engineering","correspondingAuthor":false,"prefix":"","firstName":"P","middleName":"","lastName":"Balamanikandan","suffix":""}],"badges":[],"createdAt":"2026-03-30 10:58:57","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9265672/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9265672/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105904152,"identity":"ed78b802-6f34-4d42-9263-317099ccef06","added_by":"auto","created_at":"2026-04-01 10:05:13","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1649506,"visible":true,"origin":"","legend":"","description":"","filename":"MemristiveLungOnChipJOURNAL.V1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9265672/v1_covered_ae183c4a-e91b-4c52-8a5d-a07d20ae7f6e.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eA Memristive Model of Trans-Epithelial Electrical Resistance in a Breathing Lung-on-Chip: Mathematical Framework, Simulation, Advanced Analysis Extensions, and Experimental Validation Strategy\u003c/strong\u003e\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Thiagarajar College of Engineeering, Madurai","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"lung-on-chip, memristor, TEER, tight junction, Chua fingerprints, VILI, Sobol sensitivity, Damköhler, organ-on-chip, design","lastPublishedDoi":"10.21203/rs.3.rs-9265672/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9265672/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe present the first memristive model of trans-epithelial electrical resistance (TEER) for a cyclic-strain Lung-on-Chip device. Classical circuit models treat TEER as a memoryless resistor, failing to capture tight-junction fatigue, mechanical pre-conditioning, and breathing-rate-dependent barrier remodelling. A scalar state variable w(t) \u0026isin; [0,1] governs TEER through algebraic memristance M(w) = TEER₀(1\u0026thinsp;\u0026minus;\u0026thinsp;αw), satisfying all three Chua fingerprints: pinched hysteresis loop, frequency-dependent loop-area shrinkage, and single-valued monotone state map. An adaptive RK45 solver over 200 breathing cycles reveals steady-state TEER depression of 3.9% within two cycles, spectral doubling at 2f_b as a falsifiable on-chip diagnostic signature, a stable toroidal limit cycle (Lyapunov λ\u0026thinsp;\u0026asymp;\u0026thinsp;0), and 107 Ω\u0026middot;cm\u0026sup2; cumulative fatigue depression modelling ventilator-induced lung injury. Damk\u0026ouml;hler classification confirms recovery-dominant dynamics across all five canonical organ barriers, validating multi-organ framework universality. Global Sobol analysis identifies α as the dominant parameter for barrier integrity (S_T\u0026thinsp;=\u0026thinsp;0.43) and τ_rec for fatigue dynamics (S_T\u0026thinsp;=\u0026thinsp;0.81); only two new parameters are required, both identifiable from standard TEER time-series protocols. A protective ventilation target (ε_max\u0026thinsp;=\u0026thinsp;7%, f_b\u0026thinsp;=\u0026thinsp;0.25 Hz) achieving 31% VILI reduction below eupnoea is identified. This framework establishes the alveolar epithelium as a genuine biological memristive system, providing a quantitative foundation for real-time impedance monitoring, VILI risk assessment, and lung-protective ventilation design in organ-on-chip platforms.\u003c/p\u003e","manuscriptTitle":"A Memristive Model of Trans-Epithelial Electrical Resistance in a Breathing Lung-on-Chip: Mathematical Framework, Simulation, Advanced Analysis Extensions, and Experimental Validation Strategy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-31 03:27:04","doi":"10.21203/rs.3.rs-9265672/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73e72b12-a688-48b6-bf47-fc1fb12ec193","owner":[],"postedDate":"March 31st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":65431791,"name":"Biomedical Engineering"},{"id":65431792,"name":"Applied Mathematics"}],"tags":[],"updatedAt":"2026-03-31T03:27:04+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-31 03:27:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9265672","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9265672","identity":"rs-9265672","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}