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Disruption of these mechanisms, through immobility, valve dysfunction, or inflammation, creates disturbed flow and heterogeneous shear that drive venous dysfunction and disease progression. Traditional animal models, though informative, fail to replicate human venous geometry and hemodynamics. This review critically evaluates current\u00a0in vitro\u00a0and\u00a0in silico\u00a0venous models, highlighting their capabilities and limitations in reproducing physiological flow, endothelial responses, and thrombus dynamics. By systematically comparing design parameters, cellular configurations, and flow regimes, we identify key gaps limiting the translational relevance of current NAMs. Building on this analysis, we propose future directions emphasizing\u00a0hybrid patient\u2010specific modeling, where imaging\u2010derived geometries and\u00a0digital twins\u00a0are integrated with venous NAMs to capture individualized hemodynamics and immune\u2013endothelial interactions. We further outline\u00a0validation strategies\u00a0linking NAM outputs with clinical and animal benchmarks to establish predictive fidelity. Together, these perspectives position venous NAMs as next\u2010Generation tools to mechanistically dissect thrombosis, advance personalized risk assessment, and accelerate the development of targeted venous therapeutics.<\/jats:p>","DOI":"10.1002\/smll.202510352","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T15:34:17Z","timestamp":1768232057000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Next Generation Experimental Models of Venous Physiology and Pathology: Examining Human Relevance in Recapitulating Lower Extremity Flow and Valve Function in New Approach Methods (NAMs)"],"prefix":"10.1002","volume":"22","author":[{"given":"Sreelakshmy","family":"Suresh","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Texas A&amp;M College of Engineering  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Dhar","sequence":"additional","affiliation":[{"name":"Cardiovascular Translational Research Center University of South Carolina School of Medicine  Columbia South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin E.","family":"Evans","sequence":"additional","affiliation":[{"name":"Cardiovascular Translational Research Center University of South Carolina School of Medicine  Columbia South Carolina USA"},{"name":"Department of Biomedical Engineering and Department of Cell Biology and Anatomy University of South Carolina School of Medicine  Columbia South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hoofnagle","sequence":"additional","affiliation":[{"name":"Department of Surgery Washington University in St Louis School of Medicine  St Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2235-5139","authenticated-orcid":false,"given":"Abhishek","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Texas A&amp;M College of Engineering  College Station Texas USA"},{"name":"Department of Medical Physiology Naresh K. 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