{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:07:40Z","timestamp":1789168060402,"version":"build-2803163510"},"reference-count":24,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T00:00:00Z","timestamp":1770422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006590","name":"UMKC SOM Bridge Fund","doi-asserted-by":"publisher","award":["Bridge 2025"],"award-info":[{"award-number":["Bridge 2025"]}],"id":[{"id":"10.13039\/100006590","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Human sepsis is a complex disease that manifests with a diverse range of phenotypes and inherent variability among individuals, making it hard to develop a comprehensive animal model. Despite this difficulty, numerous animal models have been developed that capture many key aspects of human sepsis. Though the animal models have contributed to the fundamental advances in understanding the pathogenesis of septic patients, the translational value of these models has been constantly questioned because many clinical trials of targeted therapies based on the advances in animal models have failed, highlighting the urgent need for developing new research models or refining previous animal models for sepsis research. In this review, we will summarize recent advances in new and emerging research models for sepsis, including human-based in vitro systems, highly tailored animal models, AI and digital models analyzing vast datasets to define patient subgroups and predict outcomes, and the FAMOUS framework ensuring that therapies are tested against the specific mechanism they are designed to target. We will discuss the strengths and limitations of these models, reflecting the clinical course of sepsis, and discuss the future directions in this subject area.<\/jats:p>","DOI":"10.3390\/cells15040312","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T10:45:31Z","timestamp":1770633931000},"page":"312","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["New and Emerging Research Models for Sepsis"],"prefix":"10.3390","volume":"15","author":[{"given":"Saichaitanya","family":"Nallajennugari","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, Shock\/Trauma Research Center, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7260-8133","authenticated-orcid":false,"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Shock\/Trauma Research Center, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6315-8372","authenticated-orcid":false,"given":"Mingui","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Shock\/Trauma Research Center, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.ijmm.2007.03.005","article-title":"Advances in sepsis research derived from animal models","volume":"297","year":"2007","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1189\/jlb.0806542","article-title":"The disconnect between animal models of sepsis and human sepsis","volume":"81","author":"Rittirsch","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/nrd1854","article-title":"Animal models of sepsis: Setting the stage","volume":"4","author":"Buras","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s002689900077","article-title":"Animal models as the basis of pharmacologic intervention in trauma and sepsis patients","volume":"20","author":"Redl","year":"1996","journal-title":"World J. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"120","DOI":"10.5152\/eurasianjmed.2023.23364","article-title":"Experimental Sepsis Models: Advantages and Limitations","volume":"55","author":"Bekmez","year":"2023","journal-title":"Eurasian J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e21156","DOI":"10.1096\/fj.202002150R","article-title":"Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis","volume":"35","author":"Efron","year":"2021","journal-title":"FASEB J."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dickson, K., and Lehmann, C. (2019). Inflammatory Response to Different Toxins in Experimental Sepsis Models. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184341"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1128\/iai.61.7.2741-2747.1993","article-title":"Choice of bacteria in animal models of sepsis","volume":"61","author":"Cross","year":"1993","journal-title":"Infect. Immun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1097\/01.shk.0000126906.52367.dd","article-title":"Cecal ligation and puncture versus colon ascendens stent peritonitis: Two distinct animal models for polymicrobial sepsis","volume":"21","author":"Maier","year":"2004","journal-title":"Shock"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1042\/CS20200679","article-title":"Rethinking animal models of sepsis\u2014Working towards improved clinical translation whilst integrating the 3Rs","volume":"134","author":"Nandi","year":"2020","journal-title":"Clin. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119504","DOI":"10.1016\/j.bbamcr.2023.119504","article-title":"Organ-on-a-chip models for elucidating the cellular biology of infectious diseases","volume":"1870","author":"Yokoi","year":"2023","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"pwaf058","DOI":"10.1093\/procel\/pwaf058","article-title":"Synergistic innovation in organ-on-a-chip and organoid technologies: Reshaping the future of disease modeling, drug development, and precision medicine","volume":"13","author":"Li","year":"2025","journal-title":"Protein Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/s41576-022-00466-9","article-title":"Human organs-on-chips for disease modelling, drug development and personalized medicine","volume":"23","author":"Ingber","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.tig.2023.01.002","article-title":"iPSC-derived organ-on-a-chip models for personalized human genetics and pharmacogenomics studies","volume":"39","author":"Palasantzas","year":"2023","journal-title":"Trends Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1039\/C8LC00827B","article-title":"Personalised organs-on-chips: Functional testing for precision medicine","volume":"19","author":"Mummery","year":"2019","journal-title":"Lab A Chip"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.1097\/CM9.0000000000002348","article-title":"Lipopolysaccharide induced intestinal epithelial injury: A novel organoids-based model for sepsis in vitro","volume":"135","author":"Huang","year":"2022","journal-title":"Chin. Med. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1111\/ajt.13562","article-title":"Ex Vivo Perfusion Treatment of Infection in Human Donor Lungs","volume":"16","author":"Nakajima","year":"2016","journal-title":"Am. J. Transpl."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Laudanski, K. (2021). Humanized Mice as a Tool to Study Sepsis-More Than Meets the Eye. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052403"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s40635-024-00609-8","article-title":"Impact of age on the host response to sepsis in a murine model of fecal-induced peritonitis","volume":"12","author":"Sharma","year":"2024","journal-title":"Intensive Care Med. Exp."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1093\/gerona\/63.4.391","article-title":"The physical and biological characterization of a frail mouse model","volume":"63","author":"Walston","year":"2008","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103081","DOI":"10.1016\/j.ebiom.2020.103081","article-title":"Deep learning-based clustering robustly identified two classes of sepsis with both prognostic and predictive values","volume":"62","author":"Zhang","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40560-025-00802-1","article-title":"Molecular endotypes in sepsis: Integration of multicohort transcriptomics based on RNA sequencing","volume":"13","author":"Mekata","year":"2025","journal-title":"J. Intensive Care"},{"key":"ref_23","first-page":"e0249","article-title":"Development and Verification of a Digital Twin Patient Model to Predict Specific Treatment Response During the First 24 Hours of Sepsis","volume":"2","author":"Lal","year":"2020","journal-title":"Crit. Care Explor."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.molmed.2014.01.007","article-title":"Why have clinical trials in sepsis failed?","volume":"20","author":"Marshall","year":"2014","journal-title":"Trends Mol. 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