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For reproducible and accurate information, sample preparation methods need to be optimized. Paraformaldehyde fixation of a delicate multilayer structure like human retina facilitates the preservation of tissue morphology by forming methylene bridge crosslinks between formaldehyde and amine\/thiols in biomolecules; however, retina sections analyzed by IMS are typically fresh\u2010frozen. To determine if clinically significant inferences could be reliably based on fixed tissue, we evaluated the effect of fixation on analyte detection, spatial localization, and introduction of artifactual signals. Hence, we assessed the molecular identity of lipids generated by matrix\u2010assisted laser desorption ionization (MALDI\u2010IMS) and liquid chromatography coupled tandem mass spectrometry (LC\u2013MS\/MS) for fixed and fresh\u2010frozen retina tissues in positive and negative ion modes. Based on MALDI\u2010IMS analysis, more lipid signals were observed in fixed compared with fresh\u2010frozen retina. More potassium adducts were observed in fresh\u2010frozen tissues than fixed as the fixation process caused displacement of potassium adducts to protonated and sodiated species in ion positive ion mode. LC\u2013MS\/MS analysis revealed an overall decrease in lipid signals due to fixation that reduced glycerophospholipids and glycerolipids and conserved most sphingolipids and cholesteryl esters. The high quality and reproducible information from untargeted lipidomics analysis of fixed retina informs on all major lipid classes, similar to fresh\u2010frozen retina, and serves as a steppingstone towards understanding of lipid alterations in retinal diseases.<\/jats:p>","DOI":"10.1002\/jms.4798","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T10:43:41Z","timestamp":1637318621000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Tissue fixation effects on human retinal lipid analysis by MALDI imaging and LC\u2013MS\/MS technologies"],"prefix":"10.1002","volume":"56","author":[{"given":"Ankita","family":"Kotnala","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Mass Spectrometry Research Center Vanderbilt University School of Medicine  Nashville Tennessee USA"},{"name":"Department of Ophthalmology and Visual Sciences University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M. 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