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(2) To compare proteomes of PTF from teeth with normal apical tissues (NAT) and asymptomatic apical periodontitis (AAP) using high\u2010throughput panels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methodology<\/jats:title><jats:p>(1) To assess volume absorbance, paper points (<jats:italic>n<\/jats:italic>\u2009=\u200920) of multiple brands, sizes and sampling durations were inserted into PBS\/1%BSA at several depths. Wetted lengths (mm) were measured against standard curves to determine volume absorbance (\u03bcL). To assess analyte recovery, paper points (<jats:italic>n<\/jats:italic>\u2009=\u20096) loaded with 2\u2009\u03bcL recombinant IL\u20101\u03b2 (15.6\u2009ng\/mL) were eluted into 250\u2009\u03bcL: (i) PBS; (ii) PBS\/1% BSA; (iii) PBS\/0.1% Tween20; (iv) PBS\/0.25\u2009M NaCl. These then underwent: (i) vortexing; (ii) vortexing\/centrifugation; (iii) centrifugation; (iv) incubation\/vortexing\/centrifugation. Sandwich\u2010ELISAs determined analyte recovery (%) against positive controls.<\/jats:p><jats:p>(2) Using optimized protocols, PTF was retrieved from permanent teeth with NAT or AAP after accessing root canals. Samples, normalized to total fluid volume (TFV), were analysed to determine proteomic profiles (pg\/TFV) of NAT and AAP via O\u2010link Target\u201048 panel. Correlations between AAP and diagnostic accuracy were explored using principal\u2010component analysis (PCA) and area under receive\u2010operating\u2010characteristic curves (AUC [95% CI]), respectively. Statistical comparisons were made using Mann\u2013Whitney <jats:italic>U<\/jats:italic>, <jats:sc>anova<\/jats:sc> and <jats:italic>post hoc<\/jats:italic> Bonferonni tests (<jats:italic>\u03b1<\/jats:italic>\u2009&lt;\u2009.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>(1) UnoDent's \u2018Classic\u2019 points facilitated maximum volume absorbance (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.05), with no significant differences after 60\u2009s (1.6\u2009\u03bcL [1.30\u20131.73]), 1\u2009mm depth and up to 40\/0.02 (2.2\u2009\u03bcL [1.98\u20132.20]). For elution, vortexing (89.3%) and PBS\/1% BSA (86.9%) yielded the largest IL\u20101\u03b2 recovery (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.05).<\/jats:p><jats:p>(2) 41 (NAT: 13; AAP: 31) PTF samples proceeded to analysis. The panel detected 18 analytes (CCL\u20102, \u20103, \u20104; CSF\u20101; CXCL\u20108, \u20109; HGF; IL\u20101\u03b2, \u20106, \u201017A, \u201018; MMP\u20101, \u201012; OLR\u20101; OSM; TNFSF\u201010, \u201012; VEGF\u2010A) in \u226575% of AAP samples at statistically higher concentrations (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.01). CXCL\u20108, IL\u20101\u03b2, OLR\u20101, OSM and TNFSF\u201012 were strongly correlated to AAP. \u2018Excellent\u2019 diagnostic performance was observed for TNFSF\u201012 (AUC: 0.94 [95% CI: 0.86\u20131.00]) and the PCA\u2010derived cluster (AUC: 0.96 [95% CI: 0.89\u20131.00]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Optimized PTF sampling parameters were identified in this study. When applied clinically, high\u2010throughput proteomic analyses revealed complex interconnected networks of potential biomarkers. TNFSF\u201012 discriminated periradicular disease from health the greatest; however, clustering analytes further improved diagnostic accuracy. Additional independent investigations are required to validate these findings.<\/jats:p><\/jats:sec>","DOI":"10.1111\/iej.13956","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T04:24:20Z","timestamp":1689740660000},"page":"1222-1240","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Periradicular tissue fluid\u2010derived biomarkers for apical periodontitis: An <i>in vitro<\/i> methodological and <i>in vivo<\/i> cross\u2010sectional study"],"prefix":"10.1111","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8046-1805","authenticated-orcid":false,"given":"Satnam S.","family":"Virdee","sequence":"first","affiliation":[{"name":"Institute of Clinical Sciences, School of Dentistry &amp; Birmingham Dental Hospital University of Birmingham  Birmingham 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