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Macrophages play critical roles in the modulation of the host immune response and are the cells responsible for persistent inflammatory reactions to implanted biomaterials. Two novel immune\u2010instructive polymers that stimulate pro\u2010 or anti\u2010inflammatory responses from macrophages in vitro are investigated. These also modulate in vivo foreign body responses (FBR) when implanted subcutaneously in mice. Immunofluorescent staining of tissue abutting the polymer reveals responses consistent with pro\u2010 or anti\u2010inflammatory responses previously described for these polymers. Three Dimensional OrbiTrap Secondary Ion Mass Spectrometry (3D OrbiSIMS) analysis to spatially characterize the metabolites in the tissue surrounding the implant, providing molecular histology insight into the metabolite response in the host is applied. For the pro\u2010inflammatory polymer, monoacylglycerols (MG) and diacylglycerols (DG) are observed at increased intensity, while for the anti\u2010inflammatory coating, the number of phospholipid species detected decreased, and pyridine and pyrimidine levels are elevated. Small molecule signatures from single\u2010cell studies of M2 macrophages in vitro correlate with the in vivo observations, suggesting potential for prediction. Metabolite characterization by the 3D OrbiSIMS is shown to provide insight into the mechanism of bio\u2010instructive materials as medical devices and to inform on the FBR to biomaterials.<\/jats:p>","DOI":"10.1002\/advs.202306000","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T01:08:31Z","timestamp":1707959311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Spatially Resolved Molecular Analysis of Host Response to Medical Device Implantation Using the 3D OrbiSIMS Highlights a Critical Role for Lipids"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9138-9418","authenticated-orcid":false,"given":"Waraporn","family":"Suvannapruk","sequence":"first","affiliation":[{"name":"Advanced Materials and Healthcare Technologies Division School of Pharmacy University of Nottingham  University Park Nottingham Nottingham NG7 2RD 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