{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:15:35Z","timestamp":1789168535935,"version":"build-2803163510"},"reference-count":57,"publisher":"Wiley","issue":"34","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI152568"],"award-info":[{"award-number":["R01AI152568"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32GM144291"],"award-info":[{"award-number":["T32GM144291"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Adv Healthcare Materials"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Microporous annealed particle (MAP) scaffolds are injectable hydrogel biomaterials that promote tissue regeneration by enabling rapid cell infiltration and presenting reparative cues. Previous work showed that substituting L\u2010 with D\u2010chiral residues in matrix metalloproteinase (MMP)\u2010degradable crosslinkers induces adaptive immune\u2010mediated skin regeneration and balanced macrophage responses in vivo, but the underlying mechanisms remain unclear. Here, we identify myeloid differentiation factor 2 (MD\u20102)\u2010associated TLR4 signaling as a key mechanistic contributor to macrophage polarization driven by crosslinker chirality in MAP scaffolds. Macrophages cultured in D\u2010chiral MAP (DMAP) scaffolds exhibited reduced iNOS, CD86, and TNF\u2010\u03b1 expression and shifted from an M1\u2010like state toward M0\u2010like phenotypes compared to L\u2010chiral MAP (LMAP) and 2D controls. Competitive inhibition with soluble D\u2010chiral MMP crosslinker peptide (DMMP) partially restored M1 activation, implicating direct peptide\u2013macrophage interactions. Docking and surface plasmon resonance (SPR) analyses revealed higher\u2010affinity binding of DMMP to MD\u20102 relative to L\u2010chiral peptides. Accordingly, DMAP altered TLR4\/MD\u20102 trafficking and attenuated endocytosis\u2010dependent signaling. Engineering a second D\u2010peptide crosslinker with enhanced MD\u20102 affinity (DMMP2) reduced inflammatory markers and promoted regenerative macrophage polarization. Together, these results establish peptide chirality as a tunable design parameter for modulating TLR4\/MD\u20102 signaling and engineering immunomodulatory MAP scaffolds.<\/jats:p>","DOI":"10.1002\/adhm.71572","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:48:04Z","timestamp":1786682884000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MAP Crosslinker Chirality Regulates Macrophage Polarization Through MD\u20102 Engagement and Enables Tunable Immunomodulation Through Novel Peptide Design"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9235-0910","authenticated-orcid":false,"given":"Alejandra","family":"Suarez\u2010Arnedo","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4061-9655","authenticated-orcid":false,"given":"Jeremy L.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4326-1067","authenticated-orcid":false,"given":"Pablo","family":"Cordero\u2010Alvarado","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8225-6209","authenticated-orcid":false,"given":"Amy","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4960-7048","authenticated-orcid":false,"given":"April Chavez","family":"Espinoza","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leica","family":"Harvey","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7280-7094","authenticated-orcid":false,"given":"Koravit","family":"Poysungnoen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayanne","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyou","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1569-8686","authenticated-orcid":false,"given":"Tatiana","family":"Segura","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"},{"name":"Clinical Science Departments of Neurology and Dermatology Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a041216","article-title":"Role of Macrophages in Wound Healing","volume":"14","author":"Willenborg S.","year":"2022","journal-title":"Cold Spring Harbor Perspectives in Biology"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.201801451"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.609297"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.5772\/57541"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202111003"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202303005"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202304049"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2025.123667"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2018.11.001"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmat4294"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41563\u2010020\u201000844\u2010w"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202204882"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202300823"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41563\u2010018\u20100190\u20106"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202401253"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2024.123013"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1349461"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596\u2010020\u20100312\u2010x"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.2741\/2692"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13062\u2010015\u20100103\u20104"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.075127"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010025\u201002149\u20104"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2013.00003"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.11.1777"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201059550\u20103"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1016\u20108478(23)10763\u20101"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24098395"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20108760\u20103_12"},{"key":"e_1_2_10_30_1","first-page":"325","volume-title":"Methods in Enzymology","author":"Myszka D. G.","year":"2000"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1NR02083H"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200502794"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1569"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44319\u2010025\u201000444\u20102"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1424980112"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2006.04.002"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.349"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12979\u2010023\u201000383\u20103"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00461"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1133354"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.12679.1"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M901429200"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2021.0124"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S527764"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010023\u201001068\u2010z"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mattod.2015.01.019"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2017.12.007"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102105\u201012\u2010190"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.98850"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.3390\/bioengineering9070324"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-809841-7.00025-3"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22837"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.21105\/joss.00861"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22625"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0076\u20106879(00)23372\u20107"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xjidi.2024.100332"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw419"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201076603\u20103"}],"container-title":["Advanced Healthcare Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.71572","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/adhm.71572","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.71572","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:40:51Z","timestamp":1789166451000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adhm.71572"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":57,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/adhm.71572"],"URL":"https:\/\/doi.org\/10.1002\/adhm.71572","archive":["Portico"],"relation":{},"ISSN":["2192-2640","2192-2659"],"issn-type":[{"value":"2192-2640","type":"print"},{"value":"2192-2659","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]},"assertion":[{"value":"2026-02-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71572"}}