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However, the in vivo degradation rate of these materials is difficult to control because of site\u2010specific enzymatic activity, implant design, and disease state, impairing tissue regeneration. Hydrogels with crosslinks that degrade hydrolytically offer an alternate route to tune in vivo degradation profile. In this study, a synthetic 4\u2010arm maleimide\u2010terminated poly(ethylene glycol) (PEG\u20104MAL) hydrogel system that combines hydrolytic ester\u2010linked PEG\u20104MAL (PEG\u20104eMAL) macromer with nondegradable amide\u2010linked PEG\u20104MAL (PEG\u20104aMAL) macromer in various stoichiometric ratios to tune the degradability rate is engineered. The macromers are crosslinked with dithiothreitol (DTT) via thiol\u2010maleimide click reaction. Rheological analysis shows that a family of PEG\u20104eMAL\/PEG\u20104aMAL hydrogels has equivalent mechanical properties, but increasing the PEG\u20104eMAL content increases the rate of degradation in vitro and in vivo. PEG\u20104eMAL\/PEG\u20104aMAL hydrogels support high viability of encapsulated human cells. Notably, the ratio of PEG\u20104eMAL\/PEG\u20104aMAL modulates local immune cell recruitment when implanted in the subcutaneous space. These results establish the use of PEG\u20104eMAL\/PEG\u20104aMAL hydrogels as a hydrolytically degradable platform to tune in vivo degradation and immune responses.<\/jats:p>","DOI":"10.1002\/adhm.202502475","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T08:36:01Z","timestamp":1759307761000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Synthetic Hydrogels Incorporating Hydrolytic\/Nonhydrolytic Macromer Ratios Exhibit Improved Tunability of In Vivo Degradation and Immune Responses"],"prefix":"10.1002","volume":"15","author":[{"given":"Michael D.","family":"Hunckler","sequence":"first","affiliation":[{"name":"Woodruff School of Mechanical Engineering Georgia Institute of Technology  801 Ferst Dr NW Atlanta GA 30332 USA"},{"name":"Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology  315 Ferst Dr NW Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Kioulaphides","sequence":"additional","affiliation":[{"name":"Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology  315 Ferst Dr NW Atlanta GA 30332 USA"},{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  313 Ferst Dr NW Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen E.","family":"Martin","sequence":"additional","affiliation":[{"name":"Woodruff School of Mechanical Engineering Georgia Institute of Technology  801 Ferst Dr NW Atlanta GA 30332 USA"},{"name":"Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology  315 Ferst Dr NW Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica L.","family":"Torres","sequence":"additional","affiliation":[{"name":"Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology  315 Ferst Dr NW Atlanta GA 30332 USA"},{"name":"Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology  313 Ferst Dr NW Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham F.","family":"Barber","sequence":"additional","affiliation":[{"name":"Woodruff School of Mechanical Engineering Georgia Institute of Technology  801 Ferst Dr NW Atlanta GA 30332 USA"},{"name":"Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology  315 Ferst Dr NW Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen W.","family":"Linderman","sequence":"additional","affiliation":[{"name":"Woodruff School of Mechanical Engineering Georgia Institute of Technology  801 Ferst Dr NW Atlanta GA 30332 USA"},{"name":"Emory University School of Medicine Emory University  100 Woodruff Cir Atlanta GA 30322 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca S.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology  315 Ferst Dr NW Atlanta GA 30332 USA"},{"name":"School of Chemical and Biomolecular Engineering Georgia Institute of Technology  311 Ferst Dr NW Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6602-2518","authenticated-orcid":false,"given":"Andr\u00e9s J.","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Woodruff School of Mechanical Engineering Georgia Institute of Technology  801 Ferst Dr NW Atlanta GA 30332 USA"},{"name":"Petit Institute for Bioengineering and Bioscience Georgia Institute of Technology  315 Ferst Dr NW Atlanta GA 30332 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3632"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15102370"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2017.11.016"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201506055"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1700184"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aar4008"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmacrolett.8b00664"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2007.11.004"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20030636"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13091341"},{"key":"e_1_2_9_11_1","first-page":"367","volume":"60","author":"Rotim Z.","year":"2022","journal-title":"Acta Clin. 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