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To overcome these limitations, directed evolution is used to engineer highly specific, low affinity affibody binding partners to multiple therapeutic proteins to independently control protein release rates. As a proof\u2010of\u2010concept, specific affibody binding partners for two proteins with broad therapeutic utility: insulin\u2010like growth factor\u20101 (IGF\u20101) and pigment epithelium\u2010derived factor (PEDF) are identified. Protein\u2013affibody binding interactions specific to these target proteins with equilibrium dissociation constants (<jats:italic>K<\/jats:italic><jats:sub>D<\/jats:sub>) between 10<jats:sup>\u22127<\/jats:sup> and 10<jats:sup>\u22128<\/jats:sup> <jats:sc>m<\/jats:sc> are discovered. The affibodies are covalently bound to the backbone of crosslinked hydrogels using click chemistry, enabling sustained, independent, and simultaneous release of bioactive IGF\u20101 and PEDF over 7 days. The system is tested with C57BL\/6J mice in vivo, and the affibody\u2010controlled release of IGF\u20101 results in sustained activity when compared to bolus IGF\u20101 delivery. This work demonstrates a new, broadly applicable approach to tune the release of therapeutic proteins simultaneously and independently and thus the way for precise control over the delivery of multicomponent therapies is paved.<\/jats:p>","DOI":"10.1002\/adma.202202612","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T11:30:32Z","timestamp":1657020632000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Directed Evolution Enables Simultaneous Controlled Release of Multiple Therapeutic Proteins from Biopolymer\u2010Based Hydrogels"],"prefix":"10.1002","volume":"34","author":[{"given":"Carter J.","family":"Teal","sequence":"first","affiliation":[{"name":"Institute of Biomedical Engineering  164 College Street Toronto ON M5S 3G9 Canada"},{"name":"Terrence Donnelly Centre for Cellular and Biomolecular Research University of Toronto  160 College Street Toronto ON M5S 3E1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian H.","family":"Hettiaratchi","sequence":"additional","affiliation":[{"name":"Terrence Donnelly Centre for Cellular and Biomolecular Research University of Toronto  160 College Street Toronto ON M5S 3E1 Canada"},{"name":"Department of Chemical Engineering and Applied Chemistry University of Toronto  200 College Street Toronto ON M5S 3E5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret T.","family":"Ho","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering  164 College Street Toronto ON M5S 3G9 Canada"},{"name":"Terrence Donnelly Centre for Cellular and Biomolecular Research University of Toronto  160 College Street Toronto ON M5S 3E1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo","family":"Ortin\u2010Martinez","sequence":"additional","affiliation":[{"name":"Donald K. Johnson Eye Institute Krembil Research Institute University Health Network  399 Bathurst Street Toronto ON M5T 2S8 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahil N.","family":"Ganesh","sequence":"additional","affiliation":[{"name":"Terrence Donnelly Centre for Cellular and Biomolecular Research University of Toronto  160 College Street Toronto ON M5S 3E1 Canada"},{"name":"Department of Chemical Engineering and Applied Chemistry University of Toronto  200 College Street Toronto ON M5S 3E5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Pickering","sequence":"additional","affiliation":[{"name":"Terrence Donnelly Centre for Cellular and Biomolecular Research University of Toronto  160 College Street Toronto ON M5S 3E1 Canada"},{"name":"Department of Chemical Engineering and Applied Chemistry University of Toronto  200 College Street Toronto ON M5S 3E5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex W.","family":"Golinski","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota\u2212Twin Cities  421 Washington Avenue Southeast, 356 Amundson Hall Minneapolis MN 55455 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Hackel","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science University of Minnesota\u2212Twin Cities  421 Washington Avenue Southeast, 356 Amundson Hall Minneapolis MN 55455 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie A.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Donald K. 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