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Local antimicrobial delivery may reduce the risk of SSI by increasing drug concentrations and distribution in vulnerable surgical sites compared to what is achieved using systemic antimicrobial prophylaxis alone. In this work, we describe a comprehensive in vivo evaluation of the safety and efficacy of poly(<jats:italic>N<\/jats:italic>\u2010isopropylacrylamide\u2010<jats:italic>co<\/jats:italic>\u2010dimethylbutyrolactone acrylamide\u2010<jats:italic>co<\/jats:italic>\u2010Jeffamine M\u20101000 acrylamide) [PNDJ], an injectable temperature\u2010responsive hydrogel carrier for antimicrobial delivery in surgical sites. Biodistribution data indicate that PNDJ is primarily cleared via the liver and kidneys following drug delivery. Antimicrobial\u2010loaded PNDJ was generally well\u2010tolerated locally and systemically when applied in bone, muscle, articulating joints, and intraperitoneal space, although mild renal toxicity consistent with the released antimicrobials was identified at high doses in rats. Dosing of PNDJ at bone\u2010implant interfaces did not affect normal tissue healing and function of orthopedic implants in a transcortical plug model in rabbits and in canine total hip arthroplasty. Finally, PNDJ was effective at preventing recurrence of implant\u2010associated MSSA and MRSA osteomyelitis in rabbits, showing a trend toward outperforming commercially available antimicrobial\u2010loaded bone cement and systemic antimicrobial administration. These studies indicate that antimicrobial\u2010loaded PNDJ hydrogels are well\u2010tolerated and could reduce incidence of SSI in a variety of surgical procedures.<\/jats:p>","DOI":"10.1002\/jbm.b.34894","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T07:45:29Z","timestamp":1623743129000},"page":"103-114","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In vivo evaluation of temperature\u2010responsive antimicrobial\u2010loaded <scp>PNIPAAm<\/scp> hydrogels for prevention of surgical site infection"],"prefix":"10.1002","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0817-0966","authenticated-orcid":false,"given":"John M.","family":"Heffernan","sequence":"first","affiliation":[{"name":"Sonoran Biosciences  Tempe Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0306-1541","authenticated-orcid":false,"given":"Derek J.","family":"Overstreet","sequence":"additional","affiliation":[{"name":"Sonoran Biosciences  Tempe Arizona USA"},{"name":"School of Biological &amp; Health Systems Engineering Arizona State University  Tempe Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3288-0327","authenticated-orcid":false,"given":"Brent L.","family":"Vernon","sequence":"additional","affiliation":[{"name":"Sonoran Biosciences  Tempe Arizona USA"},{"name":"School of Biological &amp; Health Systems Engineering Arizona State University  Tempe Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan Y.","family":"McLemore","sequence":"additional","affiliation":[{"name":"Sonoran Biosciences  Tempe Arizona USA"},{"name":"University of Arizona College of Medicine  Phoenix Arizona USA"},{"name":"Systems Planning and Analysis, Inc.  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