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Res."],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>\n                        <jats:sc>A<\/jats:sc>bstract<\/jats:title><jats:p>Posttraumatic osteoarthritis (PTOA) is mostly treated via corticosteroid administration, and total joint arthroplasty continues to be the sole effective intervention in severe conditions. To assess the therapeutic potential of CCR2 targeting in PTOA, we used biodegradable microplates (\u00b5PLs) to achieve a slow and sustained intraarticular release of the CCR2 inhibitor RS504393 into injured knees and followed joint damage during disease progression. RS504393<jats:bold>-<\/jats:bold>loaded \u00b5PLs (RS-\u00b5PLs) were fabricated via a template-replica molding technique. A mixture of poly(lactic-co-glycolic acid) (PLGA) and RS504393 was deposited into 20\u2009\u00d7\u200910\u00a0\u03bcm (length\u2009\u00d7\u2009height) wells in a polyvinyl alcohol (PVA) square-patterned template. After physicochemical and toxicological characterizations, the RS504393 release profile from \u00b5PL was assessed in PBS buffer. C57BL\/6\u00a0J male mice were subjected to destabilization of the medial meniscus (DMM)\/sham surgery, and RS-\u00b5PLs (1\u00a0mg\/kg) were administered intraarticularly 1\u00a0week postsurgery. Administrations were repeated at 4 and 7\u00a0weeks post-DMM. Drug free-\u00b5PLs (DF-\u00b5PLs) and saline injections were performed as controls. Mice were euthanized at 4 and 10\u00a0weeks post-DMM, corresponding to the early and severe PTOA stages, respectively. Knees were evaluated for cartilage structure score (ACS, H&amp;E), matrix loss (safranin O score), osteophyte formation and maturation from cartilage to bone (cartilage quantification), and subchondral plate thickness. The RS-\u00b5PL architecture ensured the sustained release of CCR2 inhibitors over several weeks, with\u2009~\u200920% of RS504393 still available at 21\u00a0days. This prolonged release improved cartilage structure and reduced bone damage and synovial hyperplasia at both PTOA stages. Extracellular matrix loss was also attenuated, although with less efficacy. The results indicate that local sustained delivery is needed to optimize CCR2-targeted therapies.<\/jats:p>\n                <jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s13346-022-01235-1","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T17:02:56Z","timestamp":1663261376000},"page":"689-701","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sustained inhibition of CC-chemokine receptor-2 via intraarticular deposition of polymeric microplates in post-traumatic osteoarthritis"],"prefix":"10.1007","volume":"13","author":[{"given":"Huseyin","family":"Ozkan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Di Francesco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Willcockson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Vald\u00e9s-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Di Francesco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Froil\u00e1n","family":"Granero-Molt\u00f3","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felipe","family":"Pr\u00f3sper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Decuzzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0156-847X","authenticated-orcid":false,"given":"Lara","family":"Longobardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"issue":"10","key":"1235_CR1","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1097\/01.bot.0000246468.80635.ef","volume":"20","author":"TD Brown","year":"2006","unstructured":"Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA. 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J Bone Miner Res Off J Am Soc Bone Miner Res. 2015;30(2):286\u201396.","journal-title":"J Bone Miner Res Off J Am Soc Bone Miner Res"}],"container-title":["Drug Delivery and Translational Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13346-022-01235-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s13346-022-01235-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13346-022-01235-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T20:07:55Z","timestamp":1672171675000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s13346-022-01235-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,15]]},"references-count":44,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["1235"],"URL":"https:\/\/doi.org\/10.1007\/s13346-022-01235-1","relation":{},"ISSN":["2190-393X","2190-3948"],"issn-type":[{"value":"2190-393X","type":"print"},{"value":"2190-3948","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,15]]},"assertion":[{"value":"31 August 2022","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2022","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"A provisional patent has been filed on the reported RS504393-\u00b5PLs agent (IIT Ref. PT210580\/UNC Ref. No. 21\u20130097).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. Animal use protocols were approved by the Animal Care and Use Committee of the University of North Carolina at Chapel Hill NC (IACUC # 20\u2013075.0-C<b>).<\/b>","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All institutional and national guidelines for the care and use of laboratory animals were followed.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Animal studies"}}]}}