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Encapsulating small hydrophilic molecules into hydrophobic polymer microparticles via traditional emulsion methods has long been a challenge due to rapid mass transport of small molecules out of particle pores. We have developed a simple alteration to the existing water\u2010in\u2010oil\u2010in\u2010water (W\/O\/W) drug encapsulation method that dramatically improves loading efficiency: doping external water phases with drug to mitigate drug diffusion out of the particle during fabrication. PLGA microparticles with diameters ranging from 0.6 to 0.9 micrometers were fabricated, encapsulating high loads of 0.6\u20130.9\u2009\u00b5m diameter PLGA microparticles were fabricated, encapsulating high loads of the antioxidant N\u2010acetylcysteine (NAC), and released active, ROS\u2010scavenging NAC for up to 5 weeks. Encapsulation efficiencies, normalized to the theoretical load of traditional encapsulation without doping, ranged from 96% to 400%, indicating that NAC\u2010loaded external water phases not only prevented drug loss due to diffusion, but also doped the particles with additional drug. Antioxidant\u2010doped particles positively affected the metabolism of oligodendrocyte progenitor cells (OPCs) under H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010mediated oxidative stress when administered both before (protection) or after (rescue) injury. Antioxidant doped particles improved outcomes of OPCs experiencing multiple doses of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> by increasing the intracellular glutathione content and preserving cellular viability relative to the injury control. Furthermore, antioxidant\u2010doped particles preserve cell number, number of process extensions, cytoskeletal morphology, and nuclear size of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010stressed OPCs relative to the injury control. These NAC\u2010doped particles have the potential to provide temporally\u2010controlled antioxidant therapy in neurodegenerative disorders such as multiple sclerosis (MS) that are characterized by continuous oxidative stress.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bit.26443","type":"journal-article","created":{"date-parts":[[2017,9,5]],"date-time":"2017-09-05T07:26:33Z","timestamp":1504596393000},"page":"246-256","source":"Crossref","is-referenced-by-count":22,"title":["Fabricating PLGA microparticles with high loads of the small molecule antioxidant N\u2010acetylcysteine that rescue oligodendrocyte progenitor cells from oxidative stress"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3543-9219","authenticated-orcid":false,"given":"Nicholas P.","family":"Murphy","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering University of Virginia Charlottesville Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J.","family":"Lampe","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering University of Virginia Charlottesville Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,10,6]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.26070"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(89)90066-X"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.10.013"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3989-03.2004"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2007.00107.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2038"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2008.04.002"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S34723"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(94)00209-3"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1993.1074"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0411-423"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2012.01.043"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-007-9430-1"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728220802517901"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.200702404"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02488.x"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199802000-00008"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002512-200118090-00004"},{"key":"e_1_2_7_20_1","volume-title":"Free radicals in biology and medicine","author":"Halliwell B. 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