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In this study, a cryo\u2010fracture\u2010resistant composite microcapsule has been developed using microfluidic technology, where sodium alginate was reinforced with cellulose nanocrystals (CNCs). The composite microcapsules were assessed for their ability to provide structural, mechanical, morphological, chemical, and thermal stability during cryopreservation. Additionally, red blood cells (RBCs) were used as a model to evaluate the ability of the optimized microcapsules to improve cell viability post\u2010thaw. Results revealed that the microfluidic system allowed for precise control over microcapsule size and uniformity, which is crucial for even freezing and thawing. CNCs reinforced microcapsules exhibited delayed ice formation, improved ice recrystallization inhibition, and superior protection against freeze\u2010induced deformations. Furthermore, the composite microcapsules enhanced post\u2010thaw recovery of encapsulated RBCs and enabled the incorporation of a biocompatible cryoprotectant (trehalose). This study demonstrates a novel approach to optimizing cryopreservation techniques by leveraging the enhanced properties of composite microcapsules to mitigate cryo\u2010injury and improve the functional recovery of encapsulated cells. These findings present a promising strategy for advancing microencapsulation\u2010based cell therapies and broader biomedical applications.<\/jats:p>","DOI":"10.1002\/mabi.202500217","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T08:43:47Z","timestamp":1755852227000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Microfluidics\u2010Generated Cryo\u2010Fracture Resistant CNCs\u2010Reinforced Composite Microcapsules for Enhanced Cryopreservation of Encapsulated Cells"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3330-0769","authenticated-orcid":false,"given":"Marlene Davis","family":"Ekpo","sequence":"first","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George Frimpong","family":"Boafo","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanmin","family":"Yang","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yimer","family":"Seid","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha Hunan China"},{"name":"Department of Pharmacy Wollo University College of Medicine and Health Science Wollo Tertiary Care and Teaching Hospital  Dessie Ethiopia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2689-284X","authenticated-orcid":false,"given":"Chuanpin","family":"Chen","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songwen","family":"Tan","sequence":"additional","affiliation":[{"name":"Monash Suzhou Research Institute Monash University  Suzhou Jiangsu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongrong","family":"Wang","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Critical Quality Attribute of Cell Therapy Products Hunan Institute for Drug Control  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology, Yuying Children's Hospital The Second Affiliated Hospital of Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2741\/4195"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2023.06.038"},{"key":"e_1_2_8_4_1","first-page":"47","article-title":"Cryopreservation and Xenotransplantation Studies of Microencapsulated Rat Pancreatic Islets","volume":"23","author":"Li B. 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