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We present a microfluidic cell\u2010compressing platform for reactivation (\u00b5\u2010CPR) designed to apply controlled hydrodynamic deformation to late\u2010passage stem cells. This mechanical stimulation facilitates functional reactivation without external chemical cues. Within a defined window, \u00b5\u2010CPR reduces oxidative stress, SA\u2010\u03b2\u2010gal activity, and \u03b3\u2010H2A.X foci, while enhancing proliferation and increasing the expression of canonical stemness\u2010associated markers, including OCT4, SOX2, and KLF4. Mechanical stimulation via \u00b5\u2010CPR induces coordinated structural remodeling: nuclei become more compact, actin cortex organization is restored, \u03b1\u2010actinin redistributes to focal adhesions, and microtubule networks are restructured, suggesting reorganization of intracellular mechanical architecture. Transcriptomic and proteomic analyses reveal that this process reprograms extracellular matrix remodeling and DNA repair pathways while attenuating pro\u2010fibrotic and senescence\u2010associated secretory phenotype (SASP)\u2010associated pathways. Crucially, this reactivation occurs without compromising fundamental stem cell hallmarks, preserving intrinsic immunophenotypes and multilineage differentiation potential. Functionally, \u00b5\u2010CPR\u2010processed stem cells demonstrate enhanced in vitro wound closure and improved tissue repair in vivo, with efficacy dependent on the applied mechanical dose. This platform establishes a non\u2010genetic, mechanobiological approach to functional stem cell reactivation, offering a scalable strategy for restoring stem cell function and providing a foundation for future cellular rejuvenation strategies.<\/jats:p>","DOI":"10.1002\/smll.75587","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:51:56Z","timestamp":1788961916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microfluidic Mechanical Reactivation of Senescent Stem Cells"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6491-0252","authenticated-orcid":false,"given":"Soo Bin","family":"Jang","sequence":"first","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology School of Advanced Biotechnology Molecular &amp; Cellular Reprogramming Center Institute of Advanced Regenerative Science, and Institute of Health Aging &amp; Society Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8431-2831","authenticated-orcid":false,"given":"Tak\u2010Il","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology School of Advanced Biotechnology Molecular &amp; Cellular Reprogramming Center Institute of Advanced Regenerative Science, and Institute of Health Aging &amp; Society Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7434-5672","authenticated-orcid":false,"given":"Geun\u2010Ho","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology School of Advanced Biotechnology Molecular &amp; Cellular Reprogramming Center Institute of Advanced Regenerative Science, and Institute of Health Aging &amp; Society Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2351-7427","authenticated-orcid":false,"given":"Donghwan","family":"Seo","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Interdisciplinary Program in Precision Public Health Korea University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8764-9157","authenticated-orcid":false,"given":"Hyelee","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Interdisciplinary Program in Precision Public Health Korea University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hancheol","family":"Yeo","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology School of Advanced Biotechnology Molecular &amp; Cellular Reprogramming Center Institute of Advanced Regenerative Science, and Institute of Health Aging &amp; Society Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaekwon","family":"Seok","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology School of Advanced Biotechnology Molecular &amp; Cellular Reprogramming Center Institute of Advanced Regenerative Science, and Institute of Health Aging &amp; Society Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5456-255X","authenticated-orcid":false,"given":"Kyung Min","family":"Lim","sequence":"additional","affiliation":[{"name":"R&amp;D Team, StemExOne CO., Ltd.  Seongdong\u2010gu Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3873-9903","authenticated-orcid":false,"given":"Ahmed Abdal","family":"Dayem","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology School of Advanced Biotechnology Molecular &amp; Cellular Reprogramming Center Institute of Advanced Regenerative Science, and Institute of Health Aging &amp; Society Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se Jong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology School of Advanced Biotechnology Molecular &amp; Cellular Reprogramming Center Institute of Advanced Regenerative Science, and Institute of Health Aging &amp; Society Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9150-4754","authenticated-orcid":false,"given":"Kwonwoo","family":"Song","sequence":"additional","affiliation":[{"name":"R&amp;D Team, StemExOne CO., Ltd.  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