{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:13:52Z","timestamp":1790856832237,"version":"4.1.0"},"reference-count":70,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T00:00:00Z","timestamp":1785628800000},"content-version":"vor","delay-in-days":213,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioMed Research International"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cell\u2010free fat extract (CEFFE), an adipose\u2010derived biologic, offers a potent alternative to cell\u2010based therapies by delivering a complex milieu of growth factors (e.g., VEGF, EGF, and BDNF) and regulatory proteins without the tumorigenic, immunogenic, or ethical challenges associated with stem cell applications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The objective of this study is to systematically evaluate CEFFE\u2032s regenerative efficacy across diverse tissue systems\u2014including musculoskeletal, neural, reproductive, dermal, ocular, and systemic applications\u2014while synthesizing its underlying molecular mechanisms, clinical outcomes, and translational challenges.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A comprehensive literature review was conducted utilizing databases such as PubMed, Scopus, and Web of Science, focusing on preclinical and clinical studies published from January 2018 to May 2026. Over 55 articles were analyzed to evaluate CEFFE\u2032s efficacy, dosage\u2013response patterns, and molecular pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CEFFE accelerates tissue repair through three conserved mechanistic axes: antiapoptotic survival (e.g., PI3K\u2013Akt\/mTOR activation and NRF2\u2010mediated antiferroptosis), context\u2010specific immunomodulation (e.g., Annexin A5\u2013mediated M2 macrophage polarization and NLRP3 inflammasome disruption), and extracellular matrix remodeling alongside angiogenesis (e.g., TGF\u2010\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \/Smad signaling). Emerging evidence highlights CEFFE\u2032s efficacy in novel domains such as intervertebral disc degeneration, corneal neurodegeneration, systemic sepsis, and as an IVF culture media supplement. Clinical trials confirm its safety and efficacy in dermatological applications (e.g., infraorbital aging and hyperpigmentation) and demonstrate superiority over standard treatments, such as hyaluronic acid, for early\u2010to\u2010mid\u2010stage osteoarthritis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CEFFE represents a highly versatile and precise cell\u2010free biologic capable of driving multitissue regeneration. To fully realize its clinical and commercial potential, future research must address donor variability by establishing standardized dosing protocols, implementing key\u2010molecule quantification for batch consistency, and conducting large\u2010scale, multicenter randomized controlled trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/bmri\/9479492","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T02:29:36Z","timestamp":1785724176000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cell\u2010Free Fat Extract (CEFFE) as a Versatile Cell\u2010Free Biologic for Multitissue Regeneration: From Skin and Bone to Nerve, Reproductive, and Systemic Applications\u2014A Comprehensive Review"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0239-503X","authenticated-orcid":false,"given":"Arian","family":"Karimi 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