Cell-Free Fat Extract (CEFFE) as a Versatile Cell-Free Biologic for Multitissue Regeneration: From Skin and Bone to Nerve, Reproductive, and Systemic Applications-A Comprehensive Review.

BACKGROUND

Cell-free fat extract (CEFFE), an adipose-derived biologic, offers a potent alternative to cell-based 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.

OBJECTIVE

The objective of this study is to systematically evaluate CEFFE's regenerative efficacy across diverse tissue systems-including musculoskeletal, neural, reproductive, dermal, ocular, and systemic applications-while synthesizing its underlying molecular mechanisms, clinical outcomes, and translational challenges.

METHODS

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's efficacy, dosage-response patterns, and molecular pathways.

RESULTS

CEFFE accelerates tissue repair through three conserved mechanistic axes: antiapoptotic survival (e.g., PI3K-Akt/mTOR activation and NRF2-mediated antiferroptosis), context-specific immunomodulation (e.g., Annexin A5-mediated M2 macrophage polarization and NLRP3 inflammasome disruption), and extracellular matrix remodeling alongside angiogenesis (e.g., TGF-β/Smad signaling). Emerging evidence highlights CEFFE's 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-to-mid-stage osteoarthritis.

CONCLUSIONS

CEFFE represents a highly versatile and precise cell-free 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-molecule quantification for batch consistency, and conducting large-scale, multicenter randomized controlled trials.