From waste streams to bioactive treasures: The sustainable journey of glycosaminoglycans

Glycosaminoglycans (GAGs) are structurally complex polysaccharides that play critical roles in cell–matrix interactions, signaling, and tissue homeostasis. Traditionally obtained from animal by-products, GAG production is increasingly challenged by ethical concerns, contamination risks, structural heterogeneity, and sustainability limitations. This review critically examines emerging animal by-product and microbial fermentation–based strategies for GAG production, with a specific focus on how extraction methods and biosynthetic platforms influence structural fidelity, bioactivity, and translational potential. Rather than providing a descriptive overview, we analyze the structure-function relationships governing key GAG bioactivities, including anticoagulant, anti-inflammatory, and regenerative effects, and distinguish evidence derived from in vitro, in vivo, and clinically validated studies. Particular attention is given to fine structural parameters such as sulfation patterns, chain length, and conformational flexibility that underpin biological performance yet complicate standardization and quality control. Advances in enzymatic-assisted extraction (EAE), chemoenzymatic synthesis, glycomics, and microbial engineering are evaluated alongside their current limitations, including challenges in reproducing mammalian-like structural complexity and meeting regulatory requirements. Finally, we discuss waste valorization and circular economy frameworks as enabling strategies for sustainable GAG production, while highlighting critical technological and regulatory barriers that must be addressed to enable reliable biomedical translation.