Orthobiologics are not all the same: a mechanism-based scoping review of PRP, cytokine-rich serum, and extracellular vesicle-based strategies in musculoskeletal conditions.

Autologous blood-derived orthobiologics, including platelet-rich plasma and cytokine-rich serum, are widely used in musculoskeletal medicine. Extracellular vesicle-based approaches are increasingly investigated as related biologically active strategies, although they may derive from multiple autologous or allogeneic cellular and tissue sources. However, these biologics differ significantly in composition and mechanism of action, often leading to confusion in terminology and inconsistent clinical application. This scoping review critically maps current evidence (2020-2025) from randomized trials, systematic reviews, and meta-analyses to clarify the biological heterogeneity among these products. Platelet-based PRP acts primarily via growth factor release, supporting anabolic and reparative processes. Leukocyte- and monocyte-containing PRP formulations, conversely, engage immune modulation and inflammatory signaling pathways. Acellular cytokine-rich sera (e.g., autologous conditioned serum) offer immunomodulatory effects through soluble mediators like IL-1Ra. EVs and exosomes represent a promising but still experimental approach, functioning as paracrine modulators with unclear clinical efficacy. While some formulations yield similar clinical outcomes, these cannot be interpreted as biologically equivalent. The only triple-blind randomized trial on exosomes in knee osteoarthritis confirmed safety but no superiority over placebo. A mechanism-informed, indication-driven selection is essential to optimize treatment efficacy, avoid inappropriate expectations, and advance the field responsibly. This review proposes a biologically grounded classification of orthobiologics and highlights the need for standardized reporting, accurate product characterization, and rigorous clinical validation. Clinicians and researchers are urged to abandon the "one-size-fits-all" approach and embrace biological specificity when selecting orthobiologic therapies for musculoskeletal conditions.