{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T06:24:22Z","timestamp":1786947862406,"version":"build-2736575974"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pain Res."],"abstract":"<jats:p>Autologous blood-derived orthobiologics, including platelet-rich plasma and cytokine-rich serum, are widely used in musculoskeletal medicine. Extracellular vesicle\u2013based 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\u20132025) 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 \u201cone-size-fits-all\u201d approach and embrace biological specificity when selecting orthobiologic therapies for musculoskeletal conditions.<\/jats:p>","DOI":"10.3389\/fpain.2026.1772644","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:26:26Z","timestamp":1786944386000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Orthobiologics are not all the same: a mechanism-based scoping review of PRP, cytokine-rich serum, and extracellular vesicle\u2013based strategies in musculoskeletal conditions"],"prefix":"10.3389","volume":"7","author":[{"given":"Luigi","family":"Di Lorenzo","sequence":"first","affiliation":[{"name":"Rehabilitation Department, Mediterranean Neurological Institute Neuromed (IRCCS)","place":["Pozzilli, Italy"]},{"name":"Dipartimento Vita e Salute, Link Campus University","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso M.","family":"Forte","sequence":"additional","affiliation":[{"name":"Rehabilitation Department, Gruppo Forte Research Center","place":["Salerno, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"De Meo","sequence":"additional","affiliation":[{"name":"Rehabilitation Department, Mediterranean Neurological Institute Neuromed (IRCCS)","place":["Pozzilli, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Forte","sequence":"additional","affiliation":[{"name":"Rehabilitation Department, Gruppo Forte Research Center","place":["Salerno, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"D'Avanzo","sequence":"additional","affiliation":[{"name":"ASREM Azienda Sanitaria Molise, Rehabilitation","place":["Isernia, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Zmerly","sequence":"additional","affiliation":[{"name":"Dipartimento Vita e Salute, Link Campus University","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.1177\/0363546509349921","article-title":"Platelet-rich plasma: from basic science to clinical applications","volume":"37","author":"Foster","year":"2009","journal-title":"Am J Sports Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.arthro.2011.10.018","article-title":"Platelet-rich plasma: a milieu of bioactive factors","volume":"28","author":"Boswell","year":"2012","journal-title":"Arthroscopy"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.2174\/138920112800624283","article-title":"Sports medicine applications of platelet rich plasma","volume":"13","author":"Mishra","year":"2012","journal-title":"Curr Pharm Biotechnol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1177\/1759720x17712695","article-title":"Effectiveness of autologous serum therapy in osteoarthritis of the knee: a double-blind, placebo-controlled, randomized study","volume":"15","author":"Wehling","year":"2007","journal-title":"Osteoarthr Cartil"},{"key":"B5","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.joca.2008.06.014","article-title":"Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis","volume":"17","author":"Baltzer","year":"2009","journal-title":"Osteoarthr Cartil"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.3390\/jcm8101639","article-title":"Secreted factors and EVs: therapeutic strategies for cartilage repair","volume":"8","author":"Ragni","year":"2019","journal-title":"J Clin Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1177\/03635465211064303","article-title":"Leukocyte-rich versus leukocyte-poor platelet-rich plasma for the treatment of knee osteoarthritis: a double-blind randomized trial","volume":"50","author":"Di Martino","year":"2022","journal-title":"Am J Sports Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"141","DOI":"10.3390\/biomedicines11010141","article-title":"Leukocyte-rich vs. leukocyte-poor platelet-rich plasma for the treatment of knee osteoarthritis","volume":"11","author":"Gupta","year":"2023","journal-title":"Biomedicines"},{"key":"B9","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1080\/21556660.2020.1734009","article-title":"Autologous conditioned serum: clinical and functional results using a novel disease modifying agent for the management of knee osteoarthritis","volume":"9","author":"Vitali","year":"2020","journal-title":"J Drug Assess"},{"key":"B10","doi-asserted-by":"publisher","first-page":":FSO759","DOI":"10.2144\/fsoa-2021-0069","article-title":"Effectiveness of intra-articular autologous-conditioned serum injection in knee osteoarthritis: a meta-analysis study","volume":"7","author":"Raeissadat","year":"2021","journal-title":"Future Sci OA"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3000605231203851","DOI":"10.1177\/03000605231203851","article-title":"Intra-articular autologous conditioned serum and triamcinolone injections in patients with knee osteoarthritis: a controlled, randomized, double-blind study","volume":"51","author":"Damjanov","year":"2023","journal-title":"J Int Med Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"319","DOI":"10.34172\/aim.2022.52","article-title":"Intratendinous injection of autologous conditioned Serum for treatment of lateral epicondylitis of the elbow: a pilot study","volume":"25","author":"Ipek","year":"2022","journal-title":"Arch Iran Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1016\/j.joca.2024.06.004","article-title":"Is there a role for autologous conditioned serum injections in osteoarthritis? A systematic review and meta-analysis of randomised controlled trials","volume":"32","author":"Curtis","year":"2024","journal-title":"Osteoarthr Cartil"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e68963","DOI":"10.7759\/cureus.68963","article-title":"Autologous conditioned serum in knee osteoarthritis: a systematic review of current clinical evidence","volume":"16","author":"Jeyaraman","year":"2024","journal-title":"Cureus"},{"key":"B15","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1186\/s12891-024-07979-w","article-title":"Safety and efficacy of placental mesenchymal stromal cells-derived extracellular vesicles in knee osteoarthritis: a randomized, triple-blind, placebo-controlled clinical trial","volume":"25","author":"Bolandnazar","year":"2024","journal-title":"BMC Musculoskelet Disord"},{"key":"B16","year":""},{"key":"B17","year":""},{"key":"B18","year":""}],"container-title":["Frontiers in Pain Research"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpain.2026.1772644\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:26:27Z","timestamp":1786944387000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpain.2026.1772644\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":18,"alternative-id":["10.3389\/fpain.2026.1772644"],"URL":"https:\/\/doi.org\/10.3389\/fpain.2026.1772644","relation":{},"ISSN":["2673-561X"],"issn-type":[{"value":"2673-561X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]},"article-number":"1772644"}}