{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:48:10Z","timestamp":1787496490191,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Viscosupplementation with intra-articular hyaluronic acid (HA) is a key therapeutic option for osteoarthritis (OA), yet the field is hampered by clinical controversies and an outdated classification of available products. This comprehensive review critically analyzes the current landscape, moving from a mechanical to a biological paradigm of HA\u2019s mechanism of action. We argue that the traditional HA product classification based solely on molecular weight is insufficient, as it conflates chemically distinct products. Therefore, we propose a new, two-tiered classification framework: the primary distinction is based on chemical structure, separating linear (non-modified) HA from cross-linked (chemically modified) HA. Linear HA is then sub-classified by molecular weight (Low, Intermediate, and High), while cross-linked HA is defined as a separate category of hydrogels with a ultra-high effective molecular weight. Within this clearer framework, we analyze the central controversy between formulations, highlighting the pivotal emergence of high-concentration, high-molecular-weight (&gt;2 million Dalton) linear HA. These formulations not only challenge the durability rationale for cross-linking by providing year-long efficacy but also possess a superior biological profile for chondroprotection, preserving chondrocyte viability and function. Furthermore, we explore the expanding frontier of combination therapies, where linear HA serves as the ideal physiological scaffold for agents like corticosteroids, PRP and other injectable orthobiologics such as bone marrow aspirate and stromal vascular fraction.<\/jats:p>","DOI":"10.3390\/bioengineering12101050","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T12:59:46Z","timestamp":1759150786000},"page":"1050","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Current Concepts in Viscosupplementation: New Classification System and Emerging Frontiers"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7811-7354","authenticated-orcid":false,"given":"Gustavo Constantino","family":"de Campos","sequence":"first","affiliation":[{"name":"Departamento de Ortopedia, Reumatologia e Traumatologia, Universidade Estadual de Campinas, Campinas 13083-887, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Alberto","family":"Cliquet","sequence":"additional","affiliation":[{"name":"Departamento de Ortopedia, Reumatologia e Traumatologia, Universidade Estadual de Campinas, Campinas 13083-887, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Krakowski, P., Rejniak, A., Sobczyk, J., and Karpi\u0144ski, R. (2024). Cartilage Integrity: A Review of Mechanical and Frictional Properties and Repair Approaches in Osteoarthritis. Healthcare, 12.","DOI":"10.3390\/healthcare12161648"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8293921","DOI":"10.1155\/2020\/8293921","article-title":"The Role of Inflammation in the Pathogenesis of Osteoarthritis","volume":"2020","author":"Chow","year":"2020","journal-title":"Mediat. Inflamm."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Karpi\u0144ski, R., Prus, A., Baj, J., Radej, S., Prz\u0105dka, M., Krakowski, P., and Jonak, K. (2025). Articular Cartilage: Structure, Biomechanics, and the Potential of Conventional and Advanced Diagnostics. Appl. Sci., 15.","DOI":"10.3390\/app15126896"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Iaconisi, G.N., Gallo, N., Caforio, L., Ricci, V., Fiermonte, G., Della Tommasa, S., Bernetti, A., Dolce, V., Far\u00ec, G., and Capobianco, L. (2023). Clinical and Biochemical Implications of Hyaluronic Acid in Musculoskeletal Rehabilitation: A Comprehensive Review. J. Pers. Med., 13.","DOI":"10.3390\/jpm13121647"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2478\/intox-2013-0019","article-title":"Hyaluronan and synovial joint: Function, distribution and healing","volume":"6","author":"Tamer","year":"2013","journal-title":"Interdiscip. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1590\/1413-785220192704218616","article-title":"Brazilian Consensus Statement on Viscosupplementation of the Knee (Cobravi)","volume":"27","author":"Hamdan","year":"2019","journal-title":"Acta Ortop\u00e9dica Bras."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Glinkowski, W.M., and Tomaszewski, W. (2025). Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: A Systematic Umbrella Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14041272"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e721","DOI":"10.5435\/JAAOS-D-21-01233","article-title":"AAOS Clinical Practice Guideline Summary: Management of Osteoarthritis of the Knee (Nonarthroplasty), Third Edition","volume":"30","author":"Brophy","year":"2022","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1016\/j.joca.2019.06.011","article-title":"OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis","volume":"27","author":"Bannuru","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Gupta, R.C., Lall, R., Srivastava, A., and Sinha, A. (2019). Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory. Front. Vet. Sci., 6.","DOI":"10.3389\/fvets.2019.00192"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Altman, R.D., Manjoo, A., Fierlinger, A., Niazi, F., and Nicholls, M. (2015). The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: A systematic review. BMC Musculoskelet. Disord., 16.","DOI":"10.1186\/s12891-015-0775-z"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bernetti, A., Agostini, F., Paoloni, M., Raele, M.V., Far\u00ec, G., Megna, M., and Mangone, M. (2023). Could Hyaluronic Acid Be Considered as a Senomorphic Agent in Knee Osteoarthritis? A Systematic Review. Biomedicines, 11.","DOI":"10.3390\/biomedicines11102858"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"25549","DOI":"10.52965\/001c.25549","article-title":"A Comprehensive Review of Viscosupplementation in Osteoarthritis of the Knee","volume":"13","author":"Peck","year":"2021","journal-title":"Orthop. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1590\/S0102-36162012000200003","article-title":"Viscosuplementation","volume":"47","author":"Rezende","year":"2012","journal-title":"Rev. Bras. De Ortop."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Budai, L., Budai, M., F\u00fcl\u00f6pn\u00e9 P\u00e1pay, Z.E., Vilimi, Z., and Antal, I. (2023). Rheological Considerations of Pharmaceutical Formulations: Focus on Viscoelasticity. Gels, 9.","DOI":"10.3390\/gels9060469"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"More, S., Kotiya, A., Kotia, A., Ghosh, S.K., Spyrou, L.A., and Sarris, I.E. (2020). Rheological properties of synovial fluid due to viscosupplements: A review for osteoarthritis remedy. Comput. Methods Programs Biomed., 196.","DOI":"10.1016\/j.cmpb.2020.105644"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Fallacara, A., Baldini, E., Manfredini, S., and Vertuani, S. (2018). Hyaluronic Acid in the Third Millennium. Polymers, 10.","DOI":"10.3390\/polym10070701"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1016\/j.semarthrit.2015.11.008","article-title":"Efficacy and safety of hyaluronic acid in the management of osteoarthritis: Evidence from real-life setting trials and surveys","volume":"45","author":"Maheu","year":"2016","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lee, B.M., Park, S.J., Noh, I., and Kim, C.H. (2021). The effects of the molecular weights of hyaluronic acid on the immune responses. Biomater. Res., 25.","DOI":"10.1186\/s40824-021-00228-4"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Glinkowski, W., \u015aladowski, D., Tomaszewski, W., and Pol-Iaha Study Group (2025). Molecular Mechanisms and Therapeutic Role of Intra-Articular Hyaluronic Acid in Osteoarthritis: A Precision Medicine Perspective. J. Clin. Med., 14.","DOI":"10.3390\/jcm14082547"},{"key":"ref_22","first-page":"946","article-title":"Longterm effects of intraarticular hyaluronan on synovial fluid in osteoarthritis of the knee","volume":"33","author":"Bagga","year":"2006","journal-title":"J. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"32","DOI":"10.4236\/ojo.2016.62006","article-title":"Analysis of Anthropometric Measurements and Dietary Intake in Patients Undergoing a Multi-Professional Osteoarthritis Education Program (PARQVE-Project Arthritis Recovering Quality of Life by Means of Education)","volume":"6","author":"Brito","year":"2016","journal-title":"Open J. Orthop."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1136\/ard.2008.094623","article-title":"Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: A randomised, multicentre, double-blind, placebo controlled trial","volume":"69","author":"Chevalier","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.joca.2017.10.008","article-title":"Osteoarthritis year in review 2017: Biology","volume":"26","author":"Appleton","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e069722","DOI":"10.1136\/bmj-2022-069722","article-title":"Viscosupplementation for knee osteoarthritis: Systematic review and meta-analysis","volume":"378","author":"Pereira","year":"2022","journal-title":"BMJ"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1177\/19476035231154530","article-title":"Intra-articular Hyaluronic Acid Treatments for Knee Osteoarthritis: A Systematic Review of Product Properties","volume":"14","author":"Ferkel","year":"2023","journal-title":"Cartilage"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.2106\/JBJS.RVW.15.00098","article-title":"Viscosupplementation in Knee Osteoarthritis: Evidence Revisited","volume":"4","author":"Johal","year":"2016","journal-title":"JBJS Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1021\/acsbiomaterials.5b00181","article-title":"High and low molecular weight hyaluronic acid differentially influence macrophage activation","volume":"1","author":"Rayahin","year":"2015","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1615\/JLongTermEffMedImplants.2021037770","article-title":"Delay to TKA in Patients Treated with a Multimodal Approach Using High Molecular Weight, Biologically Derived Hyaluronic Acid","volume":"31","author":"Malanga","year":"2021","journal-title":"J. Long. Term. Eff. Med. Implants"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1007\/s12325-016-0433-3","article-title":"Potential Potential Impact of Biologically Derived Hyaluronic Acid on Quality of Life in Patients with Knee Osteoarthritis in the United States","volume":"33","author":"Rosen","year":"2017","journal-title":"Adv. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.2147\/JPR.S321841","article-title":"One-year, efficacy and safety open label study, with a single injection of a new hyaluronan for knee OA: The SOYA trial","volume":"14","author":"Blanco","year":"2021","journal-title":"J. Pain Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Gav\u00edn, C., Blanco, F.J., Pablos, J.L., Caracuel, M.A., Rosas, J., G\u00f3mez-Barrena, E., Navarro, F., Coronel, M.P., and Gimeno, M. (2024). Beyond Boundaries of a Trial: Post-Market Clinical Follow-Up of SOYA Patients. J. Clin. Med., 13.","DOI":"10.3390\/jcm13216308"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.2106\/00004623-200209000-00015","article-title":"Increased frequency of acute local reaction to intra-articular hylan GF-20 (synvisc) in patients receiving more than one course of treatment","volume":"84","author":"Leopold","year":"2002","journal-title":"J. Bone Joint Surg. Am."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1097\/00003086-200402000-00021","article-title":"Pseudoseptic reactions to hylan viscosupplementation: Diagnosis and treatment","volume":"419","author":"Goldberg","year":"2004","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.2106\/00004623-200207000-00008","article-title":"Granulomatous inflammation after Hylan G-F 20 viscosupplementation of the knee: A report of six cases","volume":"84","author":"Chen","year":"2002","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1007\/s00256-024-04824-y","article-title":"Foreign body giant cell reaction due to Durolane (hyaluronic acid derivative) injection\u2014A case report","volume":"54","author":"Doddridge","year":"2024","journal-title":"Skelet. Radiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lyalina, V., Eshmotova, G., Karavan, A., Korshunov, A., Zarov, A., Bonartsev, A., Serejnikova, N., Prizov, A., Airapetov, G., and Volkov, A. (2025). Hyaluronan-Related Granulomatous Synovitis, Adipositis, and Osteomyelitis in the Osteoarthritic Knee: A Morphological Case Series of Three Patients. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26168073"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1002\/jor.20683","article-title":"The effect of hyaluronic acid on IL-1beta-induced chondrocyte apoptosis in a rat model of osteoarthritis","volume":"26","author":"Zhou","year":"2008","journal-title":"J. Orthop. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.3390\/jcm14103557","article-title":"Single Injection of Highly Concentrated Hyaluronic Acid Provides Improvement of Knee Joint Arthrokinematic Motion and Clinical Outcomes in Patients with Osteoarthritis-Non-Randomized Clinical Study","volume":"14","author":"Falkowski","year":"2025","journal-title":"J. Clin. Med."},{"key":"ref_41","first-page":"CD005328","article-title":"Intra-articular corticosteroid for knee osteoarthritis","volume":"2015","author":"Hari","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s11999-012-2659-y","article-title":"Adding triamcinolone improves viscosupplementation: A randomized clinical trial","volume":"471","author":"Rezende","year":"2013","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Glinkowski, W.M., Gut, G., and \u015aladowski, D. (2025). Platelet-Rich Plasma for Knee Osteoarthritis: A Comprehensive Narrative Review of the Mechanisms, Preparation Protocols, and Clinical Evidence. J. Clin. Med., 14.","DOI":"10.3390\/jcm14113983"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Szwedowski, D., Szczepanek, J., Paczesny, \u0141., Zabrzy\u0144ski, J., Gagat, M., Mobasheri, A., and Jeka, S. (2021). The Effect of Platelet-Rich Plasma on the Intra-Articular Microenvironment in Knee Osteoarthritis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115492"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Merch\u00e1n, E.C. (2022). Intra-Articular Platelet-Rich Plasma Injections in Knee Osteoarthritis: A Review of Their Current Molecular Mechanisms of Action and Their Degree of Efficacy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031301"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Del Amo, C., Perez-Valle, A., Atilano, L., and Andia, I. (2022). Unraveling the Signaling Secretome of Platelet-Rich Plasma: Towards a Better Understanding of Its Therapeutic Potential in Knee Osteoarthritis. J. Clin. Med., 11.","DOI":"10.3390\/jcm11030473"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Zhao, J., Huang, H., Liang, G., Zeng, L.F., Yang, W., and Liu, J. (2020). Effects and safety of the combination of platelet-rich plasma (PRP) and hyaluronic acid (HA) in the treatment of knee osteoarthritis: A systematic review and meta-analysis. BMC Musculoskelet. Disord., 21.","DOI":"10.1186\/s12891-020-03262-w"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhang, M., Chew, K., Goh, P., Tun, M.H., Sheah, K., Tan, V., Lim, B., Ng, C.S., and Tan, B. (2025). Clinical Efficacy of Platelet-Rich Plasma and Hyaluronic Acid Versus Hyaluronic Acid for Knee Osteoarthritis with MRI Analysis: A Randomized Controlled Trial. J. Clin. Med., 14.","DOI":"10.3390\/jcm14103553"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Berkani, S., Courties, A., Eymard, F., Latourte, A., Richette, P., Berenbaum, F., Sellam, J., and Louati, K. (2022). Time to Total Knee Arthroplasty after Intra-Articular Hyaluronic Acid or Platelet-Rich Plasma Injections: A Systematic Literature Review and Meta-Analysis. J. Clin. Med., 11.","DOI":"10.3390\/jcm11143985"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.knee.2021.08.008","article-title":"The efficacy of intra-articular injections in the treatment of knee osteoarthritis: A network meta-analysis of randomized controlled trials","volume":"32","author":"Anil","year":"2021","journal-title":"Knee"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Wu, Y.T., Li, T.Y., Lee, K.C., Lam, K.H.S., Chang, C.Y., Chang, C.K., and Chen, L.C. (2022). Efficacy of a Novel Intra-Articular Administration of Platelet-Rich Plasma One-Week Prior to Hyaluronic Acid versus Platelet-Rich Plasma Alone in Knee Osteoarthritis: A Prospective, Randomized, Double-Blind, Controlled Trial. J. Clin. Med., 11.","DOI":"10.3390\/jcm11113241"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Merch\u00e1n, E.C. (2022). Intraarticular Injections of Mesenchymal Stem Cells in Knee Osteoarthritis: A Review of Their Current Molecular Mechanisms of Action and Their Efficacy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314953"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Vargel, \u0130., Tuncel, A., Baysal, N., Hartu\u00e7-\u00c7evik, \u0130., and Korkusuz, F. (2022). Autologous Adipose-Derived Tissue Stromal Vascular Fraction (AD-tSVF) for Knee Osteoarthritis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113517"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Veronesi, F., Andriolo, L., Salerno, M., Boffa, A., Giavaresi, G., and Filardo, G. (2023). Adipose Tissue-Derived Minimally Manipulated Products versus Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence and Meta-Analysis. J. Clin. Med., 13.","DOI":"10.3390\/jcm13010067"}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/12\/10\/1050\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T13:41:57Z","timestamp":1759153317000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/12\/10\/1050"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["bioengineering12101050"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering12101050","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]}}}