Injection route affects intra-articular hyaluronic acid distribution and clinical outcome in viscosupplementation treatment for knee osteoarthritis: a combined cadaver study and randomized clinical trial


The coverage of hyaluronic acid (HA) on the impaired cartilage should be the precondition to exert its beneficial effect on knee osteoarthritis (KOA) according to the pharmacological mechanism. However, the intra-articular distribution of HA might be correlated with the route of drug delivery. Forty-two cadaver knees with radiographic evidence of osteoarthritis were given anteromedial (AM) or medial midpatellar (MMP) injection of HA (molecular weight 600–1500 kD) followed by gait stimulation. Although 2.5 ml HA delivered through both routes failed to cover the entire cartilage, HA covered 96.12% cartilage of patellofemoral joint (PFJ) and 71.44% of medial femorotibial joint (FTJ) through MMP route, whereas mainly distributed into FTJ and posterior condyles through AM route. HA in the MMP group distributed more in PFJ than that in the AM group (P < 0.001), but no significant difference presented in medial FTJ (P = 0.084). The clinical efficacy was also associated with the route of drug delivery. One hundred patients with unilateral mild-to-moderate KOA were recruited and randomly assigned to receive five weekly HA injections with AM route (n = 50) or MMP route (n = 50). Patients in the MMP group obtained better improvement in WOMAC index total score, pain score, stiffness score, and Lequesne index total score over the entire follow-up period, as compared to patients in the AM group (all P < 0.01). More patients in the MMP group claimed pain relief (71.7%, P = 0.024) and felt satisfying (63.1%, P = 0.007) than in the AM group at the end of follow-up. Therefore, intra-articular HA injection through MMP route is recommended in treating mild-to-moderate KOA.


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We thank the staff of anatomy department for their important support and help, the National Natural Science Foundation of China (NNSFC) for the fund source support, and Tahsin Tarik Torsha and Dr. Cindy for the generous help in modifying the grammar and spelling.

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Correspondence to Jun Xiao.

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Jun Xiao receives a grant (81101389) from the National Natural Science Foundation of China (NNSFC) to support the current research, but there is no financial conflict to disclose. The rest of the authors also certify that he or she has no commercial associations that might pose a conflict of interest in connection with the submitted article.

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Xiao, J., Hu, Y., Huang, L. et al. Injection route affects intra-articular hyaluronic acid distribution and clinical outcome in viscosupplementation treatment for knee osteoarthritis: a combined cadaver study and randomized clinical trial. Drug Deliv. and Transl. Res. 11, 279–291 (2021).

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  • Hyaluronate
  • Intra-articular distribution
  • Knee
  • Osteoarthritis
  • Medial midpatellar portal