title: Steroids, lidocain and ioxaglic acid modify the viscosity of hyaluronic acid: in vitro study and clinical implications.
abstract: BACKGROUND
  Viscosupplementaion by intra-articular injection of hyaluronic acid (HA) is a therapeutic modality for treating osteoarthritis of the knee, of the hip and less frequently of other joints. During viscosupplementation, it is usual to inject other drugs, without knowing whether this association may have a deleterious effect thereon. The rheological properties of a viscosupplement are highly dependent on the product [molecular weight × concentration] of HA. Therefore, any reduction of its viscoelastic properties is related either to a decrease of its concentration or/and of its molecular weight. The presence of other molecules can create favorable or unfavorable molecular interactions with HA. The objective of the study was to investigate the effect of products, that are commonly associated with HA (corticosteroids, lidocain, iodinated contrast media), on the rheological behavior of HA, then to try drawing practical conclusions.
  
  
  METHODS
  The rheological behavior of both a linear and a cross-linked HA, was studied before and after mixing with different volumes (ratio 1:0.5-1:4) of the following compounds: phosphate buffered saline (PBS, as a control), cortivazol, triamcinolone hexacetonide, lidocain chlorhydrate and meglumine ioxaglate. The flow curve of the different samples was obtained using a measuring method based on a constant shear rate.
  
  
  RESULTS
  Whatever the dilution and the added molecule were, viscosity of the cross-linked viscosupplement remained much higher than that of the linear one. Addition of PBS at a ratio 1:1 caused a dramatic decrease (up to 97.5 %) of HA viscosity. Cortivazol and lidocain had a similar effect than PBS on linear HA. Both were much deleterious on cross-linked HA viscosity. Among corticosteroids, triamcinolone decreased much less HA viscosity than cortivazol. The effect of meglumine ioxaglate was dose-dependent. Up to a ratio 1:1 viscosity of the linear HA remained above the dilution effect. On the cross-linked HA, the deleterious effect of the contrast agent was evident as soon as a ratio 1:1 and became very marked at 1:2.
  
  
  CONCLUSIONS
  HA viscosity varies widely in presence of other molecules. These changes are due to both dilution and molecular interactions. This study suggests that addition of other molecules with HA can lead to a major decrease of its viscosity. However, provided to respect a maximum ratio of 1:1, the contrast medium and triamcinolone seem to have no major deleterious effect on the viscosity level, especially on crosslinked HA. The study also suggests a deleterious effect of lidocain on the cross-linked HA. These in vitro data suggest that drugs associations must be avoided when they are not essential. However, clinical trials are needed to determine whether these rheological changes may have a significant impact on the clinical outcome.
authors.affiliation: Service de rhumatologie, Hôpital Nord Franche-Comté, 14 rue de Mulhouse, 90000 Belfort, France.
authors.forename: Thierry
authors.identifier: 0000-0003-0353-6292
authors.initials: T
authors.lastname: Conrozier
authors.affiliation: Rhéonova, Domaine Universitaire, 363, rue de la chimie, 38400 Saint Martin d'Hères, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Patarin
authors.affiliation: Laboratoire de Rhumatologie Appliquée, 19 place Tolozan, 69001 Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mathieu
authors.affiliation: Biomaterials Applications, 6 rue Lesdiguières, Grenoble, France.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Rinaudo
keywords: Contrast product; Cortivazol; Hyaluronic acid; Intra-articular corticosteroid; Ioxaglic acid; Lidocain; Rheology; Triamcinolone; Viscosupplementation