Methods. OA chondrocytes were cultured in alginate and exposed to 5 mu g/ml of 2,3,6-tri-O-methyl-beta-cyclodextrin (ME-CD), 2,3-di-O-methyl-6-sulphate-beta-cyclodextrin (ME-CD-6-S), 2,6-di-O-methyl-3-sulphate-beta-cyclodextrin (ME-CD-3-S), (2-carboxyethyl)-beta-CDPS (CE-CDPS), (2-hydroxypropyl)-beta-CDPS (HP-CDPS), 6-monoamino-6-monodeoxy-beta-CDPS (MA-CDPS) or beta-CDPS for 5 days. Effects on IL-1-driven chondrocyte extracellular matrix (ECM) metabolism were assayed by analysis of the accumulation of aggrecan in the interterritorial matrix, IL-6 secretion and qPCR. MA-CDPS, HP-CDPS, CE-CDPS and CDPS were analysed for their in vitro effect on coagulation and their ability to activate platelets in an in vitro assay to detect possible cross-reactivity with heparin-induced thrombocytopenia (HIT) antibodies. Results. The monosulphated cyclodextrins ME-CD-6-S and -3-S failed to affect aggrecan synthesis and IL-6 secretion by the OA chondrocytes. Polysulphated cyclodextrins MA-CDPS, HP-CDPS, CE-CDPS and CDPS at 5 mu g/ml concentrations, on the other hand, significantly induced aggrecan production and repressed IL-6 release by the chondrocytes in culture. aPTT and PT for all derivatives were lengthened for polysaccharide concentrations > 50 mu g/ml. Five micrograms per millilitre of beta-CDPS concentrations that significantly modulated ECM ground substance production in vitro did not affect aPTT or PT. Furthermore, CE-CDPS, in contrast to MA-CDPS, HP-CDPS and CDPS, did not significantly activate platelets, suggesting a minimal potential to induce HIT thromboembolic accidents in vivo. Conclusions. CE-CDPS is a new, structurally adjusted, sulphated beta-cyclodextrin derivative with preserved chondroprotective capacity and a promising safety profile.