Hyaluronic acid (HA) is a ubiquitous component of extracellular matrices. In synovial fluid it is present as a high molecular weight anionic polymer with a large hydrated volume. It forms a physically entangled interfibrillar molecular network with viscoelastic properties that help to cushion and lubricate articular joints such as the knee. The molecular weight of HA in synovial fluid decreases significantly in osteoarthritis (OA). The consequent loss in viscoelasticity results in poor mechanical protection of the joint surfaces and increased nociceptor nerve firing (a measure of pain). In order to restore viscoelasticity, intra-articular injections of high molecular weight HA are currently administered during the early stages of OA. However, the lifetime in the body of these “viscosupplements” is very short (< 5 days). Furthermore, relatively high weight concentrations of HA must be injected in order to obtain physically entangled HA networks with desirable viscoelastic properties. Therefore, to develop a better synovial fluid viscosupplement, we propose to modify HA with polypeptide side chains containing hydrophobic self-assembling residues. The comb-branched HA derivatives obtained should behave as associative thickeners as a result of hydrophobic attractions between peptide branches on neighboring HA chains. Thus, shorter HA chains can be used to obtain an equivalent boost in viscoelastic and physical properties. Dilute solution viscometry results will be presented and used to calculate the polymer coil size and the polymer overlap concentration as a function of the chemical structure of the comb-branched HA derivatives. Rheological results will be presented for time dependent network formation of the derivative, and for network re-formation after shear flows at very high shear rates (such as during injection). A new protocol will be introduced for determining the in vitro resistance of HA gels to enzymatic degradation by hyaluronidases.