(H-287) Molecular design of cartilage-binding lubricants

Introduction: Synovial fluid lubricates articular joints by forming a layer between cartilage surfaces; the key lubricating molecules of synovial fluid are hyaluronic acid (HA) and lubricin. In degenerative joint diseases like osteoarthritis, the synovial fluid is compromised, which leads to less effective innate lubrication and contribute to cartilage degeneration. Currently, viscosupplements (i.e., high molecular weight HA), are used as a late-stage treatment for osteoarthritis, to reduce the time until a knee replacement is needed. Although these viscosupplements can improve the viscoelasticity of the synovial fluid, they do not contribute the different modes of lubrication and other functions that the native synovial fluid provides. One of the limitations of the current viscosupplements is the lack of adhesion/interaction with the cartilage layer, which is important for boundary mode lubrication. To address this shortcoming, we have developed a HA-based lubricant armed with cationic branched poly-l-lysine (BPL) molecules that interact with cartilage via electrostatic interactions. The BPL molecules have a high charge density and promote interactions between HA and cartilage via electrostatic interactions. We optimized the design of HA-BPL polymers to enhance cartilage binding, while maintaining viscoelastic properties, without requiring excessive BPL molecule incorporation.

Results and Discussion: Conjugation of BPL had an effect on the viscoelasticity of the HA molecules. For example, conjugation of 2 BPL per 2500 HA dimeric repeat units showed a decrease in G’ and G’’, when compared to HA alone. On the contrary, increasing the number of BPL units within the HA showed an increase in G’ and G’’ and a decrease in the crossover frequency (Figure 1b). Additionally, light scattering showed the potential aggregation of  HA-BPL molecules with increasing the grafting density (Figure 1c). The grafting density dependent changes in rheological behavior is attributed to the differences in intermolecular interactions between the polymer chains. Experiments examining the BPL-cartilage interactions suggest spontaneous binding of HA-BPL to the cartilage explants due to the electrostatic interactions between the cartilage and HA-BPL molecules (Figure 1d).

Conclusion: Incorporation of BPL molecules promotes interactions of HA-BPL with the cartilage. Future studies will involve characterizing the in-vivo lubrication function of  HA-BPL and its ability to prevent or delay post-traumatic osteoarthritis.

Gavin Gonzales would like to acknowledge support from Duke University, NSF GRFP, and the Alfred P. Sloan Foundation (Sloan Scholar, Alfred P. Sloan Foundation’s UCEM Program, 2019). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE 1644868.