RESUMEN
Synovial fluid lubricates articular joints by forming a hydrated layer between the cartilage surfaces. In degenerative joint diseases like osteoarthritis (OA), the synovial fluid is compromised, which leads to less effective innate lubrication and exacerbated cartilage degeneration. Studies over the years have led to the development of partially or fully synthetic biolubricants to reduce the coefficient of friction with cartilage in knee joints. Cartilage-adhering, hydrated lubricants are particularly important to provide cartilage lubrication and chondroprotection under high normal load and slow speed. Here, we report the development of a hyaluronic acid (HA)-based lubricant functionalized with cationic branched poly-L-lysine (BPL) molecules that bind to cartilage via electrostatic interactions. We surmised that the electrostatic interactions between the BPL-modified HA molecules (HA-BPL) and the cartilage facilitate localization of the HA molecules to the cartilage surface. The number of BPL molecules on the HA backbone was varied to determine the optimal grafting density for cartilage binding and HA localization. Collectively, our results show that our HA-BPL molecules adhered readily to cartilage and were effective as a lubricant in cartilage-on-cartilage shear measurements where the modified HA molecules significantly reduce the coefficient of friction compared to phosphate-buffered saline or HA alone. This proof-of-concept study shows how the incorporation of cartilage adhering moieties, such as cationic molecules, can be used to enhance cartilage binding and lubrication properties of HA.
RESUMEN
Joint diseases, such as osteoarthritis, often require delivery of drugs to chondrocytes residing within the cartilage. However, intra-articular delivery of drugs to cartilage remains a challenge due to their rapid clearance within the joint. This problem is further exacerbated by the dense and negatively charged cartilage extracellular matrix (ECM). Cationic nanocarriers that form reversible electrostatic interactions with the anionic ECM can be an effective approach to overcome the electrostatic barrier presented by cartilage tissue. For an effective therapeutic outcome, the nanocarriers need to penetrate, accumulate, and be retained within the cartilage tissue. Nanocarriers that adhere quickly to cartilage tissue after intra-articular administration, transport through cartilage, and remain within its full thickness are crucial to the therapeutic outcome. To this end, we used ring-opening polymerization to synthesize branched poly(l-lysine) (BPL) cationic nanocarriers with varying numbers of poly(lysine) branches, surface charge, and functional groups, while maintaining similar hydrodynamic diameters. Our results show that the multivalent BPL molecules, including those that are highly branched (i.e., generation two), can readily adhere and transport through the full thickness of cartilage, healthy and degenerated, with prolonged intra-cartilage retention. Intra-articular injection of the BPL molecules in mouse knee joint explants and rat knee joints showed their localization and retention. In summary, this study describes an approach to design nanocarriers with varying charge and abundant functional groups while maintaining similar hydrodynamic diameters to aid the delivery of macromolecules to negatively charged tissues.