Modified polymeric nanoparticles developed by researchers at the École Polytechnique Fédérale de Lausanne in Switzerland and the University of Massachusetts in the US were found in animal studies to accumulate in an extracellular matrix (ECM) of articular cartridge at concentrations of up to 72 times more than non-targeted nanoparticles, remaining in the matrix without statistically significant clearance for up to 96 hours. As Jeffrey Hubbell et al point out in a paper published in Nature Materials, delivering drugs to cartilage for purposes such as treating early degradation in osteoarthritis is usually hampered by poor bioavailability due to the lack of vascularised tissue and the dense ECM, which acts as a barrier to entry. The avascularity of cartilage tissue favours regional administration of the drug within the joint space rather than into the systemic circulation. However, compounds are rapidly cleared from the synovial fluid into the lymphatic system, accounting for the low bioavailability and raising the possibility of adverse systemic effects. The researchers sought to overcome these obstacles by developing particles that would be small enough to enter the cartilage matrix, as it is dynamically compressed during normal movement, and would display sufficient affinity for a cartilage ECM component to be retained there. This was achieved by synthesising polypropylene sulphide (PPS) nanoparticles with average sizes of 38nm or 96nm and further modifying them with a biomolecular ligand for matrix binding. Following intra-articular injection into the knees of mice, the larger functionalised nanoparticles were generally unable to penetrate the cartilage matrix, whereas the 38nm particles were small enough to enter the matrix and convert it from a barrier to a reservoir, preventing the rapid release of the nanoparticles and their clearance from the tissue site. The targeting mechanism was the peptide sequence WYRGRL, identified through affinity selection (biopanning) of a phage display library using denuded bovine cartilage grafts. The WYRGRL ligand was selected in 94 of 96 clones sequenced after five rounds of biopanning and was shown to bind to the cartilage matrix component collagen II a 1. Modified nanoparticles displaying a scrambled peptide sequence were used as a control. By conjugating a bioaffinity ligand to the nanoparticle surface and preventing the particles from leaving the cartilage matrix, the delivery system has the potential to achieve "intra-tissue release of a therapeutic agent rather than just an intra-articular drug release", Hubbell et al comment. Targeting of the cartilage matrix "is likely to be an important factor in future pharmaceutical approaches for the treatment of osteoarthritis", they suggest.