MEPHOS · Shaping the Mechano-Pharmacological properties of Microparticles and Extracellular Vesicles for the Treatment of Osteoarthritis

Shaping the Mechano-Pharmacological properties of Microparticles and Extracellular Vesicles for the Treatment of Osteoarthritis

The MEPHOS team has designed, developed, and tested novel therapeutic strategies, drug delivery systems, and nanomedicines for the treatment and management of osteoarthritis (OA). Osteoarthritis (OA) is a chronic disease caused by the progressive degeneration of the articular cartilage and subchondral bone and is associated with extensive synovial inflammation. It most commonly affects the joints of the knees, hands, feet, and spine and is also observed in shoulder and hip joints. The MEPHOS project focused on the knee OA, where mechanical loading and interfacial lubrication play a major role, but the proposed approach and anticipated results could be applied to other joints as well as other diseases with similar manifestations. OA is not a disease of the sole cartilage but it rather affects the whole joint and its three major biological compartments (Figure 1): the articular cartilage; the synovium; and the synovial fluid. A healthy articular cartilage is composed of a highly porous matrix within which a few specialized cells – chondrocytes – reside (top inset in Figure 1). The porosity of cartilage and its water content are crucial in modulating the lubrication and load bearing capacity of the joint. Under pathological conditions, the presence of inflammatory factors negatively affect the function and viability of chondrocytes resulting in stiffer cells, reduced secretion of HA and other components of the extracellular matrix. This dictates the progressive degeneration of the cartilaginous tissue with a consequent reduction in its viscoelastic properties and overall mechanical support. A healthy synovium appears as a regular tissue populated by different cells, mostly synoviocytes and macrophages, and is properly nurtured by blood vessels and lymphatics (left inset in Figure 1). Macrophages, as sentinels of the immune system, line the interface between the tissue and the synovial fluid. Under pathological conditions, activated macrophages release inflammatory factors with the intent to recall locally additional macrophages. However, at the same time, these factors are toxic to chondrocytes and synoviocytes and affect their ability to deposit full length natural fibers, as HA, lubricin and others. Moreover, this inflammatory state makes the synovium hyperpermeable facilitating the clearance of molecules, fibers, and cells. Finally, the healthy synovial fluid is an ultrafiltrate of blood enriched with high molecular weight HA fibers, lubricin and phospholipids that are produced by synoviocytes and chondrocytes. Within this viscoelastic, non-Newtonian fluid, the most abundant HA establishes a complex, dynamic network of fibers and proteins via the creation of multiple weak, reversible bonds (right inset in Figure 1). Notably, a healthy knee can tolerate local pressures above 20 MPa while operating with friction coefficients as low as 0.001. However, under pathological conditions, the synovial fluid is progressively deprived of its precious fibers and molecules because of the higher clearance rates through the hyperpermeable synovium and lower secretion rates by inflamed synoviocytes and chondrocytes. This invariably results in higher interfacial friction and mechanical stresses that damage further the cartilage, exacerbate the synovial inflammation, harm synoviocytes and chondrocytes continuously feeding the vicious cycle and perpetuating the disease. The cross-talking among macrophages, synoviocytes and chondrocytes is key in regulating OA progression. Across the EU, over 40 million people suffer of OA. Similar numbers are documented for the US. Indeed, in developed countries, OA is the single most common cause of disability and reduced mobility. As it results from ageing, obesity, excessive exercise (sport trauma), genetic predisposition, occupational injury, the number of adults with OA is projected to double by 2040. The economic impact of OA on the National Healthcare Systems and Employment Policies is enormous. In the US, from 2013 to 2015, adults with OA reported almost 200 million total lost workdays, which constituted 34% of reported lost workdays for any medical condition. In the EU, the average costs per-person vary from about 1.5k€ of Belgium to 2k€ for Italy and up to 10k€ in the Netherlands. Moreover, it is here important to recall that OA is associated with increased comorbidity due to limited mobility, whereby it has been estimated that 60% to 90% of adult patients have at least one other significant chronic condition, with the most common being cardiovascular disease, diabetes mellitus, hypertension and cancer.

Data: CORDIS, © European Union