Cartilage on chip: Hyper-Physiological Compression in a microscale platform triggers osteoarthritic traits in a cartilage model.

Osteoarthritis (OA), the musculoskeletal disease with the highest prevalence, is characterized by pathological responses to factors such as mechanical overload. Repeated failures in translating promising disease-modifying OA drugs into clinical success highlight the requirement for more effective disease models. Organs-on-chip are micro-fabricated devices that aim at recapitulating organ functions. Here, we developed an OA-like cartilage model through a microbioreactor providing 3D micro-constructs with confined compression representative of either physiological (10%) or hyperphysiological (30%) strains. The PDMS device comprises two compartments separated by a flexible membrane. The upper compartment consists in a central channel, hosting a 3D cell-laden hydrogel, divided by two series of overhanging posts from culture medium channels. Posts were designed to limit lateral expansion. The bottom compartment is a pneumatic chamber. (Fig.1a) A poro-elastic description of the cell-laden hydrogel was adopted (Fig.1b) Human articular chondrocytes were cultured in a 3D enzymatically cross-linkable and MMP-degradable poly-(ethylene-glycol)-based hydrogel. After 14 days of static culture a cartilage on chip model was achieved (Aggrecan and Col2a1 deposition, Fig.1c increased GAG/DNA ratio). Furthermore, genes highly expressed in human articular cartilage (e.g. PRG4), and of cartilage interzone (GDF5, ATX) were upregulated. (Fig. 1d) Hyper-physiological cyclical compression, applied for 7 days, induced reduction of cartilage ECM constituents, (COL2A1, ACAN) onset of an inflammatory microenvironment (IL6 and IL8 upregulation, enhanced MMP13 production) and hypertrophy related genes (COL10A1, IHH) upregulation. Results testify the possibility of inducing OA-like traits within the model. The proposed device can thus be considered as a proof of concept for in-chip OA modelling.