INSTant CARMA · In Silico Trials for Cartilage Regenerative Medicine Applications

Osteoarthritis (OA) is a highly prevalent disease, affecting 1 in 8 adults worldwide and is projected to increase by 60% in the next two decades. Due to the intricate interplay between multiple influencing factors such as mechanical loading and inflammation playing out over multiple length scales and tissue compartments, currently no disease-modifying drugs are available on the market. The INSTAnt CARMA project aims to harness the power of in silico trials to study OA onset and progression, as well as design endogenous (drugs) and exogenous (tissue engineered) therapies.A multiscale multifactorial in silico model of the knee joint will be established and validated with dedicated in vitro and in vivo experiments. A continuous effort following targeted and untargeted approaches will take place to explore biological hypotheses and implement relevant model extensions. In parallel, computational upscaling tools will be implemented to prepare the model for execution of in silico trial simulations on virtual patient cohorts. The first in silico trial will investigate the effect of model-predicted drug combinations after experimental confirmation in a rodent model. The second trial will seek to optimize tissue engineered constructs for deep osteochondral defect regeneration, followed by experimental validation in a small and large animal model. To realize its goals, INSTAnt CARMA can build on the well-received and published work on a wide range of in silico, in vitro and in vivo tools developed by the applicant and her team. Additionally, the work will benefit from the applicant’s extensive network and involvement in regulatory science for in silico medicine. This project will further accelerate the uptake of in silico testing strategies in the development of medical therapies in general and osteoarthritis in particular.