In vivo efficacy of an injectable piezoelectric nanocomposite hydrogel and low-intensity pulsed ultrasound in two preclinical models of osteoarthritis
Matilde Tschon, Giorgia Codispoti, Paolo Cabras, Andrea Cafarelli, Diego Trucco, Lorenzo Vannozzi, Cristina Manferdini, Melania Carniato, Giorgio Cassiolas, Lúcia Martini, Milena Fini, Giovanni D’Atri, Carsten Jost, Yirij Fedutik, Gilbert Daniel Nessim, Erik Dumont, Gina Lisignoli, Leonardo Ricotti
Abstract
Smart hydrogels embedding mesenchymal stromal cells are receiving increasing attention as a potential solution for preventing articular cartilage degeneration in knee osteoarthritis (OA). In this work we demonstrate that an injectable piezoelectric hydrogel embedding autologous adipose tissue-derived mesenchymal stromal cells (ASCs), stimulated by low-intensity pulsed ultrasound (LIPUS), is effective in reducing knee OA in two preclinical surgically induced OA models. A medium-sized rabbit model was used to evaluate sex differences in treatment efficacy, while a large-sized sheep model was employed to assess the translatability of this innovative approach to a scenario with similarities to human conditions. We developed computational models to ensure reliable and precise delivery of a specific ultrasound dose to the target, modelling wave propagation through tissues and considering the anatomy of the two experimental animal models. Sex-based differences in therapy effectiveness were observed in rabbits, with better macroscopic and microscopic outcomes in counteracting OA in female animals. Furthermore, we found that the combination of ASC-laden piezoelectric hydrogel and LIPUS can be scaled in a large-sized sheep model, proving effective in counteracting OA.