In vivo efficacy of an injectable piezoelectric nanocomposite hydrogel and low-intensity pulsed ultrasound in two preclinical models of osteoarthritis

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.