Ultrasound Stimulation of Piezoelectric Nanocomposite Hydrogels Boosts Chondrogenic Differentiation in Vitro, in Both a Normal and Inflammatory Milieu

Leonardo Ricotti, Andrea Cafarelli, Cristina Manferdini, Diego Trucco, Lorenzo Vannozzi, Elena Gabusi, Francesco Fontana, Paolo Dolzani, Yasmin Saleh, Enrico Lenzi, Marta Columbaro, Manuela Piazzi, Jessika Bertacchini, Andrea Aliperta, Markys Cain, Mauro Gemmi, Paola Parlanti, Carsten Jost, Yirij Fedutik, Gilbert Daniel NessimMadina Telkhozhayeva, Eti Teblum, Erik Dumont, Chiara Delbaldo, Giorgia Codispoti, Lucia Martini, Matilde Tschon, Milena Fini, Gina Lisignoli

Research output: Contribution to journalArticlepeer-review


The use of piezoelectric nanomaterials combined with ultrasound stimulation is emerging as a promising approach for wirelessly triggering the regeneration of different tissue types. However, it has never been explored for boosting chondrogenesis. Furthermore, the ultrasound stimulation parameters used are often not adequately controlled. In this study, we show that adipose-tissue-derived mesenchymal stromal cells embedded in a nanocomposite hydrogel containing piezoelectric barium titanate nanoparticles and graphene oxide nanoflakes and stimulated with ultrasound waves with precisely controlled parameters (1 MHz and 250 mW/cm2, for 5 min once every 2 days for 10 days) dramatically boost chondrogenic cell commitment in vitro. Moreover, fibrotic and catabolic factors are strongly down-modulated: proteomic analyses reveal that such stimulation influences biological processes involved in cytoskeleton and extracellular matrix organization, collagen fibril organization, and metabolic processes. The optimal stimulation regimen also has a considerable anti-inflammatory effect and keeps its ability to boost chondrogenesis in vitro, even in an inflammatory milieu. An analytical model to predict the voltage generated by piezoelectric nanoparticles invested by ultrasound waves is proposed, together with a computational tool that takes into consideration nanoparticle clustering within the cell vacuoles and predicts the electric field streamline distribution in the cell cytoplasm. The proposed nanocomposite hydrogel shows good injectability and adhesion to the cartilage tissue ex vivo, as well as excellent biocompatibility in vivo, according to ISO 10993. Future perspectives will involve preclinical testing of this paradigm for cartilage regeneration.

Original languageEnglish
Pages (from-to)2047-2065
Number of pages19
JournalACS Nano
Issue number3
StatePublished - 23 Jan 2024


  • chondrogenesis
  • hydrogel
  • inflammation
  • mesenchymal stromal cell
  • nanomaterial
  • piezoelectric
  • ultrasound

All Science Journal Classification (ASJC) codes

  • General Engineering
  • General Materials Science
  • General Physics and Astronomy


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