Ultrasound stimulation of piezoelectric nanocomposite hydrogels boosts cartilage regeneration

Abstract Osteoarthritis implies a progressive degeneration of the whole joint. Cartilage is particularly affected, with inflammation playing a pivotal role1. In recent years, cartilage regeneration has been pursued through several bioengineering strategies and using different stem cell types2-6. Adipose -derived mesenchymal stromal cells (ASCs) constitute an intriguing and minimally invasive option. However, the use of ASCs for cartilage regeneration is hampered by a relatively inefficient expression of key chondrogenic markers7. Thus, new strategies to boost both in situ targeting and chondrogenesis of ASCs are highly desirable. Here we show that ASCs embedded in a nanocomposite hydrogel including piezoelectric nanomaterials and graphene oxide nanoflakes, and stimulated with ultrasound waves with precisely controlled parameters (1 MHz and 250 mW/cm2, for 5 min once every two days for a period of 10 days) dramatically boost cell chondrogenic commitment. Furthermore, this stimulation regimen also has a considerable anti-inflammatory effect. The proposed nanocomposite hydrogel also shows excellent biocompatibility in vivo. Our results show for the first time the chondrogenic potential of the combined piezoelectric nanoparticle-ultrasound stimulus; the proposed paradigm has the potential to trigger cartilage regeneration in osteoarthritis, focal cartilage defects and other pathological conditions involving cartilage lesions and degeneration. Future efforts should expand preclinical data, and target clinical applications of this therapeutic strategy.