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.

Osteoarthritis (OA) is a severe musculoskeletal disease with an increasing incidence in the worldwide population. Recent research has focused on the development of innovative strategies to prevent articular cartilage damage and slow down OA progression, and nanotechnologies applied to hydrogels have gained particular interest. The aim of this systematic review is to investigate the state of the art on preclinical in vitro and in vivo efficacy studies applying nanotechnologies to hydrogels in OA models to elucidate the benefits of their applications. Three databases were consulted for eligible papers. The inclusion criteria were in vitro and in vivo preclinical studies, using OA cells or OA animal models, and testing hydrogels and nanoparticles (NPs) over the last ten years. Data extraction and quality assessment were performed. Eleven papers were included. In vitro studies evidenced that NP-gels do not impact on cell viability and do not cause inflammation in OA cell phenotypes. In vivo research on rodents showed that these treatments could increase drug retention in joints, reducing inflammation and preventing articular cartilage damage. Nanotechnologies in preclinical efficacy tests are still new and require extensive studies and technical hits to determine the efficacy, safety, fate, and localization of NPs for translation into an effective therapy for OA patients.