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.

Articular cartilage (AC) is a specialized connective tissue able to provide a low‐friction gliding surface supporting shock‐absorption, reducing stresses, and guaranteeing wear‐resistance thanks to its structure and mechanical and lubrication properties. Being an avascular tissue, AC has a limited ability to heal defects. Nowadays, conventional strategies show several limitations, which results in ineffective restoration of chondral defects. Several tissue engineering approaches have been proposed to restore the AC's native properties without reproducing its mechanical and lubrication properties yet. This work reports the fabrication of a bilayered structure made of gellan gum (GG) and poly (ethylene glycol) diacrylate (PEGDA), able to mimic the mechanical and lubrication features of both AC superficial and deep zones. Through appropriate combinations of GG and PEGDA, cartilage Young's modulus is effectively mimicked for both zones. Graphene oxide is used as a dopant agent for the superficial hydrogel layer, demonstrating a lower friction than the nondoped counterpart. The bilayered hydrogel's antiwear properties are confirmed by using a knee simulator, following ISO 14243. Finally, in vitro tests with human chondrocytes confirm the absence of cytotoxicity effects. The results shown in this paper open the way to a multilayered synthetic injectable or surgically implantable filler for restoring AC defects.

A cell-laden alginate/Pluronic-based bioink doped with BaTiO ₃ piezoelectric nanoparticles (BTNPs) was investigated. BTNPs promoted myogenic differentiation and the synergy with ultrasound boosted the expression of MYOD1 , MYOG , and MYH2 genes.

This article aims at highlighting the most recent and promising research trends, the open challenges and the possible routes to follow in the field of targeted therapy. A highly interdisciplinary viewpoint has been used, trying to evidence and discuss the different opportunities deriving from recent evolutions of nanotechnology, polymer science, robotics and biotechnology. The most used vectors for nanomedicine applications are described, together with the different action strategies reported in the literature, such as passive targeting, site-directed targeting and remotely triggerable drug delivery. Special emphasis is given to magnetically triggered systems and ultrasound-responsive materials, identified as the most promising paradigms. Key competences and system integration strategies derived from robotics are also introduced, focusing the attention on the crucial issue of achieving high controllability of the vector at the micro- and nano-scale. Finally, biocomponents are described, highlighting their potential as functional sensing elements or smart mechanisms to be integrated on board of advanced micro-nano therapeutic devices. The conclusion aims at depicting the importance of novel and improved targeted therapy strategies, to be coupled with the emerging world of predicting and personalized medicine. To this aim, a real merging of skills and approaches, derived from the aforementioned research fields, is recognized as highly desirable and rich of opportunities.