The Multifunctional Purposes of Ultrasound in 3D Models

Ultrasound (US), is gaining considerable interest as therapy and diagnostic tool, being safe, deep-tissue penetrating, and enabling variegate interventions. Although some US applications have already reached the clinical practice, innovative interventions combining them to microbubbles, nanoparticles, scaffolds and novel imaging techniques have to face complex clinical translation. Here US technologies are illustrated in 3D cell structures: as in-vitro systems at different levels of complexity, 3D models can fairly recapitulate human tissue complexity, while reducing interventions on animals. First drug delivery is described as mediated by microbubbles or nanoparticles to 3D spheroids, organ-on-chip, microfluidic-embedded 3D-cell structures, and cell-seeded scaffolds, showing the important US role in achieving barriers penetration and highly localized delivery. Then, the assembly of cells in 3D structures thanks to US is highlighted, showing prominent examples of how finely tuning acoustic standing waves can guide the organization and aggregation of cells in 3D. Finally, an outlook of conventional echographic techniques up to the most innovative quantitative US imaging is reviewed, focusing on new imaging options for 3D structures. These intriguing fields of research are discussed related to their actual challenges and opportunities, level of complexity of 3D models, and ability to propose a valid tool toward clinical translation.