Acoustic trapping and navigation of microrobots in the mouse brain vasculature

Many cerebrovascular and neurodegenerative diseases are currently challenging to treat due to the complex and delicate anatomy of the brain. The use of microrobots can create new opportunities in brain research due to their ability to access hard-to-reach regions and empower various biological applications; however, little is known about the functionality of microrobots in the brain, owing to their limited imaging modalities and intravascular challenges such as high blood flow velocities, osmotic pressures, and cellular responses. Here, we present an acoustic, non-invasive, biocompatible microrobot actuation system, for in vivo navigation in the bloodstream, in which microrobots are formed by lipid-shelled microbubbles that aggregate and propel under the force of acoustic irradiation. We investigated their capacities in vitro within a microfluidic 3D setup and in vivo in a living mouse brain. We show that microrobots can self-assemble and navigate upstream in the brain vasculature. Our microrobots achieved upstream velocities of up to 1.5 m/s and overcame blood flows of ~10 mm/s. Our results prove that microbubble-based microrobots are scalable to the complex 3D living milieu. Significance StatementNumerous brain diseases, including ischemic stroke, Alzheimers disease, and glioblastoma, may benefit from local and targeted therapies. Although they show great promise, microrobots have not yet demonstrated successful in vivo navigation inside the brain, as the challenging flow conditions and the complex 3D vascular network in the brain pose fundamental limitations. Here, we apply acoustically driven microrobots with the capacity for self-assembly and real-time navigation, including navigation against blood flow up to 10 mm/s, used for the first time inside the brain vasculature of a living mouse. The ultrasound manipulation of microrobots inside animal models provides a much-needed pathway for the advancement of preclinical research.