Periodic Reporting for period 2 - SONOBOTS (Acousto-Magnetic Micro/Nanorobots for Biomedical Applications)
Reporting period: 2021-05-01 to 2022-10-31
1. Problem being issued
Nanotherapeutics face a major hurdle in that nanodrugs rarely reach tumor sites due to factors such as interstitial fluid pressure and slow diffusion. Our ultrasound-actuated robots have great potential for overcoming this hurdle. This proposal has the potential to leverage ultrasound to open up a new and exciting area relevant to fields such as targeted drug delivery and micromanipulation technologies. Micro/nanorobots can transform many aspects of medicine by enabling targeted and precise delivery of drugs or genes, as well as facilitating non-invasive surgeries. However, their practical application is fundamentally limited by lack of control; typically, micro/nanorobots can only follow along with the bloodstream, and conversely become stalled in leaky tumor vasculatures where flow and perfusion are poor.
2. Impact on Society
This proposal aims to engineer micro/nanorobots and ultrasound-based methods for their manipulation inside animal models, with ultimate applications in clinical therapeutics. Development of ultrasound-actuated microrobots will provide a much-needed pathway for advancement of preclinical research. Currently, we are developing a new type of ultrasound-actuated microrobot that is inherently biocompatible, can be easily and cheaply mass-produced, and can move against flow measured in cm/s, comparable to what occurs in human veins. Our innovative propulsion and navigation systems will thus support novel strategies for targeted drug delivery, including within the leaky vasculature of solid tumors and across the blood-brain barrier. In addition, our technology will have significant impact as a foundation for advancements in brain research and vasculature biology, as well as in furthering our understanding of diseases and the development of relevant treatments.
3. Overall objectives
The goal of the project is to further advance the field of micro/nanorobotics and utilize the capabilities of these innovative tools in important bio-related applications in animals and, eventually, in patients. First, our research will focus on some of the fundamental challenges associated with the use of micro/nanorobots in living animals, which we will assess in microfluidics, 3D arbitrarily-shaped fluidic devices, and in the vasculature of zebrafish embryos. Second, we seek to trap and manipulate nanorobots in vivo using ultrasound. Our final goals are to develop an active drug delivery platform and to investigate and study numerous disease models using zebrafish embryo models. Zebrafish embryos are excellent substitutes for higher mammalian models, and they are used frequently to elucidate the molecular mechanisms that underlie human diseases and to identify cures.
Nanotherapeutics face a major hurdle in that nanodrugs rarely reach tumor sites due to factors such as interstitial fluid pressure and slow diffusion. Our ultrasound-actuated robots have great potential for overcoming this hurdle. This proposal has the potential to leverage ultrasound to open up a new and exciting area relevant to fields such as targeted drug delivery and micromanipulation technologies. Micro/nanorobots can transform many aspects of medicine by enabling targeted and precise delivery of drugs or genes, as well as facilitating non-invasive surgeries. However, their practical application is fundamentally limited by lack of control; typically, micro/nanorobots can only follow along with the bloodstream, and conversely become stalled in leaky tumor vasculatures where flow and perfusion are poor.
2. Impact on Society
This proposal aims to engineer micro/nanorobots and ultrasound-based methods for their manipulation inside animal models, with ultimate applications in clinical therapeutics. Development of ultrasound-actuated microrobots will provide a much-needed pathway for advancement of preclinical research. Currently, we are developing a new type of ultrasound-actuated microrobot that is inherently biocompatible, can be easily and cheaply mass-produced, and can move against flow measured in cm/s, comparable to what occurs in human veins. Our innovative propulsion and navigation systems will thus support novel strategies for targeted drug delivery, including within the leaky vasculature of solid tumors and across the blood-brain barrier. In addition, our technology will have significant impact as a foundation for advancements in brain research and vasculature biology, as well as in furthering our understanding of diseases and the development of relevant treatments.
3. Overall objectives
The goal of the project is to further advance the field of micro/nanorobotics and utilize the capabilities of these innovative tools in important bio-related applications in animals and, eventually, in patients. First, our research will focus on some of the fundamental challenges associated with the use of micro/nanorobots in living animals, which we will assess in microfluidics, 3D arbitrarily-shaped fluidic devices, and in the vasculature of zebrafish embryos. Second, we seek to trap and manipulate nanorobots in vivo using ultrasound. Our final goals are to develop an active drug delivery platform and to investigate and study numerous disease models using zebrafish embryo models. Zebrafish embryos are excellent substitutes for higher mammalian models, and they are used frequently to elucidate the molecular mechanisms that underlie human diseases and to identify cures.
Micro/nanorobots can transform numerous aspects of medicine. Here I have outlined some of the major results we have achieved so far. Inspired by many naturally occurring microswimmers that exploit the nonslip boundary conditions of the wall, we developed and designed self-assembled microswarms that can execute upstream motility triggered by a combination of external acoustic and magnetic fields. The concept was published in Nature Machine Intelligence (https://doi.org/10.1038/s42256-020-00275-x) and addressed two milestones in Tasks 1 and 2. We also developed an ultrasound-based microrobots based on self-assembling clinically-approved, 1–2-micron gas-filled polymeric-shelled microbubbles. These microrobots can move against flow measured in cm/s, comparable to flow that occurs in human veins, and have been demonstrated to execute up-, down-, and cross-stream motion in artificial vasculatures. The result was published in Advanced Materials Technology (https://doi.org/10.1002/admi.202200877) and the project was invited for the front cover image. We achieved a milestone in Task 1 and a critical step in Task 4.
We demonstrate the concept of an acoustic virtual wall, in which an acoustic standing wave field forms pressure nodes in liquid; these nodes are developed in the absence of real physical boundaries to serve as virtual walls. We then, demonstrate rolling of chain-shaped microswarms along such virtual walls, impelled by the combination of a rotational magnetic field, which causes individual particles to self-assemble and rotate, and the acoustic radiation force, which pushes rotating microswarms towards a virtual wall and provides the reaction force needed to break their motion symmetry and induce rolling. Consequently, the concept of reconfigurable virtual walls developed here overcomes the fundamental limitation of a physical boundary being required for universal rolling movements. The basis of the work has already been submitted as a manuscript to Nature Communications, which is currently in the second round of revision [https://doi.org/10.21203/rs.3.rs-1505456/v1]). This project addresses the intermediate goals of Tasks 1 and 2.
Next, inspired by the natural arrangements of cilia on the surface of starfish larva, we developed ultrasound-activated ciliary bands. In this work, we leveraged nonlinear acoustics in conjunction with a source/sink arrangement of ciliary bands to develop a new physical principle of propulsion for acoustic-based microrobots. The results were published in Nature Communications (https://doi.org/10.1038/s41467-021-26607-y) and addressed the second milestone in Task 1. Finally, we have developed an acoustic manipulation chamber and demonstrated successful manipulation of our microrobots in the vasculature of zebrafish embryos. This successful high-precision, in vivo acoustic manipulation of intravenously injected microbubbles offers potential novel therapeutic options. The results were published in Science Advances (DOI: 10.1126/sciadv.abm2785) and addressed multiple milestones in Task 1, 2 and 3.
We demonstrate the concept of an acoustic virtual wall, in which an acoustic standing wave field forms pressure nodes in liquid; these nodes are developed in the absence of real physical boundaries to serve as virtual walls. We then, demonstrate rolling of chain-shaped microswarms along such virtual walls, impelled by the combination of a rotational magnetic field, which causes individual particles to self-assemble and rotate, and the acoustic radiation force, which pushes rotating microswarms towards a virtual wall and provides the reaction force needed to break their motion symmetry and induce rolling. Consequently, the concept of reconfigurable virtual walls developed here overcomes the fundamental limitation of a physical boundary being required for universal rolling movements. The basis of the work has already been submitted as a manuscript to Nature Communications, which is currently in the second round of revision [https://doi.org/10.21203/rs.3.rs-1505456/v1]). This project addresses the intermediate goals of Tasks 1 and 2.
Next, inspired by the natural arrangements of cilia on the surface of starfish larva, we developed ultrasound-activated ciliary bands. In this work, we leveraged nonlinear acoustics in conjunction with a source/sink arrangement of ciliary bands to develop a new physical principle of propulsion for acoustic-based microrobots. The results were published in Nature Communications (https://doi.org/10.1038/s41467-021-26607-y) and addressed the second milestone in Task 1. Finally, we have developed an acoustic manipulation chamber and demonstrated successful manipulation of our microrobots in the vasculature of zebrafish embryos. This successful high-precision, in vivo acoustic manipulation of intravenously injected microbubbles offers potential novel therapeutic options. The results were published in Science Advances (DOI: 10.1126/sciadv.abm2785) and addressed multiple milestones in Task 1, 2 and 3.
We have achieved important results, as demonstrated by the publications below.
Daniel Ahmed*, Alexander Sukhov, David Hauri, Dubon Rodrigue, Gian Maranta, Jens Harting & Bradley J. Nelson, Bioinspired acousto-magnetic microswarm robots with upstream motility, Nature Machine Intellegence 3, 116–124, 2021. https://doi.org/10.1038/s42256-020-00275-x
Cornel Dillinger, Nitesh Nama, Daniel Ahmed*, Starfish-Inspired Ultrasound-Activated Ciliary Bands for Microrobotic Systems, Nature Communications, 12, 6455, 2021. https://doi.org/10.1038/s41467-021-26607-y.
Viktor Jooss, Jan Stephan Bolten, Jörg Huwyler, Daniel Ahmed*, In Vivo Acoustic Manipulation of Microparticles in Zebrafish Embryos, Science Advances 8 (12), eabm2785, 2022. DOI: 10.1126/sciadv.abm2785.
Fonseca, A. D. C., Kohler, T., Ahmed, D., Ultrasound-Controlled Swarmbots Under Physiological Flow Conditions. Adv. Mater. Interfaces 2022, 2200877. https://doi.org/10.1002/admi.202200877. Invited for front cover.
Zhiyuan Zhang, Alexander Sukhov, Jens Harting, Paolo Malgaretti, Daniel Ahmed*, Rolling Microswarms along Acoustic Virtual Walls, second round of revision at Nature Communications, 2022, under second round review. [https://doi.org/10.21203/rs.3.rs-1505456/v1].
Janiak Janiak, Alexander Doinikov, Daniel Ahmed*, Microbubble Propulsion, Train-like Assembly and Cargo Transport in an Acoustic Field, second round of revision at Nature Communications, 2022, [https://doi.org/10.21203/rs.3.rs-1220770/v1]
We expect to reach the results proposed during the duration of the ERC Proposal.
Daniel Ahmed*, Alexander Sukhov, David Hauri, Dubon Rodrigue, Gian Maranta, Jens Harting & Bradley J. Nelson, Bioinspired acousto-magnetic microswarm robots with upstream motility, Nature Machine Intellegence 3, 116–124, 2021. https://doi.org/10.1038/s42256-020-00275-x
Cornel Dillinger, Nitesh Nama, Daniel Ahmed*, Starfish-Inspired Ultrasound-Activated Ciliary Bands for Microrobotic Systems, Nature Communications, 12, 6455, 2021. https://doi.org/10.1038/s41467-021-26607-y.
Viktor Jooss, Jan Stephan Bolten, Jörg Huwyler, Daniel Ahmed*, In Vivo Acoustic Manipulation of Microparticles in Zebrafish Embryos, Science Advances 8 (12), eabm2785, 2022. DOI: 10.1126/sciadv.abm2785.
Fonseca, A. D. C., Kohler, T., Ahmed, D., Ultrasound-Controlled Swarmbots Under Physiological Flow Conditions. Adv. Mater. Interfaces 2022, 2200877. https://doi.org/10.1002/admi.202200877. Invited for front cover.
Zhiyuan Zhang, Alexander Sukhov, Jens Harting, Paolo Malgaretti, Daniel Ahmed*, Rolling Microswarms along Acoustic Virtual Walls, second round of revision at Nature Communications, 2022, under second round review. [https://doi.org/10.21203/rs.3.rs-1505456/v1].
Janiak Janiak, Alexander Doinikov, Daniel Ahmed*, Microbubble Propulsion, Train-like Assembly and Cargo Transport in an Acoustic Field, second round of revision at Nature Communications, 2022, [https://doi.org/10.21203/rs.3.rs-1220770/v1]
We expect to reach the results proposed during the duration of the ERC Proposal.