Acoustic bubble-based drug manipulation: Carrying, releasing and penetrating for targeted drug delivery using an electromagnetically actuated microrobot
Graphical abstract
Introduction
According to the World Health Organization (WHO), cardiovascular diseases are the leading cause of mortality globally [1,2]. Drug therapy is the most convenient medical treatment for patients suffering from cardiovascular diseases, even though it is less effective owing to its poor pharmacokinetics [3]. To overcome the limitations of conventional drug therapy, targeted drug delivery technologies delivering therapeutic agents directly to targeted diseased tissues have been extensively investigated. Targeted drug delivery technologies can alleviate the negative side effects, enhance the drug uptake, and improve the body conformity with minimizing in vivo drug instability [4,5]. Among diverse targeted drug delivery technologies, a novel method based on microrobots swimming in in vivo environments has obtained considerable attention from the biomedical communities because the microrobots are capable of accessing the majority of locations within the human body [6,7].
To realize the concept, one of the most challenging yet important issues has been to develop a dependable propulsion technique for the microrobots; this requires a different method from propulsion techniques used in macroscale environments [7]. In microscale environments, the relative importance of the physical effects relies on the surrounding environment, although the basic physics are constant. For example, surface forces such as surface tension dominate body forces such as the inertial force and gravity, and the effect of the surrounding fluid viscosity can become significant [8]. Thus, various micropropulsion techniques of microrobots based on chemical, biological, acoustic, and magnetic actuation have been proposed and developed [[9], [10], [11]].
Since Paxton et al. presented a chemically propelled nanorod in an H2O2 aqueous medium [12], a large number of chemically driven microrobots have been proposed in the form of multiple-layer tubes [[13], [14], [15]] and Janus particles [16,17]. However, low biocompatibility and short lifetime due to the chemical fuel (mostly H2O2) loaded in the microrobots remain limitations to overcome.
A microorganism capable of swimming in a microfluidic environment can be used as a micro-propeller. The research groups of Whiteside and Sitti examined the behavior of microorganism-propelled objects and several approaches to enhance their controllability [[18], [19], [20], [21]]. In recent studies, biologically actuated microrobots (also regarded as biohybrid microrobots) have demonstrated advantages such as a biocompatible actuation source and a combination of actuating and sensing capabilities [22]. Nevertheless, the requirement of a particular environment containing the proper nutrients for fueling the microrobots remains as the main drawback [9].
An acoustic field is a compelling source to remotely propel a microrobot. Dijkink et al. initially proposed underwater propulsion utilizing acoustic streaming generated by the oscillation of an acoustically excited gaseous bubble [23]. Recently, the research group of Cho presented two-dimensional (2D) maneuvers of an acoustic bubble-driven microrobot [[24], [25], [26]]. Acoustic propulsion is new and promising for microrobot propulsion in macroscale environments. However, the design of the acoustically propelled microrobots for in vivo environments requires further development [10].
Magnetic actuation is one of the most prominent and reliable methods to remotely control in vivo microrobot locomotion. Magnetic fields can penetrate biological tissues without adverse reaction, which makes the use of the magnetic actuation highly promising in biomedical applications [27]. In magnetic actuation, the magnetic fields are utilized mainly to exert a magnetic torque to align a magnetic material along the magnetic field and a magnetic gradient force generated by the inhomogeneity of the magnetic fields [28,29]. Magnetically driven microrobots in submillimeter scales have utilized, primarily, the magnetic gradient force for their propulsion [[30], [31], [32], [33]]. For smaller scale microrobots swimming in a low-Reynolds number environment, magnetic torque-based propulsion using artificial flagellum actuated by oscillating [34] or rotating [35] magnetic fields has been used, rather than the magnetic gradient force, owing to scaling issues [36].
Based on the advance of micropropulsion technology, microrobots enabling the targeted delivery of micro/nano agents, which can be drugs, genetic materials, and cells, have been proposed using diverse manipulation methods. Park et al. proposed a bacteria-based microrobot for theragnostic activities utilizing the attraction between bacteria and protein-coated microbeads. Using the chemotactic ability of the bacteria heading to a biomarker from a diseased target, the microrobot can approach the targets and successfully deliver the synthetic drug cargo [22]. Fusco et al. proposed an untethered, self-folding, soft microrobot consisting of magnetic microbeads encapsulated by a hydrogel bilayer responding to near-infrared light (NIR). The targeted delivery of micro-agents was achieved by magnetic propulsion and NIR laser irradiation that can rapidly open the hydrogel bilayer, resulting in the release of microbeads [37]. Huang et al. reported a microtransporter consisting of a magnetically driven screw and a hollow cylinder encapsulating the screw. The microtransporter can accumulate, encapsulate, carry, and release a micro/nanoobject in a controlled manner using a wirelessly controlled Archimedes screw pumping mechanism [38]. Kwon et al. presented a non-invasive micro-object manipulation using an acoustic bubble simply attached to a magnetically driven microrobot. Using an acoustic bubble-induced radiation force as a grasping tool, the microrobot can safely transport a vulnerable biological micro-object to the target position [39,40].
This paper presents a new type of microrobotic drug delivery technology where an electromagnetically actuated untethered microrobot swimming inside the human blood vessels performs targeted drug delivery operations: carrying, releasing, and penetrating drugs to targeted tissues, using the selective acoustic excitation of bubbles. Unlike previous works, the proposed microrobot is capable of encapsulating and transporting liquid forms of drugs in an aqueous medium. This technology only utilizes compressible bubbles to manipulate drugs wirelessly without any complex mechanical parts, allowing the design of the microrobot to be simple.
A schematic diagram of the proposed targeted drug delivery technology is illustrated in Fig. 1. The novel microrobot is composed of a permanent magnet for electromagnetic actuation, and two different lengths of microtubes closed at one end. The short tube is filled with only a gaseous bubble; the long tube contains the liquid drug and two bubbles (an inner and outer bubble, respectively). When the microrobot moves to the desired location through electromagnetic actuation, the drug encapsulated by the two bubbles in the long tube is carried. At the desired position, the carried drug is released by removing the outer bubble, which covers the opening of the long tube, through the acoustic excitation of the inner bubble. Afterward, unidirectional microstreaming generated by the acoustic excitation of the center bubble in the short tube penetrates the released drug to the target tissues [41].
Section snippets
Propulsion principle
Based on the Faraday-Lenz Law, magnetic fields are induced around a coil with the presence of an electrical current in the coil. Two identical circular electrical coils placed symmetrically along a common axis separated by a distance equal to radius R can produce a nearly uniform magnetic field between them by applying the electrical current to the respective coils in the same direction, known as Helmholtz coil. The magnetic material is aligned with the same direction of the magnetic field in
Electromagnetic propulsion
To examine the performance of the fabricated electromagnetic coil system, the densities of the magnetic flux produced by the Helmholtz and Maxwell coils are verified using a gaussmeter (MG-3002, Lutron electronic enterprise Co.) and compared to the theoretical values (see Appendix A). While measuring the densities of the magnetic flux, electrical currents of 3.1 A and 1.7 A are induced to the Helmholtz and Maxwell coils, respectively, using DC power supplies (IT6720, ITECH electronics). The
Conclusion
A targeted drug delivery technology utilizing acoustic excitation of bubbles embedded in an electromagnetically actuated microrobot is proposed and experimentally verified. Two actuation schemes, electromagnetic actuation for driving the microrobot and acoustic bubble actuation for manipulating the drug are applied. The propulsion of the microrobot made of cylindrical magnet is experimentally demonstrated in the x–y plane along with a T-shaped channel filled with water by using the designed
CRediT authorship contribution statement
Jinwon Jeong: Software, Formal analysis, Investigation, Data curation. Deasung Jang: Methodology, Investigation, Writing - original draft, Writing - review & editing. Daegeun Kim: Visualization, Formal analysis. Daeyoung Lee: Data curation. Sang Kug Chung: Conceptualization, Supervision, Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2011-0025039). This work was also supported by 2020 research fund of Myongji University.
Jinwon Jeong received the Bachelor’s degree of mechanical engineering from Myongji University in 2018. He currently is a graduate student in Myongji University and his research interests lie on applications of liquid metal alloys.
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Jinwon Jeong received the Bachelor’s degree of mechanical engineering from Myongji University in 2018. He currently is a graduate student in Myongji University and his research interests lie on applications of liquid metal alloys.
Deasung Jang received his B.S. and M.S. degrees in mechanical engineering in 2016 and 2018, respectively, from Myongji University. Since 2018, he has worked at Microsystems, Inc. His research interests lie on bubble dynamics and its application.
Daegeun Kim received the Bachelor’s degree of mechanical engineering from Myongji University in 2018. He currently is a graduate student in Myongji University and his research interests lie on MEMS and Microfluidics applications.
Daeyoung Lee received the Bachelor’s degree of mechanical engineering from Myongji University in 2018. He currently is a graduate student in Myongji University and his research interests lie on MEMS and Microfluidics applications
Sang Kug Chung is a professor of the department of mechanical engineering at the Myongji University in Korea. He received the Ph.D. degree in Mechanical Engineering and Materials Science from the University of Pittsburgh in 2009 along with the Graduate Research Excellence Award. He received the M.S. degree from Pohang University of Science and Technology (POSTECH) and B.S. from Myongji University. He had worked for the development of the world first Liquid Lens at Samsung Electro-Mechanics from 2003 to 2009. Upon joining the faculty at Myongji University in 2009, he has directed the Microsystems Laboratory. And he has also served as a principal investigator in the Advanced Microfluids Engineering Research Laboratory (AMERL) since 2013. His research is in microfluidics and MEMS, including design and fabrication of micro/nano actuators and systems.
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These authors contributed equally to this work.