Lab on a Chip View Article Online CRITICAL REVIEW View Journal | View Issue Mobile microrobots for bioengineering Cite this: Lab Chip,2017,17,1705 applications Hakan Ceylan,ab Joshua Giltinan,abc Kristen Kozielskia and Metin Sitti *abc Untethered micron-scale mobile robots can navigate and non-invasively perform specific tasks inside un- precedented and hard-to-reach inner human body sites and inside enclosed organ-on-a-chip microfluidic devices with live cells. They are aimed to operate robustly and safely in complex physiological environ- ments where they will have a transforming impact in bioengineering and healthcare. Research along this line has already demonstrated significant progress, increasing attention, and high promise over the past several years. The first-generation microrobots, which could deliver therapeutics and other cargo to targeted specific body sites, have just been started to be tested inside small animals toward clinical use. Here, we review frontline advances in design, fabrication, and testing of untethered mobile microrobots for bioengineering applications. We convey the most impactful and recent strategies in actuation, mobility, Creative Commons Attribution 3.0 Unported Licence. Received 18th January 2017, sensing, and other functional capabilities of mobile microrobots, and discuss their potential advantages and Accepted 27th April 2017 drawbacks to operate inside complex, enclosed and physiologically relevant environments. We lastly draw an outlook to provide directions in the veins of more sophisticated designs and applications, considering DOI: 10.1039/c7lc00064b biodegradability, immunogenicity, mobility, sensing, and possible medical interventions in complex rsc.li/loc microenvironments. Introduction Physically intelligent material systems at the sub-millimeter This article is licensed under a a Physical Intelligence Department, Max Planck Institute for Intelligent Systems, scale are promising for applications in various fields, such as 70569 Stuttgart, Germany. E-mail: [email protected] bioengineering (e.g., targeted therapeutics1 and tissue engi- b Max Planck ETH Center for Learning Systems, 70569 Stuttgart, Germany 2 3 c Open Access Article. Published on 28 2017. Downloaded 2021/10/6 20:41:19. Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, neering ), active matter (e.g., programmable matter and 4 USA self-organizing systems ), and microrobotics (e.g., soft HakanCeylanhasbeenapost- Joshua Giltinan received his B.S doctoral researcher in the Max degree in Physics and Computer Planck Institute for Intelligent Science from Towson University Systems, Stuttgart, Germany, in 2011. He is currently pursuing and currently an associated fel- the Ph.D. degree in Department low of Max Planck ETH Center of Mechanical Engineering at for Learning Systems. He re- Carnegie Mellon University, ceived the B.Sc. degree in the De- Pittsburgh, USA. In 2014, he partment of Molecular Biology joined the Physical Intelligence and Genetics from Bilkent Uni- department at the Max-Planck versity, Ankara, Turkey, in 2010, Institute for Intelligent Systems, and the Ph.D. degree in the Insti- Stuttgart, Germany. His research Hakan Ceylan tute of Materials Science and Joshua Giltinan interest is the fabrication and Nanotechnology from National control of micro-robots and Nanotechnology Research center affiliated to Bilkent University in MEMS devices. 2014. His research interests include intelligent materials systems, active matter, micro-scale robotics, self-assembly, bio-hybrid actu- ation, hierarchical material fabrication, and two-photon microprinting. This journal is © The Royal Society of Chemistry 2017 Lab Chip,2017,17,1705–1724 | 1705 View Article Online Critical review Lab on a Chip microactuators,5 mobile microrobots6). Mobile functional de- Active and targeted delivery of therapeutic cargos, such as vices at the sub-millimeter length scales afford particular ad- drugs, imaging agents, and genetic materials, are the major vantages to pursue novel bioengineering strategies. This size objectives of the first-generation microrobotic systems. Active regime includes the average size of a mammalian cell, the ba- navigation inside the body to a specific target site with a con- sic building unit of a tissue or organ, thereby, permitting di- trollable cargo carrier is superior to relatively limited cargo rect access to deep, complex, and delicate body sites, such as delivery and distribution efficiencies provided by current pas- – brain, spinal cord, heart, bile duct, pancreas, and liver.7 9 sive routes of administrations, such as intravenous delivery Such direct access capability potentially opens up new means and local diffusion.14 Using active, drivable carriers, it is pos- of medical interventions with minimal possible tissue dam- sible to minimize systemic side effects by achieving targeted age compared with the tethered catheters, endoscopes, and local treatment options. For example, intravenously adminis- incision-based surgery. Further, operational resolution at tered interleukin-12 caused lethal systemic toxicities in a clin- sub-cellular scales would allow single cell-level manipulations ical trial.15 Active delivery and controlled on-site release with high accuracy and repeatability. In the near future, this schemes increase the overall bioavailability of single dose ad- could have tremendous applications in tissue engineering ministration. Sensitive cargo types, such as proteins, pep- and regenerative medicine; while, in the longer term, it could tides, or nucleic acids, are better protected from degradation revolutionize the treatment of genetic diseases by single cell inside a carrier, as they otherwise have very short half-lives in protein or nucleic acid delivery.6,10 serum.16 Autonomous, real-time control over cargo release Use of microrobots for lab-on-a-chip devices has already dynamics would perhaps represent the state-of-the-art of the proved to be a powerful tool. Handling small objects in very in situ therapeutic and diagnostic strategy. To this end, small fluid volumes for manipulating, moving, and microrobots that are able to navigate inside the human body, reconfiguring components in 3D by means of microrobots act intelligently in response to changing conditions, carry, de- make this route highly attractive. Assembly of 3D heteroge- liver, and release therapeutics, and perform complicated Creative Commons Attribution 3.0 Unported Licence. neous microobjects, which require orientation and positional tasks in semi- or fully autonomous manners could revolution- control, would be best addressed using microrobotic assem- ize many clinical practices. bly.11,12 Organ-on-a-chip applications could benefit from The first concept of miniaturized machines for bioengi- microrobotic operations, in which complex cellular materials neering was artistically visualized in the popular science with 3D microscale features may need to be positioned to fiction movie Fantastic Voyage (1966). In the movie, the better recapitulate the native physiological status.13 Addition- brain clot of a nearly dying scientist had to be removed ally, preclinical characterizations of microrobots for drug re- in one hour by a submarine shrunken to microscopic size lease profiles and their interactions with living tissues could and injected into his blood stream with a small crew. In be tested in organ-on-a-chip platforms. view of the scaling laws, which we discuss in the This article is licensed under a Open Access Article. Published on 28 2017. Downloaded 2021/10/6 20:41:19. Kristen Kozielski received her un- Metin Sitti received the BSc and dergraduate and Ph.D. training MSc degrees in electrical and in the Biomedical Engineering electronics engineering from Department at Johns Hopkins Bogazici University, Istanbul, University. She completed her Turkey, in 1992 and 1994, re- thesis work in the Drug Delivery spectively, and the PhD degree and Biomaterials laboratory in electrical engineering from the with Dr. Jordan Green as her University of Tokyo, Japan, in thesis advisor. Her thesis work 1999. He was a research scien- involved synthesizing nano- tist at UC Berkeley during 1999– particles optimized to deliver 2002. He is currently a director DNA, siRNA, and miRNA that in Max-Planck Institute for Intel- Kristen Kozielski could alter brain cancer behav- Metin Sitti ligent Systems, Stuttgart, Ger- ior or kill tumor cells. Kristen is many and a professor at Carne- currently a postdoctoral fellow at the Max Planck Institute for gie Mellon University, Pittsburgh, USA. His research interests Intelligent Systems, in the Physical Intelligence department. Her include mobile milli/microrobotics, advanced functional micro/ postdoctoral research focuses on microrobotic technologies for nanomaterials, medical soft robotics, and programmable self-as- medical applications. sembly. He is an IEEE Fellow. He received the SPIE Nano- engineering Pioneer Award in 2011 and NSF CAREER Award in 2005. He received many best paper and video awards in major ro- botics and adhesion conferences. He is the editor-in-chief of Jour- nal of Micro-Bio Robotics. 1706 | Lab Chip,2017,17,1705–1724 This journal is © The Royal Society of Chemistry 2017 View Article Online Lab on a Chip Critical review following section, a macroscale submarine design in the layout future challenges and critical directions to consider microscopic dimensions is highly inefficient to operate in- for rendering intelligence to microrobotic systems. side human body.