Mobile Microrobots

Mobile robotic devices smaller than one millimeter could enable new directions in healthcare, biotechnology and manufacturing. Our focus in healthcare is on medical microrobots that can leverage minimally invasive interventional and targeted delivery strategies with high precision and repeatability by navigating and performing in hard-to-reach and delicate inner body sites, such as, the central nervous system, the circulatory system and the eye. Active navigation of highly concentrated therapeutic and diagnostic agents to the site of action could represent a state-of-the-art application of microrobots, considering the limited delivery and distribution efficiencies offered by the systemic routes and local diffusion. By this means, it is possible to minimize the effects of systemic toxicity and increase the overall efficacy of single-dose administration. Autonomous release of multiple types of payloads with programmable kinetics based on the environmental sensing of local cues, e.g., disease markers, in the living milieu could pave the way for microrobotic therapy and diagnosis in the form of an orderly executed, programmable operation. A conventional robot responds to the changes in its environment by means of its on-board sensors and computational capabilities. Achieving such capabilities at the smaller dimensions, where such computational capabilities do not exist; however, remains a major research question. In nature, microorganisms, such as slime molds and bacteria have evolved to use physical intelligence as the main route of making decisions in complex and evolving conditions. Accordingly, programmed physical and chemical properties of materials can enable a robust design route for making microrobotic systems with the capabilities of motion, sensing, and functioning in dynamic interaction with their local environment. Such goals require integrated design and engineering strategies, where powering, actuation, control, environmental sensing and medical functionality need to be considered altogether.

Biohybrid microrobots: Unicellular motile organisms, e.g. flagellated bacteria and algae, are physically integrated with a microrobot that can be used as on-board microactuators and microsensors that harness the biochemical energy in the microenvironment to power the mobility of the microrobot. We exploit the microorganisms that can achieve high propulsion speeds (tens of their body lengths per second), thereby providing high thrust power to the biohybrid microrobots. Integrated sensing and motility of microorganisms further enable steering using cues in the environment chemical and pH gradients.

3D-printed microrobots: Fabrication of microrobots presents unique challenges concerning design, fabrication process, and encoding operational capabilities. Conventional microfabrication techniques usually provide relatively simple geometric structures, such as tubes, spheres, and surfaces, with limited design flexibility and function. Integration of computer-aided design to microfabrication technologies has been a significant advancement to realize sophisticated 3D designs that could not be conceivable with the alternative microfabrication methods. To this end, we explore the potential of additive manufacturing processes for making microrobots. We put a special emphasis on making new materials with tailorable local 3D chemical properties that would enable on-board programmable functionalities, and hence novel design opportunities for diverse types of microrobots.

Reconfigurable and programmable self-assembly and collective behavior of magnetic microrobotic swarms: Collectives of microrobots working cooperatively could significantly enhance their functionalities in many applications such as micro-manufacturing and biomedical engineering. We are working on programmable and reconfigurable self-assembly and collective behavior of microrobots that could enable parallel and distributed massive tasks eventually in the living environment.

Gaurav Gardi

Ph.D. Student

Vimal Kishore

Postdoctoral Researcher

Pelin Erkoc

Varun Sridhar

Ph.D. Student

Guo Zhan Lum

Alumni

Wenqi Hu

Senior Research Scientist

Onder Erin

Ph.D. Student

Xiaoguang Dong

Postdoctoral Researcher

Zhou Ye

Alumni

Hakan Ceylan

Senior Research Scientist

Joshua Giltinan

Postdoctoral Researcher

Kristen Kozielski

Mehmet Berk Yigit

Alumni

Utku Culha

Postdoctoral Researcher

Wendong Wang

Senior Research Scientist

Ajay Vikram Singh

Alumni

Babak Mostaghaci

Alumni

Byung-Wook Park

Alumni

Immihan Ceren Yasa

Postdoctoral Researcher

Jiang Zhuang

Alumni

Morgan Stanton

Alumni

Oncay Yasa

Postdoctoral Researcher

Yunus Alapan

Postdoctoral Researcher

Zeinab Hosseini

Alumni

Guillermo Amador

Alumni

Ahmet Fatih Tabak

Alumni

Ziyu Ren

Ph.D. Student

Kirstin Petersen

Alumni

Lindsey Hines

Alumni

73 results

2018

3D-Printed Biodegradable Microswimmer for Drug Delivery and Targeted Cell Labeling

Hakan Ceylan, , I. Ceren Yasa, , Oncay Yasa, , Ahmet Fatih Tabak, , Joshua Giltinan, , Sitti, M.

bioRxiv, pages: 379024, July 2018 (article)

Abstract

Miniaturization of interventional medical devices can leverage minimally invasive technologies by enabling operational resolution at cellular length scales with high precision and repeatability. Untethered micron-scale mobile robots can realize this by navigating and performing in hard-to-reach, confined and delicate inner body sites. However, such a complex task requires an integrated design and engineering strategy, where powering, control, environmental sensing, medical functionality and biodegradability need to be considered altogether. The present study reports a hydrogel-based, biodegradable microrobotic swimmer, which is responsive to the changes in its microenvironment for theranostic cargo delivery and release tasks. We design a double-helical magnetic microswimmer of 20 micrometers length, which is 3D-printed with complex geometrical and compositional features. At normal physiological concentrations, matrix metalloproteinase-2 (MMP-2) enzyme can entirely degrade the microswimmer body in 118 h to solubilized non-toxic products. The microswimmer can respond to the pathological concentrations of MMP-2 by swelling and thereby accelerating the release kinetics of the drug payload. Anti-ErbB 2 antibody-tagged magnetic nanoparticles released from the degraded microswimmers serve for targeted labeling of SKBR3 breast cancer cells to realize the potential of medical imaging of local tissue sites following the therapeutic intervention. These results represent a leap forward toward clinical medical microrobots that are capable of sensing, responding to the local pathological information, and performing specific therapeutic and diagnostic tasks as orderly executed operations using their smart composite material architectures.

DOI Project Page [BibTex]

2018

Hakan Ceylan, , I. Ceren Yasa, , Oncay Yasa, , Ahmet Fatih Tabak, , Joshua Giltinan, , Sitti, M. 3D-Printed Biodegradable Microswimmer for Drug Delivery and Targeted Cell Labeling bioRxiv, pages: 379024, July 2018 (article)

DOI Project Page [BibTex]

Light-Triggered Drug Release from 3D-Printed Magnetic Chitosan Microswimmers

Ugur Bozuyuk, , Oncay Yasa, , I. Ceren Yasa, , Hakan Ceylan, , Seda Kizilel, , Sitti, M.

ACS Nano, 12, pages: 9617-9625, September 2018 (article)

DOI Project Page [BibTex]

Ugur Bozuyuk, , Oncay Yasa, , I. Ceren Yasa, , Hakan Ceylan, , Seda Kizilel, , Sitti, M. Light-Triggered Drug Release from 3D-Printed Magnetic Chitosan Microswimmers ACS Nano, 12, pages: 9617-9625, September 2018 (article)

DOI Project Page [BibTex]

Microalga‐Powered Microswimmers toward Active Cargo Delivery

Yasa, O., Erkoc, P., Alapan, Y., Sitti, M.

Advanced Materials, pages: 1804130, September 2018 (article)

Microalga‐Powered Microswimmers toward Active Cargo Delivery DOI Project Page [BibTex]

Yasa, O., Erkoc, P., Alapan, Y., Sitti, M. Microalga‐Powered Microswimmers toward Active Cargo Delivery Advanced Materials, pages: 1804130, September 2018 (article)

Microalga‐Powered Microswimmers toward Active Cargo Delivery DOI Project Page [BibTex]

Soft erythrocyte-based bacterial microswimmers for cargo delivery

Alapan, Y., Yasa, O., Schauer, O., Giltinan, J., Tabak, A. F., Sourjik, V., Sitti, M.

Science Robotics, 3(17):eaar4423, Science Robotics, April 2018 (article)

Abstract

Bacteria-propelled biohybrid microswimmers have recently shown to be able to actively transport and deliver cargos encapsulated into their synthetic constructs to specific regions locally. However, usage of synthetic materials as cargo carriers can result in inferior performance in load-carrying efficiency, biocompatibility, and biodegradability, impeding clinical translation of biohybrid microswimmers. Here, we report construction and external guidance of bacteria-driven microswimmers using red blood cells (RBCs; erythrocytes) as autologous cargo carriers for active and guided drug delivery. Multifunctional biohybrid microswimmers were fabricated by attachment of RBCs [loaded with anticancer doxorubicin drug molecules and superparamagnetic iron oxide nanoparticles (SPIONs)] to bioengineered motile bacteria, Escherichia coli MG1655, via biotin-avidin-biotin binding complex. Autonomous and on-board propulsion of biohybrid microswimmers was provided by bacteria, and their external magnetic guidance was enabled by SPIONs loaded into the RBCs. Furthermore, bacteria-driven RBC microswimmers displayed preserved deformability and attachment stability even after squeezing in microchannels smaller than their sizes, as in the case of bare RBCs. In addition, an on-demand light-activated hyperthermia termination switch was engineered for RBC microswimmers to control bacteria population after operations. RBCs, as biological and autologous cargo carriers in the biohybrid microswimmers, offer notable advantages in stability, deformability, biocompatibility, and biodegradability over synthetic cargo-carrier materials. The biohybrid microswimmer design presented here transforms RBCs from passive cargo carriers into active and guidable cargo carriers toward targeted drug and other cargo delivery applications in medicine.

link (url) DOI Project Page Project Page [BibTex]

Alapan, Y., Yasa, O., Schauer, O., Giltinan, J., Tabak, A. F., Sourjik, V., Sitti, M. Soft erythrocyte-based bacterial microswimmers for cargo delivery Science Robotics, 3(17):eaar4423, Science Robotics, April 2018 (article)

link (url) DOI Project Page Project Page [BibTex]

Thermocapillary-driven fluid flow within microchannels

Amador, G. J., Tabak, A. F., Ren, Z., Alapan, Y., Yasa, O., Sitti, M.

ArXiv e-prints, Febuary 2018 (article)

Abstract

Surface tension gradients induce Marangoni flow, which may be exploited for fluid transport. At the micrometer scale, these surface-driven flows can be more significant than those driven by pressure. By introducing fluid-fluid interfaces on the walls of microfluidic channels, we use surface tension gradients to drive bulk fluid flows. The gradients are specifically induced through thermal energy, exploiting the temperature dependence of a fluid-fluid interface to generate thermocapillary flow. In this report, we provide the design concept for a biocompatible, thermocapillary microchannel capable of being powered by solar irradiation. Using temperature gradients on the order of degrees Celsius per centimeter, we achieve fluid velocities on the order of millimeters per second. Following experimental observations, fluid dynamic models, and numerical simulation, we find that the fluid velocity is linearly proportional to the provided temperature gradient, enabling full control of the fluid flow within the microchannels.

link (url) Project Page [BibTex]

Amador, G. J., Tabak, A. F., Ren, Z., Alapan, Y., Yasa, O., Sitti, M. Thermocapillary-driven fluid flow within microchannels ArXiv e-prints, Febuary 2018 (article)

link (url) Project Page [BibTex]

Light‐Driven Janus Hollow Mesoporous TiO2–Au Microswimmers

Sridhar, V., Park, B., Sitti, M.

Advanced Functional Materials, 28(5):1704902, January 2018 (article)

Abstract

Abstract Light‐driven microswimmers have garnered attention for their potential use in various applications, such as environmental remediation, hydrogen evolution, and targeted drug delivery. Janus hollow mesoporous TiO2/Au (JHP–TiO2–Au) microswimmers with enhanced swimming speeds under low‐intensity ultraviolet (UV) light are presented. The swimmers show enhanced swimming speeds both in presence and absence of H2O2. The microswimmers move due to self‐electrophoresis when UV light is incident on them. There is a threefold increase in speed of JHP–TiO2–Au microswimmers in comparison with Janus solid TiO2/Au (JS–TiO2–Au) microswimmers. This increase in their speed is due to the increase in surface area of the porous swimmers and their hollow structure. These microswimmers are also made steerable by using a thin Co magnetic layer. They can be used in potential environmental applications for active photocatalytic degradation of methylene blue and targeted active drug delivery of an anticancer drug (doxurobicin) in vitro in H2O2 solution. Their increased speed from the presence of a hollow mesoporous structure is beneficial for future potential applications, such as hydrogen evolution, selective heterogeneous photocatalysis, and targeted cargo delivery.

link (url) DOI Project Page [BibTex]

Sridhar, V., Park, B., Sitti, M. Light‐Driven Janus Hollow Mesoporous TiO2–Au Microswimmers Advanced Functional Materials, 28(5):1704902, January 2018 (article)

link (url) DOI Project Page [BibTex]

2017

Planning spin-walking locomotion for automatic grasping of microobjects by an untethered magnetic microgripper

Dong, X., Sitti, M.

In 2017 IEEE International Conference on Robotics and Automation (ICRA), pages: 6612-6618, 2017 (inproceedings)

Abstract

Most demonstrated mobile microrobot tasks so far have been achieved via pick-and-placing and dynamic trapping with teleoperation or simple path following algorithms. In our previous work, an untethered magnetic microgripper has been developed which has advanced functions, such as gripping objects. Both teleoperated manipulation in 2D and 3D have been demonstrated. However, it is challenging to control the magnetic microgripper to carry out manipulation tasks, because the grasping of objects so far in the literature relies heavily on teleoperation, which takes several minutes with even a skilled human expert. Here, we propose a new spin-walking locomotion and an automated 2D grasping motion planner for the microgripper, which enables time-efficient automatic grasping of microobjects that has not been achieved yet for untethered microrobots. In its locomotion, the microgripper repeatedly rotates about two principal axes to regulate its pose and move precisely on a surface. The motion planner could plan different motion primitives for grasping and compensate the uncertainties in the motion by learning the uncertainties and planning accordingly. We experimentally demonstrated that, using the proposed method, the microgripper could align to the target pose with error less than 0.1 body length and grip the objects within 40 seconds. Our method could significantly improve the time efficiency of micro-scale manipulation and have potential applications in microassembly and biomedical engineering.

DOI Project Page [BibTex]

2017

Dong, X., Sitti, M. Planning spin-walking locomotion for automatic grasping of microobjects by an untethered magnetic microgripper In 2017 IEEE International Conference on Robotics and Automation (ICRA), pages: 6612-6618, 2017 (inproceedings)

DOI Project Page [BibTex]

Design and actuation of a magnetic millirobot under a constant unidirectional magnetic field

Erin, O., Giltinan, J., Tsai, L., Sitti, M.

In 2017 IEEE International Conference on Robotics and Automation (ICRA), Proceedings 2017 IEEE International Conference on Robotics and Automation (ICRA), pages: 3404-3410, IEEE, Piscataway, NJ, USA, IEEE International Conference on Robotics and Automation (ICRA), May 2017 (inproceedings)

Abstract

Magnetic untethered millirobots, which are actuated and controlled by remote magnetic fields, have been proposed for medical applications due to their ability to safely pass through tissues at long ranges. For example, magnetic resonance imaging (MRI) systems with a 3-7 T constant unidirectional magnetic field and 3D gradient coils have been used to actuate magnetic robots. Such magnetically constrained systems place limits on the degrees of freedom that can be actuated for untethered devices. This paper presents a design and actuation methodology for a magnetic millirobot that exhibits both position and orientation control in 2D under a magnetic field, dominated by a constant unidirectional magnetic field as found in MRI systems. Placing a spherical permanent magnet, which is free to rotate inside the millirobot and located away from the center of mass, allows the generation of net forces and torques with applied 3D magnetic field gradients. We model this system in a 3D planar case and experimentally demonstrate open-loop control of both position and orientation by the applied 2D field gradients. The actuation performance is characterized across the most important design variables, and we experimentally demonstrate that the proposed approach is feasible.

DOI [BibTex]

Erin, O., Giltinan, J., Tsai, L., Sitti, M. Design and actuation of a magnetic millirobot under a constant unidirectional magnetic field In 2017 IEEE International Conference on Robotics and Automation (ICRA), Proceedings 2017 IEEE International Conference on Robotics and Automation (ICRA), pages: 3404-3410, IEEE, Piscataway, NJ, USA, IEEE International Conference on Robotics and Automation (ICRA), May 2017 (inproceedings)

DOI [BibTex]

Multifunctional Bacteria-Driven Microswimmers for Targeted Active Drug Delivery

Park, B., Zhuang, J., Yasa, O., Sitti, M.

ACS Nano, 11(9):8910-8923, September 2017, PMID: 28873304 (article)

Abstract

High-performance, multifunctional bacteria-driven microswimmers are introduced using an optimized design and fabrication method for targeted drug delivery applications. These microswimmers are made of mostly single Escherichia coli bacterium attached to the surface of drug-loaded polyelectrolyte multilayer (PEM) microparticles with embedded magnetic nanoparticles. The PEM drug carriers are 1 μm in diameter and are intentionally fabricated with a more viscoelastic material than the particles previously studied in the literature. The resulting stochastic microswimmers are able to swim at mean speeds of up to 22.5 μm/s. They can be guided and targeted to specific cells, because they exhibit biased and directional motion under a chemoattractant gradient and a magnetic field, respectively. Moreover, we demonstrate the microswimmers delivering doxorubicin anticancer drug molecules, encapsulated in the polyelectrolyte multilayers, to 4T1 breast cancer cells under magnetic guidance in vitro. The results reveal the feasibility of using these active multifunctional bacteria-driven microswimmers to perform targeted drug delivery with significantly enhanced drug transfer, when compared with the passive PEM microparticles.

link (url) DOI Project Page [BibTex]

Park, B., Zhuang, J., Yasa, O., Sitti, M. Multifunctional Bacteria-Driven Microswimmers for Targeted Active Drug Delivery ACS Nano, 11(9):8910-8923, September 2017, PMID: 28873304 (article)

link (url) DOI Project Page [BibTex]

Microemulsion-Based Soft Bacteria-Driven Microswimmers for Active Cargo Delivery

Singh, A. V., Hosseinidoust, Z., Park, B., Yasa, O., Sitti, M.

ACS Nano, 0(0):null, 2017, PMID: 28858477 (article)

Abstract

Biohybrid cell-driven microsystems offer unparalleled possibilities for realization of soft microrobots at the micron scale. Here, we introduce a bacteria-driven microswimmer that combines the active locomotion and sensing capabilities of bacteria with the desirable encapsulation and viscoelastic properties of a soft double-micelle microemulsion for active transport and delivery of cargo (e.g., imaging agents, genes, and drugs) to living cells. Quasi-monodisperse double emulsions were synthesized with an aqueous core that encapsulated the fluorescence imaging agents, as a proof-of-concept cargo in this study, and an outer oil shell that was functionalized with streptavidin for specific and stable attachment of biotin-conjugated Escherichia coli. Motile bacteria effectively propelled the soft microswimmers across a Transwell membrane, actively delivering imaging agents (i.e., dyes) encapsulated inside of the micelles to a monolayer of cultured MCF7 breast cancer and J744A.1 macrophage cells, which enabled real-time, live-cell imaging of cell organelles, namely mitochondria, endoplasmic reticulum, and Golgi body. This in vitro model demonstrates the proof-of-concept feasibility of the proposed soft microswimmers and offers promise for potential biomedical applications in active and/or targeted transport and delivery of imaging agents, drugs, stem cells, siRNA, and therapeutic genes to live tissue in in vitro disease models (e.g., organ-on-a-chip devices) and stagnant or low-flow-velocity fluidic regions of the human body.

link (url) DOI Project Page [BibTex]

Singh, A. V., Hosseinidoust, Z., Park, B., Yasa, O., Sitti, M. Microemulsion-Based Soft Bacteria-Driven Microswimmers for Active Cargo Delivery ACS Nano, 0(0):null, 2017, PMID: 28858477 (article)

link (url) DOI Project Page [BibTex]

Magnetotactic Bacteria Powered Biohybrids Target E. coli Biofilms

Stanton, M. M., Park, B., Vilela, D., Bente, K., Faivre, D., Sitti, M., Sánchez, S.

ACS Nano, 0(0):null, September 2017, PMID: 28933815 (article)

Abstract

Biofilm colonies are typically resistant to general antibiotic treatment and require targeted methods for their removal. One of these methods includes the use of nanoparticles as carriers for antibiotic delivery, where they randomly circulate in fluid until they make contact with the infected areas. However, the required proximity of the particles to the biofilm results in only moderate efficacy. We demonstrate here that the nonpathogenic magnetotactic bacteria Magnetosopirrillum gryphiswalense (MSR-1) can be integrated with drug-loaded mesoporous silica microtubes to build controllable microswimmers (biohybrids) capable of antibiotic delivery to target an infectious biofilm. Applying external magnetic guidance capability and swimming power of the MSR-1 cells, the biohybrids are directed to and forcefully pushed into matured Escherichia coli (E. coli) biofilms. Release of the antibiotic, ciprofloxacin, is triggered by the acidic microenvironment of the biofilm, ensuring an efficient drug delivery system. The results reveal the capabilities of a nonpathogenic bacteria species to target and dismantle harmful biofilms, indicating biohybrid systems have great potential for antibiofilm applications.

link (url) DOI Project Page [BibTex]

Stanton, M. M., Park, B., Vilela, D., Bente, K., Faivre, D., Sitti, M., Sánchez, S. Magnetotactic Bacteria Powered Biohybrids Target E. coli Biofilms ACS Nano, 0(0):null, September 2017, PMID: 28933815 (article)

link (url) DOI Project Page [BibTex]

Dynamic and programmable self-assembly of micro-rafts at the air-water interface

Wang, W., Giltinan, J., Zakharchenko, S., Sitti, M.

Science Advances, 3(5):e1602522, American Association for the Advancement of Science, May 2017 (article)

Abstract

Dynamic self-assembled material systems constantly consume energy to maintain their spatiotemporal structures and functions. Programmable self-assembly translates information from individual parts to the collective whole. Combining dynamic and programmable self-assembly in a single platform opens up the possibilities to investigate both types of self-assembly simultaneously and to explore their synergy. This task is challenging because of the difficulty in finding suitable interactions that are both dissipative and programmable. We present a dynamic and programmable self-assembling material system consisting of spinning at the air-water interface circular magnetic micro-rafts of radius 50 μm and with cosinusoidal edge-height profiles. The cosinusoidal edge-height profiles not only create a net dissipative capillary repulsion that is sustained by continuous torque input but also enable directional assembly of micro-rafts. We uncover the layered arrangement of micro-rafts in the patterns formed by dynamic self-assembly and offer mechanistic insights through a physical model and geometric analysis. Furthermore, we demonstrate programmable self-assembly and show that a 4-fold rotational symmetry encoded in individual micro-rafts translates into 90° bending angles and square-based tiling in the assembled structures of micro-rafts. We anticipate that our dynamic and programmable material system will serve as a model system for studying nonequilibrium dynamics and statistical mechanics in the future

DOI [BibTex]

Wang, W., Giltinan, J., Zakharchenko, S., Sitti, M. Dynamic and programmable self-assembly of micro-rafts at the air-water interface Science Advances, 3(5):e1602522, American Association for the Advancement of Science, May 2017 (article)

DOI [BibTex]

Biohybrid microtube swimmers driven by single captured bacteria

Stanton, M. M., Park, B., Miguel-López, A., Ma, X., Sitti, M., Sánchez, S.

Small, 13(19), March 2017 (article)

Abstract

Bacteria biohybrids employ the motility and power of swimming bacteria to carry and maneuver microscale particles. They have the potential to perform microdrug and cargo delivery in vivo, but have been limited by poor design, reduced swimming capabilities, and impeded functionality. To address these challenge, motile Escherichia coli are captured inside electropolymerized microtubes, exhibiting the first report of a bacteria microswimmer that does not utilize a spherical particle chassis. Single bacterium becomes partially trapped within the tube and becomes a bioengine to push the microtube though biological media. Microtubes are modified with “smart” material properties for motion control, including a bacteria-attractant polydopamine inner layer, addition of magnetic components for external guidance, and a biochemical kill trigger to cease bacterium swimming on demand. Swimming dynamics of the bacteria biohybrid are quantified by comparing “length of protrusion” of bacteria from the microtubes with respect to changes in angular autocorrelation and swimmer mean squared displacement. The multifunctional microtubular swimmers present a new generation of biocompatible micromotors toward future microbiorobots and minimally invasive medical applications.

DOI Project Page [BibTex]

Stanton, M. M., Park, B., Miguel-López, A., Ma, X., Sitti, M., Sánchez, S. Biohybrid microtube swimmers driven by single captured bacteria Small, 13(19), March 2017 (article)

DOI Project Page [BibTex]

Propulsion and Chemotaxis in Bacteria-Driven Microswimmers

Zhuang, J., Park, B., Sitti, M.

Advanced Science, 4(9):1700109, May 2017 (article)

Abstract

Despite the large body of experimental work recently on biohybrid microsystems, few studies have focused on theoretical modeling of such systems, which is essential to understand their underlying functioning mechanisms and hence design them optimally for a given application task. Therefore, this study focuses on developing a mathematical model to describe the 3D motion and chemotaxis of a type of widely studied biohybrid microswimmer, where spherical microbeads are driven by multiple attached bacteria. The model is developed based on the biophysical observations of the experimental system and is validated by comparing the model simulation with experimental 3D swimming trajectories and other motility characteristics, including mean squared displacement, speed, diffusivity, and turn angle. The chemotaxis modeling results of the microswimmers also agree well with the experiments, where a collective chemotactic behavior among multiple bacteria is observed. The simulation result implies that such collective chemotaxis behavior is due to a synchronized signaling pathway across the bacteria attached to the same microswimmer. Furthermore, the dependencies of the motility and chemotaxis of the microswimmers on certain system parameters, such as the chemoattractant concentration gradient, swimmer body size, and number of attached bacteria, toward an optimized design of such biohybrid system are studied. The optimized microswimmers would be used in targeted cargo, e.g., drug, imaging agent, gene, and RNA, transport and delivery inside the stagnant or low-velocity fluids of the human body as one of their potential biomedical applications.

DOI Project Page [BibTex]

Zhuang, J., Park, B., Sitti, M. Propulsion and Chemotaxis in Bacteria-Driven Microswimmers Advanced Science, 4(9):1700109, May 2017 (article)

DOI Project Page [BibTex]

Mobile microrobots for bioengineering applications

Ceylan, H., Giltinan, J., Kozielski, K., Sitti, M.

Lab on a Chip, 17(10):1705-1724, Royal Society of Chemistry, 2017 (article)

Abstract

Untethered micron-scale mobile robots can navigate and non-invasively perform specific tasks inside unprecedented 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 environments 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, sensing, and other functional capabilities of mobile microrobots, and discuss their potential advantages and 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 biodegradability, immunogenicity, mobility, sensing, and possible medical interventions in complex microenvironments.

DOI [BibTex]

Ceylan, H., Giltinan, J., Kozielski, K., Sitti, M. Mobile microrobots for bioengineering applications Lab on a Chip, 17(10):1705-1724, Royal Society of Chemistry, 2017 (article)

DOI [BibTex]

Bioadhesive Bacterial Microswimmers for Targeted Drug Delivery in the Urinary and Gastrointestinal Tracts

Mostaghaci, B., Yasa, O., Zhuang, J., Sitti, M.

Advanced Science, 4(6):1700058, May 2017 (article)

Abstract

Bacteria-driven biohybrid microswimmers (bacteriabots), which integrate motile bacterial cells and functional synthetic cargo parts (e.g., microparticles encapsulating drug), are recently studied for targeted drug delivery. However, adhesion of such bacteriabots to the tissues on the site of a disease (which can increase the drug delivery efficiency) is not studied yet. Here, this paper proposes an approach to attach bacteriabots to certain types of epithelial cells (expressing mannose on the membrane), based on the affinity between lectin molecules on the tip of bacterial type I pili and mannose molecules on the epithelial cells. It is shown that the bacteria can anchor their cargo particles to mannose-functionalized surfaces and mannose-expressing cells (ATCC HTB-9) using the lectin–mannose bond. The attachment mechanism is confirmed by comparing the adhesion of bacteriabots fabricated from bacterial strains with or without type I pili to mannose-covered surfaces and cells. The proposed bioadhesive motile system can be further improved by expressing more specific adhesion moieties on the membrane of the bacteria.

DOI Project Page [BibTex]

Mostaghaci, B., Yasa, O., Zhuang, J., Sitti, M. Bioadhesive Bacterial Microswimmers for Targeted Drug Delivery in the Urinary and Gastrointestinal Tracts Advanced Science, 4(6):1700058, May 2017 (article)

DOI Project Page [BibTex]

3D Chemical Patterning of Micromaterials for Encoded Functionality

Ceylan, H., Yasa, I. C., Sitti, M.

Advanced Materials, 2017 (article)

Abstract

Programming local chemical properties of microscale soft materials with 3D complex shapes is indispensable for creating sophisticated functionalities, which has not yet been possible with existing methods. Precise spatiotemporal control of two-photon crosslinking is employed as an enabling tool for 3D patterning of microprinted structures for encoding versatile chemical moieties.

DOI Project Page [BibTex]

Ceylan, H., Yasa, I. C., Sitti, M. 3D Chemical Patterning of Micromaterials for Encoded Functionality Advanced Materials, 2017 (article)

DOI Project Page [BibTex]

2016

Bioengineered and biohybrid bacteria-based systems for drug delivery

Hosseinidoust, Z., Mostaghaci, B., Yasa, O., Park, B., Singh, A. V., Sitti, M.

Advanced Drug Delivery Reviews, 106, pages: 27-44, Elsevier, November 2016 (article)

Abstract

The use of bacterial cells as agents of medical therapy has a long history. Research that was ignited over a century ago with the accidental infection of cancer patients has matured into a platform technology that offers the promise of opening up new potential frontiers in medical treatment. Bacterial cells exhibit unique characteristics that make them well-suited as smart drug delivery agents. Our ability to genetically manipulate the molecular machinery of these cells enables the customization of their therapeutic action as well as its precise tuning and spatio-temporal control, allowing for the design of unique, complex therapeutic functions, unmatched by current drug delivery systems. Early results have been promising, but there are still many important challenges that must be addressed. We present a review of promises and challenges of employing bioengineered bacteria in drug delivery systems and introduce the biohybrid design concept as a new additional paradigm in bacteria-based drug delivery.

DOI Project Page [BibTex]

2016

Hosseinidoust, Z., Mostaghaci, B., Yasa, O., Park, B., Singh, A. V., Sitti, M. Bioengineered and biohybrid bacteria-based systems for drug delivery Advanced Drug Delivery Reviews, 106, pages: 27-44, Elsevier, November 2016 (article)

DOI Project Page [BibTex]

Shape-programmable magnetic soft matter

Lum, G. Z., Ye, Z., Dong, X., Marvi, H., Erin, O., Hu, W., Sitti, M.

Proceedings of the National Academy of Sciences, 113(41):E6007–E6015, National Acad Sciences, May 2016 (article)

Abstract

Shape-programmable matter is a class of active materials whose geometry can be controlled to potentially achieve mechanical functionalities beyond those of traditional machines. Among these materials, magnetically actuated matter is particularly promising for achieving complex time-varying shapes at small scale (overall dimensions smaller than 1 cm). However, previous work can only program these materials for limited applications, as they rely solely on human intuition to approximate the required magnetization profile and actuating magnetic fields for their materials. Here, we propose a universal programming methodology that can automatically generate the required magnetization profile and actuating fields for soft matter to achieve new time-varying shapes. The universality of the proposed method can therefore inspire a vast number of miniature soft devices that are critical in robotics, smart engineering surfaces and materials, and biomedical devices. Our proposed method includes theoretical formulations, computational strategies, and fabrication procedures for programming magnetic soft matter. The presented theory and computational method are universal for programming 2D or 3D time-varying shapes, whereas the fabrication technique is generic only for creating planar beams. Based on the proposed programming method, we created a jellyfish-like robot, a spermatozoid-like undulating swimmer, and an artificial cilium that could mimic the complex beating patterns of its biological counterpart.

DOI [BibTex]

Lum, G. Z., Ye, Z., Dong, X., Marvi, H., Erin, O., Hu, W., Sitti, M. Shape-programmable magnetic soft matter Proceedings of the National Academy of Sciences, 113(41):E6007–E6015, National Acad Sciences, May 2016 (article)

DOI [BibTex]

Bacteria-Driven Particles: Patterned and Specific Attachment of Bacteria on Biohybrid Bacteria-Driven Microswimmers (Adv. Healthcare Mater. 18/2016)

Singh, A. V., Sitti, M.

Advanced Healthcare Materials, 5(18):2306-2306, September 2016 (article)

Abstract

On page 2325, Ajay Vikram Singh and Metin Sitti propose a facile surface patterning technique and a specific, strong biotin–streptavidin bonding of bacteria on patterned surfaces to fabricate Janus particles that are propelled by the attached bacteria. Such bacteria-driven Janus microswimmers could be used for future medicine in targeted drug delivery and environmental remediation.

DOI Project Page [BibTex]

Singh, A. V., Sitti, M. Bacteria-Driven Particles: Patterned and Specific Attachment of Bacteria on Biohybrid Bacteria-Driven Microswimmers (Adv. Healthcare Mater. 18/2016) Advanced Healthcare Materials, 5(18):2306-2306, September 2016 (article)

DOI Project Page [BibTex]

Programmable assembly of heterogeneous microparts by an untethered mobile capillary microgripper

Giltinan, J., Diller, E., Sitti, M.

Lab on a Chip, 16(22):4445-4457, Royal Society of Chemistry, October 2016 (article)

Abstract

At the sub-millimeter scale, capillary forces enable robust and reversible adhesion between biological organisms and varied substrates. Current human-engineered mobile untethered micromanipulation systems rely on forces which scale poorly or utilize gripper-part designs that promote manipulation. Capillary forces, alternatively, are dependent upon the surface chemistry (which is scale independent) and contact perimeter, which conforms to the part surface. We report a mobile capillary microgripper that is able to pick and place parts of various materials and geometries, and is thus ideal for microassembly tasks that cannot be accomplished by large tethered manipulators. We achieve the programmable assembly of sub-millimeter parts in an enclosed three-dimensional aqueous environment by creating a capillary bridge between the targeted part and a synthetic, untethered, mobile body. The parts include both hydrophilic and hydrophobic components: hydrogel, kapton, human hair, and biological tissue. The 200 μm untethered system can be controlled with five-degrees-of-freedom and advances progress towards autonomous desktop manufacturing for tissue engineering, complex micromachines, microfluidic devices, and meta-materials.

DOI Project Page [BibTex]

Giltinan, J., Diller, E., Sitti, M. Programmable assembly of heterogeneous microparts by an untethered mobile capillary microgripper Lab on a Chip, 16(22):4445-4457, Royal Society of Chemistry, October 2016 (article)

DOI Project Page [BibTex]

Six-degree-of-freedom magnetic actuation for wireless microrobotics

Diller, E., Giltinan, J., Lum, G. Z., Ye, Z., Sitti, M.

The International Journal of Robotics Research, 35(1-3):114-128, SAGE Publications Sage UK: London, England, June 2016 (article)

Abstract

Existing remotely actuated magnetic microrobots exhibit a maximum of only five-degree-of-freedom (DOF) actuation, as creation of a driving torque about the microrobot magnetization axis is not achievable. This lack of full orientation control limits the effectiveness of existing microrobots for precision tasks of object manipulation and orientation for advanced medical, biological and micromanufacturing applications. This paper presents a magnetic actuation method that allows remotely powered microrobots to achieve full six-DOF actuation by considering the case of a non-uniform magnetization profile within the microrobot body. This non-uniform magnetization allows for additional rigid-body torques to be induced from magnetic forces via a moment arm. A general analytical model presents the working principle for continuous and discrete magnetization profiles, which is applied to permanent or non-permanent (soft) magnet bodies. Several discrete-magnetization designs are also presented which possess reduced coupling between magnetic forces and induced rigid-body torques. Design guidelines are introduced which can be followed to ensure that a magnetic microrobot design is capable of six-DOF actuation. A simple permanent-magnet prototype is fabricated and used to quantitatively demonstrate the accuracy of the analytical model in a constrained-DOF environment and qualitatively for free motion in a viscous liquid three-dimensional environment. Results show that desired forces and torques can be created with high precision and limited parasitic actuation, allowing for full six-DOF actuation using limited feedback control

DOI [BibTex]

Diller, E., Giltinan, J., Lum, G. Z., Ye, Z., Sitti, M. Six-degree-of-freedom magnetic actuation for wireless microrobotics The International Journal of Robotics Research, 35(1-3):114-128, SAGE Publications Sage UK: London, England, June 2016 (article)

DOI [BibTex]

Chemotaxis of bio-hybrid multiple bacteria-driven microswimmers

Zhuang, J., Sitti, M.

Scientific reports, 6, pages: 32135, Nature Publishing Group, March 2016 (article)

Abstract

In this study, in a bio-hybrid microswimmer system driven by multiple Serratia marcescens bacteria, we quantify the chemotactic drift of a large number of microswimmers towards L-serine and elucidate the associated collective chemotaxis behavior by statistical analysis of over a thousand swimming trajectories of the microswimmers. The results show that the microswimmers have a strong heading preference for moving up the L-serine gradient, while their speed does not change considerably when moving up and down the gradient; therefore, the heading bias constitutes the major factor that produces the chemotactic drift. The heading direction of a microswimmer is found to be significantly more persistent when it moves up the L-serine gradient than when it travels down the gradient; this effect causes the apparent heading preference of the microswimmers and is the crucial reason that enables the seemingly cooperative chemotaxis of multiple bacteria on a microswimmer. In addition, we find that their chemotactic drift velocity increases superquadratically with their mean swimming speed, suggesting that chemotaxis of bio-hybrid microsystems can be enhanced by designing and building faster microswimmers. Such bio-hybrid microswimmers with chemotactic steering capability may find future applications in targeted drug delivery, bioengineering, and lab-on-a-chip devices.

DOI Project Page [BibTex]

Zhuang, J., Sitti, M. Chemotaxis of bio-hybrid multiple bacteria-driven microswimmers Scientific reports, 6, pages: 32135, Nature Publishing Group, March 2016 (article)

DOI Project Page [BibTex]

2015

Millimeter-scale magnetic swimmers using elastomeric undulations

Zhang, J., Diller, E.

In 2015 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS), 2015 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS), pages: 1706-1711, September 2015 (inproceedings)

Abstract

This paper presents a new soft-bodied millimeterscale swimmer actuated by rotating uniform magnetic fields. The proposed swimmer moves through internal undulatory deformations, resulting from a magnetization profile programmed into its body. To understand the motion of the swimmer, a mathematical model is developed to describe the general relationship between the deflection of a flexible strip and its magnetization profile. As a special case, the situation of the swimmer on the water surface is analyzed and predictions made by the model are experimentally verified. Experimental results show the controllability of the proposed swimmer under a computer vision-based closed-loop controller. The swimmers have nominal dimensions of 1.5×4.9×0.06 mm and a top speed of 50 mm/s (10 body lengths per second). Waypoint following and multiagent control are demonstrated for swimmers constrained at the air-water interface and underwater swimming is also shown, suggesting the promising potential of this type of swimmer in biomedical and microfluidic applications.

link (url) DOI [BibTex]

2015

Zhang, J., Diller, E. Millimeter-scale magnetic swimmers using elastomeric undulations In 2015 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS), 2015 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS), pages: 1706-1711, September 2015 (inproceedings)

link (url) DOI [BibTex]

Untethered Magnetic Micromanipulation

Diller, E., Sitti, M.

In Micro-and Nanomanipulation Tools, 13, 10, Wiley-VCH Verlag GmbH & Co. KGaA, November 2015 (inbook)

Abstract

This chapter discusses the methods and state of the art in microscale manipulation in remote environments using untethered microrobotic devices. It focuses on manipulation at the size scale of tens to hundreds of microns, where small size leads to a dominance of microscale physical effects and challenges in fabrication and actuation. To motivate the challenges of operating at this size scale, the chapter includes coverage of the physical forces relevant to microrobot motion and manipulation below the millimeter-size scale. It then introduces the actuation methods commonly used in untethered manipulation schemes, with particular focus on magnetic actuation due to its wide use in the field. The chapter divides these manipulation techniques into two types: contact manipulation, which relies on direct pushing or grasping of objects for motion, and noncontact manipulation, which relies indirectly on induced fluid flow from the microrobot motion to move objects without any direct contact.

DOI Project Page [BibTex]

Diller, E., Sitti, M. Untethered Magnetic Micromanipulation In Micro-and Nanomanipulation Tools, 13, 10, Wiley-VCH Verlag GmbH & Co. KGaA, November 2015 (inbook)

DOI Project Page [BibTex]

Biomedical applications of untethered mobile milli/microrobots

Sitti, M., Ceylan, H., Hu, W., Giltinan, J., Turan, M., Yim, S., Diller, E.

Proceedings of the IEEE, 103(2):205-224, IEEE, March 2015 (article)

Abstract

Untethered robots miniaturized to the length scale of millimeter and below attract growing attention for the prospect of transforming many aspects of health care and bioengineering. As the robot size goes down to the order of a single cell, previously inaccessible body sites would become available for high-resolution in situ and in vivo manipulations. This unprecedented direct access would enable an extensive range of minimally invasive medical operations. Here, we provide a comprehensive review of the current advances in biomedical untethered mobile milli/microrobots. We put a special emphasis on the potential impacts of biomedical microrobots in the near future. Finally, we discuss the existing challenges and emerging concepts associated with designing such a miniaturized robot for operation inside a biological environment for biomedical applications.

DOI [BibTex]

Sitti, M., Ceylan, H., Hu, W., Giltinan, J., Turan, M., Yim, S., Diller, E. Biomedical applications of untethered mobile milli/microrobots Proceedings of the IEEE, 103(2):205-224, IEEE, March 2015 (article)

DOI [BibTex]

Three-dimensional heterogeneous assembly of coded microgels using an untethered mobile microgripper

Chung, S. E., Dong, X., Sitti, M.

Lab on a Chip, 15(7):1667-1676, Royal Society of Chemistry, January 2015 (article)

Abstract

Three-dimensional (3D) heterogeneous assembly of coded microgels in enclosed aquatic environments is demonstrated using a remotely actuated and controlled magnetic microgripper by a customized electromagnetic coil system. The microgripper uses different ‘stick–slip’ and ‘rolling’ locomotion in 2D and also levitation in 3D by magnetic gradient-based pulling force. This enables the microrobot to precisely manipulate each microgel by controlling its position and orientation in all x–y–z directions. Our microrobotic assembly method broke the barrier of limitation on the number of assembled microgel layers, because it enabled precise 3D levitation of the microgripper. We used the gripper to assemble microgels that had been coded with different colours and shapes onto prefabricated polymeric microposts. This eliminates the need for extra secondary cross-linking to fix the final construct. We demonstrated assembly of microgels on a single micropost up to ten layers. By increasing the number and changing the distribution of the posts, complex heterogeneous microsystems were possible to construct in 3D.

DOI Project Page [BibTex]

Chung, S. E., Dong, X., Sitti, M. Three-dimensional heterogeneous assembly of coded microgels using an untethered mobile microgripper Lab on a Chip, 15(7):1667-1676, Royal Society of Chemistry, January 2015 (article)

DOI Project Page [BibTex]

pH-taxis of biohybrid microsystems

Zhuang, J., Carlsen, R. W., Sitti, M.

Scientific reports, 5, Nature Publishing Group, June 2015 (article)

Abstract

The last decade has seen an increasing number of studies developing bacteria and other cell-integrated biohybrid microsystems. However, the highly stochastic motion of these microsystems severely limits their potential use. Here, we present a method that exploits the pH sensing of flagellated bacteria to realize robust drift control of multi-bacteria propelled microrobots. Under three specifically configured pH gradients, we demonstrate that the microrobots exhibit both unidirectional and bidirectional pH-tactic behaviors, which are also observed in free-swimming bacteria. From trajectory analysis, we find that the swimming direction and speed biases are two major factors that contribute to their tactic drift motion. The motion analysis of microrobots also sheds light on the propulsion dynamics of the flagellated bacteria as bioactuators. It is expected that similar driving mechanisms are shared among pH-taxis, chemotaxis, and thermotaxis. By identifying the mechanism that drives the tactic behavior of bacteria-propelled microsystems, this study opens up an avenue towards improving the control of biohybrid microsystems. Furthermore, assuming that it is possible to tune the preferred pH of bioactuators by genetic engineering, these biohybrid microsystems could potentially be applied to sense the pH gradient induced by cancerous cells in stagnant fluids inside human body and realize targeted drug delivery.

DOI Project Page [BibTex]

Zhuang, J., Carlsen, R. W., Sitti, M. pH-taxis of biohybrid microsystems Scientific reports, 5, Nature Publishing Group, June 2015 (article)

DOI Project Page [BibTex]

2014

Bio-Hybrid Cell-Based Actuators for Microsystems

Carlsen, Rika Wright, Sitti, Metin

Small, 10(19):3831-3851, 2014 (article)

Abstract

As we move towards the miniaturization of devices to perform tasks at the nano and microscale, it has become increasingly important to develop new methods for actuation, sensing, and control. Over the past decade, bio-hybrid methods have been investigated as a promising new approach to overcome the challenges of scaling down robotic and other functional devices. These methods integrate biological cells with artificial components and therefore, can take advantage of the intrinsic actuation and sensing functionalities of biological cells. Here, the recent advancements in bio-hybrid actuation are reviewed, and the challenges associated with the design, fabrication, and control of bio-hybrid microsystems are discussed. As a case study, focus is put on the development of bacteria-driven microswimmers, which has been investigated as a targeted drug delivery carrier. Finally, a future outlook for the development of these systems is provided. The continued integration of biological and artificial components is envisioned to enable the performance of tasks at a smaller and smaller scale in the future, leading to the parallel and distributed operation of functional systems at the microscale.

link (url) DOI Project Page [BibTex]