Macrophage grabbing a bacterium (left, pink) and our artificial prey (right, green). Credit: Simone Schurle

Robotics, by definition, has been a discipline to aid other fields, such as manufacturing and space exploration. Over the past decade, it has become increasingly important in life sciences; a field that has been transformed by the convergence of insights and approaches from distinct scientific and technological disciplines. Robotics can help automate numerous processes — including repetitive tasks used in drug discovery, in vitro fertilization — and in lab bench work, such as analytical testing and preparation of chemical agents.

In our recent paper in Science Robotics, we show how robotics in the life sciences can also enable scientists to study and interrogate biological processes at the microscale in a dynamic and adaptive manner.

I was a PhD student in microrobotics in the Multi-scale Robotics lab at ETH, led by Prof. Brad Nelson, when we started our collaboration at the laboratory for Applied Mechanobiology at ETH Zurich, led by Pro. Viola Vogel. I became fascinated by the range of new problems to tackle in biology, such as integrating feed-back loops for cells and tracking of their shape and motion, problems I had never thought of before exchanging ideas with the Vogel group.

Similarly, Ima Avalos, co-lead author of the paper says: “When I started my PhD studies in mechanobiology, I was totally focused on bacterial adhesion and would not have anticipated that I would end up contributing to a robotics paper at all!”. Well, she did, substantially, and we teamed up to study cellular responses of immune cells when they attack foreign invaders, such as bacteria. When these phagocytes hunt for their microbial prey, they first need to recognize the prey and then form physical contacts sufficiently stable for pickup. Although the forces involved in this pickup process have been studied, little is known about their hunting behavior preceding phagocytosis because of a lack of appropriate technologies. Understanding the cues and processes that determine when phagocytes take up their prey is crucial for advances in immunology and has direct implications in pharmacology. This, in turn, demands an adaptive system that can introduce such cues and is capable of dexterous control at the microscale.

Magnetic tweezer system for 5 degrees of freedom control (5D-MTS). The system is composed of 8 electromagnets and arbitrarily shaped magnetic objects can be controlled in 3D with 3 translational DOFs and 2 rotational DOFs (top image taken for Klaus Tschira award 2015 Klaus Tschira Stiftung).

Responding to this need, we developed a platform where we coupled a magnetic tweezer system with 3 D control consisting of eight electromagnetic coils to a scanning confocal microscope that allows for life cell recording and fluorescent readout. While with this system we can apply magnetic forces in 3D, we needed as well suitable probes that could serve as microbial prey and be guided by these forces and. We chose spherical, magnetic particles, that are commercially available, and we coated them with the same antibodies that are also presented on the membrane of bacteria. But bacteria are not round in shape, they are rather cylindrical- and as we know from previous studies in this phagocytosis, shape plays a role!

We wanted to study the effect and teamed up with material experts in the Multi-scale Robotics lab. With them, we fabricated bacteria-mimicking microparticles using 2-photon polymerization, a 3D printing technology with nanoscale resolution, to form molds followed by template-assisted electrodeposition to form magnetic cores. Combining these new probes with the control system, unconstrained 3D control of the position and orientation of these artificial prey particles was provided, such as real bacteria would position themselves. Analogous to free floating bacteria and adhering biofilms, we implemented non-resistive and resistive prey modes. Therefore, the translational and rotational trapping stiffness of this artificial prey was dynamically adjusted and, using vision-based feedback control, forces and torques in the sub to low [pN] range and 105 -106 [pN nm rad-1] range, respectively, were applied in real-time.

The energy landscape that guided the translational and rotational movement of these microparticles was dynamically adjusted to explore how translational and rotational resistive forces regulate the modes of macrophage attacks. For translational resistive prey, distinct push-pull attacks were observed. For rod-shaped, nonresistive prey, which mimic free-floating pathogens, cells co-aligned their prey with their long axis to facilitate pickup. Increasing the rotational trap stiffness to mimic resistive or surface-bound prey disrupts this realignment process. At stiffness levels on the order of 105 piconewton nanometer radian−1, macrophages failed to realign their prey, inhibiting uptake.

The moment we had the system finally implemented in the microscope of the biology lab and could control our microscopic probes to interact with cells, a strong bridge was built between our disciplines and labs, and we felt we had developed a platform with which we can tackle a number of biological questions. While we have shown that this technique allows new studies of force-driven phagocytosis modes with large relevance for host defense, the system can also be used for a variety of other mechanobiology studies at length scales ranging from single cells to organ-on-a-chip devices. It can also be combined with microfluidic platforms and allows for magnetic manipulation in vivo, such as in zebrafish or mouse models, work that I have started during my postdoctoral training at the Koch Institute for Integrative Cancer Research at MIT and that I am excited to further expand soon with my own group. A version of this control system is now also commercially available from Magnebotix.com

For more information, please read our research paper:

“Robotically controlled microprey to resolve initial attack modes preceding phagocytosis” Science Robotics. https://doi.org/10.1126/scirobotics.aah6094

Unlike larger robots, microrobots for applications in the body are too small to carry batteries and motors. To address this challenge, we power and control robots made of magnetic materials using external magnetic fields. Developed at ETH Zurich’s  Multi-Scale Robotics Lab (MSRL), the OctoMag is a magnetic manipulation system that uses electromagnetic coils to wirelessly guide microrobots for ophthalmic surgery. 

The OctoMag is capable of generating magnetic forces and torques in three dimensions, and is physically restricted to a single hemisphere to allow easy access for patients and physicians. Using an early OctoMag prototype, ex-vivo experiments were performed in pig eyes to study the navigation tasks required for retinal surgery. Following these experiments, a next-generation system was built to accomodate a small animal head, allowing for in-vivo trials. With this system, mobility experiments were conducted in which a microrobot with a diameter of 285 µm (about four times the width of a hair) was navigated reliably through the eye of a rabbit, demonstrating the feasibility of using this technology in surgical applications.

Robots are capable of exploring many environments that are difficult, if not impossible, for humans to reach; the edges of the solar system, the planet Mars, the inner depths of volcanoes, and bottom of the ocean are just some examples. The goal of these robotic explorers is to obtain knowledge about our universe and to answer fundamental questions about the nature of life on Earth. Recently, micro- and nanotechnologies have fueled an exciting expansion of this field by allowing scientists to use robots to probe life at much smaller scales. Nanorobotic systems for exploring the structures of biological cells, and robotic motion planning strategies for the investigation of protein folding, are two compelling examples of the intermarriage between robotics and nanotechnology. Such efforts and others like them illustrate how several areas of science and engineering are rapidly converging to create a new, interdisciplinary approach to research that promises to revolutionize our understanding of the world around us.

While many envision a future in which intelligent nanorobots navigate throughout our bodies searching for and destroying disease, researchers are still far from realizing such advanced technologies.  However, progress is being made, and the past decade has seen impressive advances in the fabrication, control, and delivery of power to tiny motile devices.

The MiniMag is a research tool for studies at the micro scale. As a scaled-down version of the OctoMag, the MiniMag can be integrated into an upright or inverted microscope. The eight electromagnetic coils are slightly tilted and can be positioned very close to each other due to their smaller size, and, by reducing the magnetic workspace to one cubic centimetre, much higher forces can now be achieved. Combined with high-resolution optics, the MiniMag system allows for single cell manipulation and studies at the tissue level in 3D.

From the microscale to the nanoscale
As size decreases to the nanoscale, wireless magnetic manipulation becomes increasingly challenging. The magnetic force drops by a power of three as it scales with volume, and fluidic drag forces begin to dominate as inertial forces become negligible. While a number of robotic swimming methods have been proposed to aid mobility at relatively small scales, many of these methods rely on reciprocating motions and do not scale downwards.

More than three billion years ago, bacteria evolved a swimming strategy at micrometer dimensions that nature has had difficulty improving upon, and in 1973, H.C. Berg and R.A. Anderson first described a swimming technique that uses rotating helical flagella. Inspired by this work and the flagellar motion of bacteria such as Escherichia Coli, we have recently developed artificial bacterial flagella (ABF). Our ABF represents the first demonstration of wireless swimming microrobots similar in size and geometry to natural bacterial flagella, and are many orders of magnitude smaller than existing artificial helical swimmers. With the help of 3D-laser-nanolithography, arrays of thousands of such swimmers can now be fabricated. A careful choice of materials allows for cellular interaction, and fluorescent labeling of the device assists with localization and tracking. We are pursuing applications such as the treatment of breast cancer and cerebral infarctions.

The potential impact of this technology on society is high, particularly for biomedical applications, though many challenges remain in developing micro and nanorobots that will be useful to society. An overarching requirement for achieving breakthroughs in this area is the need to bring together expertise from a wide variety of science and engineering disciplines.  Robotics brings expertise in the planning and control of mechanisms with many degrees of freedom in uncertain environments. Nanotechnology teaches innovative approaches to fabricating nanoscale machines. In addition, biomedical imaging advances are needed, as is fundamental insight into the nature of fluid dynamics at very small scales.  Medical professionals must be tightly integrated into the development cycle, and experts in developing business models and intellectual property must be closely consulted.

About the researchers
Brad Nelson’s Multi-Scale Robotics Lab (MSRL) at the Institute of Robotics and Intelligent Systems, ETH Zurich, Switzerland, is a highly multi-disciplinary research group that leverages advanced robotics techniques to create intelligent machines that operate at micro- and nanometer scales.  At the MSRL, a team of nearly 30 scientists pursues a dynamic, robotics-oriented research program involving several emerging areas of science and technology.  The technical backgrounds of the scientists in the lab span such diverse fields as materials science, physics, biology, electrical and mechanical engineering, and computer science.

The materials scientists in the lab focus mainly on developing the tools and processes required to fabricate and assemble microscale robots and nanoscale robotic components.  Many of these systems are then used in the study of biological environments, including the investigation of molecular structures, cellular systems, and organism behavior.  Other members of the MSRL research team are focused on the design and implementation of systems that wirelessly control these microrobots.  Potential applications are numerous and diverse, including microrobotically-assisted surgery, magnetic micromanipulation at the cellular level, low Reynolds number locomotion, wireless power delivery, electrostimulation of biological materials, and micro- and nanostructure fabrication and characterization.

The MSRL develops systems for controlling micro- and nanorobots in liquid and pursues various applications for these devices.

[Edited by Hallie Siegel]

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