SCIENCE ROBOTICS | REVIEW BIOMATERIALS Copyright © 2017 The Authors, some rights reserved; Biohybrid actuators for robotics: A review of devices exclusive licensee American Association actuated by living cells for the Advancement Leonardo Ricotti,1* Barry Trimmer,2 Adam W. Feinberg,3 Ritu Raman,4 Kevin K. Parker,5 of Science. No claim 6 7 8 1 1 to original U.S. Rashid Bashir, Metin Sitti, Sylvain Martel, Paolo Dario, Arianna Menciassi Government Works Actuation is essential for artificial machines to interact with their surrounding environment and to accomplish the functions for which they are designed. Over the past few decades, there has been considerable progress in develop- ing new actuation technologies. However, controlled motion still represents a considerable bottleneck for many applications and hampers the development of advanced robots, especially at small length scales. Nature has solved this problem using molecular motors that, through living cells, are assembled into multiscale ensembles with integrated control systems. These systems can scale force production from piconewtons up to kilonewtons. By leveraging the performance of living cells and tissues and directly interfacing them with artificial components, Downloaded from it should be possible to exploit the intricacy and metabolic efficiency of biological actuation within artificial ma- chines. We provide a survey of important advances in this biohybrid actuation paradigm. INTRODUCTION teristics of muscles are difficult to replicate using current synthetic To efficiently tackle the challenges of today’s world, robotics is cur- actuators. Further, muscles control their stiffness by recruiting a vari- http://robotics.sciencemag.org/ rently undergoing a deep revolution in both its design principles and able number of myofibers; they are highly scalable (ranging in mass constitutive elements. New robotic paradigms are rapidly emerging from a few micrograms in small insects to several hundred kilograms at different scales. At the macroscale, soft robots are expected to lead in whales), self-healing, and eco-compatible. to the development of squeezing, stretching, climbing, growing, and Although variable stiffness actuators can be produced in electric morphing machines (1) that are intrinsically safe and can act as co- motors using combinations of impedance control, inherent compliance, operative systems in many applications (2). At the microscale, the and damping or inertial systems (5), many other key properties of nat- development of new fabrication techniques and the miniaturization ural muscles cannot be matched (6). For example, although piezo- of electronic controllers and sensors have opened the design space to electric motors can be miniaturized (7), they have a very limited stroke, make controllable robots as small as insects or even submillimeter and they need (as do all artificial motors) to be powered by batteries, devices (3). which cannot be efficiently scaled down in size at present. Most other by guest on December 12, 2017 In each of these research areas, actuation is a critical aspect. Tra- traditional actuators cannot be scaled down to the microscale without ditional and recently developed actuation technologies not only offer losing force production and controllability. Molecular motors based a wide range of opportunities but also have clear limitations. For ex- on DNA, proteins, or synthetic molecules are a fascinating option (8), ample, electromagnetic motors are used in a large set of machines, but but their success has been limited, because they are characterized by they are heavy, do not guarantee a high energy density, and make it very poor forces/torques and are challenging for system integration, difficult to design large contractile strokes with a small footprint (4). easy control, and upscaling. Other technologies have different drawbacks; for example, pneumatic This means that current machines (even soft and collaborative ones) and hydraulic actuators require a cumbersome activation system, whereas are not able to replicate many lifelike movements typical of animals (6) some electroactive polymers (EAPs) require very high driving voltages. and highlights the need for high-performance, flexible actuators able to Animal motion is driven by coordinated movements of molecular recapitulate or even outperform natural muscle functions. One potential motors only a few nanometers in size, which are hierarchically organized solution to achieve efficient actuation of minidevices (larger than 1 mm) to produce macroscopic contractile muscle tissues. The combination and microdevices (below 1 mm) is to exploit biological systems to con- of (i) individual muscle cells with intrinsic molecular machinery to struct biohybrid robots. regulate contraction and (ii) neural innervation of these muscle cells Biohybrid robotics represents an exciting paradigm based on the in three dimensions (3D) provides a scalable control scheme for mod- integration of properly engineered artificial structures and living bio- ulation of force and deformation. Most of the performance charac- systems. This approach exploits the unique characteristics of bio- logical cells and tissues, which have been refined over millions of years of natural evolution. Actuation is a key function and constitutes the 1The BioRobotics Institute, Scuola Superiore Sant’Anna, Pontedera, Pisa, Italy. 2De- partment of Biology, Tufts University, Medford, MA 02153, USA. 3Department of Biomedical main motivation for the development of biohybrid robots (9). Bio- Engineering and Department of Materials Science and Engineering, Carnegie Mellon hybrid actuators have the potential to provide artificial devices with 4 University, Pittsburgh, PA 15213, USA. Koch Institute for Integrative Cancer Research, unprecedented performances at the macroscale and to enable the de- Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 5Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School velopment of self-powered microrobots. The growing interest in this of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA. research field is demonstrated by the bibliometric analysis in Fig. 1. 6Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 7 8 Figure 1A demonstrates that, until 2011, the field of biohybrid 61801, USA. Max-Planck Institute for Intelligent Systems, Stuttgart, Germany. Nano- actuation was mainly characterized by exploratory conference papers Robotics Laboratory, Department of Computer and Software Engineering, Institute of Biomedical Engineering, Polytechnique Montréal, Montréal, Quebec, Canada. rather than journal publications. Starting from 2012, the pool of jour- *Corresponding author. Email: [email protected] nal papers published on this topic has been growing exponentially. Ricotti et al., Sci. Robot. 2, eaaq0495 (2017) 29 November 2017 1 of 17 SCIENCE ROBOTICS | REVIEW Fig. 1. Bibliometric analysis of the biohybrid actuation field and few competing ones. (A) Papers published from 2006 to 2016 on biohybrid actuators divided in conference papers, journal papers with I.F. <4, journal papers with I.F. between 4 and 10, and journal papers with I.F. >10. The analysis was conducted on the Scopus database by using the following keywords in the title and abstract: “bio-hybrid actuator,” “biohybrid actuator,” “cell-based actuator,” “bioactuation,” “bacteria robot,” “muscle cell actuator,” “muscle-based actuator,” “biohybrid robot,” “bio-hybrid robot,” “biohybrid system,” “bio-hybrid system,” “biohybrid device,” and “bio-hybrid device” (from this list, only the papers closely dealing with bioactuation were then selected manually). (B) Journal papers published from 2006 to 2016 on smart materials–based and pneumatic Downloaded from actuators. The analysis was conducted on the Scopus database by using three different keywords (in title and abstract) for the three categories analyzed: “pneumatic actuator,” “shape memory alloy actuator,” and “electroactive polymer actuator.” (C) Percentage of journal papers with I.F. >4 with respect to the overall number of journal papers published in 2016 on biohybrid actuators, EAP, SMA, and pneumatic actuators. Although the momentum generated by this research field is still rela- biological system that is not scalable in dimensions. The highly spe- http://robotics.sciencemag.org/ tively small, it is rapidly building up with a series of high-impact re- cialized nature of such biological elements makes this kind of biohybrid sults. Comparing the trend of journal papers published on biohybrid actuators suitable for specific applications, rather than general-purpose actuation (Fig. 1A) with those featuring pneumatic actuators, shape tasks. The second category deals with biological components (i.e., cells) memory alloy (SMA) actuators, and EAP actuators (Fig. 1B), it is clear that can be engineered and assembled according to the desired system that biohybrid actuation is growing more quickly. Actuators based on shape and function by pursuing a bottom-up approach. Thus, they can pneumatic and smart materials–based principles derive from more be considered general-purpose systems that can be scaled up or down consolidated technologies and are thus featured in a larger number of in a variety of dimensions. applications (explaining the larger number of papers published), but they have less potential to generate new basic knowledge. This is con- firmed in Fig.