IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013 667 Grand Challenges in Bioengineered Nanorobotics for Cancer Therapy Scott C. Lenaghan, Yongzhong Wang, Ning Xi, Toshio Fukuda, Tzyhjong Tarn, William R. Hamel, and Mingjun Zhang∗ Abstract—One of the grand challenges currently facing engi- gence in the design of bioinspired macrorobots [5], less progress neering, life sciences, and medicine is the development of fully has been made on transferring principles learned from microor- functional nanorobots capable of sensing, decision making, and ac- ganisms into nanorobotics. tuation. These nanorobots may aid in cancer therapy, site-specific drug delivery, circulating diagnostics, advanced surgery, and tissue Many of the challenges associated with the development of repair.In this paper, we will discuss, from a bioinspired perspective, nanorobots focus on the fabrication of small robots using tra- the challenges currently facing nanorobotics, including core design, ditional engineering approaches. Similarly, typical approaches propulsion and power generation, sensing, actuation, control, de- to power and control nanorobots suffer from a lack of minia- cision making, and system integration. Using strategies inspired turized electronics. In this study, we have turned our attention from microorganisms, we will discuss a potential bioengineered nanorobot for cancer therapy. to inspiration from micro/nanoscale biological systems. Hav- ing the advantage of evolution as a guiding force for design, Index Terms—Bioengineered robots, cancer therapy, biological systems have effectively developed robust strategies medical robotics, micro/nano-robotics, nanobiotechnology, nanoparticles. to overcome design limitations that currently plague tradition- ally engineered micro/nanorobots. As such, it is essential that I. INTRODUCTION an interdisciplinary bioinspired approach be used to design and ANOROBOTS have been envisioned since 1981 when fabricate future nanorobots. N Drexler penned the first journal article related to nan- Considering the near-endless applications of nanorobots in otechnology [1]. But as detailed in the debates with Nobel medicine, the design of nanorobots represents a grand challenge laureate, Richard Smalley, there have been significant gaps be- to both engineering and life sciences. Due to their small size, tween science and engineering in relation to the development nanorobots can directly interact with cells, and even penetrate and advancement of nanorobotics [2]–[4]. These gaps have led into them, providing direct access to the cellular machinery. to a decrease in the rate of progress of advanced nanorobot This intimate access may even allow nanorobots to manipulate development for biomedical applications. At the most funda- host cells, a strategy employed by viruses, but essential for mental level, biological systems function as extremely efficient nanorobotics. For the purposes of this discussion, and to put nanomanufacturing platforms. Using nanoscale building blocks, the nanorobot into a biomedical context, we will describe a biological systems are able to produce complex “machinery” nanorobot with the goal of site-specific cancer therapy. capable of actuation, propulsion, sensing, computation, and de- In cancer therapy, the basic requirements for a nanorobot are cision making. Although engineering has recently seen a resur- 1) the ability to carry a payload, essentially a drug, 2) active movement to a specific site in the body, 3) attachment to cancer- ous cells, and 4) release of the payload locally upon recognition of the binding event. This type of “targeted” therapy has cur- Manuscript received December 15, 2012; revised January 25, 2013 and rently eluded investigators, whose present goal is to develop January 27, 2013; accepted January 27, 2013. Date of publication February 1, 2013; date of current version March 7, 2013. This work was supported in “dumb” nanocarriers, which may attach to cancerous cells by part by the Office of Naval Research Young Investigator Program under Award chance. ONR-N00014-11-1-0622. Asterisk indicates corresponding author. S. C. Lenaghan, Y. Wang, and W. R. Hamel are with the Department of Me- II. KEY COMPONENTS OF NANOROBOTS chanical, Aerospace, and Biomedical Engineering, The University of Tennessee, Knoxville, TN 37996 USA (e-mail: [email protected]; [email protected]; At present, no clear strategy exists in the design of practical [email protected]). nanorobots. In this study, we will discuss the challenges inherent N. Xi is with the Department of Electrical and Computer Engineering, Michi- gan State University, East Lansing, MI 48824 USA and also with the Department in the design of a fully functional nanorobot, including core of Mechanical and Biomedical Engineering, The City University of Hong Kong, design (see Section II-A), propulsion (see Section II-B), power Tat Chee Avenue, Kowloon, Hong Kong, PRC (e-mail: [email protected]). (see Section II-C), sensing and actuation (see Section II-D), T. Fukuda is with the Department of Micro-Nano Systems Engineering, Nagoya University, Nagoya 464-8601, Japan (e-mail: [email protected]. control, and decision making (see Section II-E), and integration ac.jp). (see Section II-F). Each of these challenges will be discussed T. J. Tarn is with the Department of Electrical and Systems Engineering, using a proposed nanorobot design for cancer therapy, as shown Washington University, St. Louis, MO 63130 USA and also with the Center for Quantum Information Science and Technology, Tsinghua University, Beijing, in Fig. 1. PRC (e-mail: [email protected]). ∗M. Zhang is with the Department of Mechanical, Aerospace, and Biomedical A. Design of Nanorobot Core Engineering, The University of Tennessee, Knoxville, TN 37996 USA (e-mail: [email protected]). A variety of templates exist in nature that are ideally suited Digital Object Identifier 10.1109/TBME.2013.2244599 for use as a nanorobot core, capable of carrying a payload, 0018-9294/$31.00 © 2013 IEEE 668 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013 multiple copies of a single protein, as has been observed with the small heat shock proteins (smHSP) [8]. In this instance, the smHSPs are capable of self-assembling into 12–20 nm particles, and further can be used to synthesize both inorganic and or- ganic nanomaterials. Recent studies of secreted plant adhesives have further revealed that protein- and polysaccharide-based nanoparticles are commonly used in these systems [9], [10]. Using the inspiration provided from biological systems in the fabrication of nanoparticles, various engineered nanoparticles have been developed. Using biomolecular engineering, a wide variety of protein- based nanoparticles have been fabricated for drug delivery. One example of an engineered viral nanoparticle is the EF-cow pea mosaic virus (CPMV), which has cysteine residues expressed on the capsid surface for the attachment of colloidal gold nanopar- Fig. 1. Schematic of the envisioned nanorobot. The core of the robot is a ticles, or dye molecules [11]. Similarly, engineered adenovirus polysaccharide-based nanoparticle, where modular components can be attached nanoparticles with gold nanoparticles complexed on the sur- using known chemistry. The propulsive system is a fully functional flagella isolated from E. coli, attached to the core by means of the FLiN protein on the face have been created and used to induce hyperthermia for flagella and anti-FLiN receptors on the core. To power the propulsive system, tumor therapy [12]. In fact, many ligands, including folic acid ATP will be encapsulated into the nanoparticle core. and transferrin, have been conjugated to viral nanoparticles for specific tumor targeting in vivo [13]. Engineered phage nanopar- and modular enough to allow the incorporation of propulsive, ticles have also been used to deliver therapeutic agents to spe- sensing, and actuating components. In this study, we will con- cific tumor sites, preventing the severe toxicity associated with sider mainly a nanoparticle-based core. untargeted therapy [14]. Proof-of-concept studies using phage Nanoparticle drug delivery systems have several clinical ad- have also proven the ability of encoded DNA to fabricate a vantages that make them attractive candidates for the develop- nonpropulsive phage-like nanorobot [15]. As an alternative to ment of a nanorobot core. First, nanoparticle drug delivery sys- these engineered viral nanoparticles, bioinspiration from the tems have clinically been shown to prevent rapid renal clearance structure of protein cage nanoparticles has led to the use of and prolong the plasma half-life of complexed or encapsulated self-assembling peptides to form nanoparticles and nanotubes. drugs [6]. Second, nanoparticles are often more easily endocy- In this case, synthetic peptides have been created and modified tosed, which leaves less free drug available to “normal” cells, to self-assemble into nanoparticles. Specifically related to our reducing harmful side-effects [6]. Third, the high surface to vol- goal of cancer therapy, self-assembled peptide nanostructures ume ratio of nanoparticles allows for increased drug loading have been used for tumor therapy, often through conjugation compared to micron-sized particles [6]. Finally, nanoparticles with therapeutic agents. In some instances, the peptides them- have demonstrated the ability to passively penetrate into tumor selves are bioactive, resulting in cytotoxicity to the tumor cells, tissues [6]. Despite these advantages,