Robotics for Cell Surgery
Robotic surgery and robotically-assisted surgery are terms for technological developments that use robotic systems to aid in surgical procedures. Robotically-assisted surgery was developed to overcome the limitations of pre-existing minimally-invasive surgical procedures and to enhance the capabilities of surgeons performing open surgery. More recently, robotic-assisted surgery has emerged as an alternative minimally invasive surgical option. Robotic-assisted technology allows for 3-dimensional visualization, enhanced range of motion of the instrumentation, and improved surgeon ergonomics. Robotically assisted surgery first gained prominence for performance of radical prostatectomy, a procedure in which laparoscopic surgery was rarely performed . Since the use of the surgical robot for prostatectomy, the technology has been studied and promoted for a variety of other procedures [2-4]. A number of robotically assisted procedures have gained widespread acceptance in clinical practice despite a relative lack of data. Currently, healthcare organizations use robot technology for thoracic, abdominal, pelvic, and neurological surgical procedures. Minimally invasive surgery reduces the amount of inpatient hospital days, and the computer in the system filters any hand tremors a physician may have during the surgery. The use of robot-assisted surgery improves quality of care because the patient experiences less pain after the surgery [5, 6].
Despite widespread adoption of robotic systems for minimally invasive surgery, there are still major technical difficulties and challenges. In particular, the mechanical parts of existing medical robotic devices are still relatively large and rigid to access and treat major previously inaccessible parts of the human body. Designing miniaturized and versatile robots of a few micrometers or less would allow access throughout the whole human body, leading to new procedures down to the cellular level and offering localized diagnosis and treatment with greater precision and efficiency. Advancing the miniaturization of robotic systems at the micro- and nanoscales thus holds considerable promise for enhancing the treatment of a wide variety of diseases and disorders. The development of micro/nanoscale robots for biomedical applications has been supported by recent advances in nanotechnology and materials science and has been driven largely by the demands from the biomedical community.
Micro/NanoRobots for Cell Surgery
Recent advances in micro/nanorobots have shown considerable promise for addressing these limitations and for using these tiny devices for precision surgery. Untethered micro/nanorobotic tools, ranging from nanodrillers to microgrippers and microbullets (Fig. 1), offer unique capabilities for minimally invasive surgery. With dimensions compatible with those of the small biological entities that they need to treat, micro/nanorobots offer major advantages for high-precision, minimally invasive surgery. Powered by diverse energy sources, the moving micro/nanorobots with nanoscale surgical components are able to directly penetrate or retrieve cellular tissues for precision surgery. Unlike their large robotic counterparts, these tiny robots can navigate through the body’s narrowest capillaries and perform procedures down to the cellular level .
Tetherless microgrippers represent an important step toward the construction of autonomous robotic tools for microsurgery . These mobile microgrippers can capture and retrieve tissues and cells from hard-to-reach places. Conventional microgrippers are usually tethered and actuated by mechanical or electrical signals, generated from control systems, via external connections (e.g., wires and tubes) that restrict their miniaturization and maneuverability. Similar to their large tethered counterparts, the gripping operation of untethered microgrippers commonly involves an opening/closing of the device. These microgrippers can be mass-produced using conventional multilayer photolithography with shapes modeled after biological appendages, in which the jointed digits are arranged in different ways around a central palm. By relying on a built-in self-folding actuation response (triggered by their surrounding biological environment), such soft microgrippers obviate the need for external tethers. Different responsive mechanisms, based on temperature, pH, or enzyme stimuli, have been explored for actuating self-folding microgrippers autonomously in specific environments . For example, Fig. 1A illustrates the ability of a tetherless thermobiochemically actuated microgripper to capture a cluster of live fibroblast cells from a dense cell mass in a capillary tube. The microgripper could subsequently move out of the capillary tube with the captured cells in its grasp, demonstrating its strength for performing an in vitro tissue biopsy.
Magnetically actuated microrobots have also shown considerable promise for minimally invasive in vivo surgical operations because magnetic fields are capable of penetrating thick biological tissues. Chatzipirpiridis et al.  demonstrated that an implantable magnetic tubular microrobot was able to perform such surgery at the posterior segment of the eye (Fig. 1B). The electrochemically prepared microrobot was injected with a 23-gauge needle into the central vitreous humor of the eye and monitored with an ophthalmoscope and integrated camera. Wireless control was used to rotate the intraocular magnetic microrobot around three axes in the vitreous humor of a living rabbit eye. Similar magnetic microtubes can be developed and applied as implantable devices for targeting other diseases in different confined spaces of the human body.
Ultrasound actuation has recently been used to create powerful microrobots with remarkable tissue penetration properties. Kagan et al.  demonstrated an ultrasound-triggered, high-velocity, “bullet-like” propulsion, enabled by the fast vaporization of biocompatible fuel (i.e., perfluorocarbon). Such conically shaped tubular microbullets, containing the fuel source, display an ultrafast movement with speeds of over 6 m/s (corresponding to 160,000 body lengths per second) in response to an external ultrasound stimulus. Such remarkable speed can provide sufficient thrusts for deep tissue penetration, ablation, and destruction (Fig. 1C). Similar acoustically triggered vaporization of perfluorocarbon fuel was also used for developing tubular microscale cannons capable of loading and firing nanobullets at remarkable speeds. These microballistic tools could be used to eject high-speed nanobullets and shoot a wide range of payloads deep into diseased tissues.
Recent proof-of-concept studies have demonstrated that the untethered micro/nanorobots can perform surgical operation on a single-cell level. Solovev et al.  described nanoscale tools in the form of autonomous and remotely guided catalytic InGaAs/GaAs/(Cr)Pt microjets. With diameters of 280 to 600 nm, these self-propelled rolled-up tubes can reach a speed of up to 180 μm/s in hydrogen peroxide solutions. The effective transfer of chemical energy to a translational corkscrew-like motion has allowed these tubes to drill and embed themselves into biological samples such as a single cell (Fig. 1D). Although hydrogen peroxide may be incompatible for live-cell applications, the same team also described fuel-free rolled-up magnetic microdrillers that could be remotely controlled by a rotational magnetic field. The self-folded magnetic microtools with sharp ends enabled drilling and related incision operations of pig liver tissues ex vivo. Srivastava et al.  also demonstrated that magnetically powered microdaggers could create a cellular incision followed by drug release to facilitate highly localized drug administration (Fig. 1E).
Figure 1: Representative examples of micro/nanorobot-enabled precision surgery.
(A) Tetherless thermobiochemically actuated microgrippers capturing live fibroblast cells (B) Electroforming of implantable tubular magnetic microrobots for wireless eye surgery (C) Acoustic droplet vaporization and propulsion of perfluorocarbon-loaded microbullets for tissue ablation (D) Self-propelled nanodriller operating on a single cell (E) Medibots: dual-action biogenic microdaggers for single-cell surgery.
Cancer diagnosis and treatment are another applications of Micro/nanomotors at the cellular level. Micro/nanomotors distinguish themselves as a unique platform technology with in situ energy conversion capability for autonomous movement, a feature that confers remarkable potentials to improve cancer treatment. Three areas are highlighted, where these artificial motors have established themselves as powerful tools for potential cancer intervention: (1) through propelled navigation, micro/nanomotors act as highly diffusive delivery vehicles to promote cancer cell targeting; (2) by engaging movements powered through in situ energy conversion, micro/nanomotors gain considerable propelling force to penetrate cell membrane and enhance intracellular delivery; and (3) with built-in cargo manipulation mechanism and external steering, micro/nanomotors isolate circulating cancer cells for detection. Fig. 2 represents different types of Micro/nanomotors for cancer diagnosis and treatment .
The applications mentioned above have demonstrated the great potential of micro/nanorobots for performing precision surgery at the cellular or even subcellular level. The potential of surgical nanorobots will be greatly improved by their ability to penetrate and resect tissues and to sense specific targets, through the choice of propulsion method and the use of real-time localization and mapping with a robust control system.
Figure 2: Schematic illustration Micro/nanomotors for cancer diagnosis and treatment (left column), representative scanning electron microscopic image (middle column), and motion image (right column) of various types of micro/nanomotors.