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Swarm of nanorobots kill cancer cells, deliver drugs to target tissues, and improve vaccines

We are on the verge of new transitions that will transform robotics. One is already underway—the miniaturization of robots, to the point where invisible, microscopic robots could be around us and inside us, performing monitoring or even life-saving functions. We have seen systematic bio-inspired efforts to create microbe-like, microscopic robots. They are a part of a new trend in what is called “tiny robot” research. The range of technologies and uses for tiny robots is broad, from drones to pills, and from surveillance and rescue to biomedicine. The trend has parallels with miniaturization in the electronics industry, where exponentially smaller and more energy-efficient units have been produced each generation.

 

The field of microrobotics covers the robotic manipulation of objects with dimensions in the millimeter to micron range as well as the design and fabrication of autonomous robotic agents that fall within this size range.

 

Nanorobots are even more minute — smaller than a millionth of a metre, or about a 100th the width of a hair. Nanorobotics is an emerging technology field creating machines or robots whose components are at or near the scale of a nanometre (10−9 meters). More specifically, nanorobotics (as opposed to microrobotics) refers to the nanotechnology engineering discipline of designing and building nanorobots, with devices ranging in size from 0.1–10 micrometres and constructed of nanoscale or molecular components.

 

The terms nanobot, nanoid, nanite, nanomachine, or nanomite have also been used to describe such devices currently under research and development. Since nanorobots would be microscopic in size, it would probably be necessary for very large numbers of them to work together to perform microscopic and macroscopic tasks.

 

Nanorobotics is defined in the same way only for dimensions smaller than a micron. With the ability to position and orient objects with micron- and nanometer-scale dimensions, manipulation at each of these scales is a promising way to enable the assembly of micro- and nanosystems, including micro- and nanorobots.

 

The first useful applications of nanomachines may be in nanomedicine. Modern surgery is advancing towards the direction of non-invasive, mechanized and intelligent. Benefiting from the development of micro/nanotechnology, robotics and nanomedicine, micro/nanomachines that incorporate the advantages of multidisciplinary approaches have arisen. Different from traditional invasive manual operation, the micro/nanorobots can penetrate deep regions of the human body and cure diseases like a mini-doctor.

 

For example, biological machines could be used to identify and destroy cancer cells. Another potential application is the detection of toxic chemicals, and the measurement of their concentrations, in the environment.

 

Nanorobots types

The first nano-sized robots were reported in 2005, including the nanocar made mainly by fullerene molecules. During the 2010s, three main designs of nanorobots have emerged: helices (also called nanoswimmers), nanorods (also called nanoswimmers, nanomotors or, if longer, nanowires) and DNA nanorobots.

 

Helices

A number of robots with screw-like helix tails for movement have been developed, often resembling bacterial flagella or other biological entities. Most of them are rather to be categorized as micro-sized robots, including the above-mentioned MagnetoSperm and the MOFBOTS. However, there exist examples of helix-like robots that are approaching the nanometer size range. One example is the helical cobalt-covered glass propeller developed by Ghosh and Fischer, which is 200–300 nm wide and 1–2 μm long. The propeller is meant to mimic a bacterial flagellum in terms of swimming behavior. Thanks to the magnetic cobalt layer, the propeller can be moved and navigated through magnetic fields (both backward and forward), reaching speeds of about 40 μm s−1. The navigation control in a water-based solution is exemplified by ‘writing’ micrometer-scale letters and symbols, such as ‘R’, ‘@’ and ‘H’, using the propeller’s trajectory. Several propellers can be controlled simultaneously in this way.

 

There are also attempts to use actual bacterial flagella by de-polymerizing them into flagellin proteins using heating, then repolymerizing them back into flagella and attaching them to magnetic particles 40–400 nm in size. By applying magnetic fields, the nanoparticle–flagella clusters can swim at velocities up to 2.5 μm s−1. An advantage of this helical nanorobot design is that the specific nanoparticles can be changed for different purposes while maintaining the repolymerized flagella for movement. However, for both propulsion and navigation purposes, the nanoparticles must be magnetic.

 

Nanorods

The nanorods typically consist of cylindrical rods with different metal segments,  although different shapes are also used for the same purpose. A particularly notable example from a medical point of view is the 250 nm wide and 1800 nm long rod with gold-nickel-gold segments developed by Garcia-Gradilla et al. These nanorods move due to ultrasound waves and can move in serum at about 50 μm s−1 and, albeit at lower speed, in saliva (about 10 μm s−1). Thanks to the magnetic properties of nickel, such nanorods can be steered along predetermined trajectories. For example, the developers made it ‘write’ the letters ‘U’, ‘C’, ‘S’ and ‘D’ with its trajectory.

 

The nanorod can be functionalized, making it carry drug cargoes. An important potential application of the gold–nickel–gold nanorod was shown by functionalizing it with a polypyrrole–polystyrene sulfonate segment. This organic segment can bind to the antiseptic drug brilliant green  and deliver this drug to designated destinations. The drug can then become released due to changes in pH.

 

Another potential medical use of nanorods was demonstrated by Kiristi et al.  They used ultrasound-powered porous gold nanorods less than 300 nm wide and functionalized them with the bactericidal substance lysozyme, which can kill both Gram-negative and Gram-positive bacteria. Several nanorod designs aim at cancer detection and treatment. MicroRNAs (miRNA) are small RNA strands, some of which can be associated with diseases such as cancer and diabetes.

Moving beyond detecting cancer and towards treating it, Uygun et al.34 used gold–nickel–gold–polymer nanowires as an effective anti-cancer agent. These nanowires were propelled by ultrasound at an average speed of 32 μm s−1 in human serum and magnetically guided thanks to the nickel.

 

DNA nanorobots

DNA nanorobots consist of deoxyribonucleic acid molecules, thus using DNA as construction material for nano-sized devices. Sometimes, they are based on DNA origami, where DNA molecules are folded to create patterns and shapes. An example of such a nanorobot is the DNA walker developed by Gu et al., which consists of a trigonal arrangement of double helices, resembling a symmetrical three-legged wheel with ‘feet’ that act like ligands.

 

DNA nanorobots have also been used in the in vivo environments of living organism. An example of such a device is a DNA nanorobot called the I-switch, which consists of three DNA strands. The I-switch can change shape depending on pH and the two shapes emit light of different wavelength when the nanorobot is tagged with a fluorescent molecule. This property can be used for tempo-spatial mapping of pH changes in living organisms,

 

 

Manufacturing approaches

Manufacturing nanomachines assembled from molecular components is a very challenging task. Because of the level of difficulty, many engineers and scientists continue working cooperatively across multidisciplinary approaches to achieve breakthroughs in this new area of development.

The joint use of nanoelectronics, photolithography, and new biomaterials provides a possible approach to manufacturing nanorobots for common medical uses, such as surgical instrumentation, diagnosis, and drug delivery.This method for manufacturing on nanotechnology scale is in use in the electronics industry since 2008.  So, practical nanorobots should be integrated as nanoelectronics devices, which will allow tele-operation and advanced capabilities for medical instrumentation.

A nucleic acid robot (nubot) is an organic molecular machine at the nanoscale. DNA structure can provide means to assemble 2D and 3D nanomechanical devices. DNA based machines can be activated using small molecules, proteins and other molecules of DNA.  Biological circuit gates based on DNA materials have been engineered as molecular machines to allow in-vitro drug delivery for targeted health problems.  Such material based systems would work most closely to smart biomaterial drug system delivery, while not allowing precise in vivo teleoperation of such engineered prototypes.

Surface-bound systems: Several reports have demonstrated the attachment of synthetic molecular motors to surfaces. These primitive nanomachines have been shown to undergo machine-like motions when confined to the surface of a macroscopic material. The surface anchored motors could potentially be used to move and position nanoscale materials on a surface in the manner of a conveyor belt

Biohybrids: The emerging field of bio-hybrid systems combines biological and synthetic structural elements for biomedical or robotic applications. The constituting elements of bio-nanoelectromechanical systems (BioNEMS) are of nanoscale size, for example DNA, proteins or nanostructured mechanical parts. Thiol-ene e-beams resist allow the direct writing of nanoscale features, followed by the functionalization of the natively reactive resist surface with biomolecules. Other approaches use a biodegradable material attached to magnetic particles that allow them to be guided around the body

Bacteria-based: This approach proposes the use of biological microorganisms, like the bacterium Escherichia coli and Salmonella typhimurium. Thus the model uses a flagellum for propulsion purposes. Electromagnetic fields normally control the motion of this kind of biological integrated device. Chemists at the University of Nebraska have created a humidity gauge by fusing a bacterium to a silicon computer chip.

Virus-based: Retroviruses can be retrained to attach to cells and replace DNA. They go through a process called reverse transcription to deliver genetic packaging in a vector. Usually, these devices are Pol – Gag genes of the virus for the Capsid and Delivery system. This process is called retroviral gene therapy, having the ability to re-engineer cellular DNA by usage of viral vectors. This approach has appeared in the form of retroviral, adenoviral, and lentiviral gene delivery systems. These gene therapy vectors have been used in cats to send genes into the genetically modified organism (GMO), causing it to display the trait.

 

3D printing: 3D printing is the process by which a three-dimensional structure is built through the various processes of additive manufacturing. Nanoscale 3D printing involves many of the same process, incorporated at a much smaller scale. To print a structure in the 5-400 µm scale, the precision of the 3D printing machine needs to be improved greatly. A two-step process of 3D printing, using a 3D printing and laser etched plates method was incorporated as an improvement technique. To be more precise at a nanoscale, the 3D printing process uses a laser etching machine, which etches the details needed for the segments of nanorobots into each plate. The plate is then transferred to the 3D printer, which fills the etched regions with the desired nanoparticle. The 3D printing process is repeated until the nanorobot is built from the bottom up.

 

Challenges

There are number of challenges and problems that should be addressed when designing and building nanoscale machines with movable parts. The most obvious one is the need of developing very fine tools and manipulation techniques capable of assembling individual nanostructures with high precision into operational device. Less evident challenge is related to peculiarities of adhesion and friction on nanoscale. It is impossible to take existing design of macroscopic device with movable parts and just reduce it to the nanoscale. Such approach will not work due to high surface energy of nanostructures, which means that all contacting parts will stick together following the energy minimization principle. The adhesion and static friction between parts can easily exceed the strength of materials, so the parts will break before they start to move relative to each other. This leads to the need to design movable structures with minimal contact area

 

Micro/nanorobots are supposed to navigate in a complex, highly viscous environment with driving energy supplied externally or by themselves. As a micro medical device, these synthetic robots are fabricated in the form of spirals, rods, spheres, gears, and cells that move at microscales to complete their tasks under control. They can swim to the targeted location and deliver the drug as well as serve for in vivo imaging

 

The group of scientists – led by Selman Sakar at EPFL and Bradley Nelson at ETH Zurich – drew inspiration from bacteria to design smart, biocompatible microrobots that are highly flexible. Because these devices are able to swim through fluids and modify their shape when needed, they can pass through narrow blood vessels and intricate systems without compromising on speed or maneuverability.

 

Such machines could be especially useful in dealing with dangerous environments. Researchers at the University of Southern California are working on developing technology to build nanobots which will be able to monitor oil/water for contaminants. The sensors in nanobots will be able to communicate with one another and will be active so that they can move around and make decisions.

 

In the same ways that technology research and development drove the space race and nuclear arms race, a race for nanorobots is occurring. There is plenty of ground allowing nanorobots to be included among the emerging technologies.  Some of the reasons are that large corporations, such as General Electric, Hewlett-Packard, Synopsys, Northrop Grumman and Siemens have been recently working in the development and research of nanorobots; surgeons are getting involved and starting to propose ways to apply nanorobots for common medical procedures; universities and research institutes were granted funds by government agencies exceeding $2 billion towards research developing nanodevices for medicine.

 

For biomedical applications, the synthesis of micro/nanorobots integrating respective
functions at the microscopic scale is essential. Achieving effective actuation, transportation
and wireless manipulation on small scales has been a major challenge. Due to their unique
size and dynamics, there are many micro/nanofluidic problems involved in the propulsion
and application of swimming micro/nanorobots. Considering that micro/nanoscale objects
in the movement are limited by Brownian motion as well as low Reynolds numbers (the ratio of inertial forces over viscous forces), designs based on classical mechanics are no longer
applicable to micro/nanorobots. In addition, individual robot shows limited ability in
executing tasks. As the need for biomedical application scenarios grows, micro/nanorobots
are expected to perform in a cluster manner. There will be greater opportunities for application if the individual robot can self-assemble into cluster form and interact with each other
to carry out specified tasks cooperatively.

 

The minuscule bots are expected to arrive in the 2050s, according to Dr Del Monte, following the rise of artificial intelligence, which will help to create the revolutionary bots. While experts are developing nanobots for the good, there are fear this could quickly get out of control. Louis A Del Monte, physicist and author of the book Nanoweapons, wrote in an article for the Huffington Post: “You can think of them as the technological equivalent of bacteria and viruses.”

 

Environmental and health risks

So far, discussions and research about environmental and health risks related to nanomaterials have focused on so-called passive nanomaterials, such as metal-oxide nanoparticles and carbon nanotubes. Much less attention has been given to so-called active nanomaterials. This includes nanorobots, which are individual nano-sized devices able to perform designated tasks, so far given limited attention regarding their potential future risks.

 

The main applications envisioned for nanorobots are such that they might potentially become administrated directly to the human body or the environment. Such applications with potential for exposure, akin to those of pharmaceutical and pesticide applications, warrant consideration into the risks related to nanorobots.

 

 identified two main potential hazards related to nanorobots at this early stage: (i) the use of conventional hazards, such as hazardous materials and UV light, as well as (ii) the loss of propulsion and navigation control. Furthermore, they note a lack of nano-specific regulation, making it uncertain whether current regulation will be able to identify and regulate nanorobot hazards at an early stage of development .

 

 

 

References and Resources also include:

https://en.wikipedia.org/wiki/Nanorobotics

https://pubs.rsc.org/en/content/articlelanding/2020/en/d0en00570c

https://pubs.rsc.org/en/content/articlelanding/2020/en/d0en00570c

 

About Rajesh Uppal

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