Miniscule Medical Robots feature EU Research

Miniscule Medical Robots One of the most exciting branches of research in medical technology has to be the conception of micrometre machines and nanobots, miniature devices that can navigate our bodies from the inside.

These tiny robots typically enter the body through a syringe to monitor health or deliver treatment with pinpoint accuracy. Whilst they are not in the clinical phase yet, they likely will be in the future.

By Richard Forsyth

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evealing the hidden health of the human body, in the darkness and delicate environment of living organs has been a continual challenge for physicians. Further still, being capable of treating fluctuating or evolving health conditions in real-time in difficult-to-reach places has become a holy grail for healthcare. This is where the emerging science of micrometre and nano robotics could revolutionise how we monitor and treat patients in the future.

There are various scales of small in this world of tiny machines. For clarification, micrometre robots are usually around 1-2 micrometres but rarely are below 300 nanometres. Nanobots are even harder to imagine, they are robots at minuscule scales of 1-100 nanometres in size. A nanometre is one billionth of a metre. For perspective, the limits your naked eye can see is about the width of a human hair, and a nanometre is 1000 times smaller than that. A virus cell for comparison can be about 20-400 nanometres and a chromosome is about 100 nanometres. Anything this small can pass through bodies with ease.

Such devices can potentially monitor human health from the inside whilst also delivering treatments or carrying drugs to difficult recesses, or tumours, inside a person.

Whilst tests with such miniature marvels have been carried out in animal trials, there are safety, technical and regulatory challenges to overcome before being used in clinical applications. The impact on humans has not been thoroughly assessed yet. However, the advantages foreseen by using these tiny, often biological, machines mean it may well be only a matter of time till we see them become a solution in healthcare.

Using nature’s factory There are many challenges to creating these minuscule robots. For example, they must not affect the human body adversely, which means the materials they are made of must be compatible with our insides. For example, nanobots can be made of materials like DNA, proteins and iron. Manufacturing and programming them requires thinking differently from the usual ways we devise and construct machines. On the larger scale of the micro machines, there are some ways to top-down design and manufacture. For example, advancements in 3D printers mean it is now possible to fabricate micro-robots, but for the really minuscule devices, nature needs to lend her supportive hand and her age-old know-how during the build process. An understanding of biology is key to building these unusual devices as nature itself can manufacture them from the bottom-up. Nanobots can be built via molecular selfassembly, essentially building themselves with the right stimulus and encoding.

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‘To the left a bit…’

Making these infinitesimal devices move is the next major challenge. Again, one way is to take a steer from nature, like utilising the propelling tails of certain bacteria, or growing built-in chemical engines. Another way is to externally guide them, using magnetic fields to move them around.

Peer Ficher and Ambarish Ghosh, working at Harvard University, created a glass propeller 1-2 micrometres long that could be activated with a magnetic field. Under an electron microscope, it looked like a crude corkscrew. It could be steered through liquid with adjustments to the magnetic field. In 2018, Ficher conducted an experiment where the micro propellers were guided several centimetres to the retina in a pig’s eye in vitro, demonstrating how these devices can travel through living tissue.

There are many different approaches. A science team from Purdue University in Indiana, US, developed tiny robots a few widths of a human hair in size, relatively large compared to the nanoscale, that could do backflips and travel across the colon of a mouse. Colons are considered difficult terrain for delivering drugs. The project was promising because it showed that direct delivery was possible to the affected part, thus allowing to avert adverse side effects like hair loss and stomach bleeding. This was the first demonstration, in 2021, of a micro-bot basically tumbling down a biological system in vivo. It was controlled externally via a magnetic field and observed with ultrasound.

At this stage of research and development in the emerging science, there are all kinds of variations to technique and robot design, and whilst some are crafted and some are born from nature, there is one branch referred to as biohybrids, which even fuses microscopic organisms and cells, such as bacteria and sperm, with robotic parts and in turn creates nanoparticle swarms of these hybrid components.

It’s an area of research that needs a high degree of very specialist knowledge and equipment, as just to see the devices requires a specialist laboratory. No matter, several research teams around the world are making giant strides in this field.

In July 2022 a research team led by Inserm researcher Gaëtan Bellot at the Structural Biology Centre (Inserm/CNRS/Université de Montpellier) announced they had built a nano-robot from DNA to explore cell processes. They used what they called the DNA origami method which enables the self-assembly of 3D nanostructures in a predefined form using the DNA molecule as construction material. The researchers designed a nano-robot composed of three DNA origami structures. Of nanometric dimensions, it is compatible with the size of a human cell. It made it possible for the first time to apply and control

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Making these infinitesimal devices move is the next major challenge. Again, one way is to take a steer from nature, like utilising the propelling tails of certain bacteria, or growing built-in chemical engines.

Another way is to externally guide them, using magnetic fields to move them around. a force with a resolution of 1 piconewton, namely one trillionth of a Newton – with 1 Newton corresponding to the force of a finger clicking on a pen. This is the first time that a human-made, self-assembled DNA-based object could apply force with this accuracy.

A more unusual way to help navigate nanobots to a precise bodily location for treatment is with a laser beam. Dr Xianchuang Zheng and his research team, of the Institute of Nanophotonics at Jinan University, created microscopic robots made from white blood cells called neutrophils. They were named neurobots and could be remotely activated by light and guided to the target position via a planned route to treat life-threatening illnesses.

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Another tiny machine reliant on lasers looks like it might be more at home in rock pools, as this very sci-fi-looking microbot closely resembles a crab in appearance. A study published in May 2022 in Science Robots, revealed the tiny crustacean mimicking robots as 0.5 millimetres wide with eight little legs, and a pair of tiny pincers. They can fit through the eye of a needle and for manoeuvrability, they can bend, twist, turn and jump with the help of a laser for guidance. This tiny device starts off in flat 2-D but the heat of the laser makes them pop up into 3D, like a child’s pop-up book, and it’s that repeated motion as it heats up and quickly cools which also gives it its method of moving. The applications in the medical world for such a device could be to clear clogged arteries or stop internal bleeding, for example.

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Precision medicine The applications for medical nanobots could be far-reaching.

Nanobots can check environments in the body and monitor changes at a molecular level, diagnosing diseases and assessing someone’s condition, but more than this their highest value has to be their amazing potential for pinpoint, targeted delivery of treatments inside the body, which is highly advantageous for instance, when dealing with cancers. Attacking tumours with nanotech is becoming one of the key research areas with this type of innovation.

Researchers at Polytechnique Montréal, Université de Montréal and McGill University created nanorobotic devices made up of 100 million flagellated bacteria that could self-propel whilst loaded with drugs. Testing the swarm on mice, a synthesised chain of magnetic nanoparticles enabled the drug delivery bots to move in the direction of a magnetic field controlled by a computer. The bacteria penetrated deep into the tumour to inject the drug with great success.

Bionaut Labs Inc. in Los Angeles is also developing tiny robots, it calls

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bionauts, less than a millimetre long, to be injected into human tissue and guided to parts of the body magnetically. They were perceived as a viable way to deliver chemotherapy or other drugs to tackle cancers in the brain, which is a delicate target and considered high-risk in surgery with conventional methods, however, the nanorobot transport device they developed can be used anywhere in the body. Operators control the robots from outside the body and when they reach their target, they discharge the drugs. After the drugs are delivered, the nanorobots are guided back to the point of insertion and can be extracted.

There was an approach with a similar aim, by scientists at Arizona State University working with the National Centre for Nanoscience and Technology (NCNST) of the Chinese Academy of Sciences. They published their research on mammals in the Journal Nature Biotechnology, where they successfully programmed nanorobots to shrink tumours by cutting off their blood supply.

Cancer treatments currently can have painful and damaging side effects. Chemotherapies hit healthy cells whilst attacking tumours and many tumours are hard to reach, even when they are located. Cancer cells can be elusive when attempting to rid them by conventional methods, but nanobots would always be able to find them and work on their eradication without spill-over or provoking adverse side effects for a patient, in theory.

The potential to target a wide number of serious diseases with this unique level of accuracy is already producing some spectacular headlines in the scientific press.

In September 2022, researchers published their findings in Nature Materials where they announced they had completely eradicated a deadly pneumonia infection (Pseudomonas aeruginosa) from the lungs of two-dozen mice by injecting swarms of bacteria battling micro-robots directly into the animals’ windpipes. The robots directly targeted the infection with a 100% success rate.

This could have profound implications if the same results can be produced with human trials and they could be useful for other medical issues like stomach and blood infections.

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Co-author of the study, Dr Victor Nizet, a professor at the University of California San Diego remarked: “Based on these mouse data, we see that the microrobots could potentially improve antibiotic penetration to kill bacterial pathogens and save more patients’ lives.”

After the drugs are delivered the mouse’s immune cells mop up the microbots, which are made of natural materials such as a biodegradable polymer.

The team will be trialling the robots on larger animals as the next step toward human trials.

Medical microbots could potentially deal with the exacting needs of a patient in real-time, reacting to requirements inside the body exactly when needed. They have the potential for all kinds of healthcare tasks, such as tracking diabetes, healing wounds,

monitoring blood for clots, removing plaque from arteries, removing toxins, or perhaps acting as a scaffolding for rebuilding tissue or nerves, and the list goes on.

These micro and nano machines can carry cargo including drugs or living cells, and they have the advantage that they would not risk infection as with invasive operations. Before these marvels of science are a realistic option for widespread adoption by healthcare institutions, there is a substantial road of development ahead. From the feasibility side, these technologies need to be low-cost and scalable. With the rate of progress in this branch of science, it is likely we will one day have the option of this kind of nano-scale therapy and the hope is it may provide a far better solution for healthcare needs than some traditional treatments and surgeries.

Cancer treatments currently can have painful and damaging side effects.

Chemotherapies hit healthy cells whilst attacking tumours and many tumours are hard to reach, even when they are located. Cancer cells can be elusive when attempting to rid them by conventional methods, but nanobots would always be able to find them and work on their eradication without spill-over or provoking adverse side effects for a patient, in theory.

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