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Microbotics - miniature machines and molecular motors open new vistas for medicine

Microbotics (or micro-robotics) is a term that describes the emerging field of intelligent, miniaturized robotics. Biomedical microbotics offers a glimpse of a future where tiny, untethered devices (smaller than 1 mm in size) are inserted into patients via natural orifices or through extremely small incisions. Thereafter, they navigate autonomously through the bloodstream or inside fluids such as the vitreous humour in the eye cavity, targeting areas of interest with extreme precision.
Microbots aid medical professionals in earlier diagnosis and more effective treatment of diseases, delivering drugs to targets in the body, removing plaque deposits in the arteries or excising and repairing tissue at cellular levels - which are too small for direct manipulation.
One of the most exciting possibilities offered by medical microbotics is to enable wholly new therapies which have yet to be conceived, simply because of the lack of small, precision-access equipment.


Biomedical microbotics seeks to combine established techniques of robotics such as motion control, path planning, remote operation and sensor fusion with new tools enabled by miniaturized MEMS (Micro-Electro-Mechanical-Systems) technology, as it was known in the US; the European equivalent was micro-systems technology (MST).
Microbots are one outcome of the rapid growth in microcontroller capabilities in the 1990s, alongside the appearance of MEMS and development of high-efficiency Wi-Fi connections. MEMS, used for example in airbag sensors, opened the way for low-cost, low power consumption applications, while Wi-Fi allowed microbots to communicate and coordinate with other microbots.
Apart from coping with challenges on power and stretching the limits of material science, considerable research has also recently been focused on microbot communication. A good example of this is a 1,024 microbot swarm' at Harvard University which spontaneously' assembles itself into various shapes.

First endoscopic capsules date to mid-1990s
One of the first medical applications of microbotic technology was in the gastro-intestinal (GI) tract. The microbotic intervention in the mid-1990s, by an Italian team, was published in the book Sensors and Microsystems' (World Scientific Publishing Co, Singapore, 1996) and consisted of endoscopic capsules which were simply swallowed by the patient. They captured video images as they moved naturally through the GI tract using in-built imaging and illumination systems.
In 2012, the U.S Food and Drug Administration (FDA) authorized a much smaller swallowable technology, namely a single-square-millimeter silicon circuit embedded inside a pharmaceutical pill, and produced by Proteus Digital Health.
Other researchers have proposed robotic systems with autonomous locomotion and biopsy capabilities. Some are tested, with models already on the market.

Sequel to MIS
In many senses, medical microbotics is a natural sequel to minimally invasive surgery (MIS), which has, since the 1980s, represented one of the key developments in medical technology. MIS resulted in a leap in patient recovery time and a sharp reduction in trauma.
Microbotics is expected to go even further, into what seems eerily close to the realms of science fiction.

From microgrippers to artificial bacteria
For example, researchers at Johns Hopkins University in Baltimore have developed microgrippers, The arms' of these star-shaped devices, less than a millimeter in size from one tip to another, are temperature-sensitive grippers and react when exposed to body heat.
In sufficient numbers, they provide a less-invasive way to screen for colon cancer than a colonoscopy - which currently requires taking dozens of samples with forceps.
Moreover, when required, the arms can be closed around tissue, thereby performing what is effectively an automated biopsy.
One of the most dramatic demonstrations of microbotic miniaturization is at the Swiss Federal Institute of Technology in Zurich (ETH Zurich), where artificial bacterial flagella (ABF), about half as long as the thickness of a human hair, have been developed (See also page 23).
In initial experiments, ETH Zurich researchers have already made the ABFs transport polystyrene micro-spheres.

3D printing converges with miniaturization
New 3D printing technologies are now converging with miniaturization to open other frontiers for microbotics.
For example, the Nanoengineering Department at the University of California, San Diego (UCSD) have created 3D printed microbots in the form of a small fish (microfish), for sensing and detoxifying toxins. The microfish, with dimensions of just 120 x 30 microns, are designed for testing in applications such as directed drug delivery and microbot-assisted surgery.
UCSD researchers added a polymer nanoparticle (polydiacetylene) to capture pore-forming toxins, such as those found in the venoms of sea anemones, honeybees and spiders, in order to establish that the microfish could be both detoxification systems and toxin sensors. When the nanoparticles bound with toxin molecules, they became fluorescent and emitted red-coloured light, whose intensity correlated to their detoxification abilities.

Key design and engineering challenges
Technologically, key challenges faced by microbotics include design issues for in-vivo applications. The microbots need to be small and reliable, and equipped with all necessary tools and sub-systems on board. They must be inserted into, steered and removed from the target area of a patient's body, non-invasively.
All this means a high degree of integration. MEMS devices were traditionally designed as components for insertion into larger electro-mechanical systems, along with physical interfacing for power supply and data input-output. In contrast, sub-millimetre sized medical microrobots must be manufactured in their final, operational and deployable form.

One emerging technology which seeks to address such challenges is known as Hybrid MEMS. It seeks to combine individual MEMS components through a robotic micro-assembly process, which brings together different manufacturing technologies such as lithography, nanosystems LIGA, Micro-Opto-Electro-Mechanical Systems (MOEMS) and 3D printing.

Materials and power
Apart from these kind of structural and miniaturization issues, other challenges of a robotic operation at microscopic scale consists of biocompatibility and power. The former has sought to be addressed with new generation MIS and implantable systems. However, few could underestimate the constraints of working in the human body - not only in terms of tracking precisely where a microbot is (especially in the vicinity of vital organs), but also making sure that it is neither toxic nor poses a threat of injuring tissue, while ensuring that it degrades safely or exits the body after completing its mission.
A key condition for effectiveness, therefore, is that microbots must have similar softness' as biological tissues. This is where the difference with traditional robots is most stark. Rather than cogwheels and cranes, pistons and levers, designers of microbots are inspired by the tentacles of an octopus.
The provision of power for moving the microbot, gathering/transferring useful information and taking interventional action when necessary, is even more challenging. Microbots can use a small lightweight battery source or scavenge power from the surrounding environment in the form of vibration or light energy.
The Proteus ingestible pill authorized by the FDA in 2012 contains two electrode materials which become electrically connected when the circuitry comes into contact with the stomach's gastric juice. For 5 or 10 minutes, the chip has enough power to modulate a current, transmitting a unique identifier code that can be picked up by an external skin patch.

An alternative to an on-board battery is to power the robots using externally induced power. Examples include the use of ex-vivo electromagnetic fields, ultrasound and light to activate and control micro robots. Researchers are now also focusing efforts on wireless power transfer, such as using radio waves from outside the body to generate electricity. However, this approach too faces limitations at small scales. To be effective, a microbot would need an antenna, which needs to be large enough to collect a meaningful amount of energy and also stay fairly close to the source.

Magnetic actuation
Magnetic actuation technology has been applied in biological systems for several years, in areas such as targeted drug delivery where magnetized carrier particles coated with chemical agents are concentrated on specific target regions of the body using external magnetic fields. Magnetic beads of a few microns diameter have also been successfully steered inside cells to manipulate individual DNA molecules.
At the UC San Diego 3D printed microbots project referred to above, the microfish are powered by nanoparticles with hydrogen peroxide being the power source, while magnets provide steering.

Molecular motors
Some experiments have focused on using molecular motors for microbots. These molecular motors are the sensing and actuation systems ubiquitous in biological systems. They have been adapted over millions of years and play vital roles in processes such as cell motility, organelle movement, virus transport.
From a practical viewpoint, interest in such molecular machines for the next generation of hybrid biomotor sensing and actuation systems will be driven by biomedicine as well as related applications such as microfluidics (e.g for nano-propellors) and chemical sensing.
Nevertheless, despite some signs of progress, the use of molecular motors in hybrid living-synthetic engineered systems remains several years away.

Artificial bacterial flagella (ABF)
The bulk of research into biological motors as power sources are focused on F1-ATPase and artificial bacterial flagella (ABF).
ABFs are manufactured through a Hybrid MEMS process by vapour-depositing several ultra-thin layers of indium, gallium, arsenic and chromium onto a substrate, followed by ribbon patterning using lithography and etching. The ribbons curl into a spiral once they are detached from the substrate, due to differences in the molecular lattice structures of the various layers.
The size of the spiral, and the scrolling direction of the ribbon, can be determined in advance. The latter is due to the presence of nickel in the head' of the microbot. Nickel is soft-magnetic, in contrast to the other (non-magnetic) materials used, and enables the spiral-shaped ABF to move forward/backward as well as upward/downward within a rotating magnetic field generated by several coils, towards which the head constantly tries to orientate itself and in whose direction it moves. Steering the ABF to a specific target is achieved by adjusting the strength and direction of the rotating magnetic field.

Nevertheless, the precise placement of microbots is crucial in order to avoid a clinician's nightmare - to place something solid in the blood, and trigger clots. Even ultra-sophisticated microbots which can follow a change in temperature, may not be able to fight the powerful currents in the bloodstream.

Europe is playing a major role in microbotics, with ETH Zurich considered a world leader in the field. One of its first biomedical microbots aims at ophthalmic operations on the retina. Drugs to treat the retina can now be injected into the eye, where they diffuse. However, only a fraction of the dose reaches its target. Microbots could potentially deliver drugs in a more targeted manner, reducing doses as well as side effects.


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