Biohybrid microrobots could be prescribed to you one day

Biohybrid microrobots, or 'biobots,' have been theorized and predicted for decades in science fiction (SF) pages. One Oscar-winning depiction being the miniaturized atomic sub in the 1966 film, Fantastic Voyage. Set in the year 1995, the adventure involves humans, who are reduced to a microscale size and go on a mission to destroy a blood clot in the brain of a dying scientist. If you've watched the movie, you'd know that problems arise almost as soon as the small crew arrives in the bloodstream.

Today, biohybrid microbots appear to be on the verge of moving off the screen and becoming a reality- at least when it comes to modern medicine. Interesting Engineering (IE) interviewed Dr. Birgül Akolpoglu, a doctoral researcher at the Max Planck Institute for Intelligent Systems, who is researching biohybrid microrobots, to understand more about the potential, limitations, and misconceptions of the emerging field.

Power to biohybrid microrobots

Biohybrid microbots have been conceptualized as devices that can utilize both synthetic and biological constituents to perform tailored biochemical operations at the nano-scale level. They can be remote controlled to steer to a specific location, locate a target, and then execute an effect.

Current robots can be powered by electromagnetic motors reacting to an external field, for example, so they don't need to carry a power source, but this limits control to "on" or "off" and possibly steering by changing the shape of the field.

On the other hand, cells can sustain their functions because they have energy-producing 'factories' called mitochondria. The mitochondria generate most of the chemical energy needed to power the cell's biochemical reactions in a process called oxidative phosphorylation. This process uses oxygen available within the cell to convert chemical energy, in the form of carbohydrates and fatty acids, to energy in a form that is usable by the host cell. The process is called oxidative phosphorylation and the energy generated in this process is stored in a small molecule called adenosine triphosphate (ATP).

SF microbots, unlike mitochondria, were often imagined as using some power source to run—say, a microscopic speck of uranium. Unfortunately, ionizing radiation is intrinsically harmful to living tissue. Radioactive microbots would then have to have some shielding, and possibly also contribute to repairing damage caused by their mere presence.

Instead, a more realistic approach to powering microrobots may be to have them tap into existing mechanisms from living cells by utilizing ATP as an energy source. That is, microbots could run on the same mechanism that living bodies do—and not incidentally. Some researchers posit that this could also help them biodegrade safely after completing their task.

The complicated art of building biohybrid microrobots

Not only are microbots currently tricky to power, but they are also tough to make. Micro-scale manipulators are not something you can stamp out on an assembly line like car parts. Instead, researchers rely on processes like 3D bioprinting.

In this way, the process can be automated and also sped up.

Nonetheless, even if working 'biobots' could be generated in large numbers, there would still likely be a need for millions per patient. On average, 37.2 trillion cells exist in a human adult. If biorobots were to be used to constantly maintain cells, rather than for discrete, one-off uses, such as attacking cancer cells, then supplying just one million microbots per person would require each bot to be responsible for maintaining around 37 million individual cells. Instead, it may make more sense to utilize what already exists and tune it to accomplish required tasks.

Being time-limited and capable of self-destruction, leaving no biohazard behind, and capable of being targeted for a particular task are therefore the key characteristics for biobots.

Logical candidates for adaptation are E. coli, salmonella bacteria, and others with which scientists have vast experience. Sperm cells, too, could be promising since they already possess highly efficient motive power and 'self-destruct' in about 72 hours.

The case of the E.coli: multifunctional medical operations

"As a sub-field of microrobotics, biohybrid microrobots offer great advantages for multifunctional medical operations since they come with key inherent characteristics such as onboard actuation and sensing," Dr Birgül Akolpoglu reveals to IE.

As an example of this multifunctional capability, we only have to look to a recent study led by Akolpoglu published in Science Advances. Here, chemotherapeutic molecules were integrated onto magnetically-controlled Escherichia coli (E.Coli). Not only could the biohybrid microbots be used to trigger an immune response, but they could tap into the naturally fast and versatile swimming traits that E. coli bacteria offer in a range of liquids, including highly viscous tissues.

Additionally, the biobots could utilize the bacterium's highly advanced sensing capabilities, allowing them to be drawn, for example, to conditions indicative of tumor tissue, such as low oxygen levels or high acidity.

Still, the major challenge with the genetic modification of bacteria is related to safety concerns. Successful treatment is only possible if the toxicity generally caused by the bacteria is eliminated without compromising the therapeutic outcome.

The major promise of biohybrid microbotics is their power to heal non-invasively- at the nano-scale

"One of the biggest shortcomings of modern medicine is collateral damage during clinical interventions, such as unwanted side effects of chemotherapies on other organs," Dr Birgül Akolpoglu tells IE.

To overcome this challenge, the major promise of biohybrid microbotics, as a subfield of microrobotics, is the capability to manipulate cells at their size scale in closed environments non-invasively, for example, in blood vessels, and within tissues.

Akolpoglu highlights that while this manipulation could be performed physically, such as transporting cells or locally heating them, it could also be biochemical. Such as delivering therapeutic molecules, or chemotherapeutic drugs, to a specific location in the body. Simple triggers, such as ultrasound or infrared lasers, could cause the courier biorobot to burst or dissolve, delivering its treatment exactly where desired, providing an 'on-the-spot' delivery.

In a press release regarding the E.coli study mentioned above, co-author Dr. Yunus Alapan describes this as being "minimally invasive for the patient, painless, bear minimal toxicity, and the drugs would develop their effect where needed and not inside the entire body."

Additional capabilities could be exploited, such as applying extremely localized hyperthermia to kill unwanted cells. Other strategies could include the development of new hybrid 'bio-muscles' manufactured by growing real muscle cells on a synthetic substrate. By applying a current, the muscle cells would activate, causing movement, creating micro tools that could cut, grasp, inject, or many other options yet to be considered.

Clinical use of biohybrid microbots, while not far-fetched, requires more research

"Many of the studies in the literature show proof-of-concept applications in vitro, without taking [into account] the complexity of the human body, tissues, and tumors. We need many more in vivo studies in pre-clinical models that rigorously investigate the feasibility of the biohybrid microrobots," Dr Birgül Akolpoglu reveals to IE.

In other words, directing one of these biohybrid microbots through a cube of liver, lung, or cardiac tissue in a petri dish or bacteria is one thing, but more work needs to be done in living organisms in order to discover some of the practical problems that will arise. In vitro studies (outside the normal biological context) are hardly ever the same as in vivo (in living organisms).

"Next, to be able to track these cells-sized and even smaller biohybrid microrobots, we need sensitive and high-resolution real-time imaging modalities," Akolpuglu tells IE. Precision-directed biohybrid microbots will also need to use advanced imaging technologies in order to monitor the bots' progress and adjust their conditions and 'work' to the ever-changing microenvironments in the body.

Patient safety will also need to be guaranteed. Solid robots would have to be recovered and guided out of the body once their job was complete, or they would have to be 100 percent biodegradable. While self-destructing biohybrid microbots concepts already exist, Akolpuglu adds that scientists still need to ensure "that these microrobots can be operated within a body for the long term, even in the face of potential immunological reactions."

Simply put, scientists must ascertain whether these machines will be able to pass through the body without instigating an immune response or pose other problems that could have far-reaching consequences.

Right now, the ability to steer and direct biohybrid microbots are just beginning to be explored in the lab. Dr. Akolpuglu tells IE that "we must develop strategies to navigate and control these microrobots inside the host body, taking body fluid flows, and viscous and fibrous microenvironments found in tissues into account." A more profound knowledge of this will avoid microbots being swept away or ending up far off-target.

A dose of biobots could keep the doctor away- at least in the future

Biohybrid microbots may one day become the next "silver bullet", akin to the magnificent 1928 discovery of antibiotics. Now that antibiotic resistance is on the rise, making them less effective because of severe overuse, humanity may come to rely on these seemingly unusual devices to thwart disease processes.

As medical advances forge a path to biorobotic devices and procedures, the development of these 'biobots' could one day be used to treat a whole range of diseases and medical conditions. There may even come a time when treatment of a condition such as a torn ACL (anterior cruciate ligament) or a broken finger will involve just a simple biorobot injection.

Better yet, if you're a Star Trek fan and saw the movie Star Trek: The Voyage Home, you may want to think of that 20th-century patient Dr. McCoy found in a hallway waiting for kidney dialysis. McCoy simply gave the woman a pill and said, "any problems, just call me". In a later scene, she was being quickly wheeled down the hallway with a dozen stunned doctors around her as she proclaimed, "the doctor gave me a pill, and I grew a new kidney!"

Perhaps that pill operated as a delivery system that supplied a load of stem cells to a site. The cells could then autonomously build any required new tissue. Given the developments in biobots highlighted in this article, the reality of such a scenario may only be a few years or decades away, which is just around the corner in the scheme of things.