Tiny robots tumbling through blood vessels, making pit stops in the brain, and swimming through intestines is no longer a scene out of a science fiction movie. Scientists and engineers are developing microscale robots as small as bacterial cells to as large as the sharpened tip of a pencil with the ability to propel themselves through the body and penetrate deep into tissues. These micro machines function like mini doctors, delivering drugs and performing diagnostic tests in precise locations around the body.
Microrobots are poised to become important tools to treat diseases like cancer, which often occurs in tissues in which it is difficult or impossible to operate. The most common cancer treatments are chemotherapy and radiation, but these act on the entire body or focused regions of the body, not only the tumor, which leads to damage of healthy tissue as well.
“The idea of using the micro-nanorobots or anything that we can control or guide the trajectory… is to go directly from the injection site to the site of treatment. By doing so, we avoid this systemic circulation of very toxic [chemotherapy] drugs, so we minimize the toxicity for the patient,” said Sylvain Martel, a micro- and nanorobotics engineer at Polytechnique Montréal.
With the goal of targeting cancers and sparing healthy tissue, scientists and engineers have designed cancer-fighting microrobots that come in all shapes and sizes, from engineered bacterial and sperm cells to bubble-powered spheres and spaceship-style bots. Although none have reached human clinical trials yet, the microrobotics research field is poised to make exciting gains in the translational space in the next few years. The future of cancer treatment may just be micro.
Magnetic bacteria pinpoint tumors
One of the first tasks a microrobot needs to accomplish is determining where to go. Martel and his team wanted to direct their artificial microrobots into small blood vessels and between cells by magnetically guiding them. They soon realized that they wouldn’t be able to guide their bots through these tiny spaces because none of their visualization methods could show them cell-sized barriers that their robots might encounter in real-time. They needed something that could navigate those small barriers autonomously while traveling to their targets.
“The idea was to use microorganisms that have all the functionality of robots. So if we take bacteria, they have rotary motors, the flagella, so you can attach the cargo to that,” Martel said.
Martel’s group is not the first to use bacteria to treat cancer. In 1891, surgeon William Coley discovered that bacteria were surprisingly good at treating tumors. But with the danger of unintended bacterial infections, combined with the rise in popularity of chemotherapy and radiation as cancer treatments, bacteria fell out of favor.
Martel’s bacteria are surprisingly well-suited to treat cancer. Magnetococcus marinus strain MC-1 is magneto-aerotactic, meaning that they can sense and be guided by magnetic fields and move toward low oxygen environments. In metastasizing regions of the tumor, the proliferating cancer cells create very low oxygen concentration environments, making MC-1 cells ideal for shuttling cancer drugs to these regions.
“You direct the magnetic compound, but you leave them enough freedom to be able to go around obstacles by themselves fully autonomously,” Martel explained.
His team showed that when they injected the bacterial microrobots into a human xenograft tumor in mice, more of them made it deeper into the tumor when they were guided by a magnetic field for 30 minutes than those that were not (1). They also found that the bacterial microrobots successfully penetrated into the low oxygen regions of the tumor.
The team found that when they covalently bonded nanoliposomes, which would carry a cancer drug, to their bacterial micromotor, the microrobot still reached the low oxygen regions of the tumor.
But the same concerns that hindered Coley’s method still exist; what happens if some of the bacteria go rouge?
“Some bacteria might die on the way [to the tumor]. Some don't listen when you tell them what to do, but the majority will,” Martel said. “But it's not catastrophic because if you look at the dose we inject compared to chemotherapy, [the dose is] going to be still very small.”
Free-floating bacteria are bound to stimulate the immune system, which might trigger an unwanted immune response against the cancer-fighting microrobots. But, Martel explained, stimulating the immune system with their bacterial bots might actually function similarly to immunotherapy by stimulating immune cells to fight the tumor as well.
“What I learned in life is any problem can become a solution. So, the immune system can play against you, but it can also play with you,” he said. “You can also design the [microrobot] to release some chemical that will trigger the immune system, and that could potentially boost the treatment outcome.”
Martel hopes to get his microrobots into human clinical trials soon. The main obstacle to overcome will be scaling their microrobot to work in humans, who are much larger than mice. For example, scaling up the power of a magnetic field to go through the thicker human tissue is just one challenge. But Martel is excited to see where this young field of microrobotics is going.
One of those places also happens to be inspired by a cell, but this one often finds itself swimming in the reproductive system.
Spermbots vanquish cervical and ovarian cancers
With expertise in engineering and micro-nanotechnology, Oliver Schmidt from Chemnitz University of Technology felt at home designing tiny artificial engines, but he wondered if there were other kinds of powerful motors he could look to for inspiration.
“You look into life, into biology,” he said, “And then you think, are there any motors that are biocompatible that are directly suited to move around in the human body? And actually, there is one. These are the tiny swimmers, of course.”
With one purpose — to find an egg — sperm are an ideal cell on which to base a microrobot for ovarian and cervical cancer treatment. The female reproductive system is their natural environment.
Both ovarian and cervical cancer can be difficult to treat because there are usually no symptoms early in the disease, and they often originate in very narrow structures, for example in the fallopian tube for ovarian cancer. This makes diagnostics and treatment difficult. Sperm-based microrobots, however, would have no problem shuttling high concentrations of drugs to these narrow, hard-to-reach places.
Loading sperm cells with anti-cancer drugs is unexpectedly easy, Schmidt found. When incubating sperm cells with the cancer drug doxorubicin hydrochloride (DOX), the drug simply transfers into the head of the sperm where it is protected from degradation.
From a drug delivery standpoint, sperm couldn’t make the process any easier. They naturally penetrate tissue and seem to fuse with cells, leading to the release of the drug. The team found that DOX-loaded human sperm successfully delivered drugs to a patient-derived ovarian cancer spheroids in vitro and reduced cancer cell reattachment rate, a proxy for metastatic ability (2).
To help the spermbots find the tumor, Schmidt’s team needed to engineer a way to steer them. In one iteration of their spermbots, Schmidt’s team attached sperm cells to a magnetic scaffold, allowing them to guide the cells in the right direction via a magnetic field (3). They also designed a magnetic microcap that can guide up to three sperm cells at a time, bringing a higher concentration of drug to the tumor (2). The microcap can also hold an additional cancer drug for treatment.
The benefit of using magnetic scaffolds to guide the sperm is that once the spermbots have fused with the cancerous cells and delivered the drug, the researchers can simply guide the magnetic scaffolds back out of the body.
“That was a very clever and elegant way of dealing with this,” Schmidt said. “One of the motivations of using micromotors and robots [is] to be able to actually get rid of them again.”
Using human sperm cells as microrobots may bring up some societal or ethical push back, but when Schmidt and his colleagues talked with cancer patients about using a partner’s or anonymous donor’s sperm as the spermbots, patient response was overwhelmingly positive to both.
“If you are suffering from an illness, and there is a way of healing it… I think you're just happy that it can be done,” Schmidt said. “But I agree that this communication with patients should be carried out as early as possible.”
The next steps for Schmidt and his team are to test their spermbots in animals and to engineer their bots to selectively target cancer cells.
“This is not so much science fiction anymore. It's still basic research, but it’s not totally implausible,” he said.
While cell-based microrobots like Martel’s bacteria and Schmidt’s spermbots have the help of magnetic fields and their inherent swimming ability to propel them forward, other kinds of microrobots take a more effervescent approach.
Bubble-bots blast intestinal tumors
To Wei Gao, a nano- and microrobotics engineer at the California Institute of Technology (Caltech), bubbles are the perfect transportation mode for microbots targeting intestinal cancers.
“We were thinking about how to make the propulsion as easy as possible,” Gao said. “If I want to use it at home, I don't have to rely on any complicated setup, [so] we thought about using an autonomous microrobot that can be powered by a chemical reaction with the surrounding environment.”
Gao’s team realized that they could propel their microrobot with microbubbles. By constructing a spherical microrobot with a magnesium core and a small opening to the outside, when the team exposed their bot to fluid in the small intestine, the magnesium reacted with the water to produce hydrogen gas. Jets of hydrogen microbubbles shot out of the small opening, propelling the microrobot into the intestinal tumor environment.
The team coated the magnesium core with a thin layer of gold to facilitate the magnesium-water reaction and help with visualizing the microrobot from outside the body. On top of the gold they layered the cancer drug DOX covered by a protective polymer.
“Because you have active propulsion, they can penetrate through the [intestinal mucosal] barrier much more efficiently” than a passively delivered drug would, Gao said.
The trick with these bubble-bots, however, is getting them to the vicinity of the tumor in the intestine without destroying them in the extremely acidic stomach environment. To solve this problem, Gao and his colleagues designed a protective gelatin-based microcapsule to shuttle the microrobots into the intestines (4).
Using a visualization technique called photoacoustic computed tomography (PACT), which Gao’s Caltech engineering colleague and expert in biomedical imaging, Lihong Wang pioneered, Gao and his team tracked their microcapsule full of microrobots through the digestive tract. Wang’s team has also shown that PACT can be used to image tumors in humans as well (5), giving the researchers a way to visualize the intestinal tumor and microcapsule at the same time.
Once the microcapsule reached the tumor via the natural peristaltic waves of the digestive tract, the researchers used near-infrared (NIR) light to break open the microcapsule and release the microrobots to the tumor.
“We were pretty impressed with how efficiently this microcapsule can be activated,” said Gao. The team found that they could release the microrobots almost instantaneously. From there, the microrobots propel themselves into the tumor, delivering the cancer treatment.
So far, Gao and his team have demonstrated that their microcapsules can be successfully activated in mouse intestines and that the released microrobots localize to an intestinal tumor in a mouse (4). The research team has not yet looked at how effective their delivery system is at treating tumors, but they’re working on it.
Like Martel, Gao’s team is studying how scaling their system to work in larger mammals like pigs and eventually in humans will affect their ability to use light to release the microrobots from the microcapsule.
Because human tissue is thicker than mouse tissue, “the light penetration is limited even if we use IR. That's why we are also considering other ways, potentially [using] ultrasound to activate this microcapsule,” Gao said. “But it's all step by step, from small animal to large animal, all the way to human.”
While Gao’s microrobot may still be a few years out from the clinic, a new, slightly larger microrobot has human clinical trials in its sights, with a focus on brain cancer.
Brain cancer is no match for space-age microrobots
Sequestered behind the protective blood brain barrier, the brain is one of the most difficult organs in the body to treat. When drugs delivered into the bloodstream try to access the brain, they need help to reach the target.
Bionaut Labs is ready to break through that barrier to deliver life-saving drugs to the brain with microrobots. Their first target is brain stem glioma, a type of cancer that commonly affects children and has a poor prognosis.
“Brain stem gliomas, in general, are very treacherous beasts,” said Alex Kiselyov, the Chief Science Officer at Bionaut Labs. “It's practically impossible to access them surgically, and even if you can, you will not be able to differentiate normal cells from neoplastic ones.”
The team at Bionaut Labs named their microrobots “bionauts,” like little cancer drug-carrying astronauts exploring the universe of the human body. To get their bionaut into the central nervous system, the researchers either inject the bots into the spinal cord intrathecally or into the brain parenchyma.
To move the bionaut in the brain, the researchers developed an external controller and a helmet-like device that contains several electromagnetic coils to generate a magnetic field. With the controller, the team can use the magnetic field to move the bionaut throughout the brain to the glioma. Unlike the most skilled human surgeon, the bionaut can push through the brain tissue with a precise amount of force, reducing surgical trauma. Once the bionaut reaches the tumor, the team can remotely trigger it to release the drug.
One of the advantages of using a microrobot on the scale of hundreds of micrometers to a millimeter rather than the tens of micrometers-scale of Martel, Schmidt, and Gao’s microrobots, is that visualizing the bot in a large animal or human is not a problem.
“We send discrete particles as opposed to those fleets of millions of nanoparticles that, unfortunately, many of them get lost,” Kiselyov explained. “We do not lose particles. We have absolute and total control… We also understand what our particle does and where it is at any given moment.”
When the researchers tested their procedure with bionauts in large mammals (more than 60 pigs and sheep), they saw that whether the microrobot tumbled through the cerebral spinal fluid or gently corkscrewed through brain tissue, it caused no damage.
The team is now working to ensure that their bionauts adhere to the necessary electrical and magnetic safety standards for use in humans. They are also optimizing their surgical systems for ergonomics so that when a physician performs a procedure with a bionaut, the surgery will be streamlined and comfortable.
The researchers aim to begin clinical trials with their bionauts as soon as 2023, with the hope that their bionaut for brain stem glioma treatment will be available for FDA approval in 2025 or 2026.
“This will have a profound impact both on patients’ lives and the ability to treat conditions that are today completely untreatable, like brain stem glioma,” said Michael Shpigelmacher, the founder and CEO of Bionaut Labs.
“If you think about it for a second, how many treatments fail clinical trials because they're unable to achieve the right safety-efficacy balance. With a technology that relies on microrobots, you can engineer the therapeutic index,” he added. “We think that the bionaut will not only revolutionize the way conditions are treated, but also the way treatments are developed.”
With their ability to propel themselves into tissues and deliver drugs directly to tumors, microrobots may just be the future of cancer treatment. As exciting developments work their way toward the clinic, keep an eye out for these microscopic surgeons, primed to heal from within.
References
- Felfoul, O. et al. Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. Nature Nanotech 11, 941-947 (2016).
- Xu, H. et al. Human spermbots for patient-representative 3D ovarian cancer cell treatment. Nanoscale 12, 20467-20481 (2020).
- Xu, H. et al. Sperm-Hybrid Micromotor for Targeted Drug Delivery. ACS Nano 12, 327-337 (2018).
- Wu, Z. et al. A microrobotic system guided by photoacoustic computed tomography for targeted navigation in intestines in vivo. Science Robotics 4, eaax0613 (2019).
- Wang, L. V. & Hu, S. Photoacoustic Tomography: In Vivo Imaging from Organelles to Organs. Science 335, 1458-1462 (2012).
