A team of scientists from the Department of Physical Intelligence at the Max Planck Institute for Intelligent Systems have combined robotics with biology by equipping E.coli bacteria with artificial components to build biohybrid microrobots. First, the team attached several nanoliposomes to each bacterium. On their outer circle, these spherical supports enclose a material (ICG, green particles) which melts when illuminated by near infrared light. Further towards the middle, inside the aqueous core, liposomes encapsulate water-soluble chemotherapeutic drug molecules (DOX).
The second component that the researchers attached to the bacteria are magnetic nanoparticles. When exposed to a magnetic field, the iron oxide particles serve as a booster for this already highly mobile microorganism. This way it is easier to control the swimming of bacteria – an improved design towards in vivo application. Meanwhile, the rope binding the liposomes and magnetic particles to the bacteria is a very stable and hard-to-break complex of streptavidin and biotin, which was developed a few years ago (https://www.nature.com/articles/s41598-018-28102-9) and is useful when building biohybrid microrobots.
E. coli bacteria are fast and versatile swimmers that can navigate through materials ranging from liquids to highly viscous tissues. But that’s not all, they also have very advanced detection capabilities. Bacteria are attracted to chemical gradients such as low oxygen levels or high acidity – both prevalent near tumor tissues. Treating cancer by injecting bacteria nearby is known as bacteria-mediated tumor therapy. The microorganisms flock to the place where the tumor is, grow there and thus activate the immune system of the patients. Bacteria-mediated tumor therapy has been a therapeutic approach for more than a century.
Over the past few decades, scientists have been looking for ways to increase the superpowers of this microorganism even further. They equipped the bacteria with additional components to help them fight. However, adding artificial components is not an easy task. Complex chemical reactions are involved and the rate of density of charged particles on the bacteria is important to avoid dilution. The Stuttgart team have now set the bar quite high. They managed to equip 86 out of 100 bacteria with both liposomes and magnetic particles.
The scientists showed how they managed to externally drive such a dense solution through different pathways. First, through a narrow L-shaped channel with two compartments at each end, with a tumor spheroid in each. Second, an even narrower configuration resembling tiny blood vessels. They added an extra permanent magnet to one side and showed how they precisely control drug-loaded microrobots to tumor spheroids. And third, going even further, the team navigated the microrobots through a viscous collagen gel (resembling tumor tissue) with three levels of stiffness and porosity, ranging from soft to medium to stiff. The stiffer the collagen, the tighter the network of protein chains, the harder it becomes for bacteria to find a way through the matrix. The team showed that once they add a magnetic field, the bacteria manage to navigate to the other end of the gel because the bacteria have a higher strength. Due to the constant alignment, the bacteria have found a way through the fibers.
Once the microrobots are accumulated at the desired point (the tumor spheroid), a near infrared laser generates rays with temperatures up to 55 degrees Celsius, triggering a process of fusion of the liposome and a release of the enclosed drugs. A low pH level or an acidic environment also causes nanoliposomes to open – hence the automatic release of drugs near a tumor.
“Imagine injecting such bacteria-based microrobots into the body of a cancer patient. With a magnet, we could precisely direct the particles to the tumor. Once enough microrobots surround the tumor, we point a laser on the tissue and thus trigger the release of the drug. Now not only is the immune system triggered to wake up, but the additional drugs also help destroy the tumor,” says Birgül Akolpoglu, a PhD student at the Department of Physical Intelligence at MPI-IS She is the first author of the publication entitled “Magnetically steerable bacterial microrobots moving in 3D biological matrices for stimuli-responsive cargo delivery” co-directed by former postdoctoral researcher in the Department of Physical Intelligence, Dr. Yunus Alapan. It was published in Scientists progress July 15, 2022.
This on-the-spot administration would be minimally invasive to the patient, painless, bear minimal toxicity, and the drugs would develop their effect where needed and not inside the whole body.”
Dr. Yunus Alapan, former postdoctoral researcher in the Department of Physical Intelligence
“Bacterial-based biohybrid microrobots with medical capabilities may one day fight cancer more effectively. This is a new therapeutic approach not too far removed from the way we treat cancer today,” says Professor Metin Sitti, who heads the Department of Physical Intelligence and is the latest author of the publication. “The therapeutic effects of medical microrobots in finding and destroying tumor cells could be substantial. Our work is an excellent example of basic research that aims to benefit our society.”
Akolpoglu, MB, et al. (2022) Magnetically steerable bacterial microrobots moving in 3D biological matrices for stimuli-responsive cargo delivery. Scientific advances. doi.org/10.1126/sciadv.abo6163.