In order to create biohybrid microrobots, a group of researchers from the Max Planck Institute for Intelligent Systems’ Physical Intelligence Division modified E. coli bacteria with artificial parts.
The team started by embedding several nanoliposomes inside each bacteria. These spherical carriers contain a substance (ICG, green particles) on their outer circle that melts when exposed to near infrared light.
The liposomes enclose molecules of chemotherapeutic drugs (DOX) that are water soluble further toward the center, inside the aqueous core. Magnetic nanoparticles are the second element the researchers added to the bacterium.
The iron oxide particles act as a top booster for this already extremely mobile microbe when it is exposed to a magnetic field. This makes it simpler to regulate how bacteria float, leading to enhanced design for in vivo use.
Streptavidin and biotin complex, which was created a few years earlier and is useful when building biohybrid microrobots, serves as the rope tying the liposomes and magnetic particles to the bacterium.
E. coli bacteria are adept swimmers who can move across a variety of media, including liquids and highly viscous tissues. But that’s not all; they also possess extremely sophisticated sensory abilities.
Bacteria are drawn to chemical gradients, such as the high acidity or low oxygen levels that are common near tumor tissue. The term “bacteria-mediated tumor therapy” refers to the process of treating cancer by administering microorganisms nearby.
Bacteria-based biohybrid microrobots with medical functionalities could one day battle cancer more effectively. It is a new therapeutic approach not too far away from how we treat cancer today. The therapeutic effects of medical microrobots in seeking and destroying tumor cells could be substantial. Our work is a great example of basic research that aims to benefit our society.
Professor Dr. Metin Sitti
The patients’ immune systems are triggered as a result of the microorganisms moving to the tumor, growing there, and spreading. For more than a century, bacteria-mediated tumor therapy has been a form of treatment.
Researchers have been attempting to boost this microorganism’s superpowers for the past few decades. They provided bacteria with more tools to aid in the struggle.
However, incorporating artificial elements is not a simple operation. There are intricate chemical processes at work, and to prevent dilution, the density rate of particles placed onto the bacterium is important. The Stuttgart team has now set a very high standard. They were successful in delivering liposomes and magnetic particles to 86 out of 100 bacteria.
The researchers demonstrated how they were able to steer such a high-density solution externally in various directions. First, through a small, L-shaped conduit with two compartments on either end, each containing a tumor spheroid. Then, a setup that was much more restricted and resembled microscopic blood vessels They demonstrated how they accurately steer the drug-loaded microrobots toward tumor spheroids by adding an additional permanent magnet on one side.
Third, taking things a step further, the scientists guided the tiny robots through a thick collagen gel that had three different stiffness and porosity levels, from soft to medium to stiff, and looked like tumor tissue.
Bacteria have a harder time breaking through the matrix the stiffer the collagen is and the tighter the protein string web is. The researchers demonstrated that once a magnetic field is added, the bacteria can navigate all the way to the other end of the gel due to their increased force. The germs penetrated the fibers due to continual alignment.
A near-infrared laser that creates beams with temperatures of up to 55 degrees Celsius causes the liposome to melt and release the medications inside after the microrobots have gathered at the targeted location (the tumor spheroid).
The medications are automatically released around a tumor as a result of the nanoliposomes breaking open in an acidic or low pH environment.
“Imagine we would inject such bacteria based microrobots into a cancer patient’s body. With a magnet, we could precisely steer the particles towards the tumor. Once enough microrobots surround the tumor, we point a laser at the tissue and by that trigger the drug release. Now, not only is the immune system triggered to wake up, but the additional drugs also help destroy the tumor,” says Birgül Akolpoglu, a Ph.D. student in the Physical Intelligence Department at MPI-IS.
She is the first author of the publication titled “Magnetically steerable bacterial microrobots moving in 3D biological matrices for stimuli-responsive cargo delivery” co-led by former postdoctoral researcher in the Physical Intelligence Department, Dr. Yunus Alapan. It was published in Science Advances on July 15, 2022.
“This on-the-spot delivery would be minimally invasive for the patient, painless, bear minimal toxicity and the drugs would develop their effect where needed and not inside the entire body,” Alapan adds.
“Bacteria-based biohybrid microrobots with medical functionalities could one day battle cancer more effectively. It is a new therapeutic approach not too far away from how we treat cancer today,” says Prof. Dr. Metin Sitti, who leads the Physical Intelligence Department and is the last author of the publication.
“The therapeutic effects of medical microrobots in seeking and destroying tumor cells could be substantial. Our work is a great example of basic research that aims to benefit our society.”
