From Ant-Man to the incredible shrinking machine, society has long foresaw the development of devices tiny enough to penetrate human cells. Such nanotechnology could revolutionize the diagnosis of diseases such as cancer and neurodegeneration, embrace new methods of precise drug delivery, and even directly repair damaged organs.
Nanomaterials are already being used in a variety of products such as sunscreens, food and cosmetics, but equipping these tiny particles with more active functions is a nanomedicine's dream. Although researchers in academia and industry are equally involved in the development of nanorobotics in medicine, reducing the size of any equipment creates a fair share of problems.
DNA molecule at nanoscale A is 2.5 nm; proteins 10 nM; virus 100 nm;
bacteria 1000 nm; human cells 10,000 nm.
On a normal scale, the main task seems simple: movement. But at the nanoscale, no battery is small enough to power a nanorobot. Teams around the world are exploring various options for controlling nanorobots in the body, from the use of electromagnetic and chemical methods to the impact on nature.
The second problem is the body itself. To perform their function effectively, nanorobots must evade the many defenses that the body uses against tiny intruders, overcoming or evading natural barriers (such as the blood-brain barrier), and withstanding sometimes harsh conditions such as a sour human stomach or a T-filled stomach. cells in the bloodstream. Moreover, any nanomaterials used in the body will need to be evaluated for toxicity and to prevent unwanted immune responses.
Moreover, science itself is still understood. One nanometer is 100,000 times smaller than the diameter of a hair, and when you compress things to that size, the properties of the materials change dramatically. Forces that would normally not need to be taken into account, such as the effect of nearby molecules, are now taken into account. Despite these challenges, this area, while still in its infancy, is making progress in these areas, and researchers are optimistic about the potential of nanorobots to revolutionize targeted medicine, especially cancer.
Nature as inspiration
Most nanotechnology in medicine involves the use of small particles to transport materials and deliver them into or inside cells. Such delivery often happens by accident; However, controlled delivery efforts are aimed at developing very simple robotic systems, consisting of a payload and a shell, that can be targeted at a specific object. These devices are driven by external forces such as electromagnetic fields, or manufacturing technologies that use chemical or biological reactions.
“The topic of nanomedicine as containers that can deliver pharmaceutically active compounds in a targeted manner has been around for a long time,” says Per Fischer, professor of physical chemistry at the University of Stuttgart, who heads the independent laboratory for micronano- and molecular systems at the Max Planck Institute for Intelligent Systems in Stuttgart). “What is difficult to do and what many groups are focused on is to make these carriers active. For example, instead of relying on a passive diffusion process to distribute the drug in the blood, a controlled swarm of nanoparticles can be sent to hard-to-reach areas such as a tumor. ”
When it comes to creating motion, brute force mechanics is not a good approach at the nanoscale because it is difficult to create this force locally. What's more, nanorobots targeting organs such as the lungs, intestines, stomach or eyes, for example, must deal with one of the body's primary defenses against micro-intruders: complex body fluids such as mucus.
In an effort to solve the problem of locomotion and penetration through mucus, Fischer's team turned to the ulcer-causing bacteria Helicobacter pylori for inspiration, both because of their corkscrew shape and their ability to secrete enzymes and break down mucus. The bacteria's small size and shape allows them to move through soft tissues and fluids, such as mucus, where movement is necessary, such as drilling (rather than swimming), to propel. This is because as size decreases, what once appeared to be a homogeneous liquid transforms into a more "spaghetti-like" molecular network of macromolecules, Fisher explains. If the propeller diameter is small enough, it can drill holes in this mesh.
“This is how very small systems can actively break these penetration barriers with very little force,” says Fischer. "A bacterium is literally a drill."
Fischer's group mimics the shape of a pathogen's corkscrew, using a custom 3D manufacturing process to create small propellers roughly 400 nm long (about 20 times smaller than a human blood cell) made from silica and other materials. These propellers make a similar corkscrew motion through the liquid and can be controlled using magnets (Figure 2). A joint team led by the Max Planck Institute for Intelligent Systems reported using this technique to create slippery nanoships that successfully drilled through a dissected pig's eye without damaging tissue, demonstrating the feasibility of precision eye surgery devices.
In addition to propellers, lithography and fabrication techniques allow them to create billions of nanorobots in a matter of hours from different materials to perform different functions.
This is where the next bacteria-inspired idea comes in: tap into microparticles by giving them a chemical energy source, not mechanical or magnetic. This chemical engine will be made up of half of the nanoparticles containing chemicals that, when released, create an imbalance in concentration gradients, forcing the flows to move the particle in the desired direction. This would be better than a magnetic control system, Fischer said, because it would allow it to operate autonomously.
“We want to adapt these chemical reactions so that the particle not only moves, but also responds to external signals and gradients,” says Fischer. “In principle, it would be a very elegant way to create nanosystems that could move and move without external control.
A research team in Canada is also inspired by bacteria: Sylvain Martel, director of the Montreal Polytechnic Laboratory for Nanobotics, has worked for decades to combine living, floating bacteria with microscopic magnetic balls to create hybrid devices that can be controlled, for example, using MRI. Bacteria move on their own thanks to their tails (flagella), and magnets guide them where they need to.
These self-propelled and guided hybrid "nanobots" can potentially be used as a targeting vehicle for hard-to-reach tumors. As detailed in, Martel and his collaborators have shown how a swarm of these devices - made up of millions of bacteria combined with sensors and magnetic beads - can reach tumors in mouse models. Martel is optimistic about this approach to treating tumors that are often unavailable with conventional chemotherapy.
“Therapies nowadays work systemically, causing serious toxicity to the patient, while limiting the amount of therapeutic agents reaching tumors,” says Martel. “A robotic approach can help achieve such a goal, and to that end, a broader interdisciplinary approach involving biomedical engineers, who until now has been largely absent in this particular field, can help counter many of the major barriers that drug delivery faces in cancer therapy and where nanotechnology plays an important role. "
The world's smallest medical robot
At the moment, the device, created by professors of the University of Texas at San Antonio Ruyan Guo and Amar Bhalla, along with their doctoral student Soutik Betal, is listed in the Guinness Book of Records as the smallest medical robot in 2018. Their 120nm robot can push minuscule payloads and penetrate cell membranes, and they hope these abilities will make it useful for medical applications.
“One feature that we have documented is the ability to move cells from one position to another. The second feature is the ability to penetrate the cell membrane, which is difficult for most nanoparticles, ”says Bhalla.
"Normal nanocomposites are larger than the cell membrane channel, so they cannot easily enter the cell," adds Guo. "But because of the size of our particles and the function of the rotation and rotating element, controlled by the field, we can direct our nanorobots to penetrate the cell membrane, which would allow you to directly release a payload, for example, to kill cancer cells."
The team, which is developing partnerships and has a pending technology patent, plans to continue to understand design principles to improve the governing interactions with cell membranes. Ultimately, they target not only cancer, but blood clots as well, and may one day repair brain cells affected by Alzheimer's. Apart from medical applications, they are also exploring the possibility of using their nanoparticles in the communication field.
Combining biology and engineering
In addition to electromagnetic research, others are using biology itself to develop and control nanoparticles.
Yang (Claire) Zeng, Ph.D. and Research Assistant at Shi Laboratory at the Dana Farber Cancer Institute / Harvard Medical School's Cancer Biology Division, combines nanoscale materials research with cancer immunotherapy, with a focus on nanodevices made up of folds of DNA to store payloads - essentially , organic nanorobots (Fig. 3, right).
The origami technique, pioneered by Paul Rothemund of the California Institute of Technology, typically involves folding long strands of a DNA scaffold into smaller strands that act as staples to form two-dimensional or three-dimensional shapes. Since then, Shih Lab has built this approach and made headlines about using DNA origami to develop various forms of three-dimensional DNA nanoparticles that can hold payloads - essentially DNA nanobots designed for medical applications such as cancer and HIV. The devices consist of hundreds of short, single-stranded DNA sequences of 40-50 base pairs arranged on a scaffold, with a "hinge" at the end of the double helix to hold the payload, like a cancer drug. According to Zeng, they can hold multiple payloads simultaneously and in desired positions on the origami structure.
One of the factors influencing clinical use is the potential for unwanted toxic side effects. According to Zeng, the advantage of the organic approach is that the toxicity of this material is very low. “Once you deliver the organic nanorobot to the body, after it has completed its function, it can be digested by your cells like any other cellular debris,” she says.
Others are also accelerating medical research on nanorobots and completing clinical trials. Debabrata (Developer) Mukhopadhai, Ph.D., director of the Mayo Clinic Nanotechnology Lab in Florida, is close to completing phase 1 clinical trials of a nanotechnology-based drug delivery system targeting aggressive tumors.
“In addition to drug delivery, we aim to use nanoparticles to monitor the therapeutic outcome of a tumor in real time,” says Muhopadhai, who points out that often, when people are given chemotherapy, it will take months before it becomes clear if a therapeutic drug is working. ,
The laboratory is also engaged in the development, testing and application of nanorobots in other areas of medicine, especially in cardiovascular diseases (delivery of nanogel to repair arteries) and dementia in the early stages (for example, the biomarker nanoimaging system), as well as in other immune disorders.
Research into the use of nanobots and materials to treat cancer has been gaining momentum in the past few years, and work also being done at Mayo Clinic has made progress in the fight against a particular cancer. Research led by Professor Betty Kim has demonstrated a proof of concept that antibody-coated nanomaterials target the breast cancer receptor, combined with molecules that activate the immune system, act as flags on cancer, helping immune cells to target tumor cells to attack. And, moving towards early detection of cancer, Professor Shang Wang of the Stanford Nanotechnology Cancer Center has detailed an approach to using sensor technology and magnetic nanoparticle clusters to attach to DNA and label cancer cells.
Despite these advances, it will be time before we see fully implemented nanorobots in use.