Inspired by nature, artificial microtubules c

image: Although free-swimming microrobots have been explored as a way to precisely deliver therapeutic agents into a blood vessel, they can scatter in strong flows, failing to reach their target in high enough concentrations. By contrast, microrobots propelled along an artificial microtubule, developed by physicist Arnold Mathijssen and his colleagues, can be transported precisely, even against the current.
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Credit: Adapted from Gu, H., Hanedan, E., Boehler, Q. et al. Artificial microtubules for the rapid and collective transport of magnetic microcargoes. Nat Mach Intelligence (2022). https://doi.org/10.1038/s42256-022-00510-7

Like a microscopic bucket brigrade, an artificial microtubule can rapidly transport tiny particles along magnetic stepping stones, delivering them to a precise location even when running against a strong current.

The technology, developed by a team from the University of Pennsylvania and ETH Zürich, could one day make it easier to deliver targeted therapies through the bloodstream to treat blocked vessels or cancerous tumors.

The results are published today in the journal Intelligence of natural machines.

Researchers explored the potential for microrobots to “swim” through the bloodstream to direct drugs to exactly where they are needed. The downside of this approach is that free-swimming microrobots struggle to progress against the complex fluid flows that exist inside the human body.

“As a result, you often see the scattering of particles that you want to deliver,” says Arnold Mathijssen, corresponding author on the work and assistant professor in Penn’s Department of Physics and Astronomy. “Really what you’d like to achieve is to have the highest concentration of therapeutic at one site and not disperse it elsewhere because it could lead to toxicity.”

Catheters and microneedles have so far been the techniques of choice to complement these directed interventions. Yet catheters can only be miniaturized so far before they lack the pumping force needed to transport microscopic cargo. Likewise, even microneedles are still too big to reach the narrowest blood vessels.

To overcome these obstacles, Mathijssen and his colleagues drew inspiration from biology.

“When you look in nature, inside cells, there is a beautiful solution,” Mathjissen says. “Microtubules, which are part of the cytoskeleton, use molecular motors to transport vesicles to different places in the cell. These motors find a way to cope with the flow fluctuations we see in blood vessels and elsewhere in the body. We wanted to try to synthesize something similar in a nanotechnology context to see if we could use it as an efficient delivery mechanism.

Their bio-inspired design was an artificial microtubule, made first in Switzerland and later at the Penn’s Singh Center for Nanotechnology. These fine fibers, composed of cross-linked polymers to give them elasticity, were embedded with magnetic nickel plates, intercalated at defined distances like springboards. Only 80 microns wide, the microtubules would be narrow enough to pass through narrow blood vessels.

Applying a rotating magnetic field around the artificial microtubules turns the nickel stepping stones into magnets, along which a cargo of metallic microrobots “walk”, one after the other.

“We place the microtubules in a rotating magnetic field, just like an MRI machine,” says Mathijssen. “If you spin the field slowly, the particles move slowly, and when you spin faster, the particles also accelerate.”

There was a “sweet spot” in magnetic field strength, the scientists found; spinning too fast caused the particles to slide across the surface and away from the microtubule.

In experiments testing the performance of the transport mechanism in blood vessel-like networks, the research team found that microparticles could travel along the microtubule fiber even when subjected to strong fluid fluxes, tuned to mimic the dynamism of blood flow. Compared to existing technologies, the delivery of microcargoes happened quickly, an order of magnitude faster. And precise adjustments to the magnetic field ensured that cargo could be delivered precisely to the intended location, even in complex ship networks.

Not only is this new innovation inspired by nature, but Mathijssen notes that it can in turn provide insight into how biological systems work. He and his colleagues observed that as the microparticles moved between the stepping stones, they self-assembled, forming clusters, each attached to one of the stepping stones. Eventually, the assembled particles would push each other forward in a collective effort. While a few other groups have suggested that it might occur inside cells to enhance cytoskeletal transport, this work provides the first experimental proof of the propulsion principle.

“Sometimes you build something in the lab and it can teach you something new about biology,” he says.

To apply this microparticle transport strategy in practice, the researchers plan to replace nickel, which is toxic, with other materials, such as iron oxide, already approved by the FDA for internal use. They also keep an open mind as to how microtubules could be used. Targeted drug delivery and vascular plaque removal are obvious applications, but Mathijssen also envisions the benefits of a two-dimensional fiber. Wrapped around medical devices. Such a device could deliver antimicrobials to prevent the growth of dangerous bacterial biofilms.

“We believe these ‘micro-robotic micro-highways’ can provide an alternative to free-swimming micro-robots and other current technologies,” he says, “bringing robust biomedical microtransport closer to reality.”

Arnold Mathijssen He is an assistant professor at Department of Physics and Astronomy in the School of Arts and Sciences to University of Pennsylvania.

Mathijssen co-authored the study with Hongri Gu of ETH Zürich, Emre Hanedan, Quentin Boehler, Tian-Yun Huang and Bradley J. Nelson. Mathijssen, Gu and Nelson were corresponding co-authors.

The study was supported by the European Research Council (grant 743217), the Swiss National Science Foundation (grant 200020B_185039) and ETH (grant 1916-1).


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