Scanning electron microscope image of Caltech's
printed bioresorbable acoustic hydrogel microrobots. Credit: Hong Han
In the future,
delivering therapeutic drugs exactly where they are needed within the body
could be the task of miniature robots. Not little metal humanoids or even
bio-mimicking robots; think instead of tiny bubble-like spheres.
Such robots would have a long and challenging list of
requirements. For example, they would need to survive in bodily fluids, such as
stomach acids, and be controllable, so they could be directed precisely to
targeted sites. They also must release their medical cargo only when they reach
their target, and then be absorbable by the body without causing harm.
Now, microrobots that tick all those boxes have been
developed by a Caltech-led team. Using the bots, the team successfully
delivered therapeutics that decreased the size of bladder tumors in mice.
A paper describing the work titled "Imaging-guided bioresorbable acoustic hydrogel microrobots" appears in the journal Science Robotics.
An interdisciplinary team led by Caltech's Wei
Gao has created tiny bubble-like microrobots that can deliver therapeutics
right where they are needed and then be absorbed by the body. Using the bots,
the team successfully delivered therapeutics that decreased the size of bladder
tumors in mice. A paper describing the work appears in the journal Science
Robotics. Credit: Caltech
"We have designed a single platform that can address all of these
problems," says Wei Gao, professor of medical engineering at
Caltech, Heritage Medical Research Institute Investigator, and co-corresponding
author of the new paper about the bots, which the team calls bioresorbable
acoustic microrobots (BAM).
"Rather than putting a drug into the body and letting it diffuse
everywhere, now we can guide our microrobots directly to a tumor site and
release the drug in a controlled and efficient way," Gao says.
The concept of micro- or nanorobots is not new. People have been developing
versions of these over the past two decades. However, thus far, their
applications in living systems have been limited because it is extremely
challenging to move objects with precision in complex biofluids such as blood,
urine, or saliva, Gao says. The robots also have to be biocompatible and
bioresorbable, meaning that they leave nothing toxic behind in the body.
The Caltech-developed microrobots are spherical microstructures made of a
hydrogel called poly(ethylene glycol) diacrylate. Hydrogels are materials that
start out in liquid or resin form and become solid when the network of polymers
found within them becomes cross-linked, or hardens.
This structure and composition enable hydrogels to retain large amounts of fluid, making many of them biocompatible. The additive manufacturing fabrication method also enables the outer sphere to carry the therapeutic cargo to a target site within the body.
The flow patterns generated by an acoustic hydrogel
microrobot vibrating at its resonant frequency were analyzed using advanced
methods, including tracking tiny particles in water and computer-based
simulations. The position of the microrobot's two openings are clearly visible
here. Credit: Hong Han
To develop the
hydrogel recipe and to make the microstructures, Gao turned to Caltech's Julia
R. Greer, the Ruben F. and Donna Mettler Professor of Materials Science,
Mechanics and Medical Engineering, the Fletcher Jones Foundation Director of
the Kavli Nanoscience Institute, and co-corresponding author of the paper.
Greer's group has expertise in two-photon
polymerization (TPP) lithography, a technique that uses extremely fast pulses
of infrared laser light to selectively cross-link photosensitive polymers
according to a particular pattern in a very precise manner. The technique
allows a structure to be built up layer by layer, in a way reminiscent of 3D
printers, but in this case, with much greater precision and form complexity.
Greer's group managed to "write," or print
out, microstructures that are roughly 30 microns in diameter—about the diameter
of a human hair.
"This particular shape, this sphere, is very complicated to write," Greer says. "You have to know certain tricks of the trade to keep the spheres from collapsing on themselves. We were able to not only synthesize the resin that contains all the biofunctionalization and all the medically necessary elements, but we were able to write them in a precise spherical shape with the necessary cavity."
Caltech graduate students and lead authors of the
microrobots paper, Hong Han and Xiaotian Ma, collaborate with Professor Wei Gao
on experiments involving ultrasound imaging-guided acoustic propulsion of the
microrobots. Credit: Lance Hayashida/Caltech
In their final
form, the microrobots incorporate magnetic nanoparticles and the therapeutic
drug within the outer structure of the spheres. The magnetic nanoparticles
allow the scientists to direct the robots to a desired location using an
external magnetic field. When the robots reach their target, they remain in
that spot, and the drug passively diffuses out.
Gao and colleagues designed the exterior of the
microstructure to be hydrophilic—that is, attracted to water—which ensures that
the individual robots do not clump together as they travel through the body.
However, the inner surface of the microrobot cannot be hydrophilic because it needs to trap an air bubble, and
bubbles are easy to collapse or dissolve.
To construct hybrid microrobots that are both
hydrophilic on their exterior and hydrophobic, or repellent to water, in their
interior, the researchers devised a two-step chemical modification.
First, they attached long-chain carbon molecules to
the hydrogel, making the entire structure hydrophobic. Then the researchers
used a technique called oxygen plasma etching to remove some of those
long-chain carbon structures from the interior, leaving the outside hydrophobic
and the interior hydrophilic.
"This was one of the key innovations of this
project," says Gao, who is also a Ronald and JoAnne Willens Scholar.
"This asymmetric surface modification, where the
inside is hydrophobic and the outside is hydrophilic, really allows us to use
many robots and still trap bubbles for a prolonged period of time in biofluids,
such as urine or serum."
Indeed, the team showed that the bubbles can last for
as long as several days with this treatment versus the few minutes that would
otherwise be possible.
The presence of trapped bubbles is also crucial for
moving the robots and for keeping track of them with real-time imaging. For
example, to enable propulsion, the team designed the microrobot sphere to have
two cylinder-like openings—one at the top and another to one side.
When the robots are exposed to an ultrasound field,
the bubbles vibrate, causing the surrounding fluid to stream away from the
robots through the opening, propelling the robots through the fluid. Gao's team
found that the use of two openings gave the robots the ability to move not only
in various viscous biofluids, but also at greater speeds than can be achieved
with a single opening.
Trapped within each microstructure is an egg-like
bubble that serves as an excellent ultrasound imaging contrast agent, enabling
real-time monitoring of the bots in vivo.
The team developed a way to track the microrobots as
they move to their targets with the help of ultrasound imaging experts Mikhail
Shapiro, Caltech's Max Delbruck Professor of Chemical Engineering and Medical
Engineering, a Howard Hughes Medical Institute Investigator; co-corresponding
author Di Wu, research scientist and director of the DeepMIC Center at Caltech;
and co-corresponding author Qifa Zhou, professor of ophthalmology and
biomedical engineering at USC.
The final stage of development involved testing the
microrobots as a drug-delivery tool in mice with bladder tumors. The
researchers found that four deliveries of therapeutics provided by the
microrobots over the course of 21 days was more effective at shrinking tumors
than a therapeutic not delivered by robots.
"We think this is a very promising platform for drug delivery and precision surgery," Gao says. "Looking to the future, we could evaluate using this robot as a platform to deliver different types of therapeutic payloads or agents for different conditions. And in the long term, we hope to test this in humans."
by California Institute of Technology
Source: Tiny robots target tumors with precision drug delivery
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