In the future, tiny robots might be responsible for delivering medications precisely to where they are needed in the body. Instead of relying on miniature humanoids or robot replicas of nature, envision small bubble-like spheres.
These innovative robotic spheres must meet numerous tough requirements. They need to endure harsh bodily environments, like stomach acid, and be controllable for precise targeting. Moreover, these robots should only dispense their therapeutic contents when they arrive at the designated area and be able to be absorbed by the body without adverse effects.
Researchers at Caltech have now developed microrobots that meet these criteria. These bots successfully delivered medications that reduced the size of bladder tumors in mice, as detailed in a study published in Science Robotics.
“We’ve created a versatile platform that tackles all of these challenges,” explains Wei Gao, a medical engineering professor at Caltech and co-corresponding author of the paper on these microbots, which the team refers to as bioresorbable acoustic microrobots (BAM).
“Instead of injecting a drug and allowing it to disperse throughout the body, we can now navigate our microrobots directly to a tumor and release the medication effectively and in a controlled manner,” states Gao.
The idea of micro- or nanorobots isn’t new, with considerable research in the field over the past twenty years. However, deploying these devices in living organisms has faced challenges, primarily due to the complexities of precisely moving objects within dynamic biological fluids like blood, urine, or saliva, according to Gao. Additionally, the robots must be compatible with biological systems and not leave behind any harmful residues.
The microrobots created by Caltech are spherical microstructures made from a hydrogel known as poly(ethylene glycol) diacrylate. Hydrogels begin in a liquid state and solidify when their polymer networks cross-link. This structure enables them to hold significant amounts of liquid, and many hydrogels are biocompatible. The method used to fabricate these microrobots allows their exterior to carry therapeutic agents to the site of action inside the body.
To refine the hydrogel formulation and craft the microstructures, Gao collaborated with Julia R. Greer of Caltech, who specializes in materials science and medical engineering. Her research group employs a technique known as two-photon polymerization (TPP) lithography, which utilizes rapid infrared laser pulses to carefully cross-link photosensitive materials in a specific pattern. This method constructs structures layer by layer, similar to traditional 3D printing but with much higher precision and complexity.
Greer’s team successfully “printed” microstructures approximately 30 microns wide, similar to the thickness of a human hair.
“Creating this specific spherical shape is very tricky to achieve,” Greer points out. “It requires mastering some specialized techniques to prevent the spheres from collapsing. We not only developed a resin that contains all required medical functionalities, but we also accurately shaped these structures into perfect spheres with internal cavities.”
In their final design, the microrobots include magnetic nanoparticles and therapeutic agents integrated within the sphere’s outer layer. The presence of magnetic materials allows researchers to steer the robots using an external magnetic field. Upon reaching their destination, the robots remain in position while the medication is gradually released.
The microstructure’s surface was designed to be hydrophilic—attracted to water—to ensure the microrobots do not group together while moving through the body. Nevertheless, the internal surface must be hydrophobic to retain an air bubble, preventing it from collapsing.
To achieve a hybrid design featuring a hydrophilic exterior and a hydrophobic interior, researchers implemented a two-step chemical process. Initially, they bonded long-chain carbon molecules to the hydrogel, rendering it hydrophobic. They then used a process called oxygen plasma etching to strip some of these long-chain structures from the inner surface, creating a hydrophobic outer layer and a hydrophilic inner surface.
“This development was a significant innovation for the project,” Gao states, also noting his status as a Ronald and JoAnne Willens Scholar. “This distinct surface treatment allows us to use many robots while effectively retaining air bubbles for extended periods in biological fluids like urine or serum.”
Indeed, the team demonstrated that the air bubbles could persist for several days with this modification, compared to just a few minutes without it.
These trapped bubbles not only aid in the movement of the microrobots but also enable real-time tracking through ultrasound imaging. To facilitate propulsion, the design incorporates two cylindrical openings—one at the top and one on the side. When subjected to an ultrasound field, the bubbles vibrate, pushing fluid away through the openings, which propels the robots. Gao’s team discovered that two openings allowed for movement through various viscous biofluids and yielded faster speeds compared to a design with a single opening.
Each microrobot harbors an egg-like air bubble that serves as an effective contrast agent in ultrasound imaging, allowing for real-time monitoring of the bots in vivo. The team collaborated with ultrasound imaging specialists Mikhail Shapiro, Di Wu, and Qifa Zhou to track the microrobots as they navigate to their targets.
The concluding phase of the project involved testing the microrobots for drug delivery in mice with bladder tumors. Researchers found that administering therapeutics using the microrobots over 21 days resulted in greater tumor reduction compared to methods that did not utilize robotic delivery.
“We believe this platform shows great promise for targeted drug delivery and precision surgery,” Gao asserts. “Looking ahead, we could explore using these robots to deliver different therapeutic payloads for various conditions, and in the long run, we aspire to test this approach in human patients.”
This research was supported by the Kavli Nanoscience Institute at Caltech, National Science Foundation funding, Heritage Medical Research Institute grants, the Singapore Ministry of Education Academic Research Fund, National Institutes of Health funds, Army Research Office support via the Institute for Collaborative Biotechnologies, and contributions from the Caltech DeepMIC Center, aided by the Caltech Beckman Institute and the Arnold and Mabel Beckman Foundation, as well as the David and Lucile Packard Foundation.
