Korean scientists have developed magnetically controlled micro-robots as a platform for the culture and delivery of targeted stem cell therapy, which were shown to function successfully in a three-dimensional (3D) in vitro micro-organ model mimicking the in vivo environment.

Reported May 29, 2019, in Science Robotics, the study’s findings demonstrated that the magnetically manipulated micro-robots facilitated the rapid and precise targeting of transplanted stem cells in vivo.

The use of neural stem cells (NSCs) or neural cells differentiated from other stem cells is a promising regenerative medicine approach for treating neurodegenerative diseases.

Recent research also suggests that embryonic, adult or induced pluripotent stem cells may also be useful for treating multiple other disorders, ranging from developmental and pediatric diseases, to metabolic disorders, cancer and ischemia.

However, such stem cell therapies require the precise delivery of stem cells to the targeted tissues, with particular promise being shown in that regard by magnetically actuated micro-robots.

Magnetically actuated micro-robots

Those devices facilitate stem cell transplantation in fluid environments, they but can also be used for biomedical applications, such as the delivery and application of neural cells at neural interfaces, and cell or drug delivery.

Due to their microscopic size and magnetic controllability, micro-robots offer several advantages as medical treatments, including less pain, and reduced risks of infection and trauma.

To date, several micro-robots have been developed with different magnetic field control systems, enabling accurate and efficient propulsion in physiological fields.

“Magnetic nanoparticles are currently under evaluation for a range of biomedical applications, but nano/micro-robots are mostly at the research level or in the early stages of clinical use or trials,“ said lead researcher Hongsoo Choi, a professor in the Department of Robotics Engineering at the Daegu Gyeongbuk Institute of Science and Technology (DGIST).

“Nonetheless, I am reasonably confident that within the next five years or so, such devices will be in clinical trials or usage,” Choi told BioWorld.

Most previous micro-robot studies have been tested in 2D cell cultures and have had too few cells loaded onto the device. Those issues can be overcome by using 3D cell cultures, while a rotating magnetic field may induce more efficient and controllable maneuverability of micro-robots in a confined in vivo fluid environment.

In the new Science Robotics study, Choi and his DGIST research team developed biocompatible porous micro-robots and assessed their feasibility for 3D culture and targeted delivery of stem cells using magnetic propulsion.

The spherical and helical micro-robots, which showed rolling and corkscrew motions in response to a rotating magnetic field, showed significantly better propulsion efficiencies than those pulled by a magnetic field gradient.

Immunofluorescence staining and scanning electron microscopy were used to show that hippocampal NSCs successfully attached to the micro-robots, where they proliferated and selectively differentiated into astrocytes, oligodendrocytes and neurons.

The researchers then showed that the application of an external magnetic field enabled the micro-robots to transport human colorectal cancer cells to a tumor micro-tissue target in an in vivo body-on-a-chip liver tumor micro-organ network model.

Magnetic control of the micro-robots was further demonstrated ex vivo in a ventricle of mouse brain slice and in a rat brain blood vessel.

Moreover, micro-robots carrying mesenchymal stem cells derived from the human nose were magnetically manipulated successfully inside the peritoneal cavity of a nude mouse model.

Those are important findings, because “in our study, human stem cells were cultured, differentiated and delivered by micro-robots, demonstrating their potential for use in targeted human stem cell therapy,” Choi said.

“In most previous studies done elsewhere, researchers have only shown proliferation of cells from the micro-robot onto the bare surface of a substrate.

“Therefore, our study showed potential and proof of concept for the use of micro-robots for targeted stem cell therapy in a more physiological environment and from a more practical viewpoint than previous studies,” said Choi.

Regarding safety, he said, “we coated the outer surface of the micro-robots with titanium to enhance their biocompatibility, although long-term in vivo studies will be needed to confirm immune responses in humans.”

Moreover, the magnetic field should not prove problematic, “because the rotating magnetic field that we used in our experiments is significantly weaker than that employed in MRI.”

Together, those study findings demonstrate the feasibility of using micro-robots for targeted stem cell culture, transportation and transplantation in various in vitro, ex vivo and in vivo physiological fluid environments.

Looking forward, “long-term biocompatibility and efficacy need to be confirmed in animal studies, before clinical trials might be approved, but such approvals depend not only on the micro-robots, but also on other parameters,” said Choi.

“Meanwhile, we are planning to investigate further the differentiation and delivery of stem cells loaded onto micro-robots in in vivo models.”