Massachusetts Institute of Technology (MIT) researchers in Cambridge, Massachusetts, have taken another page right out of a science fiction novel. This time, by designing and building microscopic, wireless bioelectronics that can travel through the circulatory system and autonomously implant themselves in an inflamed region of the brain to deliver precise neuromodulation as treatment. 

All it takes is a simple injection in the arm.

While current bioelectronic implants for brain stimulation have shown promise for treating diseases such as Alzheimer’s and multiple sclerosis, they are surgically invasive, expensive, and prone to infection, morbidity, and mortality. 

This reality underscores the potential for what MIT researchers are referring to as “circulatronics” and inspired Deblina Sarkar, PhD, head of the Nano-Cybernetic Biotrek group at MIT Media Lab and senior author of the new study, to switch her research specialty from nanoelectronics to neuroscience.

The goal was to reimagine subcellular-sized wireless electronic devices (SWEDs) for the brain. “Circulatronics emerged from the idea that electronic systems should seamlessly integrate with biology — by being subcellular, autonomous, and capable of self-implantation — rather than forcing the brain to accommodate large, surgically implanted hardware,” Sarkar said.

These self-implanting electronics mark the first of their kind, potentially ushering in a new paradigm of autonomous and surgery-free brain-computer interfaces.

How They Did It

Apart from creating the devices themselves, one of the main challenges was figuring out how to make them go where they needed to go.

By integrating these minuscule implants with living immune cells (monocytes) and injecting them into mice, the MIT researchers observed their ability to take advantage of the immune cells’ natural trafficking — without getting attacked by the immune system, damaging surrounding neurons, or needing human guidance. The biocompatible implants were then able to identify, travel to, and implant themselves into sites of inflammation in the brain, successfully crossing the blood-brain barrier and leaving it intact. The team applied a fluorescent dye onto the devices to easily trace their journeys and eventual destination.

“In this study, the nanoelectronic devices are integrated with immune cells that naturally circulate and home to defined target regions in the brain,” said Sarkar. “We chose regions of inflammation as the target for the first demonstration of our technology, as inflammation is the fundamental hallmark and key therapeutic target of many diseases in the central and peripheral nervous systems, including neurodegenerative diseases, movement disorders, brain injury, chronic pain, cancers, and mental illnesses.”

And that’s the ideal outcome here: The ability to modify the cells these devices attach to so they can target specific conditions as needed. “In our lab, we have promising results in Alzheimer’s disease, glioblastoma, and chronic pain,” said Sarkar. “The electronics themselves do not independently detect disease signals; instead, they leverage the highly evolved sensing and trafficking capabilities of the cells they are attached to. Once the hybrids reach the target region and exit the vasculature, the devices autonomously self-implant within the tissue microenvironment.”

Once the devices have self-implanted, the researchers can wirelessly power them through electromagnetic fields via an external transmitter, allowing the devices to provide electrical stimulation, in the form of near-infrared light, to a precise area of the brain as treatment, especially for diseases where drugs have proved ineffective.

“The devices are untethered and do not require physical alignment or wiring. They respond to externally applied wireless electromagnetic fields generated by the transmitter,” said Sarkar. “The high precision of stimulation achieved (30 µm around the target) is due to the precise self-implantation of the electronics in the target brain region; localization of the wireless fields is not required, eliminating the need for complex transmitter design or complicated imaging to locate the target.”

Examining the Potential

Thanks to how tiny and precise the devices are, detecting these diseases much earlier and more accurately may also be possible. “The autonomous recognition of targets through biochemical sensing and the self-implantation capabilities of circulatronics enable targeting diseases at early stages where pathological sites are small or diffuse microscopic tumor sites, which cannot be detectable through imaging,” said Sarkar.

Just as the team will choose different cells to attach these devices to target different diseases, they will also have to adapt the electromagnetic waves these devices will provide depending on the disease at hand. “Different diseases will require different stimulation parameters, including frequency and temporal patterns,” said Sarkar. “These parameters are determined through computational modeling, preclinical studies, and clinical trials to establish safe and effective therapeutic windows.”

Creating and designing these devices to work as intended involved a long process of trial-and-error for more than 6 years. “Early versions were larger and less efficient,” Sarkar said, “specifically in the free-floating substrate-free format. Subsequent iterations focused on shrinking device dimensions to the sub-cellular scale, increasing wireless power conversion efficiency, improving mechanical flexibility, and enhancing long-term biocompatibility. Each iteration addressed a specific technical or biological constraint.”

After several iterations, the team ended up with a device about one-billionth the length of a grain of rice — significantly smaller than a single cell. The device is composed of semiconducting organic polymer layers sandwiched between complementary metal-oxide-semiconductors to create a three-layer heterostructure. This structure integrates with living cells to create the cell-electronic hybrids.

A glimpse into how painstaking the work could be: The devices would initially work when attached to the silicon wafer on which they were fabricated, but not when they were lifted off the substrate. Figuring out how to get the devices to work while free-floating in a solution — by splitting the wafer into smaller chips, putting them inside a glass vial of diluted tetramethylammonium hydroxide-based solution, and moving the vial into a sonification bath to etch a sacrificial aluminum layer — took the researchers more than a year.

After that, all that remained was getting devices to bond with immune cells.

“We employed a bio-orthogonal surface chemistry strategy that enables stable covalent bonding between the device surface and cell membranes under physiologic conditions without compromising cell viability,” said Sarkar. “This approach is modular and can be adapted to other immune or cell types.”

Still Many Hurdles to Clear

Before this tech becomes anywhere close to a widespread possibility, however, the team has to address major components.

One being the best way these devices might detach themselves before self-implanting. “After arriving at the site, it is inferred that SWEDs are deposited in the inflamed brain region either due to cellular processes (such as phagocytosis, apoptosis, or local microenvironmental factors) or simply by the monocyte ceasing to migrate further, leaving the device at the target site,” said Philip McCarthy, DO, practicing neurologist and epileptologist at Corewell Health in Grand Rapids, Michigan (he is not involved in the research). “The exact molecular or cellular mechanism of detachment or ‘release’ is not explicitly engineered or specified in the current study.”

The MIT researchers have ideas for this, especially if the devices might be required to stay in the target region of the brain for longer periods. In the future, the team may design the devices with attachment linkers that will self-degrade after a few days or are cleavable with external fields (such as light-cleavable linkers) or with biological cues (pH, proteases, and other biomolecules).

Another unknown: Can it work in humans? “It is unclear if the infrared light can penetrate the human skull as it does the mouse model,” said McCarthy. “There is no explanation of long-term outcomes or excretion of the device, or if additional therapies would be necessary or safe.”

That’s where Sarkar’s newly launched startup, Cahira Technologies, comes in: to accelerate the research discussed here and apply it to humans. The team’s current estimate on when they will be able to bring their work to a clinic is about 3 years.

“Safety is the biggest concern before circulatronics become commonplace,” McCarthy emphasized. “If something does go wrong with the device, there is presumably no way to extract all [the] SWEDs.”

As Sarkar’s team works to further develop and perfect the tech, they continue to focus on the potential. “It could be helpful in recovery from traumatic brain injuries, strokes, tumors, as neurostimulation could promote cellular recovery,” said McCarthy. “This would [also] have a place in epilepsy, likely from an acute status epilepticus standpoint, where the cells are seizing for such a long period of time that there is swelling and inflammation as a response.”

And more: Using self-implantation in the brain as a proof point, the team wants to make this a “platform technology” and is also pursuing self-implanting pacemakers for the heart, spinal cord stimulators, and vision prostheses.

The study was supported by research grants and philanthropy. Sarkar and three coauthors reported being inventors on a patent application related to autonomous and nonsurgical implants. Sarkar reported being the founder of the start-up Cahira Technologies. The other authors declared having no competing interests.