Cell-Electronics Hybrids: Immune Cells For Neural Modulation!

Can we merge electronics and cellular biology?

Well, today’s paper pushes us 10 steps ahead, creating cell-electronics hybrids that can modulate neuronal application! No surgery and no battery required.

Cell-Electronics Hybrids

Electrical modulation of the brain is a real treatment option for many diseases.

From Parkinson’s to Alzheimer’s, depression, and chronic pain, electrical currents can modulate the activity of neurons in specific areas, improving the lives of countless patients. And these bioelectronic implants are also used in research, helping us map the brain in ways we couldn’t have dreamed of decades ago.

But there’s a (major) catch.

These powerful methods require invasive surgery on the skull. This brings so many risks, as you can imagine: pain, infections, psychological distress, and more.

Alternatives are not great either.

Endovascular electrodes reduce the risk of the surgery, but they sacrifice spatial precision and access to most brain regions. Noninvasive methods often are not precise enough or too weak for clinical use.

BioElectronic to the Rescue

At the same time, biological systems have built-in targeting mechanisms.

Immune cells zero in on inflamed sites throughout the body, including the brain. And unlike most drugs and devices, they can cross the blood-brain barrier, a semipermeable membrane protecting the brain from pathogens and toxins.

Meanwhile, bioelectronics has pushed the miniaturization of devices to crazy levels. Researchers have fabricated functional circuits that are only a few millimeters wide, on the scale of a cell! And the devices can work remotely, using external energy sources.

The Best of Both Worlds

“Can we merge the two?”

Of course, that’s what the authors of today’s paper thought.

They built Circulatronics: tiny electronic devices covalently attached to immune cells, creating cell-electronics hybrids. They are injected intravenously, travel to inflamed brain regions, and implant themselves, ready to stimulate neurons. All of this without surgery!

Let’s see how they achieved this sci-fi-sounding feat.

Device Design and Fabrication

The authors designed the subcellular-sized wireless electronic devices (SWEDs) from scratch. They needed to be:

1. About the size of blood cells (to circulate freely)

2. Able to convert external fields into electrical neuromodulation.

For powering, they focused on the photovoltaic principle. This is what happens in solar panels: the generation of electric currents when light hits a semiconductor material.

Now, for a simple explanation (I’m no physicist, we all know it):

• Photon absorption: Photons strike the semiconductor material, which absorbs them

• Electron excitation: The energy from the absorbed photons frees electrons from their atoms

• Charge separation: An internal electric field is formed in the devices, which forces the free electrons to flow towards the negative side and the “hole” (representing missing electrons) to the positive side.

• Current generation: This separation of charges creates a voltage. Once you connect a circuit, the accumulated electrons flow from the negative to the positive side, creating a current!

Near-infrared (NIR) light activates the SWEDs, since it’s able to pass through skin and other tissues.

The authors engineered ultrathin electronics (~200 nm!) on a silicon wafer, with lateral scales ranging from 200 µm to 5 µm (subcellular size!). Even at 10 µm, the devices can generate nanowatts of power, and they can still produce usable power when NIR light passes through brain tissue (and skull) in ex vivo tests.

Crazy stuff!

Forming Cell-Electronics Hybrids

Now for the next step: attaching SWEDs to cells.

Their choice fell onto monocytes, immune cells involved in phagocytosis and antigen presentation. But more important here is their ability to freely move from the bloodstream into inflamed areas. And in this case, the inflamed regions in the brain.

So, the team attached the SWEDs to the monocytes using click chemistry, much like sticking a backpack onto them (that’s how I like to think about it). They created cell-electronics hybrids!

The hybrids are then purified using fluorescence sorting, and they are quite stable, with over 85% remaining intact during an assay for migration out of blood vessels.

Heading For the Brain and Neuromodulation

The theory sounds solid, but does it work?

The team induced focal inflammation in a mouse model to mimic a disease target. Then, they injected the cell-electronics hybrids.

The hybrids navigated through the bloodstream, with the SWEDs strapped to the cells. Once in the brain, they left the blood vessels and self-implanted in the inflamed regions. Amazing!

After this, the real question is: can the hybrids modulate neuronal activation?

Once they were implanted, the researchers illuminated the mice's heads with NIR light for 20 minutes. And the hybrids worked, activating local neurons!

They confirmed this in vivo with:

• c-Fos immunostaining: The protein c-Fos is an early marker of neural activation. In the group with hybrids + light, c-Fos showed a 3x higher expression than the control, confirming the activation!

• Single-unit physiology: They measured the electrical activity in single neurons, which showed a response specific to hybrid stimulation (versus controls).

Biocompatibility and Safety

Of course, they also checked the biocompatibility of the cell-electronics hybrids.

They performed both in vitro cytotoxicity assays and in vivo monitoring, and neither showed acute toxicity signals. Imaging and biodistribution studies indicated that the hybrids are cleared over ~10 days, with the mice maintaining normal weight.

Now, of course, these are short-term studies, and there is a need for long-term studies, but it’s a great start!

Why It’s Exciting: Strengths and Weaknesses

Well, of course it’s exciting: it’s super cool!

Okay, okay, not only because of that:

• Non-surgical and programmable: Surgery can be a real issue for people suffering from neural disease (especially if older). It’s dangerous and not always practical. Using biology to deliver minimally invasive neuromodulation offers an incredible alternative.

• Subcellular-scale electronics that demonstrate photovoltaic power? Amazing.

• Neuromodulation demonstrated in vivo: They showed that their devices work in mice, and they’re not toxic

It’s a groundbreaking study, so there are (many) limitations. But they can also open new avenues for exploration and applications:

• Limited targeting: The targeting is based on inflammation, and it doesn’t extend to other conditions. Plenty of space for different cell type choices, engineering, or surface functionalization (time to stick some DNA origami on these chips)!

• Optical powering and tissue penetration: NIR light can penetrate tissues, but it struggles with thicker ones. There might be a need for a different energy source for clinical translation.

But ehi, amazing work! Also, with electronics this small, you can load them with other functionalities: improved sensors, or nanotransistors for logic. And of course, the range of diseases is huge, even with just inflammation! Lots of possibilities.

But don’t hesitate to read the paper here! Lots of interesting details.

If you made it this far, thank you! Do you see a future for cell-electronics hybrids? Do you work on something similar? Reply and let me know!

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