MIT researchers have identified an unexpected effect in photophysics that could lead to a faster and more detailed way to image living tissue. Under certain conditions, a laser signal that normally appears scattered and chaotic can reorganize into a narrow, highly focused “pencil beam.”
Using this self-forming beam, the research team generated 3D images of the human blood-brain barrier approximately 25 times faster than current gold standard methods while maintaining similar image quality. This method also allows for real-time observation of drug uptake by individual cells. This could help scientists assess whether treatments for conditions such as Alzheimer’s disease and ALS are actually reaching their intended targets in the brain.
“A common belief in the field is that as you increase the power of this type of laser, the light inevitably becomes disordered. But we have shown that this is not the case. We have followed the evidence, accepted uncertainty, and found a way to organize light to create new solutions for bioimaging,” said MIT Department of Electrical Engineering and Computer Science (EECS) said Shixian Yu, assistant professor at , member of the Electronics Research Institute, and lead author of the imaging paper. technique.
EECS graduate student and first author Honhao Cao also contributed to the paper. EECS graduate students Li-Yu Yu and Kunzan Liu; postdocs Sara Spitz, Francesca Michela Plamotton, and Federico Presutti; Zhengyu Zhang PhD ’24; Subhash Kulkarni, assistant professor at Harvard University and Beth Israel Deaconess Medical Center. and Roger Kamm, Cecil and Ida Green Distinguished Professor of Biology and Mechanical Engineering at MIT. The paper is published today in Nature Methods.
Amazing laser behavior appears
This discovery began with an observation that was inconsistent with expectations.
Researchers had previously built precision fiber shapers, devices that can carefully control laser light passing through multimode optical fibers that can transmit high levels of power.
Cao gradually increased the laser power to test the limits of the fiber.
Typically, as power increases, light scattering increases due to imperfections inside the fiber. Instead, as the power approached the threshold at which the fiber could be damaged, the light suddenly focused into a single, very sharp beam.
“These fibers are fraught with obstacles, and the optical engineering that needs to be done to overcome them, especially at high powers, is a long and tedious task. But this self-assembly allows us to obtain stable, ultrafast pencil beams without the need for custom beam-shaping components,” You says.
Conditions that enable self-organizing light
To replicate this effect, the team identified two key requirements.
First, the laser must enter the fiber at a perfectly aligned 0 degree angle, which is more stringent than standard methods. Second, the power must be increased until the light begins to interact directly with the glass material of the fiber.
“At this critical power, the nonlinearity can counteract the inherent disorder and create a balance that transforms the input beam into a self-organized pencil beam,” Cao explains.
Such conditions are rarely investigated because researchers typically avoid high power levels to prevent fiber damage. Multimode fibers can already carry large amounts of energy, so precise alignment is usually not required either.
However, when these elements are combined, the system can generate a stable beam without the need for complex optical engineering.
“That’s the beauty of this method: You can do this with a normal optical setup without much expertise,” You says.
Clearer imaging with fewer artifacts
After testing, we found this pencil beam to be stable and highly detailed compared to similar beams. Many conventional beams produce “sidelobes,” or blurry halos that reduce image sharpness.
In contrast, this beam remains clean and tightly focused.
The researchers then applied this technique to image the blood-brain barrier in humans. The blood-brain barrier is a dense layer of cells that not only protects the brain from harmful substances but also blocks many drugs.
Faster 3D imaging of the blood-brain barrier
Scientists often need to observe how drugs move through blood vessels within this barrier and whether they successfully reach brain tissue. Traditional optical methods typically capture one 2D slice at a time, requiring repeated scans to build a complete 3D image.
Using a new pencil beam approach, the team produced rapid and highly accurate images while tracking how cells take up proteins in real time.
“The pharmaceutical industry is particularly interested in using human-based models to screen for drugs that effectively cross the barrier, as animal models often cannot predict what will happen in humans. This new method changes that by not requiring cells to be fluorescently tagged. For the first time, we can also visualize the time-dependent entry of drugs into the brain and determine the rate at which specific cell types take up the drug,” Kam said.
“But importantly, this approach is not limited to the blood-brain barrier, but allows time-resolved tracking of diverse compounds and molecular targets across engineered tissue models, providing a powerful tool for biological engineering,” Spitz added.
The system produced cellular-level 3D images of improved quality and approximately 25 times faster than existing methods.
“Typically, there is a trade-off between image resolution and depth of focus, which limits the amount of area that can be investigated at one time. However, our method overcomes this trade-off by creating a pencil beam with both high resolution and deep depth of focus,” You says.
Future applications and next steps
Looking to the future, researchers aim to better understand the physics behind this self-organizing beam and the mechanisms that enable its formation. They also plan to extend the method to other applications, such as imaging neurons, and explore ways to put the technology into practical use.
Funding for this research was provided in part by the MIT Startup Fund, the National Science Foundation (NSF), the Silicon Valley Community Foundation, the Diacomp Foundation, the Harvard Gastroenterology Core, the MathWorks Fellowship, and the Claude E. Shannon Award.
