Researchers Shrink Titanium-Sapphire Laser to Chip Scale

Lasers based on titanium-sapphire (Ti:sapphire) provide top performance in fields like quantum optics, spectroscopy, and neuroscience. But that performance comes at a steep cost of not just the multi-thousand dollar price tag, but space and power as well. Ti:sapphire lasers take up several cubic feet and require other high-powered lasers to supply them with enough energy to function. Despite their high level of performance and utility in cutting edge applications, their adoption in the industry has been slow.

Making a jump from tabletop to the microscale, engineers at Stanford University have built a Ti:sapphire laser on a chip. According to the researchers, the prototype is four orders of magnitude smaller (10,000×) and three orders less expensive (1,000×) than any Ti:sapphire laser ever produced.

“Instead of one large and expensive laser, any lab might soon have hundreds of these valuable lasers on a single chip. And you can fuel it all with a green laser pointer,” said Jelena Vuckovic, Stanford’s Jensen Huang Professor in Global Leadership and senior author of the research.

To fashion the new laser, the researchers began with a bulk layer of Ti:sapphire on a platform of silicon dioxide (SiO2), all riding atop true sapphire crystal. They then grind, etch, and polish the Ti:sapphire to an extremely thin layer just a few hundred nanometers thick. Into that thin layer, they then pattern a swirling vortex of tiny ridges, or a waveguide. These ridges are like fiber-optic cables, guiding the light around and around, building in intensity.

“Mathematically speaking, intensity is power divided by area. So, if you maintain the same power as the large-scale laser, but reduce the area in which it is concentrated, the intensity goes through the roof,” said Joshua Yang, a doctoral candidate in Vuckovic’s lab and co-first author. “The small scale of our laser actually helps us make it more efficient.”

A microscale heater that warms the light traveling through the waveguides is then added, allowing the team to change the wavelength of the emitted light to tune the color of the light anywhere between 700 nm and 1,000 nm – in the red to infrared range.

“When you leap from tabletop size and make something producible on a chip at such a low cost, it puts these powerful lasers in reach for a lot of different important applications,” Yang said.

These applications include areas like quantum physics, where the laser could provide an inexpensive and practical solution to scale down state-of-the-art quantum computers. Medical fields could see the Ti:sapphire lasers being used for optogenetics or in compact optical coherence tomography technologies for ophthalmology.

The researchers are currently working on next steps for perfecting their chip-scale Ti:sapphire laser as well as on ways to mass-produce them on wafers and bring them to market.

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Handheld Device Allows Imaging and Treatment of Oral Cancer

Oral cancer is a growing public health concern, particularly in South Asia, where it affects tens of thousands each year. In India alone, oral cancer accounts for 40% of all cancers, largely driven by the widespread use of tobacco-based products. The situation is worsened by limited access to early screening and treatment, especially in rural and underserved areas. Most cases are diagnosed at advanced stages, when treatment is more difficult and survival rates are lower.

To address this problem, a team of researchers has developed a compact, affordable device that can both image suspicious lesions and deliver light-based therapy to treat them.

The device uses a smartphone-coupled intraoral probe with specialized LEDs and filters to capture white-light and fluorescence images to pinpoint oral cancers. It also includes laser diodes to activate a light-sensitive compound called protoporphyrin IX (PpIX), which accumulates in cancerous tissue after the application of a precursor drug, 5-aminolevulinic acid (ALA). When exposed to light, PpIX produces reactive molecules that destroy cancer cells while sparing healthy tissue. This approach, known as photodynamic therapy, has shown promise in treating early oral cancers with minimal side effects.

Simulated 3D oral tissues embedded with cancer cells were used to assess how deeply the device could detect and treat lesions. The system successfully imaged PpIX fluorescence up to 2.5 mm deep and showed effective photobleaching at depths relevant to early-stage oral cancers. To further test the technology, the device was used to deliver photodynamic therapy and monitor treatment in an animal model. There, tumors treated with the device shrank significantly compared to untreated controls. Histological analysis revealed tumor cell death extending up to 3.5 mm deep, consistent with light delivery simulations.

One of the device’s key features is its capability to monitor treatment in real time. By measuring the decrease in PpIX fluorescence during light exposure, the system provides feedback on how much therapeutic dose has been delivered. This could help ensure that each treatment is effective, even in settings without advanced medical infrastructure.

The researchers also used ratiometric imaging — comparing red and green fluorescence signals — to improve the accuracy of lesion detection and treatment monitoring. This method helps distinguish cancerous tissue from surrounding healthy areas, even in complex tissue environments.

The study demonstrates that a low-cost, portable device can perform both diagnosis and treatment of early oral cancer with promising accuracy and effectiveness. By combining imaging and therapy in a single tool, the technology could streamline care in regions where access to specialists is limited.

Future work will focus on clinical trials and refining the device for broader use. The team envisions a system that not only guides treatment but also adapts in real time, making photodynamic therapy more accessible and effective for patients around the world.


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Ultrafast Microscope Images Material’s Molecular Structure and Dynamics

Perovskites, a family of organic-inorganic hybrid materials, are efficient at converting light to electricity and relatively easy to make. They absorb certain colors of the visible spectrum effectively and can be layered with other materials, such as silicon, that absorb wavelengths the perovskites cannot capture.

But the low photostability of perovskites makes it difficult to improve their performance. Perovskite solar cells can be made from many different combinations of chemical compositions and prepared under various conditions. It is hard to predict how these factors will affect the structure and performance of the perovskite cell.

Many complex materials found in semiconductors, displays, and quantum and biomedical applications present the same challenge. To better understand how to improve these materials, scientists need to be able to visualize the material’s dynamics at the subatomic, atomic, and molecular levels.

A research team at the University of Colorado-Boulder (CU Boulder) developed a microscope for spatio-spectral-temporal ultrafast nanoimaging of the structural characteristics of materials. The ultrafast microscope enables researchers to directly image the role of molecular order, disorder, and local crystallinity in the optical and electronic properties of materials.

The researchers used the microscope to perform combined ground- and ultrafast excited-state IR nanoimaging of a metal halide perovskite that is a promising candidate for tandem solar cells, photocatalysis, and optoelectronic applications.

The microscope is equipped with a metal-coated nanotip that is positioned within a nanometer of the perovskite layer, then hit with a sequence of ultrashort laser pulses. The first pulse excites the electrons in the material in the visible, and subsequent pulses in the IR capture the movement and interaction of the electrons and molecules in the material over time. The nanotip functions like an antenna for the laser light, focusing the laser to the nanoscale.

The researchers scanned the nanotip across the perovskite layer, creating an image of the material pixel by pixel. Each image was the equivalent of one movie frame, due to the temporal differences in the laser pulses.

To reduce noise, the researchers used optical amplification techniques and developed a method to modulate the laser beams. “If you shine a light on this very tiny tip, the light that comes back is very weak since it only interacts with very few electrons or molecules,” researcher Branden Esses said. “It’s so weak that you need special techniques to detect it.”

According to researcher Roland Wilcken, controlling the way the light is focused at the nanometer scale and how it is emitted and detected is essential to achieving the contrast and signal necessary to make an ultrafast movie of the material.

The researchers captured ultrahigh-resolution images of atomic and molecular movement in the perovskite at the femtosecond scale and measured atomic motion in the molecules with very high precision. The photoexcited electrons and coupled changes of the lattice structure (i.e., polarons) were diagnosed spectroscopically with ultrahigh spatiotemporal resolution, enabling the researchers to better understand the perovskite’s structure and composition and its performance as a photovoltaic material.

The team’s findings suggest that the more disorder in the material, the better the photovoltaic performance. “In contrast to conventional semiconductors, it seems that more structural disorder gives rise to more stable photogenerated electrons in hybrid perovskites,” professor Markus Raschke said.

According to Raschke, there is limited knowledge of the processes that occur after sunlight is absorbed by photovoltaic materials, and how the excited electrons move in the material without being dispersed.

“We like to say that we’re making ultrafast movies,” he said. “For the first time, we can actually sort this out, because we can record spatial, temporal, and spectral dimensions simultaneously in this microscope.”

The team expects the ultrafast microscope to have a significant impact on the ability of material scientists to improve the performance of new semiconductor and quantum materials for computing, energy, and medical applications.

“This is a way to examine the material properties on a very elementary level, so that in the future we’ll be able to design materials with certain properties in a more directed way,” professor Sean Shaheen said.

“We’re able to say, ‘We know we prefer this kind of structure, which results in, for example, longer-lived electronic excitations as linked to photovoltaic performance,’ and then we’re able to inform our material synthesis partners to help make them,” Esses said.

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Photodynamic Method Boosts Antibiotics Against Drug-Resistant Bacteria

 

Multidrug-resistant bacteria are considered a serious threat to infection control. Faced with the increasing difficulty of developing new antibiotics to combat resilient bacterial strains, scientists are turning to photodynamic inactivation (PDI), a light-based approach to breaking antimicrobial resistance.

PDI strengthens the effect of antibiotics and induces oxidative stress in microorganisms through the interaction of light with a photosensitizer. The photosensitizer is energized in PDI by absorbing visible light to form reactive oxygen species that trigger bacterial inactivation by oxidizing and destroying microorganisms or weakening their resistance to antibiotics.

In recent work, researchers at the University of São Paulo’s Optics and Photonics Research Center showed that PDI can modify bacterial sensitivity to antibiotics and reduce the resistance and persistence of both standard and clinical strains. The researchers, led by professor Vanderlei Salvador Bagnato, investigated the effects of photodynamic action on resistant bacteria collected from patients and bacterial cells with laboratory-induced resistance. They focused their investigation on Staphylococcus aureus, a bacterium that causes a range of diseases, from skin infections to pneumonia.

The researchers used 10 μM, 10 J/cm2 of the photosensitizer curcumin at 450 nm with antibiotics. Curcumin has been shown to strengthen some antibiotics by affecting the bacterial membrane and other cellular components. Three antibiotics — amoxicillin, erythromycin, and gentamicin — were treated with curcumin.

The results showed that five cycles of PDI were sufficient to break bacterial resistance. The researchers found that S. aureus was most susceptible to gentamicin, although the other two antibiotics also proved effective against the bacteria after treatment with PDI.

In addition, the researchers concluded that a reduction in the degree of antimicrobial resistance through photo-oxidative action can mitigate antibiotic failures. Photodynamic action not only improves infection control, but also modifies the degree to which antimicrobials are susceptible to bacteria by decreasing bacterial resistance to below breakpoints and controlling the biofilm formation, which is an important bacterial virulence factor.

“We discovered that PDI doesn’t always destroy the bacteria, but it does destroy part of the mechanisms they use to become drug-resistant,” Bagnato said. “This led to the idea of trying an oxidative shock to make them susceptible to antibiotics.”

Historically, the primary strategy in the fight against multidrug-resistant bacteria infections has been the development of new antimicrobial drugs. However, failures in antibiotic treatments occur. Antibiotics act on a certain bacterial cell compartment, depending on their type, while PDI acts in the entire bacterial cell, causing multiple damages.

The researchers said that an increase or a complete recovery of a bacterium’s susceptibility to antibiotics could be a way to prolong the useful life of recent classes of antibiotics, which is essential to avoid infection control collapses. They said that a broader assessment of other antibiotics, microorganisms, and photosensitizers is needed to achieve a full understanding of the mechanisms of action and interaction between PDI and antibiotics.

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Squishy Lasers Could Reveal Secrets of Cell Growth Origins

Researchers at the University of St. Andrews and the University of Cologne have developed lasers that they have described as “squishy.” These devices could help solve the biological mysteries behind the development of embryos and cancerous tumors.

Fundamental biological processes driven by mechanical forces invisible to the naked eye are currently poorly understood by scientists. The squishy lasers developed by the researchers are able to precisely measure the forces exerted by biological cells.

“Embryos and tumors both start with just a few cells,” said professor Malte Gather from the University of St. Andrews. “It is still very challenging to understand how they expand, contract, squeeze, and fold as they develop. Being able to measure biological forces in real-time could be transformative. It could hold the key to understanding the exact mechanics behind how embryos develop, whether successfully or unsuccessfully, and how cancer grows.”

These squishy microlasers can be injected directly into embryos or mixed into artificial tumors. According to Marcel Schubert, a professor at the University of Cologne, the microlasers are actually droplets of oil doped with fluorescent dye.

“As the biological forces get to work, the microlasers are squished and deformed by the cells around them. The laser light changes its color in response and reveals the force that’s acting upon it,” Schubert said.

The innovation allows researchers to measure and monitor biological forces in real time, Schubert said. Additionally, he said, it works in thick biological tissue, an area where other methods would require an almost transparent sample.

The oil and fluorescent dye used to create the microlasers are made from nontoxic, readily available materials, ensuring they do not interfere with biological processes. This aspect makes the technology not only effective but also commercially viable.

The researchers tested their method on fruit fly larvae, to see how they developed, as well as in artificial tumors made from brain tumor cells, so-called tumor spheroids.

“We measured the 3D distribution of forces within tumor spheroids and made high-resolution long-term force measurements within the fruit fly larvae,” Gather said.

The team is now seeking funding to adapt their method for clinical trials, aiming to extend its application to larger cell systems.

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Raman Approach Safely Tracks Live-Cell RNA Expression

Single-cell RNA sequencing enables scientists to interrogate cells at extraordinary resolution and scale. However, the sequencing process destroys the cell, making it difficult to use the technique to study ongoing changes in gene expression.

Raman microscopy measures the vibrational energy levels of proteins and metabolites in a nondestructive manner at subcellular spatial resolution, but it is unable to interpret genetic information.

“RNA sequencing gives you extremely detailed information, but it’s destructive,” researcher Koseki Kobayashi-Kirschvink said. “Raman is noninvasive, but it doesn’t tell you anything about RNA.”

A new technique developed at MIT combines the advantages of single-cell RNA sequencing and Raman spectroscopy to track a cell’s RNA expression without damaging the cell. Known as Raman2RNA (R2R), this technique could allow scientists to study long-term cellular processes, such as cancer progression and embryonic development, using the same cells repeatedly.

To create the technique, the team trained a computational model to translate Raman signals into RNA expression states. “The idea of this project was to use machine learning to combine the strength of both modalities, thereby allowing you to understand the dynamics of gene expression profiles at the single-cell level over time,” Kobayashi-Kirschvink said.

To generate the data needed to train the machine learning model, the researchers treated mouse fibroblast cells with factors that reprogrammed the cells, causing them to become pluripotent (i.e., undifferentiated) stem cells. Using Raman spectroscopy, the team imaged the cells at 36 time points, over an 18-day period. During that time, the pluripotent cells differentiated.

The researchers then analyzed each cell using single molecule fluorescence in situ hybridization (smFISH), a molecular cytogenetic technique that enables the detection and localization of individual RNA molecules within cells. Using smFISH, the researchers searched for RNA molecules that encoded nine different genes whose expression patterns differed between cell types.

The researchers used the data acquired via smFISH to link data obtained through Raman imaging with data obtained from single-cell RNA sequencing.

To create the link, the team trained a deep learning model to predict the expression of the nine different genes, based on the images of the cells acquired using Raman spectroscopy. The researchers then used a computational program to link the gene expression patterns identified by smFISH with entire genome profiles that they obtained by performing single-cell RNA sequencing on the sample cells.

The team combined the two computational models into one model — R2R — that could predict the entire genomic profiles of individual cells based on Raman images of the cells. In experiments, the R2R model outperformed inference from brightfield images (cosine similarities: R2R >0.85 and brightfield <0.15).

The researchers demonstrated R2R’s ability to track mouse embryonic stem cells as the cells differentiated into several other cell types over a period of several days. The team took Raman images of the cells four times a day for three days and used the R2R computational model to predict the corresponding RNA expression profile of each cell. To confirm the computational model’s ability to predict RNA expressions, the researchers compared the model’s predictions with RNA sequencing measurements.

The researchers observed the transitions that occurred in individual cells as they differentiated from embryonic stem cells into more mature cell types. With R2R, the team also was able to track the genomic changes that occurred over a two-week period as mouse fibroblasts were reprogrammed into induced pluripotent stem cells. In the reprogramming of mouse fibroblasts into induced pluripotent stem cells, R2R inferred the expression profiles of various cell states.

“It’s a demonstration that optical imaging gives additional information that allows you to directly track the lineage of the cells and the evolution of their transcription,” professor Peter So said. “With Raman imaging you can measure many more time points, which may be important for studying cancer biology, developmental biology, and a number of degenerative diseases.”

The team plans to use the R2R technique to study other types of cell populations that change over time, such as aging cells and cancerous cells. Although the researchers are currently working with cells grown in a lab dish, they hope in the future to develop the technique as a potential diagnostic for use in patients. R2R lays a foundation for the exploration of live genomic dynamics.

“One of the biggest advantages of Raman is that it’s a label-free method,” researcher Jeon Woong Kang said. “It’s a long way off, but there is potential for the human translation, which could not be done using the existing invasive techniques for measuring genomic profiles.”

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DMD-Based SIM Attains Fast Superresolution Imaging in 3D

Although structured illumination microscopy (SIM) demonstrates ultrahigh temporal and spatial resolution, the speed and intricacy of polarization modulation affect the speed and quality of its imaging resolution in 3D.

A 3DSIM technique, developed by a team led by professor Peng Xi at Peking University, leverages digital display technology to achieve a rapid, reliable, multidimensional SIM imaging tool for investigating diverse biological phenomena. The new microscopy technique blends 3D superresolution and fast temporal resolution with polarization imaging. To do so, it combines the polarization-maintaining and modulation capabilities of a digital micromirror device (DMD) with an electro-optic modulator (EOM).

A DMD uses the electromechanical rotation of micromirrors to modulate the light field reflecting off it. Since each micromirror is controlled in the binary form corresponding to “on” and “off” states, a DMD can also be used as a digital reflection grating when loading with a specific pattern, which allows it to provide a rapid switch of structured illumination patterns for 3DSIM.

After loading pattern images, the DMD maintains a working state without requiring a refresh cycle, simplifying the SIM system’s timing control. The DMD has a high switching speed, making the DMD-3DSIM system suitable for fast imaging of live cells.

In addition, due to the nature of the special coating on its surface, the DMD can maintain the polarization state continuity between incident and reflected light. When the DMD is paired with an EOM capable of switching speeds in the nanosecond range, the result is ultrafast imaging with minimal motion artifacts.

According to the researchers, the DMD-3DSIM system provides a twofold enhancement in both lateral (133 nm) and axial (300 nm) resolution compared to traditional wide-field imaging techniques. It can acquire a data set comprising 29 sections of 1024 pixels × 1024 pixels with 15-ms exposure time and 6.75 seconds per volume.

The researchers demonstrated the functionality and versatility of DMD-3DSIM by imaging various specimens, including fluorescent beads, the nuclear pore complex, microtubules, actin filaments, and mitochondria in animal cells. In a mouse kidney slice, the system revealed a pronounced polarization effect in actin filaments. The team also used the 3DSIM system to investigate highly scattering plant cell ultrastructures, examining cell walls in oleander leaves, hollow structures in black algal leaves, and features within the root tips of corn tassels.

The researchers said that a computational superresolution algorithm could further improve the resolution of the DMD-based 3DSIM system. To encourage collaboration among members of the scientific community, the team has made all the hardware components and control mechanisms for DMD-3DSIM openly available on Github. By making the hardware and software components of the system accessible to the research community, the team hopes to help pave the way for the future of multidimensional imaging.

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