Holographic Imaging Measures Cellular Structures without Distorting Them

Biomolecular condensates — membraneless, microscopic structures that concentrate proteins and other molecules in cells — are crucial to the organization of cellular biochemistry. Insight into the development and behavior of condensates could lead to better treatments for infectious diseases, cancer, and neurological disorders.

Researchers at New York University (NYU) aimed to measure condensate composition and dynamics without relying on conventional techniques, like fluorescence labeling or surface attachment, which can damage fragile condensate samples. Until now, scientists have needed to distort condensate samples to study them.

“It’s been the elephant in the room for scientists,” professor Saumya Saurabh said. “Our research provides a precise and noninvasive way to study biomolecular condensates.”

To overcome the limitations of conventional techniques, the team used label-free holographic microscopy to investigate the behavior of a condensate-forming protein in vitro. The researchers flowed thousands of droplets through a holographic microscope in a microfluidic channel to visualize and characterize each particle individually. The holographic characterization was free from perturbations and was able to gather data on thousands of particles in minutes. Precise information about the droplet’s size, shape, and refractive index was encoded in the hologram of each μm-scale droplet.

The researchers used this technique to examine PopZ, a condensate-forming protein that influences cell growth. The precision and speed provided by the digital holography technique enabled the team to monitor the kinetics of the condensate’s formation, growth, and aging over time.

By systematically varying the concentration and valence of cations, the researchers found that multivalent ions influence condensate organization and dynamics. “I was surprised by their complex and incredibly sensitive response to different ionic species,” researcher Julian von Hofe said. “Even a small change in ionic valency drastically altered both condensate concentration and dynamics.”

The researchers used superresolution microscopy to explore the architecture of PopZ at the nanoscale. Data acquired through superresolution imaging revealed that the condensates were not uniform droplets, but exhibited intricate nanoscale organization, and that PopZ droplet growth deviated from classical models. These findings were supported by molecular dynamics simulations, which provided atomic-level insights into the biocondensate assemblies.

The study thus demonstrated the value of holographic microscopy as a hypothesis-generating tool that provides noninvasive insight into condensate substructure, that can be further tested and refined using complementary, minimally perturbative methods.

“Being able to see ‘under the hood’ for the first time has revealed some big surprises about this important class of systems,” professor David Grier said.

Although the researchers observed the condensates in vitro, their findings could contribute to a more complete understanding of condensate behavior within living cells. “The intricate reality of biomolecular condensates, as revealed by our findings, goes far beyond simple liquid-liquid phase separation,” Saurabh said.

A better understanding of how biomolecular condensates are organized and grow, made possible through holographic microscopy and superresolution imaging, could help shape disease modeling and future drug development. For example, the proteins that form plaques in ALS are fluid condensates in good health. “Understanding how a spherical condensate forms into a deadly plaque is an opportunity to better understand ALS,” Saurabh said.

The biomolecular condensates in the cells can also house drug molecules that are intended for a different purpose. This phenomenon could help explain why drugs that are designed to target a specific protein still cause side effects. By using holographic microscopy to analyze condensate dynamics with extreme precision, scientists can identify the subtle differences in condensate composition and architecture that occur when drug molecules enter a condensate.

“For example, we can now explore the chemical space of drug modifications to precisely control their partitioning, achieving the specificity needed to prevent them from entering condensates,” Saurabh said. “This opens new avenues for how we think about designing drugs and their potential side effects.”

This work highlights the power of holographic microscopy, especially when used with superresolution imaging, to probe the properties and mechanistic underpinnings of biomolecular condensates. “Our collaboration has introduced fast, precise, and effective methods for measuring the composition and dynamics of macromolecular condensates,” Grier said.


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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.

To evaluate the device, the researchers conducted a series of preclinical tests. The team used tissue-mimicking phantoms and cell cultures to test the device’s ability to detect PpIX fluorescence and monitor its breakdown (photobleaching) during treatment. The device showed a strong linear response to increasing PpIX concentrations and could detect changes in fluorescence that corresponded to effective light dosing.

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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Material Innovation Keys Scalable Spectrometer Design for Diverse Applications

 

A smartphone-inspired spectrometer platform, built with low-cost plastic materials instead of glass, could make spectral imaging more accessible across the scientific, industrial, and consumer domains.

The spectrometer spans the visible to SWIR range and is fabricated using mass-producible, non-lithographic methods. These properties could make it suitable for in-home health care monitoring, food quality testing, agricultural sensing, and many other applications that require affordable, broadband sensing capabilities.

The spectrometer design is the result of a collaboration among researchers at the University of Cambridge, Zhejiang University, Zhejiang Sci-Tech University, and Nanyang Technological University, with backgrounds in materials science, optical engineering, and signal processing.

Plastic optical components are used in smartphone cameras to achieve high performance in an ultracompact format. Inspired by this approach, the research team took a similar path, using transparent shape memory epoxies to stress-engineer optical dispersive elements made from plastic. The epoxy used for the spectrometer, bisphenol A epoxy, is highly transparent across the visible to SWIR range.

Shape memory epoxies can be mechanically stretched at elevated temperatures to program precise, stable stress distributions into the material. These stresses create birefringence, an optical effect where light is split according to its wavelength.

Through temperature-controlled mechanical stretching, the team was able to stress-engineer the epoxy and tailor its optical properties. Shape memory epoxies provide superior stress storage compared to other plastic materials, which enables a wide range of spectral encoding through stress engineering.

“By shaping the internal stress within the polymer, we are able to engineer spectral behavior with high repeatability and tunability, something that’s incredibly difficult to achieve with conventional optics,” professor Gongyuan Zhang said.

The resulting films act as spectral filters, encoding information that can be read by standard CMOS image sensors and reconstructed via algorithms. The researchers demonstrated that the planar, stress-engineered epoxy films can be used to form a spectrometer device when they are integrated with a commercial CMOS image sensor and a spectral reconstruction algorithm is used for computational processing of the pixel outputs.

The use of large-scale stretched epoxy films as filters significantly enhances the yield of the spectrometer. The team realized miniaturized spectrometers with broad coverage across both the visible (400-800 nm) and NIR (800-1600 nm) ranges.

The epoxy film layer also enables the spectrometer to serve as a line-scanning device for spectral imaging on 2D images, facilitating the acquisition of corresponding spectral data cubes, and demonstrating the spectrometer’s potential as a portable tool for hyperspectral imaging.

The stress-engineered films can be fabricated in a single step, without the need for lithography or expensive nanofabrication, making the spectrometers suitable for mass production and integration into consumer electronics like mobile phones and wearable technologies.

“We’ve shown that you can use programmable plastics to cover a much broader range of the spectrum than typical miniaturized systems — right into the SWIR,” professor Zongyin Yang said. “That’s really important for applications like agricultural monitoring, mineral exploration, and medical diagnostics.”

The new spectrometer design could be used to detect pollutants, verify the authenticity of drugs, monitor blood sugar noninvasively, and even to sort recyclable materials in real-time. By eliminating the trade-offs between size, cost, and spectral range, the spectrometer could help advance research in computational photonics and sustainable sensing technologies.

“This work shows how mechanical design principles can be used to reshape photonic functionality,” professor Tawfique Hasan said. “By embedding stress into transparent polymers, we have created a new class of dispersive optics that are not only lightweight and scalable but also adaptable across a wide spectral range. This level of flexibility is very difficult to achieve with traditional optics relying on static, lithographically defined structures.”

As the team continues to refine the design and explore commercial pathways, the stress-engineered, plastic spectrometer could become a building block for the next generation of intelligent, compact sensors embedded in devices for everyday use.


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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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