Cell competition is a surveillance mechanism that ensures tissue integrity by removing less fit or aberrant cells. It is indispensable during development, immune defense, and tumor progression. While biochemical pathways mediating competition have been widely explored, the precise role of mechanical forces remains ambiguous. Most prevailing theories suggest that mechanical winners compress their neighbors, ultimately driving weaker cells into apoptosis or extrusion. Yet these accounts often fail to reconcile contradictory observations across different tissues and experimental systems, leaving gaps in understanding the true mechanical underpinnings of competition. One fundamental problem is that measuring forces at cell–cell interfaces in living tissues is technically demanding. This has left unresolved the question of whether the critical determinant is the magnitude of force generation or the ability of cells to transmit these forces across a tissue. A particular point of interest is the role of E-cadherin, the core component of adherens junctions, which provides intercellular mechanical coupling. Mutations or loss of E-cadherin are frequently associated with tumor invasion and metastasis, underscoring its biological relevance. Yet, whether differences in E-cadherin–mediated adhesion directly translate into a competitive advantage had not been established.

To this account, new research paper published in Nature Materials and conducted by Andreas Schoenit, Siavash Monfared, Lucas Anger, Carine Rosse, Varun Venkatesh, Lakshmi Balasubramaniam, Elisabetta Marangoni, Philippe Chavrier, René-Marc Mège, Amin Doostmohammadi & led by Professor Benoit Ladoux from the Université Paris Cité, CNRS, Institut Jacques Monod in France and Department of Physics, Friedrich-Alexander-Universität Erlangen-Nürnberg in Germany, the researchers developed two complementary models to dissect mechanical cell competition. A minimal energetic model showed that elimination requires more work for cells with higher intercellular adhesion, suggesting an intrinsic resistance mechanism. A detailed three-dimensional multiphase field model captured extrusion dynamics, demonstrating that stress fluctuations localize at interfaces when adhesion is weak, driving elimination. Together, these models establish that efficient stress transmission, not absolute force magnitude, underpins competitive advantage

The researchers began with patient-derived metaplastic breast cancer xenografts, chosen because these tumors contain epithelial sub-populations with strong E-cadherin expression alongside mesenchymal cells lacking it. Live imaging revealed that epithelial clusters expanded over time while surrounding E-cadherin–negative cells were progressively eliminated, but only when direct contact occurred. This indicated that differential adhesion creates a competitive imbalance rather than passive segregation.

To generalize, they turned to Madin–Darby canine kidney (MDCK) epithelial cells. When E-cadherin knockout (KO) cells were co-cultured with wild-type (WT) cells, the KO population consistently lost, regardless of initial ratios. Even more strikingly, E-cadherin KO cells could themselves dominate cadherin double-knockouts that lacked all adherens junctions, while WT cells were eliminated by E-cadherin–overexpressing counterparts. These hierarchical outcomes confirmed that relative adhesion strength, not absolute viability, determines the winner. Parallel assays with breast epithelial MCF10A cells produced identical results, underscoring the universality of this principle

Force-mapping experiments added unexpected nuance. Bayesian inversion stress microscopy showed that, in breast tumor samples, winners (E-cadherin+) were under tension while losers (E-cadherin–) were compressed—consistent with classical models. Yet, in MDCK competitions, winners (WT) were compressed and losers (KO) were tense, directly contradicting the prevailing view that losers are always squeezed. Laser ablation and traction-force assays confirmed these results, ruling out measurement artifacts. Importantly, most KO cells were extruded alive, only later dying due to loss of anchorage, demonstrating that elimination was mechanically, not biochemically, triggered.

To test environmental influence, the team cultured cells on substrates of varying stiffness. Although stress states inverted depending on substrate properties, the competitive outcome never changed: cells with stronger adherens junctions always won. Neither growth rates, apoptosis inhibition, nor differences in homeostatic density explained the observations. Intriguingly, KO cells showed larger focal adhesions, stronger traction, and greater stiffness than WT cells—factors previously thought to confer advantage. Instead, these traits correlated with their tension and inability to dissipate stress, ultimately leading to their extrusion. Further imaging localized extrusions predominantly at the interface between populations. These regions were enriched with actomyosin activity and dynamic protrusions from KO cells, producing heightened stress fluctuations. Inhibiting actin protrusions or reducing contractility suppressed elimination, confirming the causal link between mechanical noise at interfaces and extrusion events.

To probe the underlying physics, the team employed a three-dimensional multiphase field model of cell monolayers. Simulated competitions recapitulated experimental findings: cells with weaker cell–cell adhesion extruded preferentially at interfaces due to stress fluctuations that could not be transmitted away. Susceptibility analyses revealed that WT-like cells maintained correlated stress fields, whereas KO-like cells localized fluctuations into out-of-plane stresses, making extrusion energetically favorable. Thus, both experiments and modeling converged on a single conclusion: effective force transmission across adherens junctions confers resilience in competition

The discovery that force transmission, rather than raw force generation, dictates mechanical competition reshapes our understanding of how tissues regulate themselves. It introduces a paradigm in which survival is determined by collective resilience against fluctuating stresses, not individual strength. This mechanism explains why cells with stronger substrate adhesion or contractility may still lose if they cannot distribute stresses effectively across neighbors. It also clarifies longstanding inconsistencies in the literature, offering a unifying principle.

From a biological perspective, these findings highlight intercellular adhesion as a universal safeguard for tissue integrity. Strong adherens junctions allow cells to form a mechanically cohesive network, capable of buffering local perturbations by spreading forces broadly. In contrast, cells with weakened coupling localize stresses at interfaces, leading to their extrusion. This principle has profound implications during morphogenesis, when tissues must sculpt boundaries and remove misplaced cells without relying solely on programmed cell death. It also resonates with epithelial turnover in adult tissues, where extrusion maintains homeostasis. In cancer, the implications are equally compelling. Many tumors display heterogeneous cadherin expression, with subsets of cells downregulating adhesion to facilitate invasion. The present work suggests that such heterogeneity may itself trigger competitive interactions within tumors, selectively eliminating weakly adherent populations or, conversely, promoting invasive escape if extrusion events allow viable cells to disseminate. The interface-based fluctuation mechanism may thus contribute to metastasis, where mechanical surveillance fails or is subverted. Moreover, it raises the possibility that therapeutic strategies aimed at reinforcing intercellular adhesion could suppress malignant expansion by restoring tissue-level mechanical resilience.

The study also opens theoretical avenues. Stress fluctuations at interfaces resemble noise-driven instabilities observed in other physical systems, suggesting parallels between tissue mechanics and condensed matter phenomena. By showing that mechanical information flow, not force magnitude, governs outcomes, the authors underscore the need to incorporate collective stress transmission into models of tissue dynamics. This perspective could inspire new approaches to engineer synthetic tissues or design biomaterials that harness competitive elimination for regenerative medicine. Ultimately, the work establishes force transmission as a master regulator of mechanical cell competition. It broadens our view beyond the dichotomy of winners compressing losers and introduces a richer narrative where mechanical fluctuations, buffered or amplified by adhesion, decide cellular fate. This framework not only reconciles disparate experimental findings but also suggests that the ability to withstand and dissipate mechanical noise may be as fundamental to tissue survival as genetic stability or biochemical signaling.

Tissue engineering aims to develop biomimetic scaffolds that support cellular behavior and provide physiologically relevant environments for cell culture and regenerative medicine. Traditional scaffolds often fail to adequately mimic the native extracellular matrix (ECM), limiting their effectiveness in tissue engineering applications. The advent of 3D printing has enabled precise control over scaffold architecture, facilitating enhanced cell-material interactions. However, integrating electronic functionalities into 3D scaffolds remains an underdeveloped field, despite the potential of bioelectronic interfaces for cellular stimulation, monitoring, and regeneration. A primary challenge in bioelectronic scaffold design is the mechanical mismatch between conventional conducting materials and soft tissues. Most electrically conductive materials, such as metals and silicon-based structures, exhibit stiffness values several orders of magnitude higher than native soft tissues. This discrepancy can alter cell behavior, impairing attachment, proliferation, and differentiation. Additionally, while hydrogels provide an ECM-like environment due to their high water content and mechanical compliance, their electrical conductivity remains insufficient for bioelectronic applications. Efforts to enhance hydrogel conductivity often lead to increased stiffness, compromising biocompatibility.

Poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) has emerged as a promising conducting polymer due to its high electrical conductivity, biocompatibility, and stability. However, most previous studies focus on 2D film applications, with limited work on 3D scaffolds that retain soft tissue-like properties. Moreover, existing approaches to fabricating PEDOT:PSS hydrogels rely on simple molding techniques that lack the spatial control required for cell culture applications. New research paper published in Advanced Materials Technologies and conducted by Somtochukwu Okafor, Jae Park, Tianran Liu, Anna Goestenkors, Riley Alvarez, Barbar. Semar, Justin Yu, Cayleigh O’Hare, Sandra Montgomery, Lianna C. Friedman, and led by Professor Alexandra Rutz from the Washington University in St. Louis developed a 3D printing strategy for PEDOT:PSS hydrogels that achieves both soft tissue-matching stiffness and high electrical conductivity. By optimizing the printing methodology and post-processing treatments, the researchers aim to create bioelectronic scaffolds suitable for advanced tissue engineering and biointerfacing applications.

The authors employed a novel approach to fabricate PEDOT:PSS hydrogels with controlled mechanical and electrical properties through 3D printing. The researchers developed weak gel inks with low concentrations of PEDOT:PSS and ionic liquids to achieve optimal printability. By employing embedded 3D printing within a sacrificial agarose support medium, they successfully fabricated free-standing hydrogels with interconnected porosity. Post-printing, hydrogels were subjected to controlled crosslinking at elevated temperatures to enhance stability and maintain mechanical integrity. To fine-tune hydrogel properties, post-treatment with solvents and acids, including dimethyl sulfoxide (DMSO), ethanol, acetic acid, and sulfuric acid, was investigated. Acid treatments significantly increased electrical conductivity, with values reaching up to 1891 S/m while maintaining stiffness within the physiological range (6.20–99.8 kPa). X-ray photoelectron spectroscopy (XPS) analysis confirmed that these treatments reduced the PSS-to-PEDOT ratio, leading to enhanced crosslinking and improved conductivity. Furthermore, post-treated hydrogels retained high water content (89.7–99.4%), ensuring cytocompatibility. Long-term stability studies in Dulbecco’s Modified Eagle Medium (DMEM) demonstrated that hydrogel conductivity remained stable after an initial equilibration period of 3–7 days. Scaffolds maintained their structural integrity over 28 days, with no significant mass loss or fragmentation. Chemical analysis suggested that initial conductivity fluctuations were due to media absorption rather than material degradation. In vitro experiments using human dermal fibroblasts confirmed the biocompatibility of the 3D-printed scaffolds. Cells exhibited high attachment efficiency (>74%), viability (>98%), and proliferation over seven days. Microscopy images revealed that fibroblasts penetrated multiple scaffold layers and deposited extracellular matrix, supporting the suitability of these scaffolds for tissue engineering applications.

In conclusion, the research work by Professor Alexandra Rutz and colleagues is a significant advancement in bioelectronic scaffold design by overcoming the longstanding trade-off between electrical conductivity and mechanical compliance. The development of 3D-printed PEDOT:PSS hydrogels with soft tissue-like stiffness enables the integration of bioelectronics into 3D cell culture systems, opening new possibilities for tissue engineering, regenerative medicine, and organ-on-a-chip models. The ability to tune scaffold properties through post-processing treatments allows for customization across different tissue types, enhancing their applicability in various biomedical applications. Beyond in vitro studies, these scaffolds have potential applications in biohybrid devices, implantable electronic interfaces, and electroactive drug delivery systems. By providing a 3D microenvironment with electronic functionalities, these scaffolds could facilitate real-time monitoring and stimulation of cellular activity, improving the efficacy of engineered tissues and therapeutic implants.

Circulating tumor cells (CTCs) are cancer cells that have detached from a primary tumor and entered the bloodstream. These cells can travel through the blood to other parts of the body, leading to the formation of metastases in distant organs. The isolation and detection of CTCs from the peripheral blood of cancer patients are crucial for early cancer diagnosis and prognosis. However, the rarity and fragility of CTCs pose significant challenges in their separation and analysis. Traditional methods suffer from drawbacks such as low efficiency, high reagent consumption, and time-consuming procedures. To overcome these limitations, microfluidic techniques have emerged as promising tools for CTC separation and enrichment. Microfluidic devices offer advantages such as reduced sample size, lower reagent consumption, simplified operation, and high throughput capabilities. Among the various microfluidic approaches, physical separation microdevices based on biophysical differences have shown great potential. These devices utilize biophysical properties such as size, density, deformability, and dielectric properties to distinguish CTCs from normal blood cells. Unlike affinity capture microchips, physical separation modalities offer label-free separation capabilities and high recovery rates. They have demonstrated efficient separation of CTCs from the complex blood matrix, providing a valuable tool for early tumor detection.

In a new study published in the peer-reviewed journal Colloids and Surfaces B: Biointerfaces, Hui Qiu, Haoyu Wang, and Xiupei Yang, led by Professor Feng Huo from Neijiang Normal University, presented an innovative approach to address these challenges. They developed an acoustofluidic chip separation system coupled with an ultrasonic concentrated energy transducer (UCET) system, enabling efficient separation of CTCs from whole blood samples. The acoustofluidic chip employed inertial forces to pre-focus acoustically sensitive particles, followed by the application of acoustic radiation forces (ARF) to separate particles of different sizes. To simulate CTCs, aminated mesoporous acoustically sensitive particles (MSN@AM) were encapsulated within carboxylate polystyrene microspheres (PS-COOH). The resulting MSN@AM@PS-COOH particles were effectively separated using the acoustofluidic chip coupling system.

The authors demonstrated the efficient separation of MSNs agglomerates, PS microspheres, and MSN@AM@PS-COOH particles using the acoustofluidic chip coupled with the UCET system. The low-frequency traveling wave sound field generated by the UCET system (20 kHz) proved to be more effective in manipulating and separating the CTCs-like particles. By optimizing the power and time parameters, the researchers achieved remarkable separation of the target particles in mixed suspensions. The results showcased the sensitivity, responsiveness, and efficacy of the acoustofluidic chip coupled with the UCET system in sorting CTCs-like particles.

The acoustofluidic chip coupled with the UCET system offers several advantages for CTC separation. The system reduces the complexity, cost, and operation difficulties associated with existing methods. It requires fewer reagents and enables the efficient isolation of CTCs from whole blood samples. By using PS microspheres as substitutes for cells, the system provides a reliable basis for sorting out CTCs efficiently. The technology holds significant promise in early cancer diagnosis, prognosis, and monitoring. With further development and refinement, this innovative approach could revolutionize the field of cancer diagnostics.

The study conducted by Professor Feng Huo and associates presents a breakthrough in the isolation of circulating tumor cells. The acoustofluidic chip coupled with the ultrasonic separation system offers a novel and efficient method for separating CTCs from whole blood samples. The system’s ability to manipulate and separate CTCs-like particles demonstrates its potential for clinical application in cancer diagnosis and prognosis. The new study opens up new avenues for the development of innovative technologies in the field of cancer research and paves the way for early detection and improved patient outcomes.

Since the human brain is a three-dimensional structure, 3D culturing techniques can help researchers to create more accurate and realistic neural models, thus improving our understanding of the brain’s structure and function. Moreover, many neurological diseases are characterized by changes in the structure and connectivity of neurons. Creating a 3D neuronal network can be used to model a range of neurological disorders, including autism, epilepsy, and schizophrenia. This allows researchers to study disease mechanisms in a more physiologically relevant cellular context and improve the development of new treatments. Furthermore, a 3D neuronal network can be used to screen drug candidates for their efficacy and simultaneously identify neurotoxicity. This allows researchers to identify promising drug candidates early in the drug development process and avoid costly clinical trial failures.

However, developing a 3D neuronal network can be challenging, and there are several factors to consider. Some of the challenges include the choice of biomaterial since its properties highly influence the developing 3D neuronal network. To support neuronal growth and connectivity,  the materials should be biocompatible, must not elicit an immune response and must exhibit suitable mechanical properties such as stiffness and elasticity. The material should be porous, allowing for the diffusion of nutrients and waste products. Moreover, the material should be conductive to support the electrical activity of neurons.

Alginate is a natural polymer derived from seaweed that can form soft and porous gels when mixed with water and calcium ions. Laminin is a component of the extracellular matrix, which forms the scaffold that surrounds and supports cells in tissues. Laminin can bind to receptors on the surface of cells including human induced pluripotent stem cells (hiPSCs) and influence their behavior. In a new study published in the peer-reviewed Journal Advanced Materials Interfaces by PhD candidate Julia Hartmann, Dr. Ines Lauria, Ms Farina Bendt, Mr. Stephan Rütten, Dr. Katharina Koch and led by Professor Ellen Fritsche from Leibniz-Research Institute for Environmental Medicine in collaboration with Professor Andreas Blaeser at the Technical University of Darmstadt, the authors employed hiPSCs to generate human neural progenitor cells (NPCs) and subsequently let them differentiate into neural 3D models in both pure alginate hydrogels and hydrogels functionalized with the extracellular matrix protein laminin 111 (L111). The authors evaluated various properties of the tested biomaterials, such as their porosity, distribution of L111, shear viscosity, and biocompatibility. Additionally, the influence of the hydrogels on neural cell functions was studied by observing cell migration, differentiation, and the formation and activity of neural networks on multielectrode arrays (MEAs).

The research team used a 3D model of human NPCs derived from hiPSCs to study how the progenitors differentiate into functional neural networks. They found that L111 improved the survival, migration, and differentiation of NPCs into neurons and astrocytes, two key effector cell types in the brain that support each other. L111 also increased the formation of synapses, which are connections between neurons that allow them to transmit signals. They measured the electrical activity of these networks using MEAs and found that they were more mature, stable, and synchronized than those grown in alginate without L111. They also recovered faster from a drug that blocked their activity. The new 3D model established in the study provided a more physiological representation of human brain function than traditional 2D models and can be used for long-term disease models or studies of drug or chemical effects. Their work follows the 3R principles of reducing, refining, and replacing animal experiments with human-based methods.

In conclusion, Julia Hartmann and colleagues established a 3D model of hiPSC-derived neural networks embedded in alginate or alginate-laminin 111 (L111) hydrogels. They fully characterized the hydrogel’s material properties, cell compatibility, and effect on NPC differentiation and neural network formation over a long-term period of more than six months. Interestingly, L111 supplementation enhanced NPC-derived cell migration, differentiation, synaptogenesis, and electrical activity in alginate hydrogels. Moreover, neural networks in alginate-L111 hydrogel blends recovered faster from sodium channel blockage than neural networks in pure alginate hydrogels. In conclusion, alginate-L111 hydrogel is a suitable matrix for long-term cultivation and maturation of human neural networks. The new 3D neural cell model can be a powerful tool for medical research, allowing researchers to model diseases, study disease mechanisms, and develop new treatments.

Prognosis of eye diseases is vital for blindness and visual impairment prevention. Consequently, portable fundus imagers have become an essential for emerging telemedicine screening and point-of-care examination of eye diseases. Experience has shown that numerous eye diseases target the retina periphery. Unfortunately, the existing portable fundus cameras have limited field of view and frequently require pupillary dilation. Technological advances have led to the application of seven-field photography for diabetic retinopathy screening, based on traditional fundus cameras, so as to achieve the necessary view field coverage for mydriatic early treatment diabetic retinopathy study. However, the seven-field photography requires a skilled operator for pupillary dilation and image registration to produce montage images thereby making its deployment rural and underserved areas difficult.

Recently, a team of researchers led by Dr. Xincheng Yao from the Department of Bioengineering at University of Illinois at Chicago and Dr. Devrim Toslak from Department of Ophthalmology at Antalya Training and Research Hospital developed a miniaturized indirect ophthalmoscopy to enable wide-field smartphone fundus video camera. This work has been featured as a ‘New Instruments’ article in RETINA, the journal of retinal and vitreous diseases (Retina 38, 438-441, 2018).

Moreover, the team also constructed a benchtop prototype fundus camera to extend the miniaturized indirect ophthalmoscopy design for nonmydriatic wide-field photography. The nonmydriatic prototype device consists of a near-infrared light source for retinal guidance and a white light source for color retinal imaging. The authors observed that by incorporating digital image registration and glare elimination methods, a dual-image acquisition approach was applicable in achieving reflection artifact-free fundus photography. In addition, they noted that with NIR light guidance, they were able to capture at least three-color fundus images before pupil constriction could commence. This work has been published in Optics Letters.

In conclusion, the scientists at University of Illinois at Chicago presented a new miniaturized indirect ophthalmoscopy design to demonstrate a mydriatic wide-field smartphone fundus camera first, and also constructed a bench top prototype of nonmydriatic wide-field fundus camera in achieving a 67° external angle (101° eye angle) field of view in single-shot images. Altogether, the work demonstrated dual-image acquisition combined with digital data processing to achieve reflection artifact-free color fundus imaging which promises a portable next-generation, low-cost and wide-field fundus camera for affordable telemedicine and point-of-care assessment of eye diseases.

The authors anticipate that there is still a large room for further improvement of the FOV and image quality by professional optical design, promising a next-generation low-cost, non-mydriatic, wide-field fundus camera for affordable telemedicine and point-of-care assessment of eye diseases. This successful research work is now protected with a patent application (US 62/546,830).

Cardiovascular disease is still the number one cause of death around the world, with atherosclerosis playing a major role in conditions like strokes and heart disease. When it develops in the carotid arteries (vessels in the neck that deliver blood to your brain) especially at the carotid artery bifurcation, it becomes a serious risk for ischemic strokes. The way atherosclerotic plaques form—blocking or restricting blood flow to the brain—has been studied for years. However, there is still a lot we do not fully understand about the biomechanics behind it. While researchers know that low wall shear stress (WSS) is a major trigger for plaque buildup, the role that vortex structures inside the artery play in shaping these stress levels has not been studied in detail. To truly get ahead of atherosclerosis risk, scientists need to look more closely at how these swirling blood flow patterns behave in both healthy and disease-prone arteries. One of the biggest challenges in vascular research is the sheer complexity of blood flow in areas where arteries split. The carotid bifurcation is one of those zones where blood is constantly pulsing, creating vortex structures that appear and disappear throughout each heartbeat. These vortex patterns directly affect the cells lining the arteries, influencing whether plaques start forming. So far, computational fluid dynamics has been a great tool for studying blood flow, but most studies have only looked at average WSS over time rather than zooming in on the changing nature of vortices and how they break down over time. Another challenge is that research has not separated the effects of artery shape from actual blood flow conditions. Most studies compare healthy arteries to diseased ones, but they do not always break down whether geometry alone is responsible for increased plaque risk or if abnormal blood flow patterns are just as important. Some people might have arteries with high-risk geometries, like a wider bifurcation angle, but never develop plaques. Others with “normal” artery shapes might still end up with dangerous buildups due to changes in pressure gradients or flow distribution. Because these factors are not well separated in existing research, it is tough to determine who is truly at risk based on their artery structure alone.

To bridge this gap, a new study published in Physical Review Fluids—led by Professor Michael Plesniak with Dr. Nora Caroline Wild and Associate Research Professor Kartik Bulusu at George Washington University, they created three different carotid artery models: one modeled after an average healthy individual, another based on a disease-prone artery shape, and a third hybrid model that kept the healthy artery structure but imposed disease-prone flow conditions. Dr. Wild explained, “We used clinical data from the literature to design realistic geometries that captured the main features of healthy and disease prone patient populations, this makes these findings applicable beyond a single patient-specific case.” This allowed them to tease apart whether anatomy or blood flow conditions had a bigger influence on vortex formation and, ultimately, the development of plaque-promoting shear stress patterns. The team ran simulations of pulsating blood flow through the three different artery models so they could track how vortices formed, evolved, and eventually disappeared over the course of a heartbeat. The researchers used the lambda-2 (λ₂) criterion, a widely recognized method for pinpointing vortex cores, and monitored how these swirling structures changed over time. They found that the exact moment a vortex appeared depended mostly on the shape of the artery, however, how long the vortex lasted and how quickly it faded away was driven more by the actual flow conditions, such as how blood split between branches and the pressure differences along the artery walls. This was a key discovery because it showed that while anatomy plays a role in shaping blood flow, it is the forces within the blood itself that determine whether these disturbances stick around long enough to create conditions that encourage plaque buildup. The authors also focused on vortex circulation and expansion—essentially, how much space these swirling structures occupied and how strong they were. The team calculated the circulation strength of the “main vortex” (a flow pattern that is larger compared to the other concomitant smaller-sized vortices) in each model and noticed a clear pattern. In the disease-prone artery, vortices formed earlier in the heartbeat cycle but also disappeared much more quickly than those in the healthy model. In fact, in the healthy artery, the main vortex remained intact for about 75% of the cycle, while in the disease-prone model, it lasted only 25% before breaking down. Even more interesting was what happened when the unhealthy flow conditions were applied to the healthy artery shape—the main vortex also faded faster, proving that the way blood moves, rather than just the shape of the artery, plays a huge role in early vortex decay. This was a significant finding because it suggested that a high internal carotid artery blood flow rate and a stronger pressure gradient near peak systole might be strong indicators of a higher risk for atherosclerosis. Moreover, the researchers took a closer look at where exactly these vortices formed and how much space they occupied in the internal carotid artery sinus, a region known to be especially vulnerable to plaque buildup. They found that in disease-prone arteries, the main vortex started larger but shrunk and disappeared much faster, leading to an unstable flow environment where shear stress levels changed unpredictably. This was a major concern because the cells lining blood vessels depend on steady shear forces to stay healthy. When these forces fluctuate too much or drop too low, it can trigger plaque formation.

In conclusion, the research work led by Professor Michael W. Plesniak, alongside Dr. Nora Caroline Wild and Associate Research Professor Kartik V. Bulusu, is an important advancement in our understanding of how blood flow mechanics contribute to atherosclerosis. More importantly, their findings open the door to better diagnostic tools and early intervention strategies for cardiovascular disease. The study suggests that the risk of atherosclerosis may have less to do with artery shape alone and more to do with how blood actually moves through the vessel. This challenges the long-standing belief that structural abnormalities are the main culprit, shifting the focus toward fluid mechanics as a key factor in vascular health. One of the most exciting takeaways from this study is the possibility of new, non-invasive ways to assess atherosclerosis risk. Right now, doctors rely on tools like Doppler ultrasound and MRI, which focus mainly on blood flow speed and artery narrowing. However, these methods do not account for the detailed vortex structures that influence shear stress, which plays a big role in plaque formation. By incorporating vortex-based risk assessment into medical imaging, doctors could spot early signs of plaque buildup long before arteries actually start to narrow. This could allow for early treatments that dramatically lower the chances of stroke and other cardiovascular issues. The authors want to emphasize that “the significance of this result is that disease prone flow conditions that are expected to play a significant role in atherosclerotic plaque formation caused by early deterioration of the beneficial vortex structures, could be observable in medical imaging and thus lead to earlier disease detection through medical imaging.” The study also has implications for medical device design. Manufacturers of stents and vascular grafts could use the new findings to improve their designs, ensuring that implants work with the body’s natural blood flow rather than disrupting it. This could help create longer-lasting devices with a lower risk of complications like thrombosis (blood clots) and restenosis (re-narrowing of arteries), both of which are major issues in cardiovascular treatments today. Additionally, the methods could be of valuable contribution to the broader field of biofluid mechanics and applied to other parts of the body, like coronary arteries and peripheral blood vessels, where similar blood flow disturbances might contribute to vascular disease.

Conventional tumor therapy relies heavily on radiotherapy and chemotherapy that is usually associated with off-target side effects. Additionally, recurrence of many malignancies as well as the prevalence of metastasis further compromises the therapeutical outcomes of radio- and chemotherapy. Lately, immunotherapy has been identified as an effective alternative therapeutic modality. Compared to traditional therapeutical modalities, immunotherapy has several advantages that greatly benefit cancer treatment. First, it capitalizes on the advantages of adaptive and innate immune systems to fight cancer cells. Second, activated immune cells are generally recognizable to tumor-associated antigens enabling precise target of the tumor cells. Third and most importantly, immunotherapy prevents tumor relapse and metastasis via immune memory, thus proving long-lasting anti-tumor immunity. Unfortunately, clinical evidence shows that immunotherapy is only efficacious in some cancer patients due to the poor immunogenicity of most tumors. Thus, developing an efficient strategy for activating anti-tumor immunity to facilitate immunotherapy is urgent.

As signaling molecules tasked with regulating metabolic and physiological functions of organisms, chemical messengers (specifically some metal ions and gaseous molecules) are potential agents for regulating the immune system. However, most chemical messengers exhibit limited regulatory efficiency against tumor growth attributed to the complexity of biological processes. Moreover, cancer cells readily activate antideath pathways to protect themselves from chemical messenger regulation and death. To this end, efficient strategies for anti-tumor immunity activation via chemical messengers are needed to ensure anti-tumor efficacy. Nanomaterial-based cascade engineering is a promising strategy for enhancing therapeutical outcome of different components. It provides intensive correlations between different components to overcome obstacles hence providing nanoplatform with improved performance. However, most cascade engineering research concentrate on reaction cascades, and signaling transduction cascades of chemical messengers have not been fully explored.

Herein, Central South University researchers: Dr. Henan Zhao, Dr. Jianghua Li, Professor Wansong Chen and Professor You-Nian Liu, in collaboration with Professor Liqiang Wang from Zhengzhou University and Professor Ke Zeng from the University of South China, proposed a nanomessenger mediated signaling cascade (ZnPP@PAA-CaS) for regulating anti-tumor immunity. In their approach, the nanomessenger was prepared by first stabilizing CaS nanoparticles using poly(acrylic acid) (PAA) followed by loading zinc protoporphyrin (ZnPP) into porous PAA-CaS nanocomposites. Their work is currently published in the journal, ACS Nano.

The authors found the present nanomessenger gradually released chemical messengers, specifically Ca²⁺ and H₂S, within acidic endosomes of the cancer cells. The synergy between H₂S and Ca²⁺ effectively elevated the intracellular Ca²⁺ stress to induce subsequent tumor cell death. As a messenger amplifier, ZnPP played a vital role in suppressing HO-1 expression to restore the suppressed signaling pathway by preventing the antideath effects of the cancerous cells. Ca²⁺-dependent death of the tumor cells attributed to the signaling transduction cascade effects led to the release of tumor-associated antigens that functioned as in-situ tumor vaccines for activating anti-tumor immunity. This further blocked tumor metastasis and relapse.

In summary, the study presented an innovative ZnPP@PAA-CaS nanomessenger with signaling transduction cascades for efficient regulation of anti-tumor immunity. Both primary tumors and distant metastases were successfully eradicated by the present nanomessenger. The introduction of cascade engineering into chemical messengers is a promising strategy for amplifying cellular regulation and is thus suitable for designing chemical messenger-based therapeutic platforms. In a statement to Advances in Engineering, the authors expressed confidence that the new study findings would contribute to developing future chemical messenger-mediated immunotherapy for effective cancer treatment.

Ligament injuries affect millions of people around the world every year which can happen from various reasons from sports, accidents, or simple daily activities and they present a challenging problem because of the poor regenerative capacity of ligament tissue. Even with advances in medical technology, current treatment options, including biological grafts such as autografts and allografts or synthetic ligaments remain inadequate for long-term recovery. The primary complications include poor biological integration, immune rejection, and limited mechanical durability, all of which contribute to high rates of graft failure, fatigue, and re-rupture. The use of biological grafts, such as autografts harvested from the patient’s own tissue presents issues like donor site morbidity and extended recovery times. Allografts, on the other hand, carry the risk of immune rejection and infection as well as inconsistent healing outcomes. On the other hand, synthetic ligaments including materials made from polyethylene terephthalate may offer some mechanical benefits but they still fail in the long term due to their lack of biological integration, however, they are also susceptible to wear, fatigue, and even graft re-rupture due to the inability of synthetic materials to mimic the complex structural and biochemical environment of native ligaments. Therefore, there is an urgent need for innovative solutions that can better replicate the mechanical function of ligaments as well as promote tissue regeneration and biological integration. To this account, recent paper published in Advanced Materials Journal and conducted by Yu-Chung Liu, Wei-Yuan Huang, Hao-Xuan Chen, and led by Professor Tzu-Wei Wang from the National Tsing Hua University together with Dr. Shih-Heng Chen from the Chang Gung Memorial Hospital and Dr. Chen-Hsiang Kuan from the Taiwan University Hospital, the researchers developed an innovative synthetic ligament that closely mimics the natural structure and function of native ligaments.

The team used a technique known as interfacial polyelectrolyte complexation (IPC) to create fibers that can form a scaffold mimicking the hierarchical structure of native ligaments where they introduced a hydroxyapatite (HAp) mineral gradient at the ends of the scaffold and this replicated the natural transition between bone and ligament, known as the enthesis. Additionally, the authors integrated connective tissue growth factor (CTGF) and mesenchymal stem cells (MSCs) to further enhance the scaffold’s regenerative potential. To elaborate, they began their experiments by fabricating the scaffold using IPC spinning. This technique allowed the team to generate biocompatible fibers through electrostatic interactions between polycation and polyanion pairs, such as poly-D-lysine (PDL) and pectin. These fibers were assembled in a hierarchical fashion to mimic the fascicle and sub-fascicle structures found in natural ligaments. Using scanning electron microscopy, the researchers observed that the fibers displayed a porous, multi-layered architecture, with distinct primary and secondary fiber bundles that closely resembled the complex microstructure of ligaments and that confirmed to them that their novel fabrication method was successful in replicating the ligament’s complex architecture. Additionally, they further strengthen the scaffold with the incorporation of HAp mineral gradient at both ends of the structure. The HAp coating, deposited using a wet chemical synthesis method, was designed to mimic the enthesis, the natural transition zone between bone and ligament. This mineral gradient was expected to reduce stress concentration and improve integration with bone tissue. The researchers confirmed the successful creation of the gradient through advanced analytical tools including X-ray diffraction and energy-dispersive X-ray spectroscopy which demonstrated a consistent deposition of hydroxyapatite crystals and confirmed that the gradient not only improved the scaffold’s ability to integrate with bone but also enhanced its mechanical stability, thus addressing a critical issue with traditional synthetic ligaments that often fail at the bone-ligament junction.

Next the authors tested the mechanical properties of the scaffold under physiologically relevant conditions and conducted tensile tests to measure the scaffold’s ultimate tensile strength and found that cross-linking the IPC fibers using poly-D-lysine and pectin significantly increased their strength. The cross-linked fibers also showed improved stiffness and fatigue resistance which were critical for mimicking the durability of native ligaments under repetitive mechanical stress. Additionally, the introduction of a collagen coating further enhanced the scaffold’s viscoelastic properties and that allowed it to better withstand cyclic loading and stress relaxation, which are common mechanical demands in everyday movements. The researchers also focused on the scaffold’s ability to support tissue regeneration. They incorporated CTGF into the scaffold using a core-sheath structure to ensure a sustained release of the growth factor. In vitro experiments showed that the release of CTGF was well-controlled, with minimal burst release, allowing the growth factor to remain active for an extended period. Additionally, the team seeded MSCs onto the scaffold to promote healing at the cellular level and found that the scaffold did indeed support well MSC adhesion, proliferation, and differentiation with no cytotoxic effect indicating high safety. To further validate their biomedical engineering design, the team of experts implanted the scaffold in a rabbit model of anterior cruciate ligament reconstruction. Over 10 weeks, they assessed tissue integration and healing at the graft-to-bone interface where histological analysis showed significant tissue infiltration within the scaffold with enhanced collagen deposition and cellularity in the groups treated with CTGF and MSCs. By 10 weeks, the scaffold had become well-integrated with the surrounding tissue, and the groups treated with both CTGF and MSCs had the most pronounced healing, with a substantial increase in collagen content and ligament-specific protein markers like tenomodulin and tenascin C. According to the authors, these experimental findings suggested that the combined use of growth factors and stem cells improved the scaffold’s ability to promote ligament regeneration and healing at the bone-ligament interface.

The researchers also used micro-computed tomography to evaluate bone healing at the graft-bone interface and very high resolution. They observed that the scaffolds with the HAp gradient led to significantly higher bone mineral density and bone volume fraction compared to traditional grafts. This confirmed that the mineral gradient played a crucial role in promoting osseointegration and bone formation at the scaffold’s ends. In terms of mechanical performance, biomechanical testing showed that the scaffolds treated with CTGF and MSCs nearly matched the tensile strength of autografts, providing further evidence that the engineered scaffold could withstand the physical demands of ligament repair. In conclusion, Professor Tzu-Wei Wang and colleagues successfully developed a synthetic scaffold that mimics well the natural structure and function of ligaments and by this provided a long-waited solution to the major challenges faced in ligament repair and their medical treatment including poor graft integration, inadequate mechanical strength, and the risk of re-rupture. Moreover, we believe the authors’ introduction of a HAp mineral gradient at the ends of the scaffold is noteworthy as it closely replicates the natural bone-ligament interface and facilitate better integration and reduce stress concentrations that can lead to graft failure. The implications of Professor Tzu-Wei Wang and his team work are far-reaching because if these advancements are used in tissue engineering it potentially will improve patient outcomes who are undergoing orthopedic surgery with the expected advantages of faster healing times, better long-term outcomes, and reduced complications compared to current graft options, which often suffer from delayed healing or immune rejection. Additionally, the innovations of IPC spinning technique proposed can be used in other areas of tissue repair beyond ligaments to create hierarchical fiber structures could potentially be applied to other types of connective tissues, such as tendons or even more complex musculoskeletal systems.

In a statement to Advances in Engineering, Professor Tzu-Wei Wang  said: “This work introduces a physiologically-inspired strategy to devise a biomimetic ligament replacement that effectively emulate native ligament performance for facilitating ligament regeneration. The intricate hierarchical structure closely mirrors the fiber arrangement observed in native ligaments, providing guidance for regenerative process. The hydroxyapatite gradient distribution of mineralized constituents promotes the transition from soft to hard tissue and enhances the healing process at the ligament-to-bone interface. Custom-tailored viscoelastic properties are designed to mirror those inherent in native ligament, ensuring proper load-bearing capacity and stability. The introduction of stem cells and delivery of growth factors facilitate the formation of functional ligamentous tissue. Through these advancements, this research aims at improving clinical outcomes, facilitate patient recovery, and provide a long-lasting and effective solution for ligament injuries”

Researchers have been fascinated by pore-forming peptides for quite a while because these peptides can selectively permeabilize membranes, offering huge potential for use in biotechnology, drug delivery, and biosensing. A particularly famous example is melittin, the main component of honeybee venom. Melittin is well-known for its strong ability to lyse or break apart cell membranes and this characteristic has spurred interest in using it for various medical applications including antimicrobial treatments, cancer therapies, and drug delivery systems. However, melittin has some notable drawbacks. For example, it tends to lack selectivity and can be quite toxic to human cells, which limits its practical use in treatments. The problem with melittin, and other similar peptides that can permeabilize membranes, is that they often attack a wide range of cell membranes, not just their intended targets. This broad effect can lead to unwanted side effects, as it harms healthy cells in addition to any intended bacterial or cancer cells. Because of this indiscriminate cytotoxicity, melittin has a narrow therapeutic window, meaning it’s challenging to use effectively without causing harm. Despite many efforts to modify melittin, creating versions that can selectively form pores in synthetic membranes without being toxic to human cells remains an ongoing struggle. This challenge has prompted researchers like Professors William Wimley, and Kalina Hristova and their students  to dig deeper. They set out to refine melittin-like peptides, eventually developing a new family of peptides known as macrolittins. These were designed using a process called synthetic molecular evolution, where they screened successive generations of peptide libraries for desired characteristics. Their main goal was to keep melittin’s pore-forming abilities while making it more selective and less toxic. Right now, the field still faces significant challenges. One major question is how to design these peptides so they can target specific membrane types, like synthetic lipid bilayers, while sparing healthy cells. Another hurdle is figuring out how to make stable nanopores large enough to allow macromolecules to pass through, even at low peptide concentrations. Most traditional membrane-permeabilizing peptides aren’t selective enough and can cause random membrane disruptions, which isn’t ideal for many biotechnological applications.

In light of these challenges, a recent study published in ACS Nano Journal, led by Professor William Wimley from Tulane University School of Medicine, along with researchers Leisheng Sun, Professor Kalina Hristova from Johns Hopkins University, and Professor Ana-Nicoleta Bondar from the University of Bucharest, took a closer look at how macrolittins interact with synthetic membranes to try understand better the molecular mechanisms that help stabilize the nanopores formed by these peptides. The team performed a series of advanced molecular dynamics simulations to study the structural features that allow macrolittins to form selective nanopores. Using atomistic simulations, they modeled how macrolittins interact with synthetic membranes made of 1-palmitoyl, 2-oleoyl-phosphatidylcholine (POPC) which is a lipid commonly used to mimic cell membranes. The authors found that macrolittins could form stable, membrane-spanning nanopores even at very low peptide concentrations and also the simulations indicated that the nanopores were held together by a robust network of hydrogen bonds involving the peptides’ charged and polar residues, water molecules, and the lipid headgroups.  According to the authors, it is this extensive network, which seem to span the entire membrane was essential for maintaining nanopore stability. To confirm these simulation findings, the researchers moved on to lab experiments to observe how macrolittins worked in synthetic membranes. To do this, they tested the peptides’ ability to permeabilize different types of lipid bilayers, including POPC, cholesterol-containing membranes, and thicker lipid compositions. Their results were striking: macrolittins selectively formed nanopores in POPC bilayers at very low concentrations, but they didn’t affect cholesterol-rich or thicker membranes. This finding aligned with what they saw in the simulations and also in experiments with cellular membranes, demonstrating that macrolittins work well with POPC bilayers but are less active in more complex membrane environments. By contrast, melittin and its variant, MelP5, permeabilized a wide range of membranes, including cellular membranes, showing much less selectivity.

In another key experiment, the team looked at how certain polar residues influenced macrolittin activity. They swapped specific polar amino acids (glutamate at positions 4 and 8, and glutamine at position 17) for nonpolar ones, similar to those in melittin, and then tested these modified peptides in synthetic membranes. The changes revealed that while the modified versions retained some activity, they were less potent and lost much of the selectivity seen in the unmodified macrolittins. The hydrogen bond network in these modified peptides was also less organized, which led to less stable nanopores. Indeed the experiment highlighted the importance of specific polar residues in maintaining both nanopore stability and membrane selectivity. To evaluate macrolittin toxicity, the authors performed tests on human cells, including HeLa cells and red blood cells. They compared the cytotoxicity of macrolittins, MelP5, and the peptide variants. Remarkably, macrolittins showed almost no toxicity to these cells even at high concentrations which suggest that they are quite safe in mammalian systems. On the other hand, MelP5 was highly toxic and killed cells at much lower concentrations. Interestingly, the modified macrolittins, with nonpolar substitutions, displayed intermediate toxicity, highlighting again the role of the polar residues in reducing toxicity and enhancing membrane selectivity. Additionally, the researchers investigated how macrolittins could cause membrane fusion, a sign of nanopore formation. They found that, even at very low concentrations, macrolittins induced vesicle fusion in synthetic POPC membranes—a process that usually indicates large nanopores have formed. MelP5, however, caused little to no fusion, even at higher concentrations, highlighting a unique ability of macrolittins to form macromolecule-sized pores that promote fusion. Adding cholesterol to the membranes significantly reduced macrolittin-induced fusion, which was consistent with their earlier findings that macrolittins were less effective in cholesterol-rich bilayers. The peptide variants also showed reduced fusion activity, further emphasizing the importance of specific polar residues in driving both nanopore formation and membrane fusion.

Wrapping things up, Professor William Wimley and his collaborators have really pushed the envelope in understanding macrolittins and how these peptides work at the molecular level. They’ve managed to break down the complexity of how macrolittins can be fine-tuned to be more selective and stable when they interact with cell membranes. This has been a tough nut to crack because it’s always been hard to balance how powerful these peptides are with how picky they can be about which membranes they target. One of the biggest takeaways from this research is the role of certain polar residues and the intricate hydrogen bond networks they form. These details might sound technical, but they’re actually the secret sauce that could help scientists design nanopore-forming peptides that are both safe and effective. What’s really exciting is how this could change the game for drug delivery. Imagine being able to use these macrolittins to create tiny pores in synthetic membranes that release medications exactly where they’re needed, without damaging healthy cells along the way. This could make treatments not only more effective but also way safer, with fewer side effects. On top of that, this research could lead to breakthroughs in developing new antimicrobial agents. A lot of the current options are a bit of a blunt tool—they don’t just target harmful bacteria; they often end up affecting healthy cells too. But since macrolittins can be more selective, they could inspire new treatments that focus on the bad guys without harming the good ones. That’s a big deal, especially with antibiotic resistance becoming a huge concern. Beyond healthcare, these findings could have ripple effects in other areas too. For example, in biotechnology, controlled membrane permeability is a big deal. Macrolittins could be the key to biosensors that need that kind of precision. They might also be useful in bioprocessing, helping with the separation or purification of large molecules, which is often a tricky task. The research also opens up interesting paths for future studies. The team found that cholesterol-rich membranes are more resistant to macrolittins, which hints at the possibility of tailoring the lipid environment to control how these peptides behave. It’s like being able to tweak the setting to suit different needs, potentially leading to customized nanopore systems for various applications. All in all, this work is a big step forward, not just in understanding these peptides, but in finding practical ways to use them.

Patients diagnosed with cancer at an early stage have the best chance of curative treatment and long-term survival. Conventional imaging techniques offer noninvasive alternatives, but they are costly when serially used and insensitive to detect subtle invasion, micrometastases, and early stages of cancer formation.  There is currently intensive research aimed at developing intra-operative molecular imaging modalities that employ tumor-targeted fluorescent dyes to optically visualize malignant lesions. The research is mainly devoted to developing tumor-activated fluorescent probes and ligand-targeted fluorescent dyes for imaging different types of tumors. Unfortunately, no current dye can produce good quality images in all tumors despite their remarkable tumor-to-background ratios in a few selected tumors.

Cancer-associated fibroblasts (CAFs) are common components of almost all solid tumors and are biologically important in cancer initiation, progression, and metastasis. Targeting CAFs, by altering their numbers, subtype or functionality, is being explored as an avenue to improve cancer therapies and early diagnosis. Besides infiltrating nearly all solid tumors, CAFs can be easily distinguished from fibroblasts in healthy tissues based on their expression of fibroblast activation protein alpha (FAP), which is expressed in more than 90% of cancers. Nevertheless, while most FAP-targeted near-infrared dyes exhibit good tumor uptake, some suffer from short tumor retention times and most are compromised by the unwanted accumulation in healthy tissues, a big obstacle to their widespread applications.

To overcome these limitations, Purdue University researchers: Dr. Ramesh Mukkamala, Dr. Spencer Lindeman, Dr. Kate Kragness, Mr. Imrul Shahriar, Dr. Madduri Srinivasarao and led by Professor Philip Low developed a  new FAP-targeted fluorescent dye for robust and efficient fluorescence-guided imaging and surgery of solid tumors. The design and characterization of FAP-targeted pan-cancer imaging agent were discussed. The objective of their study was to develop and improve the intra-operative visualization and resection of occult malignant lesions with the ultimate goal of improving patients’ survival chances. The work is published in the Journal of Materials Chemistry B.

The research team reported the design and synthesis of a novel FAP-targeted near-infrared dye (FTL-S-S0456) with affinity (12 nM) and specificity (5000-fold over related proteins) for FAP, and negligible uptake in healthy tissues. According to the authors, the fluorescence dye was observed to concentrate in all seven sold tumor types examined and yield fluorescence images with excellent tumor-to-background ratios. The bright fluorescence remained in the tumor tissue for several days following the administration and showed not unwanted accumulation in the healthy fibroblasts and healthy cells.

In summary, a novel FTL-S-S0456 is successfully designed to image most malignant solid tumors by binding to cancer-associated fibroblasts but not healthy cells. Recently, the US Food and Drug Administration (FDA) approved a folate-targeted S0456 conjugate that allows visualization of lesions hard to detect in 27% of ovarian cancer patients. In this regard, the researchers believe that the resulting fluorophore attached to FTL-S-S0456 would also detect occult lesions when concentrated by the receptor-mediated update in such lesions. In a statement to Advances in Engineering, Distinguished Professor Philip Low, the lead and corresponding author said that the design of novel FAP-targeted fluorescent dye would advance the clinical translation of pan-cancer near-infrared fluorescence imaging agents and its use for robust and efficient surgery of various solid tumors. Indeed, this new technology should potentially enhance the surgeon’s ability to identify cancer during oncologic resection and potentially improve long-term outcomes.

Desorption electrospray ionization (DESI) is an ambient ionization technique that can be coupled to mass spectrometry imaging (MSI) for chemical analysis of samples at atmospheric conditions. DESI employs a fast-moving charged solvent spray, at an angle relative to the sample surface, to extract analytes from the surfaces and propel the secondary ions toward the mass analyzer. This tandem technique can be used to analyze a wide range of small molecules including metabolites, lipids, synthetic drugs, natural chemical products, and illegal dopants across the test sample surface. Therefore, DESI-MSI has been applied in a wide variety of sectors including food and drug administration, environmental monitoring agencies, clinical, pharmaceutical and biotechnology industries. However, a significant challenge has persisted in extending DESI-MSI to larger macromolecules, particularly proteins. The ultrahigh molecular weight, poor ionization efficiency, and low abundance of proteins make their direct analysis and imaging a formidable task. Researchers have made commendable efforts to tackle this issue through various approaches, such as ammonium bicarbonate addition, spray desorption collection-based off-line analysis, native DESI, nano-DESI, and DESI combined with FAIMS (Field Asymmetric Ion Mobility Spectrometry). While these strategies have made progress, a versatile and comprehensive solution for imaging all types of proteins without molecular weight constraints remains elusive.

In a new study published in Angewandte Chemie International Edition by Dr. Xiaowei Song,  and Richard N. Zare and their collabators Dr. Chao Li, Dr. Tianhao Zhou, and Dr. Qingce Zang developed a new immuno-DESI-MSI cutting-edge technique at Stanford University that overcomes existing limitations and provides a new perspective on the spatial distribution of functional macromolecules within biological tissues.

The new method is founded on the principle of using labeled molecules, cross-linked to bio-specific antibodies, to report the position and quantity of target macromolecules. Unlike traditional optical signal-based imaging, such as immunofluorescent microscopy (IFM), which is limited by signal overlap, mass spectrometry-based immunoassays can process thousands of ion channels simultaneously, providing a comprehensive molecular phenotype.

The authors developed water microdroplet-cleavable mass tags. These mass tags, composed of boronic acid which can bind reversibly with cross-linker with a diol end. When sprayed onto tissue sections, the highly acidic microdroplets generated by DESI hydrolyze the boronate ester bond and release the mass tag from its tethered antibody. This method enables conventional DESI-MSI to map functional macromolecules across tissue sections, overcoming previous limitations regarding macromolecular imaging. Briefly, the research team designed and synthesized a probe consisting of a boronic acid mass tag (BMT), antibody (Ab), and cross-linker. The BMT is synthesized by reacting a fluorescent compound (ATTO series N-hydroxysuccinimide ester) with 3-aminophenylboronic acid. This bifunctional molecule serves both DESI-MSI and IFM purposes. The boron element has a special isotope pattern that make mass tags differentiable with those endogenous metabolites and lipids. The use of quaternary ammonium group guarantees the high ionization efficiency and sensitivity of mass tags.

Afterward, the antibody is conjugated with BMT through a cross-linker, creating a BMT-Ab complex that can specifically bind to the target macromolecular antigen. The BMT-Ab solution is incubated on tissue cryosections, allowing BMT-Ab to recognize and bind with the corresponding antigen. Then excess unbound BMT-Ab is removed by washing with an ammonium bicarbonate buffer solution. Next, the acidic water microdroplets sprayed during DESI-MSI hydrolyze the boronate ester bond, releasing free BMT molecules for desorption, ionization, and transport into the mass spectrometer. Finally, the authors collect the sequential DESI-MS and IFM images for further analysis.

It is noteworthy to mention that the authors provided compelling evidence of its effectiveness by targeting the epithelial growth factor receptor (EGFR) pathway, an important therapeutic target in cancer research. This pathway includes EGFR itself and several downstream signaling factors (Raf, ERK, p-MEK, p-Raf, p-ERK), and enzymes (PLC, PKC). The results indicate that immuno-DESI-MSI can successfully differentiate and quantify the spatial distribution of these macromolecules, providing a comprehensive view of the EGFR pathway’s activity within a tissue section. Furthermore, the authors findings showed the downstream metabolic changes induced by the anti-tumor drug lapatinib within the context of the EGFR pathway. It identifies alterations in energy metabolism, one-carbon unit metabolism, RNA synthesis, and redox homeostasis, shedding light on the multifaceted impact of the drug on tumor cells.

Overall, this new study expands our ability to conduct spatial multi-omics studies, which hold immense potential for biomarker-based disease diagnosis and unraveling molecular mechanisms underlying disease progression. Immuno-DESI-MSI’s ability to provide subcellular resolution, coupled with its quantitative capabilities, makes it a powerful tool for the fields of molecular biology, pharmacology, and clinical research.

In conclusion, the study led by Professor Richard Zare and his collaborators introduces a game-changing technique in the field of mass spectrometry imaging. Immuno-DESI-MSI, by leveraging water microdroplet-cleavable mass tags, offers an unprecedented view of the spatial distribution of functional macromolecules within biological tissues. The ability to visualize and quantify complex pathways and metabolic changes at a subcellular level has vast implications for our understanding of disease mechanisms and the development of targeted therapies. As this innovative method gains traction and evolves, it holds the potential to drive breakthroughs in various fields, including cancer research, drug development, and personalized medicine.

Australian scientists from the Royal Melbourne Institute of Technology developed memristive nanodevices that mimic the brain’s ability to simultaneously process and store multiple strands of information. The authors used high performance memristors utilizing amorphous SrTiO3 to achieve multi-state switching. Unlike the ordinary 0s and 1s, with the new material several states may be achieved similar to the synapses of the brain. These studies get us one step closer to creating human-like artificial intelligence

One potential application memory nanodevices would be to understand better neurological conditions such as Alzheimer’s and Parkinson’s disease and test new treatments.