INTRODUCTION
Within the semiconductor and nanotechnology research community, one of the main capabilities sought is the capacity to quickly, non-destructively, and quantitatively analyze the composition of trace level dopants and nanostructures. Modern 3D finFET transistors, which are non-planar and generally use single-digit nanometer high-K dielectric insulators in place of SiO2 gate oxides, are an example of the technological advancements in electronics and materials that have created the necessity for this kind of learning.
Current Approaches: SIMS and TEM
Secondary Ion Mass (SIMS) spectrometry has been the workhorse analytical technique, in which a focused ion beam sputters the surface of a specimen, forming secondary ions that are analyzed for composition. However, the advent of new devices and materials can introduce substantial challenges in its use, including quantification inaccuracies because of sputtering rate variations, which can be due to factors such as non-planar structures and impurities in high-k gate hafnium dielectrics. In addition, the acquisition times required for accurate analysis is a bottleneck, typically taking ~30 minutes per test pad point.
To address these problems, Transmission electron microscopy (TEM) is used. TEM measures the transmission of electrons through a sample, and as a result, requires the preparation of an ultrathin lamella of <100 nm for a region-of-interest. TEM is labor-intensive and very low throughput, and the sample preparation and region-of-interest can remove or destroy features of interest.
Figure 1: Current approaches to measure thin films are SIMS or TEM sectioning, both which are low-throughput and destructive. Shown above is a TEM image of a 16-nm finFET. D James, “Moore’s Law Continues into the 1x-nm Era.” 21st Itnl Conference on Ion Implanation Technology 2016.
NOVEL APPROACH
Sigray AttoMap Patented MicroXRF System Sigray, through patented breakthroughs in x-ray source and x-ray optic technologies, has developed the AttoMap microXRF system with sub-femtogram sensitivities. The MicroXRF system is non-destructive, with a high spatial resolution of 10 µm, making it ideal as a complementary upstream technique to SIMS and TEM for identifying regions of interest for follow-on characterization.
EXPERIMENT SUMMARY
The AttoMap was used on third party prepared samples of thin films on Si substrates to validate its capabilities and to measure its lower limit of detection (LLD). Its multi-target x-ray source enabled the selection of different x-ray targets to optimize the x-ray fluorescence signal for different thin films of interest.
Figure 2: Lower Limits of Detection with 3-sigma Confidence at 400s: LDLs of well below sub-angstrom can be obtained with Sigray’s AttoMap non-destructively. Moreover, as can be seen from the Co thin film rows, choice of x-ray source target matters: Cu has a ~10X better LDL than a Mo target. This is why AttoMap uses a patented multi-target x-ray source
SUMMARY
Sigray’s AttoMap provides a non-destructive, ultrahigh sensitivity approach for quantifying thin film thicknesses and dopant concentrations. Its patented high brightness x-ray source and x-ray optics enable excellent throughput and sensitivity, and moreover, due to its multi-target x-ray source design, has optimal performance for most elements-of-interest. The system can be used for single layers (as discussed) or even multiple elements and multi-layers (microXRF provides simultaneous detection of all elements).
Because of its high spatial resolution, the AttoMap can provide rapid (seconds to minutes) region-of-interest identification for follow-on analysis with complementary approaches such as SIMS and TEM.
]]>In the ever-evolving landscape of scientific exploration, Cryo-Electron Microscopy (Cryo-EM) stands as a beacon of innovation, offering unprecedented insights into the intricate world of molecular structures. By preserving specimens in their native state at cryogenic temperatures, Cryo-EM transcends traditional limitations, enabling researchers to visualize biomolecules with exquisite detail and fidelity. This transformative technology not only unveils the hidden complexities of life's building blocks but also fuels groundbreaking discoveries across diverse scientific disciplines.
What is Cryo-electron microscopy?
In Cryo-Electron Microscopy (Cryo-EM), specimens undergo rapid freezing (vitrification), preventing crystalline ice formation and maintaining their inherent state. Subsequently, a Transmission Electron Microscope (TEM) captures two-dimensional projections of the sample. By collecting numerous projections from various angles, these images are averaged and reconstructed into a comprehensive 3D model of the sample's structure. Leveraging state-of-the-art electron detectors and advanced image-processing software, Cryo-EM achieves high-resolution imaging akin to conventional structural techniques.
"Cryo-EM is filling a gap that is typically unattainable by NMR and X-ray crystallography — allowing the visualization of cells, viruses, and molecular complexes."
Comparison between cryo-EM, X-ray crystallography, and NMR techniques
In comparison to X-ray crystallography and Nuclear Magnetic Resonance (NMR) techniques, Cryo-Electron Microscopy (Cryo-EM) offers distinct advantages. Unlike X-ray crystallography, Cryo-EM does not require crystallization of samples, allowing for the study of challenging molecules. Additionally, Cryo-EM surpasses NMR in its ability to visualize larger macromolecular complexes with greater precision. Moreover, Cryo-EM's capacity to analyze heterogeneous samples provides a significant edge over both X-ray crystallography and NMR, making it particularly valuable for structural studies of flexible or dynamic biomolecules. These attributes render Cryo-EM a versatile and powerful tool for elucidating the structures of complex biological systems, positioning it at the forefront of structural biology research.
Electron microscopy is the fastest growing technique, quickly becoming the second-most-prolific method.
Cryo-EM Workflows
Cryo-Electron Microscopy (Cryo-EM) workflows encompass two primary techniques: Single Particle Analysis and Microcrystal Electron Diffraction. These methodologies revolutionize structural biology by offering complementary approaches for elucidating the 3D structures of biological macromolecules.
Single particle analysis
Single particle analysis is a cryo-EM technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structures of biomolecular complexes or assemblies.
Cryo-electron tomography
Cryo-electron tomography (cryo-ET) delivers both structural information about individual proteins as well as their spatial arrangements within the cell. This makes it a truly unique technique, with an enormous potential for cell biology. Cryo-ET can bridge the gap between light microscopy and near-atomic-resolution techniques like single-particle analysis.
Microcrystal electron diffraction
Microcrystal electron diffraction (MicroED) is an exciting new technique with applications in the structural determination of small molecules and protein. With this method, atomic details can be extracted from individual nanocrystals (<200 nm in size), even in a heterogeneous mixture.
SFR: Your Guide to Cryo-EM in Canada
At Systems for Research (SFR) we are proud to lend a helping hand in delivering innovation and years of excellence to your doorstep every step of the way. Our partnership with Thermo Fisher Scientific, the pioneers in the Cryo-em industry is a testament to our promise of delivering the best, always.
We have been collaborating with universities, industry, and health science institutions for over 30 years, to offer an array of cutting-edge scientific instrumentation and provide greater visibility into the molecular world.
Our in-house service team, a group of highly certified Thermo Fisher Scientific engineers, work to provide our clients with uninterrupted and on-going local support for their research needs.
FTIR operates on the principle of measuring the absorption of infrared light by a sample. When infrared light interacts with a sample, certain wavelengths are absorbed, corresponding to the vibrational modes of different chemical bonds within the molecules. By analyzing the absorption spectrum, FTIR provides valuable information about the functional groups present in a compound, allowing for qualitative and quantitative analysis.
Raman Spectroscopy, on the other hand, relies on the inelastic scattering of monochromatic light by molecules. When a photon interacts with a molecule, it undergoes a change in energy corresponding to the vibrational and rotational modes of the molecular bonds. By measuring the scattered light, Raman Spectroscopy provides insights into the molecular structure and chemical composition of a sample. Unlike FTIR, Raman Spectroscopy is not dependent on sample preparation and can analyze aqueous samples efficiently.
FTIR is highly sensitive to functional groups containing polar bonds such as C=O, O-H, and N-H. It excels in the identification of organic compounds and is particularly useful in characterizing polymers, pharmaceuticals, and biomolecules. Raman Spectroscopy, on the other hand, exhibits strong signals for symmetric and polarizable bonds. It is highly selective for compounds with symmetrical structures, making it suitable for the analysis of inorganic materials, minerals, and complex mixtures.
FTIR requires samples to be in a solid state or as thin films, limiting its compatibility with certain materials and requiring meticulous sample preparation. In contrast, Raman Spectroscopy can analyze samples in various states, including solids, liquids, and gases, making it more versatile and adaptable to different sample matrices. Additionally, Raman Spectroscopy is less prone to interference from water, making it ideal for aqueous samples.
Raman Spectroscopy offers superior spatial resolution, allowing for microscopic analysis and imaging of samples with sub-micrometer resolution. Its ability to generate chemical maps and visualize molecular distributions makes it invaluable in materials science, forensics, and biomedical research. While FTIR can also be coupled with microscopy techniques, its spatial resolution is typically lower compared to Raman Spectroscopy.
In the realm of analytical chemistry, the choice between FTIR and Raman Spectroscopy depends on the nature of the sample, the information required, and the analytical objectives. While FTIR excels in the characterization of organic compounds and functional groups, Raman Spectroscopy offers versatility, compatibility with different sample states, and superior spatial resolution. By understanding the principles and comparative analysis of these techniques, researchers can make informed decisions, harnessing the power of spectroscopic methods to unravel the mysteries of molecular structures and chemical compositions.
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Scanning Electron Microscopy (SEM): Peering into Surface Morphology
At the heart of SEM lies the ability to capture high-resolution images of a material's surface morphology. SEM operates by scanning a focused beam of electrons across the specimen, eliciting various signals such as secondary electrons, backscattered electrons, and X-rays. These signals are then detected and translated into an image, providing intricate details of the surface topography and composition.
The ability of SEM to image a variety of samples, including conductive and non-conductive materials, is one of its main benefits. Moreover, SEM is a recommended option for routine analysis in disciplines like materials science, biology, and geology since it makes sample preparation very simple.
Transmission Electron Microscopy (TEM): Delving into Structural Composition
In contrast to SEM, TEM delves deeper into the structural composition of materials, offering unparalleled insights into atomic-scale features. Instead of scanning the surface, TEM transmits electrons through a thin specimen, creating a highly magnified image of the internal structure. This technique enables researchers to visualize individual atoms, crystal lattices, and defects with extraordinary clarity.
TEM's ability to resolve fine details makes it indispensable in elucidating the microstructure of materials, such as nanoparticles, semiconductors, and biological specimens. However, TEM's sample preparation is more intricate, often requiring ultrathin sections or electron-transparent grids, and its operation demands meticulous control and expertise.
Choosing the Right Tool for the Job
While both TEM and SEM provide priceless insights into the nanoworld, choosing the right method depends on the particular goals of the study as well as the properties of the material. When it comes to surface examination, SEM is excellent at delivering in-depth details about morphology, texture, and elemental composition. Conversely, the strength of TEM is in dissecting the atomic configurations and interior structure of materials.
To get a thorough grasp of a material's properties, researchers frequently use a complimentary strategy, combining TEM and SEM. Surface morphology and structural analysis together open up new creative possibilities for materials science and medicines, among other domains.
Looking Ahead: Advancements in Microscopy
To sum up, SEM and TEM are essential components of contemporary microscopy, providing distinct insights into the complex realm of nanoscale processes. With the use of these instruments, researchers can explore atomic structures and uncover hidden layers of surface morphology, therefore expanding the frontiers of scientific inquiry and creativity.
Come along as we explore the intriguing world of microscopy in more detail, where each pixel reveals a tale just waiting to be told.
]]>A pillar of contemporary scientific research, nanotechnology - the manipulation of matter at the atomic and molecular scale, has emerged as a cornerstone of modern scientific inquiry, offering unprecedented opportunities across a multitude of disciplines. In this blog, we embark on a journey to explore the diverse and transformative applications of nanotechnology, ranging from healthcare and electronics to environmental remediation and beyond.
Nanomedicine
At the forefront of nanotechnology's application lies the realm of nanomedicine, where researchers harness the unique properties of nanomaterials to revolutionize diagnostics, drug delivery, and therapeutic interventions. When designed with accuracy and specificity, nanoparticles can be used to deliver drugs to specific disease cells directly, reducing the risk of systemic adverse effects. This has great promise for targeted medication delivery. Additionally, novel insights into biological processes are provided by nanoscale imaging techniques like magnetic nanoparticles and quantum dots, which make it easier to identify diseases early and develop individualized treatment plans.
Nanoelectronics
In the realm of electronics, nanotechnology paves the way for the development of smaller, faster, and more energy-efficient devices. The development of nanoscale memory, sensors, and transistors made possible by the shrinking of electrical components to the nanoscale propels the exponential increase in processing power and data storage capacity. Furthermore, nanomaterials with remarkable electrical properties, including graphene and carbon nanotubes, hold promise for developments in flexible electronics, wearable technology, and next-generation computing.
Environmental Remediation
The application of nanotechnology extends beyond the realms of healthcare and electronics to address pressing environmental challenges. Nanomaterials, such as nanoscale catalysts and adsorbents, offer innovative solutions for pollution mitigation, water purification, and sustainable energy production. Techniques for remediation based on nanoparticles, such photocatalysis and nanofiltration, have the potential to be extremely precise and efficient in eliminating impurities, breaking down pollutants, and utilizing renewable energy sources.
Nanotechnology in Agriculture
Nanotechnology has the ability to completely transform food safety, insect control, and crop yield in agriculture. Nanomaterials provide tailored delivery methods to maximize crop output and nutrient uptake while reducing environmental effect. Examples of these materials are nanopesticides and nanofertilizers. Furthermore, real-time monitoring of plant health, soil conditions, and food quality is made possible by nanosensors, which gives farmers practical information to improve farming methods and guarantee food security.
Conclusion
As we reflect on the myriad applications of nanotechnology, it becomes evident that its impact transcends disciplinary boundaries, offering solutions to some of humanity's most pressing challenges. From revolutionizing healthcare and electronics to mitigating environmental pollution and enhancing agricultural productivity, nanotechnology holds immense promise for shaping a more sustainable, equitable, and technologically advanced future. As scientists, engineers, and policymakers continue to push the frontiers of nanoscience, let us embrace the ethos of responsible innovation, ensuring that the transformative power of nanotechnology is harnessed ethically and responsibly for the betterment of all.
]]>An acronym for the combination of the analytical technique SIMS (Secondary Ion Mass Spectrometry) with Time-of-Flight mass analysis (TOF), this sensitive technique is well established for many industrial and research applications.
The technique provides detailed elemental and molecular information about the surface, thin layers, interfaces of the sample, and gives a full three-dimensional analysis. The uses of this technique are widespread, including semiconductors, polymers, paint, coatings, glass, paper, metals, ceramics, biomaterials, pharmaceuticals and organic tissue.
SIMS is a very surface sensitive technique because the emitted particles originate from the uppermost one or two monolayers. Whereas, TOF mass spectrometry is based on the fact that ions with the same energy but different masses travel with different velocities. Major advantages of this approach over quadrupole and magnetic sector type analysers are the extremely high transmission, the parallel detection of all masses and the unlimited mass range.
Surface Spectrometry
The aim of a static SIMS investigation is the analysis of the original, non-modified surface composition. As SIMS in principle is a destructive technique this means that the contribution of those secondary ions to the spectrum originating from already bombarded surface areas to the spectrum must be negligible. This quasi non-destructive surface analysis can be achieved by the application of very low primary ion dose densities. Surface Spectroscopy provides detailed elemental and molecular information from the outer monolayers.
Surface Imaging
By rastering a fine-focused ion beam over the surface, like an electron beam in an electron microprobe, mass-resolved secondary ion images (chemical maps) can be obtained simultaneously.
Depth Profiling
For Depth Profiling two ion beams operate in the Dual Beam Mode. While the first beam is sputtering a crater, the second beam is progressively analysing the crater bottom.
3D Analysis
The visualization of 3D sample structures is possible by combining spectral, imaging and depth information. 3D Analysis is ideal for the investigation of complex and unknown structures or defects.
In particular the composition, shape and position of features and defects can be visualized.
Retrospective Analysis
As well as comprehensive on-line analysis, the parallel mass detection of the TOF-SIMS provides the means to carry out Retrospective Analysis. Regardless of the knowledge about the sample before the measurement, the data can be explored afterwards to look for unexpected results, such as unknown structures, contaminants at interfaces and so on.
Systems for Research: Your Guide to TOF-SIMS in Canada
Systems for Research is your resource and companion for IONTOF all across Canada. Together, we are making sure to provide Advanced ion beam technology for Surface Analysis accessible all across Canada.
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The paper effectively highlights the development of a suite of groundbreaking lab-based x-ray tools for energy research with performance capabilities approaching that of synchrotron-based approaches.
When it comes to x-ray techniques for battery development, we often look at four commonly used techniques:
The 3/3 part of this white paper series dives more into the use of X-ray Diffraction (XRD) with EclipseXRM and Apex XCT to study the crystal structure and bond lengths of battery materials.
A Technique Overview
X-ray microscopy (XRM) is a powerful tool for the analysis of the structure of materials at various length scales, ranging from microns to nanometers. The approach measures the absorption of x-rays to form images of the internal structures of intact samples after or during charging cycles.
Systems Overview
Sigray offers the two leading XRM models: EclipseXRM and Apex XCT. EclipseXRM is a breakthrough nanoCT system that scans a range of intact and cut battery samples at worldleading 300 nm spatial resolution. In contrast to the EclipseXRM, Sigray’s Apex XCT is specifically designed for planar samples (including pouch cell batteries) and can image such samples at 0.5 µm resolution within minutes.
X-ray Microscopy and Battery Research
Lithium ion batteries (LIBs) are complex electrochemical systems with hierarchical multiscale structures and repeated imaging of a battery between charging cycles or in operando is essential for a quantitative understanding of structural changes.
EclipseXRM: X-ray microscopy is unique as it has the power to carry out hierarchical 3D imaging at multiple length scales. EclipseXRM enables imaging of intact batteries at zoomed-out overviews (coarser resolution) and zoomed-in (0.3 nm) detailed views of defects and microstructures.
Examples of the range of battery defects that can be imaged using the EclipseXRM are shown in the figure below.
Apex XCT: Pouch cell batteries have high aspect ratios and often are difficult to image using conventional x-ray imaging approaches at high resolutions beyond 10s of microns. The Apex XCT’s patented scanning geometry is ideal for planar samples, enabling submicron resolution on intact pouch cell batteries and at high throughputs of down to single digit minutes.
Conclusion
Advances in battery research depend on a multi-technique approach to develop comprehensive understanding of chemical and structural battery degradation mechanisms. Synchrotron x-ray techniques have been critical in significant discoveries, but the lack of accessibility slows the pace of research. Sigray has developed a suite of spectroscopy and imaging laboratory tools for 24 hours a day, 7 days a week access to synchrotron-like capabilities to accelerate battery research.
Systems for Research and Sigray: A Meaningful Partnership
Systems for Research (SFR) is a proud partner of Sigray, the leading name in X-Ray Microscopy and we are diving into the potential of this suite of spectroscopy and laboratory tools in a four-part series. Stay tuned as we dive into part ¾ of this series as we discover more about X-ray Microscopy with EclipseXRM and Apex XCT.
]]>When it comes to AAV sample quality, the total concentration of AAV capsid in a sample, or capsid tier is a critical factor that influences the aggregation and represents important information for downstream recovery and purification processes.
On the other hand, titer of full AAVs also understood as the concentration of AAV capsids that contain the genetic material to be delivered is a crucial factor to determine the potency of a product and vital information for clinical dosing.
Why use mass photometry for AAV titer estimation?
When it comes to analysis of AAV samples and AAV titer estimation, mass photometers considered ideal tool due to the following reasons:
These strengths make mass photometry an efficient and easy technique to implement in environments that require repeated AAV capsid titer measurement, such as process development.
Systems for Research: Your Guide to Mass Photometry in Canada
Systems for Research is the exclusive representative for Refeyn in Canada. We work with Refeyn to make mass photometry instruments available to our customers all across Canada.
Mass photometry is a revolutionary new way to analyze molecules. It enables the accurate mass measurement of single molecules in solution, in their native state and without the need for labels. This approach opens up new possibilities for bioanalytics and research into the functions of biomolecules.
]]>We're excited to have you both join us and can't wait to see what we accomplish together!
]]>With the O-PTIR technique, several components can be spectroscopically separated and identified. Here, the top 3µm of the dark contamination has been identified as an epoxy component, which is usually the organic binder component in underfill materials.
The bottom 3µm layer appears to contain significant amounts of carbon and carboxylates; the latter may have originated from oxidized cellulosic matter. Such unprecedented details provide investigative insights into tracking down the source of the contamination, raw materials, or errors in the process. In contrast, conventional FT-IR microspectroscopy could not provide meaningful information from the same specimen.
Finally, the analysis was achieved from a cross-sectioned surface using standard chemo-mechanically polishing processes, representing a significant time savings over more involved sample preparation techniques, such as those requiring labor-intensive focused ion beam (FIB)-based thin sectioning.
Left; visible image showing location of 6µm defect, Upper Right; Comparison of unknown O-PTIR spectrum to nearest library match, Lower Right: Comparison of unknown Raman spectrum to nearest library match.
Upper Left; Schematic representation of sample and measurement, Lower Left; Visible camera image of defect, Right; O-PTIR spectra from on and off the defect. Colors correspond to markers on visible image
Simultaneous IR+Raman spectral searching with 2D search result representation with KnowItAll®
One of the goals of any FA process is the chemical identification of the unknown material and to that end, the final step, after spectral acquisition is to search against a spectral database. Traditionally IR spectra would be searched against an IR spectral library and Raman spectral would be searched, separately, against a Raman spectral library. The user would then examine the two separate so-called “hitlists” for IR and Raman spectra.
Now, with the advent of simultaneous submicron IR+Raman spectral acquisition, as seen in figure here, not only are the IR and Raman spectra simultaneously collected, but now the spectral search of both IR and Raman spectral occurs simultaneously, with a single click from the data acquisition software.
Systems for Research (SFR) is your resource and companion for Photothermal Spectroscopy Corp. all across Canada. Together, we are making sure to provide submicron spatial resolution for IR and transmission-like FTIR quality spectra in non-contact reflection mode accessible to all.
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The paper effectively highlights the development of a suite of groundbreaking lab-based x-ray tools for energy research with performance capabilities approaching that of synchrotron-based approaches.
When it comes to x-ray techniques for battery development, we often look at four commonly used techniques:
This 2/4 part of this white paper series dives more into the use of X-ray absorption spectroscopy with Quantum Leap.
A technique Overview
MicroXRF is an ultrahigh sensitivity approach for elemental mapping and quantification. X-ray Fluorescence occurs when x-rays excite atoms within a sample, promoting inner shell electrons to the outer shells or emitting them from atoms.
This relaxation produces an x-ray. Because the distances between outer shells and inner shells is characteristic to each element, measurement of the x-ray energies emitted by the sample gives not only the elements contained within the illuminated region, but also the quantity.
System Overview
Sigray AttoMap microXRF is truly unbeatable as it provides unprecedented sensitivity to detect heavy and even light elements (e.g., C, O, N) that are too low concentration to be measured using electron-based techniques such as SEM-EDS and EPMA or other microXRF systems.
Sigray’s patented x-ray energy tunable source and high efficiency double paraboloidal x-ray optics allow the instrument to provide fast, non-destructive chemical mapping at <5 µm resolution and bring the acquisition times down to 2 ms per point. A major advantage of the Attomap is its ability to tune X-ray incident energy to elements of interest to maximize fluorescence cross section. This ability to switch energy can increase sensitivity > 1000X as seen in the figure below.
Figure 1: Sigray AttoMap features a patented x-ray source with multiple x-ray targets (each target produces a different x-ray spectra). Arsenic from the same sample is shown using two different x-ray targets: tungsten and molybdenum to illustrate the major gains in sensitivity possible.
Application in Battery Research
Attomap provides high sensitivity detection levels down to sub-ppm levels for transition elements commonly used in battery research.
Unique to the AttoMap is its strength in trace-level detection (e.g., sub-0.01%) of important low Z elements such as Al, Mg, Na, F, S, P, and organics (C, O, N). This is achieved using a tilted goniometer stage and a high vacuum enclosure with 10E-5 Torr. The ability to tilt the sample stage in the Attomap also allows elemental analysis to vary from deep to shallow interaction volumes.
AttoMap’s High Sensitivity: A Key Advantage
Sigray has developed a correlative workflow to first identify the location of potential impurities using transmission X-ray microscopy, followed by AttoMap microXRF to identify the chemical composition of these impurities.
Systems for Research (SFR) is a proud partner of Sigray, the leading name in X-Ray Microscopy and we are diving into the potential of this suite of spectroscopy and laboratory tools in a four-part series. Stay tuned as we dive into part ¾ of this series as we discover more about X-ray Microscopy with EclipseXRM and Apex XCT.
]]>This process is usually followed by size exclusion chromatography (SEC) to separate the nanodisc-embedded AQP4 proteins from empty discs, aggregates and other impurities.
]]>Among these, nanodiscs are increasingly drawing interest due to improved stability and ability to dilute to low concentrations without losing integrity or shape.
Mass Photometry and AQP4 Membrane Protein
Traditionally, mass photometry was used to examine the composition and quality of protein samples at different points during the purification process.
This process is usually followed by size exclusion chromatography (SEC) to separate the nanodisc-embedded AQP4 proteins from empty discs, aggregates and other impurities.
From the figure above, it can be observed that Fraction 3 has the greatest abundance of AQP4 singlets.
This fraction was selected to undergo a further step of affinity purification which resulted in a sample composed of mostly SMALP-embedded AQP4 singlets, smaller quantities of higher-order complexes and a minor amount of contaminant.
Identification of Desired Species
The presence of natively folded AQP4 singlets in the affinity-purified sample was confirmed by an anti-AQP4 antibody. A further analysis using mass photometry of the sample incubated with the anti-AQP4 antibody showed a new population at ≈449 kDa, corresponding to anti-AQP4 antibodies bound to nanodisc-embedded AQP4 singlets.
Following this, a negative control using a non-specific antibody showed a similar distribution to the untreated sample. The combination of both experiments as shown in figure below confirm that natively folded AQP4 is present in the sample.
Takeaways
Mass photometry addresses challenges met during the purification of membrane protein, as it requires a small amount of sample and is largely compatible with most membrane mimetics.
It is worth noting that SMALP’s are known to have variable sizes.
Nevertheless, the masses of the complexes identified here are consistent with theoretical predictions, and the SMALP and protein masses of AQP4 singlets match the results of other analytical methods like SEC and SMA-PAGE.
To conclude, it can be said that mass photometry provides valuable information about complex samples, which greatly helps in making decisions during membrane protein purification.
Systems for Research: Your Guide to Mass Photometry in Canada
Systems for Research is the exclusive representative for Refeyn in Canada. We work with Refeyn to make mass photometry instruments available to our customers all across Canada.
Mass photometry is a revolutionary new way to analyze molecules. It enables the accurate mass measurement of single molecules in solution, in their native state and without the need for labels. This approach opens up new possibilities for bioanalytics and research into the functions of biomolecules.
]]>Thermo Fisher’s next generation products focus on advanced analytical capabilities for failure analysis, yield learning, and process control.
]]>The ongoing success can be traced back to 2016, when Thermo Fisher acquired FEI company, a leading electron microscopy organization in the semiconductor market. This acquisition was followed by FEI’s DualBeam systems and the world’s most powerful, commercially available transmission electron microscope (TEM).
Thermo Fisher Scientific: The Broadest Portfolio of Semiconductor Metrology Instruments
Thermo Fisher’s next generation products focus on advanced analytical capabilities for failure analysis, yield learning, and process control.
To ensure the highest yield possible, Thermo Fisher’s electron microscopes and analytical instrumentation help control process steps and analyze the wafer environment throughout semiconductor manufacturing.
Without a doubt, Thermo Fisher provides the broadest portfolio of semiconductor metrology, characterization and fault analysis instruments to accelerate pathfinding and development, maximize yields, and ensure the production of high-quality devices that meet current and future industry demands.
The Global Reach of Thermo Fisher Scientific
Thermo Fisher instruments are used in numerous research, service labs and applications worldwide. It is also the preferred supplier of EFA, PFA, and metrology solutions with leading memory and logic integrated device manufacturers.
Supporting the Evolving Needs of Semiconductor Industry
Thermo Fisher’s commitment to their customers include ongoing investment in innovative, industry leading solutions to meet evolving metrology and failure analysis needs. This promise is accompanied by the development of industry leading software for wafer, bare die or fully packaged chips to extract the cause of complex device defects. Along with, investments in local resources are done to support customer’s design verification, electrical, physical and elemental analysis, yield enhancement, process improvement and quality control analysis needs.
At Systems for Research (SFR) we are extremely proud of our partnership with Thermo Fisher Scientific. As the trusted representative and seller of Thermo Fisher Scientific all across Canada, we are proud to lend a helping hand in delivering innovation and years of excellence to your doorstep every step of the way. Our service team, a group of highly certified Thermo Fisher Scientific engineers, work to provide our clients with uninterrupted and on-going local support for their research needs.
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IONTOF’s advanced surface analysis instrumentation will provide critical insights into the material used in energy storage devices thereby giving a boost to the shared sustainability goals.
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About StoreAGE
Even though battery systems are ideally suited to accompany the expansion of renewable electricity generation, development of systems with improved storage capacity and lifetime are necessary to achieve this task.
The goal of StoreAGE is to advance and boost the development of energy storage systems, with increased storage time and efficiency and to train highly qualified personnel and researchers in this field.
When it comes to the performance of the whole battery system, the solid-liquid interface between electrode and electrolyte is crucial. StoreAFE applies advanced characterization techniques that are crucial to analyze and understand the solid-liquid interface.
The Partnership: A StepTowards Sustainability
For IONTOF, this partnership is a major step forward in advancing sustainable energy solutions.
Addressing the rising needs for cutting-edge energy storage solutions is essential, especially when this demand is driven by the transition to renewable energy sources and the rise of electric vehicles.
IONTOF’s advanced surface analysis instrumentation will provide critical insights into the material used in energy storage devices thereby giving a boost to the shared sustainability goals.
Systems for Research (SFR) is a proud representative for IONTOF all across Canada and highly appreciates this new partnership. As pioneers of the research and innovation industry, it is crucial to build sustainable resources, while playing a collaborative role in this journey together.
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The paper effectively highlights the development of a suite of groundbreaking lab-based x-ray tools for energy research with performance capabilities approaching that of synchrotron-based approaches.
When it comes to x-ray techniques for battery development, we often look at four commonly used techniques:
This 1/4 part of this white paper series dives more into the use of X-ray absorption spectroscopy with Quantum Leap.
A technique Overview
X-ray Absorption Spectroscopy (XAS) is a powerful technique to understand the local electronic structure of atoms during an electrochemical process. Unlike X-ray diffraction (XRD), XAS is not limited to crystalline materials and is often used for studying transition metals of importance in battery research. X-ray Absorption Spectroscopy (XAS) is a powerful technique to understand the local electronic structure of atoms during an electrochemical process. Unlike X-ray diffraction (XRD), XAS is not limited to crystalline materials and is often used for studying transition metals of importance in battery research.
Systems Overview
Sigray QuantumLeap XAS is the first laboratory system that provides synchrotron-like XAS capabilities with sub-eV resolution with acquisition times within minutes, and the only commercial XAS with access to both transmission-mode XAS (for concentrated samples) and fluorescence-mode XAS (low concentrations of 5% wt or lower).
QuantumLeap’s breakthrough design enables it to be the only laboratory system to enable high energy resolution acquisition at low Bragg angles.
Applications in Battery Research
QuantumLeap products span the energy range of 2.1 to 25 keV, covering a vast majority of the elements of interest in battery research, including sulfur and all transition metals (nickel, manganese, cobalt, zinc).
Li-Ion Batteries (LIBs): As the only system with fluorescence-mode XAS, QuantumLeap has become instrumental in the development of NMC-type Li-Ion battery materials, in which the goal is to minimize the weight percentage of Mn and Co to improve their cost.
Because it is the only system with fluorescence-mode XAS, QuantumLeap has become instrumental in the development of NMC-type Li-Ion battery materials, in which the goal is to minimize the weight percentage of Mn and Co to improve their cost. Such samples cannot be analyzed using conventional transmission-mode laboratory XAS because the high weight percentage of Ni and concentrations of Mn and Co do not provide adequate signal-to-noise (SNR).
Intact Pouch Cells: Keeping the electrode material within an intact pouch cell prevents environmental-induced chemistry changes and, importantly, enables in situ and repeated studies. However, intact pouch cells are highly absorbing to intact pouch cell batteries, even challenging ones with low x-ray transmission of <1% (Fig 5 shows ~0.2-0.3% transmission data).
Systems for Research is diving into the potential of this suite of spectroscopy and laboratory tools in a four-part series. Stay tuned as we dive into the potential of each of these techniques.
]]>Although low counts for aggregates impeded a quantitative analysis, MP was affirmed as an accurate and rapid method for quantifying the genome content of empty/filled/double-filled capsids.
]]>AAV sample characterization is a critical step in research, development and manufacturing processes of gene therapies involving viral vectors. There are several analytical approaches available to assess critical quality attributes (CQAs) for AAV samples, such as capsid content (empty/full ratios) and titer.
Use of MP (Mass Photometry) Analysis for AAV Samples
The new paper titled “ Characterization of Virus Particles and Submicron-Sized Particulate Impurities in Recombinant Adeno-Associated Virus Drug Product” published by Boehringer Ingelheim explore the benefits of MP analysis for assessing aggregate content in AAV samples.
Although low counts for aggregates impeded a quantitative analysis, MP was affirmed as an accurate and rapid method for quantifying the genome content of empty/filled/double-filled capsids.
This revelation is important as it confirms that MP is an accurate and robust method to determine the molecular mass of AAV capsids including genomic content on a single particle level, resolving capsid species with differing genome size.
Benefits of MP Analysis
Right off the bat, MP was found to be compatible with various excipients and a wide range of buffer conditions. This compatibility is a major benefit of MP, eliminating the needs for complex sample preparation or even excipient exchanges. In the long run, it saves researchers both time and resources.
Good for us, MP can be operated with capsid titers as low as 8 × 1010 cp mL−1 with a CV < 5% using just 10 µL total sample volume.
Another advantage of MP is the single particle-level analysis enabling a differentiation between empty, filled, and double-filled species. In comparison to the data from SV-AUC, the MP data was better which can be considered as the gold standard for this purpose.
It was found that MP outperforms other methods of assessing empty/filled capsid content. Due to its low sample consumption and user-friendly operation, MP is an indispensable instrument in the research and development environment.
Further Studies on the use of MP for AAV Analysis
Another paper, taken from Takeda, a 3rd party study and benchmarking of MP for AAV Analysis titled “Quantification of Empty, Partially Filled and Full Adeno-Associated Virus Vectors Using Mass Photometry” further confirms the benefits of MP over other commonly adopted methods to quantify AAV byproducts that are co-produced during the manufacturing process.
The paper elaborates on the use of analytical ultracentrifugation (AUC), transmission electron microscopy (TEM) and charge-detection mass spectrometry (CDMS) for quantifying AAV subspecies. However, these were associated with long turnaround times, low sample throughput and complex data analysis.
Mass Photometry is indeed a fast and label-free orthogonal technique which is applicable to multiple serotypes without the adaptation of method parameters.
Here’s a video from our leading partner, Refeyn on the application of mass photometry for AAV sample characterization in GMP-regulated environments.
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The featurefindIR provides rapid, automated detection, spectroscopic measurement, and chemical identification of microplastics and other particles, significantly improving the productivity of measurement and providing a basis for measurements of large number of samples in applications including but not limited to microplastics, defect contamination and cells analysis, as well as many other sample types.
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The featurefindIR provides rapid, automated detection, spectroscopic measurement, and chemical identification of microplastics and other particles, significantly improving the productivity of measurement and providing a basis for measurements of large number of samples in applications including but not limited to microplastics, defect contamination and cells analysis, as well as many other sample types.
As a standard product on the new MIRange systems. featureFindIR provides a standard, easy to use workflow for the detection and selection of required particles. This new automation is capable of offering rapid, automated detection, spectroscopic measurement, and chemical identification of particles.
This innovation is particularly beneficial for researchers who wish to rapidly measure a larger number of relevant microplastics while providing dimensional information and determining their chemical ID with a dedicated µChemical ID database. Moving further, this data can be exported through CSV for further analysis as required.
featurefindIR improves productivity of measurement by providing different methods for identifying microplastics types, such as single wavelength imaging and fluorescence images. It is indeed a complete solution for measurement of microplastics ranging from submicron to millimeter in size. As an option, featurefindIR is available as an upgrade on existing standard mIRage and mIRage-LS systems along with the µChemical ID database.
Here’s a video demonstrating the ease of use that comes with the featurefindIR.
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Refeyn, a leader in mass photometry technology, expands the analytical possibilities for high concentration samples by MassFluidix HC. The new microfluidic system enhances protein analysis workflows for the study of weak protein-protein interaction by mass photometry.
The new system is compatible with Refeyn’s TwoMP mass photometres and will allow for the accurate measurement of low-affinity biomolecular interactions through rapid dilution, such that the interaction state at micromolar concentrations is captured before the disruption of the equilibrium. Refeyn is building technology for researchers as they can now analyze samples with concentrations of up to 90 µM, a 100-fold increase on previous capability.
The MassFluidix HC systems provides precise and rapid dilution of up to 10,000-fold in milliseconds, facilitation detection of low-affinity complexes that was not previously observed. It consists of two parts: the microfluidics device, and a consumable chip for immediate analysis allowing for the sample to reach the observation window within <50 ms of the beginning of the dilution process.
Essentially, this approach builds up the speed and simplicity already offered by mass photometry and opens us new applications such as transient binding and oligomerization, all label-free, in solution, and at the single-molecule level.
It is interesting to highlight that the introduction of this new system builds upon Refeyn’s commitment to meeting the needs of its customers and addressing the unique challenges of protein research through the expansion of capability posed by mass photometry. The MassFluidix HC system is an essential addition for every researcher looking to expand the potential of mass photometry and streamlining the protein analysis workflow.
Systems for Research is a proud vendor of Refeyn and commends it on the development of its latest system as it keeps up with their shared goal of empowering research and innovation. As a leader in mass photometry, Refeyn is opening doors for research and unveiling greater potential into the world of innovation through mass photometry.
]]>Globally, the Hospital for Sick Children was the first institution to acquire the recently launched Thermo Scientific Glacios 2 Cryo-TEM, which they use in conjunction with a Thermo Scientific Krios Cryo-TEM to speed up their entire data collection process.
]]>About the Hospital for Sick Children
The Hospital for Sick Children (SickKids), affiliated with the University of Toronto, is Canada’s most research-intensive hospital dedicated to improving the health of children in the country.
SickKids is more than just a hospital, it is an integrated centre with the goal of providing the best in child and family-centered care, creating ground-breaking clinical and scientific advancements, and training the next generation of experts in child health.
The Role of Cryo-electron Microscopy
As an increasingly popular structural biology technique, Cryo-EM allows high-quality imaging across a range of scales from proteins up to entire cellular structures with cryo-tomography. A lot of these are highly critical systems that make up biofilms difficult to treat bacterial infections or viral structures like the coronavirus spike protein.
SickKids is efficiently leveraging this groundbreaking technology in their state-of-the-art Cryo-EM facility. In Conversation with Dr.John Rubinstein, he explores how molecular insights are shaping medical research and treatment. He further states that for many of the problems that SickKids and their collaborators are working on, cryo-EM is the only method that would give atomic-resolution insight into the structures being studied at the time.
The Need for Deeper Structural Insights
Globally, the Hospital for Sick Children was the first institution to acquire the recently launched Thermo Scientific Glacios 2 Cryo-TEM, which they use in conjunction with a Thermo Scientific Krios Cryo-TEM to speed up their entire data collection process.
The Glacios 2 Cryo-TEM is used to collect small sample datasets and quickly identify how to best optimize specimen preparation. When optimal specimens are identified during screening they are transferred to the Krios Cryo-TEM for final, high-quality data collection. This workflow enables rapid specimen optimization and consistent production of publication-quality data.
Through the highly collaborative nature of the Cryo-EM Facility, researchers throughout the Toronto area are able to see diseases at the most fundamental level, guiding the development of wholly novel treatments.
SFR’s commitment to Research and Innovation
As Canada’s largest source of surface characterization and analysis tools, Systems for Research strives to deliver research and innovation to researchers and scientists for their ongoing needs every single day. We have been collaborating with universities, industry, and health science institutions for over 30 years, to offer an array of cutting-edge scientific instrumentation and provide greater visibility into the molecular world.
Above all, SFR is proud to offer service and support for Thermo Fisher Scientific Electron Microscopes across Canada. Our in-house service team situated across Canada provides clients with uninterrupted and on-going local support for their research needs. SFR will continue to support the amazing work SickKids is doing everyday and support their future endeavors.
]]>The new software is a crucial development for Refeyn as it enables the implementation of mass photometry within AAV-based gene therapy manufacturing facilities without having to worry about the strict regulatory requirements of FDA 21 CFR and EMA Annex 11.
The newly launched GMP software package includes three different applications: AcquireMP, EvaluateMP, and ManageMP. These applications are all responsible for offering users access control, audit traits, standardized workflows, and electronic signatures for streamlines and controlled AAV analytics in manufacturing environments.
It was stated by Matthias Langhorst, Chief Product Officer at Refeyn, that the new software ensures easy and secure operation and administration, enabling manufacturers to uphold the highest standards of quality throughout their operations.
Refeyn is the sole manufacturer of mass photometry instruments and technology worldwide and Systems for Research is proud to collaborate with them while paving the way towards efficient scientific research.
By nature, mass photometry excels in terms of speed, ease of use, cost effectiveness, and high precision molecular mass measurements. With the introduction of this software package, mass photometry is readily available for AAV sample characterization in manufacturing environments, providing unparalleled insights and accelerating the development of AAV-based gene therapies.
Refeyn continues to pave the way for efficient and high-quality manufacturing processes, ultimately improving patient outcomes.
To find out more about SamuxMP software package, please visit: SamuxMP Auto for Automated AAV Characterization | Refeyn
To find out more about SFR’s partners & technologies, please visit: PARTNERS & TECHNOLOGIES - Systems for Research (sfr.ca)
]]>This sophisticated microscope was purchased with support from the Canadian Foundation for Innovation (CFI) as part of an Advanced Ceramic Microstructural Characterisation Suite including SEM, X-ray Diffraction (XRD) and X-Ray Microscopy (also known as microCT). In this context, in collaboration with its premier partners at Thermo Fisher Scientific and Bruker, SFR was uniquely positioned as a single supplier solution for all three instruments. With the ChemiSEM installation completed, SFR looks forward to completing the remaining suite installations in the upcoming months.
We take immense pride in our ongoing relationship with Dalhousie University, and this marks their second Axia ChemiSEM installation in just two years.
Stay tuned as we continue to support Dalhousie University in completing the installation of the remaining instruments in the Advanced Ceramic Microstructural Characterisation Suite. We are excited about the scientific breakthroughs that will undoubtedly emerge from this exceptional partnership.
]]>It was an amazing time of team building, vision sharing from our president, Jeff Pageau, and in-person discussions.
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