A new focused ultrasound approach — low-energy, rapid, short-pulsed ultrasound — can open the blood–brain barrier (BBB) using microbubbles and deliver drugs more uniformly and more safely than methods based on long ultrasound pulses. The technique, developed at Imperial College London and tested with laboratory mice, may eventually be used to deliver therapeutic agents and other compounds for treatment, diagnosis and study of neurologic diseases (Radiology 10.1148/radiol.2019181625).
Pre-clinical investigations into methods to safely penetrate the BBB are taking place at a global level. Focused ultrasound technology has the potential to revolutionize treatments of diseases such as Parkinson’s and Alzheimer’s, as well as brain tumours. But while focused ultrasound using long-pulse sequencing and microbubbles can disrupt the BBB and allow drugs to pass through the vessel lumen, concerns exist about the effectiveness and safety of such long-pulse sequences. Potential issues include unequal distribution of delivered drugs and biological responses such as haemorrhage, red blood cell extravasation and neuronal damage. Additionally, it takes between four and 48 hours for the permeability of the BBB to return to its natural state, allowing undesirable blood components like albumin to cross the BBB and cause neurotoxicity.
The Imperial College London researchers developed their technique to mitigate potential damage caused by long-pulse sequencing. They selected rapid, short-pulse sequence parameters to provide a time interval for microbubbles to move between pulses and not overstress any given capillary site, and chose burst-sequence parameters that allow microbubbles to replenish the vasculature exposed to the ultrasound beam. They hypothesized that this combination of short pulses and rapid emission would allow each microbubble to be gently stimulated multiple times as it flowed through the vascular network.
The researchers tested their technique on 28 female wild-type mice. They systemically administered microbubbles and the drug dextran immediately prior to the ultrasound, or at 10 or 20 minutes afterwards. Fourteen mice had their left hippocampus exposed to low-energy short pulses, specifically a pulse length of five cycles and a pulse repetition frequency of 1.25 kHz. The burst length was 10 ms or 13 pulses, and the burst repetition frequency was 0.5 Hz at 125 bursts.
The other 14 mice also had their left hippocampus exposed, but to long-pulse sequences that contained 150 times more acoustic energy. The pulse length was 10,000 cycles, with a pulse repetition frequency of 0.5 Hz at 125 pulses. The researchers used a peak negative pressure of 0.35 MPa for both groups as it is just above the acoustic pressure threshold for drug delivery.
Co-author James Choi, who leads the Noninvasive Surgery and Biopsy Laboratory at Imperial, told Physics World that the microbubbles, when activated by the ultrasound, volumetrically expand and contract within the capillaries and cause molecules within the blood plasma (such as the administered drug, for example) to be transported across the BBB. “How this transportation occurs remains a mystery,” he added.
The rapid, short-pulsed sequence delivered dextran in a uniform pattern in the ultrasound beam, providing complete coverage of the targeted tissue, reported lead author Sophie Morse, who won the Westminster Medal for this research at this year’s STEM for Britain competition. The long-pulse sequence did not, instead delivering high concentrations of dextran in some areas and none in others. The short-pulse sequence also was more efficient, producing 2.2 times more acoustic energy, as well as longer duration acoustic emissions than the long-pulse sequence.
The authors also determined that, with the short-pulse sequence, drug delivery only occurred within 10 minutes of ultrasound exposure. They observed that the BBB permeability returned to control levels in less than 10 minutes (compared with several hours for long pulses) and that only a limited amount of blood albumin was released into the brain, specifically 3.4-fold lower than with a long-pulse sequence.
“The rapid short-pulse sequence delivered dextran with a safety profile previously unachievable using ultrasound,” the authors stated.
The authors attributed these improvements in drug delivery to the stimulation of better cavitation distribution and a reduction of the cavitation magnitude and diversity with short-pulse ultrasound. They note that the sequence that they designed, which emits low-energy pulses at a carefully selected pulse repetition frequency, reduces microbubble destruction and allows microbubbles to move between excitations. All of these factors suggest that rapid short-pulse ultrasound is preferable to long-pulse sequencing.
The team is continuing its research, funded by Alzheimer’s Research UK, to determine how a rapid short-pulse sequence delivers drugs across the BBB and how this differs from delivery using long pulses. They plan to optimize the rapid short-pulse sequences for drug delivery by modifying the pulse shape and sequence, as well as the microbubbles themselves and their protocol of administration. They also plan to explore the use of rapid short-pulse sequences in other organs and diseases and to explore new pulse-sequence designs.
One of the largest inland deltas in North America, the Peace-Athabasca Delta has been inhabited for millennia. It’s economically and culturally important to local Indigenous communities, a UNESCO World Heritage Site and an internationally important wetland. But increasing river regulation since the mid-20th century has exacerbated drying that began in the late 1800s.
To quantify these changes in the flooding regime, Ellen Ward and Steven Gorelick at Stanford University, US looked at satellite images captured every summer between 1972 and 2017. In each image, individual pixels were classified as representing either water or dry land, allowing the researchers to build a 46-year inundation record of the region.
Because muskrat feed and overwinter on ephemeral water bodies and at the margins of lakes and streams, the researchers ruled out pixels that showed either water or dry land for the entire period. They considered the remaining intermittently flooded region to be potentially suitable for muskrat. Although the extent of inundation varied greatly from year to year, Ward and Gorelick found an unmistakable downward trend in habitable area, decreasing by 60% between 1973-1977 and 2013-2017.
To assess muskrat population density, the researchers used an indirect measure based on counts of muskrat houses going back to the 1970s. Muskrat nest in houses that protrude from the water; it’s best to survey them by snowmobile when lakes and ponds are frozen. Ward and Gorelick matched the counts made each winter to the habitat area measured for the preceding summer.
Every 100 square km of habitat lost was associated with a decrease of 5-6 individual muskrat per square km, and as the habitat area fluctuated, so too did the population.
Taking a small lake to represent the whole delta, Ward and Gorelick also measured the habitat persistence over five-year windows centred on three peaks in muskrat population density. All the population booms were followed by steep falls, and the speed of collapse seemed to be greater each time.
“We suggest that declines in critical habitat reliability could be the reason why the population is dropping more precipitously from peak values,” says Ward. “Together with our findings, concurrent observations of widespread loss of wetland and aquatic habitat at sites across North America suggest that critical habitat loss could be responsible for the ongoing decline of muskrat across its native range.”
Climate change, which will affect high latitudes more severely, is expected to bring further drying to the Peace-Athabasca Delta, and planned hydropower projects will restrict flooding even more. For muskrat and the other species that share the delta, the situation will only get worse.
If a picture is worth a thousand words, pictures that have even higher resolution or that record functional properties besides structural topology will surely speak volumes. It is hard to escape the role scanning probe techniques play in materials science, providing structural insights that help to explain and even predict material behaviour. Although it is over 30 years since these characterization techniques hit the scene, a constant stream of innovations and reinventions that improve their performance means they are still making headlines – the single-molecule-terminated tip developments reported this week are a case in point.
The first scanning probe technique was the scanning tunnelling microscope, a technique that can trace the topology of a surface with atomic resolution by monitoring the strength of the highly distance-dependent tunnelling current between the surface and a nanoscopically sharp tip. The first sight of atomic-scale features was so awe-inspiring that the inventors of scanning tunnelling microscopy (STM) Gerd Binnig and Heinrich Rohrer won the 1986 Nobel Prize for Physics, alongside Ernst Ruska, for the development of electron microscopy. While STM brought jaw-dropping images of conducting surfaces, there were still researchers hungry for the same resolution for insulating surfaces as well. I was lucky enough to speak to Christoph Gerber, co-inventor of the atomic force microscope alongside Gerd Binnig and Calvin Quate, about how they developed a technique that would bring high resolution to a broader range of surfaces. You can hear him describe the discovery as well as his colleagues and others working in the field in our series of short movies celebrating the invention and subsequent developments.
As Belle Dumé reports, a recent gear change in the resolution atomic force microscopy can achieve was the development of bond-imaging using a tip with a single carbon monoxide molecule at its tip. Her research update highlights work by researchers at Justus Liebig University Giessen in Germany to achieve the same resolution for 3D molecules – where the depth range had been problematic – by incorporating scanning tunnelling measurements to track the changes in topology. At the University of California at Irvine, researchers have also been extending the functionality of scanning tunnelling techniques with a single-molecule terminated tip, this time with (Ni(cyclopentadienyl)2). The magnetic properties of the (Ni(cyclopentadienyl)2) detect spin-spin interactions with magnetic features on the surface that affect the tunnelling current, providing uniquely high-resolution magnetic imaging.
These nanoscale images are possible thanks to techniques that allow ultrasensitive measurements of interactions between tip and surface. Measurement science is an often unsung hero in materials science but not on the 20th May when people all around the world will be celebrating the progress in measurement instrumentation and even the units we use for measurements on World Metrology Day.
Use of superconducting circuits in quantum computing architectures is growing, yet the greatest resistance they face might come from not having enough of it. Although superconductors are prized for being materials with negligible DC resistance, having low impedances at higher frequencies can create problems for superconducting qubits (quantum bits), such as susceptibility to noise and cross talk. To overcome this limitation, researchers from Karlsruhe Institute of Technology have built a high impedance inductor, or “superinductor”, from granular aluminium. As first reported in Nature Materials, the superinductor can be directly incorporated into superconducting qubit circuits to produce robust quantum systems.
The path to most resistance
Superinductors, inductors with characteristic impedances larger than the resistance quantum (6.4 kΩ), were initially developed in part to improve the isolation of superconducting qubits from noise. Additionally, qubits using superinductors have shown enhanced anharmonicity, a characteristic related to the difference in energies required to transition between different states, which is essential for fast qubit operation and readout.
However, creating a superinductor is often laborious. Past approaches used arrays of hundreds of superconducting devices called Josephson junctions to build up a cumulatively large inductance. This technique requires complex fabrication of many densely patterned devices, while the multitude of junctions can produce undesired resonances and parasitic effects.
As a simpler alternative, the research team turned to granular aluminium (grAl), a superconducting material containing a mixture of pure, nanoscale aluminium grains and amorphous aluminum oxide. Although people have known about grAl since the 1960s, few studies have looked at its behaviour in the high-frequency regime where quantum circuits operate. By optimizing deposition parameters and studying material characteristics at gigahertz frequencies, the team found that grAl films can achieve superinductor behaviour.
“When we started this project, little was known about the high frequency properties of grAl films,” says Ioan Pop, lead researcher of the project, “The main challenge was to get an initial intuition of which set of [deposition] parameters [was] most likely to succeed, and then commit to a fabrication procedure…In this respect the project was a bit of a gamble.”
Towards quantum compatibility
To demonstrate the material’s compatibility with qubit circuits, the team incorporated grAl inductors into both the qubit itself and the resonator used to read out the qubit state. Since the qubit included a Josephson junction that was also based on aluminium, the entire circuit could be patterned together in just a single lithographic step—a significant advantage over approaches that demand difficult fabrication. Furthermore, the qubit’s coherence times were competitive with those of current technologies, suggesting that grAl does not hinder qubit performance.
“Considering the microstructure of grAl, I think we were all a bit surprised that we did not observe a more dramatic coupling of the quantum circuits to the material defects in the [amorphous aluminum oxide] dielectric,” says Pop, “We know that the amorphous barriers are far from being perfect, and that they might contain electronic or atomic defects which could resonate with the circuit and spoil its quality factor. Fortunately, in our measurements this is almost never the case, and our circuits do not appear to be more susceptible to dielectric loss compared to standard aluminium quantum circuits.”
The successful use of grAl as a material for qubit circuits could solve many of the problems currently limiting the scaling-up of superconducting quantum processors. Beyond quantum information, grAl superinductors could also be used to make inductance-based photon detectors and high impedance resonators, opening the door for a new generation of superconducting devices.
The triangle-weaver spider uses external power amplification to ambush its prey from afar, a new study shows. Sarah Han and colleagues at the University of Akron in the US used high-speed videos of the creatures to reveal how they store and release energy in their webs. The researchers say their discovery reveals the previously underappreciated energy storage capabilities of spider silk.
The strength of many animals is not limited by their muscle power alone; species including frogs, fleas, and mantis shrimps are known punch above their weight by storing elastic energy in their limbs. When this energy is released, the creatures’ bodies recoil, producing extremely rapid motions that give them significant advantages in capturing prey and escaping predators. Known as power amplification, the process has been well studied in species that store energy within their body tissues. However, less is known about animals that exploit external, non-anatomical power amplification.
In their study, Han’s team looked at the rapid acceleration produced by power amplification in an external device: the web of the triangle-weaver spider. The biologists observed that a spider will weave an “anchor line” as it sits on its web waiting for prey. The line allows the spider to increase tension in the web by multiple cycles of limb motion. In this way the triangle-weaver stores energy in its web – often for hours – before the spider becomes a projectile in a silk catapult.
When prey approaches, the spider lets go of the anchor line, and the subsequent release of tension springs both spider and web forward 2-3 cm, with a peak acceleration of about 773 ms-2.
Because the web is moving when it hits the prey, more of it sticky strands can come into contact with the victim than if the web had been static. Then, as the web jerks to a sudden halt, the silk envelops the prey entirely. Once the prey has been captured, the triangle-weaver then walks back along the anchor line to reload the tension in its web, in preparation for its next meal.
Spider silk is well known for its strength, but Han and colleagues believe their results show that its power amplification capabilities have been underappreciated so far. By pulling their webs taut through multiple backward steps, triangle-weavers can store many times more energy than is possible with a single limb motion. The study, therefore, reveals that external power amplification has significant advantages over internal, tissue-based amplification. Indeed, the spider’s strategy is remarkably similar to the mechanics humans have exploited to create technologies including catapults.
A single magnetic molecule can act as a sensing device and produce the most detailed images yet of a material’s magnetic structure at the atomic scale. The magnetometer, which has revealed tunable quantum exchange interactions between two magnetic molecules for the first time, could make for a new microscopy technique that exploits magnetic molecules as local probes.
Ten years ago, researchers succeeded in significantly increasing the lateral resolution of low-temperature atomic force microscopy (AFM) by functionalizing the AFM tip with a single carbon monoxide molecule. This so-called bond-imaging technique was an important landmark for visualizing the atomic structure of single molecules. Researchers at the University of California, Irvine, have now taken inspiration from this strategy and have attached a single magnetic molecule (Ni(cyclopentadienyl)2) to the tip of a scanning tunnelling microscope (STM) to make an atomic-scale spin-sensing device. They did this by carefully approaching the tip to the molecule, which itself was adhered on a Ag(110) substrate surface.
“An STM measures the miniscule electric current (called the tunnelling current) flowing between the tip and a sample when the tip is positioned within a nanometre of the sample,” explains team leader Wilson Ho. “Our magnetic molecule sensor at the tip apex improves this technique by allowing us to detect spin-spin interactions with another magnetic molecule adsorbed on the sample surface by measuring minute changes in the tunnelling current.”
Spins start to couple
The technique works because the spins of both molecules start to couple as a result of, surprisingly large, quantum mechanical exchange interactions as the magnetic single-molecule sensor is brought very close (less than half a nanometre) to the other magnetic molecule, Ho tells Physics World. “This antiferromagnetic exchange coupling, as it is known, causes the two molecules to behave as a combined quantum system.
“We can probe this coupling using a technique, pioneered by our group in 1998, called inelastic electron tunnelling spectroscopy (IETS) within the STM. This technique allows us to quantitatively measure the excitation energies of the combined quantum system made up of the two magnetic molecules.”
By tuning the distance by which the two molecules were separated, in steps of several picometres, the researchers were able to explore how the coupled quantum states evolved as their spin-spin interaction strength changed. They did this by measuring the blueshift in the quantum energy levels of the combined spin states. This shift reveals strong coupling and strongly mixed quantum states.
“In this way, we found that the interaction strength exponentially decays across the (vacuum) gap between the molecules,” says Ho. “What is more, we could visualize the contours of the magnetic interaction strength in 3D. These spectroscopic images prove that the technique can image spin density and map spin quantum state mixing in real space.”
Advancing our understanding of nanoscale magnetism for future applications
“This work demonstrates that a magnetic metalorganic tip can function as a magnetometer and serve as a local spin sensor,” he adds. “We hope that our results will lead to other such experiments to help further advance our understanding of exchange interactions, spin coherence and spin coupling to the local environment – that is, magnetism at the atomic scale. Such knowledge will be essential for developing single-atom and single-molecule magnets for memory storage, as well as quantum bits (qubits) for quantum information processing.”
The researchers, reporting their work in Science DOI: 10.1126/science.aaw7505, say they now plan to investigate other magnetic molecules with different spins. “We are also looking into the time-dependent properties of single- and multiply-interacting spin systems to measure the dynamical interactions of a magnetic molecule with its environment,” reveals Ho.
“Probing the spin interaction with another adsorbed magnetic molecule is not the only thing the new magnetic single-molecule sensor is good for. The atomic-scale magnetometer could also be useful for measuring and imaging localized magnetic fields in novel 2D materials.”
Remember “that dress” that had people arguing incessantly about its colour? And then there were the running shoes of indeterminant hue. Now it is the turn of the tennis ball as Marina Koren asks are they green or are they yellow? Koren also explores why tennis balls are that particular colour in the first place.
While activities are suitable for children aged 5-11, there will be plenty for the whole family as well as free snacks and refreshments. The event celebrates World Metrology Day, which is this Monday. There is much more on the Physics World homepage about metrology – just scroll down to our Weekender box.
Meanwhile at the University of Guelph, members of the physics club have attempted to set a new world record for creating the most “elephant toothpaste”. I have no idea what that is but it seems to involve mixing chemicals together and then running away very quickly from the volcanic emission of foam. You can watch the action here.
Humanity’s love affair with my favourite element began about 3000 years ago at the dawn of the Iron Age. That is when humans worked-out how to make iron tools and weapons that were superior to those made of bronze. Iron ploughs, for example, where much better than their wooden or bronze counterparts, making agriculture more efficient and allowing it to become more widespread.
By adding a small amount of carbon to iron, cast iron and steel could be made. These two materials were the backbone of the industrial revolution, which changed civilization forever.
In the early 20th century steel allowed us to build up into the sky and today the world’s tallest building – the Burj Khalifa in Dubai – is an astonishing 828 m tall.
While plastics and other materials have begun to supplant iron for many uses, steel will remain an important material in the foreseeable future.
Iron is also the eponymous ferromagnet and in 1928 Fritz Pfleumer coated a paper strip with an iron compound and created the first magnetic recording tape. Four decades later the Beatles created masterpieces such as Revolver and Sgt. Pepper’s Lonely Hearts Club Band using tape loops and other clever manipulation of this medium.
In 1979, the Sony Walkman tape player started a phenomenon that is all too familiar today – people wandering around with headphones on listening to their own personal selection of music. Magnetic tape allowed us to record our favourite television programmes and was also used to store data for the first home computers – so iron helped usher in the digital age.
There are of course other ferromagnets – anyone around in the 1980s remembers the “chrome” cassette tapes that were supposed to be of better quality than iron-based ones.
I suppose I have a soft-spot for iron because I studied magnetic materials as a PhD student many years ago. It was then that I was very surprised to discover that despite being the most familiar of ferromagnets, physicists still do not have a very good understanding of why iron is magnetic. I was reminded of this by the Canadian physicist Michael Steinitz, who responded to our call for nominations of a favourite element (see box below). He picked chromium in part because “it is the only element for which we have a fundamental explanation of the reason for its magnetic order”.
And now for my killer argument. There would probably be no life as we know it on Earth if it were not for the convection currents in our planet’s molten iron core. These generate Earth’s magnetic field, which stops the atmosphere from being stripped away by the solar wind and cosmic rays.
What’s your favourite element? Contact us at email@example.com with your pick – and the reason why – or via Twitter using the hashtag #battleofelements.
From its orbital worksite 1.5 million kilometres from Earth, the LISA Pathfinder mission has been putting the technology required to build a space-based gravitational wave detector through its paces. In a new study, made using information collected from the satellite, scientists involved in the mission have shown that it can also shed light on another enigmatic astronomical target: interplanetary dust.
By examining data from the spacecraft’s on-board systems, the researchers have been able to pinpoint more than fifty separate instances where LISA Pathfinder “felt” a miniscule jolt as it was hit by a wandering grain of cosmic dust. Through analysis of the collisions, the scientists have even been able to work out the direction on the sky where the dust came from and so uncover clues about the origin of these tiny flecks of Solar System detritus.
The European-led LISA Pathfinder project was launched in 2015 as a test bed for projects like the Laser Interferometer Space Antenna mission, LISA, which is due to lift off in 2034. Once established in orbit, LISA will look for the ripples in the fabric of space–time that propagate across the cosmos when black holes or neutron stars collide. “[LISA] will detect passing gravitational waves by monitoring the distance between widely-separated pairs of freely-falling objects,” says team member Ira Thorpe of NASA’s Goddard Space Flight Center.
The freely-falling objects in the case of the LISA Pathfinder trial mission are a pair of two-kilogram gold and platinum cubes that float unperturbed within special voids inside the satellite. “A control system monitors the position of the spacecraft relative to the cubes and fires thrusters on the spacecraft to keep the spacecraft from touching the cubes,” explains Thorpe. “The spacecraft is like a shield that flies around the test masses and protects [them] from any external disturbances.”
By combing through the telemetry from LISA Pathfinder’s control system – which recorded how close the cubes got to the interior of the spacecraft and when the thrusters were working – Thorpe and his colleagues were able to spot moments when the satellite was responding to and correcting for the tiny bumps to its exterior from micrometeoroid impacts. “What makes this technique possible is the exquisite precision of LISA Pathfinder’s sensors,” says Thorpe. “A laser interferometer was used to measure the distance between the test masses and the spacecraft with a precision of less than one trillionth of a metre.”
Using computer-modelling methods normally used to unravel gravitational wave signals, the team were able to ascertain the direction the dust grains were coming from when they hit the spacecraft. This information suggests that the bulk of this so-called “zodiacal” dust – which is scattered across our planetary neighbourhood – was deposited by Jupiter-family comets with Halley-type comets possibly adding to the mix as well. “This is entirely consistent with models based on other independent observations,” says Thorpe.
“This is a really interesting study,” says Mark Jones, an expert in the zodiacal dust cloud based at the Open University in the UK. “In particular, [it] provides a novel way to distinguish between various cometary and asteroid dust sources – something which has been a topic of debate for many years.” Jones points out that there is not yet enough data for the study to give high-quality information about the sources of dust, but he says that the “technique appears to be sound and offers a lot of promise”.
Indeed, Thorpe and his colleagues are expecting that the forthcoming LISA mission will also be able to sense these dust impacts while it carries out its main job of hunting gravitational waves. “There will be three spacecraft and hopefully a mission of 10 years, so we will have much more data to work with,” says Thorpe.
The redefinition of four units of the International System of Units (SI) will come into effect on Monday 20 May meaning that all seven base units are now based on fundamental physical constants. The kilogram, the ampere, the kelvin and the mole are now defined in terms of physical constants rather than an object or phenomenon. The decision to redefine of the four SI base units was taken in November 2018 when metrologists and policy-makers from 60 countries around the world met at the General Conference on Weights and Measures in Versailles, France. The change will now become a reality on 20 May to mark World Metrology Day.
There are seven base units of the SI: the second, metre, kilogram, ampere, kelvin, mole and candela. Some have long been based on physical constants. The second, for example, is set as 9 192 631 770 times the period of the radiation corresponding to the transition between the two hyperfine levels of the ground state of the caesium-133 atom. The metre, meanwhile, has been defined since 1983 as the length of the path travelled by light in vacuum during a time interval of 1/299 792 458 seconds.
The biggest change is to the kilogram, which was set by a 143-year-old platinum alloy cylinder, dubbed “Le Grand K” housed in the International Bureau of Weights and Measures (BIPM) in Paris. The kilogram is now defined in terms of the Planck constant, h, which has been measured with extraordinary precision in recent years. Its agreed value will be set as 6.626 070 15 × 10-34 kg m2 s–1, with researchers able to make precise mass measurement using equipment such as the Kibble balance.
“The redefinition of the kilogram may seem like a small change, but it will have an enormous impact on science,” says Ian Robinson from the UK’s National Physical Laboratory. “There will be no change to the mass scale currently used in trade and industry, but by using a universal constant of nature to ensure the long-term stability of the kilogram, we are both reunifying the SI and setting the stage for robust, reliable science that could pave the way for new ideas and inventions.”
The ampere, meanwhile, will now be set by the elementary electrical charge, e, which is given as 1.602 176 634 × 10-19 when expressed in coulombs. The Kelvin is defined by taking the fixed numerical value of the Boltzmann constant k to be 1.380 649 × 10-23 when expressed in the unit J K-1 . Finally, the mole is defined as the amount of substance with exactly 6.02 214 076 × 1023 elementary entities. This number is the fixed numerical value of the Avogadro constant, NA, when expressed in the unit mol-1.