Innovations in embedded computing, sensors and batteries enabled the introduction of robotic prostheses designed to help restore locomotion to individuals with disabilities. Such prostheses are moved by motors that respond to the user, via signals from built-in movement sensors, for example.
To improve the response of a robotic device to the user’s intent, it can also incorporate neural information from electromyograms (EMG), which record electrical activity from residual limb muscles. With this aim, researchers from Northwestern University are developing a control system for a robotic lower limb prosthesis that incorporates EMG data and operates in real time.
“Any assistive robotic device should seamlessly and automatically respond to the user’s intent. EMG data contain the neural information that makes this possible and have been used to control prosthetic arms for decades; however, it is challenging to measure EMG data from legs,” explained first author John Spanias, who completed the study as a postdoctoral researcher at the Shirley Ryan AbilityLab. “We wanted to develop and test the technology that could incorporate this important neural information into a prosthesis over long-term use.”
In their latest work, Spanias and colleagues evaluated the performance of their technology on individuals with transfemoral amputations (J. Neural. Eng.15 016015).
Transitioning locomotion mode
State-of-the-art robotic prosthetic legs produce different mechanical responses when the user is walking on level ground, an incline or stairs, but they are currently unable to automatically transition between these modes of locomotion. This could be achieved by using EMG signals, input into a pattern recognition algorithm, to transition the device between locomotion modes (a process known as forward prediction).
As EMG signals will likely also fluctuate daily as the prosthesis is taken on and off, the team developed an adaptive forward prediction algorithm to track such changes. To prevent misclassification of locomotion mode, the algorithm can revert to sole use of mechanical sensor data when large EMG fluctuations are detected. It is then retrained with updated EMG data, determined by categorizing the user’s gait profile and labelling the patterns with the correct mode (backwards estimation).
Overview of the adaptive algorithm (click to zoom)
The researchers conducted experiments with eight transfemoral amputees over multiple days, recording eight channels of EMG data and signals from 22 mechanical sensors. In a first experiment, they collected data to train the adaptive forward predictor algorithm while the subjects used the powered prosthesis to walk on level ground, stairs and ramps. During this offline session, the experimenter manually transitioned the prosthesis between modes.
In a second experiment, the subjects completed the same tasks, but mode transitions were automatically controlled by the (previously trained) adaptive forward prediction algorithm. All subjects were able to transition between the required locomotion modes and complete the different activities with low error rates. The adaptive control system accurately responded to the user’s intent over multiple days, despite changing neural signals.
In the first quarter of such a session, EMG was used in 68.86% of forward predictions. This increased to 96.31% by the end of the experiment. The algorithm’s ability to select when to incorporate EMG is important as EMG signals will likely differ across days.
Transitions to and from ramp descent were the most problematic for the forward predictor, and were mostly frequently classified as level walking (8.45%). Such errors typically only presented a minor perturbation to the user. More substantial errors that may endanger the patient, such as inappropriately transitioning into stair ascent while on level ground, were rare (below 1%).
Comparisons between adaptive and non-adaptive algorithms showed that the adaptive system performed significantly better. The overall error rate of the adaptive forward predictor was 4.03%. For non-adaptive systems, the error rates were 4.44% for a system that used only mechanical sensors, and 4.38% for a system based on mechanical sensors and EMG.
Improved control
The researchers also examined the impact of their recent enhancements to the prosthesis control system, which included adding more mechanical sensors to the prosthesis, incorporating a 90 ms delay into the mode transitions and implementing a mode-specific classifier architecture. These modifications decreased the error rate of the forward predictor, with the lowest error rates obtained when applying all modifications. The analysis also revealed that the impact of adding EMG signals was less when these modifications were included.
EMG data do, however, still have an important role to play, says Spanias. “For example, EMG data could still be used in tasks such as moving individual prosthesis joints when the user is not walking, controlling difficult transfers into or out of chairs, or detecting stumbles and falls,” he explained. “Moreover, as our ability to acquire EMG data gets better, we expect that it will help control lots of different ambulation activities.”
As the system learns from the user while they walk, it should improve performance over time. As such, the team is now planning to allow people to use the system at home, to assess its performance over long periods of time. “We are also very excited to apply these algorithms to EMG signals measured from tiny, wirelessly powered implants,” Spanias told medicalphysicsweb. “We expect to be able to extract more information which will result in improved control of prosthetic arms and legs.”
The revised projections for energy up to 2035 from the UK Department of Business, Energy and Industrial Strategy (BEIS) are generally very optimistic. It expects low-carbon sources of electricity to supply 68% of UK power generation by 2020, 70% by 2025, 76% by 2030 and 86% by 2035. That of course includes nuclear, and assumes that the proposed new reactor projects will go ahead, although BEIS now expects one less plant will be in place by 2030 than originally hoped, so nuclear only reaches 13 GW in all by 2035. And it is now also pessimistic about carbon capture and storage (CCS); there is only 1 GW in use in its scenario even by 2035. But it is very optimistic about renewables – it sees them expanding rapidly to 45 GW by 2035, up from the 36 GW projection in 2016. Let’s hope this is right.
However, this projection, with renewables approaching a 50% share by 2035, might be seen as rather odd, given the fact that one of the cheapest renewable options, onshore wind, remains blocked by government policy. It can’t apply for Contract for Difference (CfD) slots and the planning rules have been tightened to suppress it. PV solar growth has also been constrained, with cuts to feed-in tariffs (FiTs) for small projects and a block on access to the CfD for large projects. These and other retrogressive policy moves have already had a big impact: UK investment in wind, solar and other renewable sources slumped last year by 56% to £7.5bn, while worldwide spending climbed 3% to £242.4bn, the second-highest level on record.
Looking ahead, it may get worse in the UK for all the renewables, with all new levy support, apart from those already agreed, to be frozen until after 2025, so as to avoid extra levy costs being passed on to consumers. So support levels will flatten off from around 2020 and, unless new support is offered after 2025, stay flat. Indeed, the government’s advisory Committee on Climate Change says that, unless more low carbon capacity is backed beyond that currently set for CfD support, there will be a 50–70 TWh p.a. 2030 carbon target gap. For example, the Renewable Energy Association trade lobby has called for an onshore wind CfD.
With technology costs falling, some projects may of course still go ahead without CfDs, but the rate of expansion will be less than it would have been with the support in place. And new, currently less developed, projects will stand much less chance of getting established on the path to falling costs. For example, wave and tidal projects remain outsiders. None have been able to apply for CfD contracts – the Meygen project, like other tidal and wave projects, is being funded with a mix of grants and private finance.
All this makes the prospects for tidal lagoons, at one time feted by the government as a possible way ahead, a little uncertain. The Financial Times reported that “Ministers have gone cold on the £1.3bn project to build a tidal power lagoon in Swansea Bay, concluding that the ‘eye-wateringly’ expensive project does not represent sufficient value for money for taxpayers.” A cabinet minister said it did not stack up economically and would only directly create a handful of jobs in the local economy, although The Times noted that “1000s of jobs were at risk”, from companies that were lining up to supply equipment, including GE in Rugby and Stafford, hard hit by GE’s global cuts. In a letter to UK prime minister Theresa May, the Welsh First Minister Carwyn Jones has indicated that he would “consider a substantial equity and/or loan investment by the Welsh Government if that would enable the project to move forward”, but it seems a long shot. Moreover, Ecotricity has claimed that a fully offshore lagoon would be much better, with lower impacts. Maybe, but that pushes it further off into the future.
Some of the biomass options also look a little uncertain, with opposition mounting to large biomass-fired plants like Drax, currently favoured by the government, since there are worries about the sustainability of the forest-derived fuel. John Beddington, who was the government’s chief scientific adviser in 2008–2013, is the latest to oppose the use of trees for energy.
That’s a no brainer. Trees and their roots are important carbon sinks and replacing that capacity by replanting takes a long time. But, in some renditions, this view is extended to the use of all types of wood, or even to all biomass, where the arguments are much less clear. It certainly does not apply to biomass wastes, since they already exist and using them adds little extra net CO2 and does not impact on carbon sinks. Biogas produced from biomass wastes could produce a much needed firm and storable source of energy for power supply and grid balancing, heating and transport use.
However, in its new projections report, BEIS seems to be focused on electricity production from renewables like offshore wind and also non-renewable nuclear to meet most needs, including increasingly for heat and transport, with storage providing backup for variable renewables. In its new projections, BEIS seems to think that storage will take off in a big way, with twice as much battery capacity installed than was previously thought. Some might say gas plants will be better for grid balancing, and pre-combustion gas was the best thing to store, but BEIS sees gas capacity and gas use falling.
Other pathways than just electricity were explored in the government’s earlier Clean Growth Strategy, including the use of natural gas to make hydrogen for heating and transport. This would involve the steam reformation of fossil gas, with CCS to make it low carbon.
However, there are other options, quite apart from the use of biogas. If there was a large renewable capacity, at times there would be a large surplus of electricity, which could be used to make storeable hydrogen via the electrolysis of water, with no need for CCS. That could then be used to make electricity, in gas turbines or fuel cells, when needed to balance the grid e.g. when there was a lull in wind and solar availability. The zero carbon hydrogen from this Power to Gas (P2G) process could also be used for heating, injected into the gas main direct, or converted into methane gas using captured CO2, making it negative carbon. Alternatively, the hydrogen or methane could be used as a vehicle fuel. The multiple conversion stages would add cost, but CCS is also costly, and with P2G, the input fuel is in effect free – being otherwise surplus to requirements. And P2G technology is developing rapidly, with efficiency rising.
There are other possible pathways. The Clean Growth strategy also looks at Biomass with Carbon Capture and Storage (BECCS), as a negative carbon option for power generation. But that would require large land areas for biomass growing, as well as a lot of CO2 storage, unless biomass capture and utilization (BECCU) was adopted, i.e. capturing and then using the CO2 to make synfuel (e.g. using hydrogen, as in the P2G example above). Some combination of P2G hydrogen and BECCU CO2 might make sense, although making a synfuel using P2G hydrogen and CO2 from power station exhausts, or even directly from the air, might be easier. With either, you still end up with carbon negative power but, in the P2G case, without so much land use.
Clearly, although BEIS may be over-confident about the ones it has chosen, there are plenty of options. The problem we face now is that, given current policies, the alternative ones may not be given an opportunity to develop, while some of those that are being pushed may not deliver. Some see that as inexcusable.
“In the fields of observation, fortune favours the prepared mind,” is a quote attributed to Louis Pasteur and it encapsulates the role of luck in scientific investigation. The Perimeter Institute for Theoretical Physics in Canada has put together a list of eight scientific breakthroughs that benefited from a little luck. Examples include Ernest Rutherford and colleagues measuring alpha-particle backscattering when they were really interested in how the particles travelled through the target – which resulted in the discovery of the atomic nucleus. But my favourite is how the microwave oven was invented, as described above.
Airport runways are named according to their magnetic bearings and this becomes a problem over time because the Earth’s magnetic poles are changing position. Over at Wired, Alex Davies explains why Wichita Eisenhower National Airport has been ordered to change the names of its three runways from 1L/19R, 1R/19L and 14/32 to 2L/20R, 2R/20L and 15/33, respectively. There’s much more about why these names are used and what the numbers and letters mean in “Thank the planet’s shifty magnetic poles for runway renaming”.
On 7 January a SpaceX Falcon 9 rocket lifted off with a payload called “Zuma”. SpaceX says that the launch was successful but rumours started to circulate about the fate of the payload, which is apparently top secret. Jeff Foust picks up the story in The Space Review, where he looks at the various theories of what Zuma is, what could have gone wrong and whether it reached its intended destination. See “The mystery of Zuma”.
Peritoneal cancer metastasis is a common and severe disease. Fortunately, advances in chemotherapy have resulted in encouraging treatment outcomes. However, these therapies still present major limitations such as poor tissue penetration, and current preclinical models fail to reproduce the disease conditions.
Thus, preclinical models that faithfully mimic peritoneal metastasis are needed to assess the efficacy of new therapies. To this end, Olivier De Wever and his team at Ghent University have developed a novel 3D model that combines 3D printing, multicellular cell culture and in vivo implantation. This model improved the replication of the peritoneal metastasis compared with current models (Biomaterials158 95).
Metastasis model fabrication (click to zoom)
Printing a tumour model
One of the limitations of current models is imitating the dimensions and mechanical properties of the tumour. However, with the new technologies of 3D printing, and subsequent surface modifications such as collagen coating and UV treatment, the properties of the produced scaffold model can be tuned as required. In particular, the researchers employed 3D printing of polylactic acid (PLA) and treatments with plasma, gelatin and UV to modify the surface.
Using this process, they created a scaffold with the appropriate size, porosity, and mechanical and biochemical properties to replicate metastasis conditions and promote a population of relevant cancer and interacting cells. This resulted in a more clinically relevant model than achieved in previous studies.
Cell viability and spheroid formation
Replicating tumour complexity
Solid tumours include different cell populations that interact among themselves. Such interactions play a crucial role in the fate of the tumour. Thus, they must be present to achieve a relevant model. In this study, the researchers combined cancer-associated fibroblasts (CAF) with tumour cell lines. The combination of these cell populations enabled the formation of tumour structures in vitro (spheroids), demonstrating the importance of the presence of CAF in forming a representative tumour model and providing an additional advantage over previous models.
To further assess whether these modelled constructs can reproduce metastasis conditions in vivo and serve as a representative model, the researchers implanted them in the peritoneal cavity of mice. After 11 weeks, they observed that the implanted models presented a heterogeneous cell population, including the seeded CAF and proliferating cancer cells, as well as host cells such as immune, adipose and epithelial cells.
Interestingly, these constructs also promoted the formation of blood vessels. This is thought to be dependent on the CAF-cancer cell interaction, which is able to produce specific signals that promote neovascularization. In addition, comparing the implanted constructs, a traditional metastasis model and a patient-extracted tumour revealed that the immune response and histological organization of the construct was similar to that found in the patient tumour, in contrast to the traditional model.
A step closer
Overall, the research team succeeded in developing a more representative preclinical model of peritoneal metastasis, by replicating more closely characteristics such as size, heterogeneous cell population, blood vessel formation, immune response and histological resemblance to human tumours. This study represents a step forward in the development of preclinical models to assess drug efficacy and penetrability, a major limitation in the field of peritoneal metastases. Furthermore, it provides a basis to advance screening technologies for the development of new therapies.
Histology comparison
Overall, the research team succeeded in developing a more representative preclinical model of peritoneal metastasis, by replicating more closely characteristics such as size, heterogeneous cell population, blood vessel formation, immune response and histological resemblance to human tumours. This study represents a step forward in the development of preclinical models to assess drug efficacy and penetrability, a major limitation in the field of peritoneal metastases. Furthermore, it provides a basis to advance screening technologies for the development of new therapies.
Coral reefs have always lived near the edge. Now, thanks to global warming, life there is five times more precarious.
Forty years ago, the world’s coral reefs faced a known risk: every 25 or 30 years, ocean temperatures would rise to intolerable levels.
Corals would minimise the risk of death by everting the algae with which they lived in symbiotic partnership: that is, the reef animals would avoid death by getting rid of the algae, deliberately weakening themselves.
This response is known as bleaching, and it can have a catastrophic effect on other life on the reef. In the Pacific such episodes were sometimes linked to cycles of ocean warming known as an El Niño event.
By 2018 the odds had altered. Coral reefs now face this hazard every six years. That is, in four decades of global warming and climate change, the risks have multiplied fivefold.
Bleaching breaks out
“Before the 1980s, mass bleaching of corals was unheard of, even during strong El Niño conditions, but now repeated bouts of regional-scale bleaching and mass mortality of corals has become the new normal around the world as temperatures continue to rise,” said Terry Hughes, who directs Australia’s Centre of Excellence for Coral Reef Studies at James Cook University.
He and colleagues report in the journal Science that they analysed data from bleaching events at 100 locations around the planet between 1980 and 2016. Bleaching events are a fact of life for corals: these little creatures tend to live best in temperatures near the upper limit of their tolerance levels, and respond to extreme events by rejecting the algae that normally provide the nutrients they need.
But as global air temperatures have increased, in response to profligate burning of fossil fuels that increase greenhouse gas levels in the atmosphere, so have sea temperatures. And Professor Hughes and his team report that in the last two years more than a third of all bleaching events have been “severe,” extending over hundreds of kilometres.
When they measured the growth of risk over the decades, they found that the bleaching hazard had increased by 4% per year since 1980.
The finding should be no surprise. In 2015, during a severe El Niño event, scientists began to record cases of coral death. In 2016, they observed that 93% of Australia’s Great Barrier reef had been affected. In 2017 they found that reefs in the western Pacific and off the Indian Ocean had been damaged beyond repair, and a separate set of calculations has warned that by 2100, up to 99% of the world’s coral colonies could be at risk of bleaching every year.
Reefs can recover, but this recovery can take as long as a decade. Coral reefs are among the planet’s richest habitats, and the death of a reef puts many ocean species at risk: it also damages local commercial fish catches and local tourist industries.
“Reefs have entered a distinctive human-dominated era – the Anthropocene,” said Mark Eakin of the US National Oceanic and Atmospheric Administration, a co-author. “The climate has warmed rapidly in the past 50 years, first making El Niños dangerous for corals, and now we’re seeing the emergence of bleaching in every hot summer.”
And Professor Hughes said: “We hope our stark results will help spur on the stronger action needed to reduce greenhouse gases in Australia, the United States and elsewhere.” – Climate News Network
For more than 20 years, physicists have been unable to explain why two types of experiment yield different values for the lifetime of the neutron. One or more unknown systematic errors biasing the results is a possibility. But now a pair of particle theorists in the US have come up with an alternative explanation: that occasionally neutrons decay to a previously unknown particle which might account for the universe’s dark matter. They say that such a particle could leave a very distinctive signature in nuclear physics detectors.
When isolated, neutrons decay in around 15 min. They do so via beta decay, which involves a neutron transforming into a proton, an electron and an electron antineutrino. Conservation of energy, charge, angular momentum and other quantum numbers dictates that this is the only way that neutrons can decay within the Standard Model of particle physics.
To measure the average neutron lifetime precisely, physicists employ two basic techniques. One is to house neutrons within a container, known as a bottle, and simply count how many of them remain after a fixed interval of time. The other approach is to fire a neutron beam with a known intensity through an electromagnetic trap and measure how many protons emerge in a given time.
Growing disagreement
Ongoing since the early 1990s, the two types of experiment yield results that remain at odds with one other. While the bottle method tells us that neutrons decay after about 880 s on average, the beam tests put the figure around eight seconds higher – at 888 s. The difference is significant because it can’t be accounted for through either statistical or known systematic uncertainties. Until 2013, the discrepancy amounted to 2.9σ. Then, following improvements to the world’s leading beam experiment, the mismatch hardened – rising to 3.8σ.
In the latest work, Bartosz Fornal and Benjamin Grinstein at the University of California, San Diego propose that the anomaly could be a sign of dark matter. The idea is that while most neutrons disappear via beta decay, a small fraction (about 1%) would instead decay to a “dark sector” particle – a process that would violate the conservation of baryon number. While bottle experiments would measure both beta and dark decay, beam experiments can only detect beta decay. As a result beam experiments would overestimate the neutron’s lifetime.
The new proposal does not feature a unique dark particle with specific properties. But Fornal and Grinstein have shown that several candidate particles are consistent with existing experimental results. They have also shown that some of the possible decay routes generate clear experimental signatures. These include the neutron decaying into a dark particle, plus either an electron–positron pair or a photon, with the energy available for these accompanying particles limited by the narrow range of allowed masses for the dark particle.
Lighter than a proton
The dark particle’s mass must exceed that of beryllium-9 minus that of beryllium-8, since beryllium-9 is known to be stable and therefore doesn’t decay. At the same time, the mystery particle must be lighter than the neutron if that is to decay. In fact, if the particle is indeed the dark matter that has shaped the evolution of the universe then it must obey a slightly tighter constraint – it must be lighter than the proton and electron combined otherwise dark matter would be unstable, which observations tell us it isn’t.
These constraints lead to a particle of dark matter having a mass between 937.9–938.8 MeV. Given that the neutron weighs in at 939.6 MeV, an accompanying photon would have to have an energy between about 0.8-1.7 MeV.
Fornal says that such photons could potentially be seen in many nuclear physics experiments currently operating, but would only be visible once the immense amounts of background noise are filtered out (the photon having no detectable particle companion). He adds, however, that some experimentalists are devising data analysis techniques to try to remove the noise.
Striking experimental signatures
For Susan Gardner, a theorist at the University of Kentucky in the US, the newly postulated dark matter is “feasible” and cannot be excluded by any existing data. “It is particularly exciting,” she adds, “that some of the suggested scenarios have striking experimental signatures.”
In fact, two collaborations at the Los Alamos National Laboratory in New Mexico – UCNA and UCNtau – are currently searching for the photon (gamma-ray) and electron–positron signals within data from neutron decays. “Data are in hand and analyses are under way,” says UCNA team member Peter Geltenbort of the Institut Laue-Langevin in France.
Ben Rybolt of Kennesaw State University in the US describes the latest work as “a reasonable approach” to resolving the neutron anomaly, having himself worked on possible experimental signatures of a rival exotic solution – that ordinary neutrons can sometimes oscillate into non-Standard Model “mirror neutrons”. If upcoming, improved measurements of the neutron lifetime – involving magnetic bottles and monitoring of electron emission from a neutron beam – fail to uncover any hidden systematic errors, he says “there will be even more reason to look for exotic solutions”.
A preprint describing the research is on the arXiv server.
Increasingly, radiation oncology clinics are favouring small, mobile kilovoltage X-ray tubes over radioactive sources to deliver intra-operative radiotherapy. The devices are used to irradiate surgical cavities following the excision of tumours from sites such as the breast. Short-range radiation minimizes the exposure of nearby healthy tissue, enabling large doses to be delivered in a single shot.
Introduced to clinical practice within the last 20 years, the dosimetry of such so-called electronic brachytherapy sources is still under development. Currently, manufacturers typically use their own protocols, making comparisons of doses delivered by different devices problematic.
“Having an accurate methodology for independently verifying the dosimetry of these devices is crucial for performing dose comparison studies, or for planning treatments that combine miniature X-ray sources with other radiation modalities,” says Peter Watson, a PhD candidate at McGill University in Montréal, Canada.
In a new study, Watson and co-authors Marija Popovic and Jan Seuntjens developed a formalism for the absolute dosimetry of therapeutic kilovoltage sources, applying it to the INTRABEAM system manufactured by Carl Zeiss Meditec (Phys. Med. Biol.63 015016).
Calibration check
The INTRABEAM system produces an isotropic distribution of 50 kVp bremsstrahlung and characteristic X-rays using a gold target. The manufacturers provide a factory calibration that enables reproducible doses to be delivered for treatments, correcting for fluctuations in output using daily quality assurance (QA) measurements. System output is also checked annually by the manufacturers.
“This dose is ‘correct’ in that it has been shown to be empirically safe and effective in treatments,” explained Watson. “However, exactly how closely this represents the actual physical dose, by definition of absorbed dose to water, is an open question.”
As an optional QA tool, dose delivered by the INTRABEAM system can be measured using a manufacturer-supplied water phantom and a thin window parallel plate ionization chamber. A depth-dependent correction function supplied by the system manufacturer enables comparison of the doses with system calibration data.
However, information on the correction function is “limited” and how or if the factory measurements or those using the water phantom are traceable to an absorbed dose standard is unclear. Consequently, Watson and his co-authors set out to assess doses as measured by the QA tool against their formalism.
In the new approach, absolute dose in water in the clinical beam is calculated using CQ, a depth-dependant ionization chamber conversion factor. The factor converts the chamber air kerma calibration coefficient, measured in a reference beam, to an absorbed dose to water coefficient for the INTRABEAM photon spectrum in water.
To calculate CQ, the researchers developed a Monte Carlo model of the INTRABEAM source and parallel plate chamber based on the EGSnrc particle transport code. By using direct calculations, the approach does not rely on cavity theory and its associated assumptions. The model was validated by comparing the half value layers (HVL) and depth doses it calculated with measurements, revealing good agreement between the two.
Model validation (click to zoom)
The simulations did, however, reveal significant differences between CQ and the equivalent parameter reported by the manufacturer, corresponding to discrepancies in absolute dose of up to 23%. The model consistently produced a greater CQ value. Differences were seen across the quoted tolerance in chamber plate separation and two corresponding effective points of measurement, as well as over a range of depths. Uncertainty in the plate separation alone accounted for variations in CQ of up to 15%. The results highlight a need for investigations using another chamber with more precisely known dimensions, Watson told medicalphysicsweb.
CQ comparison
In ongoing work, the authors have compared dose calculations using the formalism with the INTRABEAM manufacturer’s QA approach and prescribed doses derived from the factory calibration, as well as measurements using GafChromic film.
Research such as the ongoing TARGIT-B breast cancer trial could benefit from the greater certainty in doses provided by the formalism. In the multi-centre trial, researchers are comparing cancer control provided by whole-breast external-beam radiotherapy combined with either intra-operative or external beam boosts to the tumour bed.
Testing the effect of new drugs on heart tissue could become more straightforward, thanks to new research by a team at Harvard University’s Wyss Institute. The researchers have developed a faster method for manufacturing a “heart-on-a-chip” that can be used to test the reaction of heart tissue to external stimuli (Biofabrication10 025004).
“One of the major challenges in drug discovery and development is failure at the clinical testing stage due to cardiac toxicity,” explained co-lead author Lisa Scudder. “A way to overcome this is to develop new preclinical tests for new drugs using engineered tissues that mimic the native organs of the human body such as the heart.”
Scudder and colleagues are working to build improved platforms to test the safety and efficacy of new drugs, by engineering functional units of human organs using human tissue. For the heart-on-a-chip, they aim to build a tissue that is as contractile and organized as the human heart, enabling measurement of contractile force – a major determinant of heart pumping performance.
“The chip we’ve made is an extension of our previous work, which established a new platform using the miniaturized structural formation of cardiac muscle on a cantilever of hydrogel,” said co-lead author Janna Nawroth. “We use hydrogel because its mechanical properties are similar to the extracellular matrix of the heart. This pre-patterned substrate results in an organized growth of cardiac muscle. The end goal is to put these tissue structures into a microfluidic environment, where we can closely regulate and monitor the flow of the new drug being tested.”
For use in drug development and biomedical research within industry, the chips need to be amenable to mass manufacturing. The existing way of engineering cardiac tissues involves using photomasks, stamping, and manually moulding gelatin to create patterns in the hydrogel. This approach takes too long and is not practical for large-scale chip manufacturing.
“Our new heart-on-a-chip fabrication method uses a UV laser to pattern the hydrogel, employing riboflavin to sensitize the gel for optical ablation,” explained Scudder. “This patterning method then allows the cardiac cells to align into organized laminar tissue structures like in the native heart.”
This UV micropatterning method creates features on the gel much faster than traditional moulding techniques, but with the same resolution and reproducibility. It can generate aligned cardiac tissue and muscular thin films, which beat and contract in response to external stimuli like electrical pacing. As well as being scalable, the new fabrication scheme doesn’t alter the properties of the hydrogel and is up to 60% faster than the old process.
This method could also be used to manufacture other organs-on-a-chip, such as a brain or skeletal muscle-on-a-chip. “In the future, we hope to expand on this fabrication method to mimic disease states like fibrosis, or to create more complex three-dimensional tissue structures that could provide new tools for the preclinical drug development process,” said Scudder.
Every age has its great teachers, and in the early 18th century one of them was Nicholas Saunderson. From 1711 until his death in 1739 at the age of 57, Saunderson was the Lucasian Chair of Mathematics at the University of Cambridge in the UK – a post held just a few years previously by Isaac Newton, and in recent times by Stephen Hawking. He would lecture to packed halls for at least eight hours a day on subjects ranging from mechanics and hydrostatics, to optics and astronomy. He was said to have a tremendous feel for his subject. Literally, as it turns out: he was blind.
Times were certainly tough 300 years ago for the sightless. Having lost his eyes to smallpox as a baby, Saunderson is said to have taught himself to read by tracing out the letters on gravestones. Yet he was luckier with his situation than most. Saunderson’s father and his friends supplemented his school education by reading to him at length, and in his teens he made a learned acquaintance who brought him up to speed with the latest developments in mathematics. His ultimate accession to Lucasian professor was doubly impressive, for the university’s decision went against the wishes of Newton himself – and there are not many known instances of that.
But is it any easier to be a blind physicist today? Inclusive education policies, leaps in technology and a better awareness of the needs of the disabled all suggest a positive answer, yet blind physicists seem to be few and far between. Perhaps the most famous living example is the US astronomer Kent Cullers, whose involvement in NASA’s Search for Extra-terrestrial Intelligence (SETI) programme was fictionalized in the 1997 blockbuster Contact. “We’re in a sighted person’s world,” says Aqil Sajjad, a blind theoretical physicist who lives in Boston, US.
Sajjad knows how determined a blind person must be to have a career in science. Aged 10, he was playing with his cousins one day at home in Islamabad, Pakistan, when a large green blob entered his vision on one side. Doctors diagnosed it as a detached retina, and before long he was blind in that eye. Six years later, his sight left the other eye too – and with it, his dream of being a scientist. “The education authorities back in Pakistan basically told me that I couldn’t be a scientist,” he recalls.
Two senses are better than none: John Gardner uses audio-tactile to explore the periodic table. (Courtesy: ViewPlus)
To avoid missing out on education altogether, Sajjad switched his studies to the arts and humanities, and went to business school. Like Saunderson he benefited from having materials read to him, in this case by his mother, who had a maths degree herself. But to pursue his passion for science he applied to universities in the US, where he anticipated more encouraging attitudes. From several offers, he chose Oregon State University in Corvallis.
Hidden problems
Being blind poses all sorts of challenges in day-to-day life, but one additional difficulty is finding learning materials that are either audible, as in text-to-speech software, or tactile, as in braille. A particular problem with physics, however, is its fundamental reliance on maths, which doesn’t always convert easily to these non-visual media. Within English-speaking countries there are at least two versions of mathematical braille, which means that students have to learn the version suited to where most of their publications come from; and even then, the vast majority of publications are not available in braille in the first place, and can take months or years to translate. Meanwhile, traditional text-to-speech software – though rapidly improving – still often garbles mathematical formulae.
At Oregon State University, Sajjad rejected mathematical braille, which he says was “too slow”, and so staff instead provided specialist text-to-speech software called Triangle. Based on a simplified version of LaTeX – the widely used code to prepare documents containing mathematical formulae for publication – Triangle can read scientific learning materials out loud in a sequential manner, equations included. If an equation contains a fraction, for example, the software alerts the user to a nominator before reading through it, and then tells the user that the nominator is over before moving on to the denominator.
After his degree, Sajjad did a PhD in particle physics phenomenology at Harvard University in Cambridge, US, where he was given a graduate student to oversee the accessibility of his materials. The student wrote a new program to convert LaTeX documents directly into Triangle format, thereby making available a huge portion of the scientific literature: many of the papers on the popular arXiv server exist in LaTeX format, for example. Technical books are often also prepared in LaTeX format, although Sajjad was disappointed to find that the publishers were unwilling to share those versions, for protection of copyright.
His PhD complete, Sajjad is now in the enviable position of deciding which area of theoretical physics he wants to pursue next. He admits that he was wise to take his undergraduate studies at Oregon State University, knowing that it had already primed itself for blind students thanks to earlier work by John Gardner, a leading materials scientist at the institution. In 1988, at the age of 48, Gardner had surgery to correct vision that had long been deteriorating due to glaucoma. Instead of improving his sight, however, the surgery suddenly stole it away. “The doctor told me I needed this tiny operation to keep me from going slowly blind. And it did,” Gardner jokes now, nearly 30 years later.
Gardner was “pretty sick” for several months after his operation, he says, yet he couldn’t afford to be absent long. “I had a large research group to manage. From the hospital bed, I was fighting with the NSF [US National Science Foundation] to keep funding for a postdoc.” His established position in academia was an advantage: colleagues were almost all supportive, while the university itself “bent over backwards” to help because of the grant money he brought in. But returning to his actual research was hard, as much of it involved fitting theoretical models to experimental data. “That was the difficult bit. Everything else had a solution, but that didn’t, except using the eyes of other people.”
Learning curve: There are several different versions of mathematical braille. (Courtesy: iStock/Olga Raktiva)
The magic touch
Before long, Gardner found himself brainstorming ways to overcome the hurdles he faced. Triangle – the mathematics-to-speech software to which Sajjad would turn years later – was in fact one of his inventions. But the real test was how to deal with graphs, diagrams and other graphics. In the early 1990s studies of accessibility had identified “audio-tactile” as an effective way of presenting graphical information to the blind. The method involves an embossed hard copy of a graphic that is linked to an audio system, which has been taught (e.g. by a sighted colleague) to describe different parts of the graphic when those parts are touched. In the dark, an embossed bicycle might feel like a bunch of random squiggles, for example, but it quickly comes to light with touch-sensitive audio descriptions of “wheel”, “crossbar” and “pedal”. “I knew audio-tactile was the right method,” says Gardner, “but there was no software or hardware to support it.”
The key was an embosser – a printer that prints a raised surface – with sufficient resolution. One type of embosser already available at the time used a viscous polymer ink, but Gardner found that the images it produced were too low, too subtle, for his fingers to discern. When he made the embosser use more of the ink, the shapes simply peeled off the surface. His student finally came up with the answer: an electronic device that looks like the face of a miniature meat tenderizer, with an array of tiny pyramids. With a spacing of just 0.127 mm, these independently moving pyramids could stamp a distinct image onto paper with enough resolution for even the most sensitive finger.
Despite the innovative solution, no existing braille companies wanted to license the patent, so Gardner started a company, ViewPlus, to manufacture the embosser himself. Today, ViewPlus sells an entire solution for blind students and academics: a range of embossers, touch pads on which to place the embossed pages, and software to interpret the signals and describe what a user is feeling. Business has been steady, though not as much as Gardner would like. “The hope is that a student can be given an embosser by their university, to take back to the lab,” he says. “It will save the university money, because the students can do things themselves.”
For Gardner, though, the main stumbling block for blind physicists today is not technology but prejudice. One year after the US Department of Energy labelled one of his research projects “world class”, the body stripped funding for it. “The review panel was not convinced that a blind person could continue to do physics, even though I had been doing it as a blind person for a long time,” he says.
But overt discrimination is not the only kind that blind physicists face. Sajjad borrows a phrase used in gender studies, “death by a thousand cuts”, to describe the small incidents that can gradually deter the blind from science academia. These could be unconscious expressions of prejudice, or day-to-day obstacles that the sighted get over without thinking twice, such as recognizing a face across a crowd. Sajjad laughs that his inability to recognize faces has also led to embarrassing instances, when he has said something awkward in the presence of someone he didn’t even know was there. “Sometimes it’s not one bullet that kills you,” he says. “It’s those various little things.”
Into the deep end
Michael Whapples, a blind physics graduate based in the UK, struggled to find employment after studying at the University of Nottingham, and was not helped by poorly educated employers. “I couldn’t prove that they were discriminating,” he says. “But there were some who didn’t seem to have enough awareness.” In fact, Whapples’ frustrations began as a child. Having lost his sight young due to glaucoma and other complications, he attended a small, specialist secondary school for the visually impaired in Worcester, but had a shock once he enrolled at Nottingham. “The classes were big,” he says. “The tutors didn’t even know about braille.”
That is not to say the university didn’t offer help. Whapples was given an assistant to take notes in lectures, he had weekly tutorials, and one member of the teaching staff provided dedicated support. But he had the impression that the administration was improvising as it went along: for example, the conversion of text and maths to braille was sent to a central disability assistant, who did not have a scientific background. “Sometimes it would work, sometimes it wouldn’t,” he says.
Based on his experience, Whapples thinks it would be better if universities thought about potential accessibility issues in advance of blind students matriculating; he also thinks the particular needs of science, technology, engineering and mathematics (STEM) subjects should be better integrated into central disability support services. “I don’t want to deter anyone, but I would say be prepared to be actively involved in finding the solutions to some of the issues you will encounter. It may seem like hard work at the time, and it probably is harder than studying some other subjects, but if you really are interested in the subject then hopefully it will be worth it in the end.”
Worth it indeed – for in a subject that can appear to delve further from everyday reality with every passing decade, Whapples even wonders whether blind physicists could have an advantage over their sighted counterparts. “When people are taught, for example, about the 10 or so dimensions in string theory, a lot of them ask how they ought to imagine those dimensions. But me, I don’t feel such a need to think about them in a visual sense. They’re just more sets of co-ordinates.”
Whapples isn’t the first scientist to believe sight could, in some instances, be regarded as an encumbrance. Bernard Morin, a blind French mathematician who is now retired, once remarked that he could determine the sign of a variable “by feeling the weight of the thing, by pondering it”. The non-visual senses of Saunderson were heightened, too: reportedly he could recognize where he was, and the size of a room, by hearing alone.
Seeing the unseeable
Daniel Hajas, who graduated from the University of Sussex in the UK last year, believes modern physics ought to be suited to the blind. “Aside from light, no-one can actually see electromagnetic waves,” he says. “No-one can see gravitational waves. No-one can see quantum physics in action.” Of course, all these phenomena are probed by instruments – instruments whose outputs are primarily visual.
Hajas’s plunge into darkness was as much of a jolt as it could be: he lost his sight just one year before he left for university in the UK, away from his native Hungary. From the start he was determined to make his subject more accessible. In the second and third years of his course he designed a refreshable electromechanical display for tactile images: a 100 by 100 grid of tightly spaced pins, whose vertical movements were controlled with low-cost actuators. Developing such actuators proved to be too ambitious on a short timescale, so he and six collaborators have since begun another project, for immediate impact: a website that he calls Grapheel IRIS. The idea is that enough sighted scientists sign up to the website as volunteers, so that when a blind person uploads an image, at least one of the volunteers can spare a moment to describe what that image is.
Over just a few months from the end of 2016 to the beginning of 2017, Hajas and colleagues got more than 50 volunteers to sign up, from 14 different countries. He is now developing a version of Grapheel Iris for testing. Ideally, he wants users to be able to install a Grapheel IRIS extension button on Internet browsers, so that they need only click on an image for it to be returned from the Iris community with an audio description.
A service like that would certainly make life easier for blind physicists. Hajas also applauds developments in policy such as the Institute of Physics (IOP) Diversity Programme, which aims to encourage disabled students into physics with evidence-based models of good practice. The IOP, which publishes Physics World, is also a member of a collaborative group known as the STEMM Disability Advisory Committee, which helps disabled education and employment in STEM and medicine.
Yet with all this focus on the needs of the visually impaired, Hajas wonders whether sighted physicists couldn’t relax their sensory preferences at the same time. “I don’t see why we should be using just sight,” he says. “We could all be using a multi-sensory approach.”
A new system for delivering targeted cancer therapies has been developed by researchers in China and Sweden. The biodegradable drug-delivery system uses an external light source to degrade black phosphorous (BP) hydrogel nanostructures containing drugs for cancer therapies. As the structure degrades, it releasesA new system for delivering targeted cancer therapies has been developed by researchers in China and Sweden. The biodegradable drug-delivery system uses an external light source to degrade black phosphorous (BP) hydrogel nanostructures containing drugs for cancer therapies. As the structure degrades, it releases the drugs at tumour sites. the drugs at tumour sites.
Targeted drug delivery to tumours is a very attractive option for cancer therapies as it provides treatment directly at the point of the tumour. However, localized approaches such as injections of chemotherapy drugs are invasive, and are often painful. Polymer-based drug-delivery systems that are inserted into the body and degrade to release drugs are encouraging, but often cannot be controlled. The result is therapies that don’t work, which contributes to the increased risk of resistance in cancer cells.
The team led by Han Zhang at the Shenzhen University, China, and Yihai Cao at the Karolinska Institutet, Sweden trialled the use of black phosphorous. The newly discovered material boasts high photothermal conversion efficiency, easy fabrication and excellent biocompatibility and biodegradation. Their BP@Hydrogel system is comprised of BP Nanosheets (BPNSs) and a hydrogel (a hydrophilic network of polymer chains), and releases its cargo when exposed to a near-infrared light source. The black phosphorous photothermal transducing agents convert light to thermal energy, which increases the temperature of the hydrogel matrix. The agarose hydrogel then softens, which releases the drug from the black phosphorous scaffold into the body.
The process of softening is reversible, meaning the release can be controlled in bursts, so that the drug is discharged where it will be most effective. At the end of the treatment, enhanced laser power can be used to melt the hydrogel completely, degrading it into oligomers that are excreted through the urine.
Highly controllable drug release
The researchers loaded the hydrogel with Doxorubicin (DOX) – a commonly used cancer therapy – to measure the light-controlled drug release. When irradiated with a near-infrared source, the concentration of DOX increased dramatically compared with the control without irradiation. The researchers also showed that both light intensity and exposure duration accurately controlled the device.
Irradiation of 1 W·cm-1 applied to the BP@Hydrogel was sufficient for drug release. The temperature increase softens the device due to the hydrolysis of cross-linking. Complete melting occurs at 2 W·cm-1 irradiation, at which point the BPNSs are no longer encased by the hydrogel and degrade rapidly.
Safely degrades and shrinks tumours
The waste products were found to be non-toxic. Studies on mice found that tumours treated with a DOX-loaded BP@Hydrogel device, which were irradiated with an NIR light source, were notably smaller, demonstrating an excellent tumour ablation effect in vivo.
The BP@Hydrogel system can be loaded with other drugs to target a wide range of tumour types and other diseases, while minimizing unpleasant side effects. The authors believe a design such as this has the potential to help millions of patients suffering from cancer.
