Category Archives: medicine

Weirdly fascinating account of malaria-carrying mosquitoes and insecticide-treated bed nets

Researchers at the Liverpool School of Tropical Medicine (LSTM) have tracked mosquitoes to observe how they interact with insecticide-laden nets. From a Sept. 1, 2015 LSTM press release (also on EurekAlert),

LSTM vector biologists Dr Philip McCall and Ms Josie Parker worked with optical engineers Prof David Towers, Dr Natalia Angarita and Dr Catherine Towers from the University of Warwick’s School of Engineering to develop infrared video tracking technology that follows individual mosquitoes in flight as they try to reach a human sleeper inside a bed net. This system allowed the scientists to measure, define and characterise in fine detail, the behavioural events and sequences of the main African malaria vector, Anopheles gambiae, as it interacts with the net. Funded as part of the €12M AvecNet research consortium, the team’s initial results are published today in the journal Nature Scientific Reports.

Dr Philip McCall, senior author on the paper, said: “Essentially, the results demonstrated that an LLIN [Long-lasting insecticidal bed net] functions as a highly efficient, fast-acting, human-baited insecticidal trap. LLINs do not repel mosquitoes – they deliver insecticide very rapidly after the briefest contact: LLIN contact of less than 1 minute per mosquito during the first ten minutes can reduce mosquito activity such that after thirty minutes, virtually no mosquitoes are still flying. Surprisingly, mosquitoes were able to detect nets of any kind while still in flight, allowing them to decelerate before they ‘collided’ with the net surface.”

The use of this innovative approach to mosquito behaviour has provided unprecedented insight into the mode of action of our most important tool for preventing malaria transmission, under conditions that are as close to natural as possible. The findings potentially could influence many aspects of mosquito control, ranging from how we test mosquito populations for insecticide resistance to the design of a next generation of LLINs. An MRC Confidence in Concept grant has funded the team to use the tracking system to explore a number of novel LLIN designs, already patented as an outcome from the current research.

The tracking system also has been deployed in a rural Tanzania, results of which will be reported shortly. The team recently was awarded £0.9M support from the Medical Research Council (MRC) for the next stage of this project, where they will use a larger three-dimensional system to track mosquitoes throughout the entire domestic environment, in experimental houses in Tanzania.

Dr McCall continued: “preliminary results in field tests indicate that these laboratory findings are consistent with behaviour of wild mosquito populations which is very encouraging. We are at the early stages of this research, but we hope that our findings, and the use of this cutting edge technology, can contribute to the development of new and advanced vector control tools that will continue to save lives in endemic countries throughout the world.”

The fascinating part follows the link to and citation for the paper,

Infrared video tracking of Anopheles gambiae at insecticide-treated bed nets reveals rapid decisive impact after brief localised net contact by Josephine E.A. Parker, Natalia Angarita-Jaimes, Mayumi Abe, Catherine E. Towers, David Towers, & Philip J. McCall. Scientific Reports 5, Article number: 13392 (2015) doi:10.1038/srep13392 Published online: 01 September 2015

This open access paper provides an explanation for why this work was undertaken,

Delivering the ‘next generation’ of LLINs or similar tools will require a thorough understanding of how LLINs function, yet remarkably little is known of the mode of action or of precisely how mosquitoes behave at the LLIN interface. Recent studies using ‘sticky-nets’ reported that host-seeking female Anopheles spp. landed preferentially on the top surface of bed nets7,8 but that lethal capture method recorded only a single landing event and no other behaviours before or after. Although clustering at the net roof is likely to be a response to an attractant ‘plume’ rising from the human beneath [emphasis mine], this too remains speculative because knowledge of mosquito flight behaviour prior to blood-feeding and of the identity and location of the key attractants that mediate the host-seeking response is limited9,10,11,12. Importantly, how insecticide treatments influence that response is unclear. Some studies reported that insecticide residues repelled mosquitoes prior to contact13,14, which would reduce or eliminate the chance of mosquitoes receiving an effective dose and potentially divert them to unprotected hosts15. Others found no evidence for such repellency16,17,18,19 indicating that LLINs attract and impact on mosquitoes by direct contact.

A further complication is the existence of what is termed ‘contact-irritancy’ or ‘excito-repellency’ [emphasis miine], whereby brief exposure to an insecticide can result in mosquitoes exhibiting avoidance behaviour, potentially before a lethal dose has been delivered13,20. Remarkably, some basic details are missing: e.g. the minimum duration of LLIN contact necessary to deliver an effective dosage is not known. Despite these phenomena being recognised for decades20,21,22, when and how they occur and their relative importance in selecting for insecticide resistance have never been fully elucidated.

Consequently, behavioural resistance [emphasis mine] to insecticides remains poorly understood and rarely reported in mosquitoes, though the risk of vector populations switching blood-feeding times, locations or host preferences in order to avoid LLINs is recognized and closely monitored today23,24,25. However, additional but less apparent or detectable behavioural changes also might exist, potentially conferring partial or complete insecticide resistance (e.g. changes in sensitivity to repellents, attractants, or modified flight or resting behaviours). In the absence of definitions or quantifications of the basic behavioural events likely to be affected26,27, these changes cannot be investigated, let alone monitored.

I am fascinated by the ‘attractant plume’, ‘excito-repellency’, and the (new to me) notion that mosquitoes can exhibit behavioural resistance.

People for the Ethical Treatment of Animals (PETA) and a grant for in vitro nanotoxicity testing

This grant seems to have gotten its start at a workshop held at the US Environmental Protection Agency (EPA) in Washington, D.C., Feb. 24-25, 2015 as per this webpage on the People for Ethical Treatment of Animals (PETA) International Science Consortium Limited website,

The invitation-only workshop included experts from different sectors (government, industry, academia and NGO) and disciplines (in vitro and in vivo inhalation studies of NMs, fibrosis, dosimetry, fluidic models, aerosol engineering, and regulatory assessment). It focused on the technical details for the development and preliminary assessment of the relevance and reliability of an in vitro test to predict the development of pulmonary fibrosis in cells co-cultured at the air-liquid interface following exposure to aerosolized multi-walled carbon nanotubes (MWCNTs). During the workshop, experts made recommendations on cell types, exposure systems, endpoints and dosimetry considerations required to develop the in vitro model for hazard identification of MWCNTs.

The method is intended to be included in a non-animal test battery to reduce and eventually replace the use of animals in studies to assess the inhalation toxicity of engineered NMs. The long-term vision is to develop a battery of in silico and in vitro assays that can be used in an integrated testing strategy, providing comprehensive information on biological endpoints relevant to inhalation exposure to NMs which could be used in the hazard ranking of substances in the risk assessment process.

A September 1, 2015 news item on Azonano provides an update,

The PETA International Science Consortium Ltd. announced today the winners of a $200,000 award for the design of an in vitro test to predict the development of lung fibrosis in humans following exposure to nanomaterials, such as multi-walled carbon nanotubes.

Professor Dr. Barbara Rothen-Rutishauser of the Adolphe Merkle Institute at the University of Fribourg, Switzerland and Professor Dr. Vicki Stone of the School of Life Sciences at Heriot-Watt University, Edinburgh, U.K. will jointly develop the test method. Professor Rothen-Rutishauser co-chairs the BioNanomaterials research group at the Adolphe Merkle Institute, where her research is focused on the study of nanomaterial-cell interactions in the lung using three-dimensional cell models. Professor Vicki Stone is the Director of the Nano Safety Research Group at Heriot-Watt University and the Director of Toxicology for SAFENANO.

The Science Consortium is also funding MatTek Corporation for the development of a three-dimensional reconstructed primary human lung tissue model to be used in Professors Rothen-Rutishauser and Stone’s work. MatTek Corporation has extensive expertise in manufacturing human cell-based, organotypic in vitro models for use in regulatory and basic research applications. The work at MatTek will be led by Dr. Patrick Hayden, Vice President of Scientific Affairs, and Dr. Anna Maione, head of MatTek’s airway models research group.

I was curious about MatTek Corporation and found this on company’s About Us webpage,

MatTek Corporation was founded in 1985 by two chemical engineering professors from MIT. In 1991 the company leveraged its core polymer surface modification technology into the emerging tissue engineering market.

MatTek Corporation is at the forefront of tissue engineering and is a world leader in the production of innovative 3D reconstructed human tissue models. Our skin, ocular, and respiratory tissue models are used in regulatory toxicology (OECD, EU guidelines) and address toxicology and efficacy concerns throughout the cosmetics, chemical, pharmaceutical and household product industries.

EpiDerm™, MatTek’s first 3D human cell based in vitro model, was introduced in 1993 and became an immediate technical and commercial success.

I wish them good luck in their research on developing better ways to test toxicity.

Synthetic microfish (nanoengineered and 3D printed) to inspire ‘smart’ microbots

An August 26, 2015 news item on Nanowerk features some microfish (they look like sharks to me) fabricated in University of California at San Diego (UCSD) laboratories,

Nanoengineers at the University of California, San Diego used an innovative 3D printing technology they developed to manufacture multipurpose fish-shaped microrobots — called microfish — that swim around efficiently in liquids, are chemically powered by hydrogen peroxide and magnetically controlled. These proof-of-concept synthetic microfish will inspire a new generation of “smart” microrobots that have diverse capabilities such as detoxification, sensing and directed drug delivery, researchers said.

3D-printed microfish contain functional nanoparticles that enable them to be self-propelled, chemically powered and magnetically steered. The microfish are also capable of removing and sensing toxins. Image credit: J. Warner, UC San Diego Jacobs School of Engineering.

3D-printed microfish contain functional nanoparticles that enable them to be self-propelled, chemically powered and magnetically steered. The microfish are also capable of removing and sensing toxins. Image credit: J. Warner, UC San Diego Jacobs School of Engineering.

An August 25, 2015 UCSD news release (also on EurekAlert) by Liezel Labios, which originated the news item, provides more detail,

The technique used to fabricate the microfish provides numerous improvements over other methods traditionally employed to create microrobots with various locomotion mechanisms, such as microjet engines, microdrillers and microrockets. Most of these microrobots are incapable of performing more sophisticated tasks because they feature simple designs — such as spherical or cylindrical structures — and are made of homogeneous inorganic materials. In this new study, researchers demonstrated a simple way to create more complex microrobots.

By combining Chen’s 3D printing technology with Wang’s expertise in microrobots, the team was able to custom-build microfish that can do more than simply swim around when placed in a solution containing hydrogen peroxide. Nanoengineers were able to easily add functional nanoparticles into certain parts of the microfish bodies. They installed platinum nanoparticles in the tails, which react with hydrogen peroxide to propel the microfish forward, and magnetic iron oxide nanoparticles in the heads, which allowed them to be steered with magnets.

Here’s an illustration of the platinum and iron oxide microfish,

Schematic illustration of the process of functionalizing the microfish. Platinum nanoparticles are first loaded into the tail of the fish for propulsion via reaction with hydrogen peroxide. Next, iron oxide nanoparticles are loaded into the head of the fish for magnetic control. Image credit: W. Zhu and J. Li, UC San Diego Jacobs School of Engineering.

Schematic illustration of the process of functionalizing the microfish. Platinum nanoparticles are first loaded into the tail of the fish for propulsion via reaction with hydrogen peroxide. Next, iron oxide nanoparticles are loaded into the head of the fish for magnetic control. Image credit: W. Zhu and J. Li, UC San Diego Jacobs School of Engineering.

Back to the news release,

“We have developed an entirely new method to engineer nature-inspired microscopic swimmers that have complex geometric structures and are smaller than the width of a human hair. With this method, we can easily integrate different functions inside these tiny robotic swimmers for a broad spectrum of applications,” said the co-first author Wei Zhu, a nanoengineering Ph.D. student in Chen’s research group at the Jacobs School of Engineering at UC San Diego.

As a proof-of-concept demonstration, the researchers incorporated toxin-neutralizing nanoparticles throughout the bodies of the microfish. Specifically, the researchers mixed in polydiacetylene (PDA) nanoparticles, which capture harmful pore-forming toxins such as the ones found in bee venom. The researchers noted that the powerful swimming of the microfish in solution greatly enhanced their ability to clean up toxins. When the PDA nanoparticles bind with toxin molecules, they become fluorescent and emit red-colored light. The team was able to monitor the detoxification ability of the microfish by the intensity of their red glow.

“The neat thing about this experiment is that it shows how the microfish can doubly serve as detoxification systems and as toxin sensors,” said Zhu.

“Another exciting possibility we could explore is to encapsulate medicines inside the microfish and use them for directed drug delivery,” said Jinxing Li, the other co-first author of the study and a nanoengineering Ph.D. student in Wang’s research group.

For anyone curious about the new 3D printing technique, the news release provides more information about that too,

The new microfish fabrication method is based on a rapid, high-resolution 3D printing technology called microscale continuous optical printing (μCOP), which was developed in Chen’s lab. Some of the benefits of the μCOP technology are speed, scalability, precision and flexibility. Within seconds, the researchers can print an array containing hundreds of microfish, each measuring 120 microns long and 30 microns thick. This process also does not require the use of harsh chemicals. Because the μCOP technology is digitized, the researchers could easily experiment with different designs for their microfish, including shark and manta ray shapes. [emphasis mine] “With our 3D printing technology, we are not limited to just fish shapes. We can rapidly build microrobots inspired by other biological organisms such as birds,” said Zhu.

The key component of the μCOP technology is a digital micromirror array device (DMD) chip, which contains approximately two million micromirrors. Each micromirror is individually controlled to project UV light in the desired pattern (in this case, a fish shape) onto a photosensitive material, which solidifies upon exposure to UV light. The microfish are built using a photosensitive material and are constructed one layer at a time, allowing each set of functional nanoparticles to be “printed” into specific parts of the fish bodies.

“This method has made it easier for us to test different designs for these microrobots and to test different nanoparticles to insert new functional elements into these tiny structures. It’s my personal hope to further this research to eventually develop surgical microrobots that operate safer and with more precision,” said Li.

Nice to see I can recognize a shark shape when I see one. Getting back to the research, yet again, here’s a link to and a citation for the paper.

3D-Printed Artificial Microfish by Wei Zhu, Jinxing Li, Yew J. Leong, Isaac Rozen, Xin Qu, Renfeng Dong, Zhiguang Wu, Wei Gao, Peter H. Chung, Joseph Wang, and Shaochen Chen. Advanced Materials Volume 27, Issue 30, pages 4411–4417, August 12, 2015 DOI: 10.1002/adma.201501372 Article first published online: 29 JUN 2015

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Does the universe have a heartbeat?

It may be a bit fanciful to suggest the universe has a heartbeat but if University of Warwick (UK) researchers can state that dying stars have ‘irregular heartbeats’ then why can’t the universe have a heartbeat of sorts? Getting back to the University of Warwick, their August 26, 2015 press release (also on EurekAlert) has this to say,

Some dying stars suffer from ‘irregular heartbeats’, research led by astronomers at the University of Warwick has discovered.

The research confirms rapid brightening events in otherwise normal pulsating white dwarfs, which are stars in the final stage of their life cycles.

In addition to the regular rhythm from pulsations they expected on the white dwarf PG1149+057, which cause the star to get a few percent brighter and fainter every few minutes, the researchers also observed something completely unexpected every few days: arrhythmic, massive outbursts, which broke the star’s regular pulse and significantly heated up its surface for many hours.

The discovery was made possible by using the planet-hunting spacecraft Kepler, which stares unblinkingly at a small patch of sky, uninterrupted by clouds or sunrises.

Led by Dr JJ Hermes of the University of Warwick’s Astrophysics Group, the astronomers targeted the Kepler spacecraft on a specific star in the constellation Virgo, PG1149+057, which is roughly 120 light years from Earth.

Dr Hermes explains:

“We have essentially found rogue waves in a pulsating star, akin to ‘irregular heartbeats’. These were truly a surprise to see: we have been watching pulsating white dwarfs for more than 50 years now from the ground, and only by being able to stare uninterrupted for months from space have we been able to catch these events.”

The star with the irregular beat, PG1149+057, is a pulsating white dwarf, which is the burnt-out core of an evolved star, an extremely dense star which is almost entirely made up of carbon and oxygen. Our Sun will eventually become a white dwarf in more than six billion years, after it runs out of its nuclear fuel.

White dwarfs have been known to pulsate for decades, and some are exceptional clocks, with pulsations that have kept nearly perfect time for more than 40 years. Pulsations are believed to be a naturally occurring stage when a white dwarf reaches the right temperature to generate a mix of partially ionized hydrogen atoms at its surface.

That mix of excited atoms can store up and then release energy, causing the star to resonate with pulsations characteristically every few minutes. Astronomers can use the regular periods of these pulsations just like seismologists use earthquakes on Earth, to see below the surface of the star into its exotic interior. This was why astronomers targeted PG1149+057 with Kepler, hoping to learn more about its dense core. In the process, they caught a new glimpse at these unexpected outbursts.

“These are highly energetic events, which can raise the star’s overall brightness by more than 15% and its overall temperature by more than 750 degrees in a matter of an hour,” said Dr Hermes. “For context, the Sun will only increase in overall brightness by about 1% over the next 100 million years.”

Interestingly, this is not the only white dwarf to show an irregular pulse. Recently, the Kepler spacecraft witnessed the first example of these strange outbursts while studying another white dwarf, KIC 4552982, which was observed from space for more than 2.5 years.

There is a narrow range of surface temperatures where pulsations can be excited in white dwarfs, and so far irregularities have only been seen in the coolest of those that pulsate. Thus, these irregular outbursts may not be just an oddity; they have the potential to change the way astronomers understand how pulsations, the regular heartbeats, ultimately cease in white dwarfs.

“The theory of stellar pulsations has long failed to explain why pulsations in white dwarfs stop at the temperature we observe them to,” argues Keaton Bell of the University of Texas at Austin, who analysed the first pulsating white dwarf to show an irregular heartbeat, KIC 4552982. “That both stars exhibiting this new outburst phenomenon are right at the temperature where pulsations shut down suggests that the outbursts could be the key to revealing the missing physics in our pulsation theory.”

Astronomers are still trying to settle on an explanation for these never-before-seen outbursts. Given the similarity between the first two stars to show this behaviour, they suspect it might have to do with how the pulsation waves interact with themselves, perhaps via a resonance.

“Ultimately, this may be a new type of nonlinear behaviour that is triggered when the amplitude of a pulsation passes a certain threshold, perhaps similar to rogue waves on the open seas here on Earth, which are massive, spontaneous waves that can be many times larger than average surface waves,” said Dr Hermes. “Still, this is a fresh discovery from observations, and there may be more to these irregular stellar heartbeats than we can imagine yet.”

Here’s a link to and a citation for the paper,

A Second Case of Outbursts in a Pulsating White Dwarf Observed by Kepler by J. J. Hermes, M. H. Montgomery, Keaton J. Bell, P. Chote, B. T. Gänsicke, Steven D. Kawaler, J. C. Clemens, Bart H. Dunlap, D. E. Winget, and D. J. Armstrong.
2015 ApJ 810 L5 (The Astrophysical Journal Letters Volume 810 Number 1). doi:10.1088/2041-8205/810/1/L5
Published 24 August 2015.

© 2015. The American Astronomical Society. All rights reserved.

This paper is behind a paywall but there is an earlier open access version available at arXiv.org,

A second case of outbursts in a pulsating white dwarf observed by Kepler by J. J. Hermes, M. H. Montgomery, Keaton J. Bell, P. Chote, B. T. Gaensicke, Steven D. Kawaler, J. C. Clemens, B. H. Dunlap, D. E. Winget, D. J. Armstrong.  arXiv.org > astro-ph > arXiv:1507.06319

In an attempt to find some live heart beats to illustrate this piece, I found this video from Wake Forest University’s body-on-a-chip program,

The video was released in an April 14, 2015 article by Joe Bargmann for Popular Mechanics,

A groundbreaking program has converted human skin cells into a network of functioning heart cells, and also fused them with lab-grown liver cells using a specialized 3D printer. Researchers at the Wake Forest Baptist Medical Center’s Institute for Regenerative Medicine provided Popular Mechanics with both still and moving images of the cells for a fascinating first look.

“The heart organoid beats because it contains specialized cardiac cells and because those cells are receiving the correct environmental cues,” says Ivy Mead, a Wake Forest graduate student and member of the research team. “We give them a special medium and keep them at the same temperature as the human body, and that makes them beat. We can also stimulate the miniature organ with electrical or chemical cues to alter the beating patterns. Also, when we grow them in three-dimensions it allows for them to interact with each other more easily, as they would in the human body.”

If you’re interested in body-on-a-chip projects, I have several stories here (suggestion: use body-on-a-chip as your search term in the blog search engine) and I encourage you to read Bargmann’s story in its entirety (the video no longer seems to be embedded there).

One final comment, there seems to be some interest in relating large systems to smaller ones. For example, humans and other animals along with white dwarf stars have heartbeats (as in this story) and patterns in a gold nanoparticle of 133 atoms resemble the Milky Way (my April 14, 2015 posting titled: Nature’s patterns reflected in gold nanoparticles).

Getting a glimpse of the Alzheimer’s (amyloid beta) molecule

I’m not sure an amyloid beta molecule (or amyloid beta peptide) the ‘Alzheimer’s molecule’ as that has yet to be proved although I gather there are strong suspicions. That quibble aside, there’s some exciting news in an August 25, 2015 news item on ScienceDaily,

Scientists have caught a glimpse of the elusive toxic form of the Alzheimer’s molecule, during its attempt to bore into the outer covering of a cell decoy, using a new method involving laser light and fat-coated silver nano-particles.

While the origin of Alzheimer’s Disease, one that robs the old of their memory, is still hotly debated, it is likely that a specific form of the Amyloid beta molecule, which is able to attack cell membranes, is a major player. Defeating this molecule would be easier if its shape and form were known better, but that has proven to be a difficult task until now.

An August 25, 2015 Tata Institute of Fundamental Research (TIFR) press release on EurekAlert, which originated the news item, provides more detail,

“Everybody wants to make the key to solve Alzheimer’s Disease, but we don’t know what the lock looks like. We now have a glimpse of something which could be the lock. May be it’s still not the real thing, but as of now, this is our best bet”, says Sudipta Maiti, who co-directed the efforts with P. K. Madhu (both from TIFR). If they are right, then designing the key, i.e. making a drug molecule which can attack the lock, may be more achievable now.

The lock looks like a bunch of amyloid beta molecules in the shape of a hairpin, but with a twist. Debanjan Bhowmik, the lead contributor of the study says “This has been suspected earlier, but what we found was an unexpected twist in the structure, now becoming a beta-hairpin – very different from the typical hairpin structure people imagined. This may allow these bunch of amyloid beta molecules to form toxic pores in the cell membranes”.

The findings published in the journal ACS Nano this week by a joint team of researchers from the Tata Institute of Fundamental Research, Indian Institute of Science and the University of Toronto, have cracked the problem that has eluded scientists for years, by using a modified version of Raman Spectroscopy.

They studied a tiny laser-induced signal from the amyloid beta which reported their shape. A critical modification in the original Raman Spectroscopy technique allowed the measurement of tiny signals that would otherwise have gone unnoticed. They encased silver nanoparticles in a fat layer (“membrane”) that mimicked the outer membranes of living cells. According to co-author Gilbert Walker, “While the amyloid beta got fooled by it and stuck to the membrane, the silver inside enhanced the signal to a measurable level and acted as a light beacon to reveal the peptide signature”. The technique offers promise for deciphering the shape of many such membrane molecules, some of which may be related to other types of diseases.

Each research team brought something different to the table. As Jaydeep Basu, who led the IISc team, says, “It’s a great example of how contemporary science breaks all barriers to bring people together for the pure love of science and the quest for the unknown!” One hopes that the search for the key to solve Alzheimer’s has taken a step forward with this finding.

Here’s a link to and a citation for the paper,

Cell-Membrane-Mimicking Lipid-Coated Nanoparticles Confer Raman Enhancement to Membrane Proteins and Reveal Membrane-Attached Amyloid-β Conformation by
Debanjan Bhowmik, Kaustubh R. Mote, Christina M. MacLaughlin, Nupur Biswas, Bappaditya Chandra, Jaydeep K. Basu, Gilbert C. Walker, Perunthiruthy K. Madhu, and Sudipta Maiti. ACS Nano, Article ASAP DOI: 10.1021/acsnano.5b03175 Publication Date (Web): August 25, 2015

Copyright © 2015 American Chemical Society

This paper is behind a paywall.

Carbon nanotubes as sensors in the body

Rachel Ehrenberg has written an Aug. 21, 2015 news item about the latest and greatest carbon nanotube-based biomedical sensors for the journal Nature,

The future of medical sensors may be going down the tubes. Chemists are developing tiny devices made from carbon nanotubes wrapped with polymers to detect biologically important compounds such as insulin, nitric oxide and the blood-clotting protein fibrinogen. The hope is that these sensors could simplify and automate diagnostic tests.

Preliminary experiments in mice, reported by scientists at a meeting of the American Chemical Society in Boston, Massachusetts, this week [Aug. 16 – 20, 2015], suggest that the devices are safe to introduce into the bloodstream or implant under the skin. Researchers also presented data showing that the nanotube–polymer complexes could measure levels of large molecules, a feat that has been difficult for existing technologies.

Ehrenberg focuses on one laboratory in particular (Note: Links have been removed),

“Anything the body makes, it is meant to degrade,” says chemical engineer Michael Strano, whose lab at the Massachusetts Institute of Technology (MIT) in Cambridge is behind much of the latest work1. “Our vision is to make a sensing platform that can monitor a whole range of molecules, and do it in the long term.”

To design one sensor, MIT  researchers coated nanotubes with a mix of polymers and nucleotides and screened for configurations that would bind to the protein fibrinogen. This large molecule is important for building blood clots; its concentration can indicate bleeding disorders, liver disease or impending cardiovascular trouble. The team recently hit on a material that worked — a first for such a large molecule, according to MIT nanotechnology specialist Gili Bisker. Bisker said at the chemistry meeting that the fibrinogen-detecting nanotubes could be used to measure levels of the protein in blood samples, or implanted in body tissue to detect changing fibrinogen levels that might indicate a clot.

The MIT team has also developed2 a sensor that can be inserted beneath the skin to monitor glucose or insulin levels in real time, Bisker reported. The team imagines putting a small patch that contains a wireless device on the skin just above the embedded sensor. The patch would shine light on the sensor and measure its fluorescence, then transmit that data to a mobile phone for real-time monitoring.

Another version of the sensor, developed3 at MIT by biomedical engineer Nicole Iverson and colleagues, detects nitric oxide. This signalling molecule typically indicates inflammation and is associated with many cancer cells. When embedded in a hydrogel matrix, the sensor kept working in mice for more than 400 days and caused no local inflammation, MIT chemical engineer Michael Lee reported. The nitric oxide sensors also performed well when injected into the bloodstreams of mice, successfully passing through small capillaries in the lungs, which are an area of concern for nanotube toxicity. …

There’s at least one corporate laboratory (Google X), working on biosensors although their focus is a little different. From a Jan. 9, 2015 article by Brian Womack and Anna Edney for BloombergBusiness,

Google Inc. sent employees with ties to its secretive X research group to meet with U.S. regulators who oversee medical devices, raising the possibility of a new product that may involve biosensors from the unit that developed computerized glasses.

The meeting included at least four Google workers, some of whom have connections with Google X — and have done research on sensors, including contact lenses that help wearers monitor their biological data. Google staff met with those at the Food and Drug Administration who regulate eye devices and diagnostics for heart conditions, according to the agency’s public calendar. [emphasis mine]

This approach from Google is considered noninvasive,

“There is actually one interface on the surface of the body that can literally provide us with a window of what happens inside, and that’s the surface of the eye,” Parviz [Babak Parviz, … was involved in the Google Glass project and has talked about putting displays on contact lenses, including lenses that monitor wearer’s health]  said in a video posted on YouTube. “It’s a very interesting chemical interface.”

Of course, the assumption is that all this monitoring is going to result in  healthier people but I can’t help thinking about an old saying ‘a little knowledge can be a dangerous thing’. For example, we lived in a world where bacteria roamed free and then we learned how to make them visible, determined they were disease-causing, and began campaigns for killing them off. Now, it turns out that at least some bacteria are good for us and, moreover, we’ve created other, more dangerous bacteria that are drug-resistant. Based on the bacteria example, is it possible that with these biosensors we will observe new phenomena and make similar mistakes?

Self-assembling copper and physiology

An Aug. 24, 2015 news item on Nanowerk highlights work at Louisiana Tech University (US) on self-assembling copper nanocomposites in liquid form,

Faculty at Louisiana Tech University have discovered, for the first time, a new nanocomposite formed by the self-assembly of copper and a biological component that occurs under physiological conditions, which are similar those found in the human body and could be used in targeted drug delivery for fighting diseases such as cancer.

The team, led by Dr. Mark DeCoster, the James E. Wyche III Endowed Associate Professor in Biomedical Engineering at Louisiana Tech, has also discovered a way for this synthesis to be carried out in liquid form. This would allow for controlling the scale of the synthesis up or down, and to grow structures with larger features, so they can be observed.

An Aug. 24, 2015 Louisiana Tech University news release by Dave Guerin, which originated the news item, describes possible future  applications and the lead researcher’s startup company,

“We are currently investigating how this new material interacts with cells,” said DeCoster. “It may be used, for example for drug delivery, which could be used in theory for fighting diseases such as cancer. Also, as a result of the copper component that we used, there could be some interesting electronics, energy, or optics applications that could impact consumer products. In addition, copper has some interesting and useful antimicrobial features.

“Finally, as the recent environmental spill of mining waste into river systems showed us, metals, including copper, can sometimes make their way into freshwater systems, so our newly discovered metal-composite methods could provide a way to “bind up” unwanted copper into a useful or more stable form.”

DeCoster said there were two aspects of this discovery that surprised him and his research team. First, they found that once formed, these copper nanocomposites were incredibly stable both in liquid or dried form, and remained stable for years. “We have been carrying out this research for at least four years and have a number of samples that are at least two years old and still stable,” DeCoster said.

Second, DeCoster’s group was very surprised that these composites are resistant to agglomeration, which is the process by which material clumps or sticks together.

“This is of benefit because it allows us to work with individual structures in order to separate or modify them chemically,” explains DeCoster. “When materials stick together and clump, as many do, it is much harder to work with them in a logical way. Both of these aspects, however, fit with our hypothesis that the self-assembly that we have discovered is putting positively charged copper together with negatively charged sulfur-containing cystine.”

The research discovery was a team effort that included DeCoster and Louisiana Tech students at the bachelor, master and doctoral level. “The quality of my team in putting together a sustained effort to figure out what was needed to reproducibly carry out the new self-assembly methods and to simplify them really speaks well as to what can be accomplished at Louisiana Tech University,” DeCoster said. “Furthermore, the work is very multi-disciplinary, meaning that it required nanotechnology as well as biological and biochemical insights to make it all work, as well as some essential core instrumentation that we have at Louisiana Tech.”

DeCoster says the future of this research has some potentially high impacts. He and his team are speaking with colleagues and collaborators about how to test these new nanocomposites for applications in bioengineering and larger composites such as materials that would be large enough to be hand-held.

“Our recent publication of the work could generate some interest and new ideas,” said DeCoster. “We are working on new proposals to fund the research and to keep it moving forward. We are currently making these materials on an ‘as needed’ basis, knowing that they can be stored once generated, and if we discover new uses for the nanocomposites, then applications for the materials could lead to income generation through a start-up company that I have formed.”

Here’s a link to and a citation for the paper,

MediumGeneration of Scalable, Metallic High-Aspect Ratio Nanocomposites in a Biological Liquid Medium by Kinsey Cotton Kelly, Jessica R. Wasserman, Sneha Deodhar, Justin Huckaby, and Mark A. DeCoster. J. Vis. Exp. [Journal of Visual Experimentation; JoVE] (101), e52901, doi:10.3791/52901 (2015).

This paper/video is behind a paywall.

Wound healing with cellulose acetate nanofibres

This work on cellulose acetate nanofibres and wound healing (tested on mice) comes from Egypt according to an Aug. 10, 2015 news item on ScienceDaily,

People with diabetes mellitus often suffer from impaired wound healing. Now, scientists in Egypt have developed antibacterial nanofibres of cellulose acetate loaded with silver that could be used in a new type of dressing to promote tissue repair.

An Aug. 10, 2015 Inderscience Publishers press release on the Alpha Galileo website, which originated the news item, provides more detail about the research,

Thanaa Ibrahim Shalaby and colleagues, Nivan Mahmoud Fekry, Amal Sobhy El Sodfy, Amel Gaber El Sheredy and Maisa El Sayed Sayed Ahmed Moustafa, at Alexandria University, prepared nanofibres from cellulose acetate, an inexpensive and easily fabricated, semisynthetic polymer used in everything from photographic film to coatings for eyeglasses and even cigarette filters. It can be spun into fibres and thus used to make an absorbent and safe wound dressing. Shalaby and co-workers used various analytical techniques including scanning electron microscope (SEM) and Fourier-transform infrared (FTIR) spectroscopy to characterise their fibres in which they incorporated silver nanoparticles.

Having characterised the material the team then successfully tested its antibacterial activity against various strains of bacteria that might infect an open wound. They next used the material as a dressing on skin wounds on mice with diabetes and determined how quickly the wound healed with and without the nano dressing. The dressing absorbs fluids exuded by the wound, but also protects the wound from infectious agents while being permeable to air and moisture, the team reports. The use of this dressing also promotes collagen production as the wound heals, which helps to recreate normal skin strength and texture something that is lacking in unassisted wound healing in diabetes mellitus.

Here’s a link to and a citation for the paper,

Preparation and characterisation of antibacterial silver-containing nanofibres for wound healing in diabetic mice by Thanaa Ibrahim Shalaby; Nivan Mahmoud Fekry; Amal Sobhy El Sodfy; Amel Gaber El Sheredy; Maisa El Sayed Sayed Ahmed Moustafa. International Journal of Nanoparticles (IJNP), Vol. 8, No. 1, p. 82 2015 DOI: 10.1504/IJNP.2015.070346

This paper is behind a paywall although there are some exceptions.

Acoustofluidics and lab-on-a-chip for asthma and tuberculosis diagnostics

This is my first exposure to acoustofluidics (although it’s been around for a few years) and it concerns lab-on-a-chip diagnostics for asthma and tuberculosis. From an Aug. 3, 2015 news item on Azonano,

A device to mix liquids utilizing ultrasonics is the first and most difficult component in a miniaturized system for low-cost analysis of sputum from patients with pulmonary diseases such as tuberculosis and asthma.

The device, developed by engineers at Penn State in collaboration with researchers at the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, and the Washington University School of Medicine, will benefit patients in the U.S., where 12 percent of the population, or around 19 million people, have asthma, and in undeveloped regions where TB is still a widespread and often deadly contagion.

“To develop more accurate diagnosis and treatment approaches for patients with pulmonary diseases, we have to analyze sample cells directly from the lungs rather than by drawing blood,” said Tony Jun Huang, professor of engineering science and mechanics at Penn State and the inventor, with his group, of this and other acoustofluidic devices based on ultrasonic waves. “For instance, different drugs are used to treat different types of asthma patients. If you know what a person’s immunophenotype is, you can provide personalized medicine for their particular disease.

A July 29, 2015 Pennsylvania State University news release, which originated the news item, describes the disadvantages of the current sputum analyses techniques and explains how this new technique in an improvement,

There are several issues with the current standard method for sputum analysis. The first is that human specimens can be contagious, and sputum analysis requires handling of specimens in several discrete machines. With a lab on a chip device, all biospecimens are safely contained in a single disposable component.

Another issue is the sample size required for analysis in the current system, which is often larger than a person can easily produce. The acoustofluidic sputum liquefier created by Huang’s group requires 100 times less sample while still providing accuracy equivalent to the standard system.

A further issue is that current systems are difficult to use and require trained operators. With the lab on a chip system, a nurse can operate the device with a touch of a few buttons and get a read out, or the patient could even operate the device at home. In addition, the disposable portion of the device should cost less than a dollar to manufacture.

Po-Hsun Huang, a graduate student in the Huang group and the first author on the recent paper describing the device in the Royal Society of Chemistry journal Lab on a Chip, said “This will offer quick analysis of samples without having to send them out to a centralized lab. While I have been working on the liquefaction component of the device, my lab mates are working on the flow cytometry analysis component, which should be ready soon. This is the first on-chip sputum liquefier anyone has developed.”

Stewart J. Levine, a Senior Investigator and Chief of the Laboratory of Asthma and Lung Inflammation in the Division of Intramural Research at NHLBI, said “This on-chip sputum liquefier is a significant advance regarding our goal of developing a point-of-care diagnostic device that will determine the type of inflammation present in the lungs of asthmatics. This will allow health care providers to individualize asthma treatments for each patient and advance the goal of bringing precision medicine into clinical practice.”

Here’s a link to and a citation for the paper,

An acoustofluidic sputum liquefier by Po-Hsun Huang, Liqiang Ren, Nitesh Nama, Sixing Li, Peng Li, Xianglan Yao, Rosemarie A. Cuento, Cheng-Hsin Wei, Yuchao Chen, Yuliang Xie, Ahmad Ahsan Nawaz, Yael G. Alevy, Michael J. Holtzman, J. Philip McCoy, Stewart J. Levine, and  Tony Jun Huang. Lab Chip, 2015,15, 3125-3131 DOI: 10.1039/C5LC00539F

First published online 17 Jun 2015

This is an open access paper but you do need to register for a free (British) Royal Society of Chemistry publishing personal account.

Single molecule nanogold-based probe for photoacoustic Imaging and SERS biosensing

As I understand it, the big deal is that A*STAR (Singapore’s Agency for Science, Rechnology and Research) scientists have found a way to make a single molecule probe do the work of a two-molecule probe when imaging tumours. From a July 29, 2015 news item on Nanowerk (Note: A link has been removed),

An organic dye that can light up cancer cells for two powerful imaging techniques providing complementary diagnostic information has been developed and successfully tested in mice by A*STAR researchers (“Single Molecule with Dual Function on Nanogold: Biofunctionalized Construct for In Vivo Photoacoustic Imaging and SERS Biosensing”).

A July 29, 2015 A*STAR news release, which originated the news item, describes the currently used multimodal imaging technique and provides details about the new single molecule technique,

Imaging tumors is vitally important for cancer research, but each imaging technique has its own limitations for studying cancer in living organisms. To overcome the limitations of individual techniques, researchers typically employ a combination of various imaging methods — a practice known as multimodal imaging. In this way, they can obtain complementary information and hence a more complete picture of cancer.

Two very effective methods for imaging tumors are photoacoustic imaging and surface-enhanced Raman scattering (SERS). Photoacoustic imaging can image deep tissue with a good resolution, whereas SERS detects miniscule amounts of a target molecule. To simultaneously use both photoacoustic imaging and SERS, a probe must produce signals for both imaging modalities.

In multimodal imaging, researchers typically combine probes for each imaging modality into a single two-molecule probe. However, the teams of Malini Olivo at the A*STAR Singapore Bioimaging Consortium and Bin Liu at the A*STAR Institute of Materials Research and Engineering, along with overseas collaborator Ben Zhong Tang from the Hong Kong University of Science and Technology, adopted a different approach — they developed single-molecule probes that can be used for both photoacoustic imaging and SERS. The probes are based on organic cyanine dyes that absorb near-infrared light, which has the advantage of being able to deeply penetrate tissue, enabling tumors deep within the body to be imaged.

Once the team had verified that the probes worked for both imaging modalities, they optimized the performances of the probes by adding gold nanoparticles to them to amplify the SERS signal and by encapsulating them in the polymer polyethylene glycol to stabilize their structures.

The researchers then deployed these optimized probes in live mice. By functionalizing the probes with an antibody that recognizes a tumor cell-surface protein, they were able to use them to target tumors. The scientists found that, in photoacoustic imaging, the tumor-targeted probes produced signals that were roughly three times stronger than those of unmodified probes. Using SERS, the team was also able to monitor the concentrations of the probes in the tumor, spleen and liver in real time with a high degree of sensitivity.

U. S. Dinish, a senior scientist in Olivo’s group, recalls the team’s “surprise at the sensitivity and potential of the nanoconstruct.” He anticipates that the probe could be used to guide surgical removal of tumors.

Here’s a link to and a citation for the paper,

Single Molecule with Dual Function on Nanogold: Biofunctionalized Construct for In Vivo Photoacoustic Imaging and SERS Biosensing by U. S. Dinish, Zhegang Song, Chris Jun Hui Ho, Ghayathri Balasundaram, Amalina Binte Ebrahim Attia, Xianmao Lu, Ben Zhong Tang, Bin Liu, and Malini Olivo. Advanced Functional Materials, Vol 25 Issue 15
pages 2316–2325, April 15, 2015 DOI: 10.1002/adfm.201404341 Article first published online: 11 MAR 2015

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.