Tag Archives: pain

Prosthetic pain

Leave a reply

“Feeling no pain” can be a euphemism for being drunk. However, there are some people for whom it’s not a euphemism and they literally feel no pain for one reason or another. One group of people who feel no pain are amputees and a researcher at Johns Hopkins University (Maryland, US) has found a way so they can feel pain again.

A June 20, 2018 news item on ScienceDaily provides an introduction to the research and to the reason for it,

Amputees often experience the sensation of a “phantom limb” — a feeling that a missing body part is still there.

That sensory illusion is closer to becoming a reality thanks to a team of engineers at the Johns Hopkins University that has created an electronic skin. When layered on top of prosthetic hands, this e-dermis brings back a real sense of touch through the fingertips.

“After many years, I felt my hand, as if a hollow shell got filled with life again,” says the anonymous amputee who served as the team’s principal volunteer tester.

Made of fabric and rubber laced with sensors to mimic nerve endings, e-dermis recreates a sense of touch as well as pain by sensing stimuli and relaying the impulses back to the peripheral nerves.

A June 20, 2018 Johns Hopkins University news release (also on EurekAlert), which originated the news item, explores the research in more depth,

“We’ve made a sensor that goes over the fingertips of a prosthetic hand and acts like your own skin would,” says Luke Osborn, a graduate student in biomedical engineering. “It’s inspired by what is happening in human biology, with receptors for both touch and pain.

“This is interesting and new,” Osborn said, “because now we can have a prosthetic hand that is already on the market and fit it with an e-dermis that can tell the wearer whether he or she is picking up something that is round or whether it has sharp points.”

The work – published June 20 in the journal Science Robotics – shows it is possible to restore a range of natural, touch-based feelings to amputees who use prosthetic limbs. The ability to detect pain could be useful, for instance, not only in prosthetic hands but also in lower limb prostheses, alerting the user to potential damage to the device.

Human skin contains a complex network of receptors that relay a variety of sensations to the brain. This network provided a biological template for the research team, which includes members from the Johns Hopkins departments of Biomedical Engineering, Electrical and Computer Engineering, and Neurology, and from the Singapore Institute of Neurotechnology.

Bringing a more human touch to modern prosthetic designs is critical, especially when it comes to incorporating the ability to feel pain, Osborn says.

“Pain is, of course, unpleasant, but it’s also an essential, protective sense of touch that is lacking in the prostheses that are currently available to amputees,” he says. “Advances in prosthesis designs and control mechanisms can aid an amputee’s ability to regain lost function, but they often lack meaningful, tactile feedback or perception.”

That is where the e-dermis comes in, conveying information to the amputee by stimulating peripheral nerves in the arm, making the so-called phantom limb come to life. The e-dermis device does this by electrically stimulating the amputee’s nerves in a non-invasive way, through the skin, says the paper’s senior author, Nitish Thakor, a professor of biomedical engineering and director of the Biomedical Instrumentation and Neuroengineering Laboratory at Johns Hopkins.

“For the first time, a prosthesis can provide a range of perceptions, from fine touch to noxious to an amputee, making it more like a human hand,” says Thakor, co-founder of Infinite Biomedical Technologies, the Baltimore-based company that provided the prosthetic hardware used in the study.

Inspired by human biology, the e-dermis enables its user to sense a continuous spectrum of tactile perceptions, from light touch to noxious or painful stimulus. The team created a “neuromorphic model” mimicking the touch and pain receptors of the human nervous system, allowing the e-dermis to electronically encode sensations just as the receptors in the skin would. Tracking brain activity via electroencephalography, or EEG, the team determined that the test subject was able to perceive these sensations in his phantom hand.

The researchers then connected the e-dermis output to the volunteer by using a noninvasive method known as transcutaneous electrical nerve stimulation, or TENS. In a pain-detection task, the team determined that the test subject and the prosthesis were able to experience a natural, reflexive reaction to both pain while touching a pointed object and non-pain when touching a round object.

The e-dermis is not sensitive to temperature–for this study, the team focused on detecting object curvature (for touch and shape perception) and sharpness (for pain perception). The e-dermis technology could be used to make robotic systems more human, and it could also be used to expand or extend to astronaut gloves and space suits, Osborn says.

The researchers plan to further develop the technology and better understand how to provide meaningful sensory information to amputees in the hopes of making the system ready for widespread patient use.

Johns Hopkins is a pioneer in the field of upper limb dexterous prostheses. More than a decade ago, the university’s Applied Physics Laboratory led the development of the advanced Modular Prosthetic Limb, which an amputee patient controls with the muscles and nerves that once controlled his or her real arm or hand.

In addition to the funding from Space@Hopkins, which fosters space-related collaboration across the university’s divisions, the team also received grants from the Applied Physics Laboratory Graduate Fellowship Program and the Neuroengineering Training Initiative through the National Institute of Biomedical Imaging and Bioengineering through the National Institutes of Health under grant T32EB003383.

The e-dermis was tested over the course of one year on an amputee who volunteered in the Neuroengineering Laboratory at Johns Hopkins. The subject frequently repeated the testing to demonstrate consistent sensory perceptions via the e-dermis. The team has worked with four other amputee volunteers in other experiments to provide sensory feedback.

Here’s a video about this work,

Sarah Zhang’s June 20, 2018 article for The Atlantic reveals a few more details while covering some of the material in the news release,

Osborn and his team added one more feature to make the prosthetic hand, as he puts it, “more lifelike, more self-aware”: When it grasps something too sharp, it’ll open its fingers and immediately drop it—no human control necessary. The fingers react in just 100 milliseconds, the speed of a human reflex. Existing prosthetic hands have a similar degree of theoretically helpful autonomy: If an object starts slipping, the hand will grasp more tightly. Ideally, users would have a way to override a prosthesis’s reflex, like how you can hold your hand on a stove if you really, really want to. After all, the whole point of having a hand is being able to tell it what to do.

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

Prosthesis with neuromorphic multilayered e-dermis perceives touch and pain by Luke E. Osborn, Andrei Dragomir, Joseph L. Betthauser, Christopher L. Hunt, Harrison H. Nguyen, Rahul R. Kaliki, and Nitish V. Thakor. Science Robotics 20 Jun 2018: Vol. 3, Issue 19, eaat3818 DOI: 10.1126/scirobotics.aat3818

This paper is behind a paywall.

Bioelectronics: creating components that speak the body’s own language

Leave a reply

This is work is still in its early stages but the idea that the body could be stimulated to release more of its own pain relievers is exciting. From a Nov. 2, 2016 news item on ScienceDaily,

With a microfabricated ion pump built from organic electronic components, ions can be sent to nerve or muscle cells at the speed of the nervous system and with a precision of a single cell. “Now we can start to develop components that speak the body’s own language,” says Daniel Simon, head of bioelectronics research at the Laboratory of Organic Electronics, Linköping University, Campus Norrköping.

A Nov. 2, 2016 Linköping University press release (also on EurekAlert), which originated the news item, discusses the research in more detail,

Our nerve and muscle cells send signals to each other using ions and molecules. Certain substances, such as the neurotransmitter GABA (gamma aminobutyric acid), are important signal substances throughout the central nervous system. Eighteen months ago, researchers at the Laboratory of Organic Electronics demonstrated an ion pump which researchers at the Karolinska Institutet could use to reduce the sensation of pain in awake, freely-moving rats. The ion pump delivered GABA directly to the rat´s spinal cord. The news that researchers could deliver the body’s own neurotransmitters was published in Science Advances and garnered intense interest all over the world.

The research group at the Laboratory of Organic Electronics has now achieved another major advance and developed a significantly smaller and more rapid ion pump that transmits signals nearly as rapidly as the cells themselves, and with a precision on the scale of an individual cell. …

“Our skilled doctoral students, Amanda Jonsson and Theresia Arbring Sjöström, have succeeded with the last important part of the puzzle in the development of the ion pump. When a signal passes between two synapses it takes 1-10 milliseconds, and we are now very close to the nervous system’s own speed,” says Magnus Berggren, professor of organic electronics and director of the Laboratory of Organic Electronics.

“We conclude that we have produced artificial nerves that can communicate seamlessly with the nervous system. After more than 10 years’ research we have finally got all the parts of the puzzle in place,” he says.

Amanda Jonsson, who together with Theresia Arbring Sjöström is principal author of the article in Science Advances, has developed the pain-alleviating ion pump as part of her doctoral studies. She proudly presents a glass disk with many of the new miniaturized ion pumps. Some pumps have only a single outlet, but others have six tiny point outlets.

“We can make them with several outlets, it’s just as easy as making one. And all of the outlets can be individually controlled. Previously we could only transport ions horizontally and from all outputs at the same time. Now, however, we can deliver the ions vertically, which makes the distance they have to be transported as short as a micrometre,” she explains.

All of the outputs of the ion pump can also be rapidly switched on or off with the aid of micrometre-sized ion diodes.

“The ions are released rapidly by an electrical signal, in the same way that the neurotransmitter is released in a synapse,” says Theresia Arbring Sjöström.

Organic electronic components have a major advantage here: they can conduct both ions and electricity. In this case, the material PEDOT:PSS enables the electrical signals to be converted to chemical signals that the body understands.

The ion diode has recently been developed, as has the material that forms the basis of the new rapid ion pump.

“The new material makes it possible to build with a precision and reliability not possible in previous versions of the ion pump,” says Daniel Simon.

The new ion pump has so far only been tested in the laboratory. The next step will be to test it with live cells and the researchers hope eventually to, for example alleviate pain, stop epileptic seizures, and reduce the symptoms of Parkinsons disease, using exactly the required dose at exactly the affected cells. Communication using the cell´s own language, and the cell´s own speed.

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

Chemical delivery array with millisecond neurotransmitter release by Amanda Jonsson, Theresia Arbring Sjöström, Klas Tybrandt, Magnus Berggren, and Daniel T. Simon. Science Advances  02 Nov 2016: Vol. 2, no. 11, e1601340 DOI: 10.1126/sciadv.1601340

This paper is open access.

Westworld: a US television programme investigating AI (artificial intelligence) and consciousness

Leave a reply

The US television network, Home Box Office (HBO) is getting ready to première Westworld, a new series based on a movie first released in 1973. Here’s more about the movie from its Wikipedia entry (Note: Links have been removed),

Westworld is a 1973 science fiction Western thriller film written and directed by novelist Michael Crichton and produced by Paul Lazarus III about amusement park robots that malfunction and begin killing visitors. It stars Yul Brynner as an android in a futuristic Western-themed amusement park, and Richard Benjamin and James Brolin as guests of the park.

Westworld was the first theatrical feature directed by Michael Crichton.[3] It was also the first feature film to use digital image processing, to pixellate photography to simulate an android point of view.[4] The film was nominated for Hugo, Nebula and Saturn awards, and was followed by a sequel film, Futureworld, and a short-lived television series, Beyond Westworld. In August 2013, HBO announced plans for a television series based on the original film.

The latest version is due to start broadcasting in the US on Sunday, Oct. 2, 2016 and as part of the publicity effort the producers are profiled by Sean Captain for Fast Company in a Sept. 30, 2016 article,

As Game of Thrones marches into its final seasons, HBO is debuting this Sunday what it hopes—and is betting millions of dollars on—will be its new blockbuster series: Westworld, a thorough reimagining of Michael Crichton’s 1973 cult classic film about a Western theme park populated by lifelike robot hosts. A philosophical prelude to Jurassic Park, Crichton’s Westworld is a cautionary tale about technology gone very wrong: the classic tale of robots that rise up and kill the humans. HBO’s new series, starring Evan Rachel Wood, Anthony Hopkins, and Ed Harris, is subtler and also darker: The humans are the scary ones.

“We subverted the entire premise of Westworld in that our sympathies are meant to be with the robots, the hosts,” says series co-creator Lisa Joy. She’s sitting on a couch in her Burbank office next to her partner in life and on the show—writer, director, producer, and husband Jonathan Nolan—who goes by Jonah. …

Their Westworld, which runs in the revered Sunday-night 9 p.m. time slot, combines present-day production values and futuristic technological visions—thoroughly revamping Crichton’s story with hybrid mechanical-biological robots [emphasis mine] fumbling along the blurry line between simulated and actual consciousness.

Captain never does explain the “hybrid mechanical-biological robots.” For example, do they have human skin or other organs grown for use in a robot? In other words, how are they hybrid?

That nitpick aside, the article provides some interesting nuggets of information and insight into the themes and ideas 2016 Westworld’s creators are exploring (Note: A link has been removed),

… Based on the four episodes I previewed (which get progressively more interesting), Westworld does a good job with the trope—which focused especially on the awakening of Dolores, an old soul of a robot played by Evan Rachel Wood. Dolores is also the catchall Spanish word for suffering, pain, grief, and other displeasures. “There are no coincidences in Westworld,” says Joy, noting that the name is also a play on Dolly, the first cloned mammal.

The show operates on a deeper, though hard-to-define level, that runs beneath the shoot-em and screw-em frontier adventure and robotic enlightenment narratives. It’s an allegory of how even today’s artificial intelligence is already taking over, by cataloging and monetizing our lives and identities. “Google and Facebook, their business is reading your mind in order to advertise shit to you,” says Jonah Nolan. …

…

“Exist free of rules, laws or judgment. No impulse is taboo,” reads a spoof home page for the resort that HBO launched a few weeks ago. That’s lived to the fullest by the park’s utterly sadistic loyal guest, played by Ed Harris and known only as the Man in Black.

The article also features some quotes from scientists on the topic of artificial intelligence (Note: Links have been removed),

“In some sense, being human, but less than human, it’s a good thing,” says Jon Gratch, professor of computer science and psychology at the University of Southern California [USC]. Gratch directs research at the university’s Institute for Creative Technologies on “virtual humans,” AI-driven onscreen avatars used in military-funded training programs. One of the projects, SimSensei, features an avatar of a sympathetic female therapist, Ellie. It uses AI and sensors to interpret facial expressions, posture, tension in the voice, and word choices by users in order to direct a conversation with them.

“One of the things that we’ve found is that people don’t feel like they’re being judged by this character,” says Gratch. In work with a National Guard unit, Ellie elicited more honest responses about their psychological stresses than a web form did, he says. Other data show that people are more honest when they know the avatar is controlled by an AI versus being told that it was controlled remotely by a human mental health clinician.

…

“If you build it like a human, and it can interact like a human. That solves a lot of the human-computer or human-robot interaction issues,” says professor Paul Rosenbloom, also with USC’s Institute for Creative Technologies. He works on artificial general intelligence, or AGI—the effort to create a human-like or human level of intellect.

Rosenbloom is building an AGI platform called Sigma that models human cognition, including emotions. These could make a more effective robotic tutor, for instance, “There are times you want the person to know you are unhappy with them, times you want them to know that you think they’re doing great,” he says, where “you” is the AI programmer. “And there’s an emotional component as well as the content.”

Achieving full AGI could take a long time, says Rosenbloom, perhaps a century. Bernie Meyerson, IBM’s chief innovation officer, is also circumspect in predicting if or when Watson could evolve into something like HAL or Her. “Boy, we are so far from that reality, or even that possibility, that it becomes ludicrous trying to get hung up there, when we’re trying to get something to reasonably deal with fact-based data,” he says.

Gratch, Rosenbloom, and Meyerson are talking about screen-based entities and concepts of consciousness and emotions. Then, there’s a scientist who’s talking about the difficulties with robots,

…

… Ken Goldberg, an artist and professor of engineering at UC [University of California] Berkeley, calls the notion of cyborg robots in Westworld “a pretty common trope in science fiction.” (Joy will take up the theme again, as the screenwriter for a new Battlestar Galactica movie.) Goldberg’s lab is struggling just to build and program a robotic hand that can reliably pick things up. But a sympathetic, somewhat believable Dolores in a virtual setting is not so farfetched.

Captain delves further into a thorny issue,

“Can simulations, at some point, become the real thing?” asks Patrick Lin, director of the Ethics + Emerging Sciences Group at California Polytechnic State University. “If we perfectly simulate a rainstorm on a computer, it’s still not a rainstorm. We won’t get wet. But is the mind or consciousness different? The jury is still out.”

…

While artificial consciousness is still in the dreamy phase, today’s level of AI is serious business. “What was sort of a highfalutin philosophical question a few years ago has become an urgent industrial need,” says Jonah Nolan. It’s not clear yet how the Delos management intends, beyond entrance fees, to monetize Westworld, although you get a hint when Ford tells Theresa Cullen “We know everything about our guests, don’t we? As we know everything about our employees.”

AI has a clear moneymaking model in this world, according to Nolan. “Facebook is monetizing your social graph, and Google is advertising to you.” Both companies (and others) are investing in AI to better understand users and find ways to make money off this knowledge. …

As my colleague David Bruggeman has often noted on his Pasco Phronesis blog, there’s a lot of science on television.

For anyone who’s interested in artificial intelligence and the effects it may have on urban life, see my Sept. 27, 2016 posting featuring the ‘One Hundred Year Study on Artificial Intelligence (AI100)’, hosted by Stanford University.

Points to anyone who recognized Jonah (Jonathan) Nolan as the producer for the US television series, Person of Interest, a programme based on the concept of a supercomputer with intelligence and personality and the ability to continuously monitor the population 24/7.

Opioid addiction and nanotechnology in Pennsylvania, US

2 Replies

Combating a drug addiction ‘crisis’ with a nanotechnology-enabled solution is the main topic although the technology is being implemented for another problem first according to this May 4, 2016 article by John Luciew for pennlive.com (Note: Links have been removed),

Treating pain is a constant in medicine. It’s part of the human condition, known as the “fifth vital sign” among physicians. Effectively treating pain will continue to play a central role in medicine, despite the societal shock waves brought on by the rapid rise in opioid addiction across America.

The fallout from our nation’s opioid addiction crisis is roiling the medical and pharmaceutical industries, where regulatory action is rapidly reining in opioid painkiller prescriptions with new guidelines and stricter controls.

…

By harnessing nanotechnology and small-particles physics, Iroko Pharmaceuticals is developing a new class of low-dose prescription painkillers. Company executives say their line of nonsteroidal anti-inflammatory drugs could be the opioid alternative that the medical community has been looking for amid America’s addiction crisis.

The pharmaceutical company is Pennsylvania-based (US) and it isn’t tackling the ‘opioid addiction crisis’ yet. First, there’s this,

Its new line of prescription painkillers are predicated upon a highly patented process of pulverizing drug molecules so they are up to 100 times smaller, which markedly increases their pain-killing effectiveness at dramatically lower doses.

Right now, Iroko is focusing this nanotechnology on creating a full line of low-dose prescription painkillers based upon the class of drugs known as nonsteroidal anti-inflammatories, or NSAIDs. There are six NSAID molecules, the most common being Ibuprofen. Iroko is planning nanotechnology technology versions for all six NSAID molecules, three of which have already received approval from the Food and Drug Administration.

Luciew has done some homework on the technology,

“We solved a chemistry problem by using physics,” explained Iroko Chairman Osagie Imasogie, who founded the company [Iroko Pharmaceuticals] in 2007.

Yet, the company that actually solved the physics problem was iCeutica, founded in Australia and now based in King of Prussia, Pa.

iCeutica owns the patented SoluMatrix fine particle process that pulverizes drug molecules into nano-sized particles, enabling low doses of a drug to be better absorbed by the body, thus providing faster and far more effective pain relief.

Of course, the practice of crushing and grinding drug powders is as old as the pharmacist’s mortar and pestle. But there’s never been a way of pulverizing a drug molecule into nano particles that was scalable for industrial production — not until iCeutica created its SoluMatrix process, that is.

iCeutica provides a description of the technology on its SoluMatrix webpage,

iCeutica’s proprietary SoluMatrix™ Fine Particle Technology fuels new product development and solves problems of bioavailability, variability, side effects and delivery of marketed or development-stage pharmaceuticals.

The SoluMatrix technology is a scaleable and cost-effective manufacturing process that can produce submicron-sized drug particles that are 10 to 200 times smaller than conventional drug particles. The particles generated using this technology, which both grinds the drug particles into a superfine powder and protects those submicron particles from subsequent agglomeration (or clumping together into big particles), comprise a single unit operation and can be manufactured into tablets, capsules and other dosage forms without further processing.

…

The SoluMatrix technology improves the performance of pharmaceuticals by dramatically changing how the drug dissolves and is absorbed. By making submicron-sized particles of a drug, it is possible to:

Unfortunately there aren’t more details. I’m somewhat puzzled  by the submicron measurement why not state the size using the term nanometre?

Getting back  to Iroko, Imasogie, impressed with the SoluMatrix technology, has made a major investment in iCeutica and is chair of iCeutica’s board. His homebase company, Iroko holds exclusive global rights to SoluMatrix.

Luciew’s article describes the current situation in the NSAID market,

Iroko officials acknowledge that NSAID painkillers carry their own health risks, including the potential for stomach ulcers, kidney problems and cardio-vascular ailments, up to and including stroke and heart attack. The fears associated with NSAIDs peaked a decade ago with the Vioxx case, a popular prescription NSAID that was eventually taken off the market due to associated cardiac and other risks.

The latest FDA guidelines for NSAID use calls for the lowest effective dose, which precisely describes the nanotechnology-driven low-dose NSAID drugs Iroko is rolling out. What is more, due to the ongoing opioid crisis, both the FDA and the Centers for Disease Control are heavily emphasizing non-opioid alternatives for pain relief, further opening to door for Iroko’s pain products.

That said about the issues with NSAIDs, Luciew outlines Iroko’s current offerings and explains what makes this technology so attractive,

According to Imasogie, Iroko’s line of low-dose, nanotechnology NSAIDs fits both sets of regulatory safety criteria. The new drugs are the lowest effective dose for NSAIDs, and are a viable pain-killing alternative to opioids, especially when it comes to treating osteoarthritis and other moderate pain.

“No one is going to give an NSAID if you have cancer,” Imasogie says. “But for chronic low back pain, yes.”

Three of Iroko’s six low-dose NSAID offerings have already received FDA approval and are on the market:

  • Zorvolex (diclofenac), approved in October 2013 for the management of mild to moderate acute pain in adults and in August 2014 for the management of osteoarthritis pain.
  • Tivorbex, approved in February 2014 for treatment of mild to moderate acute pain in adults.
  • Vivlodex, approved in October 2015 as another option for treatment of osteoarthritis pain. Three more of Iroko’s low-dose NSAIDs are awaiting approval.

These nano drugs are effective at doses of 35 to 40 milligrams to as low as 10 milligrams, the company says. That’s compared to other NSAID doses that start at 200 milligrams. As a result, Iroko’s low-dose NSAID drugs are being marketed as providing a prescription alternative to opioids at the precise moment everyone from the White House to the white-coat-clad family physician is searching for one.

If you the have time and interest, I encourage you to read Luciew’s article in its entirety. He covers more market issues and includes an enbedded video in his piece.

One last note about Iroko Pharmaceuticals, the company is named after a tree found on the African continent and executives of the company have hinted they are experimenting with SoluMatrix to make low-dose opioids available in the future.

While I have my doubts about the opioid addiction ‘crisis’, I do believe that lower, more effective doses of painkillers, regardless of their drug class, can only benefit patients.

Arbro Pharmaceuticals and its bioavailable curcumin

Leave a reply

Curcumin (a constituent of the spice turmeric) is reputed to have health benefits and has been used in traditional medicine in Asia (notably India) for millenia. Recently scientists have been trying to render curcumin more effective which means increasing its bioavailability (my Nov. 7, 2014 posting features some of that research). According to an April 29, 2016 Arbro Pharmaceuticals press release, the goal of increased bioavailability has been reached and a product is now available commercially,

Arbro Pharmaceuticals has launched SNEC30, a patented highly bioavailable self-nanoemulsifying curcumin formulation in the dosage of 30mg.

Curcumin is the active ingredient of turmeric or haldi, which has been widely used in traditional medicine and home remedies in India for hundreds of years.

Clinical research conducted over the last 25 years has shown curcumin to be effective against various diseases like cancer, pain, inflammation, arthritis, ulcers, psoriasis, arteriosclerosis, diabetes and many more pro-inflammatory conditions.

Despite its effectiveness against so many medical conditions, scientists have come to believe that curcumin’s true potential has been limited by its poor bioavailability which is caused by the fact that it has poor solubility and extensive pre-systemic metabolism.

Arbro Pharmaceuticals partnered with Jamia Hamdard University to carry out research and develop a novel formulation, which can overcome curcumin’s poor bioavailability. The development project was jointly funded by Arbro and the Department of Science and Technology, Government of India under its DPRP (Drug and Pharmaceutical Research Programme) scheme.

SNEC30 is the outcome of this joint research and is based on a novel self-nanoemulsifying drug delivery systems (SNEDDS) for which patents have been filed and the US patent has been granted.

“There has been tremendous interest in the therapeutic potential of curcumin but its poor bioavailability was a limiting factor, our research group together with Arbro took the challenge and applied nanotechnology to overcome this limitation and achieve highest ever bioavailability for curcumin,” said Dr. Kanchan Kohli, Asst. Prof, Faculty of Pharmacy, Jamia Hamdard University, who is one of the main developers of the formulation.

Nanotechnology is the engineering of functional systems at the molecular scale (CRN – Centre for Responsible Nanotechnology). The name stems from the fact that the structures are in the nano-metre (10-9 mm) in range. In pharmaceutics, nano-formulations are used for targeted drug-delivery, particularly in cancer therapy. It also finds numerous other applications in medicine.

“Just 30mg of curcumin that is contained in one capsule of SNEC30 has shown higher blood levels than what can be achieved by consuming the curcumin content of 1kg of raw haldi or turmeric,” said Mr. Vijay Kumar Arora, Managing Director, Arbro Pharmaceuticals.

About Arbro Pharmaceuticals:

Arbro Pharmaceuticals is a 30-year-old research oriented company with its own research and development, testing and manufacturing facilities. Arbro has been manufacturing and exporting hundreds of formulations under its own brand name to more than 10 countries.

I am not endorsing this product but if you are interested the SNEC30 website is here. I believe Arbro Pharmaceuticals’ headquarters, the company which produces SNEC30, are located in India.

Café Scientifique (Vancouver, Canada) hosts ‘pain’ talk on Sept. 29, 2015

Leave a reply

The first Café Scientifique (Vancouver, Canada edition) event of the fall will feature a previously postponed (due to one of the speakers becoming a father) talk on pain.

On Tuesday, September 29, 2015  Café Scientifique, held in the back room of The Railway Club (2nd floor of 579 Dunsmuir St. [at Seymour St.]), will be hosting a talk on pain: the good and the bad (from the April 13, 2015 and Sept. 7, 2015 announcements),

Our speakers for the evening will be Dr. Matthew Ramer and Dr. John Kramer.  The title of their talk is:

Knowing Pains: How can we study pain to better treat it?

Pain is arguably the most useful of sensations.  It is nature’s way of telling us to stop doing whatever it is we are doing in order to prevent damage, and to protect injured body parts during the healing process.  In the absence of pain (in certain congenital conditions and in advanced diabetes, for example), the consequence can be loss of limbs and even of life.

There are circumstances, however, when pain serves no useful purpose:  it persists when the injury has healed or occurs in the absence of any frank tissue damage, and is inappropriate in context (previously innocuous stimuli become painful) and magnitude (mildly painful stimuli become excruciating).  This is called neuropathic pain and is incredibly difficult to treat because it is unresponsive to all of the drugs we use to treat normal, useful (“acute”) pain.

Ultimately, our research is aimed at finding new ways to minimise suffering from neuropathic pain.  Prerequisites to this goal include understanding how normal and neuropathic pain are encoded and perceived by the nervous system, and accurately measuring and quantifying pain so that we can draw reasonable conclusions about whether or not a particular treatment is effective.  We will discuss some historical and current ideas of how pain is transmitted from body to brain, and emphasize that the pain “channel” is not hard-wired, but like the process of learning, it is plastic, labile, and subject to “top-down” control.  We will also tackle the contentious issue of pain measurement in the clinic and laboratory.*

Both speakers are from iCORD (International Collaboration On Repair Discoveries), an interdisciplinary research centre focused on spinal cord injury located at Vancouver General Hospital. There’s more about Dr. Matt Ramer here and Dr. John Kramer here.

BTW, Dr. Kramer is the new father.

On the verge of controlling neurons by wireless?

Leave a reply

Scientists have controlled a mouse’s neurons with a wireless device (and unleashed some paranoid fantasies? well, mine if no one else’s) according to a July 16, 2015 news item on Nanowerk (Note: A link has been removed),

A study showed that scientists can wirelessly determine the path a mouse walks with a press of a button. Researchers at the Washington University School of Medicine, St. Louis, and University of Illinois, Urbana-Champaign, created a remote controlled, next-generation tissue implant that allows neuroscientists to inject drugs and shine lights on neurons deep inside the brains of mice. The revolutionary device is described online in the journal Cell (“Wireless Optofluidic Systems for Programmable In Vivo Pharmacology and Optogenetics”). Its development was partially funded by the [US] National Institutes of Health [NIH].

The researchers have made an image/illustration of the probe available,

Mind Bending Probe Scientists used soft materials to create a brain implant a tenth the width of a human hair that can wirelessly control neurons with lights and drugs. Courtesy of Jeong lab, University of Colorado Boulder.

A July 16, 2015 US NIH National Institute of Neurological Disorders and Stroke news release, which originated the news item, describes the study and notes that instructions for building the implant are included in the published study,

“It unplugs a world of possibilities for scientists to learn how brain circuits work in a more natural setting.” said Michael R. Bruchas, Ph.D., associate professor of anesthesiology and neurobiology at Washington University School of Medicine and a senior author of the study.

The Bruchas lab studies circuits that control a variety of disorders including stress, depression, addiction, and pain. Typically, scientists who study these circuits have to choose between injecting drugs through bulky metal tubes and delivering lights through fiber optic cables. Both options require surgery that can damage parts of the brain and introduce experimental conditions that hinder animals’ natural movements.

To address these issues, Jae-Woong Jeong, Ph.D., a bioengineer formerly at the University of Illinois at Urbana-Champaign, worked with Jordan G. McCall, Ph.D., a graduate student in the Bruchas lab, to construct a remote controlled, optofluidic implant. The device is made out of soft materials that are a tenth the diameter of a human hair and can simultaneously deliver drugs and lights.

“We used powerful nano-manufacturing strategies to fabricate an implant that lets us penetrate deep inside the brain with minimal damage,” said John A. Rogers, Ph.D., professor of materials science and engineering, University of Illinois at Urbana-Champaign and a senior author. “Ultra-miniaturized devices like this have tremendous potential for science and medicine.”

With a thickness of 80 micrometers and a width of 500 micrometers, the optofluidic implant is thinner than the metal tubes, or cannulas, scientists typically use to inject drugs. When the scientists compared the implant with a typical cannula they found that the implant damaged and displaced much less brain tissue.

The scientists tested the device’s drug delivery potential by surgically placing it into the brains of mice. In some experiments, they showed that they could precisely map circuits by using the implant to inject viruses that label cells with genetic dyes. In other experiments, they made mice walk in circles by injecting a drug that mimics morphine into the ventral tegmental area (VTA), a region that controls motivation and addiction.

The researchers also tested the device’s combined light and drug delivery potential when they made mice that have light-sensitive VTA neurons stay on one side of a cage by commanding the implant to shine laser pulses on the cells. The mice lost the preference when the scientists directed the device to simultaneously inject a drug that blocks neuronal communication. In all of the experiments, the mice were about three feet away from the command antenna.

“This is the kind of revolutionary tool development that neuroscientists need to map out brain circuit activity,” said James Gnadt, Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).  “It’s in line with the goals of the NIH’s BRAIN Initiative.”

The researchers fabricated the implant using semi-conductor computer chip manufacturing techniques. It has room for up to four drugs and has four microscale inorganic light-emitting diodes. They installed an expandable material at the bottom of the drug reservoirs to control delivery. When the temperature on an electric heater beneath the reservoir rose then the bottom rapidly expanded and pushed the drug out into the brain.

“We tried at least 30 different prototypes before one finally worked,” said Dr. McCall.

“This was truly an interdisciplinary effort,” said Dr. Jeong, who is now an assistant professor of electrical, computer, and energy engineering at University of Colorado Boulder. “We tried to engineer the implant to meet some of neurosciences greatest unmet needs.”

In the study, the scientists provide detailed instructions for manufacturing the implant.

“A tool is only good if it’s used,” said Dr. Bruchas. “We believe an open, crowdsourcing approach to neuroscience is a great way to understand normal and healthy brain circuitry.”

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

Wireless Optofluidic Systems for Programmable In Vivo Pharmacology and Optogenetics by Jae-Woong Jeong, Jordan G. McCall, Gunchul Shin, Yihui Zhang, Ream Al-Hasani, Minku Kim, Shuo Li, Joo Yong Sim, Kyung-In Jang, Yan Shi, Daniel Y. Hong, Yuhao Liu, Gavin P. Schmitz, Li Xia, Zhubin He, Paul Gamble, Wilson Z. Ray, Yonggang Huang, Michael R. Bruchas, and John A. Rogers.  Cell, July 16, 2015. DOI: 10.1016/j.cell.2015.06.058

This paper is behind a paywall.

I last wrote about wireless activation of neurons in a May 28, 2014 posting which featured research at the University of Massachusetts Medical School.

Pain in your blood—converting blood cells to neurons at McMaster University (Canada)

Leave a reply

Having once spent several months doing a literature search on pain and morphine, I have a particular interest in this breakthrough from McMaster University (Canada) announced in a May 21, 2015 news item on ScienceDaily,

Scientists at McMaster University have discovered how to make adult sensory neurons from human patients simply by having them roll up their sleeve and providing a blood sample.

Specifically, stem cell scientists at McMaster can now directly convert adult human blood cells to both central nervous system (brain and spinal cord) neurons as well as neurons in the peripheral nervous system (rest of the body) that are responsible for pain, temperature and itch perception. This means that how a person’s nervous system cells react and respond to stimuli, can be determined from his blood.

A May 21, 2015 McMaster University news release on EurekAlert, which originated the news item, describes why this will make a difference for pain management,

Currently, scientists and physicians have a limited understanding of the complex issue of pain and how to treat it. The peripheral nervous system is made up of different types of nerves – some are mechanical (feel pressure) and others detect temperature (heat). In extreme conditions, pain or numbness is perceived by the brain using signals sent by these peripheral nerves.

“The problem is that unlike blood, a skin sample or even a tissue biopsy, you can’t take a piece of a patient’s neural system. It runs like complex wiring throughout the body and portions cannot be sampled for study,” said Bhatia [Mick Bhatia, director of the McMaster Stem Cell and Cancer Research Institute and much more].

“Now we can take easy to obtain blood samples, and make the main cell types of neurological systems – the central nervous system and the peripheral nervous system – in a dish that is specialized for each patient,” said Bhatia. “Nobody has ever done this with adult blood. Ever.

“We can actually take a patient’s blood sample, as routinely performed in a doctor’s office, and with it we can produce one million sensory neurons, that make up the peripheral nerves in short order with this new approach. We can also make central nervous system cells, as the blood to neural conversion technology we developed creates neural stem cells during the process of conversion.”

His team’s revolutionary, patented direct conversion technology has “broad and immediate applications,” said Bhatia, adding that it allows researchers to start asking questions about understanding disease and improving treatments such as: Why is it that certain people feel pain versus numbness? Is this something genetic? Can the neuropathy that diabetic patients experience be mimicked in a dish?

It also paves the way for the discovery of new pain drugs that don’t just numb the perception of pain. Bhatia said non-specific opioids used for decades are still being used today.

“If I was a patient and I was feeling pain or experiencing neuropathy, the prized pain drug for me would target the peripheral nervous system neurons, but do nothing to the central nervous system, thus avoiding non-addictive drug side effects,” said Bhatia.

“You don’t want to feel sleepy or unaware, you just want your pain to go away. But, up until now, no one’s had the ability and required technology to actually test different drugs to find something that targets the peripheral nervous system and not the central nervous system in a patient specific, or personalized manner.”

Bhatia’s team successfully tested their process using fresh blood, but also cryopreserved (frozen) blood. Since blood samples are taken and frozen with many clinical trials, this allows them “almost a bit of a time machine” to go back and explore questions around pain or neuropathy to run tests on neurons created from blood samples of patients taken in past clinical trials where responses and outcomes have already been recorded”.

In the future, the process may have prognostic potential, explained Bhatia, in that one might be able to look at a patient with Type 2 Diabetes and predict whether they will experience neuropathy by running tests in the lab using their own neural cells derived from their blood sample.

“This bench to bedside research is very exciting and will have a major impact on the management of neurological diseases, particularly neuropathic pain,” said Akbar Panju, medical director of the Michael G. DeGroote Institute for Pain Research and Care, a clinician and professor of medicine.

“This research will help us understand the response of cells to different drugs and different stimulation responses, and allow us to provide individualized or personalized medical therapy for patients suffering with neuropathic pain.”

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

Single Transcription Factor Conversion of Human Blood Fate to NPCs with CNS and PNS Developmental Capacity by Jong-Hee Lee, Ryan R. Mitchell, Jamie D. McNicol, Zoya Shapovalova, Sarah Laronde, Borko Tanasijevic, Chloe Milsom, Fanny Casado, Aline Fiebig-Comyn, Tony J. Collins, Karun K. Singh, and Mickie Bhatia.
Publication stage: In Press Corrected Proof Open Access DOI: http://dx.doi.org/10.1016/j.celrep.2015.04.056 Open access funded by the Author(s)

This is an open access paper. h/t Speaking Up For Science May 21, 2015 item

Three Vancouver (Canada) science events: Vancouver Public Library on April 27, 2015, Café Scientifique on April 28, 2015, and the Wall Exchange on May 26, 2015

Leave a reply

Monday, April 27, 2015, 7:00 pm – 8:30 pm is a combined bee/poetry event at the main branch of the Vancouver Public Library. From the Vancouver Public Library “Honey, Hives, and Poetry in the City” event page,

Celebrate National Poetry Month by investigating food and poetry as a means of cultural and social activism and community building. Featured will be:

  • Rachel Rose, Poet Laureate of Vancouver
  • A collaborative reading by scientist and author Mark L. Winston (Bee Time: Lessons from the Hive) and award winning poet Renee Sarojini Saklikar (Children of Air India)
  • Readings from author and poet Elee Kraljii Gardiner and the Thursdays Writing Collective.
  • Presentation and honey tasting with Hives for Humanity.

Location:

Address: 350 West Georgia St.
VancouverV6B 6B1

  • Phone:

Location Details: Alice MacKay Room, Lower Level

[ETA April 21, 2015 at 1000 PST: I’ve just embedded a video which launches a new year of Science Rap Academy (Tom McFadden) in my April 21, 2015 post titled: Please, don’t kill my hive! (a Science Rap Academy production).]

*Change of Speaker for April 28, 2015  Café Scientifique, see Café Scientifique (Vancouver, Canada) makes a ‘happy’ change: new speaker for April 28, 2015 posting.”*

The day after the bee/poetry event, Tuesday, April 28, 2015  Café Scientifique, held in the back room of The Railway Club (2nd floor of 579 Dunsmuir St. [at Seymour St.], will be hosting a talk on pain (from the April 13, 2015 announcement,

Our speakers for the evening will be Dr. Matthew Ramer and Dr. John Kramer.  The title of their talk is:

Knowing Pains: How can we study pain to better treat it?

Pain is arguably the most useful of sensations.  It is nature’s way of telling us to stop doing whatever it is we are doing in order to prevent damage, and to protect injured body parts during the healing process.  In the absence of pain (in certain congenital conditions and in advanced diabetes, for example), the consequence can be loss of limbs and even of life.

There are circumstances, however, when pain serves no useful purpose:  it persists when the injury has healed or occurs in the absence of any frank tissue damage, and is inappropriate in context (previously innocuous stimuli become painful) and magnitude (mildly painful stimuli become excruciating).  This is called neuropathic pain and is incredibly difficult to treat because it is unresponsive to all of the drugs we use to treat normal, useful (“acute”) pain.

Ultimately, our research is aimed at finding new ways to minimise suffering from neuropathic pain.  Prerequisites to this goal include understanding how normal and neuropathic pain are encoded and perceived by the nervous system, and accurately measuring and quantifying pain so that we can draw reasonable conclusions about whether or not a particular treatment is effective.  We will discuss some historical and current ideas of how pain is transmitted from body to brain, and emphasize that the pain “channel” is not hard-wired, but like the process of learning, it is plastic, labile, and subject to “top-down” control.  We will also tackle the contentious issue of pain measurement in the clinic and laboratory.*

Both speakers are from iCORD (International Collaboration On Repair Discoveries), an interdisciplinary research centre focused on spinal cord injury located at Vancouver General Hospital. There’s more about Dr. Matt Ramer here and Dr. John Kramer here.

*Change of Speaker for April 28, 2015  Café Scientifique, see Café Scientifique (Vancouver, Canada) makes a ‘happy’ change: new speaker for April 28, 2015 posting.”*

The Wall Institute for Advanced Studies is bringing Dr. Bonnie Bassler, the bacteria whisperer, to speak in Vancouver. From the Wall Exchange series event page,

Dr. Bonnie Bassler, Molecular Biology, Princeton University

The Secret Social Lives of Bacteria

May 26, 2015
7:30 pm. Doors open at 6:30 pm.
Vogue Theatre, 918 Granville Street, Vancouver

Tickets available online, 2015 or by calling the Vogue Theatre Box Office: 604-569-1144

Learn more:

Bacterial behaviour may hold key to combatting antibiotic resistance
The Wall Papers

Here are some more details about the tickets, the event, and the speaker from the Northern Tickets event page,

Bonnie Bassler
The Secret, Social Lives of Bacteria
Vogue Theatre
Tuesday May 26th, 2015
Doors 6:30PM, Begins 7:30PM
Free Entry
**Tickets must be redeemed by 7:15PM to be valid**

Dr. Bonnie Bassler is an investigator with the Howard Hughes Medical Institute and Squibb Professor and Chair of the Department of Molecular Biology at Princeton University. The research in Dr. Bassler’s laboratory focuses on the chemical signaling mechanisms that bacteria use to communicate with each other known as “quorum sensing.” Therapies that block quorum sensing activity may represent an important new strategy for combating bacterial infections. Her research reveals new insights into the basic biology and ecology of bacteria; findings that may have direct application in the future treatment of disease.
…
Vogue Theatre
918 Granville Street – Vancouver

Go forth and enjoy!

* Removed ‘,t’ at very end of Café Scientifique excerpt on April 24, 2015.

Graphene-based sensor mimics pain (mu-opioid) receptor

Leave a reply

I once had a job where I had to perform literature searches and read papers on pain research as it related to morphine tolerance. Not a pleasant task, it has left me eager to encourage and write about alternatives to animal testing, a key component of pain research. So, with a ‘song in my heart’, I feature this research from the University of Pennsylvania written up in a May 12, 2014 news item on ScienceDaily,

Almost every biological process involves sensing the presence of a certain chemical. Finely tuned over millions of years of evolution, the body’s different receptors are shaped to accept certain target chemicals. When they bind, the receptors tell their host cells to produce nerve impulses, regulate metabolism, defend the body against invaders or myriad other actions depending on the cell, receptor and chemical type.

Now, researchers from the University of Pennsylvania have led an effort to create an artificial chemical sensor based on one of the human body’s most important receptors, one that is critical in the action of painkillers and anesthetics. In these devices, the receptors’ activation produces an electrical response rather than a biochemical one, allowing that response to be read out by a computer.

By attaching a modified version of this mu-opioid receptor to strips of graphene, they have shown a way to mass produce devices that could be useful in drug development and a variety of diagnostic tests. And because the mu-opioid receptor belongs to the most common class of such chemical sensors, the findings suggest that the same technique could be applied to detect a wide range of biologically relevant chemicals.

A May 6, 2014 University of Pennsylvania news release, which originated the news item, describes the main teams involved in this research along with why and how they worked together (Note: Links have been removed),

The study, published in the journal Nano Letters, was led by A.T. Charlie Johnson, director of Penn’s Nano/Bio Interface Center and professor of physics in Penn’s School of Arts & Sciences; Renyu Liu, assistant professor of anesthesiology in Penn’s Perelman School of Medicine; and Mitchell Lerner, then a graduate student in Johnson’s lab. It was made possible through a collaboration with Jeffery Saven, professor of chemistry in Penn Arts & Sciences. The Penn team also worked with researchers from the Seoul National University in South Korea.

Their study combines recent advances from several disciplines.

Johnson’s group has extensive experience attaching biological components to nanomaterials for use in chemical detectors. Previous studies have involved wrapping carbon nanotubes with single-stranded DNA to detect odors related to cancer and attaching antibodies to nanotubes to detect the presence of the bacteria associated with Lyme disease.

After Saven and Liu addressed these problems with the redesigned receptor, they saw that it might be useful to Johnson, who had previously published a study on attaching a similar receptor protein to carbon nanotubes. In that case, the protein was difficult to grow genetically, and Johnson and his colleagues also needed to include additional biological structures from the receptors’ natural membranes in order to keep them stable.

In contrast, the computationally redesigned protein could be readily grown and attached directly to graphene, opening up the possibility of mass producing biosensor devices that utilize these receptors.

“Due to the challenges associated with isolating these receptors from their membrane environment without losing functionality,” Liu said, “the traditional methods of studying them involved indirectly investigating the interactions between opioid and the receptor via radioactive or fluorescent labeled ligands, for example. This multi-disciplinary effort overcame those difficulties, enabling us to investigate these interactions directly in a cell free system without the need to label any ligands.”

…

With Saven and Liu providing a version of the receptor that could stably bind to sheets of graphene, Johnson’s team refined their process of manufacturing those sheets and connecting them to the circuitry necessary to make functional devices.

The news release provides more technical details about the graphene sensor,

“We start by growing a piece of graphene that is about six inches wide by 12 inches long,” Johnson said. “That’s a pretty big piece of graphene, but we don’t work with the whole thing at once. Mitchell Lerner, the lead author of the study, came up with a very clever idea to cut down on chemical contamination. We start with a piece that is about an inch square, then separate them into ribbons that are about 50 microns across.

“The nice thing about these ribbons is that we can put them right on top of the rest of the circuitry, and then go on to attach the receptors. This really reduces the potential for contamination, which is important because contamination greatly degrades the electrical properties we measure.”

Because the mechanism by which the device reports on the presence of the target molecule relies only on the receptor’s proximity to the nanostructure when it binds to the target, Johnson’s team could employ the same chemical technique for attaching the antibodies and other receptors used in earlier studies.

Once attached to the ribbons, the opioid receptors would produce changes in the surrounding graphene’s electrical properties whenever they bound to their target. Those changes would then produce electrical signals that would be transmitted to a computer via neighboring electrodes.

The high reliability of the manufacturing process — only one of the 193 devices on the chip failed — enables applications in both clinical diagnostics and further research. [emphasis mine]

“We can measure each device individually and average the results, which greatly reduces the noise,” said Johnson. “Or you could imagine attaching 10 different kinds of receptors to 20 devices each, all on the same chip, if you wanted to test for multiple chemicals at once.”

In the researchers’ experiment, they tested their devices’ ability to detect the concentration of a single type of molecule. They used naltrexone, a drug used in alcohol and opioid addiction treatment, because it binds to and blocks the natural opioid receptors that produce the narcotic effects patients seek.

“It’s not clear whether the receptors on the devices are as selective as they are in the biological context,” Saven said, “as the ones on your cells can tell the difference between an agonist, like morphine, and an antagonist, like naltrexone, which binds to the receptor but does nothing. By working with the receptor-functionalized graphene devices, however, not only can we make better diagnostic tools, but we can also potentially get a better understanding of how the bimolecular system actually works in the body.”

“Many novel opioids have been developed over the centuries,” Liu said. “However, none of them has achieved potent analgesic effects without notorious side effects, including devastating addiction and respiratory depression. This novel tool could potentially aid the development of new opioids that minimize these side effects.”

Wherever these devices find applications, they are a testament to the potential usefulness of the Nobel-prize winning material they are based on.

“Graphene gives us an advantage,” Johnson said, “in that its uniformity allows us to make 192 devices on a one-inch chip, all at the same time. There are still a number of things we need to work out, but this is definitely a pathway to making these devices in large quantities.”

There is no mention of animal research but it seems likely to me that this work could lead to a decreased use of animals in pain research.

This project must have been quite something as it involved collaboration across many institutions (from the news release),

Also contributing to the study were Gang Hee Han, Sung Ju Hong and Alexander Crook of Penn Arts & Sciences’ Department of Physics and Astronomy; Felipe Matsunaga and Jin Xi of the Department of Anesthesiology at the Perelman School of Medicine, José Manuel Pérez-Aguilar of Penn Arts & Sciences’ Department of Chemistry; and Yung Woo Park of Seoul National University. Mitchell Lerner is now at SPAWAR Systems Center Pacific, Felipe Matsunaga at Albert Einstein College of Medicine, José Manuel Pérez-Aguilar at Cornell University and Sung Ju Hong at Seoul National University.

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

Scalable Production of Highly Sensitive Nanosensors Based on Graphene Functionalized with a Designed G Protein-Coupled Receptor by Mitchell B. Lerner, Felipe Matsunaga, Gang Hee Han, Sung Ju Hong, Jin Xi, Alexander Crook, Jose Manuel Perez-Aguilar, Yung Woo Park, Jeffery G. Saven, Renyu Liu, and A. T. Charlie Johnson.Nano Lett., Article ASAP
DOI: 10.1021/nl5006349 Publication Date (Web): April 17, 2014
Copyright © 2014 American Chemical Society

This paper is behind a paywall.