It seems researchers at the Toronto-based (Canada), Princess Margaret Cancer Centre, have developed a new theranostic tool made of microbubbles used for imaging that are then burst into nanoparticles delivering therapeutics. From a March 30, 2015 news item on phys.org,
Biomedical researchers led by Dr. Gang Zheng at Princess Margaret Cancer Centre have successfully converted microbubble technology already used in diagnostic imaging into nanoparticles that stay trapped in tumours to potentially deliver targeted, therapeutic payloads.
The discovery, published online today [March 30, 2015] in Nature Nanotechnology, details how Dr. Zheng and his research team created a new type of microbubble using a compound called porphyrin – a naturally occurring pigment in nature that harvests light.
In the lab in pre-clinical experiments, the team used low-frequency ultrasound to burst the porphyrin containing bubbles and observed that they fragmented into nanoparticles. Most importantly, the nanoparticles stayed within the tumour and could be tracked using imaging.
“Our work provides the first evidence that the microbubble reforms into nanoparticles after bursting and that it also retains its intrinsic imaging properties. We have identified a new mechanism for the delivery of nanoparticles to tumours, potentially overcoming one of the biggest translational challenges of cancer nanotechnology. In addition, we have demonstrated that imaging can be used to validate and track the delivery mechanism,” says Dr. Zheng, Senior Scientist at the Princess Margaret and also Professor of Medical Biophysics at the University of Toronto.
Conventional microbubbles, on the other hand, lose all intrinsic imaging and therapeutic properties once they burst, he says, in a blink-of-an-eye process that takes only a minute or so after bubbles are infused into the bloodstream.
“So for clinicians, harnessing microbubble to nanoparticle conversion may be a powerful new tool that enhances drug delivery to tumours, prolongs tumour visualization and enables them to treat cancerous tumours with greater precision.”
For the past decade, Dr. Zheng’s research focus has been on finding novel ways to use heat, light and sound to advance multi-modality imaging and create unique, organic nanoparticle delivery platforms capable of transporting cancer therapeutics directly to tumours.
Interesting development, although I suspect there are many challenges yet to be met such as ensuring the microbubbles consistently arrive at their intended destination in sufficient mass to be effective both for imaging purposes and, later, as nanoparticles for drug delivery purposes.
This paper is behind a paywall but a free preview is available via ReadCube Access.
This is one of those times where I’m including the funding agencies and the ‘About’ portions of the news release,
The research published today was funded by the Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarship, the Emerging Team Grant on Regenerative Medicine and Nanomedicine co-funded by the CIHR and the Canadian Space Agency, the Natural Sciences and Engineering Research Council of Canada, the Ontario Institute for Cancer Research, the International Collaborative R&D Project of the Ministry of Knowledge Economy, South Korea, the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research, the Canada Foundation for Innovation and The Princess Margaret Cancer Foundation.
About Princess Margaret Cancer Centre, University Health Network
The Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital and Toronto Rehabilitation Institute. All are research hospitals affiliated with the University of Toronto. For more information, go to http://www.theprincessmargaret.ca or http://www.uhn.ca .
I was not expecting to see South Korea or Brazil mentioned in the funding. Generally, when multiple countries are funding research, their own research institutions are also involved. As for the Princess Margaret Cancer Centre being one of the top five such centres internationally, I wonder how these rankings are determined.
As nanotechnology makes possible a world of machines too tiny to see, researchers are finding ways to combine living organisms with nonliving machinery to solve a variety of problems.
Like other first-generation bio-robots, the new nanobot engineered at the University of Illinois at Chicago [UIC] is a far cry from Robocop. It’s a robotic germ.
UIC researchers created an electromechanical device–a humidity sensor–on a bacterial spore. They call it NERD, for Nano-Electro-Robotic Device. …
“We’ve taken a spore from a bacteria, and put graphene quantum dots on its surface–and then attached two electrodes on either side of the spore,” said Vikas Berry, UIC associate professor of chemical engineering and principal investigator on the study.
“Then we change the humidity around the spore,” he said.
When the humidity drops, the spore shrinks as water is pushed out. As it shrinks, the quantum dots come closer together, increasing their conductivity, as measured by the electrodes.
“We get a very clean response–a very sharp change the moment we change humidity,” Berry said. The response was 10 times faster, he said, than a sensor made with the most advanced man-made water-absorbing polymers.
There was also better sensitivity in extreme low-pressure, low-humidity situations.
“We can go all the way down to a vacuum and see a response,” said Berry, which is important in applications where humidity must be kept low, for example, to prevent corrosion or food spoilage. “It’s also important in space applications, where any change in humidity could signal a leak,” he said.
Currently available sensors increase in sensitivity as humidity rises, Berry said. NERD’s sensitivity is actually higher at low humidity.
“This is a fascinating device,” Berry said. “Here we have a biological entity. We’ve made the sensor on the surface of these spores, with the spore a very active complement to this device. The biological complement is actually working towards responding to stimuli and providing information.”
Interesting, yes? Here’s a link to and a citation for the research paper,
Dexter Johnson provides more context for this research in a March 26, 2015 post on his Nanoclast blog (on the IEEE [institute of Electrical and Electronics Engineers]) where he notes,
Recently, James Tours’ group at Rice University, who were the first to develop GQCs [graphene quantum dots] in 2013, created an improved way to manufacture them that promised to open them up to a new range of applications in optics.
In 1996, a trio of scientists won the Nobel Prize for Chemistry for their discovery of Buckminsterfullerene — soccer-ball-shaped spheres of 60 joined carbon atoms that exhibit special physical properties.
Now, 20 years later, scientists have figured out how to turn them into Buckybombs.
These nanoscale explosives show potential for use in fighting cancer, with the hope that they could one day target and eliminate cancer at the cellular level — triggering tiny explosions that kill cancer cells with minimal impact on surrounding tissue.
“Future applications would probably use other types of carbon structures — such as carbon nanotubes, but we started with Bucky-balls because they’re very stable, and a lot is known about them,” said Oleg V. Prezhdo, professor of chemistry at the USC [University of Southern California] Dornsife College of Letters, Arts and Sciences and corresponding author of a paper on the new explosives that was published in The Journal of Physical Chemistry on February 24 .
A March 19, 2015 USC news release by Robert Perkins, which despite its publication date originated the news item, describes current cancer treatments with carbon nanotubes and this new technique with fullerenes,
Carbon nanotubes, close relatives of Bucky-balls, are used already to treat cancer. They can be accumulated in cancer cells and heated up by a laser, which penetrates through surrounding tissues without affecting them and directly targets carbon nanotubes. Modifying carbon nanotubes the same way as the Buckybombs will make the cancer treatment more efficient — reducing the amount of treatment needed, Prezhdo said.
To build the miniature explosives, Prezhdo and his colleagues attached 12 nitrous oxide molecules to a single Bucky-ball and then heated it. Within picoseconds, the Bucky-ball disintegrated — increasing temperature by thousands of degrees in a controlled explosion.
The source of the explosion’s power is the breaking of powerful carbon bonds, which snap apart to bond with oxygen from the nitrous oxide, resulting in the creation of carbon dioxide, Prezhdo said.
I’m glad this technique would make treatment more effective but I do pause at the thought of having exploding buckyballs in my body or, for that matter, anyone else’s.
The buckybomb combines the unique properties of two classes of materials: carbon structures and energetic nanomaterials. Carbon materials such as C60 can be chemically modified fairly easily to change their properties. Meanwhile, NO2 groups are known to contribute to detonation and combustion processes because they are a major source of oxygen. So, the scientists wondered what would happen if NO2 groups were attached to C60 molecules: would the whole thing explode? And how?
The simulations answered these questions by revealing the explosion in step-by-step detail. Starting with an intact buckybomb (technically called dodecanitrofullerene, or C60(NO2)12), the researchers raised the simulated temperature to 1000 K (700 °C). Within a picosecond (10-12 second), the NO2 groups begin to isomerize, rearranging their atoms and forming new groups with some of the carbon atoms from the C60. As a few more picoseconds pass, the C60 structure loses some of its electrons, which interferes with the bonds that hold it together, and, in a flash, the large molecule disintegrates into many tiny pieces of diatomic carbon (C2). What’s left is a mixture of gases including CO2, NO2, and N2, as well as C2.
I encourage you to read Zynga’s article in whole as she provides more scientific detail and she notes that this discovery could have applications for the military and for industry.
Here’s a link to and a citation for the researchers’ paper,
In the spirit of full disclosure, the March 25, 2014 news item on ScienceDaily describing the research about breeching the blood-brain barrier uses the term nanorobotic agents rather than nanobots, a term which makes my headline a lot catchier although less accurate. Getting back to the research,
Magnetic nanoparticles can open the blood-brain barrier and deliver molecules directly to the brain, say researchers from the University of Montreal, Polytechnique Montréal, and CHU Sainte-Justine. This barrier runs inside almost all vessels in the brain and protects it from elements circulating in the blood that may be toxic to the brain. The research is important as currently 98% of therapeutic molecules are also unable to cross the blood-brain barrier.
“The barrier is temporary [sic] opened at a desired location for approximately 2 hours by a small elevation of the temperature generated by the nanoparticles when exposed to a radio-frequency field,” explained first author and co-inventor Seyed Nasrollah Tabatabaei. “Our tests revealed that this technique is not associated with any inflammation of the brain. This new result could lead to a breakthrough in the way nanoparticles are used in the treatment and diagnosis of brain diseases,” explained the co-investigator, Hélène Girouard. “At the present time, surgery is the only way to treat patients with brain disorders. Moreover, while surgeons are able to operate to remove certain kinds of tumors, some disorders are located in the brain stem, amongst nerves, making surgery impossible,” added collaborator and senior author Anne-Sophie Carret.
Although the technology was developed using murine models and has not yet been tested in humans, the researchers are confident that future research will enable its use in people. “Building on earlier findings and drawing on the global effort of an interdisciplinary team of researchers, this technology proposes a modern version of the vision described almost 40 years ago in the movie Fantastic Voyage, where a miniature submarine navigated in the vascular network to reach a specific region of the brain,” said principal investigator Sylvain Martel. In earlier research, Martel and his team had managed to manipulate the movement of nanoparticles through the body using the magnetic forces generated by magnetic resonance imaging (MRI) machines.
To open the blood-brain barrier, the magnetic nanoparticles are sent to the surface of the blood-brain barrier at a desired location in the brain. Although it was not the technique used in this study, the placement could be achieved by using the MRI technology described above. Then, the researchers generated a radio-frequency field. The nanoparticles reacted to the radio-frequency field by dissipating heat thereby creating a mechanical stress on the barrier. This allows a temporary and localized opening of the barrier for diffusion of therapeutics into the brain.
The technique is unique in many ways. “The result is quite significant since we showed in previous experiments that the same nanoparticles can also be used to navigate therapeutic agents in the vascular network using a clinical MRI scanner,” Martel remarked. “Linking the navigation capability with these new results would allow therapeutics to be delivered directly to a specific site of the brain, potentially improving significantly the efficacy of the treatment while avoiding systemic circulation of toxic agents that affect healthy tissues and organs,” Carret added. “While other techniques have been developed for delivering drugs to the blood-brain barrier, they either open it too wide, exposing the brain to great risks, or they are not precise enough, leading to scattering of the drugs and possible unwanted side effect,” Martel said.
Although there are many hurdles to overcome before the technology can be used to treat humans, the research team is optimistic. “Although our current results are only proof of concept, we are on the way to achieving our goal of developing a local drug delivery mechanism that will be able to treat oncologic, psychiatric, neurological and neurodegenerative disorders, amongst others,” Carret concluded.
Happily, I’m getting more nanotechnology (for the most part) information from Japan. Given Japan’s prominence in this field of endeavour I’ve long felt FrogHeart has not adequately represented Japanese contributions. Now that I’m receiving English language translations, I hope to better address the situation.
This morning (March 26, 2015), there were two news releases from Kawasaki INnovation Gateway at SKYFRONT (KING SKYFRONT), Coastal Area International Strategy Office, Kawasaki City, Japan in my mailbox. Before getting on to the news releases, here’s a little about the city of Kawasaki and about its innovation gateway. From the Kawasaki, Kanagawa entry in Wikipedia (Note: Links have been removed),
Kawasaki (川崎市 Kawasaki-shi?) is a city in Kanagawa Prefecture, Japan, located between Tokyo and Yokohama. It is the 9th most populated city in Japan and one of the main cities forming the Greater Tokyo Area and Keihin Industrial Area.
Kawasaki occupies a belt of land stretching about 30 kilometres (19 mi) along the south bank of the Tama River, which divides it from Tokyo. The eastern end of the belt, centered on JR Kawasaki Station, is flat and largely consists of industrial zones and densely built working-class housing, the Western end mountainous and more suburban. The coastline of Tokyo Bay is occupied by vast heavy industrial complexes built on reclaimed land.
There is a 2014 video about Kawasaki’s innovation gateway, which despite its 14 mins. 39 secs. running time I am embedding here. (Caution: They highlight their animal testing facility at some length.)
Now on to the two news releases. The first concerns research on gold nanoparticles that was published in 2014. From a March 26, 2015 Kawasaki INnovation Gateway news release,
Gold nanoparticles size up to cancer treatment
Incorporating gold nanoparticles helps optimise treatment carrier size and stability to improve delivery of cancer treatment to cells.
Treatments that attack cancer cells through the targeted silencing of cancer genes could be developed using small interfering RNA molecules (siRNA). However delivering the siRNA into the cells intact is a challenge as it is readily degraded by enzymes in the blood and small enough to be eliminated from the blood stream by kidney filtration. Now Kazunori Kataoka at the University of Tokyo and colleagues at Tokyo Institute of Technology have designed a protective treatment delivery vehicle with optimum stability and size for delivering siRNA to cells.
The researchers formed a polymer complex with a single siRNA molecule. The siRNA-loaded complex was then bonded to a 20 nm gold nanoparticle, which thanks to advances in synthesis techniques can be produced with a reliably low size distribution. The resulting nanoarchitecture had the optimum overall size – small enough to infiltrate cells while large enough to accumulate.
In an assay containing heparin – a biological anti-coagulant with a high negative charge density – the complex was found to release the siRNA due to electrostatic interactions. However when the gold nanoparticle was incorporated the complex remained stable. Instead, release of the siRNA from the complex with the gold nanoparticle could be triggered once inside the cell by the presence of glutathione, which is present in high concentrations in intracellular fluid. The glutathione bonded with the gold nanoparticles and the complex, detaching them from each other and leaving the siRNA prone to release.
The researchers further tested their carrier in a subcutaneous tumour model. The authors concluded that the complex bonded to the gold nanoparticle “enabled the efficient tumor accumulation of siRNA and significant in vivo gene silencing effect in the tumor, demonstrating the potential for siRNA-based cancer therapies.”
The news release provides links to the March 2015 newsletter which highlights this research and to the specific article and video,
The second March 26, 2015 Kawasaki INnovation Gateway news release concerns a DNA chip and food-borne pathogens,
Rapid and efficient DNA chip technology for testing 14 major types of food borne pathogens
Conventional methods for testing food-borne pathogens is based on the cultivation of pathogens, a process that is complicated and time consuming. So there is demand for alternative methods to test for food-borne pathogens that are simpler, quick and applicable to a wide range of potential applications.
Now Toshiba Ltd and Kawasaki City Institute for Public Health have collaborated in the development of a rapid and efficient automatic abbreviated DNA detection technology that can test for 14 major types of food borne pathogens. The so called ‘DNA chip card’ employs electrochemical DNA chips and overcomes the complicated procedures associated with genetic testing of conventional methods. The ‘DNA chip card’ is expected to find applications in hygiene management in food manufacture, pharmaceuticals, and cosmetics.
The so-called automatic abbreviated DNA detection technology ‘DNA chip card’ was developed by Toshiba Ltd and in a collaboration with Kawasaki City Institute for Public Health, used to simultaneously detect 14 different types of food-borne pathogens in less than 90 minutes. The detection sensitivity depends on the target pathogen and has a range of 1E+01~05 cfu/mL.
Notably, such tests would usually take 4-5 days using conventional methods based on pathogen cultivation. Furthermore, in contrast to conventional DNA protocols that require high levels of skill and expertise, the ‘DNA chip card’ only requires the operator to inject nucleic acid, thereby making the procedure easier to use and without specialized operating skills.
Examples of pathogens associated with food poisoning that were tested with the “DNA chip card”
Enterohemorrhagic Escherichia coli
Enterotoxigenic Escherichia coli
Enteroaggregative Escherichia coli
Enteropathogenic Escherichia coli
I think 14 is the highest number of tests I’ve seen for one of these chips. This chip is quite an achievement.
One final bit from the news release about the DNA chip provides a brief description of the gateway and something they call King SkyFront,
About KING SKYFRONT
The Kawasaki INnovation Gateway (KING) SKYFRONT is the flagship science and technology innovation hub of Kawasaki City. KING SKYFRONT is a 40 hectare area located in the Tonomachi area of the Keihin Industrial Region that spans Tokyo and Kanagawa Prefecture and Tokyo International Airport (also often referred to as Haneda Airport).
KING SKYFRONT was launched in 2013 as a base for scholars, industrialists and government administrators to work together to devise real life solutions to global issues in the life sciences and environment.
I find this emphasis on the city interesting. It seems that cities are becoming increasingly important and active where science research and development are concerned. Europe seems to have adopted a biannual event wherein a city is declared a European City of Science in conjunction with the EuroScience Open Forum (ESOF) conferences. The first such city was Dublin in 2012 (I believe the Irish came up with the concept themselves) and was later adopted by Copenhagen for 2014. The latest city to embrace the banner will be Manchester in 2016.
I have two items about implants and brains and an item about being able to exert remote control of the brain, all of which hint at a cyborg future for at least a few of us.
e-Dura, the spinal column, and the brain
The first item concerns some research, at the École Polytechnique de Lausanne (EPFL) which features flexible electronics. From a March 24, 2015 article by Ben Schiller for Fast Company (Note: Links have been removed),
Researchers at the Swiss Federal Institute of Technology, in Lausanne, have developed the e-Dura—a tiny skinlike device that attaches directly to damaged spinal cords. By sending out small electrical pulses, it stimulates the cord as if it were receiving signals from the brain, thus allowing movement.
“The purpose of the neuro-prosthesis is to excite the neurons that are on the spinal cord below the site of the injury and activate them, just like if they were receiving information from the brain,” says Stéphanie Lacour, a professor at the institute.
EPFL scientists have managed to get rats walking on their own again using a combination of electrical and chemical stimulation. But applying this method to humans would require multifunctional implants that could be installed for long periods of time on the spinal cord without causing any tissue damage. This is precisely what the teams of professors Stéphanie Lacour and Grégoire Courtine have developed. Their e-Dura implant is designed specifically for implantation on the surface of the brain or spinal cord. The small device closely imitates the mechanical properties of living tissue, and can simultaneously deliver electric impulses and pharmacological substances. The risks of rejection and/or damage to the spinal cord have been drastically reduced. An article about the implant will appear in early January  in Science Magazine.
So-called “surface implants” have reached a roadblock; they cannot be applied long term to the spinal cord or brain, beneath the nervous system’s protective envelope, otherwise known as the “dura mater,” because when nerve tissues move or stretch, they rub against these rigid devices. After a while, this repeated friction causes inflammation, scar tissue buildup, and rejection.
Here’s what the implant looks like,
The press release describes how the implant is placed (Note: A link has been removed),
Flexible and stretchy, the implant developed at EPFL is placed beneath the dura mater, directly onto the spinal cord. Its elasticity and its potential for deformation are almost identical to the living tissue surrounding it. This reduces friction and inflammation to a minimum. When implanted into rats, the e-Dura prototype caused neither damage nor rejection, even after two months. More rigid traditional implants would have caused significant nerve tissue damage during this period of time.
The researchers tested the device prototype by applying their rehabilitation protocol — which combines electrical and chemical stimulation – to paralyzed rats. Not only did the implant prove its biocompatibility, but it also did its job perfectly, allowing the rats to regain the ability to walk on their own again after a few weeks of training.
“Our e-Dura implant can remain for a long period of time on the spinal cord or the cortex, precisely because it has the same mechanical properties as the dura mater itself. This opens up new therapeutic possibilities for patients suffering from neurological trauma or disorders, particularly individuals who have become paralyzed following spinal cord injury,” explains Lacour, co-author of the paper, and holder of EPFL’s Bertarelli Chair in Neuroprosthetic Technology.
The press release goes on to describe the engineering achievements,
Developing the e-Dura implant was quite a feat of engineering. As flexible and stretchable as living tissue, it nonetheless includes electronic elements that stimulate the spinal cord at the point of injury. The silicon substrate is covered with cracked gold electric conducting tracks that can be pulled and stretched. The electrodes are made of an innovative composite of silicon and platinum microbeads. They can be deformed in any direction, while still ensuring optimal electrical conductivity. Finally, a fluidic microchannel enables the delivery of pharmacological substances – neurotransmitters in this case – that will reanimate the nerve cells beneath the injured tissue.
The implant can also be used to monitor electrical impulses from the brain in real time. When they did this, the scientists were able to extract with precision the animal’s motor intention before it was translated into movement.
“It’s the first neuronal surface implant designed from the start for long-term application. In order to build it, we had to combine expertise from a considerable number of areas,” explains Courtine, co-author and holder of EPFL’s IRP Chair in Spinal Cord Repair. “These include materials science, electronics, neuroscience, medicine, and algorithm programming. I don’t think there are many places in the world where one finds the level of interdisciplinary cooperation that exists in our Center for Neuroprosthetics.”
For the time being, the e-Dura implant has been primarily tested in cases of spinal cord injury in paralyzed rats. But the potential for applying these surface implants is huge – for example in epilepsy, Parkinson’s disease and pain management. The scientists are planning to move towards clinical trials in humans, and to develop their prototype in preparation for commercialization.
EPFL has provided a video of researcher Stéphanie Lacour describing e-Dura and expressing hopes for its commercialization,
Here’s a link to and a citation for the paper,
Electronic dura mater for long-term multimodal neural interfaces by Ivan R. Minev, Pavel Musienko, Arthur Hirsch, Quentin Barraud, Nikolaus Wenger, Eduardo Martin Moraud, Jérôme Gandar, Marco Capogrosso, Tomislav Milekovic, Léonie Asboth, Rafael Fajardo Torres, Nicolas Vachicouras, Qihan Liu, Natalia Pavlova, Simone Duis, Alexandre Larmagnac, Janos Vörös, Silvestro Micera, Zhigang Suo, Grégoire Courtine, Stéphanie P. Lacour. Science 9 January 2015: Vol. 347 no. 6218 pp. 159-163 DOI: 10.1126/science.1260318
This paper is behind a paywall.
Carbon nanotube fibres could connect to the brain
Researchers at Rice University (Texas, US) are excited about the possibilities that carbon nanotube fibres offer in the field of implantable electronics for the brain. From a March 25, 2015 news item on Nanowerk,
Carbon nanotube fibers invented at Rice University may provide the best way to communicate directly with the brain.
The fibers have proven superior to metal electrodes for deep brain stimulation and to read signals from a neuronal network. Because they provide a two-way connection, they show promise for treating patients with neurological disorders while monitoring the real-time response of neural circuits in areas that control movement, mood and bodily functions.
New experiments at Rice demonstrated the biocompatible fibers are ideal candidates for small, safe electrodes that interact with the brain’s neuronal system, according to the researchers. They could replace much larger electrodes currently used in devices for deep brain stimulation therapies in Parkinson’s disease patients.
They may also advance technologies to restore sensory or motor functions and brain-machine interfaces as well as deep brain stimulation therapies for other neurological disorders, including dystonia and depression, the researchers wrote.
The fibers created by the Rice lab of chemist and chemical engineer Matteo Pasquali consist of bundles of long nanotubes originally intended for aerospace applications where strength, weight and conductivity are paramount.
The individual nanotubes measure only a few nanometers across, but when millions are bundled in a process called wet spinning, they become thread-like fibers about a quarter the width of a human hair.
“We developed these fibers as high-strength, high-conductivity materials,” Pasquali said. “Yet, once we had them in our hand, we realized that they had an unexpected property: They are really soft, much like a thread of silk. Their unique combination of strength, conductivity and softness makes them ideal for interfacing with the electrical function of the human body.”
The simultaneous arrival in 2012 of Caleb Kemere, a Rice assistant professor who brought expertise in animal models of Parkinson’s disease, and lead author Flavia Vitale, a research scientist in Pasquali’s lab with degrees in chemical and biomedical engineering, prompted the investigation.
“The brain is basically the consistency of pudding and doesn’t interact well with stiff metal electrodes,” Kemere said. “The dream is to have electrodes with the same consistency, and that’s why we’re really excited about these flexible carbon nanotube fibers and their long-term biocompatibility.”
Weeks-long tests on cells and then in rats with Parkinson’s symptoms proved the fibers are stable and as efficient as commercial platinum electrodes at only a fraction of the size. The soft fibers caused little inflammation, which helped maintain strong electrical connections to neurons by preventing the body’s defenses from scarring and encapsulating the site of the injury.
The highly conductive carbon nanotube fibers also show much more favorable impedance – the quality of the electrical connection — than state-of-the-art metal electrodes, making for better contact at lower voltages over long periods, Kemere said.
The working end of the fiber is the exposed tip, which is about the width of a neuron. The rest is encased with a three-micron layer of a flexible, biocompatible polymer with excellent insulating properties.
The challenge is in placing the tips. “That’s really just a matter of having a brain atlas, and during the experiment adjusting the electrodes very delicately and putting them into the right place,” said Kemere, whose lab studies ways to connect signal-processing systems and the brain’s memory and cognitive centers.
Doctors who implant deep brain stimulation devices start with a recording probe able to “listen” to neurons that emit characteristic signals depending on their functions, Kemere said. Once a surgeon finds the right spot, the probe is removed and the stimulating electrode gently inserted. Rice carbon nanotube fibers that send and receive signals would simplify implantation, Vitale said.
The fibers could lead to self-regulating therapeutic devices for Parkinson’s and other patients. Current devices include an implant that sends electrical signals to the brain to calm the tremors that afflict Parkinson’s patients.
“But our technology enables the ability to record while stimulating,” Vitale said. “Current electrodes can only stimulate tissue. They’re too big to detect any spiking activity, so basically the clinical devices send continuous pulses regardless of the response of the brain.”
Kemere foresees a closed-loop system that can read neuronal signals and adapt stimulation therapy in real time. He anticipates building a device with many electrodes that can be addressed individually to gain fine control over stimulation and monitoring from a small, implantable device.
“Interestingly, conductivity is not the most important electrical property of the nanotube fibers,” Pasquali said. “These fibers are intrinsically porous and extremely stable, which are both great advantages over metal electrodes for sensing electrochemical signals and maintaining performance over long periods of time.”
The paper is open access provided you register on the website.
Remote control for stimulation of the brain
Mo Costandi, neuroscientist and freelance science writer, has written a March 24, 2015 post for the Guardian science blog network focusing on neuronal remote control,
Two teams of scientists have developed new ways of stimulating neurons with nanoparticles, allowing them to activate brain cells remotely using light or magnetic fields. The new methods are quicker and far less invasive than other hi-tech methods available, so could be more suitable for potential new treatments for human diseases.
Researchers have various methods for manipulating brain cell activity, arguably the most powerful being optogenetics, which enables them to switch specific brain cells on or off with unprecedented precision, and simultaneously record their behaviour, using pulses of light.
This is very useful for probing neural circuits and behaviour, but involves first creating genetically engineered mice with light-sensitive neurons, and then inserting the optical fibres that deliver light into the brain, so there are major technical and ethical barriers to its use in humans.
Nanomedicine could get around this. Francisco Bezanilla of the University of Chicago and his colleagues knew that gold nanoparticles can absorb light and convert it into heat, and several years ago they discovered that infrared light can make neurons fire nervous impulses by heating up their cell membranes.
Polina Anikeeva’s team at the Massachusetts Institute of Technology adopted a slightly different approach, using spherical iron oxide particles that give off heat when exposed to an alternating magnetic field.
Although still in the experimental stages, research like this may eventually allow for wireless and minimally invasive deep brain stimulation of the human brain. Bezanilla’s group aim to apply their method to develop treatments for macular degeneration and other conditions that kill off light-sensitive cells in the retina. This would involve injecting nanoparticles into the eye so that they bind to other retinal cells, allowing natural light to excite them into firing impulses to the optic nerve.
Costandi’s article is intended for an audience that either understands the science or can deal with the uncertainty of not understanding absolutely everything. Provided you fall into either of those categories, the article is well written and it provides links and citations to the papers for both research teams being featured.
Taken together, the research at EPFL, Rice University, University of Chicago, and Massachusetts Institute of Technology provides a clue as to how much money and intellectual power is being directed at the brain.
Engineers at the University of California, Berkeley, are developing a new type of bandage that does far more than stanch the bleeding from a paper cut or scraped knee. Thanks to advances in flexible electronics, the researchers, in collaboration with colleagues at UC San Francisco, have created a new “smart bandage” that uses electrical currents to detect early tissue damage from pressure ulcers, or bedsores, before they can be seen by human eyes – and while recovery is still possible.
“We set out to create a type of bandage that could detect bedsores as they are forming, before the damage reaches the surface of the skin,” said Michel Maharbiz, a UC Berkeley associate professor of electrical engineering and computer sciences and head of the smart-bandage project. “We can imagine this being carried by a nurse for spot-checking target areas on a patient, or it could be incorporated into a wound dressing to regularly monitor how it’s healing.”
The researchers exploited the electrical changes that occur when a healthy cell starts dying. They tested the thin, non-invasive bandage on the skin of rats and found that the device was able to detect varying degrees of tissue damage consistently across multiple animals.
Bed sores are a big problem now and I imagine that as the population ages and more people find themselves in ill health, the problem will increase (from the news release),
Tackling a growing health problem
The findings, to be published Tuesday, March 17, in the journal Nature Communications, could provide a major boost to efforts to stem a health problem that affects an estimated 2.5 million U.S. residents at an annual cost of $11 billion.
Pressure ulcers, or bedsores, are injuries that can result after prolonged pressure cuts off adequate blood supply to the skin. Areas that cover bony parts of the body, such as the heels, hips and tailbone, are common sites for bedsores. Patients who are bedridden or otherwise lack mobility are most at risk.
“By the time you see signs of a bedsore on the surface of the skin, it’s usually too late,” said Dr. Michael Harrison, a professor of surgery at UCSF and a co-investigator of the study. “This bandage could provide an easy early-warning system that would allow intervention before the injury is permanent. If you can detect bedsores early on, the solution is easy. Just take the pressure off.”
Bedsores are associated with deadly septic infections, and recent research has shown that odds of a hospital patient dying are 2.8 times higher when they have pressure ulcers. The growing prevalence of diabetes and obesity has increased the risk factors for bedsores.
“The genius of this device is that it’s looking at the electrical properties of the tissue to assess damage. We currently have no other way to do that in clinical practice,” said Harrison. “It’s tackling a big problem that many people have been trying to solve in the last 50 years. As a clinician and someone who has struggled with this clinical problem, this bandage is great.”
The electrical components and their role in detecting bed sores is fascinating (from the news release),
Cells as capacitors and resistors
The researchers printed an array of dozens of electrodes onto a thin, flexible film. They discharged a very small current between the electrodes to create a spatial map of the underlying tissue based upon the flow of electricity at different frequencies, a technique called impedance spectroscopy.
The researchers pointed out that a cell’s membrane is relatively impermeable when functioning properly, thus acting like an insulator to the cell’s conductive contents and drawing the comparison to a capacitor. As a cell starts to die, the integrity of the cell wall starts to break down, allowing electrical signals to leak through, much like a resistor.
“Our device is a comprehensive demonstration that tissue health in a living organism can be locally mapped using impedance spectroscopy,” said study lead author Sarah Swisher, a Ph.D. candidate in electrical engineering and computer sciences at UC Berkeley.
To mimic a pressure wound, the researchers gently squeezed the bare skin of rats between two magnets. They left the magnets in place for one or three hours while the rats resumed normal activity. The resumption of blood flow after the magnets were removed caused inflammation and oxidative damage that accelerated cell death. The smart bandage was used to collect data once a day for at least three days to track the progress of the wounds.
The smart bandage was able to detect changes in electrical resistance consistent with increased membrane permeability, a mark of a dying cell. Not surprisingly, one hour of pressure produced mild, reversible tissue damage while three hours of pressure produced more serious, permanent injury.
“One of the things that makes this work novel is that we took a comprehensive approach to understanding how the technique could be used to observe developing wounds in complex tissue,” said Swisher. “In the past, people have used impedance spectroscopy for cell cultures or relatively simple measurements in tissue. What makes this unique is extending that to detect and extract useful information from wounds developing in the body. That’s a big leap.”
Maharbiz said the outlook for this and other smart bandage research is bright.
“As technology gets more and more miniaturized, and as we learn more and more about the responses the body has to disease and injury, we’re able to build bandages that are very intelligent,” he said. “You can imagine a future where the bandage you or a physician puts on could actually report a lot of interesting information that could be used to improve patient care.”
Here’s a link to and a citation for the paper,
Impedance sensing device enables early detection of pressure ulcers in vivo by Sarah L. Swisher, Monica C. Lin, Amy Liao, Elisabeth J. Leeflang, Yasser Khan, Felippe J. Pavinatto, Kaylee Mann, Agne Naujokas, David Young, Shuvo Roy, Michael R. Harrison, Ana Claudia Arias, Vivek Subramanian, & Michel M. Maharbiz. Nature Communications 6, Article number: 6575 doi:10.1038/ncomms7575 Published 17 March 2015
This paper is behind a paywall but there is a free preview available via ReadCube Access.
Finally, one of the researchers describes the work in this 1 min. 31 secs. video,
Green tea’s popularity has grown quickly in recent years. Its fans can drink it, enjoy its flavor in their ice cream and slather it on their skin with lotions infused with it. Now, the tea could have a new, unexpected role — to improve the image quality of MRIs. Scientists report in the journal ACS Applied Materials & Interfaces that they successfully used compounds from green tea to help image cancer tumors in mice.
Sanjay Mathur and colleagues note that recent research has revealed the potential usefulness of nanoparticles — iron oxide in particular — to make biomedical imaging better. But the nanoparticles have their disadvantages. They tend to cluster together easily and need help getting to their destinations in the body. To address these issues, researchers have recently tried attaching natural nutrients to the nanoparticles. Mathur’s team wanted to see if compounds from green tea, which research suggests has anticancer and anti-inflammatory properties, could play this role.
Using a simple, one-step process, the researchers coated iron-oxide nanoparticles with green-tea compounds called catechins and administered them to mice with cancer. MRIs demonstrated that the novel imaging agents gathered in tumor cells and showed a strong contrast from surrounding non-tumor cells. The researchers conclude that the catechin-coated nanoparticles are promising candidates for use in MRIs and related applications.
Researchers at the University of Utah have developed a molecular ruler which could help to determine the length at which a nanoscale needle is effective. From a March 17, 2015 news item on Azonano,
When a salmonella bacterium attacks a cell, it uses a nanoscopic needle to inject it with proteins to aid the infection. If the needle is too short, the cell won’t be infected. Too long, and the needle breaks. Now, University of Utah biologists report how a disposable molecular ruler or tape measure determines the length of the bacterial needle so it is just right.
The findings have potential long-term applications for developing new antibiotics against salmonella and certain other disease-causing bacteria, for designing bacteria that could inject cancer cells with chemotherapy drugs, and for helping people how to design machines at the nanoscopic or molecular scale.
“If you look at important pathogens – the bubonic plague bacterium, salmonella, shigella and plant pathogens like fire blight – they all use hypodermic-like needles to inject proteins that facilitate disease processes,” Hughes [University of Utah biology professor Kelly Hughes] says.
“Our work says that there is one mechanism – the molecular ruler – to explain how the lengths are controlled for needles in gram-negative bacteria and for hooks on flagella [the U-joints in propellers bacteria use to move] in all bacteria,” he adds.
In their study, Wee [University of Utah doctoral student Daniel Wee] and Hughes found that as a bacterial needle or “injectisome” grows, a molecular ruler – really, more like a gooey tape measure – is secreted from within the needle’s base. It oozes up through the tube-like needle, and when the bottom end of the ruler reaches the bottom end of the needle, the needle stops growing and begins to inject proteins into the target cell to help the infection process.
The biologists say the [US] National Institutes of Health-funded study refutes other theories for how salmonella and some other disease bacteria determine needle lengths.
The news release also explains how this finding could be made useful,
“What we understand from bacteria can help us build nanomachines and nanobots,” Hughes says, noting that bacterial flagella – the nanoscopic motor-and-propeller system they use to swim to dinner or to targets – are “the most sophisticated nanomachines in the universe.”
In one example, Swiss scientists are using the design of bacterial flagella as the basis for a nanobot that will be put inside the eye to do nanoscale surgery, he adds.
In addition to flagella, a number of disease-causing bacteria also have injectisomes, which also are built of proteins, as are most structures in living organisms.
“In the case of the needle, you have a structure that extends from the surface of the bacterium like a hypodermic,” Hughes says. “These needles are fragile. If one is too long, it will break off and be useless. If you make it too short, then it can’t get past the surface proteins on cells it needs to invade.”
By understanding how bacteria determine the length for their needles, it someday may be possible to engineer bacteria to inject chemotherapy drugs right into cancer cells.
“People would like to design bacteria that can get to cancer cells and inject poisons into just those cells and kill them, and not harm the rest of us,” Hughes says.
And by understanding how certain disease-causing bacteria build their injectisomes, new antibiotics might be developed in a decade or so to target and destroy the needles and thus deter bacterial infections. The rulers that help build flagella also might be attacked by drugs to prevent bacteria from reaching target cells, “so you can kill two birds with one stone by hitting the two machines at the same time,” Hughes says.
He says that approach might work against injectisome-equipped bacteria such as salmonella species that cause typhoid fever and food poisoning; shigella species that cause dysentery; the bubonic plague bacterium Yersinia pestis; disease-causing E. coli; sexually transmitted Chlamydia trachomatis; many plant pathogens; and Pseudomonas aeruginosa, which often infects burn patients and the lungs of cystic fibrosis patients.
Not usually my kind of thing, I find this quite fascinating (from the news release),
Bacteria secrete a molecular ruler to measure needle length
Bacterial injectisomes are incredibly small, measuring only 20 to 100 nanometers long. A nanometer is one billionth of a meter, and a meter is about 39 inches long. The width of a typical human hair often is given as 100 microns, so the maximum length of a bacterial needle, 100 nanometers, is one-thousandth of the width of a human hair.
Gram-negative, disease-causing bacteria “are very closely related species, so how do they subtly control the various needle lengths to be perfect?” Hughes asks. “In one case it might be 40 nanometers versus 55 nanometers. These are small sizes. So to do this, the bacteria developed molecular rulers to differentiate needles of different lengths.”
(Gram-negative bacteria are those with membranes lining both the inside and outside of their cell wall, while gram-positive bacteria have only an inner membrane.)
Like any cell, a bacterium is encased in a cell wall. So bacteria developed all kinds of secretions to make contact with and infect other cells: flagellar propellers to swim to food or target cells, docking structures to help bacteria stick to targets, and injectisomes to inject infection-promoting proteins into targets.
When a bacterium builds a needle, it first builds a base. “A series of proteins form a doughnut, and inside the doughnut hole, the actual secretion machine gets constructed,” Hughes says. “It’s the same for the flagella as it is for these needles.”
Next, proteins start assembling to form the needle or injectisome.
The new study demonstrated that in salmonella, the ruler or tape measure is secreted slowly through the channel of the growing needle. Once amino acids at the bottom end of the ruler pass through the base of the needle, they tell the bacterium that the needle is long enough and to stop growing. They also tell the needle to injecting virulence proteins into the target cell, and the molecular ruler is ejected, Wee says.
Here’s an image of what the injectisome looks like,
On the left is an electron microscope image of an injectisome, the nanoscopic needle that salmonella and certain other bacteria use to inject proteins into target cells as part of the infection process. The illustration at center depicts the exterior of the needle and its base. The cross-section at right shows the string-like molecular ruler that determines the length of salmonella’s bacteria needle, according to a new University of Utah study by doctoral student Daniel Wee and biology professor Kelly Hughes. Credit: Daniel Wee, University of Utah
The news release also offers some specific details about the research,
How the study was performed
The new study used the Typhimurium strain of Salmonella enterica, which causes food poisoning. The researchers proved the molecular ruler determines needle length in salmonella by inserting amino acids from the plague bacterium’s molecular ruler genes into genes for salmonella’s molecular ruler, making rulers with seven different lengths.
Genetically engineered salmonella with seven ruler lengths were grown in a flask, their needles isolated, and the needle lengths measured under an electron microscope.
Wee found the ruler lengths correlated precisely with the lengths of the resulting needles or injectisomes, with each amino acid added to the ruler gene making the resulting needle 0.2 nanometers longer.
Previous studies found the molecular ruler determines the length of the hook or U-joint that helps turn flagella or propellers in many bacteria. Research also found the molecular ruler determines the length of both the flagellar hook and the needle in plague bacteria. But some researchers argued salmonella needle’s length was determined by some other mechanism:
– One theory holds that a molecular measuring cup in the needle’s base sends a cupful of needle components to assemble the needle, and the length of the needle is determined by the size of the cup. The new study disproved that by genetically removing the cup and showing that the injectisomes or needles still grew to correct lengths.
– Another theory says that as needle components assemble outside the needle’s base, a rod-shaped structure assembles inside the base to link the base and needle, and that when the rod is complete, needle assembly stops, thus determining needle length. But the Utah study found the rod and needle components are not made simultaneously, but compete with each other, so as more rod parts are made, fewer needle parts are made, giving an illusion that rod completion controls needle length.
In early 2003, the European Science Foundation launched its Scientific Forward Look on Nanomedicine, a foresight study (report here ;pdf) and in 2004, the U.S. National Institute[s] of Health (NIH) published its Roadmap (now Common Fund) of the Nanomedicine Initiative. This program began in 2005 with a national network of eight Nanomedicine Development Centers. Now, in the second half of this 10-year program, the four centers best positioned to effectively apply their findings to translational studies were selected to continue receiving support.
A generally accepted definition of nanomedicine refers to highly specific medical intervention at the molecular scale for curing disease or repairing damaged tissues, such as bone, muscle, or nerve.
Much of Berger’s article is based on Subbu Venkatraman’s, Director of the NTU (Nanyang Technological University)-Northwestern Nanomedicine Institute in Singapore, paper, Has nanomedicine lived up to its promise?, 2014 Nanotechnology 25 372501 doi:10.1088/0957-4484/25/37/372501 (Note: Links have been removed),
… Historically, the approval of Doxil as the very first nanotherapeutic product in 1995 is generally regarded as the dawn of nanomedicine for human use. Since then, research activity in this area has been frenetic, with, for example, 2000 patents being generated in 2003, in addition to 1200 papers . In the same time period, a total of 207 companies were involved in developing nanomedicinal products in diagnostics, imaging, drug delivery and implants. About 38 products loosely classified as nanomedicine products were in fact approved by 2004. Out of these, however, a number of products (five in all) were based on PEG-ylated proteins, which strictly speaking, are not so much nanomedicine products as molecular therapeutics. Nevertheless, the promise of nanomedicine was being translated into funding for small companies, and into clinical success, so that by 2013, the number of approved products had reached 54 in all, with another 150 in various stages of clinical trials . The number of companies and institutions had risen to 241 (including research centres that were working on nanomedicine). A PubMed search on articles relating to nanomedicine shows 7400 hits over 10 years, of which 1874 were published in 2013 alone. Similarly, the US patent office database shows 409 patents (since 1976) that were granted in nanomedicine, with another 679 applications awaiting approval. So judging by research activity and funding the field of nanomedicine has been very fertile; however, when we use the yardstick of clinical success and paradigm shifts in treatment, the results appear more modest.
Both Berger’s spotlight article and Venkatraman’s review provide interesting reading and neither is especially long.