Category Archives: medicine

See-through medical sensors from the University of Wisconsin-Madison

This is quite the week for see-through medical devices based on graphene. A second team has developed a transparent sensor which could allow scientists to make observations of brain activity that are now impossible, according to an Oct. 20, 2014 University of Wisconsin-Madison news release (also on EurekAlert),

Neural researchers study, monitor or stimulate the brain using imaging techniques in conjunction with implantable sensors that allow them to continuously capture and associate fleeting brain signals with the brain activity they can see.

However, it’s difficult to see brain activity when there are sensors blocking the view.

“One of the holy grails of neural implant technology is that we’d really like to have an implant device that doesn’t interfere with any of the traditional imaging diagnostics,” says Justin Williams, the Vilas Distinguished Achievement Professor of biomedical engineering and neurological surgery at UW-Madison. “A traditional implant looks like a square of dots, and you can’t see anything under it. We wanted to make a transparent electronic device.”

The researchers chose graphene, a material gaining wider use in everything from solar cells to electronics, because of its versatility and biocompatibility. And in fact, they can make their sensors incredibly flexible and transparent because the electronic circuit elements are only 4 atoms thick—an astounding thinness made possible by graphene’s excellent conductive properties. “It’s got to be very thin and robust to survive in the body,” says Zhenqiang (Jack) Ma, the Lynn H. Matthias Professor and Vilas Distinguished Achievement Professor of electrical and computer engineering at UW-Madison. “It is soft and flexible, and a good tradeoff between transparency, strength and conductivity.”

Drawing on his expertise in developing revolutionary flexible electronics, he, Williams and their students designed and fabricated the micro-electrode arrays, which—unlike existing devices—work in tandem with a range of imaging technologies. “Other implantable micro-devices might be transparent at one wavelength, but not at others, or they lose their properties,” says Ma. “Our devices are transparent across a large spectrum—all the way from ultraviolet to deep infrared.”

The transparent sensors could be a boon to neuromodulation therapies, which physicians increasingly are using to control symptoms, restore function, and relieve pain in patients with diseases or disorders such as hypertension, epilepsy, Parkinson’s disease, or others, says Kip Ludwig, a program director for the National Institutes of Health neural engineering research efforts. “Despite remarkable improvements seen in neuromodulation clinical trials for such diseases, our understanding of how these therapies work—and therefore our ability to improve existing or identify new therapies—is rudimentary.”

Currently, he says, researchers are limited in their ability to directly observe how the body generates electrical signals, as well as how it reacts to externally generated electrical signals. “Clear electrodes in combination with recent technological advances in optogenetics and optical voltage probes will enable researchers to isolate those biological mechanisms. This fundamental knowledge could be catalytic in dramatically improving existing neuromodulation therapies and identifying new therapies.”

The advance aligns with bold goals set forth in President Barack Obama’s BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative. Obama announced the initiative in April 2013 as an effort to spur innovations that can revolutionize understanding of the brain and unlock ways to prevent, treat or cure such disorders as Alzheimer’s and Parkinson’s disease, post-traumatic stress disorder, epilepsy, traumatic brain injury, and others.

The UW-Madison researchers developed the technology with funding from the Reliable Neural-Interface Technology program at the Defense Advanced Research Projects Agency.

While the researchers centered their efforts around neural research, they already have started to explore other medical device applications. For example, working with researchers at the University of Illinois-Chicago, they prototyped a contact lens instrumented with dozens of invisible sensors to detect injury to the retina; the UIC team is exploring applications such as early diagnosis of glaucoma.

Here’s an image of the see-through medical implant,

Caption: A blue light shines through a clear implantable medical sensor onto a brain model. See-through sensors, which have been developed by a team of University of Wisconsin Madison engineers, should help neural researchers better view brain activity. Credit: Justin Williams research group

Caption: A blue light shines through a clear implantable medical sensor onto a brain model. See-through sensors, which have been developed by a team of University of Wisconsin Madison engineers, should help neural researchers better view brain activity.
Credit: Justin Williams research group

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

Graphene-based carbon-layered electrode array technology for neural imaging and optogenetic applications by Dong-Wook Park, Amelia A. Schendel, Solomon Mikael, Sarah K. Brodnick, Thomas J. Richner, Jared P. Ness, Mohammed R. Hayat, Farid Atry, Seth T. Frye, Ramin Pashaie, Sanitta Thongpang, Zhenqiang Ma, & Justin C. Williams. Nature Communications 5, Article number: 5258 doi:10.1038/ncomms6258 Published
20 October 2014

This is an open access paper.

Graphene used to create electrodes one atom thick and transparent for brain research applications

It’s usually a ‘John Rogers (at the University of Illinois)’ story when there’s mention of transparent electronic devices but not this time. In an Oct. 20, 2014 news item on ScienceDaily, the University of Pennsylvania’s researchers are in the spotlight,

Researchers from the Perelman School of Medicine and School of Engineering at the University of Pennsylvania and The Children’s Hospital of Philadelphia have used graphene — a two-dimensional form of carbon only one atom thick — to fabricate a new type of microelectrode that solves a major problem for investigators looking to understand the intricate circuitry of the brain.

Pinning down the details of how individual neural circuits operate in epilepsy and other neurological disorders requires real-time observation of their locations, firing patterns, and other factors, using high-resolution optical imaging and electrophysiological recording. But traditional metallic microelectrodes are opaque and block the clinician’s view and create shadows that can obscure important details. In the past, researchers could obtain either high-resolution optical images or electrophysiological data, but not both at the same time.

The Center for NeuroEngineering and Therapeutics (CNT), under the leadership of senior author Brian Litt, PhD, has solved this problem with the development of a completely transparent graphene microelectrode that allows for simultaneous optical imaging and electrophysiological recordings of neural circuits. [emphasis mine] Their work was published this week in Nature Communications.

An Oct. 20, 2014 University of Pennsylvania news release (also on EurekAlert), which originated the news item, further describes the research,

“There are technologies that can give very high spatial resolution such as calcium imaging; there are technologies that can give high temporal resolution, such as electrophysiology, but there’s no single technology that can provide both,” says study co-first-author Duygu Kuzum, PhD. Along with co-author Hajime Takano, PhD, and their colleagues, Kuzum notes that the team developed a neuroelectrode technology based on graphene to achieve high spatial and temporal resolution simultaneously.

Aside from the obvious benefits of its transparency, graphene offers other advantages: “It can act as an anti-corrosive for metal surfaces to eliminate all corrosive electrochemical reactions in tissues,” Kuzum says. “It’s also inherently a low-noise material, which is important in neural recording because we try to get a high signal-to-noise ratio.”

While previous efforts have been made to construct transparent electrodes using indium tin oxide, they are expensive and highly brittle, making that substance ill-suited for microelectrode arrays. “Another advantage of graphene is that it’s flexible, so we can make very thin, flexible electrodes that can hug the neural tissue,” Kuzum notes.

In the study, Litt, Kuzum, and their colleagues performed calcium imaging of hippocampal slices in a rat model with both confocal and two-photon microscopy, while also conducting electrophysiological recordings. On an individual cell level, they were able to observe temporal details of seizures and seizure-like activity with very high resolution. The team also notes that the single-electrode techniques used in the Nature Communications study could be easily adapted to study other larger areas of the brain with more expansive arrays.

The graphene microelectrodes developed could have wider application. “They can be used in any application that we need to record electrical signals, such as cardiac pacemakers or peripheral nervous system stimulators,” says Kuzum. Because of graphene’s nonmagnetic and anti-corrosive properties, these probes “can also be a very promising technology to increase the longevity of neural implants.” Graphene’s nonmagnetic characteristics also allow for safe, artifact-free MRI reading, unlike metallic implants.

Kuzum emphasizes that the transparent graphene microelectrode technology was achieved through an interdisciplinary effort of CNT and the departments of Neuroscience, Pediatrics, and Materials Science at Penn and the division of Neurology at CHOP.

Ertugrul Cubukcu’s lab at Materials Science and Engineering Department helped with the graphene processing technology used in fabricating flexible transparent neural electrodes, as well as performing optical and materials characterization in collaboration with Euijae Shim and Jason Reed. The simultaneous imaging and recording experiments involving calcium imaging with confocal and two photon microscopy was performed at Douglas Coulter’s Lab at CHOP with Hajime Takano. In vivo recording experiments were performed in collaboration with Halvor Juul in Marc Dichter’s Lab. Somatasensory stimulation response experiments were done in collaboration with Timothy Lucas’s Lab, Julius De Vries, and Andrew Richardson.

As the technology is further developed and used, Kuzum and her colleagues expect to gain greater insight into how the physiology of the brain can go awry. “It can provide information on neural circuits, which wasn’t available before, because we didn’t have the technology to probe them,” she says. That information may include the identification of specific marker waveforms of brain electrical activity that can be mapped spatially and temporally to individual neural circuits. “We can also look at other neurological disorders and try to understand the correlation between different neural circuits using this technique,” she says.

It’s fascinating work and I hope it’s helpful but I can’t help noticing that these researchers, in common with most, tend to view the brain or whatever body part they’re examining in isolation from the rest of the body, whatever species is being examined. The answers as to why there are brain disorders and diseases may not lie wholly within the brain itself but within the totality of the organism in which the brain resides, i.e., the body. That reservation aside, there’s a link to and a citation for the research paper,

Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging by Duygu Kuzum, Hajime Takano, Euijae Shim, Jason C. Reed, Halvor Juul, Andrew G. Richardson, Julius de Vries, Hank Bink, Marc A. Dichter, Timothy H. Lucas, Douglas A. Coulter, Ertugrul Cubukcu, & Brian Litt. Nature Communications 5, Article number: 5259 doi:10.1038/ncomms6259 Published 20 October 2014

This paper is behind a paywall but there is a free preview available through ReadCube Access.

Like a starfish shell, facetless crystals

Made by accident, these facetless crystals could prove useful in applications for cells, medications, and more according to researchers at the University of Michigan in an Oct. 20, 2014 news item on Nanowerk,

In a design that mimics a hard-to-duplicate texture of starfish shells, University of Michigan engineers have made rounded crystals that have no facets.

“We call them nanolobes. They look like little hot air balloons that are rising from the surface,” said Olga Shalev, a doctoral student in materials science and engineering who worked on the project.

There is a video with the researcher, Olga Shalev, describing the nanolobes in more detail,

An Oct. 17, 2014 University of Michigan news release (also on EurekAlert*), which originated the news item, offers text for those who prefer to read about the science rather than receive it by video,

Both the nanolobes’ shape and the way they’re made have promising applications, the researchers say. The geometry could potentially be useful to guide light in advanced LEDs, solar cells and nonreflective surfaces. A layer might help a material repel water or dirt. And the process used to manufacture them – organic vapor jet printing – might lend itself to 3D-printing medications that absorb better into the body and make personalized dosing possible.

The nanoscale shapes are made out of boron subphthalocyanine chloride, a material often used in organic solar cells. It’s in a family of small molecular compounds that tend to make either flat films or faceted crystals with sharp edges, says Max Shtein, an associate professor of materials science and engineering, macromolecular science and engineering, chemical engineering, and art and design.

“In my years of working with these kinds of materials, I’ve never seen shapes that looked like these. They’re reminiscent of what you get from biological processes,” Shtein said. “Nature can sometimes produce crystals that are smooth, but engineers haven’t been able to do it reliably.”

Echinoderm sea creatures such as brittle stars have ordered rounded structures on their bodies that work as lenses to gather light into their rudimentary eyes. But in a lab, crystals composed of the same minerals tend either to be faceted with flat faces and sharp angles, or smooth, but lacking molecular order.

The U-M researchers made the curved crystals by accident several years ago. They’ve since traced their steps and figured out how to do it on purpose.

In 2010, Shaurjo Biswas, then a doctoral student at U-M, was making solar cells with the organic vapor jet printer. He was recalibrating the machine after switching between materials. Part of the recalibration process involves taking a close look at the fresh layers of material, of films, printed on a plate. Biswas X-rayed several films of different thicknesses to observe the crystal structure. He noticed that the boron subphthalocyanine chloride, which typically does not form ordered shapes, started to do so once the film got thicker than 600 nanometers. He made some thicker films to see what would happen.

“At first, we wondered if our apparatus was functioning properly,” Shtein said.

At 800 nanometers thick, the repeating nanolobe pattern emerged every time.

For a long while, the blobs were lab curiosities. Researchers were focused on other things. Then doctoral student Shalev got involved. She was fascinated by the structures and wanted to understand the reason for the phenomenon. She repeated the experiments in a modified apparatus that gave more control over the conditions to vary them systematically. She collaborated with physics professor Roy Clarke to gain a better understanding of the crystallization, and mechanical engineering professor Wei Lu to simulate the evolution of the surface.. She’s first author of a paper on the findings published in the current edition of Nature Communications.

“As far as we know, no other technology can do this,” Shalev said.

The organic vapor jet printing process the researchers use is a technique Shtein helped to develop when he was in graduate school. He describes it as spray painting, but with a gas rather than with a liquid. It’s cheaper and easier to do for certain applications than competing approaches that involve stencils or can only be done in a vacuum, Shtein says. He’s especially hopeful about the prospects for this technique to advance emerging 3D-printed pharmaceutical concepts.

For example, Shtein and Shalev believe this method offers a precise way to control the size and shape of the medicine particles, for easier absorption into the body. It could also allow drugs to be attached directly to other materials and it doesn’t require solvents that might introduce impurities.

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

Growth and modelling of spherical crystalline morphologies of molecular materials by O. Shalev, S. Biswas, Y. Yang, T. Eddir, W. Lu, R. Clarke,  & M. Shtein. Nature Communications 5, Article number: 5204 doi:10.1038/ncomms6204 Published 16 October 2014

This paper is behind a paywall.

* EurekAlert link added on Oct. 20, 2014 at 1035 hours PDT.

SLIPS (Slippery Liquid-Infused Porous Surfaces) technology repels blood and bacteria from medical devices

Researchers at Harvard University’s Wyss Institute for Biologically Inspired Engineering have developed a coating for medical devices that helps to address some of these devices’ most  troublesome aspects. From an Oct. 12, 2014 news item on ScienceDaily,

From joint replacements to cardiac implants and dialysis machines, medical devices enhance or save lives on a daily basis. However, any device implanted in the body or in contact with flowing blood faces two critical challenges that can threaten the life of the patient the device is meant to help: blood clotting and bacterial infection.

A team of Harvard scientists and engineers may have a solution. They developed a new surface coating for medical devices using materials already approved by the Food and Drug Administration (FDA). The coating repelled blood from more than 20 medically relevant substrates the team tested — made of plastic to glass and metal — and also suppressed biofilm formation in a study reported in Nature Biotechnology. But that’s not all.

The team implanted medical-grade tubing and catheters coated with the material in large blood vessels in pigs, and it prevented blood from clotting for at least eight hours without the use of blood thinners such as heparin. Heparin is notorious for causing potentially lethal side-effects like excessive bleeding but is often a necessary evil in medical treatments where clotting is a risk.

“Devising a way to prevent blood clotting without using anticoagulants is one of the holy grails in medicine,” said Don Ingber, M.D., Ph.D., Founding Director of Harvard’s Wyss Institute for Biologically Inspired Engineering and senior author of the study. Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, as well as professor of bioengineering at Harvard School of Engineering and Applied Sciences (SEAS).

An Oct. 12, 2014 Wyss Institute news release (also on EurekAlert), which originated the news item, describes the inspiration for this work,

The idea for the coating evolved from SLIPS, a pioneering surface technology developed by coauthor Joanna Aizenberg, Ph.D., who is a Wyss Institute Core Faculty member and the Amy Smith Berylson Professor of Materials Science at Harvard SEAS. SLIPS stands for Slippery Liquid-Infused Porous Surfaces. Inspired by the slippery surface of the carnivorous pitcher plant, which enables the plant to capture insects, SLIPS repels nearly any material it contacts. The liquid layer on the surface provides a barrier to everything from ice to crude oil and blood.

“Traditional SLIPS uses porous, textured surface substrates to immobilize the liquid layer whereas medical surfaces are mostly flat and smooth – so we further adapted our approach by capitalizing on the natural roughness of chemically modified surfaces of medical devices,” said Aizenberg, who leads the Wyss Institute’s Adaptive Materials platform. “This is yet another incarnation of the highly customizable SLIPS platform that can be designed to create slippery, non-adhesive surfaces on any material.”

The Wyss team developed a super-repellent coating that can be adhered to existing, approved medical devices. In a two-step surface-coating process, they chemically attached a monolayer of perfluorocarbon, which is similar to Teflon. Then they added a layer of liquid perfluorocarbon, which is widely used in medicine for applications such as liquid ventilation for infants with breathing challenges, blood substitution, eye surgery, and more. The team calls the tethered perfluorocarbon plus the liquid layer a Tethered-Liquid Perfluorocarbon surface, or TLP for short.

In addition to working seamlessly when coated on more than 20 different medical surfaces and lasting for more than eight hours to prevent clots in a pig under relatively high blood flow rates without the use of heparin, the TLP coating achieved the following results:

  • TLP-treated medical tubing was stored for more than a year under normal temperature and humidity conditions and still prevented clot formation
  • The TLP surface remained stable under the full range of clinically relevant physiological shear stresses, or rates of blood flow seen in catheters and central lines, all the way up to dialysis machines
  • It repelled the components of blood that cause clotting (fibrin and platelets)
  • When bacteria called Pseudomonas aeruginosa were grown in TLP-coated medical tubing for more than six weeks, less than one in a billion bacteria were able to adhere. Central lines coated with TLP significantly reduce sepsis from Central-Line Mediated Bloodstream Infections (CLABSI). (Sepsis is a life-threatening blood infection caused by bacteria, and a significant risk for patients with implanted medical devices.)

Out of sheer curiosity, the researchers even tested a TLP-coated surface with a gecko – the superstar of sticking whose footpads contain many thousands of hairlike structures with tremendous adhesive strength. The gecko was unable to hold on.

“We were wonderfully surprised by how well the TLP coating worked, particularly in vivo without heparin,” said one of the co-lead authors, Anna Waterhouse, Ph.D., a Wyss Institute Postdoctoral Fellow. “Usually the blood will start to clot within an hour in the extracorporeal circuit, so our experiments really demonstrate the clinical relevance of this new coating.”

While most of the team’s demonstrations were performed on medical devices such as catheters and perfusion tubing using relatively simple setups, they say there is a lot more on the horizon.

“We feel this is just the beginning of how we might test this for use in the clinic,” said co-lead author Daniel Leslie, Ph.D., a Wyss Institute Staff Scientist, who aims to test it on more complex systems such as dialysis machines and ECMO, a machine used in the intensive care unit to help critically ill patients breathe.

I first featured SLIPS technology in a Jan. 15, 2014 post about its possible use for stain-free, self-cleaning clothing. This Wyss Institute video about the latest work featuring the use of  SLIPS technology in medical devices also describes its possible use in pipelines and airplanes,

You can find research paper with this link,

A bioinspired omniphobic surface coating on medical devices prevents thrombosis and biofouling by Daniel C Leslie, Anna Waterhouse, Julia B Berthet, Thomas M Valentin, Alexander L Watters, Abhishek Jain, Philseok Kim, Benjamin D Hatton, Arthur Nedder, Kathryn Donovan, Elana H Super, Caitlin Howell, Christopher P Johnson, Thy L Vu, Dana E Bolgen, Sami Rifai, Anne R Hansen, Michael Aizenberg, Michael Super, Joanna Aizenberg, & Donald E Ingber. Nature Biotechnology (2014) doi:10.1038/nbt.3020 Published online 12 October 2014

This paper is behind a paywall but there is a free preview available via ReadCube Access.

Gold nanorods and mucus

Mucus can kill. Most of us are lucky enough to produce mucus appropriate for our bodies’ needs but people who have cystic fibrosis and other kinds of lung disease suffer greatly from mucus that is too thick to pass easily through the body. An Oct. 9, 2014 Optical Society of America (OSA) news release (also on EurekAlert) ‘shines’ a light on the topic of mucus and viscosity,

Some people might consider mucus an icky bodily secretion best left wrapped in a tissue, but to a group of researchers from the University of North Carolina at Chapel Hill, snot is an endlessly fascinating subject. The team has developed a way to use gold nanoparticles and light to measure the stickiness of the slimy substance that lines our airways.  The new method could help doctors better monitor and treat lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease.

“People who are suffering from certain lung diseases have thickened mucus,” explained Amy Oldenburg, a physicist at the University of North Carolina at Chapel Hill whose research focuses on biomedical imaging systems. “In healthy adults, hair-like cell appendages called cilia line the airways and pull mucus out of the lungs and into the throat. But if the mucus is too viscous it can become trapped in the lungs, making breathing more difficult and also failing to remove pathogens that can cause chronic infections.”

Doctors can prescribe mucus-thinning drugs, but have no good way to monitor how the drugs affect the viscosity of mucus at various spots inside the body. This is where Oldenburg and her colleagues’ work may help.

The researchers placed coated gold nanorods on the surface of mucus samples and then tracked the rods’ diffusion into the mucus by illuminating the samples with laser light and analyzing the way the light bounced off the nanoparticles. The slower the nanorods diffused, the thicker the mucus. The team found this imaging method worked even when the mucus was sliding over a layer of cells—an important finding since mucus inside the human body is usually in motion.

“The ability to monitor how well mucus-thinning treatments are working in real-time may allow us to determine better treatments and tailor them for the individual,” said Oldenburg.

It will likely take five to 10 more years before the team’s mucus measuring method is tested on human patients, Oldenburg said. Gold is non-toxic, but for safety reasons the researchers would want to ensure that the gold nanorods would eventually be cleared from a patient’s system.

“This is a great example of interdisciplinary work in which optical scientists can meet a specific need in the clinic,” said Nozomi Nishimura, of Cornell University … . “As these types of optical technologies continue to make their way into medical practice, it will both expand the market for the technology as well as improve patient care.”

The team is also working on several lines of ongoing study that will some day help bring their monitoring device to the clinic. They are developing delivery methods for the gold nanorods, studying how their imaging system might be adapted to enter a patient’s airways, and further investigating how mucus flow properties differ throughout the body.

This work is being presented at:

The research team will present their work at The Optical Society’s (OSA) 98th Annual Meeting, Frontiers in Optics, being held Oct. 19-23 [2014] in Tucson, Arizona, USA.

Presentation FTu5F.2, “Imaging Gold Nanorod Diffusion in Mucus Using Polarization Sensitive OCT,” takes place Tuesday, Oct. 21 at 4:15 p.m. MST [Mountain Standard Time] in the Tucson Ballroom, Salon A at the JW Marriott Tucson Starr Pass Resort.

People with cystic fibrosis tend to have short lives (from the US National Library of Medicine MedLine Plus webpage on cystic fibrosis),

Most children with cystic fibrosis stay in good health until they reach adulthood. They are able to take part in most activities and attend school. Many young adults with cystic fibrosis finish college or find jobs.

Lung disease eventually worsens to the point where the person is disabled. Today, the average life span for people with CF who live to adulthood is about 37 years.

Death is most often caused by lung complications.

I hope this work proves helpful.

Nanoparticle-based radiogenetics to control brain cells

While the title for this post sounds like an opening for a zombie-themed story, this Oct. 8, 2014 news item on Nanowerk actually concerns brain research at Rockefeller University (US), Note: A link has been removed,

A proposal to develop a new way to remotely control brain cells from Sarah Stanley, a Research Associate in Rockefeller University’s Laboratory of Molecular Genetics, headed by Jeffrey M. Friedman, is among the first to receive funding from the BRAIN initiative. The project will make use of a technique called radiogenetics that combines the use of radio waves or magnetic fields with nanoparticles to turn neurons on or off.

An Oct. 7, 2014 Rockefeller University news release, which originated the news item, further describes the BRAIN initiative and the research (Note: Links have been removed),

The NIH [National Institutes of Health]  is one of four federal agencies involved in the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative. Following in the ambitious footsteps of the Human Genome Project, the BRAIN initiative seeks to create a dynamic map of the brain in action, a goal that requires the development of new technologies. The BRAIN initiative working group, which outlined the broad scope of the ambitious project, was co-chaired by Rockefeller’s Cori Bargmann, head of the Laboratory of Neural Circuits and Behavior.

Stanley’s grant, for $1.26 million over three years, is one of 58 projects to get BRAIN grants, the NIH announced. The NIH’s plan for its part of this national project, which has been pitched as “America’s next moonshot,” calls for $4.5 billion in federal funds over 12 years.

The technology Stanley is developing would enable researchers to manipulate the activity of neurons, as well as other cell types, in freely moving animals in order to better understand what these cells do. Other techniques for controlling selected groups of neurons exist, but her new nanoparticle-based technique has a unique combination of features that may enable new types of experimentation. For instance, it would allow researchers to rapidly activate or silence neurons within a small area of the brain or dispersed across a larger region, including those in difficult-to-access locations. Stanley also plans to explore the potential this method has for use treating patients.

“Francis Collins, director of the NIH, has discussed the need for studying the circuitry of the brain, which is formed by interconnected neurons. Our remote-control technology may provide a tool with which researchers can ask new questions about the roles of complex circuits in regulating behavior,” Stanley says.

Here’s an image that Rockefeller University has used to illustrate the concept of radio-controlled brain cells,

 

BRAIN control: The new technology uses radio waves to activate or silence cells remotely. The bright spots above represent cells with increased calcium after treatment with radio waves, a change that would allow neurons to fire. [downloaded from: http://newswire.rockefeller.edu/2014/10/07/rockefeller-neurobiology-lab-is-awarded-first-round-brain-initiative-grant/]

BRAIN control: The new technology uses radio waves to activate or silence cells remotely. The bright spots above represent cells with increased calcium after treatment with radio waves, a change that would allow neurons to fire. [downloaded from: http://newswire.rockefeller.edu/2014/10/07/rockefeller-neurobiology-lab-is-awarded-first-round-brain-initiative-grant/]

You can find out more about the US BRAIN initiative here.

Nanotechnology for better treatment of eye conditions and a perspective on superhuman sight

There are three ‘eye’-related items in this piece, two of them concerning animal eyes and one concerning a camera-eye or the possibility of superhuman sight.

Earlier this week researchers at the University of Reading (UK) announced they have achieved a better understanding of how nanoparticles might be able to bypass some of the eye’s natural barriers in the hopes of making eye drops more effective in an Oct. 7, 2014 news item on Nanowerk,

Sufferers of eye disorders have new hope after researchers at the University of Reading discovered a potential way of making eye drops more effective.

Typically less than 5% of the medicine dose applied as drops actually penetrates the eye – the majority of the dose will be washed off the cornea by tear fluid and lost.

The team, led by Professor Vitaliy Khutoryanskiy, has developed novel nanoparticles that could attach to the cornea and resist the wash out effect for an extended period of time. If these nanoparticles are loaded with a drug, their longer attachment to the cornea will ensure more medicine penetrates the eye and improves drop treatment.

An Oct. 6, 2014 University of Reading press release, which originated the news item, provides more information about the hoped for impact of this work while providing few details about the research (Note: A link has been removed),

The research could also pave the way for new treatments of currently incurable eye-disorders such as Age-related Macular Degeneration (AMD) – the leading cause of visual impairment with around 500,000 sufferers in the UK.

There is currently no cure for this condition but experts believe the progression of AMD could be slowed considerably using injections of medicines into the eye. However, eye-drops with drug-loaded nanoparticles could be a potentially more effective and desirable course of treatment.

Professor Vitaliy Khutoryanskiy, from the University of Reading’s School of Pharmacy, said: “Treating eye disorders is a challenging task. Our corneas allow us to see and serve as a barrier that protects our eyes from microbial and chemical intervention. Unfortunately this barrier hinders the effectiveness of eye drops. Many medicines administered to the eye are inefficient as they often cannot penetrate the cornea barrier. Only the very small molecules in eye drops can penetrate healthy cornea.

“Many recent breakthroughs to treat eye conditions involve the use of drugs incorporated into nano-containers; their role being to promote drug penetration into the eye.  However the factors affecting this penetration remain poorly understood. Our research also showed that penetration of small drug molecules could be improved by adding enhancers such as cyclodextrins. This means eye drops have the potential to be a more effective, and a more comfortable, future treatment for disorders such as AMD.”

The finding is one of a number of important discoveries highlighted in a paper published today in the journal Molecular Pharmaceutics. The researchers revealed fascinating insights into how the structure of the cornea prevents various small and large molecules, as well as nanoparticles, from entering into the eye. They also examined the effects any damage to the eye would have in allowing these materials to enter the body.

Professor Khutoryanskiy continued: “There is increasing concern about the safety of environmental contaminants, pollutants and nanoparticles and their potential impacts on human health. We tested nanoparticles whose sizes ranged between 21 – 69 nm, similar to the size of viruses such as polio, or similar to airborn particles originating from building industry and found that they could not penetrate healthy and intact cornea irrespective of their chemical nature.

“However if the top layer of the cornea is damaged, either after surgical operation or accidentally, then the eye’s natural defence may be compromised and it becomes susceptible to viral attack which could result in eye infections.

“The results show that our eyes are well-equipped to defend us against potential airborne threats that exist in a fast-developing industrialised world. However we need to be aware of the potential complications that may arise if the cornea is damaged, and not treated quickly and effectively.”

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

On the Barrier Properties of the Cornea: A Microscopy Study of the Penetration of Fluorescently Labeled Nanoparticles, Polymers, and Sodium Fluorescein by Ellina A. Mun, Peter W. J. Morrison, Adrian C. Williams, and Vitaliy V. Khutoryanskiy. Mol. Pharmaceutics, 2014, 11 (10), pp 3556–3564 DOI: 10.1021/mp500332m Publication Date (Web): August 28, 2014

Copyright © 2014 American Chemical Society

There’s a little more information to be had in the paper’s abstract, which is, as these things go, is relatively accessible,

[downloaded from http://pubs.acs.org/doi/abs/10.1021/mp500332m]

[downloaded from http://pubs.acs.org/doi/abs/10.1021/mp500332m]

Overcoming the natural defensive barrier functions of the eye remains one of the greatest challenges of ocular drug delivery. Cornea is a chemical and mechanical barrier preventing the passage of any foreign bodies including drugs into the eye, but the factors limiting penetration of permeants and nanoparticulate drug delivery systems through the cornea are still not fully understood. In this study, we investigate these barrier properties of the cornea using thiolated and PEGylated (750 and 5000 Da) nanoparticles, sodium fluorescein, and two linear polymers (dextran and polyethylene glycol). Experiments used intact bovine cornea in addition to bovine cornea de-epithelialized or tissues pretreated with cyclodextrin. It was shown that corneal epithelium is the major barrier for permeation; pretreatment of the cornea with β-cyclodextrin provides higher permeation of low molecular weight compounds, such as sodium fluorescein, but does not enhance penetration of nanoparticles and larger molecules. Studying penetration of thiolated and PEGylated (750 and 5000 Da) nanoparticles into the de-epithelialized ocular tissue revealed that interactions between corneal surface and thiol groups of nanoparticles were more significant determinants of penetration than particle size (for the sizes used here). PEGylation with polyethylene glycol of a higher molecular weight (5000 Da) allows penetration of nanoparticles into the stroma, which proceeds gradually, after an initial 1 h lag phase.

The paper is behind a paywall. No mention is made in the abstract or in the press release as to how the bovine (ox, cow, or buffalo) eyes were obtained but I gather these body parts are often harvested from animals that have been previously slaughtered for food.

This next item also concerns research about eye drops but this time the work comes from the University of Waterloo (Ontario, Canada). From an Oct. 8, 2014 news item on Azonano,

For the millions of sufferers of dry eye syndrome, their only recourse to easing the painful condition is to use drug-laced eye drops three times a day. Now, researchers from the University of Waterloo have developed a topical solution containing nanoparticles that will combat dry eye syndrome with only one application a week.

An Oct. 8, 2014 University of Waterloo news release (also on EurekAlert), which originated the news item, describes the results of the work without providing much detail about the nanoparticles used to deliver the treatment via eye drops,

The eye drops progressively deliver the right amount of drug-infused nanoparticles to the surface of the eyeball over a period of five days before the body absorbs them.  One weekly dose replaces 15 or more to treat the pain and irritation of dry eyes.

The nanoparticles, about 1/1000th the width of a human hair, stick harmlessly to the eye’s surface and use only five per cent of the drug normally required.

“You can’t tell the difference between these nanoparticle eye drops and water,” said Shengyan (Sandy) Liu, a PhD candidate at Waterloo’s Faculty of Engineering, who led the team of researchers from the Department of Chemical Engineering and the Centre for Contact Lens Research. “There’s no irritation to the eye.”

Dry eye syndrome is a more common ailment for people over the age of 50 and may eventually lead to eye damage. More than six per cent of people in the U.S. have it. Currently, patients must frequently apply the medicine three times a day because of the eye’s ability to self-cleanse—a process that washes away 95 per cent of the drug.

“I knew that if we focused on infusing biocompatible nanoparticles with Cyclosporine A, the drug in the eye drops, and make them stick to the eyeball without irritation for longer periods of time, it would also save patients time and reduce the possibility of toxic exposure due to excessive use of eye drops,” said Liu.

The research team is now focusing on preparing the nanoparticle eye drops for clinical trials with the hope that this nanoparticle therapy could reach the shelves of drugstores within five years.

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

Phenylboronic acid modified mucoadhesive nanoparticle drug carriers facilitate weekly treatment of experimentallyinduced dry eye syndrome by Shengyan Liu, Chu Ning Chang, Mohit S. Verma, Denise Hileeto, Alex Muntz, Ulrike Stahl, Jill Woods, Lyndon W. Jones, and Frank X. Gu. Nano Research (October 2014) DOI: 10.1007/s12274-014-0547-3

This paper is behind a paywall. There is a partial preview available for free. As per the paper’s abstract, research was performed on healthy rabbit eyes.

The last ‘sight’ item I’m featuring here comes from the Massachusetts Institute of Technology (MIT) and does not appear to have been occasioned by the publication of a research paper or some other event. From an Oct. 7, 2014 news item on Azonano,

All through his childhood, Ramesh Raskar wished fervently for eyes in the back of his head. “I had the notion that the world did not exist if I wasn’t looking at it, so I would constantly turn around to see if it was there behind me.” Although this head-spinning habit faded during his teen years, Raskar never lost the desire to possess the widest possible field of vision.

Today, as director of the Camera Culture research group and associate professor of Media Arts and Sciences at the MIT Media Lab, Raskar is realizing his childhood fantasy, and then some. His inventions include a nanocamera that operates at the speed of light and do-it-yourself tools for medical imaging. His scientific mission? “I want to create not just a new kind of vision, but superhuman vision,” Raskar says.

An Oct. 6, 2014 MIT news release, which originated the news item, provides more information about Raskar and his research,

He avoids research projects launched with a goal in mind, “because then you only come up with the same solutions as everyone else.” Discoveries tend to cascade from one area into another. For instance, Raskar’s novel computational methods for reducing motion blur in photography suggested new techniques for analyzing how light propagates. “We do matchmaking; what we do here can be used over there,” says Raskar.

Inspired by the famous microflash photograph of a bullet piercing an apple, created in 1964 by MIT professor and inventor Harold “Doc” Edgerton, Raskar realized, “I can do Edgerton millions of times faster.” This led to one of the Camera Culture group’s breakthrough inventions, femtophotography, a process for recording light in flight.

Manipulating photons into a packet resembling Edgerton’s bullet, Raskar and his team were able to “shoot” ultrashort laser pulses through a Coke bottle. Using a special camera to capture the action of these pulses at half a trillion frames per second with two-trillionths of a second exposure times, they captured moving images of light, complete with wave-like shadows lapping at the exterior of the bottle.

Femtophotography opened up additional avenues of inquiry, as Raskar pondered what other features of the world superfast imaging processes might reveal. He was particularly intrigued by scattered light, the kind in evidence when fog creates the visual equivalent of “noise.”

In one experiment, Raskar’s team concealed an object behind a wall, out of camera view. By firing super-short laser bursts onto a surface nearby, and taking millions of exposures of light bouncing like a pinball around the scene, the group rendered a picture of the hidden object. They had effectively created a camera that peers around corners, an invention that might someday help emergency responders safely investigate a dangerous environment.

Raskar’s objective of “making the invisible visible” extends as well to the human body. The Camera Culture group has developed a technique for taking pictures of the eye using cellphone attachments, spawning inexpensive, patient-managed vision and disease diagnostics. Conventional photography has evolved from time-consuming film development to instantaneous digital snaps, and Raskar believes “the same thing will happen to medical imaging.” His research group intends “to break all the rules and be at the forefront. I think we’ll get there in the next few years,” he says.

Ultimately, Raskar predicts, imaging will serve as a catalyst of transformation in all dimensions of human life — change that can’t come soon enough for him. “I hate ordinary cameras,” he says. “They record only what I see. I want a camera that gives me a superhuman perspective.”

Following the link to the MIT news release will lead you to more information about Raskar and his work. You can also see and hear Raskar talk about his femtophotography in a 2012 TEDGlobal talk here.

Murdoch University (Australia) encourages* bone formation in sheep

It’s time to finally publish this which has been languishing in drafts folder: from a Sept. 16, 2014 news item on Nanowerk (Note: A link has been removed),

Murdoch University [Australia] nanotechnology researchers have successfully engineered synthetic materials which encouraged bone formation in sheep (“The synthesis, characterisation and in vivo study of a bioceramic for potential tissue regeneration applications”).

The advancement means the successful use of synthetic materials in bone grafts for human patients is a step closer. The material could also have potential future applications in fracture repair and reconstructive surgery.

A Sept. 16, 2014 Murdoch University news release, which originated the news item, notes

Currently the patient’s own bone, donated bone or artificial materials are used for bone grafts but limitations with all these options have prompted researchers to investigate how synthetic materials can be enhanced.

Dr Eddy Poinern and his team from the Murdoch Applied Nanotechnology Research Group worked with powdered forms of the bio ceramic hydroxyapatite (HAP) to form pellets with a sponge-like structure which were then successfully implanted behind the shoulders of four sheep by collaborators from the School of Veterinary and Life Sciences at Murdoch University.

HAP is already being used in a number of biomedical applications such as bone augmentation in dentistry because of its similarity to the inorganic mineral component of human bone. But treatments of HAP so that it can be successfully used in a bone graft have yet to be developed because of the complexities involved with compatibility and HAP’s load bearing limitations.

The news release goes on to provide a few technical details,

Dr Poinern and his team prepared pellets with varying density and porosity using a variety of chemical methods including sintering, ultrasound and microwaves. Four pellets were implanted into muscles in each of the sheep, later demonstrating good bio-compatibility, including mixed cell colonisation after four weeks and even new bone formation 12 weeks after the surgery.

“Using synthetic materials in this way is difficult and complicated because they need to be engineered to be porous and to replicate the various physical, chemical and mechanical properties found in natural bone tissue,” explained Dr Poinern.

“They also need to be non-toxic and have a degradation rate which will allow for cells from the host to steadily recolonize the area and permit the formation of blood vessels necessary for the delivery of nutrients to the forming bone tissues.

“We already knew that synthetic HAP was a good material to study for possible use in bone-related medicine, but we needed to find out if the pellets we’d engineered were bio-compatible.

“Our results were very positive – our pellets acted as a scaffold for the growth of bone material, made possible because of its porous properties allowing cells to infiltrate.

“The pellets were also very cost effective to make.”

Although the study was small scale and originally intended to test the bio-compatibility of the HAP pellets, the bone growth was beyond what the interdisciplinary team expected.

Associate Professor Martin Cake, who surgically implanted the pellets into the sheep, described the results as “stunning” and said they boded well for the use of engineered HAP in bone implants.

“This material begins as a powder that can be theoretically moulded to any shape, or perhaps one day even 3D printed, then sintered to harden it,” he said.

Dr Poinern said he was hoping to improve and match the physical and mechanical properties of the pellets with those of natural bone tissue in a new study.

“Once these properties have been achieved, further implantation studies will be carried out to establish the feasibility of using this scaffold for bone grafts,” he said.

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

The synthesis, characterisation and in vivo study of a bioceramic for potential tissue regeneration applications by Gérrard Eddy Jai Poinern, Ravi Krishna Brundavanam, Xuan Thi Le, Philip K. Nicholls, Martin A. Cake, & Derek Fawcett. Scientific Reports 4, Article number: 6235 doi:10.1038/srep06235 Published 29 August 2014

This paper is open access.

This news release included information of a type I haven’t previously seen included,

The implantation study was carried out in non pregnant Merino ewes with the approval of Murdoch University’s Animal Ethics Committee and all experiments were conducted in accordance with the Australian National Health and Medical Research Council’s (NHMRC) Code of Practice for the care and use of animals for scientific purposes.

In accordance with the ethical principles of the Code, the sheep were simultaneously used in an unrelated trial involving surgery of the stifle joints.

After the pellets were removed, the sheep were humanely euthanased.

I’m glad to see the information and hope more research groups follow suit.

One final note, Murdoch University, Eddy Poinern, and Dereck Fawcett have been mentioned here before in an Aug. 1, 2014 posting about ‘green’ chemistry involving eucalyptus leaves, and gold nanoparticles.

* ‘encourage’ corrected to ‘encourages’ on Oct. 7, 2014 at 1315 hours PDT.

‘Glow in the dark’, paint-on bandage heals

Somewhat unexpectedly (to me), this research about a ‘smart’ paint-on bandage is being published by The Optical Society of America (OSA). Here’s more about the work from an Oct. 1, 2014 news item on Nanowerk,

Inspired by a desire to help wounded soldiers, an international, multidisciplinary team of researchers led by Assistant Professor Conor L. Evans at the Wellman Center for Photomedicine of Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) has created a paint-on, see-through, “smart” bandage that glows to indicate a wound’s tissue oxygenation concentration. Because oxygen plays a critical role in healing, mapping these levels in severe wounds and burns can help to significantly improve the success of surgeries to restore limbs and physical functions.

An Oct. 1, 2014 OSA news release (also on EurekAlert), which originated the news item, describes the interest in oxygenation in more detail,

“Information about tissue oxygenation is clinically relevant but is often inaccessible due to a lack of accurate or noninvasive measurements,” explained lead author Zongxi Li, an HMS research fellow on Evans’ team.

Now, the “smart” bandage developed by the team provides direct, noninvasive measurement of tissue oxygenation by combining three simple, compact and inexpensive components: a bright sensor molecule with a long phosphorescence lifetime and appropriate dynamic range; a bandage material compatible with the sensor molecule that conforms to the skin’s surface to form an airtight seal; and an imaging device capable of capturing the oxygen-dependent signals from the bandage with high signal-to-noise ratio.

This work is part of the team’s long-term program “to develop a Sensing, Monitoring And Release of Therapeutics (SMART) bandage for improved care of patients with acute or chronic wounds,” says Evans …

The news release goes on to briefly explain the technology,

For starters, the bandage’s not-so-secret key ingredient is phosphors—molecules that absorb light and then emit it via a process known as phosphorescence.

Phosphorescence is encountered by many on a daily basis—ranging from glow-in-the-dark dials on watches to t-shirt lettering. “How brightly our phosphorescent molecules emit light depends on how much oxygen is present,” said Li. “As the concentration of oxygen is reduced, the phosphors glow both longer and more brightly.” To make the bandage simple to interpret, the team also incorporated a green oxygen-insensitive reference dye, so that changes in tissue oxygenation are displayed as a green-to-red colormap.

The bandage is applied by “painting” it onto the skin’s surface as a viscous liquid, which dries to a solid thin film within a minute. Once the first layer has dried, a transparent barrier layer is then applied atop it to protect the film and slow the rate of oxygen exchange between the bandage and room air—making the bandage sensitive to the oxygen within tissue.

The final piece involves a camera-based readout device, which performs two functions: it provides a burst of excitation light that triggers the emission of the phosphors inside the bandage, and then it records the phosphors’ emission. “Depending on the camera’s configuration, we can measure either the brightness or color of the emitted light across the bandage or the change in brightness over time,” Li said. “Both of these signals can be used to create an oxygenation map.”  The emitted light from the bandage is bright enough that it can be acquired using a regular camera or smartphone—opening the possibility to a portable, field-ready device.

There are some immediate applications, as well as, plans for research that will yield applications (from the news release),

Immediate applications for the oxygen-sensing bandage include monitoring patients with a risk of developing ischemic (restricted blood supply) conditions, postoperative monitoring of skin grafts or flaps, and burn-depth determination as a guide for surgical debridement—the removal of dead or damaged tissue from the body.

“The need for a reliable, accurate and easy-to-use method of rapid assessment of blood flow to the skin for patients remains a clinical necessity,” said co-author Samuel Lin, an HMS associate professor of surgery at Beth Israel Deaconess Medical Center. “Plastic surgeons continuously monitor the state of blood flow to the skin, so the liquid-bandage oxygenation sensor is an exciting step toward improving patient care within the realm of vascular blood flow examination of the skin.”

What’s the next step for the bandage? “We’re developing brighter sensor molecules to improve the bandage’s oxygen sensing efficiency,” said Emmanuel Roussakis, another research fellow in Evans’ laboratory and co-author, who is leading the sensor development effort.  The team’s laboratory research will also focus on expanding the sensing capability of the bandage to other treatment-related parameters—such as pH, bacterial load, oxidative states and specific disease markers—and incorporating an on-demand drug release capacity.

“In the future, our goal for the bandage is to incorporate therapeutic release capabilities that allow for on-demand drug administration at a desired location,” says Evans. “It allows for the visual assessment of the wound bed, so treatment-related wound parameters are readily accessible without the need for bandage removal—preventing unnecessary wound disruption and reducing the chance for bacterial infection.”

Should you be interested, the researchers are looking for industry partners,

Beyond the lab, the team’s aim is to move this technology from the bench to the bedside, so they are actively searching for industry partners. They acknowledge research support from the Military Medical Photonics Program from the U.S. Department of Defense, and National Institutes of Health.

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

Non-invasive transdermal two-dimensional mapping of cutaneous oxygenation with a rapid-drying liquid bandage by Zongxi Li, Emmanuel Roussakis, Pieter G. L. Koolen, Ahmed M. S. Ibrahim, Kuylhee Kim, Lloyd F. Rose, Jesse Wu, Alexander J. Nichols, Yunjung Baek, Reginald Birngruber, Gabriela Apiou-Sbirlea, Robina Matyal, Thomas Huang, Rodney Chan, Samuel J. Lin, and Conor L. Evans. Biomedical Optics Express, Vol. 5, Issue 11, pp. 3748-3764 (2014) http://dx.doi.org/10.1364/BOE.5.003748

This article is open access.

The researcher’s have provided an illustration of the bandage,

Caption: The transparent liquid bandage displays a quantitative, oxygenation-sensitive colormap that can be easily acquired using a simple camera or smartphone. Credit: Li/Wellman Center for Photomedicine.

Caption: The transparent liquid bandage displays a quantitative, oxygenation-sensitive colormap that can be easily acquired using a simple camera or smartphone. Credit: Li/Wellman Center for Photomedicine.