Sensors slip into the brain, then dissolve when the job is done

A team of neurosurgeons and engineers has developed wireless brain sensors that monitor intracranial pressure and temperature and then are absorbed by the body, negating the need for surgery to remove the devices.

Such implants, developed by scientists at Washington University School of Medicine in St. Louis and engineers at the University of Illinois at Urbana-Champaign, potentially could be used to monitor patients with traumatic brain injuries, but the researchers believe they can build similar absorbable sensors to monitor activity in organ systems throughout the body. Their findings are published online Jan. 18 in the journal Nature.

"Electronic devices and their biomedical applications are advancing rapidly," said co-first author Rory K. J. Murphy, MD, a neurosurgery resident at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. "But a major hurdle has been that implants placed in the body often trigger an immune response, which can be problematic for patients. The benefit of these new devices is that they dissolve over time, so you don't have something in the body for a long time period, increasing the risk of infection, chronic inflammation and even erosion through the skin or the organ in which it's placed. Plus, using resorbable devices negates the need for surgery to retrieve them, which further lessens the risk of infection and further complications."

Murphy is most interested in monitoring pressure and temperature in the brains of patients with traumatic brain injury.

About 50,000 people die of such injuries annually in the United States. When patients with such injuries arrive in the hospital, doctors must be able to accurately measure intracranial pressure in the brain and inside the skull because an increase in pressure can lead to further brain injury, and there is no way to reliably estimate pressure levels from brain scans or clinical features in patients.

"However, the devices commonly used today are based on technology from the 1980s," Murphy explained. "They're large, they're unwieldy, and they have wires that connect to monitors in the intensive care unit. They give accurate readings, and they help, but there are ways to make them better."

Murphy collaborated with engineers in the laboratory of John A. Rogers, PhD, a professor of materials science and engineering at the University of Illinois, to build new sensors. The devices are made mainly of polylactic-co-glycolic acid (PLGA) and silicone, and they can transmit accurate pressure and temperature readings, as well as other information.

"With advanced materials and device designs, we demonstrated that it is possible to create electronic implants that offer high performance and clinically relevant operation in hardware that completely resorbs into the body after the relevant functions are no longer needed," Rogers said. "This type of bio-electric medicine has great potential in many areas of clinical care."

The researchers tested the sensors in baths of saline solution that caused them to dissolve after a few days. Next, they tested the devices in the brains of laboratory rats.

Having shown that the sensors are accurate and that they dissolve in the solution and in the brains of rats, the researchers now are planning to test the technology in patients.

"In terms of the major challenges involving size and scale, we've already crossed some key bridges," said co-senior author Wilson Z. Ray, MD, assistant professor of neurological and orthopaedic surgery at Washington University.

In patients with traumatic brain injuries, neurosurgeons attempt to decrease the pressure inside the skull using medications. If pressure cannot be reduced sufficiently, patients often undergo surgery. The new devices could be placed into the brain at multiple locations during such operations.

"The ultimate strategy is to have a device that you can place in the brain -- or in other organs in the body -- that is entirely implanted, intimately connected with the organ you want to monitor and can transmit signals wirelessly to provide information on the health of that organ, allowing doctors to intervene if necessary to prevent bigger problems," Murphy said. "And then after the critical period that you actually want to monitor, it will dissolve away and disappear."

Washington University School of Medicine

Scientists manipulate consciousness in rats

NIH-funded study may guide deep brain stimulation therapies used for neurological disorders

Scientists showed that they could alter brain activity of rats and either wake them up or put them in an unconscious state by changing the firing rates of neurons in the central thalamus, a region known to regulate arousal. The study, published ineLIFE, was partially funded by the National Institutes of Health.

"Our results suggest the central thalamus works like a radio dial that tunes the brain to different states of activity and arousal," said Jin Hyung Lee, Ph.D., assistant professor of neurology, neurosurgery and bioengineering at Stanford University, and a senior author of the study.

Located deep inside the brain the thalamus acts as a relay station sending neural signals from the body to the cortex. Damage to neurons in the central part of the thalamus may lead to problems with sleep, attention, and memory. Previous studies suggested that stimulation of thalamic neurons may awaken patients who have suffered a traumatic brain injury from minimally conscious states.

Dr. Lee's team flashed laser pulses onto light sensitive central thalamic neurons of sleeping rats, which caused the cells to fire. High frequency stimulation of 40 or 100 pulses per second woke the rats. In contrast, low frequency stimulation of 10 pulses per second sent the rats into a state reminiscent of absence seizures that caused them to stiffen and stare before returning to sleep.

"This study takes a big step towards understanding the brain circuitry that controls sleep and arousal," Yejun (Janet) He, Ph.D., program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS).

When the scientists used functional magnetic resonance imaging (fMRI) to scan brain activity, they saw that high and low frequency stimulation put the rats in completely different states of activity.

Cortical brain areas where activity was elevated during high frequency stimulation became inhibited with low frequency stimulation. Electrical recordings confirmed the results. Neurons in the somatosensory cortex fired more during high frequency stimulation of the central thalamus and less during low frequency stimulation.

"Dr. Lee's innovative work demonstrates the power of using imaging technologies to study the brain at work," said Guoying Liu, Ph.D., a program director at the NIH's National Institute of Biomedical Imaging and Bioengineering (NIBIB).

How can changing the firing rate of the same neurons in one region lead to different effects on the rest of the brain?

Further experiments suggested the different effects may be due to a unique firing pattern by inhibitory neurons in a neighboring brain region, the zona incerta, during low frequency stimulation. Cells in this brain region have been shown to send inhibitory signals to cells in the sensory cortex.

Electrical recordings showed that during low frequency stimulation of the central thalamus, zona incerta neurons fired in a spindle pattern that often occurs during sleep. In contrast, sleep spindles did not occur during high frequency stimulation. Moreover, when the scientists blocked the firing of the zona incerta neurons during low frequency stimulation of the central thalamus, the average activity of sensory cortex cells increased.

Although deep brain stimulation of the thalamus has shown promise as a treatment for traumatic brain injury, patients who have decreased levels of consciousness show slow progress through these treatments.

"We showed how the circuits of the brain can regulate arousal states," said Dr. Lee. "We hope to use this knowledge to develop better treatments for brain injuries and other neurological disorders."

National Institute of Neurological Disorders and Stroke

Nanotechnology World Association

Nanocarriers May Carry New Hope for Brain Cancer Therapy

Berkeley Lab Researchers Develop Nanoparticles That Can Carry Therapeutics Across the Brain Blood Barrier

Glioblastoma multiforme, a cancer of the brain also known as “octopus tumors” because of the manner in which the cancer cells extend their tendrils into surrounding tissue, is virtually inoperable, resistant to therapies, and always fatal, usually within 15 months of onset. Each year, glioblastoma multiforme (GBM) kills approximately 15,000 people in the United States. One of the major obstacles to treatment is the blood brain barrier, the network of blood vessels that allows essential nutrients to enter the brain but blocks the passage of other substances. What is desperately needed is a means of effectively transporting therapeutic drugs through this barrier. A nanoscience expert at Lawrence Berkeley National Laboratory (Berkeley Lab) may have the solution.

Ting Xu, a polymer scientist with Berkeley Lab’s Materials Sciences Division who specializes in self-assembling bio/nano hybrid materials, has developed a new family of nanocarriers formed from the self-assembly of amphiphilic peptides and polymers. Called “3HM” for coiled-coil 3-helix micelles, these new nanocarriers meet all the size and stability requirements for effectively delivering a therapeutic drug to GBM tumors. Amphiphiles are chemical compounds that feature both hydrophilic (water-loving) and lipophilic (fat-loving) properties. Micelles are spherical aggregates of amphiphiles.

In a recent collaboration between Xu, Katherine Ferrara at the University of California (UC) Davis, and John Forsayeth and Krystof Bankiewicz of UC San Francisco, 3HM nanocarriers were tested on GBM tumors in rats. Using the radioactive form of copper (copper-64) in combination with positron emission tomography (PET) and magnetic resonance imaging (MRI), the collaboration demonstrated that 3HM can cross the blood brain barrier and accumulate inside GBM tumors at nearly double the concentration rate of current FDA-approved nanocarriers.

“Our 3HM nanocarriers show very good attributes for the treatment of brain cancers in terms of long circulation, deep tumor penetration and low accumulation in off-target organs such as the liver and spleen,” says Xu, who also holds a joint appointment with the UC Berkeley’s Departments of Materials Sciences and Engineering, and Chemistry. “The fact that 3HM is able to cross the blood brain barrier of GBM-bearing rats and selectively accumulate within tumor tissue, opens the possibility of treating GBM via intravenous drug administration rather than invasive measures.

While there is still a lot to learn about why 3HM is able to do what it does, so far all the results have been very positive.”

Glial cells provide physical and chemical support for neurons. Approximately 90-percent of all the cells in the brain are glial cells which, unlike neurons, undergo a cycle of birth, differentiation, and mitosis. Undergoing this cycle makes glial cells vulnerable to becoming cancerous. When they do, as the name “multiforme” suggests, they can take on different shapes, which often makes detection difficult until the tumors are dangerously large. The multiple shapes of a cancerous glial cell also make it difficult to identify and locate all of the cell’s tendrils. Removal or destruction of the main tumor mass while leaving these tendrils intact is ineffective therapy: like the mythical Hydra, the tendrils will sprout new tumors.

Although there are FDA approved therapeutic drugs for the treatment of GBM, these treatments have had little impact on patient survival rate because the blood brain barrier has limited the accumulation of therapeutics within the brain. Typically, GBM therapeutics are ferried across the blood brain barrier in special liposomes that are approximately 110 nanometers in size. The 3HM nanocarriers developed by Xu and her group are only about 20 nanometers in size. Their smaller size and unique hierarchical structure afforded the 3HM nanocarriers much greater access to rat GBM tumors than 110-nanometer liposomes in the tests carried out by Xu and her colleagues.

“3HM is a product of basic research at the interface of materials science and biology,” Xu says. “When I first started at Berkeley, I explored hybrid nanomaterials based on proteins, peptides and polymers as a new family of biomaterials. During the process of understanding the hierarchical assembly of amphiphilic peptide-polymer conjugates, my group and I noticed some unusual behavior of these micelles, especially their unusual kinetic stability in the 20 nanometer size range.

We looked into critical needs for nanocarriers with these attributes and identified the treatment of GBM cancer as a potential application.”

Copper-64 was used to label both 3HM and liposome nanocarriers for systematic PET and MRI studies to find out how a nanocarrier’s size might affect the pharmacokinetics and biodistribution in rats with GBM tumors. The results not only confirmed the effectiveness of 3HM as GBM delivery vessels, they also suggest that PET and MRI imaging of nanoparticle distribution and tumor kinetics can be used to improve the future design of nanoparticles for GBM treatment.

“I thought our 3HM hybrid materials could bring new therapeutic opportunities for GBM but I did not expect it to happen so quickly,” says Xu, who has been awarded a patent for the 3HM technology.

A paper describing this research has been published in The Journal of Controlled Release. The paper is titled “Self-assembled 20-nm 64Cu-micelles enhance accumulation in rat glioblastoma.”

Xu, Ferrara and Bankiewicz are the senior authors. Other authors, in addition to Forsayeth, are Jai Woong Seo, Joo Chuan Ang, Lisa Mahakian, Sarah Tam, Brett Fite, Elizabeth Ingham and Janine Beyer.

This research was funded by the National Institutes of Health and the UC Davis Research Investments in Science and Engineering.

Lawrence Berkeley National Laboratory

Tracking individual carbon atoms deep into the brain’s neurons

Using a geologist’s imaging tool, researchers have made unprecedented high-resolution images of how carbon atoms from glucose are integrated into brain cells, providing new insight and opening new doors into the fate of glucose in the brain.

Glucose – a form of sugar – fuels the brain. But how it goes from the blood to the brain cells and where it ultimately winds up are not yet well understood. Harnessing the power of a special kind of microscope that was used for the first time to image metabolism of the brain, researchers from EPFL, the Nestlé Health Institute, and the University of Lausanne have tracked the fate of individual carbon atoms deep into the brain’s neurons and astrocytes. Their work, published in the Journal of Chemical Neuroanatomy, paves the way for a better understanding of how healthy and diseased brains metabolize glucose, which in the future could contribute to the development of new methods to diagnose and treat neurological diseases.

“Half of the glucose we have in our blood is consumed by our brain; this we know. But what we don’t know, at least not in detail, is what this glucose is used for and where it winds up,” says Arnaud Comment, one of the study’s lead investigators. The reason for this is that existing experimental methods have been unable to conclusively resolve this question. But thanks to a microscope originally developed to study the isotopic composition of rock samples called a NanoSIMS, it looks like researchers may finally have a tool to help them find an answer.

“The NanoSIMS gives us a view of what goes on at the sub-cellular level that nobody has had access to before. It is an example of a geochemical technology that is being pushed into the realm of life sciences through a cross-campus collaboration,” says Meibom, whose EPFL research lab runs the NanoSIMS, the only one of its kind in Switzerland. Combining transmission electron microscopy (TEM) with secondary ion mass spectroscopy, the device lets researchers locate trace amounts of labeled atoms down to a resolution of only a few hundred nanometers.

“In this study, we imaged the fate of glucose, the brain’s main energy source, at the cellular level,” says Meibom, who is also the study’s second lead investigator. “Our question was: where is the brain putting its money? We do not have an answer quite yet, but we do have data showing that after a few hours, neurons have accumulated more carbon from the glucose in their structure than astrocytes. We can find high concentrations of carbon atoms from the glucose in the neurons’ nuclei and other cellular compartments – a sign of increased metabolic activity.”

While their findings neither refute nor validate current theory holding that astrocytes extract glucose from the blood stream and deliver some of it to neurons, they provide an unprecedented and very accurate snapshot into exactly where the carbon from the glucose is going in the brain.

But, the researchers hope, their method could help determine the early metabolic signature of certain types of disease, which could be a boon to research and the development of treatment strategies. Catching the onset of Alzheimer’s, for example, is complicated by the fact that, by the time the structure of the brain’s cells is visibly affected, it is already too late. Instead, more subtle cues would have to be picked up, such as changes to the cells’ metabolism – the chemical reactions that sustain them, providing them with energy and matter. Changes in glucose metabolism of specific parts of the brain could, for example, provide an early warning for the onset of Alzheimer’s.

Today, the NanoSIMS lets researchers study the incorporation of labeled atoms into solid structures, but Meibom wants to take it one step further. “We are working on extending the capabilities of the NanoSIMS to be able to work with frozen samples, giving us a means of visualizing soluble compounds as well. Using such a CryoNanoSIMS, we will not only be able to see where specific compounds have been integrated into the proteins that make up the cell, but we will also be able to trace their dissolved metabolite precursors,” he says.

Reference: Yuhei Takado et al. Imaging the time-integrated cerebral metabolic activity with subcellular resolution through nanometer-scale detection of biosynthetic products deriving from 13C-glucose, Journal of Chemical Neuroanatomy, Available online 25 September 2015,

EPFL

Injectable electronics promise sharper view of brain

It’s a notion that might have come from the pages of a science-fiction novel — an electronic device that can be injected directly into the brain, or other body parts, and treat everything from neurodegenerative disorders to paralysis.

Sounds unlikely, until you visit Charles Lieber’s lab.

Led by Lieber, the Mark Hyman Jr. Professor of Chemistry, an international team of researchers has developed a method of fabricating nanoscale electronic scaffolds that can be injected via syringe. The scaffolds can then be connected to devices and used to monitor neural activity, stimulate tissues, or even promote regeneration of neurons. The research is described in a June 8 paper in Nature Nanotechnology.

Contributors to the work include Jia Liu, Tian-Ming Fu, Zengguang Cheng, Guosong Hong, Tao Zhou, Lihua Jin, Madhavi Duvvuri, Zhe Jiang, Peter Kruskal, Chong Xie, Zhigang Suo, and Ying Fang.

“I do feel that this has the potential to be revolutionary,” Lieber said. “This opens up a completely new frontier where we can explore the interface between electronic structures and biology. For the past 30 years, people have made incremental improvements in micro-fabrication techniques that have allowed us to make rigid probes smaller and smaller, but no one has addressed this issue — the electronics/cellular interface — at the level at which biology works.”

In an earlier study, scientists in Lieber’s lab demonstrated that cardiac or nerve cells grown with embedded scaffolds could be used to create “cyborg” tissue. Researchers were then able to record electrical signals generated by the tissue, and to measure changes in those signals as they administered cardio- or neuro-stimulating drugs.

“We were able to demonstrate that we could make this scaffold and culture cells within it, but we didn’t really have an idea how to insert that into pre-existing tissue,” Lieber said. “But if you want to study the brain or develop the tools to explore the brain-machine interface, you need to stick something into the body. When releasing the electronics scaffold completely from the fabrication substrate, we noticed that it was almost invisible and very flexible, like a polymer, and could literally be sucked into a glass needle or pipette. From there, we simply asked, ‘Would it be possible to deliver the mesh electronics by syringe needle injection?’”

Though not the first attempt at implanting electronics into the brain — deep brain stimulation has been used to treat a variety of disorders for decades — the nanofabricated scaffolds operate on a completely different scale.

“Existing techniques are crude relative to the way the brain is wired,” Lieber said. “Whether it’s a silicon probe or flexible polymers … they cause inflammation in the tissue that requires periodically changing the position or the stimulation.

“But with our injectable electronics, it’s as if it’s not there at all. They are one million times more flexible than any state-of-the-art flexible electronics and have subcellular feature sizes. They’re what I call ‘neuro-philic’ — they actually like to interact with neurons.”

The process for fabricating the scaffolds is similar to that used to etch microchips, and begins with a dissolvable layer deposited on a substrate. To create the scaffold, researchers lay out a mesh of nanowires sandwiched in layers of organic polymer. The first layer is then dissolved, leaving the flexible mesh, which can be drawn into a needle and administered like any other injection.

The input-output of the mesh can then be connected to standard measurement electronics so that the integrated devices can be addressed and used to stimulate or record neural activity.

“These type of things have never been done before, from both a fundamental neuroscience and medical perspective,” Lieber said. “It’s really exciting — there are a lot of potential applications.”

Going forward, researchers hope to better understand how the body reacts to the injectable electronics over longer periods.

Harvard’s Office of Technology Development has filed for a provisional patent on the technology and is actively seeking commercialization opportunities.

“The idea of being able to precisely position and record from very specific areas, or even from specific neurons over an extended period of time — this could, I think, make a huge impact on neuroscience,” Lieber said.

Source: http://www.nanotechnologyworld.org/#!Injectable-electronics-promise-sharper-view-of-brain/c89r/5575efe90cf219f1772f8682