International trial evaluates focused ultrasound for essential tremor

A study published today in the prestigious New England Journal of Medicine offers the most in-depth assessment yet of the safety and effectiveness of a high-tech alternative to brain surgery to treat the uncontrollable shaking caused by the most common movement disorder. And the news is very good.

The paper outlines the results of an international clinical trial, led by Jeff Elias, MD, of the UVA Health System, that evaluated the scalpel-free approach called focused ultrasound for the treatment of essential tremor (ET), a condition that afflicts an estimated 10 million Americans. Not only did the researchers determine that the procedure was safe and effective, they found that it offered a lasting benefit, reducing shaking for trial participants throughout the 12-month study period.

“This study represents a major advance for neurosurgery, treatment of brain disease and specifically the treatment of ET,” Elias said. “For the first time in a randomized controlled trial, we have shown that ultrasound can be precisely delivered through the intact human skull to treat a difficult neurological disease.”

Pioneering tremor trial

The multi-site clinical trial included 76 participants with moderate to severe essential tremor, a condition that often robs people of their ability to write, feed themselves and carry out their normal daily activities. The trial participants all had tried existing medications, without success. The mean age was 71, and most had suffered with their tremor for many years.

Seventy-five percent of participants received the experimental treatment using focused ultrasound guided by magnetic resonance imaging. The remaining 25 percent underwent a sham procedure, to act as the control group. (They were later given the opportunity to undergo the real procedure.)

Participants who received the treatment showed dramatic improvement, with the beneficial effects continuing throughout the study period. The researchers employed a 32-point scale to assess tremor severity, and they found that mean tremor scores improved by 47 percent at three months and 40 percent at 12 months. Participants reported major improvements in their quality of life. People who couldn’t feed themselves soup or cereal could again do so.

Participants who received the sham procedure, on the other hand, showed no significant improvements.

“The degree of tremor control was very good overall in the study, but the most important aspects were the significant gains in disabilities and quality of life – that’s what patients really care about,” Elias said.

The most commonly reported side effects were gait disturbances and numbness in the hand or face; in most instances, these side effects were temporary but some were permanent.

Full story can be found from University of Virginia website.




No more dry mucous membranes when flying

Hovering at around 20 percent, the relative humidity in aircraft is kept very low to keep condensation from building up in the cabin. The downside for passengers and the crew is that this dries out the mucous membranes. Now a vortex ring generator will direct humidified air to passengers, increasing the humidity of the air they breathe without causing the overall relative humidity to skyrocket.

Your throat is dry, and taking a drink of water offers only brief respite: that is because the air humidity in aircraft is sometimes not even 20 percent. This has to do with the flight altitude and the low outside temperatures encountered at this height: not only does the air contain very little moisture, it also cools the aircraft fuselage. If the inside air were more humid, additional water would condense on the shell. All the same, the dry climate is unpleasant for passengers.

Vortex rings to supply humidified air

Now a new technology from the Fraunhofer Institute for Building Physics IBP in Valley aims to solve the problem in the future. “A vortex ring generator humidifies the air in passengers’ breathing zones, thereby increasing comfort levels without any material increase in the overall relative humidity in the cabin,” says Thomas Kirmayr, group manager at Fraunhofer IBP. The basic principle is that a generator produces small vortex rings of humid air – rather like the rings sometimes expelled by smokers. The vortex effect keeps the rings stable over a certain distance while preventing them from mixing to any significant extent with the surrounding air. The researchers have designed the generator so that the vortex rings make contact with the passengers’ upper torso; body heat then causes them to rise towards the nose and mouth. Since the chest area is covered by clothing, it is less sensitive than the face would be to the light airflow. The researchers’ goal is to increase air humidity in the breathing zone by up to 15 percent to reach a level of around 30 percent. This can be done by conditioning a minimal amount of air directed in the form of vortex rings exactly where it is needed.
Dummy helps in testing

The generator itself resembles an air pump; its pistons are driven by a linear motor. For the demonstration, the researchers produce the rings using smoke instead of water – this makes them easy to see. First tests have now been conducted with the prototype, using a dummy as the test subject. The dummy comes with an artificial nose that takes in and analyzes the air. This helps the researchers to pin down the system’s basic settings, for instance the size of the rings, and the pace and rate at which they are expelled. There are plans to use real human test subjects for the final fine tuning.

Another step involves humidifying the air. Here the researchers are drawing on a development from another of Fraunhofer IBP’s projects: a membrane that separates water from air, with the concentration gradient forcing water molecules through the membrane. The amount of water that is permitted into the air can be regulated via the membrane’s active surface area and the temperature of the water – the bigger the active surface and the higher the water temperature, the more moisture enters the air. Meanwhile, the distance the vortex ring travels before breaking up is regulated by the original impulse delivered to it.

The vortex rings can deliver more than just humidified air; another potential application could be to use vortex rings to channel the fragrances increasingly used in ventilation systems. However, since this could also reach people with allergies, it would have to be in minimal doses and only at the request of the passenger. “The certification process in the aviation industry is extremely long, and it will be some time before the system is employed in aircraft,” says Kirmayr. “Our plan is to integrate the generator into the back of the seats.”

More information can be found from Fraunhofer Institute Website.

ReliantHeart’s aVAD Gets CE Mark

ReliantHeart’s next-generation aVAD left ventricular assist device has just earned CE Mark approval and implants are set to begin in September.

The LVAD market is going through an evolution right now as major commercial players Thoratec and HeartWare have both been acquired by large medtech companies. Thoratec was acquired by St. Jude Medical last year; St. Jude Medical has since been purchased by Abbott ($ABT). Medtronic ($MDT) announced its acquisition of HeartWare in June.

Manufacturing of the aVAD is underway and 65 units are scheduled to be shipped in September and October, with 100 pumps expected to be available by year end, according to Ford. Pricing for the aVAD is expected to be equivalent to Thoratec’s HeartMate 3 LVAD.

Implants are set to start in Europe in September, with plans for a controlled launch at centers in Germany, Turkey, and London first. Up to 50 patients will be implanted and Ford said data will be collected at several timepoints after the procedure, including one, seven, 30, 90, and 160 days, or at the time of any adverse event. Some of the centers that will be part of the controlled launch are already familiar with ReliantHeart’s HeartAssist5 LVAD, which has had CE Mark since 2013.

Surgeons will be able to implant the aVAD using the surgical approach of their choice, including a sternotomy or a left thoracotomy. “It’s going to be dealer’s choice,” Ford said. “Why limit it? Some of these [surgeons] are really good at left thoracotomies. Let them do it.”

The novel features aVAD offers may mean some surgeons need training to optimize its capabilities. Ford explained that because other LVADs have a calculated flow measurement, as opposed to the flow sensor aVAD uses, “the first thing [physicians] need to do is trust the flow.” In addition, clinicians will need to gain experience with remote monitoring. Physicians will need to “set the alarms properly so that the thresholds for low flow or high power provide an advance warning of something that could be a bad outcome,” Ford said.

ReliantHeart was able to attain CE Mark for aVAD without a trial because the pump’s blood path is the same as the company’s HeartAssist 5 LVAD, which already has CE Mark. “We’ve made this really powerful new pump but the blood path is exactly the same,” Ford said.

An FDA animal trial is scheduled to begin this month and ReliantHeart is still anticipating a human FDA IDE trial to begin in early 2017. The animal trial is studying the aVAD with a disconnectable cable—a feature that is not yet incorporated into the CE Mark device. Once the aVAD with a disconnectable cable has been studied in animals, it will be substituted into Europe.

That disconnectable cable is important because it is intended to reduce the need for LVAD pump replacements due to driveline infections. It also is a stepping stone to ReliantHeart’s next goal—the Liberty, a wirelessly-powered, fully implantable LVAD that would allow patients to live without being tethered to a battery pack or a cable emerging from their body.

A press release can be found from ReliantHeart website.

Sprinkling of neural dust opens door to electroceuticals

UC Berkeley engineers have built the first dust-sized, wireless sensors that can be implanted in the body, bringing closer the day when a Fitbit-like device could monitor internal nerves, muscles or organs in real time.

Because these batteryless sensors could also be used to stimulate nerves and muscles, the technology also opens the door to “electroceuticals” to treat disorders such as epilepsy or to stimulate the immune system or tamp down inflammation.

The so-called neural dust, which the team implanted in the muscles and peripheral nerves of rats, is unique in that ultrasound is used both to power and read out the measurements. Ultrasound technology is already well-developed for hospital use, and ultrasound vibrations can penetrate nearly anywhere in the body, unlike radio waves, the researchers say.

“I think the long-term prospects for neural dust are not only within nerves and the brain, but much broader,“ said Michel Maharbiz, an associate professor of electrical engineering and computer sciences and one of the study’s two main authors. “Having access to in-body telemetry has never been possible because there has been no way to put something supertiny superdeep. But now I can take a speck of nothing and park it next to a nerve or organ, your GI tract or a muscle, and read out the data.“

Maharbiz, neuroscientist Jose Carmena, a professor of electrical engineering and computer sciences and a member of the Helen Wills Neuroscience Institute, and their colleagues will report their findings in the August 3 issue of the journal Neuron.

The sensors, which the researchers have already shrunk to a 1 millimeter cube – about the size of a large grain of sand – contain a piezoelectric crystal that converts ultrasound vibrations from outside the body into electricity to power a tiny, on-board transistor that is in contact with a nerve or muscle fiber. A voltage spike in the fiber alters the circuit and the vibration of the crystal, which changes the echo detected by the ultrasound receiver, typically the same device that generates the vibrations. The slight change, called backscatter, allows them to determine the voltage.

Motes sprinkled thoughout the body

In their experiment, the UC Berkeley team powered up the passive sensors every 100 microseconds with six 540-nanosecond ultrasound pulses, which gave them a continual, real-time readout. They coated the first-generation motes – 3 millimeters long, 1 millimeter high and 4/5 millimeter thick – with surgical-grade epoxy, but they are currently building motes from biocompatible thin films which would potentially last in the body without degradation for a decade or more.

While the experiments so far have involved the peripheral nervous system and muscles, the neural dust motes could work equally well in the central nervous system and brain to control prosthetics, the researchers say. Today’s implantable electrodes degrade within 1 to 2 years, and all connect to wires that pass through holes in the skull. Wireless sensors – dozens to a hundred – could be sealed in, avoiding infection and unwanted movement of the electrodes.

“The original goal of the neural dust project was to imagine the next generation of brain-machine interfaces, and to make it a viable clinical technology,” said neuroscience graduate student Ryan Neely. “If a paraplegic wants to control a computer or a robotic arm, you would just implant this electrode in the brain and it would last essentially a lifetime.”

In a paper published online in 2013, the researchers estimated that they could shrink the sensors down to a cube 50 microns on a side – about 2 thousandths of an inch, or half the width of a human hair. At that size, the motes could nestle up to just a few nerve axons and continually record their electrical activity.

“The beauty is that now, the sensors are small enough to have a good application in the peripheral nervous system, for bladder control or appetite suppression, for example,“ Carmena said. “The technology is not really there yet to get to the 50-micron target size, which we would need for the brain and central nervous system. Once it’s clinically proven, however, neural dust will just replace wire electrodes. This time, once you close up the brain, you’re done.“

The team is working now to miniaturize the device further, find more biocompatible materials and improve the surface transceiver that sends and receives the ultrasounds, ideally using beam-steering technology to focus the sounds waves on individual motes. They are now building little backpacks for rats to hold the ultrasound transceiver that will record data from implanted motes.

They’re also working to expand the motes’ ability to detect non-electrical signals, such as oxygen or hormone levels.

“The vision is to implant these neural dust motes anywhere in the body, and have a patch over the implanted site send ultrasonic waves to wake up and receive necessary information from the motes for the desired therapy you want,” said Dongjin Seo, a graduate student in electrical engineering and computer sciences. “Eventually you would use multiple implants and one patch that would ping each implant individually, or all simultaneously.”

Ultrasound vs radio

Maharbiz and Carmena conceived of the idea of neural dust about five years ago, but attempts to power an implantable device and read out the data using radio waves were disappointing. Radio attenuates very quickly with distance in tissue, so communicating with devices deep in the body would be difficult without using potentially damaging high-intensity radiation.

Marharbiz hit on the idea of ultrasound, and in 2013 published a paper with Carmena, Seo and their colleagues describing how such a system might work. “Our first study demonstrated that the fundamental physics of ultrasound allowed for very, very small implants that could record and communicate neural data,” said Maharbiz. He and his students have now created that system.

“Ultrasound is much more efficient when you are targeting devices that are on the millimeter scale or smaller and that are embedded deep in the body,” Seo said. “You can get a lot of power into it and a lot more efficient transfer of energy and communication when using ultrasound as opposed to electromagnetic waves, which has been the go-to method for wirelessly transmitting power to miniature implants”

“Now that you have a reliable, minimally invasive neural pickup in your body, the technology could become the driver for a whole gamut of applications, things that today don’t even exist,“ Carmena said.

Full story can be found from UC Berkeley website.

Zimmer Biomet Strengthens Musculoskeletal Diagnostic Offering with Acquisition of CD Diagnostics

Zimmer Biomet announced the acquisition of CD Diagnostics, a fully-integrated, Delaware-based diagnostics company focused on developing immunoassays and biomarker testing to inform treatment decisions that improve patient outcomes. The financial terms of the transaction were not disclosed.

Zimmer Biomet and CD Diagnostics initially partnered in 2012 to co-develop and market diagnostics in the field of musculoskeletal healthcare. As part of the original agreement, Zimmer Biomet successfully marketed the Synovasure® Periprosthetic Joint Infection (PJI) test, the first and only test specifically designed and validated for the diagnosis of PJI.

“I formed CD Diagnostics to solve the frustrating problem of diagnosing PJI and the complications associated with misdiagnosis, including the pain and incremental costs-of-care following joint replacement surgery. As a leader and visionary in musculoskeletal healthcare, Zimmer Biomet is the ideal partner to leverage our expertise in biomarker detection and immunoassay development, and to elevate the value of diagnostics in the treatment of musculoskeletal conditions,” said Carl Deirmengian, M.D., Scientific Founder of CD Diagnostics.

“Our acquisition of CD Diagnostics cements our leadership and competitive advantage in musculoskeletal diagnostics, strengthens our Signature Solutions™ offering, and advances our mission to provide comprehensive musculoskeletal healthcare,” said Dan Williamson, Group President, Joint Reconstruction for Zimmer Biomet. “As value-based healthcare replaces fee-for-service models, there will be a growing need for diagnostics that can either prevent or minimize costly complications, or personalize the course of treatment to speed up recovery time and optimize the patient experience and, ultimately, the patient’s outcome.”

Mr. Williamson added, “We’re excited to team up with CD Diagnostics to accelerate the pace of innovation in musculoskeletal diagnostics, ramp up adoption of testing into standard protocols, and arm surgeons with critical data to inform diagnosis, staging, treatment and recovery.”

CD Diagnostics is focused on analyzing biomarker profiles for various clinical conditions in synovial fluid (a viscous fluid that reduces friction between articular cartilage), and creating diagnostic assays that help physicians make informed decisions that optimize patient care. More than 40,000 samples have been evaluated at CD Diagnostics’ laboratories resulting in more than 15 peer-reviewed publications.

“The Synovasure test is having an impact on patient outcomes because with this new test device, we are able to detect the periprosthetic infection with high accuracy. This is the first time we are able to tell the patient if they have an infection within hours of testing,” said Prof. Dr. Thorsten Gehrke, Helios Indo-Klinik, Hamburg, Germany.

A press release can be found from Zimmer website.

Recording analog memories in human cells

MIT biological engineers have devised a way to record complex histories in the DNA of human cells, allowing them to retrieve “memories” of past events, such as inflammation, by sequencing the DNA.

This analog memory storage system — the first that can record the duration and/or intensity of events in human cells — could also help scientists study how cells differentiate into various tissues during embryonic development, how cells experience environmental conditions, and how they undergo genetic changes that lead to disease.

“To enable a deeper understanding of biology, we engineered human cells that are able to report on their own history based on genetically encoded recorders,” says Timothy Lu, an associate professor of electrical engineering and computer science, and of biological engineering. This technology should offer insights into how gene regulation and other events within cells contribute to disease and development, he adds.

Lu, who is head of the Synthetic Biology Group at MIT’s Research Laboratory of Electronics, is the senior author of the new study, which appears in the Aug. 18 online edition of Science. The paper’s lead authors are Samuel Perli SM ’10, PhD ’15 and graduate student Cheryl Cui.

Analog memory

Many scientists, including Lu, have devised ways to record digital information in living cells. Using enzymes called recombinases, they program cells to flip sections of their DNA when a particular event occurs, such as exposure to a particular chemical. However, that method reveals only whether the event occurred, not how much exposure there was or how long it lasted.

Lu and other researchers have previously devised ways to record that kind of analog information in bacteria, but until now, no one has achieved it in human cells.

The new MIT approach is based on the genome-editing system known as CRISPR, which consists of a DNA-cutting enzyme called Cas9 and a short RNA strand that guides the enzyme to a specific area of the genome, directing Cas9 where to make its cut.

CRISPR is widely used for gene editing, but the MIT team decided to adapt it for memory storage. In bacteria, where CRISPR originally evolved, the system records past viral infections so that cells can recognize and fight off invading viruses.

“We wanted to adapt the CRISPR system to store information in the human genome,” Perli says.

When using CRISPR to edit genes, researchers create RNA guide strands that match a target sequence in the host organism’s genome. To encode memories, the MIT team took a different approach: They designed guide strands that recognize the DNA that encodes the very same guide strand, creating what they call “self-targeting guide RNA.”

Led by this self-targeting guide RNA strand, Cas9 cuts the DNA encoding the guide strand, generating a mutation that becomes a permanent record of the event. That DNA sequence, once mutated, generates a new guide RNA strand that directs Cas9 to the newly mutated DNA, allowing further mutations to accumulate as long as Cas9 is active or the self-targeting guide RNA is expressed.

By using sensors for specific biological events to regulate Cas9 or self-targeting guide RNA activity, this system enables progressive mutations that accumulate as a function of those biological inputs, thus providing genomically encoded memory.

For example, the researchers engineered a gene circuit that only expresses Cas9 in the presence of a target molecule, such as TNF-alpha, which is produced by immune cells during inflammation. Whenever TNF- alpha is present, Cas9 cuts the DNA encoding the guide sequence, generating mutations. The longer the exposure to TNF-alpha or the greater the TNF-alpha concentration, the more mutations accumulate in the DNA sequence.

By sequencing the DNA later on, researchers can determine how much exposure there was.

“This is the rich analog behavior that we are looking for, where, as you increase the amount or duration of TNF-alpha, you get increases in the amount of mutations,” Perli says.

“Moreover, we wanted to test our system in living animals. Being able to record and extract information from live cells in mice can help answer meaningful biological questions,” Cui says. The researchers showed that the system is capable of recording inflammation in mice.

Most of the mutations result in deletion of part of the DNA sequence, so the researchers designed their RNA guide strands to be longer than the usual 20 nucleotides, so they won’t become too short to function. Sequences of 40 nucleotides are more than long enough to record for a month, and the researchers have also designed 70-nucleotide sequences that could be used to record biological signals for even longer.

Tracking development and disease

The researchers also showed that they could engineer cells to detect and record more than one input, by producing multiple self-targeting RNA guide strands in the same cell. Each RNA guide is linked to a specific input and is only produced when that input is present. In this study, the researchers showed that they could record the presence of both the antibiotic doxycycline and a molecule known as IPTG.

Currently this method is most likely to be used for studies of human cells, tissues, or engineered organs, the researchers say. By programming cells to record multiple events, scientists could use this system to monitor inflammation or infection, or to monitor cancer progression. It could also be useful for tracing how cells specialize into different tissues during development of animals from embryos to adults.

“With this technology you could have different memory registers that are recording exposures to different signals, and you could see that each of those signals was received by the cell for this duration of time or at that intensity,” Perli says. “That way you could get closer to understanding what’s happening in development.”

Full story can be found from MIT website.