The Technion Researchers Find to NanoParticles may Threaten Heart

Nanoparticles, extremely tiny particles measured in billionths of a meter, are increasingly everywhere, and especially in biomedical products. Their toxicity has been researched in general terms, but now a team of Israeli scientists has for the first time found that exposure nanoparticles (NPs) of silicon dioxide (SiO2) can play a major role in the development of cardiovascular diseases when the NP cross tissue and cellular barriers and also find their way into the circulatory system. Their study is published in the December 2014 issue of Environmental Toxicology.

Prof. Michael Aviram
The research team was comprised of scientists from the Technion Rappaport Faculty of Medicine, Rambam Medical Center, and the Center of Excellence in Exposure Science and Environmental Health (TCEEH).

“Environmental exposure to nanoparticles is becoming unavoidable due to the rapid expansion of nanotechnology,” says the study’s lead author, Prof. Michael Aviram, of the Technion Faculty of Medicine, “This exposure may be especially chronic for those employed in research laboratories and in high tech industry where workers handle, manufacture, use and dispose of nanoparticles. Products that use silica-based nanoparticles for biomedical uses, such as various chips, drug or gene delivery and tracking, imaging, ultrasound therapy, and diagnostics, may also pose an increased cardiovascular risk for consumers as well.”

In this study, researchers exposed cultured laboratory mouse cells resembling the arterial wall cells to NPs of silicon dioxide and investigated the effects. SiO2 NPs are toxic to and have significant adverse effects on macrophages. a type of white blood cell that take up lipids, leading to atherosclerotic lesion development and its consequent cardiovascular events, such as heart attack or stroke. Macrophages accumulation in the arterial wall under atherogenic conditions such as high cholesterol, triglycerides, oxidative stress – are converted into lipids, or laden “foam cells” which, in turn, accelerate atherosclerosis development.

“Macrophage foam cells accumulation in the arterial wall are a key cell type in the development of atherosclerosis, which is an inflammatory disease” says co-author Dr. Lauren Petrick. “The aims of our study were to gain additional insight into the cardiovascular risk associated with silicon dioxide nanoparticle exposure and discover the mechanisms behind Si02’s induced atherogenic effects on macrophages. We also wanted to use nanoparticles as a model for ultrafine particle (UFP) exposure as cardiovascular disease risk factors.”

Both NPs and UFPs can be inhaled and induce negative biological effects. However, until this study, their effect on the development of atherosclerosis has been largely unknown. Here, researchers have discovered for the first time that the toxicity of silicon dioxide nanoparticles has a “significant and substantial effect on the accumulation of triglycerides in the macrophages,” at all exposure concentrations analyzed, and that they also “increase oxidative stress and toxicity.”

A recent update from the American Heart Association also suggested that “fine particles” in air pollution leads to elevated risk for cardiovascular diseases. However, more research was needed to examine the role of “ultrafine particles” (which are much smaller than “fine particles”) on atherosclerosis development and cardiovascular risk.

“The number of nano-based consumer products has risen a thousand fold in recent years, with an estimated world market of $3 trillion by the year 2020,” conclude the researchers. “This reality leads to increased human exposure and interaction of silica-based nanoparticles with biological systems. Because our research demonstrates a clear cardiovascular health risk associated with this trend, steps need to be taken to help ensure that potential health and environmental hazards are being addressed at the same time as the nanotechnology is being developed.

The Technion-Israel Institute of Technology is a major source of the innovation and brainpower that drives the Israeli economy, and a key to Israel’s renown as the world’s “Start-Up Nation.” Its three Nobel Prize winners exemplify academic excellence. Technion people, ideas and inventions make immeasurable contributions to the world including life-saving medicine, sustainable energy, computer science, water conservation and nanotechnology. The Joan and Irwin Jacobs Technion-Cornell Institute is a vital component of Cornell NYC Tech, and a model for graduate applied science education that is expected to transform New York City’s economy.

American Technion Society (ATS) donors provide critical support for the Technion—more than $1.95 billion since its inception in 1940. Based in New York City, the ATS and its network of chapters across the U.S. provide funds for scholarships, fellowships, faculty recruitment and chairs, research, buildings, laboratories, classrooms and dormitories, and more.

Source: ATS

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Adults Sought for Study on Aging and Mobility

                                                               Walking stickman
The Biomechanics Laboratory in the kinesiology department is recruiting volunteers for a study about the effects of age and exercise on walking and muscle function. The researchers hope to learn about how changes in muscle function with age are related to the onset of disability.

The lab is looking for individuals who meet the following criteria: ages 55-70 with healthy body weight who participate in fewer than five 30-minute bouts of exercise per week (or less than a total of 150 minutes of planned exercise per week), no history of reconstructive surgery of the legs, no major health issues (heart disease, diabetes, neurological disease), able to walk for 30 minutes and no contraindications to MRI (metal implant, claustrophobia).

The study consists of two visits: a 1-hour visit to an MRI facility in Amherst and one 3-hour visit to the Biomechanics Lab on campus. During the lab visit researchers will collect data on how participants’ joints move as they walk over the ground and on a treadmill. The study will also collect data on the strength of the muscles in participants’ thighs. All procedures are non-invasive.

Source: UMass

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Virtual reality speeds up rehabilitation: Integrating force feedback into therapies

A child is receiving virtual door opening training under the guidance of a therapist. Credit: Copyright The Hong Kong Polytechnic University

The Hong Kong Polytechnic University has successfully developed a novel training programme using haptic technology for impaired hands that cannot function normally. This programme is unique as it provides force feedback, which creates a true sense of weight to the user through the control device.

Our hands are essential to our lives; we need them in all daily tasks including eating, bathing and getting dressed. However, even the simplest tasks are challenging for people with impaired hands due to various conditions such as cerebral palsy, stroke and ageing. Fortunately, they will soon benefit from a new training technology which may greatly improve their conditions.

In response to therapeutic needs, a computerized training programme against impaired hands has been developed at the School of Nursing of The Hong Kong Polytechnic University. Patients being trained are supposed to exercise their hands through playing a series of well-designed computer games that simulate everyday tasks, such as opening a locked door with a key or pouring tea into a cup. While playing, their hand movements are monitored and recorded by a haptic device, which is connected to the control unit held by the patient at one end, and a computer at the other. The haptic device then feeds the data into the computer, resulting in the instant reflection of the patient's actions in the animation on screen.

In addition, the haptic technology which the programme employs is more true-to-life than similar programmes, as feedback is provided through the force created by the control unit to players. For example, they can literally feel the weight of a simulated bottle diminishing as the water is being poured out. Such kind of precision will greatly enhance training effectiveness and improve the patient's coordination.

Game-based therapies are highly motivating. Firstly, playing 3D games in colourful animation is more interesting than monotonous physical exercises. Secondly, a reward system incorporated in the programme is sure to fuel a sense of competition and accomplishment. "Our games are designed to be engaging. When players make successful attempts, they get bonus points. And as they win, they move on to the next level, where more attractive rewards are waiting," said Dr Kup-sze Choi, the leader of the research team. It is satisfying for players to work their way up and keep going with the therapy, thereby improving their hand functions.

Compared to physical training, computer simulated training is a safer option when sharp or breakable objects are involved, making practices on preparing simple meals with a knife possible. It is also less likely to be interrupted by undesired circumstances. Dr Choi explained, "For instance, the hands of cerebral palsy sufferers are usually stiff, weak and prone to uncontrolled movements. If they practise pouring real tea in repeated sessions, they may make spills all over the place and end up soaking wet, requiring the healthcare workers to clean up the mess. That is not a good thing for both the trainee and the trainer." With computer simulation, there will be no such interruptions.

To cater to different degrees of disability, the programme has a built-in difficulty mode with which the level of difficulty can be adjusted with the touch of a button. Therapists can also monitor their patients' progress easily, as the system keeps track of their movements and performance.

The effectiveness of this training programme was preliminarily confirmed, as a similar tool aimed to improve hand-writing was tested on the children at the Hong Kong Red Cross Princess Alexandra School. The results have shown a marked improvement in the time they needed to complete the task after two weeks of training. More tests and trials are on the way, and the team expect that a longer period of computer-assisted training will yield greater benefits. The training system has already won a Silver Medal at the 42nd International Exhibition of Inventions of Geneva in Switzerland.

According to Dr Choi, computer simulated training using haptic technology will widen the access to rehabilitation and help more patients with impaired hands . In the future, the team will work on combining this computer-aided rehabilitation programme with traditional therapy in order to optimize the training system and benefit more patients. The prototype of the haptic platform customized for self-care training Copyright : The Hong Kong Polytechnic University The haptic platform technology developed by Dr Kup-sze Choi and his team has won a Silver Medal at the 42nd International Exhibition of Inventions of Geneva. 

Copyright : The Hong Kong Polytechnic University

Source: The Hong Kong Polytechnic University

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Handheld scanner could make brain tumor removal more complete, reducing recurrence

A handheld device that resembles a laser pointer could someday help surgeons remove all of the cells in a brain tumor. Credit: Moritz Kircher

Cancerous brain tumors are notorious for growing back despite surgical attempts to remove them -- and for leading to a dire prognosis for patients. But scientists are developing a new way to try to root out malignant cells during surgery so fewer or none get left behind to form new tumors. The method, reported in the journal ACS Nano, could someday vastly improve the outlook for patients.

Moritz F. Kircher and colleagues at Memorial Sloan Kettering Cancer Center point out that malignant brain tumors, particularly the kind known as glioblastoma multiforme (GBM), are among the toughest to beat. Although relatively rare, GBM is highly aggressive, and its cells multiply rapidly. Surgical removal is one of the main weapons doctors have to treat brain tumors. The problem is that currently, there's no way to know if they have taken out all of the cancerous cells. And removing extra material "just in case" isn't a good option in the brain, which controls so many critical processes. The techniques surgeons have at their disposal today are not accurate enough to identify all the cells that need to be excised. So Kircher's team decided to develop a new method to fill that gap.

The researchers used a handheld device resembling a laser pointer that can detect "Raman nanoprobes" with very high accuracy. These nanoprobes are injected the day prior to the operation and go specifically to tumor cells, and not to normal brain cells. Using a handheld Raman scanner in a mouse model that mimics human GBM, the researchers successfully identified and removed all malignant cells in the rodents' brains. Also, because the technique involves steps that have already made it to human testing for other purposes, the researchers conclude that it has the potential to move readily into clinical trials. Surgeons might be able to use the device in the future to treat other types of brain cancer, they say.

The authors acknowledge funding from the National Institutes of Health.

Source: American Chemical Society

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Bio-inspired bleeding control: Synthesized platelet-like nanoparticles created

Artist's rendering of synthetic platelets. Credit: Peter Allen illustration

Stanching the free flow of blood from an injury remains a holy grail of clinical medicine. Controlling blood flow is a primary concern and first line of defense for patients and medical staff in many situations, from traumatic injury to illness to surgery. If control is not established within the first few minutes of a hemorrhage, further treatment and healing are impossible.

At UC Santa Barbara, researchers in the Department of Chemical Engineering and at Center for Bioengineering (CBE) have turned to the human body's own mechanisms for inspiration in dealing with the necessary and complicated process of coagulation. By creating nanoparticles that mimic the shape, flexibility and surface biology of the body's own platelets, they are able to accelerate natural healing processes while opening the door to therapies and treatments that can be customized to specific patient needs.

"This is a significant milestone in the development of synthetic platelets, as well as in targeted drug delivery," said Samir Mitragotri, CBE director, who specializes in targeted therapy technologies. Results of the researchers' findings appear in the current issue of the journal ACS Nano.

The process of coagulation is familiar to anyone who has suffered even the most minor of injuries, such as a scrape or paper cut. Blood rushes to the site of the injury, and within minutes the flow stops as a plug forms at the site. The tissue beneath and around the plug works to knit itself back together and eventually the plug disappears.

But what we don't see is the coagulation cascade, the series of signals and other factors that promote the clotting of blood and enable the transition between a free-flowing fluid at the site and a viscous substance that brings healing factors to the injury. Coagulation is actually a choreography of various substances, among the most important of which are platelets, the blood component that accumulates at the site of the wound to form the initial plug.

"While these platelets flow in our blood, they're relatively inert," said graduate student researcher Aaron Anselmo, lead author of the paper. As soon as an injury occurs, however, the platelets, because of the physics of their shape and their response to chemical stimuli, move from the main flow to the side of the blood vessel wall and congregate, binding to the site of the injury and to each other. As they do so, the platelets release chemicals that "call" other platelets to the site, eventually plugging the wound.

But what happens when the injury is too severe, or the patient is on anti-coagulation medication, or is otherwise impaired in his or her ability to form a clot, even for a modest or minor injury?

That's where platelet-like nanoparticles (PLNs) come in. These tiny, platelet-shaped 

particles that behave just like their human counterparts can be added to the blood flow to supply or augment the patient's own natural platelet supply, stemming the flow of blood and initiating the healing process, while allowing physicians and other caregivers to begin or continue the necessary treatment. Emergency situations can be brought under control faster, injuries can heal more quickly and patients can recover with fewer complications.

"We were actually able to render a 65 percent decrease in bleeding time compared to no treatment," said Anselmo.

According to Mitragotri, the key lies in the PLNs' mimicry of the real thing. By imitating the shape and flexibility of natural platelets, PLNs can also flow to the injury site and congregate there. With surfaces functionalized with the same biochemical motifs found in their human counterparts, these PLNs also can summon other platelets to the site and bind to them, increasing the chances of forming that essential plug. In addition, and very importantly, these platelets are engineered to dissolve into the blood after their usefulness has run out. This minimizes complications that can arise from emergency hemostatic procedures.

"The thing about hemostatic agents is that you have to intervene to the right extent," said Mitragotri. "If you do too much, you cause problems. If you do too little, you cause problems."

These synthetic platelets also let the researchers improve on nature. According to Anselmo's investigations, for the same surface properties and shape, nanoscale particles can perform even better than micron-size platelets. Additionally, this technology allows for customization of the particles with other therapeutic substances -- medications, therapies and such -- that patients with specific conditions might need.

"This technology could address a plethora of clinical challenges," said Dr. Scott Hammond, director of UCSB's Translational Medicine Research Laboratories. "One of the biggest challenges in clinical medicine right now -- which also costs a lot of money -- is that we're living longer and people are more likely to end up on blood thinners. When an elderly patient presents at a clinic, it's a huge challenge because you have no idea what their history is and you might need an intervention."

With optimizable PLNs, physicians would be able to strike a finer balance between anticoagulant therapy and wound healing in older patients, by using nanoparticles that can target where clots are forming without triggering unwanted bleeding. In other applications, bloodborne pathogens and other infectious agents could be minimized with antibiotic-carrying nanoparticles. Particles could be made to fulfill certain requirements to travel to certain parts of the body -- across the blood-brain barrier, for instance -- for better diagnostics and truly targeted therapies.

Additionally, according to the researchers, these synthetic platelets cost relatively less, and have a longer shelf life than do human platelets -- a benefit in times of widespread emergency or disaster, when the need for these blood components is at its highest and the ability to store them onsite is essential.

Further research into PLNs will involve investigations to see how well the technology and synthesis can scale up, as well as assessments into the more practical matters involved in translating the technology from the lab to the clinic, such as manufacturing, storage, sterility and stability as well as pre-clinical and clinical testing.

Source: University of California - Santa Barbara

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New way to diagnose brain damage from concussions, strokes, and dementia

A new tool to assess cerebrovascular health: Coherent Hemodynamics Spectroscopy (CHS).
Credit: Tufts University Professor of Biomedical Engineering Sergio Fantini

New optical diagnostic technology developed at Tufts University School of Engineering promises new ways to identify and monitor brain damage resulting from traumatic injury, stroke or vascular dementia -- in real time and without invasive procedures.

Coherent hemodynamics spectroscopy (CHS), developed and published by Tufts Professor of Biomedical Engineering Sergio Fantini, measures blood flow, blood volume, and oxygen consumption in the brain. It uses non-invasive near infrared (NIR) light technology to scan brain tissue, and then applies mathematical algorithms to interpret that information.

"CHS is based on measurements of brain hemodynamics that are interpreted according to unique algorithms that generate measures of cerebral blood flow, blood volume and oxygen consumption," says Fantini. "This technique can be used not only to assess brain diseases but also to study the blood flow and how it is regulated in the healthy brain."

Tufts has licensed CHS on a non-exclusive basis to ISS, a Champaign, Ill.-based company that specializes in technology to measure hemoglobin concentration and oxygenation in brain and muscle tissue.

"Potentially the market for CHS is large as it encompasses several applications from the monitoring of cerebrovascular disorders to assessing neurological disorders," says Beniamino Barbieri, president of ISS. "It reminds me of the introduction of ultrasound technology at beginning of the seventies; nobody back then knew how to utilize the new technology and of course, nowadays, its applications are ubiquitous in any medical center."

How It Works

CHS uses laser diodes which emit NIR light that is delivered to the scalp by fiber optics. Light waves are absorbed by the blood vessels in the brain. Remaining light is reflected back to sensors, resulting in optical signals that oscillate with time as a result of the heartbeat, respiration, or other sources of variations in the blood pressure.

By analyzing the light signals with algorithms developed for this purpose, Fantini's model is able to evaluate blood flow and the way the brain regulates it--which is one marker for brain health.

CHS technology has been tested among patients undergoing hemodialysis at Tufts Medical Center. Published research reported a lower cerebral blood flow in dialysis patients compared with healthy patients.

"Non-invasive ways to measure local changes in cerebral blood flow, particularly during periods of stress such as hemodialysis, surgeries, and in the setting of stroke, could have major implications for maintaining healthy brain function," says Daniel Weiner, M.D., a nephrologist at Tufts Medical Center (Tufts MC) and associate professor of medicine at Tufts University School of Medicine (TUSM), who is a member of the research team.

Josh Kornbluth, M.D., a neurologist at Tufts MC and associate professor of medicine at TUSM, is also working with Fantini to explore CHS's potential to assess the cerebrovascular state of patients who suffer traumatic brain injury or stroke. They hope to test CHS further among neurological critical care patients.

"Having data about local cerebral blood flow and whether it is properly regulated can allow us to more accurately develop individualized therapy and interventions instead of choosing a 'one size fits all' approach to traumatic brain injury, stroke, or subarachnoid hemorrhage," Kornbluth says.

Source: Tufts University

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Technique for cardiovascular diagnostics shows promise

Researcher Elira Maksuti is involved in developing and testing a promising method for diagnosing atherosclerosis, or hardening of the arteries. Credit: Staffan Larsson

A new technique developed at Sweden's KTH Royal Institute of Technology shows promise for early diagnosis and treatment of cardiovascular disease.

Hardening of the arteries, or atherosclerosis, is a common disorder that occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques. The condition can lead to heart attacks and strokes.

To diagnose atherosclerosis, doctors today rely on ultrasonic grayscale images to visually assess vascular function and how very large arteries move. The less mobility, the more developed the case of atherosclerosis.

But it is an indirect measurement. Better diagnoses can be made when the stiffness of the blood vessels can be analysed, explains Elira Maksuti, a researcher at the Department of Medical Imaging Technology at KTH.

"You need a doctor who is an expert and has extensive experience in order to get a good diagnosis," she says.

But by combining the technologies of shear wave elastography and ultrasound, Maksuti and researcher Erik Widmanh, have developed an inexpensive and non-invasive method not only for checking the stiffness of blood vessels, but for analysing the type of plaque present in the artery.

Maksuit says their method not only offers a potentially more effective way to diagnose atherosclerosis, but the ultrasound technology that it relies on is less expensive -- and safer -- than other imaging alternatives, such as magnetic resonance imaging (MRI) or computed tomography (CT).

The technique was tested on artificial blood vessels, or "phantom" vessels, which allowed the researchers to experiment with not only vascular stiffness, but also pressure and flow.

Maksuti says that with the success of tests on these phantoms, the next step is testing the technique with blood vessels from pigs. "These tests also look very promising," she says.

"We see two major future applications before us," she says. "The first is to determine when a patient's blood vessels are becoming rigid, that is, when the atherosclerosis process begins.

"The second application is to be able to diagnose the type of calcification -- or plaque -- present in the blood vessel." Not all plaque is the same: it ranges from hard to soft. If the plaque is soft and has a thin, hard shell, it is more likely to come loose inside the blood vessel.

It's a difficult distinction to determine. But the information is critical in deciding whether to open the artery surgically. "Today it is rather a matter of guessing. A doctor cannot know," she says. And to complicate matters, such operations can also generate strokes.

Source: KTH The Royal Institute of Technology

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Early results indicate potential for focused ultrasound to treat OCD

Dr. Chang (in sweater) and treatment team with the first patient in the OCD study. Credit: Image courtesy of Focused Ultrasound Foundation

A recently published report in the Journal of Molecular Psychiatry supports the potential of focused ultrasound to treat certain patients with obsessive-compulsive disorder (OCD).

In a study of feasibility, safety and preliminary efficacy, four patients with disabling OCD unresponsive to medical therapy were treated by ablating small targets deep in the brain (anterior internal capsule) using the InSightec ExAblate Neuro MR-guided focused ultrasound system. This proof-of-concept study is being conducted with 12 patients by Jin Woo Chang, MD, PhD, at the Yonsei University Medical Center in Seoul, Korea. The results of the first four patients with six months follow-up were published.

All four patients had the targeted areas of the brain successfully ablated. The procedures were accomplished without complications or side effects and resulted in gradual improvement in obsessive-compulsive thoughts and behaviors as well as showing the nearly immediate and sustained improvement in depression and anxiety over six months.

"There is a need for non-invasive treatment options for patients with OCD that cannot be managed through medication," says Dr. Chang. "Using focused ultrasound, we were able to reduce the symptoms for these patients and help them get some of their life back without the risks or complications of the more invasive surgical approaches that are currently available."

"If these initial results are confirmed in the remaining eight patients in this study as well as in a larger pivotal trial of safety and efficacy, focused ultrasound could emerge as an alternative to surgery for improving quality of life in a cost-effective manner for patients with OCD," said Foundation Chairman Neal F. Kassell, MD. "This could also serve as the predicate for non-invasive therapy for other psychiatric disorders."

Dr. Chang plans to start a study using focused ultrasound to treat depression in 2015.

Current Treatment for OCD

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurring anxiety-provoking thoughts (obsessions) that are alleviated only by ritualistic actions (compulsions) such as hand washing. OCD symptoms can be overwhelming and result in severe impairment and dysfunction. Patients also have a high risk for depression, with two-thirds of OCD patients developing major depression.

Although a large portion of OCD patients improve with drug therapy, some patients have debilitating symptoms that are resistant to treatment. For these patients, psychosurgery can be performed to destroy (ablate) a targeted region of the brain (anterior internal capsule) associated with the disorder. The currently available ablative approaches are invasive or involve radiation:

• Radiofrequency ablation requires drilling into the skull and inserting a probe through 
   the brain.

• Stereotactic radiosurgery takes months to achieve an effect and may be associated with
   side effects of radiation.

• Deep brain stimulation has been used as a reversible and adjustable alternative to ablation, but it involves the risks and complications of surgery to implant the system and additional operations for battery changes.

Source: Focused Ultrasound Foundation

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High-intensity sound waves may aid regenerative medicine

This is a cross section through a histotripsy lesion created in bovine liver tissue with the liquified cellular contents washed out revealing the remaining extracellular matrix. The scale bar represents 5mm. Credit: T.Khoklova/UW

Researchers at the University of Washington have developed a way to use sound to create cellular scaffolding for tissue engineering, a unique approach that could help overcome one of regenerative medicine's significant obstacles. The researchers will present their technique at the 168th meeting of the Acoustical Society of America (ASA), held October 27-31, 2014, at the Indianapolis Marriott Downtown Hotel.

The development of the new technique started with somewhat of a serendipitous discovery. The University of Washington team had been studying boiling histotripsy -- a technique that uses millisecond-long bursts of high-intensity ultrasound waves to break apart tissue -- as a method to eliminate cancerous tumors by liquefying them with ultrasound waves. After the sound waves destroy the tumors, the body should eliminate them as cellular waste. When the researchers examined these 'decellularized' tissues, however, they were surprised by what the boiling left intact.

"In some of our experiments, we discovered that some of the stromal tissue and vasculature was being left behind," said Yak-Nam Wang, a senior engineer at the University of Washington's Applied Physics Laboratory. "So we had the idea about using this to decellularize tissues for tissue engineering and regenerative medicine."

The structure that remains after decellularizing tissues is known as the extracellular matrix, a fibrous network that provides a scaffold for cells to grow upon. Most other methods for decellularizing tissues and organs involve chemical and enzymatic treatments that can cause damage to the tissues and fibers and takes multiple days. Histrostipsy, on the other hand, offers the possibility of fast decellularization of tissue with minimal damage to the matrix.

"In tissue engineering, one of the holy grails is to develop biomimetic structures so that you can replace tissues with native tissue," Wang said. Stripping away cells from already developed tissue could provide a good candidate for these structures, since the extracellular matrix already acts as the cellular framework for tissue systems, Wang said.

Due to its bare composition, the matrix also induces only a relatively weak immune response from the host. The matrix could then theoretically be fed with stem cells or cells from the same person to effectively re-grow an organ.

"The other thought is that maybe you could just implant the extracellular matrix and then the body itself would self-seed the tissues, if it's just a small patch of tissue that you're replacing," Wang said. "You won't have any immune issues, and because you have this biomimetic scaffold that's closer to the native tissue, healing would be better, and the body would recognize it as normal tissue."

Wang is currently investigating decellularization of kidney and liver tissue from large animals. Future work involves increasing the size of the decellularized tissues and assessing their in-vivo regenerative efficacy.

Source: Acoustical Society of America (ASA)

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Powerful imaging for optical point-of-care diagnostics

The new imaging system consists of a handheld probe (on the right), and an ultrasound scanning display system (on the left). It can be easily transported between rooms in a clinic. Credit: Pim van den Berg/ Khalid Daoudi

A new handheld probe developed by a team of university and industry researchers in the Netherlands and France could give doctors powerful new imaging capabilities right in the palms of their hands. The imaging system, which is described in a paper published in The Optical Society's (OSA) open-access journal Optics Express, shrinks a technology that once filled a whole lab bench down to a computer screen and a small probe about the size of a stapler.

The new device combines two imaging modalities: ultrasound and photoacoustics. Ultrasound is a well-established technology that analyzes how sound pulses echo off internal body parts. It is good at revealing anatomical structures and is, perhaps most familiarly, used to image a developing fetus in a mother's womb.

Photoacoustics is a relatively new imaging technique, still making its way toward widespread clinical applications. In photoacoustic imaging, short pulses of light heat up internal tissue. The slight temperature change leads to a change in pressure,
which in turn produces a wave of ultrasound that can be analyzed to reveal information about the body's internal workings. Since this technique ultimately produces ultrasound waves as well, existing technology can be used to analyze and display the images.

The advantage of photoacoustics is that it can reveal important medical information that other imaging techniques cannot, including the presence of molecules like hemoglobin and melanin and the sub-millimeter structure of networks of blood vessels several centimeters beneath the skin. When combined with spectroscopic measurements, photoacoustics can also quantify hemoglobin oxygen saturation within single vessels, providing metabolic information that could be helpful for monitoring tumor progression, for example.

Yet despite these benefits, the cost and size of most photoacoustic systems limit their widespread use, said Khalid Daoudi, a researcher in the Biomedical Photonic Imaging Group at the University of Twente in the Netherlands. Most systems on the market require costly and bulky lasers that make the systems impractical for point-of-care diagnostics. "Our research aimed to break through these hindering factors," Daoudi said.

The project started as collaboration between the University of Twente and three European companies: ESAOTE Europe, a maker of medical diagnostic systems, Quantel, a maker of solid state lasers, and SILIOS Technologies, a maker of optical components.

The team's key innovation, which allowed them to dramatically shrink the system, was the design of an ultra-compact laser based on an efficient and inexpensive laser diode. By stacking multiple diodes to increase the power and carefully designing optical elements to shape the laser beam, the team was able to generate laser pulses with energies higher than had ever been achieved before with diode technology.

Diode lasers can also provide many laser pulses per second, which in turn allows real time imaging, another advantage of the new system, Daoudi noted.

The researchers tested the imaging performance of the system in different types of phantoms -- materials designed to mimic a tissue's optical properties -- and in a healthy human finger joint.

The new compact probe and imaging system can be easily transported between rooms in a clinical setting, an attractive feature for future commercialization, the researchers said.

The team is currently working with a European consortium of industrial and academic partners to take the next steps from the research to the commercialization phase. The current system operates at a single wavelength in the near infrared, but the team has plans to expand the design to multi-wavelength imaging.

"Some applications targeted are rheumatoid arthritis in finger joints, oncology, cardiovascular disease and burn wounds," Daoudi said.

Source: The Optical Society

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Ultrasound guides tongue to pronounce 'R' sounds

Using ultrasound technology to visualize the tongue's shape and movement can help children with difficulty pronouncing "r" sounds, according to research led by NYU Steinhardt assistant professor Tara McAllister Byun. Credit: Ramsay de Give / NYU Steinhardt

Using ultrasound technology to visualize the tongue's shape and movement can help children with difficulty pronouncing "r" sounds, according to a small study by NYU's Steinhardt School of Culture, Education, and Human Development and Montclair State University.

The ultrasound intervention was effective when individuals were allowed to make different shapes with their tongue in order to produce the "r" sound, rather than being instructed to make a specific shape. The findings appear online in the Journal of Speech, Language, and Hearing Research.

The "r" sound is one of the most frequent speech errors, and can be challenging to correct. For other sounds -- such as "t" or "p" -- speech pathologists can give clear verbal, visual or tactile cues to help children understand how the sound is created. "R" is difficult to show or describe in an easy-to-understand fashion.

In addition, most speech sounds are produced in the same way, but with "r," normal speakers use widely different tongue shapes to create the sound. The two primary strategies to create the "r" sound include a retroflex tongue shape, where the tongue tip is pointed up, and the bunched tongue shape, where the tongue tip is pointed down and body of tongue bunches up toward the top of the mouth.

Up to 10 percent of children have speech sound disorders, according to the National Institutes of Health. Some children respond well to conventional forms of speech therapy, but others have errors that persist despite their therapists' best efforts. A growing body of evidence suggests that treatment incorporating visual biofeedback, which uses various technologies to create a dynamic visual representation of speech, could fill this need.

"The idea that you could get around the challenges with 'r' sounds by showing children their tongues as they are talking is really appealing to clinicians," says Tara McAllister Byun, an assistant professor in NYU Steinhardt's Department of Communicative Sciences and Disorders and the study's lead author. "That's what ultrasound technology lets us do."

Linguists have used ultrasound in the past to study basic functions of speech, and in recent years, speech pathologists have begun exploring using ultrasound to treat children with speech errors. An ultrasound probe -- similar to ones used in cardiac and tissue imaging -- is held under the chin, and sound waves capture real-time images of the tongue. The images provide both the child and speech pathologist with information about the tongue's position and shape.

Using the ultrasound images as a guide, children learn how to manipulate their tongues, and speech pathologists advise them on how to make adjustments to better achieve different sounds.

Several case studies and small studies suggest that ultrasound biofeedback can successfully correct "r" speech errors. Byun and her colleagues set out to gather systematic evidence on the effectiveness of the treatment, studying eight children with difficulty pronouncing "r" sounds. Seven of the eight had previous speech therapy that was unsuccessful.

Four children participated in the initial eight-week study. They were taught to make a bunched tongue shape, guided by ultrasound, in an effort to better pronounce "r." The researchers saw only small improvements among the four participants.

However, while trying to create a bunched tongue, one child stumbled upon a retroflex tongue shape and was able to improve her "r" sound. As a result of her success, the researchers altered their study design to allow participants to choose their own tongue shape, with individualized guidance from speech language pathologists.

A different four children participated in the second study over an eight-week period. Using ultrasound to visualize their tongues, all four participants in the second study showed significant improvement in their "r" sounds.

"Our second study offers evidence that when flexibility is given to choose a tongue shape, rather than a one-size-fits all approach, ultrasound biofeedback treatment can be a highly effective intervention for children with trouble pronouncing 'r' sounds," Byun says.

The researchers noted that the two studies were not a controlled comparison, thus additional systematic research is needed before drawing strong conclusions about the importance of individualized tongue shapes.

Source: New York University

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Engineers develop new sensor to detect tiny individual nanoparticles

The image shows arrays of self-referenced and self-heterodyned Whispering-Gallery Raman microlasers for single nanoparticle detection. A "pump" laser generates a single Raman lasing mode inside the silica resonators. Upon landing of a nanoparticle on the resonator, Raman laser circulating inside the resonator undergo mode splitting leading to two new lasing modes in different colors. Monitoring the changes in the color difference (frequency difference) enables detecting and measuring of nanoparticles with single particle resolution. Credit: J. Zhu, B. Peng, S.K. Ozdemir, L. Yang

Nanoparticles, engineered materials about a billionth of a meter in size, are around us every day. Although they are tiny, they can benefit human health, as in some innovative early cancer treatments, but they can also interfere with it through viruses, air pollution, traffic emissions, cosmetics, sunscreen and electronics.

A team of researchers at Washington University in St. Louis, led by Lan Yang, PhD, the Das Family Career Development Associate Professor in Electrical & Systems Engineering, and their collaborators at Tsinghua University in China have developed a new sensor that can detect and count nanoparticles, at sizes as small as 10 nanometers, one at a time. The researchers say the sensor could potentially detect much smaller particles, viruses and small molecules.

The research appears in the Proceedings of the National Academy of Sciences online Early Edition Sept. 1, 2014.

Yang and her colleagues have created the Raman microlaser sensor in a silicon dioxide chip to find individual nanoparticles without the need to "dope" the chip with chemicals called rare-earth ions to provide optical gain for the microlaser. Incorporating additions to the microresonator creates the need for more processing steps and increased costs and invites biocompatibility risks. In addition, the use of rare-earth ions requires specific "pump" lasers matching the energy transitions of the ions to generate optical gain, so for different rare-earth ions, different pump lasers must be used. Using the Raman process loosens the requirement of specific wavelength bands for pump lasers because Raman gain can be obtained using pump at any wavelength band, Yang says.

"This gives us the advantage of using the same dopant-free sensor at different sensing environments by tailoring the lasing frequency for the specific environment, for example, at the band where the environment has minimum absorption, and for the properties of the targeted nanoparticles by just changing the wavelength of the pump laser," says Sahin Kaya Ozdemir, PhD, a research scientist in Yang's group and the first author of the paper.

Yang's team integrated Raman lasing in a silica microcavity with the mode splitting technique pioneered by her group to develop a new, powerful sensor that more readily detects nanoparticles. The technology will benefit the electronics, acoustics, biomedical, plasmonics, security and metamaterials fields.

Yang's microsensor is in a class called whispering gallery mode resonators (WGMRs) because it works similarly to the renowned whispering gallery in London's St. Paul's Cathedral, where a person on one side of the dome can hear a message spoken to the wall by another person on the other side. Yang's device does much the same thing with light frequencies rather than audible ones.

One of the main differences between early resonators and the novel resonator, known as a morphology dependent resonator, was they didn't use mirrors to reflect light. Yang's WGMR is an actual mini-laser that supports "frequency degenerate modes," patterns of excitation inside the mini-laser's doughnut-shaped ring that are of the same frequency. One portion of light beamed by the Raman laser goes counterclockwise, another goes clockwise. When a particle lands on the ring and scatters energy between these modes, the single Raman lasing line splits into two lasing lines with different frequencies.

When a Raman laser beam is generated in the resonator, it likely will encounter a particle, such as a virus nanoparticle, on the circle. When the beam initially sees the particle, the beam splits into two, generating two lasing lines that serve as reference to the other to form a self-referenced sensing technique.

"Our new sensor differs from the earlier whispering gallery sensors in that it relies on Raman gain, which is inherent in silica, thereby eliminating the need for doping the microcavity with gain media, such as rare-earth ions or optical dyes, to boost detection capability," Ozdemir says. "This new sensor retains the biocompatibility of silica and could find widespread use for sensing in biological media."

"It doesn't matter what kind of wavelength is used, once you have the Raman laser circulating inside and there is a molecule sitting on the circle, when the beam sees the particle it will scatter in all kinds of directions," Yang says. "Initially you have a counterclockwise mode, then a clockwise mode, and by analyzing the characterization of the two split modes, we confirm the detection of nanoparticles."

In addition to the demonstration of Raman microlasers for particle sensing, the team says their work shows the possibility of using intrinsic gain mechanisms, such as Raman and parametric gain, instead of optical dyes, rare-earth ions or quantum dots, for loss compensation in optical and plasmonic systems where dissipation hinders progress and limits applications.

Source: Washington University in St. Louis

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Football players found to have brain damage from mild 'unreported' concussions

The images from the Ben-Gurion University of the Negev JAMA Neurology study represent Blood-Brain Barrier (BBB) Permeability in Football Players (A) vs. a control group (B). The players in the pathological-BBB group (B) presented focal BBB lesions in different cortical regions including the temporal (player 4), frontal (player 5), and parietal (player 6) lobes. Both gray and white matter were involved. Credit: Image courtesy of American Associates, Ben-Gurion University of the Negev

A new, enhanced MRI diagnostic approach was, for the first time, able to identify significant damage to the blood-brain barrier (BBB) of professional football players following "unreported" trauma or mild concussions. Published in the current issue of JAMA Neurology, this study could improve decision making on when an athlete should "return to play."

According to Prof. Alon Friedman, from the Ben-Gurion University Brain Imaging Research Center and discoverer of the new diagnostic, "until now, there wasn't a diagnostic capability to identify mild brain injury early after the trauma. In the NFL, other professional sports and especially school sports, concern has grown about the long-term neuropsychiatric consequences of repeated mild Traumatic Brain Injury (mTBI) and specifically sports-related concussive and sub-concussive head impacts."

The paper, published by researchers at Ben-Gurion University of the Negev (BGU) and Soroka University Medical Center, describes a new diagnostic approach using Magnetic Resonance Imaging (MRI) for detection and localization of vascular pathology and blood-brain barrier breakdown in football players.

The images from the Ben-Gurion University of the Negev JAMA Neurology study represent Blood-Brain Barrier (BBB) Permeability in Football Players (A) vs. a control group (B). The players in the pathological-BBB group (B) presented focal BBB lesions in different cortical regions including the temporal (player 4), frontal (player 5), and parietal (player 6) lobes. Both gray and white matter were involved.

"The goal of our study was to use our new method to visualize the extent and location of BBB dysfunction in football players using Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) on a Phillips 3-T Ingenia. Specifically, it generates more detailed brain maps showing brain regions with abnormal vasculature, or a 'leaky BBB.' "

Study participants included 16 football players from Israel's professional football team, Black Swarm, as well as 13 track and field athletes from Ben-Gurion University who served as controls. All underwent the newly developed MRI-based diagnostic.

The DCE-MRIs were given between games during the season and revealed significant damage.

Forty percent of the examined football players with unreported concussions had evidence of "leaky BBB" compared to 8.3 percent of the control athletes.

"The group of 29 volunteers was clearly differentiated into an intact-BBB group and a pathological-BBB group," Friedman explains. "This showed a clear association between football and increased risk for BBB pathology that we couldn't see before. In addition, high-BBB permeability was found in six players and in only one athlete from the control group."

Friedman also explains that not all the players showed pathology. This indicates that repeated, mild concussive events might impact some players differently than others. This level of diagnosis of individual players can provide the basis of more rational decision making on "return to play" for professionals as well amateurs of any age.

"Generally, players return to the game long before the brain's physical healing is complete, which could exacerbate the possibility of brain damage later in life," says Friedman.

A decade of research in the BGU Laboratory for Experimental Neurosurgery has shown that vascular pathology, and specifically dysfunction of the blood-brain barrier (BBB), plays a key role in brain dysfunction and degeneration, and may be an underlying cause of neurodegenerative complications after brain injuries.

The BBB is a highly selective permeable membrane that separates circulating blood from extracellular fluid. It protects the brain by preventing many dangerous substances from penetrating, and therefore is not meant to be damaged.

Medical researchers, including Friedman's group at BGU, are working to find ways to find drugs that will target the BBB and facilitate its repair, allowing for the prevention of Alzheimer's disease and other brain-related disease.

"Prof. Friedman has been able to conduct this breakthrough brain research using the state-of-the-art MRI machine donated as a result of contributions from American Associates, Ben-Gurion University of the Negev (AABGU)," explains Doron Krakow, AABGU executive vice president. "We believe that with continued support, Prof. Friedman and the DCE-MRI can help render more accurate and informed decisions by athletes and others exposed to mild concussions about when to resume activities."

Source: American Associates, Ben-Gurion University of the Negev

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First contracting human muscle grown in laboratory

This is a microscopic view of lab-grown human muscle bundles stained to show patterns made by basic muscle units and their associated proteins (red), which are a hallmark of human muscle.
Credit: Nenad Bursac, Duke University

In a laboratory first, Duke researchers have grown human skeletal muscle that contracts and responds just like native tissue to external stimuli such as electrical pulses, biochemical signals and pharmaceuticals.

The lab-grown tissue should soon allow researchers to test new drugs and study diseases in functioning human muscle outside of the human body.

The study was led by Nenad Bursac, associate professor of biomedical engineering at Duke University, and Lauran Madden, a postdoctoral researcher in Bursac's laboratory. It appears January 13 in the open-access journal eLife

"The beauty of this work is that it can serve as a test bed for clinical trials in a dish," said Bursac. "We are working to test drugs' efficacy and safety without jeopardizing a patient's health and also to reproduce the functional and biochemical signals of diseases -- especially rare ones and those that make taking muscle biopsies difficult."

Bursac and Madden started with a small sample of human cells that had already progressed beyond stem cells but hadn't yet become muscle tissue. They expanded these "myogenic precursors" by more than a 1000-fold, and then put them into a supportive, 3D scaffolding filled with a nourishing gel that allowed them to form aligned and functioning muscle fibers.

"We have a lot of experience making bioartifical muscles from animal cells in the laboratory, and it still took us a year of adjusting variables like cell and gel density and optimizing the culture matrix and media to make this work with human muscle cells," said Madden.

Madden subjected the new muscle to a barrage of tests to determine how closely it resembled native tissue inside a human body. She found that the muscles robustly contracted in response to electrical stimuli -- a first for human muscle grown in a laboratory. She also showed that the signaling pathways allowing nerves to activate the muscle were intact and functional.

To see if the muscle could be used as a proxy for medical tests, Bursac and Madden studied its response to a variety of drugs, including statins used to lower cholesterol and clenbuterol, a drug known to be used off-label as a performance enhancer for athletes.

The effects of the drugs matched those seen in human patients. The statins had a dose-dependent response, causing abnormal fat accumulation at high concentrations. Clenbuterol showed a narrow beneficial window for increased contraction. Both of these effects have been documented in humans. Clenbuterol does not harm muscle tissue in rodents at those doses, showing the lab-grown muscle was giving a truly human response.

"One of our goals is to use this method to provide personalized medicine to patients," said Bursac. "We can take a biopsy from each patient, grow many new muscles to use as test samples and experiment to see which drugs would work best for each person."

This goal may not be far away; Bursac is already working on a study with clinicians at Duke Medicine -- including Dwight Koeberl, associate professor of pediatrics -- to try to correlate efficacy of drugs in patients with the effects on lab-grown muscles. Bursac's group is also trying to grow contracting human muscles using induced pluripotent stem cells instead of biopsied cells.

"There are a some diseases, like Duchenne Muscular Dystrophy for example, that make taking muscle biopsies difficult," said Bursac. "If we could grow working, testable muscles from induced pluripotent stem cells, we could take one skin or blood sample and never have to bother the patient again."

Other investigators involved in this study include George Truskey, the R. Eugene and Susie E. Goodson Professor of Biomedical Engineering and senior associate dean for research for the Pratt School of Engineering, and William Krauss, professor of biomedical engineering, medicine and nursing at Duke University.

The research was supported by NIH Grants R01AR055226 and R01AR065873 from the National Institute of Arthritis and Musculoskeletal and Skin Disease and UH2TR000505 from the NIH Common Fund for the Microphysiological Systems Initiative.

Source: Duke University

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