TAG: "Nanotechnology"

Measuring ‘brainstorms’


Researchers pioneer technique permitting peek inside neurons at activity of ion channels.

A team led by Peter Burke, UC Irvine professor of electrical engineering & computer science, developed a detector that offers a window into the inner workings of the brain and a brand-new tool for future research. (Photo by Steve Zylius, UC Irvine)

By Pat Brennan, UC Irvine

Like a gathering storm, tiny electrical pulses in a brain cell coalesce into a kind of explosion: the firing of a single neuron.

And the firing of billions of neurons provides each of us with the inner experiences that define our lives – seeing, hearing, thinking, even noting the passage of time between heartbeats.

In a feat of engineering that could extend the reach of both nanotechnology and neurobiology, UC Irvine researchers have found a way to peer inside a neuron and watch as the storm gathers.

Using carbon nanowires only a few atoms thick, the team – led by electrical engineering & computer science professor Peter Burke – managed to eavesdrop on the opening and closing of ion channels at the scale of a single brain cell.

Ions are charged particles that transmit electrical signals. The collective activity of thousands or millions of channels through which they flow is what causes a neuron to fire.

“When it rains, you get a weather report that tells how many inches of rain fell in a given period,” says Burke, whose work was published last month in Scientific Reports. “The weatherman doesn’t measure each drop.”

But the technique his team developed, he says, is the equivalent of “measuring each individual drop of rain.”

That’s a first. “No one has ever measured a single ion channel with a single nanowire before,” Burke says.

The method offers a window into the inner workings of the brain and a brand-new tool for future research.

And it could significantly advance the goals of President Barack Obama’s BRAIN Initiative, announced in 2013, which seeks to map brain functions and attack neurological disorders such as Alzheimer’s, epilepsy and autism.

The team began by creating an artificial cell. Its wall, like that of a real cell, is pockmarked with pores that open and close, allowing ions to flow in and out.

Next, the scientists installed nanowires just outside the artificial cell’s wall. The wires are capable of registering minuscule fluxes of energy and picked up the pelting of “raindrops” – in this case, the size of atoms – signaling the opening and closing of ion channels.

For now, the nanowire detector is confined to its carefully constructed laboratory setting. Asked to speculate, however, Burke sees a number of potentially revolutionary applications in the years and decades ahead.

A nanowire detector, for example, could be implanted in a living human brain, perhaps providing therapy for brain disorders or simply monitoring the organ itself and learning the submicroscopic details of information traffic among brain cells.

No one has yet developed a way to implant such a device, Burke notes, and doing so might be difficult. One possible avenue: attach the detector to a free-floating “nano radio” that could broadcast data about the state of ion channels.

“So many processes in life, in biology, are using electricity,” Burke says. “The cell, in a sense, is converting some physical phenomenon into an electrical signal. It all involves these ion channels.”

All our senses, from vision to smell, rely on these channels, he says, adding that in the future “you could have an artificial nose, an artificial eye.”

Electricity is critical to coordinate the beating of our hearts and other life-or-death bodily functions, such as the release of insulin in response to sugar in the blood. So the new detectors could, for instance, lead to a better understanding of diabetes.

And the ability to spy on ion channel activity could prove invaluable for cancer researchers. “You could use this technique to measure how chemotherapy affects cell death or to figure out why cancer cells don’t die,” Burke says.

Another important potential use is in drug screening. Fifteen percent of all pharmaceuticals act on ion channels; knowing how they do it could greatly improve the reliability of testing to ensure a drug’s safety and effectiveness.

“This wire, a few atoms across, is sensitive enough to measure with unprecedented resolution the way neurons work,” Burke says.

The study’s lead author is Weiwei Zhou, and co-authors are Yung Yu Wang, Tae-Sun Lim, Ted Pham and Dheeraj Jain.

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Gel filled with nanosponges cleans up MRSA infections


Nanosponge-hydrogel minimizes growth of skin lesions on mice infected with MRSA.

oxin-absorbing nanoparticles are loaded into a holding gel to make a nanosponge-hydrogel, which can potentially treat local bacterial infections.

By Liezel Labios, UC San Diego

Nanoengineers at UC San Diego developed a gel filled with toxin-absorbing nanosponges that could lead to an effective treatment for skin and wound infections caused by MRSA (methicillin-resistant Staphylococcus aureus), an antibiotic-resistant bacteria. This nanosponge-hydrogel minimized the growth of skin lesions on mice infected with MRSA – without the use of antibiotics. The researchers recently published their findings online in Advanced Materials.

To make the nanosponge-hydrogel, the team mixed nanosponges, which are nanoparticles that absorb dangerous toxins produced by MRSA, E. coli and other antibiotic-resistant bacteria, into a hydrogel, which is a gel made of water and polymers. The hydrogel holds the nanosponges in place so that they can remove toxins at the infected spot.

“We combined the strengths of two different materials – nanosponges and hydrogels – to create a powerful formulation to treat local bacterial infections,” said Liangfang Zhang, nanoengineering professor in the Jacobs School of Engineering at UC San Diego, who led the team. “Nanosponges alone are difficult to use on local tissues because they diffuse away to other parts of the body very quickly. By integrating the nanosponges into a hydrogel, we can retain them at the site of infection.”

Since the nanosponge-hydrogel treatment does not involve antibiotics, the researchers say that it will not likely be affected by existing bacterial antibiotic resistance. Also, because antibiotics are not involved, the treatment will likely not cause bacteria to develop new resistance.

This work is a follow-up to a study that the team presented in Nature Nanotechnology in 2013. The previous study showed that nanosponges absorbed harmful bacterial toxins in the bloodstream and drew them away from their real targets: red blood cells. In this new study, the team reports that removing bacterial toxins could potentially lead to clearing up antibiotic-resistant bacterial infections.

“One way to treat these infections is to remove the toxins, which act as a weapon and a defense shield for the bacteria that produce them,” said Zhang. “We hypothesize that without the toxins, the bacteria become significantly weakened and exposed, allowing the body’s immune system to kill them more easily without the use of drugs.”

Nanosponge-hydrogel treatment

How does the nanosponge-hydrogel treatment work? Each nanosponge is a nanoparticle coated in a red blood cell membrane. This coating disguises the nanosponges as red blood cells, which are the real targets of the harmful toxins produced by MRSA. By masquerading as red blood cells, the nanosponges attract harmful toxins and remove them from the bloodstream. In order for the nanosponges to remove toxins from a specific spot, such as an infected skin wound, a lot of them need to be held at that spot. This is where the hydrogel plays a role; it can hold billions of nanosponges per milliliter in one spot. The hydrogel’s pores are also small enough to keep most of the nanosponges from escaping, but big enough so that toxins can easily get inside and attach to the nanosponges.

The researchers showed that the nanosponge-hydrogel treatment kept down the size of skin lesions caused by MRSA infections. In mice, the skin lesions that were treated with the nanosponge-hydrogel were significantly smaller than those that were left untreated.

“After injecting the nanosponge-hydrogel at the infected spot, we observed that it absorbed the toxins secreted by the bacteria and prevented further damage to the local blood, skin and muscle tissues,” said Zhang.

The team also showed that the hydrogel was effective at holding the nanosponges in place within the body. Two days after the nanosponge-hydrogel was injected underneath the skin of a mouse, nearly 80 percent of the nanosponges were still found at the injection site. When nanosponges were injected without the hydrogel, only 20 percent of them remained at the injection site after two hours. Most of them diffused to the surrounding tissues.

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

Journal reference:

Fei Wang, Weiwei Gao, Soracha Thamphiwatana, Brian T. Luk, Pavimol Angsantikul, Qiangzhe Zhang, Che-Ming J. Hu, Ronnie H. Fang, Jonathan A. Copp, Dissaya Pornpattananangkul, Weiyue Lu and Liangfang Zhang. “Hydrogel Retaining Toxin-Absorbing Nanosponges for Local Treatment of Methicillin-Resistant Staphylococcus aureus Infection.” Advanced Materials 2015. DOI: 10.1002/adma.201501071

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Nanotech platform shows promise for treating pancreatic cancer


Researchers create new method that may solve some problems of using chemotherapy.

Andre Nel, UCLA

By Shaun Mason, UCLA

Scientists at UCLA’s California NanoSystems Institute and Jonsson Comprehensive Cancer Center have combined their nanotechnology expertise to create a new treatment that may solve some of the problems of using chemotherapy to treat pancreatic cancer.

The study, published online in the journal ACS Nano, describes successful experiments to combine two drugs within a specially designed mesoporous silica nanoparticle that looks like a glass bubble. The drugs work together to shrink human pancreas tumors in mice as successfully as the current standard treatment, but at one-twelfth the dosage. This lower dosage could reduce both the cost of treatment and the side effects that people suffer from the current method.

The study was led by Dr. Huan Meng, assistant adjunct professor of medicine, and Dr. Andre Nel, distinguished professor of medicine, both at the Jonsson Cancer Center.

Pancreatic cancer, a devastating disease with a five-year survival rate of 5 percent, is difficult to detect early and symptoms do not usually appear until the disease is advanced. As a result, many people are not diagnosed until their tumors are beyond the effective limits of surgery, leaving chemotherapy as the only viable treatment option. The chemotherapy drug most often used for pancreas cancer is gemcitabine, but its impact is often limited.

Recent research has found that combining gemcitabine with another drug called paclitaxel can improve the overall treatment effect. In the current method, Abraxane — a nano complex containing paclitaxel — and gemcitabine are given separately, which works to a degree, but because the drugs may stay in the body for different lengths of time, the combined beneficial effect is not fully synchronized.

“The beauty of the silica nanoparticle technology is that gemcitabine and paclitaxel are placed together in one special lipid-coated nanoparticle at the exact ratio that makes them synergistic with one another when co-delivered at the cancer site, giving us the best possible outcome by using a single drug carrier,” Meng said. “This enables us to reduce the dose and maintain the combinatorial effect.”

After the scientists constructed the silica nanoparticles, they suspended them in blood serum and injected them into mice that had human pancreas tumors growing under their skin. Other mice with tumors were given injections of saline solution (a placebo with no effect), gemcitabine (the treatment standard), and gemcitabine and Abraxane (an FDA-approved combination shown to improve pancreas cancer survival in humans).

In the mice that received the two drugs inside the nanoparticle, pancreas tumors shrank dramatically compared with those in the other mice.

Similar comparisons were made with mouse models, in which the human tumors were surgically implanted into the mice’s abdomens in order to more closely emulate the natural point of origin of pancreatic tumors and provide a better parallel to the tumors in humans. In these experiments, the tumors in the mice receiving silica nanoparticles shrank more than the comparative controls. Also, metastasis, or tumor spread, to nearby organs was eradicated in these mice.

“Instead of just a laboratory proof-of-principle study of any cancer, we specifically attacked pancreatic cancer with a custom-designed nanocarrier,” said Nel, who is also associate director for research of the California NanoSystems Institute. “In our platform, the drugs are truly synergistic because we have control over drug mixing, allowing us to incorporate optimal ratios in our particles, making the relevance of our models very high and our results very strong.”

Meng said the silica nanocarrier must still be refined for use in humans. The researchers hope to test the platform in human clinical trials within the next five years.

The research was supported by the U.S. Public Health Service and the National Science Foundation.

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Spot treatment


Researchers use latest in nanotechnology, drug delivery to take on an old problem: acne.

Samir Mitragotri, UC Santa Barbara

By Sonia Fernandez, UC Santa Barbara

Acne, a scourge of adolescence, may be about to meet its ultra high-tech match. By using a combination of ultrasound, gold-covered particles and lasers, researchers from UC Santa Barbara and the private medical device company Sebacia have developed a targeted therapy that could potentially lessen the frequency and intensity of breakouts, relieving acne sufferers the discomfort and stress of dealing with severe and recurring pimples.

“Through this unique collaboration, we have essentially established the foundation of a novel therapy,” said Samir Mitragotri, professor of chemical engineering at UCSB.

Pimples form when follicles get blocked by sebum, an oily, waxy substance secreted by sebaceous glands located adjacent to the follicle. Excretion of sebum is a natural process and functions to lubricate and waterproof the skin. Occasionally, however, the openings of the follicles (pores) get blocked, typically by bits of hair, skin, dirt or other debris mixed in with the sebum. Overproduction of sebum is also a problem, which can be caused by hormones or medications. Changes in the skin, such as its thickening during puberty, can also contribute to follicle blockage. Whatever the cause, the accumulating sebum harbors bacteria, which results in the inflammation and local infection that we call acne.

The new technology builds on Mitragotri’s specialties in targeted therapy and transdermal drug delivery. Using low-frequency ultrasound, the therapy pushes gold-coated silica particles through the follicle into the sebaceous glands. Postdoctoral research associate Byeong Hee Hwang, now an assistant professor at Incheon National University, conducted research at UCSB.

“The unique thing about these particles is that when you shine a laser on them, they efficiently convert light into heat via a process called surface plasmon resonance,” said Mitragotri. This also marks the first time ultrasound, which has been proved for years to deliver drugs through the skin, has been used to deliver the particles into humans.

These silica and gold particles are exceedingly tiny — about a hundredth of the width of a human hair — but they are key to the therapy. Once the particles are deposited in the target areas, lasers are aimed at them and, because the gold shells are designed specifically to interact with the near-infrared wavelengths of the lasers, the light becomes heat. The heated particles essentially cause deactivation of the sebaceous glands. The sebum, pore-blocking substances and particles are excreted normally.

“If you deactivate these overproducing glands, you’re basically treating the root cause of the acne,” said Mitragotri.

According to the research, which is published in the Journal of Controlled Release, this protocol would have several benefits over conventional treatments. Called selective photothermolysis, the method does not irritate or dry the skin’s surface. In addition, it poses no risk of resistance or long-term side effects that can occur with antibiotics or other systemic treatments.

“It’s highly local but highly potent as well,” Mitragotri said of the treatment. “I think this would be beneficial in addressing the concerns regarding other, conventional treatments.” According to Mitragotri, this photothermolysis method is particularly suited to patients with advanced, severe or difficult-to-treat acne. The research has gone from concept to clinical trials in a relatively short amount of time. However, other more long-term elements of this therapy have yet to be studied, such as the extent of follicular damage, if any; what the most effective and beneficial parameters of this treatment may be; and what contraindications exist.

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Pens filled with high-tech inks for do-it-yourself sensors


New simple tool is opening door to where anyone will be able to build sensors, anywhere.

By Ioana Patringenaru, UC San Diego

A new simple tool developed by nanoengineers at the University of California, San Diego, is opening the door to an era when anyone will be able to build sensors, anywhere, including physicians in the clinic, patients in their home and soldiers in the field.

The team from the University of California, San Diego, developed high-tech bio-inks that react with several chemicals, including glucose. They filled off-the-shelf ballpoint pens with the inks and were able to draw sensors to measure glucose directly on the skin and sensors to measure pollution on leaves.

Skin and leaves aren’t the only media on which the pens could be used. Researchers envision sensors drawn directly on smart phones for personalized and inexpensive health monitoring or on external building walls for monitoring of toxic gas pollutants. The sensors also could be used on the battlefield to detect explosives and nerve agents.

The team, led by Joseph Wang, the chairman of the Department of NanoEngineering at the University of California, San Diego, published their findings in the Feb. 26 issue of Advanced Healthcare Materials. Wang also directs the Center for Wearable Sensors at UC San Diego.

“Our new biocatalytic pen technology, based on novel enzymatic inks, holds considerable promise for a broad range of applications on site and in the field,” Wang said.

The biggest challenge the researchers faced was making inks from chemicals and biochemicals that aren’t harmful to humans or plants; could function as the sensors’ electrodes; and retain their properties over long periods in storage and in various conditions. Researchers turned to biocompatible polyethylene glycol, which is used in several drug delivery applications, as a binder. To make the inks conductive to electric current they used graphite powder. They also added chitosan, an antibacterial agent which is used in bandages to reduce bleeding, to make sure the ink adhered to any surfaces it was used on. The inks’ recipe also includes xylitol, a sugar substitute, which helps stabilize enzymes that react with several chemicals the do-it-yourself sensors are designed to monitor.

Reusable glucose sensors

Wang’s team has been investigating how to make glucose testing for diabetics easier for several years. The same team of engineers recently developed non-invasive glucose sensors in the form of temporary tattoos. In this study, they used pens, loaded with an ink that reacts to glucose, to draw reusable glucose-measuring sensors on a pattern printed on a transparent, flexible material which includes an electrode. Researchers then pricked a subject’s finger and put the blood sample on the sensor. The enzymatic ink reacted with glucose and the electrode recorded the measurement, which was transmitted to a glucose-measuring device. Researchers then wiped the pattern clean and drew on it again to take another measurement after the subject had eaten.

Researchers estimate that one pen contains enough ink to draw the equivalent of 500 high-fidelity glucose sensor strips. Nanoengineers also demonstrated that the sensors could be drawn directly on the skin and that they could communicate with a Bluetooth-enabled electronic device that controls electrodes called a potentiostat, to gather data.

Sensors for pollution and security

The pens would also allow users to draw sensors that detect pollutants and potentially harmful chemicals sensors on the spot. Researchers demonstrated that this was possible by drawing a sensor on a leaf with an ink loaded with enzymes that react with phenol, an industrial chemical, which can also be found in cosmetics, including sunscreen. The leaf was then dipped in a solution of water and phenol and the sensor was connected to a pollution detector. The sensors could be modified to react with many pollutants, including heavy metals or pesticides.

Next steps include connecting the sensors wirelessly to monitoring devices and investigating how the sensors perform in difficult conditions, including extreme temperatures, varying humidity and extended exposure to sunlight.

“Biocompatible Enzymatic Roller Pens for Direct Writing of Biocatalytic Materials: ‘Do-it-yourself’ Electrochemical Biosensors” is authored by Amay J. Bandodkar, Wenzhao Jia, Julian Ramirez and Wang.

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Technology optimizes cancer therapy with nanomedicine drug combinations


UCLA bioengineers develop platform that offers personalized approach to treatment.

By Brianna Aldrich, UCLA

In greater than 90 percent of cases in which treatment for metastatic cancer fails, the reason is that the cancer is resistant to the drugs being used. To treat drug-resistant tumors, doctors typically use multiple drugs simultaneously, a practice called combination therapy. And one of their greatest challenges is determining which ratio and combination — from the large number of medications available — is best for each individual patient.

Dr. Dean Ho, a professor of oral biology and medicine at the UCLA School of Dentistry, and Dr. Chih-Ming Ho, a professor of mechanical engineering at the UCLA Henry Samueli School of Engineering and Applied Science, have developed a revolutionary approach that brings together traditional drugs and nanotechnology-enhanced medications to create safer and more effective treatments. Their results are published in the peer-reviewed journal ACS Nano.

Chih-Ming Ho, the paper’s co-corresponding author, and his team have developed a powerful new tool to address drug resistance and dosing challenges in cancer patients. The tool, Feedback System Control.II, or FSC.II, considers drug efficacy tests and analyzes the physical traits of cells and other biological systems to create personalized “maps” that show the most effective and safest drug-dose combinations.

Currently, doctors use people’s genetic information to identify the best possible combination therapies, which can make treatment difficult or impossible when the genes in the cancer cells mutate. The new technique does not rely on genetic information, which makes it possible to quickly modify treatments when mutations arise: the drug that no longer functions can be replaced, and FSC.II can immediately recommend a new combination.

“Drug combinations are conventionally designed using dose escalation,” said Dean Ho, a co-corresponding author of the study and the co-director of the Jane and Jerry Weintraub Center for Reconstructive Biotechnology at the School of Dentistry. “Until now, there hasn’t been a systematic way to even know where the optimal drug combination could be found, and the possible drug-dose combinations are nearly infinite. FSC.II circumvents all of these issues and identifies the best treatment strategy.”

The researchers demonstrated that combinations identified by FSC.II could treat multiple lines of breast cancer that had varying levels of drug resistance. They evaluated the commonly used cancer drugs doxorubicin, mitoxantrone, bleomycin and paclitaxel, all of which can be rendered ineffective when cancer cells eject them before they have had a chance to function.

The researchers also studied the use of nanodiamonds to make combination treatments even more effective. Nanodiamonds — byproducts of conventional mining and refining operations — have versatile characteristics that allow drugs to be tightly bound to their surface, making it much harder for cancer cells to eliminate them and allowing toxic drugs to be administered over a longer period of time.

The use of nanodiamonds to treat cancer was pioneered by Dean Ho, a professor of bioengineering and member of the UCLA Jonsson Comprehensive Cancer Center and the California NanoSystems Institute.

“This study has the capacity to turn drug development, nano or non-nano, upside-down,” he said. “Even though FSC.II now enables us to rapidly identify optimized drug combinations, it’s not just about the speed of discovering new combinations. It’s the systematic way that we can control and optimize different therapeutic outcomes to design the most effective medicines possible.”

The study found that FSC.II-optimized drug combinations that used nanodiamonds were safer and more effective than optimized drug-only combinations. Optimized nanodrug combinations also outperformed randomly designed nanodrug combinations.

“This optimized nanodrug combination approach can be used for virtually every type of disease model and is certainly not limited to cancer,” said Chih-Ming Ho, who also holds UCLA’s Ben Rich Lockheed Martin Advanced Aerospace Tech Endowed Chair. “Additionally, this study shows that we can design optimized combinations for virtually every type of drug and any type of nanotherapy.”

Both Dean Ho and Chih-Ming Ho have collaborated with other researchers and have validated FSC.II’s efficacy in many other types of cancers, infectious diseases and other diseases.

Other co-authors were Hann Wang, Dong-Keun Lee, Kai-Yu Chen and Kangyi Zhang, all of UCLA’s department of bioengineering, School of Dentistry, California NanoSystems Institute and Jonsson Cancer Center; Jing-Yao Chen of UCLA’s department of chemical and biomolecular engineering; and Aleidy Silva of UCLA’s department of mechanical and aerospace engineering.

The work was supported in part by the National Cancer Institute, the National Science Foundation, the V Foundation for Cancer Research, the Wallace H. Coulter Foundation, the Society for Laboratory Automation and Screening, and Beckman Coulter Life Sciences.

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Stomach acid-powered micromotors get first test in living animal


Tiny motors may someday offer safer, more efficient way to deliver drugs or diagnose tumors.

By Becky Ham, UC San Diego

Researchers at UC San Diego have shown that a micromotor fueled by stomach acid can take a bubble-powered ride inside a mouse. These tiny motors, each about one-fifth the width of a human hair, may someday offer a safer and more efficient way to deliver drugs or diagnose tumors.

The experiment is the first to show that these micromotors can operate safely in a living animal, said professors Joseph Wang and Liangfang Zhang of the NanoEngineering Department at the UC San Diego Jacobs School of Engineering.

Wang, Zhang and others have experimented with different designs and fuel systems for micromotors that can travel in water, blood and other body fluids in the lab. “But this is the first example of loading and releasing a cargo in vivo,” said Wang. “We thought it was the logical extension of the work we have done, to see if these motors might be able to swim in stomach acid.”

Stomach acid reacts with the zinc body of the motors to generate a stream of hydrogen microbubbles that propel the motors forward. In their study published in the journal ACS Nano, the researchers report that the motors lodged themselves firmly in the stomach lining of mice. As the zinc motors are dissolved by the acid, they disappear within a few days leaving no toxic chemical traces.

“This initial work verifies that this motor can function in a real animal and is safe to use,” said Zhang.

In the experiment, the mice ingested tiny drops of solution containing hundreds of the micromotors. The motors become active as soon as they hit the stomach acid and zoom toward the stomach lining at a speed of 60 micrometers per second. They can self-propel like this for up to 10 minutes.

This propulsive burst improved how well the cone-shaped motors were able to penetrate and stick in the mucous layer covering the stomach wall, explained Zhang. “It’s the motor that can punch into this viscous layer and stay there, which is an advantage over more passive delivery systems,” he said.

The researchers found that nearly four times as many zinc micromotors found their way into the stomach lining compared with platinum-based micromotors, which don’t react with and can’t be fueled by stomach acid.

Wang said it may be possible to add navigation capabilities and other functions to the motors, to increase their targeting potential. Now that his team has demonstrated that the motors work in living animals, he noted, similar nanomachines soon may find a variety of applications including drug delivery, diagnostics, nanosurgery and biopsies of hard-to-reach tumors.

Wang and Zhang were joined on the study by UC San Diego nanoengineers Wei Gao, Renfeng Dong, Soracha Thamphiwatana, Jinxing Li and Weiwei Gao.

The publication is “Artificial Micromotors in the Mouse’s Stomach: A Step toward in Vivo Use of Synthetic Motors,” published online Dec. 30 in the journal ACS Nano.

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Temporary tattoo offers needle-free way to monitor glucose


‘Proof-of-concept’ tattoo could pave way for UC San Diego to explore others uses of device.

Nanoengineers at UC San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells.

By Ioana Patringenaru

Nanoengineers at UC San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells. This first-ever example of the flexible, easy-to-wear device could be a promising step forward in noninvasive glucose testing for patients with diabetes.

The sensor was developed and tested by graduate student Amay Bandodkar and colleagues in professor Joseph Wang’s laboratory at the NanoEngineering Department and the Center for Wearable Sensors at the Jacobs School of Engineering at UC San Diego. Bandodkar said this “proof-of-concept” tattoo could pave the way for the center to explore other uses of the device, such as detecting other important metabolites in the body or delivering medicines through the skin.

At the moment, the tattoo doesn’t provide the kind of numerical readout that a patient would need to monitor his or her own glucose. But this type of readout is being developed by electrical and computer engineering researchers in the Center for Wearable Sensors. “The readout instrument will also eventually have Bluetooth capabilities to send this information directly to the patient’s doctor in real-time or store data in the cloud,” said Bandodkar.

The research team is also working on ways to make the tattoo last longer while keeping its overall cost down, he noted. “Presently the tattoo sensor can easily survive for a day. These are extremely inexpensive — a few cents — and hence can be replaced without much financial burden on the patient.”

The center “envisions using these glucose tattoo sensors to continuously monitor glucose levels of large populations as a function of their dietary habits,” Bandodkar said. Data from this wider population could help researchers learn more about the causes and potential prevention of diabetes, which affects hundreds of millions of people and is one of the leading causes of death and disability worldwide.

People with diabetes often must test their glucose levels multiple times per day, using devices that use a tiny needle to extract a small blood sample from a fingertip. Patients who avoid this testing because they find it unpleasant or difficult to perform are at a higher risk for poor health, so researchers have been searching for less invasive ways to monitor glucose.

In their report in the journal Analytical Chemistry, Wang and his co-workers describe their flexible device, which consists of carefully patterned electrodes printed on temporary tattoo paper. A very mild electrical current applied to the skin for 10 minutes forces sodium ions in the fluid between skin cells to migrate toward the tattoo’s electrodes. These ions carry glucose molecules that are also found in the fluid. A sensor built into the tattoo then measures the strength of the electrical charge produced by the glucose to determine a person’s overall glucose levels.

“The concentration of glucose extracted by the non-invasive tattoo device is almost hundred times lower than the corresponding level in the human blood,” Bandodkar explained. “Thus we had to develop a highly sensitive glucose sensor that could detect such low levels of glucose with high selectivity.”

A similar device called GlucoWatch from Cygnus Inc. was marketed in 2002, but the device was discontinued because it caused skin irritation, the UC San Diego researchers note. Their proof-of-concept tattoo sensor avoids this irritation by using a lower electrical current to extract the glucose.

Wang and colleagues applied the tattoo to seven men and women between the ages of 20 and 40 with no history of diabetes. None of the volunteers reported feeling discomfort during the tattoo test, and only a few people reported feeling a mild tingling in the first 10 seconds of the test.

To test how well the tattoo picked up the spike in glucose levels after a meal, the volunteers ate a carb-rich meal of a sandwich and soda in the lab. The device performed just as well at detecting this glucose spike as a traditional finger-stick monitor.

The researchers say the device could be used to measure other important chemicals such as lactate, a metabolite analyzed in athletes to monitor their fitness. The tattoo might also someday be used to test how well a medication is working by monitoring certain protein products in the intercellular fluid, or to detect alcohol or illegal drug consumption.

Bandodkar was joined on the study by UC San Diego nanoengineers Wenzhao Jia, Ceren Yardımcı, Xuan Wang, Julian Ramirez and Wang, director of the Center for Wearable Sensors and SAIC Endowed Chair and distinguished professor in the NanoEngineering Department.

The publication is “Tattoo-Based Noninvasive Glucose Monitoring: A Proof-of-Concept Study,” published Dec. 12 in the journal Analytical Chemistry.

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‘NanoVelcro,’ temperature control used to extract tumor cells from blood


System could allow doctors to detect, analyze cancer to tailor treatment for individuals.

The device, developed at UCLA, enables scientists to control the blood’s temperature — the way coffeehouses would with an espresso machine — to capture and release the cancer cells in optimal conditions. (Credit: Tseng Lab, UCLA)

By Shaun Mason, UCLA

An international group led by scientists at UCLA’s California NanoSystems Institute has developed a new method for effectively extracting and analyzing cancer cells circulating in patients’ blood.

Circulating tumor cells are cancer cells that break away from tumors and travel in the blood, looking for places in the body to start growing new tumors called metastases. Capturing these rare cells would allow doctors to detect and analyze the cancer so they could tailor treatment for individual patients.

In his laboratory at the UCLA California NanoSystems Institute, Hsian-Rong Tseng, a professor of molecular and medical pharmacology, used a device he invented to capture circulating tumor cells from blood samples.

The device, called the NanoVelcro Chip, is a postage-stamp–sized chip with nanowires that are 1,000 times thinner than a human hair and are coated with antibodies that recognize circulating tumor cells. When 2 milliliters of blood are run through the chip, the tumor cells stick to the nanowires like Velcro.

Capturing the tumor cells was just part of the battle, though. To analyze them, Tseng’s team needed to be able to separate the cells from the chip without damaging them.

In earlier experiments with NanoVelcro, the scientists used a technique called laser capture microdissection that was effective in removing individual cells from the chip without damaging them, but the method was time-consuming and labor intensive, and it required highly specialized equipment.

Now Tseng and his colleagues have developed a thermoresponsive NanoVelcro purification system, which enables them to raise and lower the temperature of the blood sample to capture (at 37 degrees Celsius) and release (at 4 degrees Celsius) circulating tumor cells at their optimal purity. Polymer brushes on the NanoVelcro’s nanowires respond to the temperature changes by altering their physical properties, allowing them to capture or release the cells.

Because it could make extracting the cancer cells much more efficient and cost-effective at a time in a patient’s life when information is needed as quickly as possible, Tseng said it is conceivable that the new system will replace laser capture microdissection as the standard protocol.

“With our new system, we can control the blood’s temperature — the way coffeehouses would with an espresso machine — to capture and then release the cancer cells in great purity, ” said Tseng, who is also a member of UCLA’s Jonsson Comprehensive Cancer Center. “We combined the thermoresponsive system with downstream mutational analysis to successfully monitor the disease evolution of a lung cancer patient. This shows the translational value of our device in managing non–small-cell lung cancer with underlying mutations.”

The study, which was published online by the journal ACS Nano, brought together an interdisciplinary team from the U.S., China, Taiwan and Japan. The research was supported by the National Institutes of Health, RIKEN (Japan), Academia Sinica (Taiwan), Sun Yat-sen University (China) and the National Natural Science Foundation of China.

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New therapy holds promise for restoring vision


It has several advantages over other sight restoration therapies now under investigation.

Benjamin Gaub and John Flannery observing a mouse in a water maze, in which the mouse swims to a platform designated by bright flashing lights. (Photo by Mervi Kuronen)

By Robert Sanders, UC Berkeley

A new genetic therapy not only helped blind mice regain enough light sensitivity to distinguish flashing from non-flashing lights, but also restored light response to the retinas of dogs, setting the stage for future clinical trials of the therapy in humans.

The therapy employs a virus to insert a gene for a common ion channel into normally blind cells of the retina that survive after the light-responsive rod and cone photoreceptor cells die as a result of diseases such as retinitis pigmentosa. Photoswitches – chemicals that change shape when hit with light – are then attached to the ion channels to make them open in response to light, activating the retinal cells and restoring light sensitivity.

Afflicting people of all ages, retinitis pigmentosa causes a gradual loss of vision, akin to losing pixels in a digital camera. Sight is lost from the periphery to the center, usually leaving people with the inability to navigate their surroundings. Some 100,000 Americans suffer from this group of inherited retinal diseases.

In a paper appearing online this week in the early edition of the journal Proceedings of the National Academy of Sciences, University of California, Berkeley, scientists who invented the photoswitch therapy and vision researchers at the School of Veterinary Medicine of the University of Pennsylvania (PennVet) report that blind mice regained the ability to navigate a water maze as well as normal mice.

The treatment worked equally well to restore light responses to the degenerated retinas of mice and dogs, indicating that it may be feasible to restore some light sensitivity in blind humans.

“The dog has a retina very similar to ours, much more so than mice, so when you want to bring a visual therapy to the clinic, you want to first show that it works in a large animal model of the disease,” said lead researcher Ehud Isacoff, professor of molecular and cell biology at UC Berkeley. “We’ve now showed that we can deliver the photoswitch and restore light response to the blind retina in the dog as well as in the mouse, and that the treatment has the same sensitivity and speed of response. We can reanimate the dog retina.”

The therapy has several advantages over other sight restoration therapies now under investigation, says vision scientist John Flannery, UC Berkeley professor of vision science and of molecular and cell biology. It uses a virus already approved by the Food and Drug Administration for other genetic therapies in the eye; it delivers an ion channel gene similar to one normally found in humans, unlike others that employ genes from other species; and it can easily be reversed or adjusted by supplying new chemical photoswitches. Dogs with the retinal degeneration provide a key test of the new therapy.

“Our ability to test vision is very, very limited in mice because, even in the healthy state, they are not very visual animals, their behaviors are largely driven by their other senses,” he says. “Dogs have a very sophisticated visual system, and are being used already for testing ophthalmic gene therapy.”

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Vegetable oil ingredient is key to destroying gastric disease bacteria


Therapeutic nanoparticle that contains linolenic acid shows promise.

Liangfang Zhang, UC San Diego

By Heather Buschman, UC San Diego

The bacterium Helicobacter pylori is strongly associated with gastric ulcers and cancer. To combat the infection, researchers at the UC San Diego School of Medicine and Jacobs School of Engineering developed LipoLLA, a therapeutic nanoparticle that contains linolenic acid, a component in vegetable oils. In mice, LipoLLA was safe and more effective against H. pylori infection than standard antibiotic treatments.

The results are published online Nov. 24 in the Proceedings of the National Academy of Sciences.

“Current H. pylori treatments are facing a major challenge — antibiotic resistance,” said Liangfang Zhang, Ph.D., professor in the UC San Diego Moores Cancer Center and Department of Nanoengineering. “Our goal was to develop a nanotherapeutic that can tolerate the harsh gastric environment, kill H. pylori and avoid resistance.” Zhang and Marygorret Obonyo, Ph.D., assistant professor in the Moores Cancer Center and Department of Medicine, are co-senior authors of the study.

LipoLLA is a lipid (fat) particle that contains linolenic acid. When LipoLLA encounters H. pylori, it fuses with the bacterial membrane. Then the particle’s linolenic acid payload spills out, disrupting the membrane and killing the bacteria.

Zhang, Obonyo and their team labeled LipoLLA particles with fluorescent markers, fed them to mice and watched as the particles distributed themselves in the stomach lining — and stayed there. After treatment, they measured bacterial load in the stomach and markers of inflammation. Compared to standard antibiotic therapies, LipoLLA was more effective at getting rid of H. pylori. What’s more, LipoLLA was not toxic to the mice and the bacteria did not develop resistance to the therapy.

“This is the first step to verify that we can make this therapeutic nanoparticle and demonstrate that it works to reduce H. pylori colonization. We’re now working to further enhance the particle, making it more stable and more effective,” Zhang said.

Co-authors include Soracha Thamphiwatana and Weiwei Gao, UC San Diego.

This research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (grant R01DK095168), part of the National Institutes of Health.

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Biochemists build largest synthetic molecular ‘cage’ ever


New nanoscale protein container could lead to synthetic vaccines.

Todd Yeates and Yen-Ting Lai, UCLA

UCLA biochemists have created the largest-ever protein that self-assembles into a molecular “cage.” The research could lead to synthetic vaccines that protect people from the flu, HIV and other diseases.

At a size hundreds of times smaller than a human cell, it also could lead to new methods of delivering pharmaceuticals inside of cells, or to the creation of new nanoscale materials.

The protein assembly, which is shaped like a cube, was constructed from 24 copies of a protein designed in the laboratory of Todd Yeates, a UCLA professor of chemistry and biochemistry. It is porous — more so than any other protein assembly ever created — with large openings that would enable other large protein molecules to enter and exit.

The research was recently published online in the journal Nature Chemistry and will appear in a future print edition.

Yeates, the study’s senior author, has sought to build complex protein structures that self-assemble since he first published research on self-assembling proteins in 2001. In 2012, he and colleagues produced a self-assembling molecular cage made from 12 protein pieces combined perfectly like pieces of a puzzle. Now they have done so with 24 pieces, and they are currently attempting to design a molecular cage with 60 pieces. Building each larger protein presented new scientific challenges, but the bigger sizes could potentially carry more “cargo.”

In principle, these molecular structures should be able to carry cargo that could then be released inside of cells, said Yeates, who is a member of the UCLA–Department of Energy Institute of Genomics and Proteomics and the California NanoSystems Institute at UCLA.

Yeates’ research was funded by the National Science Foundation and the UCLA–DOE Institute of Genomics and Proteomics. The lead author was Yen-Ting Lai, who conducted the research as a UCLA graduate student in Yeates’ laboratory and is now a postdoctoral scholar at Arizona State University.

The molecular cube is probably too porous to serve as a container — for medicine, for example — inside a human body. “But the design principles for making a cage that is more closed would be the same,” Yeates said, adding that there are ways to make the cage less stable when it gets into a cell, so that it would release its cargo, such as a toxin that could kill a cancer cell.

Yeates said that his lab’s method also could lead to the production of synthetic vaccines that would mimic what a cell sees when it’s infected by a virus. The vaccines would provoke a strong response from the body’s immune system and perhaps provide better protection from diseases than traditional vaccines.

Yeates has started a research collaboration with Peter Kwong, chief of the structural biology section at the National Institutes of Health and a national leader in the structural biology of disease viruses. They will conduct research on attaching viral antigens to molecular cages.

Other co-authors of the Nature Chemistry research were Carol Robinson, Eamonn Reading and Arthur Laganowsky of the University of Oxford; Francisco Asturias and Kuang-Lei Tsai of the Scripps Research Institute; and John Tainer and Greg Hura of the Lawrence Berkeley National Laboratory.

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Building molecular ‘cages’ to fight disease

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