Making it big: Metamaterial applications a step closer to reality

 

May 9, 2014

The Agency for Science, Technology and Research (A*STAR)

The use of a fabrication technique borrowed from the semiconductor industry brings metamaterial applications a step closer to reality. Artificial materials engineered to have properties not found in nature, such as a negative refractive index are engineered to interact with light and sound waves in ways that natural materials cannot. They thus have the potential to be used in exciting new applications, such as invisibility cloaks, high-resolution lenses, efficient and compact antennas, and highly sensitive sensors.

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Metamaterials are engineered to interact with light and sound waves in ways that natural materials cannot. They thus have the potential to be used in exciting new applications, such as invisibility cloaks, high-resolution lenses, efficient and compact antennas, and highly sensitive sensors.

While the theory of this interaction is relatively well understood, it has been challenging to fabricate metamaterials that are large enough to be practical. Now, Yi Zhou and colleagues at the A*STAR Data Storage Institute in Singapore have demonstrated a promising new fabrication technique that can produce large areas of an important class of metamaterial, known as fishnet metamaterials1.

Most optical metamaterials consist of tiny repeated metallic structures. When light of a particular frequency falls on them, it establishes oscillating fields inside each structure. These fields can resonate with each other and thereby produce desirable collective behavior. Fishnet metamaterials usually have several vertically stacked repeat units spread out over much larger lateral dimensions. Because they are structured both vertically and laterally, they are called three-dimensional materials.

Fishnet metamaterials are usually made in one of two ways. They can be fabricated by carefully patterning individual films and then stacking these films on top of each other. However, this multilayer process is difficult, as it requires careful alignment of the films.

The second approach is to pattern a sacrificial substrate and then deposit repeated layers onto it. This 'pattern-first' process suffers from its own difficulties, the most important of which is that the total thickness of the final fishnet material is typically limited to tens of nanometers or less. This restricts the kind of resonances that can be achieved and, in turn, the functionality of the final film.

Zhou and colleagues were able to increase the total thickness of pattern-first fishnet films to around 300 nanometers, allowing five bilayers of film to be deposited and resulting in a strong characteristic resonance and pronounced metamaterial behavior. To achieve this, they adopted a technique called trilayer lift-off, which is commonly used in industry but seldom applied in research laboratories. It involves patterning a sacrificial layer of a photoresist resting on a layer of silicon dioxide under which lies a second photoresist layer.

By alternating the patterning and etching steps, the A*STAR team could achieve a film thickness greatly exceeding the size of the lateral patterns etched into the film. "This technique will help researchers design large-area three-dimensional nanodevices more easily," says Zhou, "and help bring the science of metamaterials to reality."

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The above story is based on materials provided by The Agency for Science, Technology and Research (A*STAR). Note: Materials may be edited for content and length.

Conducting polymer films decorated with biomolecules for cell research use

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This is an image of stamp and substrate.

The ability to create conducting polymer films in a variety of shapes, thicknesses and surface properties rapidly and inexpensively will make growing and testing cells easier and more flexible, according to a team of Penn State bioengineers.

"The ultimate goal of this collaborative project is to be able to create a substrate for growth and manipulation of cells," said Sheereen Majd, assistant professor of bioengineering. "Cells on a surface need to recognize biomolecules like extracellular matrix proteins to be able to adhere and grow. We ultimately would like to be able to use these polymer films to manipulate adhesion, growth, proliferation and migration of cells." Majd and her team are creating patterned films of conducting polymers on gold substrates by electrodeposition through hydrogel stamps. They report their results today (May 9) in Advanced Materials.

The researchers create their hydrogel stamps from agarose -- a sugar extracted from seaweed -- poured into molds. While most of the current experiments use arrays of dots, because the researchers use molded stamps, a wide variety of shapes -- dots, squares, lines -- are possible. The stamp is dipped in a solution of monomer and a dopant and placed on the gold surface. An electrical current through the hydrogel and gold polymerizes the monomer and dopant at the surface. If a biomolecule of interest is also included in the stamping solution, it becomes embedded in the polymer film as well.

Because the presence of dopant is important for the electrical conductivity of these polymers, only areas where monomer and dopant exist together form conductive films of polymer. The process takes from one to two minutes and the longer the current is applied, the thicker the film.

The researchers were able to produce a series of films using the same monomer but different dopants and biomolecules by altering the solution on various parts of the stamp. In this way researchers can change the surface properties and functionality of the films. The stamp can also be used multiple times before re-inking becomes necessary, simplifying and speeding up the process.

Creating arrays of different biomolecules and different shapes in conducting polymers is especially important when studying excitable cells like neurons or muscle cells because they react to electricity.

Conducting polymer arrays will allow manipulation of cells using chemical and electrical signals, expanding the ways cells can be treated. Varying films laid down on one substrate can put multiple experiments all in one

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The above story is based on materials provided by Penn State. The original article was written by A'ndrea Elyse Messer. Note: Materials may be edited for content and length.

Epigenetic mechanisms distinguishing stem cell function, blood cancer decoded

 

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Researchers at Dartmouth's Norris Cotton Cancer Center have published results from a study in Cell Reports that discovers a new mechanism that distinguishes normal blood stem cells from blood cancers.

"These findings constitute a significant advance toward the goal of killing leukemia cells without harming the body's normal blood stem cells which are often damaged by chemotherapy," said Patricia Ernst, PhD, co-director of the Cancer Mechanisms Program of the Norris Cotton Cancer Center and an associate professor in Genetics at the Geisel School of Medicine.

The study focused on a pathway regulated by a gene called MLL1 (for Mixed Lineage Leukemia). Ernst served as principal investigator; Bibhu Mishra, PhD, as lead author.

When the MLL1 gene is damaged, it can cause leukemia, which is a cancer of the blood, often occurring in very young patients. Researchers found that the normal version of the gene controls many other genes in a manner that maintains the production of blood cells.

"This control becomes chaotic when the gene is damaged or 'broken' and that causes the normal blood cells to turn into leukemia," said Ernst.

The researchers showed that the normal gene acts with a partner gene called MOF that adds small "acetyl" chemical modification around the genes that it controls. The acetyl modification acts as a switch to turn genes on. When this function is disrupted, MLL1 cannot maintain normal blood stem cells.

The researchers also found that a gene called Sirtuin1 (more commonly known for controlling longevity) works against MLL1 to keep the proper amount of "acetyl" modifications on important stem cell genes. Blood cancers involving MLL1, in contrast, do not have this MOF-Sirtuin balance and place a different chemical modification on genes that result in leukemia.

Blood stem cells also represent an important therapy for patients whose own stem cells are destroyed by chemotherapy. This study also reveals a new way to treat blood stem cells from donors that would expand their numbers.

"These finding suggest that drugs that block Sirtuin1 may be combined with MLL1 blocking drugs in certain leukemia to both preserve stem cells that make normal blood at the same time as killing leukemia cells," said Ernst.

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The above story is based on materials provided by The Geisel School of Medicine at Dartmouth. Note: Materials may be edited for content and length.

Intestinal enzyme maintains microbial balance: Study shows how

 

May 9, 2014

Massachusetts General Hospital

The mechanism by which an enzyme produced in the intestinal lining helps to maintain a healthy population of gastrointestinal microbes has been identified by researchers. The research team describes finding that intestinal alkaline phosphatase promotes the growth of beneficial bacteria by blocking the growth-inhibiting action of adenosine triphosphate -- an action first described in this paper -- within the intestine.

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Massachusetts General Hospital (MGH) investigators have identified the mechanism by which an enzyme produced in the intestinal lining helps to maintain a healthy population of gastrointestinal microbes. In their report in American Journal of Physiology -- Gastrointestinal and Liver Physiology, the research team describes finding that intestinal alkaline phosphatase (IAP) promotes the growth of beneficial bacteria by blocking the growth-inhibiting action of adenosine triphosphate (ATP) -- an action first described in this paper -- within the intestine.

"We found that ATP is a natural inhibitor of bacteria in our intestines and that IAP promotes the growth of 'good' bacteria by blocking ATP," says Richard Hodin, MD, of the MGH Department of Surgery, senior author of the report which has been released online. "By helping to keep these healthy bacteria happy, IAP protects us against dangerous pathogens that can get the upper hand when the balance is disrupted."

The beneficial bacteria and other microbes that normally populate the human digestive system contribute to the digestive process and also prevent the proliferation of any disease-causing bacteria that may be present. A drop in the number of beneficial species -- which may be caused by antibiotic treatment, poor nutrition or other health conditions -- can allow the population of harmful bacteria to rise, contributing to serious medical problems including chronic diarrhea from pathogenic species such as C. difficile, inflammatory bowel disease, and metabolic syndrome.

Previous research by Hodin's team found that IAP keeps pathogenic bacteria in the gastrointestinal tract from passing through the intestinal wall, and a 2010 study in mice revealed that the enzyme plays an important role in maintaining levels of beneficial bacteria, including restoring levels reduced by antibiotic treatment. However, that study also showed that IAP does not directly promote bacterial growth, leaving exactly how the enzyme helps maintain the microbial population an open question that the current study was designed to investigate.

A series of experiments first confirmed that mice lacking intestinal IAP had significant reductions in populations of several important bacterial species. Hypothesizing that IAP may act by blocking a growth-inhibiting activity of one of its target molecules, the researchers tested how well bacteria in stool samples would grow in the presence of four known IAP targets. Among the tested targets, only ATP significantly reduced bacterial growth; and ATP's inhibitory effects were reversed by application of IAP. Best known as the primary energy supply within cells, ATP also acts as a signaling molecule both inside and outside of cells, and this study is the first to identify such an activity for ATP within the gastrointestinal system.

Experiments in living mice revealed that IAP knockout animals had 10 times the normal level of ATP within their intestines and that fasting animals, in which IAP levels would be expected to drop, also had elevated intestinal ATP. Adding ATP to the intestines of mice in which IAP activity had been inhibited reduced levels of beneficial E.coli bacteria in the animals' digestive systems. Altogether the results show that ATP inhibits the growth of intestinal bacteria in mice and that IAP's growth-promoting effects result from the enzyme's inactivation of ATP and possibly of related molecules.

"Now we need to find out whether IAP also promotes the growth of beneficial intestinal bacteria in humans," says Hodin, who is a professor of Surgery at Harvard Medical School. "If it does, IAP-based therapies could offer a simple and safe approach to treating the millions of patients who suffer serious health problems caused by disruptions to intestinal microbial balance."

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The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.

Toxicologists outline key health and environmental concerns associated with hydraulic fracturing

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Since the rise in the use of hydraulic fracturing of shale to produce natural gas and oil, scientists, politicians, industrialists, and others have debated the merits and detractions of the practice. In a newly published paper in Toxicological Sciences, members of the Society of Toxicology (SOT), alongside other experts, outline how toxicological sciences can be used to determine what risks may or may not be associated with hydraulic fracturing.

"Toxicology is the study of the effects of chemical, physical, or biological agents on living organisms and the environment. As such, toxicologists should be at the forefront of discussions of hydraulic fracturing," says Society of Toxicology President Norbert E. Kaminski, PhD. "We can provide information on the potential toxicity of the chemical and physical agents associated with the process, individually and in combination."

In "The Role of Toxicological Science in Meeting the Challenges and Opportunities of Hydraulic Fracturing" Bernard D. Goldstein, et al, identify a series of potential pathways of contamination and toxicological effects associated with hydraulic fracturing that should and are being explored by researchers:

• Water pollution: There is a potential for surface or groundwater contamination by hydraulic fracturing fluids and their constituents. The authors found that there are few confirmed cases of groundwater contamination, but that there is little research available on the chemical baselines of drinking and surface waters prior to hydraulic fracturing practices to determine contamination with toxicologically significant levels of chemicals as a result of routine hydraulic fracturing.
• Air Pollution: The authors write, "A single hydraulic fracturing site is unlikely to produce significant increments of ozone precursors. However, there is concern that in aggregate hydraulic fracturing activities in regions with thousands of wells, and which already have ozone levels close to the allowable health-based standard, such as the Northeast, may be tipped into nonattainment of the standard." Potential contaminants that are being studied include methane gas, diesel emissions, volatile organic compounds, and benzene, among others.
• Occupational Exposure: Workers at hydraulic fracturing sites are exposed to a series of potential hazards to their health. These potential hazards range from inhalation of gases and particulate matter to dermal exposure to these same elements. Evaluating exposure amounts, types of exposure, and lengths of exposure to various individual chemicals and the chemicals in combination is necessary to determine potential risks to hydraulic fracturing workers.

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The above story is based on materials provided by Society of Toxicology. Note: Materials may be edited for content and length.

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Journal Reference:

1. B. D. Goldstein, B. W. Brooks, S. D. Cohen, A. E. Gates, M. E. Honeycutt, J. B. Morris, J. Orme-Zavaleta, T. M. Penning, J. Snawder. The Role of Toxicological Science in Meeting the Challenges and Opportunities of Hydraulic Fracturing. Toxicological Sciences, 2014; 139 (2): 271 DOI: 10.1093/toxsci/kfu061

Chemotherapy timing is key to success, research shows

 

In studies with mice, the research team showed that this one-two punch, which relies on a nanoparticle that carries two drugs and releases them at different times, dramatically shrinks lung and breast tumors. The MIT team, led by Michael Yaffe, the David H. Koch Professor in Science, and Paula Hammond, the David H. Koch Professor in Engineering, describe the findings in the May 8 online edition of Science Signaling.

"I think it's a harbinger of what nanomedicine can do for us in the future," says Hammond, who is a member of MIT's Koch Institute for Integrative Cancer Research. "We're moving from the simplest model of the nanoparticle -- just getting the drug in there and targeting it -- to having smart nanoparticles that deliver drug combinations in the way that you need to really attack the tumor."

Doctors routinely give cancer patients two or more different chemotherapy drugs in hopes that a multipronged attack will be more successful than a single drug. While many studies have identified drugs that work well together, a 2012 paper from Yaffe's lab was the first to show that the timing of drug administration can dramatically influence the outcome.

In that study, Yaffe and former MIT postdoc Michael Lee found they could weaken cancer cells by administering the drug erlotinib, which shuts down one of the pathways that promote uncontrolled tumor growth. These pretreated tumor cells were much more susceptible to treatment with a DNA-damaging drug called doxorubicin than cells given the two drugs simultaneously.

"It's like rewiring a circuit," says Yaffe, who is also a member of the Koch Institute. "When you give the first drug, the wires' connections get switched around so that the second drug works in a much more effective way."

Erlotinib, which targets a protein called the epidermal growth factor (EGF) receptor, found on tumor cell surfaces, has been approved by the Food and Drug Administration to treat pancreatic cancer and some types of lung cancer. Doxorubicin is used to treat many cancers, including leukemia, lymphoma, and bladder, breast, lung, and ovarian tumors.

Staggering these drugs proved particularly powerful against a type of breast cancer cell known as triple-negative, which doesn't have overactive estrogen, progesterone, or HER2 receptors. Triple-negative tumors, which account for about 16 percent of breast cancer cases, are much more aggressive than other types and tend to strike younger women.

That was an exciting finding, Yaffe says. "The problem was," he adds, "how do you translate that into something you can actually give a cancer patient?"

From lab result to drug delivery

To approach this problem, Yaffe teamed up with Hammond, a chemical engineer who has previously designed several types of nanoparticles that can carry two drugs at once. For this project, Hammond and her graduate student, Stephen Morton, devised dozens of candidate particles. The most effective were a type of particle called liposomes -- spherical droplets surrounded by a fatty outer shell.

The MIT team designed their liposomes to carry doxorubicin inside the particle's core, with erlotinib embedded in the outer layer. The particles are coated with a polymer called PEG, which protects them from being broken down in the body or filtered out by the liver and kidneys. Another tag, folate, helps direct the particles to tumor cells, which express high quantities of folate receptors.

Once the particles reach a tumor and are taken up by cells, the particles start to break down. Erlotinib, carried in the outer shell, is released first, but doxorubicin release is delayed and takes more time to seep into cells, giving erlotinib time to weaken the cells' defenses. "There's a lag of somewhere between four and 24 hours between when erlotinib peaks in its effectiveness and the doxorubicin peaks in its effectiveness," Yaffe says.

The researchers tested the particles in mice implanted with two types of human tumors: triple-negative breast tumors and non-small-cell lung tumors. Both types shrank significantly. Furthermore, packaging the two drugs in liposome nanoparticles made them much more effective than the traditional forms of the drugs, even when those drugs were given in a time-staggered order.

As a next step before possible clinical trials in human patients, the researchers are now testing the particles in mice that are genetically programmed to develop tumors on their own, instead of having human tumor cells implanted in them.

The researchers believe that time-staggered delivery could also improve other types of chemotherapy. They have devised several combinations involving cisplatin, a commonly used DNA-damaging drug, and are working on other combinations to treat prostate, head and neck, and ovarian cancers. At the same time, Hammond's lab is working on more complex nanoparticles that would allow for more precise loading of the drugs and fine-tuning of their staggered release.

"With a nanoparticle delivery platform that allows us to control the relative rates of release and the relative amounts of loading, we can put these systems together in a smart way that allows them to be as effective as possible," Hammond says.