Tag Archives: Northwestern University

A view to controversies about nanoparticle drug delivery, sticky-flares, and a PNAS surprise

Despite all the excitement and claims for nanoparticles as vehicles for drug delivery to ‘sick’ cells there is at least one substantive problem, the drug-laden nanoparticles don’t actually enter the interior of the cell. They are held in a kind of cellular ‘waiting room’.

Leonid Schneider in a Nov. 20, 2015 posting on his For Better Science blog describes the process in more detail,

A large body of scientific nanotechnology literature is dedicated to the biomedical aspect of nanoparticle delivery into cells and tissues. The functionalization of the nanoparticle surface is designed to insure their specificity at targeting only a certain type of cells, such as cancers cells. Other technological approaches aim at the cargo design, in order to ensure the targeted release of various biologically active agents: small pharmacological substances, peptides or entire enzymes, or nucleotides such as regulatory small RNAs or even genes. There is however a main limitation to this approach: though cells do readily take up nanoparticles through specific membrane-bound receptor interaction (endocytosis) or randomly (pinocytosis), these nanoparticles hardly ever truly reach the inside of the cell, namely its nucleocytoplasmic space. Solid nanoparticles are namely continuously surrounded by the very same membrane barrier they first interacted with when entering the cell. These outer-cell membrane compartments mature into endosomal and then lysosomal vesicles, where their cargo is subjected to low pH and enzymatic digestion. The nanoparticles, though seemingly inside the cell, remain actually outside. …

What follows is a stellar piece featuring counterclaims about and including Schneider’s own journalistic research into scientific claims that the problem of gaining entry to a cell’s true interior has been addressed by technologies developed in two different labs.

Having featured one of the technologies here in a July 24, 2015 posting titled: Sticky-flares nanotechnology to track and observe RNA (ribonucleic acid) regulation and having been contacted a couple of times by one of the scientists, Raphaël Lévy from the University of Liverpool (UK), challenging the claims made (Lévy’s responses can be found in the comments section of the July 2015 posting), I thought a followup of sorts was in order.

Scientific debates (then and now)

Scientific debates and controversies are part and parcel of the scientific process and what most outsiders, such as myself, don’t realize is how fraught it is. For a good example from the past, there’s Leviathan and the Air-Pump: Hobbes, Boyle, and the Experimental Life (from its Wikipedia entry), Note: Links have been removed),

Leviathan and the Air-Pump: Hobbes, Boyle, and the Experimental Life (published 1985) is a book by Steven Shapin and Simon Schaffer. It examines the debate between Robert Boyle and Thomas Hobbes over Boyle’s air-pump experiments in the 1660s.

The style seems more genteel than what a contemporary Canadian or US audience is accustomed to but Hobbes and Boyle (and proponents of both sides) engaged in bruising communication.

There was a lot at stake then and now. It’s not just the power, prestige, and money, as powerfully motivating as they are, it’s the research itself. Scientists work for years to achieve breakthroughs or to add more to our common store of knowledge. It’s painstaking and if you work at something for a long time, you tend to be invested in it. Saying you’ve wasted ten years of your life looking at the problem the wrong way or have misunderstood your data is not easy.

As for the current debate, Schneider’s description gives no indication that there is rancour between any of the parties but it does provide a fascinating view of two scientists challenging one of the US’s nanomedicine rockstars, Chad Mirkin. The following excerpt follows the latest technical breakthroughs to the interior portion of the cell through three phases of the naming conventions (Nano-Flares, also known by its trade name, SmartFlares, which is a precursor technology to Sticky-Flares), Note: Links have been removed,

The next family of allegedly nucleocytoplasmic nanoparticles which Lévy turned his attention to, was that of the so called “spherical nucleic acids”, developed in the lab of Chad Mirkin, multiple professor and director of the International Institute for Nanotechnology at the Northwestern University, USA. These so called “Nano-Flares” are gold nanoparticles, functionalized with fluorophore-coupled oligonucleotides matching the messenger RNA (mRNA) of interest (Prigodich et al., ACS Nano 3:2147-2152, 2009; Seferos et al., J Am. Chem.Soc. 129:15477-15479, 2007). The mRNA detection method is such that the fluorescence is initially quenched by the gold nanoparticle proximity. Yet when the oligonucleotide is displaced by the specific binding of the mRNA molecules present inside the cell, the fluorescence becomes detectable and serves thus as quantitative read-out for the intracellular mRNA abundance. Exactly this is where concerns arise. To find and bind mRNA, spherical nucleic acids must leave the endosomal compartments. Is there any evidence that Nano-Flares ever achieve this and reach intact the nucleocytoplasmatic space, where their target mRNA is?

Lévy’s lab has focused its research on the commercially available analogue of the Nano-Flares, based on the patent to Mirkin and Northwestern University and sold by Merck Millipore under the trade name of SmartFlares. These were described by Mirkin as “a powerful and prolific tool in biology and medical diagnostics, with ∼ 1,600 unique forms commercially available today”. The work, led by Lévy’s postdoctoral scientist David Mason, now available in post-publication process at ScienceOpen and on Figshare, found no experimental evidence for SmartFlares to be ever found outside the endosomal membrane vesicles. On the contrary, the analysis by several complementary approaches, i.e., electron, fluorescence and photothermal microscopy, revealed that the probes are retained exclusively within the endosomal compartments.

In fact, even Merck Millipore was apparently well aware of this problem when the product was developed for the market. As I learned, Merck performed a number of assays to address the specificity issue. Multiple hundred-fold induction of mRNA by biological cell stimulation (confirmed by quantitative RT-PCR) led to no significant changes in the corresponding SmartFlare signal. Similarly, biological gene downregulation or experimental siRNA knock-down had no effect on the corresponding SmartFlare fluorescence. Cell lines confirmed as negative for a certain biomarker proved highly positive in a SmartFlare assay.  Live cell imaging showed the SmartFlare signal to be almost entirely mitochondrial, inconsistent with reported patterns of the respective mRNA distributions.  Elsewhere however, cyanine dye-labelled oligonucleotides were found to unspecifically localise to mitochondria   (Orio et al., J. RNAi Gene Silencing 9:479-485, 2013), which might account to the often observed punctate Smart Flare signal.

More recently, Mirkin lab has developed a novel version of spherical nucleic acids, named Sticky-Flares (Briley et al., PNAS 112:9591-9595, 2015), which has also been patented for commercial use. The claim is that “the Sticky-flare is capable of entering live cells without the need for transfection agents and recognizing target RNA transcripts in a sequence-specific manner”. To confirm this, Lévy used the same approach as for the striped nanoparticles [not excerpted here]: he approached Mirkin by email and in person, requesting the original microscopy data from this publication. As Mirkin appeared reluctant, Lévy invoked the rules for data sharing by the journal PNAS, the funder NSF as well as the Northwestern University. After finally receiving Mirkin’s thin-optical microscopy data by air mail, Lévy and Mason re-analyzed it and determined the absence of any evidence for endosomal escape, while all Sticky-Flare particles appeared to be localized exclusively inside vesicular membrane compartments, i.e., endosomes (Mason & Levy, bioRxiv 2015).

I encourage you to read Schneider’s Nov. 20, 2015 posting in its entirety as these excerpts can’t do justice to it.

The PNAS surprise

PNAS (Proceedings of the National Academy of Science) published one of Mirkin’s papers on ‘Sticky-flares’ and is where scientists, Raphaël Lévy and David Mason, submitted a letter outlining their concerns with the ‘Sticky-flares’ research. Here’s the response as reproduced in Lévy’s Nov. 16, 2015 posting on his Rapha-Z-Lab blog

Dear Dr. Levy,

I regret to inform you that the PNAS Editorial Board has declined to publish your Letter to the Editor. After careful consideration, the Board has decided that your letter does not contribute significantly to the discussion of this paper.

Thank you for submitting your comments to PNAS.

Sincerely yours,
Inder Verma
Editor-in-Chief

Judge for yourself, Lévy’s and Mason’s letter can be found here (pdf) and here.

Conclusions

My primary interest in this story is in the view it provides of the scientific process and the importance of and difficulty associated with the debates.

I can’t venture an opinion about the research or the counterarguments other than to say that Lévy’s and Mason’s thoughtful challenge bears more examination than PNAS is inclined to accord. If their conclusions or Chad Mirkin’s are wrong, let that be determined in an open process.

I’ll leave the very last comment to Schneider who is both writer and cartoonist, from his Nov. 20, 2015 posting,

LeonidSchneiderImagination

A perovskite memristor with three stable resistive states

Thanks to Dexter Johnson’s Oct. 22, 2015 posting on his Nanoclast blog (on the IEEE [Institute of Electrical and Electronics Engineers]) website, I’ve found information about a second memristor with three terminals, aka, three stable resistive states,  (the first is mentioned in my April 10, 2015 posting). From Dexter’s posting (Note: Links have been removed),

Now researchers at ETH Zurich have designed a memristor device out of perovskite just 5 nanometres thick that has three stable resistive states, which means it can encode data as 0,1 and 2, or a “trit” as opposed to a “bit.”

The research, which was published in the journal ACS Nano, developed model devices that have two competing nonvolatile resistive switching processes. These switching processes can be alternatively triggered by the effective switching voltage and time applied to the device.

“Our component could therefore also be useful for a new type of IT (Information Technology) that is not based on binary logic, but on a logic that provides for information located ‘between’ the 0 and 1,” said Jennifer Rupp, professor in the Department of Materials at ETH Zurich, in a press release. “This has interesting implications for what is referred to as fuzzy logic, which seeks to incorporate a form of uncertainty into the processing of digital information. You could describe it as less rigid computing.”

An Oct. 19, 2015 Swiss National Science Foundation press release provides context for the research,

Two IT giants, Intel and HP, have entered a race to produce a commercial version of memristors, a new electronics component that could one day replace flash memory (DRAM) used in USB memory sticks, SD cards and SSD hard drives. “Basically, memristors require less energy since they work at lower voltages,” explains Jennifer Rupp, professor in the Department of Materials at ETH Zurich and holder of a SNSF professorship grant. “They can be made much smaller than today’s memory modules, and therefore offer much greater density. This means they can store more megabytes of information per square millimetre.” But currently memristors are only at the prototype stage. [emphasis mine]

There is a memristor-based product on the market as I noted in a Sept. 10, 2015 posting, although that may not be the type of memristive device that Rupp seems to be discussing. (Should you have problems accessing the Swiss National Science Foundation press release, you can find a lightly edited version (a brief [two sentences] history of the memristor has been left out) here on Azonano.

Jacopo Prisco wrote for CNN online in a March 2, 2015 article about memristors and Rupp’s work (Note: A link has been removed),

Simply put, the memristor could mean the end of electronics as we know it and the beginning of a new era called “ionics”.

The transistor, developed in 1947, is the main component of computer chips. It functions using a flow of electrons, whereas the memristor couples the electrons with ions, or electrically charged atoms.

In a transistor, once the flow of electrons is interrupted by, say, cutting the power, all information is lost. But a memristor can remember the amount of charge that was flowing through it, and much like a memory stick it will retain the data even when the power is turned off.

This can pave the way for computers that will instantly turn on and off like a light bulb and never lose data: the RAM, or memory, will no longer be erased when the machine is turned off, without the need to save anything to hard drives as with current technology.

Jennifer Rupp is a Professor of electrochemical materials at ETH Zurich, and she’s working with IBM to build a memristor-based machine.

Memristors, she points out, function in a way that is similar to a human brain: “Unlike a transistor, which is based on binary codes, a memristor can have multi-levels. You could have several states, let’s say zero, one half, one quarter, one third, and so on, and that gives us a very powerful new perspective on how our computers may develop in the future,” she told CNN’s Nick Glass.

This is the CNN interview with Rupp,

Prisco also provides an update about HP’s memristor-based product,

After manufacturing the first ever memristor, Hewlett Packard has been working for years on a new type of computer based on the technology. According to plans, it will launch by 2020.

Simply called “The Machine”, it uses “electrons for processing, photons for communication, and ions for storage.”

I first wrote about HP’s The Machine in a June 25, 2014 posting (scroll down about 40% of the way).

There are many academic teams researching memristors including a team at Northwestern University. I highlighted their announcement of a three-terminal version in an April 10, 2015 posting. While Rupp’s team achieved its effect with a perovskite substrate, the Northwestern team used a molybdenum disulfide (MoS2) substrate.

For anyone wanting to read the latest research from ETH, here’s a link to and a citation for the paper,

Uncovering Two Competing Switching Mechanisms for Epitaxial and Ultrathin Strontium Titanate-Based Resistive Switching Bits by Markus Kubicek, Rafael Schmitt, Felix Messerschmitt, and Jennifer L. M. Rupp. ACS Nano, Article ASAP DOI: 10.1021/acsnano.5b02752 Publication Date (Web): October 8, 2015

Copyright © 2015 American Chemical Society

This paper is behind a paywall.

Finally, should you find the commercialization aspects of the memristor story interesting, there’s a June 6, 2015 posting by Knowm CEO (chief executive officer) Alex Nugent waxes eloquent on HP Labs’ ‘memristor problem’ (Note: A link has been removed),

Today I read something that did not surprise me. HP has said that their memristor technology will be replaced by traditional DRAM memory for use in “The Machine”. This is not surprising for those of us who have been in the field since before HP’s memristor marketing engine first revved up in 2008. While I have to admit the miscommunication between HP’s research and business development departments is starting to get really old, I do understand the problem, or at least part of it.

There are two ways to develop memristors. The first way is to force them to behave as you want them to behave. Most memristors that I have seen do not behave like fast, binary, non-volatile, deterministic switches. This is a problem because this is how HP wants them to behave. Consequently a perception has been created that memristors are for non-volatile fast memory. HP wants a drop-in replacement for standard memory because this is a large and established market. Makes sense of course, but its not the whole story on memristors.

Memristors exhibit a huge range of amazing phenomena. Some are very fast to switch but operate probabilistically. Others can be changed a little bit at a time and are ideal for learning. Still others have capacitance (with memory), or act as batteries. I’ve even seen some devices that can be programmed to be a capacitor or a resistor or a memristor. (Seriously).

Nugent, whether you agree with him or not provides, some fascinating insight. In the excerpt I’ve included here, he seems to provide confirmation that it’s possible to state ‘there are no memristors on the market’ and ‘there are memristors on the market’ because different devices are being called memristors.

$81M for US National Nanotechnology Coordinated Infrastructure (NNCI)

Academics, small business, and industry researchers are the big winners in a US National Science Foundation bonanza according to a Sept. 16, 2015 news item on Nanowerk,

To advance research in nanoscale science, engineering and technology, the National Science Foundation (NSF) will provide a total of $81 million over five years to support 16 sites and a coordinating office as part of a new National Nanotechnology Coordinated Infrastructure (NNCI).

The NNCI sites will provide researchers from academia, government, and companies large and small with access to university user facilities with leading-edge fabrication and characterization tools, instrumentation, and expertise within all disciplines of nanoscale science, engineering and technology.

A Sept. 16, 2015 NSF news release provides a brief history of US nanotechnology infrastructures and describes this latest effort in slightly more detail (Note: Links have been removed),

The NNCI framework builds on the National Nanotechnology Infrastructure Network (NNIN), which enabled major discoveries, innovations, and contributions to education and commerce for more than 10 years.

“NSF’s long-standing investments in nanotechnology infrastructure have helped the research community to make great progress by making research facilities available,” said Pramod Khargonekar, assistant director for engineering. “NNCI will serve as a nationwide backbone for nanoscale research, which will lead to continuing innovations and economic and societal benefits.”

The awards are up to five years and range from $500,000 to $1.6 million each per year. Nine of the sites have at least one regional partner institution. These 16 sites are located in 15 states and involve 27 universities across the nation.

Through a fiscal year 2016 competition, one of the newly awarded sites will be chosen to coordinate the facilities. This coordinating office will enhance the sites’ impact as a national nanotechnology infrastructure and establish a web portal to link the individual facilities’ websites to provide a unified entry point to the user community of overall capabilities, tools and instrumentation. The office will also help to coordinate and disseminate best practices for national-level education and outreach programs across sites.

New NNCI awards:

Mid-Atlantic Nanotechnology Hub for Research, Education and Innovation, University of Pennsylvania with partner Community College of Philadelphia, principal investigator (PI): Mark Allen
Texas Nanofabrication Facility, University of Texas at Austin, PI: Sanjay Banerjee

Northwest Nanotechnology Infrastructure, University of Washington with partner Oregon State University, PI: Karl Bohringer

Southeastern Nanotechnology Infrastructure Corridor, Georgia Institute of Technology with partners North Carolina A&T State University and University of North Carolina-Greensboro, PI: Oliver Brand

Midwest Nano Infrastructure Corridor, University of  Minnesota Twin Cities with partner North Dakota State University, PI: Stephen Campbell

Montana Nanotechnology Facility, Montana State University with partner Carlton College, PI: David Dickensheets
Soft and Hybrid Nanotechnology Experimental Resource,

Northwestern University with partner University of Chicago, PI: Vinayak Dravid

The Virginia Tech National Center for Earth and Environmental Nanotechnology Infrastructure, Virginia Polytechnic Institute and State University, PI: Michael Hochella

North Carolina Research Triangle Nanotechnology Network, North Carolina State University with partners Duke University and University of North Carolina-Chapel Hill, PI: Jacob Jones

San Diego Nanotechnology Infrastructure, University of California, San Diego, PI: Yu-Hwa Lo

Stanford Site, Stanford University, PI: Kathryn Moler

Cornell Nanoscale Science and Technology Facility, Cornell University, PI: Daniel Ralph

Nebraska Nanoscale Facility, University of Nebraska-Lincoln, PI: David Sellmyer

Nanotechnology Collaborative Infrastructure Southwest, Arizona State University with partners Maricopa County Community College District and Science Foundation Arizona, PI: Trevor Thornton

The Kentucky Multi-scale Manufacturing and Nano Integration Node, University of Louisville with partner University of Kentucky, PI: Kevin Walsh

The Center for Nanoscale Systems at Harvard University, Harvard University, PI: Robert Westervelt

The universities are trumpeting this latest nanotechnology funding,

NSF-funded network set to help businesses, educators pursue nanotechnology innovation (North Carolina State University, Duke University, and University of North Carolina at Chapel Hill)

Nanotech expertise earns Virginia Tech a spot in National Science Foundation network

ASU [Arizona State University] chosen to lead national nanotechnology site

UChicago, Northwestern awarded $5 million nanotechnology infrastructure grant

That is a lot of excitement.

Center for Sustainable Nanotechnology or how not to poison and make the planet uninhabitable

I received notice of the Center for Sustainable Nanotechnology’s newest deal with the US National Science Foundation in an August 31, 2015 email University of Wisconsin-Madison (UWM) news release,

The Center for Sustainable Nanotechnology, a multi-institutional research center based at the University of Wisconsin-Madison, has inked a new contract with the National Science Foundation (NSF) that will provide nearly $20 million in support over the next five years.

Directed by UW-Madison chemistry Professor Robert Hamers, the center focuses on the molecular mechanisms by which nanoparticles interact with biological systems.

Nanotechnology involves the use of materials at the smallest scale, including the manipulation of individual atoms and molecules. Products that use nanoscale materials range from beer bottles and car wax to solar cells and electric and hybrid car batteries. If you read your books on a Kindle, a semiconducting material manufactured at the nanoscale underpins the high-resolution screen.

While there are already hundreds of products that use nanomaterials in various ways, much remains unknown about how these modern materials and the tiny particles they are composed of interact with the environment and living things.

“The purpose of the center is to explore how we can make sure these nanotechnologies come to fruition with little or no environmental impact,” explains Hamers. “We’re looking at nanoparticles in emerging technologies.”

In addition to UW-Madison, scientists from UW-Milwaukee, the University of Minnesota, the University of Illinois, Northwestern University and the Pacific Northwest National Laboratory have been involved in the center’s first phase of research. Joining the center for the next five-year phase are Tuskegee University, Johns Hopkins University, the University of Iowa, Augsburg College, Georgia Tech and the University of Maryland, Baltimore County.

At UW-Madison, Hamers leads efforts in synthesis and molecular characterization of nanomaterials. soil science Professor Joel Pedersen and chemistry Professor Qiang Cui lead groups exploring the biological and computational aspects of how nanomaterials affect life.

Much remains to be learned about how nanoparticles affect the environment and the multitude of organisms – from bacteria to plants, animals and people – that may be exposed to them.

“Some of the big questions we’re asking are: How is this going to impact bacteria and other organisms in the environment? What do these particles do? How do they interact with organisms?” says Hamers.

For instance, bacteria, the vast majority of which are beneficial or benign organisms, tend to be “sticky” and nanoparticles might cling to the microorganisms and have unintended biological effects.

“There are many different mechanisms by which these particles can do things,” Hamers adds. “The challenge is we don’t know what these nanoparticles do if they’re released into the environment.”

To get at the challenge, Hamers and his UW-Madison colleagues are drilling down to investigate the molecular-level chemical and physical principles that dictate how nanoparticles interact with living things.
Pedersen’s group, for example, is studying the complexities of how nanoparticles interact with cells and, in particular, their surface membranes.

“To enter a cell, a nanoparticle has to interact with a membrane,” notes Pedersen. “The simplest thing that can happen is the particle sticks to the cell. But it might cause toxicity or make a hole in the membrane.”

Pedersen’s group can make model cell membranes in the lab using the same lipids and proteins that are the building blocks of nature’s cells. By exposing the lab-made membranes to nanomaterials now used commercially, Pedersen and his colleagues can see how the membrane-particle interaction unfolds at the molecular level – the scale necessary to begin to understand the biological effects of the particles.

Such studies, Hamers argues, promise a science-based understanding that can help ensure the technology leaves a minimal environmental footprint by identifying issues before they manifest themselves in the manufacturing, use or recycling of products that contain nanotechnology-inspired materials.

To help fulfill that part of the mission, the center has established working relationships with several companies to conduct research on materials in the very early stages of development.

“We’re taking a look-ahead view. We’re trying to get into the technological design cycle,” Hamers says. “The idea is to use scientific understanding to develop a predictive ability to guide technology and guide people who are designing and using these materials.”

What with this initiative and the LCnano Network at Arizona State University (my April 8, 2014 posting; scroll down about 50% of the way), it seems that environmental and health and safety studies of nanomaterials are kicking into a higher gear as commercialization efforts intensify.

Sticky-flares nanotechnology to track and observe RNA (ribonucleic acid) regulation

I like the name ‘sticky-flares’ and had hoped there was an amusing story about its origins. Ah well, perhaps I’ll have better luck next time.

This work comes out of Chad Mirkin’s lab at Northwestern University (Chicago, US) according to a July 21, 2015 news item on Azonano,

RNA [ribonucleic acid] is a fundamental ingredient in all known forms of life — so when RNA goes awry, a lot can go wrong. RNA misregulation plays a critical role in the development of many disorders, such as mental disability, autism and cancer.

A new technology — called “Sticky-flares” — developed by nanomedicine experts at Northwestern University offers the first real-time method to track and observe the dynamics of RNA distribution as it is transported inside living cells.

A July 20, 2015 Northwestern University news release by Erin Spain, which originated the news item, describes the research in a little more detail also including information about predecessor technology,

Sticky-flares have the potential to help scientists understand the complexities of RNA better than any analytical technique to date and observe and study the biological and medical significance of RNA misregulation.

Previous technologies made it possible to attain static snapshots of RNA location, but that isn’t enough to understand the complexities of RNA transport and localization within a cell. Instead of analyzing snapshots of RNA to try to understand functioning, Sticky-flares help create an experience that is more like watching live-streaming video.

“This is very exciting because much of the RNA in cells has very specific quantities and localization, and both are critical to the cell’s function, but until this development it has been very difficult, and often impossible, to probe both attributes of RNA in a live cell,” said Chad A. Mirkin, a nanomedicine expert and corresponding author of the study. “We hope that many more researchers will be able to use this platform to increase our understanding of RNA function inside cells.”

Sticky-flares are tiny spherical nucleic acid gold nanoparticle conjugates that can enter living cells and target and transfer a fluorescent reporter or “tracking device” to RNA transcripts. This fluorescent labeling can be tracked via fluorescence microscopy as it is transported throughout the cell, including the nucleus.

In the … paper, the scientists explain how they used Sticky-flares to quantify β–actin mRNA in HeLa cells (the oldest and most commonly used human cell line) as well as to follow the real-time transport of β–actin mRNA in mouse embryonic fibroblasts.

Sticky-flares are built upon another technology from Mirkin’s group called NanoFlares, which was the first genetic-based approach that is able to detect live circulating tumor cells out of the complex matrix that is human blood.

NanoFlares have been very useful for researchers that operate in the arena of quantifying gene expression. AuraSense, Inc., a biotechnology company that licensed the NanoFlare technology from Northwestern University, and EMD-Millipore, another biotech company, have commercialized NanoFlares. There are now more than 1,700 commercial forms of NanoFlares sold under the SmartFlareä name in more than 230 countries.

The Sticky-flare is designed to address limitations of SmartFlares, most notably their inability to track RNA location and enter the nucleus. The Northwestern team believes Sticky-flares are poised to become a valuable tool for researchers who desire to understand the function of RNA in live cells.

Based on the paragraph about the precursor technology’s commercial success , I gather they are excited about similar possibilities for sticky-flares.

Here’s a link to and a citation for the paper,

Quantification and real-time tracking of RNA in live cells using Sticky-flares by William E. Briley, Madison H. Bondy, Pratik S. Randeria, Torin J. Dupper, and Chad A. Mirkin. Published online before print July 20, 2015, doi: 10.1073/pnas.1510581112 PNAS July 20, 2015

This paper is behind a paywall.

Northwestern University’s (US) International Institute for Nanotechnology (IIN) rakes in some cash

Within less than a month Northwestern University’s International Institute for Nanotechnology (IIN) has been granted awarded two grants by the US Department of Defense.

4D printing

The first grant, for 4D printing, was announced in a June 11, 2015 Northwestern news release by Megan Fellman (Note: A link has been removed),

Northwestern University’s International Institute for Nanotechnology (IIN) has received a five-year, $8.5 million grant from the U.S. Department of Defense’s competitive Multidisciplinary University Research Initiative (MURI) program to develop a “4-dimensional printer” — the next generation of printing technology for the scientific world.

Once developed, the 4-D printer, operating on the nanoscale, will be used to construct new devices for research in chemistry, materials sciences and U.S. defense-related areas that could lead to new chemical and biological sensors, catalysts, microchip designs and materials designed to respond to specific materials or signals.

“This research promises to bring transformative advancement to the development of biosensors, adaptive optics, artificially engineered tissues and more by utilizing nanotechnology,” said IIN director and chemist Chad A. Mirkin, who is leading the multi-institution project. Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences.

The award, issued by the Air Force Office of Scientific Research, supports a team of experts from Northwestern, the University of Miami, the University of California, San Diego, and the University of Maryland.

In science, “printing” encodes information at specific locations on a material’s surface, similar to how we print words on paper with ink. The 4-dimensional printer will consist of millions of tiny elastomeric “pens” that can be used individually and independently to create nanometer-size features composed of hard or soft materials.

The information encoded can be in the form of materials with a defined set of chemical and physical properties. The printing speed and resolution determine the amount and complexity of the information that can be encoded.

Progress in fields ranging from biology to chemical sensing to computing currently are limited by the lack of low-cost equipment that can perform high-resolution printing and 3-dimensional patterning on hard materials (e.g., metals and semiconductors) and soft materials (e.g., organic and biological materials) at nanometer resolution (approximately 1,000 times smaller than the width of a human hair).

“Ultimately, the 4-D printer will provide a foundation for a new generation of tools to develop novel architectures, wherein the hard materials that form the functional components of electronics can be merged with biological or soft materials,” said Milan Mrksich, a co-principal investigator on the grant.

Mrksich is the Henry Wade Rogers Professor of Biomedical Engineering, Chemistry and Cell and Molecular Biology, with appointments in the McCormick School of Engineering and Applied Science, Weinberg and Northwestern University Feinberg School of Medicine.

A July 10, 2015 article about the ‘4D printer’ grant  by Madeline Fox for the Daily Northwestern features a description of 4D printing from Milan Mrksich, a co-principal investigator on the grant,

Milan Mrksich, one of the project’s five senior participants, said that while most people are familiar with the three dimensions of length, width and depth, there are often misconceptions about the fourth property of a four-dimensional object. Mrksich used Legos as an analogy to describe 4D printing technology.

“If you take Lego blocks, you can basically build any structure you want by controlling which Lego is connected to which Lego and controlling all their dimensions in space,” Mrksich said. “Within an object made up of nanoparticles, we’re controlling the placement — as we use a printer to control the placement of every particle, our fourth dimension lets us choose which nanoparticle with which property would be at each position.”

Thank you Dr. Mrksich and Ms. Fox for that helpful analogy.

Designing advanced bioprogrammable nanomaterials

The second grant, announced in a July 6, 2015 Northwestern news release by Megan Fellman, is apparently the only one of its kind in the US (Note: A link has been removed),

Northwestern University’s International Institute for Nanotechnology (IIN) has been awarded a U.S. Air Force Center of Excellence grant to design advanced bioprogrammable nanomaterials for solutions to challenging problems in the areas of energy, the environment, security and defense, as well as for developing ways to monitor and mitigate human stress.

The five-year, $9.8 million grant establishes the Center of Excellence for Advanced Bioprogrammable Nanomaterials (C-ABN), the only one of its kind in the country. After the initial five years, the grant potentially could be renewed for an additional five years.

“Northwestern University was chosen to lead this Center of Excellence because of its investment in infrastructure development, including new facilities and instrumentation; its recruitment of high-caliber faculty members and students; and its track record in bio-nanotechnology and cognitive sciences,” said Timothy Bunning, chief scientist at the U.S. Air Force Research Laboratory (AFRL) Materials and Manufacturing Directorate.

Led by IIN director Chad A. Mirkin, C-ABN will support collaborative, discovery-based research projects aimed at developing bioprogrammable nanomaterials that will meet both military and civilian needs and facilitate the efficient transition of these new technologies from the laboratory to marketplace.

Bioprogrammable nanomaterials are structures that typically contain a biomolecular component, such as nucleic acids or proteins, which give the materials a variety of novel capabilities. [emphasis mine] Nanomaterials can be designed to assemble into large 3-D structures, to interface with biological structures inside cells or tissues, or to interface with existing macroscale devices, for example. These new bioprogrammable nanomaterials and the fundamental knowledge gained through their development will ultimately lead to the creation of wearable, portable and/or human-interactive devices with extraordinary capabilities that will significantly impact both civilian and Air Force needs.

In one research area, scientists will work to understand the molecular underpinnings of vulnerability and resilience to stress. They will use bioprogrammable nanomaterials to develop ultrasensitive sensors capable of detecting and quantifying biomarkers for human stress in biological fluids (e.g., saliva, perspiration or blood), providing means to easily monitor the soldier during times of extreme stress. Ultimately, these bioprogrammable materials may lead to methods to increase human cellular resilience to the effects of stress and/or to correct genetic mutations that decrease cellular resilience of susceptible individuals.

Other research projects, encompassing a wide variety of nanotechnology-enabled goals, include:

Developing hybrid wearable energy-storage devices;
Developing devices to identify chemical and biological targets in a field environment;
Developing flexible bio-electronic circuits;
Designing a new class of flat optics; and
Advancing understanding of design rules between 2-D and 3-D architectures.

The analysis of these nanostructures also will extend fundamental knowledge in the fields of materials science and engineering, human performance, chemistry, biology and physics.

The center will be housed under the IIN, providing researchers with access to IIN’s strong entrepreneurial community and its close ties with Northwestern’s renowned Kellogg School of Management.

This second news release provides an interesting contrast to a recent news release from Sweden’s Karolinska Intitute where the writer was careful to note that the enzymes and organic electronic ion pumps were not living as noted in my June 26, 2015 posting. It seems nucleic acids (as in RNA and DNA) can be mentioned without a proviso in the US. as there seems to be little worry about anti-GMO (genetically modified organisms) and similar backlashes affecting biotechnology research.

TRIUMF accelerator used by US researchers to visualize properties of nanoscale materials

The US researchers are at the University of California at Los Angeles (UCLA) and while it’s not explicitly stated I’m assuming the accelerator they mention at TRIUMF (Canada’s national laboratory for particle and nuclear physics) has something special as there are accelerators in California and other parts of the US.

A July 15, 2015 news item on Nanotechnology Now announces the latest on visualizing the properties of nanoscale materials,

Scientists trying to improve the semiconductors that power our electronic devices have focused on a technology called spintronics as one especially promising area of research. Unlike conventional devices that use electrons’ charge to create power, spintronic devices use electrons’ spin. The technology is already used in computer hard drives and many other applications — and scientists believe it could eventually be used for quantum computers, a new generation of machines that use quantum mechanics to solve complex problems with extraordinary speed.

A July 15, 2015 UCLA news release, which originated the news item, expands on the theme and briefly mentions TRIUMF’s accelerator (Note: A link has been removed),

Emerging research has shown that one key to greatly improving performance in spintronics could be a class of materials called topological insulators. Unlike ordinary materials that are either insulators or conductors, topological insulators function as both simultaneously — on the inside, they are insulators but on their exteriors, they conduct electricity.

But topological insulators have certain defects that have so far limited their use in practical applications, and because they are so tiny, scientists have so far been unable to fully understand how the defects impact their functionality.

The UCLA researchers have overcome that challenge with a new method to visualize topological insulators at the nanoscale. An article highlighting the research, which was which led by Louis Bouchard, assistant professor of chemistry and biochemistry, and Dimitrios Koumoulis, a UCLA postdoctoral scholar, was published online in the Proceedings of the National Academy of Sciences.

The new method is the first use of beta‑detected nuclear magnetic resonance to study the effects of these defects on the properties of topological insulators.

The technique involves aiming a highly focused stream of ions at the topological insulator. To generate that beam of ions, the researchers used a large particle accelerator called a cyclotron, which accelerates protons through a spiral path inside the machine and forces them to collide with a target made of the chemical element tantalum. This collision produces lithium-8 atoms, which are ionized and slowed down to a desired energy level before they are implanted in the topological insulators.

In beta‑detected nuclear magnetic resonance, ions (in this case, the ionized lithium-8 atoms) of various energies are implanted in the material of interest (the topological insulator) to generate signals from the material’s layers of interest.

Bouchard said the method is particularly well suited for probing regions near the surfaces and interfaces of different materials.

In the UCLA research, the high sensitivity of the beta‑detected nuclear magnetic resonance technique and its ability to probe materials allowed the scientists to “see” the impacts of the defects in the topological insulators by viewing the electronic and magnetic properties beneath the surface of the material.

The researchers used the large TRIUMF cyclotron in Vancouver, British Columbia.

According to the UCLA news release, there were also researchers from the University of British Columbia, the University of Texas at Austin and Northwestern University *were* involved with the work.

Here’s a link to and a citation for the paper,

Nanoscale β-nuclear magnetic resonance depth imaging of topological insulators by Dimitrios Koumoulis, Gerald D. Morris, Liang He, Xufeng Kou, Danny King, Dong Wang, Masrur D. Hossain, Kang L. Wang, Gregory A. Fiete, Mercouri G. Kanatzidis, and Louis-S. Bouchard. PNAS July 14, 2015 vol. 112 no. 28 doi: 10.1073/pnas.1502330112

This paper is behind a paywall.

*’were’ added Jan. 20, 2016.

Nanoscale imaging gets rough

Smooth is easier than rough when imaging at the nanoscale according to a June 17, 2015 Northwestern University news release by Megan Fellman (also on EurekAlert),

A multi-institutional team of scientists has taken an important step in understanding where atoms are located on the surfaces of rough materials, information that could be very useful in diverse commercial applications, such as developing green energy and understanding how materials rust.

Researchers from Northwestern University, Brookhaven National Laboratory, Lawrence Berkeley National Laboratory and the University of Melbourne, Australia, have developed a new imaging technique that uses atomic resolution secondary electron images in a quantitative way to determine the arrangement of atoms on the surface.

Many important processes take place at surfaces, ranging from the catalysis used to generate energy-dense fuels from sunlight and carbon dioxide to how bridges and airplanes corrode, or rust. Every material interacts with the world through its surface, which is often different in both structure and chemistry from the bulk of the material.

The real focus of the work is on corrosion, according to the news release,

“We are excited by the possibilities of applying our imaging technique to corrosion and catalysis problems,” said Laurence Marks, a co-author of the paper and a professor of materials science and engineering at Northwestern’s McCormick School of Engineering and Applied Science. “The cost of corrosion to industry and the military is enormous, and we do not understand everything that is taking place. We must learn more, so we can produce materials that will last longer.”

To understand these processes and improve material performance, it is vital to know how the atoms are arranged on surfaces. While there are many good methods for obtaining this information for rather flat surfaces, most currently available tools are limited in what they can reveal when the surfaces are rough.

Scanning electron microscopes are widely used to produce images of many different materials, and roughness of the surface is not that important. Until very recently, instruments could not obtain clear atomic images of surfaces until a group at Brookhaven managed in 2011 to get the first images that seemed to show the surfaces very clearly. However, it was not clear to what extent they really were able to image the surface, as there was no theory for the imaging and many uncertainties.

The new work has answered all these questions, Marks said, providing a definitive way of understanding the surfaces in detail. What was needed was to use a carefully controlled sample of strontium titanate and perform a large range of different types of imaging to unravel the precise details of how secondary electron images are produced.

“We started this work by investigating a well-studied material,” said Jim Ciston, a staff scientist at Lawrence Berkeley National Laboratory and the lead author of the paper, who obtained the experimental images. “This new technique is so powerful that we had to revise much of what was already thought to be well-known. This is an exciting prospect because the surface of every material can act as its own nanomaterial coating, which can greatly change the chemistry and behavior.”

“The beauty of the technique is that we can image surface atoms and bulk atoms simultaneously,” said Yimei Zhu, a scientist at Brookhaven National Laboratory. “Currently, no existing methods can achieve that.”

Les Allen, who led the theoretical and modeling aspects of the new imaging technique in Melbourne, said, “We now have a sophisticated understanding of what the images mean. It now will be full steam ahead to apply them to many different types of problems.”

Here’s a link to and citation for the paper,

Surface determination through atomically resolved secondary-electron imaging by J. Ciston, H. G. Brown, A. J. D’Alfonso, P. Koirala, C. Ophus, Y. Lin, Y. Suzuki, H. Inada, Y. Zhu, L. J. Allen, & L. D. Marks. Nature Communications 6, Article number: 7358 doi:10.1038/ncomms8358 Published 17 June 2015

This paper is open access.

Liquid nanolaser: the first one

According to an April 24, 2015 news item on Nanowerk, there has been a big discovery at Northwestern University (located in Chicago, Illinois, US),

Northwestern University scientists have developed the first liquid nanoscale laser. And it’s tunable in real time, meaning you can quickly and simply produce different colors, a unique and useful feature. The laser technology could lead to practical applications, such as a new form of a “lab on a chip” for medical diagnostics.

To understand the concept, imagine a laser pointer whose color can be changed simply by changing the liquid inside it, instead of needing a different laser pointer for every desired color.

In addition to changing color in real time, the liquid nanolaser has additional advantages over other nanolasers: it is simple to make, inexpensive to produce and operates at room temperature.

An April 24, 2015 Northwestern University news release by Megan Fellman (also on EurekAlert), which originated the news item, offers a little history buttressed by some technical details (Note: Links have been removed),

Nanoscopic lasers — first demonstrated in 2009 — are only found in research labs today. They are, however, of great interest for advances in technology and for military applications.

“Our study allows us to think about new laser designs and what could be possible if they could actually be made,” said Teri W. Odom, who led the research. “My lab likes to go after new materials, new structures and new ways of putting them together to achieve things not yet imagined. We believe this work represents a conceptual and practical engineering advance for on-demand, reversible control of light from nanoscopic sources.”

The liquid nanolaser in this study is not a laser pointer but a laser device on a chip, Odom explained. The laser’s color can be changed in real time when the liquid dye in the microfluidic channel above the laser’s cavity is changed.

The laser’s cavity is made up of an array of reflective gold nanoparticles, where the light is concentrated around each nanoparticle and then amplified. (In contrast to conventional laser cavities, no mirrors are required for the light to bounce back and forth.) Notably, as the laser color is tuned, the nanoparticle cavity stays fixed and does not change; only the liquid gain around the nanoparticles changes.

The main advantages of very small lasers are:

• They can be used as on-chip light sources for optoelectronic integrated circuits;

• They can be used in optical data storage and lithography;

• They can operate reliably at one wavelength; and

• They should be able to operate much faster than conventional lasers because they are made from metals.

Some technical background

Plasmon lasers are promising nanoscale coherent sources of optical fields because they support ultra-small sizes and show ultra-fast dynamics. Although plasmon lasers have been demonstrated at different spectral ranges, from the ultraviolet to near-infrared, a systematic approach to manipulate the lasing emission wavelength in real time has not been possible.

The main limitation is that only solid gain materials have been used in previous work on plasmon nanolasers; hence, fixed wavelengths were shown because solid materials cannot easily be modified. Odom’s research team has found a way to integrate liquid gain materials with gold nanoparticle arrays to achieve nanoscale plasmon lasing that can be tuned dynamical, reversibly and in real time.

The use of liquid gain materials has two significant benefits:

• The organic dye molecules can be readily dissolved in solvents with different refractive indices. Thus, the dielectric environment around the nanoparticle arrays can be tuned, which also tunes the lasing wavelength.

• The liquid form of gain materials enables the fluid to be manipulated within a microfluidic channel. Thus, dynamic tuning of the lasing emission is possible simply by flowing liquid with different refractive indices. Moreover, as an added benefit of the liquid environment, the lasing-on-chip devices can show long-term stability because the gain molecules can be constantly refreshed.

These nanoscale lasers can be mass-produced with emission wavelengths over the entire gain bandwidth of the dye. Thus, the same fixed nanocavity structure (the same gold nanoparticle array) can exhibit lasing wavelengths that can be tuned over 50 nanometers, from 860 to 910 nanometers, simply by changing the solvent the dye is dissolved in.

Here’s a link to and a citation for the paper,

Real-time tunable lasing from plasmonic nanocavity arrays by Ankun Yang, Thang B. Hoang, Montacer Dridi, Claire Deeb, Maiken H. Mikkelsen, George C. Schatz, & Teri W. Odom. Nature Communications 6, Article number: 6939 doi:10.1038/ncomms7939 Published 20 April 2015

This paper is open access.

A more complex memristor: from two terminals to three for brain-like computing

Researchers have developed a more complex memristor device than has been the case according to an April 6, 2015 Northwestern University news release (also on EurekAlert),

Researchers are always searching for improved technologies, but the most efficient computer possible already exists. It can learn and adapt without needing to be programmed or updated. It has nearly limitless memory, is difficult to crash, and works at extremely fast speeds. It’s not a Mac or a PC; it’s the human brain. And scientists around the world want to mimic its abilities.

Both academic and industrial laboratories are working to develop computers that operate more like the human brain. Instead of operating like a conventional, digital system, these new devices could potentially function more like a network of neurons.

“Computers are very impressive in many ways, but they’re not equal to the mind,” said Mark Hersam, the Bette and Neison Harris Chair in Teaching Excellence in Northwestern University’s McCormick School of Engineering. “Neurons can achieve very complicated computation with very low power consumption compared to a digital computer.”

A team of Northwestern researchers, including Hersam, has accomplished a new step forward in electronics that could bring brain-like computing closer to reality. The team’s work advances memory resistors, or “memristors,” which are resistors in a circuit that “remember” how much current has flowed through them.

“Memristors could be used as a memory element in an integrated circuit or computer,” Hersam said. “Unlike other memories that exist today in modern electronics, memristors are stable and remember their state even if you lose power.”

Current computers use random access memory (RAM), which moves very quickly as a user works but does not retain unsaved data if power is lost. Flash drives, on the other hand, store information when they are not powered but work much slower. Memristors could provide a memory that is the best of both worlds: fast and reliable. But there’s a problem: memristors are two-terminal electronic devices, which can only control one voltage channel. Hersam wanted to transform it into a three-terminal device, allowing it to be used in more complex electronic circuits and systems.

The memristor is of some interest to a number of other parties prominent amongst them, the University of Michigan’s Professor Wei Lu and HP (Hewlett Packard) Labs, both of whom are mentioned in one of my more recent memristor pieces, a June 26, 2014 post.

Getting back to Northwestern,

Hersam and his team met this challenge by using single-layer molybdenum disulfide (MoS2), an atomically thin, two-dimensional nanomaterial semiconductor. Much like the way fibers are arranged in wood, atoms are arranged in a certain direction–called “grains”–within a material. The sheet of MoS2 that Hersam used has a well-defined grain boundary, which is the interface where two different grains come together.

“Because the atoms are not in the same orientation, there are unsatisfied chemical bonds at that interface,” Hersam explained. “These grain boundaries influence the flow of current, so they can serve as a means of tuning resistance.”

When a large electric field is applied, the grain boundary literally moves, causing a change in resistance. By using MoS2 with this grain boundary defect instead of the typical metal-oxide-metal memristor structure, the team presented a novel three-terminal memristive device that is widely tunable with a gate electrode.

“With a memristor that can be tuned with a third electrode, we have the possibility to realize a function you could not previously achieve,” Hersam said. “A three-terminal memristor has been proposed as a means of realizing brain-like computing. We are now actively exploring this possibility in the laboratory.”

Here’s a link to and a citation for the paper,

Gate-tunable memristive phenomena mediated by grain boundaries in single-layer MoS2 by Vinod K. Sangwan, Deep Jariwala, In Soo Kim, Kan-Sheng Chen, Tobin J. Marks, Lincoln J. Lauhon, & Mark C. Hersam. Nature Nanotechnology (2015) doi:10.1038/nnano.2015.56 Published online 06 April 2015

This paper is behind a paywall but there is a few preview available through ReadCube Access.

Dexter Johnson has written about this latest memristor development in an April 9, 2015 posting on his Nanoclast blog (on the IEEE [Institute for Electrical and Electronics Engineers] website) where he notes this (Note: A link has been removed),

The memristor seems to generate fairly polarized debate, especially here on this website in the comments on stories covering the technology. The controversy seems to fall along the lines that the device that HP Labs’ Stan Williams and Greg Snider developed back in 2008 doesn’t exactly line up with the original theory of the memristor proposed by Leon Chua back in 1971.

It seems the ‘debate’ has evolved from issues about how the memristor is categorized. I wonder if there’s still discussion about whether or not HP Labs is attempting to develop a patent thicket of sorts.