Tag Archives: US National Science Foundation

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

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


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,


(US) Contest: Design a nanotechnology-themed superhero

This contest is open to students enrolled in US high schools or home-schooled and the deadline is Feb. 2, 2016.

High school students can lend their creativity to engineering, science and nanotechnology. Credit: NSF

High school students can lend their creativity to engineering, science and nanotechnology. Credit: NSF

Here are more details from the US National Science Foundation (NSF) Nov. 19, 2015 news release,

A brand-new competition, awarding finalists the opportunity to present their entries at the 2016 USA Science & Engineering Festival [held April 16 & 17, 2016] and compete for cash prizes, opens today for high school students interested in science, engineering and superpowers.

Generation Nano: Small Science, Superheroes is sponsored by the National Science Foundation (NSF) and the National Nanotechnology Initiative (NNI). The competition invites individual students enrolled in U.S. high schools, or who are home-schooled, to submit an original idea for a superhero who uses unique nanotechnology-inspired “gear,” such as a vehicle, costume or tool.

Generation Nano encourages students to think big–which, in this case, means super small–when pondering their hero’s gear: shoelaces that decode secret radio waves, nanotechnology-infused blood cells that supercharge adrenaline or clothing that can change color to camouflage its wearer.

“The wonders of nanotechnology are inspiring an increasing number of young students to pursue science and engineering,” said NSF Senior Advisor for Science and Engineering Mihail C. Roco. “The Generation Nano competition recognizes and channels that interest, while giving students the chance to showcase their creativity at a national level.”

“I’m just thrilled about Generation Nano,” said Lisa Friedersdorf, deputy director of the National Nanotechnology Coordination Office. “This competition has the potential to excite students about science and introduce them to the novel world of nanotechnology. I can’t wait to see the submissions.”

Competition details:

  • Students must submit a written entry explaining their superhero and nanotechnology-driven gear, along with a one-page comic or 90-second video.
  • Cash prizes are $1,500 for first place, $1,000 for second place and $500 for third place.
  • Finalists will showcase their comic or video at the 2016 USA Science and Engineering Festival in Washington, D.C. Final-round judging will take place at the festival.
  • Submissions are due by midnight on Feb. 2, 2016.

Through nanotechnology applications like targeted drugs, self-assembled nanodevices, molecular motors and other innovations, students never have to endure a radioactive spider bite to realize their full potential.

Visit the Generation Nano competition website for full eligibility criteria, entry guidelines, timeline and prize information.

The Generation Nano website offers resources for generating comics, accessing images and audio on this page.

For inspiration, you can take a look at my May 11, 2012 posting which features a description of the nanotechnology-enabled Extremis storyline in the Iron Man comic book series in the context of plans for the Iron Man 3 movie.

For more inspiration from 2012, there was a special exhibit at the Science Gallery in Dublin, Ireland featuring six superheroes created for the exhibit (my Sept. 14, 2012 posting; scroll down about 25% of the way to where I discuss the Magical Materials; Unleash Your Superpowers exhibit).

Good luck!

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.

US White House establishes new initiatives to commercialize nanotechnology

As I’ve noted several times, there’s a strong push in the US to commercialize nanotechnology and May 20, 2015 was a banner day for the efforts. The US White House announced a series of new initiatives to speed commercialization efforts in a May 20, 2015 posting by Lloyd Whitman, Tom Kalil, and JJ Raynor,

Today, May 20 [2015], the National Economic Council and the Office of Science and Technology Policy held a forum at the White House to discuss opportunities to accelerate the commercialization of nanotechnology.

In recognition of the importance of nanotechnology R&D, representatives from companies, government agencies, colleges and universities, and non-profits are announcing a series of new and expanded public and private initiatives that complement the Administration’s efforts to accelerate the commercialization of nanotechnology and expand the nanotechnology workforce:

  • The Colleges of Nanoscale Science and Engineering at SUNY Polytechnic Institute in Albany, NY and the National Institute for Occupational Safety and Health are launching the Nano Health & Safety Consortium to advance research and guidance for occupational safety and health in the nanoelectronics and other nanomanufacturing industry settings.
  • Raytheon has brought together a group of representatives from the defense industry and the Department of Defense to identify collaborative opportunities to advance nanotechnology product development, manufacturing, and supply-chain support with a goal of helping the U.S. optimize development, foster innovation, and take more rapid advantage of new commercial nanotechnologies.
  • BASF Corporation is taking a new approach to finding solutions to nanomanufacturing challenges. In March, BASF launched a prize-based “NanoChallenge” designed to drive new levels of collaborative innovation in nanotechnology while connecting with potential partners to co-create solutions that address industry challenges.
  • OCSiAl is expanding the eligibility of its “iNanoComm” matching grant program that provides low-cost, single-walled carbon nanotubes to include more exploratory research proposals, especially proposals for projects that could result in the creation of startups and technology transfers.
  • The NanoBusiness Commercialization Association (NanoBCA) is partnering with Venture for America and working with the National Science Foundation (NSF) to promote entrepreneurship in nanotechnology.  Three companies (PEN, NanoMech, and SouthWest NanoTechnologies), are offering to support NSF’s Innovation Corps (I-Corps) program with mentorship for entrepreneurs-in-training and, along with three other companies (NanoViricides, mPhase Technologies, and Eikos), will partner with Venture for America to hire recent graduates into nanotechnology jobs, thereby strengthening new nanotech businesses while providing needed experience for future entrepreneurs.
  • TechConnect is establishing a Nano and Emerging Technologies Student Leaders Conference to bring together the leaders of nanotechnology student groups from across the country. The conference will highlight undergraduate research and connect students with venture capitalists, entrepreneurs, and industry leaders.  Five universities have already committed to participating, led by the University of Virginia Nano and Emerging Technologies Club.
  • Brewer Science, through its Global Intern Program, is providing more than 30 students from high schools, colleges, and graduate schools across the country with hands-on experience in a wide range of functions within the company.  Brewer Science plans to increase the number of its science and engineering interns by 50% next year and has committed to sharing best practices with other nanotechnology businesses interested in how internship programs can contribute to a small company’s success.
  • The National Institute of Standards and Technology’s Center for Nanoscale Science and Technology is expanding its partnership with the National Science Foundation to provide hands-on experience for students in NSF’s Advanced Technology Education program. The partnership will now run year-round and will include opportunities for students at Hudson Valley Community College and the University of the District of Columbia Community College.
  • Federal agencies participating in the NNI [US National Nanotechnology Initiative], supported by the National Nanotechnology Coordination Office [NNCO], are launching multiple new activities aimed at educating students and the public about nanotechnology, including image and video contests highlighting student research, a new webinar series focused on providing nanotechnology information for K-12 teachers, and a searchable web portal on nano.gov of nanoscale science and engineering resources for teachers and professors.

Interestingly, May 20, 2015 is also the day the NNCO held its second webinar for small- and medium-size businesses in the nanotechnology community. You can find out more about that webinar and future ones by following the links in my May 13, 2015 posting.

Since the US White House announcement, OCSiAl has issued a May 26, 2015 news release which provides a brief history and more details about its newly expanded NanoComm program,

OCSiAl launched the iNanoComm, which stands for the Integrated Nanotube Commercialization Award, program in February 2015 to help researchers lower the cost of their most promising R&D projects dedicated to SWCNT [single-walled carbon nanotube] applications. The first round received 33 applications from 28 university groups, including The Smalley-Curl Center for Nanoscale Science and Technology at Rice University and the Concordia Center for Composites at Concordia University [Canada] among others. [emphasis mine] The aim of iNanoComm is to stimulate universities and research organizations to develop innovative market products based on nano-augmented materials, also known as clean materials.

Now the program’s criteria are being broadened to enable greater private sector engagement in potential projects and the creation of partnerships in commercializing nanotechnology. The program will now support early stage commercialization efforts connected to university research in the form of start-ups, technology transfers, new businesses and university spinoffs to support the mass commercialization of SWCNT products and technologies.

The announcement of the program’s expansion took place at the 2015 Roundtable of the US NanoBusiness Commercialization Association (NanoBCA), the world’s first non-profit association focused on the commercialization of nanotechnologies. NanoBCA is dedicated to creating an environment that nurtures research and innovation in nanotechnology, promotes tech-transfer of nanotechnology from academia to industry, encourages private capital investments in nanotechnology companies, and helps its corporate members bring innovative nanotechnology products to market.

“Enhancing iNanoComm as a ‘start-up incubator’ is a concrete step in promoting single-wall carbon nanotube applications in the commercial world,” said Max Atanassov, CEO of OCSiAl USA. “It was the logical thing for us to do, now that high quality carbon nanotubes have become broadly available and are affordably priced to be used on a mass industrial scale.”

Vince Caprio, Executive Director of NanoBCA, added that “iNanoComm will make an important contribution to translating fundamental nanotechnology research into commercial products. By facilitating the formation of more start-ups, it will encourage more scientists to pursue their dreams and develop their ideas into commercially successful businesses.”

For more information on the program expansion and how it can reduce the cost of early stage research connected to university projects, visit the iNanoComm website at www.inanocomm.org or contact info@inanocomm.org.

h/t Azonano May 27, 2015 news item

I sing the body cyber: two projects funded by the US National Science Foundation

Points to anyone who recognized the reference to Walt Whitman’s poem, “I sing the body electric,” from his classic collection, Leaves of Grass (1867 edition; h/t Wikipedia entry). I wonder if the cyber physical systems (CPS) work being funded by the US National Science Foundation (NSF) in the US will occasion poetry too.

More practically, a May 15, 2015 news item on Nanowerk, describes two cyber physical systems (CPS) research projects newly funded by the NSF,

Today [May 12, 2015] the National Science Foundation (NSF) announced two, five-year, center-scale awards totaling $8.75 million to advance the state-of-the-art in medical and cyber-physical systems (CPS).

One project will develop “Cyberheart”–a platform for virtual, patient-specific human heart models and associated device therapies that can be used to improve and accelerate medical-device development and testing. The other project will combine teams of microrobots with synthetic cells to perform functions that may one day lead to tissue and organ re-generation.

CPS are engineered systems that are built from, and depend upon, the seamless integration of computation and physical components. Often called the “Internet of Things,” CPS enable capabilities that go beyond the embedded systems of today.

“NSF has been a leader in supporting research in cyber-physical systems, which has provided a foundation for putting the ‘smart’ in health, transportation, energy and infrastructure systems,” said Jim Kurose, head of Computer & Information Science & Engineering at NSF. “We look forward to the results of these two new awards, which paint a new and compelling vision for what’s possible for smart health.”

Cyber-physical systems have the potential to benefit many sectors of our society, including healthcare. While advances in sensors and wearable devices have the capacity to improve aspects of medical care, from disease prevention to emergency response, and synthetic biology and robotics hold the promise of regenerating and maintaining the body in radical new ways, little is known about how advances in CPS can integrate these technologies to improve health outcomes.

These new NSF-funded projects will investigate two very different ways that CPS can be used in the biological and medical realms.

A May 12, 2015 NSF news release (also on EurekAlert), which originated the news item, describes the two CPS projects,

Bio-CPS for engineering living cells

A team of leading computer scientists, roboticists and biologists from Boston University, the University of Pennsylvania and MIT have come together to develop a system that combines the capabilities of nano-scale robots with specially designed synthetic organisms. Together, they believe this hybrid “bio-CPS” will be capable of performing heretofore impossible functions, from microscopic assembly to cell sensing within the body.

“We bring together synthetic biology and micron-scale robotics to engineer the emergence of desired behaviors in populations of bacterial and mammalian cells,” said Calin Belta, a professor of mechanical engineering, systems engineering and bioinformatics at Boston University and principal investigator on the project. “This project will impact several application areas ranging from tissue engineering to drug development.”

The project builds on previous research by each team member in diverse disciplines and early proof-of-concept designs of bio-CPS. According to the team, the research is also driven by recent advances in the emerging field of synthetic biology, in particular the ability to rapidly incorporate new capabilities into simple cells. Researchers so far have not been able to control and coordinate the behavior of synthetic cells in isolation, but the introduction of microrobots that can be externally controlled may be transformative.

In this new project, the team will focus on bio-CPS with the ability to sense, transport and work together. As a demonstration of their idea, they will develop teams of synthetic cell/microrobot hybrids capable of constructing a complex, fabric-like surface.

Vijay Kumar (University of Pennsylvania), Ron Weiss (MIT), and Douglas Densmore (BU) are co-investigators of the project.

Medical-CPS and the ‘Cyberheart’

CPS such as wearable sensors and implantable devices are already being used to assess health, improve quality of life, provide cost-effective care and potentially speed up disease diagnosis and prevention. [emphasis mine]

Extending these efforts, researchers from seven leading universities and centers are working together to develop far more realistic cardiac and device models than currently exist. This so-called “Cyberheart” platform can be used to test and validate medical devices faster and at a far lower cost than existing methods. CyberHeart also can be used to design safe, patient-specific device therapies, thereby lowering the risk to the patient.

“Innovative ‘virtual’ design methodologies for implantable cardiac medical devices will speed device development and yield safer, more effective devices and device-based therapies, than is currently possible,” said Scott Smolka, a professor of computer science at Stony Brook University and one of the principal investigators on the award.

The group’s approach combines patient-specific computational models of heart dynamics with advanced mathematical techniques for analyzing how these models interact with medical devices. The analytical techniques can be used to detect potential flaws in device behavior early on during the device-design phase, before animal and human trials begin. They also can be used in a clinical setting to optimize device settings on a patient-by-patient basis before devices are implanted.

“We believe that our coordinated, multi-disciplinary approach, which balances theoretical, experimental and practical concerns, will yield transformational results in medical-device design and foundations of cyber-physical system verification,” Smolka said.

The team will develop virtual device models which can be coupled together with virtual heart models to realize a full virtual development platform that can be subjected to computational analysis and simulation techniques. Moreover, they are working with experimentalists who will study the behavior of virtual and actual devices on animals’ hearts.

Co-investigators on the project include Edmund Clarke (Carnegie Mellon University), Elizabeth Cherry (Rochester Institute of Technology), W. Rance Cleaveland (University of Maryland), Flavio Fenton (Georgia Tech), Rahul Mangharam (University of Pennsylvania), Arnab Ray (Fraunhofer Center for Experimental Software Engineering [Germany]) and James Glimm and Radu Grosu (Stony Brook University). Richard A. Gray of the U.S. Food and Drug Administration is another key contributor.

It is fascinating to observe how terminology is shifting from pacemakers and deep brain stimulators as implants to “CPS such as wearable sensors and implantable devices … .” A new category has been created, CPS, which conjoins medical devices with other sensing devices such as wearable fitness monitors found in the consumer market. I imagine it’s an attempt to quell fears about injecting strange things into or adding strange things to your body—microrobots and nanorobots partially derived from synthetic biology research which are “… capable of performing heretofore impossible functions, from microscopic assembly to cell sensing within the body.” They’ve also sneaked in a reference to synthetic biology, an area of research where some concerns have been expressed, from my March 19, 2013 post about a poll and synthetic biology concerns,

In our latest survey, conducted in January 2013, three-fourths of respondents say they have heard little or nothing about synthetic biology, a level consistent with that measured in 2010. While initial impressions about the science are largely undefined, these feelings do not necessarily become more positive as respondents learn more. The public has mixed reactions to specific synthetic biology applications, and almost one-third of respondents favor a ban “on synthetic biology research until we better understand its implications and risks,” while 61 percent think the science should move forward.

I imagine that for scientists, 61% in favour of more research is not particularly comforting given how easily and quickly public opinion can shift.

Synthesizing nerve tissues with 3D printers and cellulose nanocrystals (CNC)

There are lots of stories about bioprinting and tissue engineering here and I think it’s time (again) for one which one has some good, detailed descriptions and, bonus, it features cellulose nanocrystals (CNC) and graphene. From a May 13, 2015 news item on Azonano,

The printer looks like a toaster oven with the front and sides removed. Its metal frame is built up around a stainless steel circle lit by an ultraviolet light. Stainless steel hydraulics and thin black tubes line the back edge, which lead to an inner, topside box made of red plastic.

In front, the metal is etched with the red Bio Bot logo. All together, the gray metal frame is small enough to fit on top of an old-fashioned school desk, but nothing about this 3D printer is old school. In fact, the tissue-printing machine is more like a sci-fi future in the flesh—and it has very real medical applications.

Researchers at Michigan Technological University hope to use this newly acquired 3D bioprinter to make synthesized nerve tissue. The key is developing the right “bioink” or printable tissue. The nanotechnology-inspired material could help regenerate damaged nerves for patients with spinal cord injuries, says Tolou Shokuhfar, an assistant professor of mechanical engineering and biomedical engineering at Michigan Tech.

Shokuhfar directs the In-Situ Nanomedicine and Nanoelectronics Laboratory at Michigan Tech, and she is an adjunct assistant professor in the Bioengineering Department and the College of Dentistry at the University of Illinois at Chicago.

In the bioprinting research, Shokuhfar collaborates with Reza Shahbazian-Yassar, the Richard and Elizabeth Henes Associate Professor in the Department of Mechanical Engineering-Engineering Mechanics at Michigan Tech. Shahbazian-Yassar’s highly interdisciplinary background on cellulose nanocrystals as biomaterials, funded by the National Science Foundation’s (NSF) Biomaterials Program, helped inspire the lab’s new 3D printing research. “Cellulose nanocrystals with extremely good mechanical properties are highly desirable for bioprinting of scaffolds that can be used for live tissues,” says Shahbazian-Yassar. [emphases mine]

A May 11, 2015 Michigan Technological University (MTU) news release by Allison Mills, which originated the news item, explains the ‘why’ of the research,

“We wanted to target a big issue,” Shokuhfar says, explaining that nerve regeneration is a particularly difficult biomedical engineering conundrum. “We are born with all the nerve cells we’ll ever have, and damaged nerves don’t heal very well.”

Other facilities are trying to address this issue as well. Many feature large, room-sized machines that have built-in cell culture hoods, incubators and refrigeration. The precision of this equipment allows them to print full organs. But innovation is more nimble at smaller scales.

“We can pursue nerve regeneration research with a simpler printer set-up,” says Shayan Shafiee, a PhD student working with Shokuhfar. He gestures to the small gray box across the lab bench.

He opens the red box under the top side of the printer’s box. Inside the plastic casing, a large syringe holds a red jelly-like fluid. Shafiee replenishes the needle-tipped printer, pulls up his laptop and, with a hydraulic whoosh, he starts to print a tissue scaffold.

The news release expands on the theme,

At his lab bench in the nanotechnology lab at Michigan Tech, Shafiee holds up a petri dish. Inside is what looks like a red gummy candy, about the size of a half-dollar.

Here’s a video from MTU illustrating the printing process,

Back to the news release, which notes graphene could be instrumental in this research,

“This is based on fractal geometry,” Shafiee explains, pointing out the small crenulations and holes pockmarking the jelly. “These are similar to our vertebrae—the idea is to let a nerve pass through the holes.”

Making the tissue compatible with nerve cells begins long before the printer starts up. Shafiee says the first step is to synthesize a biocompatible polymer that is syrupy—but not too thick—that can be printed. That means Shafiee and Shokuhfar have to create their own materials to print with; there is no Amazon.com or even a specialty shop for bioprinting nerves.

Nerves don’t just need a biocompatible tissue to act as a carrier for the cells. Nerve function is all about electric pulses. This is where Shokuhfar’s nanotechnology research comes in: Last year, she was awarded a CAREER grant from NSF for her work using graphene in biomaterials research. [emphasis mine] “Graphene is a wonder material,” she says. “And it has very good electrical conductivity properties.”

The team is extending the application of this material for nerve cell printing. “Our work always comes back to the question, is it printable or not?” Shafiee says, adding that a successful material—a biocompatible, graphene-bound polymer—may just melt, mush or flat out fail under the pressure of printing. After all, imagine building up a substance more delicate than a soufflé using only the point of a needle. And in the nanotechnology world, a needlepoint is big, even clumsy.

Shafiee and Shokuhfar see these issues as mechanical obstacles that can be overcome.

“It’s like other 3D printers, you need a design to work from,” Shafiee says, adding that he will tweak and hone the methodology for printing nerve cells throughout his dissertation work. He is also hopeful that the material will have use beyond nerve regeneration.

This looks like a news release designed to publicize work funded at MTU by the US National Science Foundation (NSF) which is why there is no mention of published work.

One final comment regarding cellulose nanocrystals (CNC). They have also been called nanocrystalline cellulose (NCC), which you will still see but it seems CNC is emerging as the generic term. NCC has been trademarked by CelluForce, a Canadian company researching and producing CNC (or if you prefer, NCC) from forest products.

Entangling thousands of atoms

Quantum entanglement as an idea seems extraordinary to me like something from of the fevered imagination made possible only with certain kinds of hallucinogens. I suppose you could call theoretical physicists who’ve conceptualized entanglement a different breed as they don’t seem to need chemical assistance for their flights of fancy, which turn out to be reality. Researchers at MIT (Massachusetts Institute of Technology) and the University of Belgrade (Serbia) have entangled thousands of atoms with a single photon according to a March 26, 2015 news item on Nanotechnology Now,

Physicists from MIT and the University of Belgrade have developed a new technique that can successfully entangle 3,000 atoms using only a single photon. The results, published today in the journal Nature, represent the largest number of particles that have ever been mutually entangled experimentally.

The researchers say the technique provides a realistic method to generate large ensembles of entangled atoms, which are key components for realizing more-precise atomic clocks.

“You can make the argument that a single photon cannot possibly change the state of 3,000 atoms, but this one photon does — it builds up correlations that you didn’t have before,” says Vladan Vuletic, the Lester Wolfe Professor in MIT’s Department of Physics, and the paper’s senior author. “We have basically opened up a new class of entangled states we can make, but there are many more new classes to be explored.”

A March 26, 2015 MIT news release by Jennifer Chu (also on EurekAlert but dated March 25, 2015), which originated the news item, describes entanglement with particular attention to how it relates to atomic timekeeping,

Entanglement is a curious phenomenon: As the theory goes, two or more particles may be correlated in such a way that any change to one will simultaneously change the other, no matter how far apart they may be. For instance, if one atom in an entangled pair were somehow made to spin clockwise, the other atom would instantly be known to spin counterclockwise, even though the two may be physically separated by thousands of miles.

The phenomenon of entanglement, which physicist Albert Einstein once famously dismissed as “spooky action at a distance,” is described not by the laws of classical physics, but by quantum mechanics, which explains the interactions of particles at the nanoscale. At such minuscule scales, particles such as atoms are known to behave differently from matter at the macroscale.

Scientists have been searching for ways to entangle not just pairs, but large numbers of atoms; such ensembles could be the basis for powerful quantum computers and more-precise atomic clocks. The latter is a motivation for Vuletic’s group.

Today’s best atomic clocks are based on the natural oscillations within a cloud of trapped atoms. As the atoms oscillate, they act as a pendulum, keeping steady time. A laser beam within the clock, directed through the cloud of atoms, can detect the atoms’ vibrations, which ultimately determine the length of a single second.

“Today’s clocks are really amazing,” Vuletic says. “They would be less than a minute off if they ran since the Big Bang — that’s the stability of the best clocks that exist today. We’re hoping to get even further.”

The accuracy of atomic clocks improves as more and more atoms oscillate in a cloud. Conventional atomic clocks’ precision is proportional to the square root of the number of atoms: For example, a clock with nine times more atoms would only be three times as accurate. If these same atoms were entangled, a clock’s precision could be directly proportional to the number of atoms — in this case, nine times as accurate. The larger the number of entangled particles, then, the better an atomic clock’s timekeeping.

It seems weak lasers make big entanglements possible (from the news release),

Scientists have so far been able to entangle large groups of atoms, although most attempts have only generated entanglement between pairs in a group. Only one team has successfully entangled 100 atoms — the largest mutual entanglement to date, and only a small fraction of the whole atomic ensemble.

Now Vuletic and his colleagues have successfully created a mutual entanglement among 3,000 atoms, virtually all the atoms in the ensemble, using very weak laser light — down to pulses containing a single photon. The weaker the light, the better, Vuletic says, as it is less likely to disrupt the cloud. “The system remains in a relatively clean quantum state,” he says.

The researchers first cooled a cloud of atoms, then trapped them in a laser trap, and sent a weak laser pulse through the cloud. They then set up a detector to look for a particular photon within the beam. Vuletic reasoned that if a photon has passed through the atom cloud without event, its polarization, or direction of oscillation, would remain the same. If, however, a photon has interacted with the atoms, its polarization rotates just slightly — a sign that it was affected by quantum “noise” in the ensemble of spinning atoms, with the noise being the difference in the number of atoms spinning clockwise and counterclockwise.

“Every now and then, we observe an outgoing photon whose electric field oscillates in a direction perpendicular to that of the incoming photons,” Vuletic says. “When we detect such a photon, we know that must have been caused by the atomic ensemble, and surprisingly enough, that detection generates a very strongly entangled state of the atoms.”

Vuletic and his colleagues are currently using the single-photon detection technique to build a state-of-the-art atomic clock that they hope will overcome what’s known as the “standard quantum limit” — a limit to how accurate measurements can be in quantum systems. Vuletic says the group’s current setup may be a step toward developing even more complex entangled states.

“This particular state can improve atomic clocks by a factor of two,” Vuletic says. “We’re striving toward making even more complicated states that can go further.”

This research was supported in part by the National Science Foundation, the Defense Advanced Research Projects Agency, and the Air Force Office of Scientific Research.

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

Entanglement with negative Wigner function of almost 3,000 atoms heralded by one photon by Robert McConnell, Hao Zhang, Jiazhong Hu, Senka Ćuk & Vladan Vuletić. Nature 519 439–442 (26 March 2015) doi:10.1038/nature14293 Published online 25 March 2015

This article is behind a paywall but there is a free preview via ReadCube Access.

This image illustrates the entanglement of a large number of atoms. The atoms, shown in purple, are shown mutually entangled with one another. Image: Christine Daniloff/MIT and Jose-Luis Olivares/MIT

This image illustrates the entanglement of a large number of atoms. The atoms, shown in purple, are shown mutually entangled with one another.
Image: Christine Daniloff/MIT and Jose-Luis Olivares/MIT

From monitoring glucose in kidneys to climate change in trees

That headline is almost poetic but I admit It’s a bit of a stretch rhymewise, kidneys/trees. In any event, a Feb. 6, 2015 news item on Azonano describes research into monitoring the effects of climate change on trees,

Serving as a testament to the far-reaching impact of Governor Andrew M. Cuomo’s commitment to maintaining New York State’s global leadership in nanotechnology innovation, SUNY Polytechnic Institute’s Colleges of Nanoscale Science and Engineering (SUNY Poly CNSE) today announced the National Science Foundation (NSF) has awarded $837,000 to support development of a first of its kind nanoscale sensor to monitor the effects of climate change on trees.

A Feb. 5, 2015 SUNY Poly CNSE news release, which originated the news item, provides more details including information about the sensor’s link to measuring glucose in kidneys,

The NSF grant was generated through the Instrument Development for Biological Research (IDBR) program, which provides funds to develop new classes of devices for bio-related research. The NANAPHID, a novel aphid-like nanosensor, will provide real-time measurements of carbohydrates in live plant tissue. Carbohydrate levels in trees are directly connected to plant productivity, such as maple sap production and survival. The NANAPHID will enable researchers to determine the effects of a variety of environmental changes including temperature, precipitation, carbon dioxide, soil acidity, pests and pathogens. The nanosensor can also provide real-time monitoring of sugar concentration levels, which are of signficant importance in maple syrup production and apple and grape farming.

“The technology for the NANAPHID is rooted in a nanoscale sensor SUNY Poly CNSE developed to monitor glucose levels in human kidneys being prepared for transplant. Our team determined that certain adjustments would enable the sensor to provide similar monitoring for plants, and provide a critical insight to the effects of climate change on the environment,” said Dr. James Castracane, professor and head of the Nanobioscience Constellation at SUNY Polytechnic Institute. “This is a perfect example of the cycle of innovation made possible through the ongoing nanotechnology research and development at SUNY Poly CNSE’s NanoTech Complex.”

“This new sensor will be used in several field experiments on measuring sensitivity of boreal forest to climate warming. Questions about forest response to rising air and soil temperatures are extremely important for forecasting future atmospheric carbon dioxide levels, climate change and forest health,” said Dr. Andrei Lapenas, principal investigator and associate professor of climatology at the University at Albany. “At the same time, we already see some potential commercial application for NANAPHID-type sensors in agriculture, food industry and other fields. Our collaboration with SUNY Poly CNSE has been extremely productive and I look forward to continuing our work together.”

The NANAPHID project began in 2014 with a $135,000 SUNY Research Foundation Network of Excellence grant. SUNY Poly CNSE will receive $400,000 of the NSF award for the manufacturing aspects of the sensor array development and testing. The remaining funds will be shared between Dr. Lapenas and researchers Dr. Ruth Yanai (ESF), Dr. Thomas Horton (ESF), and Dr. Pamela Templer (Boston University) for data collection and analysis.

“With current technology, analyzing carbohydrates in plant tissues requires hours in the lab or more than $100 a sample if you want to send them out. And you can’t sample the same tissue twice, the sample is destroyed in the analysis,” said Dr. Yanai. “The implantable device will be cheap to produce and will provide continuous monitoring of sugar concentrations, which is orders of magnitude better in both cost and in the information provided. Research questions we never dreamed of asking before will become possible, like tracking changes in photosynthate over the course of a day or along the stem of a plant, because it’s a nondestructive assay.”

“I see incredible promise for the NANAPHID device in plant ecology. We can use the sensors at the root tip where plants give sugars to symbiotic fungi in exchange for soil nutrients,” said Dr. Horton. “Some fungi are believed to be significant carbon sinks because they produce extensive fungal networks in soils and we can use the sensors to compare the allocation of photosynthate to roots colonized by these fungi versus the allocation to less carbon demanding fungi. Further, the vast majority of these symbiotic fungi cannot be cultured in lab. These sensors will provide valuable insights into plant-microbe interactions under field conditions.”

“The creation of this new sensor will make understanding the effects of a variety of environmental changes, including climate change, on the health and productivity of forests much easier to measure,” said Dr. Templer. “For the first time, we will be able to measure concentrations of carbohydrates in living trees continuously and in real-time, expanding our ability to examine controls on photosynthesis, sap flow, carbon sequestration and other processes in forest ecosystems.”

Fascinating, eh? I wonder who made the connection between human kidneys and plants and how that person made the connection.

Poopy gold, silver, platinum, and more

In the future, gold rushes could occur in sewage plants. Precious metals have been found in large quantity by researchers investigating waste and the passage of nanoparticles (gold, silver, platinum, etc.) into our water. From a Jan. 29, 2015 news article by Adele Peters for Fast Company (Note: Links have been removed),

One unlikely potential source of gold, silver, platinum, and other metals: Sewage sludge. A new study estimates that in a city of a million people, $13 million of metals could be collecting in sewage every year, or $280 per ton of sludge. There’s gold (and silver, copper, and platinum) in them thar poop.

Funded in part by a grant for “nano-prospecting,” the researchers looked at a huge sample of sewage from cities across the U.S., and then studied several specific waste treatment plants. “Initially we thought gold was at just one or two hotspots, but we find it even in smaller wastewater treatment plants,” says Paul Westerhoff, an engineering professor at Arizona State University, who led the new study.

Some of the metals likely come from a variety of sources—we may ingest tiny particles of silver, for example, when we eat with silverware or when we drink water from pipes that have silver alloys. Medical diagnostic tools often use gold or silver. …

The metallic particles Peters is describing are nanoparticles some of which are naturally occurring  as she notes but, increasingly, we are dealing with engineered nanoparticles making their way into the environment.

Engineered or naturally occurring, a shocking quantity of these metallic nanoparticles can be found in our sewage. For example, a waste treatment centre in Japan recorded 1,890 grammes of gold per tonne of ash from incinerated sludge as compared to the 20 – 40 grammes of gold per tonne of ore recovered from one of the world’s top producing gold mines (Miho Yoshikawa’s Jan. 30, 2009 article for Reuters).

While finding it is one thing, extracting it is going to be something else as Paul Westerhoff notes in Peters’ article. For the curious, here’s a link to and a citation for the research paper,

Characterization, Recovery Opportunities, and Valuation of Metals in Municipal Sludges from U.S. Wastewater Treatment Plants Nationwide by Paul Westerhoff, Sungyun Lee, Yu Yang, Gwyneth W. Gordon, Kiril Hristovski, Rolf U. Halden, and Pierre Herckes. Environ. Sci. Technol., Article ASAP DOI: 10.1021/es505329q Publication Date (Web): January 12, 2015

Copyright © 2015 American Chemical Society

This paper is behind a paywall.

On a completely other topic, this is the first time I’ve noticed this type of note prepended to an abstract,


This article published January 26, 2015 with errors throughout the text. The corrected version published January 27, 2015.

Getting back to the topic at hand, I checked into nano-prospecting and found this Sept. 19, 2013 Arizona State University news release describing the project launch,

Growing use of nanomaterials in manufactured products is heightening concerns about their potential environmental impact – particularly in water resources.

Tiny amounts of materials such as silver, titanium, silica and platinum are being used in fabrics, clothing, shampoos, toothpastes, tennis racquets and even food products to provide antibacterial protection, self-cleaning capability, food texture and other benefits.

Nanomaterials are also put into industrial polishing agents and catalysts, and are released into the environment when used.

As more of these products are used and disposed of, increasing amounts of the nanomaterials are accumulating in soils, waterways and water-systems facilities. That’s prompting efforts to devise more effective ways of monitoring the movement of the materials and assessing their potential threat to environmental safety and human health.

Three Arizona State University faculty members will lead a research project to help improve methods of gathering accurate information about the fate of the materials and predicting when, where and how they may pose a hazard.

Their “nanoprospecting” endeavor is supported by a recently awarded $300,000 grant from the National Science Foundation.

You can find out more about Paul Westerhoff and his work here.