Category Archives: medicine

Inhibiting viruses with nanocrystalline cellulose (NCC) in Finland

Research and interest in cellulose nanomaterials of one kind or another seems to be reaching new heights. That’s my experience since this is my third posting on the topic in one week.

The latest research features NCC (nanocrystalline cellulose [NCC] or, as it’s sometimes known, cellulose nanocrystals [CNC]) ,as a ‘viral inhibitor’ and is described in an April 15, 2014 news item on Nanowerk,

Researchers from Aalto University [Finland] and and the University of Eastern Finland have succeeded in creating a surface on nano-sized cellulose crystals that imitates a biological structure. The surface adsorbs viruses and disables them. The results can prove useful in the development of antiviral ointments and surfaces, for instance.

There are many viral diseases in the world for which no pharmaceutical treatment exists. These include, among others, dengue fever, which is spread by mosquitoes in the tropics, as well as a type of diarrhea, which is more familiar in Finland and is easily spread by the hands and can be dangerous especially for small children and the elderly.

An April 15, 2014 Aalto University news release, which originated the news item, provides more detail,

Researchers at Aalto University and the University of Eastern Finland have now succeeded in preliminary tests to prevent the spread of one type of virus into cells with the help of a new type of nanocrystalline cellulose. Nano-sized cellulose crystals were manufactured out of cotton fibre or filter paper with the help of sulphuric acid, causing sulphate ions with negative charges to attach to their surfaces. The ions then attached to alphaviruses used in the test and neutralised them. When the researchers replaced the sulphate ions with cellulose derivatives that imitate tyrosine sulphates, the activity of the viruses was further reduced. The experiments succeeded in preventing viral infection in 88-100 percent of the time with no noticeable effect on the viability of the cells by the nanoparticles. The research findings were published in the journal Biomacromolecules.

Here’s a diagram illustrating how the new type of NCC works,

Courtesy of Aalto University

Courtesy of Aalto University

The news release includes perspectives from the researchers,

’Certain cellulose derivatives had been seen to have an impact on viruses before. The nano scale increases the proportion of the surface area to that of the number of grams to a very high level, which is an advantage, because viruses specifically attach themselves to surfaces. Making the cellulose crystals biomimetic, which means that they mimic biological structures, was an important step, as we know that in nature viruses often interact specifically with tyrosine structures,’ he [Jukka Seppälä, Professor of Polymer Technology at Aalto University] says.

Both Jukka Seppälä and Ari Hinkkanen, Professor of Gene Transfer Technology at the University of Eastern Finland, emphasise that the research is still in the early stages.

‘Now we know that the attachment of a certain alphavirus can be effectively prevented when we use large amounts of nanocrystalline cellulose.  Next we need to experiment with other alpha viruses and learn to better understand the mechanisms that prevent viral infection. In addition, it is necessary to ascertain if cellulose can also block other viruses and in what conditions, and to investigate whether or not the sulphates have a deleterious effects on an organism,’ Ari Hinkkanen explains.

According to Kristiina Järvinen, Professor of Pharmaceutical Technology at the University of Eastern Finland, there are many routes that can be taken in the commercialisation of the results. The development of an antiviral medicine is the most distant of these; the idea could be sooner applied in disinfectant ointments and coatings, for instance.

‘It would be possible to provide protection against viruses, spread by mosquitoes, by applying ointment containing nanocrystalline cellulose onto the skin. Nanocrystalline cellulose applied on hospital door handles could kill viruses and prevent them from spreading.  However, we first need to ascertain if the compounds will remain effective in a non-liquid form and how they work in animal tests,’ she ponders.

For the curious, here’s a link to and a citation for the paper,

Synthesis of Cellulose Nanocrystals Carrying Tyrosine Sulfate Mimetic Ligands and Inhibition of Alphavirus Infection by Justin O. Zoppe, Ville Ruottinen, Janne Ruotsalainen, Seppo Rönkkö, Leena-Sisko Johansson, Ari Hinkkanen, Kristiina Järvinen, and Jukka Seppälä. Biomacromolecules, 2014, 15 (4), pp 1534–1542 DOI: 10.1021/bm500229d Publication Date (Web): March 14, 2014

Copyright © 2014 American Chemical Society

This paper is behind a paywall.

As for my other recent postings on cellulose nanomaterials, there’s this April 14, 2014 piece titled: Preparing nanocellulose for eventual use in dressings for wounds and this from April 10, 2014 titled: US Dept. of Agriculture wants to commercialize cellulose nanomaterials.

Using magnets to attract nanoparticles containing anesthesia

An April 11, 2014 news item on ScienceDaily, researchers describe a technique that would require far less anesthesia to numb the pain of various surgical procedures,

A technique using anesthesia-containing nanoparticles — drawn to the targeted area of the body by magnets — could one day provide a useful alternative to nerve block for local anesthesia in patients, suggests an experimental study in the April issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).

“We have established proof of principle that it is possible to produce ankle block in the rat by intravenous injection of magnetic nanoparticles associated with ropivacaine and magnet application at the ankle,” write Dr Venkat R.R. Mantha and colleagues of University of Pittsburgh School of Medicine. With further study, the nano-anesthesia technique might allow more potent doses of local anesthetics to be delivered safely during local anesthesia in humans.

The April 11, 2014 Walters Kluwer news release, which originated the news item, preliminary research,

The experimental pilot study evaluated the use of magnet-directed nanoparticles containing the local anesthetic drug ropivacaine (MNP/Ropiv) to produce anesthesia of the limbs.  The researchers engineered nanoparticle complexes containing small amounts of ropivacaine and the iron oxide mineral magnetite.  The MNP/Ropiv complexes were injected into the veins (intravenously, or IV) of anesthetized rats.

The researchers then placed magnets around the ankle of the right paw for 15, 30, or 60 minutes.  The goal was to use the magnets to draw the nanoparticles to ankle. Once there, the particles would release the anesthetic, numbing the nerves around the ankle.

Sensation in the right paw was assessed by comparing the right paw to the left paw, which was not affected. Other groups of rats received standard nerve block, with ropivacaine injected directly into the ankle; or IV injection of ropivacaine alone, not incorporated into nanoparticles.

Injection of MNP/Ropiv complexes followed by magnet application produced significant nerve block in the right ankle, similar to a standard nerve block.  The left ankle was unaffected.

The ankle block produced by MNP/Ropiv injection was greatest when the magnet was applied for 30 minutes—likely reflecting the time of maximum ropivacaine release.  High ropivacaine concentrations were found in right ankles of the MNP/Ropiv group, suggesting “sequestration of the drug locally by the magnet.”
 
In rats receiving MNP/Ropiv, the nanoparticles contained a total of 14 milligrams of ropivacaine—a dose high enough to cause potentially fatal toxic effects.  Yet none of the animals in the MNP/Ropiv group had apparent adverse effects of ropivacaine.  This was similar to the findings in rats receiving 1 milligram of plain ropivacaine.  Thus the safe dose of ropivacaine combined with nanoparticles could be at least 14 times higher, compared to IV ropivacaine alone.

Magnet-directed nanoparticles have previously been used for targeted delivery of chemotherapy drugs.  The new study suggests that a similar technique could be used to attract local anesthetic-containing nanoparticles to specific areas, as an alternative to local anesthetic block—like that used for foot and ankle surgery, for example.

Additional animal experiments would be needed before the MNP/Ropiv technique can be tested in humans.  But if it proved safe, the magnet-directed approach could provide a useful new alternative for regional anesthesia—delivering high concentrations of local anesthetics directly to the desired area, without increasing toxic effects.

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

Nanoanesthesia: A Novel, Intravenous Approach to Ankle Block in the Rat by Magnet-Directed Concentration of Ropivacaine-Associated Nanoparticles by Venkat R. R. Mantha, Harsha K. Nair, Raman Venkataramanan, Yuan Yue Gao, Krzysztof Matyjaszewski, Hongchen Dong, Wenwen Li, Doug Landsittel, Elan Cohen, William R. Lariviere. Anesthesia & Analgesia: doi: 10.1213/ANE.0000000000000175

This paper is open access.

Preparing nanocellulose for eventual use in* dressings for wounds

Michael Berger writes about a medical application for wood-based nanocellulose in an April 10, 2014 Nanowerk Spotlight article by featuring some recent research from Norway (Note: Links have been removed),

Cellulose is a biopolymer consisting of long chains of glucose with unique structural properties whose supply is practically inexhaustible. It is found in the cell walls of plants where it serves to provide a supporting framework – a sort of skeleton. Nanocellulose from wood – i.e. wood fibers broken down to the nanoscale – is a promising nanomaterial with potential applications as a substrate for printing electronics, filtration, or biomedicine.

Researchers have now reported on a method to control the surface chemistry of nanocellulose. The paper appeared in the April 8, 2014 online edition of the Journal of Biomaterials Applications (“Pretreatment-dependent surface chemistry of wood nanocellulose for pH-sensitive hydrogels”).

Using a specific chemical pretreatment as example (carboxymethylation and periodate oxidation), a team from the Paper and Fibre Research Institute (PFI) in Norway demonstrated that they could manufacture nanofibrils with a considerable amount of carboxyl groups and aldehyde groups, which could be applied for functionalizing the material.

The Norwegian researchers are working within the auspices of PFI‘s NanoHeal project featured in my Aug. 23, 2012 posting. It’s good to see that progress is being made. From the Berger’s article,

A specific activity that the PFI researchers and collaborators are working with in the NanoHeal project is the production of an ultrapure nanocellulose which is important for biomedical applications. Considering that the nanocellulose hydrogel material can be cross-linked and have a reactive surface chemistry there are various potential applications.

“A concrete application that we are working with in this specific case is as dressing for wound healing, another is scaffolds,” adds senior research scientist and co-author Kristin Syverud.

“Production of an ultrapure nanocellulose quality is an activity that we are intensifying together with our research partners at the Institute of Cancer Research and Molecular Medicine in Trondheim,” notes Chinga-Carrasco [Gary Chinga-Carrasco, a senior research scientist at PFI]. “The results look good and we expect to have a concrete protocol for production of ultrapure nanocellulose soon, for an adequate assessment of its biocompatibility.”

“We have various groups working with assessment of the suitability of nanocellulose as a barrier against wound bacteria and also with the assessment of the cytotoxicity and biocompatibility,” he says. “However, as a first step we have intensified our work on the production of nanocellulose that we expect will be adequate for wound dressings, part of these activities are described in this paper.”

I suggest reading Berger’s article in its totality for a more detailed description of the many hurdles researchers still have to overcome. For the curious, here’s a link to and a citation for the paper,

Pretreatment-dependent surface chemistry of wood nanocellulose for pH-sensitive hydrogels by Gary Chinga-Carrasco & Kristin Syverud. Published online before print April 8, 2014, doi: 10.1177/0885328214531511 J Biomater Appl April 8, 2014 0885328214531511

This paper is behind a paywall.

I was hoping to find someone from this group in the list of speakers for 2014 TAPPI Nanotechnology conference website here (officially known as 2014 TAPPI [Technical Association of the Pulp and Paper Industry] International Conference on Nanotechnology for Renewable Materials) being held in Vancouver, Canada (June 23-26, 2014) but had no luck.

* ‘as’ changed to ‘in’ Apr.14.14 10:50 am PDT in headline

Computerized cockroaches as precursors to new healing techniques

The last time I wrote about cockroaches was in a June 26, 2013 posting about cyborg cockroaches and neuroscience. This latest cockroach item, which concerns new therapeutic approaches, comes from an April 8, 2014 article by Sarah Spickernell for New Scientist (Note: A link has been removed),

It’s a computer – inside a cockroach. Nano-sized entities made of DNA that are able to perform the same kind of logic operations as a silicon-based computer have been introduced into a living animal.

The DNA computers – known as origami robots because they work by folding and unfolding strands of DNA – travel around the insect’s body and interact with each other, as well as the insect’s cells. When they uncurl, they can dispense drugs carried in their folds.

“DNA nanorobots could potentially carry out complex programs that could one day be used to diagnose or treat diseases with unprecedented sophistication,” says Daniel Levner, a bioengineer at the Wyss Institute at Harvard University.

Levner and his colleagues at Bar Ilan University in Ramat-Gan, Israel, made the nanobots by exploiting the binding properties of DNA. When it meets a certain kind of protein, DNA unravels into two complementary strands. By creating particular sequences, the strands can be made to unravel on contact with specific molecules – say, those on a diseased cell. When the molecule unravels, out drops the package wrapped inside.

Spickernell’s description of the researchers’ plan to increase the amount of computing power in a cockroach to the equivalent of an eight-bit computer seems eye-opening until you read about their plans for preliminary human clinical trials using the same technique for mammals as they have in insects.

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

Universal computing by DNA origami robots in a living animal by Yaniv Amir, Eldad Ben-Ishay, Daniel Levner, Shmulik Ittah, Almogit Abu-Horowitz, & Ido Bachelet. Nature Nanotechnology (2014) doi:10.1038/nnano.2014.58 Published online 06 April 2014

The paper is behind a paywall but there is an option for a free preview via ReadCube access.

Good lignin, bad lignin: Florida researchers use plant waste to create lignin nanotubes while researchers in British Columbia develop trees with less lignin

An April 4, 2014 news item on Azonano describes some nanotube research at the University of Florida that reaches past carbon to a new kind of nanotube,

Researchers with the University of Florida’s [UF] Institute of Food and Agricultural Sciences took what some would consider garbage and made a remarkable scientific tool, one that could someday help to correct genetic disorders or treat cancer without chemotherapy’s nasty side effects.

Wilfred Vermerris, an associate professor in UF’s department of microbiology and cell science, and Elena Ten, a postdoctoral research associate, created from plant waste a novel nanotube, one that is much more flexible than rigid carbon nanotubes currently used. The researchers say the lignin nanotubes – about 500 times smaller than a human eyelash – can deliver DNA directly into the nucleus of human cells in tissue culture, where this DNA could then correct genetic conditions. Experiments with DNA injection are currently being done with carbon nanotubes, as well.

“That was a surprising result,” Vermerris said. “If you can do this in actual human beings you could fix defective genes that cause disease symptoms and replace them with functional DNA delivered with these nanotubes.”

An April 3, 2014 University of Florida’s Institute of Food and Agricultural Sciences news release, which originated the news item, describes the lignin nanotubes (LNTs) and future applications in more detail,

The nanotube is made up of lignin from plant material obtained from a UF biofuel pilot facility in Perry, Fla. Lignin is an integral part of the secondary cell walls of plants and enables water movement from the roots to the leaves, but it is not used to make biofuels and would otherwise be burned to generate heat or electricity at the biofuel plant. The lignin nanotubes can be made from a variety of plant residues, including sorghum, poplar, loblolly pine and sugar cane. [emphasis mine]

The researchers first tested to see if the nanotubes were toxic to human cells and were surprised to find that they were less so than carbon nanotubes. Thus, they could deliver a higher dose of medicine to the human cell tissue.  Then they researched if the nanotubes could deliver plasmid DNA to the same cells and that was successful, too. A plasmid is a small DNA molecule that is physically separate from, and can replicate independently of, chromosomal DNA within a cell.

“It’s not a very smooth road because we had to try different experiments to confirm the results,” Ten said. “But it was very fruitful.”

In cases of genetic disorders, the nanotube would be loaded with a functioning copy of a gene, and injected into the body, where it would target the affected tissue, which then makes the missing protein and corrects the genetic disorder.

Although Vermerris cautioned that treatment in humans is many years away, among the conditions that these gene-carrying nanotubes could correct include cystic fibrosis and muscular dystrophy. But, he added, that patients would have to take the corrective DNA via nanotubes on a continuing basis.

Another application under consideration is to use the lignin nanotubes for the delivery of chemotherapy drugs in cancer patients. The nanotubes would ensure the drugs only get to the tumor without affecting healthy tissues.

Vermerris said they created different types of nanotubes, depending on the experiment. They could also adapt nanotubes to a patient’s specific needs, a process called customization.

“You can think about it as a chest of drawers and, depending on the application, you open one drawer or use materials from a different drawer to get things just right for your specific application,” he said.  “It’s not very difficult to do the customization.”

The next step in the research process is for Vermerris and Ten to begin experiments on mice. They are in the application process for those experiments, which would take several years to complete.  If those are successful, permits would need to be obtained for their medical school colleagues to conduct research on human patients, with Vermerris and Ten providing the nanotubes for that research.

“We are a long way from that point,” Vermerris said. “That’s the optimistic long-term trajectory.”

I hope they have good luck with this work. I have emphasized the plant waste the University of Florida scientists studied due to the inclusion of poplar, which is featured in the University of British Columbia research work also being mentioned in this post.

Getting back to Florida for a moment, here’s a link to and a citation for the paper,

Lignin Nanotubes As Vehicles for Gene Delivery into Human Cells by Elena Ten, Chen Ling, Yuan Wang, Arun Srivastava, Luisa Amelia Dempere, and Wilfred Vermerris. Biomacromolecules, 2014, 15 (1), pp 327–338 DOI: 10.1021/bm401555p Publication Date (Web): December 5, 2013
Copyright © 2013 American Chemical Society

This is an open access paper.

Meanwhile, researchers at the University of British Columbia (UBC) are trying to limit the amount of lignin in trees (specifically poplars, which are not mentioned in this excerpt but in the next). From an April 3, 2014 UBC news release,

Researchers have genetically engineered trees that will be easier to break down to produce paper and biofuel, a breakthrough that will mean using fewer chemicals, less energy and creating fewer environmental pollutants.

“One of the largest impediments for the pulp and paper industry as well as the emerging biofuel industry is a polymer found in wood known as lignin,” says Shawn Mansfield, a professor of Wood Science at the University of British Columbia.

Lignin makes up a substantial portion of the cell wall of most plants and is a processing impediment for pulp, paper and biofuel. Currently the lignin must be removed, a process that requires significant chemicals and energy and causes undesirable waste.

Researchers used genetic engineering to modify the lignin to make it easier to break down without adversely affecting the tree’s strength.

“We’re designing trees to be processed with less energy and fewer chemicals, and ultimately recovering more wood carbohydrate than is currently possible,” says Mansfield.

Researchers had previously tried to tackle this problem by reducing the quantity of lignin in trees by suppressing genes, which often resulted in trees that are stunted in growth or were susceptible to wind, snow, pests and pathogens.

“It is truly a unique achievement to design trees for deconstruction while maintaining their growth potential and strength.”

The study, a collaboration between researchers at the University of British Columbia, the University of Wisconsin-Madison, Michigan State University, is a collaboration funded by Great Lakes Bioenergy Research Center, was published today in Science.

Here’s more about lignin and how a decrease would free up more material for biofuels in a more environmentally sustainable fashion, from the news release,

The structure of lignin naturally contains ether bonds that are difficult to degrade. Researchers used genetic engineering to introduce ester bonds into the lignin backbone that are easier to break down chemically.

The new technique means that the lignin may be recovered more effectively and used in other applications, such as adhesives, insolation, carbon fibres and paint additives.

Genetic modification

The genetic modification strategy employed in this study could also be used on other plants like grasses to be used as a new kind of fuel to replace petroleum.

Genetic modification can be a contentious issue, but there are ways to ensure that the genes do not spread to the forest. These techniques include growing crops away from native stands so cross-pollination isn’t possible; introducing genes to make both the male and female trees or plants sterile; and harvesting trees before they reach reproductive maturity.

In the future, genetically modified trees could be planted like an agricultural crop, not in our native forests. Poplar is a potential energy crop for the biofuel industry because the tree grows quickly and on marginal farmland. [emphasis mine] Lignin makes up 20 to 25 per cent of the tree.

“We’re a petroleum reliant society,” says Mansfield. “We rely on the same resource for everything from smartphones to gasoline. We need to diversify and take the pressure off of fossil fuels. Trees and plants have enormous potential to contribute carbon to our society.”

As noted earlier, the researchers in Florida mention poplars in their paper (Note: Links have been removed),

Gymnosperms such as loblolly pine (Pinus taeda L.) contain lignin that is composed almost exclusively of G-residues, whereas lignin from angiosperm dicots, including poplar (Populus spp.) contains a mixture of G- and S-residues. [emphasis mine] Due to the radical-mediated addition of monolignols to the growing lignin polymer, lignin contains a variety of interunit bonds, including aryl–aryl, aryl–alkyl, and alkyl–alkyl bonds.(3) This feature, combined with the association between lignin and cell-wall polysaccharides, which involves both physical and chemical interactions, make the isolation of lignin from plant cell walls challenging. Various isolation methods exist, each relying on breaking certain types of chemical bonds within the lignin, and derivatizations to solubilize the resulting fragments.(5) Several of these methods are used on a large scale in pulp and paper mills and biorefineries, where lignin needs to be removed from woody biomass and crop residues(6) in order to use the cellulose for the production of paper, biofuels, and biobased polymers. The lignin is present in the waste stream and has limited intrinsic economic value.(7)

Since hydroxyl and carboxyl groups in lignin facilitate functionalization, its compatibility with natural and synthetic polymers for different commercial applications have been extensively studied.(8-12) One of the promising directions toward the cost reduction associated with biofuel production is the use of lignin for low-cost carbon fibers.(13) Other recent studies reported development and characterization of lignin nanocomposites for multiple value-added applications. For example, cellulose nanocrystals/lignin nanocomposites were developed for improved optical, antireflective properties(14, 15) and thermal stability of the nanocomposites.(16) [emphasis mine] Model ultrathin bicomponent films prepared from cellulose and lignin derivatives were used to monitor enzyme binding and cellulolytic reactions for sensing platform applications.(17) Enzymes/“synthetic lignin” (dehydrogenation polymer (DHP)) interactions were also investigated to understand how lignin impairs enzymatic hydrolysis during the biomass conversion processes.(18)

The synthesis of lignin nanotubes and nanowires was based on cross-linking a lignin base layer to an alumina membrane, followed by peroxidase-mediated addition of DHP and subsequent dissolution of the membrane in phosphoric acid.(1) Depending upon monomers used for the deposition of DHP, solid nanowires, or hollow nanotubes could be manufactured and easily functionalized due to the presence of many reactive groups. Due to their autofluorescence, lignin nanotubes permit label-free detection under UV radiation.(1) These features make lignin nanotubes suitable candidates for numerous biomedical applications, such as the delivery of therapeutic agents and DNA to specific cells.

The synthesis of LNTs in a sacrificial template membrane is not limited to a single source of lignin or a single lignin isolation procedure. Dimensions of the LNTs and their cytotoxicity to HeLa cells appear to be determined primarily by the lignin isolation procedure, whereas the transfection efficiency is also influenced by the source of the lignin (plant species and genotype). This means that LNTs can be tailored to the application for which they are intended. [emphasis mine] The ability to design LNTs for specific purposes will benefit from a more thorough understanding of the relationship between the structure and the MW of the lignin used to prepare the LNTs, the nanomechanical properties, and the surface characteristics.

We have shown that DNA is physically associated with the LNTs and that the LNTs enter the cytosol, and in some case the nucleus. The LNTs made from NaOH-extracted lignin are of special interest, as they were the shortest in length, substantially reduced HeLa cell viability at levels above approximately 50 mg/mL, and, in the case of pine and poplar, were the most effective in the transfection [penetrating the cell with a bacterial plasmid to leave genetic material in this case] experiments. [emphasis mine]

As I see the issues presented with these two research efforts, there are environmental and energy issues with extracting the lignin while there seem to be some very promising medical applications possible with lignin ‘waste’. These two research efforts aren’t necessarily antithetical but they do raise some very interesting issues as to how we approach our use of resources and future policies.

E-tattoo without the nanotech

John Rogers and his team at the University of Illinois and a colleague’s (Yonggang Huang) team at Northwestern University have devised an ‘electronic tattoo’ (a soft, stick-on patch) made up from materials that anyone can purchase off-the-shelf. Rogers is known for his work with nanomaterials (my Aug. 10, 2012 posting titled ‘Surgery with fingertip control‘ mentioned a silicon nanomembrane that can be fitted onto the fingertips for possible use in surgical procedures) and with electronics (my Aug. 12, 2011 posting titled: ‘Electronic tattoos‘ mentioned his earlier attempts at developing e-tattoos).

This latest effort from Rogers and his multi-university team is mentioned in an April 4, 2014 article by Mark Wilson for Fast Company,

About a year ago, University of Illinois researcher John Rogers revealed a pretty amazing creation: a circuit that, rather than living on an inflexible board, could stick to and move with someone’s skin just like an ink stamp. But like any early research, it was mostly a proof-of-concept, and it would require relatively expensive, custom-printed electronics to work.

Today, Rogers, in conjunction with Northwestern University’s Yonggang Huang, has published details on version 2.0 in Science, revealing that this once-esoteric project has more immediate, mass market appeal.

… It means that you could create a wearable electronic that’s one-part special sticky circuit board, every other part whatever-the-hell-you-manufactured-in-China. This flexible circuit could accommodate a stock battery, an accelerometer, a Wi-Fi chip, and a Bluetooth circuitry, for instance, all living on your skin rather than inside your iPhone. And as an added bonus, it would be relatively cheap.

A University of Illinois April ?, 2014 news release describes Rogers, his multi-university team, and their current (pun intended) e-tattoo,

Engineers at the University of Illinois at Urbana-Champaign and Northwestern University have demonstrated thin, soft stick-on patches that stretch and move with the skin and incorporate commercial, off-the-shelf chip-based electronics for sophisticated wireless health monitoring.

The patches stick to the skin like a temporary tattoo and incorporate a unique microfluidic construction with wires folded like origami to allow the patch to bend and flex without being constrained by the rigid electronics components. The patches could be used for everyday health tracking – wirelessly sending updates to your cellphone or computer – and could revolutionize clinical monitoring such as EKG and EEG testing – no bulky wires, pads or tape needed.

“We designed this device to monitor human health 24/7, but without interfering with a person’s daily activity,” said Yonggang Huang, the Northwestern University professor who co-led the work with Illinois professor John A. Rogers. “It is as soft as human skin and can move with your body, but at the same time it has many different monitoring functions. What is very important about this device is it is wirelessly powered and can send high-quality data about the human body to a computer, in real time.”

The researchers did a side-by-side comparison with traditional EKG and EEG monitors and found the wireless patch performed equally to conventional sensors, while being significantly more comfortable for patients. Such a distinction is crucial for long-term monitoring, situations such as stress tests or sleep studies when the outcome depends on the patient’s ability to move and behave naturally, or for patients with fragile skin such as premature newborns.

Rogers’ group at Illinois previously demonstrated skin electronics made of very tiny, ultrathin, specially designed and printed components. While those also offer high-performance monitoring, the ability to incorporate readily available chip-based components provides many important, complementary capabilities in engineering design, at very low cost.

“Our original epidermal devices exploited specialized device geometries – super thin, structured in certain ways,” Rogers said. “But chip-scale devices, batteries, capacitors and other components must be re-formulated for these platforms. There’s a lot of value in complementing this specialized strategy with our new concepts in microfluidics and origami interconnects to enable compatibility with commercial off-the-shelf parts for accelerated development, reduced costs and expanded options in device types.”

The multi-university team turned to soft microfluidic designs to address the challenge of integrating relatively big, bulky chips with the soft, elastic base of the patch. The patch is constructed of a thin elastic envelope filled with fluid. The chip components are suspended on tiny raised support points, bonding them to the underlying patch but allowing the patch to stretch and move.

One of the biggest engineering feats of the patch is the design of the tiny, squiggly wires connecting the electronics components – radios, power inductors, sensors and more. The serpentine-shaped wires are folded like origami, so that no matter which way the patch bends, twists or stretches, the wires can unfold in any direction to accommodate the motion. Since the wires stretch, the chips don’t have to.

Skin-mounted devices could give those interested in fitness tracking a more complete and accurate picture of their activity level.

“When you measure motion on a wristwatch type device, your body is not very accurately or reliably coupled to the device,” said Rogers, a Swanlund Professor of Materials Science and Engineering at the U. of I. “Relative motion causes a lot of background noise. If you have these skin-mounted devices and an ability to locate them on multiple parts of the body, you can get a much deeper and richer set of information than would be possible with devices that are not well coupled with the skin. And that’s just the beginning of the rich range of accurate measurements relevant to physiological health that are possible when you are softly and intimately integrated onto the skin.”

The researchers hope that their sophisticated, integrated sensing systems could not only monitor health but also could help identify problems before the patient may be aware. For example, according to Rogers, data analysis could detect motions associated with Parkinson’s disease at its onset.

“The application of stretchable electronics to medicine has a lot of potential,” Huang said. “If we can continuously monitor our health with a comfortable, small device that attaches to our skin, it could be possible to catch health conditions before experiencing pain, discomfort and illness.”

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

Soft Microfluidic Assemblies of Sensors, Circuits, and Radios for the Skin by Sheng Xu, Yihui Zhang, Lin Jia, Kyle E. Mathewson, Kyung-In Jang, Jeonghyun Kim, Haoran Fu, Xian Huang, Pranav Chava, Renhan Wang, Sanat Bhole, Lizhe Wang, Yoon Joo Na, Yue Guan, Matthew Flavin, Zheshen Han, Yonggang Huang, & John A. Rogers. Science 4 April 2014: Vol. 344 no. 6179 pp. 70-74 DOI: 10.1126/science.1250169

This paper is behind a paywall.

Storing isotopes in nanocontainers for safer radiation therapy

While it can be effective, radiation therapy is known to be destructive  for cancerous cells and healthy cells. Researchers at Kansas State University and their colleagues in other institutions have devised a new technique that contains the isotopes so they reach the cancerous cells only. From an April 2, 2014 news item in ScienceDaily,

Researchers have discovered that microscopic “bubbles” developed at Kansas State University are safe and effective storage lockers for harmful isotopes that emit ionizing radiation for treating tumors.

The findings can benefit patient health and advance radiation therapy used to treat cancer and other diseases, said John M. Tomich, a professor of biochemistry and molecular biophysics who is affiliated with the university’s Johnson Cancer Research Center.

Tomich conducted the study with Ekaterina Dadachova, a radiochemistry specialist at Albert Einstein College of Medicine in New York, along with researchers from his group at Kansas State University, the University of Kansas, Jikei University School of Medicine in Japan and the Institute for Transuranium Elements in Germany. They recently published their findings in the study “Branched Amphiphilic Peptide Capsules: Cellular Uptake and Retention of Encapsulated Solutes,” which appears in the scientific journal Biochimica et Biophysica Acta.

The study looks at the ability of nontoxic molecules to store and deliver potentially harmful alpha emitting radioisotopes — one of the most effective forms of radiation therapy.

An April 2, 2014 Kansas State University news release (also on EurekAlert), which originated the news item, provides more details about this research that in some ways dates from 2012,

The study looks at the ability of nontoxic molecules to store and deliver potentially harmful alpha emitting radioisotopes — one of the most effective forms of radiation therapy.

In 2012, Tomich and his research lab team combined two related sequences of amino acids to form a very small, hollow nanocapsule similar to a bubble.

“We found that the two sequences come together to form a thin membrane that assembled into little spheres, which we call capsules,” Tomich said. “While other vesicles have been created from lipids, most are much less stable and break down. Ours are like stones, though. They’re incredibly stable and are not destroyed by cells in the body.”

The ability of the capsules to stay intact with the isotope inside and remain undetected by the body’s clearance systems prompted Tomich to investigate using the capsules as unbreakable storage containers that can be used for biomedical research, particularly in radiation therapies.

“The problem with current alpha-particle radiation therapies used to treat cancer is that they lead to the release of nontargeted radioactive daughter ions into the body,” Tomich said. “Radioactive atoms break down to form new atoms, called daughter ions, with the release of some form of energy or energetic particles. Alpha emitters give off an energetic particle that comes off at nearly the speed of light.”

These particles are like a car careening on ice, Tomich said. They are very powerful but can only travel a short distance. On collision, the alpha particle destroys DNA and whatever vital cellular components are in its path. Similarly, the daughter ions recoil with high energy on ejection of the alpha particle — similar to how a gun recoils as it is fired. The daughter ions have enough energy to escape the targeting and containment molecules that currently are in use.

“Once freed, the daughter isotopes can end up in places you don’t want them, like bone marrow, which can then lead to leukemia and new challenges,” Tomich said. “We don’t want any stray isotopes because they can harm the body. The trick is to get the radioactive isotopes into and contained in just diseases cells where they can work their magic.”

The radioactive compound that the team works with is 225Actinium, which on decay releases four alpha particles and numerous daughter ions.

Tomich and Dadachova tested the retention and biodistribution of alpha-emitting particles trapped inside the peptide capsules in cells. The capsules readily enter cells. Once inside, they migrate to a position alongside the nucleus, where the DNA is.

Tomich and Dadachova found that as the alpha particle-emitting isotopes decayed, the recoiled daughter ion collides with the capsule walls and essentially bounces off them and remains trapped inside the capsule. This completely blocked the release of the daughter ions, which prevented uptake in certain nontarget tissues and protected the subject from harmful radiation that would have otherwise have been releases into the body.

Tomich said that more studies are needed to add target molecules to the surface of the capsules. He anticipates that this new approach will provide a safer option for treating tumors with radiation therapy by reducing the amount of radioisotope required for killing the cancer cells and reducing the side effects caused by off-target accumulation of the radioisotopes.

“These capsules are easy to make and easy to work with,” Tomich said. “I think we’re just scratching the surface of what we can do with them to improve human health and nanomaterials.”

I hope this new technique proves effective and travels soon from the laboratory to clinical practice in the foreseeable future.

In the meantime, here’s a link to and a citation for the paper,

Branched amphiphilic peptide capsules: Cellular uptake and retention of encapsulated solutes by Pinakin Sukthankar, L. Adriana Avila, Susan K. Whitaker, Takeo Iwamoto, Alfred Morgenstern, Christos Apostolidis, Ke Liu, Robert P. Hanzlik, Ekaterina Dadachova, and John M. Tomich. Biochimica et Biophysica Acta (BBA) – Biomembranes (Biochim Biophys Acta) 2014 Feb 22. pii: S0005-2736(14)00069-8. doi: 10.1016/j.bbamem.2014.02.005. Available online 22 February 2014

This paper is behind a paywall.

Canadian government funding announced for nanotechnology research in Saskatchewan and Alberta

Canada’s Western Economic Diversification and Canada Research Chairs (CRC) programmes both made nanotechnology funding announcements late last week on March 28, 2014.

From a March 28, 2014 news item on CJME radio online,

Funding for nanotechnology was announced at the University of Saskatchewan (U of S) on Friday [March 28, 2014].

Researchers will work on developing nanostructured coatings for parts of artificial joints and even mining equipment.

The $183,946 investment from the Western Economic Diversification Canada will go towards purchasing tailor-made equipment that will help apply the coating.

A March 29, 2014 article by Scott Larson for the Leader-Post provides more details,

In the near future when someone has a hip replacement, the new joint might actually last a lifetime thanks to cutting edge nanotechnology research being done by Qiaoqin Yang and her team. Yang, Canada Research Chair in nanoengineering coating technologies and professor of mechanical engineering at the University of Saskatchewan, has received $183,946 from Western Economic Diversification (WD) to purchase specially made equipment for nanotechnology research.

The equipment will help in developing and testing nanostructured coatings to increase the durability of hard-to-reach industrial and medical components.

“The diamond-based coating is biocompatible and has high wear resistance,” Yang said of the coating material.

There will be four industry-specific coating prototypes tested for projects such as solar energy systems, artificial joints, and mining and oilsands equipment.

Yang said artificial joints usually only last 10-20 years.

I have written about hip and knee replacements and issues with the materials most recently in a Feb. 5, 2013 posting.

As for the CRC announcement about the University of Alberta, here’s more from the March 28, 2014 article by Catherine Griwkowsky for the Edmonton Sun,

The Canadian Research Chairs funding announcement means 11 chair appointments, renewals and tier advancements, part of the 100 faculty who are chair holders at the university.

Carlo Montemagno, Canada Research Chair in Intelligent Nanosystems, said the funding will usher in the next generation in nanotechnology.

“It’s not just the money, it’s the recognition and the visibility that comes with the title,” Montemagno said. “That provides an opportunity for me to be more effective recruiting talent into my laboratory.”

He said the chair position at the University of Alberta allows him to go after riskier projects with a higher impact.

“It provides a nucleating force that allows us to gravitationally pull in talent and resources to position ourselves as global leaders,” Montemagno said.

Previously, he had worked at Cornell University, department head at University of California Los Angeles and dean of engineering at the University of Cincinnati.

Minister of State for Science and Technology Ed Holder said the $88 million will help with Canada’s economic prosperity and will attract more researchers to the country from around the world. …

“I think it’s a huge compliment to what the government of Canada is doing in terms of research and I think it’s a great, great credit to those Canadians who say I can do the best and the greatest research right here in Canada.

He said the success is attracting Canadians back.

Holder, who took over as science boss just over a week ago, said the government has received acknowledgment from granting councils. …

Holder said the proposed budget has an additional $1.5 billion in new money in the budget for research.

Upcoming research projects from the National Institute for Nanotechnology at the University of Alberta:

Artificially engineered system that incorporates the process of photosynthesis in a non-living thing with living elements to convert CO2 emissions to a sellable commodity like rare earth and precious metals.
Extracting minerals and chemicals in waste treatment such as tailings ponds, to clean up polluted water and take out valuable resources.
Cleaning and purifying water with an engineered variant of a molecule 100 times more efficient than current technology, opening land for agricultural development, or industrial plants.

Montemagno has an intriguing turn of phrase “a nucleating force that allows us to gravitationally pull in talent and resources” which I think could be summed up as “money lets us buy what we want with regard to researchers and equipment.” (I first mentioned Montegmagno in a Nov. 19, 2013 post about Alberta’s nanotechnology-focused Ingenuity Lab which he heads.) Holder’s comments are ‘on message’ as they say these days or, as old-timers would say, his comments follow the government’s script.

The listing of the National Institute of Nanotechnology (NINT) projects in Griwkowsky’s article seems a bit enigmatic since there’s no explanation offered as to why these are being included in the newspaper article. The confusion can be cleared up by reading the March 28, 2014 University of Alberta news release,

“Our work is about harnessing the power of ‘n’—nature, nanotechnology and networks,” said Montemagno, one of 11 U of A faculty members who received CRC appointments, renewals or tier advancements. “We use living systems in nature as the inspiration; we use nanotechnology, the ability to manipulate matter at its smallest scale; and we build systems in the understanding that we have to make these small elements work together in complex networks.”

The physical home of this work is Ingenuity Lab, a collaboration between the U of A, the National Institute for Nanotechnology and Alberta Innovates – Technology Futures. Montemagno is the director, and he has assembled a team of top scientists with backgrounds in biochemistry, organic chemistry, neurobiology, molecular biology, physics, computer science, engineering and material science.

Turning CO2 in something valuable

Reducing greenhouse gases is one of the challenges his team is working to address, by capturing carbon dioxide emissions and converting them into high-value chemicals.

Montemagno said the process involves mimicking photosynthesis, using engineered molecules to create a structure that metabolizes CO2. Unlike fermentation and other processes used to convert chemicals, this method is far more energy-efficient, he said.

“You make something that has the same sort of features that are associated with a living process that you want to emulate.”

In another project, Montemagno’s team has turned to cells, viruses and bacteria and how they identify chemicals to react to their environment, with the aim of developing “an exquisite molecular recognition technology” that can find rare precious metals in dilute quantities for extraction. This type of bio-mining is being explored to transform waste from a copper mine into a valuable product, and ultimately could benefit oilsands operations as well.

“The idea is converting waste into a resource and doing it in a way in which you provide more economic opportunity while you’re being a stronger steward of our natural resources.”

Congratulations to the University of Saskatchewan and the University of Alberta!

(A University of British Columbia CRC founding announcement was mentioned in my March 31, 2014 posting about Ed Holder, the new Minister of State (Science and Technology).

Bone goo

Most of us think of our bones as being solid matter and in the light of some new research at the University of Cambridge, it seems that we (including scientists and doctors) have not entirely understood the true nature of bone matter. From a March 24, 2014 University of Cambridge news release (also on EurekAlert),

Latest research shows that the chemical citrate – a by-product of natural cell metabolism – is mixed with water to create a viscous fluid that is trapped between the nano-scale crystals that form our bones.

This fluid allows enough movement, or ‘slip’, between these crystals so that bones are flexible, and don’t shatter under pressure. It is the inbuilt shock absorber in bone that, until now, was unknown.

If citrate leaks out, the crystals – made of calcium phosphate – fuse together into bigger and bigger clumps that become inflexible, increasingly brittle and more likely to shatter. This could be the root cause of osteoporosis.

The team from Cambridge’s Department of Chemistry used a combination of NMR spectroscopy, X-ray diffraction, imaging and high-level molecular modelling to reveal the citrate layers in bone.

They say that this is the start of what needs to be an entire shift in focus for studying the cause of brittle bone diseases like osteoporosis, and bone pathologies in general. The study is published today [March 24, 2014] in the journal Proceedings of the National Academy of Sciences.

“Bone mineral was thought to be closely related to this substance called hydroxyapatite. But what we’ve shown is that a large part of bone mineral – possibly as much as half of it in fact – is made up of this goo, where citrate is binding like a gel between mineral crystals,” said Dr Melinda Duer, who led the study.

“This nano-scopic layering of citrate fluid and mineral crystals in bone means that the crystals stay in flat, plate-like shapes that have the facility to slide with respect to each other. Without citrate, all crystals in bone mineral would collapse together, become one big crystal and shatter.

“It’s this layered structure that’s been missing from our knowledge, and we can now see that without it you’re stuffed.”

I appreciate the lively quotes (“… without it you’re stuffed”) and the description which follows,

Duer compares it to two panes of glass with water in the middle, which stick together but are able to slide: “it’s the same thing in these flat bone crystals. But you’ve got to have something that keeps the water there, stops it from drying out and stops the plates from either flying apart or sticking fast together. We now know that thing is citrate.”

Citrate is a ‘spidery’ molecule with four arms, all of which can bond easily to calcium – which bone is packed with, explains Duer. This means that citrate can hold the mineral crystals together at the same time as preventing them from fusing, while trapping the water that allows for the slippery movement which provides bone flexibility. “Without citrate, water would just flow straight through these gaps,” she said.

The body actually delivers bone calcium wrapped in citrate, to prevent it fusing with phosphate and forming large solid – and brittle – mineral crystals in the wrong places. Bone tissue has a protein mesh with holes where the calcium is deposited. In healthy tissue, the holes are very small, so that when the calcium is deposited, the citrate that comes with it can’t escape and is trapped between crystals – creating the flexible layers of fluid and bone plates.

As people age or suffer repeated bone trauma, the protein mesh isn’t repaired so well by the cells that try to replace damaged tissue, but often end up chewing away tissue faster than it can be re-deposited. This causes progressively larger holes in the protein mesh, citrate fluid escapes and crystals fuse together.

What happens then is pure chemistry, says Duer, with little biological control.

The body instigates a form of biological control through the tiny holes in the protein mesh that trap the citrate fluid, along with other molecules that normally control the deposit of mineral. These small spaces force the molecules to be involved with the forming mineral, controlling the process. But if you haven’t got the confined space the chemical reactions spiral out of control.

“In the bigger holes in damaged tissue, pure chemistry takes over. Pretty much the moment calcium and phosphate touch, they form a solid. You end up with these expanding clumps of brittle crystal, with water and citrate relegated to the outside of them,” she said.

“In terms of chemistry, that solid clump of mineral is the most stable structure. Biomechanically, however, it’s hopeless – as soon as you stand on it, it shatters. If we want to cure osteoporosis, we need to figure out how to stop the bigger holes forming in the protein matrix.”

The study is the first in a series of findings, with other studies from the team’s work on bone chemistry expected to come out later in the year.

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

Citrate bridges between mineral platelets in bone by Erika Davies, Karin H. Müller, Wai Ching Wong, Chris J. Pickard, David G. Reid, Jeremy N. Skepper, and Melinda J. Duer. PNAS doi: 10.1073/pnas.1315080111

This paper is made available through the PNAS open access option.