Category Archives: medicine

Predicting drug side effects with guts-on-a-chip

It’s been a while since I’ve featured a story about a technology that could drastically reduce (or even eliminate) animal testing. Researchers in the Netherlands have announced some guts-on-a-chip research that may do just that. From an Aug. 22, 2017 news item on ScienceDaily,

Research conducted at Leiden has established that guts-on-chips respond in the same way to aspirin as real human organs do. This is a sign that these model organs are good predictors of the effect of medical drugs on the human body.

A method to test medical drugs for efficacy and potential side-effects, but then much cheaper and using the fewest possible lab animals: this is likely to be possible in future thanks to organs-on-chips, miniature model organs on microchips. In these model organs, which are equipped with human organ cells and microfluidic channels, researchers and pharmacists can mimic the working of an organ.

An Aug. 17, 2017 University of Leiden (Universiteit Leiden) press release, which originated the news item, provides more detail,

Leiden researchers, their spin-off company Mimetas and pharmaceutical company Roche have now shown that one type of organ chip experiences the same side-effects from the drug aspirin as the same organ in the human body. This is good news, because it is a sign that these miniature model organs are good predictors of the effect of medical drugs in the human body.

Aspirin

The researchers exposed 357 guts-on-chips for a significant period to the substance acetylsalicylic acid, better known as the analgesic aspirin. It has been known for a long time already that this substance can lead to gastrointestinal perforation, a complication that can be fatal if untreated. ‘We saw exactly the same side-effects occur in our guts-on-chips,’ says Professor of Analytical Biosciences Thomas Hankemeier. ‘In our model guts the gut wall also became more permeable after the drug had been administered.’

Effectiveness of candidate drugs

According to Hankemeier, the research shows that organs-on-chips are suited to testing a medical drug for efficacy and side-effects. This is good news for pharmacists, because the model organs make it easier for them to evaluate whether candidate drugs are effective or harmful. Many substances would be excluded from futher research before a drug entered the lab animal phase. This would help reduce the cost of drug production and mean less animal testing.

Diagnosing diseases

Organs-on-chips have taken off in recent years. They will be increasingly important in the near future, not just in drug development but also in the diagnosis of disease. Leiden researchers are at the forefront of this development. Hankemeier and a number of other groups (Erasmus MC, VUmc, RU Groningen) have been awared a 1.5 million ZonMW grant to research the effect of the body’s micro-organisms in the gut on the development of dementia. Organ-on-a-chip technology will play an important role here. Mimetas is the first company in the world to produce and sell organ chips on a large scale.

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

Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes by Sebastiaan J. Trietsch, Elena Naumovska, Dorota Kurek, Meily C. Setyawati, Marianne K. Vormann, Karlijn J. Wilschut, Henriëtte L. Lanz, Arnaud Nicolas, Chee Ping Ng, Jos Joore, Stefan Kustermann, Adrian Roth, Thomas Hankemeier, Annie Moisan, & Paul Vulto. Nature Communications 8, Article number: 262 (2017) doi:10.1038/s41467-017-00259-3 Published online: 15 August 2017

This paper is open access.

You can find Mimetas here.

Nanomesh for hypoallergenic wearable electronics

It stands to reason that sensors and monitoring devices held against the skin (wearable electronics) for long periods of time could provoke an allergic reaction. Scientists at the University of Tokyo have devised a possible solution according to a July 17, 2017 news item on ScienceDaily,

A hypoallergenic electronic sensor can be worn on the skin continuously for a week without discomfort, and is so light and thin that users forget they even have it on, says a Japanese group of scientists. The elastic electrode constructed of breathable nanoscale meshes holds promise for the development of noninvasive e-skin devices that can monitor a person’s health continuously over a long period.

Here’s an image illustrating the hypoallergenic electronics,

Caption: The electric current from a flexible battery placed near the knuckle flows through the conductor and powers the LED just below the fingernail. Credit: 2017 Someya Laboratory.

A University of Tokyo press release on EurekAlert, which originated the news item, expands on the theme,

Wearable electronics that monitor heart rate and other vital health signals have made headway in recent years, with next-generation gadgets employing lightweight, highly elastic materials attached directly onto the skin for more sensitive, precise measurements. However, although the ultrathin films and rubber sheets used in these devices adhere and conform well to the skin, their lack of breathability is deemed unsafe for long-term use: dermatological tests show the fine, stretchable materials prevent sweating and block airflow around the skin, causing irritation and inflammation, which ultimately could lead to lasting physiological and psychological effects.

“We learned that devices that can be worn for a week or longer for continuous monitoring were needed for practical use in medical and sports applications,” says Professor Takao Someya at the University of Tokyo’s Graduate School of Engineering whose research group had previously developed an on-skin patch that measured oxygen in blood.

In the current research, the group developed an electrode constructed from nanoscale meshes containing a water-soluble polymer, polyvinyl alcohol (PVA), and a gold layer–materials considered safe and biologically compatible with the body. The device can be applied by spraying a tiny amount of water, which dissolves the PVA nanofibers and allows it to stick easily to the skin–it conformed seamlessly to curvilinear surfaces of human skin, such as sweat pores and the ridges of an index finger’s fingerprint pattern.

The researchers next conducted a skin patch test on 20 subjects and detected no inflammation on the participants’ skin after they had worn the device for a week. The group also evaluated the permeability, with water vapor, of the nanomesh conductor–along with those of other substrates like ultrathin plastic foil and a thin rubber sheet–and found that its porous mesh structure exhibited superior gas permeability compared to that of the other materials.

Furthermore, the scientists proved the device’s mechanical durability through repeated bending and stretching, exceeding 10,000 times, of a conductor attached on the forefinger; they also established its reliability as an electrode for electromyogram recordings when its readings of the electrical activity of muscles were comparable to those obtained through conventional gel electrodes.

“It will become possible to monitor patients’ vital signs without causing any stress or discomfort,” says Someya about the future implications of the team’s research. In addition to nursing care and medical applications, the new device promises to enable continuous, precise monitoring of athletes’ physiological signals and bodily motion without impeding their training or performance.

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

Inflammation-free, gas-permeable, lightweight, stretchable on-skin electronics with nanomeshes by Akihito Miyamoto, Sungwon Lee, Nawalage Florence Cooray, Sunghoon Lee, Mami Mori, Naoji Matsuhisa, Hanbit Jin, Leona Yoda, Tomoyuki Yokota, Akira Itoh, Masaki Sekino, Hiroshi Kawasaki, Tamotsu Ebihara, Masayuki Amagai, & Takao Someya. Nature Nanotechnology (2017) doi:10.1038/nnano.2017.125 Published online 17 July 2017

This paper is behind a paywall.

Sugar in your bones might be better for you than you think

These days sugar is often  viewed as leading to health problems but there is an instance where it may be useful—bone regeneration. From a June 19, 2017 news item on Nanowerk (Note: A link has been removed),

There hasn’t been a gold standard for how orthopaedic spine surgeons promote new bone growth in patients, but now Northwestern University scientists have designed a bioactive nanomaterial that is so good at stimulating bone regeneration it could become the method surgeons prefer.

While studied in an animal model of spinal fusion, the method for promoting new bone growth could translate readily to humans, the researchers say, where an aging but active population in the U.S. is increasingly receiving this surgery to treat pain due to disc degeneration, trauma and other back problems. Many other procedures could benefit from the nanomaterial, ranging from repair of bone trauma to treatment of bone cancer to bone growth for dental implants.

“Regenerative medicine can improve quality of life by offering less invasive and more successful approaches to promoting bone growth,” said Samuel I. Stupp, who developed the new nanomaterial. “Our method is very flexible and could be adapted for the regeneration of other tissues, including muscle, tendons and cartilage.”

Stupp is director of Northwestern’s Simpson Querrey Institute for BioNanotechnology and the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering.

For the interdisciplinary study, Stupp collaborated with Dr. Wellington K. Hsu, associate professor of orthopaedic surgery, and Erin L. K. Hsu, research assistant professor of orthopaedic surgery, both at Northwestern University Feinberg School of Medicine. The husband-and-wife team is working to improve clinically employed methods of bone regeneration.

Sugar molecules on the surface of the nanomaterial provide its regenerative power. The researchers studied in vivo the effect of the “sugar-coated” nanomaterial on the activity of a clinically used growth factor, called bone morphogenetic protein 2 (BMP-2). They found the amount of protein needed for a successful spinal fusion was reduced to an unprecedented level: 100 times less of BMP-2 was needed. This is very good news, because the growth factor is known to cause dangerous side effects when used in the amounts required to regenerate high-quality bone, and it is expensive as well.

A June 19, 2017 Northwestern University news release by Megan Fellman, which originated the news item, tells the rest of the story,

Stupp’s biodegradable nanomaterial functions as an artificial extracellular matrix, which mimics what cells in the body usually interact with in their surroundings. BMP-2 activates certain types of stem cells and signals them to become bone cells. The Northwestern matrix, which consists of tiny nanoscale filaments, binds the protein by molecular design in the way that natural sugars bind it in our bodies and then slowly releases it when needed, instead of in one early burst, which can contribute to side effects.

To create the nanostructures, the research team led by Stupp synthesized a specific type of sugar that closely resembles those used by nature to activate BMP-2 when cell signaling is necessary for bone growth. Rapidly moving flexible sugar molecules displayed on the surface of the nanostructures “grab” the protein in a specific spot that is precisely the same one used in biological systems when it is time to deploy the signal. This potentiates the bone-growing signals to a surprising level that surpasses even the naturally occurring sugar polymers in our bodies.

In nature, the sugar polymers are known as sulfated polysaccharides, which have super-complex structures impossible to synthesize at the present time with chemical techniques. Hundreds of proteins in biological systems are known to have specific domains to bind these sugar polymers in order to activate signals. Such proteins include those involved in the growth of blood vessels, cell recruitment and cell proliferation, all very important biologically in tissue regeneration. Therefore, the approach of the Stupp team could be extended to other regenerative targets.

Spinal fusion is a common surgical procedure that joins adjacent vertebra together using a bone graft and growth factors to promote new bone growth, which stabilizes the spine. The bone used in the graft can come from the patient’s pelvis — an invasive procedure — or from a bone bank.

“There is a real need for a clinically efficacious, safe and cost-effective way to form bone,” said Wellington Hsu, a spine surgeon. “The success of this nanomaterial makes me excited that every spine surgeon may one day subscribe to this method for bone graft. Right now, if you poll an audience of spine surgeons, you will get 15 to 20 different answers on what they use for bone graft. We need to standardize choice and improve patient outcomes.”

In the in vivo portion of the study, the nanomaterial was delivered to the spine using a collagen sponge. This is the way surgeons currently deliver BMP-2 clinically to promote bone growth.

The Northwestern research team plans to seek approval from the Food and Drug Administration to launch a clinical trial studying the nanomaterial for bone regeneration in humans.

“We surgeons are looking for optimal carriers for growth factors and cells,” Wellington Hsu said. “With its numerous binding sites, the long filaments of this new nanomaterial is more successful than existing carriers in releasing the growth factor when the body is ready. Timing is critical for success in bone regeneration.”

In the new nanomaterial, the sugars are displayed in a scaffold built from self-assembling molecules known as peptide amphiphiles, first developed by Stupp 15 years ago. These synthetic molecules have been essential in his work on regenerative medicine.

“We focused on bone regeneration to demonstrate the power of the sugar nanostructure to provide a big signaling boost,” Stupp said. “With small design changes, the method could be used with other growth factors for the regeneration of all kinds of tissues. One day we may be able to fully do away with the use of growth factors made by recombinant biotechnology and instead empower the natural ones in our bodies.”

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

Sulfated glycopeptide nanostructures for multipotent protein activation by Sungsoo S. Lee, Timmy Fyrner, Feng Chen, Zaida Álvarez, Eduard Sleep, Danielle S. Chun, Joseph A. Weiner, Ralph W. Cook, Ryan D. Freshman, Michael S. Schallmo, Karina M. Katchko, Andrew D. Schneider, Justin T. Smith, Chawon Yun, Gurmit Singh, Sohaib Z. Hashmi, Mark T. McClendon, Zhilin Yu, Stuart R. Stock, Wellington K. Hsu, Erin L. Hsu, & Samuel I. Stupp. Nature Nanotechnology 12, 821–829 (2017) doi:10.1038/nnano.2017.109 Published online 19 June 2017

This paper is behind a paywall.

‘Origami organs’ for tissue engineering

This is a different approach to tissue engineering and its the consequence of a serendipitous accident.  From an Aug. 7, 2017 Northwestern University news release (also on EurekAlert),

Northwestern Medicine scientists and engineers have invented a range of bioactive “tissue papers” made of materials derived from organs that are thin and flexible enough to even fold into an origami bird. The new biomaterials can potentially be used to support natural hormone production in young cancer patients and aid wound healing.

The tissue papers are made from structural proteins excreted by cells that give organs their form and structure. The proteins are combined with a polymer to make the material pliable.

In the study, individual types of tissue papers were made from ovarian, uterine, kidney, liver, muscle or heart proteins obtained by processing pig and cow organs. Each tissue paper had specific cellular properties of the organ from which it was made.

The article describing the tissue paper and its function will be published Aug. 7 in the journal Advanced Functional Materials.

“This new class of biomaterials has potential for tissue engineering and regenerative medicine as well as drug discovery and therapeutics,” corresponding author Ramille Shah said. “It’s versatile and surgically friendly.”

Shah is an assistant professor of surgery at the Feinberg School of Medicine and an assistant professor of materials science and engineering at McCormick School of Engineering. She also is a member of the Simpson Querrey Institute for BioNanotechnology.

For wound healing, Shah thinks the tissue paper could provide support and the cell signaling needed to help regenerate tissue to prevent scarring and accelerate healing.

The tissue papers are made from natural organs or tissues. The cells are removed, leaving the natural structural proteins – known as the extracellular matrix – that then are dried into a powder and processed into the tissue papers. Each type of paper contains residual biochemicals and protein architecture from its original organ that can stimulate cells to behave in a certain way.

In the lab of reproductive scientist Teresa Woodruff, the tissue paper made from a bovine ovary was used to grow ovarian follicles when they were cultured in vitro. The follicles (eggs and hormone-producing cells) grown on the tissue paper produced hormones necessary for proper function and maturation.

“This could provide another option to restore normal hormone function to young cancer patients who often lose their hormone function as a result of chemotherapy and radiation,” Woodruff, a study coauthor, said.

A strip of the ovarian paper with the follicles could be implanted under the arm to restore hormone production for cancer patients or even women in menopause.

Woodruff is the director of the Oncofertility Consortium and the Thomas J. Watkins Memorial Professor of Obstetrics and Gynecology at Feinberg.

In addition, the tissue paper made from various organs separately supported the growth of adult human stem cells. Scientists placed human bone marrow stem cells on the tissue paper, and all the stem cells attached and multiplied over four weeks.

“That’s a good sign that the paper supports human stem cell growth,” said first author Adam Jakus, who developed the tissue papers. “It’s an indicator that once we start using tissue paper in animal models it will be biocompatible.”

The tissue papers feel and behave much like standard office paper when they are dry, Jakus said. Jakus simply stacks them in a refrigerator or a freezer. He even playfully folded them into an origami bird.

“Even when wet, the tissue papers maintain their mechanical properties and can be rolled, folded, cut and sutured to tissue,” he said.

Jakus was a Hartwell postdoctoral fellow in Shah’s lab for the study and is now chief technology officer and cofounder of the startup company Dimension Inx, LLC, which was also cofounded by Shah. The company will develop, produce and sell 3-D printable materials primarily for medical applications. The Intellectual Property is owned by Northwestern University and will be licensed to Dimension Inx.

An Accidental Spill Sparked Invention

An accidental spill of 3-D printing ink in Shah’s lab by Jakus sparked the invention of the tissue paper. Jakus was attempting to make a 3-D printable ovary ink similar to the other 3-D printable materials he previously developed to repair and regenerate bone, muscle and nerve tissue. When he went to wipe up the spill, the ovary ink had already formed a dry sheet.

“When I tried to pick it up, it felt strong,” Jakus said. “I knew right then I could make large amounts of bioactive materials from other organs. The light bulb went on in my head. I could do this with other organs.”

“It is really amazing that meat and animal by-products like a kidney, liver, heart and uterus can be transformed into paper-like biomaterials that can potentially regenerate and restore function to tissues and organs,” Jakus said. “I’ll never look at a steak or pork tenderloin the same way again.”

For those who like their news in a video,

As someone who once made baklava, that does not look like filo pastry, where an individual sheet is quite thin and rips easily. Enough said.

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

“Tissue Papers” from Organ-Specific Decellularized Extracellular Matrices by Adam E. Jakus, Monica M. Laronda, Alexandra S. Rashedi, Christina M. Robinson, Chris Lee, Sumanas W. Jordan, Kyle E. Orwig, Teresa K. Woodruff, and Ramille N. Shah. Advnaced Functional Materials DOI: 10.1002/adfm.201700992 Version of Record online: 7 AUG 2017

© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Ceria-zirconia nanoparticles for sepsis treatment

South Korean researchers are looking at a new way of dealing with infections (sepsis) according to a July 6, 2017 news item on phys.org,

During sepsis, cells are swamped with reactive oxygen species generated in an aberrant response of the immune system to a local infection. If this fatal inflammatory path could be interfered, new treatment schemes could be developed. Now, Korean scientists report in the journal Angewandte Chemie that zirconia-doped ceria nanoparticles act as effective scavengers of these oxygen radicals, promoting a greatly enhanced surviving rate in sepsis model organisms.

A July 6, 2017 Wiley (Publishers) press release, which originated the news item, provides more detail,

Sepsis proceeds as a vicious cycle of inflammatory reactions of the immune system to a local infection. Fatal consequences can be falling blood pressure and the collapse of organ function. As resistance against antibiotics is growing, scientists turn to the inflammatory pathway as an alternative target for new treatment strategies. Taeghwan Heyon from Seoul National University, Seung-Hoon Lee at Seoul National University Hospital, South Korea, and collaborators explore ceria nanoparticles for their ability to scavenge reactive oxygen species, which play a key role in the inflammatory process. By quickly converting between two oxidation states, the cerium ion can quench typical oxygen radical species like the superoxide anion, the hydroxyl radical anion, or even hydrogen peroxide. But in the living cell, this can only happen if two conditions are met.

The first condition is the size and nature of the particles. Small, two-nanometer-sized particles were coated by a hydrophilic shell of poly(ethylene glycol)-connected phospholipids to make them soluble so that they can enter the cell and remain there. Second, the cerium ion responsible for the quenching (Ce3+) should be accessible on the surface of the nanoparticles, and it must be regenerated after the reactions. Here, the scientists found out that a certain amount of zirconium ions in the structure helped, because “the Zr4+ ions control the Ce3+-to-Ce4+ ratio as well as the rate of conversion between the two oxidation states,” they argued.

The prepared nanoparticles were then tested for their ability to detoxify reactive oxygen species, not only in the test tube, but also in live animal models. The results were clear, as the authors stated: “A single dose of ceria-zirconia nanoparticles successfully attenuated the vicious cycle of inflammatory responses in two sepsis models.” The nanoparticles accumulated in organs where severe immune responses occurred, and they were successful in the eradication of reactive oxygen species, as evidenced with fluorescence microscopy and several other techniques. And importantly, the treated mice and rats had a far higher survival rate.

This work demonstrates that other approaches in sepsis treatment than killing bacteria with antibiotics are possible. Targeting the inflammatory signal pathways in macrophages is a very promising option, and the authors have shown that effective scavenging of reactive oxygen species and stopping inflammation is possible with a suitably designed chemical system like this cerium ion redox system provided by nanoparticles.

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

Ceria–Zirconia Nanoparticles as an Enhanced Multi-Antioxidant for Sepsis Treatment by Min Soh, Dr. Dong-Wan Kang, Dr. Han-Gil Jeong, Dr. Dokyoon Kim, Dr. Do Yeon Kim, Dr. Wookjin Yang, Changyeong Song, Seungmin Baik, In-Young Choi, Seul-Ki Ki, Hyek Jin Kwon, Dr. Taeho Kim, Prof. Dr. Chi Kyung Kim, Prof. Dr. Seung-Hoon Lee, and Prof. Dr. Taeghwan Hyeon. Angewandte Chemie DOI: 10.1002/anie.201704904 Version of Record online: 5 JUL 2017

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Training drugs

This summarizes some of what’s happening in nanomedicine and provides a plug (boost) for the  University of Cambridge’s nanotechnology programmes (from a June 26, 2017 news item on Nanowerk),

Nanotechnology is creating new opportunities for fighting disease – from delivering drugs in smart packaging to nanobots powered by the world’s tiniest engines.

Chemotherapy benefits a great many patients but the side effects can be brutal.
When a patient is injected with an anti-cancer drug, the idea is that the molecules will seek out and destroy rogue tumour cells. However, relatively large amounts need to be administered to reach the target in high enough concentrations to be effective. As a result of this high drug concentration, healthy cells may be killed as well as cancer cells, leaving many patients weak, nauseated and vulnerable to infection.

One way that researchers are attempting to improve the safety and efficacy of drugs is to use a relatively new area of research known as nanothrapeutics to target drug delivery just to the cells that need it.

Professor Sir Mark Welland is Head of the Electrical Engineering Division at Cambridge. In recent years, his research has focused on nanotherapeutics, working in collaboration with clinicians and industry to develop better, safer drugs. He and his colleagues don’t design new drugs; instead, they design and build smart packaging for existing drugs.

The University of Cambridge has produced a video interview (referencing a 1966 movie ‘Fantastic Voyage‘ in its title)  with Sir Mark Welland,

A June 23, 2017 University of Cambridge press release, which originated the news item, delves further into the topic of nanotherapeutics (nanomedicine) and nanomachines,

Nanotherapeutics come in many different configurations, but the easiest way to think about them is as small, benign particles filled with a drug. They can be injected in the same way as a normal drug, and are carried through the bloodstream to the target organ, tissue or cell. At this point, a change in the local environment, such as pH, or the use of light or ultrasound, causes the nanoparticles to release their cargo.

Nano-sized tools are increasingly being looked at for diagnosis, drug delivery and therapy. “There are a huge number of possibilities right now, and probably more to come, which is why there’s been so much interest,” says Welland. Using clever chemistry and engineering at the nanoscale, drugs can be ‘taught’ to behave like a Trojan horse, or to hold their fire until just the right moment, or to recognise the target they’re looking for.

“We always try to use techniques that can be scaled up – we avoid using expensive chemistries or expensive equipment, and we’ve been reasonably successful in that,” he adds. “By keeping costs down and using scalable techniques, we’ve got a far better chance of making a successful treatment for patients.”

In 2014, he and collaborators demonstrated that gold nanoparticles could be used to ‘smuggle’ chemotherapy drugs into cancer cells in glioblastoma multiforme, the most common and aggressive type of brain cancer in adults, which is notoriously difficult to treat. The team engineered nanostructures containing gold and cisplatin, a conventional chemotherapy drug. A coating on the particles made them attracted to tumour cells from glioblastoma patients, so that the nanostructures bound and were absorbed into the cancer cells.

Once inside, these nanostructures were exposed to radiotherapy. This caused the gold to release electrons that damaged the cancer cell’s DNA and its overall structure, enhancing the impact of the chemotherapy drug. The process was so effective that 20 days later, the cell culture showed no evidence of any revival, suggesting that the tumour cells had been destroyed.

While the technique is still several years away from use in humans, tests have begun in mice. Welland’s group is working with MedImmune, the biologics R&D arm of pharmaceutical company AstraZeneca, to study the stability of drugs and to design ways to deliver them more effectively using nanotechnology.

“One of the great advantages of working with MedImmune is they understand precisely what the requirements are for a drug to be approved. We would shut down lines of research where we thought it was never going to get to the point of approval by the regulators,” says Welland. “It’s important to be pragmatic about it so that only the approaches with the best chance of working in patients are taken forward.”

The researchers are also targeting diseases like tuberculosis (TB). With funding from the Rosetrees Trust, Welland and postdoctoral researcher Dr Íris da luz Batalha are working with Professor Andres Floto in the Department of Medicine to improve the efficacy of TB drugs.

Their solution has been to design and develop nontoxic, biodegradable polymers that can be ‘fused’ with TB drug molecules. As polymer molecules have a long, chain-like shape, drugs can be attached along the length of the polymer backbone, meaning that very large amounts of the drug can be loaded onto each polymer molecule. The polymers are stable in the bloodstream and release the drugs they carry when they reach the target cell. Inside the cell, the pH drops, which causes the polymer to release the drug.

In fact, the polymers worked so well for TB drugs that another of Welland’s postdoctoral researchers, Dr Myriam Ouberaï, has formed a start-up company, Spirea, which is raising funding to develop the polymers for use with oncology drugs. Ouberaï is hoping to establish a collaboration with a pharma company in the next two years.

“Designing these particles, loading them with drugs and making them clever so that they release their cargo in a controlled and precise way: it’s quite a technical challenge,” adds Welland. “The main reason I’m interested in the challenge is I want to see something working in the clinic – I want to see something working in patients.”

Could nanotechnology move beyond therapeutics to a time when nanomachines keep us healthy by patrolling, monitoring and repairing the body?

Nanomachines have long been a dream of scientists and public alike. But working out how to make them move has meant they’ve remained in the realm of science fiction.

But last year, Professor Jeremy Baumberg and colleagues in Cambridge and the University of Bath developed the world’s tiniest engine – just a few billionths of a metre [nanometre] in size. It’s biocompatible, cost-effective to manufacture, fast to respond and energy efficient.

The forces exerted by these ‘ANTs’ (for ‘actuating nano-transducers’) are nearly a hundred times larger than those for any known device, motor or muscle. To make them, tiny charged particles of gold, bound together with a temperature-responsive polymer gel, are heated with a laser. As the polymer coatings expel water from the gel and collapse, a large amount of elastic energy is stored in a fraction of a second. On cooling, the particles spring apart and release energy.

The researchers hope to use this ability of ANTs to produce very large forces relative to their weight to develop three-dimensional machines that swim, have pumps that take on fluid to sense the environment and are small enough to move around our bloodstream.

Working with Cambridge Enterprise, the University’s commercialisation arm, the team in Cambridge’s Nanophotonics Centre hopes to commercialise the technology for microfluidics bio-applications. The work is funded by the Engineering and Physical Sciences Research Council and the European Research Council.

“There’s a revolution happening in personalised healthcare, and for that we need sensors not just on the outside but on the inside,” explains Baumberg, who leads an interdisciplinary Strategic Research Network and Doctoral Training Centre focused on nanoscience and nanotechnology.

“Nanoscience is driving this. We are now building technology that allows us to even imagine these futures.”

I have featured Welland and his work here before and noted his penchant for wanting to insert nanodevices into humans as per this excerpt from an April 30, 2010 posting,
Getting back to the Cambridge University video, do go and watch it on the Nanowerk site. It is fun and very informative and approximately 17 mins. I noticed that they reused part of their Nokia morph animation (last mentioned on this blog here) and offered some thoughts from Professor Mark Welland, the team leader on that project. Interestingly, Welland was talking about yet another possibility. (Sometimes I think nano goes too far!) He was suggesting that we could have chips/devices in our brains that would allow us to think about phoning someone and an immediate connection would be made to that person. Bluntly—no. Just think what would happen if the marketers got access and I don’t even want to think what a person who suffers psychotic breaks (i.e., hearing voices) would do with even more input. Welland starts to talk at the 11 minute mark (I think). For an alternative take on the video and more details, visit Dexter Johnson’s blog, Nanoclast, for this posting. Hint, he likes the idea of a phone in the brain much better than I do.

I’m not sure what could have occasioned this latest press release and related video featuring Welland and nanotherapeutics other than guessing that it was a slow news period.

DNA sunscreen: the longer you wear it, the better it gets due to its sacrificial skin

Using this new sunscreen does mean slathering on salmon sperm, more or lees, (read the Methods section of the academic paper cited later in this post). Considering that you’ve likely eaten (insect parts in chocolate) and slathered on more discomfiting stuff already and this development gives you access to an all natural, highly effective sunscreen, if it ever makes its way out of the laboratory, it might not be so bad. From a July 26, 2017 article by Sarah Knapton for The Telegraph,

Sunscreen made from DNA [deoxyribonucleic acid] which acts like a second skin to prevent sun damage is on the horizon.

Scientists in the US have developed a film from the DNA of salmon which gets better at protecting the skin from ultraviolet light the more it is exposed to the Sun.

It also helps lock in moisture beneath the surface which is usually lost during tanning.

Exciting, yes? A July 27, 2017 Binghamton University news release (also on EurekAlert but dated July 26, 2017) provides more detail,

“Ultraviolet (UV) light can actually damage DNA, and that’s not good for the skin,” said Guy German, assistant professor of biomedical engineering at Binghamton University. “We thought, let’s flip it. What happens instead if we actually used DNA as a sacrificial layer? So instead of damaging DNA within the skin, we damage a layer on top of the skin.”

German and a team of researchers developed thin and optically transparent crystalline DNA films and irradiated them with UV light. They found that the more they exposed the film to UV light, the better the film got at absorbing it.

“If you translate that, it means to me that if you use this as a topical cream or sunscreen, the longer that you stay out on the beach, the better it gets at being a sunscreen,” said German.

As an added bonus, the DNA coatings are also hygroscopic, meaning that skin coated with the DNA films can store and hold water much more than uncoated skin. When applied to human skin, they are capable of slowing water evaporation and keeping the tissue hydrated for extended periods of time.

German intends to see next if these materials might be good as a wound covering for hostile environments where 1) you want to be able to see the wound healing without removing the dressing, 2) you want to protect the wound from the sun and 3) you want to keep the wound in a moist environment, known to promote faster wound healing rates.

“Not only do we think this might have applications for sunscreen and moisturizers directly, but if it’s optically transparent and prevents tissue damage from the sun and it’s good at keeping the skin hydrated, we think this might be potentially exploitable as a wound covering for extreme environments,” he said.

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

Non-ionising UV light increases the optical density of hygroscopic self assembled DNA crystal films by Alexandria E. Gasperini, Susy Sanchez, Amber L. Doiron, Mark Lyles & Guy K. German. Scientific Reports 7, Article number: 6631 (2017) doi:10.1038/s41598-017-06884-8 Published online: 26 July 2017

This paper is open access.

Detecting peanut allergies with nanoparticles

Researchers at Notre Dame University are designing a platform that will make allergy detection easier and more precise according to a June 26, 2017 news item on phys.org,

Researchers have developed a novel platform to more accurately detect and identify the presence and severity of peanut allergies, without directly exposing patients to the allergen, according to a new study published in the journal Scientific Reports.

A team of chemical and biomolecular engineers at the University of Notre Dame designed nanoparticles that mimic natural allergens by displaying each allergic component one at a time on their surfaces. The researchers named the nanoparticles “nanoallergens” and used them to dissect the critical components of major peanut allergy proteins and evaluate the potency of the allergic response using the antibodies present in a blood sample from a patient.

“The goal of this study was to show how nanoallergen technology could be used to provide a clearer and more accurate assessment of the severity of an allergic condition,” said Basar Bilgicer, associate professor of chemical and biomolecular engineering and a member of the Advanced Diagnostics and Therapeutics initiative at Notre Dame. “We are currently working with allergy specialist clinicians for further testing and verification of the diagnostic tool using a larger patient population. Ultimately, our vision is to take this technology and make it available to all people who suffer from food allergies.”

A June 26, 2017 University of Notre Dame news release, which originated the news item, explains the need for better allergy detection,

Food allergies are a growing problem in developing countries and are of particular concern to parents. According to the study, 8 percent of children under the age of 4 have a food allergy. Bilgicer said a need exists for more accurate testing, improved diagnostics and better treatment options.

Current food allergy testing methods carry risks or fail to provide detailed information on the severity of the allergic response. For instance, a test known as the oral food challenge requires exposing a patient to increasing amounts of a suspected allergen. Patients must remain under close observation in clinics with highly trained specialists. The test is stopped only when the patient exhibits an extreme allergic response, such as anaphylactic shock. Doctors then treat the reaction with epinephrine injections, antihistamines and steroids.

The skin prick test, another common diagnostic tool, can indicate whether a patient is allergic to a particular food. However, it provides no detail on the severity of those allergies.

During skin prick testing, doctors place a drop of liquid containing the allergen on the patient’s skin, typically on their back, and then scratch the skin to expose the patient. Skin irritations, such as redness, itching and white bumps, are indications that the patient has an allergy.

“Most of the time, parents of children with food allergies are not inclined to have their child go through such excruciating experiences of a food challenge,” Bilgicer said. “Rather than investigate the severity of the allergy, they respond to it with most extreme caution and complete avoidance of the allergen. Meanwhile, there are cases where the skin prick test might have yielded a positive result for a child, and yet the child can consume a handful of the allergen and demonstrate no signs of any allergic response.”

While the study focused on peanut allergens, Bilgicer said he and his team are working on testing the platform on additional allergens and allergic conditions.

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

Determination of Crucial Immunogenic Epitopes in Major Peanut Allergy Protein, Ara h2, via Novel Nanoallergen Platform by Peter E. Deak, Maura R. Vrabel, Tanyel Kiziltepe & Basar Bilgicer. Scientific Reports 7, Article number: 3981 (2017) doi:10.1038/s41598-017-04268-6 Published online: 21 June 2017

This paper is open access.

Carbon nanotubes to repair nerve fibres (cyborg brains?)

Can cyborg brains be far behind now that researchers are looking at ways to repair nerve fibers with carbon nanotubes (CNTs)? A June 26, 2017 news item on ScienceDaily describes the scheme using carbon nanotubes as a material for repairing nerve fibers,

Carbon nanotubes exhibit interesting characteristics rendering them particularly suited to the construction of special hybrid devices — consisting of biological issue and synthetic material — planned to re-establish connections between nerve cells, for instance at spinal level, lost on account of lesions or trauma. This is the result of a piece of research published on the scientific journal Nanomedicine: Nanotechnology, Biology, and Medicine conducted by a multi-disciplinary team comprising SISSA (International School for Advanced Studies), the University of Trieste, ELETTRA Sincrotrone and two Spanish institutions, Basque Foundation for Science and CIC BiomaGUNE. More specifically, researchers have investigated the possible effects on neurons of the interaction with carbon nanotubes. Scientists have proven that these nanomaterials may regulate the formation of synapses, specialized structures through which the nerve cells communicate, and modulate biological mechanisms, such as the growth of neurons, as part of a self-regulating process. This result, which shows the extent to which the integration between nerve cells and these synthetic structures is stable and efficient, highlights the great potentialities of carbon nanotubes as innovative materials capable of facilitating neuronal regeneration or in order to create a kind of artificial bridge between groups of neurons whose connection has been interrupted. In vivo testing has actually already begun.

The researchers have included a gorgeous image to illustrate their work,

Caption: Scientists have proven that these nanomaterials may regulate the formation of synapses, specialized structures through which the nerve cells communicate, and modulate biological mechanisms, such as the growth of neurons, as part of a self-regulating process. Credit: Pixabay

A June 26, 2017 SISSA press release (also on EurekAlert), which originated the news item, describes the work in more detail while explaining future research needs,

“Interface systems, or, more in general, neuronal prostheses, that enable an effective re-establishment of these connections are under active investigation” explain Laura Ballerini (SISSA) and Maurizio Prato (UniTS-CIC BiomaGUNE), coordinating the research project. “The perfect material to build these neural interfaces does not exist, yet the carbon nanotubes we are working on have already proved to have great potentialities. After all, nanomaterials currently represent our best hope for developing innovative strategies in the treatment of spinal cord injuries”. These nanomaterials are used both as scaffolds, a supportive framework for nerve cells, and as means of interfaces releasing those signals that empower nerve cells to communicate with each other.

Many aspects, however, still need to be addressed. Among them, the impact on neuronal physiology of the integration of these nanometric structures with the cell membrane. “Studying the interaction between these two elements is crucial, as it might also lead to some undesired effects, which we ought to exclude”. Laura Ballerini explains: “If, for example, the mere contact provoked a vertiginous rise in the number of synapses, these materials would be essentially unusable”. “This”, Maurizio Prato adds, “is precisely what we have investigated in this study where we used pure carbon nanotubes”.

The results of the research are extremely encouraging: “First of all we have proved that nanotubes do not interfere with the composition of lipids, of cholesterol in particular, which make up the cellular membrane in neurons. Membrane lipids play a very important role in the transmission of signals through the synapses. Nanotubes do not seem to influence this process, which is very important”.

There is more, however. The research has also highlighted the fact that the nerve cells growing on the substratum of nanotubes, thanks to this interaction, develop and reach maturity very quickly, eventually reaching a condition of biological homeostasis. “Nanotubes facilitate the full growth of neurons and the formation of new synapses. This growth, however, is not indiscriminate and unlimited since, as we proved, after a few weeks a physiological balance is attained. Having established the fact that this interaction is stable and efficient is an aspect of fundamental importance”. Maurizio Prato and Laura Ballerini conclude as follows: “We are proving that carbon nanotubes perform excellently in terms of duration, adaptability and mechanical compatibility with the tissue. Now we know that their interaction with the biological material, too, is efficient. Based on this evidence, we are already studying the in vivo application, and preliminary results appear to be quite promising also in terms of recovery of the lost neurological functions”.

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

Sculpting neurotransmission during synaptic development by 2D nanostructured interfaces by Niccolò Paolo Pampaloni, Denis Scaini, Fabio Perissinotto, Susanna Bosi, Maurizio Prato, Laura Ballerini. Nanomedicine: Nanotechnology, Biology and Medicine, DOI: http://dx.doi.org/10.1016/j.nano.2017.01.020 Published online: May 25, 2017

This paper is open access.

Brain stuff: quantum entanglement and a multi-dimensional universe

I have two brain news bits, one about neural networks and quantum entanglement and another about how the brain operates on more than three dimensions.

Quantum entanglement and neural networks

A June 13, 2017 news item on phys.org describes how machine learning can be used to solve problems in physics (Note: Links have been removed),

Machine learning, the field that’s driving a revolution in artificial intelligence, has cemented its role in modern technology. Its tools and techniques have led to rapid improvements in everything from self-driving cars and speech recognition to the digital mastery of an ancient board game.

Now, physicists are beginning to use machine learning tools to tackle a different kind of problem, one at the heart of quantum physics. In a paper published recently in Physical Review X, researchers from JQI [Joint Quantum Institute] and the Condensed Matter Theory Center (CMTC) at the University of Maryland showed that certain neural networks—abstract webs that pass information from node to node like neurons in the brain—can succinctly describe wide swathes of quantum systems.

An artist’s rendering of a neural network with two layers. At the top is a real quantum system, like atoms in an optical lattice. Below is a network of hidden neurons that capture their interactions (Credit: E. Edwards/JQI)

A June 12, 2017 JQI news release by Chris Cesare, which originated the news item, describes how neural networks can represent quantum entanglement,

Dongling Deng, a JQI Postdoctoral Fellow who is a member of CMTC and the paper’s first author, says that researchers who use computers to study quantum systems might benefit from the simple descriptions that neural networks provide. “If we want to numerically tackle some quantum problem,” Deng says, “we first need to find an efficient representation.”

On paper and, more importantly, on computers, physicists have many ways of representing quantum systems. Typically these representations comprise lists of numbers describing the likelihood that a system will be found in different quantum states. But it becomes difficult to extract properties or predictions from a digital description as the number of quantum particles grows, and the prevailing wisdom has been that entanglement—an exotic quantum connection between particles—plays a key role in thwarting simple representations.

The neural networks used by Deng and his collaborators—CMTC Director and JQI Fellow Sankar Das Sarma and Fudan University physicist and former JQI Postdoctoral Fellow Xiaopeng Li—can efficiently represent quantum systems that harbor lots of entanglement, a surprising improvement over prior methods.

What’s more, the new results go beyond mere representation. “This research is unique in that it does not just provide an efficient representation of highly entangled quantum states,” Das Sarma says. “It is a new way of solving intractable, interacting quantum many-body problems that uses machine learning tools to find exact solutions.”

Neural networks and their accompanying learning techniques powered AlphaGo, the computer program that beat some of the world’s best Go players last year (link is external) (and the top player this year (link is external)). The news excited Deng, an avid fan of the board game. Last year, around the same time as AlphaGo’s triumphs, a paper appeared that introduced the idea of using neural networks to represent quantum states (link is external), although it gave no indication of exactly how wide the tool’s reach might be. “We immediately recognized that this should be a very important paper,” Deng says, “so we put all our energy and time into studying the problem more.”

The result was a more complete account of the capabilities of certain neural networks to represent quantum states. In particular, the team studied neural networks that use two distinct groups of neurons. The first group, called the visible neurons, represents real quantum particles, like atoms in an optical lattice or ions in a chain. To account for interactions between particles, the researchers employed a second group of neurons—the hidden neurons—which link up with visible neurons. These links capture the physical interactions between real particles, and as long as the number of connections stays relatively small, the neural network description remains simple.

Specifying a number for each connection and mathematically forgetting the hidden neurons can produce a compact representation of many interesting quantum states, including states with topological characteristics and some with surprising amounts of entanglement.

Beyond its potential as a tool in numerical simulations, the new framework allowed Deng and collaborators to prove some mathematical facts about the families of quantum states represented by neural networks. For instance, neural networks with only short-range interactions—those in which each hidden neuron is only connected to a small cluster of visible neurons—have a strict limit on their total entanglement. This technical result, known as an area law, is a research pursuit of many condensed matter physicists.

These neural networks can’t capture everything, though. “They are a very restricted regime,” Deng says, adding that they don’t offer an efficient universal representation. If they did, they could be used to simulate a quantum computer with an ordinary computer, something physicists and computer scientists think is very unlikely. Still, the collection of states that they do represent efficiently, and the overlap of that collection with other representation methods, is an open problem that Deng says is ripe for further exploration.

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

Quantum Entanglement in Neural Network States by Dong-Ling Deng, Xiaopeng Li, and S. Das Sarma. Phys. Rev. X 7, 021021 – Published 11 May 2017

This paper is open access.

Blue Brain and the multidimensional universe

Blue Brain is a Swiss government brain research initiative which officially came to life in 2006 although the initial agreement between the École Politechnique Fédérale de Lausanne (EPFL) and IBM was signed in 2005 (according to the project’s Timeline page). Moving on, the project’s latest research reveals something astounding (from a June 12, 2017 Frontiers Publishing press release on EurekAlert),

For most people, it is a stretch of the imagination to understand the world in four dimensions but a new study has discovered structures in the brain with up to eleven dimensions – ground-breaking work that is beginning to reveal the brain’s deepest architectural secrets.

Using algebraic topology in a way that it has never been used before in neuroscience, a team from the Blue Brain Project has uncovered a universe of multi-dimensional geometrical structures and spaces within the networks of the brain.

The research, published today in Frontiers in Computational Neuroscience, shows that these structures arise when a group of neurons forms a clique: each neuron connects to every other neuron in the group in a very specific way that generates a precise geometric object. The more neurons there are in a clique, the higher the dimension of the geometric object.

“We found a world that we had never imagined,” says neuroscientist Henry Markram, director of Blue Brain Project and professor at the EPFL in Lausanne, Switzerland, “there are tens of millions of these objects even in a small speck of the brain, up through seven dimensions. In some networks, we even found structures with up to eleven dimensions.”

Markram suggests this may explain why it has been so hard to understand the brain. “The mathematics usually applied to study networks cannot detect the high-dimensional structures and spaces that we now see clearly.”

If 4D worlds stretch our imagination, worlds with 5, 6 or more dimensions are too complex for most of us to comprehend. This is where algebraic topology comes in: a branch of mathematics that can describe systems with any number of dimensions. The mathematicians who brought algebraic topology to the study of brain networks in the Blue Brain Project were Kathryn Hess from EPFL and Ran Levi from Aberdeen University.

“Algebraic topology is like a telescope and microscope at the same time. It can zoom into networks to find hidden structures – the trees in the forest – and see the empty spaces – the clearings – all at the same time,” explains Hess.

In 2015, Blue Brain published the first digital copy of a piece of the neocortex – the most evolved part of the brain and the seat of our sensations, actions, and consciousness. In this latest research, using algebraic topology, multiple tests were performed on the virtual brain tissue to show that the multi-dimensional brain structures discovered could never be produced by chance. Experiments were then performed on real brain tissue in the Blue Brain’s wet lab in Lausanne confirming that the earlier discoveries in the virtual tissue are biologically relevant and also suggesting that the brain constantly rewires during development to build a network with as many high-dimensional structures as possible.

When the researchers presented the virtual brain tissue with a stimulus, cliques of progressively higher dimensions assembled momentarily to enclose high-dimensional holes, that the researchers refer to as cavities. “The appearance of high-dimensional cavities when the brain is processing information means that the neurons in the network react to stimuli in an extremely organized manner,” says Levi. “It is as if the brain reacts to a stimulus by building then razing a tower of multi-dimensional blocks, starting with rods (1D), then planks (2D), then cubes (3D), and then more complex geometries with 4D, 5D, etc. The progression of activity through the brain resembles a multi-dimensional sandcastle that materializes out of the sand and then disintegrates.”

The big question these researchers are asking now is whether the intricacy of tasks we can perform depends on the complexity of the multi-dimensional “sandcastles” the brain can build. Neuroscience has also been struggling to find where the brain stores its memories. “They may be ‘hiding’ in high-dimensional cavities,” Markram speculates.

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About Blue Brain

The aim of the Blue Brain Project, a Swiss brain initiative founded and directed by Professor Henry Markram, is to build accurate, biologically detailed digital reconstructions and simulations of the rodent brain, and ultimately, the human brain. The supercomputer-based reconstructions and simulations built by Blue Brain offer a radically new approach for understanding the multilevel structure and function of the brain. http://bluebrain.epfl.ch

About Frontiers

Frontiers is a leading community-driven open-access publisher. By taking publishing entirely online, we drive innovation with new technologies to make peer review more efficient and transparent. We provide impact metrics for articles and researchers, and merge open access publishing with a research network platform – Loop – to catalyse research dissemination, and popularize research to the public, including children. Our goal is to increase the reach and impact of research articles and their authors. Frontiers has received the ALPSP Gold Award for Innovation in Publishing in 2014. http://www.frontiersin.org.

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

Cliques of Neurons Bound into Cavities Provide a Missing Link between Structure and Function by Michael W. Reimann, Max Nolte, Martina Scolamiero, Katharine Turner, Rodrigo Perin, Giuseppe Chindemi, Paweł Dłotko, Ran Levi, Kathryn Hess, and Henry Markram. Front. Comput. Neurosci., 12 June 2017 | https://doi.org/10.3389/fncom.2017.00048

This paper is open access.