Category Archives: medicine

Device detects molecules associated with neurodegenerative diseases

It’s nice to get notice of research in South America, an area for which I rarely stumble across any news releases. Brazilian researchers have developed a device that could help diagnose neurodegenerative diseases such as Alzheimer’s and and Parkinson’s as well as some cancers according to a May 20, 2016 news item on Nanotechnology Now,

A biosensor developed by researchers at the National Nanotechnology Laboratory (LNNano) in Campinas, São Paulo State, Brazil, has been proven capable of detecting molecules associated with neurodegenerative diseases and some types of cancer.

The device is basically a single-layer organic nanometer-scale transistor on a glass slide. It contains the reduced form of the peptide glutathione (GSH), which reacts in a specific way when it comes into contact with the enzyme glutathione S-transferase (GST), linked to Parkinson’s, Alzheimer’s and breast cancer, among other diseases. The GSH-GST reaction is detected by the transistor, which can be used for diagnostic purposes.

The project focuses on the development of point-of-care devices by researchers in a range of knowledge areas, using functional materials to produce simple sensors and microfluidic systems for rapid diagnosis.

A May 19, 2016 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) press release, which originated the news item, provides more detail,

“Platforms like this one can be deployed to diagnose complex diseases quickly, safely and relatively cheaply, using nanometer-scale systems to identify molecules of interest in the material analyzed,” explained Carlos Cesar Bof Bufon, Head of LNNano’s Functional Devices & Systems Lab (DSF) and a member of the research team for the project, whose principal investigator is Lauro Kubota, a professor at the University of Campinas’s Chemistry Institute (IQ-UNICAMP).

In addition to portability and low cost, the advantages of the nanometric biosensor include its sensitivity in detecting molecules, according to Bufon.

“This is the first time organic transistor technology has been used in detecting the pair GSH-GST, which is important in diagnosing degenerative diseases, for example,” he explained. “The device can detect such molecules even when they’re present at very low levels in the examined material, thanks to its nanometric sensitivity.” A nanometer (nm) is one billionth of a meter (10-9 meter), or one millionth of a millimeter.

The system can be adapted to detect other substances, such as molecules linked to different diseases and elements present in contaminated material, among other applications. This requires replacing the molecules in the sensor with others that react with the chemicals targeted by the test, which are known as analytes.

The team is working on paper-based biosensors to lower the cost even further and to improve portability and facilitate fabrication as well as disposal.

The challenge is that paper is an insulator in its usual form. Bufon has developed a technique to make paper conductive and capable of transporting sensing data by impregnating cellulose fibers with polymers that have conductive properties.

The technique is based on in situ synthesis of conductive polymers. For the polymers not to remain trapped on the surface of the paper, they have to be synthesized inside and between the pores of the cellulose fibers. This is done by gas-phase chemical polymerization: a liquid oxidant is infiltrated into the paper, which is then exposed to monomers in the gas phase. A monomer is a molecule of low molecular weight capable of reacting with identical or different molecules of low molecular weight to form a polymer.

The monomers evaporate under the paper and penetrate the pores of the fibers at the submicrometer scale. Inside the pores, they blend with the oxidant and begin the polymerization process right there, impregnating the entire material.

The polymerized paper acquires the conductive properties of the polymers. This conductivity can be adjusted by manipulating the element embedded in the cellulose fibers, depending on the application for which the paper is designed. Thus, the device can be electrically conductive, allowing current to flow without significant losses, or semiconductive, interacting with specific molecules and functioning as a physical, chemical or electrochemical sensor.

There’s no mention of a published paper.

Injectable medicine made safer?

The lede for this May 19, 2016 news item on Nanowerk is great,

Bring the drugs, hold the suds.

The May 19, 2016 University of Buffalo news release (also on EurekAlert) by Cory Nealon, which originated the news item, quickly gets to the point,

That summarizes a promising new drug-making technique designed to reduce serious allergic reactions and other side effects from anti-cancer medicine, testosterone and other drugs that are administered with a needle.

Developed by University at Buffalo researchers, the breakthrough removes potentially harmful additives – primarily soapy substances known as surfactants – from common injectable drugs.

“We’re excited because this process can be scaled up, which could make existing injectable drugs safer and more effective for millions of people suffering from serious diseases and ailments,” says Jonathan F. Lovell, a biomedical engineer at UB and the study’s corresponding author.

Pharmaceutical companies use surfactants to dissolve medicine into a liquid solution, a process that makes medicine suitable for injection. While effective, the process is seldom efficient. Solutions loaded with surfactant and other nonessential ingredients can carry the risk of causing anaphylactic shock, blood clotting, hemolysis and other side effects.

Researchers have tried to address this problem in two ways, each with varying degrees of success.

Some have taken the so-called “top down” approach, in which they shrink drug particles to nanoscale sizes to eliminate excess additives. While promising, the method doesn’t work well in injectable medicine because the drug particles are still too large to safely inject.

Other researchers work from the “bottom up” using nanotechnology to build new drugs from scratch. This may yield tremendous results; however, developing new drug formulations takes years, and drugs are coupled with new additives that create new side effects.

The technique under development at UB differs because it improves existing injectable drug-making methods by taking the unusual step of stripping away all of the excess surfactant.

In laboratory experiments, researchers dissolved 12 drugs – cabazitaxel (anti-cancer), testosterone, cyclosporine (an immunosuppressant used during organ transplants) and others – one at a time into a surfactant called Pluronic. Then, by lowering the solution’s temperature to 4 degrees Celsius (most drugs are made at room temperature), they were able to remove the excess Pluronic via a membrane.

The end result are drugs that contain 100 to 1,000 times less excess additives.

“For the drugs we looked at, this is as close as anyone has gotten to introducing pure, injectable medicine into the body,” says Lovell, PhD, assistant professor in the Department of Biomedical Engineering in UB’s School of Engineering and Applied Sciences. “Essentially, it’s a new way to package drugs.”

The findings are significant, he says, because they show that many injectable drug formulations may be improved through an easy-to-adopt process. Future experiments are planned to further refine the method, he says.

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

Therapeutic surfactant-stripped frozen micelles by Yumiao Zhang, Wentao Song, Jumin Geng, Upendra Chitgupi, Hande Unsal, Jasmin Federizon, Javid Rzayev, Dinesh K. Sukumaran, Paschalis Alexandridis, & Jonathan F. Lovell. Nature Communications 7, Article number: 11649 doi:10.1038/ncomms11649 Published 19 May 2016

This is an open access paper.

A few years back, a friend got a flu shot and became ill (not the flu). Suspicions  (my friend is a doctor) centered on the additives in the shot as that particular year a number of people got sick from the shot.

First Canadian Governor-General’s innovation award goes to professor Robert Burrell (nanoscientist) at the University of Alberta

The first innovation award ever given by the Canadian Governor General* has gone to a nanomedicine pioneer at the University of Alberta. From a May 12, 2016 news article by Marc Montgomery for Radio Canada International*, Note: A link has been removed,

Professor Robert Burrell of the University of Alberta has won a prestigious Governor-General’s Innovation Award for the world’s first therapeutic use of nanotechnology.

Professor Burrell used nano-technology on a wound bandage that has already begun transforming treatment of wounds in situations around the world.

Robert Burrell,  Professor in the Faculty of Chemical and Mechanical Engineering at the University of Alberta, is also Canada Research Chair in Nanostructured Biomaterials, and Chair, Biomedical Engineering at the university.

Burrell’s development called Acticoat came from research into nano-forms of silver.  When silver is reduced to nano scale it’s properties and chemical activity change.

In his research prior to joining the University in 2002, Burrell created a coating of nano-crystals of silver which not only kills bacteria but also has anti-inflammatory properties.

A May 9, 2016 University of Alberta news release has a bit more information,

… The chair of the U of A Department of Biomedical Engineering has been awarded a new national innovation prize in recognition of an invention that transformed wound care around the world.

Rob Burrell PhD, FCAHS, who holds the Canada Research Chair in Nanostructure Biomaterials and leads the Department of Biomedical Engineering, is one of six Canadians to win the inaugural round of the Governor General’s Innovation Awards. The awards recognize “exceptional and transformative work” that has helped “shape our future and positively impact our quality of life.”

“It was a nice surprise,” Burrell says of receiving the award. “I got an email in April—and was wondering why the Secretary to the Governor General of Canada [David Johnston is the current Governor General] wanted to talk to me. When we had our phone call he congratulated me on winning the award.”

Burrell invented Acticoat, a new wound dressing that uses nanocrystalline silver to fight bacteria and inflammation in wounds, while working for Westaim Biomedical, later Nucryst Pharmaceuticals. He joined the Faculty of Engineering in 2002.

The dressing was the world’s first therapeutic use of nanotechnology and has saved thousands of lives and limbs, transforming the treatment of burns and wounds.

“We have three projects on the go now. We’ve developed a new dressing and applied for a patent on it for scar control and we’re looking at commercializing that,” he said. “I have two of my grad students—and this summer we will have three summer students—working on a diagnostic tool that will allow a surgeon in an operating room to assess a tumour in 10 to 15 minutes. The analysis of the tumour can determine the type of surgery and post-surgical care the patient receives.”

You can find out more about the Governor General awards, which include, in addition to the new innovation category, the arts,  the sciences and humanities, and more here.

* I have a couple of explanatory notes for those unfamiliar with the concept of a Governor General and/or those who may be curious about Radio Canada International.

The Governor General is the Queen’s or the British monarch’s representative in Canada. Here’s another more general definition from a Wikipedia entry,

Governor-general or governor general, in modern usage, is the title of an office-holder appointed to represent the monarch of a sovereign state in the governing of an independent realm. Governors-general have also previously been appointed in respect of major colonial states or other territories held by either a monarchy or republic, such as French Indochina.

Radio Canada International is a little complicated. Radio Canada is the French language arm of the Canadian Broadcasting Corporation (CBC) and the name ‘Radio Canada’ refers to its radio, television, and internet services.

Interestingly Radio Canada International is the global outreach for both Radio Canada and CBC, presumably, uniting the English and French language services under one banner.

Ingestible origami robot gets one step closer

Fiction, more or less seriously, has been exploring the idea of ingestible, tiny robots that can enter the human body for decades (Fantastic Voyage and Innerspace are two movie examples). The concept is coming closer to being realized as per a May 12, 2016 news item on phys.org,

In experiments involving a simulation of the human esophagus and stomach, researchers at MIT [Massachusetts Institute of Technology], the University of Sheffield, and the Tokyo Institute of Technology have demonstrated a tiny origami robot that can unfold itself from a swallowed capsule and, steered by external magnetic fields, crawl across the stomach wall to remove a swallowed button battery or patch a wound.

A May 12, 2016 MIT news release (also on EurekAlert), which originated the news item, provides some fascinating depth to this story (Note: Links have been removed),

The new work, which the researchers are presenting this week at the International Conference on Robotics and Automation, builds on a long sequence of papers on origami robots from the research group of Daniela Rus, the Andrew and Erna Viterbi Professor in MIT’s Department of Electrical Engineering and Computer Science.

“It’s really exciting to see our small origami robots doing something with potential important applications to health care,” says Rus, who also directs MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL). “For applications inside the body, we need a small, controllable, untethered robot system. It’s really difficult to control and place a robot inside the body if the robot is attached to a tether.”

Although the new robot is a successor to one reported at the same conference last year, the design of its body is significantly different. Like its predecessor, it can propel itself using what’s called a “stick-slip” motion, in which its appendages stick to a surface through friction when it executes a move, but slip free again when its body flexes to change its weight distribution.

Also like its predecessor — and like several other origami robots from the Rus group — the new robot consists of two layers of structural material sandwiching a material that shrinks when heated. A pattern of slits in the outer layers determines how the robot will fold when the middle layer contracts.

Material difference

The robot’s envisioned use also dictated a host of structural modifications. “Stick-slip only works when, one, the robot is small enough and, two, the robot is stiff enough,” says Guitron [Steven Guitron, a graduate student in mechanical engineering]. “With the original Mylar design, it was much stiffer than the new design, which is based on a biocompatible material.”

To compensate for the biocompatible material’s relative malleability, the researchers had to come up with a design that required fewer slits. At the same time, the robot’s folds increase its stiffness along certain axes.

But because the stomach is filled with fluids, the robot doesn’t rely entirely on stick-slip motion. “In our calculation, 20 percent of forward motion is by propelling water — thrust — and 80 percent is by stick-slip motion,” says Miyashita [Shuhei Miyashita, who was a postdoc at CSAIL when the work was done and is now a lecturer in electronics at the University of York, England]. “In this regard, we actively introduced and applied the concept and characteristics of the fin to the body design, which you can see in the relatively flat design.”

It also had to be possible to compress the robot enough that it could fit inside a capsule for swallowing; similarly, when the capsule dissolved, the forces acting on the robot had to be strong enough to cause it to fully unfold. Through a design process that Guitron describes as “mostly trial and error,” the researchers arrived at a rectangular robot with accordion folds perpendicular to its long axis and pinched corners that act as points of traction.

In the center of one of the forward accordion folds is a permanent magnet that responds to changing magnetic fields outside the body, which control the robot’s motion. The forces applied to the robot are principally rotational. A quick rotation will make it spin in place, but a slower rotation will cause it to pivot around one of its fixed feet. In the researchers’ experiments, the robot uses the same magnet to pick up the button battery.

Porcine precedents

The researchers tested about a dozen different possibilities for the structural material before settling on the type of dried pig intestine used in sausage casings. “We spent a lot of time at Asian markets and the Chinatown market looking for materials,” Li [Shuguang Li, a CSAIL postdoc] says. The shrinking layer is a biodegradable shrink wrap called Biolefin.

To design their synthetic stomach, the researchers bought a pig stomach and tested its mechanical properties. Their model is an open cross-section of the stomach and esophagus, molded from a silicone rubber with the same mechanical profile. A mixture of water and lemon juice simulates the acidic fluids in the stomach.

Every year, 3,500 swallowed button batteries are reported in the U.S. alone. Frequently, the batteries are digested normally, but if they come into prolonged contact with the tissue of the esophagus or stomach, they can cause an electric current that produces hydroxide, which burns the tissue. Miyashita employed a clever strategy to convince Rus that the removal of swallowed button batteries and the treatment of consequent wounds was a compelling application of their origami robot.

“Shuhei bought a piece of ham, and he put the battery on the ham,” Rus says. [emphasis mine] “Within half an hour, the battery was fully submerged in the ham. So that made me realize that, yes, this is important. If you have a battery in your body, you really want it out as soon as possible.”

“This concept is both highly creative and highly practical, and it addresses a clinical need in an elegant way,” says Bradley Nelson, a professor of robotics at the Swiss Federal Institute of Technology Zurich. “It is one of the most convincing applications of origami robots that I have seen.”

I wonder if they ate the ham afterwards.

Happily, MIT has produced a video featuring this ingestible, origami robot,

Finally, this team has a couple more members than the previously mentioned Rus, Miyashita, and Li,

…  Kazuhiro Yoshida of Tokyo Institute of Technology, who was visiting MIT on sabbatical when the work was done; and Dana Damian of the University of Sheffield, in England.

As Rus notes in the video, the next step will be in vivo (animal) studies.

Cutting into a cell with a nanoblade

A May 11, 2016 news item on Nanotechnology Now features a type of surgery that could aid in cell engineering,

To study certain aspects of cells, researchers need the ability to take the innards out, manipulate them, and put them back. Options for this kind of work are limited, but researchers reporting May 10 [2016] in Cell Metabolism describe a “nanoblade” that can slice through a cell’s membrane to insert mitochondria. The researchers have previously used this technology to transfer other materials between cells and hope to commercialize the nanoblade for wider use in bioengineering.

Caption: This diagram illustrates the process of transferring mitochondria between cells using the nanoblade technology. Credit: Alexander N. Patananan Courtesy UCLA

Caption: This diagram illustrates the process of transferring mitochondria between cells using the nanoblade technology.
Credit: Alexander N. Patananan Courtesy UCLA

A May 10, 2016 Cell Press news release on EurekAlert, which originated the news item, expands on the theme,

“As a new tool for cell engineering, to truly engineer cells for health purposes and research, I think this is very unique,” says Mike Teitell, a pathologist and bioengineer at the University of California, Los Angeles (UCLA). “We haven’t run into anything so far, up to a few microns in size, that we can’t deliver.”

Teitell and Pei-Yu “Eric” Chiou, also a bioengineer at UCLA, first conceived the idea of a nanoblade several years ago to transfer a nucleus from one cell to another. However, they soon delved into the intersection of stem cell biology and energy metabolism, where the technology could be used to manipulate a cell’s mitochondria. Studying the effects of mutations in the mitochondrial genome, which can cause debilitating or fatal diseases in humans, is tricky for a number of reasons.

“There’s a bottleneck in the field for modifying a cell’s mitochondrial DNA,” says Teitell. “So we are working on a two-step process: edit the mitochondrial genome outside of a cell, and then take those manipulated mitochondria and put them back into the cell. We’re still working on the first step, but we’ve solved that second one quite well.”

The nanoblade apparatus consists of a microscope, laser, and titanium-coated micropipette to act as the “blade,” operated using a joystick controller. When a laser pulse strikes the titanium, the metal heats up, vaporizing the surrounding water layers in the culture media and forming a bubble next to a cell. Within a microsecond, the bubble expands, generating a local force that punctures the cell membrane and creates a passageway several microns long that the “cargo”–in this case, mitochondria–can be pushed through. The cell then rapidly repairs the membrane defect.

Teitell, Chiou, and their team used the nanoblade to insert tagged mitochondria from human breast cancer cells and embryonic kidney cells into cells without mitochondrial DNA. When they sequenced the nuclear and mitochondrial DNA afterwards, the researchers saw that the mitochondria had been successfully transferred and replicated by 2% of the cells, with a range of functionality. Other methods of mitochondrial transfer are hard to control, and when they have been reported to work, the success rates have been only 0.0001%-0.5% according to the researchers.

“The success of the mitochondrial transfer was very encouraging,” says Chiou. “The most exciting application for the nanoblade, to me, is in the study of mitochondria and infectious diseases. This technology brings new capabilities to help advance these fields.”

The team’s aspirations also go well beyond mitochondria, and they’ve already scaled up the nanoblade apparatus into an automated high-throughput version. “We want to make a platform that’s easy to use for everyone and allow researchers to devise anything they can think of a few microns or smaller that would be helpful for their research–whether that’s inserting antibodies, pathogens, synthetic materials, or something else that we haven’t imagined,” says Teitell. “It would be very cool to allow people to do something that they can’t do right now.”

The pipette being used is measured at the microscale but it’s called a nanoblade? Well, perhaps the tip or the edge of the pipette is measured at the nanoscale.

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

Mitochondrial Transfer by Photothermal Nanoblade Restores Metabolite Profile in Mammalian Cells by Ting-Hsiang Wu, Enrico Sagullo, Dana Case, Xin Zheng, Yanjing Li, Jason S. Hong, Tara TeSlaa, Alexander N. Patananan, J. Michael McCaffery, Kayvan Niazi, Daniel Braas, Carla M. Koehler, Thomas G. Graeber, Pei-Yu Chiou, Michael A. Teitell. Cell Metabolism Volume 23, Issue 5, p921–929, 10 May 2016  DOI: http://dx.doi.org/10.1016/j.cmet.2016.04.007

This paper appears to be open access.

Calming a synapse (part of a neuron) with graphene flakes

As we continue to colonize our own brains, there’s more news of graphene and neurons (see my Feb. 1, 2016 post featuring research from the same team in Italy featured in this post). A May 10, 2016 news item on ScienceDaily highlights work that could be used for epilepsy,

Innovative graphene technology to buffer the activity of synapses– this is the idea behind a recently-published study in the journal ACS Nano coordinated by the International School for Advanced Studies in Trieste (SISSA) and the University of Trieste. In particular, the study showed how effective graphene oxide flakes are at interfering with excitatory synapses, an effect that could prove useful in new treatments for diseases like epilepsy.

I guess the press release took a while to make its way through translation, here’s more from the April 10, 2016 SISSA (International School for Advanced Studies) press release (also on EurekAlert),

The laboratory of SISSA’s Laura Ballerini in collaboration with the University of Trieste, the University of Manchester and the University of Castilla -la Mancha, has discovered a new approach to modulating synapses. This methodology could be useful for treating diseases in which electrical nerve activity is altered. Ballerini and Maurizio Prato (University of Trieste) are the principal investigators of the project within the European flagship on graphene, a far-reaching 10-year international collaboration (one billion euros in funding) that studies innovative uses of the material.

Traditional treatments for neurological diseases generally include drugs that act on the brain or neurosurgery. Today however, graphene technology is showing promise for these types of applications, and is receiving increased attention from the scientific community. The method studied by Ballerini and colleagues uses “graphene nano-ribbons” (flakes) which buffer activity of synapses simply by being present.

“We administered aqueous solutions of graphene flakes to cultured neurons in ‘chronic’ exposure conditions, repeating the operation every day for a week. Analyzing functional neuronal electrical activity, we then traced the effect on synapses” says Rossana Rauti, SISSA researcher and first author of the study.

In the experiments, size of the flakes varied (10 microns or 80 nanometers) as well as the type of graphene: in one condition graphene was used, in another, graphene oxide. “The ‘buffering’ effect on synaptic activity happens only with smaller flakes of graphene oxide and not in other conditions,” says Ballerini. “The effect, in the system we tested, is selective for the excitatory synapses, while it is absent in inhibitory ones”

A Matter of Size

What is the origin of this selectivity? “We know that in principle graphene does not interact chemically with synapses in a significant way- its effect is likely due to the mere presence of synapses,” explains SISSA researcher and one of the study’s authors, Denis Scaini. “We do not yet have direct evidence, but our hypothesis is that there is a link with the sub-cellular organization of the synaptic space.”

A synapse is a contact point between one neuron and another where the nervous electrical signal “jumps” between a pre and post-synaptic unit. [emphasis mine] There is a small gap or discontinuity where the electrical signal is “translated” by a neurotransmitter and released by pre-synaptic termination into the extracellular space and reabsorbed by the postsynaptic space, to be translated again into an electrical signal. The access to this space varies depending on the type of synapses: “For the excitatory synapses, the structure’s organization allows higher exposure for the graphene flakes interaction, unlike inhibitory synapses, which are less physically accessible in this experimental model,” says Scaini.

Another clue that distance and size could be crucial in the process is found in the observation that graphene performs its function only in the oxidized form. “Normal graphene looks like a stretched and stiff sheet while graphene oxide appears crumpled, and thus possibly favoring interface with the synaptic space, ” adds Rauti.

Administering graphene flake solutions leaves the neurons alive and intact. For this reason the team thinks they could be used in biomedical applications for treating certain diseases. “We may imagine to target a drug by exploiting the apparent flakes’ selectivity for synapses, thus targeting directly the basic functional unit of neurons”concludes Ballerini.

That’s a nice description of neurons, synapses, and neurotransmitters.

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

Graphene Oxide Nanosheets Reshape Synaptic Function in Cultured Brain Networks by Rossana Rauti, Neus Lozano, Veronica León, Denis Scaini†, Mattia Musto, Ilaria Rago, Francesco P. Ulloa Severino, Alessandra Fabbro, Loredana Casalis, Ester Vázquez, Kostas Kostarelos, Maurizio Prato, and Laura Ballerini. ACS Nano, 2016, 10 (4), pp 4459–4471
DOI: 10.1021/acsnano.6b00130 Publication Date (Web): March 31, 2016

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

Tightening the skin (and protecting it and removing wrinkles, temporarily)

“It’s an invisible layer that can provide a barrier, provide cosmetic improvement, and potentially deliver a drug locally to the area that’s being treated. Those three things together could really make it ideal for use in humans,” Daniel Anderson says. Photo: Melanie Gonick/MIT

“It’s an invisible layer that can provide a barrier, provide cosmetic improvement, and potentially deliver a drug locally to the area that’s being treated. Those three things together could really make it ideal for use in humans,” Daniel Anderson says. Photo: Melanie Gonick/MIT

It almost looks like he’s peeling off his own skin and I imagine that’s the secret to this polymer’s success. A May 9, 2016 news item on phys.org describes the work being done at the Massachusetts Institute of Technology (MIT) and elsewhere with collaborators,

Scientists at MIT, Massachusetts General Hospital, Living Proof, and Olivo Labs have developed a new material that can temporarily protect and tighten skin, and smooth wrinkles. With further development, it could also be used to deliver drugs to help treat skin conditions such as eczema and other types of dermatitis.

A May 9, 2016 MIT news release (also on EurekAlert), which originated the news item, provides more detail,

The material, a silicone-based polymer that could be applied on the skin as a thin, imperceptible coating, mimics the mechanical and elastic properties of healthy, youthful skin. In tests with human subjects, the researchers found that the material was able to reshape “eye bags” under the lower eyelids and also enhance skin hydration. This type of “second skin” could also be adapted to provide long-lasting ultraviolet protection, the researchers say.

“It’s an invisible layer that can provide a barrier, provide cosmetic improvement, and potentially deliver a drug locally to the area that’s being treated. Those three things together could really make it ideal for use in humans,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

Anderson is one of the authors of a paper describing the polymer in the May 9 online issue of Nature Materials. Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, is the paper’s senior author, and the paper’s lead author is Betty Yu SM ’98, ScD ’02, former vice president at Living Proof. Langer and Anderson are co-founders of Living Proof and Olivo Labs, and Yu earned her master’s and doctorate at MIT.

Mimicking skin

As skin ages, it becomes less firm and less elastic — problems that can be exacerbated by sun exposure. This impairs skin’s ability to protect against extreme temperatures, toxins, microorganisms, radiation, and injury. About 10 years ago, the research team set out to develop a protective coating that could restore the properties of healthy skin, for both medical and cosmetic applications.

“We started thinking about how we might be able to control the properties of skin by coating it with polymers that would impart beneficial effects,” Anderson says. “We also wanted it to be invisible and comfortable.”

The researchers created a library of more than 100 possible polymers, all of which contained a chemical structure known as siloxane — a chain of alternating atoms of silicon and oxygen. These polymers can be assembled into a network arrangement known as a cross-linked polymer layer (XPL). The researchers then tested the materials in search of one that would best mimic the appearance, strength, and elasticity of healthy skin.

“It has to have the right optical properties, otherwise it won’t look good, and it has to have the right mechanical properties, otherwise it won’t have the right strength and it won’t perform correctly,” Langer says.

The best-performing material has elastic properties very similar to those of skin. In laboratory tests, it easily returned to its original state after being stretched more than 250 percent (natural skin can be elongated about 180 percent). In laboratory tests, the novel XPL’s elasticity was much better than that of two other types of wound dressings now used on skin — silicone gel sheets and polyurethane films.

“Creating a material that behaves like skin is very difficult,” says Barbara Gilchrest, a dermatologist at MGH and an author of the paper. “Many people have tried to do this, and the materials that have been available up until this have not had the properties of being flexible, comfortable, nonirritating, and able to conform to the movement of the skin and return to its original shape.”

The XPL is currently delivered in a two-step process. First, polysiloxane components are applied to the skin, followed by a platinum catalyst that induces the polymer to form a strong cross-linked film that remains on the skin for up to 24 hours. This catalyst has to be added after the polymer is applied because after this step the material becomes too stiff to spread. Both layers are applied as creams or ointments, and once spread onto the skin, XPL becomes essentially invisible.

High performance

The researchers performed several studies in humans to test the material’s safety and effectiveness. In one study, the XPL was applied to the under-eye area where “eye bags” often form as skin ages. These eye bags are caused by protrusion of the fat pad underlying the skin of the lower lid. When the material was applied, it applied a steady compressive force that tightened the skin, an effect that lasted for about 24 hours.

In another study, the XPL was applied to forearm skin to test its elasticity. When the XPL-treated skin was distended with a suction cup, it returned to its original position faster than untreated skin.

The researchers also tested the material’s ability to prevent water loss from dry skin. Two hours after application, skin treated with the novel XPL suffered much less water loss than skin treated with a high-end commercial moisturizer. Skin coated with petrolatum was as effective as XPL in tests done two hours after treatment, but after 24 hours, skin treated with XPL had retained much more water. None of the study participants reported any irritation from wearing XPL.

“I think it has great potential for both cosmetic and noncosmetic applications, especially if you could incorporate antimicrobial agents or medications,” says Thahn Nga Tran, a dermatologist and instructor at Harvard Medical School, who was not involved in the research.

Living Proof has spun out the XPL technology to Olivo Laboratories, LLC, a new startup formed to focus on the further development of the XPL technology. Initially, Olivo’s team will focus on medical applications of the technology for treating skin conditions such as dermatitis.

 

This video supplied by MIT shows how to apply the polymer and offers a description and demonstration of its properties once applied,

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

An elastic second skin by Betty Yu, Soo-Young Kang, Ariya Akthakul, Nithin Ramadurai, Morgan Pilkenton, Alpesh Patel, Amir Nashat, Daniel G. Anderson, Fernanda H. Sakamoto, Barbara A. Gilchrest, R. Rox Anderson & Robert Langer. Nature Materials (2016) doi:10.1038/nmat4635 Published online 09 May 2016

This paper is behind a paywall.

One final comment, I wonder who’s lining up to invest in this product.

Opioid addiction and nanotechnology in Pennsylvania, US

Combating a drug addiction ‘crisis’ with a nanotechnology-enabled solution is the main topic although the technology is being implemented for another problem first according to this May 4, 2016 article by John Luciew for pennlive.com (Note: Links have been removed),

Treating pain is a constant in medicine. It’s part of the human condition, known as the “fifth vital sign” among physicians. Effectively treating pain will continue to play a central role in medicine, despite the societal shock waves brought on by the rapid rise in opioid addiction across America.

The fallout from our nation’s opioid addiction crisis is roiling the medical and pharmaceutical industries, where regulatory action is rapidly reining in opioid painkiller prescriptions with new guidelines and stricter controls.

By harnessing nanotechnology and small-particles physics, Iroko Pharmaceuticals is developing a new class of low-dose prescription painkillers. Company executives say their line of nonsteroidal anti-inflammatory drugs could be the opioid alternative that the medical community has been looking for amid America’s addiction crisis.

The pharmaceutical company is Pennsylvania-based (US) and it isn’t tackling the ‘opioid addiction crisis’ yet. First, there’s this,

Its new line of prescription painkillers are predicated upon a highly patented process of pulverizing drug molecules so they are up to 100 times smaller, which markedly increases their pain-killing effectiveness at dramatically lower doses.

Right now, Iroko is focusing this nanotechnology on creating a full line of low-dose prescription painkillers based upon the class of drugs known as nonsteroidal anti-inflammatories, or NSAIDs. There are six NSAID molecules, the most common being Ibuprofen. Iroko is planning nanotechnology technology versions for all six NSAID molecules, three of which have already received approval from the Food and Drug Administration.

Luciew has done some homework on the technology,

“We solved a chemistry problem by using physics,” explained Iroko Chairman Osagie Imasogie, who founded the company [Iroko Pharmaceuticals] in 2007.

Yet, the company that actually solved the physics problem was iCeutica, founded in Australia and now based in King of Prussia, Pa.

iCeutica owns the patented SoluMatrix fine particle process that pulverizes drug molecules into nano-sized particles, enabling low doses of a drug to be better absorbed by the body, thus providing faster and far more effective pain relief.

Of course, the practice of crushing and grinding drug powders is as old as the pharmacist’s mortar and pestle. But there’s never been a way of pulverizing a drug molecule into nano particles that was scalable for industrial production — not until iCeutica created its SoluMatrix process, that is.

iCeutica provides a description of the technology on its SoluMatrix webpage,

iCeutica’s proprietary SoluMatrix™ Fine Particle Technology fuels new product development and solves problems of bioavailability, variability, side effects and delivery of marketed or development-stage pharmaceuticals.

The SoluMatrix technology is a scaleable and cost-effective manufacturing process that can produce submicron-sized drug particles that are 10 to 200 times smaller than conventional drug particles. The particles generated using this technology, which both grinds the drug particles into a superfine powder and protects those submicron particles from subsequent agglomeration (or clumping together into big particles), comprise a single unit operation and can be manufactured into tablets, capsules and other dosage forms without further processing.

The SoluMatrix technology improves the performance of pharmaceuticals by dramatically changing how the drug dissolves and is absorbed. By making submicron-sized particles of a drug, it is possible to:

Unfortunately there aren’t more details. I’m somewhat puzzled  by the submicron measurement why not state the size using the term nanometre?

Getting back  to Iroko, Imasogie, impressed with the SoluMatrix technology, has made a major investment in iCeutica and is chair of iCeutica’s board. His homebase company, Iroko holds exclusive global rights to SoluMatrix.

Luciew’s article describes the current situation in the NSAID market,

Iroko officials acknowledge that NSAID painkillers carry their own health risks, including the potential for stomach ulcers, kidney problems and cardio-vascular ailments, up to and including stroke and heart attack. The fears associated with NSAIDs peaked a decade ago with the Vioxx case, a popular prescription NSAID that was eventually taken off the market due to associated cardiac and other risks.

The latest FDA guidelines for NSAID use calls for the lowest effective dose, which precisely describes the nanotechnology-driven low-dose NSAID drugs Iroko is rolling out. What is more, due to the ongoing opioid crisis, both the FDA and the Centers for Disease Control are heavily emphasizing non-opioid alternatives for pain relief, further opening to door for Iroko’s pain products.

That said about the issues with NSAIDs, Luciew outlines Iroko’s current offerings and explains what makes this technology so attractive,

According to Imasogie, Iroko’s line of low-dose, nanotechnology NSAIDs fits both sets of regulatory safety criteria. The new drugs are the lowest effective dose for NSAIDs, and are a viable pain-killing alternative to opioids, especially when it comes to treating osteoarthritis and other moderate pain.

“No one is going to give an NSAID if you have cancer,” Imasogie says. “But for chronic low back pain, yes.”

Three of Iroko’s six low-dose NSAID offerings have already received FDA approval and are on the market:

  • Zorvolex (diclofenac), approved in October 2013 for the management of mild to moderate acute pain in adults and in August 2014 for the management of osteoarthritis pain.
  • Tivorbex, approved in February 2014 for treatment of mild to moderate acute pain in adults.
  • Vivlodex, approved in October 2015 as another option for treatment of osteoarthritis pain. Three more of Iroko’s low-dose NSAIDs are awaiting approval.

These nano drugs are effective at doses of 35 to 40 milligrams to as low as 10 milligrams, the company says. That’s compared to other NSAID doses that start at 200 milligrams. As a result, Iroko’s low-dose NSAID drugs are being marketed as providing a prescription alternative to opioids at the precise moment everyone from the White House to the white-coat-clad family physician is searching for one.

If you the have time and interest, I encourage you to read Luciew’s article in its entirety. He covers more market issues and includes an enbedded video in his piece.

One last note about Iroko Pharmaceuticals, the company is named after a tree found on the African continent and executives of the company have hinted they are experimenting with SoluMatrix to make low-dose opioids available in the future.

While I have my doubts about the opioid addiction ‘crisis’, I do believe that lower, more effective doses of painkillers, regardless of their drug class, can only benefit patients.

Combining chitosan, agarose, and protein gelatine with clay nanotubes to create scaffolds for tissue engineering

Russian scientists have published work on clay nanotube-bipolymer composite scaffolds according to an April 29, 2016 news item on ScienceDaily,

Scientists combined three biopolymers, chitosan and agarose (polysaccharides), and a protein gelatine, as the materials to produce tissue engineering scaffolds and demonstrated the enhancement of mechanical strength (doubled pick load), higher water uptake and thermal properties in chitosan-gelatine-agarose hydrogels doped with halloysite [a clay mineral and a naturally occurring nanotube].

An April 29, 2016 Kazan Federal University (Russia) press release on EurekAlert, which originated the news item, provides more detail and context,

The fabrication of a prototype tissue having functional properties close to the natural ones is crucial for effective transplantation. Tissue engineering scaffolds are typically used as supports which allow cells to form tissue-like structures essentially required for the correct functioning of the cells under the conditions close to the three-dimensional tissue.

Chitosan, a natural biodegradable and chemically versatile biopolymer, has been effectively used in antibacterial, antifungal, anti-tumour and immunostimulating formulations. To overcome the disadvantages of pure chitosan scaffolds such as mechanical fragility and low biological resistance, chitosan scaffolds are typically doped with other supporting compounds which allow for mechanical strengthening, thus yielding ?omposite biologically resistant scaffolds.

Agarose is a galactose-based backbone polysaccharide isolated from red algae, having remarkable mechanical properties which are useful in the design of tissue engineering scaffolds.

Gelatine is formed from collagen by hydrolysis (breaking the triple-helix structure into single-strand molecules) and has a number of advantages over its precursor. It is less immunogenic compared with collagen and it retains informational signal sequences promoting cell adhesion, migration, differentiation and proliferation.

The surface irregularities of the scaffold pores due to the insoluble nanosized components promote the best adhesion of the cells on scaffold materials, while the nanoparticle fillers increase the composites’ strength. Thus, researchers doped halloysite nanotubes into a chitosan-agarose-gelatine matrix to design the implantable 3D cell scaffolds.

The resulting scaffolds demonstrate the shape memory upon deformation and have the porous structure suitable for cell adhesion and proliferation which is essential for artificial tissue fabrication. Macroscopic observations have confirmed that all the samples of scaffolds exhibited the sponge-like behaviour with the shape memory and shape reconstitution after deformation both in wet and dry states.

The swelling experiments indicated that the addition of halloysite can greatly improve the hydrophilicity and wetting of composite scaffolds. The incorporation of halloysite nanotubes into the scaffolds increases the water uptake and subsequently improves the biocompatibility. The intrinsic properties of halloysite nanotubes can be used for further improving the biocompatibility of scaffolds by the loading and sustained release of different bioactive compounds. This opens the prospect for fabrication of scaffolds with defined properties for directed differentiation of cells on matrixes due to gradual release of differentiation factors.

Experiments on two types of human cancer cells (A549 and Hep3B) show that in vitro cell adhesion and proliferation on the nanocomposites occur without changes in viability and cytoskeleton formation.

Further in vivo biocompatibility and biodegradability evaluation in rats has confirmed that the scaffolds promote the formation of novel blood vessels around the implantation sites. The scaffolds show excellent resorption within six weeks after implantation in rats. Neo-vascularization observed in newly formed connective tissue placed near the scaffold allows for the complete restoration of blood flow.

The results obtained indicate that the halloysite doped scaffolds are biocompatible as demonstrated both in vitro and in vivo. In addition, they confirm the great potential of chitosan-agarose-gelatine nanocomposite porous scaffolds doped with halloysite in tissue engineering with potential for sustained nanotube drug delivery.

For anyone interested about drug delivery and nanoparticles, there’s some interesting research profiled in my April 27, 2016 posting which describes how very few nanoparticles are actually delivered to specific sites.

Getting back to the regular program, here’s a link to and a citation for the paper on scaffolds and clay nanotubes,

Clay nanotube–biopolymer composite scaffolds for tissue engineering by Ekaterina A. Naumenko, Ivan D. Guryanov, Raghuvara Yendluri, Yuri M. Lvova, and Rawil F. Fakhrullin. Nanoscale, 2016,8, 7257-7271 DOI: 10.1039/C6NR00641H First published online 01 Mar 2016

This paper is behind a paywall.

Possible nanoparticle-based vaccine/microbiocide for herpes simplex virus-2

An April 27, 2016 news item on ScienceDaily describes a new therapeutic and preventative technology for herpes,

An effective vaccine against the virus that causes genital herpes has evaded researchers for decades. But now, researchers from the University of Illinois at Chicago [UIC] working with scientists from Germany have shown that zinc-oxide nanoparticles shaped like jacks can prevent the virus from entering cells, and help natural immunity to develop.

“We call the virus-trapping nanoparticle a microbivac, because it possesses both microbicidal and vaccine-like properties,” says corresponding author Deepak Shukla, professor of ophthalmology and microbiology & immunology in the UIC College of Medicine. “It is a totally novel approach to developing a vaccine against herpes, and it could potentially also work for HIV and other viruses,” he said.

The particles could serve as a powerful active ingredient in a topically-applied vaginal cream that provides immediate protection against herpes virus infection while simultaneously helping stimulate immunity to the virus for long-term protection, explained Shukla.

An April 27, 2016 UIC news release (also on EurekAlert), which originated the news item, provides more context for the work,

Herpes simplex virus-2, which causes serious eye infections in newborns and immunocompromised patients as well as genital herpes, is one of the most common human viruses. According to the Centers for Disease Control and Prevention, about 15 percent of people from ages 14-49 carry HSV-2, which can hide out for long periods of time in the nervous system. The genital lesions caused by the virus increase the risk for acquiring human immunodeficiency virus, or HIV.

“Your chances of getting HIV are three to four times higher if you already have genital herpes, which is a very strong motivation for developing new ways of preventing herpes infection,” Shukla said.

Treatments for HSV-2 include daily topical medications to suppress the virus and shorten the duration of outbreaks, when the virus is active and genital lesions are present. However, drug resistance is common, and little protection is provided against further infections. Efforts to develop a vaccine have been unsuccessful because the virus does not spend much time in the bloodstream, where most traditional vaccines do their work.

The news release goes on to provide technical details,

The tetrapod-shaped zinc-oxide nanoparticles, called ZOTEN, have negatively charged surfaces that attract the HSV-2 virus, which has positively charged proteins on its outer envelope. ZOTEN nanoparticles were synthesized using technology developed by material scientists at Germany’s Kiel University and protected under a joint patent with UIC.

When bound to the nanoparticles, HSV-2 cannot infect cells. But the bound virus remains susceptible to processing by immune cells called dendritic cells that patrol the vaginal lining. The dendritic cells “present” the virus to other immune cells that produce antibodies. The antibodies cripple the virus and trigger the production of customized killer cells that identify infected cells and destroy them before the virus can take over and spread.

The researchers showed that female mice swabbed with HSV-2 and an ointment containing ZOTEN had significantly fewer genital lesions than mice treated with a cream lacking ZOTEN. Mice treated with ZOTEN also had less inflammation in the central nervous system, where the virus can hide out.

The researchers were able to watch immune cells pry the virus off the nanoparticles for immune processing, using high-resolution fluorescence microscopy.

“It’s very clear that ZOTEN facilitates the development of immunity by holding the virus and letting the dendritic cells get to it,” Shukla said.

If found safe and effective in humans, a ZOTEN-containing cream ideally would be applied vaginally just prior to intercourse, Shukla said. But if a woman who had been using it regularly missed an application, he said, she may have already developed some immunity and still have some protection. Shukla hopes to further develop the nanoparticles to work against HIV, which like HSV-2 also has positively charged proteins embedded in its outer envelope.

ZOTEN particles are uniform in size and shape, making them attractive for use in other biomedical applications. The novel flame transport synthesis technology used to make them allows large-scale production, said Rainer Adelung, professor of nanomaterials at Kiel University. And, because no chemicals are used, the production process is green.

Adelung hopes to begin commercial production of ZOTEN through a startup company that will be run jointly with his colleagues at UIC.

Here’s an image of the particles, courtesy of UIC,

Zinc oxide tetrapod nanoparticles. Credit: Deepak Shukla

Zinc oxide tetrapod nanoparticles. Credit: Deepak Shukla

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

Intravaginal Zinc Oxide Tetrapod Nanoparticles as Novel Immunoprotective Agents against Genital Herpes by Thessicar E. Antoine, Satvik R. Hadigal, Abraam M. Yakoub, Yogendra Kumar Mishra, Palash Bhattacharya, Christine Haddad, Tibor Valyi-Nagy, Rainer Adelung, Bellur S. Prabhakar, and Deepak Shukla. The Journal of Immunology April 27, 2016 1502373  doi: 10.4049/jimmunol.1502373 Published online before print April 27, 2016

This paper is behind a paywall.

One final comment, it’s a long from a mouse vagina in this study to a human one.