Category Archives: medicine

Powering up your graphene implants so you don’t get fried in the process

A Sept. 23, 2016 news item on describes a way of making graphene-based medical implants safer,

In the future, our health may be monitored and maintained by tiny sensors and drug dispensers, deployed within the body and made from graphene—one of the strongest, lightest materials in the world. Graphene is composed of a single sheet of carbon atoms, linked together like razor-thin chicken wire, and its properties may be tuned in countless ways, making it a versatile material for tiny, next-generation implants.

But graphene is incredibly stiff, whereas biological tissue is soft. Because of this, any power applied to operate a graphene implant could precipitously heat up and fry surrounding cells.

Now, engineers from MIT [Massachusetts Institute of Technology] and Tsinghua University in Beijing have precisely simulated how electrical power may generate heat between a single layer of graphene and a simple cell membrane. While direct contact between the two layers inevitably overheats and kills the cell, the researchers found they could prevent this effect with a very thin, in-between layer of water.

A Sept. 23, 2016 MIT news release by Emily Chu, which originated the news item, provides more technical details,

By tuning the thickness of this intermediate water layer, the researchers could carefully control the amount of heat transferred between graphene and biological tissue. They also identified the critical power to apply to the graphene layer, without frying the cell membrane. …

Co-author Zhao Qin, a research scientist in MIT’s Department of Civil and Environmental Engineering (CEE), says the team’s simulations may help guide the development of graphene implants and their optimal power requirements.

“We’ve provided a lot of insight, like what’s the critical power we can accept that will not fry the cell,” Qin says. “But sometimes we might want to intentionally increase the temperature, because for some biomedical applications, we want to kill cells like cancer cells. This work can also be used as guidance [for those efforts.]”

Sandwich model

Typically, heat travels between two materials via vibrations in each material’s atoms. These atoms are always vibrating, at frequencies that depend on the properties of their materials. As a surface heats up, its atoms vibrate even more, causing collisions with other atoms and transferring heat in the process.

The researchers sought to accurately characterize the way heat travels, at the level of individual atoms, between graphene and biological tissue. To do this, they considered the simplest interface, comprising a small, 500-nanometer-square sheet of graphene and a simple cell membrane, separated by a thin layer of water.

“In the body, water is everywhere, and the outer surface of membranes will always like to interact with water, so you cannot totally remove it,” Qin says. “So we came up with a sandwich model for graphene, water, and membrane, that is a crystal clear system for seeing the thermal conductance between these two materials.”

Qin’s colleagues at Tsinghua University had previously developed a model to precisely simulate the interactions between atoms in graphene and water, using density functional theory — a computational modeling technique that considers the structure of an atom’s electrons in determining how that atom will interact with other atoms.

However, to apply this modeling technique to the group’s sandwich model, which comprised about half a million atoms, would have required an incredible amount of computational power. Instead, Qin and his colleagues used classical molecular dynamics — a mathematical technique based on a “force field” potential function, or a simplified version of the interactions between atoms — that enabled them to efficiently calculate interactions within larger atomic systems.

The researchers then built an atom-level sandwich model of graphene, water, and a cell membrane, based on the group’s simplified force field. They carried out molecular dynamics simulations in which they changed the amount of power applied to the graphene, as well as the thickness of the intermediate water layer, and observed the amount of heat that carried over from the graphene to the cell membrane.

Watery crystals

Because the stiffness of graphene and biological tissue is so different, Qin and his colleagues expected that heat would conduct rather poorly between the two materials, building up steeply in the graphene before flooding and overheating the cell membrane. However, the intermediate water layer helped dissipate this heat, easing its conduction and preventing a temperature spike in the cell membrane.

Looking more closely at the interactions within this interface, the researchers made a surprising discovery: Within the sandwich model, the water, pressed against graphene’s chicken-wire pattern, morphed into a similar crystal-like structure.

“Graphene’s lattice acts like a template to guide the water to form network structures,” Qin explains. “The water acts more like a solid material and makes the stiffness transition from graphene and membrane less abrupt. We think this helps heat to conduct from graphene to the membrane side.”

The group varied the thickness of the intermediate water layer in simulations, and found that a 1-nanometer-wide layer of water helped to dissipate heat very effectively. In terms of the power applied to the system, they calculated that about a megawatt of power per meter squared, applied in tiny, microsecond bursts, was the most power that could be applied to the interface without overheating the cell membrane.

Qin says going forward, implant designers can use the group’s model and simulations to determine the critical power requirements for graphene devices of different dimensions. As for how they might practically control the thickness of the intermediate water layer, he says graphene’s surface may be modified to attract a particular number of water molecules.

“I think graphene provides a very promising candidate for implantable devices,” Qin says. “Our calculations can provide knowledge for designing these devices in the future, for specific applications, like sensors, monitors, and other biomedical applications.”

This research was supported in part by the MIT International Science and Technology Initiative (MISTI): MIT-China Seed Fund, the National Natural Science Foundation of China, DARPA [US Defense Advanced Research Projects Agency], the Department of Defense (DoD) Office of Naval Research, the DoD Multidisciplinary Research Initiatives program, the MIT Energy Initiative, and the National Science Foundation.

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

Intercalated water layers promote thermal dissipation at bio–nano interfaces by Yanlei Wang, Zhao Qin, Markus J. Buehler, & Zhiping Xu. Nature Communications 7, Article number: 12854 doi:10.1038/ncomms12854 Published 23 September 2016

This paper is open access.

Tattoo therapy for chronic disease?

It’s good to wake up to something truly new. In this case, it’s using tattoos and nanoparticles for medical applications. From a Sept. 22, 2016 news item on ScienceDaily,

A temporary tattoo to help control a chronic disease might someday be possible, according to scientists at Baylor College of Medicine [Texas, US] who tested antioxidant nanoparticles created at Rice University [Texas, US].

A Sept. 22, 2016 Rice University news release, which originated the news item, provides more information and some good explanations of the terms used (Note: Links have been removed),

A proof-of-principle study led by Baylor scientist Christine Beeton published today by Nature’s online, open-access journal Scientific Reports shows that nanoparticles modified with polyethylene glycol are conveniently choosy as they are taken up by cells in the immune system.

That could be a plus for patients with autoimmune diseases like multiple sclerosis, one focus of study at the Beeton lab. “Placed just under the skin, the carbon-based particles form a dark spot that fades over about one week as they are slowly released into the circulation,” Beeton said.

T and B lymphocyte cells and macrophages are key components of the immune system. However, in many autoimmune diseases such as multiple sclerosis, T cells are the key players. One suspected cause is that T cells lose their ability to distinguish between invaders and healthy tissue and attack both.

In tests at Baylor, nanoparticles were internalized by T cells, which inhibited their function, but ignored by macrophages. “The ability to selectively inhibit one type of cell over others in the same environment may help doctors gain more control over autoimmune diseases,” Beeton said.

“The majority of current treatments are general, broad-spectrum immunosuppressants,” said Redwan Huq, lead author of the study and a graduate student in the Beeton lab. “They’re going to affect all of these cells, but patients are exposed to side effects (ranging) from infections to increased chances of developing cancer. So we get excited when we see something new that could potentially enable selectivity.” Since the macrophages and other splenic immune cells are unaffected, most of a patient’s existing immune system remains intact, he said.

The soluble nanoparticles synthesized by the Rice lab of chemist James Tour have shown no signs of acute toxicity in prior rodent studies, Huq said. They combine polyethylene glycol with hydrophilic carbon clusters, hence their name, PEG-HCCs. The carbon clusters are 35 nanometers long, 3 nanometers wide and an atom thick, and bulk up to about 100 nanometers in globular form with the addition of PEG. They have proven to be efficient scavengers of reactive oxygen species called superoxide molecules, which are expressed by cells the immune system uses to kill invading microorganisms.

T cells use superoxide in a signaling step to become activated. PEG-HCCs remove this superoxide from the T cells, preventing their activation without killing the cells.

Beeton became aware of PEG-HCCs during a presentation by former Baylor graduate student Taeko Inoue, a co-author of the new study. “As she talked, I was thinking, ‘That has to work in models of multiple sclerosis,’” Beeton said. “I didn’t have a good scientific rationale, but I asked for a small sample of PEG-HCCs to see if they affected immune cells.

“We found they affected the T lymphocytes and not the other splenic immune cells, like the macrophages. It was completely unexpected,” she said.

The Baylor lab’s tests on animal models showed that small amounts of PEG-HCCs injected under the skin are slowly taken up by T lymphocytes, where they collect and inhibit the cell’s function. They also found the nanoparticles did not remain in T cells and dispersed within days after uptake by the cells.

“That’s an issue because you want a drug that’s in the system long enough to be effective, but not so long that, if you have a problem, you can’t remove it,” Beeton said. “PEG-HCCs can be administered for slow release and don’t stay in the system for long. This gives us much better control over the circulating half-life.”

“The more we study the abilities of these nanoparticles, the more surprised we are at how useful they could be for medical applications,” Tour said. The Rice lab has published papers with collaborators at Baylor and elsewhere on using functionalized nanoparticles to deliver cancer drugs to tumors and to quench the overproduction of superoxides after traumatic brain injuries.

Beeton suggested delivering carbon nanoparticles just under the skin rather than into the bloodstream would keep them in the system longer, making them more available for uptake by T cells. And the one drawback – a temporary but visible spot on the skin that looks like a tattoo – could actually be a perk to some.

“We saw it made a black mark when we injected it, and at first we thought that’s going to be a real problem if we ever take it into the clinic,” Beeton said. “But we can work around that. We can inject into an area that’s hidden, or use micropattern needles and shape it.

“I can see doing this for a child who wants a tattoo and could never get her parents to go along,” she said. “This will be a good way to convince them.”

The research was supported by Baylor College of Medicine, the National Multiple Sclerosis Society, National Institutes of Health, the Dan L. Duncan Cancer Center, John S. Dunn Gulf Coast Consortium for Chemical Genomics and the U.S. Army-funded Traumatic Brain Injury Consortium.

That’s an interesting list of funders at the end of the news release.

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

Preferential uptake of antioxidant carbon nanoparticles by T lymphocytes for immunomodulation by Redwan Huq, Errol L. G. Samuel, William K. A. Sikkema, Lizanne G. Nilewski, Thomas Lee, Mark R. Tanner, Fatima S. Khan, Paul C. Porter, Rajeev B. Tajhya, Rutvik S. Patel, Taeko Inoue, Robia G. Pautler, David B. Corry, James M. Tour, & Christine Beeton. Scientific Reports 6, Article number: 33808 (2016) doi:10.1038/srep33808 Published online: 22 September 2016

This paper is open access.

Here’s an image provided by the researchers,

Polyethylene glycol-hydrophilic carbon clusters developed at Rice University were shown to be selectively taken up by T cells, which inhibits their function, in tests at Baylor College of Medicine. The researchers said the nanoparticles could lead to new strategies for controlling autoimmune diseases like multiple sclerosis. (Credit: Errol Samuel/Rice University) - See more at:

Polyethylene glycol-hydrophilic carbon clusters developed at Rice University were shown to be selectively taken up by T cells, which inhibits their function, in tests at Baylor College of Medicine. The researchers said the nanoparticles could lead to new strategies for controlling autoimmune diseases like multiple sclerosis. (Credit: Errol Samuel/Rice University)

Ginger-derived nano-lipids for colorectal cancer

Didier Merlin’s team at the US Dept. of Veteran’s Affairs along with researchers from Georgia State University and from two Chinese universities have published more research on what they are calling, GDNPs, or ginger-derived nanoparticles. (See my Sept. 8, 2016 posting for my first post about ginger nanoparticles and the US Dept. of Veterans Affairs.)

Ginger, well known for relieving nausea, may soon be able to claim another health benefit according to a Sept. 6, 2016 news item on ScienceDaily,

Edible ginger-derived nano-lipids created from a specific population of ginger nanoparticles show promise for effectively targeting and delivering chemotherapeutic drugs used to treat colon cancer, according to a study by researchers at the Institute for Biomedical Sciences at Georgia State University, the Atlanta Veterans Affairs Medical Center and Wenzhou Medical University and Southwest University in China.

A Sept. 6, 2016 Georgia State University news release (also on EurekAlert), which originated the news item, describes both the situation with colorectal cancer in the US and the research,

Colorectal cancer is the third most common cancer among men and women in the United States, and the second-leading cause of cancer-related deaths among men and women worldwide. The incidence of colorectal cancer has increased over the last few years, with about one million new cases diagnosed annually. Non-targeted chemotherapy is the most common therapeutic strategy available for colon cancer patients, but this treatment method is unable to distinguish between cancerous and healthy cells, leading to poor therapeutic effects on tumor cells and severe toxic side effects on healthy cells. Enabling chemotherapeutic drugs to target cancer cells would be a major development in the treatment of colon cancer.

In this study, the researchers isolated a specific nanoparticle population from edible ginger (GDNP 2) and reassembled their lipids, naturally occurring molecules that include fats, to form ginger-derived nano-lipids, also known as nanovectors. To achieve accurate targeting of tumor tissues, the researchers modified the nanovectors with folic acid to create FA-modified nanovectors (FA nanovectors). Folic acid shows high-affinity binding to the folate receptors that are highly expressed on many tumors and almost undetectable on non-tumor cells.

The FA nanovectors were tested as a delivery platform for doxorubicin, a chemotherapeutic drug used to treat colon cancer. The researchers found that doxorubicin was efficiently loaded into the FA nanovectors, and the FA nanovectors were efficiently taken up by colon cancer cells, exhibited excellent biocompatibility and successfully inhibited tumor growth. Compared to a commercially available option for delivering doxorubicin, the FA nanovectors released the drug more rapidly in an acidic pH that resembled the tumor environment, suggesting this delivery strategy could decrease the severe side effects of doxorubicin. These findings were published in the journal Molecular Therapy.

“Our results show that FA nanovectors made of edible ginger-derived lipids could shift the current paradigm of drug delivery away from artificially synthesized nanoparticles toward the use of nature-derived nanovectors from edible plants,” said Dr. Didier Merlin, a professor in the Institute for Biomedical Sciences at Georgia State and a Research Career Scientist at the VA Medical Center. “Because they are nontoxic and can be produced on a large scale, FA nanovectors derived from edible plants could represent one of the safest targeted therapeutic delivery platforms.”

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

Edible Ginger-derived Nano-lipids Loaded with Doxorubicin as a Novel Drug-delivery Approach for Colon Cancer Therapy by Mingzhen Zhang, Bo Xiao, Huan Wang, Moon Kwon Han, Zhan Zhang, Emilie Viennois, Changlong Xu, and Didier Merlin. Molecular Therapy (2016); doi:10.1038/mt.2016.159 Advance online publication 13 September 2016

This paper is behind a paywall.

Graphene in the bone

An international team of US, Brazilian, and Indian scientists has developed a graphene-based material they believe could be used in bone implants. From a Sept. 2, 2016 news item on ScienceDaily,

Flakes of graphene welded together into solid materials may be suitable for bone implants, according to a study led by Rice University scientists.

The Rice lab of materials scientist Pulickel Ajayan and colleagues in Texas, Brazil and India used spark plasma sintering to weld flakes of graphene oxide into porous solids that compare favorably with the mechanical properties and biocompatibility of titanium, a standard bone-replacement material.

A Sept. 2, 2016 Rice University news release (also on EurekAlert), which originated the news item, explains the work in more detail,

The researchers believe their technique will give them the ability to create highly complex shapes out of graphene in minutes using graphite molds, which they believe would be easier to process than specialty metals.

“We started thinking about this for bone implants because graphene is one of the most intriguing materials with many possibilities and it’s generally biocompatible,” said Rice postdoctoral research associate Chandra Sekhar Tiwary, co-lead author of the paper with Dibyendu Chakravarty of the International Advanced Research Center for Powder Metallurgy and New Materials in Hyderabad, India. “Four things are important: its mechanical properties, density, porosity and biocompatibility.”

Tiwary said spark plasma sintering is being used in industry to make complex parts, generally with ceramics. “The technique uses a high pulse current that welds the flakes together instantly. You only need high voltage, not high pressure or temperatures,” he said. The material they made is nearly 50 percent porous, with a density half that of graphite and a quarter of titanium metal. But it has enough compressive strength — 40 megapascals — to qualify it for bone implants, he said. The strength of the bonds between sheets keeps it from disintegrating in water.

The researchers controlled the density of the material by altering the voltage that delivers the highly localized blast of heat that makes the nanoscale welds. Though the experiments were carried out at room temperature, the researchers made graphene solids of various density by raising these sintering temperatures from 200 to 400 degrees Celsius. Samples made at local temperatures of 300 C proved best, Tiwary said. “The nice thing about two-dimensional materials is that they give you a lot of surface area to connect. With graphene, you just need to overcome a small activation barrier to make very strong welds,” he said.

With the help of colleagues at Hysitron in Minnesota, the researchers measured the load-bearing capacity of thin sheets of two- to five-layer bonded graphene by repeatedly stressing them with a picoindenter attached to a scanning electron microscope and found they were stable up to 70 micronewtons. Colleagues at the University of Texas MD Anderson Cancer Center successfully cultured cells on the material to show its biocompatibility. As a bonus, the researchers also discovered the sintering process has the ability to reduce graphene oxide flakes to pure bilayer graphene, which makes them stronger and more stable than graphene monolayers or graphene oxide.

“This example demonstrates the possible use of unconventional materials in conventional technologies,” Ajayan said. “But these transitions can only be made if materials such as 2-D graphene layers can be scalably made into 3-D solids with appropriate density and strength.

“Engineering junctions and strong interfaces between nanoscale building blocks is the biggest challenge in achieving such goals, but in this case, spark plasma sintering seems to be effective in joining graphene sheets to produce strong 3-D solids,” he said.

The researchers have produced an animation depicting of graphene oxide layers being stacked,

A molecular dynamics simulation shows how graphene oxide layers stack when welded by spark plasma sintering. The presence of oxygen molecules at left prevents the graphene layers from bonding, as they do without oxygen at right. Courtesy of the Ajayan and Galvão groups

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

3D Porous Graphene by Low-Temperature Plasma Welding for Bone Implants by Dibyendu Chakravarty, Chandra Sekhar Tiwary, Cristano F. Woellner, Sruthi Radhakrishnan4, Soumya Vinod, Sehmus Ozden, Pedro Alves da Silva Autreto, Sanjit Bhowmick, Syed Asif, Sendurai A Mani, Douglas S. Galvao, and Pulickel M. Ajayan. Advanced Materials DOI: 10.1002/adma.201603146 Version of Record online: 26 AUG 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Long-term brain mapping with injectable electronics

Charles Lieber and his team at Harvard University announced a success with their work on injectable electronics last year (see my June 11, 2015 posting for more) and now they are reporting on their work with more extensive animal studies according to an Aug. 29, 2016 news item on,

Scientists in recent years have made great strides in the quest to understand the brain by using implanted probes to explore how specific neural circuits work.

Though effective, those probes also come with their share of problems as a result of rigidity. The inflammation they produce induces chronic recording instability and means probes must be relocated every few days, leaving some of the central questions of neuroscience – like how the neural circuits are reorganized during development, learning and aging- beyond scientists’ reach.

But now, it seems, things are about to change.

Led by Charles Lieber, The Mark Hyman Jr. Professor of Chemistry and chair of the Department of Chemistry and Chemical Biology, a team of researchers that included graduate student Tian-Ming Fu, postdoctoral fellow Guosong Hong, graduate student Tao Zhou and others, has demonstrated that syringe-injectable mesh electronics can stably record neural activity in mice for eight months or more, with none of the inflammation

An Aug. 29, 2016 Harvard University press release, which originated the news item, provides more detail,

“With the ability to follow the same individual neurons in a circuit chronically…there’s a whole suite of things this opens up,” Lieber said. “The eight months we demonstrate in this paper is not a limit, but what this does show is that mesh electronics could be used…to investigate neuro-degenerative diseases like Alzheimer’s, or processes that occur over long time, like aging or learning.”

Lieber and colleagues also demonstrated that the syringe-injectable mesh electronics could be used to deliver electrical stimulation to the brain over three months or more.

“Ultimately, our aim is to create these with the goal of finding clinical applications,” Lieber said. “What we found is that, because of the lack of immune response (to the mesh electronics), which basically insulates neurons, we can deliver stimulation in a much more subtle way, using lower voltages that don’t damage tissue.”

The possibilities, however, don’t end there.

The seamless integration of the electronics and biology, Lieber said, could open the door to an entirely new class of brain-machine interfaces and vast improvements in prosthetics, among other fields.

“Today, brain-machine interfaces are based on traditional implanted probes, and there has been some impressive work that’s been done in that field,” Lieber said. “But all the interfaces rely on the same technique to decode neural signals.”

Because traditional rigid implanted probes are invariably unstable, he explained, researchers and clinicians rely on decoding what they call the “population average” – essentially taking a host of neural signals and applying complex computational tools to determine what they mean.

Using tissue-like mesh electronics, by comparison, researchers may be able to read signals from specific neurons over time, potentially allowing for the development of improved brain-machine interfaces for prosthetics.

“We think this is going to be very powerful, because we can identify circuits and both record and stimulate in a way that just hasn’t been possible before,” Lieber said. “So what I like to say is: I think therefore it happens.”

Lieber even held out the possibility that the syringe-injectable mesh electronics could one day be used to treat catastrophic injuries to the brain and spinal cord.

“I don’t think that’s science-fiction,” he said. “Other people may say that will be possible through, for example, regenerative medicine, but we are pursuing this from a different angle.

“My feeling is that this is about a seamless integration between the biological and the electronic systems, so they’re not distinct entities,” he continued. “If we can make the electronics look like the neural network, they will work together…and that’s where you want to be if you want to exploit the strengths of both.”

In the 2015 posting, Lieber was discussing cyborgs, here he broaches the concept without using the word, “… seamless integration between the biological and the electronic systems, so they’re not distinct entities.”

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

Stable long-term chronic brain mapping at the single-neuron level by Tian-Ming Fu, Guosong Hong, Tao Zhou, Thomas G Schuhmann, Robert D Viveros, & Charles M Lieber. Nature Methods (2016) doi:10.1038/nmeth.3969 Published online 29 August 2016

This paper is behind a paywall.

Improving the quality of sight in artificial retinas

Researchers at France’s Centre national de la recherche scientifique (CNRS) and elsewhere have taken a step forward to improving sight derived from artificial retinas according to an Aug. 25, 2016 news item on Nanowerk (Note: A link has been removed),

A major therapeutic challenge, the retinal prostheses that have been under development during the past ten years can enable some blind subjects to perceive light signals, but the image thus restored is still far from being clear. By comparing in rodents the activity of the visual cortex generated artificially by implants against that produced by “natural sight”, scientists from CNRS, CEA [Commissariat à l’énergie atomique et aux énergies alternatives is the French Alternative Energies and Atomic Energy Commission], INSERM [Institut national de la santé et de la recherche médicale is the French National Institute of Health and Medical Research], AP-HM [Assistance Publique – Hôpitaux de Marseille] and Aix-Marseille Université identified two factors that limit the resolution of prostheses.

Based on these findings, they were able to improve the precision of prosthetic activation. These multidisciplinary efforts, published on 23 August 2016 in eLife (“Probing the functional impact of sub-retinal prosthesis”), thus open the way towards further advances in retinal prostheses that will enhance the quality of life of implanted patients.

An Aug. 24, 2015 CNRS press release, which originated the news item, expands on the theme,

A retinal prosthesis comprises three elements: a camera (inserted in the patient’s spectacles), an electronic microcircuit (which transforms data from the camera into an electrical signal) and a matrix of microscopic electrodes (implanted in the eye in contact with the retina). This prosthesis replaces the photoreceptor cells of the retina: like them, it converts visual information into electrical signals which are then transmitted to the brain via the optic nerve. It can treat blindness caused by a degeneration of retinal photoreceptors, on condition that the optical nerve has remained functional1. Equipped with these implants, patients who were totally blind can recover visual perceptions in the form of light spots, or phosphenes.  Unfortunately, at present, the light signals perceived are not clear enough to recognize faces, read or move about independently.

To understand the resolution limits of the image generated by the prosthesis, and to find ways of optimizing the system, the scientists carried out a large-scale experiment on rodents.  By combining their skills in ophthalmology and the physiology of vision, they compared the response of the visual system of rodents to both natural visual stimuli and those generated by the prosthesis.

Their work showed that the prosthesis activated the visual cortex of the rodent in the correct position and at ranges comparable to those obtained under natural conditions.  However, the extent of the activation was much too great, and its shape was much too elongated.  This deformation was due to two separate phenomena observed at the level of the electrode matrix. Firstly, the scientists observed excessive electrical diffusion: the thin layer of liquid situated between the electrode and the retina passively diffused the electrical stimulus to neighboring nerve cells. And secondly, they detected the unwanted activation of retinal fibers situated close to the cells targeted for stimulation.

Armed with these findings, the scientists were able to improve the properties of the interface between the prosthesis and retina, with the help of specialists in interface physics.  Together, they were able to generate less diffuse currents and significantly improve artificial activation, and hence the performance of the prosthesis.

This lengthy study, because of the range of parameters covered (to study the different positions, types and intensities of signals) and the surgical problems encountered (in inserting the implant and recording the images generated in the animal’s brain) has nevertheless opened the way towards making promising improvements to retinal prostheses for humans.

This work was carried out by scientists from the Institut de Neurosciences de la Timone (CNRS/AMU) and AP-HM, in collaboration with CEA-Leti and the Institut de la Vision (CNRS/Inserm/UPMC).

Artificial retinas

© F. Chavane & S. Roux.

Activation (colored circles at the level of the visual cortex) of the visual system by prosthetic stimulation (in the middle, in red, the insert shows an image of an implanted prosthesis) is greater and more elongated than the activation achieved under natural stimulation (on the left, in yellow). Using a protocol to adapt stimulation (on the right, in green), the size and shape of the activation can be controlled and are more similar to natural visual activation (yellow).

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

Probing the functional impact of sub-retinal prosthesis by Sébastien Roux, Frédéric Matonti, Florent Dupont, Louis Hoffart, Sylvain Takerkart, Serge Picaud, Pascale Pham, and Frédéric Chavane. eLife 2016;5:e12687 DOI: Published August 23, 2016

This paper appears to be open access.

Nanotubes tunnel between neurons in Parkinson’s disease

An Aug. 22, 2016 news item on ScienceDaily describes how scientists from the Institut Pasteur (France) have developed insight into one of the processes in Parkinson’s disease,

Scientists have demonstrated the role of lysosomal vesicles in transporting alpha-synuclein aggregates, responsible for Parkinson’s and other neurodegenerative diseases, between neurons. These proteins move from one neuron to the next in lysosomal vesicles which travel along the ‘tunneling nanotubes’ between cells.

An Aug. 22, 2016 Institut Pasteur press release (also on EurekAlert), expands on the theme,

Synucleinopathies, a group of neurodegenerative diseases including Parkinson’s disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs.

In this study, scientists from the Membrane Traffic and Pathogenesis Unit, directed by Chiara Zurzolo at the Institut Pasteur, used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.

After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons.

This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies.

These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.

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

Tunneling nanotubes spread fibrillar α‐synuclein by intercellular trafficking of lysosomes by Saïda Abounit, Luc Bousset, Frida Loria, Seng Zhu, Fabrice de Chaumont, Laura Pieri, Jean-Christophe Olivo-Marin, Ronald Melki, Chiara Zurzolo. The EMBO Journal (2016) e201593411 DOI 10.15252/embj.201593411 Published online 22.08.2016

This paper is behind a paywall.

Just swallow your battery, eh? Ingestible batteries

Christopher Bettinger, Ph.D., is developing an edible battery made with melanin and dissolvable materials. Courtesy of: Bettinger lab

Christopher Bettinger, Ph.D., is developing an edible battery made with melanin and dissolvable materials. Courtesy of: Bettinger lab

An Aug. 23, 2016 news item on describes a session at the 252nd American Chemical Society (ACS) meeting held Aug. 21 – 25, 2016 in Philadelphia,

Non-toxic, edible batteries could one day power ingestible devices for diagnosing and treating disease. One team reports new progress toward that goal with their batteries made with melanin pigments, naturally found in the skin, hair and eyes.

“For decades, people have been envisioning that one day, we would have edible electronic devices to diagnose or treat disease,” says Christopher Bettinger, Ph.D. “But if you want to take a device every day, you have to think about toxicity issues. That’s when we have to think about biologically derived materials that could replace some of these things you might find in a RadioShack.”

An Aug. 23, 2016 ACS news release (also on EurekAlert), which originated the news item, further describes the work featured in the ACS meeting session,

About 20 years ago, scientists did develop a battery-operated ingestible camera as a complementary tool to endoscopies. It can image places in the digestive system that are inaccessible to the traditional endoscope. But it is designed to pass through the body and be excreted. For a single use, the risk that the camera with a conventional battery will get stuck in the gastrointestinal tract is small. But the chances of something going wrong would increase unacceptably if doctors wanted to use it more frequently on a single patient.

The camera and some implantable devices such as pacemakers run on batteries containing toxic components that are sequestered away from contact with the body. But for low-power, repeat applications such as drug-delivery devices that are meant to be swallowed, non-toxic and degradable batteries would be ideal.

“The beauty is that by definition an ingestible, degradable device is in the body for no longer than 20 hours or so,” Bettinger says. “Even if you have marginal performance, which we do, that’s all you need.”

While he doesn’t have to worry about longevity, toxicity is an issue. To minimize the potential harm of future ingestible devices, Bettinger’s team at Carnegie Mellon University (CMU) decided to turn to melanins and other naturally occurring compounds. In our skin, hair and eyes, melanins absorb ultraviolet light to quench free radicals and protect us from damage. They also happen to bind and unbind metallic ions. “We thought, this is basically a battery,” Bettinger says.

Building on this idea, the researchers experimented with battery designs that use melanin pigments at either the positive or negative terminals; various electrode materials such as manganese oxide and sodium titanium phosphate; and cations such as copper and iron that the body uses for normal functioning.

“We found basically that they work,” says Hang-Ah Park, Ph.D., a post-doctoral researcher at CMU. “The exact numbers depend on the configuration, but as an example, we can power a 5 milliWatt device for up to 18 hours using 600 milligrams of active melanin material as a cathode.”

Although the capacity of a melanin battery is low relative to lithium-ion, it would be high enough to power an ingestible drug-delivery or sensing device. For example, Bettinger envisions using his group’s battery for sensing gut microbiome changes and responding with a release of medicine, or for delivering bursts of a vaccine over several hours before degrading.

In parallel with the melanin batteries, the team is also making edible batteries with other biomaterials such as pectin, a natural compound from plants used as a gelling agent in jams and jellies. Next, they plan on developing packaging materials that will safely deliver the battery to the stomach.

When these batteries will be incorporated into biomedical devices is uncertain, but Bettinger has already found another application for them. His lab uses the batteries to probe the structure and chemistry of the melanin pigments themselves to better understand how they work.

I previously wrote about an ingestible battery in a November 23, 2015 posting featuring work from MIT (Massachusetts Institute of Technology).

Counteracting chemotherapy resistance with nanoparticles that mimic salmonella

Given the reputation that salmonella (for those who don’t know, it’s a toxin you don’t want to find in your food) has, a nanoparticle which mimics its effects has a certain cachet. An Aug. 22, 2016 news item on Nanowerk,

Researchers at the University of Massachusetts Medical School have designed a nanoparticle that mimics the bacterium Salmonella and may help to counteract a major mechanism of chemotherapy resistance.

Working with mouse models of colon and breast cancer, Beth McCormick, Ph.D., and her colleagues demonstrated that when combined with chemotherapy, the nanoparticle reduced tumor growth substantially more than chemotherapy alone.

Credit: Rocky Mountain Laboratories,NIAID,NIHColor-enhanced scanning electron micrograph showing Salmonella typhimurium (red) invading cultured human cells.

Credit: Rocky Mountain Laboratories,NIAID,NIHColor-enhanced scanning electron micrograph showing Salmonella typhimurium (red) invading cultured human cells.

An Aug. 22, 2016 US National Institute of Cancer news release, which originated the news item, explains the research in more detail,

A membrane protein called P-glycoprotein (P-gp) acts like a garbage chute that pumps waste, foreign particles, and toxins out of cells. P-gp is a member of a large family of transporters, called ATP-binding cassette (ABC) transporters, that are active in normal cells but also have roles in cancer and other diseases. For instance, cancer cells can co-opt P-gp to rid themselves of chemotherapeutic agents, severely limiting the efficacy of these drugs.

In previous work, Dr. McCormick and her colleagues serendipitously discovered that Salmonella enterica, a bacterium that causes food poisoning, decreases the amount of P-gp on the surface of intestinal cells. Because Salmonella has the capacity to grow selectively in cancer cells, the researchers wondered whether there was a way to use the bacterium to counteract chemotherapy resistance caused by P-gp.

“While trying to understand how Salmonella invades the human host, we made this other observation that may be relevant to cancer therapeutics and multidrug resistance,” explained Dr. McCormick.

Salmonella and Cancer Cells

To determine the specific bacterial component responsible for reducing P-gp levels, the researchers engineered multiple Salmonella mutant strains and tested their effect on P-gp levels in colon cells. They found that a Salmonella strain lacking the bacterial protein SipA was unable to reduce P-gp levels in the colon of mice or in a human colon cancer cell line. Salmonella secretes SipA, along with other proteins, to help the bacterium invade human cells.

The researchers then showed that treatment with SipA protein alone decreased P-gp levels in cell lines of human colon cancer, breast cancer, bladder cancer, and lymphoma.

Because P-gp can pump drugs out of cells, the researchers next sought to determine whether SipA treatment would prevent cancer cells from expelling chemotherapy drugs.

When they treated human colon cancer cells with the chemotherapy agents doxorubicin or vinblastine, with or without SipA, they found that the addition of SipA increased drug retention inside the cells. SipA also increased the cancer cells’ sensitivity to both drugs, suggesting that it could possibly be used to enhance chemotherapy.

“Through millions of years of co-evolution, Salmonella has figured out a way to remove this transporter from the surface of intestinal cells to facilitate host infection,” said Dr. McCormick. “We capitalized on the organism’s ability to perform that function.”

A Nanoparticle Mimic

It would not be feasible to infect people with the bacterium, and SipA on its own will likely deteriorate quickly in the bloodstream, coauthor Gang Han, Ph.D., of the University of Massachusetts Medical School, explained in a press release. The researchers therefore fused SipA to gold nanoparticles, generating what they refer to as a nanoparticle mimic of Salmonella. They designed the nanoparticle to enhance the stability of SipA, while retaining its ability to interact with other proteins.

In an effort to target tumors without harming healthy tissues, the researchers used a nanoparticle of specific size that should only be able to access the tumor tissue due to its “leaky” architecture. “Because of this property, we are hoping to be able to avoid negative effects to healthy tissues,” said Dr. McCormick. Another benefit of this technology is that the nanoparticle can be modified to enhance tumor targeting and minimize the potential for side effects, she added.

The researchers showed that this nanoparticle was 100 times more effective than SipA protein alone at reducing P-gp levels in a human colon cancer cell line. The enhanced function of the nanoparticle is likely due to stabilization of SipA, explained the researchers.

The team then tested the nanoparticle in a mouse model of colon cancer, because this cancer type is known to express high levels of P-gp. When they treated tumor-bearing mice with the nanoparticle plus doxorubicin, P-gp levels dropped and the tumors grew substantially less than in mice treated with the nanoparticle or doxorubicin alone. The researchers observed similar results in a mouse model of human breast cancer.

There are concerns about the potential effect of nanoparticles on normal tissues. “P-gp has evolved as a defense mechanism” to rid healthy cells of toxic molecules, said Suresh Ambudkar, Ph.D., deputy chief of the Laboratory of Cell Biology in NCI’s Center for Cancer Research. It plays an important role in protecting cells of the blood-brain barrier, liver, testes, and kidney. “So when you try to interfere with that, you may create problems,” he said.

The researchers, however, found no evidence of nanoparticle accumulation in the brain, heart, kidney, or lungs of mice, nor did it appear to cause toxicity. They did observe that the nanoparticles accumulated in the liver and spleen, though this was expected because these organs filter the blood, said Dr. McCormick.

Moving Forward

The research team is moving forward with preclinical studies of the SipA nanoparticle to test its safety and toxicity, and to establish appropriate dosage levels.

However, Dr. Ambudkar noted, “the development of drug resistance in cancer cells is a multifactorial process. In addition to the ABC transporters, other phenomena are involved, such as drug metabolism.” And because there is a large family of ABC transporters, one transporter can compensate if another is blocked, he explained.

For the last 25 years, clinical trials with drugs that inhibit P-gp have failed to overcome chemotherapy resistance, Dr. Ambudkar said. Tackling the issue of multidrug resistance in cancer, he continued, “is not something that can be solved easily.”

Dr. McCormick and her team are also pursuing research to better characterize and understand the biology of SipA. “We are not naïve about the complexity of the problem,” she said. “However, if we know more about the biology, we believe we can ultimately make a better drug.”

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

A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours by Regino Mercado-Lubo, Yuanwei Zhang, Liang Zhao, Kyle Rossi, Xiang Wu, Yekui Zou, Antonio Castillo, Jack Leonard, Rita Bortell, Dale L. Greiner, Leonard D. Shultz, Gang Han, & Beth A. McCormick. Nature Communications 7, Article number: 12225  doi:10.1038/ncomms12225 Published 25 July 2016

This paper is open access.

Nanoparticles could make blood clot faster

It was the 252nd meeting for the American Chemical Society from Aug. 21 – 25, 2016 and that meant a flurry of news about the latest research. From an Aug. 23, 2016 news item on Nanowerk,

Whether severe trauma occurs on the battlefield or the highway, saving lives often comes down to stopping the bleeding as quickly as possible. Many methods for controlling external bleeding exist, but at this point, only surgery can halt blood loss inside the body from injury to internal organs. Now, researchers have developed nanoparticles that congregate wherever injury occurs in the body to help it form blood clots, and they’ve validated these particles in test tubes and in vivo [animal testing].

The researchers will present their work today [Aug. 22, 2016] at the 252nd National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,000 presentations on a wide range of science topics.

An Aug. 22, 2016 American Chemical Society (ACS) news release (also on EurekAlert), which originated the news item, provided more detail,

“When you have uncontrolled internal bleeding, that’s when these particles could really make a difference,” says Erin B. Lavik, Sc.D. “Compared to injuries that aren’t treated with the nanoparticles, we can cut bleeding time in half and reduce total blood loss.”

Trauma remains a top killer of children and younger adults, and doctors have few options for treating internal bleeding. To address this great need, Lavik’s team developed a nanoparticle that acts as a bridge, binding to activated platelets and helping them join together to form clots. To do this, the nanoparticle is decorated with a molecule that sticks to a glycoprotein found only on the activated platelets.

Initial studies suggested that the nanoparticles, delivered intravenously, helped keep rodents from bleeding out due to brain and spinal injury, Lavik says. But, she acknowledges, there was still one key question: “If you are a rodent, we can save your life, but will it be safe for humans?”

As a step toward assessing whether their approach would be safe in humans, they tested the immune response toward the particles in pig’s blood. If a treatment triggers an immune response, it would indicate that the body is mounting a defense against the nanoparticle and that side effects are likely. The team added their nanoparticles to pig’s blood and watched for an uptick in complement, a key indicator of immune activation. The particles triggered complement in this experiment, so the researchers set out to engineer around the problem.

“We made a battery of particles with different charges and tested to see which ones didn’t have this immune-response effect,” Lavik explains. “The best ones had a neutral charge.” But neutral nanoparticles had their own problems. Without repulsive charge-charge interactions, the nanoparticles have a propensity to aggregate even before being injected. To fix this issue, the researchers tweaked their nanoparticle storage solution, adding a slippery polymer to keep the nanoparticles from sticking to each other.

Lavik also developed nanoparticles that are stable at higher temperatures, up to 50 degrees Celsius (122 degrees Fahrenheit). This would allow the particles to be stored in a hot ambulance or on a sweltering battlefield.

In future studies, the researchers will test whether the new particles activate complement in human blood. Lavik also plans to identify additional critical safety studies they can perform to move the research forward. For example, the team needs to be sure that the nanoparticles do not cause non-specific clotting, which could lead to a stroke. Lavik is hopeful though that they could develop a useful clinical product in the next five to 10 years.

It’s not unusual for scientists to give an estimate of 5 – 10 years before their science reaches the market.  Another popular range is 3 – 5 years.