Tag Archives: US National Institutes of Health

Nanoelectronic thread (NET) brain probes for long-term neural recording

A rendering of the ultra-flexible probe in neural tissue gives viewers a sense of the device’s tiny size and footprint in the brain. Image credit: Science Advances.

As long time readers have likely noted, I’m not a big a fan of this rush to ‘colonize’ the brain but it continues apace as a Feb. 15, 2017 news item on Nanowerk announces a new type of brain probe,

Engineering researchers at The University of Texas at Austin have designed ultra-flexible, nanoelectronic thread (NET) brain probes that can achieve more reliable long-term neural recording than existing probes and don’t elicit scar formation when implanted.

A Feb. 15, 2017 University of Texas at Austin news release, which originated the news item, provides more information about the new probes (Note: A link has been removed),

A team led by Chong Xie, an assistant professor in the Department of Biomedical Engineering in the Cockrell School of Engineering, and Lan Luan, a research scientist in the Cockrell School and the College of Natural Sciences, have developed new probes that have mechanical compliances approaching that of the brain tissue and are more than 1,000 times more flexible than other neural probes. This ultra-flexibility leads to an improved ability to reliably record and track the electrical activity of individual neurons for long periods of time. There is a growing interest in developing long-term tracking of individual neurons for neural interface applications, such as extracting neural-control signals for amputees to control high-performance prostheses. It also opens up new possibilities to follow the progression of neurovascular and neurodegenerative diseases such as stroke, Parkinson’s and Alzheimer’s diseases.

One of the problems with conventional probes is their size and mechanical stiffness; their larger dimensions and stiffer structures often cause damage around the tissue they encompass. Additionally, while it is possible for the conventional electrodes to record brain activity for months, they often provide unreliable and degrading recordings. It is also challenging for conventional electrodes to electrophysiologically track individual neurons for more than a few days.

In contrast, the UT Austin team’s electrodes are flexible enough that they comply with the microscale movements of tissue and still stay in place. The probe’s size also drastically reduces the tissue displacement, so the brain interface is more stable, and the readings are more reliable for longer periods of time. To the researchers’ knowledge, the UT Austin probe — which is as small as 10 microns at a thickness below 1 micron, and has a cross-section that is only a fraction of that of a neuron or blood capillary — is the smallest among all neural probes.

“What we did in our research is prove that we can suppress tissue reaction while maintaining a stable recording,” Xie said. “In our case, because the electrodes are very, very flexible, we don’t see any sign of brain damage — neurons stayed alive even in contact with the NET probes, glial cells remained inactive and the vasculature didn’t become leaky.”

In experiments in mouse models, the researchers found that the probe’s flexibility and size prevented the agitation of glial cells, which is the normal biological reaction to a foreign body and leads to scarring and neuronal loss.

“The most surprising part of our work is that the living brain tissue, the biological system, really doesn’t mind having an artificial device around for months,” Luan said.

The researchers also used advanced imaging techniques in collaboration with biomedical engineering professor Andrew Dunn and neuroscientists Raymond Chitwood and Jenni Siegel from the Institute for Neuroscience at UT Austin to confirm that the NET enabled neural interface did not degrade in the mouse model for over four months of experiments. The researchers plan to continue testing their probes in animal models and hope to eventually engage in clinical testing. The research received funding from the UT BRAIN seed grant program, the Department of Defense and National Institutes of Health.

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

Ultraflexible nanoelectronic probes form reliable, glial scar–free neural integration by Lan Luan, Xiaoling Wei, Zhengtuo Zhao, Jennifer J. Siegel, Ojas Potnis, Catherine A Tuppen, Shengqing Lin, Shams Kazmi, Robert A. Fowler, Stewart Holloway, Andrew K. Dunn, Raymond A. Chitwood, and Chong Xie. Science Advances  15 Feb 2017: Vol. 3, no. 2, e1601966 DOI: 10.1126/sciadv.1601966

This paper is open access.

You can get more detail about the research in a Feb. 17, 2017 posting by Dexter Johnson on his Nanoclast blog (on the IEEE [International Institute for Electrical and Electronics Engineers] website).

Hopes for nanocellulose in the fields of medicine and green manufacturing

Initially this seemed like an essay extolling the possibilities for nanocellulose but it is also a research announcement. From a Nov. 7, 2016 news item on Nanowerk,

What if you could take one of the most abundant natural materials on earth and harness its strength to lighten the heaviest of objects, to replace synthetic materials, or use it in scaffolding to grow bone, in a fast-growing area of science in oral health care?

This all might be possible with cellulose nanocrystals, the molecular matter of all plant life. As industrial filler material, they can be blended with plastics and other synthetics. They are as strong as steel, tough as glass, lightweight, and green.

“Plastics are currently reinforced with fillers made of steel, carbon, Kevlar, or glass. There is an increasing demand in manufacturing for sustainable materials that are lightweight and strong to replace these fillers,” said Douglas M. Fox, associate professor of chemistry at American University.
“Cellulose nanocrystals are an environmentally friendly filler. If there comes a time that they’re used widely in manufacturing, cellulose nanocrystals will lessen the weight of materials, which will reduce energy.”

A Nov. 7, 2016 American University news release on EurekAlert, which originated the news item, continues into the research,

Fox has submitted a patent for his work with cellulose nanocrystals, which involves a simple, scalable method to improve their performance. Published results of his method can be found in the chemistry journal ACS Applied Materials and Interfaces. Fox’s method could be used as a biomaterial and for applications in transportation, infrastructure and wind turbines.

The power of cellulose

Cellulose gives stems, leaves and other organic material in the natural world their strength. That strength already has been harnessed for use in many commercial materials. At the nano-level, cellulose fibers can be broken down into tiny crystals, particles smaller than ten millionths of a meter. Deriving cellulose from natural sources such as wood, tunicate (ocean-dwelling sea cucumbers) and certain kinds of bacteria, researchers prepare crystals of different sizes and strengths.

For all of the industry potential, hurdles abound. As nanocellulose disperses within plastic, scientists must find the sweet spot: the right amount of nanoparticle-matrix interaction that yields the strongest, lightest property. Fox overcame four main barriers by altering the surface chemistry of nanocrystals with a simple process of ion exchange. Ion exchange reduces water absorption (cellulose composites lose their strength if they absorb water); increases the temperature at which the nanocrystals decompose (needed to blend with plastics); reduces clumping; and improves re-dispersal after the crystals dry.

Cell growth

Cellulose nanocrystals as a biomaterial is yet another commercial prospect. In dental regenerative medicine, restoring sufficient bone volume is needed to support a patient’s teeth or dental implants. Researchers at the National Institute of Standards and Technology [NIST], through an agreement with the National Institute of Dental and Craniofacial Research of the National Institutes of Health, are looking for an improved clinical approach that would regrow a patient’s bone. When researchers experimented with Fox’s modified nanocrystals, they were able to disperse the nanocrystals in scaffolds for dental regenerative medicine purposes.

“When we cultivated cells on the cellulose nanocrystal-based scaffolds, preliminary results showed remarkable potential of the scaffolds for both their mechanical properties and the biological response. This suggests that scaffolds with appropriate cellulose nanocrystal concentrations are a promising approach for bone regeneration,” said Martin Chiang, team leader for NIST’s Biomaterials for Oral Health Project.

Another collaboration Fox has is with Georgia Institute of Technology and Owens Corning, a company specializing in fiberglass insulation and composites, to research the benefits to replace glass-reinforced plastic used in airplanes, cars and wind turbines. He also is working with Vireo Advisors and NIST to characterize the health and safety of cellulose nanocrystals and nanofibers.

“As we continue to show these nanomaterials are safe, and make it easier to disperse them into a variety of materials, we get closer to utilizing nature’s chemically resistant, strong, and most abundant polymer in everyday products,” Fox said.

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

Simultaneously Tailoring Surface Energies and Thermal Stabilities of Cellulose Nanocrystals Using Ion Exchange: Effects on Polymer Composite Properties for Transportation, Infrastructure, and Renewable Energy Applications by Douglas M. Fox, Rebeca S. Rodriguez, Mackenzie N. Devilbiss, Jeremiah Woodcock, Chelsea S. Davis, Robert Sinko, Sinan Keten, and Jeffrey W. Gilman. ACS Appl. Mater. Interfaces, 2016, 8 (40), pp 27270–27281 DOI: 10.1021/acsami.6b06083 Publication Date (Web): September 14, 2016

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

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: http://news.rice.edu/2016/09/22/tattoo-therapy-could-ease-chronic-disease/#sthash.sIfs3b0S.dpuf

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)

Cornell University researchers breach blood-brain barrier

There are other teams working on ways to breach the blood-brain barrier (my March 26, 2015 post highlights work from a team at the University of Montréal) but this team from  Cornell is working with a drug that has already been approved by the US Food and Drug Administration (FDA) according to an April 8, 2016 news item on ScienceDaily,

Cornell researchers have discovered a way to penetrate the blood brain barrier (BBB) that may soon permit delivery of drugs directly into the brain to treat disorders such as Alzheimer’s disease and chemotherapy-resistant cancers.

The BBB is a layer of endothelial cells that selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose and water, while keeping others out.

Cornell researchers report that an FDA-approved drug called Lexiscan activates receptors — called adenosine receptors — that are expressed on these BBB cells.

An April 4, 2016 Cornell University news release by Krishna Ramanujan, which originated the news item, expands on the theme,

“We can open the BBB for a brief window of time, long enough to deliver therapies to the brain, but not too long so as to harm the brain. We hope in the future, this will be used to treat many types of neurological disorders,” said Margaret Bynoe, associate professor in the Department of Microbiology and Immunology in Cornell’s College of Veterinary Medicine. …

The researchers were able to deliver chemotherapy drugs into the brains of mice, as well as large molecules, like an antibody that binds to Alzheimer’s disease plaques, according to the paper.

To test whether this drug delivery system has application to the human BBB, the lab engineered a BBB model using human primary brain endothelial cells. They observed that Lexiscan opened the engineered BBB in a manner similar to its actions in mice.

Bynoe and Kim discovered that a protein called P-glycoprotein is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Lexiscan acts on one of the adenosine receptors expressed on BBB endothelial cells specifically activating them. They showed that Lexiscan down-regulates P-glycoprotein expression and function on the BBB endothelial cells. It acts like a switch that can be turned on and off in a time dependent manner, which provides a measure of safety for the patient.

“We demonstrated that down-modulation of P-glycoprotein function coincides exquisitely with chemotherapeutic drug accumulation” in the brains of mice and across an engineered BBB using human endothelial cells, Bynoe said. “The amount of chemotherapeutic drugs that accumulated in the brain was significant.”

In addition to P-glycoprotein’s role in inhibiting foreign substances from penetrating the BBB, the protein is also expressed by many different types of cancers and makes these cancers resistant to chemotherapy.

“This finding has significant implications beyond modulation of the BBB,” Bynoe said. “It suggests that in the future, we may be able to modulate adenosine receptors to regulate P-glycoprotein in the treatment of cancer cells resistant to chemotherapy.”

Because Lexiscan is an FDA-approved drug, ”the potential for a breakthrough in drug delivery systems for diseases such as Alzheimer’s disease, Parkinson’s disease, autism, brain tumors and chemotherapy-resistant cancers is not far off,” Bynoe said.

Another advantage is that these molecules (adenosine receptors  and P-glycoprotein are naturally expressed in mammals. “We don’t have to knock out a gene or insert one for a therapy to work,” Bynoe said.

The study was funded by the National Institutes of Health and the Kwanjung Educational Foundation.

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

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier by Do-Geun Kim and Margaret S. Bynoe. J Clin Invest. doi:10.1172/JCI76207 First published April 4, 2016

Copyright © 2016, The American Society for Clinical Investigation.

This paper appears to be open access.

3D microtopographic scaffolds for transplantation and generation of reprogrammed human neurons

Should this technology prove successful once they start testing on people, the stated goal is to use it for the treatment of human neurodegenerative disorders such as Parkinson’s disease.  But, I can’t help wondering if they might also consider constructing an artificial brain.

Getting back to the 3D scaffolds for neurons, a March 17, 2016 US National Institutes of Health (NIH) news release (also on EurekAlert), makes the announcement,

National Institutes of Health-funded scientists have developed a 3D micro-scaffold technology that promotes reprogramming of stem cells into neurons, and supports growth of neuronal connections capable of transmitting electrical signals. The injection of these networks of functioning human neural cells — compared to injecting individual cells — dramatically improved their survival following transplantation into mouse brains. This is a promising new platform that could make transplantation of neurons a viable treatment for a broad range of human neurodegenerative disorders.

Previously, transplantation of neurons to treat neurodegenerative disorders, such as Parkinson’s disease, had very limited success due to poor survival of neurons that were injected as a solution of individual cells. The new research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of NIH.

“Working together, the stem cell biologists and the biomaterials experts developed a system capable of shuttling neural cells through the demanding journey of transplantation and engraftment into host brain tissue,” said Rosemarie Hunziker, Ph.D., director of the NIBIB Program in Tissue Engineering and Regenerative Medicine. “This exciting work was made possible by the close collaboration of experts in a wide range of disciplines.”

The research was performed by researchers from Rutgers University, Piscataway, New Jersey, departments of Biomedical Engineering, Neuroscience and Cell Biology, Chemical and Biochemical Engineering, and the Child Health Institute; Stanford University School of Medicine’s Institute of Stem Cell Biology and Regenerative Medicine, Stanford, California; the Human Genetics Institute of New Jersey, Piscataway; and the New Jersey Center for Biomaterials, Piscataway. The results are reported in the March 17, 2016 issue of Nature Communications.

The researchers experimented in creating scaffolds made of different types of polymer fibers, and of varying thickness and density. They ultimately created a web of relatively thick fibers using a polymer that stem cells successfully adhered to. The stem cells used were human induced pluripotent stem cells (iPSCs), which can be readily generated from adult cell types such as skin cells. The iPSCs were induced to differentiate into neural cells by introducing the protein NeuroD1 into the cells.

The space between the polymer fibers turned out to be critical. “If the scaffolds were too dense, the stem cell-derived neurons were unable to integrate into the scaffold, whereas if they are too sparse then the network organization tends to be poor,” explained Prabhas Moghe, Ph.D., distinguished professor of biomedical engineering & chemical engineering at Rutgers University and co-senior author of the paper. “The optimal pore size was one that was large enough for the cells to populate the scaffold but small enough that the differentiating neurons sensed the presence of their neighbors and produced outgrowths resulting in cell-to-cell contact. This contact enhances cell survival and development into functional neurons able to transmit an electrical signal across the developing neural network.”

To test the viability of neuron-seeded scaffolds when transplanted, the researchers created micro-scaffolds that were small enough for injection into mouse brain tissue using a standard hypodermic needle. They injected scaffolds carrying the human neurons into brain slices from mice and compared them to human neurons injected as individual, dissociated cells.

The neurons on the scaffolds had dramatically increased cell-survival compared with the individual cell suspensions. The scaffolds also promoted improved neuronal outgrowth and electrical activity. Neurons injected individually in suspension resulted in very few cells surviving the transplant procedure.

Human neurons on scaffolds compared to neurons in solution were then tested when injected into the brains of live mice. Similar to the results in the brain slices, the survival rate of neurons on the scaffold network was increased nearly 40-fold compared to injected isolated cells. A critical finding was that the neurons on the micro-scaffolds expressed proteins that are involved in the growth and maturation of neural synapses–a good indication that the transplanted neurons were capable of functionally integrating into the host brain tissue.

The success of the study gives this interdisciplinary group reason to believe that their combined areas of expertise have resulted in a system with much promise for eventual treatment of human neurodegenerative disorders. In fact, they are now refining their system for specific use as an eventual transplant therapy for Parkinson’s disease. The plan is to develop methods to differentiate the stem cells into neurons that produce dopamine, the specific neuron type that degenerates in individuals with Parkinson’s disease. The work also will include fine-tuning the scaffold materials, mechanics and dimensions to optimize the survival and function of dopamine-producing neurons, and finding the best mouse models of the disease to test this Parkinson’s-specific therapy.

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

Generation and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds by Aaron L. Carlson, Neal K. Bennett, Nicola L. Francis, Apoorva Halikere, Stephen Clarke, Jennifer C. Moore, Ronald P. Hart, Kenneth Paradiso, Marius Wernig, Joachim Kohn, Zhiping P. Pang, & Prabhas V. Moghe. Nature Communications 7, Article number: 10862  doi:10.1038/ncomms10862 Published 17 March 2016

This paper is open access.

North Carolina universities go beyond organ-on-a-chip

The researchers in the North Carolina universities involved in this project have high hopes according to an Oct. 9, 2015 news item on Nanowerk,

A team of researchers from the University of North Carolina at Chapel Hill and NC State University has received a $5.3 million, five-year Transformative Research (R01) Award from the National Institutes of Health (NIH) to create fully functioning versions of the human gut that fit on a chip the size of a dime.

Such “organs-on-a-chip” have become vital for biomedical research, as researchers seek alternatives to animal models for drug discovery and testing. The new grant will fund a technology that represents a major step forward for the field, overcoming limitations that have mired other efforts.

The technology will use primary cells derived directly from human biopsies, which are known to provide more relevant results than the immortalized cell lines used in current approaches. In addition, the device will sculpt these cells into the sophisticated architecture of the gut, rather than the disorganized ball of cells that are created in other miniature organ systems.

“We are building a device that goes far beyond the organ-on-a-chip,” said Nancy L. Allbritton, MD, PhD, professor and chair of the UNC-NC State joint department of biomedical engineering and one of four principle investigators on the NIH grant. “We call it a ‘simulacrum,’ [emphasis mine] a term used in science fiction to describe a duplicate. The idea is to create something that is indistinguishable from your own gut.”

I’ve come across the term ‘simulacrum’ in relation to philosophy so it’s a bit of a surprise to find it in a news release about an organ-on-a-chip where it seems to have been redefined somewhat. Here’s more from the Simulacrum entry on Wikipedia (Note: Links have been removed),

A simulacrum (plural: simulacra from Latin: simulacrum, which means “likeness, similarity”), is a representation or imitation of a person or thing.[1] The word was first recorded in the English language in the late 16th century, used to describe a representation, such as a statue or a painting, especially of a god. By the late 19th century, it had gathered a secondary association of inferiority: an image without the substance or qualities of the original.[2] Philosopher Fredric Jameson offers photorealism as an example of artistic simulacrum, where a painting is sometimes created by copying a photograph that is itself a copy of the real.[3] Other art forms that play with simulacra include trompe-l’œil,[4] pop art, Italian neorealism, and French New Wave.[3]

Philosophy

The simulacrum has long been of interest to philosophers. In his Sophist, Plato speaks of two kinds of image making. The first is a faithful reproduction, attempted to copy precisely the original. The second is intentionally distorted in order to make the copy appear correct to viewers. He gives the example of Greek statuary, which was crafted larger on the top than on the bottom so that viewers on the ground would see it correctly. If they could view it in scale, they would realize it was malformed. This example from the visual arts serves as a metaphor for the philosophical arts and the tendency of some philosophers to distort truth so that it appears accurate unless viewed from the proper angle.[5] Nietzsche addresses the concept of simulacrum (but does not use the term) in the Twilight of the Idols, suggesting that most philosophers, by ignoring the reliable input of their senses and resorting to the constructs of language and reason, arrive at a distorted copy of reality.[6]

Postmodernist French social theorist Jean Baudrillard argues that a simulacrum is not a copy of the real, but becomes truth in its own right: the hyperreal. Where Plato saw two types of representation—faithful and intentionally distorted (simulacrum)—Baudrillard sees four: (1) basic reflection of reality; (2) perversion of reality; (3) pretence of reality (where there is no model); and (4) simulacrum, which “bears no relation to any reality whatsoever”.[7] In Baudrillard’s concept, like Nietzsche’s, simulacra are perceived as negative, but another modern philosopher who addressed the topic, Gilles Deleuze, takes a different view, seeing simulacra as the avenue by which an accepted ideal or “privileged position” could be “challenged and overturned”.[8] Deleuze defines simulacra as “those systems in which different relates to different by means of difference itself. What is essential is that we find in these systems no prior identity, no internal resemblance”.[9]

Getting back to the proposed research, an Oct. (?), 2015 University of North Carolina news release, which originated the news item, describes the proposed work in more detail,

Allbritton is an expert at microfabrication and microengineering. Also on the team are intestinal stem cell expert Scott T. Magness, associate professor of medicine, biomedical engineering, and cell and molecular physiology in the UNC School of Medicine; microbiome expert Scott Bultman, associate professor of genetics in the UNC School of Medicine; and bioinformatics expert Shawn Gomez, associate professor of biomedical engineering in UNC’s College of Arts and Sciences and NC State.

The impetus for the “organ-on-chip” movement comes largely from the failings of the pharmaceutical industry. For just a single drug to go through the discovery, testing, and approval process can take as many as 15 years and as much as $5 billion dollars. Animal models are expensive to work with and often don’t respond to drugs and diseases the same way humans do. Human cells grown in flat sheets on Petri dishes are also a poor proxy. Three-dimensional “organoids” are an improvement, but these hollow balls are made of a mishmash of cells that doesn’t accurately mimic the structure and function of the real organ.

Basically, the human gut is a 30-foot long hollow tube made up of a continuous single-layer of specialized cells. Regenerative stem cells reside deep inside millions of small pits or “crypts” along the tube, and mature differentiated cells are linked to the pits and live further out toward the surface. The gut also contains trillions of microbes, which are estimated to outnumber human cells by ten to one. These diverse microbial communities – collectively known as the microbiota – process toxins and pharmaceuticals, stimulate immunity, and even release hormones to impact behavior.

To create a dime-sized version of this complex microenvironment, the UNC-NC State team borrowed fabrication technologies from the electronics and microfluidics world. The device is composed of a polymer base containing an array of imprinted or shaped “hydrogels,” a mesh of molecules that can absorb water like a sponge. These hydrogels are specifically engineered to provide the structural support and biochemical cues for growing cells from the gut. Plugged into the device will be various kinds of plumbing that bring in chemicals, fluids, and gases to provide cues that tell the cells how and where to differentiate and grow. For example, the researchers will engineer a steep oxygen gradient into the device that will enable oxygen-loving human cells and anaerobic microbes to coexist in close proximity.

“The underlying concept – to simply grow a piece of human tissue in a dish – doesn’t seem that groundbreaking,” said Magness. “We have been doing that for a long time with cancer cells, but those efforts do not replicate human physiology. Using native stem cells from the small intestine or colon, we can now develop gut tissue layers in a dish that contains stem cells and all the differentiated cells of the gut. That is the thing stem cell biologists and engineers have been shooting for, to make real tissue behave properly in a dish to create better models for drug screening and cell-based therapies. With this work, we made a big leap toward that goal.”

Right now, the team has a working prototype that can physically and chemically guide mouse intestinal stem cells into the appropriate structure and function of the gut. For several years, Magness has been isolating and banking human stem cells from samples from patients undergoing routine colonoscopies at UNC Hospitals.

As part of the grant, he will work with the rest of the team to apply these stem cells to the new device and create “simulacra” that are representative of each patient’s individual gut. The approach will enable researchers to explore in a personalized way how both the human and microbial cells of the gut behave during healthy and diseased states.

“Having a system like this will advance microbiota research tremendously,” said Bultman. “Right now microbiota studies involve taking samples, doing sequencing, and then compiling an inventory of all the microbes in the disease cases and healthy controls. These studies just draw associations, so it is difficult to glean cause and effect. This device will enable us to probe the microbiota, and gain a better understanding of whether changes in these microbial communities are the cause or the consequence of disease.”

I wish them good luck with their work and to end on another interesting note, the concept of organs-on-a-chip won a design award. From a June 22, 2015 article by Oliver Wainwright for the Guardian (Note: Links have been removed),

Meet the Lung-on-a-chip, a simulation of the biological processes inside the human lung, developed by the Wyss Institute for Biologically Inspired Engineering at Harvard University – and now crowned Design of the Year by London’s Design Museum.

Lined with living human cells, the “organs-on-chips” mimic the tissue structures and mechanical motions of human organs, promising to accelerate drug discovery, decrease development costs and potentially usher in a future of personalised medicine.

“This is the epitome of design innovation,” says Paola Antonelli, design curator at New York’s Museum of Modern Art [MOMA], who nominated the project for the award and recently acquired organs-on-chips for MoMA’s permanent collection. “Removing some of the pitfalls of human and animal testing means, theoretically, that drug trials could be conducted faster and their viable results disseminated more quickly.”

Whodathunkit? (Tor those unfamiliar with slang written in this form: Who would have thought it?)

Acoustofluidics and lab-on-a-chip for asthma and tuberculosis diagnostics

This is my first exposure to acoustofluidics (although it’s been around for a few years) and it concerns lab-on-a-chip diagnostics for asthma and tuberculosis. From an Aug. 3, 2015 news item on Azonano,

A device to mix liquids utilizing ultrasonics is the first and most difficult component in a miniaturized system for low-cost analysis of sputum from patients with pulmonary diseases such as tuberculosis and asthma.

The device, developed by engineers at Penn State in collaboration with researchers at the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, and the Washington University School of Medicine, will benefit patients in the U.S., where 12 percent of the population, or around 19 million people, have asthma, and in undeveloped regions where TB is still a widespread and often deadly contagion.

“To develop more accurate diagnosis and treatment approaches for patients with pulmonary diseases, we have to analyze sample cells directly from the lungs rather than by drawing blood,” said Tony Jun Huang, professor of engineering science and mechanics at Penn State and the inventor, with his group, of this and other acoustofluidic devices based on ultrasonic waves. “For instance, different drugs are used to treat different types of asthma patients. If you know what a person’s immunophenotype is, you can provide personalized medicine for their particular disease.

A July 29, 2015 Pennsylvania State University news release, which originated the news item, describes the disadvantages of the current sputum analyses techniques and explains how this new technique in an improvement,

There are several issues with the current standard method for sputum analysis. The first is that human specimens can be contagious, and sputum analysis requires handling of specimens in several discrete machines. With a lab on a chip device, all biospecimens are safely contained in a single disposable component.

Another issue is the sample size required for analysis in the current system, which is often larger than a person can easily produce. The acoustofluidic sputum liquefier created by Huang’s group requires 100 times less sample while still providing accuracy equivalent to the standard system.

A further issue is that current systems are difficult to use and require trained operators. With the lab on a chip system, a nurse can operate the device with a touch of a few buttons and get a read out, or the patient could even operate the device at home. In addition, the disposable portion of the device should cost less than a dollar to manufacture.

Po-Hsun Huang, a graduate student in the Huang group and the first author on the recent paper describing the device in the Royal Society of Chemistry journal Lab on a Chip, said “This will offer quick analysis of samples without having to send them out to a centralized lab. While I have been working on the liquefaction component of the device, my lab mates are working on the flow cytometry analysis component, which should be ready soon. This is the first on-chip sputum liquefier anyone has developed.”

Stewart J. Levine, a Senior Investigator and Chief of the Laboratory of Asthma and Lung Inflammation in the Division of Intramural Research at NHLBI, said “This on-chip sputum liquefier is a significant advance regarding our goal of developing a point-of-care diagnostic device that will determine the type of inflammation present in the lungs of asthmatics. This will allow health care providers to individualize asthma treatments for each patient and advance the goal of bringing precision medicine into clinical practice.”

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

An acoustofluidic sputum liquefier by Po-Hsun Huang, Liqiang Ren, Nitesh Nama, Sixing Li, Peng Li, Xianglan Yao, Rosemarie A. Cuento, Cheng-Hsin Wei, Yuchao Chen, Yuliang Xie, Ahmad Ahsan Nawaz, Yael G. Alevy, Michael J. Holtzman, J. Philip McCoy, Stewart J. Levine, and  Tony Jun Huang. Lab Chip, 2015,15, 3125-3131 DOI: 10.1039/C5LC00539F

First published online 17 Jun 2015

This is an open access paper but you do need to register for a free (British) Royal Society of Chemistry publishing personal account.

A pragmatic approach to alternatives to animal testing

Retitled and cross-posted from the June 30, 2015 posting (Testing times: the future of animal alternatives) on the International Innovation blog (a CORDIS-listed project dissemination partner for FP7 and H2020 projects).

Maryse de la Giroday explains how emerging innovations can provide much-needed alternatives to animal testing. She also shares highlights of the 9th World Congress on Alternatives to Animal Testing.

‘Guinea pigging’ is the practice of testing drugs that have passed in vitro and in vivo tests on healthy humans in a Phase I clinical trial. In fact, healthy humans can make quite a bit of money as guinea pigs. The practice is sufficiently well-entrenched that there is a magazine, Guinea Pig Zero, devoted to professionals. While most participants anticipate some unpleasant side effects, guinea pigging can sometimes be a dangerous ‘profession’.

HARMFUL TO HEALTH

One infamous incident highlighting the dangers of guinea pigging occurred in 2006 at Northwick Park Hospital outside London. Volunteers were offered £2,000 to participate in a Phase I clinical trial to test a prospective treatment – a monoclonal antibody designed for rheumatoid arthritis and multiple sclerosis. The drug, called TGN1412, caused catastrophic systemic organ failure in participants. All six individuals receiving the drug required hospital treatment. One participant reportedly underwent amputation of fingers and toes. Another reacted with symptoms comparable to John Merrick, the Elephant Man.

The root of the disaster lay in subtle immune system differences between humans and cynomolgus monkeys – the model animal tested prior to the clinical trial. The drug was designed for the CD28 receptor on T cells. The monkeys’ receptors closely resemble those found in humans. However, unlike these monkeys, humans have other immune cells that carry CD28. The trial participants received a starting dosage that was 0.2 per cent of what the monkeys received in their final tests, but failure to take these additional receptors into account meant a dosage that was supposed to occupy 10 per cent of the available CD28 receptors instead occupied 90 per cent. After the event, a Russian inventor purchased the commercial rights to the drug and renamed it TAB08. It has been further developed by Russian company, TheraMAB, and TAB08 is reportedly in Phase II clinical trials.

HUMAN-ON-A-CHIP AND ORGANOID PROJECTS

While animal testing has been a powerful and useful tool for determining safe usage for pharmaceuticals and other types of chemicals, it is also a cruel and imperfect practice. Moreover, it typically only predicts 30-60 per cent of human responses to new drugs. Nanotechnology and other emerging innovations present possibilities for reducing, and in some cases eliminating, the use of animal models.

People for the Ethical Treatment of Animals (PETA), still better known for its publicity stunts, maintains a webpage outlining a number of alternatives including in silico testing (computer modelling), and, perhaps most interestingly, human-on-a-chip and organoid (tissue engineering) projects.

Organ-on-a-chip projects use stem cells to create human tissues that replicate the functions of human organs. Discussions about human-on-a-chip activities – a phrase used to describe 10 interlinked organ chips – were a highlight of the 9th World Congress on Alternatives to Animal Testing held in Prague, Czech Republic, last year. One project highlighted at the event was a joint US National Institutes of Health (NIH), US Food and Drug Administration (FDA) and US Defense Advanced Research Projects Agency (DARPA) project led by Dan Tagle that claimed it would develop functioning human-on-a-chip by 2017. However, he and his team were surprisingly close-mouthed and provided few details making it difficult to assess how close they are to achieving their goal.

By contrast, Uwe Marx – Leader of the ‘Multi-Organ-Chip’ programme in the Institute of Biotechnology at the Technical University of Berlin and Scientific Founder of TissUse, a human-on-a-chip start-up company – claims to have sold two-organ chips. He also claims to have successfully developed a four-organ chip and that he is on his way to building a human-on-a-chip. Though these chips remain to be seen, if they are, they will integrate microfluidics, cultured cells and materials patterned at the nanoscale to mimic various organs, and will allow chemical testing in an environment that somewhat mirrors a human.

Another interesting alternative for animal testing is organoids – a feature in regenerative medicine that can function as test sites. Engineers based at Cornell University recently published a paper on their functional, synthetic immune organ. Inspired by the lymph node, the organoid is comprised of gelatin-based biomaterials, which are reinforced with silicate nanoparticles (to keep the tissue from melting when reaching body temperature) and seeded with cells allowing it to mimic the anatomical microenvironment of a lymphatic node. It behaves like its inspiration converting B cells to germinal centres which activate, mature and mutate antibody genes when the body is under attack. The engineers claim to be able to control the immune response and to outperform 2D cultures with their 3D organoid. If the results are reproducible, the organoid could be used to develop new therapeutics.

Maryse de la Giroday is a science communications consultant and writer.

Full disclosure: Maryse de la Giroday received transportation and accommodation for the 9th World Congress on Alternatives to Animal Testing from SEURAT-1, a European Union project, making scientific inquiries to facilitate the transition to animal testing alternatives, where possible.

ETA July 1, 2015: I would like to acknowledge more sources for the information in this article,

Sources:

The guinea pigging term, the ‘professional aspect, the Northwick Park story, and the Guinea Pig Zero magazine can be found in Carl Elliot’s excellent 2006 story titled ‘Guinea-Pigging’ for New Yorker magazine.

http://www.newyorker.com/magazine/2008/01/07/guinea-pigging

Information about the drug used in the Northwick Park Hospital disaster, the sale of the rights to a Russian inventor, and the June 2015 date for the current Phase II clinical trials were found in this Wikipedia essay titled, TGN 1412.

http://en.wikipedia.org/wiki/TGN1412

Additional information about the renamed drug, TAB08 and its Phase II clinical trials was found on (a) a US government website for information on clinical trials, (b) in a Dec. 2014 (?) TheraMAB  advertisement in a Nature group magazine and a Jan. 2014 press release,

https://www.clinicaltrials.gov/ct2/show/NCT01990157?term=TAB08_RA01&rank=1

http://www.theramab.ru/TheraMAB_NAture.pdf

http://theramab.ru/en/news/phase_II

An April 2015 article (Experimental drug that injured UK volunteers resumes in human trials) by Owen Dyer for the British Medical Journal also mentioned the 2015 TheraMab Phase II clinical trials and provided information about the information about Macaque (cynomolgus) monkey tests.

http://www.bmj.com.proxy.lib.sfu.ca/content/350/bmj.h1831

BMJ 2015; 350 doi: http://dx.doi.org.proxy.lib.sfu.ca/10.1136/bmj.h1831 (Published 02 April 2015) Cite this as: BMJ 2015;350:h1831

A 2009 study by Christopher Horvath and Mark Milton somewhat contradicts the Dyer article’s contention that a species Macaque monkey was used as an animal model. (As the Dyer article is more recent and the Horvath/Milton analysis is more complex covering TGN 1412 in the context of other MAB drugs and their precursor tests along with specific TGN 1412 tests, I opted for the simple description.)

The TeGenero Incident [another name for the Northwick Park Accident] and the Duff Report Conclusions: A Series of Unfortunate Events or an Avoidable Event? by Christopher J. Horvath and Mark N. Milton. Published online before print February 24, 2009, doi: 10.1177/0192623309332986 Toxicol Pathol April 2009 vol. 37 no. 3 372-383

http://tpx.sagepub.com/content/37/3/372.full

Philippa Roxbuy’s May 24, 2013 BBC news online article provided confirmation and an additional detail or two about the Northwick Park Hospital accident. It notes that other models, in addition to animal models, are being developed.

http://www.bbc.com/news/health-22556736

Anne Ju’s excellent June 10,2015 news release about the Cornell University organoid (synthetic immune organ) project was very helpful.

http://www.news.cornell.edu/stories/2015/06/engineers-synthetic-immune-organ-produces-antibodies

There will also be a magazine article in International Innovation, which will differ somewhat from the blog posting, due to editorial style and other requirements.

ETA July 22, 2015: I now have a link to the magazine article.

‘Glow in the dark’, paint-on bandage heals

Somewhat unexpectedly (to me), this research about a ‘smart’ paint-on bandage is being published by The Optical Society of America (OSA). Here’s more about the work from an Oct. 1, 2014 news item on Nanowerk,

Inspired by a desire to help wounded soldiers, an international, multidisciplinary team of researchers led by Assistant Professor Conor L. Evans at the Wellman Center for Photomedicine of Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) has created a paint-on, see-through, “smart” bandage that glows to indicate a wound’s tissue oxygenation concentration. Because oxygen plays a critical role in healing, mapping these levels in severe wounds and burns can help to significantly improve the success of surgeries to restore limbs and physical functions.

An Oct. 1, 2014 OSA news release (also on EurekAlert), which originated the news item, describes the interest in oxygenation in more detail,

“Information about tissue oxygenation is clinically relevant but is often inaccessible due to a lack of accurate or noninvasive measurements,” explained lead author Zongxi Li, an HMS research fellow on Evans’ team.

Now, the “smart” bandage developed by the team provides direct, noninvasive measurement of tissue oxygenation by combining three simple, compact and inexpensive components: a bright sensor molecule with a long phosphorescence lifetime and appropriate dynamic range; a bandage material compatible with the sensor molecule that conforms to the skin’s surface to form an airtight seal; and an imaging device capable of capturing the oxygen-dependent signals from the bandage with high signal-to-noise ratio.

This work is part of the team’s long-term program “to develop a Sensing, Monitoring And Release of Therapeutics (SMART) bandage for improved care of patients with acute or chronic wounds,” says Evans …

The news release goes on to briefly explain the technology,

For starters, the bandage’s not-so-secret key ingredient is phosphors—molecules that absorb light and then emit it via a process known as phosphorescence.

Phosphorescence is encountered by many on a daily basis—ranging from glow-in-the-dark dials on watches to t-shirt lettering. “How brightly our phosphorescent molecules emit light depends on how much oxygen is present,” said Li. “As the concentration of oxygen is reduced, the phosphors glow both longer and more brightly.” To make the bandage simple to interpret, the team also incorporated a green oxygen-insensitive reference dye, so that changes in tissue oxygenation are displayed as a green-to-red colormap.

The bandage is applied by “painting” it onto the skin’s surface as a viscous liquid, which dries to a solid thin film within a minute. Once the first layer has dried, a transparent barrier layer is then applied atop it to protect the film and slow the rate of oxygen exchange between the bandage and room air—making the bandage sensitive to the oxygen within tissue.

The final piece involves a camera-based readout device, which performs two functions: it provides a burst of excitation light that triggers the emission of the phosphors inside the bandage, and then it records the phosphors’ emission. “Depending on the camera’s configuration, we can measure either the brightness or color of the emitted light across the bandage or the change in brightness over time,” Li said. “Both of these signals can be used to create an oxygenation map.”  The emitted light from the bandage is bright enough that it can be acquired using a regular camera or smartphone—opening the possibility to a portable, field-ready device.

There are some immediate applications, as well as, plans for research that will yield applications (from the news release),

Immediate applications for the oxygen-sensing bandage include monitoring patients with a risk of developing ischemic (restricted blood supply) conditions, postoperative monitoring of skin grafts or flaps, and burn-depth determination as a guide for surgical debridement—the removal of dead or damaged tissue from the body.

“The need for a reliable, accurate and easy-to-use method of rapid assessment of blood flow to the skin for patients remains a clinical necessity,” said co-author Samuel Lin, an HMS associate professor of surgery at Beth Israel Deaconess Medical Center. “Plastic surgeons continuously monitor the state of blood flow to the skin, so the liquid-bandage oxygenation sensor is an exciting step toward improving patient care within the realm of vascular blood flow examination of the skin.”

What’s the next step for the bandage? “We’re developing brighter sensor molecules to improve the bandage’s oxygen sensing efficiency,” said Emmanuel Roussakis, another research fellow in Evans’ laboratory and co-author, who is leading the sensor development effort.  The team’s laboratory research will also focus on expanding the sensing capability of the bandage to other treatment-related parameters—such as pH, bacterial load, oxidative states and specific disease markers—and incorporating an on-demand drug release capacity.

“In the future, our goal for the bandage is to incorporate therapeutic release capabilities that allow for on-demand drug administration at a desired location,” says Evans. “It allows for the visual assessment of the wound bed, so treatment-related wound parameters are readily accessible without the need for bandage removal—preventing unnecessary wound disruption and reducing the chance for bacterial infection.”

Should you be interested, the researchers are looking for industry partners,

Beyond the lab, the team’s aim is to move this technology from the bench to the bedside, so they are actively searching for industry partners. They acknowledge research support from the Military Medical Photonics Program from the U.S. Department of Defense, and National Institutes of Health.

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

Non-invasive transdermal two-dimensional mapping of cutaneous oxygenation with a rapid-drying liquid bandage by Zongxi Li, Emmanuel Roussakis, Pieter G. L. Koolen, Ahmed M. S. Ibrahim, Kuylhee Kim, Lloyd F. Rose, Jesse Wu, Alexander J. Nichols, Yunjung Baek, Reginald Birngruber, Gabriela Apiou-Sbirlea, Robina Matyal, Thomas Huang, Rodney Chan, Samuel J. Lin, and Conor L. Evans. Biomedical Optics Express, Vol. 5, Issue 11, pp. 3748-3764 (2014) http://dx.doi.org/10.1364/BOE.5.003748

This article is open access.

The researcher’s have provided an illustration of the bandage,

Caption: The transparent liquid bandage displays a quantitative, oxygenation-sensitive colormap that can be easily acquired using a simple camera or smartphone. Credit: Li/Wellman Center for Photomedicine.

Caption: The transparent liquid bandage displays a quantitative, oxygenation-sensitive colormap that can be easily acquired using a simple camera or smartphone. Credit: Li/Wellman Center for Photomedicine.