Category Archives: medicine

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This paper is behind a paywall.

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

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

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

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

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

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

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

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

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

The news release goes on to provide technical details,

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

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

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

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

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

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

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

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

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

Zinc oxide tetrapod nanoparticles. Credit: Deepak Shukla

Zinc oxide tetrapod nanoparticles. Credit: Deepak Shukla

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

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

This paper is behind a paywall.

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

Bacteria and an anti-superbug coating from Ireland’s Sligo Institute of Technology

Unlike today’s (April 28, 2016) earlier piece about dealing with bacteria, the focus for this research is on superbugs and not the bacteria which form biofilm on medical implants and such. An April 21, 2016 news item on RTE News makes the announcement about a new means of dealing with superbugs,

A discovery by a team of scientists in Ireland could stem the spread of deadly superbugs predicted to kill millions of people worldwide over the coming decades.

The research has found an agent that can be baked into everyday items like smart-phones and door handles to combat the likes of MRSA and E. coli.

The nanotechnology has a 99.9 % kill rate of potentially lethal and drug-resistant bacteria, they say.

Lead scientist Professor Suresh C. Pillai, of Sligo Institute of Technology’s Nanotechnology Research Group, says the discovery is the culmination of 12 years work.

“This is a game changer,” he said.

“This breakthrough will change the whole fight against superbugs. It can effectively control the spread of bacteria.”

An April 21, 2016 Sligo Institute of Technology press release provides some context for the work and a few details about the coating,

News of the discovery comes just days after UK Chancellor of the Exchequer George Osborne warned that superbugs could become deadlier than cancer and are on course to kill 10 million people globally by 2050.

Speaking at the International Monetary Fund (IMF) in Washington, Mr Osborne warned that the problem would slash global GDP by around €100 trillion if it was not tackled.

Using nanotechnology, the discovery is an effective and practical antimicrobial solution — an agent that kills microorganisms or inhibits their growth — that can be used to protect a range of everyday items.

Items include anything made from glass, metallics and ceramics including computer or tablet screens, smartphones, ATMs, door handles, TVs, handrails, lifts, urinals, toilet seats, fridges, microwaves and ceramic floor or wall tiles.

It will be of particular use in hospitals and medical facilities which are losing the battle against the spread of killer superbugs.

Other common uses would include in swimming pools and public buildings, on glass in public buses and trains, sneeze guards protecting food in delis and restaurants as well as in clean rooms in the medical sector.

“It’s absolutely wonderful to finally be at this stage. This breakthrough will change the whole fight against superbugs. It can effectvely control the spread of bacteria,” said Prof. Pillai.

He continued: “Every single person has a sea of bacteria on their hands. The mobile phone is the most contaminated personal item that we can have. Bacteria grows on the phone and can live there for up to five months. As it is contaminated with proteins from saliva and from the hand, It’s fertile land for bacteria and has been shown to carry 30 times more bacteria than a toilet seat.”

The research started at Dublin Institute of Technology (DIT)’s CREST and involves scientists now based at IT Sligo, Dublin City University (DCU) and the University of Surrey. Major researchers included Dr Joanna Carroll and Dr Nigel S. Leyland.

It has been funded for the past eight years by John Browne, founder and CEO of Kastus Technologies Ltd, who is bringing the product to a global market. He was also supported by significant investment from Enterprise Ireland.

As there is nothing that will effectively kill antibiotic-resistant superbugs completely from the surface of items, scientists have been searching for a way to prevent the spread.

This has been in the form of building or ‘baking’ antimicrobial surfaces into products during the manufacturing process.

However, until now, all these materials were toxic or needed UV light in order to make them work. This meant they were not practical for indoor use and had limited commercial application.

“The challenge was the preparation of a solution that was activated by indoor light rather than UV light and we have now done that,” said Prof Pillai.

The new water-based solution can be sprayed onto any glass, ceramic or metallic surface during the production process, rendering the surface 99.9 per cent resistant to superbugs like MRSA, E. coli and other fungi. [emphasis mine]

The solution is sprayed on the product — such as a smartphone glass surface — and then ‘baked’ into it, forming a super-hard surface. The coating is transparent, permanent and scratch resistant and actually forms a harder surface than the original glass or ceramic material.

The team first developed the revolutionary material to work on ceramics and has spent the last five years adapting the formula – which is non-toxic and has no harmful bi-products ‑- to make it work on glass and metallic surfaces.

Research is now underway by the group on how to adapt the solution for use in plastics and paint, allowing even wider use of the protective material.

Prof Pillai, Kastus and the team have obtained a US and a UK patent on the unique process with a number of global patent applications pending. It is rare for such an academic scientific discovery to have such commercial viability.

“I was sold on this from the first moment I heard about it. It’s been a long road to here but it was such a compelling story that it was hard to walk away from so I had to see it through to the end,” said John Browne, Kastus CEO.

He continued: “This is a game changer. The uniqueness of antimicrobia surface treatment means that the applications for it in the real world are endless. The multinational glass manufacturers we are in negotiations with to sell the product to have been searching for years to come up with such a solution but have failed.”

If the coating kills 99.9%, doesn’t that mean 0.1% are immune? If that’s the case, won’t they reproduce and eventually establish themselves as a new kind of superbug?

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

Highly Efficient F, Cu doped TiO2 anti-bacterial visible light active photocatalytic coatings to combat hospital-acquired infections by Nigel S. Leyland, Joanna Podporska-Carroll, John Browne, Steven J. Hinder, Brid Quilty, & Suresh C. Pillai. Scientific Reports 6, Article number: 24770 (2016) doi:10.1038/srep24770 Published online: 21 April 2016

This paper is open access.

Bacteria and an anti-biofilm coating from Ben Gurion University of the Negev (Israel)

This anti-biofilm acts as an anti-adhesive and is another approach to dealing with unwanted bacteria on medical implants and on marine equipment. From an April 25, 2016 news item about the Israeli research on ScienceDaily,

Researchers at Ben-Gurion University of the Negev (BGU) have developed an innovative anti-biofilm coating, which has significant anti-adhesive potential for a variety of medical and industrial applications.

According to the research published in Advanced Materials Interfaces, anti-adhesive patches that are developed from naturally occurring biomaterials can prevent destructive bacterial biofilm from forming on metal surfaces when they are immersed in water and other damp environments.

An April 25, 2016 American Associates Ben Gurion University of the Negev news release (also on EurekAlert), which originated the news item, describes the research further without adding much detail (Note: A link has been removed),

“Our solution addresses a pervasive need to design environmentally friendly materials to impede dangerous surface bacteria growth,” the BGU researchers from the Avram and Stella Goldstein-Goren Department of Biotechnology Engineering explain. “This holds tremendous potential for averting biofilm formed by surface-anchored bacteria and could have a tremendous impact.”

biofouling

Above: SEM micrographs of A. baumannii, P. aeruginosa (PA14), S. marcescens and P.stuartii biofilm architectures. The untreated control surface shows intricate bacteria densely embedded in the matrix. Biofilms were grown statically on the different surfaces.

The anti-adhesive could be used on medical implants, devices and surgical equipment where bacteria can contribute to chronic diseases, resist antibiotic treatment and thereby compromise the body’s defense system. The prevention of aquatic biofouling on ships and bridges is one of the industrial applications.

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

Novel Anti-Adhesive Biomaterial Patches: Preventing Biofilm with Metal Complex Films (MCF) Derived from a Microalgal Polysaccharide by Karina Golberg, Noa Emuna, T. P. Vinod, Dorit van Moppes, Robert S. Marks, Shoshana Malis Arad, and Ariel Kushmaro. Advanced Materials DOI: 10.1002/admi.201500486 Article first published online: 17 MAR 2016

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

This article is behind a paywall.

How many nanoparticle-based drugs does it take to kill a cancer tumour? More than 1%

According to an April 27, 2016 news item on Nanowerk researchers at the University of Toronto (Canada) along with their collaborators in the US (Harvard Medical School) and Japan (University of Tokyo) have determined that less than 1% of nanoparticle-based drugs reach their intended destination (Note: A link has been removed),

Targeting cancer cells for destruction while leaving healthy cells alone — that has been the promise of the emerging field of cancer nanomedicine. But a new meta-analysis from U of T’s [University of Toronto] Institute of Biomaterials & Biomedical Engineering (IBBME) indicates that progress so far has been limited and new strategies are needed if the promise is to become reality.

“The amount of research into using engineered nanoparticles to deliver cancer drugs directly to tumours has been growing steadily over the last decade, but there are very few formulations used in patients. The question is why?” says Professor Warren Chan (IBBME, ChemE, MSE), senior author on the review paper published in Nature Reviews Materials (“Analysis of nanoparticle delivery to tumours”). “We felt it was time to look at the field more closely.”

An April 25, 2016 U of T news release, which originated the news item, details the research,

Chan and his co-authors analysed 117 published papers that recorded the delivery efficiency of various nanoparticles to tumours — that is, the percentage of injected nanoparticles that actually reach their intended target. To their surprise, they found that the median value was about 0.7 per cent of injected nanoparticles reaching their targets, and that this number has not changed for the last ten years. “If the nanoparticles do not get delivered to the tumour, they cannot work as designed for many nanomedicines,” says Chan.

Even more surprising was that altering nanoparticles themselves made little difference in the net delivery efficiency. “Researchers have tried different materials and nanoparticle sizes, different surface coatings, different shapes, but all these variations lead to no difference, or only small differences,” says Stefan Wilhelm, a post-doctoral researcher in Chan’s lab and lead author of the paper. “These results suggest that we have to think more about the biology and the mechanisms that are involved in the delivery process rather than just changing characteristics of nanoparticles themselves.”

Wilhelm points out that nanoparticles do have some advantages. Unlike chemotherapy drugs which go everywhere in the body, drugs delivered by nanoparticles accumulate more in some organs and less in others. This can be beneficial: for example, one current treatment uses nanoparticles called liposomes to encapsulate the cancer drug doxorubicin.

This encapsulation reduces the accumulation of doxorubicin in the heart, thereby reducing cardiotoxicity compared with administering the drug on its own.

Unfortunately, the majority of injected nanoparticles, including liposomes, end up in the liver, spleen and kidneys, which is logical since the job of these organs is to clear foreign substances and poisons from the blood. This suggests that in order to prevent nanoparticles from being filtered out of the blood before they reach the target tumour, researchers may have to control the interactions of those organs with nanoparticles.

It may be that there is an optimal particle surface chemistry, size, or shape required to access each type of organ or tissue.  One strategy the authors are pursuing involves engineering nanoparticles that can dynamically respond to conditions in the body by altering their surfaces or other properties, much like proteins do in nature. This may help them to avoid being filtered out by organs such as the liver, but at the same time to have the optimal properties needed to enter tumors.

More generally, the authors argue that, in order to increase nanoparticle delivery efficiency, a systematic and coordinated long-term strategy is necessary. To build a strong foundation for the field of cancer nanomedicine, researchers will need to understand a lot more about the interactions between nanoparticles and the body’s various organs than they do today. To this end, Chan’s lab has developed techniques  to visualize these interactions across whole organs using 3D optical microscopy, a study published in ACS Nano this week.

In addition to this, the team has set up an open online database, called the Cancer Nanomedicine Repository that will enable the collection and analysis of data on nanoparticle delivery efficiency from any study, no matter where it is published. The team has already uploaded the data gathered for the latest paper, but when the database goes live in June, researchers from all over the world will be able to add their data and conduct real-time analysis for their particular area of interest.

“It is a big challenge to collect and find ways to summarize data from a decade of research but this article will be immensely useful to researchers in the field,” says Professor Julie Audet (IBBME), a collaborator on the study.

Wilhelm says there is a long way to go in order to improve the clinical translation of cancer nanomedicines, but he’s optimistic about the results. “From the first publication on liposomes in 1965 to when they were first approved for use in treating cancer, it took 30 years,” he says. “In 2016, we already have a lot of data, so there’s a chance that the translation of new cancer nanomedicines for clinical use could go much faster this time. Our meta-analysis provides a ‘reality’ check of the current state of cancer nanomedicine and identifies the specific areas of research that need to be investigated to ensure that there will be a rapid clinical translation of nanomedicine developments.”

I made time to read this paper,

Analysis of nanoparticle delivery to tumours by Stefan Wilhelm, Anthony J. Tavares, Qin Dai, Seiichi Ohta, Julie Audet, Harold F. Dvorak, & Warren C. W. Chan. Nature Reviews Materials 1, Article number: 16014 (2016  doi:10.1038/natrevmats.2016.14 Published online: 26 April 2016

It appears to be open access.

The paper is pretty accessible but it does require that you have some tolerance for your own ignorance (assuming you’re not an expert in this area) and time. If you have both, you will find a good description of the various pathways scientists believe nanoparticles take to enter a tumour. In short, they’re not quite sure how nanoparticles gain entry. As well, there are discussions of other problems associated with the field such as producing enough nanoparticles for general usage.

More than an analysis, there’s also a proposed plan for future action (from Analysis of nanoparticle delivery to tumours ),

UofT_30yrCancerMedicine

Current research in using nanoparticles in vivo has focused on innovative design and demonstration of utility of these nanosystems for imaging and treating cancer. The poor clinical translation has encouraged the researchers in the field to investigate the effect of nanoparticle design (for example, size, shape and surface chemistry) on its function and behaviour in the body in the past 10 years. From a cancer-targeting perspective, we do not believe that nanoparticles will be successfully translated to human use if the current ‘research paradigm’ of nanoparticle targeting continues because the delivery efficiency is too low. We propose a long-term strategy to increase the delivery efficiency and enable nanoparticles to be translated to patient care in a cost-effective manner from the research stage. A foundation for the field will be built by obtaining a detailed view of nanoparticle–organ interaction during nanoparticle transport to the tumour, using computational strategies to organize and simulate the results and the development of new tools to assess nanoparticle delivery. In addition, we propose that these results should be collected in a central database to allow progress in the field to be monitored and correlations to be established. A 30-year strategy was proposed and seemed to be a reasonable time frame because the first liposome system was reported in 1965 (Ref. 122) and the first liposome formulation (Doxil) was approved by the US Food and Drug Administration (FDA) in 1995 (Refs 91,92). This 30-year time frame may be shortened as a research foundation has already been established but only if the community can parse the immense amount of currently published data. NP, nanoparticle.

Another paper was mentioned in the news release,

Three-Dimensional Optical Mapping of Nanoparticle Distribution in Intact Tissues by Shrey Sindhwani, Abdullah Muhammad Syed, Stefan Wilhelm, Dylan R Glancy, Yih Yang Chen, Michael Dobosz, and Warren C.W. Chan.ACS Nano, Just Accepted Manuscript Publication Date (Web): April 21, 2016 DOI: 10.1021/acsnano.6b01879

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

Finally, Melanie Ward in an April 26, 2016 article for Science News Hub has another approach to describing the research. Oddly, she states this,

However, the study warns about the lack of efficiency despite major economic investments (more than one billion dollars in the US in the past decade).

She’s right; the US has spent more than $1B in the last decade. In fact, they’ve allocated over $1B every year to the National Nanotechnology Initiative (NNI) for almost two decades for a total of more than $20B. You might want to apply some caution when reading. BTW, I think that’s a wise approach for everything you read including the blog postings here.

Trojan horse nanoparticle for asthma

A brand new technique for dealing with asthma is being proposed by researchers at Northwestern University (US), according to an April 18, 2016 news item on ScienceDaily,

In an entirely new approach to treating asthma and allergies, a biodegradable nanoparticle acts like a Trojan horse, hiding an allergen in a friendly shell, to convince the immune system not to attack it, according to new Northwestern Medicine research. As a result, the allergic reaction in the airways is shut down long- term and an asthma attack prevented.

The technology can be applied to food allergies as well. The nanoparticle is currently being tested in a mouse model of peanut allergy, similar to food allergy in humans.

“The findings represent a novel, safe and effective long-term way to treat and potentially ‘cure’ patients with life-threatening respiratory and food allergies,” said senior author Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “This may eliminate the need for life-long use of medications to treat lung allergy.”

An April 18, 2016 Northwestern University news release (also on EurekAlert) by Marla Paul, which originated the news item, expands on the theme,

It’s the first time this method for creating tolerance in the immune system has been used in allergic diseases. The approach has been used in autoimmune diseases including multiple sclerosis and celiac disease in previous preclinical Northwestern research.

The asthma allergy study was in mice, but the technology is progressing to clinical trials in autoimmune disease. The nanoparticle technology is being developed commercially by Cour Pharmaceuticals Development Co., which is working with Miller to bring this new approach to patients. A clinical trial using the nanoparticles to treat celiac disease is in development.

“It’s a universal treatment,” Miller said. “Depending on what allergy you want to eliminate, you can load up the nanoparticle with ragweed pollen or a peanut protein.”

The nanoparticles are composed of an FDA-approved biopolymer called PLGA that includes lactic acid and glycolic acid.

Also a senior author is Lonnie Shea, adjunct professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and of obstetrics and gynecology at Feinberg, and chair of biomedical engineering at the University of Michigan.

When the allergen-loaded nanoparticle is injected into the bloodstream of mice, the immune system isn’t concerned with it because it sees the particle as innocuous debris. Then the nanoparticle and its hidden cargo are consumed by a macrophage, essentially a vacuum-cleaner cell.

“The vacuum-cleaner cell presents the allergen or antigen to the immune system in a way that says, ‘No worries, this belongs here,’” Miller said. The immune system then shuts down its attack on the allergen, and the immune system is reset to normal.

The allergen, in this case egg protein, was administered into the lungs of mice who have been pretreated to be allergic to the protein and already had antibodies in their blood against it. So when they were re-exposed to it, they responded with an allergic response like asthma. After being treated with the nanoparticle, they no longer had an allergic response to the allergen.

The approach also has a second benefit. It creates a more normal, balanced immune system by increasing the number of regulatory T cells, immune cells important for recognizing the airway allergens as normal. This method turns off the dangerous Th2 T cell that causes the allergy and expands the good, calming regulatory T cells.

If I understand this rightly, they’re rebalancing the immune system so it doesn’t treat innocuous material (dust, mould, etc.) as an allergen.

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

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization by Charles B. Smarr, Woon Teck Yap, Tobias P. Neef, Ryan M. Pearson, Zoe N. Hunter, Igal Ifergan, Daniel R. Getts, Paul J. Bryce, Lonnie D. Shea, and Stephen D. Miller. PNAS 2016 doi: 10.1073/pnas.1505782113 Published ahead of print April 18, 2016,

This paper is behind a paywall.

Macchiarini controversy and synthetic trachea transplants (part 2 of 2)

For some bizarre frosting on this disturbing cake (see part 1 of the Macchiarini controversy and synthetic trachea transplants for the medical science aspects), a January 5, 2016 Vanity Fair article by Adam Ciralsky documents Macchiarini’s courtship of an NBC ([US] National Broadcasting Corporation) news producer who was preparing a documentary about him and his work,

Macchiarini, 57, is a magnet for superlatives. He is commonly referred to as “world-renowned” and a “super-surgeon.” He is credited with medical miracles, including the world’s first synthetic organ transplant, which involved fashioning a trachea, or windpipe, out of plastic and then coating it with a patient’s own stem cells. That feat, in 2011, appeared to solve two of medicine’s more intractable problems—organ rejection and the lack of donor organs—and brought with it major media exposure for Macchiarini and his employer, Stockholm’s Karolinska Institute, home of the Nobel Prize in Physiology or Medicine. Macchiarini was now planning another first: a synthetic-trachea transplant on a child, a two-year-old Korean-Canadian girl named Hannah Warren, who had spent her entire life in a Seoul hospital. …

Macchiarini had come to Vieira’s [Meredith Vieira, American journalist] attention in September 2012, when she read a front-page New York Times story about the doctor. She turned to [Benita] Alexander, one of her most seasoned and levelheaded producers, to look into a regenerative-medicine story for television.

When Alexander and Macchiarini found themselves together in Illinois for a period of weeks in the spring of 2013—brought there by the NBC special—they met frequently for quiet dinners. The trachea transplant on Hannah Warren, the Korean-Canadian girl, was being performed at Children’s Hospital of Illinois, in Peoria, and the procedure was fraught with risks, not least because Macchiarini’s technique was still a work in progress even for adults. (Christopher Lyles, an American who became the second person to receive an artificial trachea, died less than four months after his surgery at Karolinska.) “He’s a brilliant scientist and a great technical surgeon,” said Dr. Richard Pearl, who operated alongside Macchiarini in Illinois. Like others, Pearl described his Italian colleague as a Renaissance man, fluent in half a dozen languages. Another person, who would get to know him through Alexander, compared Macchiarini to “the Most Interesting Man in the World,” the character made famous in Dos Equis beer commercials.

In Peoria, Macchiarini’s medical magic appeared to have its limitations. Hannah Warren died from post-surgical complications less than three months after the transplant. Her anatomy “was much more challenging than we realized,” Pearl recounted. “Scientifically, the operation itself worked. It was just a shame what happened. When you’re doing something for the first time, you don’t have a textbook. It was the hardest operation I’ve ever scrubbed on.”

Then, there was the romance (from the Ciralsky article),

The personal relationship between Alexander and Macchiarini continued to blossom. In June 2013, they flew to Venice for what Alexander called “an incredibly romantic weekend.” Macchiarini bought her red roses and Venetian-glass earrings and took her on a gondola ride under the Bridge of Sighs. Like a pair of teenagers, they attached love locks to the Ponte dell’Accademia bridge, one of them bearing the inscription “B—P 23/6/13, 4 Ever.” Alexander told me that, “when he took me to Venice, we were still shooting the story … He always paid for everything … gifts, expensive dinners, flowers—the works. When it came to money, he was incredibly generous.”

It is a bedrock principle at NBC and every other news organization that journalists must avoid conflicts of interest, real or apparent. Alexander was not oblivious to this. “I knew that I was crossing the line in the sense that it’s a basic and well-understood rule of journalism that you don’t become involved with one of the subjects of your story, because your objectivity could clearly become compromised,” she told me. “I never once thought about him paying for the trip as him ‘buying’ me in some fashion, or potentially using money to influence me, because, from my perspective anyway … that just wasn’t the case. We were just crazy about each other, and I was falling in love.”

Alexander made her way to Stockholm at a later date (from the Ciralsky article),

Macchiarini was in Stockholm to attend to Yesim Cetir, a 25-year-old Turkish woman whose artificial trachea had failed. As Swedish television later reported, “It has taken nearly 100 surgeries to support the cell tissue around the airpipes. Her breathing is bad, and to avoid suffocation, her respiratory tract must be cleansed from mucus every fourth hour. She has now been lying in the hospital for nearly 1,000 days.” NBC’s special would come to include skeptical commentary from Dr. Joseph Vacanti, who questioned the sufficiency of Macchiarini’s research, but Cetir’s post-operative complications were not mentioned.

Prior to the NBC documentary’s (A Leap of Faith) airing, the romance became an engagement (from the Ciralsky article),

Macchiarini proposed to Benita Alexander on Christmas Day 2013, Alexander said. In the months leading up to the airing of A Leap of Faith, in June 2014, Macchiarini and Alexander went on trips to the Bahamas, Turkey, Mexico, Greece, and Italy. They went on shopping sprees and ate their way through Michelin-starred restaurants. Macchiarini even took Alexander and her daughter to meet his mother at her home, in Lucca. “She cooked homemade gnocchi,” Alexander recalled. Macchiarini’s mother shared pictures from the family photo album while her son translated. Emanuela Pecchia, the woman whom Macchiarini had married years earlier, lived only a short distance away. When Macchiarini informed Alexander, during a dinner cruise later that summer, that his divorce had finally come through, she recounted, he gave her an engagement ring.

In the months that followed, the doctor and his fiancée began planning their wedding in earnest. They set a date for July 11, 2015, in Rome. But their desire to marry in the Catholic Church was complicated by the fact that she is Episcopalian and divorced. Divorce would have been an issue for Macchiarini as well. However, Alexander said, Macchiarini insisted that he would fix things by visiting his friend and patient in the Vatican.

In October 2014, Alexander recalled, Macchiarini told her that he had met with Pope Francis for four hours and that the Pontiff consented to the couple’s marriage and, in yet another sign of his progressive tenure, vowed to officiate. Alexander said Macchiarini referred to himself as Pope Francis’s “personal doctor” and maintained that in subsequent meetings his patient offered to host the wedding at his summer residence, the Apostolic Palace of Castel Gandolfo.

Shortly after quitting her job in anticipation of her July 2015 wedding to Macchiarini, Alexander learned that Pope Francis who was supposed to officiate was in fact scheduled to be in South America during that time.  From the Ciralsky article,

As Alexander would discover with the help of a private investigator named Frank Murphy, virtually every detail Macchiarini provided about the wedding was false. A review of public records in Italy would also seem to indicate that Macchiarini remains married to Emanuela Pecchia, his wife of nearly 30 years. Murphy, who spent 15 years as a Pennsylvania State Police detective, told me, “I’ve never in my experience witnessed a fraud like this, with this level of international flair…. The fact that he could keep all the details straight and compartmentalize these different lives and lies is really amazing.

Ciralsky broaches the question of why someone with Macchiarini’s accomplishments would jeopardize his position in such a way,

To understand why someone of considerable stature could construct such elaborate tales and how he could seemingly make others believe them, I turned to Dr. Ronald Schouten, a Harvard professor who directs the Law and Psychiatry Service at Massachusetts General Hospital. “We’re taught from an early age that when something is too good to be true, it’s not true,” he said. “And yet we ignore the signals. People’s critical judgment gets suspended. In this case, that happened at both the personal and institutional level.” Though he will not diagnose from a distance, Schouten, who is one of the nation’s foremost authorities on psychopathy, observed, “Macchiarini is the extreme form of a con man. He’s clearly bright and has accomplishments, but he can’t contain himself. There’s a void in his personality that he seems to want to fill by conning more and more people.” When I asked how Macchiarini stacks up to, say, Bernie Madoff, he laughed and said, “Madoff was an ordinary con man with a Ponzi scheme. He never claimed to be the chairman of the Federal Reserve. He didn’t suggest he was part of a secret international society of bankers. This guy is really good.”

In addition to the romance, Ciralsky and Vanity Fair checked out Macchiarini’s résumé,

Vanity Fair contacted many of the schools at which Macchiarini claimed to have either earned a degree or held an academic post. While the University of Pisa confirmed that he indeed received an M.D. and had specialized in surgery, the University of Alabama at Birmingham denied that Macchiarini earned a master’s in biostatistics or that he participated in a two-year fellowship in thoracic surgery. In fact, according to U.A.B. spokesman Bob Shepard, the only record the school has for Macchiarini indicates that he did a six-month non-surgical fellowship in hematology/oncology—which according to the current Accreditation Council for Graduate Medical Education guidelines is 30 months shy of what is required for a clinical fellowship in that field. The University of Paris—Sud never responded to repeated requests for comment, but Hannover Medical School wrote to say that Macchiarini had been neither a full nor an associate professor there, merely an adjunct.

Comments

As I noted in part 1, there are medical science and ethical issues to be considered. As well, Macchiarini’s romantic behaviour certainly seems fraudulent as do parts of his curriculum vitae (CV) and there’s more about Macchiarini’s professional accomplishments (read Ciralsky’s entire January 5, 2016 Vanity Fair article for details).

The romantic and CV chicanery may or may not suggest serious problems with Macchiarini’s revolutionary procedure and ethics. History is littered with stories of people who achieved extraordinary advances and were not the most exemplary human beings. Paracelsus, founder of the field of toxicology and an important contributor in the fields of medicine and science, was reputedly a sketchy character. Caravaggio now remembered for his art, killed someone (accidentally or not) and was known for his violent behaviour even in a time when there was higher tolerance for it.

What I’m saying is that Macchiarini may be pioneering something important regardless of how you view his romantic chicanery and falsified CV. Medical research can be high risk and there is no way to avoid that sad fact. However, criticisms of the work from Macchiarini’s colleagues need to be addressed and the charge that a Russian patient who was not in imminent danger and not properly advised of the extremely high risk must also be addressed.

It should also be remembered that Macchiarini did not pull this off by himself. Institutions such as the Karolinska Institute failed to respond appropriately in the initial stages. As well, the venerable medical journal, The Lancet seems reluctant to address the situation even now.

Before dissecting the Alexander situation, it should be said that she showed courage in admitting her professional transgression and discussing a painful and humiliating romantic failure. All of us are capable of misjudgments and wishful thinking, unfortunately for her, this became an international affair.

More critically, Alexander, a journalist, set aside her ethics for a romance and what seems to be surprisingly poor research by Alexander’s team.  (Even I had a little something about this in 2013.) How did a crack NBC research team miss the problems? (For the curious, this Bryan Burrough April 30, 2015 article for Vanity Fair highlighting scandals plaguing NBC News may help to answer the question about NBC research.)

Finally, there’s an enormous amount of pressure on stem cell scientists due to the amounts of money and the degree of prestige involved. Ciralsky’s story notes the pressure when he describes how Macchiarini got one of this positions at an Italian facility in Florence through political machinations. (The situation is a little more complicated than I’ve described here but an accommodation in Macchiarini’s favour was made.) Laura Margottini’s Oct. 7, 2014 article for Science magazine provides a synopsis of another stem cell controversy in Italy.

Stem cell controversies have not been confined to Italy or Europe for that matter. There was the South Korean scandal in 2006 (see a Sept. 19, 2011 BBC [British Broadcasting Corporation] news online post for an update and synopsis) when a respected scientist was found to have falsified research results. Up to that  point, South Korea was considered the world leader in the field.

Finally,  if there are two survivors, is there a possibility that this procedure could be made successful for more patients or that some patients are better candidates than others?

Additional notes

Macchiarini is mounting a defence for himself according to a March 30, 2016 news item on phys.org and a Swedish survey indicates that the average Swede’s trust in researchers still remains high despite the Macchiarini imbroglio according to an April 15, 2016 news item on phys.org.

For anyone interested in the timeline and updates for this scandal, Retraction Watch offers this: http://retractionwatch.com/2016/02/12/reading-about-embattled-trachea-surgeon-paolo-macchiarini-heres-what-you-need-to-know/

Macchiarini controversy and synthetic trachea transplants (part 1 of 2)

Having featured Paolo Macchiarini and his work on transplanting synthetic tracheas into humans when it was lauded (in an Aug. 2, 2011 post titled: Body parts nanostyle), it seems obligatory to provide an update now that he and his work are under a very large cloud. Some of this is not new, there were indications as early as this Dec. 27, 2013 post titled: Trachea transplants: an update which featured an article by Gretchen Vogel in Science magazine hinting at problems.

Now, a Feb. 4, 2016 article by Gretchen Vogel for Science magazine provides a more current update and opens with this (Note: Links have been removed),

The Karolinska Institute (KI) in Stockholm “has lost its confidence” in surgeon Paolo Macchiarini, a senior researcher at the institute, and will end its ties with him. In a statement issued today, KI said that it won’t renew Macchiarini’s contract after it expires on 30 November 2016.

The move comes in the wake of a chilling three-part TV documentary about Macchiarini, a former media darling who was cleared of scientific misconduct charges by KI vice-chancellor Anders Hamsten last summer. Among other things, The Experiments, broadcast in January by Swedish public television channel SVT, suggests that Macchiarini didn’t fully inform his patients about the risks of his pioneering trachea implants. Most of the patients died, including at least one—a woman treated in Krasnodar, Russia—who was not seriously ill before the surgery.

For a profession that has “do no harm” as one of its universal tenets, the hint that a patient not in dire need agreed to a very risky procedure without being properly apprised of the risks is chilling.

Macchiarini’s behavriour is not the only concern, the Karolinska Institute is also being held to account (from the Vogel article),

The film has also raised questions about the way Hamsten and other administrators at KI, Sweden’s most prestigious university and home of the selection committee for the Nobel Prize in Physiology or Medicine, have handled the scandal. Today [Feb. 4, 2016], the Institute’s Board decided to launch an independent review, to be led by an experienced lawyer, into KI’s 5-year relationship with Macchiarini. Among the things the inquiry should address is whether any errors were made or laws were broken when Macchiarini was hired; whether misconduct charges against him were handled properly; and why, given the controversy, he was given a new 1-year contract  as a senior researcher after his appointment as a visiting professor at KI ended in October 2015.

Getting back to Macchiarini (from the Vogel article),

In 2014, colleagues at KI alleged that Macchiarini’s papers made his transplants seem more successful than they were, omitting serious complications. Two patients treated at Karolinska died, and a third has been in intensive care since receiving a trachea in 2012. The Illinois patient also died, as did three patients in Russia. Bengt Gerdin, a professor emeritus of surgery at Uppsala University in Sweden who investigated the charges at KI’s request, concluded in May 2015 that differences between published papers and lab records constituted scientific misconduct. But Hamsten rejected that conclusion in August, based on additional material Macchiarini submitted later.

The documentary shows footage of a patient who says Macchiarini reassured him before the surgery that experiments had been done on pigs, when in fact none had taken place. It also follows the wrenching story of the first patient in Krasnodar. A 33-year-old woman, she was living with a tracheostomy that she said caused her pain, but her condition was not life-threatening. The film suggests that she wasn’t fully aware of the risks of the operation, and that Macchiarini and his colleagues knew about problems with the implant before the surgery. The patient’s first implant failed, and she received a second one in 2013. She died in 2014.

So in May 2015, an investigator concluded there had been scientific misconduct and, yet, Macchiarini’s contract is renewed in the fall of 2015.

Kerry Grens in a March 7, 2016 article for The Scientist provides information about the consequences of the latest investigation into Macchiarini’s work (Note: Links have been removed),

Karl-Henrik Grinnemo, a surgeon at the Karolinska Institute and one of a number of colleagues who voiced concerns about the conduct of fellow surgeon Paolo Macchiarini, is no longer a coauthor on a 2011 The Lancet study led by Macchiarini that described an artificial windpipe. Grinnemo asked to be removed from the paper, and the journal complied last week (March 3).

Grinnemo’s removal from the study is the latest in a string of repercussions related to an investigation of Macchiarini’s work. Last month, the head of the Karolinska Institute, Anders Hamsten, resigned because the institution’s initial investigation concluded no wrongdoing. Hamsten said he and his colleagues were probably wrong about Macchiarini; the institute has launched another investigation into the surgeon’s work.

A March 23, 2016 news item on phys.org announces Macchiarini’s firing from the Karolinska Institute and provides a brief description of his work with synthetic tracheas (Note: A link has been removed),

Sweden’s Karolinska Institute (KI), which awards the Nobel Prize for Medicine, on Wednesday [March 23, 2016] dismissed a Italian transplant surgeon suspected of research fraud and ethical breaches, in an affair that has plunged the renowned institution into crisis.

“It is impossible for KI to continue to have any cooperation with Paolo Macchiarini. He has acted in a way that has had very tragic consequences for the people affected and their families. His conduct has seriously damaged confidence in KI,” human resource director Mats Engelbrektson said in a statement.

Macchiarini, a 57-year-old visiting professor at Karolinska since 2010, rose to fame for carrying out the first synthetic trachea, or windpipe, transplant in 2011.

It was a plastic structure seeded with the patient’s own stem cells—immature cells that grow into specialised cells of the body’s organs.

The surgeon performed three such operations in Stockholm and five others around the world, and the exploit was initially hailed as a game-changer for transplant medicine.

But six of the eight patients reportedly died, and allegations ensued that the risky procedure had been carried out on at least one individual who had not been life-threateningly ill.

Macchiarini is also suspected of lying about his scientific research and his past experience with prestigious medical research centres.

“Paolo Macchiarini supplied false or misleading information in the CV he submitted to KI” and “demonstrated scientific negligence” in his research, said the institute.

H/t to Don Bright, a reader who informed me about this April 2, 2016 posting by Pierre Delaere (a long time Macchiarini critic), published in Leonid Schneider’s blog, For Better Science,

I have written this overview as a trachea surgeon working at KU Leuven and privileged witness of the “Tracheal regeneration scandal” from the very start.

Because of its immense scale, the scandal is difficult to grasp and explain. Fortunately, we have recently been provided with an excellent overview in the 3 x 1-hour documentary by Bosse Lindquist on Swedish national TV. Due to Paolo Macchiarini’s appetite for the spotlights and thanks to the professional standards of the Swedish top producer this is probably the very first case of a medical crime played out in the media. Anyone who has seen this brilliant investigative documentary cannot help but wonder why there are still people who doubt that this is a case of gross medical misconduct.

The story began in Barcelona in 2008 with the publication in The Lancet of a report on a regenerated windpipe, featuring Paolo Macchiarini (PM) as its first author (Macchiarini et al. Lancet 2008). This ground-breaking achievement consisted of bringing to life a dead windpipe from a donor, by putting it in a plastic box, a so-called ‘bioreactor’ together with bone marrow fluid (stem cells). A few weeks later, I wrote a letter to The Lancet, pointing out:

    “The main drawback of the proposed reconstruction is the lack of an intrinsic blood supply to the trachea. We know that a good blood supply is the first requirement in all other tissue and organ transplantations. Therefore, the reported success of this technique is questionable” (correspondence by Delaere and Hermans, Lancet 2009).

Delaere goes on to recount and critique the story of the first synthetic trachea,

…  PM had mounted bone marrow extract (‘stem cells’) on a plastic tube (‘bioartificial trachea’) in a plastic box (‘bioreactor’). After a day or two this creation was ‘successfully’ transplanted in a patient with a trachea defect. This occurred in the Karolinska hospital in July 2011 and was reported on in The Lancet shortly afterwards . Biologically speaking, the procedure is absolutely implausible.

In reality an important part of the windpipe had been replaced by a synthetic tube, and the presence of stem cells made no difference to this whatsoever.

For those not in the field, this procedure may still seem acceptable. A blood vessel can also be replaced by synthetic material because the material can grow into the sterile environment of the blood stream. However, this is completely impossible if the synthetic material is exposed to an environment of inhaled air full of bacteria. The laws of biology allow us to predict accurately what will happen after part of the windpipe has been replaced by a synthetic tube. After some time, the suturing between the synthetic tube and the surrounding tissue will come loose, leading to a number of serious complications. These complications inevitably lead to death in the short (months) or in the mid-long term (a few years). How long the patient will survive also depends on the options still left to treat complications. In most cases so far, a metal stent had to be implanted to keep the airway open in the sutured area.It is entirely predictable that additional complications after placement of the metal stent will ultimately lead to the patient’s death, usually by asphyxiation or by bleeding out after complete rupture of the sutures. This gruesome fate awaiting patients was clearly shown in the documentary. Replacing a part of the trachea by a synthetic tube can therefore be compared to death by medical torture. The amount of suffering it induces is directly proportional to the duration between implantation and the patient’s death.

Delaere describes his own and others’ efforts to bring these issues to light,

Since 2011, I have contacted both the President of KI and the Editors of The Lancet with well-documented information to clarify that what had happened was completely unacceptable. These alerts were repeated in 2013 and 2014. Since 2014, four doctors from KI, who had seen it all happen, have been collecting evidence to show the extent of misconduct [Matthias Corbascio, Thomas Fux, Karl-Henrik Grinnemo and Oscar Simonsson, their letter to Vice-Chancellor Hamsten from June 22, 2015, and its attachments available here; -LS]. Not only did KI not react to the doctors’ complaint, these doctors were in fact intimidated and threatened with dismissal. KI’s Ethical Commission came to a verdict of ‘no misconduct’ in April 2015 following an inquiry based on a series of complaints filed by myself [verdict available from SVT here, -LS]. The Lancet Editor did not even bother to reply to my complaints.

In the reports, eight patients were given synthetic tracheas with six now dead and, allegedly, two still living. Delaere comments,

… To prove that this transplantation technique is effective, reports about the long-term success of this technique in the first 2 patients in Barcelona and London is still being spread. What the real situation of the two patients is at the moment is very difficult to establish. For some time now, reports about these two cases seem to have disappeared from the face of the earth. After the air has been cleared in Sweden, the same will probably happen in London and Barcelona.

Comments

Sometimes medical research can be very dangerous. While, a 25% chance of success (two of Macchiarini’s eight patients undergoing the synthetic trachea transplant have allegedly survived) is not encouraging, it’s understandable that people in dire circumstances and with no other options might want to take a chance.

It’s troubling that the woman in Russia was not in dire straights and that she may not have known how dangerous the procedure is. It would have been unethical of Macchiarini to knowingly perform the procedure under those circumstances.

I am wrestling with some questions about the composite used to create the synthetic trachea and the surviving patients. My understanding is that the composite was designed for eventual deterioration as the patient’s own harvested stem cells fully formed the trachea. Whether the trachea is the one I imagined or he plastic one described by Delaere, how did two patients survive and what is their condition now? The first patient Andemariam Teklesenbet Beyene in 2011 had apparently completed his PhD studies by 2013 (my Dec. 27, 2013 posting). Assuming Beyene is one of the two survivors, what has happened to him and the other one?

As for Delaere’s comments, he certainly raises some red flags not only regarding the procedure but the behaviour of the Lancet editorial team and the Karolinska Institute (they seem to be addressing the issues by firing Macchiarini and with the  resignations of the staff and board).

There are two more twists to this story, which carries on in part 2.

Embroidering electronics into clothing

Researchers at The Ohio State University are developing embroidered antennas and circuits with 0.1 mm precision—the perfect size to integrate electronic components such as sensors and computer memory devices into clothing. Photo by Jo McCulty, courtesy of The Ohio State University.

Researchers at The Ohio State University are developing embroidered antennas and circuits with 0.1 mm precision—the perfect size to integrate electronic components such as sensors and computer memory devices into clothing. Photo by Jo McCulty, courtesy of The Ohio State University.

An April 13, 2016 news item on Nanowerk describes an advance in the field of wearable electronics,

Researchers who are working to develop wearable electronics have reached a milestone: They are able to embroider circuits into fabric with 0.1 mm precision—the perfect size to integrate electronic components such as sensors and computer memory devices into clothing.

With this advance, the Ohio State University researchers have taken the next step toward the design of functional textiles—clothes that gather, store, or transmit digital information. With further development, the technology could lead to shirts that act as antennas for your smart phone or tablet, workout clothes that monitor your fitness level, sports equipment that monitors athletes’ performance, a bandage that tells your doctor how well the tissue beneath it is healing—or even a flexible fabric cap that senses activity in the brain.

That last item is one that John Volakis, director of the ElectroScience Laboratory at Ohio State, and research scientist Asimina Kiourti are investigating. The idea is to make brain implants, which are under development to treat conditions from epilepsy to addiction, more comfortable by eliminating the need for external wiring on the patient’s body.

An April 13, 2016 Ohio State University news release by Pam Frost Gorder, which originated the news item, expands on the theme (Note: Links have been removed),

“A revolution is happening in the textile industry,” said Volakis, who is also the Roy & Lois Chope Chair Professor of Electrical Engineering at Ohio State. “We believe that functional textiles are an enabling technology for communications and sensing—and one day even medical applications like imaging and health monitoring.”

Recently, he and Kiourti refined their patented fabrication method to create prototype wearables at a fraction of the cost and in half the time as they could only two years ago. With new patents pending, they published the new results in the journal IEEE Antennas and Wireless Propagation Letters.

In Volakis’ lab, the functional textiles, also called “e-textiles,” are created in part on a typical tabletop sewing machine—the kind that fabric artisans and hobbyists might have at home. Like other modern sewing machines, it embroiders thread into fabric automatically based on a pattern loaded via a computer file. The researchers substitute the thread with fine silver metal wires that, once embroidered, feel the same as traditional thread to the touch.

“We started with a technology that is very well known—machine embroidery—and we asked, how can we functionalize embroidered shapes? How do we make them transmit signals at useful frequencies, like for cell phones or health sensors?” Volakis said. “Now, for the first time, we’ve achieved the accuracy of printed metal circuit boards, so our new goal is to take advantage of the precision to incorporate receivers and other electronic components.”

The shape of the embroidery determines the frequency of operation of the antenna or circuit, explained Kiourti.

The shape of one broadband antenna, for instance, consists of more than half a dozen interlocking geometric shapes, each a little bigger than a fingernail, that form an intricate circle a few inches across. Each piece of the circle transmits energy at a different frequency, so that they cover a broad spectrum of energies when working together—hence the “broadband” capability of the antenna for cell phone and internet access.

“Shape determines function,” she said. “And you never really know what shape you will need from one application to the next. So we wanted to have a technology that could embroider any shape for any application.”

The researchers’ initial goal, Kiourti added, was just to increase the precision of the embroidery as much as possible, which necessitated working with fine silver wire. But that created a problem, in that fine wires couldn’t provide as much surface conductivity as thick wires. So they had to find a way to work the fine thread into embroidery densities and shapes that would boost the surface conductivity and, thus, the antenna/sensor performance.

Previously, the researchers had used silver-coated polymer thread with a 0.5-mm diameter, each thread made up of 600 even finer filaments twisted together. The new threads have a 0.1-mm diameter, made with only seven filaments. Each filament is copper at the center, enameled with pure silver.

They purchase the wire by the spool at a cost of 3 cents per foot; Kiourti estimated that embroidering a single broadband antenna like the one mentioned above consumes about 10 feet of thread, for a material cost of around 30 cents per antenna. That’s 24 times less expensive than when Volakis and Kiourti created similar antennas in 2014.

In part, the cost savings comes from using less thread per embroidery. The researchers previously had to stack the thicker thread in two layers, one on top of the other, to make the antenna carry a strong enough electrical signal. But by refining the technique that she and Volakis developed, Kiourti was able to create the new, high-precision antennas in only one embroidered layer of the finer thread. So now the process takes half the time: only about 15 minutes for the broadband antenna mentioned above.

She’s also incorporated some techniques common to microelectronics manufacturing to add parts to embroidered antennas and circuits.

One prototype antenna looks like a spiral and can be embroidered into clothing to improve cell phone signal reception. Another prototype, a stretchable antenna with an integrated RFID (radio-frequency identification) chip embedded in rubber, takes the applications for the technology beyond clothing. (The latter object was part of a study done for a tire manufacturer.)

Yet another circuit resembles the Ohio State Block “O” logo, with non-conductive scarlet and gray thread embroidered among the silver wires “to demonstrate that e-textiles can be both decorative and functional,” Kiourti said.

They may be decorative, but the embroidered antennas and circuits actually work. Tests showed that an embroidered spiral antenna measuring approximately six inches across transmitted signals at frequencies of 1 to 5 GHz with near-perfect efficiency. The performance suggests that the spiral would be well-suited to broadband internet and cellular communication.

In other words, the shirt on your back could help boost the reception of the smart phone or tablet that you’re holding – or send signals to your devices with health or athletic performance data.

The work fits well with Ohio State’s role as a founding partner of the Advanced Functional Fabrics of America Institute, a national manufacturing resource center for industry and government. The new institute, which joins some 50 universities and industrial partners, was announced earlier this month by U.S. Secretary of Defense Ashton Carter.

Syscom Advanced Materials in Columbus provided the threads used in Volakis and Kiourti’s initial work. The finer threads used in this study were purchased from Swiss manufacturer Elektrisola. The research is funded by the National Science Foundation, and Ohio State will license the technology for further development.

Until then, Volakis is making out a shopping list for the next phase of the project.

“We want a bigger sewing machine,” he said.

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

Fabrication of Textile Antennas and Circuits With 0.1 mm Precision by A. Kiourti, C. Lee, and J. L. Volakis.  IEEE Antennas and Wireless Propagation Letters (Volume:15 ) Page(s): 151 – 153 ISSN : 1536-1225 INSPEC Accession Number: 15785288 DOI: 10.1109/LAWP.2015.2435257 Date of Publication: 20 May 2015 Issue Date: 2016

This paper is behind a paywall.

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.