Category Archives: medicine

Gold on the brain, a possible nanoparticle delivery system for drugs

A July 21, 2014 news item on Nanowerk describes special gold nanoparticles that could make drug delivery to cells easier,

A special class of tiny gold particles can easily slip through cell membranes, making them good candidates to deliver drugs directly to target cells.

A new study from MIT materials scientists reveals that these nanoparticles enter cells by taking advantage of a route normally used in vesicle-vesicle fusion, a crucial process that allows signal transmission between neurons.

A July 21, 2014 MIT (Massachusetts Institute of Technology) news release (also on EurekAlert), which originated the news item, provides more details,

The findings suggest possible strategies for designing nanoparticles — made from gold or other materials — that could get into cells even more easily.

“We’ve identified a type of mechanism that might be more prevalent than is currently known,” says Reid Van Lehn, an MIT graduate student in materials science and engineering and one of the paper’s lead authors. “By identifying this pathway for the first time it also suggests not only how to engineer this particular class of nanoparticles, but that this pathway might be active in other systems as well.”

The paper’s other lead author is Maria Ricci of École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland. The research team, led by Alfredo Alexander-Katz, an associate professor of materials science and engineering, and Francesco Stellacci from EPFL, also included scientists from the Carlos Besta Institute of Neurology in Italy and Durham University in the United Kingdom.

Most nanoparticles enter cells through endocytosis, a process that traps the particles in intracellular compartments, which can damage the cell membrane and cause cell contents to leak out. However, in 2008, Stellacci, who was then at MIT, and Darrell Irvine, a professor of materials science and engineering and of biological engineering, found that a special class of gold nanoparticles coated with a mix of molecules could enter cells without any disruption.

“Why this was happening, or how this was happening, was a complete mystery,” Van Lehn says.

Last year, Alexander-Katz, Van Lehn, Stellacci, and others discovered that the particles were somehow fusing with cell membranes and being absorbed into the cells. In their new study, they created detailed atomistic simulations to model how this happens, and performed experiments that confirmed the model’s predictions.

Gold nanoparticles used for drug delivery are usually coated with a thin layer of molecules that help tune their chemical properties. Some of these molecules, or ligands, are negatively charged and hydrophilic, while the rest are hydrophobic. The researchers found that the particles’ ability to enter cells depends on interactions between hydrophobic ligands and lipids found in the cell membrane.

Cell membranes consist of a double layer of phospholipid molecules, which have hydrophobic lipid tails and hydrophilic heads. The lipid tails face in toward each other, while the hydrophilic heads face out.

In their computer simulations, the researchers first created what they call a “perfect bilayer,” in which all of the lipid tails stay in place within the membrane. Under these conditions, the researchers found that the gold nanoparticles could not fuse with the cell membrane.

However, if the model membrane includes a “defect” — an opening through which lipid tails can slip out — nanoparticles begin to enter the membrane. When these lipid protrusions occur, the lipids and particles cling to each other because they are both hydrophobic, and the particles are engulfed by the membrane without damaging it.

In real cell membranes, these protrusions occur randomly, especially near sites where proteins are embedded in the membrane. They also occur more often in curved sections of membrane, because it’s harder for the hydrophilic heads to fully cover a curved area than a flat one, leaving gaps for the lipid tails to protrude.

“It’s a packing problem,” Alexander-Katz says. “There’s open space where tails can come out, and there will be water contact. It just makes it 100 times more probable to have one of these protrusions come out in highly curved regions of the membrane.”

This phenomenon appears to mimic a process that occurs naturally in cells — the fusion of vesicles with the cell membrane. Vesicles are small spheres of membrane-like material that carry cargo such as neurotransmitters or hormones.

The similarity between absorption of vesicles and nanoparticle entry suggests that cells where a lot of vesicle fusion naturally occurs could be good targets for drug delivery by gold nanoparticles. The researchers plan to further analyze how the composition of the membranes and the proteins embedded in them influence the absorption process in different cell types. “We want to really understand all the constraints and determine how we can best design nanoparticles to target particular cell types, or regions of a cell,” Van Lehn says.

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

Lipid tail protrusions mediate the insertion of nanoparticles into model cell membranes by Reid C. Van Lehn, Maria Ricci, Paulo H.J. Silva, Patrizia Andreozzi, Javier Reguera, Kislon Voïtchovsky, Francesco Stellacci, & Alfredo Alexander-Katz. Nature Communications 5, Article number: 4482 doi:10.1038/ncomms5482 Published 21 July 2014

This article is behind a paywall but there is a free preview available via ReadCube Access.

I last featured this multi-country team’s work on gold nanoparticles in an Aug. 23, 2013 posting.

Extracting biomolecules from live cells with carbon nanotubes

Being able to extract biomolecules from living cells means nondestruction of the rest of the cell and the ability to observe the consequences of the extraction. From a July 18, 2014 news item on Azonano,

University of Houston researchers have devised a new method for extracting molecules from live cells without disrupting cell development, work that could provide new avenues for the diagnosis of cancer and other diseases.

The researchers used magnetized carbon nanotubes to extract biomolecules from live cells, allowing them to retrieve molecular information without killing the individual cells. A description of the work appears this week in the Proceedings of the National Academy of Sciences.

A July 16, 2014 University of Houston news release by Jeannie Kever, which originated the news item, provides more detail,

Most current methods of identifying intracellular information result in the death of the individual cells, making it impossible to continue to gain information and assess change over time, said Zhifeng Ren, M.D. Anderson Chair professor of physics and principal investigator at the Center for Superconductivity at UH and lead author of the paper. The work was a collaboration between Ren’s lab and that of Paul Chu, T.L.L. Temple Chair of Science and founding director of the Texas Center for Superconductivity.

Chu, a co-author of the paper, said the new technique will allow researchers to draw fundamental information from a single cell.The researchers said the steps outlined in the paper offer proof of concept. Ren said the next step “will be more study of the biological and chemical processes of the cell, more analysis.”

The initial results hold promise for biomedicine, he said.  “This shows how nanoscience and nanoengineering can help the medical field.”

Cai said the new method will be helpful for cancer drug screening and carcinogenesis study, as well as for studies that allow researchers to obtain information from single cells, replacing previous sampling methods that average out cellular diversity and obscure the specificity of the biomarker profiles.

In the paper, the researchers explain their rationale for the work – most methods for extracting molecular information result in cell death, and those that do spare the cell carry special challenges, including limited efficiency.

This method is relatively straightforward, requiring the use of magnetized carbon nanotubes as the transporter and a polycarbonate filter as a collector, they report. Cells from a human embryonic kidney cancer cell line were used for the experiment.

The work builds on a 2005 paper published by Ren’s group in Nature Methods, which established that magnetized carbon nanotubes can deliver molecular payloads into cells. The current research takes that one step further to move molecules out of cells by magnetically driving them through the cell walls.

The carbon nanotubes were grown with a plasma-enhanced chemical vapor deposition system, with magnetic nickel particles enclosed at the tips. A layer of nickel was also deposited along the surface of individual nanotubes in order to make the nanotubes capable of penetrating a cell wall guided by a magnet.

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

Molecular extraction in single live cells by sneaking in and out magnetic nanomaterials by Zhen Yang, Liangzi Deng, Yucheng Lan, Xiaoliu Zhang, Zhonghong Gao, Ching-Wu Chu, Dong Cai, and Zhifeng Ren. PNAS 2014 ; published ahead of print July 16, 2014, doi:10.1073/pnas.1411802111

This paper is behind a paywall.

Nanojuice in your gut

A July 7, 2014 news item on Azonano features a new technique that could help doctors better diagnose problems in the intestines (guts),

Located deep in the human gut, the small intestine is not easy to examine. X-rays, MRIs and ultrasound images provide snapshots but each suffers limitations. Help is on the way.

University at Buffalo [State University of New York] researchers are developing a new imaging technique involving nanoparticles suspended in liquid to form “nanojuice” that patients would drink. Upon reaching the small intestine, doctors would strike the nanoparticles with a harmless laser light, providing an unparalleled, non-invasive, real-time view of the organ.

A July 5, 2014 University of Buffalo news release (also on EurekAlert) by Cory Nealon, which originated the news item, describes some of the challenges associated with medical imaging of small intestines,

“Conventional imaging methods show the organ and blockages, but this method allows you to see how the small intestine operates in real time,” said corresponding author Jonathan Lovell, PhD, UB assistant professor of biomedical engineering. “Better imaging will improve our understanding of these diseases and allow doctors to more effectively care for people suffering from them.”

The average human small intestine is roughly 23 feet long and 1 inch thick. Sandwiched between the stomach and large intestine, it is where much of the digestion and absorption of food takes place. It is also where symptoms of irritable bowel syndrome, celiac disease, Crohn’s disease and other gastrointestinal illnesses occur.

To assess the organ, doctors typically require patients to drink a thick, chalky liquid called barium. Doctors then use X-rays, magnetic resonance imaging and ultrasounds to assess the organ, but these techniques are limited with respect to safety, accessibility and lack of adequate contrast, respectively.

Also, none are highly effective at providing real-time imaging of movement such as peristalsis, which is the contraction of muscles that propels food through the small intestine. Dysfunction of these movements may be linked to the previously mentioned illnesses, as well as side effects of thyroid disorders, diabetes and Parkinson’s disease.

The news release goes on to describe how the researchers manipulated dyes that are usually unsuitable for the purpose of imaging an organ in the body,

Lovell and a team of researchers worked with a family of dyes called naphthalcyanines. These small molecules absorb large portions of light in the near-infrared spectrum, which is the ideal range for biological contrast agents.

They are unsuitable for the human body, however, because they don’t disperse in liquid and they can be absorbed from the intestine into the blood stream.

To address these problems, the researchers formed nanoparticles called “nanonaps” that contain the colorful dye molecules and added the abilities to disperse in liquid and move safely through the intestine.

In laboratory experiments performed with mice, the researchers administered the nanojuice orally. They then used photoacoustic tomography (PAT), which is pulsed laser lights that generate pressure waves that, when measured, provide a real-time and more nuanced view of the small intestine.

The researchers plan to continue to refine the technique for human trials, and move into other areas of the gastrointestinal tract.

Here’s an image of the nanojuice in the guts of a mouse,

The combination of "nanojuice" and photoacoustic tomography illuminates the intestine of a mouse. (Credit: Jonathan Lovell)

The combination of “nanojuice” and photoacoustic tomography illuminates the intestine of a mouse. (Credit: Jonathan Lovell)

This is an international collaboration both from a research perspective and a funding perspective (from the news release),

Additional authors of the study come from UB’s Department of Chemical and Biological Engineering, Pohang University of Science and Technology in Korea, Roswell Park Cancer Institute in Buffalo, the University of Wisconsin-Madison, and McMaster University in Canada.

The research was supported by grants from the National Institutes of Health, the Department of Defense and the Korean Ministry of Science, ICT and Future Planning.

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

Non-invasive multimodal functional imaging of the intestine with frozen micellar naphthalocyanines by Yumiao Zhang, Mansik Jeon, Laurie J. Rich, Hao Hong, Jumin Geng, Yin Zhang, Sixiang Shi, Todd E. Barnhart, Paschalis Alexandridis, Jan D. Huizinga, Mukund Seshadri, Weibo Cai, Chulhong Kim, & Jonathan F. Lovell. Nature Nanotechnology (2014) doi:10.1038/nnano.2014.130 Published online 06 July 2014

This paper is behind a paywall.

Canada’s Ingenuity Lab looks for the causes of cataract formation and preventive treatment

The Ingenuity Lab (based in Alberta) is pursuing three queries in its Health portfolio,

WHAT IF we could develop a way to replace lost neurological functions?
WHAT IF we can improve the delivery of oral vaccinations to maximize the efficiency of absorption?
WHAT IF we can treat cataracts without surgery?

Here’s how they describe the situation regarding sight and cataracts, from the WHAT IF we can treat cataracts without surgery? webpage,

Cataracts is an aggregation of lens proteins that lead to a decrease in vision. [emphasis mine] It is one of the biggest challenges in ophthalmic research due to accessibility to the lens and highly structured proteins in the lens that make it difficult to treat.

It is estimated that 88 per cent of people older than 75 years will have some form of this condition which is the leading cause of blindness worldwide. Currently, there are more than 2.5 million Canadians who are affected by cataracts and that number is expected to double by 2031.

While cataract surgery remains an effective option for many, Ingenuity researchers have their sights set on a new model of cataract treatment that does not rely on surgical intervention, by engineering molecules that would have capabilities to detect, inhibit and restore the affected proteins in the lens. The technology would also prevent further formation of the aggregate proteins that decrease vision.

This potential technology is particularly exciting for developing nations where surgical access is often limited and holds great promise for ageing populations around the world.

I’d never previously noticed ‘cataracts’ used with the singular version of a verb. It seems this is a matter for some debate as per this 2007 discussion resulting in a ‘ymmv’ (your mileage may vary) situation with an edge given to the use of the plural version of the verb. Personally, I prefer the plural with ‘cataracts’.

Getting back to Ingenuity Lab and its ‘cataracts’ query, there’s a July 4, 2014 Nanowerk Spotlight article written by someone from Ingenuity Lab describing their latest developments,

At Ingenuity Lab in Edmonton, a multidisciplinary team of researchers with partners in Alberta, U.S.A. and Nepal, are busy trying to understand the fundamental mechanisms of how the aggregates that cause cataracts form, and how nanotechnology may be used to prevent or at least inhibit them.

Researchers are taking lessons learned from earlier discoveries and have honed in on target specific peptide screening techniques in the hopes that they will provide a much-needed solution for communities around the world. The work aims to harness the specific binding abilities of peptides for recognition of crystallin protein aggregates7, as well as the unique peptide characteristics that influence stabilization of protein/aggregate and activity depending on the binding region8.

This research is encouraging because it recognizes the potential of crystallin specific peptides not only as drug delivery mediators but also as aggregation inhibitory molecules. Using combinatorial biology approaches, the team has is working to select peptides in both recombinant and ex vivo systems. Once the specific peptides are chosen, their effect on the aggregation process is will be carefully followed by in-situ time sequenced atomic force microscopy visualizations. These peptides will then be screened for particular inhibitory properties, considered as a potential therapeutical agent and evaluated on lens tissue and animal models at the state-of-the art lab in Alberta.

An added benefit to identifying peptides that bind to crystallin aggregates, is that their application extends beyond the treatment of cataract. While the hope and goal is that the peptides themselves will serve as a biologically based, mild, non-invasive treatment, these molecules could also serve to selectively target affected areas of the lens for delivery of other therapies.

The Nanowerk Spotlight article includes more information about the condition. about eyes, references, and an image illustrating the effects of peptides.

Tackling antibiotic resistance with inhalable nanotherapeutics

A June 25, 2014 news item on Nanowerk highlights PneumoNP a new European Union ‘theragnostic’ research project (Note: Links have been removed) ,

A new research project (PneumoNP) is aimed at tackling antibiotic resistance in respiratory tract infections via the use of inhalable nanotherapeutic compounds. Funded under the FP7 programme by the European Commission, the 4-year long PneumoNP project brings together top research institutes, universities, clinicians and enterprises from 6 EU member states. This novel collaboration will contribute to answer the call of the World Health Organization (WHO), who recently released an alarming report on the global threat of antibiotic resistance.

The project will develop an innovative solution to antibiotic resistance by coupling new antibiotics to inhalable carrier molecules, resulting in more efficient targeting of antibiotics to infection-causing bacteria present in the respiratory tract.

An April 30, 2014 WHO news release details the level of antibiotic resistance,

New WHO report provides the most comprehensive picture of antibiotic resistance to date, with data from 114 countries

A new report by WHO–its first to look at antimicrobial resistance, including antibiotic resistance, globally–reveals that this serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country. Antibiotic resistance–when bacteria change so antibiotics no longer work in people who need them to treat infections–is now a major threat to public health.

The report, “Antimicrobial resistance: global report on surveillance”, notes that resistance is occurring across many different infectious agents but the report focuses on antibiotic resistance in seven different bacteria responsible for common, serious diseases such as bloodstream infections (sepsis), diarrhoea, pneumonia, urinary tract infections and gonorrhoea. The results are cause for high concern, documenting resistance to antibiotics, especially “last resort” antibiotics, in all regions of the world.

Key findings from the report include:

Resistance to the treatment of last resort for life-threatening infections caused by a common intestinal bacteria, Klebsiella pneumoniae–carbapenem antibiotics–has spread to all regions of the world. K. pneumoniae is a major cause of hospital-acquired infections such as pneumonia, bloodstream infections, infections in newborns and intensive-care unit patients. In some countries, because of resistance, carbapenem antibiotics would not work in more than half of people treated for K. pneumoniae infections.

Resistance to one of the most widely used antibacterial medicines for the treatment of urinary tract infections caused by E. coli–fluoroquinolones–is very widespread. In the 1980s, when these drugs were first introduced, resistance was virtually zero. Today, there are countries in many parts of the world where this treatment is now ineffective in more than half of patients.

Treatment failure to the last resort of treatment for gonorrhoea–third generation cephalosporins–has been confirmed in Austria, Australia, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden and the United Kingdom. More than 1 million people are infected with gonorrhoea around the world every day.

Antibiotic resistance causes people to be sick for longer and increases the risk of death. For example, people with MRSA (methicillin-resistant Staphylococcus aureus) are estimated to be 64% more likely to die than people with a non-resistant form of the infection. Resistance also increases the cost of health care with lengthier stays in hospital and more intensive care required.

The suggestions offered for tackling antibiotic resistance will be familiar to many (from the news release),

 People can help tackle resistance by:

  •  using antibiotics only when prescribed by a doctor;
  •  completing the full prescription, even if they feel better;
  •  never sharing antibiotics with others or using leftover prescriptions.

A June 25, 2014 PneumoNP press release describes both the European Union’s response to massive, global antibiotic resistance and the specifics of the new programme (PneumoNP),

In this context, the European Commission launched 15 projects under its7 Framework Programme to fight antimicrobial resistance, with PneumoNP being one of these projects. Started in 2014, the aim of this 4-year project is to develop novel therapeutic and diagnostic tools for bacterial respiratory tract infections, focusing on infections caused by Klebsiella pneumoniae. PneumoNP will pioneer the development of a therapeutic treatment based on a combination of nanocarriers coupled to new antibiotics. This novel combination is expected to enhance the efficiency of antibiotic delivery to the patient. The project is expected to generate:

  • a new inhalable drug system made of a new nanotherapeutic system (an antimicrobial peptide or an active pharmaceutical ingredient and a nanocarrier);
  • a new aerosol technology that will allow direct access to the main focus of infection;
  • an innovative efficiency-efficacy test to follow-up the treatment;
  • a new diagnostic test for faster detection and identification of antibiotic resistance in bacteria causing respiratory infections.

European funding allows PneumoNP to combine scientific research capacities with the expert healthcare capabilities of European enterprises. The result is an interdisciplinary collaboration between 11 teams from 6 EU member states – Spain, Italy, France, Germany, The Netherlands, and Denmark. Each partner has a distinct yet collaborative role according to its own expertise involving a total of 8 work packages.

There is a figure in the news release which illustrates the PneumoNP concept,

Figure 2: PneumoNP concept

Figure 2: PneumoNP concept

There is more information about PneumoNP on its website. I wasn’t able to glean much in the way of technical details (are they using silver nanoparticles, what kind of nanocarriers are they considering, etc.) but I imagine those will emerge with time. There is this from the homepage which features the relatively new (to me) word, theragnostic,

Development of a theragnostic system for the treatment of lung Gram-negative bacterial infections

I assume they are conflating two processes, therapeutics and diagnostics for theragnostics.

Ferroelectric switching in the lung, heart, and arteries

A June 23, 2014 University of Washington (state) news release (also on EurekAlert) describes how the human body (and other biological tissue) is capable of generating ferroelectricity,

University of Washington researchers have shown that a favorable electrical property is present in a type of protein found in organs that repeatedly stretch and retract, such as the lungs, heart and arteries. These findings are the first that clearly track this phenomenon, called ferroelectricity, occurring at the molecular level in biological tissues.

The news release gives a brief description of ferroelectricity and describes the research team’s latest work with biological tissues,

Ferroelectricity is a response to an electric field in which a molecule switches from having a positive to a negative charge. This switching process in synthetic materials serves as a way to power computer memory chips, display screens and sensors. This property only recently has been discovered in animal tissues and researchers think it may help build and support healthy connective tissues in mammals.

A research team led by Li first discovered ferroelectric properties in biological tissues in 2012, then in 2013 found that glucose can suppress this property in the body’s connective tissues, wherever the protein elastin is present. But while ferroelectricity is a proven entity in synthetic materials and has long been thought to be important in biological functions, its actual existence in biology hasn’t been firmly established.

This study proves that ferroelectric switching happens in the biological protein elastin. When the researchers looked at the base structures within the protein, they saw similar behavior to the unit cells of solid-state materials, where ferroelectricity is well understood.

“When we looked at the smallest structural unit of the biological tissue and how it was organized into a larger protein fiber, we then were able to see similarities to the classic ferroelectric model found in solids,” Li said.

The researchers wanted to establish a more concrete, precise way of verifying ferroelectricity in biological tissues. They used small samples of elastin taken from a pig’s aorta and poled the tissues using an electric field at high temperatures. They then measured the current with the poling field removed and found that the current switched direction when the poling electric field was switched, a sign of ferroelectricity.

They did the same thing at room temperature using a laser as the heat source, and the current also switched directions.

Then, the researchers tested for this behavior on the smallest-possible unit of elastin, called tropoelastin, and again observed the phenomenon. They concluded that this switching property is “intrinsic” to the molecular make-up of elastin.

The next step is to understand the biological and physiological significance of this property, Li said. One hypothesis is that if ferroelectricity helps elastin stay flexible and functional in the body, a lack of it could directly affect the hardening of arteries.

“We may be able to use this as a very sensitive technique to detect the initiation of the hardening process at a very early stage when no other imaging technique will be able to see it,” Li said.

The team also is looking at whether this property plays a role in normal biological functions, perhaps in regulating the growth of tissue.

Co-authors are Pradeep Sharma at the University of Houston, Yanhang Zhang at Boston University, and collaborators at Nanjing University and the Chinese Academy of Sciences.

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

Ferroelectric switching of elastin by Yuanming Liu, Hong-Ling Cai, Matthew Zelisko, Yunjie Wang, Jinglan Sun, Fei Yan, Feiyue Ma, Peiqi Wang, Qian Nataly Chen, Hairong Zheng, Xiangjian Meng, Pradeep Sharma, Yanhang Zhang, and Jiangyu Li. Proceedings of the National Academy of Sciences (PNAS) doi: 10.1073/pnas.1402909111

This paper is behind a paywall.

I think this is a new practice. There is a paragraph on the significance of this work (follow the link to the paper),

Ferroelectricity has long been speculated to have important biological functions, although its very existence in biology has never been firmly established. Here, we present, to our knowledge, the first macroscopic observation of ferroelectric switching in a biological system, and we elucidate the origin and mechanism underpinning ferroelectric switching of elastin. It is discovered that the polarization in elastin is intrinsic at the monomer level, analogous to the unit cell level polarization in classical perovskite ferroelectrics. Our findings settle a long-standing question on ferroelectric switching in biology and establish ferroelectricity as an important biophysical property of proteins. We believe this is a critical first step toward resolving its physiological significance and pathological implications.

Cardiac pacemakers: Korea’s in vivo demonstration of a self-powered and UK’s breath-based approach

As i best I can determine ,the last mention of a self-powered pacemaker and the like on this blog was in a Nov. 5, 2012 posting (Developing self-powered batteries for pacemakers). This latest news from The Korea Advanced Institute of Science and Technology (KAIST) is, I believe, the first time that such a device has been successfully tested in vivo. From a June 23, 2014 news item on ScienceDaily,

As the number of pacemakers implanted each year reaches into the millions worldwide, improving the lifespan of pacemaker batteries has been of great concern for developers and manufacturers. Currently, pacemaker batteries last seven years on average, requiring frequent replacements, which may pose patients to a potential risk involved in medical procedures.

A research team from the Korea Advanced Institute of Science and Technology (KAIST), headed by Professor Keon Jae Lee of the Department of Materials Science and Engineering at KAIST and Professor Boyoung Joung, M.D. of the Division of Cardiology at Severance Hospital of Yonsei University, has developed a self-powered artificial cardiac pacemaker that is operated semi-permanently by a flexible piezoelectric nanogenerator.

A June 23, 2014 KAIST news release on EurekAlert, which originated the news item, provides more details,

The artificial cardiac pacemaker is widely acknowledged as medical equipment that is integrated into the human body to regulate the heartbeats through electrical stimulation to contract the cardiac muscles of people who suffer from arrhythmia. However, repeated surgeries to replace pacemaker batteries have exposed elderly patients to health risks such as infections or severe bleeding during operations.

The team’s newly designed flexible piezoelectric nanogenerator directly stimulated a living rat’s heart using electrical energy converted from the small body movements of the rat. This technology could facilitate the use of self-powered flexible energy harvesters, not only prolonging the lifetime of cardiac pacemakers but also realizing real-time heart monitoring.

The research team fabricated high-performance flexible nanogenerators utilizing a bulk single-crystal PMN-PT thin film (iBULe Photonics). The harvested energy reached up to 8.2 V and 0.22 mA by bending and pushing motions, which were high enough values to directly stimulate the rat’s heart.

Professor Keon Jae Lee said:

“For clinical purposes, the current achievement will benefit the development of self-powered cardiac pacemakers as well as prevent heart attacks via the real-time diagnosis of heart arrhythmia. In addition, the flexible piezoelectric nanogenerator could also be utilized as an electrical source for various implantable medical devices.”

This image illustrating a self-powered nanogenerator for a cardiac pacemaker has been provided by KAIST,

This picture shows that a self-powered cardiac pacemaker is enabled by a flexible piezoelectric energy harvester. Credit: KAIST

This picture shows that a self-powered cardiac pacemaker is enabled by a flexible piezoelectric energy harvester.
Credit: KAIST

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

Self-Powered Cardiac Pacemaker Enabled by Flexible Single Crystalline PMN-PT Piezoelectric Energy Harvester by Geon-Tae Hwang, Hyewon Park, Jeong-Ho Lee, SeKwon Oh, Kwi-Il Park, Myunghwan Byun, Hyelim Park, Gun Ahn, Chang Kyu Jeong, Kwangsoo No, HyukSang Kwon, Sang-Goo Lee, Boyoung Joung, and Keon Jae Lee. Advanced Materials DOI: 10.1002/adma.201400562
Article first published online: 17 APR 2014

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

There was a May 15, 2014 KAIST news release on EurekAlert announcing this same piece of research but from a technical perspective,

The energy efficiency of KAIST’s piezoelectric nanogenerator has increased by almost 40 times, one step closer toward the commercialization of flexible energy harvesters that can supply power infinitely to wearable, implantable electronic devices

NANOGENERATORS are innovative self-powered energy harvesters that convert kinetic energy created from vibrational and mechanical sources into electrical power, removing the need of external circuits or batteries for electronic devices. This innovation is vital in realizing sustainable energy generation in isolated, inaccessible, or indoor environments and even in the human body.

Nanogenerators, a flexible and lightweight energy harvester on a plastic substrate, can scavenge energy from the extremely tiny movements of natural resources and human body such as wind, water flow, heartbeats, and diaphragm and respiration activities to generate electrical signals. The generators are not only self-powered, flexible devices but also can provide permanent power sources to implantable biomedical devices, including cardiac pacemakers and deep brain stimulators.

However, poor energy efficiency and a complex fabrication process have posed challenges to the commercialization of nanogenerators. Keon Jae Lee, Associate Professor of Materials Science and Engineering at KAIST, and his colleagues have recently proposed a solution by developing a robust technique to transfer a high-quality piezoelectric thin film from bulk sapphire substrates to plastic substrates using laser lift-off (LLO).

Applying the inorganic-based laser lift-off (LLO) process, the research team produced a large-area PZT thin film nanogenerators on flexible substrates (2 cm x 2 cm).

“We were able to convert a high-output performance of ~250 V from the slight mechanical deformation of a single thin plastic substrate. Such output power is just enough to turn on 100 LED lights,” Keon Jae Lee explained.

The self-powered nanogenerators can also work with finger and foot motions. For example, under the irregular and slight bending motions of a human finger, the measured current signals had a high electric power of ~8.7 μA. In addition, the piezoelectric nanogenerator has world-record power conversion efficiency, almost 40 times higher than previously reported similar research results, solving the drawbacks related to the fabrication complexity and low energy efficiency.

Lee further commented,

“Building on this concept, it is highly expected that tiny mechanical motions, including human body movements of muscle contraction and relaxation, can be readily converted into electrical energy and, furthermore, acted as eternal power sources.”

The research team is currently studying a method to build three-dimensional stacking of flexible piezoelectric thin films to enhance output power, as well as conducting a clinical experiment with a flexible nanogenerator.

In addition to the 2012 posting I mentioned earlier, there was also this July 12, 2010 posting which described research on harvesting biomechanical movement ( heart beat, blood flow, muscle stretching, or even irregular vibration) at the Georgia (US) Institute of Technology where the lead researcher observed,

…  Wang [Professor Zhong Lin Wang at Georgia Tech] tells Nanowerk. “However, the applications of the nanogenerators under in vivo and in vitro environments are distinct. Some crucial problems need to be addressed before using these devices in the human body, such as biocompatibility and toxicity.”

Bravo to the KAIST researchers for getting this research to the in vivo testing stage.

Meanwhile at the University of Bristol and at the University of Bath, researchers have received funding for a new approach to cardiac pacemakers, designed them with the breath in mind. From a June 24, 2014 news item on Azonano,

Pacemaker research from the Universities of Bath and Bristol could revolutionise the lives of over 750,000 people who live with heart failure in the UK.

The British Heart Foundation (BHF) is awarding funding to researchers developing a new type of heart pacemaker that modulates its pulses to match breathing rates.

A June 23, 2014 University of Bristol press release, which originated the news item, provides some context,

During 2012-13 in England, more than 40,000 patients had a pacemaker fitted.

Currently, the pulses from pacemakers are set at a constant rate when fitted which doesn’t replicate the natural beating of the human heart.

The normal healthy variation in heart rate during breathing is lost in cardiovascular disease and is an indicator for sleep apnoea, cardiac arrhythmia, hypertension, heart failure and sudden cardiac death.

The device is then briefly described (from the press release),

The novel device being developed by scientists at the Universities of Bath and Bristol uses synthetic neural technology to restore this natural variation of heart rate with lung inflation, and is targeted towards patients with heart failure.

The device works by saving the heart energy, improving its pumping efficiency and enhancing blood flow to the heart muscle itself.  Pre-clinical trials suggest the device gives a 25 per cent increase in the pumping ability, which is expected to extend the life of patients with heart failure.

One aim of the project is to miniaturise the pacemaker device to the size of a postage stamp and to develop an implant that could be used in humans within five years.

Dr Alain Nogaret, Senior Lecturer in Physics at the University of Bath, explained“This is a multidisciplinary project with strong translational value.  By combining fundamental science and nanotechnology we will be able to deliver a unique treatment for heart failure which is not currently addressed by mainstream cardiac rhythm management devices.”

The research team has already patented the technology and is working with NHS consultants at the Bristol Heart Institute, the University of California at San Diego and the University of Auckland. [emphasis mine]

Professor Julian Paton, from the University of Bristol, added: “We’ve known for almost 80 years that the heart beat is modulated by breathing but we have never fully understood the benefits this brings. The generous new funding from the BHF will allow us to reinstate this natural occurring synchrony between heart rate and breathing and understand how it brings therapy to hearts that are failing.”

Professor Jeremy Pearson, Associate Medical Director at the BHF, said: “This study is a novel and exciting first step towards a new generation of smarter pacemakers. More and more people are living with heart failure so our funding in this area is crucial. The work from this innovative research team could have a real impact on heart failure patients’ lives in the future.”

Given some current events (‘Tesla opens up its patents’, Mike Masnick’s June 12, 2014 posting on Techdirt), I wonder what the situation will be vis à vis patents by the time this device gets to market.

Cloud and molecular aesthetics; an art/science conference features a bionanotechnology speaker

Here’s a notice from a June 19, 2014 from OCR (Operational and Curatorial Research in Art Design Science and Technology) organization newsletter highlighting an upcoming conference in Istanbul, Turkey, which includes a nanotechnology speaker,

Lanfranco Aceti, the founder of OCR; Edward Colless Head of Critical and Theoretical Studies and Paul Thomas, Program Director of Fine Art at COFA, are the lead chairs and organizers of the conference Cloud & Molecular Aesthetics from June 26 to 28, 2014, at the Pera Museum.

We invite you to three stimulating days that explores new perspectives and evolutions in contemporary art were acclaimed professionals including curators,historians, creative arts practitioners, critics and theorists consider transdisciplinary imaging relating to the theme of cloud, dispersal, infinitesimally small and molecular aesthetics. The conference is free and open to all. The program is available here.

The conference keynotes are Professor Anne Balsamo, Dean of the School of Media Studies at The New School, Dr. Ljiljana Fruk co-author of Molecular Aesthetics, Dr. Jussi Parikka who authored Insect Media: An Archaeology of Animals and Technology; and Prof. Darren Tofts author of Alephbet: Essays on Ghost-writing, Nutshells & Infinite Space.

The notice doesn’t mention the most interesting aspect (for me, anyway) of Dr. Ljiljana Fruk’s work. Here’s more from her OCR Cloud and Molecular Aesthetics Keynote bio page,

Dr. Fruk is a scientist and lecturer at Karlsruhe Institute of Technology, Germany working on the development of photosensitive bio nano hybrid systems to be used in the design of new catalysts, artificial enzymes and biosensors for nanomedicinal applications. [emphases mine] She studied chemistry at University of Zagreb and continued to pursue her PhD at the University of Strathclyde in Glasgow, where she worked on the development of advanced tools for DNA detection. After award of Humboldt Fellowship and Marie Curie International Incoming Fellowship she conducted a postdoctoral research on artificial enzyme catalysts at the University of Dortmund in Germany. Since 2009 she leads her own research group and is also active in exploring the interface of art and science, in particular the cultural and societal impact of new technologies such as nanotechnology and synthetic biology. Besides number of scientific activities, she was also a co-organizer of the first symposium on Molecular Aesthetics (2011), 3D interactive exhibition on Molecules that Changed the World, and together with artist Peter Weibel, a co-editor of Molecular Aesthetic book (2013).

The official title for the conference is this: ‘The Third International Conference on Transdisciplinary Imaging at the Intersections of Art, Science and Culture’ although the organizers seem to be using the theme, Cloud and Molecular Aesthetics, as an easy way to refer to it. You can still register for the conference here:

I last mentioned the OCR in a March 24, 2014 posting about a call for papers for a conference on sound curation.

DARPA (US Defense Advanced Research Projects Agency) awards funds for implantable neural interface

I’m not a huge fan of neural implantable devices (at least not the ones that facilitate phone calls directly to and from the brain as per my April 30, 2010 posting; scroll down about 40% of the way) but they are important from a therapeutic perspective. On that  note, the Lawrence Livermore National Laboratory (LLNL) has received an award of $5.6M from the US Defense Advanced Research Projects Agency (DARPA) to advance their work on neural implantable interfaces. From a June 13, 2014 news item on Azonano,

Lawrence Livermore National Laboratory recently received $5.6 million from the Department of Defense’s Defense Advanced Research Projects Agency (DARPA) to develop an implantable neural interface with the ability to record and stimulate neurons within the brain for treating neuropsychiatric disorders.

The technology will help doctors to better understand and treat post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), chronic pain and other conditions.

Several years ago, researchers at Lawrence Livermore in conjunction with Second Sight Medical Products developed the world’s first neural interface (an artificial retina) that was successfully implanted into blind patients to help partially restore their vision. The new neural device is based on similar technology used to create the artificial retina.

An LLNL June 11, 2014 news release, which originated the news item, provides some fascinating insight into the interrelations between various US programs focused on the brain and neural implants,

“DARPA is an organization that advances technology by leaps and bounds,” said LLNL’s project leader Satinderpall Pannu, director of the Lab’s Center for Micro- and Nanotechnology and Center for Bioengineering, a facility dedicated to fabricating biocompatible neural interfaces. “This DARPA program will allow us to develop a revolutionary device to help patients suffering from neuropsychiatric disorders and other neural conditions.”

The project is part of DARPA’s SUBNETS (Systems-Based Neurotechnology for Emerging Therapies) program. The agency is launching new programs to support President Obama’s BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative, a new research effort aimed to revolutionize our understanding of the human mind and uncover ways to treat, prevent and cure brain disorders.

LLNL and Medtronic are collaborating with UCSF, UC Berkeley, Cornell University, New York University, PositScience Inc. and Cortera Neurotechnologies on the DARPA SUBNETS project. Some collaborators will be developing the electronic components of the device, while others will be validating and characterizing it.

As part of its collaboration with LLNL, Medtronic will consult on the development of new technologies and provide its investigational Activa PC+S deep brain stimulation (DBS) system, which is the first to enable the sensing and recording of brain signals while simultaneously providing targeted DBS. This system has recently been made available to leading researchers for early-stage research and could lead to a better understanding of how various devastating neurological conditions develop and progress. The knowledge gained as part of this collaboration could lead to the next generation of advanced systems for treating neural disease.

As for what LLNL will contribute (from the news release),

The LLNL Neural Technology group will develop an implantable neural device with hundreds of electrodes by leveraging their thin-film neural interface technology, a more than tenfold increase over current Deep Brain Stimulation (DBS) devices. The electrodes will be integrated with electronics using advanced LLNL integration and 3D packaging technologies. The goal is to seal the electronic components in miniaturized, self-contained, wireless neural hardware. The microelectrodes that are the heart of this device are embedded in a biocompatible, flexible polymer.

Surgically implanted into the brain, the neural device is designed to help researchers understand the underlying dynamics of neuropsychiatric disorders and re-train neural networks to unlearn these disorders and restore proper function. This will enable the device to be eventually removed from the patient instead of being dependent on it.

This image from LLNL illustrates their next generation neural implant,

This rendering shows the next generation neural device capable of recording and stimulating the human central nervous system being developed at Lawrence Livermore National Laboratory. The implantable neural interface will record from and stimulate neurons within the brain for treating neuropsychiatric disorders.

This rendering shows the next generation neural device capable of recording and stimulating the human central nervous system being developed at Lawrence Livermore National Laboratory. The implantable neural interface will record from and stimulate neurons within the brain for treating neuropsychiatric disorders.

i expect there will be many more ‘brain’ projects to come with the advent of the US BRAIN initiative (funds of $100M in 2014 and $200M in 2015) and the European Union’s Human Brain Project (1B Euros to be spent on research over a 10 year period).

‘Llam’ me lend you some antibodies—antibody particles extracted from camels and llamas

Sometimes the urge for wordplay overwhelms me as it did this morning (June 12, 2014) when I saw llamas mentioned in a news item. For anyone unfamiliar with how Canadian English (and I can safely include American English here but am not sure about any other Englishes) is spoken, we leave out consonants in some phrases. For example, ‘let me’ becomes ‘lemme’, which when you’re playing with ‘llama,’ becomes ‘llam’me. As for the verb ‘lend’, I used it for its alliterative quality and used more accurate verb ‘extracted’ later in the headline.

Getting on to the antibodies and the camels and llamas, here’s more from a June 12, 2014 news item on Nanowerk (Note: A link has been removed),

The use of nanoparticles in cancer research is considered as a promising approach in detecting and fighting tumour cells. The method has, however, often failed because the human immune system recognizes the particles as foreign objects and rejects them before they can fulfil their function. Researchers at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and at University College Dublin [UCD[ in Ireland have, along with other partners, developed nanoparticles that not only bypass the body’s defence system, but also find their way to the diseased cells ("Diagnostic nanoparticle targeting of the EGF-receptor in complex biological conditions using single-domain antibodies"). This procedure uses fragments from a particular type of antibody that only occurs in camels and llamas. The small particles were even successful under conditions which are very similar to the situation within potential patients’ bodies.

A June 12, 2014 HZDR press release, which originated the news item, supplies a quote from one of the researchers where he explains the problems he and his colleagues were attempting to address,

Describing the current state of research, Dr. Kristof Zarschler of the Helmholtz Virtual Institute NanoTracking at the HZDR explains, "At the moment we must overcome three challenges. First, we need to produce the smallest possible nanoparticles. We then need to modify their surface in a way that the proteins in the human bodies do not envelop them, which would thus render them ineffective. In order to ensure, that the particles do their job, we must also somehow program them to find the diseased cells." Therefore, the Dresden [HZDR is in Dresden] and Dublin researchers combined expertise to develop nanoparticles made of silicon dioxide with fragments of camel antibodies.

The press release and Zarschler go on to explain the advantages of camel and llama antibodies,

In contrast to conventional antibodies, which consist of two light and two heavy protein chains, those taken from camels and llamas are less complex and are made up of only two heavy chains. “Due to this simplified structure, they are easier to produce than normal antibodies,” explains Zarschler. “We also only need one particular fragment – the portion of the molecule that binds to certain cancer cells – which makes the production of much smaller nanoparticles possible.” By modifying the surface of the nanoparticle, it also gets more difficult for the immune system to recognize the foreign material, which allows the nanoparticles to actually reach their target.

The ultra-small particles should then detect the so-called epidermal growth factor receptor (EGFR) in the human body. In various types of tumours, this molecule is overexpressed and/or exists in a mutated form, which allows the cells to grow and multiply uncontrollably. The Dresden researchers could demonstrate in experiments that nanoparticles that have been combined with the camel antibody fragments can more firmly bind to the cancer cells. “The EGFR is a virtual lock to which our antibody fits like a key,” explains Zarschler.

Most exciting are the experiments the researchers performed with human blood (from the press release),

They even obtained the same results in experiments involving human blood serum – a biologically relevant environment the scientists point out: “This means that we carried out the tests under conditions that are very similar to the reality of the human body,” explains Dr. Holger Stephan, who leads the project. “The problem with many current studies is that artificial conditions are chosen where no disruptive factors exist. While this provides good results, it is ultimately useless because the nanoparticles fail finally in experiments conducted under more complex conditions. In our case, we could at least reduce this error source.”

There are no immediate plans for clinical trials according to the press release,

However, more time is required before the nanoparticles can be utilized in diagnosing human tumours. “The successful tests have brought us one step further,” explains Stephan. “The road, however, to its clinical use is long.” The next aim is to reduce the size of the nanoparticles, which are now approximately fifty nanometres in diameter, to less than ten nanometres. “That would be optimal,” according to Zarschler. “Then they would only remain in the human body for a short period – just long enough to detect the tumour.”

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

Diagnostic nanoparticle targeting of the EGF-receptor in complex biological conditions using single-domain antibodies by K. Zarschler, K. Prapainop, E. Mahon, L. Rocks,  M. Bramini, P. M. Kelly, H. Stephan, and K. A. Dawson. Nanoscale, 2014,6, 6046-6056 DOI: 10.1039/C4NR00595C
First published online 16 Apr 2014

This paper is in an open access journal.

The researchers have provided an illustration of the new antibody particles,

 Title Bild Nanopartikel Copyright 	CBNI, UCD

Title Bild Nanopartikel
With help of proteins, nanoparticles can be produced, which bind specifically to cancer cells, thus making it possible to detect tumours. Copyright CBNI, UCD