Tag Archives: University of California at San Diego

Tattoos that detect glucose levels

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Temporary tattoos with a biomedical function are a popular topic and one of the latest detects glucose levels without subjecting a person with diabetes to pin pricks. From a Jan. 14, 2015 news item on ScienceDaily,

Scientists have developed the first ultra-thin, flexible device that sticks to skin like a rub-on tattoo and can detect a person’s glucose levels. The sensor, reported in a proof-of-concept study in the ACS [American Chemical Society] journal Analytical Chemistry, has the potential to eliminate finger-pricking for many people with diabetes.

A Jan. 14, 2015 ACS news release on EurekAlert, which originated the news item, describes the current approaches to testing glucose and the new painless technique,

Joseph Wang and colleagues in San Diego note that diabetes affects hundreds of millions of people worldwide. Many of these patients are instructed to monitor closely their blood glucose levels to manage the disease. But the standard way of checking glucose requires a prick to the finger to draw blood for testing. The pain associated with this technique can discourage people from keeping tabs on their glucose regularly. A glucose sensing wristband had been introduced to patients, but it caused skin irritation and was discontinued. Wang’s team wanted to find a better approach.

The researchers made a wearable, non-irritating platform that can detect glucose in the fluid just under the skin based on integrating glucose extraction and electrochemical biosensing. Preliminary testing on seven healthy volunteers showed it was able to accurately determine glucose levels. The researchers conclude that the device could potentially be used for diabetes management and for other conditions such as kidney disease.

There is a Jan. 14, 2015 University of California at San Diego news release (also on EurekAlert) describing the work in more detail,

Nanoengineers at the University of California, San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells. …

The sensor was developed and tested by graduate student Amay Bandodkar and colleagues in Professor Joseph Wang’s laboratory at the NanoEngineering Department and the Center for Wearable Sensors at the Jacobs School of Engineering at UC San Diego. Bandodkar said this “proof-of-concept” tattoo could pave the way for the Center to explore other uses of the device, such as detecting other important metabolites in the body or delivering medicines through the skin.

At the moment, the tattoo doesn’t provide the kind of numerical readout that a patient would need to monitor his or her own glucose. But this type of readout is being developed by electrical and computer engineering researchers in the Center for Wearable Sensors. “The readout instrument will also eventually have Bluetooth capabilities to send this information directly to the patient’s doctor in real-time or store data in the cloud,” said Bandodkar.

The research team is also working on ways to make the tattoo last longer while keeping its overall cost down, he noted. “Presently the tattoo sensor can easily survive for a day. These are extremely inexpensive—a few cents—and hence can be replaced without much financial burden on the patient.”

The Center “envisions using these glucose tattoo sensors to continuously monitor glucose levels of large populations as a function of their dietary habits,” Bandodkar said. Data from this wider population could help researchers learn more about the causes and potential prevention of diabetes, which affects hundreds of millions of people and is one of the leading causes of death and disability worldwide.

People with diabetes often must test their glucose levels multiple times per day, using devices that use a tiny needle to extract a small blood sample from a fingertip. Patients who avoid this testing because they find it unpleasant or difficult to perform are at a higher risk for poor health, so researchers have been searching for less invasive ways to monitor glucose.

In their report in the journal Analytical Chemistry, Wang and his co-workers describe their flexible device, which consists of carefully patterned electrodes printed on temporary tattoo paper. A very mild electrical current applied to the skin for 10 minutes forces sodium ions in the fluid between skin cells to migrate toward the tattoo’s electrodes. These ions carry glucose molecules that are also found in the fluid. A sensor built into the tattoo then measures the strength of the electrical charge produced by the glucose to determine a person’s overall glucose levels.

“The concentration of glucose extracted by the non-invasive tattoo device is almost hundred times lower than the corresponding level in the human blood,” Bandodkar explained. “Thus we had to develop a highly sensitive glucose sensor that could detect such low levels of glucose with high selectivity.”

A similar device called GlucoWatch from Cygnus Inc. was marketed in 2002, but the device was discontinued because it caused skin irritation, the UC San Diego researchers note. Their proof-of-concept tattoo sensor avoids this irritation by using a lower electrical current to extract the glucose.

Wang and colleagues applied the tattoo to seven men and women between the ages of 20 and 40 with no history of diabetes. None of the volunteers reported feeling discomfort during the tattoo test, and only a few people reported feeling a mild tingling in the first 10 seconds of the test.

To test how well the tattoo picked up the spike in glucose levels after a meal, the volunteers ate a carb-rich meal of a sandwich and soda in the lab. The device performed just as well at detecting this glucose spike as a traditional finger-stick monitor.

The researchers say the device could be used to measure other important chemicals such as lactate, a metabolite analyzed in athletes to monitor their fitness. The tattoo might also someday be used to test how well a medication is working by monitoring certain protein products in the intercellular fluid, or to detect alcohol or illegal drug consumption.

This reminds me a little of the Google moonshot project concerning health diagnostics. Announced in Oct. 2014, that project involved swallowing a pill containing nanoparticles that would circulate through your body monitoring your health and recongregating at your wrist so a band worn there could display your health status (Oct. 30, 2014 article by Signe Brewster for GigaOm). Experts welcomed the funding while warning the expectations seemed unrealistic given the current state of research and technology. This temporary tattoo seems much better grounded in terms of the technology used and achievable results.

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

Tattoo-Based Noninvasive Glucose Monitoring: A Proof-of-Concept Study by Amay J. Bandodkar, Wenzhao Jia, Ceren Yardımcı, Xuan Wang, Julian Ramirez, and Joseph Wang. Anal. Chem., 2015, 87 (1), pp 394–398 DOI: 10.1021/ac504300n Publication Date (Web): December 12, 2014

Copyright © 2014 American Chemical Society

This appears to be an open access paper.

My latest posting posting on medical tattoos (prior to this) is an Aug. 13, 2014 post about a wearable biobattery.

RNA interference: a Tekmira deal and a new technique births Solstice Biologics

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I have two news items concerning ribonucleic acid interference (RNAi). The first item features Tekmira Pharmaceuticals Corporation (a Canadian company located in the Vancouver area) and a licencing deal with Dicerna Pharmaceuticals (Massachusetts, US), according to a Nov. 18, 2014 news item on Azonano,

Tekmira Pharmaceuticals Corporation a leading developer of RNA interference (RNAi) therapeutics, today announces a licensing and collaboration agreement with Dicerna Pharmaceuticals, Inc. Tekmira has licensed its proprietary lipid nanoparticle (LNP) delivery technology for exclusive use in Dicerna’s primary hyperoxaluria type 1 (PH1) development program.

Under the agreement, Dicerna will pay Tekmira $2.5 million upfront and payments of $22 million in aggregate development milestones, plus a mid-single-digit royalty on future PH1 sales. This new partnership also includes a supply agreement with Tekmira providing clinical drug supply and regulatory support in the rapid advancement of the product candidate.

The agreement announced today follows the successful testing and demonstration of positive results combining Tekmira’s LNP technology with DCR-PH1 in pre-clinical animal models.

I don’t entirely understand what they mean by “pre-clinical animal models” as I’ve not noticed the term “pre-clinical” applied to animal testing before this. It’s possible they mean they’ve run tests on animals (in vivo) and are now proceeding to human clinical trials or it could mean they’ve run in silico (computer modeling) or in vitro (test tube/test slide) tests and are now proceeding to animal tests. If anyone should have some insights, please do share them with me in the comments section.

A Nov. 17, 2014 Tekmira news release, which originated the news item, describes the deal in more detail,

Dicerna will use Tekmira’s third generation LNP technology for delivery of DCR-PH1, Dicerna’s Dicer substrate RNA (DsiRNA) molecule, for the treatment of PH1, a rare, inherited liver disorder that often results in kidney failure and for which there are no approved therapies.

“This new agreement validates our leadership position in RNAi delivery with LNP technology, and it underscores the significant value we can bring to partners who leverage our technology. Our LNP technology is enabling the most advanced applications of RNAi therapeutics in the clinic, and it continues to do so. We are excited to be working with Dicerna to be able to advance a needed therapeutic for the treatment of PH1,” said Dr. Mark J. Murray, Tekmira’s President and CEO.

“As a core pillar of our business strategy, we continue to engage in partnerships where our technology improves the risk profile and accelerates the development programs of our collaborators and provides meaningful non-dilutive financing to TKMR,” added Dr. Murray.

“Dicerna is focused on realizing the full clinical potential of our proprietary pipeline of highly targeted RNAi therapies by applying proven technologies,” said Douglas Fambrough, Ph.D., Chief Executive Officer of Dicerna. “By drawing on Tekmira’s extensive and deep experience with lipid nanoparticle delivery to the liver, the agreement will streamline the development path for DCR-PH1. We look forward to initiating Phase 1 trials of DCR-PH1 in 2015, aiming to fill a high unmet medical need for patients with PH1.”

The news release also provides a high level description of the various technologies being researched and brought to market and a bit more information about the liver disorder being addressed by this research,

About RNAi

RNAi therapeutics have the potential to treat a number of human diseases by “silencing” disease-causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi trigger molecules often require delivery technology to be effective as therapeutics.

AboutTekmira’s LNP Technology

Tekmira believes its LNP technology represents the most widely adopted delivery technology for the systemic delivery of RNAi triggers. Tekmira’s LNP platform is being utilized in multiple clinical trials by Tekmira and its partners. Tekmira’s LNP technology (formerly referred to as stable nucleic acid-lipid particles, or SNALP) encapsulates RNAi triggers with high efficiency in uniform lipid nanoparticles that are effective in delivering these therapeutic compounds to disease sites. Tekmira’s LNP formulations are manufactured by a proprietary method which is robust, scalable and highly reproducible, and LNP-based products have been reviewed by multiple regulatory agencies for use in clinical trials. LNP formulations comprise several lipid components that can be adjusted to suit the specific application.

About Primary Hyperoxaluria Type 1 ( PH1)

PH1 is a rare, inherited liver disorder that often results in severe damage to the kidneys. The disease can be fatal unless the patient undergoes a liver-kidney transplant, a major surgical procedure that is often difficult to perform due to the lack of donors and the threat of organ rejection. In the event of a successful transplant, the patient must live the rest of his or her life on immunosuppressant drugs, which have substantial associated risks. Currently, there are no FDA approved treatments for PH1.

PH1 is characterized by a genetic deficiency of the liver enzyme alanine:glyoxalate-aminotransferase (AGT), which is encoded by the AGXT gene. AGT deficiency induces overproduction of oxalate by the liver, resulting in the formation of crystals of calcium oxalate in the kidneys. Oxalate crystal formation often leads to chronic and painful cases of kidney stones and subsequent fibrosis (scarring), which is known as nephrocalcinosis. Many patients progress to end-stage renal disease (ESRD) and require dialysis or transplant. Aside from having to endure frequent dialysis, PH1 patients with ESRD may experience a build-up of oxalate in the bone, skin, heart and retina, with concomitant debilitating complications. While the true prevalence of primary hyperoxaluria is unknown, it is estimated to be one to three cases per one million people.1 Fifty percent of patients with PH1 reach ESRD by their mid-30s.2

About DCR-PH1

Dicerna is developing DCR-PH1, which is in preclinical development, for the treatment of PH1. DCR-PH1 is engineered to address the pathology of PH1 by targeting and destroying the messenger RNA (mRNA) produced by HAO1, a gene implicated in the pathogenesis of PH1. HAO1 encodes glycolate oxidase, a protein involved in producing oxalate. By reducing oxalate production, this approach is designed to prevent the complications of PH1. In preclinical studies, DCR-PH1 has been shown to induce potent and long-term inhibition of HAO1 and to significantly reduce levels of urinary oxalate, while demonstrating long-term efficacy and tolerability in animal models of PH1.

About Dicerna’s Dicer Substrate Technology

Dicerna’s proprietary RNAi molecules are known as Dicer substrates, or DsiRNAs, so called because they are processed by the Dicer enzyme, which is the initiation point for RNAi in the human cell cytoplasm. Dicerna’s discovery approach is believed to maximize RNAi potency because the DsiRNAs are structured to be ideal for processing by Dicer. Dicer processing enables the preferential use of the correct RNA strand of the DsiRNA, which may increase the efficacy of the RNAi mechanism, as well as the potency of the DsiRNA molecules relative to other molecules used to induce RNAi.

You can find more information about Tekmira here and about Dicerna here. I mentioned Tekmira previously in a Sept. 28, 2014 post about Ebola and treatments.

Further south at the University of California at San Diego (UCSD), researcher and founder of Solstice Biologics, Dr Steven Dowdy has developed and patented a new technique for delivering RNAi drugs into cells according to a Nov. 18, 2014 news item on Azonano,

Small pieces of synthetic RNA trigger a RNA interference (RNAi) response that holds great therapeutic potential to treat a number of diseases, especially cancer and pandemic viruses. The problem is delivery — it is extremely difficult to get RNAi drugs inside the cells in which they are needed. To overcome this hurdle, researchers at University of California, San Diego School of Medicine have developed a way to chemically disguise RNAi drugs so that they are able to enter cells. Once inside, cellular machinery converts these disguised drug precursors — called siRNNs — into active RNAi drugs. …

A Nov. 17, 2014 UCSD news release (also on EurekAlert) by Heather Buschman, which originated the news item, describes the issues with delivering RNAi drugs to cells and the new technique,

“Many current approaches use nanoparticles to deliver RNAi drugs into cells,” said Steven F. Dowdy, PhD, professor in the Department of Cellular and Molecular Medicine and the study’s principal investigator. “While nanotechnology protects the RNAi drug, from a molecular perspective nanoparticles are huge, some 5,000 times larger than the RNAi drug itself. Think of delivering a package into your house by having an 18-wheeler truck drive it through your living room wall — that’s nanoparticles carrying standard RNAi drugs. Now think of a package being slipped through the mail slot — that’s siRNNs.”

The beauty of RNAi is that it selectively blocks production of target proteins in a cell, a finding that garnered a Nobel Prize in 2006. While this is a normal process that all cells use, researchers have taken advantage of RNAi to inhibit specific proteins that cause disease when overproduced or mutated, such as in cancer. First, researchers generate RNAi drugs with a sequence that corresponds to the gene blueprint for the disease protein and then delivers them into cells. Once inside the cell, the RNAi drug is loaded into an enzyme that specifically slices the messenger RNA encoding the target protein in half. This way, no protein is produced.

As cancer and viral genes mutate, RNAi drugs can be easily evolved to target them. This allows RNAi therapy to keep pace with the genetics of the disease — something that no other type of therapy can do. Unfortunately, due to their size and negatively charged chemical groups (phosphates) on their backbone, RNAi drugs are repelled by the cellular membrane and cannot be delivered into cells without a special delivery agent.

It took Dowdy and his team, including Bryan Meade, PhD, Khirud Gogoi, PhD, and Alexander S. Hamil, eight years to find a way to mask RNAi’s negative phosphates in such a way that gets them into cells, but is still capable of inducing an RNAi response once inside.

In the end, the team added a chemical tag called a phosphotriester group. The phosphotriester neutralizes and protects the RNA backbone — converting the ribonucleic acid (RNA) to ribonucleic neutral (RNN), and thus giving the name siRNN. The neutral (uncharged) nature of siRNNs allows them to pass into the cell much more efficiently. Once inside the cell, enzymes cleave off the neutral phosphotriester group to expose a charged RNAi drug that shuts down production of the target disease protein. siRNNs represent a transformational next-generation RNAi drug.

“siRNNs are precursor drugs, or prodrugs, with no activity. It’s like having a tool still in the box, it won’t work until you take it out,” Dowdy said. “Only when the packaging — the phosphotriester groups — is removed inside the cells do you have an active tool or RNAi drug.”

The findings held up in a mouse model, too. There, Dowdy’s team found that siRNNs were significantly more effective at blocking target protein production than typical RNAi drugs — demonstrating that once siRNNs get inside a cell they can do a better job.

“There remains a lot of work ahead to get this into the clinics. But, in theory, the therapeutic potential of siRNNs is endless,” Dowdy said. “Particularly for cancer, viral infections and genetic diseases.”

The siRNN technology forms the basis for Solstice Biologics, a biotech company in La Jolla, Calif. that is now taking the technique to the next level. Dowdy is a co-founder of Solstice Biologics and serves as a Board Director.

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

Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications by Bryan R Meade, Khirud Gogoi, Alexander S Hamil, Caroline Palm-Apergi, Arjen van den Berg, Jonathan C Hagopian, Aaron D Springer, Akiko Eguchi, Apollo D Kacsinta, Connor F Dowdy, Asaf Presente, Peter Lönn, Manuel Kaulich, Naohisa Yoshioka, Edwige Gros, Xian-Shu Cui, & Steven F Dowdy. Nature Biotechnology (2014) doi:10.1038/nbt.3078 Published online 17 November 2014

This paper is behind a paywall.

I have not been able to locate a website for Solstice Biologics but did find a rather curious item about Dr. Dowdy and a shooting incident last year. From a Sept. 18, 2013 news article by Kat Robinson for thewire.sheknows.com,

A wealthy San Diego community is shaken after a man opens fire on his former neighborhood early Wednesday morning. Police say Hans Petersen, a 48-year-old man, is the prime suspect in the shooting of Steven Dowdy and Michael Fletcher.

There’s also a Nov. 8, 2013 article about the incident by Lucas Laursen for Nature magazine,

On September 18 [2013], former Traversa Therapeutics CEO Hans Petersen went on a shooting spree. One of two people wounded was molecular biologist Steven Dowdy, a professor at University of California San Diego (UCSD) School of Medicine, in La Jolla, and cofounder of Traversa, according to a San Diego police report.…

The rest of the article is behind a paywall.

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

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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.

* ‘one’ added to title on Aug. 13, 2014.

Your plant feeling stressed? Have we got a nanosensor for you!

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An April 15, 2014 news item on ScienceDaily features an intriguing application for nansensors on plants that may have an important impact as we deal with the problems associated with droughts. This work comes from the University of California at San Diego (UCSD),

Biologists have succeeded in visualizing the movement within plants of a key hormone responsible for growth and resistance to drought. The achievement will allow researchers to conduct further studies to determine how the hormone helps plants respond to drought and other environmental stresses driven by the continuing increase in the atmosphere’s carbon dioxide, or CO2, concentration.

The April 15, 2014 UCSD news release by Kim McDonald, which originated the news item, describes the plant hormone being tracked and the tracking tool developed by the researchers,

The plant hormone the biologists directly tracked is abscisic acid, or ABA, which plays a major role in activating drought resistance responses of plants and in regulating plant growth under environmental stress conditions. The ABA stress hormone also controls the closing of stomata, the pores within leaves through which plants lose 95 percent of their water while taking in CO2 for growth.

Scientists already know the general role that ABA plays within plants, but by directly visualizing the hormone they can now better understand the complex interactions involving ABA when a plant is subjected to drought or other stress.

“Understanding the dynamic distribution of ABA in plants in response to environmental stimuli is of particular importance in elucidating the action of this important plant hormone,” says Julian Schroeder, a professor of biology at UC San Diego who headed the research effort. “For example, we can now investigate whether an increase in the leaf CO2 concentration that occurs every night due to respiration in leaves affects the ABA concentration in stomatal cells.”

The researchers developed what they call a “genetically-encoded reporter” in order to directly and instantaneously observe the movements of ABA within the mustard plant Arabidopsis. These reporters, called “ABAleons,” contain two differentially colored fluorescent proteins attached to an ABA-binding sensor protein. Once bound to ABA, the ABAleons change their fluorescence emission, which can be analyzed using a microscope. The researchers showed that ABA concentration changes and waves of ABA movement could be monitored in diverse tissues and individual cells over time and in response to stress.

“Using this reporter, we directly observed long distance ABA movements from the stem of a germinating seedling to the leaves and roots of the growing plant and, for the first time, we were able to determine the rate of ABA movement within the growing plant,” says Schroeder.

“Using this tool, we now can detect ABA in live plants and see how it is distributed,” says Rainer Waadt, a postdoctoral associate in Schroeder’s laboratory and the first author of the paper. “We are also able to directly see that environmental stress causes an increase in the ABA concentration in the stomatal guard cells that surround each stomatal pore. In the future, our sensors can be used to study ABA distribution in response to different stresses, including CO2 elevations, and to identify other molecules and proteins that affect the distribution of this hormone. We can also learn how fast plants respond to stresses and which tissues are important for the response.”

…

The researchers demonstrated that their new ABA nanosensors also function effectively as isolated proteins. This means that the sensors could be directly employed using state-of-the-art high-throughput screening platforms to screen for chemicals that could activate or enhance a drought resistance response. The scientists say such chemicals could become useful in the future for enhancing a drought resistance response, when crops experience a severe drought, like the one that occurred in the Midwest in the summer of 2012.

The scientists have provided a 1 min. 30 sec. (roughly) video where you can watch a vastly speeded up version of the process (Courtesy: UCSD),

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

FRET-based reporters for the direct visualization of abscisic acid concentration changes and distribution in Arabidopsis by Rainer Waadt, Kenichi Hitomi, Noriyuki Nishimura, Chiharu Hitomi, Stephen R Adams, Elizabeth D Getzoff, & Julian I Schroeder. eLife 2014;3:e01739 DOI: http://dx.doi.org/10.7554/eLife.01739 Published April 15, 2014

This paper is open access.

Shapeshifting, paradigm shifting nanoparticles

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Scientists at the University of California at San Diego (UCSD) had approached the problem of targeting diseased cells in a new way, according to the May 28, 2013 UCSD news release (also available on EurekAlert) by Susan Brown,

Targeting treatments specifically to cancerous or other diseased cells depends on some means of accumulating high levels of a drug or other therapeutic agent at the specific site and keeping it there. Most efforts so far depend on matching a piece of the drug-delivering molecule to specific receptors on the surface of the target cell.

Inspiration for this new strategy came from biological systems that use shape to alter the ability of something to lock in place or slip away and escape, said Nathan Gianneschi, a professor of chemistry and biochemistry, who led the project.

“We wanted to come up with a new approach,” Gianneschi said. “Specifically, we wanted to design switchable materials that we could inject in one shape and have them change to another between the blood and tumors.”

Here’s how they did it,

Some cancerous tissues produce high levels of a class of molecules called MMPs, for matrix metalloproteinases. These enzymes change how other proteins behave by altering their molecular configuration, leading to metastasis. Gianneschi and colleagues harnessed this ability to alter their nanoparticles in ways that would cause them to linger at the site of the tumor.

“We figured out how to make an autonomous material that could sense its environment and change accordingly,” Gianneschi said.

Each nanoparticle is made of many detergent-like molecules with one end that mixes readily with water and another that repels it. In solution, they self assemble into balls with the water-repellant ends inside, and in that configuration can easily be injected into a vein.

When mixed with MMPs in vials, the enzymes nicked the peptides on the surface of the spheres, which reassembled into netlike threads.

The team tested the concept further by injecting their new nanoparticles into mice with human fibrosarcomas, a kind of cancer that produces high levels of MMPs.

To mark when the spheres broke down to form other structures, the chemists placed one of two fluorecent dyes, rhodamine or fluorescein, inside the spheres. In close proximity, the dyes interact to create a specific light signal called FRET for Förster Resonance Energy Transfer, when energy jumps from rhodamine to fluorescein.

Within a day they detected FRET signals indicating that the spheres had reassembled at the sites of the tumors, and the signal persisted for at least a week.

The treatment is not inherently toxic. [emphasis mine] It did not appear to change the tumors in any way, and liver and kidney, the organs most vulnerable to collateral damage from treatments because they clear toxins from the body, were normal and healthy eight days after injection.

Different versions of these nanoparticles could be designed to respond to signals inherent to other types of cancers and inflamed tissue, the authors say. The spheres can also be engineered to carry drugs, or different diagnostic probes.

Right now, this same team is developing nanoparticles that carry an infrared dye, which would enable them to visualize tumors deeper inside the body along with other materials that can be imaged with instruments commonly available in the clinic.

I’m not sure I’d call this a ‘treatment’, it seems more like a new technique for drug delivery, diagnosis, etc. That quibble aside, this sounds very exciting and I hope the researchers will be able to start human clinical trials in the near future.

For those who’d like to read the research,

Enzyme-Directed Assembly of a Nanoparticle Probe in Tumor Tissue by Miao-Ping Chien, Matthew P. Thompson, Christopher V. Barback, David J. Hall, and Nathan C. Gianneschi.
ADVANCED MATERIALS, 2013, DOI: 10.1002/adma.201300823

This paper is behind a paywall.

Water, water, everywhere in cages, prisms, and books according to new study

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Researchers at the University of California at San Diego (UCSD) and at Emory University (Georgia, US) have a better understanding of hexamers found in the smallest of water droplets. From the Aug.16, 2012 news item on Nanowerk,

A new study by researchers at the University of California, San Diego, and Emory University has uncovered fundamental details about the hexamer structures that make up the tiniest droplets of water, the key component of life – and one that scientists still don’t fully understand.

The Aug. 15, 2012 news release by Jan Zverina for UCSD offers an explanation for why scientists would put effort into understanding the structure of tiny water droplets,

“About 60% of our bodies are made of water that effectively mediates all biological processes,” said Francesco Paesani, one of the paper’s corresponding authors who is an assistant professor in the Department of Chemistry and Biochemistry at UC San Diego and a computational researcher with the university’s San Diego Supercomputer Center (SDSC). “Without water, proteins don’t work and life as we know it wouldn’t exist. Understanding the molecular properties of the hydrogen bond network of water is the key to understanding everything else that happens in water. And we still don’t have a precise picture of the molecular structure of liquid water in different environments.”

Researchers know that the unique properties of water are due to its capability of forming a highly flexible but still dense hydrogen bond network which adapts according to the surrounding environment. As described in the JACS [Journal of the American Chemical Society] paper, researchers have determined the relative populations of the different isomers of the water hexamer as they assemble into various configurations called ‘cage’, ‘prism’, and ‘book’.

Here in more technical terms is a discussion about the importance of water hexamers,

The water hexamer is considered the smallest drop of water because it is the smallest water cluster that is three dimensional, i.e., a cluster where the oxygen atoms of the molecules do not lie on the same plane. As such, it is the prototypical system for understanding the properties of the hydrogen bond dynamics in the condensed phases because of its direct connection with ice, as well as with the structural arrangements that occur in liquid water.

This system also allows scientists to better understand the structure and dynamics of water in its liquid state, which plays a central role in many phenomena of relevance to different areas of science, including physics, chemistry, biology, geology, and climate research. For example, the hydration structure around proteins affects their stability and function, water in the active sites of enzymes affects their catalytic power, and the behavior of water adsorbed on atmospheric particles drives the formation of clouds.

The scientists have provided an illustration of two water hexamer structures,

Three-dimensional representations of the prism (left) and cage (right) structures of the water hexamer, the smallest drop of water. The mesh contours represent the actual quantum-mechanical densities of the oxygen (red) and hydrogen (white) atoms. The small yellow spheres represent the hydrogen bonds between the six water molecules. Characterizing the hydrogen-bond topology of the water hexamer at the molecular level is key to understanding the unique and often surprising properties of liquid water, our life matrix. Images courtesy of Volodymyr Babin and Francesco Paesani, UC San Diego.

Here’s the full citation for the research paper if you want to follow up on it or you can read more in either the news item or news release,

The Water Hexamer: Cage, Prism, or Both. Full Dimensional Quantum Simulations Say Both; Yimin Wang, Volodymyr Babin, Joel M. Bowman, and Francesco Paesani; J. Am. Chem. Soc., 2012, 134 (27), pp 11116–11119 DOI: 10.1021/ja304528m

The article is behind a paywall.

Bacteria that glow and light your way

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It’s a light show of sorts but it involves bacteria and fluorescent protein,

Thanks to the Dec. 19, 2011 news item on Nanwerk, I was able to access both the video and some additional information,

In an example of life imitating art, biologists and bioengineers at UC [University of California] San Diego have created a living neon sign composed of millions of bacterial cells that periodically fluoresce in unison like blinking light bulbs. Their achievement, detailed in this week’s advance online issue of the journal Nature  (“A sensing array of radically coupled genetic ‘biopixels'”), involved attaching a fluorescent protein to the biological clocks of the bacteria, synchronizing the clocks of the thousands of bacteria within a colony, then synchronizing thousands of the blinking bacterial colonies to glow on and off in unison.

Here’s how scientists think this could be useful,

 Using the same method to create the flashing signs, the researchers engineered a simple bacterial sensor capable of detecting low levels of arsenic. In this biological sensor, decreases in the frequency of the oscillations of the cells’ blinking pattern indicate the presence and amount of the arsenic poison.

Because bacteria are sensitive to many kinds of environmental pollutants and organisms, the scientists believe this approach could be also used to design low cost bacterial biosensors capable of detecting an array of heavy metal pollutants and disease-causing organisms. And because the senor is composed of living organisms, it can respond to changes in the presence or amount of the toxins over time unlike many chemical sensors.

“These kinds of living sensors are intriguing as they can serve to continuously monitor a given sample over long periods of time, whereas most detection kits are used for a one-time measurement,” said Jeff Hasty, a professor of biology and bioengineering at UC San Diego who headed the research team in the university’s Division of Biological Sciences and BioCircuits Institute. “Because the bacteria respond in different ways to different concentrations by varying the frequency of their blinking pattern, they can provide a continual update on how dangerous a toxin or pathogen is at any one time.”

There are more details in the news item on Nanowerk.

Scientists have been experimenting with other uses for fluorescent bacteria, lighting. From the Nov. 28, 2011 article by Jaymi Heimbuch for Treehugger,

Here, Philips has shown off a concept for a light that runs on not grid electricity, not solar power, not even wind power. Nope, it runs on bacteria.

According to Philips, “The concept explores the use of bioluminescent bacteria, which are fed with methane and composted material (drawn from the methane digester in the Microbial Home system). Alternatively the cellular light array can be filled with fluorescent proteins that emit different frequencies of light.”

I gather the concept isn’t ready for houselighting yet but Philips does have some proposals (from the Philips Bio-light page),

 Bioluminescence produces low-intensity light, more suitable for tracing, warning, ambience and indication than functional illumination. Its speed of generation, being dependent on chemical reaction, is slower than most conventional light sources and the life form itself must be kept alive. But it needs no wires and is independent of the electricity grid. The living nature of the material provides interesting possibilities for changing, unpredictable, environmentally responsible ambient effects.

…

    • Night-time road markings, eg bioluminescent plants that indicate where the edge of the road is
    • Warning strips on flights of stairs, kerbsides etc
    • Informational markings in low-light settings, eg. theatres, cinemas, nightclubs
    • Diagnostic indicators, eg. a colored body health map in the home apothecary, pollution levels, local bacterial ecology etc
    • Monitoring the status of diseases like diabetes in individual patients, using bioluminescent biosensors

New genres of atmospheric interior lighting with, for example, possible therapeutic and mood-enhancing effects.

There you have it, bacteria will light the way.

Social research and nano plus 2 million jobs

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There’s a new report on social and ethical issues, as they pertain to nanotechnology, that’s just been issued by the Project on Emerging Nanotechnologies. It was written by Ronald Sandler, a philosophy professor at Northeastern University. You can find the report here and you can find articles about it here and here. The articles have a very hopeful tone (due to some recent action in the US Congress) suggesting that there will be money for social research programs. After reading a couple of articles about science and its new found status within the new Obama administration, I’m guessing the euphoria is spreading from the science community to the social science community.

I imagine this news will add even more fuel to the prospective science and social science renaissance. The US National Science Foundation has estimated that the US will need 2 million workers who are nano-tech savvy by 2014. A non-profit group in the US has developed a program to help with this upcoming shortage of workers. The program is being instituted at the University of California at San Diego. I don’t entirely understand how a non-profit group can develop curriculum for a university (as far as I know that can’t be done in Canada). Here are links to two articles about it, one here and one here.