Category Archives: medicine

A carbon nanomaterial ‘pot’ for drug delivery

Japanese scientists have developed a new material, which could be used as a carrier for drugs. From an Aug. 5, 2016 news item on phys.org,

A novel, pot-shaped, carbon nanomaterial developed by researchers from Kumamoto University, Japan is several times deeper than any hollow carbon nanostructure previously produced. This unique characteristic enables the material to gradually release substances contained within and is expected to be beneficial in applications such as drug delivery systems.

An Aug. 5, 2016 Kumamoto University press release on EurekAlert, which despite the discrepancy in the dates originated the news item, discusses carbon and the discovery in more detail,

Carbon is an element that is light, abundant, has a strong binding force, and eco-friendly. The range of carbon-based materials is expected to become more widespread in the eco-friendly society of the future. Recently, nanosized (one-billionth of a meter) carbon materials have been developed with lengths, widths, or heights below 100 nm [nanometre]. These materials take extreme forms such as tiny grained substances, thin sheet-like substances, and slim fibrous substances. Example of these new materials are fullerenes, which are hollow cage-like carbon molecules; carbon nanotubes, cylindrical nanostructures of carbon molecules; and graphene, one-atom thick sheets of carbon molecules.

Why are these tiny substances needed? One reason is that reactions with other materials can be much larger if a substance has an increased surface area. When using nanomaterials in place of existing materials, it is possible to significantly change surface area without changing weight and volume, thereby improving both size and performance. The development of carbon nanomaterials has provided novel nanostructured materials with shapes and characteristics that surpass existing materials.

Now, research from the laboratory of Kumamoto University’s Associate Prof. Yokoi has resulted in the successful development of a container-type carbon nanomaterial with a much deeper orifice than that found in similar materials. To create the new material, researchers used their own, newly developed method of material synthesis. The container-shaped nanomaterial has a complex form consisting of varied layers of stacked graphene at the bottom, the body, and the neck areas of the container, and the graphene edges along the outer surface of the body were found to be very dense. Due to these innovate features, Associate Prof. Yokoi and colleagues named the material the “carbon nanopot.”

The carbon nanopot has an outer diameter of 20 ~ 40 nm, an inner diameter of 5 ~ 30 nm, and a length of 100 ~ 200 nm. During its creation, the carbon nanopot is linked to a carbon nanofiber with a length of 20 ~ 100 μm [micrometre] meaning that the carbon nanopot is also available as a carbon nanofiber. At the junction between nanopots, the bottom of one pot simply sits on the opening of the next without sharing a graphene sheet connection. Consequently, separating nanopots is very easy.

“From a detailed surface analysis, hydrophilic hydroxyl groups were found clustered along the outer surface of the carbon nanopot body,” said Associate Prof. Yokoi. “Graphene is usually hydrophobic however, if hydroxyl groups are densely packed on the outer surface of the body, that area will be hydrophilic. In other words, carbon nanopots could be a unique nanomaterial with both hydrophobic and hydrophilic characteristics. We are currently in the process of performing a more sophisticated surface analysis in order to get that assurance.”

Since this new carbon nanopot has a relatively deep orifice, one of its expected uses is to improve drug delivery systems by acting as a new foundation for medicine to be carried into and be absorbed by the body.

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

Novel pot-shaped carbon nanomaterial synthesized in a submarine-style substrate heating CVD method by Hiroyuki Yokoi, Kazuto Hatakeyama, Takaaki Taniguchi, Michio Koinuma, Masahiro Hara, and Yasumichi Matsumoto. Journal of Materials Research / Volume 31 / Issue 01 / 2016, pp 117-126 DOI: http://dx.doi.org/10.1557/jmr.2015.389 (About DOI) Published online: 13 January 2016

Copyright © Materials Research Society 2016

I’m not sure why there’s this push for publicity so long after the publication date. In any event, this paper is behind a paywall.

Canada’s Nanorobotics Laboratory unveils its ‘medical interventional infrastructure’

Located at the Polytechnique Montréal (Canada), the Nanorobotics Laboratory has built a one-of-a-kind ‘medical interventional infrastructure’, the result of a $4.6M investment from various levels of government and from private enterprise.

Before getting to the news release, here’s a video featuring Prof. Sylvain Martel who discusses his work by referencing the movie, Fantastic Voyage. There are subtitles for those whose French fails them,

From an Aug. 24, 2016 Polytechnique Montréal news release (also on EurekAlert),

Fifty years to the day after the film Fantastic Voyage was first shown in theatres, the Polytechnique Montréal Nanorobotics Laboratory is unveiling a unique medical interventional infrastructure devoted to the fight against cancer. The outcome of 15 years of research conducted by Professor Sylvain Martel and his team, it enables microscopic nanorobotic agents to be guided through the vascular systems of living bodies, delivering drugs to targeted areas.

An action-packed 100,000-kilometre journey in the human body

Fantastic Voyage recounted the adventure of a team of researchers shrunk to microscopic size who, aboard a miniature submarine, travelled into a patient’s body to conduct a medical operation in a surgically inoperable area. This science fiction classic has now been eclipsed by procedures and protocols developed by Professor Martel’s multidisciplinary team comprising engineers, scientists and experts from several medical specialties working together on these projects that herald the future of medicine.

“Our work represents a new vision of cancer treatments, with our goal being to develop the most effective transportation systems for the delivery of therapeutic agents right to tumour cells, to areas unreachable by conventional treatments,” says Professor Martel, holder of the Canada Research Chair in Medical Nanorobotics and Director of the Polytechnique Montréal Nanorobotics Laboratory.

Conveying nanorobotic agents into the bloodstream to reach the targeted area right up to the tiniest capillaries without getting lost in this network stretching about 100,000 kilometres—two-and-a-half times the Earth’s circumference—is a scenario that has been turned into reality. This is an adventure-filled journey for these microscopic vehicles that must confront the powerful onslaught of arterial blood flow, the mazes of the vascular network and the narrowness of the capillaries—just like the film’s heroes!

“Doctors” invisible to the naked eye

To conduct this fantastic voyage, Professor Martel’s team is developing various procedures, often playing a pioneering role. These include navigating carriers just a fraction of the thickness of a hair through the arteries using a clinical magnetic resonance imaging (MRI) platform, the first in the world to achieve this in a living organism, in 2006. This exploit was followed in 2011 by the guidance of drug-loaded micro-transporters into the liver of a rabbit.

Limits to the miniaturization of artificial nanorobots prevent them from penetrating the smallest blood vessels, however. For this, Professor Martel plans to have them play the role of Trojan horses, enclosing an “army” of special bacteria loaded with drugs that they will release at the edges of these small vessels.

Able to follow paths smaller than a red blood cell, these self-propelled bacteria move at high speed (200 microns per second, or 200 times their size per second). Once they are inside a tumour, they are able to naturally detect hypoxic (oxygen-starved) zones, which are the most active zones and the hardest to treat by conventional means, including radiotherapy, and then deliver the drug.

Professor Martel’s team has succeeded in using this procedure to administer therapeutic agents in colorectal tumours in mice, guiding them through a magnetic field. This has just been the subject of an article in the renowned journal Nature Nanotechnology, titled Magneto-gerotactic Bacteria Deliver Drug-containing Nanoliposomes to Tumour Hypoxic Regions. “This advanced procedure, which provides optimal targeting of a tumour while preserving surrounding healthy organs and tissue, unlike current chemotherapy or radiotherapy, heralds a new era in cancer treatment,” says Dr. Gerald Batist, Director of the McGill Centre for Translational Research in Cancer, based at the Jewish General Hospital, which is collaborating on the project.

Professor Martel’s projects also focus on the inaccessibility of certain parts of the body, such as the brain, to transporting agents. In 2015, his team also stood out by successfully opening a rat’s blood-brain barrier, temporarily and without damage, providing access to targeted areas of the brain. This feat was achieved through a slight rise in temperature caused by exposing nanoparticles to a radiofrequency field.

“At present, 98% of drug molecules cross the blood-brain barrier only with great difficulty,” notes Dr. Anne-Sophie Carret, a specialist in hematology-oncology at Montréal’s Centre hospitalier universitaire Sainte-Justine and one of the doctors collaborating on the project. “This means surgery is often the only way to treat some patients who have serious brain diseases. But certain tumours are inoperable because of their location. Radiation therapy, for its part, is not without medium- and long-term risk for the brain. This work therefore offers real hope to patients suffering from a brain tumour.”

Here’s who invested, how much they invested, and what the Nanorobotics Laboratory got for its money,

This new investment in the Nanorobotics Laboratory represents $4.6 million in infrastructure, with contributions of $1.85 million each from the Canada Foundation for Innovation (CFI), and the Government of Québec. Companies including Siemens Canada and Mécanik have also made strategic contributions to the project. This laboratory now combines platforms to help develop medical protocols for transferring the procedures developed by Professor Martel to a
clinical setting.

The laboratory contains the following equipment:

  • a clinical MRI platform to navigate microscopic carriers directly into specific areas in the vascular system and for 3D visualization of these carriers in the body;
  • a specially-developed platform that generates the required magnetic field sequences to guide special bacteria loaded with therapeutic agents into tumours;
  • a robotic station (consisting of a robotized bed) for moving a patient from one platform to another;
  • a hyperthermia platform for temporary opening of the blood-brain barrier;
  • a mobile X-ray system;
  • a facility to increase the production of these cancer-fighting bacteria.

Sylvain Martel’s most recent work with nanorobotic agents (as cited in the news release) was featured here in an Aug. 16, 2016 post.

‘Neural dust’ could lead to introduction of electroceuticals

In case anyone is wondering, the woman who’s manipulating a prosthetic arm so she can eat or a drink of coffee probably has a bulky implant/docking station in her head. Right now that bulky implant is the latest and greatest innovation for tetraplegics (aka, quadriplegics) as it frees, to some extent, people who’ve had no independent movement of any kind. By virtue of the juxtaposition of the footage of the woman with the ‘neural dust’ footage, they seem to be suggesting that neural dust might some day accomplish the same type of connection. At this point, hopes for the ‘neural dust’ are more modest.

An Aug. 3, 2016 news item on ScienceDaily announces the ‘neural dust’,

University of California, Berkeley engineers have built the first dust-sized, wireless sensors that can be implanted in the body, bringing closer the day when a Fitbit-like device could monitor internal nerves, muscles or organs in real time.

Because these batteryless sensors could also be used to stimulate nerves and muscles, the technology also opens the door to “electroceuticals” to treat disorders such as epilepsy or to stimulate the immune system or tamp down inflammation.

An Aug. 3, 2016 University of California at Berkeley news release (also on EurekAlert) by Robert Sanders, which originated the news item, explains further and describes the researchers’ hope that one day the neural dust could be used to control implants and prosthetics,

The so-called neural dust, which the team implanted in the muscles and peripheral nerves of rats, is unique in that ultrasound is used both to power and read out the measurements. Ultrasound technology is already well-developed for hospital use, and ultrasound vibrations can penetrate nearly anywhere in the body, unlike radio waves, the researchers say.

“I think the long-term prospects for neural dust are not only within nerves and the brain, but much broader,“ said Michel Maharbiz, an associate professor of electrical engineering and computer sciences and one of the study’s two main authors. “Having access to in-body telemetry has never been possible because there has been no way to put something supertiny superdeep. But now I can take a speck of nothing and park it next to a nerve or organ, your GI tract or a muscle, and read out the data.“

Maharbiz, neuroscientist Jose Carmena, a professor of electrical engineering and computer sciences and a member of the Helen Wills Neuroscience Institute, and their colleagues will report their findings in the August 3 [2016] issue of the journal Neuron.

The sensors, which the researchers have already shrunk to a 1 millimeter cube – about the size of a large grain of sand – contain a piezoelectric crystal that converts ultrasound vibrations from outside the body into electricity to power a tiny, on-board transistor that is in contact with a nerve or muscle fiber. A voltage spike in the fiber alters the circuit and the vibration of the crystal, which changes the echo detected by the ultrasound receiver, typically the same device that generates the vibrations. The slight change, called backscatter, allows them to determine the voltage.

Motes sprinkled thoughout the body

In their experiment, the UC Berkeley team powered up the passive sensors every 100 microseconds with six 540-nanosecond ultrasound pulses, which gave them a continual, real-time readout. They coated the first-generation motes – 3 millimeters long, 1 millimeter high and 4/5 millimeter thick – with surgical-grade epoxy, but they are currently building motes from biocompatible thin films which would potentially last in the body without degradation for a decade or more.

While the experiments so far have involved the peripheral nervous system and muscles, the neural dust motes could work equally well in the central nervous system and brain to control prosthetics, the researchers say. Today’s implantable electrodes degrade within 1 to 2 years, and all connect to wires that pass through holes in the skull. Wireless sensors – dozens to a hundred – could be sealed in, avoiding infection and unwanted movement of the electrodes.

“The original goal of the neural dust project was to imagine the next generation of brain-machine interfaces, and to make it a viable clinical technology,” said neuroscience graduate student Ryan Neely. “If a paraplegic wants to control a computer or a robotic arm, you would just implant this electrode in the brain and it would last essentially a lifetime.”

In a paper published online in 2013, the researchers estimated that they could shrink the sensors down to a cube 50 microns on a side – about 2 thousandths of an inch, or half the width of a human hair. At that size, the motes could nestle up to just a few nerve axons and continually record their electrical activity.

“The beauty is that now, the sensors are small enough to have a good application in the peripheral nervous system, for bladder control or appetite suppression, for example,“ Carmena said. “The technology is not really there yet to get to the 50-micron target size, which we would need for the brain and central nervous system. Once it’s clinically proven, however, neural dust will just replace wire electrodes. This time, once you close up the brain, you’re done.“

The team is working now to miniaturize the device further, find more biocompatible materials and improve the surface transceiver that sends and receives the ultrasounds, ideally using beam-steering technology to focus the sounds waves on individual motes. They are now building little backpacks for rats to hold the ultrasound transceiver that will record data from implanted motes.

They’re also working to expand the motes’ ability to detect non-electrical signals, such as oxygen or hormone levels.

“The vision is to implant these neural dust motes anywhere in the body, and have a patch over the implanted site send ultrasonic waves to wake up and receive necessary information from the motes for the desired therapy you want,” said Dongjin Seo, a graduate student in electrical engineering and computer sciences. “Eventually you would use multiple implants and one patch that would ping each implant individually, or all simultaneously.”

Ultrasound vs radio

Maharbiz and Carmena conceived of the idea of neural dust about five years ago, but attempts to power an implantable device and read out the data using radio waves were disappointing. Radio attenuates very quickly with distance in tissue, so communicating with devices deep in the body would be difficult without using potentially damaging high-intensity radiation.

Marharbiz hit on the idea of ultrasound, and in 2013 published a paper with Carmena, Seo and their colleagues describing how such a system might work. “Our first study demonstrated that the fundamental physics of ultrasound allowed for very, very small implants that could record and communicate neural data,” said Maharbiz. He and his students have now created that system.

“Ultrasound is much more efficient when you are targeting devices that are on the millimeter scale or smaller and that are embedded deep in the body,” Seo said. “You can get a lot of power into it and a lot more efficient transfer of energy and communication when using ultrasound as opposed to electromagnetic waves, which has been the go-to method for wirelessly transmitting power to miniature implants”

“Now that you have a reliable, minimally invasive neural pickup in your body, the technology could become the driver for a whole gamut of applications, things that today don’t even exist,“ Carmena said.

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

Wireless Recording in the Peripheral Nervous System with Ultrasonic Neural Dust by Dongjin Seo, Ryan M. Neely, Konlin Shen, Utkarsh Singhal, Elad Alon, Jan M. Rabaey, Jose M. Carmena. and Michel M. Maharbiz. Neuron Volume 91, Issue 3, p529–539, 3 August 2016 DOI: http://dx.doi.org/10.1016/j.neuron.2016.06.034

This paper appears to be open access.

Better contrast agents for magnetic resonance imaging with nanoparticles

I wonder what’s going on in the field of magnetic resonance imaging. This is the third news item I’ve stumbled across related to the topic in the last couple of months. (Links to the other two posts follow at the end of this post.) By comparison, that’s the more than in the previous seven years (2008 – 2015) combined.

The latest research concerns a new and better contrast agent. From an Aug. 3, 2016 news item on Nanowerk,

Scientists at the University of Basel [Switzerland] have developed nanoparticles which can serve as efficient contrast agents for magnetic resonance imaging. This new type of nanoparticles [sic] produce around ten times more contrast than the actual contrast agents and are responsive to specific environments.

An Aug. 3, 2016 University of Basel press release (also on EurekAlert), which originated the news item, explains further,

Contrast agents are usually based on the metal Gadolinium, which is injected and serves for an improved imaging of various organs in an MRI. Gadolinium ions should be bound with a carrier compound to avoid the toxicity to the human body of the free ions. Therefore, highly efficient contrast agents requiring lower Gadolinium concentrations represent an important step for advancing diagnosis and improving patient health prognosis.

Smart nanoparticles as contrast agents

The research groups of Prof. Cornelia Palivan and Prof. Wolfgang Meier from the Department of Chemistry at the University of Basel have introduced a new type of nanoparticles [sic], which combine multiple properties required for contrast agents: an increased MRI contrast for lower concentration, a potential for long blood circulation and responsiveness to different biochemical environments. These nanoparticles were obtained by co-assembly of heparin-functionalized polymers with trapped gadolinium ions and stimuli-responsive peptides.

The study shows, that the nanoparticles have the capacity of enhancing the MRI signal tenfold higher than the current agents. In addition, they have an enhanced efficacy in reductive milieu, characteristic for specific regions, such as cancerous tissues. These nanoparticles fulfill numerous key criteria for further development, such as absence of cellular toxicity, no apparent anticoagulation property, and high shelf stability. The concept developed by the researchers at the University of Basel to produce better contrast agents based on nanoparticles highlights a new direction in the design of MRI contrast agents, and supports their implementation for future applications.

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

Nanoparticle-based highly sensitive MRI contrast agents with enhanced relaxivity in reductive milieu by
Severin J. Sigg, Francesco Santini, Adrian Najer, Pascal U. Richard, Wolfgang P. Meier, and Cornelia G. Palivan. Chem. Commun., 2016,52, 9937-9940 DOI: 10.1039/C6CC03396B First published online 13 Jul 2016

This paper is behind a paywall.

The other two MRI items featured here are in a June 10, 2016 posting (pH dependent nanoparticle-based contrast agent for MRIs [magnetic resonance images]) and in an Aug. 1, 2016 posting (Nuclear magnetic resonance microscope breaks records).

Selecta Biosciences’ proprietary tolerogenic nanoparticles improve efficacy and safety of biologic drugs

Although it may not seem like it initially, there is a nanotechnology element to this piece of news. From an Aug. 1, 2016 news item on Nanotechnology Now ,

Selecta Biosciences, Inc. (NASDAQ: SELB), a clinical-stage biopharmaceutical company developing targeted antigen-specific immune therapies for rare and serious diseases, announced today that Nature Nanotechnology has published an article that presents preclinical results from Selecta’s research which demonstrate the broad potential applicability of Selecta’s novel immune tolerance platform. Details that elucidate the mechanism of action of the company’s immune tolerance therapy, SVP [Synthetic Vaccine Particle]-Rapamycin (SEL-110), were also shown. Data in the publication support the Company’s lead clinical program, showing Selecta’s SVP-Rapamycin (SEL-110) induces antigen-specific immune tolerance and mitigates the formation of anti-drug antibodies (ADAs) to biologic drugs, including pegsiticase (for gout) and adalimumab (for rheumatoid arthritis).

An Aug. 1, 2016 Selecta Biosciences news release (also on EurekAlert), which originated the news item, provides more information,

“Undesired immune responses affect both the efficacy and safety of marketed biologic therapies and the development of otherwise promising new technologies. Selecta’s SVP platform positions the company to enhance biologic therapy and to advance a pipeline of proprietary products that meet the therapeutic needs of patients with rare and serious diseases,” said Werner Cautreels, PhD,Chairman of the Board, CEO and President of Selecta Biosciences. “This publication in Nature Nanotechnology highlights the mechanism by which Selecta’s proprietary nanoparticles induce lasting antigen-specific tolerance. We believe that SVP-Rapamycin has the potential to mitigate ADAs against a broad range of biologic therapies.”

In the Nature Nanotechnology journal article, Selecta presents validation of the immune tolerance mechanism of action of the company’s technology, demonstrating that poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins. This robust immune tolerance is characterized immunologically by: (1) induction of tolerogenic dendritic cells; (2) an increase in regulatory T cells; (3) reduction in B cell activation and germinal center formation; and (4) inhibition of antigen-specific hypersensitivity reactions.

Data presented in the journal article support the Company’s clinical lead program in gout, showing that intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and nonhuman primates and normalized serum uric acid levels in uricase-deficient mice. Underscoring the broad potential of the approach, results additionally show that subcutaneous co-administration of nanoparticles with adalimumab durably inhibited ADAs, resulting in normalized pharmacokinetics of the anti-TNFα antibody and protection against arthritis in TNFα transgenic mice.

In the published research, the induction of specific immune tolerance by SVP-Rapamycin (SEL-110) versus chronic immune suppression is supported by the findings that: (1) antigen must be co-administered at the time of SVP-Rapamycin (SEL-110) treatment; (2) immune tolerance is durable to many challenges of antigen alone; (3) animals tolerized to a specific antigen are capable of responding to an unrelated antigen, meaning that SVP-Rapamycin (SEL-110) does not induce a broad immune suppression; and (4) activation of naïve T cells is inhibited when adoptively transferred into previously tolerized mice. In contrast, daily administration of free rapamycin, at five times the total weekly rapamycin dose as that administered in the SVP-Rapamycin, was observed to transiently suppress the immune response, but did not induce durable immunological tolerance.

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

Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles by Takashi K. Kishimoto, Joseph D. Ferrari, Robert A. LaMothe, Pallavi N. Kolte, Aaron P. Griset, Conlin O’Neil, Victor Chan, Erica Browning, Aditi Chalishazar, William Kuhlman, Fen-ni Fu, Nelly Viseux, David H. Altreuter, Lloyd Johnston, & Roberto A. Maldonado. Nature Nanotechnology (2016)  doi:10.1038/nnano.2016.135 Published online 01 August 2016

This paper is behind a paywall.

Enzyme-based sustainable sensing devices

This story about a sustainable sensing device involves sweat. A July 28, 2016 news item on ScienceDaily describes the sweaty situation,

It may be clammy and inconvenient, but human sweat has at least one positive characteristic — it can give insight to what’s happening inside your body. A new study published in the ECS [Electrochemical Society] Journal of Solid State Science and Technology aims to take advantage of sweat’s trove of medical information through the development of a sustainable, wearable sensor to detect lactate levels in your perspiration.

Caption: Depiction of patch sensor via CFDRC. Credit: Sergio Omar Garcia/CFDRC

Caption: Depiction of patch sensor via CFDRC. Credit: Sergio Omar Garcia/CFDRC

The patch in that image doesn’t seem all that wearable but presumably there will be some changes made. A July 28, 2016 Electrochemical Society news release on EurekAlert, which originated the news item, provides more detail about the technology,

“When the human body undergoes strenuous exercise, there’s a point at which aerobic muscle function becomes anaerobic muscle function,” says Jenny Ulyanova, CFD Research Corporation (CFDRC) researcher and co-author of the paper. “At that point, lactate is produce at a faster rate than it is being consumed. When that happens, knowing what those levels are can be an indicator of potentially problematic conditions like muscle fatigue, stress, and dehydration.”

Utilizing green technology

Using sweat to track changes in the body is not a new concept. While there have been many developments in recent years to sense changes in the concentrations of the components of sweat, no purely biological green technology has been used for these devices. The team of CFDRC researchers, in collaboration with the University of New Mexico, developed an enzyme-based sensor powered by a biofuel cell – providing a safe, renewable power source.

Biofuel cells have become a promising technology in the field of energy storage, but still face many issues related to short active lifetimes, low power densities, and low efficiency levels. However, they have several attractive points, including their ability to use renewable fuels like glucose and implement affordable, renewable catalysts.

“The biofuel cell works in this particular case because the sensor is a low-power device,” Ulyanova says. “They’re very good at having high energy densities, but power densities are still a work in progress. But for low-power applications like this particular sensor, it works very well.”

In their research, entitled “Wearable Sensor System Powered by a Biofuel Cell for Detection of Lactate Levels in Sweat,” the team powered the biofuel cells with a fuel based on glucose. This same enzymatic technology, where the enzymes oxidize the fuel and generate energy, is used at the working electrode of the sensor which allows for the detection of lactate in your sweat.

Targeting lactate

While the use of the biofuel cell is a novel aspect of this work, what sets it apart from similar developments in the field is the use of electrochemical processes to very accurately detect a specific compound in a very complex medium like sweat.

“We’re doing it electrochemically, so we’re looking at applying a constant load to the sensor and generating a current response,” Ulyanova says, “which is directly proportional to the concentration of our target analyte.”

Practical applications

Originally, the sensor was developed to help detect and predict conditions related to lactate levels (i.e. fatigue and dehydration) for military personnel.

“The sensor was designed for a soldier in training at boot camp,” says Sergio Omar Garcia, CFDRC researcher and co-author of the paper, “but it could be applied to people that are active and anyone participating in strenuous activity.”

As for commercial applications, the researchers believe the device could be used as a training aid to monitor lactate changes in the same way that athletes use heart rate monitors to see how their heart rate changes during exercise.

On-body testing

The team is currently working to redesign the physical appearance of the patch to move from laboratory research to on-body tests. Once the scientists optimize how the sensor adheres to the skin, its sweat sample delivery/removal, and the systems electronic components, volunteers will test its capabilities while exercising.

“We had actually talked about this idea to some local high school football coaches,” Ulyanova says, “and they seem to really like it and are willing to put forth the use of their players to beta test the idea.”

After initial data is gathered, the team will be able to work with other groups to interpret the data and relate it to the physical condition of the person. With this, predictive models could be built to potentially help prevent conditions related to individual overexertion.

Future plans for the device include implementing wireless transmission of results and the development of a suite of sensors (a hybrid sensor) that can detect various other biomolecules, indicative of physical or physiological stressors.

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

Wearable Sensor System Powered by a Biofuel Cell for Detection of Lactate Levels in Sweat by S. O. Garcia, Y. V. Ulyanova, R. Figueroa-Teran, K. H. Bhatt, S. Singhal and P. Atanassov. ECS J. Solid State Sci. Technol. 2016 volume 5, issue 8, M3075-M3081 doi: 10.1149/2.0131608jss

This paper is behind a paywall.

Very precise nanorobots redefine the administration of anti-cancer drugs

A very exuberant announcement has been made about cancer drug delivery by precise nanorobots, which have been tested in mice, in an Aug. 15, 2016 news item on ScienceDaily,

Researchers from Polytechnique Montréal, Université de Montréal and McGill University have just achieved a spectacular breakthrough in cancer research. They have developed new nanorobotic agents capable of navigating through the bloodstream to administer a drug with precision by specifically targeting the active cancerous cells of tumours. This way of injecting medication ensures the optimal targeting of a tumour and avoids jeopardizing the integrity of organs and surrounding healthy tissues. As a result, the drug dosage that is highly toxic for the human organism could be significantly reduced.

This scientific breakthrough has just been published in the prestigious journal Nature Nanotechnology in an article titled “Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions.” The article notes the results of the research done on mice, which were successfully administered nanorobotic agents into colorectal tumours.

An Aug. 15, 2016 Polytechnique Montréal news release (also on EurekAlert), which originated the news item, describes the work and the nanorobots or nanorobotic agents (bacteria) in more detail,

“These legions of nanorobotic agents were actually composed of more than 100 million flagellated bacteria – and therefore self-propelled – and loaded with drugs that moved by taking the most direct path between the drug’s injection point and the area of the body to cure,” explains Professor Sylvain Martel, holder of the Canada Research Chair in Medical Nanorobotics and Director of the Polytechnique Montréal Nanorobotics Laboratory, who heads the research team’s work. “The drug’s propelling force was enough to travel efficiently and enter deep inside the tumours.”

When they enter a tumour, the nanorobotic agents can detect in a wholly autonomous fashion the oxygen-depleted tumour areas, known as hypoxic zones, and deliver the drug to them. This hypoxic zone is created by the substantial consumption of oxygen by rapidly proliferative tumour cells. Hypoxic zones are known to be resistant to most therapies, including radiotherapy.

But gaining access to tumours by taking paths as minute as a red blood cell and crossing complex physiological micro-environments does not come without challenges. So Professor Martel and his team used nanotechnology to do it.

Bacteria with compass

To move around, bacteria used by Professor Martel’s team rely on two natural systems. A kind of compass created by the synthesis of a chain of magnetic nanoparticles allows them to move in the direction of a magnetic field, while a sensor measuring oxygen concentration enables them to reach and remain in the tumour’s active regions. By harnessing these two transportation systems and by exposing the bacteria to a computer-controlled magnetic field, researchers showed that these bacteria could perfectly replicate artificial nanorobots of the future designed for this kind of task.

“This innovative use of nanotransporters will have an impact not only on creating more advanced engineering concepts and original intervention methods, but it also throws the door wide open to the synthesis of new vehicles for therapeutic, imaging and diagnostic agents,” Professor Martel adds. “Chemotherapy, which is so toxic for the entire human body, could make use of these natural nanorobots to move drugs directly to the targeted area, eliminating the harmful side effects while also boosting its therapeutic effectiveness.”

This news contrasts somewhat with research at the University of Toronto (my April 27, 2016 posting) investigating how many drug-carrying nanoparticles find the cancer tumours they are intended for. The answer was that less than 1% make their way to the tumour and the conclusion those scientists reached was that we don’t know enough about how materials are delivered to the cells. My question, are the bacteria/nanorobots better at finding the tumours/cells? It’s not clear from the news release.

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

Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions by Ouajdi Felfoul, Mahmood Mohammadi, Samira Taherkhani, Dominic de Lanauze, Yong Zhong Xu, Dumitru Loghin, Sherief Essa, Sylwia Jancik, Daniel Houle, Michel Lafleur, Louis Gaboury, Maryam Tabrizian, Neila Kaou, Michael Atkin, Té Vuong, Gerald Batist, Nicole Beauchemin, Danuta Radzioch, & Sylvain Martel. Nature Nanotechnology (2016)  doi:10.1038/nnano.2016.137 Published online 15 August 2016

This paper is behind a paywall.

Fido’s osteosarcoma and nanoparticle drug delivery

Researchers at the University of Illinois at Urbana-Champaign have started testing nanoparticle drug delivery for bone tumours in dogs. From a July 25, 2016 news item on ScienceDaily,

At the University of Illinois, an engineer teamed up with a veterinarian to test a bone cancer drug delivery system in animals bigger than the standard animal model, the mouse. They chose dogs — mammals closer in size and biology to humans — with naturally occurring bone cancers, which also are a lot like human bone tumors.

A July 25, 2016 University of Illinois at Urbana-Champaign news release (also on EurekAlert) by Diana Yates, which originated the news item, provides more detail about the research,

In clinical trials, the dogs tolerated the highest planned doses of cancer-drug-laden nanoparticles with no signs of toxicity. As in mice, the particles homed in on tumor sites, thanks to a coating of the drug pamidronate, which preferentially binds to degraded sites in bone. The nanoparticles also showed anti-cancer activity in mice and dogs.

These findings are a proof-of-concept that nanoparticles can be used to target bone cancers in large mammals, the researchers said. The approach may one day be used to treat metastatic skeletal cancers, they said.

The dogs were companion animals with bone cancer that were submitted for the research trials by their owners, said U. of I. veterinary clinical medicine professor Dr. Timothy Fan, who led the study with materials science and engineering professor Jianjun Cheng. All of the dogs were 40 to 60 kilograms (88 to 132 pounds) in weight, he said.

“We wanted to see if we could evaluate these drug-delivery strategies, not only in a mouse model, but also at a scale that would mimic what a person would get,” Fan said. “The amount of nanoparticle that we ended up giving to these dogs was a thousand-fold greater in quantity than what we would typically give a mouse.” Fan is a faculty member of the Anticancer Discovery from Pets to People research theme at the IGB [Institute for Genomic Biology).

Using nanoparticles with payloads of drugs to target specific tissues in the body is nothing new, Cheng said. Countless studies test such approaches in mice, and dozens of “nanopharmaceuticals” are approved for use in humans. But the drug-development pipeline is long, and the leap from mouse models to humans is problematic, he said.

“Human bone tumors are much bigger than those of mice,” Cheng, an affiliate of the IGB’s Regenerative Biology & Tissue Engineering theme, said. “Nanoparticles must penetrate more deeply into larger tumors to be effective. That is why we must find animal models that are closer in scale to those of humans.”

Mice used in cancer research have other limitations. Researchers usually inject human or other tumor cells into their bodies to mimic human cancers, Fan said. They also are bred to have compromised immune systems, to prevent them from rejecting the tumors.

“That is one of the very clear drawbacks of using a mouse model,” Fan said. “it doesn’t recapitulate the normal immune system that we deal with every day in the person or in a dog.”

There also are limitations to working with dogs, he said. Dogs diagnosed with bone cancer often arrive at the clinic at a very advanced stage of the disease, whereas in humans, bone cancer is usually detected early because people complain about the pain and have it investigated.

“On the flip side of that, I would say that if you are able to demonstrate anti-cancer activity in a dog with very advanced disease, then it would be likely that you would have equivalent or better activity in people with a less advanced stage of the disease,” Fan said.

Many more years of work remain before this or a similar drug-delivery system can be tested in humans with inoperable bone cancer, the researchers said.

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

Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis by Qian Yin, Li Tang, Kaimin Cai, Rong Tong, Rachel Sternberg, Xujuan Yang, Lawrence W. Dobrucki, Luke B. Borst, Debra Kamstock, Ziyuan Song, William G. Helferich, Jianjun Cheng, and Timothy M. Fan. Proceedings of the National Academy of Sciences 2016 doi: 10.1073/pnas.1603316113

This paper is behind a paywall.

A grant for regenerating bones with injectable stem cell microspheres

I have a longstanding interest in bones partly due to my introduction to a skeleton in a dance course and to US artist Georgia O’Keeffe’s paintings. In any event, it’s been too long since I’ve featured any research on bones here.

This news comes from the UK’s University of Nottingham. A July 25, 2016 news item on Nanowerk announced a grant for stem cell research,

The University of Nottingham has secured £1.2m to develop injectable stem cell-carrying materials to treat and prevent fractures caused by osteoporosis and other bone-thinning diseases.

A July 25, 2016 University of Nottingham press release, which originated the news item, offers more information about the proposed therapy and the research project (Note: Links have been removed),

The experimental materials consist of porous microspheres produced from calcium phosphates – a key component in bones – to be filled with stem cells extracted from the patient.

The targeted therapy could offer a quick, easy and minimally-invasive treatment that is injected into areas considered to be at high-risk of fracture to promote bone regeneration.

The funding grant, from the National Institute for Health Research (NIHR i4i Challenge Award), also supports the development of a prototype delivery device to inject these stem cell loaded microspheres to the sites of interest.

In addition, project partners will investigate how well the materials stay in place once they have been injected inside the body.

Research leads, Dr Ifty Ahmed and Professor Brigitte Scammell explained that the aim was to develop a preventive treatment option to address the growing issue of fractures occurring due to bone-thinning diseases, which is exacerbated due to the worldwide ageing population.

Osteoporosis-related conditions affect some three million Britons, and cost the NHS over £1.73bn each year, according to the National Osteoporotic Society.

Dr Ahmed, from the Faculty of Engineering at The University of Nottingham, said, “We would advocate a national screening program, using a DEXA scan, which measures bone mineral density, to identify people at high risk of fracture due to osteoporosis.

“If we could strengthen these peoples bone before they suffered from fractures, using a simple injection procedure, it would save people the pain and trauma of broken bones and associated consequences such as surgery and loss of independence.”

The NIHR grant will also fund a Patient and Public Involvement study on the suitability of the technology, gauging the opinions and personal experience of people affected by osteoporosis as sufferers or carers, for example.

The project has already undertaken proof-of-concept work to test the feasibility of manufacturing the microsphere materials and lab work to ensure that stem cells attach and reside within these novel microsphere carriers.

The research is still at an early stage and the project team are working towards next phase pre-clinical trials.

This work reminded me of an unfinished piece of science fiction where I developed a society that had the ability to grow bone to replace lost limbs, replace lost bone matter, and restructure faces. I should get back to it one of these days. In the meantime, here’s an image of a microsphere,

A close-up of a injectable stem-cell carrying microsphere made of calcium phosphate which are injected to prevent and treat fractures caused by bone-thinning diseases. (Image: Ifty Ahmed; University of Nottingham)

A close-up of a injectable stem-cell carrying microsphere made of calcium phosphate which are injected to prevent and treat fractures caused by bone-thinning diseases. (Image: Ifty Ahmed; University of Nottingham)

One final note, fragile bones are no joke but there does seem to be a movement to diagnose more and more people with osteoporosis. Alan Cassels, in his July/August 2016 article for Common Ground magazine, points out that the guidelines for diagnosis have changed and more healthy people are being targeted,

… Americans, the experts tell us, are suffering an epidemic of osteoporosis. A new US osteoporosis guideline says that 72% of women over 65 are considered ‘diseased’ – a number which rises to 93% for those over 75 years old – and hence in need of drug therapy.

What is going on here?

Clearly, the only real ‘epidemic’ is the growing phenomenon where risks for disease are being turned into diseases, in and of themselves. In this racket, ‘high’ blood pressure, elevated cholesterol, low bone density, fluctuating blood sugars, high eyeball pressure and low testosterone, among other things, become worrying signs of chronic, lifelong conditions that demand attention and medication. As I’ve said in the past, “If you want to know why pharma is increasingly targeting healthy people with ‘preventive medicine,’ it’s because that’s where the money is.”

One thing all these risks-as-disease models have in common is they are shaped and supported by clinical practice guidelines. In these guidelines, doctors are told to measure their patients’ parameters. If your measurements are outside some preset levels deemed ‘high risk’ by the expert guidelines, you know what that means: more frequent trips to the pharmacy. The main downside of guidelines is they slap labels on people who aren’t sick and instill in physicians the constant idea their healthy patients are really disease-ridden.

But this is a good news story and if you haven’t sensed it, there’s a rising backlash against medical guidelines, mostly led by doctors, researchers and even some patients outraged at what they see going on. …

I don’t wish to generalize from the situation in the US to the situation in the UK. The medical systems and models are quite different but since at least some of my readership is from the US, I thought this digression might prove helpful. Regardless of where you live, it never hurts to ask questions.

Placenta-on-a-chip for research into causes for preterm birth

Preterm birth (premature baby) research has received a boost with this latest work from the University of Pennsylvania. A July 21, 2016 news item on phys.org tells us more,

Researchers at the University of Pennsylvania have developed the first placenta-on-a-chip that can fully model the transport of nutrients across the placental barrier.

A July 21, 2016 University of Pennsylvania news release, which originated the news item, provides more detail about the chip and the research (Note: Links have been removed),

The flash-drive-sized device contains two layers of human cells that model the interface between mother and fetus. Microfluidic channels on either side of those layers allow researchers to study how molecules are transported through, or are blocked by, that interface.

Like other organs-on-chips, such as ones developed to simulate lungs, intestines and eyes, the placenta-on-a-chip provides a unique capability to mimic and study the function of that human organ in ways that have not been possible using traditional tools.

Research on the team’s placenta-on-a-chip is part of a nationwide effort sponsored by the March of Dimes to identify causes of preterm birth and ways to prevent it. Prematurely born babies may experience lifelong, debilitating consequences, but the underlying mechanisms of this condition are not well understood due in part to the difficulties of experimenting with intact, living human placentae.

The research was led by Dan Huh, the Wilf Family Term Assistant Professor of Bioengineering in Penn’s School of Engineering and Applied Science, and Cassidy Blundell, a graduate student in the Huh lab. They collaborated with Samuel Parry, the Franklin Payne Professor of Obstetrics and Gynecology; Christos Coutifaris, the Nancy and Richard Wolfson Professor of Obstetrics and Gynecology in Penn’s Perelman School of Medicine; and Emily Su, assistant professor of obstetrics and gynecology in the Anschutz Medical School of the University of Colorado Denver.

The researchers’ placenta-on-a-chip is a clear silicone device with two parallel microfluidic channels separated by a porous membrane. On one side of those pores, trophoblast cells, which are found at the placental interface with maternal blood, are grown. On the other side are endothelial cells, found on the interior of fetal blood vessels. The layers of those two cell types mimic the placental barrier, the gatekeeper between the maternal and fetal circulatory systems.

“That barrier,” Blundell said, “mediates all transport between mother and fetus during pregnancy. Nutrients, but also foreign agents like viruses, need to be either transported by that barrier or stopped.”

“One of the most important function of the placental barrier is transport,” Huh said, “so it’s essential for us to mimic that functionality.”

In 2013, Huh and his collaborators at Seoul National University conducted a preliminary study to create a microfluidic device for culturing trophoblast cells and fetal endothelial cells. This model, however, lacked the ability to form physiological placental tissue and accurately simulate transport function of the placental barrier.

In their new study, the Penn researchers have demonstrated that the two layers of cells continue to grow and develop while inside the chip, undergoing a process known as “syncytialization.”

“The placental cells change over the course of pregnancy,” Huh said. “During pregnancy, the placental trophoblast cells actually fuse with one another to form an interesting tissue called syncytium. The barrier also becomes thinner as the pregnancy progresses, and with our new model we’re able to reproduce this change.

“This process is very important because it affects placental transport and was a critical aspect not represented in our previous model.”

The Penn team validated the new model by showing glucose transfer rates across this syncytialized barrier matched those measured in perfusion studies of donated human placentae.

While useful in providing this type of baseline, donated placental tissue can be problematic for doing many of the types of studies necessary for fully understanding the structure and function of the placenta, especially as it pertains to diseases and disorders.

“The placenta is arguably the least understood organ in the human body,” Huh said, “and much remains to be learned about how transport between mother and fetus works at the tissue, cellular and molecular levels. An isolated whole organ is an not ideal platform for these types of mechanistic studies.”

“Beyond the scarcity of samples,” Blundell said, “there’s a limited lifespan of how long the tissue remains viable, for only a few hours after delivery, and the system that is used to perfuse the tissue and perform transport studies is complex.”

While the placenta-on-a-chip is still in the early stages of testing, researchers at Penn and beyond are already planning to use it in studies on preterm birth.

“This effort,” Parry said, “was part of the much larger Prematurity Research Center here at Penn, one of five centers around the country funded by the March of Dimes to study the causes of preterm birth. The rate of preterm birth is about 10 to 11 percent of all pregnancies. That rate has not been decreasing, and interventions to prevent preterm birth have been largely unsuccessful.”

As part of a $10 million grant from the March of Dimes that established the Center, Parry and his colleagues research metabolic changes that may be associated with preterm birth using in vitro placental cell lines and ex vivo placental tissue. The grant also supported their work with the Huh lab to develop new tools that could model preterm birth-associated placental dysfunction and inform such research efforts.

“Since publishing this paper,” Samuel Parry said, “we’ve reached out to the principal investigators at the other four March of Dimes sites and offered to provide them this model to use in their experiments.”

“Eventually,” Huh said, “we hope to leverage the unique capabilities of our model to demonstrate the potential of organ-on-a-chip technology as a new strategy to innovate basic and translational research in reproductive biology and medicine.”

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

A microphysiological model of the human placental barrier by Cassidy Blundell, Emily R. Tess, Ariana S. R. Schanzer, Christos Coutifaris, Emily J. Su, Samuel Parry. and Dongeun Huh. Lab Chip, 2016, Advance Article DOI: 10.1039/C6LC00259E First published online 20 May 2016

I believe this paper is behind a paywall.

One final note, I thought this was a really well written news release.