Tag Archives: blood-brain barrier

Accelerated healing of the tissue in the blood-brain barrier with gelatin

It’s been a few years since my last brain and gelatin story (Dec. 24, 2014 posting: Gelatin nanoparticles for drug delivery after stroke) and this time they’re trying to make brain surgery easier and to reduce any attendant brain damage according to a Nov. 6, 2017 news item on ScienceDaily,

Researchers already know that gelatin-covered electrode implants cause less damage to brain tissue than electrodes with no gelatin coating. Researchers at the Neuronano Research Centre (NRC) at Lund University in Sweden have now shown that microglia, the brain’s cleansing cells, and the enzymes that the cells use in the cleaning process, change in the presence of gelatin.

“Knowledge about the beneficial effects of gelatin could be significant for brain surgery, but also in the development of brain implants,” say the researchers behind the study.

Our brains are surrounded by a blood brain barrier which protects the brain from harmful substances that could enter it via the bloodstream. When the barrier is penetrated, as in the case of biopsy or brain surgery for example, leaks can occur and cause serious inflammation. Researchers at the NRC have previously shown that gelatin accelerates brain tissue healing and reduces damage to nerve cells in the case of electrode implants, but only now are they starting to understand how.

A November 6, 2017 Lund University press release, which originated the news item, provides more details,

The researchers used sedated rats to investigate how the brain is repaired after an injury. Gelatin-coated needles were used in one group, and needles without gelatin in the other.

“The use of gelatin-coated needles reduced or eliminated the leakage of molecules (which normally don’t get through) through the blood brain barrier within twenty-four hours. Without gelatin, the leakage continued for up to three days”, says Lucas Kumosa, one of the researchers behind the study, which was recently published in the research journal Acta Biomaterialia.

Gelatin

The images in the left-hand column show the healing of an injury caused by a stainless steel needle. The images in the right-hand column show what the process looked like when the researchers used a gelatin-coated needle. Gelatin accelerated the healing process and reduced the leakage of blood-borne molecules capable of passing through the blood brain barrier into the brain and causing inflammation.

FEWER INFLAMMATORY CLEANING CELLS

When there is an injury to the brain, microglial cells – the brain’s cleaning cells – gather at the site. They clean up, but can also damage the nerve cell tissue through enzymes they release. In their study, the researchers observed a change in which cleaning cells moved towards the injury site.

“When we used gelatin, we saw only a small number of the inflammatory microglial cells. Instead, we observed cells of a different kind, that are anti-inflammatory, which we believe could be significant in accelerating healing”, explains Lucas Kumosa.

The hypothesis is that the potentially damaging enzymes are occupied with the gelatin instead.

“Gelatin is a protein and its decomposition releases amino-acids that we believe could promote the reconstruction of blood vessels and tissue”, explains Jens Schouenborg, professor of neurophysiology at Lund University.

SURGICAL SIGNIFICANCE

Research is currently underway on how electrodes implanted in the brain could be used in the treatment of various diseases, such as epilepsy or Parkinson’s. A major challenge has been to find ways of reducing damage to the area when using such implants.

“Although the research field of brain electrodes is promising, it has been a challenge to find solutions that don’t damage the brain tissue. Knowledge of how injuries heal faster with gelatin could therefore be significant for the development of surgical treatment as well,” says Jens Schouenborg.

The research is funded by the Knut and Alice Wallenberg Foundation, the Swedish Research Council, Lund University and the Sven-Olof Jansons livsverk Foundation.

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

Gelatin promotes rapid restoration of the blood brain barrier after acute brain injury by Lucas S. Kumosa, Valdemar Zetterberg, Jens Schouenborg. Acta Biomaterialia https://doi.org/10.1016/j.actbio.2017.10.020 Available online 14 October 2017

This paper is open access.

Locusts inspire new aerosol-based nanoparticle drug delivery system

Getting medication directly to the brain is a worldwide medical research goal and it seems that a team of scientists at the Washington University at St. Louis (WUSTL) has taken a step forward to accomplishing the goal. From an April 12, 2017 news item on ScienceDaily,

Delivering life-saving drugs directly to the brain in a safe and effective way is a challenge for medical providers. One key reason: the blood-brain barrier, which protects the brain from tissue-specific drug delivery. Methods such as an injection or a pill aren’t as precise or immediate as doctors might prefer, and ensuring delivery right to the brain often requires invasive, risky techniques.

A team of engineers from Washington University in St. Louis has developed a new nanoparticle generation-delivery method that could someday vastly improve drug delivery to the brain, making it as simple as a sniff.

“This would be a nanoparticle nasal spray, and the delivery system could allow a therapeutic dose of medicine to reach the brain within 30 minutes to one hour,” said Ramesh Raliya, research scientist at the School of Engineering & Applied Science.

Caption: Engineers at Washington University have discovered a new technique that could change drug delivery to the brain. They were able to apply a nanoparticle aerosol spray to the antenna of locusts, then track the nanoparticles as they traveled through the olfactory nerves, crossed the blood-brain barrier and accumulated in the brain. This new, non-invasive approach could someday make drug delivery as simple as a sniff for patients with brain injuries or tumors.

Credit: Washington University in St. Louis

An April 12, 2017 WUSTL news release by Erika Ebsworth-Goold (also on EurekAlert), which originated the news item, describes the work in more detail,

“The blood-brain barrier protects the brain from foreign substances in the blood that may injure the brain,” Raliya said. “But when we need to deliver something there, getting through that barrier is difficult and invasive. Our non-invasive technique can deliver drugs via nanoparticles, so there’s less risk and better response times.”

The novel approach is based on aerosol science and engineering principles that allow the generation of monodisperse nanoparticles, which can deposit on upper regions of the nasal cavity via diffusion. Working with Assistant Vice Chancellor Pratim Biswas, chair of the Department of Energy, Environmental & Chemical Engineering and the Lucy & Stanley Lopata Professor, Raliya developed an aerosol consisting of gold nanoparticles of controlled size, shape and surface charge. The nanoparticles were tagged with fluorescent markers, allowing the researchers to track their movement.

Next, Raliya and biomedical engineering postdoctoral fellow Debajit Saha exposed locusts’ antennae to the aerosol, and observed the nanoparticles travel from the antennas up through the olfactory nerves. Due to their tiny size, the nanoparticles passed through the brain-blood barrier, reaching the brain and suffusing it in a matter of minutes.

The team tested the concept in locusts because the blood-brain barriers in the insects and humans have anatomical similarities, and the researchers consider going through the nasal regions to neural pathways as the optimal way to access the brain.

“The shortest and possibly the easiest path to the brain is through your nose,” said Barani Raman, associate professor of biomedical engineering. “Your nose, the olfactory bulb and then olfactory cortex: two relays and you’ve reached the cortex. The same is true for invertebrate olfactory circuitry, although the latter is a relatively simpler system, with supraesophageal ganglion instead of an olfactory bulb and cortex.”

To determine whether or not the foreign nanoparticles disrupted normal brain function, Saha examined the physiological response of olfactory neurons in the locusts before and after the nanoparticle delivery. Several hours after the nanoparticle uptake, no noticeable change in the electrophysiological responses was detected.

“This is only a beginning of a cool set of studies that can be performed to make nanoparticle-based drug delivery approaches more principled,” Raman said.

The next phase of research involves fusing the gold nanoparticles with various medicines, and using ultrasound to target a more precise dose to specific areas of the brain, which would be especially beneficial in brain-tumor cases.

“We want to drug target delivery within the brain using this non-invasive approach,” Raliya said.  “In the case of a brain tumor, we hope to use focused ultrasound so we can guide the particles to collect at that particular point.”

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

Non-invasive aerosol delivery and transport of gold nanoparticles to the brain by Ramesh Raliya, Debajit Saha, Tandeep S. Chadha, Baranidharan Raman, & Pratim Biswas. Scientific Reports 7, Article number: 44718 (2017) doi:10.1038/srep44718 Published online: 16 March 2017

This paper is open access.

I featured another team working on delivering drugs directly to the brain via the olfactory system, except their nanoparticles were gelatin and they were testing stroke medication on rats, in my Sept. 24, 2014 posting.

Nanotechnology and cybersecurity risks

Gregory Carpenter has written a gripping (albeit somewhat exaggerated) piece for Signal, a publication of the  Armed Forces Communications and Electronics Association (AFCEA) about cybersecurity issues and  nanomedicine endeavours. From Carpenter’s Jan. 1, 2016 article titled, When Lifesaving Technology Can Kill; The Cyber Edge,

The exciting advent of nanotechnology that has inspired disruptive and lifesaving medical advances is plagued by cybersecurity issues that could result in the deaths of people that these very same breakthroughs seek to heal. Unfortunately, nanorobotic technology has suffered from the same security oversights that afflict most other research and development programs.

Nanorobots, or small machines [or nanobots[, are vulnerable to exploitation just like other devices.

At the moment, the issue of cybersecurity exploitation is secondary to making nanobots, or nanorobots, dependably functional. As far as I’m aware, there is no such nanobot. Even nanoparticles meant to function as packages for drug delivery have not been perfected (see one of the controversies with nanomedicine drug delivery described in my Nov. 26, 2015 posting).

That said, Carpenter’s point about cybersecurity is well taken since security features are often overlooked in new technology. For example, automated banking machines (ABMs) had woefully poor (inadequate, almost nonexistent) security when they were first introduced.

Carpenter outlines some of the problems that could occur, assuming some of the latest research could be reliably  brought to market,

The U.S. military has joined the fray of nanorobotic experimentation, embarking on revolutionary research that could lead to a range of discoveries, from unraveling the secrets of how brains function to figuring out how to permanently purge bad memories. Academia is making amazing advances as well. Harnessing progress by Harvard scientists to move nanorobots within humans, researchers at the University of Montreal, Polytechnique Montreal and Centre Hospitalier Universitaire Sainte-Justine are using mobile nanoparticles inside the human brain to open the blood-brain barrier, which protects the brain from toxins found in the circulatory system.

A different type of technology presents a risk similar to the nanoparticles scenario. A DARPA-funded program known as Restoring Active Memory (RAM) addresses post-traumatic stress disorder, attempting to overcome memory deficits by developing neuroprosthetics that bridge gaps in an injured brain. In short, scientists can wipe out a traumatic memory, and they hope to insert a new one—one the person has never actually experienced. Someone could relish the memory of a stroll along the French Riviera rather than a terrible firefight, even if he or she has never visited Europe.

As an individual receives a disruptive memory, a cyber criminal could manage to hack the controls. Breaches of the brain could become a reality, putting humans at risk of becoming zombie hosts [emphasis mine] for future virus deployments. …

At this point, the ‘zombie’ scenario Carpenter suggests seems a bit over-the-top but it does hearken to the roots of the zombie myth where the undead aren’t mindlessly searching for brains but are humans whose wills have been overcome. Mike Mariani in an Oct. 28, 2015 article for The Atlantic has presented a thought-provoking history of zombies,

… the zombie myth is far older and more rooted in history than the blinkered arc of American pop culture suggests. It first appeared in Haiti in the 17th and 18th centuries, when the country was known as Saint-Domingue and ruled by France, which hauled in African slaves to work on sugar plantations. Slavery in Saint-Domingue under the French was extremely brutal: Half of the slaves brought in from Africa were worked to death within a few years, which only led to the capture and import of more. In the hundreds of years since, the zombie myth has been widely appropriated by American pop culture in a way that whitewashes its origins—and turns the undead into a platform for escapist fantasy.

The original brains-eating fiend was a slave not to the flesh of others but to his own. The zombie archetype, as it appeared in Haiti and mirrored the inhumanity that existed there from 1625 to around 1800, was a projection of the African slaves’ relentless misery and subjugation. Haitian slaves believed that dying would release them back to lan guinée, literally Guinea, or Africa in general, a kind of afterlife where they could be free. Though suicide was common among slaves, those who took their own lives wouldn’t be allowed to return to lan guinée. Instead, they’d be condemned to skulk the Hispaniola plantations for eternity, an undead slave at once denied their own bodies and yet trapped inside them—a soulless zombie.

I recommend reading Mariani’s article although I do have one nit to pick. I can’t find a reference to brain-eating zombies until George Romero’s introduction of the concept in his movies. This Zombie Wikipedia entry seems to be in agreement with my understanding (if I’m wrong, please do let me know and, if possible, provide a link to the corrective text).

Getting back to Carpenter and cybersecurity with regard to nanomedicine, while his scenarios may seem a trifle extreme it’s precisely the kind of thinking you need when attempting to anticipate problems. I do wish he’d made clear that the technology still has a ways to go.

Titanium dioxide nanoparticles and the brain

This research into titanium dioxide nanoparticles and possible effects on your brain should they pass the blood-brain barrier comes from the University of Nebraska-Lincoln (US) according to a Dec. 15, 2015 news item on Nanowerk (Note: A link has been removed),

Even moderate concentrations of a nanoparticle used to whiten certain foods, milk and toothpaste could potentially compromise the brain’s most numerous cells, according to a new study from the University of Nebraska-Lincoln (Nanoscale, “Mitochondrial dysfunction and loss of glutamate uptake in primary astrocytes exposed to titanium dioxide nanoparticles”).

A Dec. 14, 2015 University of Nebraska-Lincoln news release, which originated the news item, provides more detail (Note: Links have been removed),

The researchers examined how three types of titanium dioxide nanoparticles [rutile, anatase, and commercially available P25 TiO2 nanoparticles], the world’s second-most abundant nanomaterial, affected the functioning of astrocyte cells. Astrocytes help regulate the exchange of signal-carrying neurotransmitters in the brain while also supplying energy to the neurons that process those signals, among many other functions.

The team exposed rat-derived astrocyte cells to nanoparticle concentrations well below the extreme levels that have been shown to kill brain cells but are rarely encountered by humans. At the study’s highest concentration of 100 parts per million, or PPM, two of the nanoparticle types still killed nearly two-thirds of the astrocytes within a day. That mortality rate fell to between half and one-third of cells at 50 PPM, settling to about one-quarter at 25 PPM.

Yet the researchers found evidence that even surviving cells are severely impaired by exposure to titanium dioxide nanoparticles. Astrocytes normally take in and process a neurotransmitter called glutamate that plays wide-ranging roles in cognition, memory and learning, along with the formation, migration and maintenance of other cells.

When allowed to accumulate outside cells, however, glutamate becomes a potent toxin that kills neurons and may increase the risk of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. The study reported that one of the nanoparticle types reduced the astrocytes’ uptake of glutamate by 31 percent at concentrations of just 25 PPM. Another type decreased that uptake by 45 percent at 50 PPM.

The team further discovered that the nanoparticles upset the intricate balance of protein dynamics occurring within astrocytes’ mitochondria, the cellular organelles that help regulate energy production and contribute to signaling among cells. Titanium dioxide exposure also led to other signs of mitochondrial distress, breaking apart a significant proportion of the mitochondrial network at 100 PPM.

“These events are oftentimes predecessors of cell death,” said Oleh Khalimonchuk, a UNL assistant professor of biochemistry who co-authored the study. “Usually, people are looking at those ultimate consequences, but what happens before matters just as much. Those little damages add up over time. Ultimately, they’re going to cause a major problem.”

Khalimonchuk and fellow author Srivatsan Kidambi, assistant professor of chemical and biomolecular engineering, cautioned that more research is needed to determine whether titanium dioxide nanoparticles can avoid digestion and cross the blood-brain barrier that blocks the passage of many substances. [emphasis mine]

However, the researchers cited previous studies that have discovered these nanoparticles in the brain tissue of animals with similar blood-brain barriers. [emphasis mine] The concentrations of nanoparticles found in those specimens served as a reference point for the levels examined in the new study.

“There’s evidence building up now that some of these particles can actually cross the (blood-brain) barrier,” Khalimonchuk said. “Few molecules seem to be able to do so, but it turns out that there are certain sites in the brain where you can get this exposure.”

Kidambi said the team hopes the study will help facilitate further research on the presence of nanoparticles in consumer and industrial products.

“We’re hoping that this study will get some discussion going, because these nanoparticles have not been regulated,” said Kidambi, who also holds a courtesy appointment with the University of Nebraska Medical Center. “If you think about anything white – milk, chewing gum, toothpaste, powdered sugar – all these have nanoparticles in them.

“We’ve found that some nanoparticles are safe and some are not, so we are not saying that all of them are bad. Our reasoning is that … we need to have a classification of ‘safe’ versus ‘not safe,’ along with concentration thresholds (for each type). It’s about figuring out how the different forms affect the biology of cells.

I notice the researchers are being careful about alarming anyone unduly while emphasizing the importance of this research. For anyone curious enough to read the paper, here’s a link to and a citation for it,

Mitochondrial dysfunction and loss of glutamate uptake in primary astrocytes exposed to titanium dioxide nanoparticles by Christina L. Wilson, Vaishaali Natarajan, Stephen L. Hayward, Oleh Khalimonchuk and   Srivatsan Kidambi. Nanoscale, 2015,7, 18477-18488 DOI: 10.1039/C5NR03646A First published online 31 Jul 2015

This is paper is open access although you may need to register on the site.

Final comment, I note this was published online way back in July 2015. Either the paper version of the journal was just published and that’s what’s being promoted or the media people thought they’d try to get some attention for this work by reissuing the publicity. Good on them! It’s hard work getting people to notice things when there is so much information floating around.

Université de Montréal (Canada) and nanobots breech blood-brain barrier to deliver drugs to the brain

In the spirit of full disclosure, the March 25, 2014 news item on ScienceDaily describing the research about breeching the blood-brain barrier uses the term nanorobotic agents rather than nanobots, a term which makes my headline a lot catchier although less accurate. Getting back to the research,

Magnetic nanoparticles can open the blood-brain barrier and deliver molecules directly to the brain, say researchers from the University of Montreal, Polytechnique Montréal, and CHU Sainte-Justine. This barrier runs inside almost all vessels in the brain and protects it from elements circulating in the blood that may be toxic to the brain. The research is important as currently 98% of therapeutic molecules are also unable to cross the blood-brain barrier.

“The barrier is temporary [sic] opened at a desired location for approximately 2 hours by a small elevation of the temperature generated by the nanoparticles when exposed to a radio-frequency field,” explained first author and co-inventor Seyed Nasrollah Tabatabaei. “Our tests revealed that this technique is not associated with any inflammation of the brain. This new result could lead to a breakthrough in the way nanoparticles are used in the treatment and diagnosis of brain diseases,” explained the co-investigator, Hélène Girouard. “At the present time, surgery is the only way to treat patients with brain disorders. Moreover, while surgeons are able to operate to remove certain kinds of tumors, some disorders are located in the brain stem, amongst nerves, making surgery impossible,” added collaborator and senior author Anne-Sophie Carret.

A March 25, 2015 University of Montreal news release (also on EurekAlert), which originated the news item, notes that the technique was tested or rats or mice (murine model) and explains how the technology breeches the blood-brain barrier,

Although the technology was developed using murine models and has not yet been tested in humans, the researchers are confident that future research will enable its use in people. “Building on earlier findings and drawing on the global effort of an interdisciplinary team of researchers, this technology proposes a modern version of the vision described almost 40 years ago in the movie Fantastic Voyage, where a miniature submarine navigated in the vascular network to reach a specific region of the brain,” said principal investigator Sylvain Martel. In earlier research, Martel and his team had managed to manipulate the movement of nanoparticles through the body using the magnetic forces generated by magnetic resonance imaging (MRI) machines.

To open the blood-brain barrier, the magnetic nanoparticles are sent to the surface of the blood-brain barrier at a desired location in the brain. Although it was not the technique used in this study, the placement could be achieved by using the MRI technology described above. Then, the researchers generated a radio-frequency field. The nanoparticles reacted to the radio-frequency field by dissipating heat thereby creating a mechanical stress on the barrier. This allows a temporary and localized opening of the barrier for diffusion of therapeutics into the brain.

The technique is unique in many ways. “The result is quite significant since we showed in previous experiments that the same nanoparticles can also be used to navigate therapeutic agents in the vascular network using a clinical MRI scanner,” Martel remarked. “Linking the navigation capability with these new results would allow therapeutics to be delivered directly to a specific site of the brain, potentially improving significantly the efficacy of the treatment while avoiding systemic circulation of toxic agents that affect healthy tissues and organs,” Carret added. “While other techniques have been developed for delivering drugs to the blood-brain barrier, they either open it too wide, exposing the brain to great risks, or they are not precise enough, leading to scattering of the drugs and possible unwanted side effect,” Martel said.

Although there are many hurdles to overcome before the technology can be used to treat humans, the research team is optimistic. “Although our current results are only proof of concept, we are on the way to achieving our goal of developing a local drug delivery mechanism that will be able to treat oncologic, psychiatric, neurological and neurodegenerative disorders, amongst others,” Carret concluded.

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

Remote control of the permeability of the blood–brain barrier by magnetic heating of nanoparticles: A proof of concept for brain drug delivery by Seyed Nasrollah Tabatabaei, Hélène Girouard, Anne-Sophie Carret, and Sylvain Martel.Journal of Controlled Release, Volume 206, 28 May 2015, Pages 49–57,  DOI: 10.1016/j.jconrel.2015.02.027  Available online 25 February 2015

This paper is behind a paywall.

For anyone unfamiliar with French, University of Montreal is Université de Montréal.

US Federal Bureau of Investigation talked nano at the University of Notre Dame

A Sept. 2012 US Federal Bureau of Investigation (FBI) workshop held at the University of Notre Dame (Indiana) has spawned an article about ‘dual-use’ nanotechnology by Professor Kathleen Eggleson of the University of Notre Dame’s Center for Nano Science and Technology, from the Jan. 25, 2013 news release on EurekAlert,

Every day scientists learn more about how the world works at the smallest scales. While this knowledge has the potential to help others, it’s possible that the same discoveries can also be used in ways that cause widespread harm.

A new article in the journal Nanomedicine, born out of a Federal Bureau of Investigation workshop held at the University of Notre Dame in September 2012, tackles this complex “dual-use” aspect of nanotechnology research.

Here are the specifics,

The report examines the potential for nano-sized particles (which are measured in billionths of a meter) to breach the blood-brain barrier, the tightly knit layers of cells that afford the brain the highest level of protection—from microorganisms, harmful molecules, etc.—in the human body. Some neuroscientists are purposefully engineering nanoparticles that can cross the blood-brain barrier (BBB) so as to deliver medicines in a targeted and controlled way directly to diseased parts of the brain.

At the same time, the report notes, “nanoparticles designed to cross the BBB constitute a serious threat…in the context of combat.” For example, it is theorized that “aerosol delivery” of some nano-engineered agent in “a crowded indoor space” could cause serious harm to many people at once.

The problem of dual-use research was highlighted last year when controversy erupted over the publication of findings that indicate how, with a handful modifications, the H5N1 influenza virus (“bird flu”) can be altered in a way that would enable it to be transmitted between mammalian populations.

After a self-imposed one-year moratorium on this research, several laboratories around the world announced that they will restart the work in early 2013.

The FBI is actively responding to these developments in the scientific community.

This is what the FBI and Eggleson have to say about the relation between science and law enforcement,

“The law enforcement-security community seeks to strengthen the existing dialogue with researchers,” William So of the FBI’s Biological Countermeasures Unit says in the study.

“Science flourishes because of the open and collaborative atmosphere for sharing and discussing ideas. The FBI believes this model can do the same for our two communities…[and] create effective safeguards for science and national interests.”

The scientists and engineers who conduct nanoscale research have the ability and responsibility to consider the public safety aspects of their research and to act to protect society when necessary, argues Eggleson.

“The relationship between science and society is an uneasy one, but it is undeniable on the whole and not something any individual can opt out of in the name of progress for humanity’s benefit,” she says.

“Thought about dual-use, and action when appropriate, is inherent to socially responsible practice of nanobiomedical science.”

Here’s a citation and link to Eggleson’s article,

Dual-use nanoresearch of concern: Recognizing threat and safeguarding the power of nanobiomedical research advances in the wake of the H5N1 controversy by Kathleen Eggleson. In Nanomedicine: Nanotechnology, Biology and Medicine (article in press) advance article published online 17 January 2013.

This article is behind a paywall. There are two abstracts, one is a standard text-based abstract and the other is a graphical abstract,

Graphical Abstract 

From deliberate translocation of nanoparticles across the blood-brain barrier to virulence factors in the genomic era, this article argues that issues of dual-use or DURC are pertinent to the broader scientific community. Awareness of potential misuse, and communicative action when warranted, is of particular importance for nanobiomedical researchers.

GraphicalAbstractjpg