Investigating the optimum size of nanoparticles for their delivery into the brain assisted by focused ultrasound-induced blood–brain barrier opening

 For when our researchers find a drug they need to get across the blood brain barrier. Assuming that our fucking failures of stroke associations  can remember this when researchers need it.

Investigating the optimum size of nanoparticles for their delivery into the brain assisted by focused ultrasound-induced blood–brain barrier opening

• Seiichi Ohta,
• Emi Kikuchi,
• Ayumu Ishijima,
• Takashi Azuma,
• Ichiro Sakuma &
• Taichi Ito 

Scientific Reports volume 10, Article number: 18220 (2020) Cite this article

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Abstract

The blood–brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies. The widening of BBB tight junctions via focused ultrasound (FUS) offers a promising approach for enhancing the delivery of nanoparticles into the brain. However, there is currently an insufficient understanding of how nanoparticles pass through the opened BBB gaps. Here we investigated the size-dependence of nanoparticle delivery into the brain assisted by FUS-induced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. For 3- and 15-nm AuNPs, FUS exposure significantly increased permeation across an in vitro BBB model by up to 9.5 times, and the permeability was higher with smaller diameter. However, in vivo transcranial FUS exposure in mice demonstrated that smaller particles were not necessarily better for delivery into the brain. Medium-sized (15 nm) AuNPs showed the highest delivery efficiency (0.22% ID), compared with 3- and 120-nm particles. A computational model suggested that this optimum size was determined by the competition between their permeation through opened BBB gaps and their excretion from blood. Our results would greatly contribute to designing nanoparticles for their delivery into the brain for the treatment of central nervous system diseases.

Introduction

Nanoparticles have attracted global attention in the biomedical field. It has been revealed that their interaction with cells and/or tissues can be tailored through nanoparticle design, such as their size, shape, and surface chemistry¹. Combined with the advances in nanoparticle functionalization methods, this has opened the way for various biomedical applications of nanoparticles, including drug delivery, imaging, and therapies^2,3. However, despite the promise of nanoparticle-based systems, their translation to clinical use remains a challenge, mainly due to the low efficiency of their delivery to target sites^4,5. Various factors have been proposed as hampering nanoparticle delivery, including uptake by the reticuloendothelial system (RES), restricted diffusion in dense extracellular matrix (ECM), resistance by interstitial pressure, and clearance via the renal system^6,7,8.

The brain is one of the most difficult target organs to deliver nanoparticles to because of the existence of the blood–brain barrier (BBB). The BBB is composed of brain endothelial cells attached to a continuous basement membrane and linked together by tight junctions that prevents foreign substances from entering into the brain⁹. Even small molecular drugs can barely cross the BBB, which is a major limitation for the treatment of central nervous system (CNS) diseases, such as Alzheimer’s disease and Parkinson’s disease; diseases whose prevalence is rapidly increasing as societies around the world are aging. In the case of nanoparticles, the restriction of their permeation across the BBB is even more pronounced because of their relatively large size. Although various delivery methods have been attempted, e.g., using receptor-mediated endocytosis^10,11,12, transcytosis^13,14, or transporters^15,16, the efficiency of delivering nanoparticles into the brain is insufficient to fully exploit their therapeutic and diagnostic potential. For example, using transferrin receptor-targeted nanoparticles is one of the most widely used strategies to get nanoparticles across the BBB, but it typically results in < 0.1% delivery efficiency to the brain¹⁰.

Focused ultrasound (FUS) in combination with the administration of microbubbles (MBs) is an emerging technique being investigated to enhance the permeation of therapeutics across the BBB in a noninvasive, localized, and transient manner¹⁷. FUS induces inertial or stable cavitation with MBs that exerts a mechanical force onto capillary walls, leading to a temporary opening of the BBB via the widening of tight junctions^17,18,19. The enhanced delivery of small molecular drugs^20,21, oligonucleotides^22,23, and antibodies^24,25,26 into the brain via FUS-induced BBB opening has been demonstrated in vivo. In addition, clinical trials are now being conducted into the FUS-assisted delivery of small molecular drugs into gliomas^27,28. This technology could provide a promising strategy for improving the efficiency of nanoparticle delivery to the brain, although there are still only a limited number of reports on its application for nanoparticles^{29,30,31,32,33,34}.

To employ FUS-induced BBB opening for nanoparticle delivery, a question that must be addressed is how the size of nanoparticles can affect the enhanced permeation through opened BBB gaps. It is expected that the optimum nanoparticle design for this delivery mechanism would be different from that usually employed for enhanced permeation and retention (EPR)-based delivery strategies for tumors, in which nanoparticles are extravasated from naturally leaky blood vessels¹. However, although some previous studies investigated the effect of the size of nanoparticles, such as liposomes, on this strategy³⁴, the mechanism still needs to be clarified, especially in single to sub-hundred nanometer range. Here, we explored the effect of nanoparticle size on their delivery into the brain assisted by FUS-induced BBB opening, using polyethylene glycol (PEG)-coated gold nanoparticles (AuNPs) of different sizes, 3 to 120 nm, as a model (Fig. 1). An in vitro BBB model capable of FUS exposure was developed to examine the size-dependent permeation behavior of these particles. The size-dependent delivery of AuNPs into the brain was further investigated in vivo via transcranial FUS exposure in mice. Based on the obtained results, a kinetic model was proposed to estimate the optimum nanoparticle size for delivery into the brain assisted by FUS-induced BBB opening.

 

 

Historic breakthrough: WVU Rockefeller Neuroscience team first to use ultrasound to treat Alzheimer's

Well shit, this is probably based on this earlier research. Is it the gas used inside the bubbles rather than the ultrasound? Maybe this:the xenon gas in the bubbles.

Alzheimer’s breakthrough uses ultrasound technology March 2015

Historic breakthrough: WVU Rockefeller Neuroscience team first to use ultrasound to treat Alzheimer's 

MORGANTOWN — World-leading brain experts at West Virginia University’s Rockefeller Neuroscience Institute are celebrating the historic breakthrough Alzheimer patients around the globe have been awaiting.

“For Alzheimer’s, there’s not that many treatments available, despite hundreds of clinical trials over the past two decades and billions of dollars spent,” said Dr. Ali R. Rezai, a neurosurgeon at WVU who led the team of investigators that successfully performed a phase II trial using focused ultrasound to treat a patient with early stage Alzheimer’s.

The WVU team tested the innovative treatment in collaboration with INSIGHTEC, an Israeli medical technology company. Earlier this year, INSIGHTEC was approved by the U.S. Food and Drug Administration to begin a phase II clinical trial of the procedure, and selected the WVU Rockefeller Neuroscience Institute as the first site in the United States for that trial.

Last summer, researchers at Sunnybrook Health Sciences Centre in Toronto reported the results of a phase I safety trial showing they could reversibly open the blood-brain barrier in Alzheimer’s patients.

“And when we put a different frequency of ultrasound on the bubbles, they start oscillating,” he said.

The reaction opens up the brain-blood barrier — a nearly impenetrable shield between the brain’s blood vessels and cells that make up brain tissue.

“It’s protected on one end for us to function but also prevents larger molecules or chemotherapy or medications or anti-bodies or immune system cells or amino therapy or stem cells to get in,” he said.

In this case, the West Virginia team targeted the hippocampus and the memory and cognitive centers of the brain that are impacted by plaques found in patients with Alzheimer’s.

“Plaques are these clusters of proteins that accumulate and they block-up the brain’s connectivity,” he said. “In animal studies it showed that these plaques are cleared with ultrasound technology.

The first patient, a person Rezai called a pioneer and hero, is West Virginia health care worker and former WVU Children’s Hospital Neonatal Intensive Care Unit nurse Judi Polak.

“I think that with Alzheimer’s there’s so much in the unknown and I’ve been with H

ealth Science for a long time and I understand that we need to be able to step forward and look into the future,” Polak said.

But getting to this point was a long journey beginning five years ago when she was first diagnosed with early-onset Alzheimer’s.

“That took me a while to deal with,” Polak admitted while sitting with her husband of 36 years, Mark Polak. “It was hard to say that I have Alzheimer’s. I didn’t want to be the person who felt sorry for myself and so we looked at clinical trials as a way to help not only me but other people too.”

Early-onset Alzheimer’s is an uncommon form of dementia that strikes people younger than age 65. Of all the people who have Alzheimer’s disease, according to research conducted by the Mayo Clinic, about 5 percent develop symptoms before age 65.

Judi Polak’s willingness to be the center of a study or research experiment in hopes of finding a cure for Alzheimer’s took an emotional toll, Mark Polak said, referring to a controlled drug-placebo trial at the University of Pittsburgh several years ago.

Guess what, the drug didn’t work,” he said with contempt. “Just like every drug that has been tried doesn’t work.”

However, Judi Polak’s patience and persistence appears to have paid off. The procedure, which lasted three hours, safely and successfully opened her blood-brain barrier for a record 36 hours.

“It was opened longer than they expected,” Mark Polak said. “They were actually, I think both excited and scared. The team was ecstatic.”

One member of the team Mark Polak mentioned is Dr. Jeff Carpenter, a professor of neurology, neurosurgery and an interventional neuroradiologist at WVU.

Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain

For whenever we do have drugs that need to be delivered to the brain. Assuming our researchers read other research. 
https://www.ncbi.nlm.nih.gov/pubmed/30009893

Ye D¹, Zhuang X², Yue Y³, Raliya R⁴, Biswas P⁴, Taylor S⁵, Tai YC², Rubin JB⁶, Liu Y², Chen H⁷.

Author information

Abstract

Focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) is a new brain drug delivery technique. FUSIN utilizes the nasal route for direct nose-to-brain drug administration, thereby bypassing the blood-brain barrier (BBB) and minimizing systemic exposure. It also uses FUS-induced microbubble cavitation to enhance transport of intranasally (IN) administered agents to the FUS-targeted brain location. Previous studies have provided proof-of-concept data showing the feasibility of FUSIN to deliver dextran and the brain-derived neurotrophic factor to the caudate putamen of mouse brains. The objective of this study was to evaluate the biodistribution of IN administered gold nanoclusters (AuNCs) and assess the feasibility and short-term safety of FUSIN for the delivery of AuNCs to the brainstem. Three experiments were performed. First, the whole-body biodistribution of IN administered ⁶⁴Cu-alloyed AuNCs (⁶⁴Cu-AuNCs) was assessed using in vivo positron emission tomography/computed tomography (PET/CT) and verified with ex vivo gamma counting. Control mice were intravenously (IV) injected with the ⁶⁴Cu-AuNCs. Second, ⁶⁴Cu-AuNCs and Texas red-labeled AuNCs (TR-AuNCs) were used separately to evaluate FUSIN delivery outcome in the brain. ⁶⁴Cu-AuNCs or TR-AuNCs were administered to mice through the nasal route, followed by FUS sonication at the brainstem in the presence of systemically injected microbubbles. The spatial distribution of ⁶⁴Cu-AuNCs and TR-AuNCs were examined by autoradiography and fluorescence microscopy of ex vivo brain slices, respectively. Third, histological analysis was performed to evaluate any potential histological damage to the nose and brain after FUSIN treatment. The experimental results revealed that IN administration induced significantly lower ⁶⁴Cu-AuNCs accumulation in the blood, lungs, liver, spleen, kidney, and heart compared with IV injection. FUSIN enhanced the delivery of ⁶⁴Cu-AuNCs and TR-AuNCs at the FUS-targeted brain region compared with IN delivery alone. No histological-level tissue damage was detected in the nose, trigeminal nerve, and brain. These results suggest that FUSIN is a promising technique for noninvasive, spatially targeted, and safe delivery of nanoparticles to the brain with minimal systemic exposure.

KEYWORDS:

Blood-brain barrier; Brain drug delivery; Brainstem; Focused ultrasound; Intranasal delivery; Nanoparticle; Positron emission tomography

PMID:

30009893

DOI:

10.1016/j.jconrel.2018.07.020

Microbubbles and Ultrasound Open the Blood-Brain Barrier to Administer Drugs

For when we actually get drugs that can help improve neuroplasticity and neurogenesis.  I wonder what researcher is working on kickstarting neuroplasticity and neurogenesis? A great stroke association would know exactly what stroke research is going on, who funded it, status, and what part of the stroke strategy it is addressing. That is what these employees should be doing instead of writing press releases and setting up awareness crap like marathon teams. 

Microbubbles and Ultrasound Open the Blood-Brain Barrier to Administer Drugs

Summary: Researchers have developed a new method that could allow for the delivery of drugs across the blood-brain barrier.
Source: FECYT.
The impassable blood-brain barrier prevents microorganisms from entering our brain, however it also blocks medicines that could help treat Parkinson’s, Alzheimer’s and other neurodegenerative diseases. Now, a Spanish physicist and other researchers at the University of Columbia (USA) have succeeded in embedding these substances in tiny lipid bubbles, in such a way that ultrasound can be used to release them into the specific area of the brain where they are needed.
A defence mechanism as sophisticated as the blood-brain barrier, which protects our brains from viruses, bacteria and fungi that filter into our blood, can become our worst enemy when it comes to treating certain illnesses. This “wall” is an impassable obstacle for 98% of drugs, which it treats as pathogens and blocks from passing from patients’ bloodstream into their brain.
Scientists have for years been trying to break through this natural barrier, but almost none of the techniques developed to date (such as intracranial injections, gene therapy and the chemical modification of the medicine) have been able to transport the drug to where it is needed, without it affecting the rest of the body and with the action being reversible (where the barrier opens and closes very rapidly).
The only method that has been capable of overcoming all these conditions is based on the use of ultrasound (sound whose frequency is higher than the range of human hearing) after drugs are administered with an independent intravenous injection of lipid-coated gas microbubbles (which are completely innocuous).
Like a laser, the ultrasound is focused on a specific region of the brain, where the microbubbles begin to oscillate and increase in size due to their interaction with the acoustic waves. When these tiny bubbles reach the critical size of 8 microns, the blood-brain barrier near to them opens, allowing the medicine circulating in the blood to pass through.
This technique has been used successfully for over ten years, but it does have a disadvantage: the drugs move through the entire circulatory system and reach organs where they are not needed, causing adverse effects. However, it appears that scientists at the Ultrasound Elasticity Imaging Laboratory (UEIL) at New York’s Columbia University have found the solution.
“We’ve made a step forward by incorporating the substance we’re interested in into the lipid coating of the microbubbles. This makes the substance stay adhered to the microbubbles and prevents it circulating freely through the body,” SINC was told by the physicist Carlos Sierra, a UEIL researcher who receives a grant from A Coruña’s Berrié Foundation and the lead author of the paper on this new advance, published in the Journal of Cerebral Blood Flow and Metabolism.
With this technique, the microbubbles flow through the entire body with the potential drug adhered to them, but only release it in the area of the brain where it is required, where the effect of the ultrasound causes them to rupture and open the blood-brain barrier. “It does all this, while being non-invasive, reversible and completely safe,” Sierra stresses.
From experiments on mice to human trials
So far, the researchers have proven the efficacy of their technique on mice. They chose a fluorescent molecule called 5-dodecanoylaminofluorescein and confirmed that it was reaching the brain without affecting other parts of the animal. At the same time, they identified the acoustic pressure thresholds from which the substance is guaranteed to reach its target in vivo.

Microbubbles with the fluorescent substance in their lipid coating, from which the effect of the ultrasound causes them to be released into the desired area of the brain.

“Defining these parameters means we can think about how to transfer the technique to human patients, although it has to be tested on monkeys first,” the researcher explains, adding that “it could be applied to diseases like Parkinson’s, Alzheimer’s, Huntington’s diseases, brain tumours, strokes, multiple sclerosis and amyotrophic lateral sclerosis, where we expect to see a very significant rise in the efficacy of treatment and a considerable reduction in side-effects.”
The team has now started administering potentially therapeutic compounds for treating Parkinson’s disease “with promising initial findings,” Sierra points out, concluding that “the success of this technique in mice, and even in monkeys, can’t guarantee it will be effective in people, but if we continue to get satisfactory results then pre-clinical trials on humans would begin.”

About this neurology research article

Source: FECYT
Image Source: This NeuroscienceNews.com image is credited to UEIL, C. Sierra et al..
Original Research: Abstract for “Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood–brain barrier opening” by Carlos Sierra, Camilo Acosta, Cherry Chen, Shih-Ying Wu, Maria E Karakatsani, Manuel Bernal, and Elisa E Konofagou in Journal of Cerebral Blood Flow and Metabolism. Published online June 8 2016 doi:10.1177/0271678X16652630

Micro-Bubbles Make Big Impact for biomedical applications

Our researchers should be jumping for joy.  This breakthru should allow them to design robots that could deliver drugs directly to the site of the clot or bleed and release tPA if a clot or glue into the aneurysm to stop the bleed. Further research should allow the robots to drill thru the clot. If our fucking failures of stroke associations do nothing with this information that just proves why they are fucking failures.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=170175&CultureCode=en
The quest to develop a wireless micro-robot for biomedical applications requires a small-scale “motor” that can be wirelessly powered through biological media. While magnetic fields can be used to power small robots wirelessly, they do not provide selectivity since all actuators (the components controlling motion) under the same magnetic field just follow the same motion. To address this intrinsic limitation of magnetic actuation, a team of German researchers has developed a way to use microbubbles to provide the specificity needed to power micro-robots for biomedical applications.
This week in Applied Physics Letters, from AIP Publishing, the team describes this new approach that offers multiple advantages over previous techniques.
“First, by applying ultrasound at different frequencies, multiple actuators can be individually addressed; second, the actuators require no on-board electronics which make them smaller, lighter and safer; and third, the approach is scalable to the sub-millimeter size,” said Tian Qiu, a researcher at the Max Planck Institute for Intelligent Systems in Germany.
The research team encountered some surprises along the way. Normally a special material, like a magnetic or piezoelectric material, is required for an actuator. In this case, they used a standard commercial polymer that simply traps air bubbles, and then used the air-liquid interface of the trapped bubbles to convert the ultrasound power into mechanical motion.
“We found that a thin surface (30-120 micrometers effective thickness) with appropriate topological patterning can provide propulsion force using ultrasound, and thousands of these bubbles together can push a device at millimeter scale,” Qiu said. “The simplicity of the structure and material to accomplish this task was a pleasant surprise.”
The team is already looking forward to developing their actuator further.
“The next steps are to increase the propulsive force of the functional surface, to integrate the actuator into a useful biomedical device, and then to test it in a real biological environment, including in vivo,” Qiu said.
The adoption of micro-structured surfaces as wireless actuators opens promising new possibilities in the development of miniaturized devices and tools for fluidic environments accessible by low intensity ultrasound fields. These functional surfaces could serve as ready-to-attach wireless actuators, powering miniaturized biomedical devices for applications such as active endoscopes.
###
http://scitation.aip.org/content/aip/journal/apl/109/19/10.1063/1.4967194

• Full bibliographic informationThe article, "Wireless actuation with functional acoustic surfaces," is authored by T. Qiu, S. Palagi, A.G. Mark, K. Melde, F. Adams and P. Fischer. The article will appear in the journal Applied Physics Letter on November 22, 2016 (DOI: 10.1063/1.4945311). After that date, it can be accessed at http://scitation.aip.org/content/aip/journal/apl/109/19/10.1063/1.4967194.

NTU scientists invent bubble technology which can shoot drugs deep into tumours

Our researchers should look into this possibility for delivering tPA. I'm sure a much smaller and less dangerous bolus might be able to be delivered this way. Maybe way past the 4.5 hour current timeframe. But this is a BHAG(Big Hairy Audacious Goal) that will never be attempted because we don't have persons willing to take risks.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=163208&CultureCode=en
Using ultrasound, drug particles can be directed to a specific area
Scientists at Nanyang Technological University (NTU Singapore) have invented a new way to deliver cancer drugs deep into tumour cells.
The NTU scientists create micro-sized gas bubbles coated with cancer drug particles and iron oxide nanoparticles, and then use magnets to direct these bubbles to gather around a specific tumour.
Ultrasound is then used to vibrate the microbubbles, providing the energy to direct the drug particles into a targeted area.
This innovative technique was developed by a multidisciplinary team of scientists, led by Asst Prof Xu Chenjiefrom the School of Chemical and Biomedical Engineering and Assoc Prof Claus-Dieter Ohl from the School of Physical and Mathematical Sciences.
NTU’s microbubbles were successfully tested in mice and the study has been published by the Nature Publishing Group in Asia Materials, the top journal for materials sciences in the Asia-Pacific region.
Overcoming limitations of chemotherapy
Asst Prof Xu, who is also a researcher at the NTU-Northwestern Institute for Nanomedicine, said their new method may solve some of the most pressing problems faced in chemotherapy used to treat cancer.
The main issue is that current chemotherapy drugs are largely non-targeted. The drug particles flow in the bloodstream, damaging both healthy and cancerous cells. Typically, these drugs are flushed away quickly in organs such as the lungs and liver, limiting their effectiveness.
The remaining drugs are also unable to penetrate deep into the core of the tumour, leaving some cancer cells alive, which could lead to a resurgence in tumour growth.
“The first unique characteristic of our microbubbles is that they are magnetic. After injecting them into the bloodstream, we are able to gather them around the tumour using magnets and ensure that they don’t kill the healthy cells,” explains Asst Prof Xu, who has been working on cancer diagnosis and drug delivery systems since 2004.
“More importantly, our invention is the first of its kind that allows drug particles to be directed deep into a tumour in a few milliseconds. They can penetrate a depth of 50 cell layers or more – which is about 200 micrometres, twice the width of a human hair. This helps to ensure that the drugs can reach the cancer cells on the surface and also inside the core of the tumour.”
Clinical Associate Professor Chia Sing Joo, a Senior Consultant at the Tan Tock Seng Hospital’s Endoscopy Centre and the Urology & Continence Clinic, was one of the consultants for this study.
A trained robotic surgeon experienced in the treatment of prostate, bladder and kidney cancer, Assoc Prof Chia said, “For anticancer drugs to achieve their best effectiveness, they need to penetrate into the tumour efficiently in order to reach the cystoplasm of all the cancer cells that are being targeted without affecting the normal cells.
“Currently, these can be achieved by means of a direct injection into the tumour or by administering a large dosage of anticancer drugs, which can be painful, expensive, impractical and might have various side effects.”
The specialist in Uro-oncology added that if NTU’s technology proves to be viable, clinicians might be able to localise and concentrate the anticancer drugs around a tumour, and introduce the drugs deep into tumour tissues in just a few seconds using a clinical ultrasound system.
“If successful, I envisage it can be a good alternative treatment in the future, one which is low cost and yet effective for the treatment of cancers involving solid tumours, as it might minimise the side effects of drugs.”
New drug delivery system
The motivation for this research project is to find alternative solutions for drug delivery systems that are non-invasive and safe.
Ultrasound uses soundwaves with frequencies higher than those heard by the human ear. It is commonly used for medical imaging such as to get diagnostic images.
Magnets, which can draw and attract the microbubbles, are already in use in diagnostic machines such the Magnetic Resonance Imaging (MRI).
“We are looking at developing novel drug carriers – essentially better ways of delivering drugs with minimum side effects,” explained Prof Ohl, an expert in biophysics who had published previous studies involving drug delivery systems and bubble dynamics.
“Most prototype drug delivery systems on the market face three main challenges before they can be commercially successful: they have to be non-invasive, patient-friendly and yet cost-effective.
“Using the theory of microbubbles and how their surface vibrates under ultrasound, we were able to come up with our solution that addresses these three challenges.”
Interdisciplinary team
This study, which took two and a half years, involved a 12-man international interdisciplinary team consisting of NTU scientists as well as scientists from City University of Hong Kong and Tel Aviv University in Israel. Two NTU undergraduates doing their Final Year Project and one student in Summer Research Internship Programme (NTU) were also part of the team.
Moving forward, the team will be adopting this new drug delivery system in studies on lung and liver cancer using animal models, and eventually clinical studies.
They estimate that it will take another eight to ten years before it reaches human clinical trials.
http://media.ntu.edu.sg/NewsReleases/Pages/newsdetail.aspx?news=581d56b4-84d3-46a9-a155-3a68431d615d

Alzheimer’s breakthrough uses ultrasound technology

What else is your doctor using to treat this? You'll have to ask what is inside the microbubbles.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=150641&CultureCode=en
Queensland scientists have found that non-invasive ultrasound technology can be used to treat Alzheimer’s disease and restore memory.
University of Queensland researchers discovered that the innovative drug-free approach breaks apart the neurotoxic amyloid plaques that result in memory loss and cognitive decline.
Welcoming the findings today at UQ’s Queensland Brain Institute, Queensland Premier Annastacia Palaszczuk said they could have a wide impact for the community.
“The Government’s $9 million investment into this technology was to drive discoveries into clinics, and today’s announcement indicates that together with the Queensland Brain Institute, it was a worthwhile investment,” Ms Palaszczuk said.
“I want my Government to encourage more of this type of innovative research.
“Our Advance Queensland initiative aims to increase research and discoveries like this and to put this state’s research at the forefront internationally by supporting local researchers and helping to keep them in Queensland.
“These exciting findings will hopefully be of benefit to all Australians in the future.”
QBI Founding Director Professor Perry Bartlett said the discovery – a result of ‘game-changing’ work performed at the Queensland Brain Institute’s Clem Jones Centre for Ageing Dementia Research – was made possible through the support of the State and Federal Governments and philanthropic support led by the Clem Jones Foundation.

“The farsighted investment of government and philanthropic partners has allowed us to build the research excellence and capacity required to make major discoveries such as this,” Professor Perry Bartlett said.
“I believe the work opens up an entirely novel avenue for future therapeutic treatment.”
Clem Jones Centre for Ageing Dementia Research director Professor Jürgen Götz said the new treatment method could revolutionise Alzheimer’s treatment by restoring memory.
“We’re extremely excited by this innovation of treating Alzheimer’s without using drug therapeutics,” Professor Götz said.
“The ultrasound waves oscillate tremendously quickly, activating microglial cells that digest and remove the amyloid plaques that destroy brain synapses.
“The word ‘breakthrough’ is often mis-used, but in this case I think this really does fundamentally change our understanding of how to treat this disease, and I foresee a great future for this approach.”
Alzheimer’s affects more than two-thirds of dementia patients, and approximately a quarter of a million Australians.
The total number of dementia cases in Australia is expected to rise to 900,000 by 2050.
“With an ageing population placing an increasing burden on the health system, an important factor is cost, and other potential drug treatments using antibodies will be expensive,” Professor Götz said.
“In contrast, this method uses relatively inexpensive ultrasound and microbubble technology which is non-invasive and appears highly effective.
The approach is able to temporarily open the blood-brain barrier, activating mechanisms that clear toxic protein clumps and restoring memory functions.
“With our approach the blood-brain barrier’s opening is only temporary for a few hours, so it quickly restores its protective role,” Professor Götz said.
Research has been conducted using mice with an Alzheimer’s model, with the next step being to scale the research in higher animal models ahead of human clinical trials, which are at least two years away.
“This treatment restored memory function to the same level of normal healthy mice,” Professor Götz said.
“We’re also working on seeing whether this method clears toxic protein aggregates in neurodegenerative diseases other than Alzheimer’s and whether this also restores executive functions, including decision-making and motor control.”
Findings of the research, “Scanning ultrasound efficiently removes amyloid-β and restores memory in an Alzheimer's model”, are published in the journal Science Translational Medicine.
Media: Mikaeli Costello, +61 401 580 685 or mikaeli.costello@uq.edu.au; Professor Jürgen Götz, +61 7 3346 6329, j.goetz@uq.edu.au.
http://stm.sciencemag.org/content/7/278/278ra3

Detection and control of cavitation during blood–brain barrier opening: Applications and clinical considerations

How is your doctor going to use this knowledge of how to cross the blood brain barrier to deliver therapeutic interventions?
http://scitation.aip.org/content/asa/journal/jasa/136/4/10.1121/1.4900320
Applications and clinical considerations

Meaghan A. O'Reilly¹, Ryan M. Jones¹, Alison Burgess¹, Cassandra Tyson¹ and Kullervo Hynynen¹
View Affiliations
J. Acoust. Soc. Am. 136, 2300 (2014); http://dx.doi.org/10.1121/1.4900320

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Microbubble-mediated opening of the blood–brain barrier (BBB) using ultrasound is a targeted technique that provides a transient time window during which circulating therapeutics that are normally restricted to the vasculature can pass into the brain. This effect has been associated with increases in cavitation activity of the circulating microbubbles, and our group has previously described a method to actively control treatments in pre-clinical rodent models based on acoustic emissions recorded by a single transducer. Recently, we have developed a clinical-scale receiver array capable of detecting bubble activity through ex vivo human skullcaps starting at pressure levels below the threshold for BBB opening. The use of this array to spatially map cavitation activity in the brain during ultrasound therapy will be discussed, including considerations for compensating for the distorting effects of the skull bone. Additionally, results from pre-clinical investigations examining safety and therapeutic potential will be presented, and receiver design considerations for both pre-clinical and clinical scale systems will be discussed.

Targeted drug delivery to the brain and brain tumors using focused ultrasound and microbubbles

The targeting piece sounds very important to position drugs in the right location whenever we do find out how to stop the neuronal cascade of death.
http://europepmc.org/abstract/MED/24181339
McDannold N

Radiology, Brigham and Women's Hospital, 75 Francis St., Boston, MAnjm@bwh.harvard.edu.

The Journal of the Acoustical Society of America [2013, 134(5):4089]

Type: Journal Article
DOI: 10.1121/1.4830934

Abstract

Highlight Terms Gene Ontology(1) Diseases(3) Species(1) Chemicals(2)

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, severely limits the delivery of most drugs to the brain and to brain tumors. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets and enhance delivery across the "blood-tumor barrier." This talk aims to provide insight on the current status of this unique drug delivery technique, experience with it in preclinical models, and its potential for clinical translation. In particular, methods to monitor the procedure using acoustic receivers and the feasibility of controlling and predicting drug deposition will be reviewed. If this method, which offers a flexible means to target therapeutics to desired points or volumes in the brain, can be translated to the use in humans, it can enable the use of the whole arsenal of drugs in the CNS that are currently prevented by the BBB

Microbubbles improve myocardial remodelling after infarction

Ok, its not just the stroke medical world that is stupid. Throughout this article they never once consider that maybe the gas is the cause of better outcomes. Something similar was tried  for stroke and the assumption was also that the vibration was the effective factor rather that the xenon gas in the bubbles.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=128689&CultureCode=en
Scientists from the Bonn University Hospital successfully tested a method in mice allowing the morphological and functional sequelae of a myocardial infarction to be reduced. Tiny gas bubbles are made to oscillate within the heart via focused ultrasound - this improves microcirculation and decreases the size of the scar tissue. The results show that the mice, following myocardial infarction, have improved cardiac output as a result of this method, as compared to untreated animals. The study is now being presented in the professional journal PLOS ONE.
Every year in Germany, approximately 280,000 people suffer a myocardial infarction; more than 52,000 die as a result. Due to an occluded vessel, parts of the heart muscle no longer have sufficient circulation and the tissue dies off. These regions are not replaced by new heart muscle cells but instead by scar tissue – this generally causes the pump function of the heart to decrease following an infarction. Scientists from the Bonn University Hospital have now successfully tested a new method on mice with which scar tissue can be reduced and cardiac output increased.
Microbubbles are made to oscillate within the heart
“There are attempts to treat the scar tissue with gene therapy or stem cells - by contrast, we have chosen a physical approach to treatment,“ reports Adj. Professor Dr. med. Alexander Ghanem from the Department of Cardiology of the Bonn University Hospital. The researchers injected a total of 17 mice which had previously had a myocardial infarction with microscopically small, gas-filled bubbles in the bloodstream. Once the microbubbles reached the heart, they were made to vibrate there using focused ultrasound. “Through this mechanical stimulation, the circulation of the area of the infarction is improved - and the scar shrinks,“ says the cardiac specialist.
Treated animals demonstrate ameliorated post-infarction remodelling
The scientists compared the results of the mice treated with the microbubbles to those of a control group. Two weeks after the myocardial infarction, there was expected worsening of heart function in the control group due to the maturing of the scar tissue. In contrast, the mice treated with the microbubbles did not develop any cardiac insufficiency. Jonas Dörner, the first author of the study, summarizes the results: “The pumping function was significantly better in the treated animals as compared to the control group; there was also a significantly smaller amount of decayed heart muscle tissue.” Along with the Department of Cardiology, the Departments of Cardiac Surgery and Anesthesiology and the Institute of Physiology took part in the investigations.
Ultrasound treatment stimulates growth hormones
The scientists sought the causes of the positive treatment success which is, however, unexplained to date. Following ultrasound treatment of the mice, it was demonstrated that the amount of the body’s own growth hormones significantly increased in the heart. “This is evidently the reason why the scar formation decreased as a result of the oscillating microbubbles,“ says Dr. Ghanem. The scientists now hope that humans will also be able to eventually be treated with the microbubble-ultrasound method, however further investigations are still needed. “Potentially, all patients who have had an acute myocardial infarction are eligible for this follow-up treatment,“ explains the cardiologist of the Bonn University Hospital. Interestingly, microbubbles are already used as a diagnostic contrast agent.
Patent for novel ultrasound method filed
The study, conducted with support from the BONFOR funding program of the Medical Faculty of Bonn University and the German Heart Foundation [Deutsche Herzstiftung e.V.], gave rise to a patent application. “Together with the company Philips Medical, we developed a novel ultrasonic probe which enables a standardized impulse discharge in the heart,“ reports the cardiologist. The special feature is that two ultrasound sources linked together are contained in one hybrid ultrasonic probe: one with low frequency for the focused stimulation of the microbubbles in the target organ and one with higher frequency for imaging. In this way, it can be very precisely determined where the scar tissue and the microbubbles are located. “This study demonstrates again that university research inspires technological developments in medicine,“ says Dr. Ghanem.

bubbles with ultrasound - stroke drugs directly into the brain

So I wonder which would be better, nanoparticles or bubbles? Or is it the xenon gas?

bubbles with ultrasound  - stroke drugs directly into the brain

Now, stroke drugs directly into the brain (Thinkstock photos/Getty Images)
Scientists believe that bubbles could deliver a devastating blow to disease.
Injected into the blood, tiny bubbles of gas can ease the passage of vital stroke drugs into the brain, helping prevent damage to the grey matter.
Now, a group of researchers calling themselves ''the bubble community'' are studying how they could help fight disease.
They have shown that blasting bubbles with ultrasound makes them move back and forth, and, bizarrely, makes it easier for nearby cells to take up medicines.
"The theory is that the bubbles are stimulating the natural uptake mechanisms," the Daily Mail quoted Eleanor Stride, of University College London, as saying.
"Exactly which mechanisms, we're not sure."
Bubbles can even open up the blood-brain barrier, the protective blockade that regularly stops drugs from getting into the brain from the bloodstream.
Stride told New Scientist : "If you expose the blood-brain barrier to bubbles and ultrasound, you can temporarily and reversibly enhance its permeability, which is potentially interesting for a lot of brain treatments."
Examples include the treatment of stroke, in which an interruption of the blood supply to the brain causes cells to become damaged or die.
Researchers from the University of Cinncinnati in Ohio filled microbubbles with xenon - a gas known to protect brain cells from dying an improve blood flow, but difficult to administer.
Rats treated with the xenon-filled bubbles had smaller areas of brain damage than untreated animals.
In another piece of research, bubbles filled with a drug used to break down clots, were used to treat people who had strokes.
The technique eased the passage of the drug to the brain, speeding up the restoration of the blood flow to the brain.
But not without a cost - two of the patients given the highest dosage of the ''bubble drug'' in combination with ultrasound started haemorrhaging and died.