Category Archives: medicine

Treatment for patients infected with the ebola virus (a response to crisis in West African countries)

I’ve not actively kept up with the situation in the West African countries suffering an outbreak of the ebola virus other than to note that it is ongoing. My Aug. 15, 2014 post provides a snapshot of the situation and various new treatments, including one based on tobacco, which could be helpful but appeared not to have been tested and/or deployed. There was a lot of secrecy (especially from Medicago, a Canadian company) regarding the whole matter of treatments and vaccines.

There seem to have been some new developments on the treatment side, involving yet another Canadian company, Tekmira, according to a Sept. 23, 2013 news item on Azonano,

Tekmira Pharmaceuticals Corporation, a leading developer of RNA interference (RNAi) therapeutics, today announced that the FDA [US Food and Drug Administration] has authorized Tekmira to provide TKM-Ebola for treatment under expanded access protocols to subjects with confirmed or suspected Ebola virus infections.

A Sept. 22, 2014 Tekmira news release, which originated the news item, expands on the topic of regulatory issues associated with bringing this treatment to the areas suffering the outbreak,

“Tekmira is reporting that an appropriate regulatory and clinical framework is now in place to allow the use of TKM-Ebola in patients. We have worked with the FDA and Health Canada to establish this framework and a treatment protocol allowing us to do what we can to help these patients,” said Dr. Mark J. Murray Tekmira’s President and CEO.

“We have insisted on acting responsibly in the interest of patients and our stakeholders,” added Dr. Murray. “Today we are reporting that, working closely with regulators in the United States and Canada, we have established a framework for TKM-Ebola use in multiple patients. In the US, the FDA has granted expanded access use of TKM-Ebola under our Investigational New Drug application (IND) and Health Canada has established a similar framework, both of which allow the use of our investigational therapeutic in more patients.”

“We have already responded to requests for the use of our investigational agent in several patients under emergency protocols, in an effort to help these patients, a goal we share with the FDA and Health Canada. TKM-Ebola has been administered to a number of patients and the repeat infusions have been well tolerated. However, it must be kept in mind that any uses of the product under expanded access, does not constitute controlled clinical trials. These patients may be infected with a strain of Ebola virus which has emerged subsequent to the strain that our product is directed against, and physicians treating these patients may use more than one therapeutic intervention in an effort to achieve the best outcome,” said Dr. Murray. “Our TKM-Ebola drug supplies are limited, but we will continue to help where we can, as we continue to focus on the other important objectives we have to advance therapies to meet the unmet needs of patients.”

TKM-Ebola is an investigational therapeutic, being developed under an FDA approved IND, which is currently the subject of a partial clinical hold under which the FDA has allowed the potential use of TKM-Ebola in individuals with a confirmed or suspected Ebola virus infection.

About FDA Expanded Access Program

Expanded access is the use of an investigational drug outside of a clinical trial to treat a patient, with a serious or immediately life-threatening disease or condition, who has no comparable or satisfactory alternative treatment options. FDA regulations allow access to investigational drugs for treatment purposes on a case-by-case basis for an individual patient, or for intermediate-size groups of patients with similar treatment needs who otherwise do not qualify to participate in a clinical trial. (Source: www.fda.com)

About TKM-Ebola, an Anti-Ebola Virus RNAi Therapeutic

TKM-Ebola, an anti-Ebola virus RNAi therapeutic, is being developed under a $140 million contract with the U.S. Department of Defense’s Medical Countermeasure Systems BioDefense Therapeutics (MCS-BDTX) Joint Product Management Office. Earlier preclinical studies were published in the medical journal The Lancet and demonstrated that when siRNA targeting the Ebola virus and delivered by Tekmira’s LNP [Lipid Nanoparticle] technology were used to treat previously infected non-human primates, the result was 100 percent protection from an otherwise lethal dose of Zaire Ebola virus (Geisbert et al., The Lancet, Vol. 375, May 29, 2010). In March 2014, Tekmira was granted a Fast Track designation from the U.S. Food and Drug Administration for the development of TKM-Ebola.

About Joint Project Manager Medical Countermeasure Systems (JPM-MCS)

This work is being conducted under contract with the U.S. Department of Defense Joint Project Manager Medical Countermeasure Systems (JPM-MCS). JPM-MCS, a component of the Joint Program Executive Office for Chemical and Biological Defense, aims to provide U.S. military forces and the nation with safe, effective, and innovative medical solutions to counter chemical, biological, radiological, and nuclear threats. JPM-MCS facilitates the advanced development and acquisition of medical countermeasures and systems to enhance biodefense response capability. For more information, visit www.jpeocbd.osd.mil.

About Tekmira

Tekmira Pharmaceuticals Corporation is a biopharmaceutical company focused on advancing novel RNAi therapeutics and providing its leading lipid nanoparticle (LNP) delivery technology to pharmaceutical partners. Tekmira has been working in the field of nucleic acid delivery for over a decade and has broad intellectual property covering LNPs. Further information about Tekmira can be found at www.tekmira.com. Tekmira is based in Vancouver, B.C. Canada.

Forward-Looking Statements and Information

This news release contains “forward-looking statements” or “forward-looking information” within the meaning of applicable securities laws (collectively, “forward-looking statements”). Forward-looking statements in this news release include statements about Tekmira’s strategy, future operations, clinical trials, prospects and the plans of management; an appropriate regulatory and clinical  framework for emergency use of TKM-Ebola in subjects with confirmed or suspected Ebola infections; FDA grant of expanded access use of TKM-Ebola under Tekmira’s IND; Health Canada’s establishment of a similar framework for TKM-Ebola; Tekmira’s response to requests for the use of TKM-Ebola in several patients under emergency protocols and the results thereon; the current supply of TKM-Ebola drug; the partial clinical hold on the TKM-Ebola IND by the FDA (enabling the potential use of TKM-Ebola in individuals with a confirmed or suspected Ebola virus infection); the quantum value of the contract with the JPM-MCS; and Fast Track designation from the FDA for the development of TKM-Ebola.

With respect to the forward-looking statements contained in this news release, Tekmira has made numerous assumptions regarding, among other things, the clinical framework for emergency use of TKM-Ebola. While Tekmira considers these assumptions to be reasonable, these assumptions are inherently subject to significant business, economic, competitive, market and social uncertainties and contingencies.

Additionally, there are known and unknown risk factors which could cause Tekmira’s actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements contained herein. Known risk factors include, among others: TKM-Ebola may not prove to be effective in the treatment of Ebola infection under the emergency use framework, or at all; any uses of TKM-Ebola under emergency INDs are not controlled trails, and TKM-Ebola may be used on Ebola strains that have diverged from the strain to which TKM-Ebola is directed, and physicians treating patients may use more than one therapeutic intervention in addition to TKM-Ebola; the current supply of TKM-Ebola is limited, and Tekmira may not be able to respond to future requests for help in the current Ebola outbreak; the FDA may not remove the partial clinical hold on the TKM-Ebola IND; the FDA may refuse to approve Tekmira’s products, or place restrictions on Tekmira’s ability to commercialize its products; anticipated pre-clinical and clinical trials may be more costly or take longer to complete than anticipated, and may never be initiated or completed, or may not generate results that warrant future development of the tested drug candidate; and Tekmira may not receive the necessary regulatory approvals for the clinical development of Tekmira’s products.

A more complete discussion of the risks and uncertainties facing Tekmira appears in Tekmira’s Annual Report on Form 10-K and Tekmira’s continuous disclosure filings, which are available at www.sedar.com or www.sec.gov. All forward-looking statements herein are qualified in their entirety by this cautionary statement, and Tekmira disclaims any obligation to revise or update any such forward-looking statements or to publicly announce the result of any revisions to any of the forward-looking statements contained herein to reflect future results, events or developments, except as required by law.

In the midst of all those ‘cover your rear end’ statements to investors, it’s easy to miss the fact that people are actually being treated and the results are promising, if not guaranteed,

Tekmira has distributed a Sept. 23, 2014 news release touting its membership in a new consortium, which suggests that in parallel with offering treatment, human clinical trials will  also be conducted,

Tekmira Pharmaceuticals Corporation (Nasdaq:TKMR) (TSX:TKM), a leading developer of RNA interference (RNAi) therapeutics, today reported that it is collaborating with an international consortium to provide an RNAi based investigational therapeutic for expedited clinical studies in West Africa.

Led by Dr. Peter Horby of the Centre for Tropical Medicine and Global Health at the University of Oxford and the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), the consortium includes representatives from the World Health Organization (WHO), US Centers for Disease Control, Médecins Sans Frontières – Doctors without Borders (MSF), ISARIC, and Fondation Mérieux, among others.

The Wellcome Trust has announced it has awarded £3.2 million to the consortium to fund this initiative. The award will include funds for the manufacture of investigational therapeutics as well as the establishment of an operational clinical trials platform in two or more Ebola Virus Disease (EVD) treatment centers in West Africa. RNAi has been prioritized as an investigational therapeutic and may be selected for clinical trials at these centers.

The objective of the clinical trials is to assess the efficacy and safety of promising therapeutics and vaccines, reliably and safely, in patients with EVD by adopting strict protocols that comply with international standards.  It is hoped this initiative will permit the adoption of safe and effective interventions rapidly.

The genetic sequence of the Ebola virus variant responsible for the ongoing outbreak in West Africa is now available. Under this program, Tekmira will produce an RNAi based product specifically targeting the viral variant responsible for this outbreak.  The ability to rapidly and accurately match the evolving genetic sequences of emerging infectious agents is one of the powerful features of RNAi therapeutics.

“We commend the Wellcome Trust for their leadership in providing the necessary funds to launch and expedite this ground breaking initiative. We are gratified that RNAi has been prioritized as a potential investigational therapeutic to assist in the ongoing public health and humanitarian crisis in Africa,” said Dr. Murray, Tekmira’s President and CEO.

“We are an active collaborator in this consortium and through our ongoing dialogue with the WHO, NGOs and governments in various countries; we have been discussing the creation of appropriate clinical and regulatory frameworks for the potential use of investigational therapeutics in Africa. This initiative goes a long way towards achieving this aim.  Many complex decisions remain to fully implement this unique clinical trial platform.  At this time, there can be no assurances that our product will be selected by the consortium for clinical trials in Africa,” said Dr. Murray.

About Wellcome Trust

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. For more information, visit www.wellcome.ac.uk

I’m glad they’re being careful while giving people treatment, i. e., trying to do something rather than waiting to conduct human clinical trials as has sometimes been the case in the past. This business of running the trials almost parallel to offering treatment suggests an agility not often associated with the international health care community.

ETA Sept. 23 2014 1200 hours PDT: For more information about the status of the Ebola outbreak read Tara Smith’s Sept. 22, 2014 article Slate titled, Here’s Where We Stand With Ebola; Even experienced international disaster responders are shocked at how bad it’s gotten (Note: Links have been removed).

Now, terms like “exponential spread” are being thrown around as the epidemic continues to expand more and more rapidly. Just last week, an increase of 700 new cases was reported, and the case count is now doubling in size approximately every three weeks.

A Doctors Without Borders worker in Monrovia, Liberia, named Jackson Naimah describes the situation in his home country, noting that patients are literally dying at the front door of his treatment center because it lacks patient beds and assistance; the sufferers are left to die a “horrible, undignified death” and potentially infect others as they do so: …

… Health care workers who are treating the sick are dying because they also lack basic protective equipment, or because they have been so overwhelmed by taking care of the ill and dying that they begin to make potentially fatal errors. They have gone on strike in Liberia because they are not being adequately protected or even paid for their risky service.

Fear and misinformation are as deadly as the virus itself. Eight Ebola workers were recently murdered in Guinea, in the area where the virus first came to the world’s attention in March. Liberia’s largest newspaper featured a story describing Ebola as a man-made virus being purposely unleashed upon Africans by Western pharmaceutical companies. Reports abound of doctors and other workers being chased away, sometimes violently, by fearful families. …

It’s not a pleasant read but, I think, a necessary one. For anyone who may think the panic and fear are unique to this situation, I once worked with a nurse who described being lifted by her neck after someone came through the door of a clinic demanding a vaccine and had been refused. He was in such a panic and so fearful he wasn’t going to take a ‘no’. The incident took place in Vancouver (Canada) in a ‘nice’ part of town.

ETA Sept. 24, 2014: Kelly Grant has written a Sept. 22, 2014 article for the Globe and Mail which provides more information about Tekmira, some of which contradicts the details I have here about TKM-Ebola and clinical trials in Africa although the key points remain the same. She also provides more information about the ZMapp therapy mentioned in my Aug. 15, 2014 post mentioning yet a third Canadian connection. Canada’s National Microbiology Laboratory was somehow involved in developing ZMApp, unfortunately, Grant does not or is not able to provide more details about that involvement.

Bone implants and restorative dentistry at the University of Malaya

The research into biomedical implants at the University of Malaya is part of an international effort and is in response to a demographic reality, hugely increased populations of the aged. From a Sept. 18, 2014 news item on ScienceDaily,

A major success in developing new biomedical implants with the ability to accelerate bone healing has been reported by a group of scientists from the Department of Restorative Dentistry, University of Malaya. This stems from a project partly funded by HIR [High Impact Research] and also involves Mr. Alireza Yaghoubi, HIR Young Scientist.

According to WHO (World Health Organization), between 2000 and 2050, the world’s population over 60 years is expected to increase from 605 million to more than 2 billion. This trend is particularly more prominent in Asia and Europe where in some countries by 2050, the majority of people will be older than 50. That is why in recent years, regenerative medicine has been among the most active and well-funded research areas in many developing nations.

As part of this global effort to realize better treatments for age-related conditions, a group of scientists from the department of restorative dentistry, University of Malaya and four other universities in the US have recently reported a major success in developing new biomedical implants with the ability to accelerate bone healing.

Two studies were published according to the Sept.15, 2014 University of Malaya news release, which originated the news item,

The two studies funded by the National Science Fund (NSF) in the US and the High Impact Research (HIR) program in Malaysia tackled the issue of bone-implant integration from different angles. In the first study appearing on the front cover of the July issue of Applied Surface Science, researchers demonstrated a mechanically superior bioactive coating based on magnesium silicates rather than the commercially available calcium phosphate which develops microcracks during preparation and delaminates under pressure. The new material owing to its lower thermal mismatch with titanium can prolong the durability of load-bearing orthopedic implants and reduce chances of post-surgery complications.

The other study published in the American Chemical Society’s Applied Materials & Interfaces reported a method for fabricating titanium implants with special surface topographies which double the chance of cell viability in early stages. The new technique is also much simpler as compared to the existing ones and therefore enables the preparation of personalized implants at the fraction of time and cost while offering a higher mechanical reliability.

Alireza Yaghoubi, the corresponding author of both studies believes that we are moving toward a future of personalized products. “It is very much like your taste in music and TV shows. People are different and the new trend in biotechnology is to make personalized medicine that matches the patient’s needs” Yaghoubi said. He continued “With regard to implants, we have the problem of variations in bone density in patients with osteoporosis and in some cases, even healthy individuals. Finding ways to integrate the implants with bone tissues can be challenging. There are also problems with the long-term performance of implants, such as release of debris from bioactive films which can potentially lead to osteolysis and chronic inflammation”.

The new technique employed by the scientists to create titanium implants with desirable surface properties uses microwave heating to create a porosity gradient on top of a dense core. The principles are very similar to a kitchen microwave and how it can make cooking easier, however apparently the fast heating capability is not only useful in cooking but it has numerous industrial applications. Prof. Bhaduri, the Director of Multi-functional materials laboratory at University of Toledo says that they have been using microwave for years to simplify fabrication of complex metallic components. “We needed a way to streamline the process and microwave sintering was a natural fit. With our new method, making the implant from titanium powder in custom sizes and with specific surface topographies is achieved through one easy step.” Bhaduri elaborated.

Researchers are hoping to carry out the clinical trial for this new generation of implants in order to make them available to the market soon. Dr. Kutty, one of the lead authors suggests that there is still room for improvement. Kutty concluded that “Roughened surfaces and bioceramics have desirable effects on osseointegration, but we are not stopping there. We are now developing new ways to use peptides for enhancing the performance of implants even further.”

This image provides an illustration of the proposed new material for implants,

The artwork appeared on the front cover of Applied Surface Science summarizes the benefits of a new bioceramic coating versus the commercially available Calcium Phosphate which develops microcracks during processing and may later cause osteolysis in load-bearing orthopedic implants. Courtesy: University of Malaya

The artwork appeared on the front cover of Applied Surface Science summarizes the benefits of a new bioceramic coating versus the commercially available Calcium Phosphate which develops microcracks during processing and may later cause osteolysis in load-bearing orthopedic implants. Courtesy: University of Malaya

Here are links to and citations for the papers,

Electrophoretic deposition of magnesium silicates on titanium implants: Ion migration and silicide interfaces by M. Afshar-Mohajer, A. Yaghoubi, S. Ramesh, A.R. Bushroa, K.M.C. Chin, C.C. Tin, and W.S. Chiu.  Applied Surface Science (2014) , Volume 307, 15 July 2014, Pages 1–6, DOI: 10.1016/j.apsusc.2014.04.033

Microwave-assisted Fabrication of Titanium Implants with Controlled Surface Topography for Rapid Bone Healing by Muralithran G. Kutty, Alok De, Sarit B. Bhaduri, and Alireza Yaghoubi. ACS Appl. Mater. Interfaces, 2014, 6 (16), pp 13587–13593 DOI: 10.1021/am502967n Publication Date (Web): August 6, 2014

Copyright © 2014 American Chemical Society

Both of these papers are behind paywalls.

Sharklet’s sharkskin-like material

It’s one of my favourite technologies but there hasn’t been much talk about Sharklet for the last few years. My Feb. 10, 2011 posting about it had this,

They used sharkskin as an example for making a ‘smarter’ material. Scientists have observed that nanoscale structures on a shark’s skin have antibacterial properties. This is especially important when we have a growing problem with bacteria that are antibiotic resistant. David Pogue’s (the program host) interviewed scientists at Sharklet and highlighted their work producing a plastic with nanostructures similar to those found on sharkskin for use in hospitals, restaurants, etc.  I found this on the Sharklet website (from a rotating graphic on the home page),

The World Health Organization calls antibiotic resistance a leading threat to human health.

Sharkjet provides a non-toxic approach to bacterial control and doesn’t create resistance.

The reason that the material does not create resistance is that it doesn’t kill the bacteria (antibiotics kill most bacteria but cannot kill all of them with the consequence that only the resistant survive and reproduce). Excerpted from Sharklet’s technology page,

While the Sharklet pattern holds great promise to improve the way humans co-exist with microorganisms, the pattern was developed far outside of a laboratory. In fact, Sharklet was discovered via a seemingly unrelated problem: how to keep algae from coating the hulls of submarines and ships. In 2002, Dr. Anthony Brennan, a materials science and engineering professor at the University of Florida, was visiting the U.S. naval base at Pearl Harbor in Oahu as part of Navy-sponsored research. The U.S. Office of Naval Research solicited Dr. Brennan to find new antifouling strategies to reduce use of toxic antifouling paints and trim costs associated with dry dock and drag.

The most recent news from Sharklet comes in a Sept. 16, 2014 news release on EurekAlert which refines the definition for Sharklet and provides research about the latest research on this material,

Transmission of bacterial infections, including MRSA and MSSA could be curbed by coating hospital surfaces with microscopic bumps that mimic the scaly surface of shark skin, according to research published in the open access journal Antimicrobial Resistance and Infection Control.

The study modelled how well different materials prevented the spread of human disease bacteria through touching, sneezes or spillages. The micropattern, named Sharklet™, is an arrangement of ridges formulated to resemble shark skin. The study showed that Sharklet harboured 94% less MRSA bacteria than a smooth surface, and fared better than copper, a leading antimicrobial material. The bacteria were less able to attach to Sharklet’s imperceptibly textured surface, suggesting it could reduce the spread of superbugs in hospital settings.

The surfaces in hospitals and healthcare settings are often rife with bacteria and patients are vulnerable to bacterial infection. Scientists are investigating the ability of different materials to prevent the spread of bacteria. Copper alloys are a popular option, as they are toxic to bacterial cells, interfering with their cellular processes and killing them. The Sharklet micropattern works differently – the size and composition of its microscopic features prevent bacteria from attaching to it. It mimics the unique qualities of shark skin, which, unlike other underwater surfaces, inhibits bacteria, because it is covered with a natural micropattern of tooth-like structures, called denticles.

Dr Ethan Mann, a research scientist at Sharklet Technologies, the manufacturer of the micropattern, says: “The Sharklet texture is designed to be manufactured directly into the surfaces of plastic products that surround patients in hospital, including environmental surfaces as well as medical devices. Sharklet does not introduce new materials or coatings – it simply alters the shape and texture of existing materials to create surface properties that are unfavorable for bacterial contamination.”

The researchers from Sharklet Technologies compared how well two types of infection-causing bacteria, methicillin-resistant or susceptible Staphylococcus aureus (MRSA and MSSA), fared at contaminating three surfaces – the Sharklet micropattern, a copper alloy, and a smooth control surface. They created experimental procedures to mimic common ways bacteria infect surfaces. Sneezing was mimicked by using a paint sprayer to spread the bacterial solution on 10 samples of each surface. To mimic infected patients touching the surfaces, velveteen cloth was put in contact with bacteria for 10s, and then placed on another set of each test surface for 10s. A third set of each surface was immersed in bacterial solution for an hour, then rinsed and dried, to mimic spills.

Surfaces were sampled for remaining contaminations either immediately following exposure to MSSA and MRSA or 90 minutes after being exposed. The Sharklet micropattern reduced transmission of MSSA by 97% compared to the smooth control, while copper was no better than the control. The micropattern also harboured 94% less MRSA bacteria than the control surface, while the copper had 80% less.

Dr Mann says: “Shark skin itself is not an antimicrobial surface, rather it seems highly adapted to resist attachment of living organisms such as algae and barnacles. Shark skin has a specific roughness and certain properties that deter marine organisms from attaching to the skin surface. We have learned much from nature in building this material texture for the future.”

Here’s an illustration the researchers have provided,

Caption: This is an image of the Sharklet micropattern, which mimics the denticles of shark skin. Credit: Mann et al.

Caption: This is an image of the Sharklet micropattern, which mimics the denticles of shark skin.
Credit: Mann et al.

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

Surface micropattern limits bacterial contamination by Ethan E Mann, Dipankar Manna, Michael R Mettetal, Rhea M May, Elisa M Dannemiller, Kenneth K Chung, Anthony B Brennan, and Shravanthi T Reddy. Antimicrobial Resistance and Infection Control 2014, 3:28  doi:10.1186/2047-2994-3-28

This is an open access paper.

Targeted nanoparticles stimulate growth of healthy heart cells in damaged hearts

Don’t get too excited, the research is at the rat stage sometimes called ‘animal models’ as in ‘these nanoparticles are being tested on animal models’. Still it’s exciting news from North Carolina State University (NCSU; my second item from that university today, Sept. 12, 2014).

From a Sept. 12, 2014 news item on Azonano,

A targeted nanoparticle created by researchers at North Carolina State University and the Cedars-Sinai Heart Institute may help heart attack patients regenerate healthy heart tissue without using donated or processed stem cells. This new nanomedicine could also alleviate some of the difficulties involved with stem cell therapy, including treatment delays and invasive procedures.

A Sept. ?, 2014 NCSU news release, which originated the news item, provides a little more detail about the work,

The particle, a “magnetic bi-functional cell engager” called MagBICE, consists of an iron platform with two different antibodies attached. These antibodies have different functions – one locates a patient’s own stem cells after a heart attack, and the other grabs injured tissue, allowing MagBICE to act as a matchmaker between injury and repair crew. The iron platform makes MagBICE magnetically active, allowing physicians to direct the particles to the heart with an external magnetic field. The iron platform also enables magnetic resonance imaging (MRI).

Ke Cheng, associate professor of regenerative medicine at NC State, and his colleagues at Cedars-Sinai Heart Institute tested MagBICE in rats and found that the particle was effective in redirecting stem cells in the blood to the injured heart. [emphasis] Additionally, MagBICE was easier and faster to administer than current stem cell therapy products.

“MagBICE optimizes and amplifies the body’s own repair process, which means we don’t have to worry about patient rejection of donated stem cells, or delay treatment while a patient’s stem cells are being processed, purified and prepared,” Cheng says. “The drug can be offered to patients immediately after blood vessels to the damaged areas are reopened and can be given intravenously, which isn’t possible with stem cell therapy.”

Courtesy of NCSU, there’s an artist’s illustration of the MagBICE and the heart,

MagBICE engaging therapeutic stem cells with injured cardiomyocytes. Credit: Alice Harvey, NC State

MagBICE engaging therapeutic stem cells with injured cardiomyocytes. Credit: Alice Harvey, NC State

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

Magnetic antibody-linked nanomatchmakers for therapeutic cell targeting by Ke Cheng, Deliang Shen, M. Taylor Hensley, Ryan Middleton, Baiming Sun, Weixin Liu, Geoffrey De Couto, & Eduardo Marbán. Nature Communications 5, Article number: 4880 doi:10.1038/ncomms5880 Published 10 September 2014

This is an open access paper.

Nanorobotic approach to studying how skin falls apart

Scientists have combined robotic techniques with atomic force microscopy to achieve understanding of how skin falls apart at the nanoscale. From a Sept. 11, 2014 news item on Azonano,

University at Buffalo researchers and colleagues studying a rare, blistering disease have discovered new details of how autoantibodies destroy healthy cells in skin. This information provides new insights into autoimmune mechanisms in general and could help develop and screen treatments for patients suffering from all autoimmune diseases, estimated to affect 5-10 percent of the U.S. population.

“Our work represents a unique intersection between the fields of biology and engineering that allowed for entirely new investigational strategies applied to the study of clinical disease,” says Animesh A. Sinha, MD, PhD, Rita M. and Ralph T. Behling Professor and chair of the Department of Dermatology in the UB School of Medicine and Biomedical Sciences and senior author on the study.

A Sept. 9, 2014 University of Buffalo news release by Ellen Goldbaum (also on EurekAlert dated Sept. 10, 2014), which originated the news item, describes the condition and the research in more detail,

PV [Pemphigus Vulgaris] results in the often painful blistering of the skin and mucous membranes. Generally treated with corticosteroids and other immunosuppressive agents, the condition is life-threatening if untreated.

Sinha’s research team, in collaboration with scientists at Michigan State University, describe the use of atomic force microscopy (AFM), a technique originally developed to study nonbiological materials, to look at cell junctions and how they rupture, a process called acantholysis.

“It has been very difficult to study cell junctions, which maintain the skin’s barrier function by keeping cells attached to each other,” says Sinha. “These junctions, micron-sized spots on cell membranes, are very complex molecular structures. Their small size has made them resistant to detailed investigation.”

Sinha’s interest lies in determining what destroys those junctions in Pemphigus Vulgaris.

“We haven’t understood why some antibodies generated by the condition cause blisters and why other antibodies it generates do not,” says Sinha.

By studying the connections between skin cells using AFM and other techniques that probe cells at the nanoscale, Sinha and his colleagues report that pathogenic antibodies change structural and functional properties of skin cells in distinct ways.

“Our data suggest a new model for the action of autoantibodies in which there are two steps or ‘hits’ in the development of lesions,” says Sinha. “The first hit results in the initial separation of cells but only the pathogenic antibodies drive further intracellular changes that lead to the breaking of the cell junction and blistering.”

The researchers examined the cells using AFM, which requires minimal sample preparation and provides three-dimensional images of cell surfaces.

The AFM tip acts like a little probe, explains Sinha. When tapped against a cell, it sends back information regarding the cell’s mechanical properties, such as thickness, elasticity, viscosity and electrical potential.

“We combined existing and novel nanorobotic techniques with AFM, including a kind of nanodissection, where we physically detached cells from each other at certain points so that we could test what that did to their mechanical and biological functions,” Sinha adds.

Those data were then combined with information about functional changes in cell behavior to develop a nanomechanical profile, or phenotype, for specific cellular states.

He also envisions that this kind of nanomechanical phenotyping should allow for the development of predictive models for cellular behavior for any kind of cell.

“Ultimately, in the case of autoimmunity, we should be able to use these techniques as a high-throughput assay to screen hundreds or thousands of compounds that might block the effects of autoantibodies and identify novel agents with therapeutic potential in given individuals,” says Sinha.  “Such strategies aim to advance us toward a new era of personalized medicine”.

I found some more information about the nanorobotics technique, mentioned in the news release, in the researchers’ paper (Note: A link has been removed),

Nanorobotic surgery

AFM-based nanorobotics enables accurate and convenient sample manipulation and drug delivery. This capability was used in the current study to control the AFM tip position over the intercellular junction area, and apply vertical indentation forces, so that bundles of intercellular adhesion structures can be dissected precisely with an accuracy of less than 100 nm in height. We used a tip sharp enough (2 nm in tip apex diameter) to penetrate the cell membrane and the intermediate filaments. It has been shown that intermediate filaments have extremely high tensile strength by in vitro AFM stretching [19]. Thus, the vertical force and moving speed of the AFM cantilever (0.06 N/m in vertical spring constant) was controlled at a vertical force of 5 nN at an indentation speed of 0.1 µm/s to guarantee the rupture of the filament and to partially dissect cell adhesion structures between two neighboring cells.

For those who want to know more, here’s a link to and a citation for the paper,

Nanorobotic Investigation Identifies Novel Visual, Structural and Functional Correlates of Autoimmune Pathology in a Blistering Skin Disease Model by Kristina Seiffert-Sinha, Ruiguo Yang, Carmen K. Fung, King W. Lai, Kevin C. Patterson, Aimee S. Payne, Ning Xi, Animesh A. Sinha. PLOSONE Published: September 08, 2014 DOI: 10.1371/journal.pone.0106895

This is an open access paper.

Biosensing devices from Scotland

The timing for Deborah Rowe’s article in the Guardian newspaper is fascinating. Rowe is writing about nanoscale biosensors developed at the University of Edinburgh, research published in Dec. 2013, while her piece, published Sept. 9, 2014, appears less than 10 days before Scotland’s vote (Sept. 18, 2014) on the question of whether or not it should be independent. Also interesting, the published paper is available as open access until the end of Sept. 2014, which seems like a strategic time period to give open access to your paper.

That said, this is an exciting piece of research if you’re particularly interested in biosensors and ways to produce them more cheaply and at a higher volume (from Rowe’s Sept. 9, 2014 article),

An interdisciplinary research team from the Schools of Engineering and Chemistry at the University of Edinburgh (in association with Nanoflex Ltd), has overcome some of the constraints associated with conventional nano-scale electrode arrays, to develop the first precision-engineered nanoelectrode array system with the promise of high-volume and low-cost.*

Such miniaturised electrode arrays have the potential to provide a faster and more sensitive response to, for example, biomolecules than current biosensors. This would make them invaluable components in the increasingly sensitive devices being developed for biomedical sensing and electrochemical applications.

Rowe goes on to describe the researchers’ Microsquare Nanoband Edge Electrode (MNEE) array technology in lucid and brief detail. For those who want more, here’s a link to and a citation for the paper,

Nanoscale electrode arrays produced with microscale lithographic techniques for use in biomedical sensing applications by Jonathan G. Terry, Ilka Schmüser, Ian Underwood, Damion K. Corrigan, Neville J. Freeman, Andrew S. Bunting, Andrew R. Mount, Anthony J. Walton. IET Nanobiotechnology, Volume 7, Issue 4, December 2013, p. 125 – 134
DOI:  10.1049/iet-nbt.2013.0049 , Print ISSN 1751-8741, Online ISSN 1751-875X Published Oct. 29, 2013

Given the timing of the Guardian article and the availability of the paper for free access, I was moved to find information about the funding agencies, from the researchers’ IET paper,

Support from the Scottish Funding Council (SFC) is acknowledged through the Edinburgh Research Partnership in engineering and mathematics (ERPem) and the Edinburgh and St Andrews Chemistry (EaStCHEM) initiatives, along with knowledge transfer funding. Support from the Engineering and Physical Sciences Research Council (EPSRC) of the UK through the IeMRC (Smart Microsystems – FS/01/02/10) Grant is acknowledged. Ilka Schmüser thanks the EPSRC and the University of Edinburgh for financial support.

And, there was this from Rowe’s article,

The work is part of a larger R&D programme on the development of smart sensors at the University of Edinburgh. It involves staff and students from the Schools of Engineering and Chemistry thus providing the required broad set of skills and experience. The resulting MNEE technology is currently being commercialised by Nanoflex Ltd.

So, the funding comes from Scottish and UK sources and the company which is commercializing the MNEE is located in the North West of England in the  Sci-Tech Daresbury Campus (from the company’s LinkedIn page). This certainly illustrates how entwined the Scottish and UK science scenes are entwined as is the commercialization process.

I last mentioned Scotland, science, and the independence vote in a July 8, 2014 posting which covers some of the ‘pro’ and ‘con’ thinking at the time.

The Danes get more from their marijuana

A Sept. 8, 2014 news item on ScienceDaily features work at the University of Copenhagen where scientists are researching a new method for reducing consumption of drugs such as adrenaline and cannabis when used therapeutically,

About 40% of all medicines used today work through the so-called “G protein-coupled receptors.” These receptors react to changes in the cell environment, for example, to increased amounts of chemicals like cannabis, adrenaline or the medications we take and are therefore of paramount importance to the pharmaceutical industry.

“There is a lot of attention on research into “G protein-coupled receptors,” because they have a key roll in recognizing and binding different substances. Our new method is of interest to the industry because it can contribute to faster and cheaper drug development,” explains Professor Dimitrios Stamou, who heads the Nanomedicine research group at the Nano-Science Center, where the method has been developed. …

A Sept. 8, 2014 University of Copenhagen news release on EurekAlert, which originated the news item, provides a little more detail,

The new method will reduce dramatically the use of precious membrane protein samples. Traditionally, you test a medicinal substance by using small drops of a sample containing the protein that the medicine binds to. If you look closely enough however, each drop is composed of thousands of billions of small nano-containers containing the isolated proteins. Until now, it has been assumed that all of these nano-containers are identical. But it turns out this is not the case and that is why researchers can use a billion times smaller samples for testing drug candidates than hitherto.

“We have discovered that each one of the countless nano-containers is unique. Our method allows us to collect information about each individual nano-container. We can use this information to construct high-throughput screens, where you can, for example, test how medicinal drugs bind G protein-coupled receptors”, explains Signe Mathiasen, who is first author of the paper describing the screening method in Nature Methods. Signe Mathiasen has worked on developing a screening method over the last four years at the University of Copenhagen, where she wrote her PhD thesis research project under the supervision of Professor Stamou.

Although the title doesn’t betray its marijuana orientation, this is a link to and a citation for the researchers’ work,

Nanoscale high-content analysis using compositional heterogeneities of single proteoliposomes by Signe Mathiasen, Sune M Christensen, Juan José Fung, Søren G F Rasmussen, Jonathan F Fay, Sune K Jorgensen, Salome Veshaguri, David L Farrens, Maria Kiskowski, Brian Kobilka, & Dimitrios Stamou. Nature Methods 11, 931–934 (2014) doi:10.1038/nmeth.3062 Published online 03 August 2014

This paper is behind a paywall.

Following the sound of a nanoparticle through the body

I was hoping for some actual sound files of nanoparticles in the body but for some rason the researchers don’t seem to have made them freely available. However, there is this textual description in a Sept. 5, 2014 news item on Nanowerk,

Nanoparticles have become interesting means for biomedical applications. Thanks to their minute dimensions and large surface areas, they can often penetrate cellular membranes and deliver high payloads of targeting agents and drugs to achieve better specificity and therapeutic effects than non-targeted treatments. Yet, quantitative in vivo measurements of nanoparticle concentrations are essential for nanotechnology-based preclinical research.

To date, tedious ex vivo analysis of nanoparticle concentrations in organs of test animals remains a standard approach in such biodistribution studies. Most current imaging methods remain limited due to several disadvantages and/or high costs. Optoacoustic tomography (OAT), a method that utilizes ultrasound generated by absorption of nanosecond-scale laser pulses to recreate an image of the absorbing volume based on the spatial variation of optical absorption coefficients, is a potential alternative.

Usually, due to the unknown light distribution in a complex optical scattering environment, tomographic images of live animals contain only qualitative information and are not suitable for quantitative biodistribution analysis. …

A Sept. 3, 2014 Wiley-VCH publishers press release by K. Maedefessel-Herrmann, which originated the news item, provides more details about the work,

… A team of researchers from TomoWave Laboratories, Inc., Rice University, and the University of Houston now developed a methodology to correlate changes in optoacoustic signal intensity from organs of live animals detected with OAT in relation to changes of optical absorption coefficient in those organs caused by nanoparticle accumulation.

The researchers quantified localized OAT brightness changes induced by accumulation of single-walled carbon nanotubes (SWCNTs) in liver, kidney and spleen of nude mice. Using the intrinsic fluorescence properties of disaggregated nanotubes, they measured SWCNT concentrations in the parts-per-million range in the harvested organs and defined the corresponding changes in optical absorption coefficient. The observed increases in optoacoustic signal brightness in tissues were compared with the increases in optical absorption coefficients caused by SWCNT accumulation.
The combination of these methods allows one to perform sensitivity calibration of an OAT system for a selected type of animal and for a range of optical absorption coefficient values of their organs to enable non-invasive concentration measurements of optically absorbing nanoparticles and dyes in vivo.

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

Enabling in vivo measurements of nanoparticle concentrations with three-dimensional optoacoustic tomography by Dmitri A. Tsyboulski, Anton V. Liopo, Richard Su, Sergey A. Ermilov, Sergei M. Bachilo, R. Bruce Weisman, and Alexander A. Oraevsky. Journal of Biophotonics, Volume 7, Issue 8, pages 581–588, August 2014. DOI: 10.1002/jbio.201200233  Article first published online: 2 APR 2013

This is an open access article.

SWEET, sweet transporters

A Sept. 4, 2014 news item on Azonano is all about sugar,

Sugars are an essential source of energy for microrganisms, animals and humans. They are produced by plants, which convert energy from sunlight into chemical energy in the form of sugars through photosynthesis.

These sugars are taken up into cells, no matter whether these are bacteria, yeast, human cells or plant cells, by proteins that create sugar-specific pores in the membrane that surrounds a cell. These transport proteins are thus essential in all organisms. It is not surprising that the transporters of humans and plants are very similar since they evolved from their bacterial ancestors.

Sugar transporters can also be a source of vulnerability for plants and animals alike. In plants they can be susceptible to takeover by pathogens, hijacking the source of the plant’s food and energy. In animals, mutations in sugar transporters can lead to diseases, such as diabetes.

New work from a team led by the Stanford University School of Medicine’s Liang Feng and including Carnegie’s [Carnegie Institution for Science] Wolf Frommer has for the first time elucidated the atomic structures of the prototype of the sugar transporters (termed “SWEET” transporters) in plants and humans. These are bacterial sugar transporters, called SemiSWEETs (because they are just half the size of the human and plant ones). …

A Sept. 3, 2014 Carnegie Institution for Science news release, which originated the news item, describes the importance of understanding these transporters,

Until now, there was very limited information about the unique structures of these important transport proteins, which it turns out are different from all other known sugar transporters.

Discovering the structure of these proteins is important, as it is the key to unlocking the mechanism by which they work. And understanding their mechanism is crucial for figuring out what happens when these functions fail to work properly, because that knowledge can help in addressing the resulting diseases or growth problems in both plants and animals.

The research team performed a combination of structural and functional analyses of SemiSWEETs and SWEETs and was able to crystallize two examples in different states, demonstrating not only the protein’s structure, but much about its functionality as well.

They found that the SemiSWEETs do not act as a sugar channel, or tunnel, which allow sugars to pass across the membrane. Rather they act like an airlock, moving the sugars in multiple stages, two of which can be observed in the crystal structures. The SemiSWEETs, among the smallest known transport proteins, assemble in pairs, thereby creating a structure that looks like their bigger plant and human SWEET homologs. This marks the SWEET family of proteins as drastically different from other sugar transport proteins.

“One of the most-exciting parts of this discovery is the speed with which we were able to move from discovering these novel sugar transporters, to determining their actual structure, to showing how they work,” Frommer said. “Fantastic progress made possible by a collaboration with a structural biologist from Stanford University. Our findings highlight the potential practical applications of this information in improving crop yields as well as in addressing human diseases.”

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

Structures of bacterial homologues of SWEET transporters in two distinct conformations by Yan Xu, Yuyong Tao, Lily S. Cheung, Chao Fan, Li-Qing Chen, Sophia Xu, Kay Perry, Wolf B. Frommer, & Liang Feng. Nature (2014) doi:10.1038/nature13670 Published online 03 September 2014

This paper is behind a paywall.

Malaria vaccine with self-assembling nanoparticles

This research was published in April 2013 so I’m not sure what has occasioned a Sept. 2014 push for publicity. Still, it’s interesting work which may lead to a more effective vaccine for malaria than some of the other solutions being tested.  From a Sept. 4, 2014 news item on Nanowerk,

A self-assembling nanoparticle designed by a University of Connecticut (UConn) professor is the key component of a potent new malaria vaccine that is showing promise in early tests.

For years, scientists trying to develop a malaria vaccine have been stymied by the malaria parasite’s ability to transform itself and “hide” in the liver and red blood cells of an infected person to avoid detection by the immune system.

But a novel protein nanoparticle developed by Peter Burkhard, a professor in the Department of Molecular & Cell Biology, in collaboration with David Lanar, an infectious disease specialist with the Walter Reed Army Institute of Research, has shown to be effective at getting the immune system to attack the most lethal species of malaria parasite, Plasmodium falciparum, after it enters the body and before it has a chance to hide and aggressively spread.

Sept. 3, 2014 University of Connecticut news release by Colin Poitras, which originated the news item, describes the particle and the research in greater detail,

The key to the vaccine’s success lies in the nanoparticle’s perfect icosahedral symmetry (think of the pattern on a soccer ball) and ability to carry on its surface up to 60 copies of the parasite’s protein. The proteins are arranged in a dense, carefully constructed cluster that the immune system perceives as a threat, prompting it to release large amounts of antibodies that can attack and kill the parasite.

In tests with mice, the vaccine was 90-100 percent effective in eradicating the Plasmodium falciparum parasite and maintaining long-term immunity over 15 months. That success rate is considerably higher than the reported success rate for RTS,S, the world’s most advanced malaria vaccine candidate currently undergoing phase 3 clinical trials, which is the last stage of testing before licensing.

“Both vaccines are similar, it’s just that the density of the RTS,S protein displays is much lower than ours,” says Burkhard. “The homogeneity of our vaccine is much higher, which produces a stronger immune system response. That is why we are confident that ours will be an improvement.

“Every single protein chain that forms our particle displays one of the pathogen’s protein molecules that are recognized by the immune system,” adds Burkhard, an expert in structural biology affiliated with UConn’s Institute of Materials Science. “With RTS,S, only about 14 percent of the vaccine’s protein is from the malaria parasite. We are able to achieve our high density because of the design of the nanoparticle, which we control.”

Here’s an image illustrating the nanoparticle,

This self-assembling protein nanoparticle relies on rigid protein structures called ‘coiled coils’ (blue and green in the image) to create a stable framework upon which scientists can attach malaria parasite antigens. Early tests show that injecting the nanoparticles into the body as a vaccine initiates a strong immune system response that destroys a malarial parasite when it enters the body and before it has time to spread. (Image courtesy of Peter Burkhard)

This self-assembling protein nanoparticle relies on rigid protein structures called ‘coiled coils’ (blue and green in the image) to create a stable framework upon which scientists can attach malaria parasite antigens. Early tests show that injecting the nanoparticles into the body as a vaccine initiates a strong immune system response that destroys a malarial parasite when it enters the body and before it has time to spread. (Image courtesy of Peter Burkhard)

The news release goes on to explain why malaria is considered a major, global health problem and how the researchers approached the problem with developing a malaria vaccine for humans,

The search for a malaria vaccine is one of the most important research projects in global public health. The disease is commonly transported through the bites of nighttime mosquitoes. Those infected suffer from severe fevers, chills, and a flu-like illness. In severe cases, malaria causes seizures, severe anemia, respiratory distress, and kidney failure. Each year, more than 200 million cases of malaria are reported worldwide. The World Health Organization estimated that 627,000 people died from malaria in 2012, many of them children living in sub-Saharan Africa.

It took the researchers more than 10 years to finalize the precise assembly of the nanoparticle as the critical carrier of the vaccine and find the right parts of the malaria protein to trigger an effective immune response. The research was further complicated by the fact that the malaria parasite that impacts mice used in lab tests is structurally different from the one infecting humans.

The scientists used a creative approach to get around the problem.

“Testing the vaccine’s efficacy was difficult because the parasite that causes malaria in humans only grows in humans,” Lanar says. “But we developed a little trick. We took a mouse malaria parasite and put in its DNA a piece of DNA from the human malaria parasite that we wanted our vaccine to attack. That allowed us to conduct inexpensive mouse studies to test the vaccine before going to expensive human trials.”

The pair’s research has been supported by a $2 million grant from the National Institutes of Health and $2 million from the U.S. Military Infectious Disease Research Program. A request for an additional $7 million in funding from the U.S. Army to conduct the next phase of vaccine development, including manufacturing and human trials, is pending.

“We are on schedule to manufacture the vaccine for human use early next year,” says Lanar. “It will take about six months to finish quality control and toxicology studies on the final product and get permission from the FDA to do human trials.”

Lanar says the team hopes to begin early testing in humans in 2016 and, if the results are promising, field trials in malaria endemic areas will follow in 2017. The required field trial testing could last five years or more before the vaccine is available for licensure and public use, Lanar says.

Martin Edlund, CEO of Malaria No More, a New York-based nonprofit focused on fighting deaths from malaria, says, “This research presents a promising new approach to developing a malaria vaccine. Innovative work such as what’s being done at the University of Connecticut puts us closer than we’ve ever been to ending one of the world’s oldest, costliest, and deadliest diseases.”

A Switzerland-based company, Alpha-O-Peptides, founded by Burkhard, holds the patent on the self-assembling nanoparticle used in the malaria vaccine. Burkhard is also exploring other potential uses for the nanoparticle, including a vaccine that will fight animal flu and one that will help people with nicotine addiction. Professor Mazhar Khan from UConn’s Department of Pathobiology is collaborating with Burkhard on the animal flu vaccine.

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

Mechanisms of protective immune responses induced by the Plasmodium falciparum circumsporozoite protein-based, self-assembling protein nanoparticle vaccine by Margaret E McCoy, Hannah E Golden, Tais APF Doll, Yongkun Yang, Stephen A Kaba, Peter Burkhard, and David E Lanar. Malaria Journal 2013, 12:136 doi:10.1186/1475-2875-12-136

This is an open access article.