Tag Archives: FDA

AquAdvantage salmon (genetically modified) approved for consumption in Canada

This is an update of the AquAdvantage salmon story covered in my Dec. 4, 2015 post (scroll down about 40% of the way). At the time, the US Food and Drug Administration (FDA) had just given approval for consumption of the fish. There was speculation there would be a long hard fight over approval in Canada. This does not seem to have been the case, according to a May 10, 2016 news item announcing Health Canada’s on phys.org,

Canada’s health ministry on Thursday [May 19, 2016] approved a type of genetically modified salmon as safe to eat, making it the first transgenic animal destined for Canadian dinner tables.

This comes six months after US authorities gave the green light to sell the fish in American grocery stores.

The decisions by Health Canada and the US Food and Drug Administration follow two decades of controversy over the fish, which is an Atlantic salmon injected with genes from Pacific Chinook salmon and a fish known as the ocean pout to make it grow faster.

The resulting fish, called AquAdvantage Salmon, is made by AquaBounty Technologies in Massachusetts, and can reach adult size in 16 to 18 months instead of 30 months for normal Atlantic salmon.

A May 19, 2016 BIOTECanada news release on businesswire provides more detail about one of the salmon’s Canadian connections,

Canadian technology emanating from Memorial University developed the AquAdvantage salmon by introducing a growth hormone gene from Chinook salmon into the genome of Atlantic salmon. This results in a salmon which grows faster and reaches market size quicker and AquAdvantage salmon is identical to other farmed salmon. The AquAdvantage salmon also received US FDA approval in November 2015. With the growing world population, AquaBounty is one of many biotechnology companies offering safe and sustainable means to enhance the security and supply of food in the world. AquaBounty has improved the productivity of aquaculture through its use of biotechnology and modern breeding technics that have led to the development of AquAdvantage salmon.

“Importantly, today’s approval is a result of a four year science-based regulatory approval process which involved four federal government departments including Agriculture and AgriFood, Canada Food Inspection Agency, Environment and Climate Change, Fisheries and Oceans and Health which demonstrates the rigour and scope of science based regulatory approvals in Canada. Coupled with the report from the [US] National Academy of Sciences today’s [May 19, 2016] approval clearly demonstrates that genetic engineering of food is not only necessary but also extremely safe,” concluded Casey [Andrew Casey, President and CEO BIOTECanada].

There’s another connection, the salmon hatcheries are based in Prince Edward Island.

While BIOTECanada’s Andrew Casey is crowing about this approval, it should be noted that there was a losing court battle with British Columbia’s Living Oceans Society and Nova Scotia’s Ecology Action Centre both challenging the federal government’s approval. They may have lost *the* battle but, as the cliché goes, ‘the war is not over yet’. There’s an Issue about the lack of labeling and there’s always the  possibility that retailers and/or consumers may decide to boycott the fish.

As for BIOTECanada, there’s this description from the news release,

BIOTECanada is the national industry association with more than 230 members reflecting the diverse nature of Canada’s health, industrial and agricultural biotechnology sectors. In addition to providing significant health benefits for Canadians, the biotechnology industry has quickly become an essential part of the transformation of many traditional cornerstones of the Canadian economy including manufacturing, automotive, energy, aerospace and forestry industries. Biotechnology in all of its applications from health, agriculture and industrial is offering solutions for the collective population.

You can find the BIOTECanada website here.

Personally, I’m a bit ambivalent about it all. I understand the necessity for changing our food production processes but I do think more attention should be paid to consumers’ concerns and that organizations such as BIOTECanada could do a better job of communicating.

*’the’ added on Aug. 4, 2016.

Opioid addiction and nanotechnology in Pennsylvania, US

Combating a drug addiction ‘crisis’ with a nanotechnology-enabled solution is the main topic although the technology is being implemented for another problem first according to this May 4, 2016 article by John Luciew for pennlive.com (Note: Links have been removed),

Treating pain is a constant in medicine. It’s part of the human condition, known as the “fifth vital sign” among physicians. Effectively treating pain will continue to play a central role in medicine, despite the societal shock waves brought on by the rapid rise in opioid addiction across America.

The fallout from our nation’s opioid addiction crisis is roiling the medical and pharmaceutical industries, where regulatory action is rapidly reining in opioid painkiller prescriptions with new guidelines and stricter controls.

By harnessing nanotechnology and small-particles physics, Iroko Pharmaceuticals is developing a new class of low-dose prescription painkillers. Company executives say their line of nonsteroidal anti-inflammatory drugs could be the opioid alternative that the medical community has been looking for amid America’s addiction crisis.

The pharmaceutical company is Pennsylvania-based (US) and it isn’t tackling the ‘opioid addiction crisis’ yet. First, there’s this,

Its new line of prescription painkillers are predicated upon a highly patented process of pulverizing drug molecules so they are up to 100 times smaller, which markedly increases their pain-killing effectiveness at dramatically lower doses.

Right now, Iroko is focusing this nanotechnology on creating a full line of low-dose prescription painkillers based upon the class of drugs known as nonsteroidal anti-inflammatories, or NSAIDs. There are six NSAID molecules, the most common being Ibuprofen. Iroko is planning nanotechnology technology versions for all six NSAID molecules, three of which have already received approval from the Food and Drug Administration.

Luciew has done some homework on the technology,

“We solved a chemistry problem by using physics,” explained Iroko Chairman Osagie Imasogie, who founded the company [Iroko Pharmaceuticals] in 2007.

Yet, the company that actually solved the physics problem was iCeutica, founded in Australia and now based in King of Prussia, Pa.

iCeutica owns the patented SoluMatrix fine particle process that pulverizes drug molecules into nano-sized particles, enabling low doses of a drug to be better absorbed by the body, thus providing faster and far more effective pain relief.

Of course, the practice of crushing and grinding drug powders is as old as the pharmacist’s mortar and pestle. But there’s never been a way of pulverizing a drug molecule into nano particles that was scalable for industrial production — not until iCeutica created its SoluMatrix process, that is.

iCeutica provides a description of the technology on its SoluMatrix webpage,

iCeutica’s proprietary SoluMatrix™ Fine Particle Technology fuels new product development and solves problems of bioavailability, variability, side effects and delivery of marketed or development-stage pharmaceuticals.

The SoluMatrix technology is a scaleable and cost-effective manufacturing process that can produce submicron-sized drug particles that are 10 to 200 times smaller than conventional drug particles. The particles generated using this technology, which both grinds the drug particles into a superfine powder and protects those submicron particles from subsequent agglomeration (or clumping together into big particles), comprise a single unit operation and can be manufactured into tablets, capsules and other dosage forms without further processing.

The SoluMatrix technology improves the performance of pharmaceuticals by dramatically changing how the drug dissolves and is absorbed. By making submicron-sized particles of a drug, it is possible to:

Unfortunately there aren’t more details. I’m somewhat puzzled  by the submicron measurement why not state the size using the term nanometre?

Getting back  to Iroko, Imasogie, impressed with the SoluMatrix technology, has made a major investment in iCeutica and is chair of iCeutica’s board. His homebase company, Iroko holds exclusive global rights to SoluMatrix.

Luciew’s article describes the current situation in the NSAID market,

Iroko officials acknowledge that NSAID painkillers carry their own health risks, including the potential for stomach ulcers, kidney problems and cardio-vascular ailments, up to and including stroke and heart attack. The fears associated with NSAIDs peaked a decade ago with the Vioxx case, a popular prescription NSAID that was eventually taken off the market due to associated cardiac and other risks.

The latest FDA guidelines for NSAID use calls for the lowest effective dose, which precisely describes the nanotechnology-driven low-dose NSAID drugs Iroko is rolling out. What is more, due to the ongoing opioid crisis, both the FDA and the Centers for Disease Control are heavily emphasizing non-opioid alternatives for pain relief, further opening to door for Iroko’s pain products.

That said about the issues with NSAIDs, Luciew outlines Iroko’s current offerings and explains what makes this technology so attractive,

According to Imasogie, Iroko’s line of low-dose, nanotechnology NSAIDs fits both sets of regulatory safety criteria. The new drugs are the lowest effective dose for NSAIDs, and are a viable pain-killing alternative to opioids, especially when it comes to treating osteoarthritis and other moderate pain.

“No one is going to give an NSAID if you have cancer,” Imasogie says. “But for chronic low back pain, yes.”

Three of Iroko’s six low-dose NSAID offerings have already received FDA approval and are on the market:

  • Zorvolex (diclofenac), approved in October 2013 for the management of mild to moderate acute pain in adults and in August 2014 for the management of osteoarthritis pain.
  • Tivorbex, approved in February 2014 for treatment of mild to moderate acute pain in adults.
  • Vivlodex, approved in October 2015 as another option for treatment of osteoarthritis pain. Three more of Iroko’s low-dose NSAIDs are awaiting approval.

These nano drugs are effective at doses of 35 to 40 milligrams to as low as 10 milligrams, the company says. That’s compared to other NSAID doses that start at 200 milligrams. As a result, Iroko’s low-dose NSAID drugs are being marketed as providing a prescription alternative to opioids at the precise moment everyone from the White House to the white-coat-clad family physician is searching for one.

If you the have time and interest, I encourage you to read Luciew’s article in its entirety. He covers more market issues and includes an enbedded video in his piece.

One last note about Iroko Pharmaceuticals, the company is named after a tree found on the African continent and executives of the company have hinted they are experimenting with SoluMatrix to make low-dose opioids available in the future.

While I have my doubts about the opioid addiction ‘crisis’, I do believe that lower, more effective doses of painkillers, regardless of their drug class, can only benefit patients.

Chip in brain lets quadriplegic (tetraplegic) move hands and fingers

An April 13, 2016 news item on ScienceDaily describes the latest brain implant,

Six years ago, he was paralyzed in a diving accident. Today, he participates in clinical sessions during which he can grasp and swipe a credit card or play a guitar video game with his own fingers and hand. These complex functional movements are driven by his own thoughts and a prototype medical system that are detailed in a study published online today in the journal Nature.

The device, called NeuroLife, was invented at Battelle, which teamed with physicians and neuroscientists from The Ohio State University Wexner Medical Center to develop the research approach and perform the clinical study. Ohio State doctors identified the study participant and implanted a tiny computer chip into his brain.

An April 13, 2016 Ohio State University news release on EurekAlert, which originated the news item, provides more details about the participant and the technology,

That pioneering participant, Ian Burkhart, is a 24-year-old quadriplegic from Dublin, Ohio, and the first person to use this technology. This electronic neural bypass for spinal cord injuries reconnects the brain directly to muscles, allowing voluntary and functional control of a paralyzed limb by using his thoughts. The device interprets thoughts and brain signals then bypasses his injured spinal cord and connects directly to a sleeve that stimulates the muscles that control his arm and hand.

“We’re showing for the first time that a quadriplegic patient is able to improve his level of motor function and hand movements,” said Dr. Ali Rezai, a co-author of the study and a neurosurgeon at Ohio State’s Wexner Medical Center.

Burkhart first demonstrated the neural bypass technology in June 2014, when he was able to open and close his hand simply by thinking about it. Now, he can perform more sophisticated movements with his hands and fingers such as picking up a spoon or picking up and holding a phone to his ear — things he couldn’t do before and which can significantly improve his quality of life.

“It’s amazing to see what he’s accomplished,” said Nick Annetta, electrical engineering lead for Battelle’s team on the project. “Ian can grasp a bottle, pour the contents of the bottle into a jar and put the bottle back down. Then he takes a stir bar, grips that and then stirs the contents of the jar that he just poured and puts it back down. He’s controlling it every step of the way.”

The neural bypass technology combines algorithms that learn and decode the user’s brain activity and a high-definition muscle stimulation sleeve that translates neural impulses from the brain and transmits new signals to the paralyzed limb.

The Battelle team has been working on this technology for more than a decade. To develop the algorithms, software and stimulation sleeve, Battelle scientists first recorded neural impulses from an electrode array implanted in a paralyzed person’s brain. They used that recorded data to illustrate the device’s effect on the patient and prove the concept.

Four years ago, former Battelle researcher Chad Bouton and his team began collaborating with Ohio State Neurological Institute researchers and clinicians Rezai and Dr. Jerry Mysiw to design the clinical trials and validate the feasibility of using the neural bypass technology in patients.

“In the 30 years I’ve been in this field, this is the first time we’ve been able to offer realistic hope to people who have very challenging lives,” said Mysiw, chair of the Department of Physical Medicine and Rehabilitation at Ohio State. “What we’re looking to do is help these people regain more control over their bodies.”

During a three-hour surgery in April 2014, Rezai implanted a computer chip smaller than a pea onto the motor cortex of Burkhart’s brain.

The Ohio State and Battelle teams worked together to figure out the correct sequence of electrodes to stimulate to allow Burkhart to move his fingers and hand functionally. For example, Burkhart uses different brain signals and muscles to rotate his hand, make a fist or pinch his fingers together to grasp an object. As part of the study, Burkhart worked for months using the electrode sleeve to stimulate his forearm to rebuild his atrophied muscles so they would be more responsive to the electric stimulation.

“During the last decade, we’ve learned how to decipher brain signals in patients who are completely paralyzed and now, for the first time, those thoughts are being turned into movement,” said study co-author Bouton, who directed Battelle’s team before he joined the New York-based Feinstein Institute for Medical Research. “Our findings show that signals recorded from within the brain can be re-routed around an injury to the spinal cord, allowing restoration of functional movement and even movement of individual fingers.”

Burkhart said it was an easy decision to participate in the FDA-approved clinical trial at Ohio State’s Wexner Medical Center because he wanted to try to help others with spinal cord injuries. “I just kind of think that it’s my obligation to society,” Burkhart said. “If someone else had an opportunity to do it in some other part of the world, I would hope that they would commit their time so that everyone can benefit from it in the future.”

Rezai and the team from Battelle agree that this technology holds the promise to help patients affected by various brain and spinal cord injuries such as strokes and traumatic brain injury to be more independent and functional.

“We’re hoping that this technology will evolve into a wireless system connecting brain signals and thoughts to the outside world to improve the function and quality of life for those with disabilities,” Rezai said. “One of our major goals is to make this readily available to be used by patients at home.”

Burkhart is the first of a potential five participants in a clinical study. Mysiw and Rezai have identified a second patient who is scheduled to start the study in the summer.

“Participating in this research has changed me in the sense that I have a lot more hope for the future now,” Burkhart said. “I always did have a certain level of hope, but now I know, first-hand, that there are going to be improvements in science and technology that will make my life better.”

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

Restoring cortical control of functional movement in a human with quadriplegia by Chad E. Bouton, Ammar Shaikhouni, Nicholas V. Annetta, Marcia A. Bockbrader, David A. Friedenberg, Dylan M. Nielson, Gaurav Sharma, Per B. Sederberg, Bradley C. Glenn, W. Jerry Mysiw, Austin G. Morgan, Milind Deogaonkar, & Ali R. Rezai. Nature (2016)  doi:10.1038/nature17435 Published online 13 April 2016

This paper is behind a paywall but there is an in depth April 13, 2016 article by Linda Geddes in Nature providing nuggets of new insight such as this,

Previous studies have suggested that after spinal-cord injuries, the brain undergoes ‘reorganization’ — a rewiring of its connections. But this new work suggests that the degree of reorganization occurring after such injuries may be less than previously assumed. “It gives us a lot of hope that there are perhaps not as many neural changes in the brain as we might have imagined [emphasis mine] after an injury like this, and we can bypass damaged areas of the spinal cord to regain movement,” says Bouton.

The Geddes article is open access.

Finally, there’s an April 13, 2016 article by Will Oremus for Slate.com, which notes that this story is not a fairy tale as there’s a possibility the chip will be removed in the near future as the US Food and Drug Administration’s approval of the device was conditional due to this,

Burkhart knows the device was never meant to last forever. The brain implant’s efficacy gradually degrades over time due to scarring in the brain tissue, and eventually that hardware degradation will start to undo the progress that Burkhart and the software have made together.

He told me he has accepted that his newfound mobility is temporary, and that the progress he has made is likely to benefit posterity more than it benefits him. “I now know that when I’m connected to the system I can do all these great things. It won’t be too much of a shock to me [when it’s over], because even now I can only use the system for a few hours a week when I’m down in the lab. But it will be something I’ll certainly miss.”

Cornell University researchers breach blood-brain barrier

There are other teams working on ways to breach the blood-brain barrier (my March 26, 2015 post highlights work from a team at the University of Montréal) but this team from  Cornell is working with a drug that has already been approved by the US Food and Drug Administration (FDA) according to an April 8, 2016 news item on ScienceDaily,

Cornell researchers have discovered a way to penetrate the blood brain barrier (BBB) that may soon permit delivery of drugs directly into the brain to treat disorders such as Alzheimer’s disease and chemotherapy-resistant cancers.

The BBB is a layer of endothelial cells that selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose and water, while keeping others out.

Cornell researchers report that an FDA-approved drug called Lexiscan activates receptors — called adenosine receptors — that are expressed on these BBB cells.

An April 4, 2016 Cornell University news release by Krishna Ramanujan, which originated the news item, expands on the theme,

“We can open the BBB for a brief window of time, long enough to deliver therapies to the brain, but not too long so as to harm the brain. We hope in the future, this will be used to treat many types of neurological disorders,” said Margaret Bynoe, associate professor in the Department of Microbiology and Immunology in Cornell’s College of Veterinary Medicine. …

The researchers were able to deliver chemotherapy drugs into the brains of mice, as well as large molecules, like an antibody that binds to Alzheimer’s disease plaques, according to the paper.

To test whether this drug delivery system has application to the human BBB, the lab engineered a BBB model using human primary brain endothelial cells. They observed that Lexiscan opened the engineered BBB in a manner similar to its actions in mice.

Bynoe and Kim discovered that a protein called P-glycoprotein is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Lexiscan acts on one of the adenosine receptors expressed on BBB endothelial cells specifically activating them. They showed that Lexiscan down-regulates P-glycoprotein expression and function on the BBB endothelial cells. It acts like a switch that can be turned on and off in a time dependent manner, which provides a measure of safety for the patient.

“We demonstrated that down-modulation of P-glycoprotein function coincides exquisitely with chemotherapeutic drug accumulation” in the brains of mice and across an engineered BBB using human endothelial cells, Bynoe said. “The amount of chemotherapeutic drugs that accumulated in the brain was significant.”

In addition to P-glycoprotein’s role in inhibiting foreign substances from penetrating the BBB, the protein is also expressed by many different types of cancers and makes these cancers resistant to chemotherapy.

“This finding has significant implications beyond modulation of the BBB,” Bynoe said. “It suggests that in the future, we may be able to modulate adenosine receptors to regulate P-glycoprotein in the treatment of cancer cells resistant to chemotherapy.”

Because Lexiscan is an FDA-approved drug, ”the potential for a breakthrough in drug delivery systems for diseases such as Alzheimer’s disease, Parkinson’s disease, autism, brain tumors and chemotherapy-resistant cancers is not far off,” Bynoe said.

Another advantage is that these molecules (adenosine receptors  and P-glycoprotein are naturally expressed in mammals. “We don’t have to knock out a gene or insert one for a therapy to work,” Bynoe said.

The study was funded by the National Institutes of Health and the Kwanjung Educational Foundation.

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

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier by Do-Geun Kim and Margaret S. Bynoe. J Clin Invest. doi:10.1172/JCI76207 First published April 4, 2016

Copyright © 2016, The American Society for Clinical Investigation.

This paper appears to be open access.

$1.4B for US National Nanotechnology Initiative (NNI) in 2017 budget

According to an April 1, 2016 news item on Nanowerk, the US National Nanotechnology (NNI) has released its 2017 budget supplement,

The President’s Budget for Fiscal Year 2017 provides $1.4 billion for the National Nanotechnology Initiative (NNI), affirming the important role that nanotechnology continues to play in the Administration’s innovation agenda. NNI
Cumulatively totaling nearly $24 billion since the inception of the NNI in 2001, the President’s 2017 Budget supports nanoscale science, engineering, and technology R&D at 11 agencies.

Another 9 agencies have nanotechnology-related mission interests or regulatory responsibilities.

An April 1, 2016 NNI news release, which originated the news item, affirms the Obama administration’s commitment to the NNI and notes the supplement serves as an annual report amongst other functions,

Throughout its two terms, the Obama Administration has maintained strong fiscal support for the NNI and has implemented new programs and activities to engage the broader nanotechnology community to support the NNI’s vision that the ability to understand and control matter at the nanoscale will lead to new innovations that will improve our quality of life and benefit society.

This Budget Supplement documents progress of these participating agencies in addressing the goals and objectives of the NNI. It also serves as the Annual Report for the NNI called for under the provisions of the 21st Century Nanotechnology Research and Development Act of 2003 (Public Law 108-153, 15 USC §7501). The report also addresses the requirement for Department of Defense reporting on its nanotechnology investments, per 10 USC §2358.

For additional details and to view the full document, visit www.nano.gov/2017BudgetSupplement.

I don’t seem to have posted about the 2016 NNI budget allotment but 2017’s $1.4B represents a drop of $100M since 2015’s $1.5 allotment.

The 2017 NNI budget supplement describes the NNI’s main focus,

Over the past year, the NNI participating agencies, the White House Office of Science and Technology Policy (OSTP), and the National Nanotechnology Coordination Office (NNCO) have been charting the future directions of the NNI, including putting greater focus on promoting commercialization and increasing education and outreach efforts to the broader nanotechnology community. As part of this effort, and in keeping with recommendations from the 2014 review of the NNI by the President’s Council of Advisors for Science and Technology, the NNI has been working to establish Nanotechnology-Inspired Grand Challenges, ambitious but achievable goals that will harness nanotechnology to solve National or global problems and that have the potential to capture the public’s imagination. Based upon inputs from NNI agencies and the broader community, the first Nanotechnology-Inspired Grand Challenge (for future computing) was announced by OSTP on October 20, 2015, calling for a collaborative effort to “create a new type of computer that can proactively interpret and learn from data, solve unfamiliar problems using what it has learned, and operate with the energy efficiency of the human brain.” This Grand Challenge has generated broad interest within the nanotechnology community—not only NNI agencies, but also industry, technical societies, and private foundations—and planning is underway to address how the agencies and the community will work together to achieve this goal. Topics for additional Nanotechnology-Inspired Grand Challenges are under review.

Interestingly, it also offers an explanation of the images on its cover (Note: Links have been removed),

US_NNI_2017_budget_cover

About the cover

Each year’s National Nanotechnology Initiative Supplement to the President’s Budget features cover images illustrating recent developments in nanotechnology stemming from NNI activities that have the potential to make major contributions to National priorities. The text below explains the significance of each of the featured images on this year’s cover.

US_NNI_2017_front_cover_CloseUp

Front cover featured images (above): Images illustrating three novel nanomedicine applications. Center: microneedle array for glucose-responsive insulin delivery imaged using fluorescence microscopy. This “smart insulin patch” is based on painless microneedles loaded with hypoxia-sensitive vesicles ~100 nm in diameter that release insulin in response to high glucose levels. Dr. Zhen Gu and colleagues at the University of North Carolina (UNC) at Chapel Hill and North Carolina State University have demonstrated that this patch effectively regulates the blood glucose of type 1 diabetic mice with faster response than current pH-sensitive formulations. The inset image on the lower right shows the structure of the nanovesicles; each microneedle contains more than 100 million of these vesicles. The research was supported by the American Diabetes Association, the State of North Carolina, the National Institutes of Health (NIH), and the National Science Foundation (NSF). Left: colorized rendering of a candidate universal flu vaccine nanoparticle. The vaccine molecule, developed at the NIH Vaccine Research Center, displays only the conserved part of the viral spike and stimulates the production of antibodies to fight against the ever-changing flu virus. The vaccine is engineered from a ~13 nm ferritin core (blue) combined with a 7 nm influenza antigen (green). Image credit: NIH National Institute of Allergy and Infectious Diseases (NIAID). Right: colorized scanning electron micrograph of Ebola virus particles on an infected VERO E6 cell. Blue represents individual Ebola virus particles. The image was produced by John Bernbaum and Jiro Wada at NIAID. When the Ebola outbreak struck in 2014, the Food and Drug Administration authorized emergency use of lateral flow immunoassays for Ebola detection that use gold nanoparticles for visual interpretation of the tests.

US_NNI_2017_back_cover._CloseUp

Back cover featured images (above): Images illustrating examples of NNI educational outreach activities. Center: Comic from the NSF/NNI competition Generation Nano: Small Science Superheroes. Illustration by Amina Khan, NSF. Left of Center: Polymer Nanocone Array (biomimetic of antimicrobial insect surface) by Kyle Nowlin, UNC-Greensboro, winner from the first cycle of the NNI’s student image contest, EnvisioNano. Right of Center: Gelatin Nanoparticles in Brain (nasal delivery of stroke medication to the brain) by Elizabeth Sawicki, University of Illinois at Urbana-Champaign, winner from the second cycle of EnvisioNano. Outside right: still photo from the video Chlorination-less (water treatment method using reusable nanodiamond powder) by Abelardo Colon and Jennifer Gill, University of Puerto Rico at Rio Piedras, the winning video from the NNI’s Student Video Contest. Outside left: Society of Emerging NanoTechnologies (SENT) student group at the University of Central Florida, one of the initial nodes in the developing U.S. Nano and Emerging Technologies Student Network; photo by Alexis Vilaboy.

A couple of lawyers talk wrote about managing nanotechnology risks

Because they are lawyers, I was intrigued by a Nov. 4, 2015 article on managing nanotechnology risks by Michael Lisak and James Mizgala of Sidley Austin LLP for Industry Week. I was also intrigued by the language (Note: A link has been removed),

The inclusion of nanotechnologies within manufacturing processes and products has increased exponentially over the past decade. Fortune recently noted that nanotechnology touches almost all Fortune 500 companies and that the industry’s $20 billion worldwide size is expected to double over the next decade. [emphasis mine]

Yet, potential safety issues have been raised and regulatory uncertainties persist. As such, proactive manufacturers seeking to protect their employees, consumers, the environment and their businesses – while continuing to develop, manufacture and market their products – may face difficult choices in how to best navigate this challenging and fluid landscape, while avoiding potential “nanotort,”  [emphasis mine] whistleblower, consumer fraud and regulatory enforcement lawsuits. Doing so requires forward-thinking advice based upon detailed analyses of each manufacturer’s products and conduct in the context of rapidly evolving scientific, regulatory and legal developments.

I wonder how many terms lawyers are going to coin in addition to “nanotort”?

The lawyers focus largely on two types of nanoparticles, carbon nanotubes, with a special emphasis on multi-walled carbon nantubes (MWCNT) and nano titanium dioxide,

Despite this scientific uncertainty, international organizations, such as the International Agency for Research on Cancer [a World Health Organization agency], have already concluded that nano titanium dioxide in its powder form and multi-walled carbon nanotube-7 (“MWCNT-7”) [emphasis mine] are “possibly carcinogenic to humans.” As such, California’s Department of Public Health lists titanium dioxide and MWCNT-7 as “ingredients known or suspected to cause cancer, birth defects, or other reproductive toxicity as determined by the authoritative scientific bodies.”  Considering that processed (i.e., non-powdered) titanium dioxide is found in products like toothpaste, shampoo, chewing gum and candies, it is not surprising that some have focused upon such statements.

There’s a lot of poison in the world, for example, apples contain seeds which have arsenic in them and, for another, peanuts can be carcinogenic and they can also kill you, as they are poison to people who are allergic to them.

On the occasion of Dunkin’ Donuts removing nano titanium dioxide as an ingredient in the powdered sugar used to coat donuts, I wrote a March 13, 2015 posting, where I quote extensively from Dr. Andrew Maynard’s (then director of the University of Michigan Risk Science Center now director of the Risk Innovation Lab at Arizona State University) 2020 science blog posting about nano titanium dioxide and Dunkin’ Donuts,

He describes some of the research on nano titanium dioxide (Note: Links have been removed),

… In 2004 the European Food Safety Agency carried out a comprehensive safety review of the material. After considering the available evidence on the same materials that are currently being used in products like Dunkin’ Donuts, the review panel concluded that there no evidence for safety concerns.

Most research on titanium dioxide nanoparticles has been carried out on ones that are inhaled, not ones we eat. Yet nanoparticles in the gut are a very different proposition to those that are breathed in.

Studies into the impacts of ingested nanoparticles are still in their infancy, and more research is definitely needed. Early indications are that the gastrointestinal tract is pretty good at handling small quantities of these fine particles. This stands to reason given the naturally occurring nanoparticles we inadvertently eat every day, from charred foods and soil residue on veggies and salad, to more esoteric products such as clay-baked potatoes. There’s even evidence that nanoparticles occur naturally inside the gastrointestinal tract.

You can find Andrew’s entire discussion in his March 12, 2015 post on the 2020 Science blog. Andrew had written earlier in a July 12, 2014 posting about something he terms ‘nano donut math’ as reported by As You Sow, the activist group that made a Dunkin’ Donuts shareholder proposal which resulted in the company’s decision to stop using nano titanium dioxide in the powdered sugar found on their donuts. In any event, Andrew made this point,

In other words, if a Dunkin’ Donut Powdered Cake Donut contained 8.9 mg of TiO2 particles smaller than 10 nm, it would have to have been doused with over 1 million tons of sugar coating! (Note update at the end of this piece)

Clearly something’s wrong here – either Dunkin’ Donuts are not using food grade TiO2 but a nanopowder with particle so small they would be no use whatsoever in the sugar coating (as well as being incredibly expensive, and not FDA approved).  Or there’s something rather wrong with the analysis!

If it’s the latter – and it’s hard to imagine any other plausible reason for the data – it looks like As You Sow ended up using rather dubious figures to back up their stakeholder resolution.  I’d certainly be interested in more information on the procedures Analytical Sciences used and the checks and balances they had in place, especially as there are a number of things that can mess up a particle analysis like this.

Update July 14: My bad, I made a slight error in the size distribution calculation first time round.  This has been corrected in the article above.  Originally, I cited the estimated Mass Median Diameter (MMD) of the TiO2 particles as 167 nm, and the Geometric Standard Deviation (GSD) as 1.6.  Correcting an error in the Excel spreadsheet used to calculate the distribution (these things happen!) led to a revised estimate of MMD = 168 nm and a GSD of 1.44.  These may look like subtle differences, but when calculating the estimated particle mass below 10 nm, they make a massive difference.  With the revised figures, you’d expect less than one trillionth of  a percent of the mass of the TiO2 powder to be below 10 nm!! (the original estimate was a tenth of a millionth of a percent).  In other words – pretty much nothing!  The full analysis can be found here.

Update November 16 2014.  Based on this post, As You Sow checked the data from Analytical Sciences LLC and revised the report accordingly.  This is noted above.

It would seem that if there are concerns over nano titanium dioxide in food, the biggest would not be the amounts ingested by consumers but inhalation by workers should they breathe in large quantities when they are handling the material.

As for the MWCNTs, they have long raised alarms but most especially the long MWCNTs and for people handling them during the course of their work day. Any MWCNTs found in sports equipment and other consumer products are bound in the material and don’t pose any danger of being inhaled into the lungs, unless they should be released from their bound state (e.g. fire might release them).

After some searching for MWCNT-7, I found something which seems also to be known as Mitsui MWCNT-7 or Mitsui 7-MWCNT (here’s one of my sources). As best I understand it, Mitsui is a company that produces an MWCNT which they have coined an MWCNT-7 and which has been used in nanotoxicity testing. As best I can tell, MWCNT is MWCNT-7.

The lawyers (Lisak and Mizgala) note things have changed for manufacturers since the early days and they make some suggestions,

One thing is certain – gone are the days when “sophisticated” manufacturers incorporating nanotechnologies within their products can reasonably expect to shield themselves by pointing to scientific and regulatory uncertainties, especially given the amount of money they are spending on research and development, as well as sales and marketing efforts.

Accordingly, manufacturers should consider undertaking meaningful risk management analyses specific to their applicable products. …

First, manufacturers should fully understand the life-cycle of nanomaterials within their organization. For some, nanomaterials may be an explicit focus of innovation and production, making it easier to pinpoint where nanotechnology fits into their processes and products. For others, nanomaterials may exist either higher-up or in the back-end of their products’ supply chain. …

Second, manufacturers should understand and stay current with the scientific state-of-the-art as well as regulatory requirements and developments potentially applicable to their employees, consumers and the environment. An important consideration related to efforts to understand the state-of-the-art is whether or not manufacturers should themselves expend resources to advance “the science” in seeking to help find answers to some of the aforementioned uncertainties. …

The lawyers go on to suggest that manufacturers should consider proactively researching nanotoxicity so as to better defend themselves against any future legal suits.

Encouraging companies to proactive with toxicity issues is in line with what seems to be an international (Europe & US) regulatory movement putting more onus on producers and manufacturers to take responsibility for safety testing. (This was communicated to me in a conversation I had with an official at the European Union Joint Research Centre where he mentioned REACH regulations and the new emphasis in response to my mention of similar FDA (US Food and Drug Administration) regulations. (We were at the 2014 9th World Congress on Alternatives to Animal Testing in Prague, Czech republic.)

For anyone interested in the International Agency for Research on Cancer you can find it here.

Use of nanomaterials in food for animals: the US Food and Drug Administration (FDA) issues a final guidance

Bureaucratese is not my first language so the US Food and Drug Administration’s final guidance on the use of nanomaterials in animal food seems a little vague to me. That said, here’s the Aug. 5, 2015 news item on Nanowerk, which announced the guidance (Note: A link has been removed),

The U.S. Food and Drug Administration has issued a final guidance for industry, ‘Use of Nanomaterials in Food for Animals’ (pdf), which is intended to assist industry and other stakeholders in identifying potential issues related to safety or regulatory status of food for animals containing nanomaterials or otherwise involving the application of nanotechnology. This guidance is applicable to food ingredients intended for use in animal food which (1) consist entirely of nanomaterials, (2) contain nanomaterials as a component or (3) otherwise involve the application of nanotechnology.

An Aug. 4, 2015 FDA announcement, which originated the news item, provides more detail,

This final guidance addresses the legal framework for adding nanomaterial substances to food for animals and includes recommendations for submitting a Food Additive Petition (FAP) for a nanomaterial animal food ingredient. This guidance also recommends manufacturers consult with FDA early in the development of their nanomaterial animal food ingredient and before submitting an FAP. At this time, we are not aware of any animal food ingredient engineered on the nanometer scale for which there is generally available safety data sufficient to serve as the foundation for a determination that the use of such an animal food ingredient is generally recognized as safe (GRAS).

Nanotechnology is an emerging technology that allows scientists to create, explore, and manipulate materials on a scale measured in nanometers – particles so small that they cannot be seen with a regular microscope. These particles can have chemical, physical, and biological properties that differ from those of their larger counterparts, and nanotechnology has a broad range of potential applications.

Guidance documents represent the FDA’s current thinking on particular topics, policies, and regulatory issues. While “guidance for industry” documents are prepared primarily for industry, they also are used by FDA staff and other stakeholders to understand the agency’s interpretation of laws and policies.

Although this guidance has been finalized, you can submit comments at any time. To submit comments to the docket by mail, use the following address. Be sure to include docket number FDA-2013-D-1009 on each page of your written comments.

Division of Dockets Management
HFA-305
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852

You can find the guidance here.

Commercializing Titan Spine’s next generation spinal interbody fusion implant

The July 22, 2015 Titan Spine news release on BusinessWire is mainly focused on the appointment of a senior nanotechnology specialist; I’m more interested in the mention of product commercialization (first mentioned in my Nov. 26, 2014 post) in the fourth quarter of 2015,

Titan Spine, a medical device surface technology company focused on developing innovative spinal interbody fusion implants, today announced the appointment of Jim Sevey as the Company’s Senior Nanotechnology Specialist. The appointment follows the Company’s receipt of 510(k) clearance from the U.S. Food and Drug Administration (FDA) to market its Endoskeleton® line of interbody fusion implants featuring its next generation nanoLOCKTM surface technology and precedes the Company’s full commercialization of the new line, planned for the fourth quarter of this year. The nanoLOCK™ surface represents the only FDA-cleared nanotechnology for spinal implant applications.

Mr. Sevey’s role will include leading the educational initiatives to further demonstrate and communicate the scientific evidence supporting the advantages of Titan Spine’s unique nanoLOCKTM surface technology. The surface features an increased amount of nano-scaled textures that result in the up-regulation of a greater amount of osteogenic and angiogenic growth factors critical for bone growth and fusion as compared to PEEK and the company’s current surface.1

Kevin Gemas, President of Titan Spine, commented, “As our body of science continues to grow, we identified the need to bring onboard someone of Jim’s caliber to educate the spinal surgeon community and our sales force on the science and associated benefits of our current and nanoLOCK™ proprietary surface technologies. With more than 22 years of experience with medical devices and biomaterials, Jim is the right person to lead these efforts. One of Jim’s initial tasks will be to clearly differentiate the science of our nanotechnology platform from those that claim to have nanotechnology but have not been cleared by the FDA to do so. We are proud to add Jim to our ever-growing scientific team.”

Barbara Boyan, Ph.D., Dean of the School of Engineering at Virginia Commonwealth University, and lead author of several studies supporting Titan Spine surfaces, added, “The spine industry is beginning to recognize ‘nanotechnology’ as more than a marketing concept and now as a design approach that has the potential to improve spinal fusion results for patients. Titan Spine has been at the forefront of this charge for nearly a decade, conducting studies to evaluate and refine the benefits of nanotechnology for interbody fusions. I look forward to working closely with Jim to further these efforts.”

Before joining Titan Spine, Mr. Sevey held several positions at Synthes/Depuy Biomaterials, including most recently, Manager, Biomaterials Technical Specialist. In this role, he generated multidivisional sales of osteobiologic product lines by providing clinical and technical consulting, training, and education for surgeons, residents, operating room personnel, and sales consultants. Prior to Synthes/Depuy Biomaterials, Mr. Sevey was part of the founding team of Skeletal Kinetics, LLC, (Cupertino, CA) as Director of Marketing. Mr. Sevey holds a Bachelor of Science in Health Science from St. Mary’s College of California (Moraga, CA).

The full line of Endoskeleton® devices features Titan Spine’s proprietary implant surface technology, consisting of a unique combination of roughened topographies at the macro, micro, and cellular levels. This unique combination of surface topographies is designed to create an optimal host-bone response and actively participate in the fusion process by promoting the up-regulation of osteogenic and angiogenic factors necessary for bone growth, encouraging natural production of bone morphogenetic proteins (BMPs), down-regulating inflammatory factors, and creating the potential for a faster and more robust fusion.2,3,4

About Titan Spine

Titan Spine, LLC is a surface technology company focused on the design and manufacture of interbody fusion devices for the spine. The company is committed to advancing the science of surface engineering to enhance the treatment of various pathologies of the spine that require fusion. Titan Spine, located in Mequon, Wisconsin and Laichingen, Germany, markets a full line of Endoskeleton® interbody devices featuring its proprietary textured surface in the U.S. and portions of Europe through its sales force and a network of independent distributors. To learn more, visit www.titanspine.com.

Titan Spine Study References:

1 Olivares-Navarrete, R., Hyzy, S. L., Berg, M. E., Schneider, J. M., Hotchkiss, K., Schwartz, Z., & Boyan, B. D. Osteoblast Lineage Cells Can Discriminate Microscale Topographic Features on Titanium–Aluminum–Vanadium Surfaces.Ann Biomed Eng. 2014; 1-11.

2 Olivares-Navarrete, R., Hyzy, S.L., Slosar, P.J., Schneider, J.M., Schwartz, Z., and Boyan, B.D. (2015). Implant materials generate different peri-implant inflammatory factors: PEEK promotes fibrosis and micro-textured titanium promotes osteogenic factors. Spine, Volume 40, Issue 6, 399–404.

3 Olivares-Navarrete, R., Gittens, R.A., Schneider, J.M., Hyzy, S.L., Haithcock, D.A., Ullrich, P.F., Schwartz, Z., Boyan, B.D. (2012). Osteoblasts exhibit a more differentiated phenotype and increased bone morphogenetic production on titanium alloy substrates than poly-ether-ether-ketone. The Spine Journal, 12, 265-272.

4 Olivares-Navarrete, R., Hyzy, S.L., Gittens, R.A., Schneider, J.M., Haithcock, D.A., Ullrich, P.F., Slosar, P. J., Schwartz, Z., Boyan, B.D. (2013). Rough titanium alloys regulate osteoblast production of angiogenic factors. The Spine Journal, 13, 1563-1570.

It’s unusual (and welcome) to see citations included with a business news release for a new medical device.

I didn’t think to pose the query in my last post but I wonder if Barbara Boyan has some sort of financial interest in Titan Spine? Her Virginia Commonwealth University faculty webpage suggests the answer is no,

Experience

  • Associate Dean for Research and Innovation in the College of Engineering at Georgia Institute of Technology
  • Professor and Price Gilbert, Jr. Chair in Tissue Engineering in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University
  • Deputy Director of Research at Georgia Tech and at the Emory Center for the Engineering of Living Tissues at the Georgia Institute of Technology
  • Professor and Vice Chair for Research in the Department of Orthopaedics at the University of Texas Health Science Center at San Antonio
  • Co-founder of Osteobiologics, Inc.
  • Founder and Chief Scientific Officer of SpherIngenics, Inc.
  • Member, Board of Directors, ArthroCare Corporation and Carticept Medical, Inc.

Still, I wish there was a statement that spelled out Boyan’s relationship or lack of with Titan Spine.

A pragmatic approach to alternatives to animal testing

Retitled and cross-posted from the June 30, 2015 posting (Testing times: the future of animal alternatives) on the International Innovation blog (a CORDIS-listed project dissemination partner for FP7 and H2020 projects).

Maryse de la Giroday explains how emerging innovations can provide much-needed alternatives to animal testing. She also shares highlights of the 9th World Congress on Alternatives to Animal Testing.

‘Guinea pigging’ is the practice of testing drugs that have passed in vitro and in vivo tests on healthy humans in a Phase I clinical trial. In fact, healthy humans can make quite a bit of money as guinea pigs. The practice is sufficiently well-entrenched that there is a magazine, Guinea Pig Zero, devoted to professionals. While most participants anticipate some unpleasant side effects, guinea pigging can sometimes be a dangerous ‘profession’.

HARMFUL TO HEALTH

One infamous incident highlighting the dangers of guinea pigging occurred in 2006 at Northwick Park Hospital outside London. Volunteers were offered £2,000 to participate in a Phase I clinical trial to test a prospective treatment – a monoclonal antibody designed for rheumatoid arthritis and multiple sclerosis. The drug, called TGN1412, caused catastrophic systemic organ failure in participants. All six individuals receiving the drug required hospital treatment. One participant reportedly underwent amputation of fingers and toes. Another reacted with symptoms comparable to John Merrick, the Elephant Man.

The root of the disaster lay in subtle immune system differences between humans and cynomolgus monkeys – the model animal tested prior to the clinical trial. The drug was designed for the CD28 receptor on T cells. The monkeys’ receptors closely resemble those found in humans. However, unlike these monkeys, humans have other immune cells that carry CD28. The trial participants received a starting dosage that was 0.2 per cent of what the monkeys received in their final tests, but failure to take these additional receptors into account meant a dosage that was supposed to occupy 10 per cent of the available CD28 receptors instead occupied 90 per cent. After the event, a Russian inventor purchased the commercial rights to the drug and renamed it TAB08. It has been further developed by Russian company, TheraMAB, and TAB08 is reportedly in Phase II clinical trials.

HUMAN-ON-A-CHIP AND ORGANOID PROJECTS

While animal testing has been a powerful and useful tool for determining safe usage for pharmaceuticals and other types of chemicals, it is also a cruel and imperfect practice. Moreover, it typically only predicts 30-60 per cent of human responses to new drugs. Nanotechnology and other emerging innovations present possibilities for reducing, and in some cases eliminating, the use of animal models.

People for the Ethical Treatment of Animals (PETA), still better known for its publicity stunts, maintains a webpage outlining a number of alternatives including in silico testing (computer modelling), and, perhaps most interestingly, human-on-a-chip and organoid (tissue engineering) projects.

Organ-on-a-chip projects use stem cells to create human tissues that replicate the functions of human organs. Discussions about human-on-a-chip activities – a phrase used to describe 10 interlinked organ chips – were a highlight of the 9th World Congress on Alternatives to Animal Testing held in Prague, Czech Republic, last year. One project highlighted at the event was a joint US National Institutes of Health (NIH), US Food and Drug Administration (FDA) and US Defense Advanced Research Projects Agency (DARPA) project led by Dan Tagle that claimed it would develop functioning human-on-a-chip by 2017. However, he and his team were surprisingly close-mouthed and provided few details making it difficult to assess how close they are to achieving their goal.

By contrast, Uwe Marx – Leader of the ‘Multi-Organ-Chip’ programme in the Institute of Biotechnology at the Technical University of Berlin and Scientific Founder of TissUse, a human-on-a-chip start-up company – claims to have sold two-organ chips. He also claims to have successfully developed a four-organ chip and that he is on his way to building a human-on-a-chip. Though these chips remain to be seen, if they are, they will integrate microfluidics, cultured cells and materials patterned at the nanoscale to mimic various organs, and will allow chemical testing in an environment that somewhat mirrors a human.

Another interesting alternative for animal testing is organoids – a feature in regenerative medicine that can function as test sites. Engineers based at Cornell University recently published a paper on their functional, synthetic immune organ. Inspired by the lymph node, the organoid is comprised of gelatin-based biomaterials, which are reinforced with silicate nanoparticles (to keep the tissue from melting when reaching body temperature) and seeded with cells allowing it to mimic the anatomical microenvironment of a lymphatic node. It behaves like its inspiration converting B cells to germinal centres which activate, mature and mutate antibody genes when the body is under attack. The engineers claim to be able to control the immune response and to outperform 2D cultures with their 3D organoid. If the results are reproducible, the organoid could be used to develop new therapeutics.

Maryse de la Giroday is a science communications consultant and writer.

Full disclosure: Maryse de la Giroday received transportation and accommodation for the 9th World Congress on Alternatives to Animal Testing from SEURAT-1, a European Union project, making scientific inquiries to facilitate the transition to animal testing alternatives, where possible.

ETA July 1, 2015: I would like to acknowledge more sources for the information in this article,

Sources:

The guinea pigging term, the ‘professional aspect, the Northwick Park story, and the Guinea Pig Zero magazine can be found in Carl Elliot’s excellent 2006 story titled ‘Guinea-Pigging’ for New Yorker magazine.

http://www.newyorker.com/magazine/2008/01/07/guinea-pigging

Information about the drug used in the Northwick Park Hospital disaster, the sale of the rights to a Russian inventor, and the June 2015 date for the current Phase II clinical trials were found in this Wikipedia essay titled, TGN 1412.

http://en.wikipedia.org/wiki/TGN1412

Additional information about the renamed drug, TAB08 and its Phase II clinical trials was found on (a) a US government website for information on clinical trials, (b) in a Dec. 2014 (?) TheraMAB  advertisement in a Nature group magazine and a Jan. 2014 press release,

https://www.clinicaltrials.gov/ct2/show/NCT01990157?term=TAB08_RA01&rank=1

http://www.theramab.ru/TheraMAB_NAture.pdf

http://theramab.ru/en/news/phase_II

An April 2015 article (Experimental drug that injured UK volunteers resumes in human trials) by Owen Dyer for the British Medical Journal also mentioned the 2015 TheraMab Phase II clinical trials and provided information about the information about Macaque (cynomolgus) monkey tests.

http://www.bmj.com.proxy.lib.sfu.ca/content/350/bmj.h1831

BMJ 2015; 350 doi: http://dx.doi.org.proxy.lib.sfu.ca/10.1136/bmj.h1831 (Published 02 April 2015) Cite this as: BMJ 2015;350:h1831

A 2009 study by Christopher Horvath and Mark Milton somewhat contradicts the Dyer article’s contention that a species Macaque monkey was used as an animal model. (As the Dyer article is more recent and the Horvath/Milton analysis is more complex covering TGN 1412 in the context of other MAB drugs and their precursor tests along with specific TGN 1412 tests, I opted for the simple description.)

The TeGenero Incident [another name for the Northwick Park Accident] and the Duff Report Conclusions: A Series of Unfortunate Events or an Avoidable Event? by Christopher J. Horvath and Mark N. Milton. Published online before print February 24, 2009, doi: 10.1177/0192623309332986 Toxicol Pathol April 2009 vol. 37 no. 3 372-383

http://tpx.sagepub.com/content/37/3/372.full

Philippa Roxbuy’s May 24, 2013 BBC news online article provided confirmation and an additional detail or two about the Northwick Park Hospital accident. It notes that other models, in addition to animal models, are being developed.

http://www.bbc.com/news/health-22556736

Anne Ju’s excellent June 10,2015 news release about the Cornell University organoid (synthetic immune organ) project was very helpful.

http://www.news.cornell.edu/stories/2015/06/engineers-synthetic-immune-organ-produces-antibodies

There will also be a magazine article in International Innovation, which will differ somewhat from the blog posting, due to editorial style and other requirements.

ETA July 22, 2015: I now have a link to the magazine article.