Tag Archives: US Food and Drug Administration

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 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.

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.

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.

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.

Clinical trial for bionic eye (artificial retinal implant) shows encouraging results (safety and efficacy)

The Argus II artificial retina was first mentioned here in a Feb. 15, 2013 posting (scroll down about 50% of the way) when it received US Food and Drug Administration (FDA) commercial approval. In retrospect that seems puzzling since the results of a three-year clinical trial have just been reported in a June 23, 2015 news item on ScienceDaily (Note: There was one piece of information about the approval which didn’t make its way into the information disseminated in 2013),

The three-year clinical trial results of the retinal implant popularly known as the “bionic eye,” have proven the long-term efficacy, safety and reliability of the device that restores vision in those blinded by a rare, degenerative eye disease. The findings show that the Argus II significantly improves visual function and quality of life for people blinded by retinitis pigmentosa. They are being published online in Ophthalmology, the journal of the American Academy of Ophthalmology.

A June 23, 2015 American Academy of Ophthalmology news release (also on EurekAlert), which originated the news item, describes the condition the Argus II is designed for and that crucial bit of FDA information,

Retinitis pigmentosa is an incurable disease that affects about 1 in 4,000 Americans and causes slow vision loss that eventually leads to blindness.[1] The Argus II system was designed to help provide patients who have lost their sight due to the disease with some useful vision. Through the device, patients with retinitis pigmentosa are able to see patterns of light that the brain learns to interpret as an image. The system uses a miniature video camera stored in the patient’s glasses to send visual information to a small computerized video processing unit which can be stored in a pocket. This computer turns the image to electronic signals that are sent wirelessly to an electronic device implanted on the retina, the layer of light-sensing cells lining the back of the eye.

The Argus II received Food and Drug Administration (FDA) approval as a Humanitarian Use Device (HUD) in 2013, which is an approval specifically for devices intended to benefit small populations and/or rare conditions. [emphasis mine]

I don’t recall seeing “Humanitarian Use Device (HUD)” in the 2013 materials which focused on the FDA’s commercial use approval. I gather from this experience that commercial use doesn’t necessarily mean they’ve finished with clinical trials and are ready to start selling the product. In any event, I will try to take a closer look at the actual approvals the next time, assuming I can make sense of the language.

After all the talk about it, here’s what the device looks like,

 Caption: Figure A, The implanted portions of the Argus II System. Figure B, The external components of the Argus II System. Images in real time are captured by camera mounted on the glasses. The video processing unit down-samples and processes the image, converting it to stimulation patterns. Data and power are sent via radiofrequency link form the transmitter antenna on the glasses to the receiver antenna around the eye. A removable, rechargeable battery powers the system. Credit: Photo courtesy of Second Sight Medical Products, Inc.


Caption: Figure A, The implanted portions of the Argus II System. Figure B, The external components of the Argus II System. Images in real time are captured by camera mounted on the glasses. The video processing unit down-samples and processes the image, converting it to stimulation patterns. Data and power are sent via radiofrequency link form the transmitter antenna on the glasses to the receiver antenna around the eye. A removable, rechargeable battery powers the system.
Credit: Photo courtesy of Second Sight Medical Products, Inc.

The news release offers more details about the recently completed clinical trial,

To further evaluate the safety, reliability and benefit of the device, a clinical trial of 30 people, aged 28 to 77, was conducted in the United States and Europe. All of the study participants had little or no light perception in both eyes. The researchers conducted visual function tests using both a computer screen and real-world conditions, including finding and touching a door and identifying and following a line on the ground. A Functional Low-vision Observer Rated Assessment (FLORA) was also performed by independent visual rehabilitation experts at the request of the FDA to assess the impact of the Argus II system on the subjects’ everyday lives, including extensive interviews and tasks performed around the home.

The visual function results indicated that up to 89 percent of the subjects performed significantly better with the device. The FLORA found that among the subjects, 80 percent received benefit from the system when considering both functional vision and patient-reported quality of life, and no subjects were affected negatively.

After one year, two-thirds of the subjects had not experienced device- or surgery-related serious adverse events. After three years, there were no device failures. Throughout the three years, 11 subjects experienced serious adverse events, most of which occurred soon after implantation and were successfully treated. One of these treatments, however, was to remove the device due to recurring erosion after the suture tab on the device became damaged.

“This study shows that the Argus II system is a viable treatment option for people profoundly blind due to retinitis pigmentosa – one that can make a meaningful difference in their lives and provides a benefit that can last over time,” said Allen C. Ho, M.D., lead author of the study and director of the clinical retina research unit at Wills Eye Hospital. “I look forward to future studies with this technology which may make possible expansion of the intended use of the device, including treatment for other diseases and eye injuries.”

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

Long-Term Results from an Epiretinal Prosthesis to Restore Sight to the Blind by Allen C. Ho,Mark S. Humayun, Jessy D. Dorn, Lyndon da Cruz, Gislin Dagnelie,James Handa, Pierre-Olivier Barale, José-Alain Sahel, Paulo E. Stanga, Farhad Hafezi, Avinoam B. Safran, Joel Salzmann, Arturo Santos, David Birch, Rand Spencer, Artur V. Cideciyan, Eugene de Juan, Jacque L. Duncan, Dean Eliott, Amani Fawzi, Lisa C. Olmos de Koo, Gary C. Brown, Julia A. Haller, Carl D. Regillo, Lucian V. Del Priore, Aries Arditi, Duane R. Geruschat, Robert J. Greenberg. Opthamology, June 2015 http://dx.doi.org/10.1016/j.ophtha.2015.04.032

This paper is open access.

Dunkin’ Donuts and nano titanium dioxide

It’s been a busy few days for titanium dioxide, nano and otherwise, as the news about its removal from powdered sugar in Dunkin’ Donuts products ripples through the nano blogosphere. A March 6, 2015 news item on Azonano kicks off the discussion with an announcement,

Dunkin’ Brands, the parent company of the Dunkin’ Donuts chain, has agreed to remove titanium dioxide, a whitening agent that is commonly a source of nanomaterials, from all powdered sugar used to make the company’s donuts. As a result of this progress, the advocacy group As You Sow has withdrawn a shareholder proposal asking Dunkin’ to assess and reduce the risks of using nanomaterials in its food products.

Here’s a brief recent history of Dunkin’ Donuts and nano titanium dioxide from my Aug. 21, 2014 posting titled, FOE, nano, and food: part two of three (the problem with research),

Returning to the ‘debate’, a July 11, 2014 article by Sarah Shemkus for a sponsored section in the UK’s Guardian newspaper highlights an initiative taken by an environmental organization, As You Sow, concerning titanium dioxide in Dunkin’ Donuts’ products (Note: A link has been removed),

The activists at environmental nonprofit As You Sow want you to take another look at your breakfast doughnut. The organization recently filed a shareholder resolution asking Dunkin’ Brands, the parent company of Dunkin’ Donuts, to identify products that may contain nanomaterials and to prepare a report assessing the risks of using these substances in foods.

Their resolution received a fair amount of support: at the company’s annual general meeting in May, 18.7% of shareholders, representing $547m in investment, voted for it. Danielle Fugere, As You Sow’s president, claims that it was the first such resolution to ever receive a vote. Though it did not pass, she says that she is encouraged by the support it received.

“That’s a substantial number of votes in favor, especially for a first-time resolution,” she says.

The measure was driven by recent testing sponsored by As You Sow, which found nanoparticles of titanium dioxide in the powdered sugar that coats some of the donut chain’s products. [emphasis mine] An additive widely used to boost whiteness in products from toothpaste to plastic, microscopic titanium dioxide has not been conclusively proven unsafe for human consumption. Then again, As You Sow contends, there also isn’t proof that it is harmless.

“Until a company can demonstrate the use of nanomaterials is safe, we’re asking companies either to not use them or to provide labels,” says Fugere. “It would make more sense to understand these materials before putting them in our food.”

As I understand it, Dunkin’ Donuts will be removing all titanium dioxide, nano-sized or other, from powdered sugar used in its products. It seems As You Sow’s promise to withdraw its July 2104 shareholder resolution is the main reason for Dunkin’ Donuts’ decision. While I was and am critical of Dunkin’ Donuts’ handling of the situation with As You Sow, I am somewhat distressed that the company seems to have acquiesced on the basis of research which is, at best, inconclusive.

Dr. Andrew Maynard, director of the University of Michigan Risk Science Centre, has written a substantive analysis of the current situation regarding nano titanium dioxide in a March 12, 2015 post on his 2020 Science blog (Note: Links have been removed),

Titanium dioxide (which isn’t the same thing as the metal titanium) is an inert, insoluble material that’s used as a whitener in everything from paper and paint to plastics. It’s the active ingredient in many mineral-based sunscreens. And as a pigment, is also used to make food products look more appealing.

Part of the appeal to food producers is that titanium dioxide is a pretty dull chemical. It doesn’t dissolve in water. It isn’t particularly reactive. It isn’t easily absorbed into the body from food. And it doesn’t seem to cause adverse health problems. It just seems to do what manufacturers want it to do – make food look better. It’s what makes the powdered sugar coating on donuts appear so dense and snow white. Titanium dioxide gives it a boost.

And you’ve probably been consuming it for years without knowing. In the US, the Food and Drug Administration allows food products to contain up to 1% food-grade titanium dioxide without the need to include it on the ingredient label. Help yourself to a slice of bread, a bar of chocolate, a spoonful of mayonnaise or a donut, and chances are you’ll be eating a small amount of the substance.

Andrew goes on to describe the concerns that groups such as You As Sow have (Note: Links have been removed),

For some years now, researchers have recognized that some powders become more toxic the smaller the individual particles are, and titanium dioxide is no exception. Pigment grade titanium dioxide – the stuff typically used in consumer products and food – contains particles around 200 nanometers in diameter, or around one five hundredth the width of a human hair. Inhale large quantities of these titanium dioxide particles (I’m thinking “can’t see your hand in front of your face” quantities), and your lungs would begin to feel it.

If the particles are smaller though, it takes much less material to cause the same effect.

But you’d still need to inhale very large quantities of the material for it to be harmful. And while eating a powdered donut can certainly be messy, it’s highly unlikely that you’re going to end up stuck in a cloud of titanium dioxide-tinted powdered sugar coating!

… Depending on what they are made of and what shape they are, research has shown that some nanoparticles are capable of getting to parts of the body that are inaccessible to larger particles. And some particles are more chemically reactive because of their small size. Some may cause unexpected harm simply because they are small enough to throw a nano-wrench into the nano-workings of your cells.

This body of research is why organizations like As You Sow have been advocating caution in using nanoparticles in products without appropriate testing – especially in food. But the science about nanoparticles isn’t as straightforward as it seems.

As Andrew notes,

First of all, particles of the same size but made of different materials can behave in radically different ways. Assuming one type of nanoparticle is potentially harmful because of what another type does is the equivalent of avoiding apples because you’re allergic to oysters.

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.

He also probes the issue’s, nanoparticles, be they titanium dioxide or otherwise, and toxicity, complexity (Note: Links have been removed),

There’s a small possibility that we haven’t been looking in the right places when it comes to possible health issues. Maybe – just maybe – there could be long term health problems from this seemingly ubiquitous diet of small, insoluble particles that we just haven’t spotted yet. It’s the sort of question that scientists love to ask, because it opens up new avenues of research. It doesn’t mean that there is an issue, just that there is sufficient wiggle room in what we don’t know to ask interesting questions.

… While there is no evidence of a causal association between titanium dioxide in food and ill health, some studies – but not all by any means – suggest that large quantities of titanium dioxide nanoparticles can cause harm if they get to specific parts of the body.

For instance, there are a growing number of published studies that indicate nanometer sized titanium dioxide particles may cause DNA damage at high concentrations if it can get into cells. But while these studies demonstrate the potential for harm to occur, they lack information on how much material is needed, and under what conditions, for significant harm. And they tend to be associated with much larger quantities of material than anyone is likely to be ingesting on a regular basis.

They are also counterbalanced by studies that show no effects, indicating that there is still considerable uncertainty over the toxicity or otherwise of the material. It’s as if we’ve just discovered that paper can cause cuts, but we’re not sure yet whether this is a minor inconvenience or potentially life threatening. In the case of nanoscale titanium dioxide, it’s the classic case of “more research is needed.”

I strongly suggest reading Andrew’s post in its entirety either here on the University of Michigan website or here on The Conversation website.

Dexter Johnson in a March 11, 2015 post on his Nanoclast blog also weighs in on the discussion. He provides a very neat summary of the issues along with these observations (Note Links have been removed),

With decades of TiO2 being in our food supply and no reports of toxic reactions, it would seem that the threshold for proof is extremely high, especially when you combine the term “nano” with “asbestos”.

As You Sow makes sure to point out that asbestos is a nanoparticle. While the average diameter of an asbestos fiber is around 20 to 90 nm, their lengths varied between 200 nm and 200 micrometers.

The toxic aspect of asbestos was not its diameter, but its length. …

In addition to his summary Dexter highlights As You Sows attempt to link titanium dioxide nanoparticles to asbestos. I suggest reading his post for an informed description of what made asbestos so toxic (here) and why the linkage seems specious at this time.

For anyone interested in how As You Sow managed to introduce asbestos toxicity issues into a discussion about nano titanium dioxide and food products, there’s this from As You Sow’s FAQs (frequently asked questions) about nanomaterials in food page,

Why are nanomaterials in food important to investors?

When technology is used before ensuring that it is safe for humans and the environment, and before regulatory standards exist, companies can be exposed to significant financial, legal, and reputational risk. The limited studies that exist on nanomaterials, including nanoscale titanium dioxide*, have indicated that ingestion of these particles may pose health hazards.

The inaction of regulators does not protect companies, especially when the regulators themselves warn of the dangers of nanoparticles’ largely unknown risks. Draft guidance issued by the U.S. Food and Drug Administration raises questions about the safety of nanoparticles and demonstrates the general lack of knowledge about the technology and its effects. (1)

Asbestos litigation is a good example of the risks that can arise from using an emerging technology before it is proven safe. Use of asbestos (a nanomaterial) has created the longest, most expensive mass tort in national history with total U.S. costs now standing at over $250 billion. (2) If companies been asked to investigate and minimize or avoid risks prior to adopting asbestos technology, a sad and expensive chapter in worker harm could have been avoided.

* Titanium dioxide is a common pigment and FDA-approved food additive. It is used as a whitener, a dispersant, and a thickener.

While I don’t particularly appreciate fear-mongering as a tactic, the strategy of targeting investors and their concerns, seems to have helped As You Sow win its way.

US Food and Drug Administration approval for next generation spinal interbody fusion implant

For the first time, the US Food and Drug Administration (FDA) has approved a nanotechnology-enabled interbody spinal fusion implant, according to a Nov. 12, 2014 news item on Azonano,

Titan Spine, a medical device surface technology company focused on developing innovative spinal interbody fusion implants, today announced that it has received 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.

This clearance marks Titan’s line of Endoskeleton® spinal implants as the first FDA-approved interbody fusion devices to feature nanotechnology.

A Nov. 22, 2014 news item on Today’s Medical Developments.com provides more detail about the implants,

Titan’s new nanoLOCK surface technology enhances the company’s line of Endoskeleton devices with an increased amount of nano-scaled textures to up-regulate a statistically significant greater amount of the osteogenic and angiogenic growth factors that are critical for bone growth and fusion when compared to PEEK and the company’s current surface.

Barbara Boyan, Ph.D., dean of the School of Engineering at Virginia Commonwealth University, and an investigator in various Titan Spine studies, said, “This new surface technology further enhances Titan’s current surface and is the result of extensive research in how to create a significantly greater amount of nano-scaled textures that we have shown to be important for the osteogenic response necessary for fusion. The nanoLOCK surface topography is far different than what is found on titanium-coated PEEK implants. In addition, the nanoLOCK surface is not created by applying a coating, but rather is formed by a reductive process of the titanium itself. This eliminates the potential for delamination, which is a concern for products with a PEEK-titanium interface. My team is proud to collaborate with Titan Spine to help develop such a differentiated technology that is truly designed to benefit both patients and surgeons.”

Titan’s nanoLOCK surface is a significant advancement of the company’s first-generation surface. The patented nanoLOCK manufacturing process creates additional textures at the critical nano level. However, there are no changes to the device indications for use, design, dimensions, or materials. Additionally, mechanical testing demonstrated that the strength of the company’s line of Endoskeletonimplants are unaffected by the new surface treatment.

Earlier this year Titan Spine announced the first surgery using one of its Endoskeleton implants. From a July 14, 2014 Titan Spine press release,

Titan Spine, a medical device surface technology company focused on developing innovative spinal interbody fusion implants, today announced that it has received clearance from the U.S. Food and Drug Administration (FDA) to commercially release its Endoskeleton® TL system, a spinal fusion system utilizing a lateral approach. The Endoskeleton® TL represents the first lateral fusion device to feature surface technology that is designed to participate in the fusion process by creating an osteogenic response to the implant’s topography.

The Endoskeleton® TL device utilizes Titan’s proprietary roughened titanium surface technology which has been shown to upregulate the production of osteogenic and angiogenic factors that are critical for bone growth and fusion. In addition, the design of the TL device incorporates large windows and large internal volumes to allow for significant bone graft packing, clear CT and MRI imaging, desired bone graft loading, and the ability to pack additional bone graft material within the device following implantation. Members of the TL design team include Kade Huntsman, M.D., Orthopedic Spine Surgeon with the Salt Lake Orthopaedic Clinic in Salt Lake City, Utah; Andy Kranenburg, M.D., Co-Medical Director of the Providence Medford Medical Center Spine Institute in Medford, OR; Axel Reinhardt, M.D., Head of the Department of Spinal Surgery at the Specialized Orthopaedic Hospital in Potsdam, Germany; and Paul Slosar, M.D., Chief Medical Officer for Titan Spine.

Dr. Huntsman performed the first surgeries utilizing the Endoskeleton® TL on July 9th, 2014 at St. Mark’s Hospital in Salt Lake City, Utah. …

“The Endoskeleton® TL device is the first application of surface technology to the lateral approach,” commented Dr. Slosar. “The ability to orchestrate cellular behavior and promote bone growth in response to an interbody device has not been in the lateral surgeon’s armamentarium until now. The TL is the byproduct of a unique collaboration between academic biomaterial scientists, spine surgeons, and industry experts to create a truly differentiated lateral interbody device that is designed to benefit both patients and surgeons. With the addition of the TL device, Titan Spine now offers its surface technology and complete line of titanium devices for virtually all interbody fusion spine surgery procedures in the cervical and lumbar spine.”

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. [emphasis mine] This combination of surface topographies is designed to create an optimal host-bone response and actively participate in the fusion process by promoting new bone growth, encouraging natural production of bone morphogenetic proteins (BMP’s) and creating the potential for a faster and more robust fusion.

It would seem the implant used in the July 2014 surgery is not nanotechnology-enabled, which suggests nanoLOCK is a next-generation implant being marketed only a few months after the first generation was made available. Unfortunately, the Titan Spine website is still partially (‘surface technology’ tab) under construction so I was not able to find more details about the technology. In any event, that’s quite a development pace.