Tag Archives: Robert Langer

Inspired by babies, scientists consider* popping nanoparticle pills and downing nanoparticle potions

Given the choice over injections or suppositories most of us will choose to take medication orally (pills or liquids). It may be a surprise to some but with all the talk about nanomedicine there has been a problem with using nanoparticles in an oral delivery system which scientists at the Brigham and Women’s Hospital (BWH) and Massachusetts Institute of Technology (MIT) have solved. From a Nov. 27, 2013 BWH news release, on EurekAlert,

… a study led by researchers at Brigham and Women’s Hospital (BWH) and Massachusetts Institute of Technology (MIT) is the first to report in the field of nanomedicine a new type of nanoparticle that can be successfully absorbed through the digestive tract. The findings may one day allow patients to simply take a pill instead of receiving injections.

Until recently, after being injected into the body, nanoparticles travelled to their destination, such as a tumor, by seeping through leaky vessels. The research team, led by Farokhzad [Omid Farokhzad, MD, director of the BWH Laboratory of Nanomedicine and Biomaterials, senior study author] and Robert Langer, ScD of MIT, developed nanoparticles that could reach the target site without relying on injection nor leaky vessels.

For nanoparticles to be taken orally they need to cross the intestinal lining. This lining is composed of a layer of epithelial cells joined together to form impenetrable barriers called tight junctions. To ensure that the nanoparticles could cross these barriers, the researchers took a cue from research on how babies absorb antibodies from their mothers’ milk. The antibodies would grab onto a receptor, known as neonatal Fc receptors, found on the cell surface. This gave them access across the cells of the intestinal lining into neighboring blood vessels.

Based on this knowledge, the researchers decorated nanoparticles with Fc proteins that targeted and bound to these receptors, which are also found in adult intestinal cells. After attaching to the receptors, the Fc-protein-decorated nanoparticles—toting their drug payload—are all absorbed into the intestinal lining and into the bloodstream at a high concentration.

According to the researchers, these receptors can be used to transport nanoparticles carrying different kinds of drugs and other materials—a feat that combines a versatile vehicle and an easily accessible passageway across cellular barriers.

To demonstrate how transport of Fc-targeted nanoparticles could impact the clinical space, the researchers focused on a diabetes treatment scenario, showing how oral delivery of insulin via these targeted nanoparticles could alter blood sugar levels in mice.

Insulin carried in nanoparticles decorated with Fc proteins reached the bloodstream more efficiently than those without the proteins. Moreover, the amount of insulin delivered was large enough to lower the mice’s blood sugar levels. Aside from insulin, the researchers note that the nanoparticles can be used to carry any kind of drug to treat many diseases.

“Being able to deliver nanomedicine orally would offer clinicians broad and novel ways to treat today’s many chronic diseases that require daily therapy, such as diabetes and cancer,” said Langer. “Imagine being able to take RNA or proteins orally; that would be paradigm shift.”

In terms of next steps, the researchers are working to enhance the nanoparticles’ drug-releasing abilities to prepare for future pre-clinical testing with insulin and other drugs. They also plan to design nanoparticles that can cross other barriers, such as the blood-brain barrier, which prevents many drugs from reaching the brain.

The Nov. 27, 2013 MIT news release by Anne Trafton on EurekAlert provides additional insight into the difficulties of getting nanoparticles past our digestive tracts (this is a bit repetitive but there’s enough new detail to make it worth my while to include it here),,

Several types of nanoparticles carrying chemotherapy drugs or short interfering RNA, which can turn off selected genes, are now in clinical trials to treat cancer and other diseases. These particles exploit the fact that tumors and other diseased tissues are surrounded by leaky blood vessels. After the particles are intravenously injected into patients, they seep through those leaky vessels and release their payload at the tumor site.

For nanoparticles to be taken orally, they need to be able to get through the intestinal lining, which is made of a layer of epithelial cells that join together to form impenetrable barriers called tight junctions.

“The key challenge is how to make a nanoparticle get through this barrier of cells. Whenever cells want to form a barrier, they make these attachments from cell to cell, analogous to a brick wall where the bricks are the cells and the mortar is the attachments, and nothing can penetrate that wall,” Farokhzad says.

Researchers have previously tried to break through this wall by temporarily disrupting the tight junctions, allowing drugs through. However, this approach can have unwanted side effects because when the barriers are broken, harmful bacteria can also get through.

To build nanoparticles that can selectively break through the barrier, the researchers took advantage of previous work that revealed how babies absorb antibodies from their mothers’ milk, boosting their own immune defenses. Those antibodies grab onto a cell surface receptor called the FcRN, granting them access through the cells of the intestinal lining into adjacent blood vessels.

The researchers coated their nanoparticles with Fc proteins — the part of the antibody that binds to the FcRN receptor, which is also found in adult intestinal cells. The nanoparticles, made of a biocompatible polymer called PLA-PEG, can carry a large drug payload, such as insulin, in their core.

After the particles are ingested, the Fc proteins grab on to the FcRN in the intestinal lining and gain entry, bringing the entire nanoparticle along with them.

“It illustrates a very general concept where we can use these receptors to traffic nanoparticles that could contain pretty much anything. Any molecule that has difficulty crossing the barrier could be loaded in the nanoparticle and trafficked across,” Karnik [Rohit Karnik, an MIT associate professor of mechanical engineering] says.

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

Transepithelial Transport of Fc-Targeted Nanoparticles by the Neonatal Fc Receptor for Oral Delivery by Eric M. Pridgen, Frank Alexis, Timothy T. Kuo, Etgar Levy-Nissenbaum, Rohit Karnik, Richard S. Blumberg, Robert Langer, and Omid C. Farokhzad.
Sci Transl Med 27 November 2013: Vol. 5, Issue 213, p. 213ra167 DOI: 10.1126/scitranslmed.3007049

This article is behind a paywall.

*  ‘consdier’ corrected to ‘consider’ on June 5, 2014.

Russia’s nanotechnology efforts falter?

The title for Leonid Bershidksy’s May 16, 2013 Bloomberg.com article, Power Grab Trumps Nanotechnology in Putin’s Russia, casts an ominous shadow over Rusnano’s situation (Note: Links have been removed),

The projects, known as Rusnano and Skolkovo, were meant to propel Russia’s raw-material economy into the technology age. They involved multibillion-dollar government investments, the first in nanotechnology and the second in a new city that would become Russia’s answer to Silicon Valley. They were supposed to provide the infrastructure and stability required to attract large amounts of foreign investment.

Now, both have become targets in Putin’s campaign to demonstrate that he’s being tough on corruption and mismanagement of government funds. As a result, their chances of succeeding are looking increasingly remote.

Trouble came in April [2013], when the Accounting Chamber, a body charged with auditing government spending, accused Rusnano of inefficient management in a report that received ample coverage on state-owned TV. It said that Rusnano had transferred about $40 million to shell companies and pointed out that a silicon factory in which Rusnano invested about $450 million was not functioning and was about to be declared insolvent. The report also highlighted the state company’s 2012 losses of 2.5 billion rubles ($80 million) and the 24.4-billion-ruble (about $800 million) in reserves Rusnano had formed against potential losses from risky ventures.

Anatoly Medetsky’s Apr. 29, 2013 article for The Moscow Times provides more insight into the situation,

The government’s Audit Chamber on Friday [April 26, 2013] accused state-owned Rusnano of multiple infractions in a blow to the high-tech corporation’s chief, Anatoly Chubais.

The chamber’s critical conclusions followed President Vladimir Putin’s reproof of the company during a live call-in show the previous day.

Auditors made their statement after examining Rusnano’s records in response to a request by Chubais’ political nemesis, the Communist Party.

“The audit’s materials attest that Rusnano’s performance was inappropriate to attain the goals that it was entrusted with, which are the development of the national nano industry,” the Audit Chamber said in a statement.

Auditor Sergei Agaptsov said separately that Rusnano is unlikely to achieve the goal of 300 billion rubles in annual sales of nano-tech products by the companies it co-owns in 2015 — the target that the government set for the company, Interfax reported.

I’m sorry to read about Rusnano’s difficulties especially in light my first piece about it where I compared the Canadian effort unfavourably to, what was then, a relatively new and promising organization in my Apr. 14, 2009 posting. About seventeen months later, officials with Rusnano signed a memorandum of understanding with John Varghese, CEO and Managing Partner of Toronto based venture capital firm, VentureLink Funds as noted in my Sept. 14, 2010 posting. Nothing further seemed to come of that agreement.

I have one last thought about Rusnano’s current travails, will they have an impact on US commercialization efforts? In my Oct. 28, 2011 posting where I was contrasting nanotechnology commercialization efforts by the US, Spain, and Rusnano, I mentioned this deal Rusnano had made with two US nanomedicine companies,

Then RUSNANO announced its investments in Selecta Biosciences and BIND Biosiences, from the Oct. 27, 2011 news item on Nanowerk,

BIND Biosciences and Selecta Biosciences, two leading nanomedicine companies, announced today that they have entered into investment agreements with RUSNANO, a $10-billion Russian Federation fund that supports high-tech and nanotechnology advances. [emphasis mine]

RUSNANO is co-investing $25 million in BIND and $25 million in Selecta, for a total RUSNANO investment of $50 million within the total financing rounds of $94.5 million in the two companies combined. …

The proprietary technology platforms of BIND and Selecta originated in laboratories at Harvard Medical School directed by Professor Omid Farokhzad, MD, and in laboratories at MIT directed by Professor Robert Langer, ScD, a renowned scientist who is a recipient of the US National Medal of Science, the highest US honor for scientists, and is an inventor of approximately 850 patents issued or pending worldwide. Drs. Langer and Farokhzad are founders of both companies.

Ripple effects, eh? Rusnano was very active internationally.

ETA June 14, 2013:  Nanowerk has a June 13, 2013 news item, which updates the situation with the news that Rusnano has opted out of presenting an ‘initial public offering’, aka, listing itself on a stock exchange in 2015 and will instead attract private investment.

Evolution is the best problem-solver

Dr. Jeffrey Karp of Brigham and Women’s Hospital says, “I truly believe evolution is the best problem-solver,” when discussing his medical biomimcry work in this video,

You can find the video and more in a Mar. 20, 2013 news item on Nanowerk which was originated by a Mar. 6, 2013 article by Alisa Zapp Machalek for the US National Institutes of Health (NIH) National Institute of General Medical Sciences (NGMS) Inside Life Science webpage,

Velcro® was inspired by the grappling hooks of burrs. Supersonic jets have structures that work like the nostrils of peregrine falcons in a speed dive. Full-body swimsuits, now banned from the Olympics, lend athletes a smooth, streamlined shape like fish.

Nature’s designs are also giving researchers funded by the National Institutes of Health ideas for new technologies that could help wounds heal, make injections less painful and provide new materials for a variety of purposes.

… scientists [Jeffrey Karp and Robert Langer] discovered, to their surprise, that a [porcupine] quill’s puncture power comes from its barbed tip. Barbs seem to work like the points on a serrated knife, concentrating pressure onto small areas to aid penetration. Because they require significantly less force to puncture skin, barbed shafts don’t hurt as much when they enter flesh as their smooth-tipped counterparts do.

Zapp Machalek goes on to detail work inspired by gecko feet and spider webs, as well as, porcupine quills.

Forbes magazine and US science culture

Forbes magazine, which is based in the US but now has editions produced in many countries, describes its focus as business and finance. So, it might seem a little unexpected to find a list of rising stars in the fields of science and health until one remembers the current fascination, worldwide, with innovation which often seems to mean science research which can be commercialized.

Forbes has just published its list of ’30 under 30′ rising stars in the fields of Science and Health Care. Pedro Valencia, who studied with and worked in Robert Langer’s lab at the Massachusetts Institute of Technology (MIT), was one of the 30 cited in the 2012 list. From the Dec. 27, 2012 news item on Azonano,

Valencia was cited for figuring out “how to more quickly synthesize nanoparticles that can be used to make drugs more effective and less toxic and to put multiple drugs inside the same nanotech medicine. This has resulted in many top-notch scientific publications and the formation of a start-up, Blend Therapeutics.”

Valencia was the recipient of the NSF Graduate Fellowship. He was co-advised by Professor Langer and Dr. Omid Farokhzad of the Brigham Women’s Hospital – Harvard Medical School.

Langer and Farokhzad were mentioned in my Oct. 28, 2011 posting about nanotechnology commercialization efforts,

… BIND Biosciences and Selecta Biosciences, two leading nanomedicine companies, announced today that they have entered into investment agreements with RUSNANO, a $10-billion Russian Federation fund that supports high-tech and nanotechnology advances.

RUSNANO is co-investing $25 million in BIND and $25 million in Selecta, for a total RUSNANO investment of $50 million within the total financing rounds of $94.5 million in the two companies combined. …

The proprietary technology platforms of BIND and Selecta originated in laboratories at Harvard Medical School directed by Professor Omid Farokhzad, MD, and in laboratories at MIT directed by Professor Robert Langer, ScD, a renowned scientist who is a recipient of the US National Medal of Science, the highest US honor for scientists, and is an inventor of approximately 850 patents issued or pending worldwide. Drs. Langer and Farokhzad are founders of both companies. [Farokhzad was featured in a recent Canadian Broadcasting Corporation {CBC}, Nature of Things, television episode about nanomedicine, titled More than human.] Professor Ulrich von Andrian, MD, PhD, head of the immunopathology laboratory at Harvard Medical School, is a founder of Selecta.

It is fascinating to observe not only the linkages between business and science/health but also the way in which those linkages contribute to a larger ‘science culture’, which includes science festivals, science-oriented popular culture, science talks for just a few examples.

Gluing blood vessels with mussel goo

The University of British Columbia [UBC] Dec. 11, 2012 news release states,

A University of British Columbia researcher has helped create a gel – based on the mussel’s knack for clinging to rocks, piers and boat hulls – that can be painted onto the walls of blood vessels and stay put, forming a protective barrier with potentially life-saving implications.

Co-invented by Assistant Professor Christian Kastrup while a postdoctoral student at the Massachusetts Institute of Technology, the gel is similar to the amino acid that enables mussels to resist the power of churning water. The variant that Kastrup and his collaborators created, described in the current issue of the online journal PNAS [Proceeings of the National Academy of Sciences of the US] Early Edition, can withstand the flow of blood through arteries and veins.

Here’s the citation and a link to the article (which is behind a paywall),

Painting blood vessels and atherosclerotic plaques with an adhesive drug depot by Christian J. Kastrup, Matthias Nahrendorf, Jose Luiz Figueiredo, Haeshin Lee, Swetha Kambhampati, Timothy Lee, Seung-Woo Cho, Rostic Gorbatov, Yoshiko Iwamoto, Tram T. Dang, Partha Dutta, Ju Hun Yeon, Hao Cheng, Christopher D. Pritchard, Arturo J. Vegas, Cory D. Siegel, Samantha MacDougall, Michael Okonkwo, Anh Thai, James R. Stone, Arthur J. Coury, Ralph Weissleder, Robert Langer, and Daniel G. Anderson.  PNAS, December 11, 2012 DOI: 10.1073/pnas.1217972110

For those of a more technical turn of mind, here’s the abstract (from PNAS),

The treatment of diseased vasculature remains challenging, in part because of the difficulty in implanting drug-eluting devices without subjecting vessels to damaging mechanical forces. Implanting materials using adhesive forces could overcome this challenge, but materials have previously not been shown to durably adhere to intact endothelium under blood flow. Marine mussels secrete strong underwater adhesives that have been mimicked in synthetic systems. Here we develop a drug-eluting bioadhesive gel that can be locally and durably glued onto the inside surface of blood vessels. In a mouse model of atherosclerosis, inflamed plaques treated with steroid-eluting adhesive gels had reduced macrophage content and developed protective fibrous caps covering the plaque core. Treatment also lowered plasma cytokine levels and biomarkers of inflammation in the plaque. The drug-eluting devices developed here provide a general strategy for implanting therapeutics in the vasculature using adhesive forces and could potentially be used to stabilize rupture-prone plaques.

The news release describes the work layperson’s terms,

The gel’s “sheer strength” could shore up weakened vessel walls at risk of rupturing – much like the way putty can fill in dents in a wall, says Kastrup, a member of the Department of Biochemistry and Molecular Biology and the Michael Smith Laboratories.

By forming a stable barrier between blood and the vessel walls, the gel could also prevent the inflammation that typically occurs when a stent is inserted to widen a narrowed artery or vein; that inflammation often counteracts the opening of the vessel that the stent was intended to achieve.

The widest potential application would be preventing the rupture of blood vessel plaque. When a plaque ruptures, the resulting clot can block blood flow to the heart (triggering a heart attack) or the brain (triggering a stroke). Mice treated with a combination of the gel and an anti-inflammatory steroid had more stable plaque than a control group of untreated mice.

“By mimicking the mussel’s ability to cling to objects, we created a substance that stays in place in a very dynamic environment with high flow velocities,” says Kastrup, a member of UBC’s Centre for Blood Research.

Robert Langer, one of the paper’s co-authors, was mentioned here in an Aug. 27, 2012 posting about nanoelectronics, tissue engineering, and medicine.

Medicine, nanoelectronics, social implications, and figuring it all out

Given today’s (Aug. 27, 2012) earlier posting about nanoelectronics and tissue engineering, I though it was finally time to feature Michael Berger’s Aug. 16, 2012 Nanowerk Spotlight essay, The future of nanotechnology electronics in medicine, which discusses the integration of electronics into the human body.

First, Berger offers a summary of some of the latest research (Note: I have removed  links),

In previous Nanowerk Spotlights we have already covered numerous research advances in this area: The development of a nanobioelectronic system that triggers enzyme activity and, in a similar vein, the electrically triggered drug release from smart nanomembranes; an artificial retina for color vision; nanomaterial-based breathalyzers as diagnostic tools; nanogenerators to power self-sustained biosystems and implants; future bio-nanotechnology might even use computer chips inside living cells.

A lot of nanotechnology work is going on in the area of brain research. For instance the use of a carbon nanotube rope to electrically stimlate neural stem cells; nanotechnology to repair the brain and other advances in fabricating nanomaterial-neural interfaces for signal generation.

International cooperation in this field has also picked up. Just recently, scientists have formed a global alliance for nanobioelectronics to rapidly find solutions for neurological disorders; the EuroNanoBio project is a Support Action funded under the 7th Framework Programme of the European Union; and ENIAC, the European Technology Platform on nanoelectronics, has decided to make the development of medical applications one of its main objectives.

Berger cites a recent article in the American Chemical Society’s (ACS) Nano (journal) by scientists in today’s earlier posting about tissue scaffolding and 3-D electrnonics,

In a new perspective article in the July 31, 2012, online edition of ACS Nano (“The Smartest Materials: The Future of Nanoelectronics in Medicine” [behind a paywall]), Tzahi Cohen-Karni (a researcher in Kohane’s lab), Robert Langer, and Daniel S. Kohane provide an overview of nanoelectronics’ potential in the biomedical sciences.

They write that, as with many other areas of scientific endeavor in recent decades, continued progress will require the convergence of multiple disciplines, including chemistry, biology, electrical engineering, computer science, optics, material science, drug delivery, and numerous medical disciplines. ”

Advances in this research could lead to extremely sophisticated smart materials with multifunctional capabilities that are built in – literally hard-wired. The impact of this research could cover the spectrum of biomedical possibilities from diagnostic studies to the creation of cyborgs.”

Berger finishes with this thought,

Ultimately, and here we are getting almost into science fiction territory, nanostructures could not only incorporate sensing and stimulating capabilities but also potentially introduce computational capabilities and energy-generating elements. “In this way, one could fabricate a truly independent system that senses and analyzes signals, initiates interventions, and is self-sustained. Future developments in this direction could, for example, lead to a synthetic nanoelectronic autonomic nervous system.”

This Nanowerk Spotlight essay provides a good overview of nanoelectronics  research in medicine and lots of  links to previous related essays and other related materials.

I am intrigued that there is no mention of the social implications for this research and I find social science or humanities research on social social implications of emerging technology rarely discusses the technical aspects revealing what seems to be an insurmountable gulf. I suppose that’s why we need writers, artists, musicians, dancers, pop culture, and the like to create experiences, installations, and narratives that help us examine the technologies and their social implications, up close.

The body as an electronic device—adding electronics to biological tissue

What makes this particular combination of electronic s  and living tissue special is t that it was achieved in 3-D rather than 2-D.  From the Boston Children’s Hospital Aug. 26, 2012 news release on EurekAlert,

A multi-institutional research team has developed a method for embedding networks of biocompatible nanoscale wires within engineered tissues. These networks—which mark the first time that electronics and tissue have been truly merged in 3D—allow direct tissue sensing and potentially stimulation, a potential boon for development of engineered tissues that incorporate capabilities for monitoring and stimulation, and of devices for screening new drugs.

The Aug. 27, 2012 news item on Nanowerk provides more detail about integration of the cells and electronics,

Until now, the only cellular platforms that incorporated electronic sensors consisted of flat layers of cells grown on planar metal electrodes or transistors. Those two-dimensional systems do not accurately replicate natural tissue, so the research team set out to design a 3-D scaffold that could monitor electrical activity, allowing them to see how cells inside the structure would respond to specific drugs.

The researchers built their new scaffold out of epoxy, a nontoxic material that can take on a porous, 3-D structure. Silicon nanowires embedded in the scaffold carry electrical signals to and from cells grown within the structure.

“The scaffold is not just a mechanical support for cells, it contains multiple sensors. We seed cells into the scaffold and eventually it becomes a 3-D engineered tissue,” Tian says [Bozhi Tian, a former postdoc at MIT {Massachusetts Institute of Technology} and Children’s Hospital and a lead author of the paper ].

The team chose silicon nanowires for electronic sensors because they are small, stable, can be safely implanted into living tissue and are more electrically sensitive than metal electrodes. The nanowires, which range in diameter from 30 to 80 nanometers (about 1,000 times smaller than a human hair), can detect voltages less than one-thousandth of a watt, which is the level of electricity that might be seen in a cell.

Here’s more about why the researchers want to integrate living tissue and electronics, from the Harvard University Aug. 26, 2012 news release on EurekAlert,

“The current methods we have for monitoring or interacting with living systems are limited,” said Lieber [Charles M. Lieber, the Mark Hyman, Jr. Professor of Chemistry at Harvard and one of the study’s team leaders]. “We can use electrodes to measure activity in cells or tissue, but that damages them. With this technology, for the first time, we can work at the same scale as the unit of biological system without interrupting it. Ultimately, this is about merging tissue with electronics in a way that it becomes difficult to determine where the tissue ends and the electronics begin.”

The research addresses a concern that has long been associated with work on bioengineered tissue – how to create systems capable of sensing chemical or electrical changes in the tissue after it has been grown and implanted. The system might also represent a solution to researchers’ struggles in developing methods to directly stimulate engineered tissues and measure cellular reactions.

“In the body, the autonomic nervous system keeps track of pH, chemistry, oxygen and other factors, and triggers responses as needed,” Kohane [Daniel Kohane, a Harvard Medical School professor in the Department of Anesthesia at Children’s Hospital Boston and a team leader] explained. “We need to be able to mimic the kind of intrinsic feedback loops the body has evolved in order to maintain fine control at the cellular and tissue level.”

Here’s a citation and a link to the paper (which is behind a paywall),

Macroporous nanowire nanoelectronic scaffolds for synthetic tissues by Bozhi Tian, Jia Lin, Tal Dvir, Lihua Jin, Jonathan H. Tsui, Quan  Qing, Zhigang Suo, Robert Langer, Daniel S. Kohane, and Charles M. Lieber in Nature Materials (2012) doi:10.1038/nmat3404 Published onlin26 August 2012.

This is the image MIT included with its Aug 27, 2012 news release (which originated the news item on Nanowerk),

A 3-D reconstructed confocal fluorescence micrograph of a tissue scaffold.
Image: Charles M. Lieber and Daniel S. Kohane.

At this point they’re discussing therapeutic possibilities but I expect that ‘enhancement’ is also being considered although not mentioned for public consumption.

Repairing your vocal cords

In his Kavli Foundations in Chemistry Lecture at the 244th meeting of the American Chemical Society (ACS), Robert Langer, Sc.D., discussed a material that mimics vocal cords. Langer heads a team of over 100 in laboratories at the Massachusetts Institute of Technology. From the Aug. 20, 2012 news release on EurekAlert,

The artificial vocal cord material, the first designed to restore lost flexibility in human vocal cords, results from an ongoing effort to produce artificial tissues in the lab, Langer explained. Lost flexibility in the vocal cords, due to the effects of aging or disease, is a major factor in the voice loss that affects 18 million people in the United States alone.

“The synthetic vocal cord gel has similar properties as the material found in human vocal cords and flutters in response to air pressure changes, just like the real thing,” explained Langer, who is the David H. Koch Institute Professor at MIT.

The vocal cords are two folds in the “voice box” that vibrate, or come together and away from each other very quickly to produce puffs of air that help form sounds. They function in much the same way as a reed in a saxophone. The cords consist of layers of muscle, ligament and a membrane. A layer between the ligament and the membrane is very flexible, and that flexibility and pliability is critical for speech.

But when someone, such as a teacher, a politician or a performer, overuses their voice, scar tissue develops. The same thing happens when a person gets older, accounting for the lower volume and hoarseness often apparent in older people. Cancer or having a tube inserted in the throat for medical procedures also can damage the cords. Scar tissue is stiff, and scarring leaves a person with a hoarse, breathy voice.

“About 90 percent of human voice loss is because of lost pliability,” said Steven Zeitels, M.D., F.A.C.S., Langer’s collaborator on the project. Zeitels is the Eugene B. Casey Professor at Harvard Medical School and Director of the Massachusetts General Hospital Voice Center. His patients include singers Julie Andrews of The Sound of Music fame, who lost her full vocal range after surgery done elsewhere in 1997, Steven Tyler of Aerosmith and Adele. “I recognized this need in my practice over the years, after seeing many patients with voice problems. I went to Bob Langer because I knew he could help design a material that would ultimately help patients speak and sing again. Currently, no treatments exist to restore vocal cord flexibility.”

The material had to be very flexible and be able to vibrate just like human vocal cords. After trying numerous candidates, Langer’s team settled on polyethylene glycol 30 (PEG30), which is already used in personal care creams and in medical devices and drugs approved by the U.S. Food and Drug Administration (FDA), as a starting material and created polymers based on it. The PEG30 gel can flutter at a rate of 200 times per second, which is a normal rate for a woman speaking in a conversation.

Here’s a video which shows the gel and introduces you to some of the scientists working on this project accompanied by a soundtrack of Julie Andrews singing prior to her 1997 operation,

Here’s how the gel would work based on animal testing results (from the news release),

A physician would inject the gel into a patient’s vocal cords. Patients would receive different formulations, depending on how they use their voices. The most stable version is highly “cross-linked,” which means the molecules of PEG are more tightly stitched together than in other versions. That makes the material a little bit rigid, but it would still help restore someone’s speaking voice. A singer, however, would likely receive a formulation that is more loosely stitched together, or less cross-linked, which is more flexible to allow the patient to hit high notes. The gel degrades over time, so patients would receive two to five injections per year, estimated Zeitels.

Tests in animals suggest that the material is safe, and human trials will hopefully begin in mid-2013. Some of Zeitels’ patients, such as Andrews, have formed a nonprofit organization called The Voice Health Institute, which funds Langer and Zeitels’ research on the vocal cord biomaterial.

I looked at the Voice Health Institute  (VHI) website  and found this on the About Us page (Note: I have removed some links),

The Voice Health Institute (VHI) is a federally-approved non-profit organization (501-C-3) that was established in 2003 by patients with voice loss to advance voice restoration and breathing impairment as a result of throat and larynx problems through the support of innovative research, education and outreach programs. A small group of patients from around the United States convened in New York City to share their experiences with throat and larynx cancer, vocal cord paralysis and voice loss. These patients shared their gratitude to the caregivers at the Massachusetts General Hospital while acknowledging substantial frustration with their initial management.

This highlighted the wide disparity of care offered in the United States and abroad and the generalized limited awareness of the general public about issues related to the throat, larynx and voice. Julie Andrews, the iconic singer/actress who lost her singing voice joined the VHI at its incorporation as the Honorary Chairwoman through the efforts of Dr. Steven Zeitels, her current physician and surgeon. Since then, iconic rock vocalists Steven Tyler of Aerosmith and Roger Daltrey of The Who have also provided invaluable support to the VHI to forward their mission.

The VHI has funded educational and award-wining pioneering research programs at:

  • Massachusetts General Hospital
  • Harvard Medical School
  • Massachusetts Institute of Technology
  • Boston University
  • University of South Carolina
  • American Speech-Language-Hearing Association (ASHA)
  • New England Conservatory of Music and
  • American Broncho-Esophagological Association (ABEA)

I don’t see a lot  of doctors or researchers on either the ‘working’ board which features mostly business people (Julie Andrews is the honorary chair and the six business people are all male) or the advisory board (broadcasters or singers and a better gender balance [eight members, two of whom are female]). I wonder how they decide the disbursements  if neither sets of board members have medical expertise. Presumably they convene a special committee to oversee grant submissions but who’s on the committee? In a research area that’s so highly specialized all of the players are likely to know each other. So, the people adjudicating the disbursements  this time may be applying for research funds  the next time and presenting their submissions to the last round’s applicants who are now the adjudicators.

The problem which all organizations that disburse funds face is this: if you stack committees with people who don’t have expertise in the specialty you may find they don’t understand the proposed research well enough to make informed decisions or if they are experts in the field everyone is beholden to everyone else.

Enough of this excursion into the business of funding. Langer’s work extends beyond this vocal cord research, from the news release,

Artificial vocal cords are just one artificial tissue in development in Langer’s lab. He described work on building intestinal, spinal cord, pancreatic and heart tissue in the laboratory with many different types of materials. Among them: Nanowires (which are about a tenth the diameter of a human hair) and something called “biorubber.”

“It’s hard to know when they will be ready for clinical use,” Langer said. “But In Vivo Therapeutics hopes to start clinical trials for the spinal cord tissue we’ve developed within the next year.”

Langer also recently developed a pacemaker-sized microchip that delivers just the right amount of medication at just the right time, potentially allowing thousands of patients to ditch painful needles forever. A clinical trial of the device, implanted in women with osteoporosis, has just concluded and showed that it was safe to use. The device released osteoporosis medication when it received a signal from a computer. It worked just as well as daily shots of the drug. MicroCHIPS, Inc., a company that Langer co-founded, will commercialize the remote-controlled microchip.

Another way to make medicines more effective is to make sure they go exactly to the location where they are needed; this reduces harmful side effects. Langer’s targeted nanoparticles can do just that. A clinical trial run by BIND Biosciences, another company co-founded by Langer, recently found that these nanoparticles are safe in humans. The particles have a homing molecule on them that targets them to prostate cancer cells or cancer blood vessels, and they deliver an anti-cancer medication called docetaxel. All of the materials, including the drug, are already approved by the FDA.

I expect that as the 244th meeting of ACS continues there’ll be more news about chemistry and the glorious future we can look forward to due to research. I hope they’re planning a few sessions that are less laudatory to balance things out.

Don’t kill bacteria, uninvite them

The relentless campaign against bacteria has had some unintended consequences, we’ve made bacteria more resistant and more virulent. Researchers at the University of Nottingham (UK) have taken a different approach from attempting to eradicate or kill; they’ve discovered a class of polymers that ‘uninvites’ bacteria from their surfaces. From the Aug. 13, 2012 news item on ScienceDaily,

Using state-of-the-art technology, scientists at The University of Nottingham have discovered a new class of polymers that are resistant to bacterial attachment. These new materials could lead to a significant reduction in hospital infections and medical device failures.

Medical device associated infections can lead to systemic infections or device failure, costing the NHS £1bn a year. Affecting many commonly used devices including urinary and venous catheters — bacteria form communities known as biofilms. This ‘strength in numbers approach’ protects them against the bodies’ natural defences and antibiotics.

Experts in the Schools of Pharmacy and Molecular Medical Sciences, have shown that when the new materials are applied to the surface of medical devices they repel bacteria and prevent them forming biofilms.

There’s a video of the scientists discussing their work on this new class of polymers,

In order to find this new class of polymers, the scientists had to solve another problem first. From the Aug. 12, 2012 University of Nottingham press release,

Researchers believed there were new materials that could resist bacteria better but they had to find them. This meant screening thousands of different chemistries and testing their reaction to bacteria — a challenge which was beyond conventional materials development or any of our current understanding of the interaction of micro-organisms with surfaces.

The discovery has been made with the help of experts from the Massachusetts Institute of Technology (MIT) — who initially developed the process by which thousands of unique polymers can now be screened simultaneously.

Professor Alexander said: “This is a major scientific breakthrough — we have discovered a new group of structurally related materials that dramatically reduce the attachment of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli). We could not have found these materials using the current understanding of bacteria-surface interactions. The technology developed with the help of MIT means that hundreds of materials could be screened simultaneously to reveal new structure-property relationships. In total thousands of materials were investigated using this high throughput materials discovery approach leading to the identification of novel materials resisting bacterial attachment. This could not have been achieved using conventional techniques.”

Once they found this new class of polymers, researchers tested for effectiveness (from the Aug. 12, 2012 university press release),

These new materials prevent infection by stopping biofilm formation at the earliest possible stage — when the bacteria first attempt to attach themselves to the device. In the laboratory experts were able to reduce the numbers of bacteria by up to 96.7per cent — compared with a commercially available silver containing catheter — and were effective at resisting bacterial attachment in a mouse implant infection model. By preventing bacterial attachment the body’s own immune system can kill the bacteria before they have time to generate biofilms.

You can read more about this work in the paper the researchers have published (as well as, the news item on ScienceDaily or the University of Nottingham press release for more accessible explanations). You will need to get past a paywall (from the news item on ScienceDaily),

Andrew L Hook, Chien-Yi Chang, Jing Yang, Jeni Luckett, Alan Cockayne, Steve Atkinson, Ying Mei, Roger Bayston, Derek J Irvine, Robert Langer, Daniel G Anderson, Paul Williams, Martyn C Davies, Morgan R Alexander. Combinatorial discovery of polymers resistant to bacterial attachment. Nature Biotechnology, 2012; DOI: 10.1038/nbt.2316

This research reminded me of Sharklet, a product being developed in the US for use in hospitals. Designed to mimic sharkskin, the product discourages bacteria from settling on its surface. It was featured in my Feb. 10, 2011 posting.

Commercializing nano: US, Spain, and RUSNANO

Late September 2011 saw the Nanomanufacturing Summit 2011 and 10th Annual NanoBusiness conference take place in Boston, Massachusetts (my Sept. 21, 2011 posting). Dr. Scott Rickert (President and CEO of Nanofilm) writing for Industry Week noted this about the events in his Oct. 14, 2011 posting,

I witnessed an American revolution catch fire in Boston, and I feel like a latter-day Paul Revere. “The nanotech economy is coming, the nanotech economy is coming!” and that’s good news for the U.S. — and you — because we’re at the epicenter.

Let’s start with commercialization. Ten years ago, when I walked into the inaugural version of this conference, I was one of the few with money-making nanotechnology products on the market. This time? The sessions were packed with executives from multi-million dollar businesses, and the chatter was about P&L as much as R&D. Nano-companies are defying Wall Street woes and going public. And even academics were talking about business plans, not prototypes.

Dozens of companies from Europe, Asia and the Middle East were at the conference. Their goal was tapping into the American know-how for making science into business.

Seems a little euphoric, doesn’t he? It’s understandable for anyone who’s worked long and hard at an activity that’s considered obscure by great swathes of the population and finally begins to see substantive response. (Sidebar: Note the revolutionary references for a conference taking place in what’s considered the birthplace of the American Revolution.)

Speakers at MIT’s (Massachusetts Institute of Nanotechnology) EmTech event held in Spain on Oct. 26-27, 2011 were are a bit more measured, excerpted from the Oct. 27, 2011 posting featuring highlights from the conference by Cal Pierce for Opinno,

Javier García Martínez, founder of Rive Technology and Tim Harper, founder of Cientifica.com presented their view of how nanotechnology will transform our world.

Harper took the stage first.

“We have spent $67 billion on nanotechnology research this decade, so you can imagine this must be an important field,” he said.

Harper believes that nanotechnology is the most important technology that humans have developed in the past 5,000 years. However, he spoke about the difficulties in developing nanotechnology machinery in that we cannot simply shrink factories down to nano-scales. Rather, Harper said we need to look to cells in nature as they have been using nanotechnology for billions of years.

….

Harper spoke about the dire need to use nanotechnology to develop processes that replace scarce resources. However, the current economic climate is hindering these critical innovations.

Javier Garcia then spoke.

“Graphene, diamond and other carbon structures are the future of 21st-century nanotechnology,” he said.

Garcia says that the next challenge is commercialization. There are thousands of scientific articles about nanotechnology published every year which are followed by many patents, he explained. However, he reflected on Cook’s ideas about funding.

“There is still not a nanotechnology industry like there is for biotechnology,” he said.

Finally, Garcia said successful nanotechnology companies need to build strong partnerships, have strong intellectual property rights and create a healthy balance between creativity and focus. Government will also play a role with simplified bureaucracy and tax credits.

Hang on, it gets a little more confusing when you add in the news from Russia (from Dexter Johnson’s Oct. 26, 2011 posting titled, Russia Claims Revenues of One-Third-of–a-Billion Dollars in Nanotech This Year on his Nanoclast blog on the Institute for Electrical and Electronics Engineering [IEEE] website),

One of the first bits of interesting news to come out of the meeting is that: “In 2011, Rusnano has earned about 10 billion rubles ($312 million) on manufacturing products using nanotechnology — nearly half of the state corporation’s total turnover.”

We should expect these estimates to be fairly conservative, however, ever since Anatoly Chubais, RusNano’s chief, got fed up with bogus market numbers he was seeing and decided that RusNano was going to track its own development.

I have to say though, no matter how you look at it, over $300 million in revenues is pretty impressive for a project that has really only existed for three years.

Then RUSNANO announced its investments in Selecta Biosciences and BIND Biosiences, from the Oct. 27, 2011 news item on Nanowerk,

BIND Biosciences and Selecta Biosciences, two leading nanomedicine companies, announced today that they have entered into investment agreements with RUSNANO, a $10-billion Russian Federation fund that supports high-tech and nanotechnology advances.

RUSNANO is co-investing $25 million in BIND and $25 million in Selecta, for a total RUSNANO investment of $50 million within the total financing rounds of $94.5 million in the two companies combined. …

The proprietary technology platforms of BIND and Selecta originated in laboratories at Harvard Medical School directed by Professor Omid Farokhzad, MD, and in laboratories at MIT directed by Professor Robert Langer, ScD, a renowned scientist who is a recipient of the US National Medal of Science, the highest US honor for scientists, and is an inventor of approximately 850 patents issued or pending worldwide. Drs. Langer and Farokhzad are founders of both companies. [Farokhzad was featured in a recent Canadian Broadcasting Corporation {CBC}, Nature of Things, television episode about nanomedicine, titled More than human.] Professor Ulrich von Andrian, MD, PhD, head of the immunopathology laboratory at Harvard Medical School, is a founder of Selecta.

Selecta pioneers new approaches for synthetically engineered vaccines and immunotherapies. Selecta’s lead drug candidate, SEL-068, is entering human clinical studies as a vaccine for smoking cessation and relapse prevention. Other drug development programs include universal human papillomavirus (HPV) vaccine, universal influenza vaccine, malaria vaccine, and type 1 diabetes therapeutic vaccine.

BIND develops targeted therapeutics, called Accurins™, that selectively accumulate at the site of disease to dramatically enhance effectiveness for treating cancer and other diseases. BIND’s lead candidate, BIND-014, is in human clinical trials as a targeted therapy for cancer treatment. BIND’s development pipeline also includes a range of cancer treatments and drugs for anti-inflammatory and cardiovascular conditions.

Here’s an excerpt from Dexter Johnson’s Oct. 28, 2011 posting where he muses on this development,

It seems the last decade of the US—along with parts of Europe and Asia—pouring money into nanotechnology research, which led to a few fledgling nanotechnology-based businesses, is finally paying off…for Russia.

In the case of these two companies, I really don’t know to what extent their initial technology was funded or supported by the US government and I wouldn’t begrudge them a bit if it was significant. Businesses need capital just to get to production and then later to expand. It hardly matters where it comes from as long as they can survive another day.

Dexter goes on to note that RUSNANO is not the only organization investing major money to bring nanotechnology-enabled products to the next stage of commercialization; this is happening internationally.

Meanwhile, Justin Varilek posts this (Nanotech Enthusiasm Peaks) for the Moscow Times on Oct. 28, 2011,

In nanotechnology, size matters. But federal funding for the high-tech field has tapered off in Russia, flattening out at $1.88 billion per year through 2015 and losing ground in the race against the United States and Germany.

If this were a horse race, nanotechnology-enabled products are in the final stretches toward the finish line (commercialization) and it’s still anyone’s horse race.

Note: I didn’t want to interrupt the flow earlier to include this link to the EmTech conference in Spain. And, I did post a review (Oct. 26, 2011) of More than Human, which did not mention Farokhzad by name, the second episode in a special three-part series being broadcast as part of the Nature of Things series on CBC.