Selenium controls staph on implant material

A coating of selenium nanoparticles significantly reduces the growth of Staphylococcus aureus on polycarbonate, a material common in implanted devices such as catheters and endotracheal tubes, engineers at Brown University report in a new study.

PROVIDENCE, R.I. [Brown University] — Selenium is an inexpensive element that naturally belongs in the body. It is also known to combat bacteria. Still, it had not been tried as an antibiotic coating on a medical device material. In a new study, Brown University engineers report that when they used selenium nanoparticles to coat polycarbonate, the material of catheters and endotracheal tubes, the results were significant reductions in cultured populations of Staphylococcus aureus bacteria, sometimes by as much as 90 percent.

Selenium solutionQi Wang swirls a solution of selenium nanoparticles in the lab.
Coatings of the nanoparticles appear effective in fighting staph
bacteria in medical device materials, according to a new study.
Credit: Webster Lab/Brown University

“We want to keep the bacteria from generating a biofilm,” said Thomas Webster, professor of engineering and orthopaedics, who studies how nanotechnology can improve medical implants. He is the senior author of the paper, published online this week in the Journal of Biomedical Materials Research A.

Biofilms are notoriously tough colonies of bacteria to treat because they are often able to resist antibiotic drugs.

“The longer we can delay or inhibit completely the formation of these colonies, the more likely your immune system will clear them,” Webster said. “Putting selenium on there could buy more time to keep an endotracheal tube in a patient.”

Meanwhile, Webster said, because selenium is actually a recommended nutrient, it should be harmless in the body at the concentrations found in the coatings. Also, it is much less expensive than silver, a less biocompatible material that is the current state of the art for antibacterial medical device coatings.

Webster has been investigating selenium nanoparticles for years, mostly for their possible anticancer effects. As he began to look at their antibiotic properties, he consulted with Hasbro Children’s Hospital pediatrician Keiko Tarquinio, assistant professor of pediatrics, who has been eager to find ways to reduce biofilms on implants.

Studying selenium

For this study, Webster and first author Qi Wang grew selenium nanoparticles of two different size ranges and then used solutions of them to coat pieces of polycarbonate using a quick, simple process. On some of the polycarbonate, they then applied and ripped off tape not only to test the durability of the coatings but also to see how a degraded concentration of selenium would perform against bacteria.

On coated polycarbonate — both the originally coated and the tape-tested pieces — Wang and Webster used electron and atomic force microscopes to measure the concentration of nanoparticles and how much surface area of selenium was exposed to interact with bacteria.

One of their findings was that after the tape test, smaller nanoparticles adhered better to the polycarbonate than larger ones.

Then they were ready for the key step: experiments that exposed cultured staph bacteria to polycarbonate pieces, some of which were left uncoated as controls. Among the coated pieces, some had the larger nanoparticles and some had the smaller ones. Some from each of those groups had been degraded by the tape, and others had not.

All four types of selenium coatings proved effective in reducing staph populations after 24, 48, and 72 hours compared to the uncoated controls. The most potent effects — reductions larger than 90 percent after 24 hours and as much as 85 percent after 72 hours — came from coatings of either particle size range that had not been degraded by the tape. Among those coatings that had been subjected to the tape test, the smaller nanoparticle coatings proved more effective.

Staph populations exposed to any of the coated polycarbonate pieces peaked at the 48-hour timeframe, perhaps because that is when the bacteria could take fullest advantage of the in vitro culture medium. But levels always fell back dramatically by 72 hours.

The next step, Webster said, is to begin testing in animals. Such in vivo experiments, he said, will test the selenium coatings in a context where the bacteria have more available food but will also face an immune system response.

The results may ultimately have commercial relevance. Former graduate students developed a business plan for the selenium nanoparticle coatings while in school and have since licensed the technology from Brown for their company, Axena Technologies.

‘Bed-of-nails’ breast implant deters cancer cells

Researchers at Brown University have created an implant that appears to deter breast cancer cell regrowth. Made from a common federally approved polymer, the implant is the first to be modified at the nanoscale in a way that causes a reduction in the blood-vessel architecture that breast cancer tumors depend upon, while also attracting healthy breast cells. Results are published in Nanotechnology.

PROVIDENCE, R.I. [Brown University] — One in eight women in the United States will develop breast cancer. Of those, many will undergo surgery to remove the tumor and will require some kind of breast reconstruction afterward, often involving implants. Cancer is an elusive target, though, and malignant cells return for as many as one-fifth of women originally diagnosed, according to the American Cancer Society.

A selectively inhospitable surface
A bumpy “bed of nails” surface does not allow cancerous
cells to gather the nutrients they need to thrive — possibly
because cancerous cells are stiffer and less flexible than
normal cells, which can manage the bumps and thrive.
Credit: Webster Lab/Brown University

Would it be possible to engineer implant materials that might drive down that rate of relapse? Brown University biomedical scientists report some promising advances. The team has created an implant with a “bed-of-nails” surface at the nanoscale (dimensions one-billionth of a meter, or 1/50,000th the width of a human hair) that deters cancer cells from dwelling and thriving. Made out of a common federally approved polymer, the implant is the first of its kind, based on a review of the literature, with modifications at the nanoscale that cause a reduction in the blood-vessel architecture on which breast cancer tumors depend — while also attracting healthy breast cells.

“We’ve created an (implant) surface with features that can at least decrease (cancerous) cell functions without having to use chemotherapeutics, radiation, or other processes to kill cancer cells,” said Thomas Webster, associate professor of engineering and the corresponding author on the paper in Nanotechnology. “It’s a surface that’s hospitable to healthy breast cells and less so for cancerous breast cells.”

Webster and his lab have been modifying various implant surfaces to promote the regeneration of bone, cartilage, skin, and other cells. In this work, he and Lijuan Zhang, a fourth-year graduate student in chemistry, sought to reshape an implant that could be used in breast reconstruction surgery that would not only attract healthy cells but also repel any lingering breast-cancer cells. The duo created a cast on a glass plate using 23-nanometer-diameter polystyrene beads and polylactic-co-glycolic acid (PLGA), a biodegradable polymer approved by the FDA and used widely in clinical settings, such as stitches. The result: An implant whose surface was covered with adjoining, 23-nanometer-high pimples. The pair also created PLGA implant surfaces with 300-nanometer and 400-nanometer peaks for comparison.

In lab tests after one day, the 23-nanometer-peak surfaces showed a 15-percent decrease in the production of a protein (VEGF) upon which endothelial breast-cancer cells depend, compared to an implant surface with no surface modification. The 23-nanometer surface showed greater reduction in VEGF concentration when compared to the 300-nanometer and 400-nanometer-modified implants as well.

It’s unclear why the 23-nanoneter surface appears to work best at deterring breast-cancer cells. Webster thinks it may have to do something with the stiffness of malignant breast cells. When they come into contact with the bumpy surface, they are unable to fully wrap themselves around the rounded contours, depriving them of the ability to ingest the life-sustaining nutrients that permeate the surface.

“This is like a bed-of-nails surface to them,” Webster said.

“I would guess that surface peaks less than 23 nanometers would be even better,” Webster added, although polystyrene beads with such dimensions don’t yet exist. “The more you can push up that cancerous cell, the more you keep it from interacting with the surface.”

The pair also found that the 23-nanometer semispherical surface yielded 15 percent more healthy endothelial breast cells compared to normal surface after one day of lab tests.

Webster and Zhang next plan to investigate why the nanomodified surfaces deter malignant breast cells, to create surface features that yield greater results, and to determine whether other materials can be used.

The National Institutes of Health’s National Center for Research Resources and the Hermann Foundation funded the research. Michael Platek at the University of Rhode Island helped with the electron spectroscopy for chemical analysis.

- by Richard Lewis

Three Biomedical Engineering Graduate Students Win Award

Brown biomedical engineering graduate students Gozde Durmus, Kim Kummer '11, and Erik Taylor were one of ten graduate student teams to win the Prize for Primary Healthcare Award (Phase I) from the Center for Integration of Medicine and Innovative Technology (CIMIT). The title of their project is "Using Nano-material Science to Inhibit Medical Device Infections".

Each winning team received $10,000, and they will now be able to use these funds to develop a final proposal over the next few months as they compete for the top three spots and a total of $300,000 in additional funds against teams from other top schools such as MIT, Johns Hopkins, and Yale.

“This is an outstanding achievement,” said Associate Professor Thomas Webster, “and places Brown among the top biomedical programs in the country.” Webster serves as the advisor to the three students on the research.

The award is for innovative technology ideas to improve the quality and efficiency of primary care in medicine. The Brown team was selected out of 76 applicants from 38 of the top engineering programs in the country. The goal of the competition is to stimulate the development of innovative technology to serve the needs of the frontlines of healthcare.

Professor Thomas Webster Elected to College of Fellows of AIMBE

Thomas Webster, associate professor at the School of Engineering and the Department of Orthopaedics at Brown University, has been elected to the College of Fellows of the American Institute for Medical and Biological Engineering (AIMBE). Located in Washington D.C., AIMBE is the leading advocacy group for medical and biological engineering and is comprised of some of the most important leaders in science and engineering, the top 2% of medical and biological engineers.

The College of Fellows of AIMBE is comprised of an exemplary group of approximately 900 medical and biological engineers. Founded in 1991, AIMBE has earned a reputation as a prestigious public policy leader on issues impacting the medical and biological community and is regarded as the preeminent voice in the field.

Webster received his bachelor of science degree in chemical engineering from the University of Pittsburgh, and his master’s degree and and Ph.D. in biomedical engineering from Rensselaer Polytechnic Institute. Professor Webster directs the Nanomedicine Laboratory which designs, synthesizes, and evaluates nanophase materials for various implant applications. Nanophase materials are central to the field of nanotechnology and are materials with one dimension less than 100 nm. Materials investigates to date include nanophase ceramics, metals, polymers, carbon fibers, and composites. Organ systems evaluated to date include orthopedic, cartilage, vascular, bladder, and the central and peripheral nervous systems.

His lab group has generated four books, 33 book chapters, 85 invited presentations (including tutorials), 215 literature articles and/or conference proceeding, and 245 conference presentations. Professor Webster has been awarded 11 full patents plus four provisional patents in his 11 years in academics (five years at Brown and six years at Purdue). His technology has resulted in one start-up company. He is the founding editor-in-chief of the International Journal of Nanomedicine and is on the editorial board of ten other journals. He has organized over 25 symposia at academic conferences. Dr. Webster was the 2002 recipient of the Biomedical Engineering Society Rita Schaffer Young Investigator Award, the 2004 recipient of the Outstanding Young Investigator Award for the Schools of Engineering at Purdue University, the 2004 finalist for the Young Investigator Award of the American Society for Nanomedicine, and the 2005 recipient of the Wallace Coulter Foundation Early Career Award.

Erik Taylor Wins BMES Graduate Student Award

At the annual meeting of the Biomedical Engineering Society, Brown University graduate student Erik Taylor won the Graduate Student Extended Abstract Award for outstanding research. His submission, “Superparamagnetic Iron Oxide Nanoparticles Could Be Better than Antibiotics at Reducing Biofilm Produced by Staphylococcus Aureus” was considered by the committee strong enough to be only one of ten such awards presented.

This award consists of a certificate, a stipend of $500, and complimentary registration for the 2011 BMES Annual Meeting. The certificate was presented at the awards ceremony at the BMES Business Meeting on Thursday, October 13, 2011, in Hartford, Conn. The award has been presented each year since 1992 in recognition of outstanding biomedical engineering research.

Taylor, who was selected for a Fulbright Fellowship, will be leaving for India next semester to work on biofilm research and anti-infection strategies at IIT-Bombay in Mumbai for nine months. He will be working with Dr. Rinti Banerjee from IIT-Bombay through the Indo-U.S. Center for Biomaterials for Healthcare, co-directed by professors Bikram Basu and Thomas Webster.

Nanomaterials Studies Advance Cancer Research

Graduate student Lijuan Zhang and associate professor Thomas Webster have conducted research with nanomaterials that may lead to a potential breakthrough in cancer research. Their recent research, "Decreased lung carcinoma cell functions on select polymer nanometer surface features" was published in Journal of Biomedical Materials Research A.  

Behind the purple doors of a sixth-floor Barus and Holley Lab, Thomas Webster, associate professor of engineering, works small but thinks big. His work with nanomaterials, tiny devices implanted into the human body, has led to a potential breakthrough in cancer research.

Webster, director of the University's NanomedicineLaboratory, has been studying and developing nanotech implants for the past 11 years. His team had created rough implants covered in tiny "nano-features"— microscopic bumps ­— to "mimic the natural roughness of healthy skin," he said. "Current orthopedic implants are flat and smooth, but healthy skin and bone have bumps."

Two years ago, graduate student Lijuan Zhang approached Webster with a radical idea — exploring how nano-features would interact with cancer cells.

"Being the adventurous person I am, I said, ‘Let's try it,'" Webster said. It was completely new territory for Webster, but he said he was excited to see what would happen.

Within a year of research, a blink of an eye in lab time, Zhang approached Webster with results they both found fascinating. The addition of 23nm nano-features to a petri dish with both cancerous and healthy cells caused a significantly lower density of cancer cells over time.

Webster said he was pleased and intrigued by the results, but he knew the tests needed to be run at least three more times to verify any findings.

Zhang ran another trial and again found a lower density of cancer cells, but she also found something new — the nano-features inhibited the synthesis of a protein that aids in tumor growth.

The tests had initially been conducted with lung cancer cells, but later tests used breast cancer and bone cancer cells. Both reacted in the same manner — the nano-features lowered the density of cancer cells and decreased the synthesis of the tumor growth protein.

The next step is finding real-world applications, Webster said. "In order for any of this research to be useful, we need a company. We need to transition from the lab bench to a real product."

Webster said he hopes to apply their discovery to animal models and eventually human trials. "If all goes well, a product could appear in five years," he said.

By Hannah Kerman/BDH

Nanoskin Saves Lives and Limbs

Engineers and Orthopedics Experts Reduce Risk of Infection from Medical Prostheses with Nanotech that Mimics Human Skin

Engineers and orthopedics experts are applying nanotechnology to prosthetic medical devices in order to increase patient safety. By closely mimicking human skin, experts hope to reduce the infection-inducing bacteria that grow on prostheses. Changing the texture of the devices in small ways results in a big reduction in bacteria growth, as well as improvement of skin closures and bone growth.

Nanoskin saves lives and limbs - San Diego, California News Station - KFMB Channel 8 - cbs8.com

Losing a limb can be devastating and in the United States there are approximately 1.7 million people living that way. One of the biggest fears for those who use prosthetic devices is getting an infection. But researchers are working on a way to mimic the human skin to cut down on infections.

“I went to bed and woke up the next morning and my body was swollen and I had blisters all over it,” Anthony Buttaro, a man who suffered limb loss, told Ivanhoe.

That morning Anthony Buttaro rushed to the hospital. Doctors diagnosed him with MRSA the often deadly infection forced doctors to amputate his left arm. Now Anthony uses a prosthetic device but he is still concerned about infections.
“I’m always worried about it,” Buttaro said.

To ease those fears engineers and experts in orthopedics at Brown University are applying nanotechnology to medicine called nanomedicine to mimic the tiniest features and contours of human skin.

“Skin serves as a barrier to keep bacteria out of the body,” Thomas Webster an engineer at Brown University told Ivanhoe.

Screws are often used to attach the prosthetic device to bone, but bacteria can grow on the screws causing an infection.
“We are talking really, really small features that are making a difference,” Webster said.

The difference comes by changing the texture of the screw. First it is dipped into hydrofluoric acid. At the same time voltage is applied to create the tissue like features.

“What we are seeing, we’re reducing bacteria growth, on these implants, we’re improving skin closures around the implants and improving bone growth,” Webster explained.

By mimicking the skin researchers believe it will cut down on infections, saving lives and limbs. The nanoskin technology is still in the study phase, but researchers hope to start human testing in the future.


ABOUT NANOTECHNOLOGY: Nanotechnology is science at the size of individual atoms and molecules -- objects and devices measuring mere billionths of a meter, smaller than a red blood cell. At this size scale, materials have different chemical and physical properties than the same materials in bulk, because quantum mechanics is more important. For example, carbon atoms can conduct electricity and are stronger than steel when woven into hollow microscopic threads. Nanoparticles are already widely used in certain commercial consumer products, such as suntan lotions, "age-defying" make-up, and self-cleaning windows that shed dirt when it rains. One company manufactures a nanocrystal wound dressing with built-in antibiotic and anti-inflammatory properties. On the horizon is toothpaste that coats, protects and repairs damaged enamel, as well as self-cleaning shoes that never need polishing. Nanoparticles are also used as additives in building materials to strengthen the walls of any given structure, and to create tough, durable, yet lightweight fabrics.


The Biophysical Society and the Materials Research Society contributed to the information contained in the TV portion of this report.

Brown Professor Thomas Webster receives Patent for “Nanofibers as a Neural Biomaterial”

Dr. Thomas Webster, associate professor at the Brown University School of Engineering, has received a patent for "Nanofibers as a Neural Biomaterial," U.S. Patent Number: 7,993,412. Professor Webster has now been awarded 11 full patents plus four provisional patents in his 11 years in academics (five years at Brown and six years at Purdue).

The technology in this patent describes the use of carbon nanotubes/nanofibers to heal a wide range of neurological disorders, from stroke to Parkinson's disease. In this technology, carbon nanotubes and nanofibers, which are tubes and fibers formed from the helical arrangement of carbon, were shown to significantly promote the function of neurons while inhibiting glial scar tissue formation to reverse brain damage. In particular, the unique high conductivity coupled with high strength to low weight ratios of carbon nanotubes were helpful for stimulating functions of nuerons. Carbon nanotubes have even been shown to improve stem cell differentiation into neurons in animal experiments. Currently, this technology is licensed to Nanovis, Inc. (www.nanovis.com)

Webster received his bachelor of science degree in chemical engineering from the University of Pittsburgh, and his master’s degree and and Ph.D. in biomedical engineering from Rensselaer Polytechnic Institute. Professor Webster directs the Nanomedicine Laboratory which designs, synthesizes, and evaluates nanophase materials for various implant applications. Nanophase materials are central to the field of nanotechnology and are materials with one dimension less than 100 nm. Materials investigates to date include nanophase ceramics, metals, polymers, carbon fibers, and composites. Organ systems evaluated to date include orthopedic, cartilage, vascular, bladder, and the central and peripheral nervous systems.

His lab group has generated four books, 33 book chapters, 85 invited prestentations (including tutorials), 215 literature articles and/or conference proceeding, and 245 conference presentations. His technology has resulted in one start-up company. He is the founding editor-in-chief of the International Journal of Nanomedicine and is on the editorial board of ten other journals. He has organized over 25 symposia at academic conferences. Dr. Webster was the 2002 recipient of the Biomedical Engineering Society Rita Schaffer Young Investigator Award, the 2004 recipient of the Outstanding Young Investigator Award for the Schools of Engineering at Purdue University, the 2004 finalist for the Young Investigator Award of the American Society for Nanomedicine, and the 2005 recipient of the Wallance Coulter Foundation Early Career Award.

Brown Engineering researchers create nanopatch for the heart

Engineers at Brown University and in India have a promising new approach to treating heart-attack victims. The researchers created a nanopatch with carbon nanofibers and a polymer. In laboratory tests, natural heart-tissue cell density on the nanoscaffold was six times greater than the control sample, while neuron density had doubled. Results are published in Acta Biomaterialia. 

PROVIDENCE, R.I. [Brown University] — When you suffer a heart attack, a part of your heart dies. Nerve cells in the heart's  wall and a special class of cells that spontaneously expand and contract – keeping the heart beating in perfect synchronicity – are lost forever. Surgeons can’t repair the affected area. It’s as if when confronted with a road riddled with potholes, you abandon what’s there and build a new road instead.

Needless to say, this is a grossly inefficient way to treat arguably the single most important organ in the human body. The best approach would be to figure out how to resuscitate the deadened area, and in this quest, a group of researchers at Brown University and in India may have an answer.

The scientists turned to nanotechnology. In a lab, they built a scaffold-looking structure consisting of carbon nanofibers and a government-approved polymer. Tests showed the synthetic nanopatch regenerated natural heart tissue cells ­– called cardiomyocytes – as well as neurons. In short, the tests showed that a dead region of the heart can be brought back to life.

“This whole idea is to put something where dead tissue is to help regenerate it, so that you eventually have a healthy heart,” said David Stout, a graduate student in the School of Engineering at Brown and the lead author of the paper published in Acta Biomaterialia.

The approach, if successful, would help millions of people. In 2009, some 785,000 Americans suffered a new heart attack linked to weakness caused by the scarred cardiac muscle from a previous heart attack, according to the American Heart Association. Just as ominously, a third of women and a fifth of men who have experienced a heart attack will have another one within six years, the researchers added, citing the American Heart Association.

What is unique about the experiments at Brown and at the India Institute of Technology Kanpur is the engineers employed carbon nanofibers, helical-shaped tubes with diameters between 60 and 200 nanometers. The carbon nanofibers work well because they are excellent conductors of electrons, performing the kind of electrical connections the heart relies upon for keeping a steady beat. The researchers stitched the nanofibers together using a poly lactic-co-glycolic acid polymer to form a mesh about 22 millimeters long and 15 microns thick and resembling “a black Band Aid,” Stout said. They laid the mesh on a glass substrate to test whether cardiomyocytes would colonize the surface and grow more cells.

In tests with the 200-nanometer-diameter carbon nanofibers seeded with cardiomyocytes, five times as many heart-tissue cells colonized the surface after four hours than with a control sample consisting of the polymer only. After five days, the density of the surface was six times greater than the control sample, the researchers reported. Neuron density had also doubled after four days, they added.

The scaffold works because it is elastic and durable, and can thus expand and contract much like heart tissue, said Thomas Webster, associate professor in engineering and orthopaedics at Brown and the corresponding author on the paper. It’s because of these properties and the carbon nanofibers that cardiomyocytes and neurons congregate on the scaffold and spawn new cells, in effect regenerating the area.

The scientists want to tweak the scaffold pattern to better mimic the electrical current of the heart, as well as build an in-vitro model to test how the material reacts to the heart’s voltage and beat regime. They also want to make sure the cardiomyocytes that grow on the scaffolds are endowed with the same abilities as other heart-tissue cells.

Bikramjit Basu at the India Institute of Technology Kanpur contributed to the paper. The Indo-U.S. Science and Technology Forum, the Hermann Foundation, the Indian Institute of Technology, Kanpur, the government of India and California State University funded the research.

Nanomodified surfaces seal leg implants against infection

Researchers at Brown University have created nanoscale surfaces for implanted materials that mimic the contours of natural skin. The surfaces attract skin cells that, over time, are shown to build a natural seal against bacterial invasion. The group also created a molecular chain that allows an implant surface to be covered with skin cell-growing proteins, further accelerating skin growth. Results are published in theJournal of Biomedical Materials Research A.

PROVIDENCE, R.I. [Brown University] — In recent years, researchers have worked to develop more flexible, functional prosthetics for soldiers returning home from battlefields in Afghanistan or Iraq with missing arms or legs. But even new prosthetics have trouble keeping bacteria from entering the body through the space where the device has been implanted.

“You need to close (the area) where the bacteria would enter the body, and that’s where the skin is,” said Thomas Webster, associate professor of engineering and orthopaedics at Brown University.

Webster and a team of researchers at Brown may have come across the right formula to deter bacterial migrants. The group reports two ways in which it modified the surface of titanium leg implants to promote skin cell growth, thereby creating a natural skin layer and sealing the gap where the device has been implanted into the body. The researchers also created a molecular chain to sprinkle skin-growing proteins on the implant to hasten skin growth.

The findings are published in the Journal of Biomedical Materials Research A.

The researchers, including Melanie Zile, a Boston University student who worked in Webster’s lab as part of Brown’s Undergraduate Teaching and Research Awards program, and Sabrina Puckett, who earned her engineering doctorate last May, created two different surfaces at the nanoscale, dimensions less than a billionth of a meter.

In the first approach, the scientists fired an electron beam of titanium coating at the abutment (the piece of the implant that is inserted into the bone), creating a landscape of 20-nanometer mounds. Those mounds imitate the contours of natural skin and trick skin cells into colonizing the surface and growing additional keratinocytes, or skin cells.

Webster knew such a surface, roughened at the nanoscale, worked for regrowing bone cells and cartilage cells, but he was unsure whether it would be successful at growing skin cells. This may be the first time that a nanosurface created this way on titanium has been shown to attract skin cells.

The second approach, called anodization, involved dipping the abutment into hydrofluoric acid and giving it a jolt of electric current. This causes the titanium atoms on the abutment’s surface to scurry about and regather as hollow, tubular structures rising perpendicularly from the abutment’s surface. As with the nanomounds, skin cells quickly colonize the nanotubular surface.

In laboratory (in vitro) tests, the researchers report nearly a doubling of skin cell density on the implant surface; within five days, the keratinocyte density reached the point at which an impermeable skin layer bridging the abutment and the body had been created.

“You definitely have a complete layer of skin,” Webster said. “There’s no more gap for the bacteria to go through.”

To further promote skin cell growth around the implant, Webster’s team looked to FGF-2, a protein secreted by the skin to help other skin cells grow. Simply slathering the abutment with the proteins doesn’t work, as FGF-2 loses its effect when absorbed by the titanium. So the researchers came up with a synthetic molecular chain to bind FGF-2 to the titanium surface, while maintaining the protein’s skin-cell growing ability. Not surprisingly, in vitro tests showed the greatest density of skin cells on abutment surfaces using the nanomodified surfaces and laced with FGF-2. Moreover, the nanomodified surfaces create more surface area for FGF-2 proteins than would be available on traditional implants.

The next step is to perform in vivo studies; if they are successful, human trials could begin, although Webster said that could be years away.

The U.S. Department of Veterans Affairs and the U.S. National Science Foundation funded the research.

Nanotechnology research offers possible solution to common implant complication

Thomas Webster, associate professor of engineering, recently completed a study that demonstrates how medications can be deployed on demand from the surface of bone implants to reduce the prevalence of infection. The medications were administered using polypyrroles, electrically conductive polymer films that coat the implants to hold the drugs and release them when voltage is applied.

Full report online: www.nanowerk.com/spotlight/spotid=19835.php

Nanotechnology research lays the foundation for smart implants

(Nanowerk Spotlight) Imagine intelligent medical implants that can continuously monitor their condition inside the body and autonomously respond to changes such as infection by releasing anti-inflammatory agents. Thanks to nanotechnology, medical research is moving quickly towards this goal.

The market for medical implant devices is huge and growing fast – in the U.S. alone it is estimated to be $23 billion per year and it is expected to grow by about 10% annually for the next few years. Implantable cardioverter defibrillators, cardiac resynchronization therapy devices, pacemakers, tissue and spinal orthopedic implants, hip replacements, phakic intraocular lenses and cosmetic implants will be among the top sellers. Each year in the U.S., almost 500,000 patients receive hip and knee replacements, about the same number need bone reconstruction due to injuries or congenital defects and 16 million Americans loose teeth and may require dental implants.

Implant wear and infections remain the major problem facing the long-term success and survival of these artificial joints. Studies have shown that large amounts of minute wear particles are produced by orthopaedic implants (both metal and plastic), setting into motion a cascade of events that ultimately may result in the disappearance of bone around the implant (osteolysis). This can lead to implant loosening and failure of the artificial joint. Diagnosis if and what is wrong with an implant relies on X-rays or other imaging techniques. The techniques are insensitive, not in real time, and require the patient to go into a hospital. Surgery to replace these failures is more difficult to perform, is more costly, and has a poorer outcome than the original joint replacement surgery.

A new study shows that the use of polypyrrole films as electrically controlled drug release devices on implant surfaces can potentially improve bone implants. By electrodepositing antibiotics or anti-inflammatory drugs in a polymer coating on medical devices, researchers at Brown University demonstrate that such drugs can be released from polypyrrole on demand – by applying a voltage – and control cellular behavior important for orthopedic applications, i.e. inhibit inflammation and kill bacteria.

"Polypyrrole is an intrinsically conductive polymer which can be electrochemically synthesized as a thin film on conductive materials," Thomas J. Webster tells Nanowerk. "Polypyrrole has been studied for various applications such as corrosion protection, electrochemical biosensors, electrode coatings, bioelectronics, solid-state devices and patterned circuits, and, although it has emerged as a promising material with substantial potential for biomedical applications and controlled drug delivery, few studies have investigated its possible role in decreasing infection and inflammation for orthopedic applications."

Left: Polypyrrole electrodeposited on conventional titanium. Right: Polypyrrole electrodeposited on multi-walled carbon nanotubes (Images: Webster Lab, Brown University)

Reporting their findings in the January 17, 2011 online issue of Nanotechnology ("Electrically controlled drug release from nanostructured polypyrrole coated on titanium"), Webster and his team demonstrate a 'proof of concept' to develop and evaluate on-demand delivery of penicillin/streptomycin (antibiotics used to treat grampositive and gram-negative bacteria) and dexamethasone (a glucocorticoid used clinically as an anti-inflammatory and immunosuppressive agent) in situ from polypyrrole. It shows that medications can be deployed on demand from the surface of bone implants to reduce the prevalence of both septic and aseptic complications.

This work is an extension of previous studies from Webster's nanomedicine lab demonstrating that these nanostructured materials sense and promote new bone growth ("Greater osteoblast functions on multiwalled carbon nanotubes grown from anodized nanotubular titanium for orthopedic applications"and "Multiwalled carbon nanotubes enhance electrochemical properties of titanium to determine in situ bone formation").

To create their polymer coating, the researchers first grew multi-walled carbon nanotubes (approx. 55nm in diameter) out of anodized nanotubular titanium using cobalt-catalyzed chemical vapor deposition. Polypyrrole monomers were either oxidized with the antibiotics or the dexamethasone before electrochemical polymerization of the polypyrrole around these nanotubes was carried out.

"Anionic drugs, bound electrostatically inside the polypyrrole thin film, were released in our present study by the application of a negative voltage," explains Webster. "For the first five cycles, we observed the anionic molecules to move in and out of the polypyrrole thin film due to continuous oxidation and reduction. The reduction peaks of penicillin/streptomycin release disappeared after 15 cyclic voltammetry cycles. For dexamethasone, the reduction peak was still observed after 25 cycles, but disappeared after 40 cycles."

The increase in the amount of drugs released after the electrical excitation was significant until 5 cycles. The cumulative release of penicillin/streptomycin and dexamethasone approached 80% of the drug and no further drug release was observed with further cycles.

Webster notes that, although they found that polypyrrole can be overoxidized and lose its electroactivity at higher potentials or when voltages are applied for longer periods, carbon nanotubes can maintain and prolong the electroactivity of polypyrrole due to their excellent conductivity properties.

He points out that polypyrrole can be doped not only with antibiotics and drugs like dexamethasone – allowing the preloading of drugs to obtain clinically controllable and predictable doses – but also various other biomolecules such as for instance growth factors, peptides, enzymes, antibodies, proteins, etc. to alter its biological, physical, chemical and electrical properties to design a controlled released system for numerous biomedical applications.

In addition, polypyrrole can be coated on electrodes or integrated with implantable chips to introduce an electrical signal into the biological environment.

"These preliminary results lay the foundation for developing intelligent orthopedic drug delivery technologies that can utilize a closed-loop sensing process with drug administration based on that sensing information," says Webster. "Both carbon nanotube-based sensors and controllable drug delivery systems could be an excellent way to improve the lifetime of orthopedic implants, allowing implants to kill bacteria, reduce the susceptibility of implants to prolonged inflammatory responses and ultimately increase bone formation."

By Michael Berger. Copyright 2011 Nanowerk

Professor Thomas Webster Named Scientist of the Week by Laboratory Equipment

Every Thursday, Laboratory Equipment features a Scientist of the Week, chosen from the science industry’s latest headlines. This week’s scientist is Thomas Webster from Brown Univ. Webster and his team developed “liquid bone,” or a new kind of liquid that can be injected directly into broken bones and solidifies in seconds. Over time, new bone tissue will take its place, encouraged by natural growth factors embedded in the synthetic molecules of the material.

Q: Why did you decide to research and develop “liquid bone”? 
A: We received a lot of advice from medical doctors to explore materials other than titanium (or metals) for orthopedic applications. Basically, the clinical community was telling us to come up with something novel and more natural than what is being implanted today. The materials developed here, we call twin base linkers (or TBLs) originally come from DNA base pairs which are modified before use. Thus, we developed a material that comes from DNA. How natural is that!

We also got a lot of input from clinicians to develop materials which are injectable and thus would limit the amount of surgery required. Since the patient needs to heal from both the surgery and the new implant, the idea here was to limit the healing needed from the surgery by potentially using just a syringe to inject the material into the tissue defect. That way, healing time is minimized, and hopefully the healing process is accelerated to have quicker, healthier bone.

Q: Why do you feel this research is important to your field of study, and beyond?
A: I think, or rather hope, the material we developed will push the field to think outside of the box. We need to be really creative to create better implant materials. The fact that the hip implant has not changed that much since that first designed by Charnley in the 1960s disappoints me. So we are starting by throwing all conventional thinking aside to develop more natural nanostructured materials to be injected to heal tissues. Our tissues are naturally nanostructured, by the way.

Q: What was the most surprising thing you found in your research/process? 
A: The most surprising aspect of the material we developed is how quickly it solidifies into a material just as strong as bone. Usually, for injectable materials, you have to give up strength for fast solidification. By emulating DNA, we have created a material which can solidify within minutes inside the body and posses mechanical strength equivalent to bone. Of course, we can change the concentration of our material to have strengths less than bone and closer to other tissues, like cartilage.

Q: What is the take home message of your research and results? 
A: The bottom line from our approach and material is to look at the body to develop more natural materials and personalize such materials for the patient. For example, we can easily tailor the ability of these materials to grown bone to suite why a particular patient needs an implant. Consider an elderly female who broke her hip due a fall and that she has osteoporotic bone. Right now, that patient would essentially get the same implant as a teenager who was in a car accident. But our material could be modified for the elderly female to promote bone growth more than usual since her bones would be comprised in terms of their ability to grow bone. In a sense, we are creating materials for the future of personalized medicine. That can not be done with today's titanium.

Q: What is next for you and your research?
A: We need to do a lot more animal testing and then eventually human clinical trials. But we have a great team, with Dr. Hicham Fenniri from the Univ. of Alberta and our industry colleagues to help.

Compiled by Michelle Longo

In the lab, engineer’s novel liquid provides a solid fix for broken bones

A bone-healing fluid that can be injected into breaks with a syringe shows such strong promise in lab testing, that it has been licensed from Brown by a Massachusetts biotech startup for further development.

By David Orenstein

A nonmetalic solutionNanomaterials engineer Thomas Webster is
developing alternatives to metals,which do not
occur naturally in the body and can cause
problems with surrounding tissue.Credit: Webster Lab/Brown University

Here’s the vision: an elderly woman comes into the emergency room after a fall. She has broken her hip. The orthopaedic surgeon doesn’t come with metal plates or screws or shiny titanium ball joints. Instead, she pulls out a syringe filled with a new kind of liquid that will solidify in seconds and injects into the break. Over time, new bone tissue will take its place, encouraged by natural growth factors embedded in the synthetic molecules of the material.

Although still early in its development, the liquid is real. In the Brown engineering lab of professor Thomas Webster it’s called TBL, for the novel DNA-like “twin-base linker” molecules that give it seemingly ideal properties. The biotech company Audax Medical Inc., based in Littleton, Mass., has just announced an exclusive license of the technology from Brown. It brands the technology as Arxis and sees similar potential for repairing broken vertebrae.

“The reason we’re excited about this material is because it gets us away from metals,” Webster said. “Metals are not in us naturally and they can have a lot of problems with surrounding tissues.”

In some of his work, Webster employs nanotechnology to try to bridge metals to bone better than traditional bone cement. But TBL is an entirely new material, co-developed with longtime colleague and chemist Hicham Fenniri at the University of Alberta. Fenniri synthesized the molecules, while Webster’s research has focused on ensuring that TBL becomes viable material for medical use.

Buttressing bonesTwin-based linker molecules, top left, self-assemble
into six-molecule rings. Stacked in a tube shape, the
 rings of molecules not only provide a new scaffold
for bone growth, but can also store growth factors
and helpful drugs inside.
    Credit: Webster Lab/Brown University

The molecules are artificial, but made from elements that are no strangers to the body: carbon, nitrogen, and oxygen. At room temperature their aggregate form is a liquid, but the material they form solidifies at body temperature. The molecules look like nanoscale tubes (billionths of a meter wide), and when they come together, it is in a spiraling ladder-shaped arrangement reminiscent of DNA or collagen. That natural structure makes it easy to integrate with bone tissue.

In the space within the nanotubes, the team, which includes graduate student Linlin Sun, has managed to stuff in various drugs including antibiotics, anti-inflammatory agents, and bone growth factors, which the tubes release over the course of months. Even better, different recipes of TBL, or Arxis, can be chemically tuned to become as hard as bone or as soft as cartilage, and can solidify in seconds or minutes, as needed. Once it is injected, nothing else is needed.

“We really like the fact that it doesn’t need anything other than temperature to solidify,” Webster said. Other compounds that people have developed require exposure to ultraviolet light and cannot therefore be injected through a tiny syringe hole. They require larger openings to be created.


Liquid provides a solid fix for broken bones from Brown PAUR on Vimeo.


For all of TBL’s apparent benefits, they have only been demonstrated in cow bone fragments in incubators on the lab bench top, Webster said. TBL still needs to be proven in vivo and, ultimately, in human trials. Part of the agreement with Audax will include support to continue the material’s clinical development. Audax research and development director Whitney Sharp, a Brown alumna (Sc.B., 2008; Sc.M., 2009), is now working with Webster’s group.

“They see the future where hopefully we will get to the point where we won’t be implanting these huge pieces of metal into people,” Webster said. “Instead we’ll be implanting things through a needle that could be used to heal a hip that’s more natural.”