Reproductive research: This artificial human ovary surrounds granulosa cell

spheres, which are marked with fluorescent green dye.
Brown University



Tissue engineering allows for complex three-dimensional cell construction

MIT Technology Review, September 23, 2010, by Karen Weintraub  —  Researchers at Brown University have created an “artificial human ovary” using a tissue engineering approach that they hope will one day allow scientists to mature human eggs in a laboratory.

In the near term, an artificial ovary will enable researchers to better explore the impact of environmental toxins or fertility-enhancing substances on human fertility. It could also aid the development of new forms of contraceptives and the study of ovarian cancer.

Further down the line, it could also help women whose ovaries are damaged because of chemotherapy, radiation, or illness, according to a paper published in the current issue of Journal of Assisted Reproduction and Genetics. Today, those women have limited opportunities for childbirth: either a hurried in-vitro fertilization cycle that leads to a handful of frozen eggs, or freezing ovarian tissue in the hopes that healthy eggs will someday be able to be matured.

An artificial ovary, where immature eggs could be harvested by the thousands and then matured at will in the laboratory, would open up huge possibilities for the one in a 1,000 women who need it, says the paper’s first author, Stephan Krotz, who was a graduate student at Brown when he worked on the paper.

The artificial ovary marks the first time researchers have successfully created a three-dimensional environment that contains the three main types of ovarian cells: theca cells, granulosa cells, and the eggs, known as oocytes. The paper’s lead researcher is Sandra Carson, a professor of obstetrics and gynecology at Brown and Woman and Infants Hospital of Rhode Island.

Alan B. Copperman, director of infertility at Mt. Sinai Medical Center in New York, says clinical benefits are years and many scientific hurdles away, but he’s impressed by the research potential of the group’s work. “The concept of creating an artificial three-dimensional environment, and the fact that we can take out immature eggs and let them grow and mature into viable eggs, is really exciting,” he says.

Copperman says the artificial ovary could serve as a model to help researchers better understand the ovarian aging process, the focus of much of his research. “If we can establish a viable testing environment, we can learn more about how to optimize eggs, and discriminate good from bad eggs.”

The Brown researchers’ innovation was using a honeycomb-shaped mold to support the egg. Human eggs are too large to be grown without some kind of support structure. “If you try to grow it by itself, in a dish, it basically collapses on itself,” says Krotz, now a reproductive endocrinologist and fertility specialist at the Advanced Fertility Center of Texas.

The researchers broke ovarian cells out of human tissue using enzymes, and poured them into a mold made of agar, a gelatinous substance usually derived from algae. The different types of cells then assembled themselves into a honeycomb shape, with the theca and granulosa cells forming the structure. The egg cells, or oocytes, were inserted inside and bathed with hormones to stimulate the theca cells to produce androgen, and the granulosa cells to make estrogen.

“We took a different tack to rely on the inherent adhesiveness of cells to drive self-assembly,” says Jeffrey Morgan, codirector of the Center for Biomedical Engineering at Brown, who led this aspect of the research. “In that nonadhesive environment, the cells will stick to each other and self-assemble a three-dimensional structure, and it conforms to the shape of our mold.”

Researchers had assumed that, if allowed to self-assemble, cells would form a sphere, but Morgan says he showed that they can also create more complex forms with a little prompting.

Kim L. Thornton, a reproductive endocrinologist at Boston IVF, one of the nation’s largest fertility centers, says it’s tricky to re-create in a lab all of the activities that go on in a woman’s ovaries. “One of the challenges with maturation is, there are lot of things that go on locally that may affect the ability of oocytes to become mature,” she says. “We can’t duplicate all of those conditions” in a lab dish. However, Thornton says, the Brown model “is interesting, and it’s certainly promising.”

Carson says that now that the team has created the model, she wants to go back and look more closely at how it functions. She would like to identify various proteins involved in egg maturation, and be able to explore whether those proteins can be altered as a means of contraception. “We could also theoretically find something that might be important in the development of ovarian cancer,” she says.

The work can also be used to test for toxic effects from everyday products, such as plastics and insecticides, as well as medications–“anything we might be able to test against the control,” Carson says. “We’re not there yet, but I think this is going to be the most powerful use of the model.”

Brian interface: The micro electrodes shown here were used to record brain signals in order to decode ten words from a patient’s thoughts.
Credit: Spencer Kellis,
University of Utah



A new approach allows more information to be extracted from the brain

MIT Technology Review, September 23, 2010, by Duncan Graham-Rowe  —  Brain-computer interfaces could someday provide a lifeline to “locked-in” patients, who are unable to talk or move but are aware and awake. Many of these patients can communicate by blinking their eyes, but turning blinks into words is time-consuming and exhausting.

Scientists in Utah have now demonstrated a way to determine which of 10 distinct words a person is thinking by recording the electrical activity from the surface of the brain.

The new technique involves training algorithms to recognize specific brain signals picked up by an array of nonpenetrating electrodes placed over the language centers of the brain, says Spencer Kellis, one of the bioengineers who carried out the work at the University of Utah, in Salt Lake City. The approach used is known as electrocorticography (ECoG). The group was able to identify the words “yes,” “no,” “hot, “cold,” “thirsty,” “hungry,” “hello,” “goodbye,” “more,” and “less” with an accuracy of 48 percent.

“The accuracy definitely needs to be improved,” says Kellis. “But we have shown the information is there.”

Individual words have been decoded from brain signals in the past using functional magnetic resonance imaging (fMRI), says Eric Leuthardt, director of the Center for Innovation in Neuroscience and Technology at Washington University School of Medicine in St. Louis, Missouri. This is the first time that the feat has been performed using ECoG, a far more practical and portable approach than fMRI, he says.

Working with colleagues Bradley Greger and Paul House, Kellis placed 16 electrodes on the surface of the brain of a patient being treated for epilepsy. The electrodes recorded signals from the facial motor cortex–an area of the brain that controls face muscles during speech–and over the Wernicke’s area, part of the cerebral cortex that is linked with language. To train the algorithm, signals were analyzed as the patient was asked to repeatedly utter the 10 words.

ECoG has long been used to locate the source of epileptic seizures in the brain. But electrodes used are typically several hundred microns in size and are positioned centimeters apart, says Kellis. “The brain is doing processing at a much finer spatial scale than is really detectable by these standard clinical electrodes,” he says. The Utah team used a new type of microelectrode array developed by PMT Neurosurgical. The electrodes are much smaller–40 microns in size–and are separated by a couple of millimeters.

It’s possible to use less invasive techniques, such as electroencephalography (EEG), which places electrodes on the scalp, to enable brain-to-computer communications. Adrian Owen, a senior scientist in the Cognition and Brain Sciences Unit at the University of Cambridge, UK, has shown that EEG signals can be used to allow people in a persistent vegetative state to communicate “yes” and “no.”

But with EEG, many of the signals are filtered out by the skull, says Leuthardt. “What’s really nice about ECoG is its potential to give us a lot more information,” he says.

Decoding 10 words is “very cool,” says Owen, but the accuracy will need to improve dramatically, given the patients the technology is aimed at. “I don’t think even 60 percent or 70 percent accuracy is going to work for patients who cannot communicate in any other way and where there is no other margin for verification,” he says.

Ultimately, the hope is that ECoG will enable much more sophisticated communication. Last year Leuthardt showed that ECoG could be used to decode vowel and consonant sounds–an approach that might eventually be used to reconstruct a much larger number of complete words.

Silk on the brain: Thin, flexible electrodes mounted on top of a biodegradable silk substrate could provide a better brain-machine interface. The device wraps around the crevices in the surface of the brain, as shown on this model.
Credit: John Rogers




Gentler, softer electrodes wrap around the folds of the brain to take higher-resolution measurements

MIT Technology Review, by Katherine Bourzac  —  Doctors can put arrays of electrodes on the surface of the brain to pinpoint the source of epileptic seizures; patients can use such electrodes to control a computer cursor. But it’s still not safe to leave these devices in the brain over the long term, and that’s a quality that needs to be developed before researchers can develop better brain-computer interfaces.

Now a group of researchers is building biocompatible electronics on thin, flexible substrates. The group hopes to create neural interfaces that take higher-resolution measurements than what’s available today without irritating or scarring brain tissue.

“Biocompatibility is a major challenge for new generations of medical implants,” says Brian Litt, professor of neurology and bioengineering at the University of Pennsylvania Medical School. “We wanted to make devices that are ultrathin and can be inserted into the brain through small holes in the skull, and be made out of materials that are biocompatible,” he says. Litt is working with researchers at the University of Illinois at Urbana-Champaign who are building high-performance flexible electronics from silicon and other conventional materials on substrates of biodegradable, mechanically strong silk films provided by researchers at Tufts University.

This week in the journal Nature Materials, the team reports using a silk electrode device to measure electrical activity from the surface of the brain in cats. Silk is mechanically strong–that means the films can be rolled up and inserted through a small hole in the skull–yet can dissolve into harmless biomolecules over time. When it’s placed on brain tissue and wetted with saline, a silk film will shrink-wrap around the surface of the brain, bringing electrodes with it into the wrinkles of the tissue. Conventional surface electrode arrays can’t reach these crevices, which make up a large amount of the brain’s surface area.

“A device like this would completely open up new avenues in all of neuroscience and clinical applications,” says Gerwin Schalk, a researcher at the Wadsworth Center in Albany, NY, who is not affiliated with the silk electrode group. “What I foresee is placing a silk-based device all around the brain and getting a continuous image of brain function for weeks, months, or years, at high spatial and temporal resolution.”

The advantage of surface electrodes over implanted ones is that they don’t cause scarring, says Andrew Schwartz, professor of neurobiology at the University of Pittsburgh. In 2008, Schwartz demonstrated that a monkey with an electrode in its brain can control a prosthetic arm to feed itself. “This design is even better because it has a relatively small feature size and is flexible–it could make these implants less traumatic,” he says. “What would really be nice is if you could amplify the signal near where you pick it up to reduce noise, and multiplex the signal to cut down on the number of wires needed,” says Schwartz.

The silk electronics researchers say this is their next step, and one of the major promises of the technology. They’ve already demonstrated thin, flexible silicon transistor arrays built on silk, and tested them in animals–just not in the brain yet. Schwartz says other groups have recognized the importance of multiplexing and signal amplification, but have been working with rigid circuit boards that are not as biocompatible. Adding these active components would reduce the number of wires needed in these implants, which today require one wire per sensor. And active devices could respond to brain activity to provide electrical stimuli, or release drugs. (One of the collaborators on the silk project, David Kaplan at Tufts University, has demonstrated that silk devices implanted in the brain in small animals can deliver anti-epilepsy drugs.)

Adding transistors to the electronics is currently a design challenge, says John Rogers, professor of materials science and engineering at the University of Illinois at Urbana-Champaign. The electrode-array design his group found to be most compatible with brain tissue is a mesh–solid sheets won’t wrap around brain tissue as effectively. And adding silicon transistors to the mesh is more difficult than doing so on a solid substrate. Still, says Rogers, all the major pieces are in place and just need to be integrated. With further development and testing to prove the devices are safe, says Rogers, “we hope this will be the foundation for new higher quality brain-machine interfaces.”

Biometrics: Fingerprints and Beyond
Biometric recognition—the use of biological markers such as fingerprints, iris scans, facial structures or DNA for identification—has begun to move into the mainstream. Governments around the world are rolling out national identity cards that feature biometric identification. The U.S. government has been promoting biometrics-based identity cards for employees at the nation’s ports, and has already printed more than 4 million cards for government employees that contain such authentication. And nine of the top ten PC companies offer some system of biometric security on at least one laptop model.

At the present time, fraud and identity theft threaten business and government activities around the world; biometrics-based IDs can provide a level of assurance beyond the typical PIN-code and password security.
Detailing the Biology
Successful biometrics technology demands highly accurate biological images. AuthenTec, based in Melbourne, Florida, developed a sensor that goes beyond the usual practice of employing optics to recognize a fingerprint’s peaks and valleys. AuthenTec’s sensor employs radio frequencies (RFs) to excite molecules in the living layer of skin where fingerprints are formed. “This RF technology allows us to overcome surface conditions of the skin, where fingerprints can be worn, calloused, dirty, or oily,” says AuthenTec president Larry Ciaccia. AuthenTec supplies its biometrics component to consumer electronics manufacturers for use in more than 55 million PCs, cell phones, and other biometrics-enabled products.

It’s a continuing challenge to achieve the highest possible resolution and thus the most accurate identification. Cross Match Technology, based in Palm Beach Gardens, designed optical scanners that surpass FBI requirements for fingerprint collection. Its latest scanners can even identify sweat pores that dot the ridges. “More data leads to more accurate matching,” observes Michael Oehler, vice president of product management. In addition to single-finger scanners, the company has also developed two-finger, four-finger, and palm scanners, along with systems for face and iris matching.


Biometric sensors have typically been large and power hungry; the second generation of biometric devices has been designed for mobility. Law enforcement and military personnel have expressed a need for biometric ID tools that they can carry into the field, so newer readers must be small, handheld, able to operate in challenging weather conditions, and unaffected by collisions with keys, pens, and other objects. What’s more, these battery-operated devices must block electrostatic discharge, which has crashed sensor technology in the past.

Orlando-based Zvetco, one of the top sensor manufacturers, uses AuthenTec’s technology as a key component of its product. Zvetco engineers developed silicon surfaces to accept fingerprints from dry skin better; protective coatings to guard against weather; and superior electrostatic discharge protection to preclude automatic shutdowns of hand-held devices.

With the use of smart cards on the rise, Zvetco has rolled out a new line of smart-card biometrics readers. Tampa-based Ceelox, meanwhile, has created software that can combine information from different sensor models. For instance, should a company’s employees use their own laptops with different biometric sensors, the Ceelox software can integrate the information from these sources and allow all users to access company data.

The Future of ID

Biometric sensors have evolved past simple personal identification: AuthenTec has even developed smart sensors that can be programmed to respond to each individual finger so a PC user can correlate each finger to a different locked application or folder.
Customers in government, industry, and law enforcement keep pushing to increase ID speed. For instance, someone entering the U.S. may eventually have to provide a fingerprint, photo, and iris scan. “Any way we can speed that process up to cut down on queuing time without sacrificing accuracy is important to us,” says Oehler.

Security needs continue to grow as increasing numbers of the key activities that support national economies move into digital applications. This is certainly true in the energy sector, where the approaching smart grid will rely on ensuring secure communication among homes, businesses, and utility companies. AuthenTec has moved into this market, and in April the company announced a collaboration with SmartSynch, one of the country’s largest providers of smart metering systems, with more than a hundred major utility customers.