Pressure sensors wrap around and conform to the shape of the fingers while still accurately measuring pressure distribution. (credit: 2016 Someya Laboratory)
Doctors may one day be able to physically screen for breast cancer using pressure-sensitive rubber gloves to detect tumors, thanks to a transparent, bendable, and sensitive pressure sensor newly developed by Japanese and American teams.
Conventional pressure sensors can’t measure pressure changes accurately once they are twisted or wrinkled, making them unsuitable for use on complex and moving surfaces, and they can’t be miniaturized below 100 micrometers (0.1 millimeters) thickness because of limitations in current production methods.
To address these issues, an international team of researchers led by Dr. Sungwon Lee and Professor Takao Someya of the University of Tokyo’s Graduate School of Engineeringhas developed a nanofiber-type pressure sensor made from carbon nanotubes and graphene that can measure pressure distribution of rounded surfaces such as an inflated balloon and maintain its sensing accuracy even when bent over a radius of 80 micrometers, equivalent to just twice the width of a human hair. The sensor is roughly 8 micrometers thick and can measure the pressure in 144 locations at once.
The device demonstrated in this study consists of organic transistors, electronic switches made from carbon and oxygen-based organic materials, and a pressure-sensitive nanofiber structure. Carbon nanotubes and graphene were added to an elastic polymer to create nanofibers with a diameter of 300 to 700 nanometers, which were then entangled with each other to form a transparent, thin and light porous structure.
The material may also have applications in improving the touch sensitivity in robots.
Abstract of A transparent bending-insensitive pressure sensor
Measuring small normal pressures is essential to accurately evaluate external stimuli in curvilinear and dynamic surfaces such as natural tissues. Usually, sensitive and spatially accurate pressure sensors are achieved through conformal contact with the surface; however, this also makes them sensitive to mechanical deformation (bending). Indeed, when a soft object is pressed by another soft object, the normal pressure cannot be measured independently from the mechanical stress. Here, we show a pressure sensor that measures only the normal pressure, even under extreme bending conditions. To reduce the bending sensitivity, we use composite nanofibres of carbon nanotubes and graphene. Our simulations show that these fibres change their relative alignment to accommodate bending deformation, thus reducing the strain in individual fibres. Pressure sensitivity is maintained down to a bending radius of 80 μm. To test the suitability of our sensor for soft robotics and medical applications, we fabricated an integrated sensor matrix that is only 2 μm thick. We show real-time (response time of ∼20 ms), large-area, normal pressure monitoring under different, complex bending conditions.
University of Washington mechanical engineers and collaborators have developed a handheld microscope to help doctors and dentists distinguish between healthy and cancerous cells in an office setting or operating room. (credit: Dennis Wise/University of Washington)
A miniature handheld microscope being developed by University of Washington mechanical engineers could allow neurosurgeons to differentiate cancerous from normal brain tissue at cellular level in real time in the operating room and determine where to stop cutting.
The new technology is intended to solve a critical problem in brain surgery: to definitively distinguish between cancerous and normal brain cells, during an operation, neurosurgeons would have stop the operation and send tissue samples to a pathology lab — where they are typically frozen, sliced, stained, mounted on slides and investigated under a bulky microscope.
Developed in collaboration with Memorial Sloan Kettering Cancer Center, Stanford University and the Barrow Neurological Institute, the new microscope is outlined in an open-access paper published in January in the journal Biomedical Optics Express.
“Surgeons don’t have a very good way of knowing when they’re done cutting out a tumor,” said senior author Jonathan Liu, UW assistant professor of mechanical engineering. “They’re using their sense of sight, their sense of touch, and pre-operative images of the brain — and oftentimes it’s pretty subjective. “Being able to zoom and see at the cellular level during the surgery would really help them to accurately differentiate between tumor and normal tissues and improve patient outcomes.”
The handheld microscope, roughly the size of a pen, combines technologies in a novel way to deliver high-quality images at faster speeds than existing devices. Researchers expect to begin testing it as a cancer-screening tool in clinical settings next year.
It also has other uses in medicine and dentistry. For instance, dentists who find a suspicious-looking lesion in a patient’s mouth often wind up cutting it out and sending it to a lab to be biopsied for oral cancer. Most come back benign.
That process subjects patients to an invasive procedure and overburdens pathology labs. A miniature microscope with high enough resolution to detect changes at a cellular level could be used in dental or dermatological clinics to better assess which lesions or moles are normal and which ones need to be biopsied.
Key technologies: dual-axis confocal microscopy and line scanning
The real-time microscope images (left) illuminate details in mouse tissues similar to the images (right) produced during an expensive, multi-day process at a clinical pathology lab. (credit: University of Washington)
“The microscope technologies that have been developed over the last couple of decades are expensive and still pretty large, about the size of a hair dryer or a small dental x-ray machine,” said co-author Milind Rajadhyaksha, associate faculty member in the dermatology service at the Memorial Sloan Kettering Cancer Center in New York City. “So there’s a need for creating much more miniaturized microscopes.”
Making microscopes smaller, however, usually requires sacrificing some aspect of image quality or performance such as resolution, field of view, depth, imaging contrast or processing speed.
“We feel like this device does one of the best jobs ever — compared to existing commercial devices and previous research devices — of balancing all those tradeoffs,” said Liu.
The miniature microscope uses an innovative approach called “dual-axis confocal microscopy” to illuminate and more clearly see through opaque tissue. It can capture details up to a half millimeter beneath the tissue surface, where some types of cancerous cells originate.
In the video below, for instance, researchers produced images of fluorescent blood vessels in a mouse ear at various depths ranging from 0.075 to 0.125 millimeters deep.
“Trying to see beneath the surface of tissue is like trying to drive in a thick fog with your high beams on – you really can’t see much in front of you,” Liu said. “But there are tricks we can play to see more deeply into the fog, like a fog light that illuminates from a different angle and reduces the glare.”
The microscope also employs a technique called line scanning to speed up the image-collection process. It uses micro-electrical-mechanical (MEMS) mirrors to direct an optical beam that scans the tissue, line by line, and quickly builds an image.
Imaging speed is particularly important for a handheld device, which has to contend with motion jitter from the human using it. If the imaging rate is too slow, the images will be blurry.
In the paper, the researchers demonstrate that the miniature microscope has sufficient resolution to see subcellular details. Images taken of mouse tissues compare well with those produced from a multi-day process at a clinical pathology lab — the gold standard for identifying cancerous cells in tissues.
The researchers hope that after testing the microscope’s performance as a cancer-screening tool, it can be introduced into surgeries or other clinical procedures within the next 2 to 4 years.
“For brain tumor surgery, there are often cells left behind that are invisible to the neurosurgeon. This device will really be the first to let you identify these cells during the operation and determine exactly how much further you can reduce this residual,” said project collaborator Nader Sanai, professor of neurosurgery at the Barrow Neurological Institute in Phoenix. “That’s not possible to do today.”
The research was funded by the National Institutes of Health through its National Institute of Dental and Craniofacial Research and National Cancer Institute.
University of Washington | Miniature dual-axis confocal microscope imaging
Abstract of Miniature in vivo MEMS-based line-scanned dual-axis confocal microscope for point-of-care pathology
There is a need for miniature optical-sectioning microscopes to enable in vivointerrogation of tissues as a real-time and noninvasive alternative to gold-standard histopathology. Such devices could have a transformative impact for the early detection of cancer as well as for guiding tumor-resection procedures. Miniature confocal microscopes have been developed by various researchers and corporations to enable optical sectioning of highly scattering tissues, all of which have necessitated various trade-offs in size, speed, depth selectivity, field of view, resolution, image contrast, and sensitivity. In this study, a miniature line-scanned (LS) dual-axis confocal (DAC) microscope, with a 12-mm diameter distal tip, has been developed for clinical point-of-care pathology. The dual-axis architecture has demonstrated an advantage over the conventional single-axis confocal configuration for reducing background noise from out-of-focus and multiply scattered light. The use of line scanning enables fast frame rates (16 frames/sec is demonstrated here, but faster rates are possible), which mitigates motion artifacts of a hand-held device during clinical use. We have developed a method to actively align the illumination and collection beams in a DAC microscope through the use of a pair of rotatable alignment mirrors. Incorporation of a custom objective lens, with a small form factor for in vivo clinical use, enables our device to achieve an optical-sectioning thickness and lateral resolution of 2.0 and 1.1 microns respectively. Validation measurements with reflective targets, as well as in vivo and ex vivo images of tissues, demonstrate the clinical potential of this high-speed optical-sectioning microscopy device.
Japanese researchers have developed a way to measure heartbeats remotely in real time with as much accuracy as electrocardiographs. (credit: Kyoto University)
The results were published in an open-access paper in the journal IEEE Transactions on Biomedical Engineering.
The researchers say this new approach will allow for developing long-term monitoring and “casual sensing” — taking measurements as people go about their daily activities, without having to attach uncomfortable electrodes or sensors to the patient’s body. People will also be able to monitor their cardio health status themselves.
The remote sensing system transmits and receives radar signals in the 24 GHz band* using “ultra-wideband” (UWB) modulation, which is known for its ability to detect specific signals in a noisy radio-frequency environment. A unique signal analysis algorithm extracts data from radar signals reflected from the body to detect heart rate and heart-rate variability (time derivative). Future use for detection of breathing, body movement, and other data from the body is also possible, the researchers suggest.
* The 24 GHz radar band is also used for new automotive radar sensors in the U.S. and Europe for collision detection, obstacle detection, blind-spot monitoring, and automatic cruise control for cars, including self-driving cars. Speculation: it may be possible to use the new UWB-based technology on semi-automated and fully automated vehicles for detecting and tracking humans and pets in the road in real time, based on heartbeat and other characteristics, and compensating for a subject’s movement. The remote feature also suggests possible future covert use in remote polygraph, airport screening, espionage, and other applications. The authors have been asked to technically comment on these uses.
Abstract of Feature-based Correlation and Topological Similarity for Interbeat Interval Estimation using Ultra-Wideband Radar
The objectives of this paper are to propose a method that can accurately estimate the human heart rate using an ultra-wideband radar system, and to determine the performance of the proposed method through measurements. The proposed method uses the feature points of a radar signal to estimate the heart rate efficiently and accurately. Fourier- and periodicity-based methods are inappropriate for estimation of instantaneous heart rates in real time because heartbeat waveforms are highly variable, even within the beat-to-beat interval. We define six radar waveform features that enable correlation processing to be performed quickly and accurately. In addition, we propose a feature topology signal that is generated from a feature sequence without using amplitude information. This feature topology signal is used to find unreliable feature points, and thus to suppress inaccurate heart rate estimates. Measurements were taken using ultra-wideband radar, while simultaneously performing electro-cardiography measurements in an experiment that was conducted on nine participants. The proposed method achieved an average root-mean-square error in the interbeat interval of 7.17 ms for the nine participants. The results demonstrate the effectiveness and accuracy of the proposed method. The significance of this work for biomedical research is that the proposed method will be useful in the realization of a remote vital signs monitoring system that enables accurate estimation of heart-rate variability, which has been used in various clinical settings for the treatment of conditions such as diabetes and arterial hypertension.
ReDO, an international collaboration between the Belgium-based Anticancer Fund and the U.S.- based GlobalCures, has published their investigation into diclofenac in the open-access journal ecancermedicalscience.
Diclofenac is a well-known non-steroidal anti-inflammatory drug (NSAID) widely used to treat pain in conditions such as rheumatoid arthritis, migraine, fever, acute gout, and post-operative pain. Like other drugs examined by the ReDO project, diclofenac is cheap and readily accessible — and it’s already present in many medicine cabinets, so it has been carefully tested, according to ReDO researchers.
NSAIDs for cancer treatment?
NSAIDs have shown promise in cancer prevention, but there is now emerging evidence that such drugs may be useful in actually treating cancer. The ReDO researchers have examined the literature and believe that there is enough evidence to start clinical trials on the use of diclofenac in cancer treatment. For example, diclofenac taken in combination with other treatments, such as chemotherapy and radiotherapy, may improve their effectiveness, the researchers say.
They suggest that cutting down on the risk of post-surgical distant metastases through the use of drugs like diclofenac may represent a huge win in the fight against cancer.
Developed by Ciba-Geigy (now Novartis), the drug is available globally as a generic medication. In some countries, low-dose formulations of oral and gel DCF are available over-the-counter (OTC) as a general purpose analgesic or anti-pyretic. Common trade names include Voltaren, Voltarol, Cataflam, Cambia, Zipsor and Zorvolex.
As with all NSAIDs, long-term use of diclofenac is associated with a small increase in the risk of cardiovascular events, particularly myocardial infarction and stroke, the authors note, but “many of the agents currently being trialled (examples include sorafenib, imatinib and crizotinib) have greater toxicity and costs associated with them.”
The authors declare in the paper that they have no competing interests.
Abstract of Repurposing Drugs in Oncology (ReDO)—diclofenac as an anti-cancer agent
Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents – with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper.
Schematic of the leukocyte counting chip with lysing, quenching, and counter modules shown in different colors. The insert (upper left) is an enlarged view of the platinum microfabricated electrodes (yellow). (credit: U. Hassan et al./TECHNOLOGY)
A microfluidic biosensor that can count red blood cells, platelets, and white blood cells electrically using just one drop of blood (11 microL) has been developed by University of Illinois at Urbana-Champaign (UIUC) researchers, replacing the standard hematology analyzer, a large, expensive lab device that requires trained technicians and physical sample transportation.
The new biosensor can electrically count the different types of blood cells based on their size and membrane properties. To count leukocyte and its differentials, red blood cells are selectively lysed and the remaining white blood cells were individually counted. Specific cells like neutrophils are counted using multi-frequency analysis, which probe the membrane properties of the cells.
The device, which will use credit-card-size disposable cartridges, requires minimal or no experience. It is expected to find uses in hospitals at the bedside, private clinics, retail clinics, and the developing world.
Patients can perform the test at home in under 20 minutes and share the results with their primary care physicians electronically, reducing the cost of the test to less than $10, compared to $100 or more currently, says UIUc Professor Rashid Bashir, principal investigator.
The research appears in the December 2015 issue of the journal TECHNOLOGY
Abstract of A microfluidic biochip for complete blood cell counts at the point-of-care
Complete blood cell counts (CBCs) are one of the most commonly ordered and informative blood tests in hospitals. The results from a CBC, which typically include white blood cell (WBC) counts with differentials, red blood cell (RBC) counts, platelet counts and hemoglobin measurements, can have implications for the diagnosis and screening of hundreds of diseases and treatments. Bulky and expensive hematology analyzers are currently used as a gold standard for acquiring CBCs. For nearly all CBCs performed today, the patient must travel to either a hospital with a large laboratory or to a centralized lab testing facility. There is a tremendous need for an automated, portable point-of-care blood cell counter that could yield results in a matter of minutes from a drop of blood without any trained professionals to operate the instrument. We have developed microfluidic biochips capable of a partial CBC using only a drop of whole blood. Total leukocyte and their 3-part differential count are obtained from 10 μL of blood after on-chip lysing of the RBCs and counting of the leukocytes electrically using microfabricated platinum electrodes. For RBCs and platelets, 1 μL of whole blood is diluted with PBS on-chip and the cells are counted electrically. The total time for measurement is under 20 minutes. We demonstrate a high correlation of blood cell counts compared to results acquired with a commercial hematology analyzer. This technology could potentially have tremendous applications in hospitals at the bedside, private clinics, retail clinics and the developing world.
When researchers at The Scripps Research Institute (TSRI) in California administered an antidepressant called mianserin to the Caenorhabditis elegans roundworm in 2007, they discovered the drug increased the lifespan of the “young adulthood” of roundworms by 30–40 per cent.
So, does that mean it will work in humans? Not necessarily. “There are millions of years of evolution between worms and humans,” says TSRI researcher Michael Petrascheck. “We may have done this in worms, but we don’t want people to get the impression they can take the drug we used in our study to extend their own teens or early twenties.”
Nonetheless, the researchers are now aiming to find out how the drug worked. In a study published Dec. 1 in an open-access article in the journal eLife, the researchers report they treated thousands of worms with either water or mianserin. Then they looked at the activity of genes as the worms aged, compared to the activity of genes in young adults.
Curiously, as the worms aged, the team observed dramatic changes in gene expression: groups of genes that together play a role in the same function were found to unpredictably change expression in opposing directions — making it difficult to predict the effect of drugs, for example.
Extending youth only works at the right time of life
They’ve called this phenomenon “transcriptional drift.” And by examining data from mice and from 32 human brains aged 26 to 106 years, they confirmed that it also occurs in mammals.
And that means transcriptional drift can be used as a new metric for measuring age-associated changes that start in young adulthood, they believe. Using this new metric in their worm research revealed that treatment with mianserin can suppress transcriptional drift, but only when administered at the right time of life.
By 10 days old, treated worms still had the gene expression characteristics of a three-day-old — physiologically they were seven days younger. But by 12 days, the physiological changes required to extend lifespan were complete and lifelong exposure to the drug had no additional effect.
So how does this work? They suggest that mianserin blocked signals related to the regulation of serotonin and this delayed physiological changes associated with age, including transcriptional drift and degenerative processes that lead to death. But the effect only occurred during young adulthood; the duration of this period of life was significantly extended.
What about us mammals?
(credit: Kapa65/Pixabay CC)
“How much of our findings with regards to lifespan extension will spill over to mammals is anyone’s guess; for example, the extension of lifespan might not be as dramatic,” says Petrascheck.”
Meanwhile, the anomalous findings have opened up new avenues of research for the team and are likely to spawn a wealth of research by others.
A significant next step for the team will be to test the effect in mice and to investigate whether there are any side effects. Different environments could also produce different results and this will need to be explored. They would also like to test whether the impact is different for different organs in the body.
Abstract of Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality
Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift, a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young adults. Using Caenorhabditis elegans as a model, we show that extending lifespan by inhibiting serotonergic signals by the antidepressant mianserin attenuates transcriptional drift, allowing the preservation of a younger transcriptome into an older age. Our data are consistent with a model in which inhibition of serotonergic signals slows age-dependent physiological decline and the associated rise in mortality levels exclusively in young adults, thereby postponing the onset of major mortality.
(A) Three agents are encapsulated inside the nanoparticles: miR-34a mRNA drug for gene therapy of prostate cancer stem cells, indocyanine green (ICG) for absorbing laser light, and ammonium bicarbonate for gas generation under heating. (B) Laser light causes the nanoparticles to expand, penetrating the cancer cell’s endosomal/lysosomal barrier (green circles), blowing up cancer cells (yellow), and releasing the miR-34a drug to inhibit the protein CD44, which is crucial for cancer stem cell survival. (credit: Hai Wang et al./Advanced Materials)
These “nanobombs” may be able to kill cancer cells outright, or at least stall their growth — overcoming a biological barrier that has blocked development of drug agents that attempt to alter cancer-cell gene expression (conversion of genes to proteins). These kinds of drug agents are generally forms of RNA (ribonucleic acid), and are notoriously difficult to use as drugs for two main reasons:
They are quickly degraded when free in the bloodstream.
When ordinary nanoparticles are taken up by cancer cells, the cancer cells often enclose them in small compartments called endosomes, preventing the drug molecules from reaching their target, and degrading them.
Zapping tumors and cancer stem cells with laser light and nanoparticles
In this new study, published in the journal Advanced Materials, the researchers packaged nanoparticles with the RNA agent (drug) and ammonium bicarbonate, causing the nanoparticles to swell (as it does in baking bread) three times or more in size when exposed to the heat generated by near-infrared laser light. That causes the endosomes to burst, dispersing the therapeutic RNA drug into the cell.
For their study, the researchers used human prostate cancer cells and tumors in an animal model. The nanoparticles were equipped to target cancer-stem-like cells (CSCs), which are cancer cells with properties of stem cells. CSCs often resist therapy and are thought to play an important role in cancer development and recurrence.
The therapeutic agent in the nanoparticles was a form of microRNA called miR-34a. The researchers chose this molecule because it can lower the levels of a protein (CD44) that is crucial for CSC survival.
Abstract of A Near-Infrared Laser-Activated “Nanobomb” for Breaking the Barriers to MicroRNA Delivery
A near-infrared laser-activated “nanobomb” is synthesized using lipid and multiple polymers to break the extracellular and intracellular barriers to cytosolic delivery of microRNAs. The nanobomb could be used to effectively destroy tumors and cancer stem-like cells in vitro and in vivo with minimal side effect.
Google Glass allowed the surgeons to clearly visualize the distal coronary vessel and verify the direction of the guide wire advancement relative to the course of the occluded vessel segment. (credit: Maksymilian P. Opolski et al./Canadian Journal of Cardiology)
Cardiologists from the Institute of Cardiology, Warsaw, Poland have used Google Glass in a challenging surgical procedure, successfully clearing a blockage in the right coronary artery of a 49-year-old male patient and restoring blood flow, reports the Canadian Journal of Cardiology.
Chronic total occlusion, a complete blockage of the coronary artery, sometimes referred to as the “final frontier in interventional cardiology,” represents a major challenge for catheter-based percutaneous coronary intervention (PCI), according to the cardiologists.
That’s because of the difficulty of recanalizing (forming new blood vessels through an obstruction) combined with poor visualization of the occluded coronary arteries.
Coronary computed tomography angiography (CTA) is increasingly used to provide physicians with guidance when performing PCI for this procedure. The 3-D CTA data can be projected on monitors, but this technique is expensive and technically difficult, the cardiologists say.
So a team of physicists from the Interdisciplinary Centre for Mathematical and Computational Modelling of the University of Warsaw developed a way to use Google Glass to clearly visualize the distal coronary vessel and verify the direction of the guide-wire advancement relative to the course of the blocked vessel segment.
Three-dimensional reconstructions displayed on Google Glass revealed the exact trajectory of the distal right coronary artery (credit: Maksymilian P. Opolski et al./Canadian Journal of Cardiology)
The procedure was completed successfully, including implantation of two drug-eluting stents.
“This case demonstrates the novel application of wearable devices for display of CTA data sets in the catheterization laboratory that can be used for better planning and guidance of interventional procedures, and provides proof of concept that wearable devices can improve operator comfort and procedure efficiency in interventional cardiology,” said lead investigator Maksymilian P. Opolski, MD, PhD, of the Department of Interventional Cardiology and Angiology at the Institute of Cardiology, Warsaw, Poland.
“We believe wearable computers have a great potential to optimize percutaneous revascularization, and thus favorably affect interventional cardiologists in their daily clinical activities,” he said. He also advised that “wearable devices might be potentially equipped with filter lenses that provide protection against X-radiation.
Abstract of First-in-Man Computed Tomography-Guided Percutaneous Revascularization of Coronary Chronic Total Occlusion Using a Wearable Computer: Proof of Concept
We report a case of successful computed tomography-guided percutaneous revascularization of a chronically occluded right coronary artery using a wearable, hands-free computer with a head-mounted display worn by interventional cardiologists in the catheterization laboratory. The projection of 3-dimensional computed tomographic reconstructions onto the screen of virtual reality glass allowed the operators to clearly visualize the distal coronary vessel, and verify the direction of the guide wire advancement relative to the course of the occluded vessel segment. This case provides proof of concept that wearable computers can improve operator comfort and procedure efficiency in interventional cardiology.
Extracting fibroblasts and epithelial cells from donor vocal fold mucosa for culturing and application to a 3-D collagen scaffold (credit: Changying Ling et al./Tissue Engineering)
University of Wisconsin scientists have succeeded in growing functional vocal-cord tissue in the laboratory and bioengineering it to transmit sound, a major step toward restoring voice for people who have lost their vocal cords to cancer surgery or other injuries.
Dr. Nathan Welham, a speech-language pathologist and an associate professor of surgery in the UW School of Medicine and Public Health, and colleagues began with vocal-cord tissue from a cadaver and four patients who had their larynxes removed but did not have cancer. They isolated, purified, and grew the cells from the mucosa, then applied them to a 3-D collagen scaffold, similar to a system used to grow artificial skin in the laboratory.
In about two weeks, the cells grew together to form a tissue with a pliable but strong connective tissue beneath, and layered epithelial cells on top. Proteomic analysis showed the cells produced many of the same proteins as normal vocal cord cells. Physical testing showed that the epithelial cells had also begun to form an immature basement membrane which helps create a barrier against pathogens and irritants in the airway.
“Normal sound output”
Engineered vocal-cord tissue in lab (credit: UW School of Medicine and Public Health)
After testing in cadaver dogs, the researchers tested the tissue for rejection or acceptance using mice that had been engineered to have human immune systems. The tissue grew and was not rejected.
In one way, the tissue was not as good as the real thing: its fiber structure was less complex than adult vocal cords, but the authors said this was not surprising because human vocal cords continue to develop for at least 13 years after birth. But Welham said the tissue had “normal sound output” in lab tests.
Welham says vocal-cord tissue that is free of cancer is a rare commodity, so clinical applications will either require banking and expansion of human cells, or the use of stem cells derived from bone marrow or other tissues. Stem cells could be primed to differentiate into vocal-cord cells by exposing them to vibration and tensile forces in a “laryngeal bioreactor.”
Clinical applications are still years away, but Welham says this proof-of-principle study is a “robust benchmark” along the route to replacement vocal-cord tissue. Moving this promising work forward requires more testing of safety and long-term function. “Our vocal cords are made up of special tissue that has to be flexible enough to vibrate, yet strong enough to bang together hundreds of times per second. It’s an exquisite system and a hard thing to replicate.”
About 20 million Americans suffer from voice impairments, and many have damage to the vocal-cord mucosae, the specialized tissues that vibrate as air moves over them, giving rise to voice. While injections of collagen and other materials can help some in the short term, not much can be done currently for people who have had larger areas of their vocal cords damaged or removed, Welham says.
The study was published in the journal Science Translational Medicine.
UWMedicine | Engineered Vocal Fold Tissue
Abstract of Bioengineered vocal fold mucosa for voice restoration
The power of the voice cannot be disputed. For instance, Adele’s lyrics would not elicit chills (or tears) without strategic pitch and harmonizing known as appoggiatura; the chant “Yes we can” garnered more than 69 million popular votes to win Obama the 2008 presidential election; and, more simply, voice is the primary means we all use to communicate with co-workers, loved ones, and the rest of society. Dysphonia—or difficulty speaking from vocal fold tissue damage or loss—can impair one’s ability to be an effective communicator. To provide a new option for those with dysphonia, Ling et al. used two different types of human vocal fold cells to create a functional mucosa. When grafted into the dog larynx ex vivo, the engineered vocal fold reproduced natural physiology, including the vibrations necessary to transmit sound. In vivo, in humanized mice, the engineered mucosa was tolerated by functional human immune cells. These data suggest feasibility for transplant and survival in the larynx as well as for function, ultimately giving patients back their voices.
The pigeons’ training environment included a food pellet dispenser, a touch-sensitive screen which projected the medical image, as well as blue and yellow choice buttons on either side of the image. Pecks to those buttons and to the screen were automatically recorded. (credit: Levenson RM et al./PloS)
“The pigeons were able to generalize what they had learned, so that when we showed them a completely new set of normal and cancerous digitized slides, they correctly identified them,” Levenson said. “The pigeons also learned to correctly identify cancer-relevant microcalcifications on mammograms, but they had a tougher time classifying suspicious masses on mammograms — a task that is extremely difficult, even for skilled human observers.”
Although a pigeon’s brain is no bigger than the tip of an index finger, the neural pathways involved operate in ways very similar to those at work in the human brain. “Research over the past 50 years has shown that pigeons can distinguish identities and emotional expressions on human faces, letters of the alphabet, misshapen pharmaceutical capsules, and even paintings by Monet vs. Picasso,” said Edward Wasserman, professor of psychological and brain sciences at The University of Iowa and co-author of the study. “Their visual memory is equally impressive, with a proven recall of more than 1,800 images.”
Pigeons rival radiologists at discriminating breast cancer
Examples of benign (left) and malignant (right) breast specimens stained with hematoxylin and eosin, at different magnifications. The birds were remarkably adept at discriminating between benign and malignant breast cancer slides at all magnifications, a task that can perplex inexperienced human observers, who typically require considerable training to attain mastery. (credit: Levenson RM et al./PloS)
For the study, each pigeon learned to discriminate cancerous from non-cancerous images and slides using traditional “operant conditioning,” a technique in which a bird was rewarded only when a correct selection was made; incorrect selections were not rewarded and prompted correction trials. Training with stained pathology slides included a large set of benign and cancerous samples from routine cases at UC Davis Medical Center.
“The birds were remarkably adept at discriminating between benign and malignant breast cancer slides at all magnifications, a task that can perplex inexperienced human observers, who typically require considerable training to attain mastery,” Levenson said. He said the pigeons achieved nearly 85 percent correct within 15 days.
Flock-sourcing: 99 percent accuracy
“When we showed a cohort of four birds a set of uncompressed images, an approach known as “flock-sourcing,” the group’s accuracy level reached an amazing 99 percent correct, higher than that achieved by any of the four individual birds.” Wasserman has conducted studies on pigeons for more than 40 years.
The birds, however, had difficulty evaluating the malignant potential of breast masses (without microcalcifications) detected on mammograms, a task the authors acknowledge as “very challenging.”
After years of education and training, physicians can sometimes struggle with the interpretation of microscope slides and mammograms. Levenson, a pathologist who studies artificial intelligence for image analysis and other applications in biology and medicine, believes there is considerable room for enhancing the process.
“While new technologies are constantly being designed to enhance image acquisition, processing, and display, these potential advances need to be validated using trained observers to monitor quality and reliability,” Levenson said. “This is a difficult, time-consuming, and expensive process that requires the recruitment of clinicians as subjects for these relatively mundane tasks. “Pigeons’ sensitivity to diagnostically salient features in medical images suggest that they can provide reliable feedback on many variables at play in the production, manipulation, and viewing of these diagnostically crucial tools, and can assist researchers and engineers as they continue to innovate.”
This work also suggests that pigeons’ remarkable ability to discriminate between complex visual images could be put to good use as trained medical image observers, to help researchers explore image quality and the impact of color, contrast, brightness, and image compression artifacts on diagnostic performance.
Victor Navarro | Pigeons (Columba livia) as Trainable Observers of Pathology and Radiology Breast Cancer Images
Abstract of Pigeons (Columba livia) as Trainable Observers of Pathology and Radiology Breast Cancer Images
Pathologists and radiologists spend years acquiring and refining their medically essential visual skills, so it is of considerable interest to understand how this process actually unfolds and what image features and properties are critical for accurate diagnostic performance. Key insights into human behavioral tasks can often be obtained by using appropriate animal models. We report here that pigeons (Columba livia)—which share many visual system properties with humans—can serve as promising surrogate observers of medical images, a capability not previously documented. The birds proved to have a remarkable ability to distinguish benign from malignant human breast histopathology after training with differential food reinforcement; even more importantly, the pigeons were able to generalize what they had learned when confronted with novel image sets. The birds’ histological accuracy, like that of humans, was modestly affected by the presence or absence of color as well as by degrees of image compression, but these impacts could be ameliorated with further training. Turning to radiology, the birds proved to be similarly capable of detecting cancer-relevant microcalcifications on mammogram images. However, when given a different (and for humans quite difficult) task—namely, classification of suspicious mammographic densities (masses)—the pigeons proved to be capable only of image memorization and were unable to successfully generalize when shown novel examples. The birds’ successes and difficulties suggest that pigeons are well-suited to help us better understand human medical image perception, and may also prove useful in performance assessment and development of medical imaging hardware, image processing, and image analysis tools.
