3D ‘body-on-a-chip’ project aims to accelerate drug testing, reduce costs

Scientists created miniature models (“organoids”) of heart, liver, and lung  in dishes and combined them into an integrated “body-on-a-chip” system fed with nutrient-rich fluid, mimicking blood. (credit: Wake Forest Baptist Medical Center)

A team of scientists at Wake Forest Institute for Regenerative Medicine and nine other institutions has engineered miniature 3D human hearts, lungs, and livers to achieve more realistic testing of how the human body responds to new drugs.

The “body-on-a-chip” project, funded by the Defense Threat Reduction Agency, aims to help reduce the estimated $2 billion cost and 90 percent failure rate that pharmaceutical companies face when developing new medications. The research is described in an open-access paper in Scientific Reports, published by Nature.

Using the same expertise they’ve employed to build new organs for patients, the researchers connected together micro-sized 3D liver, heart, and lung organs-on-a chip (or “organoids”) on a single platform to monitor their function. They selected heart and liver for the system because toxicity to these organs is a major reason for drug candidate failures and drug recalls. And lungs were selected because they’re the point of entry for toxic particles and for aerosol drugs such as asthma inhalers.

The integrated three-tissue organ-on-a-chip platform combines liver, heart, and lung organoids. (Top) Liver and cardiac modules are created by bioprinting spherical organoids using customized bioinks, resulting in 3D hydrogel constructs (upper left) that are placed into the microreactor devices. (Bottom) Lung modules are formed by creating layers of cells over porous membranes within microfluidic devices. TEER (trans-endothelial [or epithelial] electrical resistance sensors allow for monitoring tissue barrier function integrity over time. The three organoids are placed in a sealed, monitored system with a real-time camera. A nutrient-filled liquid that circulates through the system keeps the organoids alive and is used to introduce potential drug therapies into the system. (credit: Aleksander Skardal et al./Scientific Reports)

Why current drug testing fails

Drug compounds are currently screened in the lab using human cells and then tested in animals. But these methods don’t adequately replicate how drugs affect human organs. “If you screen a drug in livers only, for example, you’re never going to see a potential side effect to other organs,” said Aleks Skardal, Ph.D., assistant professor at Wake Forest Institute for Regenerative Medicine and lead author of the paper.

In many cases during testing of new drug candidates — and sometimes even after the drugs have been approved for use — drugs also have unexpected toxic effects in tissues not directly targeted by the drugs themselves, he explained. “By using a multi-tissue organ-on-a-chip system, you can hopefully identify toxic side effects early in the drug development process, which could save lives as well as millions of dollars.”

“There is an urgent need for improved systems to accurately predict the effects of drugs, chemicals and biological agents on the human body,” said Anthony Atala, M.D., director of the institute and senior researcher on the multi-institution study. “The data show a significant toxic response to the drug as well as mitigation by the treatment, accurately reflecting the responses seen in human patients.”

Advanced drug screening, personalized medicine

The scientists conducted multiple scenarios to ensure that the body-on-a-chip system mimics a multi-organ response.

For example, they introduced a drug used to treat cancer into the system. Known to cause scarring of the lungs, the drug also unexpectedly affected the system’s heart. (A control experiment using only the heart failed to show a response.) The scientists theorize that the drug caused inflammatory proteins from the lung to be circulated throughout the system. As a result, the heart increased beats and then later stopped altogether, indicating a toxic side effect.

“This was completely unexpected, but it’s the type of side effect that can be discovered with this system in the drug development pipeline,” Skardal noted.

Test of “liver on a chip” response to two drugs to demonstrate clinical relevance. Liver construct toxicity response was assessed following exposure to acetaminophen (APAP) and the clinically-used APAP countermeasure N-acetyl-L-cysteine (NAC). Liver constructs in the fluidic system (left) were treated with no drug (b), 1 mM APAP (c), and 10 mM APAP (d) — showing progressive loss of function and cell death, compared to 10 mM APAP +20 mM NAC (e), which mitigated those negative effects. The data shows both a significant cytotoxic (cell-damage) response to APAP as well as its mitigation by NAC treatment — accurately reflecting the clinical responses seen in human patients. (credit: Aleksander Skardal et al./Scientific Reports)

The scientists are now working to increase the speed of the system for large scale screening and add additional organs.

“Eventually, we expect to demonstrate the utility of a body-on-a-chip system containing many of the key functional organs in the human body,” said Atala. “This system has the potential for advanced drug screening and also to be used in personalized medicine — to help predict an individual patient’s response to treatment.”

Several patent applications comprising the technology described in the paper have been filed.

The international collaboration included researchers at Wake Forest Institute for Regenerative Medicine at the Wake Forest School of Medicine, Harvard-MIT Division of Health Sciences and Technology, Wyss Institute for Biologically Inspired Engineering at Harvard University, Biomaterials Innovation Research Center at Harvard Medical School, Bloomberg School of Public Health at Johns Hopkins University, Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Brigham and Women’s Hospital, University of Konstanz, Konkuk University (Seoul), and King Abdulaziz University.

Abstract of Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform

Many drugs have progressed through preclinical and clinical trials and have been available – for years in some cases – before being recalled by the FDA for unanticipated toxicity in humans. One reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.

A battery-free origami robot powered and controlled by external magnetic fields

Wirelessly powered and controlled magnetic folding robot arm can grasp and bend (credit: Wyss Institute at Harvard University)

Harvard University researchers have created a battery-free, folding robot “arm” with multiple “joints,” gripper “hand,” and actuator “muscles” — all powered and controlled wirelessly by an external resonant magnetic field.

The design is inspired by the traditional Japanese art of origami (used to transform a simple sheet of paper into complex, three-dimensional shapes through a specific pattern of folds, creases, and crimps). The prototype device is capable of complex, repeatable movements at millimeter to centimeter scales.

The research, by scientists at the Wyss Institute for Biologically Inspired Engineering and the John A. Paulson School of Engineering and Applied Sciences (SEAS), is reported in Science Robotics.

How it works

Design of small-scale-structure prototype of wirelessly controlled robotic arm (credit: Mustafa Boyvat et al./Science Robotics)

The researchers designed a 0.8-gram prototype small-scale-structure* prototype robotic “arm” capable of bending and opening or closing a gripper around an object. The “arm” is constructed with a special origami-like pattern that uses hinges (“joints”) to permit it to bend. There is also a “hand” (gripper — left panel in above image) that opens or closes.

To power the device, an external coil with its own power source (see video below) is used to generate a low-frequency magnetic field that induces an electrical current in three magnetic coils. The current heats the spiral-wire shape-memory-alloy actuator wires (coiled wire shown in inset above). That causes the actuator wires (“muscles”) to contract, making the attached nearby “joints” bend, and folding the robot body.

Mechanism of the origami gripper (for small-scale prototype design). (Left) The coil SMA actuator pushes the center link connected to both fingers and the gripper opens fingers, enabled by dynamic folding at the joints (left). The plate spring, which is a passive compression spring, pulls the link back as the gripper closes the fingers, again by rotations at folding joints (center). (Right) A photo of the gripper showing the SMA actuator wire attached at the center link. (credit: Mustafa Boyvat et al./Science Robotics)

By changing the resonant frequency of the external electromagnetic field, the two longer actuator wires (coiled wires shown in above illustration) are instead heated and stretched, opening the gripper (“hand”).

In both cases, when the external field-induced current stops, the actuators relax, springing back to their “memory” positions and causing the robot body to straighten out or the gripper’s outer triangles to close.

Minimally invasive medicine and surgery applications

As an example of a practical future application, instead of having an uncomfortable endoscope put down their throat to assist a doctor with surgery, a patient could just swallow a micro-robot that could move around and perform simple tasks, like holding tissue or filming, powered by a coil outside their body.

Using a much larger source coil — on the order of yards in diameter — could enable wireless, battery-free communication between multiple “smart” objects in a room or building.

“Medical devices today are commonly limited by the size of the batteries that power them, whereas these remotely powered origami robots can break through that size barrier and potentially offer entirely new, minimally invasive approaches for medicine and surgery in the future,” says Wyss Founding Director Donald Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital, as well as a Professor of Bioengineering at Harvard’s School of Engineering and Applied Sciences.

This work was supported by the National Science Foundation, the U.S. Army Research Laboratory, and the Swiss National Science Foundation.

* A large-scale-structure prototype version has minor differences, including 12-cm folding lines vs. 1.7-cm folding lines in the smaller version.

Wyss Institute | Battery-Free Folding Robots

Abstract of Addressable wireless actuation for multijoint folding robots and devices

“Printing” robots and other complex devices through a process of origami-like folding is an emerging and promising manufacturing method due to the inherent simplicity and low cost of folding-based assembly. Folding is used in this class of device to create both complex static structures and flexure-based compliant mechanisms. Dependency on batteries to power these folds with no external wires is a hurdle to giving small-scale folding robots and devices functionality. We demonstrate a battery-free wireless folding method for dynamic multijoint structures, achieving addressable folding motions—both individual and collective folding—using only basic passive electronic components on the device. The method is based on electromagnetic power transmission and resonance selectivity for actuation of resistive shape memory alloy actuators without the need for physical connection or line of sight. We demonstrate the utility of this approach using two folded devices at different sizes using different circuit approaches.

New system allows near-zero-power sensors to communicate data over long distances

This low-cost, flexible epidermal medical-data patch prototype successfully transmitted information at up to 37500 bits per second across a 3,300-square-feet atrium. (credit: Dennis Wise/University of Washington)

University of Washington (UW) researchers have developed a low-cost, long-range data-communication system that could make it possible for medical sensors or billions of low-cost “internet of things” objects to connect via radio signals at long distances (up to 2.8 kilometers) and with 1000 times lower required power (9.25 microwatts in an experiment) compared to existing technologies.

“People have been talking about embedding connectivity into everyday objects … for years, but the problem is the cost and power consumption to achieve this,” said Vamsi Talla, chief technology officer of Jeeva Wireless, which plans to market the system within six months. “This is the first wireless system that can inject connectivity into any device with very minimal cost.”

The new system uses “backscatter,” which uses energy from ambient transmissions (from WiFi, for example) to power a passive sensor that encodes and scatter-reflects the signal. (This article explains how ambient backscatter, developed by UW, works.) Backscatter systems, used with RFID chips, are very low cost, but are limited in distance.

So the researchers combined backscatter with a “chirp spread spectrum” technique, used in LoRa (long-range) wireless data-communication systems.

This tiny off-the-shelf spread-spectrum receiver enables extremely-low-power cheap sensors to communicate over long distances. (credit: Dennis Wise/University of Washington)

This new system has three components: a power source (which can be WiFi or other ambient transmission sources, or cheap flexible printed batteries, with an expected bulk cost of 10 to 20 cents each) for a radio signal; cheap sensors (less than 10 cents at scale) that modulate (encode) information (contained in scattered reflections of the signal), and an inexpensive, off-the-shelf spread-spectrum receiver, located as far away as 2.8 kilometers, that decodes the sensor information.

Applications could include, for example, medical monitoring devices that wirelessly transmit information about a heart patient’s condition to doctors; sensor arrays that monitor pollution, noise, or traffic in “smart” cities; and farmers looking to measure soil temperature or moisture, who could affordably blanket an entire field to determine how to efficiently plant seeds or water.

The research team built a contact lens prototype and a flexible epidermal patch that attaches to human skin, which successfully used long-range backscatter to transmit information across a 3300-square-foot building.

The research, which was partially funded by the National Science Foundation, is detailed in an open-access paper presented Sept. 13, 2017 at UbiComp 2017. More information: longrange@cs.washington.edu.

UW (University of Washington) | UW team shatters long-range communication barrier for devices that consume almost no power

Abstract of LoRa Backscatter: Enabling The Vision of Ubiquitous Connectivity

The vision of embedding connectivity into billions of everyday objects runs into the reality of existing communication technologies — there is no existing wireless technology that can provide reliable and long-range communication at tens of microwatts of power as well as cost less than a dime. While backscatter is low-power and low-cost, it is known to be limited to short ranges. This paper overturns this conventional wisdom about backscatter and presents the first wide-area backscatter system. Our design can successfully backscatter from any location between an RF source and receiver, separated by 475 m, while being compatible with commodity LoRa hardware. Further, when our backscatter device is co-located with the RF source, the receiver can be as far as 2.8 km away. We deploy our system in a 4,800 ft2 (446 m2) house spread across three floors, a 13,024 ft2 (1210 m2) office area covering 41 rooms, as well as a one-acre (4046 m2) vegetable farm and show that we can achieve reliable coverage, using only a single RF source and receiver. We also build a contact lens prototype as well as a flexible epidermal patch device attached to the human skin. We show that these devices can reliably backscatter data across a 3,328 ft2 (309 m2) room. Finally, we present a design sketch of a LoRa backscatter IC that shows that it costs less than a dime at scale and consumes only 9.25 &mgr;W of power, which is more than 1000x lower power than LoRa radio chipsets.

Walking DNA nanorobot could deliver a drug to a precise location in your body

DNA nanorobot cargo carrier (artist’s impression) (credit: Ella Maru Studio)

Caltech scientists have developed a “cargo sorting” DNA nanorobot programmed to autonomously “walk” around a surface, pick up certain molecules, and drop them off in designated locations.

The research is described in a paper in the Friday, September 15, 2017 issue of Science.

The major advance in this study is “their methodology for designing simple DNA devices that work in parallel to solve nontrivial tasks,” notes Duke University computer scientist John H. Reif in an article in the same issue of Science.

Such tasks could include synthesizing a drug in a molecular factory or delivering a drug only when a specific signal is present in bloodstreams, say the researchers. “So far, the development of DNA robots has been limited to simple functions,” the researchers note.

Walking nanobots that work in parallel

Conceptual illustration of two DNA nanorobots collectively performing a cargo-sorting task on a DNA origami surface: transporting fluorescent molecules with different colors from initially random locations to ordered destinations. (credit: Demin Liu)

The DNA nanorobot, intended as a proof of concept, has a “leg” with two “feet” for walking, and an “arm” and “hand” for picking up cargo. It also has a segment that can recognize a specific drop-off point and signal to the hand to release its cargo. Each of these building blocks are made of just a few nucleotides (molecules that form DNA) within a single strand of DNA.*

As the robot encounters cargo molecules tethered to pegs, it grabs them with its “hand” components and carries them around (with a 6-nm step size) until it detects the signal of the drop-off point.

Multiple DNA nanorobots independently execute three operations in parallel: [1] cargo pickup, [2] random movement to adjacent stepping stones, and [3] cargo drop-off at ordered locations. (credit: C. Bickel/Science)

In experiments, the nanorobots successfully sorted six randomly scattered molecules into their correct places in 24 hours. The process is slow, but adding more robots to the surface shortened the time it took to complete the task. The very simple robot design utilizes very little chemical energy, according to the researchers.**

“The same system design can be generalized to work with dozens of types of cargos at any arbitrary initial location on the surface,” says lead author Anupama Thubagere. “One could also have multiple robots performing diverse sorting tasks in parallel,” [programmed] like macroscopic robots.”

Future applications

“We don’t develop DNA robots for any specific applications. Our lab focuses on discovering the engineering principles that enable the development of general-purpose DNA robots,” explains Lulu Qian, assistant professor of bioengineering.

“However, it is my hope that other researchers could use these principles for exciting applications, such as synthesizing a therapeutic chemical from its constituent parts in an artificial molecular factory, or sorting molecular components in trash for recycling. Just like electromechanical robots are sent off to faraway places, like Mars, we would like to send molecular robots to minuscule places where humans can’t go, such as the bloodstream.”

Funding was provided by Caltech Summer Undergraduate Research Fellowships, the National Science Foundation, and the Burroughs Wellcome Fund.

* The key to designing DNA machines is the fact that DNA has unique chemical and physical properties that are known and programmable. A single strand of DNA is made up of four different molecules called nucleotides—abbreviated A, G, C, and T—and arranged in a string called a sequence. These nucleotides bond in specific pairs: A with T, and G with C. When a single strand encounters a “reverse complementary strand” — for example, CGATT meets AATCG —the two strands zip together in the classic double-helix shape.

** Using these chemical and physical principles, researchers can also design “playgrounds,” such as molecular pegboards, to test them on, according to the researchers. In the current work, the DNA robot moves around on a 58-nanometer-by-58-nanometer pegboard on which the pegs are made of single strands of DNA complementary to the robot’s leg and foot. The robot binds to a peg with its leg and one of its feet — the other foot floats freely. When random molecular fluctuations cause this free foot to encounter a nearby peg, it pulls the robot to the new peg and its other foot is freed. This process continues with the robot moving in a random direction at each step.

Abstract of A cargo-sorting DNA robot

Two critical challenges in the design and synthesis of molecular robots are modularity and
algorithm simplicity.We demonstrate three modular building blocks for a DNA robot that
performs cargo sorting at themolecular level. A simple algorithm encoding recognition between
cargos and their destinations allows for a simple robot design: a single-stranded DNA with
one leg and two foot domains for walking, and one arm and one hand domain for picking up and
dropping off cargos.The robot explores a two-dimensional testing ground on the surface of
DNA origami, picks up multiple cargos of two types that are initially at unordered locations, and
delivers them to specified destinations until all molecules are sorted into two distinct piles.
The robot is designed to perform a random walk without any energy supply. Exploiting this
feature, a single robot can repeatedly sort multiple cargos. Localization on DNA origami allows
for distinct cargo-sorting tasks to take place simultaneously in one test tube or for multiple
robots to collectively perform the same task.

Miniature MRI simulator chip could help diagnose and treat diseases in the body at sub-millimeter precision

Illustration of an ATOMS microchip localized within the gastrointestinal tract (not to scale; a prototype measures just 0.7 cubic millimeters). The microchip contains a magnetic field sensor, integrated antennas, a wireless powering device, and a circuit that adjusts its radio frequency signal based on the magnetic field strength and wirelessly relays the chip’s precise location. (credit: Ella Marushchenko/Caltech)

Caltech researchers have developed a “Fantastic Voyage” style prototype microchip that could one day be used in “smart pills” to diagnose and treat diseases when inserted into the human body.

Called ATOMS (addressable transmitters operated as magnetic spins), the microchips could one day monitor a patient’s gastrointestinal tract, blood, or brain, measuring factors that indicate a patient’s health — such as pH, temperature, pressure, and sugar concentrations — with sub-millimeter localization and relay that information to doctors. Or the devices could even be instructed to release drugs at precise locations.

An open access paper describing the new device appears in the September issue of the journal Nature Biomedical Engineering. The lead author is Manuel Monge, who now works at Elon Musk’s new Neuralink company.

The ATOMS microchips, proven to work in tests with mice, mimic the way nuclear spins in atoms in the body resonate to magnetic fields in a magnetic resonance imaging (MRI) machine and can be precisely identified and localized within the body. Similarly, the ATOMS devices resonate at different frequencies depending on where they are in a magnetic field. (credit: Manuel Monge et al./ Nature Biomedical Engineering)

Abstract of Localization of Microscale Devices In Vivo using Addressable Transmitters Operated as Magnetic Spins

The function of miniature wireless medical devices, such as capsule endoscopes, biosensors and drug-delivery systems, depends critically on their location inside the body. However, existing electromagnetic, acoustic and imaging-based methods for localizing and communicating with such devices suffer from limitations arising from physical tissue properties or from the performance of the imaging modality. Here, we embody the principles of nuclear magnetic resonance in a silicon integrated-circuit approach for microscale device localization. Analogous to the behaviour of nuclear spins, the engineered miniaturized radio frequency transmitters encode their location in space by shifting their output frequency in proportion to the local magnetic field; applied field gradients thus allow each device to be located precisely from its signal’s frequency. The devices are integrated in circuits smaller than 0.7 mm3 and manufactured through a standard complementary-metal-oxide-semiconductor process, and are capable of sub-millimetre localization in vitro and in vivo. The technology is inherently robust to tissue properties, scalable to multiple devices, and suitable for the development of microscale devices to monitor and treat disease.

These fast, low-cost medical technologies will replace ultrasound and X-rays for specific uses

Smartphone instant heart diagnosis (credit: Caltech)

A radical software invention by three Caltech engineers promises to allow your smartphone camera* to provide detailed information about a critical measure of your heart’s health: the “left ventricular ejection fraction” (LVEF) — the amount of blood in the heart that is pumped out to the blood system with each beat. This figure is used by physicians as a base for diagnostic and therapeutic decisions.

You’ll simply hold your phone up to your neck for a minute or two.

In an experiment, the technique was found to be as accurate as a 45-minute echocardiography scan, which currently requires a trained technician operating an expensive ultrasound machine.

The smartphone technique measures how much the carotid artery displaces the skin of the neck as blood pumps through it. In a normal heart, the LVEF measure ranges from 50 to 70 percent. When the heart is weaker, less of the total amount of blood in the heart is pumped out with each beat, and the LVEF value is lower.

Carotid arterial waveform captured using an unmodified iPhone 5S camera by placing the iPhone camera over the carotid pulse (credit: Niema M. Pahlevan et al./Critical Card Medicine)

To test the app, clinical trials were conducted with 72 volunteers between the ages of 20 and 92 at an outpatient magnetic resonance imaging (MRI) facility. MRI is the gold standard in measuring LVEF but is seldom used clinically due to its high cost and limited availability. The measurements made by smartphone had a margin of error of ±19.1 percent compared with those done in an MRI. By way of comparison, the margin of error for echocardiography is around ±20.0 percent.

“This has the potential to revolutionize how doctors and patients can screen for and monitor heart disease, both in the U.S. and the developing world,” says Caltech’s Mory Gharib, the Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering and senior author of a paper on the study in the July issue of the Journal of Critical Care Medicine.

The researchers have founded a start-up named Avicena, LLC that has licensed this technology and will market the app. They also plan to use this approach to diagnose heart-valve diseases, like aortic stenosis and coronary artery blockage.

* For the study, the team used an iPhone 5, but they say any smartphone with a camera will work.

Seeing through the body

University of Edinburgh and Heriot-Watt University researchers have used a near-infrared camera to see through the chest to track the location of a fiber-optic endomicroscope (a long flexible tube with a light on the end) — replacing X-rays.

A “time-of-flight” camera detects light emitted from an endoscope in sheep lungs. Left: light emitted from the tip of the endoscope, revealing its precise location in the lungs. Right: an image using a conventional camera, with light scattered through the structures of the lung. (credit: Proteus)

Near-infrared light can readily pass through the body, but much of it scatters or bounces off tissues and organs rather than traveling straight through — making it nearly impossible to get a clear picture of where an object is in the body. So this camera uses a “time-of-flight” system: It calculates the distance to the endomicroscope light based on the time it takes individual photons to arrive directly (ignoring scattered photons, which take longer). That’s similar to how this camera can see an object around a corner.

The technology is so sensitive it can detect the miniscule amount of light that passes through 20 centimeters (about 8 inches) of the body’s tissue.

The research is described in an open-access paper in the journal Biomedical Optics Express.

Abstract of Noninvasive iPhone Measurement of Left Ventricular Ejection Fraction Using Intrinsic Frequency Methodology

Objective: The study is based on previously reported mathematical analysis of arterial waveform that extracts hidden oscillations in the waveform that we called intrinsic frequencies. The goal of this clinical study was to compare the accuracy of left ventricular ejection fraction derived from intrinsic frequencies noninvasively versus left ventricular ejection fraction obtained with cardiac MRI, the most accurate method for left ventricular ejection fraction measurement.

Design: After informed consent, in one visit, subjects underwent cardiac MRI examination and noninvasive capture of a carotid waveform using an iPhone camera (The waveform is captured using a custom app that constructs the waveform from skin displacement images during the cardiac cycle.). The waveform was analyzed using intrinsic frequency algorithm.

Setting: Outpatient MRI facility.

Subjects: Adults able to undergo MRI were referred by local physicians or self-referred in response to local advertisement and included patients with heart failure with reduced ejection fraction diagnosed by a cardiologist.

Interventions: Standard cardiac MRI sequences were used, with periodic breath holding for image stabilization. To minimize motion artifact, the iPhone camera was held in a cradle over the carotid artery during iPhone measurements.

Measurements and Main Results: Regardless of neck morphology, carotid waveforms were captured in all subjects, within seconds to minutes. Seventy-two patients were studied, ranging in age from 20 to 92 years old. The main endpoint of analysis was left ventricular ejection fraction; overall, the correlation between ejection fraction–iPhone and ejection fraction–MRI was 0.74 (r = 0.74; p < 0.0001; ejection fraction–MRI = 0.93 × [ejection fraction–iPhone] + 1.9).

Conclusions: Analysis of carotid waveforms using intrinsic frequency methods can be used to document left ventricular ejection fraction with accuracy comparable with that of MRI. The measurements require no training to perform or interpret, no calibration, and can be repeated at the bedside to generate almost continuous analysis of left ventricular ejection fraction without arterial cannulation.

Abstract of Ballistic and snake photon imaging for locating optical endomicroscopy fibres

We demonstrate determination of the location of the distal-end of a fibre-optic device deep in tissue through the imaging of ballistic and snake photons using a time resolved single-photon detector array. The fibre was imaged with centimetre resolution, within clinically relevant settings and models. This technique can overcome the limitations imposed by tissue scattering in optically determining the in vivo location of fibre-optic medical instruments.

Flexible ‘electronic skin’ patch provides wearable health monitoring anywhere on the body

New soft electronic stick-on patch collects, analyzes, and diagnoses biosignals and sends data wirelessly to a mobile app. (credit: DGIST)

A radical new electronic skin monitor developed by Korean and U.S. scientists tracks heart rate, respiration, muscle movement, acceleration, and electrical activity in the heart, muscles, eyes, and brain and wirelessly transmits it to a smartphone, allowing for continuous health monitoring.

KurzweilAI has covered a number of biomedical skin-monitoring devices. This new design is noteworthy because the soft, flexible self-adhesive patch (a soft silicone material about four centimeters or 1.5 inches in diameter) can be instantly stuck just about anywhere on the body as needed — no battery required (it’s powered wirelessly).

Optical image of the three-dimensional network of helical coils as electrical interconnects for soft electronics. (credit: DGIST)

The patch is designed more like a mattress or creeping vine than a conventional electronic device. It contains about 50 components connected by a network of 250 tiny flexible wire coils embedded in protective silicone. Unlike flat sensors, the tiny helical wire coils, made of gold, chromium and phosphate, are firmly connected to the base only at one end and can stretch and contract like a spring without breaking.

Helical coils serve as 3D electrical interconnects for soft electronics. (credit: DGIST)

The researchers say the microsystem could also be used in soft robotics, virtual reality, and autonomous navigation.

The microsystem was developed by an international team led by Kyung-In Jang, a professor of robotics engineering at South Korea’s Daegu Gyeongbuk Institute of Science and Technology, and John A. Rogers, the director of Northwestern University’s Center for Bio-Integrated Electronics. The research is described in the open-access journal Nature Communications.

“We have several human subject studies ongoing with our medical school at Northwestern — mostly with a focus on health status monitoring in infants,” Rogers told KurzweilAI.

Abstract of Self-assembled three dimensional network designs for soft electronics

Low modulus, compliant systems of sensors, circuits and radios designed to intimately interface with the soft tissues of the human body are of growing interest, due to their emerging applications in continuous, clinical-quality health monitors and advanced, bioelectronic therapeutics. Although recent research establishes various materials and mechanics concepts for such technologies, all existing approaches involve simple, two-dimensional (2D) layouts in the constituent micro-components and interconnects. Here we introduce concepts in three-dimensional (3D) architectures that bypass important engineering constraints and performance limitations set by traditional, 2D designs. Specifically, open-mesh, 3D interconnect networks of helical microcoils formed by deterministic compressive buckling establish the basis for systems that can offer exceptional low modulus, elastic mechanics, in compact geometries, with active components and sophisticated levels of functionality. Coupled mechanical and electrical design approaches enable layout optimization, assembly processes and encapsulation schemes to yield 3D configurations that satisfy requirements in demanding, complex systems, such as wireless, skin-compatible electronic sensors.

Drinking coffee associated with lower risk of death from all causes, study finds

(credit: iStock)

People who drink around three cups of coffee a day may live longer than non-coffee drinkers, a landmark study has found.

The findings — published in the journal Annals of Internal Medicine — come from the largest study of its kind, in which scientists analyzed data from more than half a million people across 10 European countries to explore the effect of coffee consumption on risk of mortality.

Researchers from the International Agency for Research on Cancer (IARC) and Imperial College London found that higher levels of coffee consumption were associated with a reduced risk of death from all causes, particularly from circulatory diseases and diseases related to the digestive tract.

“We found that higher coffee consumption was associated with a lower risk of death from any cause, and specifically for circulatory diseases, and digestive diseases,” said lead author Marc Gunter of the IARC and formerly at Imperial’s School of Public Health. “Importantly, these results were similar across all of the 10 European countries, with variable coffee drinking habits and customs. Our study also offers important insights into the possible mechanisms for the beneficial health effects of coffee.”

Healthier livers, better glucose control

Using data from the EPIC study (European Prospective Investigation into Cancer and Nutrition), the group analysed data from 521,330 people from over the age of 35 from 10 EU countries, including the UK, France, Denmark and Italy. People’s diets were assessed using questionnaires and interviews, with the highest level of coffee consumption (by volume) reported in Denmark (900 mL per day) and lowest in Italy (approximately 92 mL per day). Those who drank more coffee were also more likely to be younger, to be smokers, drinkers, eat more meat and less fruit and vegetables.

After 16 years of follow up, almost 42,000 people in the study had died from a range of conditions including cancer, circulatory diseases, heart failure and stroke. Following careful statistical adjustments for lifestyle factors such as diet and smoking, the researchers found that the group with the highest consumption of coffee had a lower risk for all causes of death, compared to those who did not drink coffee.

They found that decaffeinated coffee had a similar effect.

In a subset of 14,000 people, they also analyzed metabolic biomarkers, and found that coffee drinkers may have healthier livers overall and better glucose control than non-coffee drinkers.

According to the group, more research is needed to find out which of the compounds in coffee may be giving a protective effect or potentially benefiting health.* Other avenues of research to explore could include intervention studies, looking at the effect of coffee drinking on health outcomes.

However, Gunter noted that “due to the limitations of observational research, we are not at the stage of recommending people to drink more or less coffee. That said, our results suggest that moderate coffee drinking is not detrimental to your health, and that incorporating coffee into your diet could have health benefits.”

The study was funded by the European Commission Directorate General for Health and Consumers and the IARC.

* Coffee contains a number of compounds that can interact with the body, including caffeine, diterpenes and antioxidants, and the ratios of these compounds can be affected by the variety of methods used to prepare coffee.

Abstract of Coffee Drinking and Mortality in 10 European Countries: A Multinational Cohort Study

Background: The relationship between coffee consumption and mortality in diverse European populations with variable coffee preparation methods is unclear.

Objective: To examine whether coffee consumption is associated with all-cause and cause-specific mortality.

Design: Prospective cohort study.

Setting: 10 European countries.

Participants: 521 330 persons enrolled in EPIC (European Prospective Investigation into Cancer and Nutrition).

Measurements: Hazard ratios (HRs) and 95% CIs estimated using multivariable Cox proportional hazards models. The association of coffee consumption with serum biomarkers of liver function, inflammation, and metabolic health was evaluated in the EPIC Biomarkers subcohort (n = 14 800).

Results: During a mean follow-up of 16.4 years, 41 693 deaths occurred. Compared with nonconsumers, participants in the highest quartile of coffee consumption had statistically significantly lower all-cause mortality (men: HR, 0.88 [95% CI, 0.82 to 0.95]; P for trend < 0.001; women: HR, 0.93 [CI, 0.87 to 0.98]; P for trend = 0.009). Inverse associations were also observed for digestive disease mortality for men (HR, 0.41 [CI, 0.32 to 0.54]; P for trend < 0.001) and women (HR, 0.60 [CI, 0.46 to 0.78]; P for trend < 0.001). Among women, there was a statistically significant inverse association of coffee drinking with circulatory disease mortality (HR, 0.78 [CI, 0.68 to 0.90]; P for trend < 0.001) and cerebrovascular disease mortality (HR, 0.70 [CI, 0.55 to 0.90]; P for trend = 0.002) and a positive association with ovarian cancer mortality (HR, 1.31 [CI, 1.07 to 1.61]; P for trend = 0.015). In the EPIC Biomarkers subcohort, higher coffee consumption was associated with lower serum alkaline phosphatase; alanine aminotransferase; aspartate aminotransferase; γ-glutamyltransferase; and, in women, C-reactive protein, lipoprotein(a), and glycated hemoglobin levels.

Limitations: Reverse causality may have biased the findings; however, results did not differ after exclusion of participants who died within 8 years of baseline. Coffee-drinking habits were assessed only once.


Coffee drinking was associated with reduced risk for death from various causes. This relationship did not vary by country.

Primary Funding Source:

European Commission Directorate-General for Health and Consumers and International Agency for Research on Cancer.

Abstract of Association of Coffee Consumption With Total and Cause-Specific Mortality Among Nonwhite Populations

Background: Coffee consumption has been associated with reduced risk for death in prospective cohort studies; however, data in nonwhites are sparse.

Objective: To examine the association of coffee consumption with risk for total and cause-specific death.

Design: The MEC (Multiethnic Cohort), a prospective population-based cohort study established between 1993 and 1996.

Setting: Hawaii and Los Angeles, California.

Participants: 185 855 African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites aged 45 to 75 years at recruitment.

Measurements: Outcomes were total and cause-specific mortality between 1993 and 2012. Coffee intake was assessed at baseline by means of a validated food-frequency questionnaire.

Results: 58 397 participants died during 3 195 484 person-years of follow-up (average follow-up, 16.2 years). Compared with drinking no coffee, coffee consumption was associated with lower total mortality after adjustment for smoking and other potential confounders (1 cup per day: hazard ratio [HR], 0.88 [95% CI, 0.85 to 0.91]; 2 to 3 cups per day: HR, 0.82 [CI, 0.79 to 0.86]; ≥4 cups per day: HR, 0.82 [CI, 0.78 to 0.87]; Pfor trend < 0.001). Trends were similar between caffeinated and decaffeinated coffee. Significant inverse associations were observed in 4 ethnic groups; the association in Native Hawaiians did not reach statistical significance. Inverse associations were also seen in never-smokers, younger participants (<55 years), and those who had not previously reported a chronic disease. Among examined end points, inverse associations were observed for deaths due to heart disease, cancer, respiratory disease, stroke, diabetes, and kidney disease.

Limitation: Unmeasured confounding and measurement error, although sensitivity analysis suggested that neither was likely to affect results.

Conclusion: Higher consumption of coffee was associated with lower risk for death in African Americans, Japanese Americans, Latinos, and whites.

Primary Funding Source: National Cancer Institute.

Meditation, yoga, and tai chi can reverse damaging effects of stress, new study suggests

Gentle exercise like tai chi can reduce the risk of inflammation-related diseases like cancer and accelerated aging. (credit: iStock)

Mind-body interventions such as meditation, yoga*, and tai chi can reverse the molecular reactions in our DNA that cause ill-health and depression, according to a study by scientists at the universities of Coventry and Radboud.

When a person is exposed to a stressful event, their sympathetic nervous system (responsible for the “fight-or-flight” response) is triggered, which increases production of a molecule called nuclear factor kappa B (NF-kB). That molecule then activates genes to produce proteins called cytokines that cause inflammation at the cellular level, affecting the body, brain, and immune system.

That’s useful as a short-lived fight-or-flight reaction. However, if persistent, it leads to a higher risk of cancer, accelerated aging, and psychiatric disorders like depression.

But in a paper published June 16, 2017 in the open-access journal Frontiers in Immunology, the researchers reveal findings of 18 studies (featuring 846 participants over 11 years) indicating that people who practice mind-body interventions exhibit the opposite effect. They showed a decrease in production of NF-kB and cytokines — reducing the pro-inflammatory gene expression pattern and the risk of inflammation-related diseases and conditions.

David Gorski, MD, PhD, has published a critique of this study here. (Lead author Ivana Burić has replied in the comments below.)

Lowering risks from sitting

Brisk walks can offset health hazards of sitting (credit: iStock)

In addition to stress effects, increased sitting is known to be associated with an increased risk of cardiovascular disease, diabetes, and death from all causes.

But regular two-minute brisk walks every 30 minutes (in addition to daily 30-minute walks) significantly reduce levels of triglyceride (lipid, or fatty acid) levels that lead to clogged arteries, researchers from New Zealand’s University of Otago report in a paper published June 19, 2017 in the Journal of Clinical Lipidology.**

The lipid levels were measured in response to a meal consumed around 24 hours after starting the activity. High levels of triglycerides are linked to hardening of the arteries and other cardiovascular conditions.

They previously found that brisk walks for two minutes every 30 minutes also lower blood glucose and insulin levels.

OK, it’s time for that two-minute brisk walk. … So, you’re still sitting there, aren’t you? :)

* However, yoga causes musculoskeletal pain in more than 10 per cent of practitioners per year, according to recent research at the University of Sydney published in the Journal of Bodywork and Movement Therapies. “We also found that yoga can exacerbate existing pain, with 21 per cent of existing injuries made worse by doing yoga, particularly pre-existing musculoskeletal pain in the upper limbs,” said lead researcher Associate Professor Evangelos Pappas from the University’s Faculty of Health Sciences.

“In terms of severity, more than one-third of cases of pain caused by yoga were serious enough to prevent yoga participation and lasted more than 3 months.” The study found that most “new” yoga pain was in the upper extremities (shoulder, elbow, wrist, hand), possibly due to downward dog and similar postures that put weight on the upper limbs. However, 74 per cent of participants in the study reported that existing pain was actually improved by yoga, highlighting the complex relationship between musculoskeletal pain and yoga practice.

** Scientists at the University of Utah School of Medicine previously came to a similar conclusion in a 2015 paper published in the Clinical Journal of the American Society of Nephrology (CJASN).

They used observational data from the National Health and Nutrition Examination Survey (NHANES) to examine whether longer durations of low-intensity activities (e.g., standing) vs. light-intensity activities (e.g., casual walking, light gardening, cleaning) extend the lifespan of people who are sedentary for more than half of their waking hours.

They found that adding two minutes of low-intensity activities every hour (plus 2.5 hours of moderate exercise each week, which strengthens the heart, muscles, and bones) was associated with a 33 percent lower risk of dying. “It was fascinating to see the results because the current national focus is on moderate or vigorous activity,” says lead author Srinivasan Beddhu, M.D., professor of internal medicine. “To see that light activity had an association with lower mortality is intriguing.”

UPDATE July 5, 2017 — Added mention of a critique to the Coventry–Radboud study.



Common antioxidant could slow symptoms of aging in human skin

These cross-section images show three-dimensional human skin models made of living skin cells. Untreated model skin (left panel) shows a thinner dermis layer (black arrow) compared with model skin treated with the antioxidant methylene blue (right panel). A new study suggests that methylene blue could slow or reverse dermal thinning (a sign of aging) and a number of other symptoms of aging in human skin. (credit: Zheng-Mei Xiong/University of Maryland)

University of Maryland (UMD) researchers have found evidence that a common, inexpensive, and safe antioxidant chemical called methylene blue could slow the aging of human skin, based on tests in cultured human skin cells and simulated skin tissue.

“The effects we are seeing are not temporary. Methylene blue appears to make fundamental, long-term changes to skin cells,” said Kan Cao, senior author on the study and an associate professor of cell biology and molecular genetics at UMD.

The researchers tested methylene blue for four weeks in skin cells from healthy middle-aged donors, as well as those diagnosed with progeria — a rare genetic disease that mimics the normal aging process at an accelerated rate. The researchers also tested three other known antioxidants: N-Acetyl-L-Cysteine (NAC), MitoQ and MitoTEMPO (mTEM).

In these experiments, methylene blue outperformed the other three antioxidants, improving several age-related symptoms in cells from both healthy donors and progeria patients. The skin cells (fibroblasts, the cells that produce the structural protein collagen) experienced a decrease in damaging molecules known as reactive oxygen species (ROS), a reduced rate of cell death, and an increase in the rate of cell division throughout the four-week treatment.

Improvements in skin cells from older donors (>80 years old)

Next, Cao and her colleagues tested methylene blue in fibroblasts from older donors (>80 years old), again for a period of four weeks. At the end of the treatment, the cells from older donors had experienced a range of improvements, including decreased expression of two genes commonly used as indicators of cellular aging: senescence-associated beta-galactosidase and p16.

Schematic illustrations of top (left panel) and side (right panel) views of the engineered 3D skin tissue cultured on a microporous membrane insert, used for experiments and skin-irritation tests (credit: Zheng-Mei Xiong et al./Scientific Reports)

The researchers then used simulated human skin to perform several more experiments. This simulated skin — a three-dimensional model made of living skin cells — includes all the major layers and structures of skin tissue, with the exception of hair follicles and sweat glands. The model skin could also be used in skin irritation tests required by the Food and Drug Administration for the approval of new cosmetic products, Cao said.

“This system allowed us to test a range of aging symptoms that we can’t replicate in cultured cells alone,” Cao said. “Most surprisingly, we saw that model skin treated with methylene blue retained more water and increased in thickness—both of which are features typical of younger skin.”

Formulating cosmetics

The researchers also used the model skin to test the safety of cosmetic creams with methylene blue added. The results suggest that methylene blue causes little to no irritation, even at high concentrations. Encouraged by these results, Cao and colleagues hope to develop safe and effective ways for consumers to benefit from the properties of methylene blue.

“We have already begun formulating cosmetics that contain methylene blue. Now we are looking to translate this into marketable products,” Cao said. “Perhaps down the road we can customize the system with bioprinting, such that we might be able to use a patient’s own cells to provide a tailor-made testing platform specific to their needs.”

The study was published online in the Nature journal Scientific Reports on May 30, 2017.

This research was supported by the Maryland Innovation Initiative.

Abstract of Anti-Aging Potentials of Methylene Blue for Human Skin Longevity

Oxidative stress is the major cause of skin aging that includes wrinkles, pigmentation, and weakened wound healing ability. Application of antioxidants in skin care is well accepted as an effective approach to delay the skin aging process. Methylene blue (MB), a traditional mitochondrial-targeting antioxidant, showed a potent ROS scavenging efficacy in cultured human skin fibroblasts derived from healthy donors and from patients with progeria, a genetic premature aging disease. In comparison with other widely used general and mitochondrial-targeting antioxidants, we found that MB was more effective in stimulating skin fibroblast proliferation and delaying cellular senescence. The skin irritation test, performed on an in vitro reconstructed 3D human skin model, indicated that MB was safe for long-term use, and did not cause irritation even at high concentrations. Application of MB to this 3D skin model further demonstrated that MB improved skin viability, promoted wound healing and increased skin hydration and dermis thickness. Gene expression analysis showed that MB treatment altered the expression of a subset of extracellular matrix proteins in the skin, including upregulation of elastin and collagen 2A1, two essential components for healthy skin. Altogether, our study suggests that MB has a great potential for skin care.