Scientists have devised a triple-stage "cluster bomb" system for delivering the chemotherapy drug cisplatin, via tiny nanoparticles designed to break up when they reach a tumor. Details of the particles’ design and their potency against cancer in mice were published this week in PNAS. They have not been tested in humans, although similar ways of packaging cisplatin have been in clinical trials. What makes these particles distinctive is that they start out relatively large — 100 nanometers wide — to enable smooth transport into the tumor through leaky blood vessels. Then, in acidic conditions found close to tumors, the particles discharge "bomblets" just 5 nanometers in size. Inside tumor cells, a second chemical step activates the platinum-based cisplatin, which kills by crosslinking and damaging DNA. Doctors have used cisplatin to fight several types of cancer for decades, but toxic side effects — to the kidneys, nerves and inner ear — can limit its effectiveness. The PNAS paper is the result of a collaboration between a team led by professor Jun Wang, PhD at the University of Science and Technology of China, and researchers led by professor Shuming Nie, PhD, in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Nie is a member of the Discovery and Developmental Therapeutics research program at Winship Cancer Institute of Emory University. The lead authors are graduate student Hong-Jun Li and postdoctoral fellows Jinzhi Du, PhD, and Xiao-Jiao Du, PhD. "The negative side effects of cisplatin are a long-standing limitation for conventional chemotherapy," says Jinzhi Du. "In our study, the delivery system was able to improve tumor penetration to reach more cancer cells, as well as release the drugs specifically inside cancer cells through their size-transition property." The researchers showed that their nanoparticles could enhance cisplatin drug accumulation in tumor tissues. When mice bearing human pancreatic tumors were given the same doses of free cisplatin or cisplatin clothed in pH-sensitive nanoparticles, the level of platinum in tumor tissues was seven times higher with the nanoparticles. This suggests the possibility that nanoparticle delivery of a limited dose of cisplatin could restrain the toxic side effects during cancer treatment. The researchers also showed that the nanoparticles were effective against a cisplatin-resistant lung cancer model and an invasive metastatic breast cancer model in mice. In the lung cancer model, a dose of free cisplatin yielded just 10 percent growth inhibition, while the same dose clothed in nanoparticles yielded 95 percent growth inhibition, the researchers report. In the metastatic breast cancer model, treating mice with cisplatin clothed in nanoparticles prolonged animal survival by weeks; 50 percent of the mice were surviving at 54 days with nanoparticles compared with 37 days for the same dose of free cisplatin. Enhanced efficacy in three different tumor models demonstrate that this strategy may be applicable to several types of cancer, Jinzhi Du says. Source: Emory University
When the Chinese first discovered silk, its superior quality and properties were thought so special, it was reserved exclusively for clothing the emperor, his relatives, and dignitaries. And for more than two millennia, the mechanisms of silk production were a highly guarded secret. Fast forward to today: MIT and Tufts University researchers have discovered additional hidden secrets of silk, called nanofibrils, which, when expertly extracted and reassembled, can be manufactured into advanced filtration membranes. The researchers’ new silk-based filtration technique was recently described and published in the paper, "Ultrathin Free-Standing Bombyx mori Silk Nanofibril Membranes” in the journal Nano Letters. The paper reveals how silk nanofibrils (SNFs), a key nanocale building block of natural silk, can lead to new naturally-based filters that are more effective, less expensive, and “greener” compared with traditional commercial products. This discovery could portend new production methods and supply chain economics for anyone that uses the new filter membranes, including water treatment facilities, food manufacturers, and life sciences organizations. The researchers included Department of Civil and Environmental Engineering (CEE) graduate student Kai Jin; CEE postdoc Shengjie Ling; Markus J. Buehler, head of CEE and the McAfee Professor of Engineering; and Professor David L. Kaplan, chair of the Tufts Department of Biomedical Engineering. “There has been a renewed focus recently on developing these types of ultrathin filtration membranes which can provide maximum flow-through while retaining molecules or pollutants that need to be separated from the flow,” Ling says. “The challenge has always been to create these new ultrathin and low-cost devices while retaining mechanical strength and good separation performance. Cast silk fibroin membranes aren’t an option, because they do not have porous structure and dissolve in water if not pretreated. We knew there had to be a better way.” An insurmountable challenge — until now The researchers spent many months sharing ideas, working and reworking calculations, and experimenting in the lab. Their effort to find just the right solvent to dissolve the silk fibers into their most elemental compounds without destroying the samples was one of their greatest challenges. “We devoted a lot of time developing the method for extracting the nanofibrils from the natural silk fibers,” Ling says. “It’s a novel approach, so we had to use trial and error before we eventually found success. It was such a good feeling to realize in tangible results what was calculated.” Their work — a collaborative effort among civil, biomedical, and computational engineering, and materials science — found the solution in this new free-standing ultrathin filtration membrane and its innovative, advanced production technique. Natural silk fibers, which are made of pure protein, are renowned for their incredible lightness, strength, and durability. The silk nanofibrils used by the researchers were exfoliated from domesticated silkworm-produced fibers. It is the special character of the silk nanofibrils that helps the innovative membranes retain their exquisite structure and superior physical properties. Historic methods to extract or prepare these nanofibers have not always worked. The illustration in the slideshow above shows the researchers’ unique four-step approach that proved effective by overcoming prior hurdles. The first two steps were used to exfoliate the silk nanofibrils from the silk fibers by degumming, washing, drying, and incubating them at a constant temperature, before placing them in water and stirring or shaking them to remove any undissolved silk. The third step involved using ultrasonic waves to extract the silk nanofibrils, which remained stable over several months. Scanning electron micrograph imagery showed the silk nanofibrils had a diameter and contour length similar to the diameter of a single nanofibril strand. In the last step and final process, they assembled the silk nanofibrils into the ultrathin membranes using a vacuum filtration process. Success came in meeting and exceeding three important membrane attributes: thickness (40-1,500 nanometers with narrowing pore sizes of 12-8 nm); superior water permeation, known as flux; and excellent broad-spectrum separation performance for most dyes, proteins, and nanoparticles. All of these mechanical superiority results are critical to industry, especially for use in pressure-driven filtration operations, even at high applied pressures. Whether purifying waste water for drinking, or capturing the minuteness of blood clots in the human body, these new silk-based membranes offer significant advanced operational efficiencies. And one piece of silk nanofibrils membrane averages only $0.05-$0.51 compared with $1.20 per piece of commercial filtration membrane. Silk nanofibrils used in manufacturing hold other important benefits, too. As the by-products of silkworms, innovative manufacturers who leverage silk’s natural properties can enhance their industrial ecology and produce less environmental stress. And once the filters are replaced, the used ones biodegrade, leaving no lasting impact. Controlling the thickness of membranes and pore size distribution is especially important for filters to work effectively, so the researchers made sure the interconnected membrane pores produced in the lab were uniform and without cracks or pinholes. In addition, they noted the new membrane’s rejection of protein and gold nanoparticles in flow was higher than that of membranes with similar thickness. Protein molecules, colloids, nanoparticles, small molecules, and ions were all used to assess size-selectivity. The researchers experimented frequently with water fluxes through membranes of different thicknesses (40-60 nm). “What really surprised us,” says Jin, “is that one flux was faster than that of most commercial materials, in fact, more than 1,000 times higher in some cases.” The result proved better than fluxes of the most advanced ultrathin membranes. Other findings showed remarkable flexibility, ease of use and sustainability. For example, the new membranes could be removed without adhering to the supporting substrate, they appeared homogeneous, were transparent with structural color on the surface, could be cut and bent without damage, and probably most important, did not dissolve in water — a critical role in most filtration processes. And because silk nanofibrils are negatively charged at neutral pH, more positively charged molecules can be taken up by the membranes via electrostatic interactions. “These natural silkworm membranes have remarkable separation efficiency on par with current synthetic technologies,” says Professor Kristie J. Koski of Brown University’s Department of Chemistry, who was not involved in the research. “As a non-toxic, flexible, and tunable membrane, they have great potential for purification and recycling especially in applications where synthetic alternatives are not an option such as in biological systems.” Professor Thomas Scheibel of The University of Bayreuth in Germany, who also was not associated with the study, adds: “The filter efficiency is one of the most important parameters of filter materials. This parameter is mainly influenced by the structure of the filter material. Nano silk filters are consistently filled and therefore enable the retention of quite small particles. New filter devices based thereon should allow lowering the overall energy consumption in water as well as in air filtration at constant or even higher filter efficiencies than existing ones." The team’s discovery reflects ways in which silk’s hidden secrets can advance civilization in multiple new ways.
Cold winter mornings mean that our car ice scrapers start getting regular use. Freezing temperatures and morning dew create ice covered windshields that take some elbow grease to remove. While scraping our windshields is a nuisance, a buildup of ice on an aircraft can actually be quite dangerous. Airplanes are sprayed with harsh chemicals to remove ice and, in flight, warm engine air can be rerouted to keep wings from accumulating ice. When ice accumulates on wind turbine blades, they become far less efficient. Deicing measures have to be taken regularly to allow them to generate an optimum amount of energy. Researchers at Virginia Tech have come up with a solution that would prevent ice from forming on these types of surfaces so that those harsh chemicals and labor intensive practices can be done away with. The Namib Desert Beetle is one of those organisms that manages to thrive in an extreme environment. It lives in one of the hottest places of the world, but is able to collect airborne water to survive. The Virginia Tech researchers found that a material mimicking the shell of the beetle kept moisture and ice from forming on the surface. The beetle has a bumpy shell where the tips of the bumps attract moisture to form drops and the sides are smooth and repel water. That creates channels that lead directly to the beetle’s mouth. This bumpy design made researchers realize that they could control where dew drops grew. The scientists developed a patterned surface by using photolithography to create chemical arrays that attract water over top of a surface that repels water to control the spread of ice. They believe the material can be scaled-up to large surface areas like airplane wings and wind turbine blades and also heat coils and car windshields. "We made a single dry zone around a piece of ice," says Jonathan Boreyko, assistant professor of Biomedical Engineering and Mechanics at Virginia Tech. "Dew drops preferentially grow on the array of hydrophilic dots. When the dots are spaced far enough apart and one of the drops freezes into ice, the ice is no longer able to spread frost to the neighboring drops because they are too far away. Instead, the drops actually evaporate completely, creating a dry zone around the ice." A single frozen dew drop can start the spread of ice because ice harvests water from dew drops and ice bridges begin forming, creating a chain reaction. The pattern keeps dew drops separated, which keeps this chain reaction from happening. “Fluids go from high pressure to low pressure,” Boreyko said. “Ice serves as a humidity sink because the vapor pressure of ice is lower than the vapor pressure of water. The pressure difference causes ice to grow, but designed properly with this beetle-inspired pattern, this same effect creates a dry zone rather than frost.” Because keeping surfaces dry and ice-free is energy intensive, this breakthrough could save time, money and energy in a variety of applications.
News Article | April 20, 2016
Bringing a steady supply of fresh air to the lungs can seem like a simple task, but breathing is a careful orchestration of brain and body. Diseases like Rett syndrome, central sleep apnea and congenital central hypoventilation syndrome are characterized by breathing difficulties that may be caused by dysfunction in the brain's breathing center. Now, Drexel scientists have introduced a new concept of how the brain is involved in this essential function, providing new insight into how breathing disorders could be treated in the future. The brainstem, which connects the brain with the spinal cord, generates the breathing rhythm and controls its rate, depending on the body's demands. While this process normally occurs automatically, we can also control our breathing voluntarily, such as when speaking or eating. Twenty-five years ago, a cluster of neurons within the brainstem, called the pre-Bötzinger complex (pre-BötC), was identified as the likely source of rhythmic inhalation. Following this breakthrough, researchers have spent years attempting to understand how the pre-BötC operates. "For any cyclical biologic process, you need some mechanism that generates a rhythm, and then that rhythm is translated to a motor pattern. How exactly the pre-BötC generates that rhythm has remained a mystery," said Bartholomew Bacak, Ph.D., a researcher in the School of Biomedical Engineering, Science and Health Systems, and an M.D. student in the College of Medicine. Two decades after the discovery of the pre-BötC, scientists hypothesized that two distinct systems in the brain interact to initiate breathing: a "rhythm-generating" layer composed of high- frequency neurons and a "pattern-forming" layer, which signals the diaphragm to contract and the lungs to fill with air. Using a series of computational models, Drexel researchers in the Laboratory for Theoretical and Computational Neuroscience, under the leadership of Ilya Rybak, PhD, are the first to challenge this paradigm. Their study, recently published in the journal eLife, suggests that mixed-mode oscillations in the pre-BötC -- or regular back-and-forth movements -- result from synchronizations of many neurons with different levels of excitability. Neurons with low excitability have low bursting frequencies, but generate strong activity and recruit other neurons, ultimately producing the large amplitude bursts that cause breathing. The discovery could have important implications for our understanding of the brain's control of breathing. The findings may ultimately impact how scientists research and clinicians treat respiratory disorders. Many other parts of the nervous system also contain networks of neurons with diverse excitability. A challenge for future studies is to investigate whether networks similar to those in the pre-BötC complex generate the rhythms that control other repetitive actions, such as walking and chewing.
Bioengineers at Brigham and Women’s Hospital have developed a new technique to help determine if chemotherapy is working in as few as eight hours after treatment. The new approach, which can also be used for monitoring the effectiveness of immunotherapy, has shown success in pre-clinical models. The technology utilizes a nanoparticle, carrying anti-cancer drugs, that glows green when cancer cells begin dying. Researchers, using the “reporter nanoparticles” that responds to a particular enzyme known as caspase, which is activated when cells die, were able to distinguish between a tumor that is drug-sensitive or drug-resistant much faster than conventional detection methods such as PET scans, CT and MRI. The findings were published online March 28 in the Proceedings of the National Academy of Sciences. “Using this approach, the cells light up the moment a cancer drug starts working,” co-corresponding author Shiladitya Sengupta, Ph.D., principal investigator in BWH’s Division of Bioengineering, said in a prepared statement. “We can determine if a cancer therapy is effective within hours of treatment. Our long-term goal is to find a way to monitor outcomes very early so that we don’t give a chemotherapy drug to patients who are not responding to it.” Early detection of whether or not a selected treatment is working can significantly influence the direction of treatment and improve quality of life for patients. In a pre-clinical model of prostate cancer, the team saw an approximately 400 percent increase in fluorescence in tumors that were sensitive to a common chemotherapeutic agent, paclitaxel, compared to tumors that were not sensitive to the drug. When the scientists separately tested an immunotherapy that targets PD-L 1 in a pre-clinical model of melanoma, after five days they also saw a significant increase in fluorescence in tumors that were treated with the therapy-loaded nanoparticles. “We’ve demonstrated that this technique can help us directly visualize and measure the responsiveness of tumors to both types of drugs,” co-corresponding author Ashish Kulkarni, an instructor in the Division of Biomedical Engineering at BWH, said in a statement. “Current techniques, which rely on measurements of the size or metabolic state of the tumor, are sometimes unable to detect the effectiveness of an immunotherapeutic agent as the volume of the tumor may actually increase as immune cells being to flood in to attack the tumor.” The engineered reporter nanoparticles, on the other hand, can provide an accurate measure of whether or not cancer cells are dying, Kulkarni said. The team is actively working to design radiotracers that be used in humans, but safety and efficacy tests will need to be conducted before the technology can be converted into clinical applications. Establish your company as a technology leader! For more than 50 years, the R&D 100 Awards have showcased new products of technological significance. You can join this exclusive community! Learn more.