Light and nanotechnology prevent bacterial infections on medical implants – Reducing Costs and Recurring Surgeries


Image of the surgical implants, covered with gold nanoparticles (pile of meshes on the left) compared to the original surgical meshes previous to the treatment (pile of meshes on the right). Credit: ICFO

Invented approximately 50 years ago, surgical medical meshes have become key elements in the recovery procedures of damaged-tissue surgeries, the most common being hernia repair.

When implanted within the tissue of the patient, the flexible and conformable design of these meshes hold muscles securely and allows quicker recovery than conventional surgical procedures of sewing and stitching.

However, the insertion of a medical implant in a patient’s body carries the risk of bacterial contamination during surgery and subsequent formation of an infectious biofilm over the surface of the surgical .

Such biofilms tend to act like a plastic coating, preventing any sort of antibiotic agent from reaching and attacking the formed on the film in order to stop the infection. Thus, antibiotic therapies, which are time-limited, could fail against super-resistant bacteria and the patient could end up in recurring or never-ending surgeries that could even lead to death.

In fact, according to the European Antimicrobial Resistance Surveillance Network (EARS-Net), in 2015, more than 30,000 deaths in Europe were linked to infections with antibiotic-resistant bacteria.

Physicians have used several approaches to prevent implant contamination during surgery. Post-surgery aseptic protocols have been established and implemented to fight these antibiotic-resistant bacteria, but none have entirely fulfilled the role of solving this issue.

SEM micrographs of the S. aureus biofilm formed on the surgical mesh surface. Credit: ICFO

In a recent study published in Nano Letters and highlighted in Nature Photonics, ICFO researchers Dr. Ignacio de Miguel, Arantxa Albornoz, led by ICREA Prof. at ICFO Romain Quidant, in collaboration with researchers Irene Prieto, Dr. Vanesa Sanz, Dr. Christine Weis and Dr. Pau Turon from the B. Braun and pharmaceutical device company, have devised a novel technique that uses nanotechnology and photonics to dramatically improve the performance of medical meshes for surgical implants.

In collaboration since 2012, the team of researchers at ICFO and B. Braun Surgical, S.A., developed a medical mesh with a particular feature: The surface of the mesh was chemically modified to anchor millions of gold nanoparticles.

Why? Because gold nanoparticles have been proven to convert light into heat highly efficiently at localized regions.

The technique of using gold nanoparticles in light-heat conversion processes had already been tested in cancer treatments in previous studies.

Knowing that more than 20 million hernia repair operations take place every year around the world, the researchers believed this method could reduce the medical costs in recurrent operations while eliminating the expensive and ineffective antibiotic treatments that are currently being employed to tackle this problem.

Schematic view of plasmon-enabled biofilm prevention on surgical meshes. Credit: ICFO

Thus, in their in-vitro experiment and through a thorough process, the team coated the surgical mesh with millions of , uniformly spreading them over the entire structure. They tested the meshes to ensure the long-term stability of the particles, the non-degradation of the material, and the non-detachment or release of nanoparticles into the surrounding environment (flask). They were able to observe a homogenous distribution of the nanoparticles over the structure using a scanning electron microscope.

Once the modified mesh was ready, the team exposed it to S. aureus bacteria for 24 hours until they observed the formation of a biofilm on the surface. Subsequently, they began exposing the mesh to short, intense pulses of near  (800 nm) over 30 seconds to ensure  was reached, before repeating this treatment 20 times with four seconds of rest intervals between each pulse.

They discovered the following: First, they saw that illuminating the mesh at the specific frequency would induce localized surface plasmon resonances in the nanoparticles—a mode that results in the efficient conversion of light into heat, burning the bacteria at the surface.

Second, by using a fluorescence confocal microscope, they observed how much of the bacteria had died or was still alive. They observed that the remaining living biofilm bacteria became planktonic cells, recovering their sensitivity or weakness toward antibiotic therapy and to immune system response. They observed that upon increasing the amount of light delivered to the surface of the mesh, the dead bacteria would lose their adherence and peel off the surface. 

Third, they confirmed that operating at near infrared light ranges was completely compatible with in-vivo settings, meaning that such a technique would most probably not damage the surrounding healthy tissue. Finally, they repeated the treatment and confirmed that the recurrent heating of the mesh had not affected its conversion efficiency capabilities.

ICREA Prof at ICFO Romain Quidant says, “The results of this study have paved the way towards using plasmon nanotechnologies to prevent the formation of bacterial biofilm at the surface of surgical implants. There are still several issues that need to be addressed but it is important to emphasize that such a technique will indeed signify a radical change in operation procedures and further patient post recovery.”

Director of Research and Development of B. Braun Surgical, S.A. Dr. Pau Turon, says, “Our commitment to help healthcare professionals to avoid hospital related infections pushes us to develop new strategies to fight bacteria and biofilms. Additionally, the research team is exploring to extend such technology to other sectors where biofilms must be avoided.”

More information: Ignacio de Miguel et al, Plasmon-Based Biofilm Inhibition on Surgical Implants, Nano Letters(2019).  DOI: 10.1021/acs.nanolett.9b00187

Journal information: Nano Letters , Nature Photonics

Provided by ICFO

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Scientists Use Near-Infrared Light and Injected DNA Nanodevice to Guide Stem Cells to a Wound – Accelerating the Healing Process


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Researchers can guide stem cells (like those in the illustration above) to an injury by using near-infrared light and an injected DNA nanodevice. (Image credit: Juan Gaertner/Shutterstock.com)

Imagine physicians having a remote control that they could employ to drive a patient’s own cells to a wound to accelerate the healing process.

Such a device is still away from reality, however, scientists have described in the ACS journal Nano Letters of having taken a key initial step: They employed near-infrared light and an injected DNA nanodevice to direct stem cells to a wound, which helped in the regrowth of muscle tissue in mice.

Complex signaling pathways synchronize cellular activities like proliferation, movement, and even death. For instance, when signaling molecules attach to proteins known as receptor tyrosine kinases on a cell’s surface, they stimulate the receptors to pair up and phosphorylate each other. This process can trigger other proteins that eventually result in a cell moving or growing.

Hong-Hui Wang, Zhou Nie, and partners doubted if they could set up a nanodevice to cells that would rewire this system, activating the receptors by near-infrared light rather than signaling molecules. The scientists opted for near-infrared as it can penetrate living tissues, in contrast to visible or ultraviolet light. The group aimed a receptor tyrosine kinase known as MET, which is important for wound healing.

The scientists developed a DNA molecule that can attach to two MET receptors at the same time, binding them together and stimulating them. In order to make the system responsive to light, the researchers linked multiple copies of the DNA sequence to gold nanorods. On irradiating near-infrared light, the nanorods get heated up and release the DNA so that it could trigger the receptors.

The scientists introduced the DNA-bound gold nanorods into mice at the injured area and illuminated a near-infrared light on the mice for a few minutes. After three days, more muscle stem cells had moved to the wound in treated mice when compared to those in untreated mice. The treated mice also exhibited improved signs of muscle regeneration in comparison to control mice.

The researchers acknowledge funding from the National Natural Science Foundation of China, National Science and Technology Major Project, the Young Top-Notch Talent for Ten Thousand Talent Program, the Keypoint Research and Invention Program of Hunan Province, and the National Institutes of Health.

 

 

Researchers at CUNY create guidelines for morphable nanomaterials to diagnose, target and effectively treat Life-Threatening Illness such as Cancer, Cardiovascular and Autoimmune diseases


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Peptides spontaneously form spherical or worm-like nanostructures that can be morphed or broken down by enzymes overexpressed in cancer cells. By controlling the shape and charge of the nanostructures, scientists can predict the rate of …more

Scientists have long sought to develop drug therapies that can more precisely diagnose, target and effectively treat life-threatening illness such as cancer, cardiovascular and autoimmune diseases.

One promising approach is the design of morphable nanomaterials that can circulate through the body and provide diagnostic information or release precisely targeted drugs in response to disease-marker enzymes. Thanks to a newly published paper from researchers at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York, Brooklyn College, and Hunter College, scientists now have design guidance that could rapidly advance development of such nanomaterials.

In the paper, which appears online in the journal ACS Nano, researchers detail broadly applicable findings from their work to characterize a  that can predictably, specifically and safely respond when it senses overexpression of the enzyme matrix metalloproteinase-9 (MMP-9). MMP-9 helps the body breakdown unneeded extracellular materials, but when levels are too high, it plays a role in the development of cancer and several other diseases.

“Right now, there are no clear rules on how to optimize the nanomaterials to be responsive to MMP-9 in predictable ways,” said Jiye Son, the study’s lead author and a Graduate Center Ph.D. student working in one of the ASRC Nanoscience Initiative labs. “Our work outlines an approach using short peptides to create enzyme-responsive nanostructures that can be customized to take on specific therapeutic actions, like only targeting  and turning on drug release in close proximity of these cells.”

Researchers designed a modular peptide that spontaneously assembles into nanostructures, and predictably and reliably morphs or breaks down into  when they come in contact with the MMP-9 enzyme. The designed components include a charged segment of the nanostructure to facilitate its sensing and engagement with the enzyme; a cleavable segment of the structure so that it can lock onto the enzyme and determine how to respond; and a hydrophobic segment of the structure to facilitate self-assembly of the therapeutic response.

“This work is a critical step toward creating new smart-drug delivery vehicles and diagnostic methods with precisely tunable properties that could change the face of disease treatment and management,” said ASRC Nanoscience Initiative Director Rein Ulijn, whose lab is leading the work. “While we specifically focused on creating nanomaterials that could sense and respond to MMP-9, the components of our design guidance can facilitate development of nanomaterials that sense and respond to other cellular stimuli.”

Among other advances, the research team’s work builds on their previous findings, which showed that amino acid peptides can encapsulate and transform into fibrous drug depots upon interaction with MMP-9. The group is collaborating with scientists at Memorial Sloan Kettering and Brooklyn College to use their findings to create a novel cancer therapy.

 Explore further: Scientists create nanomaterials that reconfigure in response to biochemical signals

More information: Jiye Son et al, Customizing Morphology, Size, and Response Kinetics of Matrix Metalloproteinase-Responsive Nanostructures by Systematic Peptide Design, ACS Nano (2019). DOI: 10.1021/acsnano.8b07401

 

Nanomachines ‘Learn’ to Fight Cancer – ITMO University


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A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself. Credit: Vossman/ Wikipedia

Scientists from ITMO in collaboration with international colleagues have proposed new DNA-based nanomachines that can be used for gene therapy for cancer. This new invention can greatly contribute to more effective and selective treatment of oncological diseases. The results were published in Angewandte Chemie.

Gene therapy is considered one of the promising ways of treating oncological diseases, even though the current approaches are far from perfect. Oftentimes, the agents fail to discern malignant  from healthy ones, and are bad at interacting with folded RNA targets.

In order to solve this issue, scientists, including a Russian team from ITMO University headed by professor Dmitry Kolpashchikov, proposed special nanomachines. They sought to develop particular molecules, deoxyribozymes, which can interact with targeted RNA, bind them, unfold and cleave. According to the idea, these nanomachines have to recognize DNA oncomarkers and form complexes that can break down messenger RNA of vital  with high selectivity, which will then result in apoptotic death of malignant cells.

The researchers tested the efficiency of the new machines in a model experiment and learned that they can cleave folded RNA molecules better than the original deoxyribozymes. They showed that the design of the nanomachine makes it possible to break down targeted RNA in the presence of a DNA oncomarker only, and the use of RNA-unfolding arms provides for better efficiency. The scientists also learned that the nanomachine can inhibit the growth of , though cellular experiments didn’t show high specificity. The researchers associate this result with a possibly poor choice of the RNA target and a low stability of DNA structures in the cell.

The new approach differs fundamentally from the ones used before. The existing  agents are aimed at suppressing the expression of oncological markers. In the research in question, the scientists focused on the messenger RNA of vital genes, and the oncological marker was used as an activator. This makes it possible to apply the DNA nanomachine in treating any kind of cancer by using new DNA oncomarkers for activating the breakdown of targeted molecules.

The  opens new ways of treating oncological diseases. Still, there are many experiments to be conducted before it can be applied in therapy.

“For now, we are trying to introduce new functional elements in the framework that will contribute to a more effective recognition of oncological markers, and are also optimizing the DNA nanomachine for various RNA targets. In order to improve the efficiency and selectiveness of our constructions in cellular conditions, we are selecting new RNA targets and studying the stability of DNA machines in cells, which we plan to improve with the help of already existing chemical modifications,” comments Daria Nedorezova, Master’s student at ITMO University.

 Explore further: A new nanomachine shows potential for light-selective gene therapy

More information: Dmitry M Kolpashchikov et al, Towards DNA Nanomachines for Cancer Treatment: Achieving Selective and Efficient Cleavage of Folded RNA, Angewandte Chemie (2019). DOI: 10.1002/ange.201900829

 

Ultra ultrasound to revolutionize Technology – From Medical Devices to Unmanned Vehicles


ultraultraso    Credit: University of Queensland

A new and extremely sensitive method of measuring ultrasound could revolutionise everything from medical devices to unmanned vehicles.

Researchers at The University of Queensland have combined modern nanofabrication and nanophotonics techniques to build the ultraprecise  sensors on a silicon chip.

Professor Warwick Bowen, from UQ’s Precision Sensing Initiative and the Australian Centre for Engineered Quantum Systems, said the development could usher in a host of exciting new technologies.

“This is a major step forward, since accurate ultrasound measurement is critical for a range of applications,” he said.

“Ultrasound is used for medical ultrasound, often to examine , as well as for  biomedical imaging to detect tumours and other anomalies.

“It’s also commonly used for spatial applications, like in the sonar imaging of underwater objects or in the navigation of unmanned aerial vehicles.

“Improving these applications requires smaller, higher precision sensors and, with this new technique, that’s exactly what we’ve been able to develop.”

The technology is so sensitive that it can hear, for the first time, the miniscule random forces from surrounding air molecules.

“We’ve developed a near perfect ultrasound detector, hitting the limits of what the technology is capable of achieving,” Professor Bowen said.

“We’re now able to measure ultrasound waves that apply tiny forces – comparable to the gravitational force on a virus – and we can do this with sensors smaller than a millimetre across.”

Research leader Dr. Sahar Basiri-Esfahani, now at Swansea University, said the accuracy of the  could change how scientists understand biology.

“We’ll soon have the ability to listen to the sound emitted by living bacteria and cells,” she said.

“This could fundamentally improve our understanding of how these small biological systems function.

“A deeper understanding of these biological systems may lead to new treatments, so we’re looking forward to seeing what future applications emerge.”

The research is published in Nature Communications.

 Explore further: Miniaturised pipe organ could aid medical imaging

More information: Sahar Basiri-Esfahani et al. Precision ultrasound sensing on a chip, Nature Communications (2019). DOI: 10.1038/s41467-018-08038-4

 

Washington State U – Bio-inspired nanoscale Research – Nano-Flowers may lead lead to more effective drug delivery and diagnostics for cancer and other illnesses


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Schematic representation of the movement of the flower-like particle as it makes its way through a cellular trap to deliver therapeutic genes.
Credit: WSU

Washington State University researchers have developed a novel way to deliver drugs and therapies into cells at the nanoscale without causing toxic effects that have stymied other such efforts.

The work could someday lead to more effective therapies and diagnostics for cancer and other illnesses.

Led by Yuehe Lin, professor in WSU’s School of Mechanical and Materials Engineering, and Chunlong Chen, senior scientist at the Department of Energy’s Pacific Northwest National Laboratory (PNNL), the research team developed biologically inspired materials at the nanoscale that were able to effectively deliver model therapeutic genes into tumor cells. They published their results in the journal, Small.

Researchers have been working to develop nanomaterials that can effectively carry therapeutic genes directly into the cells for the treatment of diseases such as cancer. The key issues for gene delivery using nanomaterials are their low delivery efficiency of medicine and potential toxicity.

“To develop nanotechnology for medical purposes, the first thing to consider is toxicity — That is the first concern for doctors,” said Lin.

The flower-like particle the WSU and PNNL team developed is about 150 nanometers in size, or about one thousand times smaller than the width of a piece of paper. It is made of sheets of peptoids, which are similar to natural peptides that make up proteins. The peptoids make for a good drug delivery particle because they’re fairly easy to synthesize and, because they’re similar to natural biological materials, work well in biological systems.

The researchers added fluorescent probes in their peptoid nanoflowers, so they could trace them as they made their way through cells, and they added the element fluorine, which helped the nanoflowers more easily escape from tricky cellular traps that often impede drug delivery.

The flower-like particles loaded with therapeutic genes were able to make their way smoothly out of the predicted cellular trap, enter the heart of the cell, and release their drug there.

“The nanoflowers successfully and rapidly escaped (the cell trap) and exhibited minimal cytotoxicity,” said Lin.

After their initial testing with model drug molecules, the researchers hope to conduct further studies using real medicines.

“This paves a new way for us to develop nanocargoes that can efficiently deliver drug molecules into the cell and offers new opportunities for targeted gene therapies,” he said.

The WSU and PNNL team have filed a patent application for the new technology, and they are seeking industrial partners for further development.

Story Source:

Materials provided by Washington State UniversityNote: Content may be edited for style and length.


Journal Reference:

  1. Yang Song, Mingming Wang, Suiqiong Li, Haibao Jin, Xiaoli Cai, Dan Du, He Li, Chun-Long Chen, Yuehe Lin. Efficient Cytosolic Delivery Using Crystalline Nanoflowers Assembled from Fluorinated PeptoidsSmall, 2018; 14 (52): 1803544 DOI: 10.1002/smll.201803544

MIT: Wearable Medical Tech Key to Our Future Health – Provides more Targeted, Cheaper, Personalized Treatment with Fewer Negative Side Effects


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Wearables are already replacing traditional drugs and therapies – this year, they’ll go further still

Medical treatment today primarily takes the form of drugs and therapy. But a third option is slowly emerging: on-body, digital devices that can treat both mental and physical conditions. Such “wearable” therapy offers unique advantages in that it is often more targeted, cheaper, personalised and has fewer negative side effects.

Mobile and wearable devices such as phones or fitness trackers are now routinely used for preventive health. They monitor physiological data and behaviour, increase self-awareness and encourage behaviour change. They are also starting to be used by medical professionals to diagnose and monitor diseases. So far, the use of these devices for intervention and treatment has been limited to apps that issue reminders to exercise, guide us through meditation, or provide support for cognitive behavioural therapy. In 2019 this technology will expand into the world of mainstream therapeutic intervention.

2018-08-14-wearable-technologyRead More About: “Your Weekly Check-Up: The Future of Wearable and Implantable Medical Technology

Therapy by means of digital devices is so far mostly limited to information on a screen, but so much more is possible. Early experiments in both academia and industry labs point at the potential for wearable devices that don’t just collect data about our bodies – they also stimulate them through our various senses to improve our body and mind. Vibrational, temperature-based, olfactory and electrical stimulation all offer significant, largely unexplored opportunities for solving both physical and mental health issues.

I am not talking about direct brain stimulation (TMS and tDCS), which for a while now has garnered excitement among professionals as well as fearless, self-experimenting amateurs. The promise of those approaches mostly remains to be proven through rigorous, controlled studies. Instead, a relatively new approach consists of using devices that stimulate a part of the body or peripheral nervous system to solve a specific problem. These devices have the potential to be more precise, safer and easier to use than brain stimulation.

One great example is the Emma device developed by researcher Haiyan Zhang at Microsoft. This simple wristband uses a noisy vibration signal to stimulate the hand of a Parkinson’s patient who has a tremor. The result is life-changing in that the patient is once again able to perform tasks such as drawing or writing that require precise motor movements. Caitlyn Seim, a PhD student at Georgia Tech, has had similar success improving arm function after a stroke using a computerised glove that provides vibro-tactile stimulation. Her solution is not just cheaper than physical therapy, but also mobile, and requires less effort.

At the MIT Media Lab, post-doctoral associate Nataliya Kosmyna has designed a device called AttentivU that, in real time, measures a person’s attention to external stimuli using EEG and provides haptic feedback when attention is low to nudge the person to pay attention again. Her experiments show that subjects are more attentive and perform better on comprehension tasks.

The system is currently being integrated in the form of simple eye glasses to make the device socially acceptable and easy to put on or take off. In comparison with the drug-based solutions currently adopted by many of the ten per cent of schoolchildren diagnosed with ADD/ADHD, this wearable form of therapy has fewer side effects, and can be used when the moment requires.

Other researchers, such as Jean Costa at Cornell, have demonstrated how false feedback of heart rate can be used to help a person regulate their emotions. And BrightBeat, software developed by MIT Media Lab PhD student Asma Ghandeharioun, can slow a person’s breathing rate by embedding a barely noticeable rhythmic pattern in the music they listen to. In the commercial realm, a new product called Livia promises to alleviate menstrual cramps with a small, simple device that attaches to the skin of the lower abdomen and provides electric nerve stimulation to produce pain relief.

While we are already dependent on our mobile technologies for our everyday tasks and goals, we will soon also rely on digital technologies for optimal functioning of our bodies. In the true sense of the concept of cybernetics, technology is becoming a part of us, integral to our daily lives and regulating some functions on our behalf. wearable med tech 1 images

This makes a lot of sense: as our devices are with us 24/7, they not only have the potential to know us better than even our closest friend or family member, but they are able to support us in the moment, intervening when a situation calls for it. In addition, they can be highly personalised and can potentially adapt and optimise their functionality based on observed user data and machine learning. While we need to be careful to make sure these designs safeguard privacy, give complete control to the user and avoid dependency whenever possible, there are countless possibilities for digital, wearable technologies to supplement and even replace traditional drugs and therapy.

Pattie Maes is professor of media technology at MIT Media Lab

Update Rice University – Researchers develop a method to make atom-flat sensors that seamlessly integrate with devices – technique will make active sensors or devices possible for telecommunication and bio-sensing, plasmonics


Rice U Flat Atom structure DuEfkhxWwAAfEGTRice University engineers have developed a method to transfer complete, flexible, two-dimensional circuits from their fabrication platforms to curved and other smooth surfaces. Such circuits are able to couple with near-field …more

What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.

Rice engineers led by  scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices to report on what they perceive.

Electronically active 2-D materials have been the subject of much research since the introduction of graphene in 2004. Even though they are often touted for their strength, they’re difficult to move to where they’re needed without destroying them.Nano Sensor 1 FANG

The Ajayan and Lou groups, along with the lab of Rice engineer Jacob Robinson, have a new way to keep the materials and their associated circuitry, including electrodes, intact as they’re moved to curved or other smooth surfaces.

The results of their work appear in the American Chemical Society journal ACS Nano.

Rice logo_rice3The Rice team tested the concept by making a 10-nanometer-thick indium selenide photodetector with gold electrodes and placing it onto an . Because it was so close, the near-field sensor effectively coupled with an evanescent field—the oscillating electromagnetic wave that rides the surface of the fiber—and accurately detected the flow of information inside.

The benefit is that these sensors can now be imbedded into such fibers where they can monitor performance without adding weight or hindering the signal flow.

“This paper proposes several interesting possibilities for applying 2-D devices in real applications,” Lou said. “For example, optical fibers at the bottom of the ocean are thousands of miles long, and if there’s a problem, it’s hard to know where it occurred. If you have these sensors at different locations, you can sense the damage to the fiber.”

Lou said labs have gotten good at transferring the growing roster of 2-D materials from one surface to another, but the addition of electrodes and other components complicates the process. “Think about a transistor,” he said. “It has source, drain and gate electrodes and a dielectric (insulator) on top, and all of these have to be transferred intact. That’s a very big challenge, because all of those materials are different.”

Raw 2-D materials are often moved with a layer of polymethyl methacrylate (PMMA), more commonly known as Plexiglas, on top, and the Rice researchers make use of that technique. But they needed a robust bottom layer that would not only keep the circuit intact during the move but could also be removed before attaching the device to its target. (The PMMA is also removed when the circuit reaches its destination.)

The ideal solution was poly-dimethyl-glutarimide (PMGI), which can be used as a device fabrication platform and easily etched away before transfer to the target. “We’ve spent quite some time to develop this sacrificial layer,” Lou said. PMGI appears to work for any 2-D material, as the researchers experimented successfully with molybdenum diselenide and other materials as well.

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The Rice labs have only developed passive sensors so far, but the researchers believe their technique will make active  or devices possible for telecommunication, biosensing, plasmonics and other applications.

 Explore further: Fluorine flows in, makes material metal

More information: Zehua Jin et al, Near-Field Coupled Integrable Two-Dimensional InSe Photosensor on Optical Fiber, ACS Nano (2018). DOI: 10.1021/acsnano.8b07159

 

MIT – Measuring cancer cell “fitness” reveals drug susceptibility and the potential to treat non-responsive cancer cells


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MIT engineers have designed a system that can repeatedly measure cancer cells as they flow through an array of mass sensors. Once the cells reach the end, they are collected for RNA-sequencing. Image courtesy of the researchers.

Courtesy of MIT News

Together, cell growth rate and gene expression shed light on why some tumor cells survive treatment.

 

By studying both the physical and genomic features of cancer cells, MIT researchers have come up with a new way to investigate why some cancer cells survive drug treatment while others succumb.

Their new approach, which combines measurements of cell mass and growth rate with analysis of a cell’s gene expression, could be used to reveal new drug targets that would make cancer treatment more effective. Exploiting these targets could help knock out the defenses that cells use to overcome the original drug treatment, the researchers say.

In a paper appearing in the Nov. 28 issue of the journal Genome Biology, the researchers identified a growth signaling pathway that is active in glioblastoma cells that are resistant to an experimental type of drug known as an MDM2 inhibitor.

“By measuring a cell’s mass and growth rate immediately prior to single-cell RNA-sequencing, we can now use a cell’s ‘fitness’ to classify it as responsive or nonresponsive to a drug, and to relate this to underlying molecular pathways,” says Alex K. Shalek, the Pfizer-Laubach Career Development Assistant Professor of Chemistry, a member of MIT’s Institute for Medical Engineering and Science (IMES), an extramural member of the Koch Institute for Integrative Cancer Research, and an associate member of the Ragon and Broad Institutes.

Shalek and Scott Manalis, the Andrew and Erna Viterbi Professor in the MIT departments of Biological Engineering and Mechanical Engineering and a member of the Koch Institute, are the senior authors of the study. The paper’s lead author is Robert Kimmerling, a recent MIT PhD recipient.

Cancer cell analysis

About a decade ago, Manalis’ lab invented a technology that allows researchers to measure the mass of single cells. In recent years, they have adapted the device, which measures cells’ masses as they flow through tiny channels, so that it can also measure cell growth rates by repeatedly weighing the cells over short periods of time.

Last year, working with researchers at Dana-Farber Cancer Institute (DFCI), Manalis and his colleagues used this approach to test drug responses of tumor cells from patients with multiple myeloma, a type of blood cancer. After treating the cells with three different drugs, the researchers measured the cells’ growth rates and found they were correlated with the cells’ susceptibility to the treatment.

“Single-cell biophysical properties such as mass and growth rate provide early indicators of drug response, thereby offering the potential to delineate sensitive cells from resistant cells while they are still viable,” Manalis says.

In their new study, the researchers wanted to add a genomic component, which they hoped could help reveal why only certain cells are susceptible to a particular drug. “We wanted to be able to take those measurements and add on some of the biological context for why a cell is growing a certain way or behaving a certain way,” Kimmerling says.

To accomplish this, Kimmerling and Manalis teamed up with Shalek, who has extensive experience in sequencing the messenger RNA (mRNA) of individual cells. This information can provide a snapshot of which genes are being expressed in a single cell at a particular moment.

The researchers modified the cell-weighing system so that cells would be spaced evenly as they flowed through, making it easier to collect them one at a time when they exit the system. The cells are weighed several times over the course of 20 minutes to determine growth rate, and as soon as they reach the end of the channel, they are immediately captured and ruptured to release their RNA for analysis. Shalek’s lab then sequenced the RNA of each of the cells. This approach enabled the mass and growth rate of each cell to be directly linked to its gene expression.

Once they had the system working, the researchers collaborated with Keith Ligon and his lab at DFCI to analyze cancer cells derived from a patient with glioblastoma, an aggressive type of brain cancer. The researchers treated the cells with an MDM2 inhibitor, a type of drug that helps to boost the function of p53, a protein that helps cells stop tumor formation. Such drugs are now in clinical trials to treat glioblastoma. In animal studies, this drug has been effective against tumors, but the tumors often grow back later.

In this study, the researchers hoped to find out why some glioblastoma cells survive MDM2 treatment. They treated the cells, measured their growth rates about 16 hours after the treatment, and then sequenced their RNA. “Before the cells have lost viability, we can measure their mass and their growth rate to reveal drug response heterogeneity to that treatment, and then link that with their gene expression,” Kimmerling says.

Importantly, the researchers found subpopulations of cells that were not responsive to the drug. RNA sequencing revealed that in cells that were responsive, genes required for programmed cell death were turned on. Meanwhile, in cells that did not seem to be vulnerable to the drug, genes involved in mTOR, a signaling pathway involved in growth and survival, were turned up.

“What we’re excited about here is we now have this list of biological targets to look into,” Kimmerling says. “We can start to generate testable hypotheses from these gene expression signatures that are more highly expressed in the cells that continue to grow after drug treatment.”

Possible drug targets

The researchers now plan to explore the possibility of targeting some of the genes that were turned up on the non-responding cells, in hopes of developing drugs that could be used together with the original MDM2 inhibitor. They also hope to adapt this approach for other types of cancers. Some, such as blood cancers, are easier to study than solid tumors, which are more difficult to separate into single cells.

“The hope is that we’ll be able to apply this technology to any sample that can be dissociated into a single-cell population,” Kimmerling says.

Another possible application of the cell-growth measurement technology is studying tumor cells from individual patients to try to predict how they will respond to a particular drug. Kimmerling, Manalis, and others have founded a company called Travera, which has licensed the technology and hopes to develop it for patient use. The company is currently not working on the RNA sequencing aspect of the technology, but that element could also be valuable to incorporate in the future, Kimmerling says.

The research was funded by the Cancer Systems Biology Consortium U54 Research Center and the Cancer Center Support (core) Grant from the National Cancer Institute; the Searle Scholars Program; the Beckman Young Investigator Program; the National Institutes of Health, including an NIH New Innovator Award; the Pew-Stewart Scholars; and a Sloan Fellowship in Chemistry.

Healing Kidneys with Nanotechnology – ASU Researchers Explore a new horizon for DNA Nanotechnology


healingkidne (1)The illustration shows a diseased kidney on the left and a healthy kidney on the right, after rectangular DNA nanostructures migrated and accumulated in the kidney, acting to alleviate damage due to oxidative stress. Credit: Shireen Dooling

Each year, there are some 13.3 million new cases of acute kidney injury (AKI), a serious affliction. Formerly known as acute renal failure, the ailment produces a rapid buildup of nitrogenous wastes and decreases urine output, usually within hours or days of disease onset. Severe complications often ensue.

AKI is responsible for 1.7 million deaths annually. Protecting healthy kidneys from harm and treating those already injured remains a significant challenge for modern medicine.

In new research appearing in the journal Nature Biomedical Engineering, Hao Yan and his colleagues at the University of Wisconsin-Madison and in China describe a new method for treating and preventing AKI. Their technique involves the use of tiny, self-assembling forms measuring just billionths of a meter in diameter.

The triangular, tubular and rectangular shapes are designed and built using a method known as DNA origami. Here, the base pairing properties of DNA’s four nucleotides are used to engineer and fabricate DNA origami nanostructures (DONs), which self-assemble and preferentially accumulate in kidneys.

“The interdisciplinary collaboration between nanomedicine and the in-vivo imaging team led by professor Weibo Cai at the University of Wisconsin-Madison and the DNA nanotechnology team has led to a novel application—applying DNA origami nanostructures to treat ,” Yan says. “This represents a new horizon for DNA nanotechnology research.”

Experiments described in the new study—conducted in mice as well as human embryonic kidney cells—suggest that DONs act as a rapid and active kidney protectant and may also alleviate symptoms of AKI. The distribution of DONs was examined with positron emission tomography (PET). Results showed that the rectangular nanostructures were particularly successful, protecting the kidneys from harm as effectively as the leading drug therapy and alleviating a leading source of AKI known as .

The study is the first to explore the distribution of DNA nanostructures in a living system by means of quantitative imaging with PET and paves the way for a host of new therapeutic approaches for the treatment of AKI as well as other renal diseases.

“This is an excellent example of team science, with multidisciplinary and multinational collaboration,” Cai said. “The four research groups are located in different countries, but they communicate regularly and have synergistic expertise. The three equally-contributing first authors (Dawei Jiang, Zhilei Ge, Hyung-Jun Im) also have very different backgrounds, one in radiolabeling and imaging, one in DNA nanostructures, and the other in clinical nuclear medicine. Together, they drove the project forward.”

Vital organ

Kidneys perform essential roles in body, removing waste and extra water from the blood to form urine. Urine then flows from the kidneys to the bladder through the ureters. Wastes in the blood are produced from the normal breakdown of active muscle and from foods, which the body requires for energy and self-repair.

Acute kidney injury can range considerably in severity. In advanced AKI, kidney transplantation is required as well as supportive therapies including rehydration and dialysis. Contrast-induced AKI, a common form of the illness, is caused by contrast agents sometimes used to improve the clarity of medical imaging. An anti-oxidant drug known as N-acetylcysteine (NAC) is used clinically to protect the kidneys from toxic assault during such procedures, but poor bioavailability of the drug in the kidneys can limit its effectiveness. (Currently, there is no known cure for AKI.)

Nanomedicinethe engineering of atoms or molecules at the nanoscale for biomedical applications—represents a new and exciting avenue of medical exploration and therapy. Recent research in the field has driven advances leading to improved imaging and therapeutics for a range of diseases, including AKI, though the use of nanomaterials within living systems in order to treat  has thus far been limited.

Healing kidneys with nanotechnology
Hao Yan directs the Biodesign Center for Molecular Design and Biomimetics and is the Martin D. Glick Distinguished Professor in the School of Molecular Sciences at ASU. Credit: The Biodesign Institute at Arizona State University

The base-pairing properties of nucleic acids like DNA and RNA enable the design of tiny programmable structures of predictable shape and size, capable of performing a multitude of tasks. Further, these nanoarchitectures are desirable for use in living systems due to their stability, low toxicity, and low immunogenicity.

New designs

The current study marks the first investigation of DNA origami nanostructures within living organisms, using quantitative imaging to track their behavior. The PET imaging used in the study allowed for a quantitative and reliable real-time method to study the circulation of DONs in a living organism and to assess their physiological distribution. Rectangular DONs were identified as the most effective therapeutic to treat AKI in mice, based on the PET analysis.

Yan and his colleagues prepared a series of DONs and used radio labeling to study their behavior in mouse kidney, using PET imaging. The PET scans showed that the DONs had preferentially accumulated in the kidneys of healthy mice as well as those with induced AKI. Of the three shapes used in the experiments, the rectangular DONs provided the greatest benefit in terms of protection and therapy and were comparable in their effect to the drug NAC, considered the gold standard treatment for AKI.

Patients with kidney disease often have accompanying maladies, including a high incidence of cardiovascular disease and malignancy. Acute kidney illness may be induced through the process of oxidative stress, which results from an increase in oxygen-containing waste products known as , that cause damage to lipids, proteins and DNA. This can occur when the delicate balance of free radicals and anti-oxidant defenses becomes destabilized, causing inflammation and accelerating the progression of renal disease. (Foods and supplements rich in antioxidants act to protect cells from the harmful effects of reactive oxygen species.)

Safeguarding kidneys with DNA geometry

The protective and therapeutic effects of the DONs described in the new study are due to the ability of the nanostructures to scavenge reactive oxygen species, thereby insulating vulnerable cells from damage due to oxidative stress. This effect was studied in human embryonic kidney cell lines as well as in living mice. The accumulation of the nanostructures in both healthy and diseased kidneys provided an increased therapeutic effect compared with traditional AKI therapy. (DONs alleviated oxidative stress within 2 hours of incubation with affected kidney cells.)

Improvement in AKI kidney function—comparable with high-dose administration of the drug NAC— was observed following the introduction of nanostructures. Examination of stained tissue samples further confirmed the beneficial effects of the DONs in the kidney.

The authors propose several mechanisms to account for the persistence in the kidneys of properly folded origami nanostructures, including their resistance to digestive enzymes, avoidance of immune surveillance and low protein absorption.

Levels of serum creatinine and blood urea nitrogen (BUN) were used to assess renal function in mice. AKI mice treated with rectangular DONs displayed improved kidney excretory function comparable to mice receiving treatment using the mainline drug NAC.

Further, the team established the safety of rectangular DONs, evaluating their potential to elicit an immune response in mice by examining blood levels of interleukin-6 and tumor necrosis factor alpha. Results showed the DONs were non-immunogenetic and tissue staining of heart, liver, spleen lungs and kidney revealed their low toxicity in primary organs, making them attractive candidates for clinical use in humans.

Based on the effective scavenging of reactive oxygen species by DONs in both human kidney cell culture and living mouse , the study concludes that the approach may indeed provide localized protection for kidneys from AKI and may even offer effective treatment for AKI-damaged kidneys or other renal disorders.

The successful proof-of-concept study expands the potential for a new breed of therapeutic programmable nanostructures, engineered to address far-flung medical challenges, from smart drug delivery to precisely targeted organ and tissue repair.

 Explore further: YAP after acute kidney injury

More information: Dawei Jiang et al, DNA origami nanostructures can exhibit preferential renal uptake and alleviate acute kidney injury, Nature Biomedical Engineering (2018). DOI: 10.1038/s41551-018-0317-8