Rapid 3-D printing in water using novel hybrid Nanoparticles ~ Could Provide Exciting opportunities in the Biomedical Arena & Additive Manufacturing


rapid3dprintHybrid nanoparticles as photoinitiators. a. Electron microscope image of hybrid nanocrystal. The inset shows a schematic of semiconductor nanorod with a metal tip. b. Bucky ball structure produced by rapid 3D printing in water using HNPs as …more

Researchers at the Hebrew University of Jerusalem’s Center for Nanoscience and Nanotechnology have developed a new type of photoinitiator for three-dimensional (3-D) printing in water. These novel nanoparticles could allow for the creation of bio-friendly 3-D printed structures, further the development of biomedical accessories and drive progress in traditional industries such as plastics.

3-D  has become an important tool for fabricating different organic based materials for a variety of industries. However, printing structures in water has always been challenging due to a lack of water soluble molecules known as photoinitiators—the molecules that induce chemical reactions necessary to form solid printed material by light.

Now, writing in Nano Letters, Prof. Uri Banin and Prof. Shlomo Magdassi at the Hebrew University’s Institute of Chemistry describe an efficient means of 3-D printing in water using semiconductor-metal hybrid nanoparticles (HNPs) as the photoinitiators.

3-D printing in water opens exciting opportunities in the biomedical arena for tailored fabrication of medical devices and for printing scaffolds for tissue engineering. For example, the researchers envision personalized fabrication of joint replacements, bone plates, heart valves, artificial tendons and ligaments, and other artificial organ replacements.

3-D printing in  also offers an environmentally friendly approach to additive manufacturing, which could replace the current technology of printing in organic based inks.

Unlike regular photoinitiators, the novel hybrid  developed by Prof. Banin and Prof. Magdassi present tunable properties, wide excitation window in the UV and visible range, high light sensitivity, and function by a unique photocatalytic mechanism that increases printing efficiency while reducing the amount of materials required to create the final product. The whole process can also be used in advanced polymerization modalities, such as two photon printers, which allows it to produce high resolution features

 Explore further: Printed 3-D structures based on cellulose nanocrystals

More information: Amol Ashok Pawar et al. Rapid Three-Dimensional Printing in Water Using Semiconductor–Metal Hybrid Nanoparticles as Photoinitiators, Nano Letters (2017). DOI: 10.1021/acs.nanolett.7b01870

 

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Converging on Cancer at the Nanoscale


MIT-KI-Marble-Center-Faculty-00_0The Marble Center for Cancer Nanomedicine’s faculty is made up of Koch Institute members who are committed to fighting cancer with nanomedicine through research, education, and collaboration. Top row (l-r) Sangeeta Bhatia, director; Daniel Anderson; and Angela Belcher. Bottom row: Paula Hammond; Darrell Irvine; and Robert Langer. Photo: Koch Institute Marble Center for Cancer Nanomedicine

 Koch Institute – July 2017

Marking its first anniversary, the Koch Institute’s Marble Center for Cancer Nanomedicine goes full steam ahead.

This summer, the Koch Institute for Integrative Cancer Research at MIT marks the first anniversary of the launch of the Marble Center for Cancer Nanomedicine, established through a generous gift from Kathy and Curt Marble ’63.

Bringing together leading Koch Institute faculty members and their teams, the Marble Center for Cancer Nanomedicine focuses on grand challenges in cancer detection, treatment, and monitoring that can benefit from the emerging biology and physics of the nanoscale.

These challenges include detecting cancer earlier than existing methods allow, harnessing the immune system to fight cancer even as it evolves, using therapeutic insights from cancer biology to design therapies for previously undruggable targets, combining existing drugs for synergistic action, and creating tools for more accurate diagnosis and better surgical intervention. cancer-shapeshiftin

Koch Institute member Sangeeta N. Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, serves as the inaugural director for the center.

”A major goal for research at the Marble Center is to leverage the collaborative culture at the Koch Institute to use nanotechnology to improve cancer diagnosis and care in patients around the world,” Bhatia says.

Transforming nanomedicine

The Marble Center joins MIT’s broader efforts at the forefront of discovery and innovation to solve the urgent global challenge that is cancer. The concept of “convergence” — the blending of the life and physical sciences with engineering — is a hallmark of MIT, the founding principle of the Koch Institute, and at the heart of the Marble Center’s mission.

“The center galvanizes the MIT cancer research community in efforts to use nanomedicine as a translational platform for cancer care,” says Tyler Jacks, director of the Koch Institute and a David H. Koch Professor of Biology. “It’s transformative by applying these emerging technologies to push the boundaries of cancer detection, treatment, and monitoring — and translational by promoting their development and application in the clinic.”

The center’s faculty — six prominent MIT professors and Koch Institute members — are committed to fighting cancer with nanomedicine through research, education, and collaboration. They are:

Sangeeta Bhatia (director), the John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science;

Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology in the Department of Chemical Engineering and the Institute for Medical Engineering and Science;

Angela M. Belcher, the James Mason Crafts Professor in the departments of Biological Engineering and Materials Science and Engineering;

Paula T. Hammond, the David H. Koch Professor of Engineering and head of the Department of Chemical Engineering;

Darrell J. Irvine, professor in the departments of Biological Engineering and Materials Science and Engineering; and

Robert S. Langer, the David H. Koch Institute Professor.

Extending their collaboration within the walls of the Institute, Marble Center members benefit greatly from the support of the Peterson (1957) Nanotechnology Materials Core Facility in the Koch Institute’s Robert A. Swanson (1969) Biotechnology Center. The Peterson Facility’s array of technological resources and expertise is unmatched in the United States, and gives members of the center, and of the Koch Institute, a distinct advantage in the development and application of nanoscale materials and technologies.

Looking ahead

Figure-1-11-Nanocarriers-for-cancer-theranostics-Nanoparticles-based-strategies-can-beThe Marble Center has wasted no time getting up to speed in its first year, and has provided support for innovative research projects including theranostic nanoparticles that can both detect and treat cancers, real-time imaging of interactions between cancer and immune cells to better understand response to cancer immunotherapies, and delivery technologies for several powerful RNA-based therapeutics able to engage specific cancer targets with precision.

As part of its efforts to help foster a multifaceted science and engineering research force, the center has provided fellowship support for trainees — as well as valuable opportunities for mentorship, scientific exchange, and professional development.

Promoting broader engagement, the Marble Center serves as a bridge to a wide network of nanomedicine resources, connecting its members to MIT.nano, other nanotechnology researchers, and clinical collaborators across Boston and beyond. The center has also convened a scientific advisory board, whose members hail from leading academic and clinical centers around the country, and will help shape the center’s future programs and continued expansion.

As the Marble Center begins another year of collaborations and innovation, there is a new milestone in sight for 2018. Nanomedicine has been selected as the central theme for the Koch Institute’s 17th Annual Cancer Research Symposium. Scheduled for June 15, 2018, the event will bring together national leaders in the field, providing an ideal forum for Marble Center members to share the discoveries and advancements made during its sophomore year.

“Having next year’s KI Annual Symposium dedicated to nanomedicine will be a wonderful way to further expose the cancer research community to the power of doing science at the nanoscale,” Bhatia says. “The interdisciplinary approach has the power to accelerate new ideas at this exciting interface of nanotechnology and medicine.”

To learn more about the people and projects of the Koch Institute Marble Center for Cancer Nanomedicine, visit nanomedicine.mit.edu.

MIT: Antibiotic Nanoparticles Fight Drug-Resistant Bacteria


MIT-Nano-Anti_0Researchers are hoping to use nanotechnology to develop more targeted treatments for drug-resistant bacteria. In this illustration, an antimicrobial peptide is packaged in a silicon nanoparticle to target bacteria in the lung. Image: Jose-Luis Olivares/MIT

Targeted treatment could be used for pneumonia and other bacterial infections.

Antibiotic resistance is a growing problem, especially among a type of bacteria that are classified as “Gram-negative.” These bacteria have two cell membranes, making it more difficult for drugs to penetrate and kill the cells.

Researchers from MIT and other institutions are hoping to use nanotechnology to develop more targeted treatments for these drug-resistant bugs. In a new study, they report that an antimicrobial peptide packaged in a silicon nanoparticle dramatically reduced the number of bacteria in the lungs of mice infected with Pseudomonas aeruginosa, a disease causing Gram-negative bacterium that can lead to pneumonia.

This approach, which could also be adapted to target other difficult-to-treat bacterial infections such as tuberculosis, is modeled on a strategy that the researchers have previously used to deliver targeted cancer drugs.

“There are a lot of similarities in the delivery challenges. In infection, as in cancer, the name of the game is selectively killing something, using a drug that has potential side effects,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

Bhatia is the senior author of the study, which appears in the journal Advanced Materials. The lead author is Ester Kwon, a research scientist at the Koch Institute. Other authors are Matthew Skalak, an MIT graduate and former Koch Institute research technician; Alessandro Bertucci, a Marie Curie Postdoctoral Fellow at the University of California at San Diego; Gary Braun, a postdoc at the Sanford Burnham Prebys Medical Discovery Institute; Francesco Ricci, an associate professor at the University of Rome Tor Vergata; Erkki Ruoslahti, a professor at the Sanford Burnham Prebys Medical Discovery Institute; and Michael Sailor, a professor at UCSD.

Synergistic peptides

As bacteria grow increasingly resistant to traditional antibiotics, one alternative that some researchers are exploring is antimicrobial peptides — naturally occurring defensive proteins that can kill many types of bacteria by disrupting cellular targets such as membranes and proteins or cellular processes such as protein synthesis.

A few years ago, Bhatia and her colleagues began investigating the possibility of delivering antimicrobial peptides in a targeted fashion using nanoparticles. They also decided to try combining an antimicrobial peptide with another peptide that would help the drug cross bacterial membranes. This concept was built on previous work suggesting that these “tandem peptides” could kill cancer cells effectively.

For the antimicrobial peptide, the researchers chose a synthetic bacterial toxin called KLAKAK. They attached this toxin to a variety of “trafficking peptides,” which interact with bacterial membranes. Of 25 tandem peptides tested, the best one turned out to be a combination of KLAKAK and a peptide called lactoferrin, which was 30 times more effective at killing Pseudomonas aeruginosa than the individual peptides were on their own. It also had minimal toxic effects on human cells.

To further minimize potential side effects, the researchers packaged the peptides into silicon nanoparticles, which prevent the peptides from being released too soon and damaging tissue while en route to their targets. For this study, the researchers delivered the particles directly into the trachea, but for human use, they plan to design a version that could be inhaled.

After the nanoparticles were delivered to mice with an aggressive bacterial infection, those mice had about one-millionth the number of bacteria in their lungs as untreated mice, and they survived longer. The researchers also found that the peptides could kill strains of drug-resistant Pseudomonas taken from patients and grown in the lab.

Adapting concepts

Infectious disease is a fairly new area of research for Bhatia’s lab, which has spent most of the past 17 years developing nanomaterials to treat cancer. A few years ago, she began working on a project funded by the Defense Advanced Research Projects Agency (DARPA) to develop targeted treatments for infections of the brain, which led to the new lung infection project.

“We’ve adapted a lot of the same concepts from our cancer work, including boosting local concentration of the cargo and then making the cargo selectively interact with the target, which is now bacteria instead of a tumor,” Bhatia says.

She is now working on incorporating another peptide that would help to target antimicrobial peptides to the correct location in the body. A related project involves using trafficking peptides to help existing antibiotics that kill Gram-positive bacteria to cross the double membrane of Gram-negative bacteria, enabling them to kill those bacteria as well.

The research was funded by the Koch Institute Support Grant from the National Cancer Institute, the National Institute of Environmental Health Sciences, and DARPA.

Anne Trafton | MIT News Office

Arizona State University ~ ‘Living Computers’ from RNA for Nanotechnology


RNA Nano 2 bd1d43755f5067d16cb5985bd7de8ea1a3a38212

Researchers from Arizona State University have demonstrated that living cells can be induced to carry out complex computations in the manner of tiny robots or computers.

It’s an example of engineers and biologists coming together to create an innovative solution to the performing of calculations. The implications are a potential game-changer for intelligent drug design and smart drug delivery. Other fields that could be affected include green energy production, low-cost diagnostic technologies and the development of futuristic nanomachines to be used in gene-editing. ASU xximage_1.png.pagespeed.ic.dPihifYIDEThe basis of the new technology is the natural interactions between nucleic acid; in this case the predictable and programmable RNA-RNA interactions. RNA is ribonucleic acid, an important molecule with long chains of nucleotides.
A nucleotide contains a nitrogenous base, a ribose sugar, and a phosphate. RNA is involved with the coding, decoding, regulation, and expression of genes. This builds on earlier work where DNA and RNA, the molecules of life, where demonstrated as being able to perform computer-like computations by Leonard Adleman (University of Southern California) in 1994 (“Molecular Computation of Solutions To Combinatorial Problems.”)
Atomic structure of the 50S Large Subunit of the Ribosome. Proteins are colored in blue and RNA in o...

Atomic structure of the 50S Large Subunit of the Ribosome. Proteins are colored in blue and RNA in orange. RNA is central to the synthesis of proteins. Wikipedia / Vossman
From this basis, lead researcher Professor Alex Green has used computer software to design RNA sequences that behave the way researchers want them to in a cell. This makes the design process a much faster.RNA Nano 3 RNAThe output is circuit designs, which look like conventional electronic circuits, but which self-assemble inside bacterial cells. This allows the cells to sense incoming messages and respond to them by producing a computational output. To test this out, the researchers worked with specialized circuits called logic gates. The tiny circuit switches were tripped when messages (RNA fragments) which attached themselves to their complementary RNA sequences in the cellular circuit. This activated the logic gate and produced an output. A series of more complex logic gates were then designed, to respond to multiple inputs. Here logic gates known as AND, OR and NOT were designed.
The video below explains more about these switches:

From this the scientists developed the first ribocomputing devices capable of four-input AND, six-input OR and a 12-input device able to carry out a complex combination of AND, OR and NOT logic known as disjunctive normal form expression.The great strength of the new method is with its ability to perform many operations at the same time. This capacity for parallel processing allows for faster and more sophisticated computation.The example, of meshing engineering and biology together, is part of an emerging field called synthetic biology, and it is one of the fastest growing areas of scientific research. In a sense, synthetic biology is a biology-based “toolkit”. According to the European research group ERBC the science deploys abstraction, standardization, and automated construction to change how we build biological systems and expand the range of possible products. One such example of what a highly accurate platform like this could do is with diagnosing viruses the Zika virus.The research has been published in the journalNature under the title “Complex cellular logic computation using ribocomputing devices.”

 

Mayo Clinic Researchers develop new tumor-shrinking nanoparticle to fight breast cancer – prevent recurrence


Cancer New Nano Particle 58e378ef3aa34Credit: CC0 Public Domain

A Mayo Clinic research team has developed a new type of cancer-fighting nanoparticle aimed at shrinking breast cancer tumors, while also preventing recurrence of the disease. In the study, published today in Nature Nanotechnology, mice that received an injection with the nanoparticle showed a 70 to 80 percent reduction in tumor size. Most significantly, mice treated with these nanoparticles showed resistance to future tumor recurrence, even when exposed to cancer cells a month later.

The results show that the newly designed nanoparticle produced potent anti- immune responses to HER2-positive breast cancers. Breast cancers with higher levels of HER2 protein are known to grow aggressively and spread more quickly than those without the mutation.

“In this proof-of-concept study, we were astounded to find that the animals treated with these nanoparticles showed a lasting anti- effect,” says Betty Y.S. Kim, M.D., Ph.D., principal investigator, and a neurosurgeon and neuroscientist who specializes in brain tumors at Mayo Clinic’s Florida campus. “Unlike existing cancer immunotherapies that target only a portion of the immune system, our custom-designed nanomaterials actively engage the entire immune system to kill cancer , prompting the body to create its own memory system to minimize tumor recurrence. These nanomedicines can be expanded to target different types of cancer and other human diseases, including neurovascular and neurodegenerative disorders.”

Dr. Kim’s team developed the nanoparticle, which she has named “Multivalent Bi-specific Nano-Bioconjugate Engager,” a patented technology with Mayo Clinic Ventures, a commercialization arm of Mayo Clinic. It’s coated with antibodies that target the HER2 receptor, a common molecule found on 40 percent of breast cancers. It’s also coated with molecules that engage two distinct facets of the body’s immune system. The nanoparticle hones in on the tumor by recognizing HER2 and then helps the identify the tumor cells to attack them.

The molecules attached to the nanoparticle rev up the body’s nonspecific, clean-up cells (known as macrophages and phagocytes) in the immune system that engulf and destroy any foreign material. The design of the nanoparticle prompts these cells to appear in abundance and clear up abnormal cancer cells. These clean-up cells then relay information about the cancer cells to highly specialized T-cells in the immune system that help eradicate remaining , while maintaining a memory of these cells to prevent cancer recurrence. It’s the establishment of disease-fighting memory in the cells that makes the nanoparticle similar to a cancer vaccine. Ultimately, the body’s own cells become capable of recognizing and destroying recurrent tumors.

Since the late 1990s, the field of nanomedicine has focused on developing as simple drug delivery vehicles that can propel chemotherapy drugs to tumors. One pitfall is that the body tends to purge the particles before they reach their destination.

“Our study represents a novel concept of designing nanomedicine that can actively interact with the immune cells in our body and modulate their functions to treat human diseases,” says Dr. Kim. “It builds on recent developments in cancer immunotherapy, which have been successful in treating some types of tumors; however, most immunotherapy developed so far does not harness the power of the entire immune system. We’ve developed a new platform that reaches and also recruits abundant clean-up cells for a fully potent immune response.”

Future studies in the lab will explore the ability of the nanoparticle to prevent long-term recurrence of tumors, including metastases at sites distant from the primary tumor. What’s more, the nanoparticle is designed to be modular, meaning it can carry molecules to fight other types of disease. “This approach hopefully will open new doors in the design of new nanomedicine-based immunotherapies,” she says.

Explore further: Nanoparticles target and kill cancer stem cells that drive tumor growth

More information: Multivalent Bi-Specific Nano-Bioconjugate Engager for Targeted Cancer Immunotherapy, Nature Nanotechnology (2017). nature.com/articles/doi:10.1038/nnano.2017.69

 

MIT: Light-emitting particles (quantum dots) open new window for biological imaging


QD Bio Image V images

‘Quantum dots’ that emit infrared light enable highly detailed images of internal body structures

For certain frequencies of short-wave infrared light, most biological tissues are nearly as transparent as glass. Now, researchers have made tiny particles that can be injected into the body, where they emit those penetrating frequencies. The advance may provide a new way of making detailed images of internal body structures such as fine networks of blood vessels.

The new findings, based on the use of light-emitting particles called quantum dots, is described in a paper in the journal Nature Biomedical Engineering, by MIT research scientist Oliver Bruns, recent graduate Thomas Bischof PhD ’15, professor of chemistry Moungi Bawendi, and 21 others.

Near-infrared imaging for research on biological tissues, with wavelengths between 700 and 900 nanometers (billionths of a meter), is widely used, but wavelengths of around 1,000 to 2,000 nanometers have the potential to provide even better results, because body tissues are more transparent to that light. “We knew that this imaging mode would be better” than existing methods, Bruns explains, “but we were lacking high-quality emitters” — that is, light-emitting materials that could produce these precise wavelengths.

QD bio Image II imagesLight-emitting particles have been a specialty of Bawendi, the Lester Wolf Professor of Chemistry, whose lab has over the years developed new ways of making quantum dots. These nanocrystals, made of semiconductor materials, emit light whose frequency can be precisely tuned by controlling the exact size and composition of the particles.

The key was to develop versions of these quantum dots whose emissions matched the desired short-wave infrared frequencies and were bright enough to then be easily detected through the surrounding skin and muscle tissues. The team succeeded in making particles that are “orders of magnitude better than previous materials, and that allow unprecedented detail in biological imaging,” Bruns says. The synthesis of these new particles was initially described in a paper by graduate student Daniel Franke and others from the Bawendi group in Nature Communications last year.

The quantum dots the team produced are so bright that their emissions can be captured with very short exposure times, he says. This makes it possible to produce not just single images but video that captures details of motion, such as the flow of blood, making it possible to distinguish between veins and arteries.

QD Bio Image IV GAAlso Read About

Graphene Quantum Dots Expand Role In Cancer Treatment And Bio-Imaging

 

 

The new light-emitting particles are also the first that are bright enough to allow imaging of internal organs in mice that are awake and moving, as opposed to previous methods that required them to be anesthetized, Bruns says. Initial applications would be for preclinical research in animals, as the compounds contain some materials that are unlikely to be approved for use in humans. The researchers are also working on developing versions that would be safer for humans.QD Bio Image III 4260773298_1497232bef

 

The method also relies on the use of a newly developed camera that is highly sensitive to this particular range of short-wave infrared light. The camera is a commercially developed product, Bruns says, but his team was the first customer for the camera’s specialized detector, made of indium-gallium-arsenide. Though this camera was developed for research purposes, these frequencies of infrared light are also used as a way of seeing through fog or smoke.

Not only can the new method determine the direction of blood flow, Bruns says, it is detailed enough to track individual blood cells within that flow. “We can track the flow in each and every capillary, at super high speed,” he says. “We can get a quantitative measure of flow, and we can do such flow measurements at very high resolution, over large areas.”

Such imaging could potentially be used, for example, to study how the blood flow pattern in a tumor changes as the tumor develops, which might lead to new ways of monitoring disease progression or responsiveness to a drug treatment. “This could give a good indication of how treatments are working that was not possible before,” he says.

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The team included members from MIT’s departments of Chemistry, Chemical Engineering, Biological Engineering, and Mechanical Engineering, as well as from Harvard Medical School, the Harvard T.H. Chan School of Public Health, Raytheon Vision Systems, and University Medical Center in Hamburg, Germany. The work was supported by the National Institutes of Health, the National Cancer Institute, the National Foundation for Cancer Research, the Warshaw Institute for Pancreatic Cancer Research, the Massachusetts General Hospital Executive Committee on Research, the Army Research Office through the Institute for Soldier Nanotechnologies at MIT, the U.S. Department of Defense, and the National Science Foundation.

Additional background

ARCHIVE: A new contrast agent for MRI http://news.mit.edu/2017/iron-oxide-nanoparticles-contrast-agent-mri-0214

ARCHIVE: A new eye on the middle ear http://news.mit.edu/2016/shortwave-infrared-instrument-ear-infection-0822

ARCHIVE: Chemists design a quantum-dot spectrometer http://news.mit.edu/2015/quantum-dot-spectrometer-smartphone-0701

ARCHIVE: Running the color gamut http://news.mit.edu/2014/startup-quantum-dot-tv-displays-1119

ARCHIVE: Fine-tuning emissions from quantum dots http://news.mit.edu/2013/fine-tuning-emissions-from-quantum-dots-0602

MIT: New ‘Rubbery Nanowire” Fibers are Stretching the boundaries of neural implants ~ Hope for Spinal Cord Injuries


MIT-Stretch-Fiber-1_0Researchers have developed a rubber-like fiber, shown here, that can flex and stretch while simultaneously delivering both optical impulses, for optoelectronic stimulation, and electrical connections, for stimulation and monitoring. Image: Chi (Alice) Lu and Seongjun Park

Rubbery, multifunctional fibers could be used to study spinal cord neurons and potentially restore function.

Implantable fibers have been an enormous boon to brain research, allowing scientists to stimulate specific targets in the brain and monitor electrical responses. But similar studies in the nerves of the spinal cord, which might ultimately lead to treatments to alleviate spinal cord injuries, have been more difficult to carry out.

That’s because the spine flexes and stretches as the body moves, and the relatively stiff, brittle fibers used today could damage the delicate spinal cord tissue.

Now, researchers have developed a rubber-like fiber that can flex and stretch while simultaneously delivering both optical impulses, for optoelectronic stimulation, and electrical connections, for stimulation and monitoring. The new fibers are described in a paper in the journal Science Advances, by MIT graduate students Chi (Alice) Lu and Seongjun Park, Professor Polina Anikeeva, and eight others at MIT, the University of Washington, and Oxford University.

“I wanted to create a multimodal interface with mechanical properties compatible with tissues, for neural stimulation and recording,” as a tool for better understanding spinal cord functions, says Lu. But it was essential for the device to be stretchable, because “the spinal cord is not only bending but also stretching during movement.” The obvious choice would be some kind of elastomer, a rubber-like compound, but most of these materials are not adaptable to the process of fiber drawing, which turns a relatively large bundle of materials into a thread that can be narrower than a hair.

The spinal cord “undergoes stretches of about 12 percent during normal movement,” says Anikeeva, who is the Class of 1942 Career Development Professor in the Department of Materials Science and Engineering. “You don’t even need to get into a ‘downward dog’ [yoga position] to have such changes.” So finding a material that can match that degree of stretchiness could potentially make a big difference to research. “The goal was to mimic the stretchiness and softness and flexibility of the spinal cord,” she says. “You can match the stretchiness with a rubber. But drawing rubber is difficult — most of them just melt,” she says.

“Eventually, we’d like to be able to use something like this to combat spinal cord injury. But first, we have to have biocompatibility and to be able to withstand the stresses in the spinal cord without causing any damage,” she says.

 

 

 

 

 

 

 

 

 

The fibers are not only stretchable but also very flexible. “They’re so floppy, you could use them to do sutures, and do light delivery at the same time,” professor Polina Anikeeva says. (Video: Chi (Alice) Lu and Seongjun Park)

The team combined a newly developed transparent elastomer, which could act as a waveguide for optical signals, and a coating formed of a mesh of silver nanowires, producing a conductive layer for the electrical signals. To process the transparent elastomer, the material was embedded in a polymer cladding that enabled it to be drawn into a fiber that proved to be highly stretchable as well as flexible, Lu says. The cladding is dissolved away after the drawing process.

After the entire fabrication process, what’s left is the transparent fiber with electrically conductive, stretchy nanowire coatings. “It’s really just a piece of rubber, but conductive,” Anikeeva says. The fiber can stretch by at least 20 to 30 percent without affecting its properties, she says.

The fibers are not only stretchable but also very flexible. “They’re so floppy, you could use them to do sutures and deliver light  at the same time,” she says.

“We’re the first to develop something that enables simultaneous electrical recording and optical stimulation in the spinal cords of freely moving mice,” Lu says. “So we hope our work opens up new avenues for neuroscience research.” Scientists doing research on spinal cord injuries or disease usually must use larger animals in their studies, because the larger nerve fibers can withstand the more rigid wires used for stimulus and recording. While mice are generally much easier to study and available in many genetically modified strains, there was previously no technology that allowed them to be used for this type of research, she says.

“There are many different types of cells in the spinal cord, and we don’t know how the different types respond to recovery, or lack of recovery, after an injury,” she says. These new fibers, the researchers hope, could help to fill in some of those blanks.

The team included Alexander Derry, Chong Hou, Siyuan Rao, Jeewoo Kang, and professor Yoel Fink at MIT; Tom Richner and professor Chet Mortiz at the University of Washington; and Imogen Brown at Oxford University. The research was supported by the National Science Foundation, the National Institute of Neurological Disorders and Stroke, the U.S. Army Research Laboratory, and the U.S. Army Research Office through the Institute for Soldier Nanotechnologies at MIT.

Triple-threat cancer-fighting polymer capsules for guided drug delivery


drug delivery cancer 170330142230_1_540x360These micro-carriers may offer an entirely different approach to treating solid human tumors of numerous pathologic subtypes by delivering their encapsulated drug cargo to a tumor and protecting against collateral tissue damage.

Chemists at the University of Alabama at Birmingham have designed triple-threat cancer-fighting polymer capsules that bring the promise of guided drug delivery closer to preclinical testing.

These multilayer capsules show three traits that have been difficult to achieve in a single entity. They have good imaging contrast that allows detection with low-power ultrasound, they can stably and efficiently encapsulate the cancer drug doxorubicin, and both a low- and higher-power dose of ultrasound can trigger the release of that cargo.

These three features create a guided drug delivery system to target solid tumors. Therapeutic efficacy can be further improved through surface modifications to boost targeting capabilities. Diagnostic low-power ultrasound then could visualize the nanocapsules as they concentrated in a tumor, and therapeutic higher-dose ultrasound would release the drug at ground zero, sparing the rest of the body from dose-limiting toxicity.

This precise control of when and where doxorubicin or other cancer drugs are released could offer a noninvasive alternative to cancer surgery or systemic chemotherapy, the UAB researchers report in the journal ACS Nano, which has an impact factor of 13.3.

“We envision an entirely different approach to treating solid human tumors of numerous pathologic subtypes, including common metastatic malignancies such as breast, melanoma, colon, prostate and lung, utilizing these capsules as a delivery platform,” said Eugenia Kharlampieva, Ph.D., an associate professor in the Department of Chemistry, UAB College of Arts and Sciences. “These capsules can protect encapsulated therapeutics from degradation or clearance prior to reaching the target and have ultrasound contrast as a means of visualizing the drug release. They can release their encapsulated drug cargo in specific locations via externally applied ultrasound exposure.”

Kharlampieva — who creates her novel “smart” particles while working at the intersection of polymer chemistry, nanotechnology and biomedical science — says there is an urgent, and so far unmet, need for such an easily fabricated, guided drug delivery system.

The UAB researchers, led by Kharlampieva and co-first authors Jun Chen and Sithira Ratnayaka, use alternating layers of biocompatible tannic acid and poly(N-vinylpyrrolidone), or TA/PVPON, to build their microcarriers. The layers are formed around a sacrificial core of solid silica or porous calcium carbonate that is dissolved after the layers are complete.

By varying the number of layers, the molecular weight of PVPON or the ratio of shell thickness to capsule diameter, the researchers were able to alter the physical traits of the capsules and their sensitivity to diagnostic ultrasound, at power levels below the FDA maximum for clinical imaging and diagnosis.

For example, one-fourth of empty microcapsules made with four layers of TA/low-molecular weight PVPON were ruptured by three minutes of ultrasound, while capsules made of 15 layers of TA/low-molecular weight PVPON or capsules made from four layers of TA/high-molecular weight PVPON showed no rupture. The ruptured capsules had a lower mechanical rigidity that made them more sensitive to ultrasound pressure changes. Experiments showed that the ratio of the thickness of the capsule wall to the diameter of the capsule is a key variable for sensitivity to rupture.

To test the ultrasound imaging contrast of the microcapsules, the UAB researchers made capsules that were 5 micrometers wide, or about two times wider than the capsules used in the rupture experiments. This size is small enough to still pass through capillaries in the lung, while a larger size for various microparticles is known to greatly improve ultrasound contrast. Red blood cells, for a size comparison, have a diameter of about 6 to 8 micrometers.

Researchers found that 5-micrometer-wide, empty capsules that were made with eight layers of TA/low-molecular weight PVPON showed an ultrasound contrast comparable to the commercially available microsphere contrast agent Definity. When the UAB capsules — which have a shell thickness of about 50 nanometers — were loaded with doxorubicin, the ultrasound imaging contrast increased two- to eightfold compared to empty capsules, depending on the mode of ultrasound imaging used. These doxorubicin-loaded capsules were highly stable, with no change in ultrasound imaging contrast after six months of storage. Exposure to serum, known to deposit proteins on various microparticles, did not extinguish the ultrasound imaging contrast of the TA/PVPON microcapsules.

A therapeutic dose of ultrasound was able to rupture 50 percent of the 5-micrometer, doxorubicin-loaded microcapsules, releasing enough doxorubicin to induce 97 percent cytotoxicity in human breast adenocarcinoma cells in culture. Adenocarcinoma cells that were incubated with intact doxorubicin-loaded microcapsules remained viable.

Phenformin Nano Cancer Delivery id39449Thus, Kharlampieva says, these TA/PVPON capsules have strong potential as “theranostic” agents for efficient cancer therapy in conjunction with ultrasound. The term theranostic refers to nanoparticles or microcapsules that can double as diagnostic imaging agents and as therapeutic drug-delivery carriers.

The next important preclinical step, Kharlampieva says, in collaboration with Mark Bolding, Ph.D., assistant professor in the UAB Department of Radiology, and Jason Warram, Ph.D., assistant professor in the UAB Department of Otolaryngology, will be studies in animal models to explore how long the UAB capsules persist in blood circulation and where they distribute in the body.


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Materials provided by University of Alabama at Birmingham. Note: Content may be edited for style and length.


Journal Reference:

  1. Jun Chen, Sithira Ratnayaka, Aaron Alford, Veronika Kozlovskaya, Fei Liu, Bing Xue, Kenneth Hoyt, Eugenia Kharlampieva. Theranostic Multilayer Capsules for Ultrasound Imaging and Guided Drug Delivery. ACS Nano, 2017; 11 (3): 3135 DOI: 10.1021/acsnano.7b00151

Laser activated gold pyramids could deliver drugs, DNA into cells without harm


Harvard DNA Delivery 170323150417_1_540x360

Summary: The ability to deliver cargo like drugs or DNA into cells is essential for biological research and disease therapy but cell membranes are very good at defending their territory. Researchers have developed various methods to trick or force open the cell membrane but these methods are limited in the type of cargo they can deliver and aren’t particularly efficient. Harvard School of Engineering and Applied Sciences 

The ability to deliver cargo like drugs or DNA into cells is essential for biological research and disease therapy but cell membranes are very good at defending their territory. Researchers have developed various methods to trick or force open the cell membrane but these methods are limited in the type of cargo they can deliver and aren’t particularly efficient.

Now, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a new method using gold microstructures to deliver a variety of molecules into cells with high efficiency and no lasting damage. The research is published in ACS Nano.

“Being able to effectively deliver large and diverse cargos directly into cells will transform biomedical research,” said Nabiha Saklayen, a PhD candidate in the Mazur Lab at SEAS and first author of the paper. “However, no current single delivery system can do all the things you need to do at once. Intracellular delivery systems need to be highly efficient, scalable, and cost effective while at the same time able to carry diverse cargo and deliver it to specific cells on a surface without damage. It’s a really big challenge.”

In previous research, Saklayen and her collaborators demonstrated that gold, pyramid-shaped microstructures are very good at focusing laser energy into electromagnetic hotspots. In this research, the team used a fabrication method called template stripping to make surfaces — about the size of a quarter — with 10 million of these tiny pyramids.

“The beautiful thing about this fabrication process is how simple it is,” said Marinna Madrid, coauthor of the paper and PhD candidate in the Mazur Lab. “Template-stripping allows you to reuse silicon templates indefinitely. It takes less than a minute to make each substrate, and each substrate comes out perfectly uniform. That doesn’t happen very often in nanofabrication.”

Harvard DNA Delivery 170323150417_1_540x360
A scanning-electron microscope image of chemically-fixed HeLa cancer cells on the substrate. The tips of the pyramids create tiny holes in the cell membranes, allowing molecular cargo to diffuse into the cells. Credit: Harvard SEAS

The team cultured HeLa cancer cells directly on top of the pyramids and surrounded the cells with a solution containing molecular cargo.

Using nanosecond laser pulses, the team heated the pyramids until the hotspots at the tips reached a temperature of about 300 degrees Celsius. This very localized heating — which did not affect the cells — caused bubbles to form right at the tip of each pyramid. These bubbles gently pushed their way into the cell membrane, opening brief pores in the cell and allowing the surrounding molecules to diffuse into the cell.

“We found that if we made these pores very quickly, the cells would heal themselves and we could keep them alive, healthy and dividing for many days,” Saklayen said.

Each HeLa cancer cell sat atop about 50 pyramids, meaning the researchers could make about 50 tiny pores in each cell. The team could control the size of the bubbles by controlling the laser parameters and could control which side of the cell to penetrate.

The molecules delivered into the cell were about the same size as clinically relevant cargos, including proteins and antibodies.

Next, the team plans on testing the methods on different cell types, including blood cells, stem cells and T cells. Clinically, this method could be used in ex vivo therapies, where unhealthy cells are taken out of the body, given cargo like drugs or DNA, and reintroduced into the body.

“This work is really exciting because there are so many different parameters we could optimize to allow this method to work across many different cell types and cargos,” said Saklayen. “It’s a very versatile platform.”

Harvard’s Office of Technology Development has filed patent applications and is considering commercialization opportunities.

“It’s great to see how the tools of physics can greatly advance other fields, especially when it may enable new therapies for previously difficult to treat diseases,” said Eric Mazur, the Balkanski Professor of Physics and Applied Physics and senior author of the paper.

This research was supported by the National Science Foundation and the Howard Hughes Medical Institute. It was coauthored by Marinus Huber, Marinna Madrid, Valeria Nuzzo, Daryl Inna Vulis, Weilu Shen, Jeffery Nelson, Arthur McClelland and Alexander Heisterkamp.


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Journal Reference:

  1. Nabiha Saklayen, Marinus Huber, Marinna Madrid, Valeria Nuzzo, Daryl I. Vulis, Weilu Shen, Jeffery Nelson, Arthur A. McClelland, Alexander Heisterkamp, Eric Mazur. Intracellular Delivery Using Nanosecond-Laser Excitation of Large-Area Plasmonic Substrates. ACS Nano, 2017; DOI: 10.1021/acsnano.6b08162

Drug combination delivered by nanoparticles may help in melanoma treatment


Melenoma 170314140859_1_540x360Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery; director of the Penn State Melanoma and Skin Cancer Center and member of Penn State Cancer Institute, works with associates in the Melanoma Center.
Credit: Penn State College of Medicine

Summary: The first of a new class of medication that delivers a combination of drugs by nanoparticle may keep melanoma from becoming resistant to treatment, according to Penn State College of Medicine researchers.

CelePlum-777 combines a special ratio of the drugs Celecoxib, an anti-inflammatory, and Plumbagin, a toxin. By combining the drugs, the cells have difficulty overcoming the effect of having more than one active ingredient.

Celecoxib and Plumbagin work together to kill melanoma cells when used in a specific ratio. Researchers used microscopic particles called nanoparticles to deliver the drugs directly to the cancer cells. These particles are several hundred times smaller than the width of a hair and can be loaded with medications.

“Loading multiple drugs into nanoparticles is one innovative approach to deliver multiple cancer drugs to a particular site where they need to act and have them released at that optimal cancer cell killing ratio,” said Raghavendra Gowda, assistant professor of pharmacology, who is the lead author on the study. “Another advantage is that by combining the drugs, lower concentrations of each that are more effective and less toxic can be used.”

Celecoxib and Plumbagin cannot be taken by mouth because the drugs do not enter the body well this way and cannot be used together in the ratio needed because of toxicity.

CelePlum-777 can be injected intravenously without toxicity. Because of its small size, it also accumulates inside the tumors where it then releases the drugs to kill the cancer cells. Researchers report their results in the journals Molecular Cancer Therapeutics and Cancer Letters.

“This drug is the first of a new class, loaded with multiple agents to more effectively kill melanoma cells, that has potential to reduce the possibility of resistance development,” said senior author Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery; director of the Penn State Melanoma and Skin Cancer Center and member of Penn State Cancer Institute. “There is no drug like it in the clinic today and it is likely that the next breakthrough in melanoma treatment will come from a drug like this one.”

The researchers showed the results of CelePlum-777 on killing cancer cells growing in culture dishes and in tumors growing in mice following intravenous injection. The drug prevented tumor development in mice with no detectable side effects and also prevented proteins from enabling uncontrolled cancer cell growth.

More research is required by the Food and Drug Administration before CelePlum-777 can be tested in humans through clinical trials. Penn State has patented this discovery and licensed it to Cipher Pharmaceuticals, which will perform the next series of FDA-required tests.


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