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Posts Tagged ‘3D printing’


Development of 3D Human Tissue Models Awarded NIH Grants Worth $15M

Reporter: Irina Robu, PhD

NIH has awarded $15 million for Tissue Chip for Disease Modeling and Efficacy Testing to develop 3D human tissue models. The 3D platforms, also called tissue chips support living cells and human tissues, it mimics the complex biological functions of organs/tissues and at the same time provide a new way to test potential drugs and their effectiveness. The awards will allow scientists to study and understand diseases mechanism and forecast how patients respond and is part of the first phase of a five-year program.  According to NCATS Director, Dr. Christopher P. Austin “these tissue chips to provide more accurate platforms to understand diseases, and to be more predictive of the human response to drugs than current research models, thereby improving the success rate of candidate drugs in human clinical trials”.

The awards will be used to study common and rare diseases including rheumatoid arthritis, influenza A, kidney disease, amyotrophic lateral sclerosis, or ALS, arrhythmogenic cardiomyopathy, and hemorrhagic telangiectasia. Award recipients are Brigham and Women’s Hospital, Cedars-Sinai Medical Center, Columbia University, Duke University, Harvard University, Northwestern University, University of California Davis, University of California Irvine, University of Pittsburgh, University of Rochester, University of Washington Seattle and Vanderbilt University.

SOURCE

https://www.mdtmag.com/news/2017/09/nih-grants-15m-development-3d-human-tissue-models

 

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3-D Printing in Water using Novel Hybrid Nanoparticles

Reporter: Irina Robu, PhD

3D printing has become an essential tool for fabricating different organic based materials, but printing structures in water has been thought-provoking due to lack of water soluble molecules known as photo initiators. The photo initiator can induce chemical reactions needed to form solid printed material by light.  However, researchers at the Hebrew University of Jerusalem’s Center for Nanoscience and Nanotechnology have developed a new type of photo initiator for three-dimensional printing in water. This innovative nanoparticle allows the creating of bio-friendly 3D structures.

By 3D printing in water, it also opens up the digital light processing method to medical applications, leading toward a competitive response for patient specific implants and tissues because the photo initiators cause rapid solidification of a liquid material that can create faster reactions when exposed to light. 3D printing in water opens up innovative ways for tailored fabrication of medical devices and for printing hydrogels or bio-scaffolds that are typical used in tissue engineering.

The challenge of 3D printing in water is finding an initiator that is not consumed by irradiation. However, unlike regular photo initiators, the novel hybrid nanoparticles developed by Prof. Magdassi present tunable properties, wide excitation window in the UV and visible range, high light sensitivity, and their ability to split water, and absorb oxygen molecules that typically inhibit the performance of the process. The particles added as photo initiator are semi conductive hybrid nanoparticles and are used to create high resolution 3D objects at sub-microscopic scale.

Therefore, 3-D printing in water could allow personalized fabrication of joint replacements, heart valves, artificial tendons and ligaments etc.

SOURCE

  1. https://phys-org.cdn.ampproject.org/c/s/phys.org/news/2017-08-rapid-d-hybrid-nanoparticles.amp
  2. Amol Ashok Pawar et al. Rapid Three-Dimensional Printing in Water Using Semiconductor–Metal Hybrid Nanoparticles as Photoinitiators, Nano Letters (2017)

 

 

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3D Printing Technique with Non-Contact Ultrasonic Manipulation Technology

Reporter: Irina Robu, PhD

The 3D printer we think more frequently in combination with PCBs is the DragonFly 2020 from Nano Dimension which works with different with all kinds of materials in addition to PCBs as they are a great 3D printing player in electronic space.

The Ultrasound Research group at Neurotechnology (http://www.neurotechnology.com) has proclaimed a new 3D printing method using ultrasonic manipulation which are totally hands off and non-contact tech behind it, permitting for the handling of parts and particles down to submillimeter range without causing damage to sensitive components. According to the project lead for Neurotechnology Ultrasound Research Group, Dr. Osvaldas Putkis, “Ultrasonic manipulation can handle a very large range of different materials, including metals, plastics and even liquids. Not only can it manipulate material particles, it can also handle components of various shapes. Other non-contact methods, like the ones based on magnetic or electrostatic forces, can’t offer such versatility”.

Since the work from the Ultrasound Research Group embodies a new technological application, Neurotechnology has filed a patent on their system. Neurotechnology describes ultrasonic manipulation as a “non-contact material handling method which uses ultrasonic waves to trap and move small particles and components.”  It is well known that ultrasonic manipulation of particles exploits the acoustic radiation force to deliver a contactless handling method for particles suspended in a fluid. In an ultrasonic standing wave field, the viscous torque induces the rotation of an object. Alongside the translation of particles due to the acoustic radiation force an additional controlled degree of rotation is obtainable. Consequently, there is a growing interest in spreading the field of application of ultrasonic particle manipulation to the deposition of micro and nanowires and for the assembly of micro objects.

Ultrasonic transducers are arranged in an array used to position electronic components in the creation of a PCB, utilizing a camera to detect accurate positioning. Continuing on with the hands-off theme, a laser solders the PCB components after their non-contact manipulation into placement. 3D printing and PCB manufacture are increasingly coming together, as advanced technologies benefit the creation of devices in electronics, including via 3D printed workstations for PCBs.

Even though their method works with all types of materials, we expect to see further applications beyond PCB assembly.

Source

https://3dprint.com/179097/neurotechnology-ultrasonic-3dp/

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GE’s large scale 3D cookbook

Curator: Larry H. Bernstein, MD, FCAP

 

 

Major Laser: These Scientists Are Writing the 3D-Printing Cookbook for GE

Additive manufacturing engineer Brian Adkins in full gear is preparing a DMLM machine for printing. (Photo credit: GE Reports/Chris New)

It would be a stretch to say that Joe Vinciquerra is the Julia Child of GE. But Vinciquerra, the manager of the newly formed Additive Materials Lab at GE Global Research, is creating a cookbook that will likely impact manufacturing across GE the same way “Mastering the Art of French Cooking” shook up American kitchens.

Additive manufacturing, commonly known as 3D printing, is exploding right now. GE estimates that by 2025, more than 20 percent of new products will involve additive processes of some kind. But there’s no cookbook that standardizes the recipes, which have oodles of parameters that determine the properties of the final part.

“It’s like baking a cake. You need to start with the right recipe, then you need to have the right ingredients and the right oven,” Vinciquerra says. “A cup of materials science, a tablespoon of design and a whole lot of machine-control strategies must come together and yield perfection.”

Technologies like direct metal laser melting (DMLM), for example, can involve several lasers as powerful as 1 kilowatt—enough to burn a hole in a wall—fusing as many as 1,250 layers of fine superalloy powder into the desired shape. Some large builds can take days to finish.

support block with 3D printed parts inside a DMLM printed in Pittsburgh. (Photo credit: GE Reports/Chris New)

Last week, GE opened a new industrial-scale 3D-printing center in Pittsburgh, Pennsylvania. It will work closely with Vinciquerra’s team, test their findings and get GE factories quickly cooking with additive.

His team has already started testing and tabling the powdered materials used in additive manufacturing and their properties. “We want to know how they come together, how they affect each other and what machines and processes are best suited for them,” Vinciquerra says. “It’s just like a gourmet recipe. We need to know how our ingredients are going to react in a mixer or an oven. And what changes can we make to those ingredients, the mixer or the oven to produce a more palatable dish?”

The team is pulling in expertise from other labs on the GE Global Research campus in Niskayuna, New York, including scientists focusing on nanomaterials, microstructures and machine design. The company calls the cross-pollination of know-how the GE Store.

inciquerra (right) and Andy Deal, a metallurgist in the Additive Materials Lab are loading sets of sample 3D printed metal parts in a vacuum oven for post-processing at GE Global Research. (Photo credit: GE Global Research.)      http://www.pharmpro.com/sites/pharmpro.com/files/styles/content_body_image/public/embedded_image/2016/04/Major%20Laser_GE%20Reports_3.jpg?itok=GSQMNM4L

 

GE materials scientists are no strangers to new materials. They spent two decades developing light- and heat-resistant materials called ceramic matrix composites that outperform even the most advanced superalloys and make jet engines and gas turbines lighter and more efficient. But additive materials live in a different universe. “With additive, you can design as you go and create architectures that cannot be manufactured by any other means,” Vinciquerra says.

He says that GE engineers can already design components with sophisticated, performance-enhancing features previously unattainable by any other means of manufacturing. The next-generation LEAP jet engine—developed by CFM International, a joint venture between GE Aviation and France’s Snecma (Safran)—uses 3D-printed fuel nozzles, which are 25 percent lighter and five times more durable. They used to be made from 18 separate parts and now they come in one piece. A year ago, the Federal Aviation Administration (FAA) approved a fist-sized housing for a sensor as the first 3D-printed part to fly inside GE commercial jet engines.

“This is just the beginning,” Vinciquerra says. “Someday, we may even be able to combine materials together in ways previously not possible to unlock new capabilities that never existed. Can I create a new class of materials that open the design envelope and push the limits of durability and heat resistance beyond what we thought was even possible? We’re going to find out.”

To read the original story, published on GE Reports, click here

 

 

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3D revolution and tissue repair

Curator: Larry H. Bernstein, MD, FCAP

 

 

Berkeley Lab captures first high-res 3D images of DNA segments

DNA segments are targeted to be building blocks for molecular computer memory and electronic devices, nanoscale drug-delivery systems, and as markers for biological research and imaging disease-relevant proteins

In a Berkeley Lab-led study, flexible double-helix DNA segments (purple, with green DNA models) connected to gold nanoparticles (yellow) are revealed from the 3D density maps reconstructed from individual samples using a Berkeley Lab-developed technique called individual-particle electron tomography (IPET). Projections of the structures are shown in the green background grid. (credit: Berkeley Lab)

An international research team working at the Lawrence Berkeley National Laboratory (Berkeley Lab) has captured the first high-resolution 3D images of double-helix DNA segments attached at either end to gold nanoparticles — which could act as building blocks for molecular computer memory and electronic devices (see World’s smallest electronic diode made from single DNA molecule), nanoscale drug-delivery systems, and as markers for biological research and for imaging disease-relevant proteins.

The researchers connected coiled DNA strands between polygon-shaped gold nanoparticles and then reconstructed 3D images, using a cutting-edge electron microscope technique coupled with a protein-staining process and sophisticated software that provided structural details at the scale of about 2 nanometers.

“We had no idea about what the double-strand DNA would look like between the gold nanoparticles,” said Gang “Gary” Ren, a Berkeley Lab scientist who led the research. “This is the first time for directly visualizing an individual double-strand DNA segment in 3D,” he said.

The results were published in an open-access paper in the March 30 edition of Nature Communications.

The method developed by this team, called individual-particle electron tomography (IPET), had earlier captured the 3-D structure of a single protein that plays a key role in human cholesterol metabolism. By grabbing 2D images of an object from different angles, the technique allows researchers to assemble a 3D image of that object.

The team has also used the technique to uncover the fluctuation of another well-known flexible protein, human immunoglobulin 1, which plays a role in the human immune system.

https://youtu.be/lQrbmg9ry90
Berkeley Lab | 3-D Reconstructions of Double strand DNA and Gold Nanoparticle Structures

For this new study of DNA nanostructures, Ren used an electron-beam study technique called cryo-electron microscopy (cryo-EM) to examine frozen DNA-nanogold samples, and used IPET to reconstruct 3-D images from samples stained with heavy metal salts. The team also used molecular simulation tools to test the natural shape variations (“conformations”) in the samples, and compared these simulated shapes with observations.

First visualization of DNA strand dynamics without distorting x-ray crystallography

Ren explained that the naturally flexible dynamics of samples, like a man waving his arms, cannot be fully detailed by any method that uses an average of many observations.

A popular way to view the nanoscale structural details of delicate biological samples is to form them into crystals and zap them with X-rays, but that destroys their natural shape, especially fir the DNA-nanogold samples in this study, which the scientists say are incredibly challenging to crystallize. Other common research techniques may require a collection of thousands of near-identical objects, viewed with an electron microscope, to compile a single, averaged 3-D structure. But an averaged 3D image may not adequately show the natural shape fluctuations of a given object.

The samples in the latest experiment were formed from individual polygon gold nanostructures, measuring about 5 nanometers across, connected to single DNA-segment strands with 84 base pairs. Base pairs are basic chemical building blocks that give DNA its structure. Each individual DNA segment and gold nanoparticle naturally zipped together with a partner to form the double-stranded DNA segment with a gold particle at either end.

https://youtu.be/RDOpgj62PLU
Berkeley Lab | These views compare the various shape fluctuations obtained from different samples of the same type of double-helix DNA segment (DNA renderings in green, 3D reconstructions in purple) connected to gold nanoparticles (yellow).

The samples were flash-frozen to preserve their structure for study with cryo-EM imaging. The distance between the two gold nanoparticles in individual samples varied from 20 to 30 nanometers, based on different shapes observed in the DNA segments.

Researchers used a cryo-electron microscope at Berkeley Lab’s Molecular Foundry for this study. They collected a series of tilted images of the stained objects, and reconstructed 14 electron-density maps that detailed the structure of individual samples using the IPET technique.

Sub-nanometer images next

Ren said that the next step will be to work to improve the resolution to the sub-nanometer scale.

“Even in this current state we begin to see 3-D structures at 1- to 2-nanometer resolution,” he said. “Through better instrumentation and improved computational algorithms, it would be promising to push the resolution to that visualizing a single DNA helix within an individual protein.”

In future studies, researchers could attempt to improve the imaging resolution for complex structures that incorporate more DNA segments as a sort of “DNA origami,” Ren said. Researchers hope to build and better characterize nanoscale molecular devices using DNA segments that can, for example, store and deliver drugs to targeted areas in the body.

“DNA is easy to program, synthesize and replicate, so it can be used as a special material to quickly self-assemble into nanostructures and to guide the operation of molecular-scale devices,” he said. “Our current study is just a proof of concept for imaging these kinds of molecular devices’ structures.”

The team included researchers at UC Berkeley, the Kavli Energy NanoSciences Institute at Berkeley Lab and UC Berkeley, and Xi’an Jiaotong University in China. This work was supported by the National Science Foundation, DOE Office of Basic Energy Sciences, National Institutes of Health, the National Natural Science Foundation of China, Xi’an Jiaotong University in China, and the Ministry of Science and Technology in China. View more about Gary Ren’s research group here.


Abstract of Three-dimensional structural dynamics and fluctuations of DNA-nanogold conjugates by individual-particle electron tomography

DNA base pairing has been used for many years to direct the arrangement of inorganic nanocrystals into small groupings and arrays with tailored optical and electrical properties. The control of DNA-mediated assembly depends crucially on a better understanding of three-dimensional structure of DNA-nanocrystal-hybridized building blocks. Existing techniques do not allow for structural determination of these flexible and heterogeneous samples. Here we report cryo-electron microscopy and negative-staining electron tomography approaches to image, and three-dimensionally reconstruct a single DNA-nanogold conjugate, an 84-bp double-stranded DNA with two 5-nm nanogold particles for potential substrates in plasmon-coupling experiments. By individual-particle electron tomography reconstruction, we obtain 14 density maps at ~2-nm resolution. Using these maps as constraints, we derive 14 conformations of dsDNA by molecular dynamics simulations. The conformational variation is consistent with that from liquid solution, suggesting that individual-particle electron tomography could be an expected approach to study DNA-assembling and flexible protein structure and dynamics.

 

World’s smallest electronic diode made from single DNA molecule

Electronic components 1,000 times smaller than with silicon may be possible
http://www.kurzweilai.net/worlds-smallest-electronic-diode-made-from-single-dna-molecule
By inserting a small “coralyne” molecule into DNA, scientists were able to create a single-molecule diode (connected here by two gold electrodes), which can be used as an active element in future nanoscale circuits. The diode circuit symbol is shown on the left. (credit: University of Georgia and Ben-Gurion University)

Nanoscale electronic components can be made from single DNA molecules, as researchers at the University of Georgia and at Ben-Gurion University in Israel have demonstrated, using a single molecule of DNA to create the world’s smallest diode.

DNA double helix with base pairs (credit: National Human Genome Research Institute)

A diode is a component vital to electronic devices that allows current to flow in one direction but prevents its flow in the other direction. The development could help stimulate development of DNA components for molecular electronics.

As noted in an open-access Nature Chemistry paper published this week, the researchers designed a 11-base-pair (bp) DNA molecule and inserted a small molecule named coralyne into the DNA.*

They found, surprisingly, that this caused the current flowing through the DNA to be 15 times stronger for negative voltages than for positive voltages, a necessary feature of a diode.

Electronic elements 1,00o times smaller than current components

“Our discovery can lead to progress in the design and construction of nanoscale electronic elements that are at least 1,000 times smaller than current components,” says the study’s lead author, Bingqian Xu an associate professor in the UGA College of Engineering and an adjunct professor in chemistry and physics.

The research team plans to enhance the performance of the molecular diode and construct additional molecular devices, which may include a transistor (similar to a two-layer diode, but with one additional layer).

A theoretical model developed by Yanantan Dubi of Ben-Gurion University indicated the diode-like behavior of DNA originates from the bias voltage-induced breaking of spatial symmetry inside the DNA molecule after the coralyne is inserted.

The research is supported by the National Science Foundation.

*“We prepared the DNA–coralyne complex by specifically intercalating two coralyne molecules into a custom-designed 11-base-pair (bp) DNA molecule (5′-CGCGAAACGCG-3′) containing three mismatched A–A base pairs at the centre,” according to the authors.

UPDATE April 6, 2016 to clarify the coralyne intercalation (insertion) into the DNA molecule.


Abstract of Molecular rectifier composed of DNA with high rectification ratio enabled by intercalation

The predictability, diversity and programmability of DNA make it a leading candidate for the design of functional electronic devices that use single molecules, yet its electron transport properties have not been fully elucidated. This is primarily because of a poor understanding of how the structure of DNA determines its electron transport. Here, we demonstrate a DNA-based molecular rectifier constructed by site-specific intercalation of small molecules (coralyne) into a custom-designed 11-base-pair DNA duplex. Measured current–voltage curves of the DNA–coralyne molecular junction show unexpectedly large rectification with a rectification ratio of about 15 at 1.1 V, a counter-intuitive finding considering the seemingly symmetrical molecular structure of the junction. A non-equilibrium Green’s function-based model—parameterized by density functional theory calculations—revealed that the coralyne-induced spatial asymmetry in the electron state distribution caused the observed rectification. This inherent asymmetry leads to changes in the coupling of the molecular HOMO−1 level to the electrodes when an external voltage is applied, resulting in an asymmetric change in transmission.

 

A stem-cell repair system that can regenerate any kind of human tissue …including disease and aging; human trials next year
http://www.kurzweilai.net/a-stem-cell-repair-system-that-can-regenerate-any-kind-of-human-tissue

http://www.kurzweilai.net/images/spinal_disc_regeneration.jpg

UNSW researchers say the therapy has enormous potential for treating spinal disc injury and joint and muscle degeneration and could also speed up recovery following complex surgeries where bones and joints need to integrate with the body (credit: UNSW TV)

A stem cell therapy system capable of regenerating any human tissue damaged by injury, disease, or aging could be available within a few years, say University of New South Wales (UNSW Australia) researchers.

Their new repair system*, similar to the method used by salamanders to regenerate limbs, could be used to repair everything from spinal discs to bone fractures, and could transform current treatment approaches to regenerative medicine.

The UNSW-led research was published this week in the Proceedings of the National Academy of Sciences journal.

Reprogramming bone and fat cells

The system reprograms bone and fat cells into induced multipotent stem cells (iMS), which can regenerate multiple tissue types and has been successfully demonstrated in mice, according to study lead author, haematologist, and UNSW Associate Professor John Pimanda.

“This technique is a significant advance on many of the current unproven stem cell therapies, which have shown little or no objective evidence they contribute directly to new tissue formation,” Pimanda said. “We have taken bone and fat cells, switched off their memory and converted them into stem cells so they can repair different cell types once they are put back inside the body.”

“We are currently assessing whether adult human fat cells reprogrammed into iMS cells can safely repair damaged tissue in mice, with human trials expected to begin in late 2017.”

http://www.kurzweilai.net/images/UNSW-stem-cell-repair.jpg

Advantages over stem-cell types

There are different types of stem cells including embryonic stem (ES) cells, which during embryonic development generate every type of cell in the human body, and adult stem cells, which are tissue-specific, but don’t regenerate multiple tissue types. Embryonic stem cells cannot be used to treat damaged tissues because of their tumor forming capacity. The other problem when generating stem cells is the requirement to use viruses to transform cells into stem cells, which is clinically unacceptable, the researchers note.

Research shows that up to 20% of spinal implants either don’t heal or there is delayed healing. The rates are higher for smokers, older people and patients with diseases such diabetes or kidney disease.

Human trials are planned next year once the safety and effectiveness of the technique using human cells in mice has been demonstrated.

* The technique involves extracting adult human fat cells and treating them with the compound 5-Azacytidine (AZA), along with platelet-derived growth factor-AB (PDGF-AB) for about two days. The cells are then treated with the growth factor alone for a further two-three weeks.

AZA is known to induce cell plasticity, which is crucial for reprogramming cells. The AZA compound relaxes the hard-wiring of the cell, which is expanded by the growth factor, transforming the bone and fat cells into iMS cells. When the stem cells are inserted into the damaged tissue site, they multiply, promoting growth and healing.

The new technique is similar to salamander limb regeneration, which is also dependent on the plasticity of differentiated cells, which can repair multiple tissue types, depending on which body part needs replacing.

Along with confirming that human adult fat cells reprogrammed into iMS stem cells can safely repair damaged tissue in mice, the researchers said further work is required to establish whether iMS cells remain dormant at the sites of transplantation and retain their capacity to proliferate on demand.

https://youtu.be/zAMCBNujzzw

Abstract of PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells

Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineage-committed cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor–AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.

 

First transistors made entirely of nanocrystal ‘inks’ in simplified process

Transistors and other electronic components to be built into flexible or wearable applications; 3D printing planned
http://www.kurzweilai.net/first-transistors-made-entirely-of-nanocrystal-inks
Because this process works at relatively low temperatures, many transistors can be made on a flexible backing at once. (credit: University of Pennsylvania)

University of Pennsylvania engineers have developed a simplified new approach for making transistors by sequentially depositing their components in the form of liquid nanocrystal “inks.” The new process open the door for transistors and other electronic components to be built into flexible or wearable applications. It also avoids the highly complex current process for creating transistors, which requires high-temperature, high-vacuum equipment. Also, the new lower-temperature process is compatible with a wide array of materials and can be applied to larger areas.

Transistors patterned on plastic backing

The researchers’ nanocrystal-based field effect transistors were patterned onto flexible plastic backings using spin coating, but could eventually be constructed by additive manufacturing systems, like 3D printers.

Published in the journal Science,  the study was lead by Cherie Kagan, the Stephen J. Angello Professor in the School of Engineering and Applied Science, and Ji-Hyuk Choi, then a member of her lab, now a senior researcher at the Korea Institute of Geoscience and Mineral Resources. Researchers at Korea University Korea’s Yonsei University were also involved.

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Kagan’s group developed four nanocrystal inks that comprise the transistor, then deposited them on a flexible backing. (credit: University of Pennsylvania)

The researchers began by dispersing a specific type of nanocrystals in a liquid, creating nanocrystal inks. They developed a library of four of these inks: a conductor (silver), an insulator (aluminum oxide), a semiconductor (cadmium selenide), and a conductor combined with a dopant (a mixture of silver and indium). (“Doping” the semiconductor layer of a transistor with impurities controls whether the device creates a positive or negative charge.)

“These materials are colloids just like the ink in your inkjet printer,” Kagan said, “but you can get all the characteristics that you want and expect from the analogous bulk materials, such as whether they’re conductors, semiconductors or insulators.” Although the electrical properties of several of these nanocrystal inks had been independently verified, they had never been combined into full devices. “Our question was whether you could lay them down on a surface in such a way that they work together to form functional transistors.”

Laying down patterns in layers

Such a process entails layering or mixing them in precise patterns.

First, the conductive silver nanocrystal ink was deposited from liquid on a flexible plastic surface that was treated with a photolithographic mask, then rapidly spun to draw it out in an even layer. The mask was then removed to leave the silver ink in the shape of the transistor’s gate electrode.

The researchers followed that layer by spin-coating a layer of the aluminum oxide nanocrystal-based insulator, then a layer of the cadmium selenide nanocrystal-based semiconductor and finally another masked layer for the indium/silver mixture, which forms the transistor’s source and drain electrodes. Upon heating at relatively low temperatures, the indium dopant diffused from those electrodes into the semiconductor component.

“The trick with working with solution-based materials is making sure that, when you add the second layer, it doesn’t wash off the first, and so on,” Kagan said. “We had to treat the surfaces of the nanocrystals, both when they’re first in solution and after they’re deposited, to make sure they have the right electrical properties and that they stick together in the configuration we want.”

Because this entirely ink-based fabrication process works at lower temperatures than existing vacuum-based methods, the researchers were able to make several transistors on the same flexible plastic backing at the same time.

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The inks’ specialized surface chemistry allowed them to stay in configuration without losing their electrical properties. (credit: University of Pennsylvania)

“Making transistors over larger areas and at lower temperatures have been goals for an emerging class of technologies, when people think of the Internet of things, large area flexible electronics and wearable devices,” Kagan said. “We haven’t developed all of the necessary aspects so they could be printed yet, but because these materials are all solution-based, it demonstrates the promise of this materials class and sets the stage for additive manufacturing.”

Because this entirely ink-based fabrication process works at lower temperatures than existing vacuum-based methods, the researchers were able to make several transistors on the same flexible plastic backing at the same time.

3D-printing transistors for wearables

“This is the first work,” Choi said, “showing that all the components, the metallic, insulating, and semiconducting layers of the transistors, and even the doping of the semiconductor, could be made from nanocrystals.”

“Making transistors over larger areas and at lower temperatures have been goals for an emerging class of technologies, when people think of the Internet of things, large area flexible electronics and wearable devices,” Kagan said. “We haven’t developed all of the necessary aspects so they could be printed yet, but because these materials are all solution-based, it demonstrates the promise of this materials class and sets the stage for additive manufacturing.”

The research was supported by the National Science Foundation, the U.S. Department of Energy, the Office of Naval Research, and the Korea Institute of Geoscience and Mineral Resources funded by the Ministry of Science, ICT, and Future Planning of Korea.


Abstract of Exploiting the colloidal nanocrystal library to construct electronic devices

Synthetic methods produce libraries of colloidal nanocrystals with tunable physical properties by tailoring the nanocrystal size, shape, and composition. Here, we exploit colloidal nanocrystal diversity and design the materials, interfaces, and processes to construct all-nanocrystal electronic devices using solution-based processes. Metallic silver and semiconducting cadmium selenide nanocrystals are deposited to form high-conductivity and high-mobility thin-film electrodes and channel layers of field-effect transistors. Insulating aluminum oxide nanocrystals are assembled layer by layer with polyelectrolytes to form high–dielectric constant gate insulator layers for low-voltage device operation. Metallic indium nanocrystals are codispersed with silver nanocrystals to integrate an indium supply in the deposited electrodes that serves to passivate and dope the cadmium selenide nanocrystal channel layer. We fabricate all-nanocrystal field-effect transistors on flexible plastics with electron mobilities of 21.7 square centimeters per volt-second.

Best textile manufacturing methods for creating human tissues with stem cells
Bioengineers determine three best processes for engineering tissues needed for organ and tissue repair
http://www.kurzweilai.net/best-textile-manufacturing-methods-for-creating-human-tissues-with-stem-cells
All four textile manufacturing processes and corresponding scaffold (structure) types studied exhibited the presence of lipid vacuoles (small red spheres, right column, indicating stem cells undergoing random differentiation), compared to control (left). Electrospun scaffolds (row a) exhibited only a monolayer of lipid vacuoles in a single focal plane, while meltblown, spunbond, and carded scaffolds (rows b, c, d) exhibited vacuoles in multiple planes throughout the fabric thickness. Scale bars: 100 μm (credit: S. A. Tuin et al./Biomedical Materials)

Elizabeth Loboa, dean of the Missouri University College of Engineering, and her team have tested new tissue- engineering methods (based on textile manufacturing) to find ones that are most cost-effective and can be produced in larger quantities.

Tissue engineering is a process that uses novel biomaterials seeded with stem cells to grow and replace missing tissues. When certain types of materials are used, the “scaffolds” that are created to hold stem cells eventually degrade, leaving natural tissue in its place. The new tissues could help patients suffering from wounds caused by diabetes and circulation disorders, patients in need of cartilage or bone repair, and women who have had mastectomies by replacing their breast tissue. The challenge is creating enough of the material on a scale that clinicians need to treat patients.

Comparing textile manufacturing techniques

http://www.kurzweilai.net/images/electrospinning.png

Electrospinning experiment: nanofibers are collected into an ethanol bath and removed at predefined time intervals (credit: J. M. Coburn et al./The Johns Hopkins University/PNAS)

In typical tissue engineering approaches that use fibers as scaffolds, non-woven materials are often bonded together using an electrostatic field. This process, called electrospinning (see Nanoscale scaffolds and stem cells show promise in cartilage repair and Improved artificial blood vessels), creates the scaffolds needed to attach to stem cells.

However, large-scale production with electrospinning is not cost-effective. “Electrospinning produces weak fibers, scaffolds that are not consistent, and pores that are too small,” Loboa said. “The goal of ‘scaling up’ is to produce hundreds of meters of material that look the same, have the same properties, and can be used in clinical settings. So we investigated the processes that create textiles, such as clothing and window furnishings like drapery, to scale up the manufacturing process.”

The group published two papers using three industry-standard, high-throughput manufacturing techniques — meltblowing, spunbonding, and carding — to determine if they would create the materials needed to mimic native tissue.

Meltblowing is a technique during which nonwoven materials are created using a molten polymer to create continuous fibers. Spunbond materials are made much the same way but the fibers are drawn into a web while in a solid state instead of a molten one. Carding involves the separation of fibers through the use of rollers, forming the web needed to hold stem cells in place.

http://www.kurzweilai.net/images/carded-scaffold-fabrication.jpg

Schematic of gilled fiber multifilament spinning and carded scaffold fabrication (credit: Stephen A. Tuin et al./Acta Biomaterialia)

Cost-effective methods

Loboa and her colleagues tested these techniques to create polylactic acid (PLA) scaffolds (a Food and Drug Administration-approved material used as collagen fillers), seeded with human stem cells. They then spent three weeks studying whether the stem cells remained healthy and if they began to differentiate into fat and bone pathways, which is the goal of using stem cells in a clinical setting when new bone and/or new fat tissue is needed at a defect site. Results showed that the three textile manufacturing methods proved as viable if not more so than electrospinning.

“These alternative methods are more cost-effective than electrospinning,” Loboa said. “A small sample of electrospun material could cost between $2 to $5. The cost for the three manufacturing methods is between $.30 to $3.00; these methods proved to be effective and efficient. Next steps include testing how the different scaffolds created in the three methods perform once implanted in animals.”

Researchers at North Carolina State University and the University of North Carolina at Chapel Hill were also involved in the two studies, which were published in Biomedical Materials (open access) and Acta Biomaterialia. The National Science Foundation, the National Institutes of Health, and the Nonwovens Institute provided funding for the studies.


Abstract of Creating tissues from textiles: scalable nonwoven manufacturing techniques for fabrication of tissue engineering scaffolds

Electrospun nonwovens have been used extensively for tissue engineering applications due to their inherent similarities with respect to fibre size and morphology to that of native extracellular matrix (ECM). However, fabrication of large scaffold constructs is time consuming, may require harsh organic solvents, and often results in mechanical properties inferior to the tissue being treated. In order to translate nonwoven based tissue engineering scaffold strategies to clinical use, a high throughput, repeatable, scalable, and economic manufacturing process is needed. We suggest that nonwoven industry standard high throughput manufacturing techniques (meltblowing, spunbond, and carding) can meet this need. In this study, meltblown, spunbond and carded poly(lactic acid) (PLA) nonwovens were evaluated as tissue engineering scaffolds using human adipose derived stem cells (hASC) and compared to electrospun nonwovens. Scaffolds were seeded with hASC and viability, proliferation, and differentiation were evaluated over the course of 3 weeks. We found that nonwovens manufactured via these industry standard, commercially relevant manufacturing techniques were capable of supporting hASC attachment, proliferation, and both adipogenic and osteogenic differentiation of hASC, making them promising candidates for commercialization and translation of nonwoven scaffold based tissue engineering strategies.


Abstract of Fabrication of novel high surface area mushroom gilled fibers and their effects on human adipose derived stem cells under pulsatile fluid flow for tissue engineering applications

The fabrication and characterization of novel high surface area hollow gilled fiber tissue engineering scaffolds via industrially relevant, scalable, repeatable, high speed, and economical nonwoven carding technology is described. Scaffolds were validated as tissue engineering scaffolds using human adipose derived stem cells (hASC) exposed to pulsatile fluid flow (PFF). The effects of fiber morphology on the proliferation and viability of hASC, as well as effects of varied magnitudes of shear stress applied via PFF on the expression of the early osteogenic gene marker runt related transcription factor 2 (RUNX2) were evaluated. Gilled fiber scaffolds led to a significant increase in proliferation of hASC after seven days in static culture, and exhibited fewer dead cells compared to pure PLA round fiber controls. Further, hASC-seeded scaffolds exposed to 3 and 6 dyn/cm2 resulted in significantly increased mRNA expression of RUNX2 after one hour of PFF in the absence of soluble osteogenic induction factors. This is the first study to describe a method for the fabrication of high surface area gilled fibers and scaffolds. The scalable manufacturing process and potential fabrication across multiple nonwoven and woven platforms makes them promising candidates for a variety of applications that require high surface area fibrous materials.

Statement of Significance

We report here for the first time the successful fabrication of novel high surface area gilled fiber scaffolds for tissue engineering applications. Gilled fibers led to a significant increase in proliferation of human adipose derived stem cells after one week in culture, and a greater number of viable cells compared to round fiber controls. Further, in the absence of osteogenic induction factors, gilled fibers led to significantly increased mRNA expression of an early marker for osteogenesis after exposure to pulsatile fluid flow. This is the first study to describe gilled fiber fabrication and their potential for tissue engineering applications. The repeatable, industrially scalable, and versatile fabrication process makes them promising candidates for a variety of scaffold-based tissue engineering applications.

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Update on FDA Policy Regarding 3D Bioprinted Material

Curator: Stephen J. Williams, Ph.D.

Last year (2015) in late October the FDA met to finalize a year long process of drafting guidances for bioprinting human tissue and/or medical devices such as orthopedic devices.  This importance of the development of these draft guidances was highlighted in a series of articles below, namely that

  • there were no standards as a manufacturing process
  • use of human tissues and materials could have certain unforseen adverse events associated with the bioprinting process

In the last section of this post a recent presentation by the FDA is given as well as an excellent  pdf here BioprintingGwinnfinal written by a student at University of Kentucky James Gwinn on regulatory concerns of bioprinting.

Bio-Printing Could Be Banned Or Regulated In Two Years

3D Printing News January 30, 2014 No Comments 3dprinterplans

organovaliver

 

 

 

 

 

Cross-section of multi-cellular bioprinted human liver tissue Credit: organovo.com

Bio-printing has been touted as the pinnacle of additive manufacturing and medical science, but what if it might be shut down before it splashes onto the medical scene. Research firm, Gartner Inc believes that the rapid development of bio-printing will spark calls to ban the technology for human and non-human tissue within two years.

A report released by Gartner predicts that the time is drawing near when 3D-bioprinted human organs will be readily available, causing widespread debate. They use an example of 3D printed liver tissue by a San Diego-based company named Organovo.

“At one university, they’re actually using cells from human and non-human organs,” said Pete Basiliere, a Gartner Research Director. “In this example, there was human amniotic fluid, canine smooth muscle cells, and bovine cells all being used. Some may feel those constructs are of concern.”

Bio-printing 

Bio-printing uses extruder needles or inkjet-like printers to lay down rows of living cells. Major challenges still face the technology, such as creating vascular structures to support tissue with oxygen and nutrients. Additionally, creating the connective tissue or scaffolding-like structures to support functional tissue is still a barrier that bio-printing will have to overcome.

Organovo has worked around a number of issues and they hope to print a fully functioning liver for pharmaceutical industry by the end of this year.  “We have achieved thicknesses of greater than 500 microns, and have maintained liver tissue in a fully functional state with native phenotypic behavior for at least 40 days,” said Mike Renard, Organovo’s executive vice president of commercial operations.

clinical trails and testing of organs could take over a decade in the U.S. This is because of the strict rules the U.S. Food and Drug Administration (FDA) places on any new technology. Bio-printing research could outplace regulatory agencies ability to keep up.

“What’s going to happen, in some respects, is the research going on worldwide is outpacing regulatory agencies ability to keep up,” Basiliere said. “3D bio-printing facilities with the ability to print human organs and tissue will advance far faster than general understanding and acceptance of the ramifications of this technology.”

Other companies have been successful with bio-printing as well. Munich-based EnvisionTEC is already selling a printer called a Bioplotter that sells for $188,000 and can print 3D pieces of human tissue. China’s Hangzhou Dianzi University has developed a printer called Regenovo, which printed a small working kidney that lasted four months.

“These initiatives are well-intentioned, but raise a number of questions that remain unanswered. What happens when complex enhanced organs involving nonhuman cells are made? Who will control the ability to produce them? Who will ensure the quality of the resulting organs?” Basiliere said.

Gartner believes demand for bio-printing will explode in 2015, due to a burgeoning population and insufficient levels of healthcare in emerging markets. “The overall success rates of 3D printing use cases in emerging regions will escalate for three main reasons: the increasing ease of access and commoditization of the technology; ROI; and because it simplifies supply chain issues with getting medical devices to these regions,” Basiliere said. “Other primary drivers are a large population base with inadequate access to healthcare in regions often marred by internal conflicts, wars or terrorism.”

It’s interesting to hear Gartner’s bold predictions for bio-printing. Some of the experts we have talked to seem to think bio-printing is further off than many expect, possibly even 20 or 30 years away for fully functioning organs used in transplants on humans. However, less complicated bio-printing procedures and tissue is only a few years away.

 

FDA examining regulations for 3‑D printed medical devices

Renee Eaton Monday, October 27, 2014

fdalogo

The official purpose of a recent FDA-sponsored workshop was “to provide a forum for FDA, medical device manufacturers, additive manufacturing companies and academia to discuss technical challenges and solutions of 3-D printing.” The FDA wants “input to help it determine technical assessments that should be considered for additively manufactured devices to provide a transparent evaluation process for future submissions.”

Simply put, the FDA is trying to stay current with advanced manufacturing technologies that are revolutionizing patient care and, in some cases, democratizing its availability. When a next-door neighbor can print a medical device in his or her basement, it clearly has many positive and negative implications that need to be considered.

Ignoring the regulatory implications for a moment, the presentations at the workshop were fascinating.

STERIS representative Dr. Bill Brodbeck cautioned that the complex designs and materials now being created with additive manufacturing make sterilization practices challenging. For example, how will the manufacturer know if the implant is sterile or if the agent has been adequately removed? Also, some materials and designs cannot tolerate acids, heat or pressure, making sterilization more difficult.

Dr. Thomas Boland from the University of Texas at El Paso shared his team’s work on 3-D-printed tissues. Using inkjet technology, the researchers are evaluating the variables involved in successfully printing skin. Another bio-printing project being undertaken at Wake Forest by Dr. James Yoo involves constructing bladder-shaped prints using bladder cell biopsies and scaffolding.

Dr. Peter Liacouras at Walter Reed discussed his institution’s practice of using 3-D printing to create surgical guides and custom implants. In another biomedical project, work done at Children’s National Hospital by Drs. Axel Krieger and Laura Olivieri involves the physicians using printed cardiac models to “inform clinical decisions,” i.e. evaluate conditions, plan surgeries and reduce operating time.

As interesting as the presentations were, the subsequent discussions were arguably more important. In an attempt to identify and address all significant impacts of additive manufacturing on medical device production, the subject was organized into preprinting (input), printing (process) and post-printing (output) considerations. Panelists and other stakeholders shared their concerns and viewpoints on each topic in an attempt to inform and persuade FDA decision-makers.

An interesting (but expected) outcome was the relative positions of the various stakeholders. Well-established and large manufacturers proposed validation procedures: material testing, process operating guidelines, quality control, traceability programs, etc. Independent makers argued that this approach would impede, if not eliminate, their ability to provide low-cost prosthetic devices.

Comparing practices to the highly regulated food industry, one can understand and accept the need to adopt similar measures for some additively manufactured medical devices. An implant is going into someone’s body, so the manufacturer needs to evaluate and assure the quality of raw materials, processing procedures and finished product.

But, as in the food industry, this means the producer needs to know the composition of materials. Suppliers cannot hide behind proprietary formulations. If manufacturers are expected to certify that a device is safe, they need to know what ingredients are in the materials they are using.

Many in the industry are also lobbying the FDA to agree that manufacturers should be expected to certify the components and not the additive manufacturing process itself. They argue that what matters is whether the device is safe, not what process was used to make it.

Another distinction should be the product’s risk level. Devices should continue to be classified as I, II or III and that classification, not the process used, should determine its level of regulation.

 

 

Will the FDA Regulate Bioprinting?

Published by Sandra Helsel, May 21, 2014 10:20 am

(3DPrintingChannel) The FDA currently assesses 3D printed medical devices and conventionally made products under the same guidelines, despite the different manufacturing methods involved. To receive device approval, manufacturers must prove that the device is equivalent to a product already on the market for the same use, or the device must undergo the process of attaining pre-market approval. However, the approval process for 3D printed devices could become complicated because the devices are manufactured differently and can be customizable. Two teams at the agency are now trying to determine how approval process should be tweaked to account for the changes.

3D Printing and 3D Bioprinting – Will the FDA Regulate Bioprinting?

This entry was posted by Bill Decker on May 20, 2014 at 8:52 am

3dprintedskin

 

 

 

 

 

VIEW VIDEO

https://www.youtube.com/watch?v=5KY-JZCXKXQ#action=share

 

The 3d printing revolution came to medicine and is making people happy while scaring them at the same time!

3-D printing—the process of making a solid object of any shape from a digital model—has grown increasingly common in recent years, allowing doctors to craft customized devices like hearing aids, dental implants, and surgical instruments. For example, University of Michigan researchers last year used a 3-D laser printer to create an airway splint out of plastic particles. In another case, a patient had 75% of his skull replaced with a 3-D printed implant customized to fit his head. The 3d printing revolution came to medicine and is making people happy while scaring them at the same time!

Printed hearts? Doctors are getting there
FDA currently treats assesses 3-D printed medical devices and conventionally made products under the same guidelines, despite the different manufacturing methods involved. To receive device approval, manufacturers must prove that the device is equivalent to a product already on the market for the same use, or the device must undergo the process of attaining pre-market approval.

“We evaluate all devices, including any that utilize 3-D printing technology, for safety and effectiveness, and appropriate benefit and risk determination, regardless of the manufacturing technologies used,” FDA spokesperson Susan Laine said.
However, the approval process for 3-D printed devices could become complicated because the devices are manufactured differently and can be customizable. Two teams at the agency now are trying to determine how approval process should be tweaked to account for the changes:

http://product-liability.weil.com/news/the-stuff-of-innovation-3d-bioprinting-and-fdas-possible-reorganization/

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The Stuff of Innovation – 3D Bioprinting and FDA’s Possible Reorganization

Weil Product Liability Monitor on September 10, 2013 ·

Posted in News

Contributing Author: Meghan A. McCaffrey

With 3D printers, what used to exist only in the realm of science fiction — who doesn’t remember the Star Trek food replicator that could materialize a drink or meal with the mere press of a button — is now becoming more widely available with  food on demand, prosthetic devices, tracheal splintsskull implants, and even liver tissue all having recently been printed, used, implanted or consumed.  3D printing, while exciting, also presents a unique hybrid of technology and biology, making it a potentially unique and difficult area to regulate and oversee.  With all of the recent technological advances surround 3D printer technology, the FDA recently announced in a blog post that it too was going 3D, using it to “expand our research efforts and expand our capabilities to review innovative medical products.”  In addition, the agency will be investigating how 3D printing technology impacts medical devices and manufacturing processes.  This will, in turn, raise the additional question of how such technology — one of the goals of which, at least in the medical world,  is to create unique and custom printed devices, tissue and other living organs for use in medical procedures — can be properly evaluated, regulated and monitored.
In medicine, 3D printing is known as “bioprinting,” where so-called bioprinters print cells in liquid or gel format in an attempt to engineer cartilage, bone, skin, blood vessels, and even small pieces of liver and other human tissues [see a recent New York Times article here].  Not to overstate the obvious, but this is truly cutting edge science that could have significant health and safety ramifications for end users.  And more importantly for regulatory purposes, such bioprinting does not fit within the traditional category of a “device” or a “biologic.”  As was noted in Forbes, “more of the products that FDA is tasked with regulating don’t fit into the traditional categories in which FDA has historically divided its work.  Many new medical products transcend boundaries between drugs, devices, and biologics…In such a world, the boundaries between FDA’s different centers may no longer make as much sense.”  To that end, Forbes reported that FDA Commissioner Peggy Hamburg announced Friday the formation of a “Program Alignment Group” at the FDA whose goal is to identify and develop plans “to best adapt to the ongoing rapid changes in the regulatory environment, driven by scientific innovation, globalization, the increasing complexity of regulated products, new legal authorities and additional user fee programs.”

It will be interesting to see if the FDA can retool the agency to make it a more flexible, responsive, and function-specific organization.  In the short term, the FDA has tasked two laboratories in the Office of Science and Engineering Laboratories with investigating how the new 3D technology can impact the safety and efficacy of devices and materials manufactured using the technology.  The Functional Performance and Device Use Laboratory is evaluating “the effect of design changes on the safety and performance of devices when used in different patient populations” while the Laboratory for Solid Mechanics is assessing “how different printing techniques and processes affect the strength and durability of the materials used in medical devices.”  Presumably, all of this information will help the FDA evaluate at some point in the future whether a 3D printed heart is safe and effective for use in the patient population.

In any case, this type of hybrid technology can present a risk for companies and manufacturers creating and using such devices.  It remains to be seen what sort of regulations will be put in place to determine, for example, what types of clinical trials and information will have to be provided before a 3D printer capable of printing a human heart is approved for use by the FDA.  Or even on a different scale, what regulatory hurdles (and on-going monitoring, reporting, and studies) will be required before bioprinted cartilage can be implanted in a patient’s knee.  Are food replicators and holodecks far behind?

http://www.raps.org/regulatory-focus/news/2014/05/19000/FDA-3D-Printing-Guidance-and-Meeting/

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FDA Plans Meeting to Explore Regulation, Medical Uses of 3D Printing Technology

Posted 16 May 2014 By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) plans to soon hold a meeting to discuss the future of regulating medical products made using 3D printing techniques, it has announced.

fdaplanstomeetbioprinting

Background

3D printing is a manufacturing process which layers printed materials on top of one another, creating three-dimensional parts (as opposed to injection molding or routing materials).

The manufacturing method has recently come into vogue with hobbyists, who have been driven by several factors only likely to accelerate in the near future:

  • The cost of 3D printers has come down considerably.
  • Electronic files which automate the printing process are shareable over the Internet, allowing anyone with the sufficient raw materials to build a part.
  • The technology behind 3D printing is becoming more advanced, allowing for the manufacture of increasingly durable parts.

While the technology has some alarming components—the manufacture of untraceable weapons, for example—it’s increasingly being looked at as the future source of medical product innovation, and in particular for medical devices like prosthetics.

Promise and Problems

But while 3D printing holds promise for patients, it poses immense challenges for regulators, who must assess how to—or whether to—regulate the burgeoning sector.

In a recent FDA Voice blog posting, FDA regulators noted that 3D-printed medical devices have already been used in FDA-cleared clinical interventions, and that it expects more devices to emerge in the future.

Already, FDA’s Office of Science and Engineering laboratories are working to investigate how the technology will affect the future of device manufacturing, and CDRH’s Functional Performance and Device Use Laboratory is developing and adapting computer modeling methods to help determine how small design changes could affect the safety of a device. And at the Laboratory for Solid Mechanics, FDA said it is investigating the materials used in the printing process and how those might affect durability and strength of building materials.

And as Focus noted in August 2013, there are myriad regulatory challenges to confront as well. For example: If a 3D printer makes a medical device, will that device be considered adulterated since it was not manufactured under Quality System Regulation-compliant conditions? Would each device be required to be registered with FDA? And would FDA treat shared design files as unauthorized promotion if they failed to make proper note of the device’s benefits and risks? What happens if a device was never cleared or approved by FDA?

The difficulties for FDA are seemingly endless.

Plans for a Guidance Document

But there have been indications that FDA has been thinking about this issue extensively.

In September 2013, Focus first reported that CDRH Director Jeffery Shuren was planning to release a guidance on 3D printing in “less than two years.”

Responding to Focus, Shuren said the guidance would be primarily focused on the “manufacturing side,” and probably on how 3D printing occurs and the materials used rather than some of the loftier questions posed above.

“What you’re making, and how you’re making it, may have implications for how safe and effective that device is,” he said, explaining how various methods of building materials can lead to various weaknesses or problems.

“Those are the kinds of things we’re working through. ‘What are the considerations to take into account?'”

“We’re not looking to get in the way of 3D printing,” Shuren continued, noting the parallel between 3D printing and personalized medicine. “We’d love to see that.”

Guidance Coming ‘Soon’

In recent weeks there have been indications that the guidance could soon see a public release. Plastics News reported that CDRH’s Benita Dair, deputy director of the Division of Chemistry and Materials Science, said the 3D printing guidance would be announced “soon.”

“In terms of 3-D printing, I think we will soon put out a communication to the public about FDA’s thoughts,” Dair said, according to Plastics News. “We hope to help the market bring new devices to patients and bring them to the United States first. And we hope to play an integral part in that.”

Public Meeting

But FDA has now announced that it may be awaiting public input before it puts out that guidance document. In a 16 May 2014 Federal Register announcement, the agency said it will hold a meeting in October 2014 on the “technical considerations of 3D printing.”

“The purpose of this workshop is to provide a forum for FDA, medical device manufacturers, additive manufacturing companies, and academia to discuss technical challenges and solutions of 3-D printing. The Agency would like input regarding technical assessments that should be considered for additively manufactured devices to provide a transparent evaluation process for future submissions.”

That language—”transparent evaluation process for future submissions”—indicates that at least one level, FDA plans to treat 3D printing no differently than any other medical device, subjecting the products to the same rigorous premarket assessments that many devices now undergo.

FDA’s notice seems to focus on industrial applications for the technology—not individual ones. The agency notes that it has already “begun to receive submissions using additive manufacturing for both traditional and patient-matched devices,” and says it sees “many more on the horizon.”

Among FDA’s chief concerns, it said, are process verification and validation, which are both key parts of the medical device quality manufacturing regulations.

But the notice also indicates that existing guidance documents, such as those specific to medical device types, will still be in effect regardless of the 3D printing guidance.

Discussion Points

FDA’s proposed list of discussion topics include:

  • Preprinting considerations, including but not limited to:
    • material chemistry
    • physical properties
    • recyclability
    • part reproducibility
    • process validation
  • Printing considerations, including but not limited to:
    • printing process characterization
    • software used in the process
    • post-processing steps (hot isostatic pressing, curing)
    • additional machining
  • Post-printing considerations, including but not limited to:
    • cleaning/excess material removal
    • effect of complexity on sterilization and biocompatibility
    • final device mechanics
    • design envelope
    • verification

– See more at: http://www.raps.org/regulatory-focus/news/2014/05/19000/FDA-3D-Printing-Guidance-and-Meeting/#sthash.cDg4Utln.dpuf

 

FDA examining regulations for 3‑D printed medical devices

 

Renee Eaton Monday, October 27, 2014

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The official purpose of a recent FDA-sponsored workshop was “to provide a forum for FDA, medical device manufacturers, additive manufacturing companies and academia to discuss technical challenges and solutions of 3-D printing.” The FDA wants “input to help it determine technical assessments that should be considered for additively manufactured devices to provide a transparent evaluation process for future submissions.”

Simply put, the FDA is trying to stay current with advanced manufacturing technologies that are revolutionizing patient care and, in some cases, democratizing its availability. When a next-door neighbor can print a medical device in his or her basement, it clearly has many positive and negative implications that need to be considered.

Ignoring the regulatory implications for a moment, the presentations at the workshop were fascinating.

STERIS representative Dr. Bill Brodbeck cautioned that the complex designs and materials now being created with additive manufacturing make sterilization practices challenging. For example, how will the manufacturer know if the implant is sterile or if the agent has been adequately removed? Also, some materials and designs cannot tolerate acids, heat or pressure, making sterilization more difficult.

Dr. Thomas Boland from the University of Texas at El Paso shared his team’s work on 3-D-printed tissues. Using inkjet technology, the researchers are evaluating the variables involved in successfully printing skin. Another bio-printing project being undertaken at Wake Forest by Dr. James Yoo involves constructing bladder-shaped prints using bladder cell biopsies and scaffolding.

Dr. Peter Liacouras at Walter Reed discussed his institution’s practice of using 3-D printing to create surgical guides and custom implants. In another biomedical project, work done at Children’s National Hospital by Drs. Axel Krieger and Laura Olivieri involves the physicians using printed cardiac models to “inform clinical decisions,” i.e. evaluate conditions, plan surgeries and reduce operating time.

As interesting as the presentations were, the subsequent discussions were arguably more important. In an attempt to identify and address all significant impacts of additive manufacturing on medical device production, the subject was organized into preprinting (input), printing (process) and post-printing (output) considerations. Panelists and other stakeholders shared their concerns and viewpoints on each topic in an attempt to inform and persuade FDA decision-makers.

An interesting (but expected) outcome was the relative positions of the various stakeholders. Well-established and large manufacturers proposed validation procedures: material testing, process operating guidelines, quality control, traceability programs, etc. Independent makers argued that this approach would impede, if not eliminate, their ability to provide low-cost prosthetic devices.

Comparing practices to the highly regulated food industry, one can understand and accept the need to adopt similar measures for some additively manufactured medical devices. An implant is going into someone’s body, so the manufacturer needs to evaluate and assure the quality of raw materials, processing procedures and finished product.

But, as in the food industry, this means the producer needs to know the composition of materials. Suppliers cannot hide behind proprietary formulations. If manufacturers are expected to certify that a device is safe, they need to know what ingredients are in the materials they are using.

Many in the industry are also lobbying the FDA to agree that manufacturers should be expected to certify the components and not the additive manufacturing process itself. They argue that what matters is whether the device is safe, not what process was used to make it.

Another distinction should be the product’s risk level. Devices should continue to be classified as I, II or III and that classification, not the process used, should determine its level of regulation.

If you are interested in submitting comments to the FDA on this topic, post them by Nov. 10.

FDA Guidance Summary on 3D BioPrinting

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Curbing Cancer Cell Growth & Metastasis-on-a-Chip’ Models Cancer’s Spread

Curator: Larry H. Bernstein, MD, FCAP

 

New Approach to Curbing Cancer Cell Growth

http://www.technologynetworks.com/Metabolomics/news.aspx?ID=189342

Using a new approach, scientists at The Scripps Research Institute (TSRI) and collaborating institutions have discovered a novel drug candidate that could be used to treat certain types of breast cancer, lung cancer and melanoma.

The new study focused on serine, one of the 20 amino acids (protein building blocks) found in nature. Many types of cancer require synthesis of serine to sustain rapid, constant and unregulated growth.

To find a drug candidate that interfered with this pathway, the team screened a large library of compounds from a variety of sources, searching for molecules that inhibited a specific enzyme known as 3-phosphoglycerate dehydrogenase (PHGDH), which is responsible for the first committed step in serine biosynthesis.

“In addition to discovering an inhibitor that targets cancer metabolism, we also now have a tool to help answer interesting questions about serine metabolism,” said Luke L. Lairson, assistant professor of chemistry at TSRI and principal investigator of cell biology at the California Institute for Biomedical Research (CALIBR).

Lairson was senior author of the study, published recently in the Proceedings of the National Academy of Sciences (PNAS), with Lewis Cantley of Weill Cornell Medical College and Costas Lyssiotis of the University of Michigan.

Addicted to Serine

Serine is necessary for nucleotide, protein and lipid biosynthesis in all cells. Cells use two main routes for acquiring serine: through import from the extracellular environment or through conversion of 3-phosphoglycerate (a glycolytic intermediate) by PHGDH.

“Since the late 1950s, it has been known that cancer cells use the process of aerobic glycolysis to generate metabolites needed for proliferative growth,” said Lairson.

This process can lead to an overproduction of serine. The genetic basis for this abundance had remained mysterious until recently, when it was demonstrated that some cancers acquire mutations that increased the expression of PHGDH; reducing PHGDH in these “serine-addicted” cancer cells also inhibited their growth.

The labs of Lewis C. Cantley at Weill Cornell Medical College (in work published in Nature Genetics) and David Sabatini at the Whitehead Institute (in work published in Nature) suggested PHGDH as a potential drug target for cancer types that overexpress the enzyme.

Lairson and colleagues hypothesized that a small molecule drug candidate that inhibited PHGDH could interfere with cancer metabolism and point the way to the development of an effective cancer therapeutic. Importantly, this drug candidate would be inactive against normal cells because they would be able to import enough serine to support ordinary growth.

As Easy as 1-2-800,000

Lairson, in collaboration with colleagues including Cantley, Lyssiotis, Edouard Mullarky of Weill Cornell and Harvard Medical School and Natasha Lucki of CALIBR, screened through a library of 800,000 small molecules using a high-throughput in vitro enzyme assay to detect inhibition of PHGDH. The group identified 408 candidates and further narrowed this list down based on cell-type specific anti-proliferative activity and by eliminating those inhibitors that broadly targeted other dehydrogenases.

With the successful identification of seven candidate inhibitors, the team sought to determine if these molecules could inhibit PHGDH in the complex cellular environment. To do so, the team used a mass spectrometry-based assay (test) to measure newly synthesized serine in a cell in the presence of the drug candidates.

One of the seven small molecules tested, named CBR-5884, was able to specifically inhibit serine synthesis by 30 percent, suggesting that the molecule specifically targeted PHGDH. The group went on to show that CBR-5884 was able to inhibit cell proliferation of breast cancer and melanoma cells lines that overexpress PHGDH.

As expected, CBR-5884 did not inhibit cancer cells that did not overexpress PHGDH, as they can import serine; however, when incubated in media lacking serine, the presence of CBR-5884 decreased growth in these cells.

The group anticipates much optimization work before this drug candidate can become an effective therapeutic. In pursuit of this goal, the researchers plan to take a medicinal chemistry approach to improve potency and metabolic stability.

 

How Cancer Stem Cells Thrive When Oxygen Is Scarce

(Image: Shutterstock)
image: Shutterstock

Working with human breast cancer cells and mice, scientists at The Johns Hopkins University say new experiments explain how certain cancer stem cells thrive in low oxygen conditions. Proliferation of such cells, which tend to resist chemotherapy and help tumors spread, are considered a major roadblock to successful cancer treatment.

The new research, suggesting that low-oxygen conditions spur growth through the same chain of biochemical events in both embryonic stem cells and breast cancer stem cells, could offer a path through that roadblock, the investigators say.

“There are still many questions left to answer but we now know that oxygen poor environments, like those often found in advanced human breast cancers serve as nurseries for the birth of cancer stem cells,” said Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine and a member of the Johns Hopkins Kimmel Cancer Center. “That gives us a few more possible targets for drugs that diminish their threat in human cancer.”

A summary of the findings was published online March 21 in the Proceedings of the National Academy of Sciences.

“Aggressive cancers contain regions where the cancer cells are starved for oxygen and die off, yet patients with these tumors generally have the worst outcome. Our new findings tell us that low oxygen conditions actually encourage certain cancer stem cells to multiply through the same mechanism used by embryonic stem cells.”

All stem cells are immature cells known for their ability to multiply indefinitely and give rise to progenitor cells that mature into specific cell types that populate the body’s tissues during embryonic development. They also replenish tissues throughout the life of an organism. But stem cells found in tumors use those same attributes and twist them to maintain and enhance the survival of cancers.

Recent studies showed that low oxygen conditions increase levels of a family of proteins known as HIFs, or hypoxia-inducible factors, that turn on hundreds of genes, including one called NANOG that instructs cells to become stem cells.

Studies of embryonic stem cells revealed that NANOG protein levels can be lowered by a chemical process known as methylation, which involves putting a methyl group chemical tag on a protein’s messenger RNA (mRNA) precursor. Semenza said methylation leads to the destruction of NANOG’s mRNA so that no protein is made, which in turn causes the embryonic stem cells to abandon their stem cell state and mature into different cell types.

Zeroing in on NANOG, the scientists found that low oxygen conditions increased NANOG’s mRNA levels through the action of HIF proteins, which turned on the gene for ALKBH5, which decreased the methylation and subsequent destruction of NANOG’s mRNA. When they prevented the cells from making ALKBH5, NANOG levels and the number of cancer stem cells decreased. When the researchers manipulated the cell’s genetics to increase levels of ALKBH5 without exposing them to low oxygen, they found this also decreased methylation of NANOG mRNA and increased the numbers of breast cancer stem cells.

Finally, using live mice, the scientists injected 1,000 triple-negative breast cancer cells into their mammary fat pads, where the mouse version of breast cancer forms. Unaltered cells created tumors in all seven mice injected with such cells, but when cells missing ALKBH5 were used, they caused tumors in only 43 percent (six out of 14) of mice. “That confirmed for us that ALKBH5 helps preserve cancer stem cells and their tumor-forming abilities,” Semenza said.

How cancer stem cells thrive when oxygen is scarce    https://www.sciencedaily.com/releases/2016/03/160328100159.htm

The new research, suggesting that low-oxygen conditions spur growth through the same chain of biochemical events in both embryonic stem cells and breast cancer stem cells, could offer a path through that roadblock, the investigators say.

“There are still many questions left to answer but we now know that oxygen poor environments, like those often found in advanced human breast cancers serve as nurseries for the birth of cancer stem cells,” says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine and a member of the Johns Hopkins Kimmel Cancer Center.

Chuanzhao Zhang, Debangshu Samanta, Haiquan Lu, John W. Bullen, Huimin Zhang, Ivan Chen, Xiaoshun He, Gregg L. Semenza.
Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA.
Proceedings of the National Academy of Sciences, 2016; 201602883     DOI: 10.1073/pnas.1602883113

Significance

Pluripotency factors, such as NANOG, play a critical role in the maintenance and specification of cancer stem cells, which are required for primary tumor formation and metastasis. In this study, we report that exposure of breast cancer cells to hypoxia (i.e., reduced O2 availability), which is a critical feature of the tumor microenvironment, induces N6-methyladenosine (m6A) demethylation and stabilization of NANOG mRNA, thereby promoting the breast cancer stem cell (BCSC) phenotype. We show that inhibiting the expression of AlkB homolog 5 (ALKBH5), which demethylates m6A, or the hypoxia-inducible factors (HIFs) HIF-1α and HIF-2α, which activate ALKBH5 gene transcription in hypoxic breast cancer cells, is an effective strategy to decrease NANOG expression and target BCSCs in vivo.

N6-methyladenosine (m6A) modification of mRNA plays a role in regulating embryonic stem cell pluripotency. However, the physiological signals that determine the balance between methylation and demethylation have not been described, nor have studies addressed the role of m6A in cancer stem cells. We report that exposure of breast cancer cells to hypoxia stimulated hypoxia-inducible factor (HIF)-1α- and HIF-2α–dependent expression of AlkB homolog 5 (ALKBH5), an m6A demethylase, which demethylated NANOG mRNA, which encodes a pluripotency factor, at an m6A residue in the 3′-UTR. Increased NANOG mRNA and protein expression, and the breast cancer stem cell (BCSC) phenotype, were induced by hypoxia in an HIF- and ALKBH5-dependent manner. Insertion of the NANOG 3′-UTR into a luciferase reporter gene led to regulation of luciferase activity by O2, HIFs, and ALKBH5, which was lost upon mutation of the methylated residue. ALKBH5 overexpression decreased NANOG mRNA methylation, increased NANOG levels, and increased the percentage of BCSCs, phenocopying the effect of hypoxia. Knockdown of ALKBH5 expression in MDA-MB-231 human breast cancer cells significantly reduced their capacity for tumor initiation as a result of reduced numbers of BCSCs. Thus, HIF-dependent ALKBH5 expression mediates enrichment of BCSCs in the hypoxic tumor microenvironment.

Specific Proteins Found to Jump Start Spread of Cancer Cells

http://www.genengnews.com/gen-news-highlights/specific-proteins-found-to-jump-start-spread-of-cancer-cells/81252417/

Metastatic breast cancer cells. [National Cancer Institute]
http://www.genengnews.com/Media/images/GENHighlight/thumb_Feb29_2016_NCI_MetastaticBreastCancerCells1797514764.jpg

Scientists at the University of California, San Diego School of Medicine and Moores Cancer Center, with colleagues in Spain and Germany, have discovered how elevated levels of particular proteins in cancer cells trigger hyperactivity in other proteins, fueling the growth and spread of a variety of cancers. Their study (“Prognostic Impact of Modulators of G Proteins in Circulating Tumor Cells from Patients with Metastatic Colorectal Cancer”) is published in Scientific Reports.

Specifically, the international team, led by senior author Pradipta Ghosh, M.D., associate professor at the University of California San Diego School of Medicine, found that increased levels of expression of some members of a protein family called guanine nucleotide exchange factors (GEFs) triggered unsuspected hyperactivation of G proteins and subsequent progression or metastasis of cancer.

The discovery suggests GEFs offer a new and more precise indicator of disease state and prognosis. “We found that elevated expression of each GEF is associated with a shorter, progression-free survival in patients with metastatic colorectal cancer,” said Dr. Ghosh. “The GEFs fared better as prognostic markers than two well-known markers of cancer progression, and the clustering of all GEFs together improved the predictive accuracy of each individual family member.”

In recent years, circulating tumor cells (CTCs), which are shed from primary tumors into the bloodstream and act as seeds for new tumors taking root in other parts of the body, have become a prognostic and predictive biomarker. The presence of CTCs is used to monitor the efficacy of therapies and detect early signs of metastasis.

But counting CTCs in the bloodstream has limited utility, said Dr. Ghosh. “Enumeration alone does not capture the particular characteristics of CTCs that are actually tumorigenic and most likely to cause additional malignancies.”

Numerous efforts are underway to improve the value and precision of CTC analysis. According to Dr. Ghosh the new findings are a step in that direction. First, GEFs activate trimeric G proteins, and second, G protein signaling is involved in CTCs. G proteins are ubiquitous and essential molecular switches involved in transmitting external signals from stimuli into cells’ interiors. They have been a subject of heightened scientific interest for many years.

Dr. Ghosh and colleagues found that elevated expression of nonreceptor GEFs activates Gαi proteins, fueling CTCs and ultimately impacting the disease course and survival of cancer patients.

“Our work shows the prognostic impact of elevated expression of individual and clustered GEFs on survival and the benefit of transcriptome analysis of G protein regulatory proteins in cancer biology,” said Dr. Ghosh. “The next step will be to carry this technology into the clinic where it can be applied directly to deciphering a patient’s state of cancer and how best to treat.”

Metastasis-on-a-Chip’ Models Cancer’s Spread

http://www.mdtmag.com/news/2016/03/metastasis-chip-models-cancers-spread?et_cid=5200644&et_rid=461755519

In the journal Biotechnology Bioengineering, the team reports on its “metastasis-on-a-chip” system believed to be one of the first laboratory models of cancer spreading from one 3D tissue to another.

The current version of the system models a colorectal tumor spreading from the colon to the liver, the most common site of metastasis. Skardal said future versions could include additional organs, such as the lung and bone marrow, which are also potential sites of metastasis. The team also plans to model other types of cancer, such as the deadly brain tumor glioblastoma

To create the system, researchers encapsulated human intestine and colorectal cancer cells inside a biocompatible gel-like material to make a mini-organ. A mini-liver composed of human liver cells was made in the same way. These organoids were placed in a “chip” system made up of a set of micro-channels and chambers etched into the chip’s surface to mimic a simplified version of the body’s circulatory system. The tumor cells were tagged with fluorescent molecules so their activity could be viewed under a microscope.

To test whether the system could model metastasis, the researchers first used highly aggressive cancer cells in the colon organoid. Under the microscope, they saw the tumor grow in the colon organoid until the cells broke free, entered the circulatory system and then invaded the liver tissue, where another tumor formed and grew. When a less aggressive form of colon cancer was used in the system, the tumor did not metastasize, but continued to grow in the colon.

To test the system’s potential for screening drugs, the team introduced Marimastat, a drug used to inhibit metastasis in human patients, into the system and found that it significantly prevented the migration of metastatic cells over a 10-day period. Likewise, the team also tested 5-fluorouracil, a common colorectal cancer drug, which reduced the metabolic activity of the tumor cells.

“We are currently exploring whether other established anti-cancer drugs have the same effects in the system as they do in patients,” said Skardal. “If this link can be validated and expanded, we believe the system can be used to screen drug candidates for patients as a tool in personalized medicine. If we can create the same model systems, only with tumor cells from an actual patient, then we believe we can use this platform to determine the best therapy for any individual patient.”

The scientists are currently working to refine their system. They plan to use 3D printing to create organoids more similar in function to natural organs. And they aim to make the process of metastasis more realistic. When cancer spreads in the human body, the tumor cells must break through blood vessels to enter the blood steam and reach other organs. The scientists plan to add a barrier of endothelial cells, the cells that line blood vessels, to the model.

This concept of modeling the body’s processes on a miniature level is made possible because of advances in micro-tissue engineering and micro-fluidics technologies. It is similar to advances in the electronics industry made possible by miniaturizing electronics on a chip.

Scientists Synthesize Anti-Cancer Agent

A schematic shows a trioxacarcin C molecule, whose structure was revealed for the first time through a new process developed by the Rice lab of synthetic organic chemist K.C. Nicolaou. Trioxacarcins are found in bacteria but synthetic versions are needed to study them for their potential as medications. Trioxacarcins have anti-cancer properties. Source: Nicolaou Group/Rice University
A schematic shows a trioxacarcin C molecule, whose structure was revealed for the first time through a new process developed by the Rice lab of synthetic organic chemist K.C. Nicolaou. Trioxacarcins are found in bacteria but synthetic versions are needed to study them for their potential as medications. Trioxacarcins have anti-cancer properties. Source: Nicolaou Group/Rice University  http://www.dddmag.com/sites/dddmag.com/files/ddd1603_rice-anticancer.jpg

A team led by Rice University synthetic organic chemist K.C. Nicolaou has developed a new process for the synthesis of a series of potent anti-cancer agents originally found in bacteria.

The Nicolaou lab finds ways to replicate rare, naturally occurring compounds in larger amounts so they can be studied by biologists and clinicians as potential new medications. It also seeks to fine-tune the molecular structures of these compounds through analog design and synthesis to improve their disease-fighting properties and lessen their side effects.

Such is the case with their synthesis of trioxacarcins, reported this month in the Journal of the American Chemical Society.

“Not only does this synthesis render these valuable molecules readily available for biological investigation, but it also allows the previously unknown full structural elucidation of one of them,” Nicolaou said. “The newly developed synthetic technologies will allow us to construct variations for biological evaluation as part of a program to optimize their pharmacological profiles.”

At present, there are no drugs based on trioxacarcins, which damage DNA through a novel mechanism, Nicolaou said.

Trioxacarcins were discovered in the fermentation broth of the bacterial strain Streptomyces bottropensis. They disrupt the replication of cancer cells by binding and chemically modifying their genetic material.

“These molecules are endowed with powerful anti-tumor properties,” Nicolaou said. “They are not as potent as shishijimicin, which we also synthesized recently, but they are more powerful than taxol, the widely used anti-cancer drug. Our objective is to make it more powerful through fine-tuning its structure.”

He said his lab is working with a biotechnology partner to pair these cytotoxic compounds (called payloads) to cancer cell-targeting antibodies through chemical linkers. The process produces so-called antibody-drug conjugates as drugs to treat cancer patients. “It’s one of the latest frontiers in personalized targeting chemotherapies,” said Nicolaou, who earlier this year won the prestigious Wolf Prize in Chemistry.

Fluorescent Nanoparticle Tracks Cancer Treatment’s Effectiveness in Hours

Bevin Fletcher, Associate Editor    http://www.biosciencetechnology.com/news/2016/03/fluorescent-nanoparticle-tracks-cancer-treatments-effectiveness-hours

Using reporter nanoparticles loaded with either a chemotherapy or immunotherapy, researchers could distinguish between drug-sensitive and drug-resistant tumors in a pre-clinical model of prostate cancer. (Source: Brigham and Women's Hospital)

Using reporter nanoparticles loaded with either a chemotherapy or immunotherapy, researchers could distinguish between drug-sensitive and drug-resistant tumors in a pre-clinical model of prostate cancer. (Source: Brigham and Women’s Hospital)

Bioengineers at Brigham and Women’s Hospital have developed a new technique to help determine if chemotherapy is working in as few as eight hours after treatment. The new approach, which can also be used for monitoring the effectiveness of immunotherapy, has shown success in pre-clinical models.

The technology utilizes a nanoparticle, carrying anti-cancer drugs, that glows green when cancer cells begin dying. Researchers, using  the “reporter nanoparticles” that responds to a particular enzyme known as caspase, which is activated when cells die, were able to distinguish between a tumor that is drug-sensitive or drug-resistant much faster than conventional detection methods such as PET scans, CT and MRI.  The findings were published online March 28 in the Proceedings of the National Academy of Sciences.

“Using this approach, the cells light up the moment a cancer drug starts working,” co-corresponding author Shiladitya Sengupta, Ph.D., principal investigator in BWH’s Division of Bioengineering, said in a prepared statement.  “We can determine if a cancer therapy is effective within hours of treatment.  Our long-term goal is to find a way to monitor outcomes very early so that we don’t give a chemotherapy drug to patients who are not responding to it.”

Cancer killers send signal of success

Nanoparticles deliver drug, then give real-time feedback when tumor cells die   BY   SARAH SCHWARTZ

New lab-made nanoparticles deliver cancer drugs into tumors, then report their effects in real time by lighting up in response to proteins produced by dying cells. More light (right, green) indicates a tumor is responding to chemotherapy.

Tiny biochemical bundles carry chemotherapy drugs into tumors and light up when surrounding cancer cells start dying. Future iterations of these lab-made particles could allow doctors to monitor the effects of cancer treatment in real time, researchers report the week of March 28 in theProceedings of the National Academy of Sciences.

“This is the first system that allows you to read out whether your drug is working or not,” says study coauthor Shiladitya Sengupta, a bioengineer at Brigham and Women’s Hospital in Boston.

Each roughly 100-nanometer-wide particle consists of a drug and a fluorescent dye linked to a coiled molecular chain. Before the particles enter cells, the dye is tethered to a “quencher” molecule that prevents it from lighting up. When injected into the bloodstream of a mouse with cancer, the nanoparticles accumulate in tumor cells and release the drug, which activates a protein that tears a cancer cell apart. This cell-splitting protein not only kills the tumor cell, but also severs the link between the dye and the quencher, allowing the nanoparticles to glow under infrared light.

Reporter nanoparticle that monitors its anticancer efficacy in real time

Ashish Kulkarnia,b,1,Poornima Raoa,b,Siva Natarajana,b,Aaron Goldman, et al.
http://www.pnas.org/content/early/2016/03/28/1603455113.abstract

The ability to identify responders and nonresponders very early during chemotherapy by direct visualization of the activity of the anticancer treatment and to switch, if necessary, to a regimen that is effective can have a significant effect on the outcome as well as quality of life. Current approaches to quantify response rely on imaging techniques that fail to detect very early responses. In the case of immunotherapy, the early anatomical readout is often discordant with the biological response. This study describes a self-reporting nanomedicine that not only delivers chemotherapy or immunotherapy to the tumor but also reports back on its efficacy in real time, thereby identifying responders and nonresponders early on

The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.

 

Cancer Treatment’s New Direction  
Genetic testing helps oncologists target tumors and tailor treatments
http://www.wsj.com/articles/cancer-treatments-new-direction-1459193085

Evan Johnson had battled a cold for weeks, endured occasional nosebleeds and felt so fatigued he struggled to finish his workouts at the gym. But it was the unexplained bruises and chest pain that ultimately sent the then 23-year-old senior at the University of North Dakota to the Mayo Clinic. There a genetic test revealed a particularly aggressive form of acute myeloid leukemia. That was two years ago.

The harrowing roller-coaster that followed for Mr. Johnson and his family highlights new directions oncologists are taking with genetic testing to find and attack cancer. Tumors can evolve to resist treatments, and doctors are beginning to turn such setbacks into possible advantages by identifying new targets to attack as the tumors change.

His course involved a failed stem cell transplant, a half-dozen different drug regimens, four relapses and life-threatening side effects related to his treatment.

Nine months in, his leukemia had evolved to develop a surprising new mutation. The change meant the cancer escaped one treatment, but the new anomaly provided doctors with a fresh target, one susceptible to drugs approved for other cancers. Doctors adjusted Mr. Johnson’s treatment accordingly, knocked out the disease and paved the way for a second, more successful stem cell transplant. He has now been free of leukemia for a year.

Now patients with advanced cancer who are treated at major centers can expect to have their tumors sequenced, in hopes of finding a match in a growing medicine chest of drugs that precisely target mutations that drive cancer’s growth. When they work, such matches can have a dramatic effect on tumors. But these “precision medicines” aren’t cures. They are often foiled when tumors evolve, pushing doctors to take the next step to identify new mutations in hopes of attacking them with an effective treatment.

Dr. Kasi and his Mayo colleagues—Naseema Gangat, a hematologist, and Shahrukh Hashmi, a transplant specialist—are among the authors of an account of Mr. Johnson’s case published in January in the journal Leukemia Research Reports.

Before qualifying for a transplant, a patient’s blasts need to be under 5%.

To get under 5%, he started on a standard chemotherapy regimen and almost immediately, things went south. His blast cells plummeted, but “the chemo just wiped out my immune system,”

Then as mysteriously as it began, a serious mycotic throat infection stopped. But Mr. Johnson couldn’t tolerate the chemo, and his blast cells were on the rise. A two-drug combination that included the liver cancer drug Nexavar, which targets the FLT3 mutation, knocked back the blast cells. But the stem cell transplant in May, which came from one of his brothers, failed to take, and he relapsed after 67 days, around late July.

He was put into a clinical trial of an experimental AML drug being developed by Astellas Pharma of Japan. He started to regain weight. In November 2014, doctors spotted the initial signs in blood tests that Mr. Johnson’s cancer was evolving to acquire a new mutation. By late January, he relapsed again , but there was a Philadelphia chromosome mutation,  a well-known genetic alteration associated with chronic myeloid leukemia. It also is a target of the blockbuster cancer drug Gleevec and several other medicines.

Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets

Naseema GangatMark R. LitzowMrinal M. PatnaikShahrukh K. HashmiNaseema Gangat

Highlights
•   The article reports on a case of AML that underwent clonal evolution.
•   We report on novel acquisition of the Philadelphia t(9;22) translocation in AML.
•   Next generation sequencing maybe helpful in these refractory/relapse cases.
•   Novel FLT3-inhibitor targeted therapies are another option in patients with AML.
•   Personalizing cancer treatment based on evolving targets is a viable option.

For acute myeloid leukemia (AML), identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3) has led to the development of several FLT3-inhibitors. Here we present clinical and next generation sequencing data at the time of progression of a patient on a novel FLT3-inhibitor clinical trial (ASP2215) to show that employing therapeutic interventions with these novel targeted therapies can lead to consequences secondary to selective pressure and clonal evolution of cancer. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process. (Clinical Trial: NCT02014558; registered at: 〈https://clinicaltrials.gov/ct2/show/NCT02014558〉)

The development of kinase inhibitors for the treatment of leukemia has revolutionized the care of these patients. Since the introduction of imatinib for the treatment of chronic myeloid leukemia, multiple other tyrosine kinase inhibitors (TKIs) have become available[1]. Additionally, for acute myeloid leukemia (AML), identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3) has led to the development of several FLT3-inhibitors [2], [3], [4] and [5]. The article herein reports a unique case of AML that underwent clonal evolution while on a novel FLT3-inhibitor clinical trial.

Our work herein presents clinical and next generation sequencing data at the time of progression to illustrate these important concepts stemming from Darwinian evolution [6]. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process.

Our work focuses on a 23-year-old male who presented with 3 months history of fatigue and easy bruising, a white blood count of 22.0×109/L with 51% circulating blasts, hemoglobin 7.6 g/dL, and a platelet count of 43×109/L. A bone marrow biopsy confirmed a diagnosis of AML. Initial cytogenetic studies identified trisomy 8 in all the twenty metaphases examined. Mutational analysis revealed an internal tandem duplication of the FLT3 gene (FLT3-ITD).

He received standard induction chemotherapy (7+3) with cytarabine (ARA-C; 100 mg/m2for 7 days) and daunorubicin (DNM; 60 mg/m2 for 3 days). His induction chemotherapy was complicated by severe palatine and uvular necrosis of indeterminate etiology (possible mucormycosis).

Bone marrow biopsy at day 28 demonstrated persistent disease with 10% bone marrow blasts (Fig. 1). Due to his complicated clinical course and the presence of a FLT3-ITD, salvage therapy with 5-azacitidine (5-AZA) and sorafenib (SFN) was instituted. Table 1.
The highlighted therapies were employed in this particular case at various time points as shown in Fig. 1.

http://ars.els-cdn.com/content/image/1-s2.0-S221304891530025X-gr1.jpg

References

    • [1]
    • J.E. Cortes, D.W. Kim, J. Pinilla-Ibarz, et al.
    • A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias
    • New Engl. J. Med., 369 (19) (2013), pp. 1783–1796
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    • F. Ravandi, M.L. Alattar, M.R. Grunwald, et al.
    • Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation
    • Blood, 121 (23) (2013), pp. 4655–4662
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    • N.P. Shah, M. Talpaz, M.W. Deininger, et al.
    • Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study
    • Br. J. Haematol., 162 (4) (2013), pp. 548–552
    • [4]
    • Y. Alvarado, H.M. Kantarjian, R. Luthra, et al.
    • Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations
    • Cancer, 120 (14) (2014), pp. 2142–2149
    • [5]
    • C.C. Smith, C. Zhang, K.C. Lin, et al.
    • Characterizing and overriding the structural mechanism of the Quizartinib-Resistant FLT3 “Gatekeeper” F691L mutation with PLX3397
    • Cancer Discov. (2015)
    • [6]
    • M. Greaves, C.C. Maley
    • Clonal evolution in cancer
    • Nature, 481 (7381) (2012), pp. 306–313

 

 

 

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