Tag Archives: drug delivery

Training drugs

This summarizes some of what’s happening in nanomedicine and provides a plug (boost) for the  University of Cambridge’s nanotechnology programmes (from a June 26, 2017 news item on Nanowerk),

Nanotechnology is creating new opportunities for fighting disease – from delivering drugs in smart packaging to nanobots powered by the world’s tiniest engines.

Chemotherapy benefits a great many patients but the side effects can be brutal.
When a patient is injected with an anti-cancer drug, the idea is that the molecules will seek out and destroy rogue tumour cells. However, relatively large amounts need to be administered to reach the target in high enough concentrations to be effective. As a result of this high drug concentration, healthy cells may be killed as well as cancer cells, leaving many patients weak, nauseated and vulnerable to infection.

One way that researchers are attempting to improve the safety and efficacy of drugs is to use a relatively new area of research known as nanothrapeutics to target drug delivery just to the cells that need it.

Professor Sir Mark Welland is Head of the Electrical Engineering Division at Cambridge. In recent years, his research has focused on nanotherapeutics, working in collaboration with clinicians and industry to develop better, safer drugs. He and his colleagues don’t design new drugs; instead, they design and build smart packaging for existing drugs.

The University of Cambridge has produced a video interview (referencing a 1966 movie ‘Fantastic Voyage‘ in its title)  with Sir Mark Welland,

A June 23, 2017 University of Cambridge press release, which originated the news item, delves further into the topic of nanotherapeutics (nanomedicine) and nanomachines,

Nanotherapeutics come in many different configurations, but the easiest way to think about them is as small, benign particles filled with a drug. They can be injected in the same way as a normal drug, and are carried through the bloodstream to the target organ, tissue or cell. At this point, a change in the local environment, such as pH, or the use of light or ultrasound, causes the nanoparticles to release their cargo.

Nano-sized tools are increasingly being looked at for diagnosis, drug delivery and therapy. “There are a huge number of possibilities right now, and probably more to come, which is why there’s been so much interest,” says Welland. Using clever chemistry and engineering at the nanoscale, drugs can be ‘taught’ to behave like a Trojan horse, or to hold their fire until just the right moment, or to recognise the target they’re looking for.

“We always try to use techniques that can be scaled up – we avoid using expensive chemistries or expensive equipment, and we’ve been reasonably successful in that,” he adds. “By keeping costs down and using scalable techniques, we’ve got a far better chance of making a successful treatment for patients.”

In 2014, he and collaborators demonstrated that gold nanoparticles could be used to ‘smuggle’ chemotherapy drugs into cancer cells in glioblastoma multiforme, the most common and aggressive type of brain cancer in adults, which is notoriously difficult to treat. The team engineered nanostructures containing gold and cisplatin, a conventional chemotherapy drug. A coating on the particles made them attracted to tumour cells from glioblastoma patients, so that the nanostructures bound and were absorbed into the cancer cells.

Once inside, these nanostructures were exposed to radiotherapy. This caused the gold to release electrons that damaged the cancer cell’s DNA and its overall structure, enhancing the impact of the chemotherapy drug. The process was so effective that 20 days later, the cell culture showed no evidence of any revival, suggesting that the tumour cells had been destroyed.

While the technique is still several years away from use in humans, tests have begun in mice. Welland’s group is working with MedImmune, the biologics R&D arm of pharmaceutical company AstraZeneca, to study the stability of drugs and to design ways to deliver them more effectively using nanotechnology.

“One of the great advantages of working with MedImmune is they understand precisely what the requirements are for a drug to be approved. We would shut down lines of research where we thought it was never going to get to the point of approval by the regulators,” says Welland. “It’s important to be pragmatic about it so that only the approaches with the best chance of working in patients are taken forward.”

The researchers are also targeting diseases like tuberculosis (TB). With funding from the Rosetrees Trust, Welland and postdoctoral researcher Dr Íris da luz Batalha are working with Professor Andres Floto in the Department of Medicine to improve the efficacy of TB drugs.

Their solution has been to design and develop nontoxic, biodegradable polymers that can be ‘fused’ with TB drug molecules. As polymer molecules have a long, chain-like shape, drugs can be attached along the length of the polymer backbone, meaning that very large amounts of the drug can be loaded onto each polymer molecule. The polymers are stable in the bloodstream and release the drugs they carry when they reach the target cell. Inside the cell, the pH drops, which causes the polymer to release the drug.

In fact, the polymers worked so well for TB drugs that another of Welland’s postdoctoral researchers, Dr Myriam Ouberaï, has formed a start-up company, Spirea, which is raising funding to develop the polymers for use with oncology drugs. Ouberaï is hoping to establish a collaboration with a pharma company in the next two years.

“Designing these particles, loading them with drugs and making them clever so that they release their cargo in a controlled and precise way: it’s quite a technical challenge,” adds Welland. “The main reason I’m interested in the challenge is I want to see something working in the clinic – I want to see something working in patients.”

Could nanotechnology move beyond therapeutics to a time when nanomachines keep us healthy by patrolling, monitoring and repairing the body?

Nanomachines have long been a dream of scientists and public alike. But working out how to make them move has meant they’ve remained in the realm of science fiction.

But last year, Professor Jeremy Baumberg and colleagues in Cambridge and the University of Bath developed the world’s tiniest engine – just a few billionths of a metre [nanometre] in size. It’s biocompatible, cost-effective to manufacture, fast to respond and energy efficient.

The forces exerted by these ‘ANTs’ (for ‘actuating nano-transducers’) are nearly a hundred times larger than those for any known device, motor or muscle. To make them, tiny charged particles of gold, bound together with a temperature-responsive polymer gel, are heated with a laser. As the polymer coatings expel water from the gel and collapse, a large amount of elastic energy is stored in a fraction of a second. On cooling, the particles spring apart and release energy.

The researchers hope to use this ability of ANTs to produce very large forces relative to their weight to develop three-dimensional machines that swim, have pumps that take on fluid to sense the environment and are small enough to move around our bloodstream.

Working with Cambridge Enterprise, the University’s commercialisation arm, the team in Cambridge’s Nanophotonics Centre hopes to commercialise the technology for microfluidics bio-applications. The work is funded by the Engineering and Physical Sciences Research Council and the European Research Council.

“There’s a revolution happening in personalised healthcare, and for that we need sensors not just on the outside but on the inside,” explains Baumberg, who leads an interdisciplinary Strategic Research Network and Doctoral Training Centre focused on nanoscience and nanotechnology.

“Nanoscience is driving this. We are now building technology that allows us to even imagine these futures.”

I have featured Welland and his work here before and noted his penchant for wanting to insert nanodevices into humans as per this excerpt from an April 30, 2010 posting,
Getting back to the Cambridge University video, do go and watch it on the Nanowerk site. It is fun and very informative and approximately 17 mins. I noticed that they reused part of their Nokia morph animation (last mentioned on this blog here) and offered some thoughts from Professor Mark Welland, the team leader on that project. Interestingly, Welland was talking about yet another possibility. (Sometimes I think nano goes too far!) He was suggesting that we could have chips/devices in our brains that would allow us to think about phoning someone and an immediate connection would be made to that person. Bluntly—no. Just think what would happen if the marketers got access and I don’t even want to think what a person who suffers psychotic breaks (i.e., hearing voices) would do with even more input. Welland starts to talk at the 11 minute mark (I think). For an alternative take on the video and more details, visit Dexter Johnson’s blog, Nanoclast, for this posting. Hint, he likes the idea of a phone in the brain much better than I do.

I’m not sure what could have occasioned this latest press release and related video featuring Welland and nanotherapeutics other than guessing that it was a slow news period.

Nanomedicine and an enhanced uptake of nanoparticles

It’s nice to know that a step forward has been taken with regard to improving uptake in  nanoparticle-based drug delivery (see my April 27, 2016 posting titled: How many nanoparticle-based drugs does it take to kill a cancer tumour? More than 1% for insight into the difficulties of f nanoparticle-based drug delivery systems).

Here’s the latest move forward in a March 8, 2017 news item on Nanowerk (Note: A link has been removed),

Nanotechnology has become a growing part of medical research in recent years, with scientists feverishly working to see if tiny particles could revolutionize the world of drug delivery.

But many questions remain about how to effectively transport those particles and associated drugs to cells.
In an article published today in Scientific Reports (“Enhanced cellular uptake of size-separated lipophilic silicon nanoparticles”), FSU Associate Professor of Biological Science Steven Lenhert takes a step forward in the understanding of nanoparticles and how they can best be used to deliver drugs.

After conducting a series of experiments, Lenhert and his colleagues found that it may be possible to boost the efficacy of medicine entering target cells via a nanoparticle.

A March 8, 2017 Florida State University news release by Kathleen Haughney, which originated the news item, provides more detail about the research (an international collaboration involving the University of Toronto [Canada] and the Karlsruhe Institute of Technology [Germany]),

“We can enhance how cells take them up and make more drugs more potent,” Lenhert said.

Initially, Lenhert and his colleagues from the University of Toronto and the Karlsruhe Institute of Technology  wanted to see what happened when they encapsulated silicon nanoparticles in liposomes — or small spherical sacs of molecules — and delivered them to HeLa cells, a standard cancer cell model.

The initial goal was to test the toxicity of silicon-based nanoparticles and get a better understanding of its biological activity.

Silicon is a non-toxic substance and has well-known optical properties that allow their nanostructures to appear fluorescent under an infrared camera, where tissue would be nearly transparent. Scientists believe it has enormous potential as a delivery agent for drugs as well as in medical imaging.

But there are still questions about how silicon behaves at such a small size.

“Nanoparticles change properties as they get smaller, so scientists want to understand the biological activity,” Lenhert said. “For example, how does shape and size affect toxicity?”

Scientists found that 10 out of 18 types of the particles, ranging from 1.5 nanometers to 6 nanometers, were significantly more toxic than crude mixtures of the material.

At first, scientists believed this could be a setback, but they then discovered the reason for the toxicity levels. The more toxic fragments also had enhanced cellular uptake.

That information is more valuable long term, Lenhert said, because it means they could potentially alter nanoparticles to enhance the potency of a given therapeutic.

The work also paves the way for researchers to screen libraries of nanoparticles to see how cells react.

“This is an essential step toward the discovery of novel nanotechnology based therapeutics,” Lenhert said. “There’s big potential here for new therapeutics, but we need to be able to test everything first.”

Here’s a link to and a citation for the paper,

Enhanced cellular uptake of size-separated lipophilic silicon nanoparticles by Aubrey E. Kusi-Appiah, Melanie L. Mastronardi, Chenxi Qian, Kenneth K. Chen, Lida Ghazanfari, Plengchart Prommapan, Christian Kübel, Geoffrey A. Ozin, & Steven Lenhert. Scientific Reports 7, Article number: 43731 (2017) doi:10.1038/srep43731 Published online: 08 March 2017

This paper is open access.

The Swiss come to a better understanding of nanomaterials

Just to keep things interesting, after the report suggesting most of the information that the OECD (Organization for Economic Cooperation and Development) has on nanomaterials is of little value for determining risk (see my April 5, 2017 posting for more) the Swiss government has released a report where they claim an improved understanding of nanomaterials than they previously had due to further research into the matter. From an April 6, 2017 news item on Nanowerk,

In the past six years, the [Swiss] National Research Programme “Opportunities and Risks of Nanomaterials” (NRP 64) intensively studied the development, use, behaviour and degradation of engineered nanomaterials, including their impact on humans and on the environment.

Twenty-three research projects on biomedicine, the environment, energy, construction materials and food demonstrated the enormous potential of engineered nanoparticles for numerous applications in industry and medicine. Thanks to these projects we now know a great deal more about the risks associated with nanomaterials and are therefore able to more accurately determine where and how they can be safely used.

An April 6, 2017 Swiss National Science Foundation press release, which originated the news item, expands on the theme,

“One of the specified criteria in the programme was that every project had to examine both the opportunities and the risks, and in some cases this was a major challenge for the researchers,” explains Peter Gehr, President of the NRP 64 Steering Committee.

One development that is nearing industrial application concerns a building material strengthened with nanocellulose that can be used to produce a strong but lightweight insulation material. Successful research was also carried out in the area of energy, where the aim was to find a way to make lithium-ion batteries safer and more efficient.

Promising outlook for nanomedicine

A great deal of potential is predicted for the field of nanomedicine. Nine of the 23 projects in NRP 64 focused on biomedical applications of nanoparticles. These include their use for drug delivery, for example in the fight against viruses, or as immune modulators in a vaccine against asthma. Another promising application concerns the use of nanomagnets for filtering out harmful metallic substances from the blood. One of the projects demonstrated that certain nanoparticles can penetrate the placenta barrier, which points to potential new therapy options. The potential of cartilage and bone substitute materials based on nanocellulose or nanofibres was also studied.

The examination of potential health risks was the focus of NRP 64. A number of projects examined what happens when nanoparticles are inhaled, while two focused on ingestion. One of these investigated whether the human gut is able to absorb iron more efficiently if it is administered in the form of iron nanoparticles in a food additive, while the other studied silicon nanoparticles as they occur in powdered condiments. It was ascertained that further studies will be required in order to determine the doses that can be used without risking an inflammatory reaction in the gut.

What happens to engineered nanomaterials in the environment?

The aim of the seven projects focusing on environmental impact was to gain a better understanding of the toxicity of nanomaterials and their degradability, stability and accumulation in the environment and in biological systems. Here, the research teams monitored how engineered nanoparticles disseminate along their lifecycle, and where they end up or how they can be discarded.

One of the projects established that 95 per cent of silver nanoparticles that are washed out of textiles are collected in sewage treatment plants, while the remaining particles end up in sewage sludge, which in Switzerland is incinerated. In another project a measurement device was developed to determine how aquatic microorganisms react when they come into contact with nanoparticles.

Applying results and making them available to industry

“The findings of the NRP 64 projects form the basis for a safe application of nanomaterials,” says Christoph Studer from the Federal Office of Public Health. “It has become apparent that regulatory instruments such as testing guidelines will have to be adapted at both national and international level.” Studer has been closely monitoring the research programme in his capacity as the Swiss government’s representative in NRP 64. In this context, the precautionary matrix developed by the government is an important instrument by means of which companies can systematically assess the risks associated with the use of nanomaterials in their production processes.

The importance of standardised characterisation and evaluation of engineered nanomaterials was highlighted by the close cooperation among researchers in the programme. “The research network that was built up in the framework of NRP 64 is functioning smoothly and needs to be further nurtured,” says Professor Bernd Nowack from Empa, who headed one of the 23 projects.

The results of NRP 64 show that new key technologies such as the use of nanomaterials need to be closely monitored through basic research due to the lack of data on its long-term effects. As Peter Gehr points out, “We now know a lot more about the risks of nanomaterials and how to keep them under control. However, we need to conduct additional research to learn what happens when humans and the environment are exposed to engineered nanoparticles over longer periods, or what happens a long time after a one-off exposure.”

You can find out more about the Opportunities and Risks of Nanomaterials; National Research Programme (NRP 64) here.

Antibiotic synthetic spider silk

I have a couple of questions, what is ‘click’ chemistry and how does a chance meeting lead to a five-year, interdisciplinary research project on synthetic spider silk? From a Jan. 4, 2017 news item on ScienceDaily,

A chance meeting between a spider expert and a chemist has led to the development of antibiotic synthetic spider silk.

After five years’ work an interdisciplinary team of scientists at The University of Nottingham has developed a technique to produce chemically functionalised spider silk that can be tailored to applications used in drug delivery, regenerative medicine and wound healing.

The Nottingham research team has shown for the first time how ‘click-chemistry’ can be used to attach molecules, such as antibiotics or fluorescent dyes, to artificially produced spider silk synthesised by E.coli bacteria. The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) is published today in the online journal Advanced Materials.

A Jan. 3, 2016 University of Nottingham press release (also on EurekAlert), which originated the news item, provides a few more details about ‘click’ chemistry (not enough for me) and more information about the research,

The chosen molecules can be ‘clicked’ into place in soluble silk protein before it has been turned into fibres, or after the fibres have been formed. This means that the process can be easily controlled and more than one type of molecule can be used to ‘decorate’ individual silk strands.

Nottingham breakthrough

In a laboratory in the Centre of Biomolecular Sciences, Professor Neil Thomas from the School of Chemistry in collaboration with Dr Sara Goodacre from the School of Life Sciences, has led a team of BBSRC DTP-funded PhD students starting with David Harvey who was then joined by Victor Tudorica, Leah Ashley and Tom Coekin. They have developed and diversified this new approach to functionalising ‘recombinant’ — artificial — spider silk with a wide range of small molecules.

They have shown that when these ‘silk’ fibres are ‘decorated’ with the antibiotic levofloxacin it is slowly released from the silk, retaining its anti-bacterial activity for at least five days.

Neil Thomas, a Professor of Medicinal and Biological Chemistry, said: “Our technique allows the rapid generation of biocompatible, mono or multi-functionalised silk structures for use in a wide range of applications. These will be particularly useful in the fields of tissue engineering and biomedicine.”

Remarkable qualities of spider silk

Spider silk is strong, biocompatible and biodegradable. It is a protein-based material that does not appear to cause a strong immune, allergic or inflammatory reaction. With the recent development of recombinant spider silk, the race has been on to find ways of harnessing its remarkable qualities.

The Nottingham research team has shown that their technique can be used to create a biodegradable mesh which can do two jobs at once. It can replace the extra cellular matrix that our own cells generate, to accelerate growth of the new tissue. It can also be used for the slow release of antibiotics.

Professor Thomas said: “There is the possibility of using the silk in advanced dressings for the treatment of slow-healing wounds such as diabetic ulcers. Using our technique infection could be prevented over weeks or months by the controlled release of antibiotics. At the same time tissue regeneration is accelerated by silk fibres functioning as a temporary scaffold before being biodegraded.”

The medicinal properties of spider silk recognised for centuries.

The medicinal properties of spider silk have been recognised for centuries but not clearly understood. The Greeks and Romans treated wounded soldiers with spider webs to stop bleeding. It is said that soldiers would use a combination of honey and vinegar to clean deep wounds and then cover the whole thing with balled-up spider webs.

There is even a mention in Shakespeare’s Midsummer Night’s Dream: “I shall desire you of more acquaintance, good master cobweb,” the character ‘Bottom’ said. “If I cut my finger, I shall make bold of you.”

The press release goes on to describe the genesis of the project and how this multidisciplinary team was formed in more detail,

The idea came together at a discipline bridging university ‘sandpit’ meeting five years ago. Dr Goodacre says her chance meeting at that event with Professor Thomas proved to be one of the most productive afternoons of her career.

Dr Goodacre, who heads up the SpiderLab in the School of Life Sciences, said: “I got up at that meeting and showed the audience a picture of some spider silk. I said ‘I want to understand how this silk works, and then make some.’

“At the end of the session Neil came up to me and said ‘I think my group could make that.’ He also suggested that there might be more interesting ‘tweaks’ one could make so that the silk could be ‘decorated’ with different, useful, compounds either permanently or which could be released over time due to a change in the acidity of the environment.”

The approach required the production of the silk proteins in a bacterium where an amino acid not normally found in proteins was included. This amino acid contained an azide group which is widely used in ‘click’ reactions that only occur at that position in the protein. It was an approach that no-one had used before with spider silk — but the big question was — would it work?

Dr Goodacre said: “It was the start of a fascinating adventure that saw a postdoc undertake a very preliminary study to construct the synthetic silks. He was a former SpiderLab PhD student who had previously worked with our tarantulas. Thanks to his ground work we showed we could produce the silk proteins in bacteria. We were then joined by David Harvey, a new PhD student, who not only made the silk fibres, incorporating the unusual amino acid, but also decorated it and demonstrated its antibiotic activity. He has since extended those first ideas far beyond what we had thought might be possible.”

David Harvey’s work is described in this paper but Professor Thomas and Dr Goodacre say this is just the start. There are other joint SpiderLab/Thomas lab students working on uses for this technology in the hope of developing it further.

David Harvey, the lead author on this their first paper, has just been awarded his PhD and is now a postdoctoral researcher on a BBSRC follow-on grant so is still at the heart of the research. His current work is focused on driving the functionalised spider silk technology towards commercial application in wound healing and tissue regeneration.

Here’s a link to and a citation for the paper,

Antibiotic Spider Silk: Site-Specific Functionalization of Recombinant Spider Silk Using “Click” Chemistry by David Harvey, Philip Bardelang, Sara L. Goodacre, Alan Cockayne, and Neil R. Thomas. Advanced Materials DOI: 10.1002/adma.201604245 Version of Record online: 28 DEC 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

I imagine Mr. Cockayne’s name has led to much teasing over the years. People who have names with that kind of potential tend to either change them or double down and refuse to compromise.

A biocompatible (implantable) micromachine (microrobot)

I appreciate the detail and information in this well written Jan. 4, 2017 Columbia University news release (h/t Jan. 4, 2016 Nanowerk; Note: Links have been removed),

A team of researchers led by Biomedical Engineering Professor Sam Sia has developed a way to manufacture microscale-sized machines from biomaterials that can safely be implanted in the body. Working with hydrogels, which are biocompatible materials that engineers have been studying for decades, Sia has invented a new technique that stacks the soft material in layers to make devices that have three-dimensional, freely moving parts. The study, published online January 4, 2017, in Science Robotics, demonstrates a fast manufacturing method Sia calls “implantable microelectromechanical systems” (iMEMS).

By exploiting the unique mechanical properties of hydrogels, the researchers developed a “locking mechanism” for precise actuation and movement of freely moving parts, which can provide functions such as valves, manifolds, rotors, pumps, and drug delivery. They were able to tune the biomaterials within a wide range of mechanical and diffusive properties and to control them after implantation without a sustained power supply such as a toxic battery. They then tested the “payload” delivery in a bone cancer model and found that the triggering of release of doxorubicin from the device over 10 days showed high treatment efficacy and low toxicity, at 1/10 of the standard systemic chemotherapy dose.

“Overall, our iMEMS platform enables development of biocompatible implantable microdevices with a wide range of intricate moving components that can be wirelessly controlled on demand and solves issues of device powering and biocompatibility,” says Sia, also a member of the Data Science Institute. “We’re really excited about this because we’ve been able to connect the world of biomaterials with that of complex, elaborate medical devices. Our platform has a large number of potential applications, including the drug delivery system demonstrated in our paper which is linked to providing tailored drug doses for precision medicine.”

I particularly like this bit about hydrogels being a challenge to work with and the difficulties of integrating both rigid and soft materials,

Most current implantable microdevices have static components rather than moving parts and, because they require batteries or other toxic electronics, have limited biocompatibility. Sia’s team spent more than eight years working on how to solve this problem. “Hydrogels are difficult to work with, as they are soft and not compatible with traditional machining techniques,” says Sau Yin Chin, lead author of the study who worked with Sia. “We have tuned the mechanical properties and carefully matched the stiffness of structures that come in contact with each other within the device. Gears that interlock have to be stiff in order to allow for force transmission and to withstand repeated actuation. Conversely, structures that form locking mechanisms have to be soft and flexible to allow for the gears to slip by them during actuation, while at the same time they have to be stiff enough to hold the gears in place when the device is not actuated. We also studied the diffusive properties of the hydrogels to ensure that the loaded drugs do not easily diffuse through the hydrogel layers.”

The team used light to polymerize sheets of gel and incorporated a stepper mechanization to control the z-axis and pattern the sheets layer by layer, giving them three-dimensionality. Controlling the z-axis enabled the researchers to create composite structures within one layer of the hydrogel while managing the thickness of each layer throughout the fabrication process. They were able to stack multiple layers that are precisely aligned and, because they could polymerize a layer at a time, one right after the other, the complex structure was built in under 30 minutes.

Sia’s iMEMS technique addresses several fundamental considerations in building biocompatible microdevices, micromachines, and microrobots: how to power small robotic devices without using toxic batteries, how to make small biocompatible moveable components that are not silicon which has limited biocompatibility, and how to communicate wirelessly once implanted (radio frequency microelectronics require power, are relatively large, and are not biocompatible). The researchers were able to trigger the iMEMS device to release additional payloads over days to weeks after implantation. They were also able to achieve precise actuation by using magnetic forces to induce gear movements that, in turn, bend structural beams made of hydrogels with highly tunable properties. (Magnetic iron particles are commonly used and FDA-approved for human use as contrast agents.)

In collaboration with Francis Lee, an orthopedic surgeon at Columbia University Medical Center at the time of the study, the team tested the drug delivery system on mice with bone cancer. The iMEMS system delivered chemotherapy adjacent to the cancer, and limited tumor growth while showing less toxicity than chemotherapy administered throughout the body.

“These microscale components can be used for microelectromechanical systems, for larger devices ranging from drug delivery to catheters to cardiac pacemakers, and soft robotics,” notes Sia. “People are already making replacement tissues and now we can make small implantable devices, sensors, or robots that we can talk to wirelessly. Our iMEMS system could bring the field a step closer in developing soft miniaturized robots that can safely interact with humans and other living systems.”

Here’s a link to and a citation for the paper,

Additive manufacturing of hydrogel-based materials for next-generation implantable medical devices by Sau Yin Chin, Yukkee Cheung Poh, Anne-Céline Kohler, Jocelyn T. Compton, Lauren L. Hsu, Kathryn M. Lau, Sohyun Kim, Benjamin W. Lee, Francis Y. Lee, and Samuel K. Sia. Science Robotics  04 Jan 2017: Vol. 2, Issue 2, DOI: 10.1126/scirobotics.aah6451

This paper appears to be open access.

The researchers have provided a video demonstrating their work (you may want to read the caption below before watching),

Magnetic actuation of the Geneva drive device. A magnet is placed about 1cm below and without contact with the device. The rotating magnet results in the rotational movement of the smaller driving gear. With each full rotation of this driving gear, the larger driven gear is engaged and rotates by 60º, exposing the next reservoir to the aperture on the top layer of the device.

—Video courtesy of Sau Yin Chin/Columbia Engineering

You can hear some background conversation but it doesn’t seem to have been included for informational purposes.

A carbon nanomaterial ‘pot’ for drug delivery

Japanese scientists have developed a new material, which could be used as a carrier for drugs. From an Aug. 5, 2016 news item on phys.org,

A novel, pot-shaped, carbon nanomaterial developed by researchers from Kumamoto University, Japan is several times deeper than any hollow carbon nanostructure previously produced. This unique characteristic enables the material to gradually release substances contained within and is expected to be beneficial in applications such as drug delivery systems.

An Aug. 5, 2016 Kumamoto University press release on EurekAlert, which despite the discrepancy in the dates originated the news item, discusses carbon and the discovery in more detail,

Carbon is an element that is light, abundant, has a strong binding force, and eco-friendly. The range of carbon-based materials is expected to become more widespread in the eco-friendly society of the future. Recently, nanosized (one-billionth of a meter) carbon materials have been developed with lengths, widths, or heights below 100 nm [nanometre]. These materials take extreme forms such as tiny grained substances, thin sheet-like substances, and slim fibrous substances. Example of these new materials are fullerenes, which are hollow cage-like carbon molecules; carbon nanotubes, cylindrical nanostructures of carbon molecules; and graphene, one-atom thick sheets of carbon molecules.

Why are these tiny substances needed? One reason is that reactions with other materials can be much larger if a substance has an increased surface area. When using nanomaterials in place of existing materials, it is possible to significantly change surface area without changing weight and volume, thereby improving both size and performance. The development of carbon nanomaterials has provided novel nanostructured materials with shapes and characteristics that surpass existing materials.

Now, research from the laboratory of Kumamoto University’s Associate Prof. Yokoi has resulted in the successful development of a container-type carbon nanomaterial with a much deeper orifice than that found in similar materials. To create the new material, researchers used their own, newly developed method of material synthesis. The container-shaped nanomaterial has a complex form consisting of varied layers of stacked graphene at the bottom, the body, and the neck areas of the container, and the graphene edges along the outer surface of the body were found to be very dense. Due to these innovate features, Associate Prof. Yokoi and colleagues named the material the “carbon nanopot.”

The carbon nanopot has an outer diameter of 20 ~ 40 nm, an inner diameter of 5 ~ 30 nm, and a length of 100 ~ 200 nm. During its creation, the carbon nanopot is linked to a carbon nanofiber with a length of 20 ~ 100 μm [micrometre] meaning that the carbon nanopot is also available as a carbon nanofiber. At the junction between nanopots, the bottom of one pot simply sits on the opening of the next without sharing a graphene sheet connection. Consequently, separating nanopots is very easy.

“From a detailed surface analysis, hydrophilic hydroxyl groups were found clustered along the outer surface of the carbon nanopot body,” said Associate Prof. Yokoi. “Graphene is usually hydrophobic however, if hydroxyl groups are densely packed on the outer surface of the body, that area will be hydrophilic. In other words, carbon nanopots could be a unique nanomaterial with both hydrophobic and hydrophilic characteristics. We are currently in the process of performing a more sophisticated surface analysis in order to get that assurance.”

Since this new carbon nanopot has a relatively deep orifice, one of its expected uses is to improve drug delivery systems by acting as a new foundation for medicine to be carried into and be absorbed by the body.

Here’s a link to and a citation for the paper,

Novel pot-shaped carbon nanomaterial synthesized in a submarine-style substrate heating CVD method by Hiroyuki Yokoi, Kazuto Hatakeyama, Takaaki Taniguchi, Michio Koinuma, Masahiro Hara, and Yasumichi Matsumoto. Journal of Materials Research / Volume 31 / Issue 01 / 2016, pp 117-126 DOI: http://dx.doi.org/10.1557/jmr.2015.389 (About DOI) Published online: 13 January 2016

Copyright © Materials Research Society 2016

I’m not sure why there’s this push for publicity so long after the publication date. In any event, this paper is behind a paywall.

Combining chitosan, agarose, and protein gelatine with clay nanotubes to create scaffolds for tissue engineering

Russian scientists have published work on clay nanotube-bipolymer composite scaffolds according to an April 29, 2016 news item on ScienceDaily,

Scientists combined three biopolymers, chitosan and agarose (polysaccharides), and a protein gelatine, as the materials to produce tissue engineering scaffolds and demonstrated the enhancement of mechanical strength (doubled pick load), higher water uptake and thermal properties in chitosan-gelatine-agarose hydrogels doped with halloysite [a clay mineral and a naturally occurring nanotube].

An April 29, 2016 Kazan Federal University (Russia) press release on EurekAlert, which originated the news item, provides more detail and context,

The fabrication of a prototype tissue having functional properties close to the natural ones is crucial for effective transplantation. Tissue engineering scaffolds are typically used as supports which allow cells to form tissue-like structures essentially required for the correct functioning of the cells under the conditions close to the three-dimensional tissue.

Chitosan, a natural biodegradable and chemically versatile biopolymer, has been effectively used in antibacterial, antifungal, anti-tumour and immunostimulating formulations. To overcome the disadvantages of pure chitosan scaffolds such as mechanical fragility and low biological resistance, chitosan scaffolds are typically doped with other supporting compounds which allow for mechanical strengthening, thus yielding ?omposite biologically resistant scaffolds.

Agarose is a galactose-based backbone polysaccharide isolated from red algae, having remarkable mechanical properties which are useful in the design of tissue engineering scaffolds.

Gelatine is formed from collagen by hydrolysis (breaking the triple-helix structure into single-strand molecules) and has a number of advantages over its precursor. It is less immunogenic compared with collagen and it retains informational signal sequences promoting cell adhesion, migration, differentiation and proliferation.

The surface irregularities of the scaffold pores due to the insoluble nanosized components promote the best adhesion of the cells on scaffold materials, while the nanoparticle fillers increase the composites’ strength. Thus, researchers doped halloysite nanotubes into a chitosan-agarose-gelatine matrix to design the implantable 3D cell scaffolds.

The resulting scaffolds demonstrate the shape memory upon deformation and have the porous structure suitable for cell adhesion and proliferation which is essential for artificial tissue fabrication. Macroscopic observations have confirmed that all the samples of scaffolds exhibited the sponge-like behaviour with the shape memory and shape reconstitution after deformation both in wet and dry states.

The swelling experiments indicated that the addition of halloysite can greatly improve the hydrophilicity and wetting of composite scaffolds. The incorporation of halloysite nanotubes into the scaffolds increases the water uptake and subsequently improves the biocompatibility. The intrinsic properties of halloysite nanotubes can be used for further improving the biocompatibility of scaffolds by the loading and sustained release of different bioactive compounds. This opens the prospect for fabrication of scaffolds with defined properties for directed differentiation of cells on matrixes due to gradual release of differentiation factors.

Experiments on two types of human cancer cells (A549 and Hep3B) show that in vitro cell adhesion and proliferation on the nanocomposites occur without changes in viability and cytoskeleton formation.

Further in vivo biocompatibility and biodegradability evaluation in rats has confirmed that the scaffolds promote the formation of novel blood vessels around the implantation sites. The scaffolds show excellent resorption within six weeks after implantation in rats. Neo-vascularization observed in newly formed connective tissue placed near the scaffold allows for the complete restoration of blood flow.

The results obtained indicate that the halloysite doped scaffolds are biocompatible as demonstrated both in vitro and in vivo. In addition, they confirm the great potential of chitosan-agarose-gelatine nanocomposite porous scaffolds doped with halloysite in tissue engineering with potential for sustained nanotube drug delivery.

For anyone interested about drug delivery and nanoparticles, there’s some interesting research profiled in my April 27, 2016 posting which describes how very few nanoparticles are actually delivered to specific sites.

Getting back to the regular program, here’s a link to and a citation for the paper on scaffolds and clay nanotubes,

Clay nanotube–biopolymer composite scaffolds for tissue engineering by Ekaterina A. Naumenko, Ivan D. Guryanov, Raghuvara Yendluri, Yuri M. Lvova, and Rawil F. Fakhrullin. Nanoscale, 2016,8, 7257-7271 DOI: 10.1039/C6NR00641H First published online 01 Mar 2016

This paper is behind a paywall.

Eggshell-based bioplastics

Adding eggshell nanoparticles to a bioplastic (shown above) increases the strength and flexibility of the material, potentially making it more attractive for use in the packaging industry. Credit: Vijaya Rangari/Tuskegee University

Adding eggshell nanoparticles to a bioplastic (shown above) increases the strength and flexibility of the material, potentially making it more attractive for use in the packaging industry. Credit: Vijaya Rangari/Tuskegee University

A March 15, 2016 news item on Nanowerk describes the research,

Eggshells are both marvels and afterthoughts. Placed on end, they are as strong as the arches supporting ancient Roman aqueducts. Yet they readily crack in the middle, and once that happens, we discard them without a second thought. But now scientists report that adding tiny shards of eggshell to bioplastic could create a first-of-its-kind biodegradable packaging material that bends but does not easily break.

The researchers present their work today [March 15, 2016] at the 251st National Meeting & Exposition of the American Chemical Society (ACS).

A March 15, 2016 ACS news release (also on EurekAlert), which originated the news item, describes the work further,

“We’re breaking eggshells down into their most minute components and then infusing them into a special blend of bioplastics that we have developed,” says Vijaya K. Rangari, Ph.D. “These nano-sized eggshell particles add strength to the material and make them far more flexible than other bioplastics on the market. We believe that these traits — along with its biodegradability in the soil — could make this eggshell bioplastic a very attractive alternative packaging material.”

Worldwide, manufacturers produce about 300 million tons of plastic annually. Almost 99 percent of it is made with crude oil and other fossil fuels. Once it is discarded, petroleum-based plastics can last for centuries without breaking down. If burned, these plastics release carbon dioxide into the atmosphere, which can contribute to global climate change.

As an alternative, some manufacturers are producing bioplastics — a form of plastic derived from cornstarch, sweet potatoes or other renewable plant-based sources — that readily decompose or biodegrade once they are in the ground. However, most of these materials lack the strength and flexibility needed to work well in the packaging industry. And that’s a problem since the vast majority of plastic is used to hold, wrap and encase products. So petroleum-based materials continue to dominate the market, particularly in grocery and other retail stores, where estimates suggest that up to a trillion plastic bags are distributed worldwide every year.

To find a solution, Rangari, graduate student Boniface Tiimob and colleagues at Tuskegee University experimented with various plastic polymers. Eventually, they latched onto a mixture of 70 percent polybutyrate adipate terephthalate (PBAT), a petroleum polymer, and 30 percent polylactic acid (PLA), a polymer derived from cornstarch. PBAT, unlike other oil-based plastic polymers, is designed to begin degrading as soon as three months after it is put into the soil.

This mixture had many of the traits that the researchers were looking for, but they wanted to further enhance the flexibility of the material. So they created nanoparticles made of eggshells. They chose eggshells, in part, because they are porous, lightweight and mainly composed of calcium carbonate, a natural compound that easily decays.

The shells were washed, ground up in polypropylene glycol and then exposed to ultrasonic waves that broke the shell fragments down into nanoparticles more than 350,000 times smaller than the diameter of a human hair. Then, in a laboratory study, they infused a small fraction of these particles, each shaped like a deck of cards, into the 70/30 mixture of PBAT and PLA. The researchers found that this addition made the mixture 700 percent more flexible than other bioplastic blends. They say this pliability could make it ideal for use in retail packaging, grocery bags and food containers — including egg cartons.

In addition to bioplastics, Rangari’s team is investigating using eggshell nanoparticles to enhance wound healing, bone regeneration and drug delivery.

Making carbon nanoparticles at home with honey or molasses

No need to rush and buy any ingredients as the University of Illinois at Urbana-Champaign researchers do not provide a recipe for cooking up carbon nanoparticles. However, it is diverting to think that one day we might be able to make these items at home. From a June 19, 2015 news item by Stuart Milne on the Azonano website,

Researchers at the University of Illinois have discovered an easy method to produce carbon nanoparticles for biomedical applications. These carbon nanoparticles can be made at home within a couple of hours using easily available ingredients and molasses.

A June 19 (?), 2015 University of Illinois at Urbana-Champaign news release (also on EurekAlert) provides more detail about the research,

“If you have a microwave and honey or molasses, you can pretty much make these particles at home,” Pan [professor Dipanjan Pan] said. “You just mix them together and cook it for a few minutes, and you get something that looks like char, but that is nanoparticles with high luminescence. This is one of the simplest systems that we can think of. It is safe and highly scalable for eventual clinical use.”

These “next-generation” carbon spheres have several attractive properties, the researchers found. They naturally scatter light in a manner that makes them easy to differentiate from human tissues, eliminating the need for added dyes or fluorescing molecules to help detect them in the body.

The nanoparticles are coated with polymers that fine-tune their optical properties and their rate of degradation in the body. The polymers can be loaded with drugs that are gradually released.

The nanoparticles also can be made quite small, less than eight nanometers in diameter (a human hair is 80,000 to 100,000 nanometers thick).

“Our immune system fails to recognize anything under 10 nanometers,” Pan said. “So, these tiny particles are kind of camouflaged, I would say; they are hiding from the human immune system.”

The team tested the therapeutic potential of the nanoparticles by loading them with an anti-melanoma drug and mixing them in a topical solution that was applied to pig skin.

Bhargava’s [professor Rohit Bhargava] laboratory used vibrational spectroscopic techniques to identify the molecular structure of the nanoparticles and their cargo.

“Raman and infrared spectroscopy are the two tools that one uses to see molecular structure,” Bhargava said. “We think we coated this particle with a specific polymer and with specific drug-loading – but did we really? We use spectroscopy to confirm the formulation as well as visualize the delivery of the particles and drug molecules.”

The team found that the nanoparticles did not release the drug payload at room temperature, but at body temperature began to release the anti-cancer drug. The researchers also determined which topical applications penetrated the skin to a desired depth.

In further experiments, the researchers found they could alter the infusion of the particles into melanoma cells by adjusting the polymer coatings. Imaging confirmed that the infused cells began to swell, a sign of impending cell death.

“This is a versatile platform to carry a multitude of drugs – for melanoma, for other kinds of cancers and for other diseases,” Bhargava said. “You can coat it with different polymers to give it a different optical response. You can load it with two drugs, or three, or four, so you can do multidrug therapy with the same particles.”

“By using defined surface chemistry, we can change the properties of these particles,” Pan said. “We can make them glow at a certain wavelength and also we can tune them to release the drugs in the presence of the cellular environment. That is, I think, the beauty of the work.”

Here’s a link to and a citation for the paper,

Tunable Luminescent Carbon Nanospheres with Well-Defined Nanoscale Chemistry for Synchronized Imaging and Therapy by Prabuddha Mukherjee, Santosh K. Misra, Mark C. Gryka, Huei-Huei Chang, Saumya Tiwari, William L. Wilson, John W. Scott, Rohit Bhargava, and Dipanjan Pan. Small
DOI: 10.1002/smll.201500728 Article first published online: 20 MAY 2015

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Microbubbles reform into nanoparticles after bursting

It seems researchers at the Toronto-based (Canada), Princess Margaret Cancer Centre, have developed a new theranostic tool made of microbubbles used for imaging that are then burst into nanoparticles delivering therapeutics. From a March 30, 2015 news item on phys.org,

Biomedical researchers led by Dr. Gang Zheng at Princess Margaret Cancer Centre have successfully converted microbubble technology already used in diagnostic imaging into nanoparticles that stay trapped in tumours to potentially deliver targeted, therapeutic payloads.

The discovery, published online today [March 30, 2015] in Nature Nanotechnology, details how Dr. Zheng and his research team created a new type of microbubble using a compound called porphyrin – a naturally occurring pigment in nature that harvests light.

A March 30, 2015 University Health Network news release on EurekAlert, which originated the news item, describes the laboratory research on mice,

In the lab in pre-clinical experiments, the team used low-frequency ultrasound to burst the porphyrin containing bubbles and observed that they fragmented into nanoparticles. Most importantly, the nanoparticles stayed within the tumour and could be tracked using imaging.

“Our work provides the first evidence that the microbubble reforms into nanoparticles after bursting and that it also retains its intrinsic imaging properties. We have identified a new mechanism for the delivery of nanoparticles to tumours, potentially overcoming one of the biggest translational challenges of cancer nanotechnology. In addition, we have demonstrated that imaging can be used to validate and track the delivery mechanism,” says Dr. Zheng, Senior Scientist at the Princess Margaret and also Professor of Medical Biophysics at the University of Toronto.

Conventional microbubbles, on the other hand, lose all intrinsic imaging and therapeutic properties once they burst, he says, in a blink-of-an-eye process that takes only a minute or so after bubbles are infused into the bloodstream.

“So for clinicians, harnessing microbubble to nanoparticle conversion may be a powerful new tool that enhances drug delivery to tumours, prolongs tumour visualization and enables them to treat cancerous tumours with greater precision.”

For the past decade, Dr. Zheng’s research focus has been on finding novel ways to use heat, light and sound to advance multi-modality imaging and create unique, organic nanoparticle delivery platforms capable of transporting cancer therapeutics directly to tumours.

Interesting development, although I suspect there are many challenges yet to be met such as ensuring the microbubbles consistently arrive at their intended destination in sufficient mass to be effective both for imaging purposes and, later, as nanoparticles for drug delivery purposes.

Here’s a link to and citation for the paper,

In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging by Elizabeth Huynh, Ben Y. C. Leung, Brandon L. Helfield, Mojdeh Shakiba, Julie-Anne Gandier, Cheng S. Jin, Emma R. Master, Brian C. Wilson, David E. Goertz, & Gang Zheng. Nature Nanotechnology (2015) doi:10.1038/nnano.2015.25 Published online 30 March 2015

This paper is behind a paywall but a free preview is available via ReadCube Access.

This is one of those times where I’m including the funding agencies and the ‘About’ portions of the news release,

The research published today was funded by the Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarship, the Emerging Team Grant on Regenerative Medicine and Nanomedicine co-funded by the CIHR and the Canadian Space Agency, the Natural Sciences and Engineering Research Council of Canada, the Ontario Institute for Cancer Research, the International Collaborative R&D Project of the Ministry of Knowledge Economy, South Korea, the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research, the Canada Foundation for Innovation and The Princess Margaret Cancer Foundation.

About Princess Margaret Cancer Centre, University Health Network

The Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital and Toronto Rehabilitation Institute. All are research hospitals affiliated with the University of Toronto. For more information, go to http://www.theprincessmargaret.ca or http://www.uhn.ca .

I was not expecting to see South Korea or Brazil mentioned in the funding. Generally, when multiple countries are funding research, their own research institutions are also involved. As for the Princess Margaret Cancer Centre being one of the top five such centres internationally, I wonder how these rankings are determined.