Tag Archives: diabetes

Bloodless diabetes monitor enabled by nanotechnology

There have been some remarkable advances in the treatment of many diseases, diabetes being one of them. Of course, we can always make things better.and monitoring a diabetic patient’s glucose without have to draw blood is an improvement that may occur sooner rather than later as an April 9,2018 news item on Nanowerk suggests,

Scientists have created a non-invasive, adhesive patch, which promises the measurement of glucose levels through the skin without a finger-prick blood test, potentially removing the need for millions of diabetics to frequently carry out the painful and unpopular tests.

The patch does not pierce the skin, instead it draws glucose out from fluid between cells across hair follicles, which are individually accessed via an array of miniature sensors using a small electric current. The glucose collects in tiny reservoirs and is measured. Readings can be taken every 10 to 15 minutes over several hours.

Crucially, because of the design of the array of sensors and reservoirs, the patch does not require calibration with a blood sample — meaning that finger prick blood tests are unnecessary.

The device can measure glucose levels without piercing the skin Courtesy: University of Bath

An April 9, 2018 University of Bath press release, which originated the news item, expands on the theme,

Having established proof of the concept behind the device in a study published in Nature Nanotechnology, the research team from the University of Bath hopes that it can eventually become a low-cost, wearable sensor that sends regular, clinically relevant glucose measurements to the wearer’s phone or smartwatch wirelessly, alerting them when they may need to take action.

An important advantage of this device over others is that each miniature sensor of the array can operate on a small area over an individual hair follicle – this significantly reduces inter- and intra-skin variability in glucose extraction and increases the accuracy of the measurements taken such that calibration via a blood sample is not required.

The project is a multidisciplinary collaboration between scientists from the Departments of Physics, Pharmacy & Pharmacology, and Chemistry at the University of Bath.

Professor Richard Guy, from the Department of Pharmacy & Pharmacology, said: “A non-invasive – that is, needle-less – method to monitor blood sugar has proven a difficult goal to attain. The closest that has been achieved has required either at least a single-point calibration with a classic ‘finger-stick’, or the implantation of a pre-calibrated sensor via a single needle insertion. The monitor developed at Bath promises a truly calibration-free approach, an essential contribution in the fight to combat the ever-increasing global incidence of diabetes.”

Dr Adelina Ilie, from the Department of Physics, said: “The specific architecture of our array permits calibration-free operation, and it has the further benefit of allowing realisation with a variety of materials in combination. We utilised graphene as one of the components as it brings important advantages: specifically, it is strong, conductive, flexible, and potentially low-cost and environmentally friendly. In addition, our design can be implemented using high-throughput fabrication techniques like screen printing, which we hope will ultimately support a disposable, widely affordable device.”

In this study the team tested the patch on both pig skin, where they showed it could accurately track glucose levels across the range seen in diabetic human patients, and on healthy human volunteers, where again the patch was able to track blood sugar variations throughout the day.

The next steps include further refinement of the design of the patch to optimise the number of sensors in the array, to demonstrate full functionality over a 24-hour wear period, and to undertake a number of key clinical trials.

Diabetes is a serious public health problem which is increasing. The World Health Organization predicts the world-wide incidence of diabetes to rise from 171M in 2000 to 366M in 2030. In the UK, just under six per cent of adults have diabetes and the NHS spends around 10% of its budget on diabetes monitoring and treatments. Up to 50% of adults with diabetes are undiagnosed.

An effective, non-invasive way of monitoring blood glucose could both help diabetics, as well as those at risk of developing diabetes, make the right choices to either manage the disease well or reduce their risk of developing the condition. The work was funded by the Engineering and Physical Sciences Research Council (EPSRC), the Medical Research Council (MRC), and the Sir Halley Stewart Trust.

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

Non-invasive, transdermal, path-selective and specific glucose monitoring via a graphene-based platform by Luca Lipani, Bertrand G. R. Dupont, Floriant Doungmene, Frank Marken, Rex M. Tyrrell, Richard H. Guy, & Adelina Ilie. Nature Nanotechnology (2018) doi:10.1038/s41565-018-0112-4 Published online: 09 April 2018

This paper is behind a paywall.

Being smart about using artificial intelligence in the field of medicine

Since my August 20, 2018 post featured an opinion piece about the possibly imminent replacement of radiologists with artificial intelligence systems and the latest research about employing them for diagnosing eye diseases, it seems like a good time to examine some of the mythology embedded in the discussion about AI and medicine.

Imperfections in medical AI systems

An August 15, 2018 article for Slate.com by W. Nicholson Price II (who teaches at the University of Michigan School of Law; in addition to his law degree he has a PhD in Biological Sciences from Columbia University) begins with the peppy, optimistic view before veering into more critical territory (Note: Links have been removed),

For millions of people suffering from diabetes, new technology enabled by artificial intelligence promises to make management much easier. Medtronic’s Guardian Connect system promises to alert users 10 to 60 minutes before they hit high or low blood sugar level thresholds, thanks to IBM Watson, “the same supercomputer technology that can predict global weather patterns.” Startup Beta Bionics goes even further: In May, it received Food and Drug Administration approval to start clinical trials on what it calls a “bionic pancreas system” powered by artificial intelligence, capable of “automatically and autonomously managing blood sugar levels 24/7.”

An artificial pancreas powered by artificial intelligence represents a huge step forward for the treatment of diabetes—but getting it right will be hard. Artificial intelligence (also known in various iterations as deep learning and machine learning) promises to automatically learn from patterns in medical data to help us do everything from managing diabetes to finding tumors in an MRI to predicting how long patients will live. But the artificial intelligence techniques involved are typically opaque. We often don’t know how the algorithm makes the eventual decision. And they may change and learn from new data—indeed, that’s a big part of the promise. But when the technology is complicated, opaque, changing, and absolutely vital to the health of a patient, how do we make sure it works as promised?

Price describes how a ‘closed loop’ artificial pancreas with AI would automate insulin levels for diabetic patients, flaws in the automated system, and how companies like to maintain a competitive advantage (Note: Links have been removed),

[…] a “closed loop” artificial pancreas, where software handles the whole issue, receiving and interpreting signals from the monitor, deciding when and how much insulin is needed, and directing the insulin pump to provide the right amount. The first closed-loop system was approved in late 2016. The system should take as much of the issue off the mind of the patient as possible (though, of course, that has limits). Running a close-loop artificial pancreas is challenging. The way people respond to changing levels of carbohydrates is complicated, as is their response to insulin; it’s hard to model accurately. Making it even more complicated, each individual’s body reacts a little differently.

Here’s where artificial intelligence comes into play. Rather than trying explicitly to figure out the exact model for how bodies react to insulin and to carbohydrates, machine learning methods, given a lot of data, can find patterns and make predictions. And existing continuous glucose monitors (and insulin pumps) are excellent at generating a lot of data. The idea is to train artificial intelligence algorithms on vast amounts of data from diabetic patients, and to use the resulting trained algorithms to run a closed-loop artificial pancreas. Even more exciting, because the system will keep measuring blood glucose, it can learn from the new data and each patient’s artificial pancreas can customize itself over time as it acquires new data from that patient’s particular reactions.

Here’s the tough question: How will we know how well the system works? Diabetes software doesn’t exactly have the best track record when it comes to accuracy. A 2015 study found that among smartphone apps for calculating insulin doses, two-thirds of the apps risked giving incorrect results, often substantially so. … And companies like to keep their algorithms proprietary for a competitive advantage, which makes it hard to know how they work and what flaws might have gone unnoticed in the development process.

There’s more,

These issues aren’t unique to diabetes care—other A.I. algorithms will also be complicated, opaque, and maybe kept secret by their developers. The potential for problems multiplies when an algorithm is learning from data from an entire hospital, or hospital system, or the collected data from an entire state or nation, not just a single patient. …

The [US Food and Drug Administraiont] FDA is working on this problem. The head of the agency has expressed his enthusiasm for bringing A.I. safely into medical practice, and the agency has a new Digital Health Innovation Action Plan to try to tackle some of these issues. But they’re not easy, and one thing making it harder is a general desire to keep the algorithmic sauce secret. The example of IBM Watson for Oncology has given the field a bit of a recent black eye—it turns out that the company knew the algorithm gave poor recommendations for cancer treatment but kept that secret for more than a year. …

While Price focuses on problems with algorithms and with developers and their business interests, he also hints at some of the body’s complexities.

Can AI systems be like people?

Susan Baxter, a medical writer with over 20 years experience, a PhD in health economics, and author of countless magazine articles and several books, offers a more person-centered approach to the discussion in her July 6, 2018 posting on susanbaxter.com,

The fascination with AI continues to irk, given that every second thing I read seems to be extolling the magic of AI and medicine and how It Will Change Everything. Which it will not, trust me. The essential issue of illness remains perennial and revolves around an individual for whom no amount of technology will solve anything without human contact. …

But in this world, or so we are told by AI proponents, radiologists will soon be obsolete. [my August 20, 2018 post] The adaptational learning capacities of AI mean that reading a scan or x-ray will soon be more ably done by machines than humans. The presupposition here is that we, the original programmers of this artificial intelligence, understand the vagaries of real life (and real disease) so wonderfully that we can deconstruct these much as we do the game of chess (where, let’s face it, Big Blue ate our lunch) and that analyzing a two-dimensional image of a three-dimensional body, already problematic, can be reduced to a series of algorithms.

Attempting to extrapolate what some “shadow” on a scan might mean in a flesh and blood human isn’t really quite the same as bishop to knight seven. Never mind the false positive/negatives that are considered an acceptable risk or the very real human misery they create.

Moravec called it

It’s called Moravec’s paradox, the inability of humans to realize just how complex basic physical tasks are – and the corresponding inability of AI to mimic it. As you walk across the room, carrying a glass of water, talking to your spouse/friend/cat/child; place the glass on the counter and open the dishwasher door with your foot as you open a jar of pickles at the same time, take a moment to consider just how many concurrent tasks you are doing and just how enormous the computational power these ostensibly simple moves would require.

Researchers in Singapore taught industrial robots to assemble an Ikea chair. Essentially, screw in the legs. A person could probably do this in a minute. Maybe two. The preprogrammed robots took nearly half an hour. And I suspect programming those robots took considerably longer than that.

Ironically, even Elon Musk, who has had major production problems with the Tesla cars rolling out of his high tech factory, has conceded (in a tweet) that “Humans are underrated.”

I wouldn’t necessarily go that far given the political shenanigans of Trump & Co. but in the grand scheme of things I tend to agree. …

Is AI going the way of gene therapy?

Susan draws a parallel between the AI and medicine discussion with the discussion about genetics and medicine (Note: Links have been removed),

On a somewhat similar note – given the extent to which genetics discourse has that same linear, mechanistic  tone [as AI and medicine] – it turns out all this fine talk of using genetics to determine health risk and whatnot is based on nothing more than clever marketing, since a lot of companies are making a lot of money off our belief in DNA. Truth is half the time we don’t even know what a gene is never mind what it actually does;  geneticists still can’t agree on how many genes there are in a human genome, as this article in Nature points out.

Along the same lines, I was most amused to read about something called the Super Seniors Study, research following a group of individuals in their 80’s, 90’s and 100’s who seem to be doing really well. Launched in 2002 and headed by Angela Brooks Wilson, a geneticist at the BC [British Columbia] Cancer Agency and SFU [Simon Fraser University] Chair of biomedical physiology and kinesiology, this longitudinal work is examining possible factors involved in healthy ageing.

Turns out genes had nothing to do with it, the title of the Globe and Mail article notwithstanding. (“Could the DNA of these super seniors hold the secret to healthy aging?” The answer, a resounding “no”, well hidden at the very [end], the part most people wouldn’t even get to.) All of these individuals who were racing about exercising and working part time and living the kind of life that makes one tired just reading about it all had the same “multiple (genetic) factors linked to a high probability of disease”. You know, the gene markers they tell us are “linked” to cancer, heart disease, etc., etc. But these super seniors had all those markers but none of the diseases, demonstrating (pretty strongly) that the so-called genetic links to disease are a load of bunkum. Which (she said modestly) I have been saying for more years than I care to remember. You’re welcome.

The fundamental error in this type of linear thinking is in allowing our metaphors (genes are the “blueprint” of life) and propensity towards social ideas of determinism to overtake common sense. Biological and physiological systems are not static; they respond to and change to life in its entirety, whether it’s diet and nutrition to toxic or traumatic insults. Immunity alters, endocrinology changes, – even how we think and feel affects the efficiency and effectiveness of physiology. Which explains why as we age we become increasingly dissimilar.

If you have the time, I encourage to read Susan’s comments in their entirety.

Scientific certainties

Following on with genetics, gene therapy dreams, and the complexity of biology, the June 19, 2018 Nature article by Cassandra Willyard (mentioned in Susan’s posting) highlights an aspect of scientific research not often mentioned in public,

One of the earliest attempts to estimate the number of genes in the human genome involved tipsy geneticists, a bar in Cold Spring Harbor, New York, and pure guesswork.

That was in 2000, when a draft human genome sequence was still in the works; geneticists were running a sweepstake on how many genes humans have, and wagers ranged from tens of thousands to hundreds of thousands. Almost two decades later, scientists armed with real data still can’t agree on the number — a knowledge gap that they say hampers efforts to spot disease-related mutations.

In 2000, with the genomics community abuzz over the question of how many human genes would be found, Ewan Birney launched the GeneSweep contest. Birney, now co-director of the European Bioinformatics Institute (EBI) in Hinxton, UK, took the first bets at a bar during an annual genetics meeting, and the contest eventually attracted more than 1,000 entries and a US$3,000 jackpot. Bets on the number of genes ranged from more than 312,000 to just under 26,000, with an average of around 40,000. These days, the span of estimates has shrunk — with most now between 19,000 and 22,000 — but there is still disagreement (See ‘Gene Tally’).

… the inconsistencies in the number of genes from database to database are problematic for researchers, Pruitt says. “People want one answer,” she [Kim Pruitt, a genome researcher at the US National Center for Biotechnology Information {NCB}] in Bethesda, Maryland] adds, “but biology is complex.”

I wanted to note that scientists do make guesses and not just with genetics. For example, Gina Mallet’s 2005 book ‘Last Chance to Eat: The Fate of Taste in a Fast Food World’ recounts the story of how good and bad levels of cholesterol were established—the experts made some guesses based on their experience. That said, Willyard’s article details the continuing effort to nail down the number of genes almost 20 years after the human genome project was completed and delves into the problems the scientists have uncovered.

Final comments

In addition to opaque processes with developers/entrepreneurs wanting to maintain their secrets for competitive advantages and in addition to our own poor understanding of the human body (how many genes are there anyway?), there are same major gaps (reflected in AI) in our understanding of various diseases. Angela Lashbrook’s August 16, 2018 article for The Atlantic highlights some issues with skin cancer and shade of your skin (Note: Links have been removed),

… While fair-skinned people are at the highest risk for contracting skin cancer, the mortality rate for African Americans is considerably higher: Their five-year survival rate is 73 percent, compared with 90 percent for white Americans, according to the American Academy of Dermatology.

As the rates of melanoma for all Americans continue a 30-year climb, dermatologists have begun exploring new technologies to try to reverse this deadly trend—including artificial intelligence. There’s been a growing hope in the field that using machine-learning algorithms to diagnose skin cancers and other skin issues could make for more efficient doctor visits and increased, reliable diagnoses. The earliest results are promising—but also potentially dangerous for darker-skinned patients.

… Avery Smith, … a software engineer in Baltimore, Maryland, co-authored a paper in JAMA [Journal of the American Medical Association] Dermatology that warns of the potential racial disparities that could come from relying on machine learning for skin-cancer screenings. Smith’s co-author, Adewole Adamson of the University of Texas at Austin, has conducted multiple studies on demographic imbalances in dermatology. “African Americans have the highest mortality rate [for skin cancer], and doctors aren’t trained on that particular skin type,” Smith told me over the phone. “When I came across the machine-learning software, one of the first things I thought was how it will perform on black people.”

Recently, a study that tested machine-learning software in dermatology, conducted by a group of researchers primarily out of Germany, found that “deep-learning convolutional neural networks,” or CNN, detected potentially cancerous skin lesions better than the 58 dermatologists included in the study group. The data used for the study come from the International Skin Imaging Collaboration, or ISIC, an open-source repository of skin images to be used by machine-learning algorithms. Given the rise in melanoma cases in the United States, a machine-learning algorithm that assists dermatologists in diagnosing skin cancer earlier could conceivably save thousands of lives each year.

… Chief among the prohibitive issues, according to Smith and Adamson, is that the data the CNN relies on come from primarily fair-skinned populations in the United States, Australia, and Europe. If the algorithm is basing most of its knowledge on how skin lesions appear on fair skin, then theoretically, lesions on patients of color are less likely to be diagnosed. “If you don’t teach the algorithm with a diverse set of images, then that algorithm won’t work out in the public that is diverse,” says Adamson. “So there’s risk, then, for people with skin of color to fall through the cracks.”

As Adamson and Smith’s paper points out, racial disparities in artificial intelligence and machine learning are not a new issue. Algorithms have mistaken images of black people for gorillas, misunderstood Asians to be blinking when they weren’t, and “judged” only white people to be attractive. An even more dangerous issue, according to the paper, is that decades of clinical research have focused primarily on people with light skin, leaving out marginalized communities whose symptoms may present differently.

The reasons for this exclusion are complex. According to Andrew Alexis, a dermatologist at Mount Sinai, in New York City, and the director of the Skin of Color Center, compounding factors include a lack of medical professionals from marginalized communities, inadequate information about those communities, and socioeconomic barriers to participating in research. “In the absence of a diverse study population that reflects that of the U.S. population, potential safety or efficacy considerations could be missed,” he says.

Adamson agrees, elaborating that with inadequate data, machine learning could misdiagnose people of color with nonexistent skin cancers—or miss them entirely. But he understands why the field of dermatology would surge ahead without demographically complete data. “Part of the problem is that people are in such a rush. This happens with any new tech, whether it’s a new drug or test. Folks see how it can be useful and they go full steam ahead without thinking of potential clinical consequences. …

Improving machine-learning algorithms is far from the only method to ensure that people with darker skin tones are protected against the sun and receive diagnoses earlier, when many cancers are more survivable. According to the Skin Cancer Foundation, 63 percent of African Americans don’t wear sunscreen; both they and many dermatologists are more likely to delay diagnosis and treatment because of the belief that dark skin is adequate protection from the sun’s harmful rays. And due to racial disparities in access to health care in America, African Americans are less likely to get treatment in time.

Happy endings

I’ll add one thing to Price’s article, Susan’s posting, and Lashbrook’s article about the issues with AI , certainty, gene therapy, and medicine—the desire for a happy ending prefaced with an easy solution. If the easy solution isn’t possible accommodations will be made but that happy ending is a must. All disease will disappear and there will be peace on earth. (Nod to Susan Baxter and her many discussions with me about disease processes and happy endings.)

The solutions, for the most part, are seen as technological despite the mountain of evidence suggesting that technology reflects our own imperfect understanding of health and disease therefore providing what is at best an imperfect solution.

Also, we tend to underestimate just how complex humans are not only in terms of disease and health but also with regard to our skills, understanding, and, perhaps not often enough, our ability to respond appropriately in the moment.

There is much to celebrate in what has been accomplished: no more black death, no more smallpox, hip replacements, pacemakers, organ transplants, and much more. Yes, we should try to improve our medicine. But, maybe alongside the celebration we can welcome AI and other technologies with a lot less hype and a lot more skepticism.

Melting body fat with a microneedle patch

For many people this may seem like a dream come true but there is a proviso. So far researchers have gotten to the in vivo testing (mice)  with no word about human clinical trials, which means it could be quite a while, assuming human clinical trials go well, before any product comes to market. With that in mind, here’s more from a Sept.15, 2017 news item on Nanowerk,

Researchers have devised a medicated skin patch that can turn energy-storing white fat into energy-burning brown fat locally while raising the body’s overall metabolism. The patch could be used to burn off pockets of unwanted fat such as “love handles” and treat metabolic disorders like obesity and diabetes, according to researchers at Columbia University Medical Center (CUMC) and the University of North Carolina.

A Sept. 15, 2017 Columbia University Medical Center news release on EurekAlert, which originated the news item, describes the research further,

Humans have two types of fat. White fat stores excess energy in large triglyceride droplets. Brown fat has smaller droplets and a high number of mitochondria that burn fat to produce heat. Newborns have a relative abundance of brown fat, which protects against exposure to cold temperatures. But by adulthood, most brown fat is lost.

For years, researchers have been searching for therapies that can transform an adult’s white fat into brown fat–a process named browning–which can happen naturally when the body is exposed to cold temperatures–as a treatment for obesity and diabetes.

“There are several clinically available drugs that promote browning, but all must be given as pills or injections,” said study co-leader Li Qiang, PhD, assistant professor of pathology and cell biology at CUMC. “This exposes the whole body to the drugs, which can lead to side effects such as stomach upset, weight gain, and bone fractures. Our skin patch appears to alleviate these complications by delivering most drugs directly to fat tissue.”

To apply the treatment, the drugs are first encased in nanoparticles, each roughly 250 nanometers (nm) in diameter–too small to be seen by the naked eye. (In comparison, a human hair is about 100,000 nm wide.) The nanoparticles are then loaded into a centimeter-square skin patch containing dozens of microscopic needles. When applied to skin, the needles painlessly pierce the skin and gradually release the drug from nanoparticles into underlying tissue.

“The nanoparticles were designed to effectively hold the drug and then gradually collapse, releasing it into nearby tissue in a sustained way instead of spreading the drug throughout the body quickly,” said patch designer and study co-leader Zhen Gu, PhD, associate professor of joint biomedical engineering at the University of North Carolina at Chapel Hill and North Carolina State University.

The new treatment approach was tested in obese mice by loading the nanoparticles with one of two compounds known to promote browning: rosiglitazone (Avandia) or beta-adrenergic receptor agonist (CL 316243) that works well in mice but not in humans. Each mouse was given two patches–one loaded with drug-containing nanoparticles and another without drug–that were placed on either side of the lower abdomen. New patches were applied every three days for a total of four weeks. Control mice were also given two empty patches.

Mice treated with either of the two drugs had a 20 percent reduction in fat on the treated side compared to the untreated side. They also had significantly lower fasting blood glucose levels than untreated mice.

Tests in normal, lean mice revealed that treatment with either of the two drugs increased the animals’ oxygen consumption (a measure of overall metabolic activity) by about 20 percent compared to untreated controls.

Genetic analyses revealed that the treated side contained more genes associated with brown fat than on the untreated side, suggesting that the observed metabolic changes and fat reduction were due to an increase in browning in the treated mice.

“Many people will no doubt be excited to learn that we may be able to offer a noninvasive alternative to liposuction for reducing love handles,” says Dr. Qiang. “What’s much more important is that our patch may provide a safe and effective means of treating obesity and related metabolic disorders such as diabetes.” [emphasis mine]

The patch has not been tested in humans. The researchers are currently studying which drugs, or combination of drugs, work best to promote localized browning and increase overall metabolism.

The study was supported by grants from the North Carolina Translational and Clinical Sciences Institute and the National Institutes of Health (1UL1TR001111, R00DK97455, and P30DK063608).

Notice the emphasis on health and that the funding does not seem to be from industry (the National Institutes of Health is definitely a federal US agency but I’m not familiar with the North Carolina Translational and Clinical Sciences Institute).

Getting back to the research, here’s an animation featuring the work,

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

Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment by Yuqi Zhang†, Qiongming Liu, Jicheng Yu†, Shuangjiang Yu, Jinqiang Wang, Li Qiang, and Zhen Gu. ACS Nano, Article ASAP DOI: 10.1021/acsnano.7b04348 Publication Date (Web): September 15, 2017

Copyright © 2017 American Chemical Society

This paper is behind a paywall.

I would imagine that Qiang and his colleagues will find a number of business entities will be lining up to fund their work. While the researchers may be focused primarily on health issues, I imagine business types will be seeing dollar signs (very big ones with many zeroes).

Hit and run gene therapy?

The approach looks promising but there’s a still long way to go before this ‘simpler, gentler’ approach to gene therapy will make its way into any treatments. From an August 30, 2017 news item on Nanowerk,

A new biomedical tool using nanoparticles that deliver transient gene changes to targeted cells could make therapies for a variety of diseases — including cancer, diabetes and HIV — faster and cheaper to develop, and more customizable.

The tool, developed by researchers at Fred Hutchinson Cancer Research Center and tested in preclinical models, is described in a paper published August 30 [2017] in Nature Communications.

This animation demonstrates the approach,

Biodegradable nanoparticles (orange) carry short-lived gene therapy to specific cells (light teal). Animation by Kimberly Carney / Fred Hutch News Service

An August 30, 2017 Fred Hutchinson Cancer Research Center (Fred Hutch) news release (from news release received via email; also on EurekAlert) by Sabrina Richards, which originated the news item, elucidates further (Note: Some links and notes have been removed),

“Our goal is to streamline the manufacture of cell-based therapies,” said lead author DR. MATTHIAS STEPHAN [6], a faculty member in the Fred Hutch Clinical Research Division and an expert in developing biomaterials. “In this study, we created a product where you just add it to cultured cells and that’s it — no additional manufacturing steps.”

Stephan and his colleagues developed a nanoparticle delivery system to extend the therapeutic potential of messenger RNA, which delivers molecular instructions from DNA to cells in the body, directing them to make proteins to prevent or fight disease.

The researchers’ approach was designed to zero in on specific cell types — T cells of the immune system and blood stem cells — and deliver mRNA directly to the cells, triggering short-term gene expression. It’s called “hit-and-run” genetic programming because the transient effect of mRNA does not change the DNA, but it is enough to make a permanent impact on the cells’ therapeutic potential.

Stephan and colleagues used three examples in the Nature Communications paper to demonstrate their technology:

* Nanoparticles carried a gene-editing tool to T cells of the immune system that snipped out their natural T-cell receptors, and then was paired with genes encoding a “chimeric antigen receptor” or CAR, a synthetic molecule designed to attack cancer.
* Targeted to blood stem cells, nanoparticles were equipped with mRNA that enabled the stem cells to multiply and replace blood cancer cells with healthy cells when used in bone marrow transplants.
* Nanoparticles targeted to CAR-T cells and containing foxo1 mRNA, which signals the anti-cancer T cells to develop into a type of “memory” cell that is more aggressive and destroys tumor cells more effectively and maintains anti-tumor activity longer.

Other attempts to engineer mRNA into disease-fighting cells have been tricky. The large messenger molecule degrades quickly before it can have an effect, and the body’s immune system recognizes it as foreign — not coming from DNA in the nucleus of the cell — and destroys it.

Stephan and his Fred Hutch collaborators devised a workaround to those hurdles.

“We developed a nanocarrier that binds and condenses synthetic mRNA and protects it from degradation,” Stephan said. The researchers surrounded the nanoparticle with a negatively charged envelope with a targeting ligand attached to the surface so that the particle selectively homes in and binds to a particular cell type.

The cells swallow up the tiny carrier, which can be loaded with different types of manmade mRNA. “If you know from the scientific literature that a signaling pathway works in synergy, you could co-deliver mRNA in a single nanoparticle,” Stephan said. “Every cell that takes up the nanoparticle can express both.”

The approach involves mixing the freeze-dried nanoparticles with water and a sample of cells. Within four hours, cells start showing signs that the editing has taken effect. Boosters can be given if needed. Made from a dissolving biomaterial, the nanoparticles are removed from the body like other cell waste.

“Just add water to our freeze-dried product,” Stephan said. Since it’s built on existing technologies and doesn’t require knowledge of nanotechnology, he intends for it to be an off-the-shelf way for cell-therapy engineers to develop new approaches to treating a variety of diseases.

The approach could replace labor-intensive electroporation, a multistep cell-manufacturing technique that requires specialized equipment and clean rooms. All the handling ends up destroying many of the cells, which limits the amount that can be used in treatments for patients.

Gentler to cells, the nanoparticle system developed by the Fred Hutch team showed that up to 60 times more cells survive the process compared with electroporation. This is a critical feature for ensuring enough cells are viable when transferred to patients.

“You can imagine taking the nanoparticles, injecting them into a patient and then you don’t have to culture cells at all anymore,” he said.

Stephan has tested the technology is cultured cells in the lab, and it’s not yet available as a treatment. Stephan is looking for commercial partners to move the technology toward additional applications and into clinical trials where it could be developed into a therapy.

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

Hit-and-run programming of therapeutic cytoreagents using mRNA nanocarriers by H. F. Moffett, M. E. Coon, S. Radtke, S. B. Stephan, L. McKnight, A. Lambert, B. L. Stoddard, H. P. Kiem, & M. T. Stephan. Nature Communications 8, Article number: 389 (2017) doi:10.1038/s41467-017-00505-8 Published online: 30 August 2017

This paper is open access.

Arbro Pharmaceuticals and its bioavailable curcumin

Curcumin (a constituent of the spice turmeric) is reputed to have health benefits and has been used in traditional medicine in Asia (notably India) for millenia. Recently scientists have been trying to render curcumin more effective which means increasing its bioavailability (my Nov. 7, 2014 posting features some of that research). According to an April 29, 2016 Arbro Pharmaceuticals press release, the goal of increased bioavailability has been reached and a product is now available commercially,

Arbro Pharmaceuticals has launched SNEC30, a patented highly bioavailable self-nanoemulsifying curcumin formulation in the dosage of 30mg.

Curcumin is the active ingredient of turmeric or haldi, which has been widely used in traditional medicine and home remedies in India for hundreds of years.

Clinical research conducted over the last 25 years has shown curcumin to be effective against various diseases like cancer, pain, inflammation, arthritis, ulcers, psoriasis, arteriosclerosis, diabetes and many more pro-inflammatory conditions.

Despite its effectiveness against so many medical conditions, scientists have come to believe that curcumin’s true potential has been limited by its poor bioavailability which is caused by the fact that it has poor solubility and extensive pre-systemic metabolism.

Arbro Pharmaceuticals partnered with Jamia Hamdard University to carry out research and develop a novel formulation, which can overcome curcumin’s poor bioavailability. The development project was jointly funded by Arbro and the Department of Science and Technology, Government of India under its DPRP (Drug and Pharmaceutical Research Programme) scheme.

SNEC30 is the outcome of this joint research and is based on a novel self-nanoemulsifying drug delivery systems (SNEDDS) for which patents have been filed and the US patent has been granted.

“There has been tremendous interest in the therapeutic potential of curcumin but its poor bioavailability was a limiting factor, our research group together with Arbro took the challenge and applied nanotechnology to overcome this limitation and achieve highest ever bioavailability for curcumin,” said Dr. Kanchan Kohli, Asst. Prof, Faculty of Pharmacy, Jamia Hamdard University, who is one of the main developers of the formulation.

Nanotechnology is the engineering of functional systems at the molecular scale (CRN – Centre for Responsible Nanotechnology). The name stems from the fact that the structures are in the nano-metre (10-9 mm) in range. In pharmaceutics, nano-formulations are used for targeted drug-delivery, particularly in cancer therapy. It also finds numerous other applications in medicine.

“Just 30mg of curcumin that is contained in one capsule of SNEC30 has shown higher blood levels than what can be achieved by consuming the curcumin content of 1kg of raw haldi or turmeric,” said Mr. Vijay Kumar Arora, Managing Director, Arbro Pharmaceuticals.

About Arbro Pharmaceuticals:

Arbro Pharmaceuticals is a 30-year-old research oriented company with its own research and development, testing and manufacturing facilities. Arbro has been manufacturing and exporting hundreds of formulations under its own brand name to more than 10 countries.

I am not endorsing this product but if you are interested the SNEC30 website is here. I believe Arbro Pharmaceuticals’ headquarters, the company which produces SNEC30, are located in India.

Wearable device to monitor and control diabetes is based on graphene

The research comes from Korea’s Institute of Basic Science and was announced in a March 22, 2016 news article by Lee Chi-dong for Yonhap News Agency,

A team of South Korean scientists announced Tuesday [March 22, 2016] that they have developed a wearable device, based on nanotechnology, for more convenient diabetes monitoring and therapy.

The graphene-using “smart patch” has improved the accuracy of blood sugar level measurements as it checks not only glucose in sweat but also temperature and acidity, according to the Institute for Basic Science (IBS) located in Daejeon, some 160 kilometers south of Seoul.

Existing smart patches gauge blood sugar merely in sweat.

Google is working on “smart contact lens” with an ultra-tiny super sensitive glucose sensor for tear fluid. Its accuracy remains a question amid concerns about adverse effects on eye health.

A March 21, 2016 IBS press release on EurekAlert provides more details about the work,

A scientific team from the Center for Nanoparticle Research at IBS has created a wearable GP [graphene]-based patch that allows accurate diabetes monitoring and feedback therapy by using human sweat. The researchers improved the device’s detecting capabilities by integrating electrochemically active and soft functional materials on the hybrid of gold-doped graphene and a serpentine-shape gold mesh. The device’s pH and temperature monitoring functions enable systematic corrections of sweat glucose measurements as the enzyme-based glucose sensor is affected by pH (blood acidity levels) and temperature.

Diabetes and regulating glucose levels

Insulin is produced in the pancreas and regulates the use of glucose, maintaining a balance in blood sugar levels. Diabetes causes an imbalance: insufficient amounts of insulin results in high blood glucose levels, known as hyperglycemia. Type 2 diabetes is the most common form of diabetes with no known cure. It affects some 3 million Koreans with the figure increasing due to dietary patterns and an aging society. The current treatments available to diabetics are painful, inconvenient and costly; regular visits to a doctor and home testing kits are needed to record glucose levels. Patients also have to inject uncomfortable insulin shots to regulate glucose levels. There is a significant need for non-invasive, painless, and stress-free monitoring of important markers of diabetes using multifunctional wearable devices. The IBS device facilitates this and thereby reduces the lengthy and expensive cycles of visiting doctors and pharmacies.

Components of the graphene-based wearable device

KIM Dae-Hyeong, a scientist from the Center for Nanoparticle Research, describes the vast array of components: “Our wearable GP-based device is capable of not only sweat-based glucose and pH monitoring but also controlled transcutaneous drug delivery through temperature-responsive microneedles. Precise measurement of sweat glucose concentrations are used to estimate the levels of glucose in the blood of a patient. The device retains its original sensitivity after multiple uses, thereby allowing for multiple treatments. The connection of the device to a portable/ wireless power supply and data transmission unit enables the point-of-care treatment of diabetes.” The professor went on to describe how the device works, “The patch is applied to the skin where sweat-based glucose monitoring begins on sweat generation. The humidity sensor monitors the increase in relative humidity (RH). It takes an average of 15 minutes for the sweat-uptake layer of the patch to collect sweat and reach a RH over 80% at which time glucose and pH measurements are initiated.”

Merits of the device and drug administration

The device shows dramatic advances over current treatment methods by allowing non-invasive treatments. During the team’s research, two healthy males participated in tests to demonstrate the sweat-based glucose sensing of the device. Glucose and pH levels of both subjects were recorded; a statistical analysis confirmed the reliable correlation between sweat glucose data from the diabetes patch and those from commercial glucose tests. If abnormally high levels of glucose are detected, a drug is released into a patient’s bloodstream via drug loaded microneedles. The malleable, semi-transparent skin-like appearance of the GP device provides easy and comfortable contact with human skin, allowing the sensors to remain unaffected by any skin deformations. This enables stable sensing and efficient drug delivery.

The scientific team also demonstrated the therapeutic effects by experimenting on diabetic (db/db) mice. Treatment began by applying the device near the abdomen of the db mouse. Microneedles pierced the skin of the mouse and released Metformin, an insulin regulating drug, into the bloodstream. The group treated with microneedles showed a significant suppression of blood glucose concentrations with respect to control groups. “One can easily replace the used microneedles with new ones. Treatment with Metformin through the skin is more efficient than that through the digestive system because the drug is directly introduced into metabolic circulation through the skin,” commented KIM Dae-Hyeong. He went on: “These advances using nanomaterials and devices provide new opportunities for the treatment of chronic diseases like diabetes.”

The researchers have made an image illustrating their work available,

Caption: Optical image of the GP-hybrid electrochemical device array on the human skin Credit: IBS

Caption: Optical image of the GP-hybrid electrochemical device array on the human skin Credit: IBS

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

A graphene-based electrochemical device with thermoresponsive microneedles for diabetes monitoring and therapy by Hyunjae Lee, Tae Kyu Choi, Young Bum Lee, Hye Rim Cho, Roozbeh Ghaffari, Liu Wang, Hyung Jin Choi, Taek Dong Chung, Nanshu Lu, Taeghwan Hyeon, Seung Hong Choi, & Dae-Hyeong Kim. Nature Nanotechnology (2016) doi:10.1038/nnano.2016.38 Published online 21 March 2016

This paper is behind a paywall.

Tattoos that detect glucose levels

Temporary tattoos with a biomedical function are a popular topic and one of the latest detects glucose levels without subjecting a person with diabetes to pin pricks. From a Jan. 14, 2015 news item on ScienceDaily,

Scientists have developed the first ultra-thin, flexible device that sticks to skin like a rub-on tattoo and can detect a person’s glucose levels. The sensor, reported in a proof-of-concept study in the ACS [American Chemical Society] journal Analytical Chemistry, has the potential to eliminate finger-pricking for many people with diabetes.

A Jan. 14, 2015 ACS news release on EurekAlert, which originated the news item, describes the current approaches to testing glucose and the new painless technique,

Joseph Wang and colleagues in San Diego note that diabetes affects hundreds of millions of people worldwide. Many of these patients are instructed to monitor closely their blood glucose levels to manage the disease. But the standard way of checking glucose requires a prick to the finger to draw blood for testing. The pain associated with this technique can discourage people from keeping tabs on their glucose regularly. A glucose sensing wristband had been introduced to patients, but it caused skin irritation and was discontinued. Wang’s team wanted to find a better approach.

The researchers made a wearable, non-irritating platform that can detect glucose in the fluid just under the skin based on integrating glucose extraction and electrochemical biosensing. Preliminary testing on seven healthy volunteers showed it was able to accurately determine glucose levels. The researchers conclude that the device could potentially be used for diabetes management and for other conditions such as kidney disease.

There is a Jan. 14, 2015 University of California at San Diego news release (also on EurekAlert) describing the work in more detail,

Nanoengineers at the University of California, San Diego have tested a temporary tattoo that both extracts and measures the level of glucose in the fluid in between skin cells. …

The sensor was developed and tested by graduate student Amay Bandodkar and colleagues in Professor Joseph Wang’s laboratory at the NanoEngineering Department and the Center for Wearable Sensors at the Jacobs School of Engineering at UC San Diego. Bandodkar said this “proof-of-concept” tattoo could pave the way for the Center to explore other uses of the device, such as detecting other important metabolites in the body or delivering medicines through the skin.

At the moment, the tattoo doesn’t provide the kind of numerical readout that a patient would need to monitor his or her own glucose. But this type of readout is being developed by electrical and computer engineering researchers in the Center for Wearable Sensors. “The readout instrument will also eventually have Bluetooth capabilities to send this information directly to the patient’s doctor in real-time or store data in the cloud,” said Bandodkar.

The research team is also working on ways to make the tattoo last longer while keeping its overall cost down, he noted. “Presently the tattoo sensor can easily survive for a day. These are extremely inexpensive—a few cents—and hence can be replaced without much financial burden on the patient.”

The Center “envisions using these glucose tattoo sensors to continuously monitor glucose levels of large populations as a function of their dietary habits,” Bandodkar said. Data from this wider population could help researchers learn more about the causes and potential prevention of diabetes, which affects hundreds of millions of people and is one of the leading causes of death and disability worldwide.

People with diabetes often must test their glucose levels multiple times per day, using devices that use a tiny needle to extract a small blood sample from a fingertip. Patients who avoid this testing because they find it unpleasant or difficult to perform are at a higher risk for poor health, so researchers have been searching for less invasive ways to monitor glucose.

In their report in the journal Analytical Chemistry, Wang and his co-workers describe their flexible device, which consists of carefully patterned electrodes printed on temporary tattoo paper. A very mild electrical current applied to the skin for 10 minutes forces sodium ions in the fluid between skin cells to migrate toward the tattoo’s electrodes. These ions carry glucose molecules that are also found in the fluid. A sensor built into the tattoo then measures the strength of the electrical charge produced by the glucose to determine a person’s overall glucose levels.

“The concentration of glucose extracted by the non-invasive tattoo device is almost hundred times lower than the corresponding level in the human blood,” Bandodkar explained. “Thus we had to develop a highly sensitive glucose sensor that could detect such low levels of glucose with high selectivity.”

A similar device called GlucoWatch from Cygnus Inc. was marketed in 2002, but the device was discontinued because it caused skin irritation, the UC San Diego researchers note. Their proof-of-concept tattoo sensor avoids this irritation by using a lower electrical current to extract the glucose.

Wang and colleagues applied the tattoo to seven men and women between the ages of 20 and 40 with no history of diabetes. None of the volunteers reported feeling discomfort during the tattoo test, and only a few people reported feeling a mild tingling in the first 10 seconds of the test.

To test how well the tattoo picked up the spike in glucose levels after a meal, the volunteers ate a carb-rich meal of a sandwich and soda in the lab. The device performed just as well at detecting this glucose spike as a traditional finger-stick monitor.

The researchers say the device could be used to measure other important chemicals such as lactate, a metabolite analyzed in athletes to monitor their fitness. The tattoo might also someday be used to test how well a medication is working by monitoring certain protein products in the intercellular fluid, or to detect alcohol or illegal drug consumption.

This reminds me a little of the Google moonshot project concerning health diagnostics. Announced in Oct. 2014, that project involved swallowing a pill containing nanoparticles that would circulate through your body monitoring your health and recongregating at your wrist so a band worn there could display your health status (Oct. 30, 2014 article by Signe Brewster for GigaOm). Experts welcomed the funding while warning the expectations seemed unrealistic given the current state of research and technology. This temporary tattoo seems much better grounded in terms of the technology used and achievable results.

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

Tattoo-Based Noninvasive Glucose Monitoring: A Proof-of-Concept Study by Amay J. Bandodkar, Wenzhao Jia, Ceren Yardımcı, Xuan Wang, Julian Ramirez, and Joseph Wang. Anal. Chem., 2015, 87 (1), pp 394–398 DOI: 10.1021/ac504300n Publication Date (Web): December 12, 2014

Copyright © 2014 American Chemical Society

This appears to be an open access paper.

My latest posting posting on medical tattoos (prior to this) is an Aug. 13, 2014 post about a wearable biobattery.

Doctor to patient: “Where would you like your carbon nanotubes implanted?”

A Nov. 3, 2013 news item on ScienceDaily offers some context, as well as, details for a sensing research project with medical applications being conducted at the Massachusetts Institute of Technology (MIT),

Nitric oxide (NO) is one of the most important signaling molecules in living cells, carrying messages within the brain and coordinating immune system functions. In many cancerous cells, levels are perturbed, but very little is known about how NO behaves in both healthy and cancerous cells.

“Nitric oxide has contradictory roles in cancer progression, and we need new tools in order to better understand it,” says Michael Strano, the Carbon P. Dubbs Professor of Chemical Engineering at MIT. “Our work provides a new tool for measuring this important molecule, and potentially others, in the body itself and in real time.”

Led by postdoc Nicole Iverson, Strano’s lab has built a sensor that can monitor NO in living animals for more than a year. The sensors, described in the Nov. 3 issue of Nature Nanotechnology, can be implanted under the skin and used to monitor inflammation — a process that produces NO. This is the first demonstration that nanosensors could be used within the body for this extended period of time.

The Nov. 3, 2013 MIT news release (also on EurekAlert) written by Anne Trafton, which originated the news item, describes carbon nanotubes and how they are being used as sensing devices by the research team,

Carbon nanotubes — hollow, one-nanometer-thick cylinders made of pure carbon — have drawn great interest as sensors. Strano’s lab has recently developed carbon nanotube sensors for a variety of molecules, including hydrogen peroxide and toxic agents such as the nerve gas sarin. Such sensors take advantage of carbon nanotubes’ natural fluorescence, by coupling them to a molecule that binds to a specific target. When the target is bound, the tubes’ fluorescence brightens or dims.

Strano’s lab has previously shown that carbon nanotubes can detect NO if the tubes are wrapped in DNA with a particular sequence. In the new paper, the researchers modified the nanotubes to create two different types of sensors: one that can be injected into the bloodstream for short-term monitoring, and another that is embedded in a gel so it can be implanted long-term under the skin.

To make the particles injectable, Iverson attached PEG, a biocompatible polymer that inhibits particle-clumping in the bloodstream. She found that when injected into mice, the particles can flow through the lungs and heart without causing any damage. Most of the particles accumulate in the liver, where they can be used to monitor NO associated with inflammation.

“So far we have only looked at the liver, but we do see that it stays in the bloodstream and goes to kidneys. Potentially we could study all different areas of the body with this injectable nanoparticle,” Iverson says.

The longer-term sensor consists of nanotubes embedded in a gel made from alginate, a polymer found in algae. Once this gel is implanted under the skin of the mice, it stays in place and remains functional for 400 days; the researchers believe it could last even longer. This kind of sensor could be used to monitor cancer or other inflammatory diseases, or to detect immune reactions in patients with artificial hips or other implanted devices, according to the researchers.

Once the sensors are in the body, the researchers shine a near-infrared laser on them, producing a near-infrared fluorescent signal that can be read using an instrument that can tell the difference between nanotubes and other background fluorescence.

There is research into how the sensor could be adapted for use in diabetics, from the news release,

Iverson is now working on adapting the technology to detect glucose, by wrapping different kinds of molecules around the nanotubes.

Most diabetic patients must prick their fingers several times a day to take blood glucose readings. While there are electrochemical glucose sensors available that can be attached to the skin, those sensors last only a week at most, and there is a risk of infection because the electrode pierces the skin.

Furthermore, Strano says, the electrochemical sensor technology is not accurate enough to be incorporated into the kind of closed-loop monitoring system that scientists are now working toward. This type of system would consist of a sensor that offers real-time glucose monitoring, connected to an insulin pump that would deliver insulin when needed, with no need for finger pricking or insulin injection by the patient.

“The current thinking is that every part of the closed-loop system is in place except for an accurate and stable sensor. There is considerable opportunity to improve upon devices that are now on the market so that a complete system can be realized,” Strano says.

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

In vivo biosensing via tissue-localizable near-infrared-fluorescent single-walled carbon nanotubes by Nicole M. Iverson, Paul W. Barone, Mia Shandell, Laura J. Trudel, Selda Sen, Fatih Sen, Vsevolod Ivanov, Esha Atolia, Edgardo Farias, Thomas P. McNicholas, Nigel Reuel, Nicola M. A. Parry, Gerald N. Wogan & Michael S. Strano. Nature Nanotechnology (2013) doi:10.1038/nnano.2013.222 Published online 03 November 2013

There is a free preview of the article available via ReadCube Access otherwise this article is behind a paywall.

Emory University’s Shuming Nie discusses Iron Man 3 and nanotechnology and researchers develop an injectable nano-network

I have written about Iron Man 3 before (my May 11, 2012 posting) in the context of its nanotechnology inspirations, specifically, the Extremis Armor. For anyone not familiar with the story, I have a few bits which will bring you up to speed before getting to Shuming Nie’s commentary and some recent research into injectable nano-networks, which seems highly relevant to the Iron Man 3 discourse. First, here’s an excerpt from my May 11, 2012 posting,

In a search for Extremis, I found out that this story reboots the Iron Man mythology by incorporating nanotechnology and alchemy to create a new armor, the Extremis Armor, from the Extremis Armor website (I strongly suggest going to the website and reading the full text which includes a number of illustrative images if you find this sort of thing interesting),

When a bio-tech weapon of mass destruction was unleashed, Tony Stark threw himself onto the bleeding edge between science and alchemy, combining nanotechnology and his Iron Man armor.  The result, which debuted in Iron Man, Vol. IV, issue 5, was the Extremis Armor, Model XXXII, Mark I, which made him the most powerful hero in the world–but not without a price.

There were two key parts to this Extremis-enhanced suit.  The first part is the golden Undersheath, the protective interface between Stark’s nervous system and the second chief part, the External Suit Devices (ESDs), a.k.a. the red armor plating.

The Undersheath to the Iron Man suit components was super-compressed and stored in the hollows of Stark’s bones. The sheath material exited through skeletal pores and slid between all cells to self-assemble a new “skin” around him.  This skin provides a complete interface to the Iron Man suit components and can perform numerous other functions. (The process in reverse withdrew the Undersheath back into these specially modified areas of Tony Stark’s bone marrow tissue.)

The Undersheath is a nano-network that incorporates peptide-peptide logic (PPL), a molecular computational system made of superconducting plastic impregnated molecular chains. [my emphasis added for May.6.13 posting]  The PPL handles, among other things: memory, critical logic paths, comparative “truth” tables, automatic response look-up tables, data storage, communication, and external sensing material interface.

The lattice assembly is a stress-compression truss with powered interstitial joints.  This can surround the PPL material and guide it through Stark’s body.  This steerable, motile lattice framework is commanded by the PPL molecule computational mentality.  The metallic component to the lattice is a controlled mimetic artifact that can take on the characteristics of most elements.  Even unusual combinations of behaviors such as extreme hardness and flexibility.

The combination of the two nano-scale materials allows for a very dense non-traditional computer that can change the fabric of its design in very powerful ways. The incorporation of the Undersheath in Stark’s entire nervous system renders reflex-level computer responses to pan-spectrum stimuli.

Anthony Stark’s Bio/Metalo-Mimetic Material concept is a radical departure from the traditional solid-state underpinnings of his prior Iron Man suit designs.  Making use of nano-scale assembly technology, “smart” molecules can be made atom by atom. The design allows for simple computers to be linked into a massive parallel computer that synthesizes human thought protocols.

The External Suit Devices (ESDs), the red armor plates, were made via mega-nano technology that has assembled atoms into large, discreet effectors.  This allows for the plates to be collapsable to very small volumes for easy storage and carried in Stark’s briefcase. The ESDs were commanded by the Undersheath and were self-powered by high-capacity Kasimer plates.  They were equipped with large arrays of nano-fans that allow flight.  Armoring-up was done by drawing the suit to Stark via a vectored repulsor field, just lightly pushing them from different angles.

The armor’s memory-metal technology renders it lightweight and flexible while not in use, but extremely durable when polarized.  The armor was strong, of course, but it could be made even stronger by rerouting repulsor input to reinforce the armor’s mass.

Stark’s skin is now a part of the suit, when engaged.  [emphasis mine] Comfort is relative because the suit rapidly responds to any discomfort, from impacts to high temperatures, from itching to scratching.  The suit’s protocols include semi-autonomy when needed.  Where Stark ends and the suit begins is flexible.  The exact nature of the artificial Extremis Virus is not known (especially because Stark recompiled the dose, then tweaked the nutrients and suspended metals, radically altering Maya Hansen’s [the character Rebecca Hall will reputedly play] formulations).  The effect it has had on Stark’s body is to allow the presence of so much alien material within his body without trauma.

Because of the bio-interface between Tony and the armor, he could utilize the suit to its fullest potential and also instantly access computers and any digital system worldwide at the speed of thought.  He was biologically integrated with his armor, one with it, imbued with unprecedented powers and abilities.  He channeled and processed data, emergency signals, and satellite reconnaissance from every law enforcement, military, and intelligence service in the world–in his head.  He could send electronic signals and make phone calls with his mind.  He could see through satellites.  Plus he had the ability to transmit whatever he saw (from his visual cortex) to other people’s display screens.  The computer’s cybernetic link enables him to operate all of the armor’s functions, as well as providing a remote link to other computers (as Stark is now part of the armor this connection is seamless).  The armor’s system was connected to the global mainframe via StarkTech servers.

I also like this more generalized description of the technology in the Wikipedia essay on Extemis Comics (Note: A link has been removed),

Extremis has been referred to as a “virus” constantly since the story. The verbatim description offered by its inventor Maya Hansen, goes: “…Extremis is a super-soldier solution. It’s a bio-electronics package, fitted into a few billion graphite nanotubes and suspended in a carrier fluid. [emphasis mine] A magic bullet, like the original super-soldier serum—all fitted into a single injection. It hacks the body’s repair center—the part of the brain that keeps a complete blue print of the human body. When we’re injured, we refer to that area of the brain to heal properly. Extremis rewrites the repair center. In the first stage, the body essentially becomes an open wound. The normal human blueprint is being replaced with the Extremis blueprint. The brain is being told the body is wrong. Extremis protocol dictates that the subject be placed on life support and intravenously fed nutrients at this point. For the next two or three days, the patient remains unconscious within a cocoon of scabs. (…) Extremis uses the nutrients and body mass to grow new organs. Better ones…”

A Postmedia movie reviewer, Katherine Monk noted this about the plot in her May 3, 2013 review of Iron Man 3 ,

Apparently, back in the early days of genetic engineering, a brilliant, zit-faced scientist (Guy Pearce) offered Tony a piece of a lucrative patent that had the potential to alter the human body, and even regenerate amputated limbs.

Tony walked away from the offer as well as the pretty girl (Rebecca Hall) who worked for the genetic engineer, but in the opening sequence, we see the technology was successfully developed and tested. It makes people superhuman, but it can also make them spontaneously combust, leaving great craters and human casualties behind.

Now for the video commentary, Dr. Shuming Nie, Biomedical Engineering at Emory University, offers some scientific insight into the science and the fiction of ‘extremis’ as per Iron Man 3 in his YouTube video,

Keeping on the science theme,  researchers at North Carolina State University (NCSU) and other institutions announced an injectable nano-network for diabetics in a May 3, 2013 news release on EurekAlert,

In a promising development for diabetes treatment, researchers have developed a network of nanoscale particles that can be injected into the body and release insulin when blood-sugar levels rise, maintaining normal blood sugar levels for more than a week in animal-based laboratory tests. The work was done by researchers at North Carolina State University, the University of North Carolina at Chapel Hill, the Massachusetts Institute of Technology and Children’s Hospital Boston.

“We’ve created a ‘smart’ system that is injected into the body and responds to changes in blood sugar by releasing insulin, effectively controlling blood-sugar levels,” says Dr. Zhen Gu, lead author of a paper describing the work and an assistant professor in the joint biomedical engineering program at NC State and UNC Chapel Hill. “We’ve tested the technology in mice, and one injection was able to maintain blood sugar levels in the normal range for up to 10 days.”

Here’s how the smart system is achieved,

The new, injectable nano-network is composed of a mixture containing nanoparticles with a solid core of insulin, modified dextran and glucose oxidase enzymes. When the enzymes are exposed to high glucose levels they effectively convert glucose into gluconic acid, which breaks down the modified dextran and releases the insulin. The insulin then brings the glucose levels under control. The gluconic acid and dextran are fully biocompatible and dissolve in the body.

Each of these nanoparticle cores is given either a positively charged or negatively charged biocompatible coating. The positively charged coatings are made of chitosan (a material normally found in shrimp shells), while the negatively charged coatings are made of alginate (a material normally found in seaweed).

When the solution of coated nanoparticles is mixed together, the positively and negatively charged coatings are attracted to each other to form a “nano-network.” Once injected into the subcutaneous layer of the skin, the nano-network holds the nanoparticles together and prevents them from dispersing throughout the body. Both the nano-network and the coatings are porous, allowing blood – and blood sugar – to reach the nanoparticle cores.

“This technology effectively creates a ‘closed-loop’ system that mimics the activity of the pancreas in a healthy patient, releasing insulin in response to glucose level changes,” Gu says. “This has the potential to improve the health and quality of life of diabetes patients.”

For anyone who’s interested in researching further, heres’ a citation for and a link to the paper,

Injectable Nano-Network for Glucose-Mediated Insulin Delivery by Zhen Gu, Alex A. Aimetti, Qun Wang, Tram T. Dang, Yunlong Zhang, Omid Veiseh, Hao Cheng, Robert S. Langer, and Daniel G. Anderson. ACS Nano, Article ASAP DOI: 10.1021/nn400630x Publication Date (Web): May 2, 2013

Copyright © 2013 American Chemical Society

The paper is behind a paywall. Meanwhile, there are discussions about moving these injectable nano-networks into human clinical trials. As Nie notes, Iron Man 3 hints at new medical technologies which will be achievable in the next 10 or so years, although we may have to wait 100 to 150 years for  Extremis armor.

I’ll cry if I want to—measuring glucose levels in your tears

If you look closely, you’ll see a tiny sensor beneath the eye. Inside there are nano-size biosensors which can detect your glucose levels in your tears (or sweat, if prefer). For a diabetic, checking glucose levels has to be done daily by pricking the skin to draw blood.

With this nano-sized biosensor, diabetes patients can measure their glucose levels with the fluid from the tears of their eyes. (copyright Fraunhofer IMS)

Sept. 4, 2012 news item on Nanowerk provides more details,

Pricking a finger everyday is just part of everyday life for many diabetes patients. A non-invasive measurement approach could release them from the constant pain of pin pricks. The linchpin is a biosensor engineered by Fraunhofer researchers: A tiny chip combines measurement and digital analysis – and can be radioed to a mobile device.

The Sept. 3, 2012 news release from Fraunhofer, an application-oriented research organization, provides more detail about the technology and its advantages,

The principle of measurement involves an electrochemical reaction that is activated with the aid of an enzyme. Glucose oxidase converts glucose into hydrogen peroxide (H2O2) and other chemicals whose concentration can be measured with a potentiostat. This measurement is used for calculating the glucose level. The special feature of this biosensor: the chip, measuring just 0.5 x 2.0 millimeters, can fit more than just the nanopotentiostat itself. Indeed, Fraunhofer researchers have attached the entire diagnostic system to it. “It even has an integrated analog digital converter that converts the electrochemical signals into digital data,” explains Tom Zimmermann, business unit manager at IMS. The biosensor transmits the data via a wireless interface, for example to a mobile receiver. Thus, the patient can keep a steady eye on his or her glucose level. “In the past, you used to need a circuit board the size of a half-sheet of paper,” says Zimmermann. “And you also had to have a driver. But even these things are no longer necessary with our new sensor.”

The minimal size is not the only thing that provides a substantial advantage over previous biosensors of this type. In addition, the sensor consumes substantially less power. Earlier systems required about 500 microamperes at five volts; now, it is less than 100 microamperes. That increases the durability of the system – allowing the patient to wear the sensor for weeks, or even months. The use of a passive system makes this durability possible. The sensor is able to send and receive data packages, but it can also be supplied with power through radio frequency.

The glucose sensor was engineered by the researchers at Noviosens, a Dutch medical technology firm. Since it can be manufactured so cost-effectively, it is best suited for mass production.

This looks pretty exciting. Of course, I’d still like to see find out the level of accuracy for this new way to measure glucose as compared to the current technique (no mention of clinical trials). Also, how do you affix the sensor to your skin? Is there a glue? Can you accidentally wash, wipe,  or knock your sensor off? Or, is it difficult to remove? For people who do choose to wear it beneath an eye, how does makeup affect the sensor?

Assuming that the accuracy is the same or better and that any pitfalls due to wearing a sensor have been addressed, I imagine the next hurdle will be scaling up production.

As for the ‘I’ll cry if I want to’ part of the headline for this piece, I have shamelessly borrowed [corrected 2:27 pm PDT, Sept. 5, 2012] from Lesley Gore’s 1963 hit, ‘I’s my party and I’ll cry if want to’. I’ve never loved the lyrics (for the most part) but the chorus has a haunting quality (as far as I’m concerned). Here is Lesley Gore,