New Materials for Wound and Skin Healing

Good research into healing — it leverages the body’s own natural resources.

Materials are widely used to help heal wounds: Collagen sponges help treat burns and pressure sores, and scaffold-like implants are used to repair bones. However, the process of tissue repair changes over time, so scientists are developing biomaterials that interact with tissues as healing takes place.

Now, Dr Ben Almquist and his team at Imperial College London have created a new molecule that could change the way traditional materials work with the body. Known as traction force-activated payloads (TrAPs), their method lets materials talk to the body’s natural repair systems to drive healing.

The researchers say incorporating TrAPs into existing medical materials could revolutionise the way injuries are treated. Dr Almquist, from Imperial’s Department of Bioengineering, said: “Our technology could help launch a new generation of materials that actively work with tissues to drive healing.”

The findings are published today in Advanced Materials.

Cellular call to action

After an injury, cells ‘crawl’ through the collagen ‘scaffolds’ found in wounds, like spiders navigating webs. As they move, they pull on the scaffold, which activates hidden healing proteins that begin to repair injured tissue.

The researchers designed TrAPs as a way to recreate this natural healing method. They folded the DNA segments into three-dimensional shapes known as aptamers that cling tightly to proteins. Then, they attached a customisable ‘handle’ that cells can grab onto on one end, before attaching the opposite end to a scaffold such as collagen.

During laboratory testing of their technique, they found that cells pulled on the TrAPs as they crawled through the collagen scaffolds. The pulling made the TrAPs unravel like shoelaces to reveal and activate the healing proteins. These proteins instruct the healing cells to grow and multiply.

The researchers also found that by changing the cellular ‘handle’, they can change which type of cell can grab hold and pull, letting them tailor TrAPs to release specific therapeutic proteins based on which cells are present at a given point in time. In doing so, the TrAPs produce materials that can smartly interact with the correct type of cell at the correct time during wound repair.

This is the first time scientists have activated healing proteins using different types of cells in human-made materials. The technique mimics healing methods found in nature. Dr Almquist said: “Using cell movement to activate healing is found in creatures ranging from sea sponges to humans. Our approach mimics them and actively works with the different varieties of cells that arrive in our damaged tissue over time to promote healing.”

From lab to humans

This approach is adaptable to different cell types, so could be used in a variety of injuries such as fractured bones, scar tissue after heart attacks, and damaged nerves. New techniques are also desperately needed for patients whose wounds won’t heal despite current interventions, like diabetic foot ulcers, which are the leading cause of non-traumatic lower leg amputations.

TrAPs are relatively straightforward to create and are fully human-made, meaning they are easily recreated in different labs and can be scaled up to industrial quantities. Their adaptability also means they could help scientists create new methods for laboratory studies of diseases, stem cells, and tissue development.

Aptamers are currently used as drugs, meaning they are already proven safe and optimised for clinical use. Because TrAPs take advantage of aptamers that are currently optimised for use in humans, they may be able to take a shorter path to the clinic than methods that start from ground zero.

Dr Almquist said: “The TrAP technology provides a flexible method to create materials that actively communicate with the wound and provide key instructions when and where they are needed. This sort of intelligent, dynamic healing is useful during every phase of the healing process, has the potential to increase the body’s chance to recover, and has far-reaching uses on many different types of wounds. This technology has the potential to serve as a conductor of wound repair, orchestrating different cells over time to work together to heal damaged tissues.”

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Drug Price Gouging in Generics

General info on prescription drugs and generic drug price gouging.

Martin Shkreli managed to make himself a household name a few years back. His claim to fame stemmed from the decision by Turing Pharmaceuticals, a company he founded and controlled, to acquire the rights to produce Daraprim. He then raised the price of the drug by 5,000 percent.

This was very bad news for the people who were dependent on the drug. Daraprim is an anti-parasitic drug that is often taken by people with AIDS to keep them from getting opportunistic infections. People with AIDS who are being successfully treated with Daraprim are not going to want to experiment with alternatives.

Daraprim was already a 60-year-old drug at the time Turing acquired it and had long been available as a generic. This meant that other manufacturers could in principle come into the market and compete with Turing’s inflated price.

Shkreli made the bet that no other drug company would take advantage of this opportunity, because even for a generic drug, there are still substantial costs for entry. Since the market for Daraprim was small, a new entrant would be unlikely to recover these costs if Turing pushed the price back down somewhere near its original level. While Daraprim was his biggest “success,” Shkreli was trying this strategy with a number of other drugs before the Justice Department put him out of business with unrelated charges of securities fraud.

Shkreli’s days of price gouging in the generic drug world may be over, but he established a model that other ambitious entrepreneurs are likely to follow. Close to 40 percent of generic drugs have only a single manufacturer. This is partly a result of the failure of anti-trust policy to stem a wave of mergers in the industry. It is also a result of the fact that many drugs simply have very limited markets where it is difficult to support multiple producers.

Most generic producers have not tried to follow the Shkreli model and jack up prices of drugs that people need for their health or even their lives, but some have. The soaring price of insulin is one important example, EpiPen, the asthma injector, is another. Both involve well-known treatments that have long been used, but the limited number of suppliers has allowed for huge price increases in recent years.

This is the context for the public drug-manufacturing corporation being proposed in a bill by Senator Elizabeth Warren and Representative Jan Schakowsky. The idea is that the federal government should create manufacturing capacity (which could be privately licensed) that would allow it to quickly enter a market to compete with the next Martin Shkreli.

If a company tries to jack up its prices by an extraordinary amount, it would find itself soon competing with a government manufacturer that is selling the same drug for the cost of production, plus a normal profit. This is a great strategy, since simply the existence of this capacity should be sufficient to discourage the next Shkreli.

There will be little money in jacking up the price of a drug by 5,000 percent if it quickly results in the disappearance of their market. This should encourage the generic industry to keep its prices in line.

It is important to note a key difference between the generic industry and brand industry. The brand pharmaceutical companies, like Pfizer and Merck, could argue that they need high prices to pay for research. These companies hugely exaggerate their research costs and downplay the extent to which high profits just mean more money for shareholders, but they actually do research.

By contrast, the generic industry is not researching new drugs. They are manufacturing drugs that have been developed by others. In this sense they can be thought of like a company that manufacturers paper plates or shovels. They need a normal profit to stay in business, nothing more.

For this reason, the Warren-Schakowsky proposal is very much the right type of remedy for excessive prices in the generic drug industry. At the same time, we have to recognize that generic drugs are the smaller part of the problem with high drug prices.

Although generics account for almost 90 percent of prescriptions, they account for only a bit more than a quarter of spending on prescription drugs. The story of drugs costing tens or hundreds of thousands of dollars a year is almost entirely a story of brand drugs with high prices as a result of patent monopolies or related protections.

This will require a larger fix, likely along the same lines, with the government paying for research and allowing new drugs to be sold as generics. But the Warren-Schakowsky bill is a huge first step in bringing drug costs down and ensuring that people will not find themselves suddenly at the mercy of the next Martin Shkreli.

Infections During Childhood Increase Risks of Mental Disorders Developing

The connection between mind and body is further emphasized.

A new study from iPSYCH shows that the infections children contract during their childhood are linked to an increase in the risk of mental disorders during childhood and adolescence. This knowledge expands our understanding of the role of the immune system in the development of mental disorders.

High temperatures, sore throats and infections during childhood can increase the risk of also suffering from a mental disorder as a child or adolescent. This is shown by the first study of its kind to follow all children born in Denmark between 1 January 1995 and 30 June 2012. The researchers have looked at all infections that have been treated from birth and also at the subsequent risk of childhood and adolescent psychiatric disorders.

“Hospital admissions with infections are particularly associated with an increased risk of mental disorders, but so too are less severe infections that are treated with medicine from the patient’s own general practitioner,” says Ole Köhler-Forsberg from Aarhus University and Aarhus University Hospital’s Psychoses Research Unit. He is one of the researchers behind the study.

The study showed that children who had been hospitalised with an infection had an 84 per cent increased risk of suffering a mental disorder and a 42 per cent increased risk of being prescribed medicine to treat mental disorders. Furthermore, the risk for a range of specific mental disorders was also higher, including psychotic disorders, OCD, tics, personality disorders, autism and ADHD.

“This knowledge increases our understanding of the fact that there is a close connection between body and brain and that the immune system can play a role in the development of mental disorders. Once again research indicates that physical and mental health are closely connected,” says Ole Köhler-Forsberg.

Highest risk following an infection

The study has just been published in JAMA Psychiatry and is a part of the Danish iPSYCH psychiatry project.

“We also found that the risk of mental disorders is highest right after the infection, which supports the infection to some extent playing a role in the development of the mental disorder,” says Ole Köhler-Forsberg.

It therefore appears that infections and the inflammatory reaction that follows afterwards can affect the brain and be part of the process of developing severe mental disorders. This can, however, also be explained by other causes, such as some people having a genetically higher risk of suffering more infections and mental disorders.

The new knowledge could have importance for further studies of the immune system and the importance of infections for the development of a wide range of childhood and adolescent mental disorders for which the researchers have shown a correlation. This is the assessment of senior researcher on the study, Research Director Michael Eriksen Benrós from the Psychiatric Centre Copenhagen at Copenhagen University hospital.

“The temporal correlations between the infection and the mental diagnoses were particularly notable, as we observed that the risk of a newly occurring mental disorder was increased by 5.66 times in the first three months after contact with a hospital due to an infection and were also increased more than twofold within the first year,” he explains.

Michael Eriksen Benrós stresses that the study can in the long term lead to increased focus on the immune system and how infections play a role in childhood and adolescent mental disorders.

“It can have a consequence for treatment and the new knowledge can be used in making the diagnosis when new psychiatric symptoms occur in a young person. But first and foremost it corroborates our increasing understanding of how closely the body and brain are connected,” he says.

Research Into Pain Shows That When People Expect More Pain, They Feel More Pain

A good study that’s needed to be done for a while.

Expect a shot to hurt and it probably will, even if the needle poke isn’t really so painful. Brace for a second shot and you’ll likely flinch again, even though — second time around — you should know better.

That’s the takeaway of a new brain imaging study published in the journal Nature Human Behaviour which found that expectations about pain intensity can become self-fulfilling prophecies. Surprisingly, those false expectations can persist even when reality repeatedly demonstrates otherwise, the study found.

“We discovered that there is a positive feedback loop between expectation and pain,” said senior author Tor Wager, a professor of psychology and neuroscience at the University of Colorado Boulder. “The more pain you expect, the stronger your brain responds to the pain. The stronger your brain responds to the pain, the more you expect.”

For decades, researchers have been intrigued with the idea of self-fulfilling prophecy, with studies showing expectations can influence everything from how one performs on a test to how one responds to a medication. The new study is the first to directly model the dynamics of the feedback loop between expectations and pain and the neural mechanisms underlying it.

Marieke Jepma, then a postdoctoral researcher in Wager’s lab, launched the research after noticing that even when test subjects were shown time and again that something wouldn’t hurt badly, some still expected it to.

“We wanted to get a better understanding of why pain expectations are so resistant to change,” said Jepma, lead author and now a researcher at the University of Amsterdam.

The researchers recruited 34 subjects and taught them to associate one symbol with low heat and another with high, painful heat.

Then, the subjects were placed in a functional magnetic resonance imaging (fMRI) machine, which measures blood flow in the brain as a proxy for neural activity. For 60 minutes, subjects were shown low or high pain cues (the symbols, the words Low or High, or the letters L and W), then asked to rate how much pain they expected.

Then varying degrees of painful but non-damaging heat were applied to their forearm or leg, with the hottest reaching “about what it feels like to hold a hot cup of coffee” Wager explains.

Then they were asked to rate their pain.

Unbeknownst to the subjects, heat intensity was not actually related to the preceding cue.

The study found that when subjects expected more heat, brain regions involved in threat and fear were more activated as they waited. Regions involved in the generation of pain were more active when they received the stimulus. Participants reported more pain with high-pain cues, regardless of how much heat they actually got.

“This suggests that expectations had a rather deep effect, influencing how the brain processes pain,” said Jepma.

Surprisingly, their expectations also highly influenced their ability to learn from experience. Many subjects demonstrated high “confirmation bias” — the tendency to learn from things that reinforce our beliefs and discount those that don’t. For instance, if they expected high pain and got it, they might expect even more pain the next time. But if they expected high pain and didn’t get it, nothing changed.

“You would assume that if you expected high pain and got very little you would know better the next time. But interestingly, they failed to learn,” said Wager.

This phenomenon could have tangible impacts on recovery from painful conditions, suggests Jepma.

“Our results suggest that negative expectations about pain or treatment outcomes may in some situations interfere with optimal recovery, both by enhancing perceived pain and by preventing people from noticing that they are getting better,” she said. “Positive expectations, on the other hand, could have the opposite effects.”

The research also may shed light on why, for some, chronic pain can linger long after damaged tissues have healed.

Whether in the context of pain or mental health, the authors suggest that it may do us good to be aware of our inherent eagerness to confirm our expectations.

“Just realizing that things may not be as bad as you think may help you to revise your expectation and, in doing so, alter your experience,” said Jepma.

New Blood Test Offers Better or Equal Skin Cancer Detection Rate than a Biopsy

Skin cancer is the most common cancer in the world, and it’s the one that’s most easily treated when caught early. Since the blood test is less invasive than a biopsy, this new advance should be helpful in convincing more people to receive treatment early on.

It’s a world first. A newly developed blood test is capable of the early detection of melanoma, with over 80 percent accuracy.

It could help save thousands of lives, according to the Australian Edith Cowan University Melanoma Research Group scientists who developed the test.

Melanoma is the most deadly form of skin cancer, claiming 59,782 lives around the world in 2015. Australasia, North America and Europe are the regions most susceptible to the disease.

There’s good news. If caught early, the survival rate for melanoma climbs to 95 percent. But if you miss that early window, your chances will plummet to below 50 percent. This is what the blood test is designed to help prevent.

[…]

The blood test, called MelDX, works by detecting the antibodies the body produces as soon as melanoma develops. The team analysed 1,627 different types of antibodies, and narrowed them down to a combination of 10 that indicate the presence of melanoma in the body.

They then took blood from 104 people with melanoma and 105 healthy controls, and found that MelDX was capable of detecting melanoma with 81.5 percent accuracy.

More specifically, it was able to detect the cancer in 79 percent of the patients with melanoma; and has a false positive rate in only 16 percent in healthy patients.

The detection rate may actually be a little higher than the accuracy of skin biopsies, which, according to a 2012 study, was 76 percent in an Australian public hospital.

That’s not a perfect result, but it does provide a starting point before other, more invasive tests are embarked on; in conjunction with current diagnostic techniques, it could improve early diagnosis – and therefore people’s chance of survival.

The next step, the researchers said, will be to take MelDX to clinical trial, which is currently being organised, and which could help refine the test.

“We envision this taking about three years. If this is successful we would hope to be able to have a test ready for use in pathology clinics shortly afterwards,” said Melanoma Research Group head Mel Ziman.

“The ultimate goal is for this blood test to be used to provide greater diagnostic certainty prior to biopsy and for routine screening of people who are at a higher risk of melanoma, such as those with a large number of moles or those with pale skin or a family history of the disease.”

Meanwhile, there are easy ways you can help protect yourself from melanoma and other skin cancers, including wearing sunscreen, staying in the shade during the hottest hours of the day, and avoiding UV tanning beds.

Breakthrough in Making Much Less Addictive Opioids

Important research this is, for it shows that the powerful pain relief opioids provide doesn’t have to be such a dangerous double-edged sword.

In the US, more than one-third of the population experiences some form of acute or chronic pain; in older adults this number rises to 40 percent.

The most common condition linked to chronic pain is chronic depression, which is a major cause of suicide.

To relieve severe pain, people go to their physician for powerful prescription painkillers, opioid drugs such as morphine, oxycodone and hydrocodone.

Almost all the currently marketed opioid drugs exert their analgesic effects through a protein called the “mu opioid receptor” (MOR).

MORs are embedded in the surface membrane of brain cells, or neurons, and block pain signals when activated by a drug.

However, many of the current opioids stimulate portions of the brain that lead to additional sensations of “rewarding” pleasure, or disrupt certain physiological activities. The former may lead to addiction, or the latter, death.

Which part of the brain is activated plays a vital role in controlling pain. For example, MORs are also present in the brain stem, a region that controls breathing.

Activating these mu receptors not only dulls pain but also slows breathing. Large doses stop breathing, causing death.

Activating MORs in other parts of the brain, including the ventral tegmental area and the nucleus accumbens, block pain and trigger pleasure or reward, which makes them addictive. But so far there is no efficient way to turn these receptors “on” and “off” in specific areas.

But there is another approach because not all opioids are created equal. Some, such as morphine, bind to the receptor and activate two signaling pathways: one mediating pain cessation and the other producing side effects like respiratory depression.

Other drugs favor one pathway more than the other, like only blocking pain – this is the one we want.

“Biased opioids” to kill pain

But MOR isn’t the only opioid receptor. There are two other closely related proteins called kappa and delta, or KOR and DOR respectively, that also alter pain perception but in slightly different ways.

Yet, currently there are only a few opioid medications that target KOR, and none that target DOR. One reason is that the function of these receptors in the brain neurons remains unclear.

Recently KOR has been getting attention as extensive studies from different academic labs show that it blocks pain without triggering euphoria, which means it isn’t addictive.

Another benefit is that it doesn’t slow respiration, which means that it isn’t lethal. But although it isn’t as dangerous as MOR, activating KOR does promote dysphoria, or unease, and sleepiness.

This work suggests it is possible to design a drug that only targets the pain pathway, without side effects. These kind of drugs are called “biased” opioids.

[…]

The exciting news is that researchers in the Roth lab have discovered several promising compounds based on the KOR structure that selectively binds and activates KOR, without cavorting with the more than 330 other related protein receptors.

Now our challenge is to transform these molecules into safer drugs.

Regenerative Bandage Hydrogel Boosts Internal Self-Healing for Wounds

A very notable advance that should become a promising part of healing in the future.

A simple scrape or sore might not cause alarm for most people. But for diabetic patients, an untreated scratch can turn into an open wound that could potentially lead to a limb amputation or even death.

A Northwestern University team has developed a new device, called a regenerative bandage, that quickly heals these painful, hard-to-treat sores without using drugs. During head-to-head tests, Northwestern’s bandage healed diabetic wounds 33 percent faster than one of the most popular bandages currently on the market.

“The novelty is that we identified a segment of a protein in skin that is important to wound healing, made the segment and incorporated it into an antioxidant molecule that self-aggregates at body temperature to create a scaffold that facilitates the body’s ability to regenerate tissue at the wound site,” said Northwestern’s Guillermo Ameer, who led the study. “With this newer approach, we’re not releasing drugs or outside factors to accelerate healing. And it works very well.”

Because the bandage leverages the body’s own healing power without releasing drugs or biologics, it faces fewer regulatory hurdles. This means patients could see it on the market much sooner.

The research was published today, June 11, in the Proceedings of the National Academy of Sciences. Although Ameer’s laboratory is specifically interested in diabetes applications, the bandage can be used to heal all types of open wounds.

[…]

The difference between a sore in a physically healthy person versus a diabetic patient? Diabetes can cause nerve damage that leads to numbness in the extremities. People with diabetes, therefore, might experience something as simple as a blister or small scratch that goes unnoticed and untreated because they cannot feel it to know it’s there. As high glucose levels also thicken capillary walls, blood circulation slows, making it more difficult for these wounds to heal. It’s a perfect storm for a small nick to become a limb-threatening — or life-threatening — wound.

The secret behind Ameer’s regenerative bandage is laminin, a protein found in most of the body’s tissues including the skin. Laminin sends signals to cells, encouraging them to differentiate, migrate and adhere to one another. Ameer’s team identified a segment of laminin — 12 amino acids in length — called A5G81 that is critical for the wound-healing process.

[…]

The bandage’s antioxidant nature counters inflammation. And the hydrogel is thermally responsive: It is a liquid when applied to the wound bed, then rapidly solidifies into a gel when exposed to body temperature. This phase change allows it to conform to the exact shape of the wound — a property that helped it out-perform other bandages on the market.

“Wounds have irregular shapes and depths. Our liquid can fill any shape and then stay in place,” Ameer said. “Other bandages are mostly based on collagen films or sponges that can move around and shift away from the wound site.”

Patients also must change bandages often, which can rip off the healing tissue and re-injure the site. Ameer’s bandage, however, can be rinsed off with cool saline, so the regenerating tissue remains undisturbed.

Not only will the lack of drugs or biologics make the bandage move to market faster, it also increases the bandage’s safety. So far, Ameer’s team has not noticed any adverse side effects in animal models. This is a stark difference from another product on the market, which contains a growth factor linked to cancer.

“It is not acceptable for patients who are trying to heal an open sore to have to deal with an increased risk of cancer,” Ameer said.

Next, Ameer’s team will continue to investigate the bandage in a larger pre-clinical model.