Researchers test first-ever artificial kidneyy

Vanderbilt University Medical Center nephrologist and associate professor of medicine Dr William H. Fissell IV, is making major progress on a first-of-its kind device to free kidney patients from dialysis. He is building an implantable artificial kidney with microchip filters and living kidney cells that will be powered by a patient’s own heart.

“We are creating a bio-hybrid device that can mimic a kidney to remove enough waste products, salt and water to keep a patient off dialysis,” said Fissell.

Fissell says the goal is to make it small enough, roughly the size of a soda can, to be implanted inside a patient’s body.

The key to the device is a microchip.

“It’s called silicon nanotechnology. It uses the same processes that were developed by the microelectronics industry for computers,” said Fissell.

The chips are affordable, precise and make ideal filters. Fissell and his team are designing each pore in the filter one by one based on what they want that pore to do. Each device will hold roughly fifteen microchips layered on top of each other.

But the microchips have another essential role beyond filtering. “They’re also the scaffold in which living kidney cells will rest,” said Fissell.

Fissell and his team use live kidney cells that will grow on and around the microchip filters. The goal is for these cells to mimic the natural actions of the kidney.

“We can leverage Mother Nature’s 60 million years of research and development and use kidney cells that fortunately for us grow well in the lab dish, and grow them into a bioreactor of living cells that will be the only “Santa Claus” membrane in the world: the only membrane that will know which chemicals have been naughty and which have been nice. Then they can reabsorb the nutrients your body needs and discard the wastes your body desperately wants to get rid of,” said Fissell.

Because this bio-hybrid device sits out of reach from the body’s immune response, it is protected from rejection.

“The issue is not one of immune compliance, of matching, like it is with an organ transplant,” said Fissell. The device operates naturally with a patient’s blood flow.

“Our challenge is to take blood in a blood vessel and push it through the device. We must transform that unsteady pulsating blood flow in the arteries and move it through an artificial device without clotting or damage.”

And that’s where Vanderbilt biomedical engineer Amanda Buck comes in. Buck is using fluid dynamics to see if there are certain regions in the device that might cause clotting.

She uses computer models to refine the shape of the channels for the smoothest blood flow. Then they rapidly prototype the new design using 3-D printing and test it to make the blood flow as smoothly as possible.

Fissell says he has a long list of dialysis patients eager to join a future human trial. Pilot studies of the silicon filters could start in patients by the end of 2017.

“My patients are absolutely my heroes,” said Fissell. “They come back again and again and they accept a crushing burden of illness because they want to live. And they’re willing to put all of that at risk for the sake of another patient.”

The US National Institutes of Health awarded a four-year, US$6 million grant to Fissell and his research partner Shuvo Roy, from the University of California at San Francisco. The two investigators are longtime collaborators on this research. In 2003, the kidney project attracted its first NIH funding, and in 2012 the Food and Drug Administration selected the project for a fast-track approval program.


Cancer drug target visualized at atomic resolution

A new study shows that it is possible to use an imaging technique called cryo-electron microscopy (cryo-EM) to view, in atomic detail, the binding of a potential small molecule drug to a key protein in cancer cells. The cryo-EM images also helped the researchers establish, at atomic resolution, the sequence of structural changes that normally occur in the protein, p97, an enzyme critical for protein regulation that is thought to be a novel anti-cancer target.

The study appeared online 28 January 2016, in Science. Sriram Subramaniam, Ph.D., of the National Cancer Institute’s (NCI) Center for Cancer Research, led the research. NCI is part of the US National Institutes of Health.

“Cryo-EM is positioned to become an even more useful tool in structural biology and cancer drug development,” said Douglas Lowy, M.D., acting director, NCI. “This latest finding provides a tantalizing possibility for advancing effective drug development.”

To determine structures by cryo-EM, protein suspensions are flash-frozen at very low temperatures; nevertheless, the water around the protein molecules stays liquidlike. The suspensions are then bombarded with electrons to capture their images. To produce three-dimensional protein structures using cryo-EM, researchers generate thousands of two-dimensional images of the molecules in different orientations, which are then averaged together. This type of imaging procedure has gained in popularity in structural biology research because it allows for the observation of specimens that have not been stained or fixed in any way, enabling visualization of the specimens under near-native, or natural, conditions.

Earlier structural studies of full-length p97 by a well-established technique knownas X-ray crystallography have been limited so far to medium resolution (3.5 Å to 4.7 Å). With cryo-EM, however, researchers were able to image full-length p97 at an overall resolution of 2.3 Å, which is much finer, allowing them to visualize key regions of the protein in atomic detail.

Most significantly, the mode of binding and contact sites of a small molecule inhibitor of p97 activity could be observed directly. Drug development efforts often involve mapping the contacts between small molecules and their binding sites on specific proteins. With this latest finding, the resolutions achieved were significant enough to discern both the shape of the protein chain and some of the hydrogen bonds between the protein and the small molecule inhibitor.

“Our latest research provides new insights into the protein structures and interactions that are critical for the activity of a cancer cell, and this knowledge will hopefully enable the design of clinically useful drugs,” said Subramaniam.


Painless patch of insulin-producing beta cells may help control diabetes

For decades, researchers have tried to duplicate the function of beta cells, the tiny insulin-producing entities that don’t work properly in patients with diabetes. Insulin injections provide painful and often imperfect substitutes. Transplants of normal beta cells carry the risk of rejection or side effects from immunosuppressive therapies.

Now, researchers at the University of North Carolina at Chapel Hill and North Carolina State University have devised another option: a synthetic patch filled with natural beta cells that can secrete doses of insulin to control blood sugar levels on demand with no risk of inducing hypoglycaemia.

The proof-of-concept builds on an innovative technology, the “smart insulin patch,” reported last year in the Proceedings of the National Academy of Sciences. Both patches are thin polymeric squares about the size of a small coin and covered in tiny needles, like a miniature bed of nails. But whereas the former approach filled these needles with manmade bubbles of insulin, this new “smart cell patch” integrates the needles with live beta cells.

Tests of this painless patch in small animal models of type-1 diabetes demonstrated that it could quickly respond to skyrocketing blood sugar levels and significantly lower them for 10 hours at a time. The results were published in Advanced Materials.

“This study provides a potential solution for the tough problem of rejection, which has long plagued studies on pancreatic cell transplants for diabetes,” said senior author Zhen Gu, PhD, assistant professor in the joint UNC/NC State department of biomedical engineering. “Plus it demonstrates that we can build a bridge between the physiological signals within the body and these therapeutic cells outside the body to keep glucose levels under control.”

Beta cells typically reside in the pancreas, where they act as the body’s natural insulin-producing factories. In healthy people, they produce, store, and release the hormone insulin to help process sugar that builds up in the bloodstream after a meal. But in people with diabetes, these cells are either damaged or unable to produce enough insulin to keep blood sugar levels under control.

Diabetes affects more than 387 million people worldwide, and that number is expected to grow to 500 million by the year 2030. Patients with type-1 and advanced type-2 diabetes must regularly monitor their blood sugar levels and inject themselves with varying amounts of insulin, a process that is painful and imprecise. Injecting the wrong amount of medication can lead to significant complications like blindness and limb amputations, or even more disastrous consequences such as diabetic comas and death.

Since the 1970s, researchers have researched transplantation of insulin-producing cells as an alternative treatment for diabetes. The first successful transplant of human beta cells was performed in 1990, and since then hundreds of diabetic patients have undergone the procedure. Yet, only a fraction of treated patients achieved normal blood sugar levels. Most transplants are rejected, and many of the medications used to suppress the immune system wind up interfering with the activity of beta cells and insulin. More recently, researchers have been experimenting with ways to encapsulate beta cells into biocompatible polymeric cells that could be implanted in the body.

Gu, who also holds appointments in the UNC School of Medicine, the UNC Eshelman School of Pharmacy, and the UNC Diabetes Care Center, decided to create a device that would put the blood-sugar buffering properties of beta cells out of reach of the patient’s immune system. Lead author Yanqi Ye, a graduate student in Gu’s lab, constructed the “smart cell patches” using natural materials commonly found in cosmetics and diagnostics. She stuffed the hundreds of microneedles, each about the size of an eyelash, with culture media and thousands of beta cells that were encapsulated into microcapsules made from biocompatible alginate. When applied to the skin, the patch’s microneedles poked into the capillaries and blood vessels, forming a connection between the internal environment and the external cells of the patch.

Ye also created “glucose-signal amplifiers,” which are synthetic nanovesicles filled with three chemicals to make sure the beta cells could “hear” the call from rising blood sugar levels and respond accordingly.

Gu’s group showed that blood sugar levels in diabetic mice quickly declined to normal levels. To assess whether the patch could regulate blood sugar without lowering it too much, the researchers administered a second patch to the mice. As they had hoped, repeated administration of the patch did not result in excess doses of insulin, and thus did not risk hypoglycemia. Instead, the second patch extended the life of the treatment to 20 hours.

Further modifications, pre-clinical tests, and eventually clinical trials in humans will all be necessary before the patch can become a viable option for patients.


CPR administered with ventilation better than continuous compressions

In a study published online 9 November 2015 in the New England Journal of Medicine, researchers found that cardiopulmonary resuscitation (CPR) administered by emergency medical services (EMS) providers following sudden cardiac arrest that combines chest compressions with interruptions for ventilation resulted in longer survival times and shorter hospital stays than CPR that uses continuous chest compressions. Although compressions with pauses for ventilation lead to more hospital-free days within 30 days of the cardiac arrest, both methods achieved similar overall survival to hospital discharge, the study noted.

The compressions with interruptions consisted of 30 compressions then pauses for two ventilations. The continuous chest compressions consisted of 100 compressions per minute with simultaneous ventilations at 10 per minute. In both groups, emergency medical services (EMS) providers gave ventilations using a bag and mask.

The study, funded in part by the US National Heart, Lung, and Blood Institute (NHLBI), is the largest of its kind to date to evaluate CPR practices among firefighters and paramedics and suggests the importance of ventilation in CPR by EMS providers, the investigators say.

“Current CPR guidelines permit use of either continuous chest compressions or interrupted chest compressions with ventilations by EMS providers. Our trial shows that both types of CPR achieve good outcomes, but that compressions with pauses for ventilations appears to be a bit better,” said principal author Graham Nichol, M.D., director of the University of Washington-Harborview Center for Prehospital Emergency Care in Seattle.

Sudden cardiac arrest, or loss of mechanical activity of the heart, can be caused by a heart attack. Studies show that only about 10% of people who suffer cardiac arrest outside the hospital survive. But effective treatment by CPR can greatly increase a victim’s chance of survival.

Standard CPR performed by EMS providers involves chest compressions with interruptions for ventilation using a bag and mask. However, recent studies in animal models suggest that continuous chest compressions (CCC) may be just as good as standard CPR. To date, firefighters and paramedics have not had clear evidencebased guidance on which treatment method is optimal. As a result, treatment often varies from one community to another.

That variation in treatment could soon become a thing of the past, researchers suggest. An international multi-centre research team compared survival rates among 23,709 adults with cardiac arrest who were treated by EMS crews at 114 agencies from June 2011 to May 2015.

Approximately half had received continuous compressions with simultaneous ventilations, while the other half received standard CPR with pauses for ventilations. The study was conducted by the Resuscitation Outcomes Consortium (ROC), which includes clinical sites in the United States and Canada.

Overall, survival to discharge was not significantly different between the continuous chest compressions group and the standard CPR group. A total of 8.9% (about 1,126 patients) from the continuous compressions group survived to reach hospital discharge, while 9.7% (about 1,073 patients) of the standard CPR group reached hospital discharge. The proportion of patients able to carry out all usual activities or requiring some help but able to walk unassisted, was also similar between treatment groups.

However, the standard CPR group had significantly more days alive and out of hospital during the first 30 days following cardiac arrest.

The researchers believe that the benefits of compressions with pauses for ventilation are due to improved blood flow and oxygenation. They are continuing to analyze the data to gain additional insight into the study results.

“This is the first randomized trial to show a significant difference in outcomes after hospital admission among patients treated for out-of-hospital cardiac arrest,” Dr Nichol added. “We can improve outcomes for this common health condition. We believe that this study is a significant step in that direction.”


Researchers find possible cause of memory loss in Alzheimer’s

The mass die-off of nerve cells in the brains of people with Alzheimer’s disease may largely occur because an entirely different class of brain cells, called microglia, begin to fall down on the job, according to a new study by researchers at the Stanford University School of Medicine.

The researchers found that, in mice, blocking the action of a single molecule on the surface of microglia restored the cells’ ability to get the job done – and re versed memory loss and myriad other Alzheimer’s-like features in the animals.

The study, published online 8 December 2015 The Journal of Clinical Investigation, illustrates the importance of microglia and could lead to new ways of warding off the onset of Alzheimer’s disease. The study also may help explain an intriguing association between aspirin and reduced rates of Alzheimer’s.

Microglia, which constitute about 10-15% of all the cells in the brain, actually resemble immune cells considerably more than they do nerve cells.

“Microglia are the brain’s beat cops,” said Katrin Andreasson, MD, professor of neurology and neurological sciences and the study’s senior author. “Our experiments show that keeping them on the right track counters memory loss and preserves healthy brain physiology.”

A microglial cell serves as a front-line sentry, monitoring its surroundings for suspicious activities and materials by probing its local environment. If it spots trouble, it releases substances that recruit other microglia to the scene, said Andreasson. Microglia are tough cops, protecting the brain against invading bacteria and viruses by gobbling them up. They are adept at calming things down, too, clamping down on inflammation if it gets out of hand. They also work as garbage collectors, chewing up dead cells and molecular debris strewn among living cells – including clusters of a protein called A-beta, notorious for aggregating into gummy deposits called Alzheimer’s plaques, the disease’s hallmark anatomical feature.

A-beta, produced throughout the body, is as natural as it is ubiquitous. But when it clumps into soluble clusters consisting of a few molecules, it’s highly toxic to nerve cells. These clusters are believed to play a substantial role in causing Alzheimer’s.

“The microglia are supposed to be, from the get-go, constantly clearing A-beta, as well as keeping a lid on inflammation,” Andreasson said. “If they lose their ability to function, things get out of control. A-beta builds up in the brain, inducing toxic inflammation.”

The Stanford study provides strong evidence that this deterioration in microglial function is driven, in large part, by the heightened signalling activity of a single molecule that sits on the surface of microglial and nerve cells. Previous work in Andreasson’s lab and other labs has shown that this molecule, a receptor protein called EP2, has a strong potential to cause inflammation when activated by binding to a substance called prostaglandin E2, or PGE2.

“We’d previously observed that if we bioengineered mice so their brain cells lacked this receptor, there was a huge reduction in inflammatory activity in the brain,” she said. But they didn’t know whether nerve cells or microglia were responsible for that inflammatory activity, or what its precise consequences were. So they determined to find out.

Their experiments showed that knocking out EP2 action in A-betaprovoked microglia benefited memory in mice that had either gradually (the “Alzheimer’s” mice) or suddenly (the brain-injected mice) acquired excessive A-beta in their brains. Likewise, mouse microglia bioengineered to lack EP2 vastly outperformed unaltered microglia, in A-betachallenged brains, at such critical tasks as secreting recruiting chemicals and factors beneficial to nerve cells and in producing inflammationcountering, rather than inflammation-spurring, proteins.

Epidemiological reports suggest that the use of nonsteroidal anti-inflammatory drugs, such as aspirin, can prevent the onset of Alzheimer’s – although only if their use is initiated well before any signs of the disorder begin to show up in older people, Andreasson said. “Once you have any whiff of memory loss, these drugs have no effect,” she said. NSAIDs’ mainly act by blocking two enzymes called COX-1 and COX-2; these enzymes create a molecule that can be converted to several different substances, including PGE2 – the hormone-like chemical that triggers EP2 action.

Although PGE2 is known to regulate inflammatory changes in the brain, it exercises diverse, useful functions in different tissues throughout the body, from influencing blood pressure to inducing labour. Complicating matters, PGE2 is just one of five different prostaglandins originating from the precursor molecule produced by COX-1 and COX-2. So aspirin and other COX-1- and COX-2-inhibiting drugs may have myriad effects, not all of them beneficial. It may turn out that a compound blocking only EP2 activity on microglial cells, or some downstream consequences within microglial cells, would be better-suited for fending off Alzheimer’s without side effects, said Andreasson. Meanwhile, her group is exploring the biological mechanisms via which PE2 signalling pushes microglia over to the dark side.

 

 

 Date of upload: 15th May 2016

 

                                  
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