Thursday, 23 October 2014
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Body-builders: developing cyborg organs

Scientists are combining biological tissue with synthetic materials to create a new class of “cyborgans”.

When Barney Clark went into hospital, he didn’t expect to survive more than a few days. But after receiving the world’s first permanent artificial heart transplant in December 1982, the Seattle dentist went on to live for almost four more months. The second patient to receive the Jarvik-7, developed by US doctor and engineer Robert Jarvik, astounded his doctors even further by living for more than a year and a half after his operation.

Of the more than 10,000 people in the UK who are currently waiting for an organ transplant, three die every day because of a lack of donors. The development of the artificial heart means that those on the six-month NHS waiting list have an option if their situation deteriorates while they are holding out for a transplant.

Technology has improved hugely since the Jarvik-7, which was powered by a large console that made it impossible for patients to leave the hospital. Earlier this year, a TV documentary even brought together the latest developments across the spectrum of artificial organs to create a ‘bionic man’, which was until recently on display at the Science Museum in London.

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Source: Science Museum

The Bionic Man project showcased the latest in artificial organs

But doctors have yet to develop a true replacement for the real thing. And with the worldwide number of patients in need of a transplant far exceeding the small number of available donors, the need for a longer-lasting alternative certainly hasn’t gone away.

One of the key problems with artificial organs is ensuring biocompatibility, the ability of materials to provide a good environment for living cells to grow and function around them. Artificial hearts, for example, need to be haemocompatible otherwise they can destroy red blood cells or create life-threatening clots.

As scientists have become better at growing human cells in a lab, the idea has taken hold that we might be able to produce entire biological organs based on a patients’ own cells. This could not only bypass the problem of biocompatibility but also reduce the likelihood of the body rejecting the organ as a foreign body, as can happen with transplants, and of causing an infection by providing a welcome surface for bacteria. However, growing an organ for use in a patient has not proven simple.

‘In the late 1990s, people started working on developing organs using a tissue-engineering approach, and everybody thought in the next 10 years we would be growing all organs,’ said Dr Alex Seifalian, professor of nanotechnology and regenerative medicine at University College London (UCL), who was the scientific lead on the bionic man project.

‘They were trying to simulate what nature is; trying to grow, for example, a nose or ear; trying to make exactly the same cartilage and grow cells on some bio-absorbable material that disappears to leave the cartilage, and that will be placed in the patient.’

‘Everybody thought in the next 10 years we would be growing all organs’

But scientists, including Seifalian, have encountered problems with this approach. ‘In 1997 we had a grant to develop artificial arteries with tissue engineering,’ he said. ‘In animals it worked very well and then when we went to humans it just didn’t work very well because the people who needed arteries were over 50 years old, their cells weren’t growing, they’d get infections.’ The other problem was making the technology commercially viable: growing organs in a lab is a costly, time-consuming process and Seifalian’s collaborator company pulled out.

Proponents of biological organ replacements have recently been encouraged by the development of 3D tissue printing, which offers the tantalising possibility that we might build organs mechanically, layer by layer — a much faster process than growing them in the lab. But printing complex internal organs like the liver or heart is still some way off, and the technology will face similar issues to traditional tissue engineering when it comes to implanting.

In the meantime, some scientists are pursuing a different approach, combining biological tissue with synthetic materials and/or mechanical and electronic components to create what could be called hybrid or even cyborg organs (cyborgans, if you will), which are more easily manufactured, longer lasting and more successful once implanted into the body.

On one level this means incorporating some biological material into a largely man-made device. French firm Carmat, which is owned by aerospace and defence company EADS, has begun animal trials on one of the world’s most advanced designs for an artificial heart, which includes some biological elements.

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Source: Carmat

The Carmat artificial heart includes a biomembrane

The two chambers inside the Carmat heart are each divided by a biomembrane that separates blood on one side from hydraulic fluid on the other. Tiny motors controlled by an electronic sensor system pump the hydraulic fluid in and out of the chambers, in turn causing the membrane to pump the blood.

To increase haemocompatiblity, the membrane is made from animal tissue that helps move the blood without damaging cells. Microporous biological and synthetic biomaterials also cover every other surface that comes in contact with the blood, in order to prevent material from sticking to them. If trials are successful, Carmat hopes its heart could achieve a lifespan of at least five years, and potentially up to the nine years of extra life reached by 50 per cent of transplant patients.

But scientists are also combining biological and synthetic materials in a more fundamental way, creating permanent artificial structures or scaffolds and then growing living cells around them. Seifalian is already preparing to clinically trial blood vessels and tracheae (windpipes) made in this way, and is also developing urethrae, bladders and cardiac patches for healing hearts.

Although Seifalian’s organs are grown along similar lines to those based on temporary moulds and scaffolds that gradually disappear, providing the same increased biocompatibility and reduced the risk of infection, he argues that permanent internal structures provide several additional advantages.

‘The nondegradable material is more reliable,’ he said. ‘If you make a tube you can make it mechanically similar and sometimes better than a real trachea, so if you squash it, it goes back to its original shape [etc.] Also the surgeon knows the material is going to be there forever. If you put in an artery and the polymer disappears after three months, if the body doesn’t take over then the patient will die. But if you know the artery is going to be there forever then you will feel much better.’

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Source: UCL

Prof Seifalian’s material has been used to produce part-biological, part-synthetic windpipes.

The material is a nanocomposite polymer that goes by the name polyhedral oligomeric silsesquioxane-poly (carbonate-urea) urethane, or the much more manageable POSS-PCU for short. It’s strong, relatively cheap to synthesise and easy to manipulate into a range of complex structures. The silicon in it helps make it biocompatible, although scientists aren’t exactly sure why. And the material’s nanostructure, which was inspired by butterfly wings Seifalian studied at the Natural History Museum in London, also makes it hydrophobic, meaning it repels water and therefore prevents bacteria from growing and causing infections.

The other benefit is commercial: having a physical product to sell is a more attractive proposition for manufacturers. ‘If you have a material scaffold it can be tailored to patients or just made in different sizes and you can sell it,’ said Seifalian. ’You can then add cells and put it into the patient.’

This biological tissue can be grown either in a lab or, in some cases, after the artificial structure is implanted into the body. Seifalian’s blood vessels, for example, contain molecules that take stem cells from the blood and convert them into the endothelial cells that line the body’s own vessels. As well as reducing the risk of rejection, this also means the structure can be implanted as soon as it is needed, rather than having to wait several months for the cells to be grown in the lab.

The next big challenge is to build one of the body’s more complex organs such as a liver, by creating a synthetic scaffold and culturing stem cells around it that then turn into hepatic (liver) tissue. This could prove even more difficult than building an entire working heart, said Seifalian. ‘A liver stores vitamins, takes poisons out of the blood and so on, so a liver virtually is factory. To make the whole organ to become functional is quite complex.’

Several other research teams are studying the use of scaffolds to build organs, but one group in particular has managed to produce tissues that most closely fit the label ‘cyborgan’. The team, which comprised researchers based at Harvard University and the Massachusetts Institute of Technology (MIT), was able to add electronic sensors to a tissue scaffold that could be used to monitor electrical activity or other changes in the cells around it.

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Source: MIT

A 3D fluorescent image of an electronic tissue scaffold

Previous work had led to flat layers of cells grown on electrodes or transistors, but the MIT/Harvard researchers were able to build a porous epoxy scaffold embedded with silicon nanowires that carry electrical signals to and from the tissue grown around it. This could detect activity of less than one-thousandth of a watt — about the level of electricity that might be seen in a cell — and the researchers demonstrated the sensors could detect electrical activity related to cell contraction and changes in pH.

One of the researchers, Dr Tal Dvir, is now based at Tel Aviv University in Israel and working on making the sensors operate wirelessly without being attached to a semiconductor base so they can be incorporated into a cardiac patch. The idea is that the patch would help regenerate the heart after an attack, while the sensors monitor its progress by detecting electrical activity as the heart contracts to ensure the cells were acting synchronously. Eventually it could also operate as a pacemaker by using the nanowires to emit electrical signals or control a drug-delivery system.

‘In cardiac tissue engineering you want to see that the tissue you engineer is doing what you want it to do,’ said Dvir. ‘We put sensors within the scaffold and were able to record from each of these spots. It was like having a map of the contractions or the beating of the cells in three dimensions.’

The researchers also demonstrated the technology with blood-vessel cells and neurons, and Dvir believes arteries that monitor blood flow or patches that could help heal or stimulate the brain could also be possible, and perhaps one day even cyborg eyes or muscles.

The development of hybrid organs raises the question of whether they’re merely a stopgap until we can produce better biological replacements, perhaps with 3D printers as the enabling technology, or whether synthetic materials and electronics will allow us to enhance what nature has given us.

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Source: Tal Dvir

Researchers at Tel Aviv University are developing tiny sensors to implant in lab-grown organs.

Dvir thinks additive manufacturing could actually be what delivers the full possibility of cyborgans, rather than making them redundant. ‘When I think about 3D printers I immediately think about the opportunity to combine electronics with engineered tissue,’ he said. ‘So in my opinion, I think there is great potential for these cyborg tissues. If it works with patches it will work with fully engineered organs.’

Seifalian goes a step further. He sees the future as fully synthesised organs that work even better than the real thing, based on biocompatible, functional materials, perhaps with embedded electronics. ‘With growing organs we will move forward but I don’t think that’s the future. Why can’t we make a heart from functionalised material that works very well and doesn’t break, doesn’t get calcification and so on?’

‘There is great potential for these cyborg tissues. If it works with patches it will work with fully engineered organs.’

We’re actually already seeing similar ideas become reality, for example De Montfort University has developed an artificial pancreas that releases insulin via a glucose-sensitive material (see box). And Seifalian is playing around with the idea of a synthetic heart made from ionic polymers that contract when an electrical signal is applied.

‘Unfortunately it’s not as strong, it’s not fast enough to replace the heart muscle so we’re still working on it,’ he said, adding: ‘I don’t think we’re very far away from it. I think in 10 years’ time somebody will come up with such a thing.’ If that’s the case we could find ourselves going full circle and jettisoning biological replacements altogether. Perhaps the future isn’t cyborg organs but android ones.

Artificial pancreas

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The need to more carefully regulate type 1 diabetics’ insulin intake has led to several attempts to create an artificial pancreas that removes the need for sufferers to perform their own injections. Most designs include an implanted insulin pump and electronic glucose sensor regulated by an external device, but researchers led by Prof Joan Taylor at De Montfort University in Leicester have developed a self-contained implant that manages insulin release automatically and more precisely. Insulin is stored behind a polymer gel that softens in the presence of glucose molecules, releasing insulin to the liver in the right amount until the glucose drops.

Although the researchers have yet to incorporate living tissue to improve the device’s biocompatibility, the design represents how functional materials performing a more natural process can operate better than mechanical and electronic components alone. ‘It has dose-related activity just by virtue of the fact that it works on a molecular level,’ said Taylor. ‘So you don’t have to build this in digitally; it responds naturally as an absolute function of glucose content.’


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