The framework of an old lung can grow a new one with the right cells.

Scientists have used the remains of old lungs to grow new ones capable of being transplanted. Researchers led by Laura Niklason at Yale University took a set of healthy rat lungs, stripped them of their cells, grew new cells upon them, and then placed them into a new rat. According to the results recently published in Science, the lungs breathed in the new rat and exchanged air for up to two hours. The removal and culturing of cells from organs (decellularization and recellularization) could one day allow any person to become a universal donor for transplant. This would help save the lives of thousands who die each year around the world waiting for a new lung. While it is still in its preliminary stages, this research is another success story in the growing field of regenerative medicine. Check out an overview of the experiment in the video below and don’t miss watching the lungs breathe around 0:44 and 1:07.

This is only one of several attempts at constructing new organs on the scaffolds of old organs. In rats we’ve seen the same done for hearts, and very recently with livers. As with livers, the reconstructed rat lungs were capable of surviving in vivo. That’s very impressive, but we’ve already seen better, and in humans, too. Entire tracheas have been grown using a similar method, and several transplants (two in adults, one in a young boy) have proven it successful. The lungs (and liver and heart) are considerably more complex than a trachea, which is why these examples of the technology are lagging years (perhaps decades) behind. Still, the accomplishments with tracheas gives me hope that building organs on scaffolds will eventually be able to work with more complicated organs in humans as well.

But what does building an organ on a scaffold actually entail? The organs in the body have what amounts to a ‘skeleton’ – a structural framework that lung (or liver, or heart, etc) cells grow on. This framework is comprised mostly of collagen, and unlike cells, does not differ greatly between individuals. Essentially these organ scaffolds can be transplanted from almost anyone into almost anyone else without most of the worries of rejection. Of course, a scaffold with no cells wouldn’t be much help to anyone as it’s the cells that actually perform the work of the organ. So cells taken from either the eventual host or some universal donor (such as fetal stem cells) are used to repopulate the scaffold and create a new healthy organ. This stripping down and building back up may seem like a lot of work, and it is, but it will allow an organ taken from a cadaver to be eventually transplanted into almost anyone.

The following video describes the lung experiment in better detail and with some amazing images:

The Yale researchers had some pretty promising results from this series of experiments. Culturing the new organs only took a little more than a week! Not only were they able to transplant the newly grown lungs into new rats, they got them to work for 45-120 minutes with about 95% of the efficiency of normal lungs. After their brief stay in the new rat, the lungs were removed so they could be analysed. The team also explored the durability of the new lungs (these things do have to move during breathing, after all) and found they were also nearly normal in strength. These are great first steps.

As always when I see medical science that is still using animal models, I’m fairly cautious about estimating when it may become available to humans. As part of the project, Niklason’s group did decellularize and partially recellularize (in slices) a human lung from cadaver, but these tests were even more preliminary. Niklason herself, according to Technology Review, believes it may be twenty years before humans are using scaffold-grown lungs as transplants. For many that means this technique will simply not arrive in time for them to use it. Yet the current state of lung transplants isn’t really that great to begin with – only 10-20% of recipients live more than ten years past the surgery.

Even if it takes decades to perfect, the scaffolding approach for culturing new organs seems very likely to become a widespread and useful technique. Yes livers and lungs are complex and will take a while to develop, but the heart muscle tissue is (a little) simpler and could be here earlier, and we’ve already discussed how scaffolds for simple vascular-like organs such as the trachea could become accepted science very soon. In the future, decellularization and recellularization of organs will mean that every organ donor, every cadaver possibly, will be able to save as many lives as possible. No organs will have to be wasted due to mismatched immune systems. That’s a wonderful prospect, and a right step towards using science to replace and rebuild our bodies as they fail. Effective immortality here we come!

[image credit: Thomas Peterson and Laura Niklason]
[video credit: Thomas Peterson and Laura Niklason]
[source: Technology Review, Wall Street Journal, Petersen et al, Science 2010]

It's Alive!

Who says biology, engineering, and medicine are different fields? Researchers led by Dr. Donald Ingber at Harvard’s Wyss Institute reported in Science that they have engineered a coin-sized microchip that can be loaded with wet biological cells, mimicking the workings of an actual lung. The bioinspired chip can be used to model drug action, determine the effects of environmental toxins, and could even replace some animal testing – all while speeding up research and dropping its costs.

To mimic the physiology of an actual lung, the chip contains two chambers separated by a flexible, porous membrane. One chamber contains human lung cells (alveoli), which are tiny air sacs with thin walls – this chamber allows researchers to introduce foreign particles, just as breathing would do in an organism. Across the membrane, the second chamber contains capillary blood cells (endothelium) which normally take up particles into the blood stream, as well as interface the immune system with potential toxins and pathogens. The computer chip is transparent, which allows real-time observation of how the cells respond to introduced particles.

Did I mention it also breathes? Because the chip is flexible, fluctuating the air pressure within a network of channels along its surface can replicate the mechanics of breathing – stretching and expanding the cells inside the chambers, roughly as they would in real life. This capacity for the chip to mimic breathing is an important step forward, because cell culture techniques are unable to replicate how mechanical factors influence cell behavior. Filling this gap brings laboratory models closer to the real-world organs they try to represent. Think of it as a miniature version of the donated lungs made to breathe outside the body.  Check out this video of lead researcher Donald Ingber talking about the chip:

Researchers’ first test of the lung-chip looked at how the system responded to the introduction of a pathogen. E. coli was added to the first chamber containing lung cells, mimicking the exposure of lungs to airborne bacteria. The second chamber was given a healthy dose of white blood cells (leukocytes), which are the immune system’s first line of defense against foreign invaders. Show time. Through the transparent chip, researchers watched in real time as the white blood cells migrated across the porous membrane, engulfing and killing the bacterial invaders. The chip clearly modeled the body’s own inflammatory response to pathogens.

The lung-chip design, and the biological processes it models.

A second test looked at how the lung-chip responded to the introduction of nanoparticles comparable to those found in toxic pollutants. Some of the particles induced an immune response and were trapped; others crossed the chip’s membrane and entered the blood chamber. Using the chip to model the introduction of non-biological particles illustrates how some toxins can make their way past the immune system and invade the body. It also provides an excellent system to test how airborne drugs are taken up into the lungs, which will cut costs and save time in the development of inhaled medications.

The next step? Currently, the cells used come from immortalized cell lines, which aren’t patient-specific and only provide a kind of average response to different drugs. If the lung-chip could be loaded with “primary” cells from an individual patient, testing could determine individual responses to potential drug action. Induced pluripotent stem cells, which can be derived from a patient’s skin, could be stimulated into alveoli and endothelium cells and provide a personalized lung-chip for specific testing. This would fit well into the larger movement towards patient-specific medicine.

The lung-chip isn’t quite ready for broad application yet – it still needs to be cross-compared with current methods of testing inhalant effects, which use rats as experimental organisms. If these comparisons show that the chip accurately mimics a normal lung, it could eventually mean an end to animal testing for this type of research. In addition to the obvious win for animal rights folks, the chip would save time and money by replacing costly animal research.

Future research will plan to apply comparable techniques to other organs of the body – a gut-chip, kidney-chip, heart-chip, etc. This will help us understand how drugs and toxins effect the body more broadly. Imagine having a series of personalized chips for all your different organs – your doctors could custom-test any potential treatment against miniature models of your own body. The computer/body interface is already being explored with chips that can detect cancer or identify bacterial strains within the body; the lung-chip represents an exciting new application of this hybrid technology outside the body.

It’s worth recognizing how exciting the Wyss Institute itself is.  Founded last year by Ingber himself, the institute is devoted to biologically-inspired engineering: figuring out mother nature’s tricks, and replicating them in man-made systems. The faculty list reads like a who’s-who of biology (George Church and James Collins, to name a few) and if this research is any indication, we can expect more exciting research from this group in the future.

As it stands, the lung-chip is an amazing example of how biology is creating new frontiers in engineering: an impressive reminder of the sort of human-machine interface that represents the future of medicine, and potentially ourselves.

See below an exclusive pic sent to us directly from Dr. Ingber:

The blue is the lung side, the red is the vasculature side

[images courtesy of Image: Kristin Johnson/Harvard Medical School/Science]

Lung tissue attached to the XVIVO system

For patients with late-stage respiratory diseases, finding a new pair of lungs can be… well, about as hard as it sounds. Currently, about four out of five lung donations are rejected for use, as they don’t fit the criteria required for a safe transplant. Keeping an organ alive outside the body is tricky stuff, especially long enough to patch it up. But what if doctors had enough time to repair donated organs that were initially unfit for transplant?

For the first time, doctors at Toronto General Hospital have used what is called the XVIVO Lung Perfusion System to repair donated lungs. Using a ventilator, pump and filter, the new technique can keep lungs breathing in a glass dome for up to 12 hours following donation. This time window allows doctors to better assess the potential of the organs for transplant, or to repair damaged lungs. Today, only 25% of patients can find a lung donation match. Keeping the lungs alive for a longer period of time improves those odds, increasing lungs’ chances of being used by as much as 5 to 10 times.

In case you didn’t catch that, lungs are breathing in a glass dome.  Creepy?  You bet.   Check it out yourself:

The lungs are kept alive at 37°C, the same temperature as your body. Vitrolife, an international biotech group, worked with Swedish doctor Stig Steen to develop a bloodless solution that allows the functionality of lungs to be tested prior to transplant. Called Steen Solution, the fluid is rich in nutrients, oxygen, proteins, and all that good stuff that keeps your lungs happy and healthy. By running the solution through the lungs, doctors can assess how well they exchange gasses, their ability to maintain normal body temperature, and a whole host of diagnostic criteria that take valuable time to assess.

Four patients have received transplants using the technique to date, and all have been successful. Andy Dykstra was is the only successful recipient whose new lungs were unfit for transplant until the XVIVO system was used to repair them (the other three donations met criteria, but were further repaired prior to surgery). Andy could breathe without artificial help just four days following the transplant, and was discharged from the hospital after only twelve days.  Not too shabby for a complete lung switch-out.

Dr. Shaf Keshavjee, Director of the Lung Transplant Program in Toronto, put the technique in context: “Many more donor lungs which we could not have used before can now potentially be used safely, and it sets the stage for more sophisticated molecular and cellular repair techniques to be applied in the Toronto XVIVO Perfusion System so that transplant outcomes can be further improved. The potential exists to immunologically pre-prepare the organ before it even sees the recipient’s immune system.”

Individuals with cystic fibrosis and emphysema are often at risk of lung failure during the later stages of their disease. But finding a new pair of lungs is no easy feat. Normally, lungs are cooled after donation to preserve the organs prior to transplant. But the cooling process slows cellular metabolism, which inhibits active repair strategies before transplantation. Keeping them at body temperature allows more repair work to be done, improving the chances of a successful transplant.

With an active imagination, you can pretty much run wild with this one. Maybe someday, these technologies will find a use without the need for organ donation. Imagine receiving artificial respiration while your lungs were removed, repaired, and inserted back into your body. Think of it like a tune-up for your body. I, for one, would love to see a big room full of lung donations pumping away in little domes. Patients could pick their favorite transplant organ, sort of like choosing your lobster at a seafood restaurant. Well, okay… maybe not.

Regardless, this technique creates new options for lung repair and will drastically increase the success rate of donated lungs. All told, that’s pretty cool.

You can find the press release about the XVIVO system here.