Growing replacement bile ducts

Scientists in Cambridge have developed a new technique to grow replacement bile ducts for patients with liver disease. Some children are born with a defective or blocked bile duct, and some adults develop diseases affecting the bile duct system later in life. In both cases the results can be lethal, or require a transplant, if the condition isn't treated. Fotios Sampaziotis, who's a liver specialist at Addenbrooke's Hospital, took Chris Smith through what he and his colleagues have discovered...

Fotios - To give you an idea of what the bile ducts are, the bile ducts form a network of tubes in the liver. Their purpose is to transfer bile, which is a toxic product of liver in metabolism, from the liver to the gut where it helps with digestion. It’s a waste disposal system, effectively, and a waste disposal system doesn’t sound very important, but you can imagine what happens when that waste disposal system breaks down. So the toxic bile overflows into the liver, damages it to the point where we sometimes have to change the whole liver. All this starts from having a problem or a blockage in one small tube. If we could replace this tube then we could go back and solve a very big problem later on: that of liver transplantation. This is what inspired us to start looking into making a bioengineered - or an artificial - organ incorporating human cells, which is what we did in the lab.

Chris - Talk me through what it looks like in the dish then. So you’d start with a sample of, say, my liver. Take me from there...

Fotios - So we would start with a sample of the tubes of the liver, which is a sample of a bile duct; or we would start with a sample of someone’s gallbladder. The next thing we would do is we would put these cells in a dish and grow them out for a few weeks. What we would see is the cells proliferating and then we end up with a very, very large number of cells. The second important bit is that what we managed to do is get these cells to now grow onto a multitude of materials called scaffolds, and they lend to the cells the structure - the mechanical strength - and properties that they need to move from cells to tissue which you can manipulate, you can suture in place, and most important for us, you can fashion and engineer into an organ...

Chris - Because when you say "structure", it’s one thing having a sheet of cells growing in a dish, but that doesn’t make a tube which could then be implanted somewhere and that’s what you're saying the next step is having got the cells growing is to persuade them to form the right shapes and become something useful.

Fotios - Exactly, and that’s what we did. First, we managed to form a tube with human bile duct cells, which is a bioartificial bile duct.

Chris - How big are these tubes?

Fotios - In the human, a centimetre in diameter. However, what we did is we tried this construct in mice, so we had to make a mouse-sized bile duct and that was less than a millimetre!

Chris - Does it work?

Fotios - Yes, it works! We needed to convince ourselves! What we thought we would do is we would transplant these tubes into animals and then we would do a lot of the tests that we do in patients, that your GP orders - for liver blood tests. We also did some MRI imaging to make sure that the bile duct was actually in the right place and there was bile flowing through it.

Chris - So you actually took the tube that would normally connect the liver to the intestine in these animals and replaced it with one you had made yourself using this new strategy and demonstrated it’s working?

Fotios - Absolutely.

Chris - Goodness! So that’s outside the liver – that tube though but there are lots of these tubes inside the liver tissue itself – aren't there? So that’s presumably a more difficult not to crack – getting inside the liver to help those tubes if they break.

Fotios - I completely agree. This is the next big challenge. Because these tubes are so small and so many, they're not amenable to surgical intervention. You can't cut one out and put another one in - there's just too many. So, in that case, what we think might be extremely useful in the future is to deliver the cells directly into these tubes. We have ways of accessing these tubes and we could potentially inject the cells. That for us is an area of major interest.

Chris - What was the big breakthrough here that meant you were able to do this because growing some cells from bits of the body in a dish is something scientists have been doing for a hundred years? So what was the step change that meant you can now actually get this to turn into something useful?

Fotios - What we did that we think made a difference is we grew these cells in a new culture system – in 3D culture conditions. We embedded them in a drop of gel. What the cells do then is they form small tubular structures. Once you have a tube as opposed to a single sheet of cells, it’s far easier for the cells to roll back to their everyday routine and keep performing their functions. So in other words, the cells will deliver more function. Now that was one of the major problems because as I said, bile is very toxic. If the cell becomes comfortable in the dish and forgets how to fight off the bile and then all of a sudden, you expose it to a highly toxic environment, the cell will probably not have time to readjust and might die. However, if you keep them in an environment where they maintain their function, it’s so much easier to go back to their natural niche; to their natural environment.