Biofabricating organs

Antony Funnell: Hello and welcome to Future Tense, I'm Antony Funnell.

Today on the program, freelance producer William Isdale looks at the future of organ transplantation. It's a field of medicine and science that's advanced enormously over the past few decades, and, as William reports, developments are likely to continue apace.

William Isdale: A century ago the idea that you could take body parts from different people and assemble them into one person was confined to the realm of fantasy, like Mary Shelley's Frankenstein, but today it's part of everyday medicine. I'm talking of course about organ transplantation. Huge strides have been made in the past century from the world's first successful kidney transplant in 1954 to more recent developments like full‑face transplants and whole-limb transplants. Thousands of us today live longer, healthier lives thanks to other people's hearts, kidneys, livers, corneas and all sorts of other bits and pieces.

But how did we get here and what does the future of organ transplantation hold? My first guest on the program today is Dr Aric Bendorf. He's a research fellow at the Centre for Values, Ethics and the Law in Medicine at the University of Sydney and, as Dr Bendorf reminds us, people have been talking about the idea of organ transplantation for a very long time.

Aric Bendorf: when we look back at Hindu mythology, Greek history, Chinese myth, there are many legends about people giving up a heart for a wounded warrior, people giving up a part of themselves to somebody else and that miraculously helping them heal. This is from thousands and thousands of years ago. Technically, the first successful transplant occurred in 1905 and that was with a Czech doctor who transplanted a cornea from a deceased person into a person who had been blinded by caustic soda. The corneal transplant was successful and is successful for two unrelated reasons. The first is that the tissue that was selected doesn't have much blood supply so the body didn't recognise it as being foreign and would accept it, so the body accepted it, it didn't reject it immunologically. The second was the nature of how the doctor performed this and that is he did it in aseptic conditions. So these two ideas contributed to make this a successful transplant.

William Isdale: As Aric just described, one of the key hurdles in the history of transplant has been trying to overcome the body's natural immune response which causes rejection of foreign tissues and organs. Since about the 1960s a whole range of immunosuppressant drugs have been developed, and that have allowed for the rapid expansion of both the number and types of transplants being performed. But the drugs aren't always well-tolerated by patients and that remains an on‑going problem.

Dr Kellee Slater is a surgeon at the Princess Alexandria Hospital in Brisbane and she specialises in liver and pancreas surgery, including transplant.

Kellee Slater: There's new drugs coming onto the market all the time with different side effect profiles, and it's a very individualised thing, immunosuppression for patients, but in the long term it does cause significant serious side effects for the patient, so if we can find a world without those, it would be good.

William Isdale: The Princess Alexandra Hospital has been home to some pretty amazing developments over the past few decades. In 1987 Professor Russell Strong developed a new surgical technique that has become known as 'the Brisbane technique', and that involves taking a liver and from an adult and splitting it into a number of smaller segments, each of which can be transplanted into a child. The PA hospital remains a world leader in transplant, so what does Dr Kellee Slater think that the future of organ transplantation might hold?

Kellee Slater: I think where I see transplant going into the future is the manufacture of organs that are artificial, rather than relying on a deceased donor source or even a live donor source. So, for example, using 3D printing to print organs using the patient's own cells, so then we don't have to give them immune suppression drugs that knock out their immune system. That's where I hope to see transplant going towards the future.

William Isdale: The future that Dr Slater just described might not be too far away. Associate Professor Mia Woodruff heads up the Queensland University of Technology's Biomaterials and Tissue Morphology Group and they are involved in what's called biofabrication, which is using a patient's own cells to create bespoke body parts and they are doing that using 3D printers that they themselves have designed and manufactured. So let's go take a look at one.

Mia Woodruff: This one is one of our early prototypes. We make them quite big and bulky because we tend to move them around so we have to make sure they are quite sort of robust, I guess, otherwise they break. If you look over here, you can start to see that the design gets a little bit more streamlined. So this one, you've got a stage there basically which moves XYZ stage. You've got a nozzle here through which you will be printing a polymer, and also we have things like over here gel printers with cells in here, so this is where different cells will be printed out so we can interchange that into our printers.

Our vision is a hospital of the future which is effectively in the same way that you have office printers and every day you print your documents. We want to have a hospital which…every hospital in the world will have 3D printers in the operating theatre. So the patient will go in, the scan dataset, using various coding technologies, will be there ready for them as soon as they are put under the anaesthesia. Printing on the spot, a different type of polymer for different types of tissue, fast degrading for bones, slow degrading for skin. Different types of cells, depending on the tissue you are looking at, and different types of growth factors to stimulate different tissues being formed. Literally press button here, bone cartilage, size of defect, feed in the scan, print it on the spot, implant it in a sterile manner. So that's our dream, the hospital of the future, 3D printers in every hospital in the world.

William Isdale: Now having seen some of the early prototypes, I sat down with Mia to have a bit more of a talk about how the technology was developed and about what some of the future clinical applications might be.

Mia Woodruff: We can create a customised 3D printed tissue replacement for a child who is suffering from cleft palate or microtia. Often a patient who has had their skeleton shattered after a motor bike accident, we are reducing their human suffering. So we're improving their quality of life and really that's the motivator for us. So there is some fantastic work going on at QUT by Professor Dietmar Hutmacher, who is looking at treating ladies who have suffered from breast mastectomies. So what would happen here is you would take a scan of the patient prior to the operation, so prior to having the breast removed, and you would get an anatomically precise, three-dimensional image of what they looked like.

And then after the mastectomy we can start to print biologically relevant scaffolds or replacement breast tissue that can then be cultured in the laboratory using cells from that same patient, so during liposuction we can extract fat cells from that patient. We can infuse these into these breast replacements. This is still very preclinical. It's certainly not as advanced as other techniques yet but it's very pioneering research.

And so after you have cultured these three-dimensional scaffold shapes that are exactly the size of the patient, after several weeks or months we can implant those back into the patient with the patient's own cells in there and then the scaffold structure actually degrades, which means that the tissue starts to take on that three-dimensional structure and eventually the intention is that it will basically just fill that defective tissue and it will be the perfect size and shape of the patient. The scaffold has disappeared and it has just got that tissue there. So yeah, it's a big, blue-sky project. It's an incredibly relevant one and it's going to hopefully get rid of the need for silicone implants or for women to not have an option, so it's incredible research.

William Isdale: You mentioned used biologically relevant materials. What exactly are they?

Mia Woodruff: Okay. So we can't just use any old material to implant in the human body, so if you go all the way back to the history of biomaterials and how they were established, way back in the world war when pilots were flying and they crash landed, a lot of them had shards of their PMMA, so polymethylmethacrylate, screens of their planes embedded in their eyes and what happened was, doctors were astonished. They were wondering why they had these materials embedded in their eyes that weren't creating an inflammation reaction so they started to realise that certain materials are biocompatible, which means that when they enter the human body they don't really upset the balance of the human body very much, so this is how biomaterials evolved over time.

So there is historical evidence of way back in Egyptian times they would use sort of wooden teeth, different types of metal implants, but as biomaterial scientists, what we have realised over time is that we start to artificially create different types of implantable materials, based on nature. So, based on mimicking the collagen in the body, based on mimicking the hydroxyapatite in the bone, we can create artificial materials that are actually biocompatible with the body. And 3D printing has enabled us to be able to take those materials and to form those into three-dimensional objects. We have always been able to develop these biomaterials for decades and decades but forming them into the right shape to implant has been very difficult. But now 3D printing, we build our own printers to process these materials and we can create patient‑ready scaffolds that are sterile, that are biocompatible, that can have the cells put in there from the patients and that's the kind of work that we are doing here at QUT and that's biofabrication.

William Isdale: Different tissues have totally different properties so bone is very hard but, if you wanted to recreate cartilage, how do you get those different properties?

Mia Woodruff: So we basically work with fantastic biomaterial scientists, polymer chemists and different types of engineers who can make sort of specific types of polymeric structures that degrade at different rates so we can make them with different tensile stresses, with different shear stresses, with different compression, different degradability. And so the biomaterial scientists work on developing these different substances, so very hard substances for bone. For skin, shear is an issue so you need to have quite flexible, soft substances. It doesn't need to really have a huge compressive strength. For bone, it does.

And then for cartilage, cartilage is very interesting and it's very hard to regenerate, and Associate Professor Travis Klein at QUT is working on cartilage regeneration with biofabrication and he is developing a range of hydrogel substances. So hydrogels are highly hydrated jelly‑like substances that can be extruded very easily, and what we can do with those substances is we can build them into three-dimensional objects and we can put the patient's chondrocytes or cartilage cells into that substance and start to look at if we are compressing that gel, what kind of proteins are being expressed? Is it the same kind of protein that would be present in the actual native cartilage?

So he is doing a lot of work looking at developing specific hydrogel structures, which is not an easy task, and also incorporating cartilage cells, making sure they don't dedifferentiate into the wrong types of cells, and then basically checking that we are getting real human cartilage formed. And then, combining that with some of my bone research, we can start to look at osteochondral defects, so osteo and chondral bone and cartilage. So, for example, osteoarthritis, and people often have issues in the knee where they have got a bit of bone and a bit of cartilage missing and we need to make dual‑phasic scaffolds. But cartilage is a difficult substance to regenerate because it doesn't have a nerve supply and it doesn't have blood vessels. Bone does have a nerve supply and it does have blood vessels. So creating an implant that half of it has got to be anti-blood and anti-nerve and the other half has got to promote that is quite complicated, so the engineering is really, really important there and that's something that we are working on.

William Isdale: Are there any kinds of tissues that you think it would not be possible to emulate using your methods?

Mia Woodruff: I think it's a highly translatable method, the biofabrication technique. Nerves are very difficult to regenerate but what we are able to do with our biofabrication, using a process called melt electrospinning, is we can make tiny fibres that we can make into tiny hollow tubes and we can use those for blood vessels or potentially for nerve-guiding regeneration. Nerves are really difficult to heal so that's definitely an area that needs a lot more research, and also we haven't really worked very much on the brain.

But certainly the sort of tissues…there are groups all over the world and all over the country in Australia who are working on liver and they are working on heart, and people can start to look at actually building beating-heart tissue. Now, printing an entire three-dimensional heart in a machine is never going to happen but what we can do is we can create a scaffold structure and we can start to put those cardiomyocytes, using this printing technology, into the right parts of the scaffold, start to culture it in a bioreactor and then hopefully eventually be able to implant that. So that's sort of the future of heart transplants. We also have a lot of groups who are looking at making artificial heart pumps, and so we might not necessarily need a beating-heart organic tissue if we can make a pump system that can be implanted.

William Isdale: You're listening to Future Tense, I'm William Isdale. Today we're talking about the history and future of organ transplantation. We have just heard about the work of Associate Professor Mia Woodruff. She's involved in bioprinting a patient's own cells into dissolvable structures which can then be transplanted into patients.

But what about that dream of growing whole organs in the lab? Professor Melissa Little is from the Murdoch Children's Research Institute in Melbourne and she's helping make that dream become a reality.

Melissa Little: There's enormous hurdles for making something as large as the organs that we live with as adult humans. You know, a human adult kidney has tens of billions of cells. We're starting with a small culture of stem cells and just essentially proving the point that we can get them to go through what would be normal early kidney development and they really get quite complex and quite mature but you can't make an organ outside of a body that has a heart pumping blood get very big because they essentially don't have a blood supply to give them oxygen.

William Isdale: So for now it's not possible to create full‑sized organs in the lab, but Professor Little has been creating what are called kidney organoids. But what exactly are organoids and how do you create them?

Melissa Little: So organoids are a mini organ, essentially. What we do is, using cells, we actually create a structure in the laboratory that is a replica of the organ that we are interested in, and so lot of people have now shown you can make organoids of brain and of eye and liver and intestine and stomach and we've been making organoids of kidney.

William Isdale: And how do you actually create them?

Melissa Little: We are actually making kidney organoids from what we call pluripotent stem cells, so these are human cells that actually have an ability to turn into any type of adult cell. And we can actually make these by reprogramming an adult cell, so that means I can take a skin cell or a blood cell from you. I can instruct that cell to go back to a stem cell that's pretty much equivalent to the very beginning of development and then direct it towards the type of organ that I want to build.

William Isdale: And does that mean that you are able to use a particular individual's own stem cells. and are there particular benefits in doing that?

Melissa Little: Yes, there are enormous benefits. Ultimately, you know, the very long‑term goal which I would accept right now is still a very, very long way away unfortunately for those people that are looking for a replacement organ, we hope to make a whole organ and we should ultimately be able to do that with the patient's own cells. We may even be able to fix damage in the patient's own cells and rebuild an organ. At the moment what we are making is these organoids, which are very little models of the developing kidney, and we can make them from patients that have kidney disease and actually use that as a way of understanding their disease better, screening drugs for their treatment and asking whether new drugs in development are toxic to the kidney.

William Isdale: How long does it take for these organoids to grow and how long can they actually last for?

Melissa Little: So in the experiments that we do, we start with stem cells and, in about three weeks from one dish of stem cells, we can make about 20 kidneys and these kidneys are about 8 millimetres in diameter, so about the size of a small button or a snap. So that's three weeks. How long can they grow? We haven't really pushed them out to ask when do they die but we're really reaching a scale now where we're going to have to find other ways of growing them and giving them a blood supply to get them to just keep going.

William Isdale: And if it was possible to develop these into larger organs that could be transplanted later, does the fact that they are using cells from a particular patient's own body, does that have benefits in terms of the potential for rejection by the immune system?

Melissa Little: Yes, of course. I mean, when we transplant organs or even transfer blood from one person to another, we can do that from one person to a different person but, as you probably are aware, there are immune rejection problems and so there's a lot of immunology that goes into making sure that there is a reasonable chance the organ you transplant won't be completely rejected but it's never perfect. However, theoretically, if you transplant yourself into yourself, you don't have those rejection issues because your body's immune system is set up to recognise you as self and not rejected.

I think what's interesting is that this was so remarkable even 18 months ago in the Nature Cell Biology paper just to be able to show that we were getting close to something that knew what it needed to do to form a kidney, but what we've got now is a much, much larger structure with many, many different cell types in there. So this is making a patterned organ that has lots and lots of these nephrons, which is the filters that filter your blood. It's got its own blood vessels forming. It's got interstition between the nephrons and there's probably about 10 or 12 distinctly different cell types forming and what we call self‑organising. So those cells arrange themselves to form a really complex three-dimensional structure by sending signals to each other, and this is how the embryo forms. And so what we've got is a normal embryonic organisation going on in a dish.

William Isdale: So it sounds like these organoids at the moment have some of the functions that a fully-grown kidney would have.

Melissa Little: Yes.

William Isdale: But are there still a lot of things that they are not able to do yet that a fully-grown kidney would be able to?

Melissa Little: Yes. Well, right at the moment they don't make urine because they are not connected to a blood system to filter, but they are starting to show signs that they are forming many of the specific proteins at different parts that the kidney tubule does make. We know that they are selectively responding to toxins that are known to injure the kidney, so that means they are mature enough to know that they have become a kidney proximal tubule, for example. So they are still what we would regard as a developing organ. A lot of the things that you need for final renal function don't actually turn on and start working until you are born and so we are somewhere between the beginning and the functional organ.

William Isdale: And are there specific questions about the development of kidneys or their function that you are particularly interested in finding out and which these organoids might be able to help you answer?

Melissa Little: I think this is the first time we have actually been able to really take a good look at how the kidney normally forms in a human. Everything we have been able to work on before has been done in model animals, whether that's a fish or a frog or a mouse, and there are really big differences of course between the kidneys in those animals and the kidneys in humans. But we don't investigate normal human development for obvious reasons. Now we have a model of it, we can actually ask about exactly how it happens in humans and therefore we can model what goes wrong when you have a mutation.

William Isdale: And in this miniature form, are there any current medical applications or do you still need to get it to grow into the full form before those sorts of applications would become possible?

Melissa Little: So we are interested in what these can tell us now. I think we have some preliminary evidence that they will be able to act as a readout of whether a drug is toxic to the kidney and this is a major problem for the pharmaceutical industry. If these were able to tell us before a drug went into clinical trial that the drug is going to damage the kidney, then those drugs simply wouldn't reach clinical trial and that would actually save a lot of people a lot of time and a lot of money. But we are also making stem cells from families with inherited kidney disease and actually using these to understand better the disease in those families and potentially get a better idea of how we might be able to treat those particular types of kidney disease.

William Isdale: As we have heard on the program today, there are some incredible new developments that involve using a patient's own cells. But at least for now the focus has to remain on getting organs from other people. In states like Western Australia and Queensland there's a very small population over a large area, and that means that getting compatible organs to suitable recipients can take quite a bit of time. And, as Dr Aric Bendorf from the University of Sydney reminds us, time in organ donation is absolutely crucial.

Aric Bendorf: There are two types of pathways for organ donors. The first is called donation after brain death where that person's brain is declared dead and no longer functions, and the second is the more traditional what you and I would consider death, is when the heart stops beating and the person stops breathing. That's called donation after cardiocirculatory death. The problem with the latter, with cardiocirculatory death, is that as soon as the heart stops, the organs start to die because they are deprived of the oxygen and the nutrients from the blood supply, so a lot of work and a lot of research has been put into how we can improve the outcomes of donation after cardiocirculatory death donors. Australia leads the way with how do we preserve these organs once they are retrieved.

William Isdale: So some of those methods of preservation includes using cooler bags full of ice and special solutions. Dr Kellee Slater points out that increasing use is also being made of special machines which can effectively do a test run of an organ before it is transplanted.

Kellee Slater: They sort of function like a robot human, if you like, and you put the organs onto the machine, you pump oxygen and blood through the organs, and the main reason we do that is to see if organs that we think may not work in the human situation will work. So we put them on the machine and see how they go, and we measure all the toxins that come out of them and how they are functioning and, if they work well, then we transplant them into the person, and if they don't work well, they were never going to work well and we don't use them.

William Isdale: As we know, Australia has an ageing population and we are seeing an increased incidence of diseases like type II diabetes which causes kidney failure. So we are almost certainly going to need more organs in the future for transplant, but it's also important that we don't forget about the demand side of the equation. As Dr Slater points out, there is a great deal of wisdom in the old adage that prevention is better than cure.

Kellee Slater: The biggest thing we can do to improve transplant is to decrease the number of people who need a transplant, if you look at it the other way, because we have done a lot of the things in the last 10 years to try and increase donation rate and that's difficult to do for many reasons, but we are doing huge amounts to decrease the number of people needing a transplant at the moment and that's with the treatment of hepatitis C that's about to come on to the market. There is 220,000 people in Australia infected with hepatitis C and about 20% of those will go on to get liver failure towards the end of their life and those are potential patients who will need a transplant or who will get cancer because of their hepatitis C. So the treatment that is coming on to the market is 95% effective and so it will eradicate hepatitis C and we'll have that treatment within the next six months so that is going to completely change the face of liver transplant.

William Isdale: And as an early Christmas present to those Australians, in late December last year, the federal minister for health, Sussan Ley, announced that those drugs would become part of Australia's pharmaceutical benefits scheme from 1 March this year.

Let's put aside all the whizz-bang technology and the new drugs that we have talked about so far in this program. In the short to medium term at least, to come to grips with the shortage of organs in Australia is also going to involve issues of public policy. Dr Aric Bendorf from the University of Sydney argues that we need to focus on identifying patients who are likely to become brain dead and treating them through to brain death if we're going to match world-leading donation countries like Spain. But as you can imagine, that raises some hairy questions about our views on death and the ethics of treating people beyond the point at which medical care is judged futile for them as an individual.

Aric Bendorf: So going forward, if we want to increase Australia's deceased organ donation rate, it really comes down to a discussion about brain death. Do we want to change the way that we treat people in the ICU to accommodate a higher number of people being declared brain dead, or do we want to leave things the way they are and just be happy with the donation rate as it is? The sad fact is we can't have both. We can't have a high donation rate and a low brain death rate, we can only have one or the other. So this becomes more a discussion not about what we are willing to do to increase organ donation but what we might be willing to change in order to accommodate that wish.

William Isdale: We've heard about a number of new approaches on the program today that could help alleviate the shortage of tissues and organs available for transplant, including 3D bioprinting and growing artificial organs in the lab. But how will we make sure that those ideas come to fruition? Over the past six months the federal government have been talking quite a bit about the so‑called ideas boom. But will the ideas boom comes to organ donation as well? To end the program, here is Associate Professor Mia Woodruff:

Mia Woodruff: I think one of the most exciting developments from a university perspective at the moment is that there is a huge amount of traction and interest from the government, federal level and state level, into connecting universities with industry, and this is so interesting and so exciting to us because it means that all of these products that we are developing, we are able to connect them with an end user. We are able to talk to people who have…they have a need, they understand where the market value is for these products, and they are looking to invest into getting them to market a lot quicker.

So researchers can't create breakthroughs working on their own. Universities have a huge amount of unlocked potential in terms of ideas, but what we need to do is connect better with industry. Australia, currently only 5% of industry actually collaborates with universities. In Finland it's 90% and so you have to consider those statistics and start to look at ways that we have to improve on that. So this isn't a bad thing, this is an enormous opportunity for Australia. So we see it as an opportunity. The federal government is seeing that the ideas boom, the connecting industry with university is so important, and they're going to be putting incentives forward in 2016 and we are absolutely delighted about that. So we see 2016 as a huge year for us in universities doing this kind of research.

Antony Funnell: Associate Professor Mia Woodruff from the Biomaterials and Tissue Morphology Group at the Queensland University of Technology.

And that report was by freelance producer William Isdale.

We also heard today from: Dr Kellee Slater, a surgeon at the Princess Alexandra Hospital in Brisbane; research fellow Dr Aric Bendorf from the Centre for Values, Ethics and the Law in Medicine at the University of Sydney; and also Professor Melissa Little from the Murdoch Children's Research Institute in Melbourne.

A transcript of today's program will be available on our website, just search the words Future Tense and ABC RN.

I'm Antony Funnell, until next time, cheers!