So first of all I'd like to thank John and Lewis for the invitation and also Kim who's been really helpful to us. Over the next few minutes I want to just describe to you and tell you about some of the research that we're doing in Dublin on tissue engineering specifically to do with cartilage and with bone. These are my disclosures. I think what's more relevant in terms of my declarations is the practice that I have. So these are a sample of some of the cases that I've done recently. So as you look at that I think you will understand why I have a particular interest in tissue engineering of articular cartilage. As we realise and has been highlighted, when you're looking for tissue, whether it's autologous or allograft, there is a shortage of it. There's a lack of donors, there's a lack of tissue and as we have heard this applies all across the board. The group that I am part of is involved in tissue engineering looking at tissues all over the body and the areas we're interested in today are obviously bone and cartilage. This group has over the last few years researched and published on many different varieties of designer-based collagen-based scaffolds. So they've altered the composition and described the effects of that, altered the cross-linking, altered the scaffold pore size. We have successfully developed a collagen hydroxyapatite scaffold which we have tested and reported on in a rabbit and subsequently in a horse and now it has been cleared for use in humans and has been implanted into about 30 patients. However, today we're talking about cartilage and these are the lesions that we are interested in and we've heard it described very well by the previous speakers, the merits and the shortcomings of the different ways of treating these. Obviously it is a little bit more difficult to develop a plug that is osteochondral because there are three different layers at least. So at the bottom we want this to become bone, at the top we want this to be cartilage and we want a layer in between that separates them because one of the problems with these plugs is they can completely turn into bone. So by combining different types of collagen, different pore size, using all of the knowledge that was acquired over the years, we did develop an osteochondral plug and we have used this in a rabbit and reported on this. We've also reported on this in a goat and in fact the vet that works with us was looking after this horse, a show jumper that had stopped jumping and had this lesion and he used it on the horse and the horse started to jump again. So a 100% return to sport in a horse. I have to tell you that some people in Ireland are much more interested in horses than in humans but we did decide to use it and we have started between myself and Professor Cachal Morne. We have brought it through to the ethical approval and regulatory process to do safety studies and Cachal has implanted this in three patients without any detrimental effects. However, when we're starting to talk about larger defects, we do need something extra other than just a scaffold and that's when we start to introduce stem cells and biomolecules and we need safe, effective delivery systems. So in other words, instead of it just being an inert collagen scaffold, we want to implant that with either biomolecules or therapeutic molecules or cells and in fact what we've been doing is using gene activated scaffolds and what this involves is that the stem cell is modified to produce a specific therapeutic. So in other words, by delivering the genes, the cells act as a drug factory. So essentially what you've got is you've got this is the collagen scaffold. These are nanoparticles and genes. The stem cell comes in, takes up the nanoparticle and the gene, becomes transfected and then starts producing the material or the therapeutic agent you want. We have published on several of these nanoparticles and the interesting thing about the nanoparticles is that by changing the nanoparticles, you alter the way the gene is taken up, the way it is expressed and for how long it is expressed. So these things are short term. They don't last forever. They don't transfer onto the daughter cell, so they are quite safe and this is some of the data we have published on bone, empty defects, the scaffold alone or the gene activated scaffold. So by activating these scaffolds with gene, they become much more powerful. We have also looked at activating genes to look at cartilage repair and we have activated the genes to produce these different therapeutic molecules. And what we have found is that when you look at the glycosaminoglycan level, with the SOX trail activation, it is a much higher level. The other thing is that it enhances chondrogenesis but it also stops bone formation, which is what we want at the cap of that osteochondral plug. And we have seen in vivo that the gene activated scaffold promotes the formation of fairly stable cartilage. But this material, when you hold it in your hand, can be quite soft. So the next phase, and we got grant aid for this, is to combine it with 3D printing. This is the stage we are at now. So with 3D printing using polycaprolactone, we can make any shape, different pore size, different outer surfaces. And one of the things we have had to do is to make sure that when we add the collagen matrix that it does diffuse into this 3D printed structure. So that it isn't just on the surface. And then when we examine it under magnification, you can see there is a 3D printed material. This is the collagen matrix. So now what we have got is a 3D printed material with a collagen matrix, which then has nanoparticles and genes that can activate the stem cell when inserted. And in fact, using the 3D printing, we can modify the Young's modulus. But all of this, as you can see, changing the collagen, changing the nanoparticles, changing the genes, changing the 3D printing techniques, all of this adds up to literally millions of options. But we do believe that somewhere in the centre of all of that, there is a recipe, if you like, for a structure that will be metabolically active and will resemble cartilage and hopefully will function well in patients. So a long way to go, but this is the stage that we're at now. And I would like again to thank you for the opportunity to speak to you. It really is a great honour to speak in front of such a prestigious group of surgeons. And it also is an honour for me to represent and present the research that has been done by these fantastic people over many years in Dublin, in Ireland. So I'll finally say in Irish, go raibh míle maith agat, which is the Irish for, I thank you a thousand times.

tissue engineering

collagen-based scaffolds

gene-activated scaffolds

3D printing

transplants