Hello everybody, so I'm talking about the advances in imaging, and in order to communicate to you why we think we need to image the bone, why we think it's important to know about the vessels of the epiphyseal cartilage, I will help you to understand differences between articular and epiphyseal cartilage, conceptualize the articular-epiphyseal cartilage complex, we talk about vascular development during skeletal maturation, we get insights into epiphyseal vascular origin and subsequent osseous manifestation of juvenile osteochondritis dissecans, and understand the MRI bone window, T2 star, how this can predict in healing. If you heard a lot about healing and stability and instability, I would like to make a point right at the beginning, and Ted showed this in an example. Instability is important, but 50% of the patients who do not heal naturally have stable lesions, and this is important to consider. So we have MR methods which are supposed to advance diagnostic accuracy. So cartilage, articular cartilage, we are born with our articular cartilage, you know this, it's vascular and everybody in clinical practice is aware of the fact how difficult it is to repair articular cartilage, also due to the fact that there is no vascularization. To the contrary, our vascular-epiphyseal cartilage has an incredible network of vessels at the beginning of life. This is a specimen we imaged at one month. You see the avascular articular cartilage and all of this is the vascular epiphyseal cartilage with a secondary ossification center altogether called articular epiphyseal cartilage complex. So we use this technique, it's called susceptibility imaging, where on the background of just chondroit matrix, the vessels stand out because they have different properties than just the background. So this is something we use to image at very high magnetic fields, so it's not anything which one easily can do at a 1.5 Tesla machine, but it's possible to do this in humans for sure. So as you can see here, that's a vascular network you are born with at one month of age. And I will show you some more of these examples. So the vascular canal has an afferent and afferent vessel surrounded by a chondroit matrix, a resting zone, the proliferative zone, the hypertrophic zone at the junction to the secondary ossification center. So these vascular canals we are imaging here. So we observed the development of the secondary ossification center and the respective vascularity. So everybody knows we have our cartilaginous template and the secondary ossification center grows from around to a more oval shaped, almost large oval shaped aviator glasses, all still symmetric to eight years of age where we finally acquire our template of an asymmetric lateral femoral condyle versus a smaller medial femoral condyle. And even at eight years of age, you can see here the vessels traversing the epiphyseal cartilage in an immature skeleton. So if we look really into the details of this vascularity, we call it vesselness, there are some really interesting features. We have a central vascular bed here surrounding the secondary ossification center. Then we have a medial and a lateral peripheral vascular bed. And in between those, we have a completely avascular region, a watershed region. So I don't think we yet understand why nature has built that network with a total avascular region with no communication. It almost looks these are the ends of these vessels, vascular canals, these are vascular buds, and they come in five or six like grapes. And in between, there is absolutely no vascularity. So we looked into connectivity of these vascular regions and could show with post-processing methods of vesselness that the vascular beds are indeed separate and are not communicating. We followed these vascular beds over time in order to evaluate if this is of importance for OCD, if we can find kind of some reason why there are predilection sites of OCD, for instance, in the lateral or central aspect of the medial femoral condyle. And as you can see here, that very rich vascular network at one month gets slightly rarified at three months centrally. At two years, again, centrally, we lose vessels. At three years, even more. But at four years, we have no central supply anymore. So around the notch, we do not have vascular supply. And eight years, a small rem of peripheral vessels are remnants. So we also have to understand that vessels only can come through the perichondrum. They cannot come through the articular surface. So our JOCD is at the central aspect of the medial femoral condyle. There is no close perichondrium. So vessels supplied to this area at a critical age where we don't have any central vascularity anymore, let's say between four, eight, nine, ten years, has to be supplied only from the periphery. And we think that might put that specific region of predilection site of JOCD at a particular risk. So I told you the epiphyseal cartilage vascularity can also be imaged in vivo. It was published by our colleagues in Vienna at 7-Tesla. And as you know, 7-Tesla is now clinical. But I also have some preliminary data where you can see the vascularity at 3-Tesla. So that was the understanding of vesselness in development, which was promoted by Rock in the last 10 years significantly. And as you heard previously, we had input from the veterinary medicine where they found that epiphyseal cartilage necrosis was first shown in pigs and horses and that have high prevalence in these areas of osteochondrosis. And our group also reported first in humans that epiphyseal cartilage necrosis is the first step in JOCD patients. So this paper where we had patients subsequently imaged to follow healing, we saw that there is an epiphyseal cartilage origin and healing or osseous manifestation is a repair mechanism which subsequently comes into play. So previously, as you can see here, Spalterholz techniques, you see exactly what I showed you and that was in the 60s and 70s where they found that watershed area. But of course, given the new technology and our ideas how to apply these technologies, the susceptibility mapping shows unparalleled detail of these developmental stages. So this is probably the most famous radiograph of all of rock because I saw it already in two talks and I cannot miss showing it to you too. So that is how the mess of JOCD being an osseous fragment detached from your bone in principle evolved over the time. It's a late stage, that's what you really see on radiographs and not everybody, and I see this in my clinical practice, is in tune of subtle changes in radiographs. I don't think radiologists are trained to really look at the extremely subtle changes in radiographs, especially in the adolescents or children. So that is a late stage. How do we think it happens in an earlier stage? I just talked about the epiphyseal cartilage. We think there is an epiphyseal cartilage necrosis and it happens at the secondary physis. Ted pointed out the importance of the secondary physis. So there has to be vascular connection and you saw it in this graph of the cartilage between the epiphyseal cartilage vascularity and the secondary ossification vascularity. And there is in between the secondary physis. If this is disrupted and we do not really know yet what happens and why it happens, then we suddenly have a consequence of this and that is a delay in the ossification front. Here we have the ischemia in the epiphyseal cartilage. So this is the original injury. Then how does it heal? Interestingly, I could observe or we could observe that there is an algorithm how it heals. It's almost like this would be an abscess and you create a membrane around it. What happens is you have peripheral mineralization and that isolates this necrotic tissue. This time, this mineralization then ossifies. You have then osseous bridging to heal or you have the PASME2 instability with the subcortical cystic changes and here the fluid at the interface. So if it heals, it heals, it bridges and as you can see here, it seems to be a little more sclerotic and Ted showed a radiograph where it is healing but there is still some sclerosis. And the last stage in healing actually is reconstitution of the normal bone marrow and that's the same what you would find in fracture healing. So there is still some edema, the normal fatty marrow is not yet reconstituted and the trabeculae have to be reorganized. So if everything fails here, you have the loose body. So this is kind of an example. On the right, you see our clinical MRI and actually the reason I got to think about what one could do to improve the imaging was that I was so puzzled with these MRI images. I never knew what tissue is this, what am I looking at. I mean, I was pretty confident in saying what is stable and what's unstable because once you have a fluid rim and cysts, it's unstable and the cartilage is violated. But this is not the majority of the cases, especially our days, images are acquired much earlier. And so as you can see here, that is the delay in the ossification front. You can see the shark teeth. That here is the ischemic necrosis of the epithysal cartilage. It's all one sequence. It is a so-called T2 star sequence. The first echo, which is a very short echo time, we invert and make it look like a CT. So that is a normal MRI sequence. It's FDA approved. Everybody can put it on. It takes about five to six minutes to acquire. So stage one, I talked about that the healing starts with peripheral mineralization. Hard to tell if in the normal images, is this bone? I would say yes, this looks like bone. And here's the interface. So it is not bone, it's just peripheral mineralization. And you can see it very well in this bone window. So the next step which happens is an ossification. And you see this very well here. And it connects with the underlying bone at one point. It starts bridging, but at one edge, the open book maybe here, you see it is not bridged yet. So that's kind of the summary, is the, again, epiphyseal cartilage origin, peripheral mineralization, ossification, and healing. So that's an example how it looks when it heals. And it shows kind of this is a scar which we see when it's about to be fully healed. So this is the large lesion, then you see this scar. On T2, you see almost complete reconstitution of the normal bone marrow. We talked about the articular epiphyseal cartilage in the developing skeleton. We talked that it just so happens that areas of early vascular regression and late ossification coincide with predilection sites of JOCD, and that juvenile osteochondritis dissecans is a disease of vascular origin and subsequent ossification. So even so, I downloaded my talk this morning. Oh, I thought it was ending here. No, it's there. So as you can see here, that's a subtle change similar to what Ted showed. Here we have the lesion, and it's really subtle. That is the MR, and this is our bone window. It shows you, there's no doubt anymore what it is. It is a lesion which is peripherally mineralized, which starts healing at the periphery. So here you see early osseous bridging. As you can see, once you see that image, which is much more detailed than your radiograph, it's much easier, especially to follow up. As we heard, three months you follow up, and Ted showed an example. It looked stable. It wasn't unstable, but if you have this kind of detail, you have your baseline, you have your three months follow up, and you put it in your timeline, expected timeline, then you know, okay, does this patient go in the right direction or not? It's very difficult to say this on a radiograph because it's just the superimposition of so much tissue, and it's difficult on classic MR. So here this patient healed, as you can see. That was it, and that it is now. So that's, again, the very detail. I pointed out, I don't want to go into details, but I think that the general ubiquitous principle of endocontral ossification, as you see it in fracture repair, is also applying to JOCD. Again, healing, I went through all of the stages. I will probably later talk about the details of these cases, but we quantified these data. We said, okay, can we get a number for how much bone is formed within three months? And we found progeny lesion, like the lesion, in baseline and follow up. This is a group which didn't heal, and that is a group which did heal, baseline and follow up. So the group which healed got much lower signal, which means much more bone formation. And once you quantify it, it is much more accurate. Okay, these are our data. We also looked at siblings, and this were a very interesting study, and we are in the middle of it. I mean, we don't have answers. We found that siblings which had no symptoms of JOCD patients, we just said, okay, we enrolled absolutely non-symptomatic siblings of patients. And we found an abundance of symptoms. So as you can see, of phenotype, if you want, not symptoms, but MR findings. As you can see here, there is edema. It goes beyond just ossification variant. It goes into the bone. This is one which over a time period of 18 months developed something which is considered a lesion once it has the bone marrow edema. That is somebody who had at the baseline a lesion with reactive bone marrow edema, which after 12 months totally was without any lesion. So we have now the 7-Tesla Terra, a clinical machine. We are very excited to have this FDA clinical machine in our hands. We use it to image our JOCD patients. And so, bottom line, novel MR methods, advanced medical practice, we showed vesselness, short and ultra-short echo time, that's a CT like bone windows. And if you really want to go into research, we can quantify these maps. And we are a big team and we are so lucky to work with Rock and to participate in Rock, which really made this whole field explode. Thank you very much.

articular cartilage

vascular development

MRI bone window

instability

susceptibility imaging