But our final speaker will be Claudius Tomei. He's going to speak to us about regeneration and reconstructive approaches to the lumbar disc. And afterwards we'll have a Q&A with the panel as well as some case presentations by Dr. Wang, which we'll have you guys weigh in on and give an opinion on. Okay? Thank you. Claudius. Thanks for having me. It's great to talk at the National Symposium here. So I would like to summarize what we've been involved in and what we've been thinking about in the last probably 10, 15 years when we talk about the lumbar disc and how we can potentially improve how we treat those. I do have disclosures that I'm involved with some companies that work in this area. Particularly we get research grants from them. So basically we all know disc degeneration is something that occurs over time. The older we get, it's usually graded. If we're using the Philman scale from a very healthy, watery disc to a basically nonexistent disc, as you can see it here. And it's mainly a matter of dehydration of the disc because the disc loses proteoglycans. Actually, it loses cells already when we are born. This is diminishing our cell number quite, quite rapidly. And there seems to be a very strong genetic predisposition for this, probably stronger than environmental factors, even though there are some environmental factors, as you can see here. So basically the problem is that we have an imbalance between anabolism and catabolism in adult discs. And probably we are not supposed to get as old as we do today. So disc degeneration clinically, the main problem is that it can be painful by itself. And if we have a degenerated disc, we will actually have disc-height loss over time. We all know this. And if we have loss of disc-height in the front, we know that there will be more pressure on the facet joints in the back. And this is then causing even more problems down the road. So disc-height loss is critical in that. And we also know that if we have minimal disc degeneration, then the disc carries all of the load. Pretty much 95% of the load goes through the disc when we are young. And the older we get, the more load goes through the posterior structures, particularly the facet joints. And ideally, because then we think it's too late, so we would like to reverse the disc collapse and to restore the function of the disc. And this means we would have to intervene early. At the time when we don't have the disc anymore, when we've lost them, it's going to be too late for a variety of reasons. For me personally, disc surgery, microdiscectomy, is the role model of degeneration. Because if you do disc surgery, what we're brought up with, we resect the fragment or take out the fragment, and then we remove the nucleus in our microdiscectomy to reduce recurrence rates. And this by itself is what happens when you have disc degeneration. It's basically a vanishing nucleus over time. And this is a study we did quite a while ago just to illustrate this. We actually compared in a randomized trial with about 50 patients whether you do a microdiscectomy or just a fragmentectomy, how those patients do over time. And we kind of planned the study to go for five years. And we thought, well, maybe we'll find a difference after five years. Well, actually we found a difference after two years. These are the two-year results. Discectomy, sacrosectomy group, and this is clinical outcome. So early outcome was comparable in both groups, quite good. And the disc group got worse within the first two years. The sacrosectomy group even got a bit better. And if you looked at MRI, this shows the motic changes. Most of the patients who are normal before surgery didn't have motic changes. And in the microdiscectomy group after two years, so quite rapidly, if you will, those patients deteriorated radiologically, whereas the sacrosectomy group didn't change much at all. So we do know that if we take out the nucleus, we'll have a discite loss, we'll have disc degeneration, we'll have osteochondrosis, potential instability, which then, if the patients have symptoms, turn post-discectomy syndrome. And this is obviously something we don't want to have. And this is probably one of the reasons. These are re-operation rates after disc surgery. So we know our disc patients, that 20% of those, that's one out of five, will have another operation at that level within 10 years. And probably those that don't do well but don't necessarily need surgery will be even higher. So we talk about a rate probably of 30%, 40%. So that's why many of us now try to go for just doing fragmentectomy. In an attempt not to accelerate this degeneration, this has shown some positive results, particularly looking at low back pain over time, but there has to be a little higher re-operation rate. So ideally, we would also add nucleus, particularly after disc surgery, but also in general for other patients as well, because if we add nucleus and perform nucleus augmentation, we would think that we don't have that much discite loss over time, degeneration would slow down, those patients would have actually not those sequelae of this degeneration. And there have been some nuclear therapies, how they were termed here by Korich a few years back, and these are the different options you have. So you have nucleus repair, you have nucleus augmentation, you have nucleus replacement, which is then more biomechanical with elastomers or some other mechanical issues. And this has been tried. These are some of the, like the PDN you see on the lower right, that many thousands have been implanted in Europe, and you see the disc on the left. And something we have to remember is that the pressure in our discs, particularly on certain movements, is 20 atmospheres. That's 10 times what you have in your car tire. And this is just something you have to remember, that when you lift something up, you have 10 times the pressure of your car tires in your own discs. And that's the reason why if you put something in there, it all comes out. So most of these implants that have been used, if they were true non-biological, true mechanical implants, they just came out, usually through the hole you put them into. And so this didn't really work so far. There are still people working on it. Maybe it will be solved in the future, but I personally don't really think that will work with a true mechanical artificial material. So the next potential option is cell therapy. The problem is that the disc, as you all know, is a very hostile environment. We looked at a review here that we wrote some years back that if you put something in those degenerate discs, that the cells survive. It's going to be problematic for a variety of reasons. One reason is that you have poor nutrition. No vessels usually in there. The end plate's already degenerated. This is also a study from our lab, results from our lab, looking at proteoglycans and different agricans, et cetera, et cetera, and also immunological factors, how they change depending on the degeneration rate. And it's quite clear that the more degenerated your disc is, the more interleukins you have, the less proteoglycans you have. So this is something you can actually show in your clinical patients. There was this quite well-known European study, Eurodisc, led by Professor Meisel. And what they did, and they started this more than 10 years ago, they would use autologous chondrocytes. They would cultivate, and they would actually inject them, with saline into the disc space. They didn't have a specialized carrier. It was randomized, non-blinded, not that big a study. And the two-year results that have been published showed some benefit. But to be honest, there's no further data published, so we don't really know whether this did work or not. There's one study from the U.S. looking at allogenic chondrocytes from young cadaveric donors. And they used 15 patients with fiber and glue, and they found that the patients did quite well. The problem was that there was no control group, so you don't really know what the effect is. And so whether those cells survive, I'm rather critical about this. Then the study we were involved in was a Phase I and II trial out of Germany. And 4 million autologous intervertebral disc cells were injected into the disc, but they were injected in a special gel that hopefully would have a beneficial effect because it is anti-inflammatory, anti-catabolic, and anti-osteogenic. It was basically albumin-based. And so we have cells, we have the environment, and the study was done in a way that it was a randomized study. Some of the patients got the cells and the biogel. Some patients only got the biogel. And then there was the third group, which was just a control group standard of care, which ended up to be 120 patients. What's important about this, that this study was the first to actually also inject neighboring levels. So if the disc, after disc surgery, the disc was taken out, or the fragment was taken out, then this was used to cultivate new cells. And if the patient had adjacent level degeneration as well, then he would be injected three months later both in the level that was operated and in the level adjacent to that. And hopefully, we would hope that this would reduce disc degeneration and also potentially prophylactically treat the non-operated segment. Outcome, primary outcome was ODI after five years. We are not there yet. We are not even at two years now, so we don't really have our outcome data. All we have is this shows the basic setup with injecting the cells using a discography approach. And it is safe. The early results were okay. We published those last year. But there's no real data out there yet whether this does have any benefit or not, so we'll have to wait a couple of years to find out. What we do now in the lab is this. We've introduced an animal model using rabbits with a gene defect that do develop disc degeneration quite rapidly within months of their life. And we could actually reproduce those changes in proteoglycans and the immunological parameters in that model so that we are now in the lab working on gene therapeutic approaches trying to overcome this problem with gene therapy. And we found out that probably at any associated virus that different serotypes, we use serotype 6, which seems to work best if you look at the transduction of parameters. And don't really look at this in detail, but there are some issues. This may be a solution down the road. The problem, there's one main problem. If you want to put something in the disc like the PDN was done in Europe, usually that comes out through the same hole you put it in. And we did a trial just in cadaveric calf spines trying to put a certain mesh into the nucleus to re-stabilize the segment. And you see nicely that if you do a discectomy or a nucleotomy that you destabilize the segment and you re-stabilize it by putting something in there. The problem is if you then test it in a cadaveric tester, it always finds its way out. Even this mesh finds its way out. So the problem of nucleus augmentation or nucleus replacement is annular competence. And we know this from Carraghi's landmark study published more than 10 years ago. If you do have a big hole in the annulus, you will also have a very high re-herniation rate. And this clinically has been shown that in those patients that had a big defect of the annulus, this subgroup had a re-herniation rate of 27 percent. And if you look at your own results, nobody would think that they would have a re-herniation rate of almost 30 percent in a subpopulation of your patients. But others have looked at this as well and performed a systematic review that there is a direct relation between size of annular defect and re-herniation clinically after microdiscectomy. And we know for many, many years, this is a slide from the 40s actually of the last century, and it's unlikely to get repair of this annular defect after this herniation. It's a very poor scar tissue that develops. So what a couple of people looked at in Europe, they tried to identify this high-risk patient population and then tried to use annular closure devices. This is one device that was popularized in recent years, and those early prospective studies showed a dramatic reduction of re-herniation rate in those patients. Basically from the regular 15 percent or whatever in this high-risk population to almost zero. So that was the reason why there was a large randomized controlled trial studied. This was sponsored by an American company. And 554 patients were enrolled from 2010 to 2015. It's a one-to-one randomized study looking at superiority. So it's not like the regular IDE trials, for example, on cervical disc arthroplasty. We have a non-inferiority design. This was a superiority design, which is more difficult to achieve, obviously, statistically. And the patients had to have a rather large annular defect of at least 4 by 6 up to 6 by 10 millimeters. So these are those holes you see if you put your ronger in the disc and take out parts of the disc. And the patients had to have a high enough disc because those patients would be the ones that would potentially recur. So this is a high-risk subpopulation. And the first thing we found, which was surprising to some of us, that if you look at this graph on the left, you see the re-herniation rate in Karagi's study, which was the re-operation rate in Karagi's study, which is 16 percent here. And it was exactly the same in our trial. In the 550 patients, we had the same high re-operation rate for re-herniation because this is a high-risk subpopulation. So that was the first important thing we found. And if you would put, for those patients that did receive the annular closure device, you could reduce the rate of re-herniation and re-operations by about half. So it was not nearly as successful as those early small trials, but there was a clear benefit in numbers and reducing re-herniations and re-operations. This seems to come at some price. There are end-plate changes adjacent to that device when you put it in. And we were first really worried about this because in the control group, you have a 30 percent rate of those holes, end-plate changes, in the vertebral body adjacent to it. And in the group with the device, you have an 84 percent, so much, much more common. And there are now three papers out, mainly published this year, that looked at these changes to really have a solution on whether this is a problem. And interestingly enough, it doesn't seem to make a clinical difference. Actually, in the device group, it was less common to have bad outcome, which we don't really understand yet. It's not statistically significant, but there was a trend that those patients that had end-plate changes were a bit better than the ones without. So we don't really know why that is, but we are still trying to figure that out. I don't really think that any mechanical whatsoever you put in this will be the final solution when we work on this. So what we are working on, coming back to the lab and to experimental work, we've used annular cells, put them in 3D cell culture, used chemotactic factors, growth factors, trying to cure that hole in the annulus. This is data, just to briefly cover over this, where we used this type of mesh to put in a sheep model after discectomy. And what you see here is that this is the regular disc, how it looks normally. This is the disc without the implant, and this is with the implant. And you can see that the disc is actually kept inside by this scar tissue whatsoever. You can also see here. So in summary, disc degeneration is a very complex pathophysiological process. We know it's associated with disc height loss and potentially pain. And then we do think that facet joint degeneration is what's following our disc height loss over time. Nucleus augmentation would be great to have, particularly after disc surgery, but also in patients that have not been operated on. But the problem is that the environment in the disc is so hostile, and the annulus usually is not competent enough to hold something in the disc. So these pose huge problems to us. Autologous chondrocyte transplantation may be a suitable approach. We will have to wait for our results in the next one to two years. And you can use gene therapy techniques experimentally, and annular closure of this device seems to show some good results. But on the long term, I would think there has to be a biological solution for this as well. Thank you very much.

regeneration

disc degeneration

cell therapy

annular closure devices

biological solution