Okay. So I know Jason's got a tight connection, and I think we can probably between us handle any questions. So why don't we open the floor up for some questions. What you really heard is a clinical overview of the problem, some of the basic science considerations from Andrew, and then some of the sort of obvious considerations that we have available to us today that Jason just presented. So if you have any questions, please come up to the microphone. Lou. Thanks. This is great, and a question for Andrew. I mean, it seems to me like we should be working on that interface. We're not recreating the organ, right? We're just putting the cuff down on the bone and expecting it to recreate that organ, and I think we need to be paying attention to how we can try to recreate that. Maybe you could help us out in how we might start doing that, and I'm sure you're doing something like that in the laboratory. Testing. Sure, so I think that's, you know, the exact right thinking is that it is the interface, it is reestablishment of the enthesis, and the question is whether we can really drive the enthesis back to normal or whether we have to stimulate the body to recapitulate the enthesis on its own. I think, you know, there are multiple different ways with graphs and with cells, whether it's an overlay or an interposition, and right now none of that gets back to the normal interface. There are some thoughts to try to stimulate cells from within, but there are so many different pathways and so many different signaling groups involved that it's going to be a huge challenge to get back to that normal interface, and we don't see anything that really gets close yet. Buddy? So, a couple of questions. One is, how do you think nutritional status plays a role in this, vitamin D especially, calcium? Do you think supplementation on that side will help this? And then more to Scott, you did a lot of work on doxycycline. Anything clinical on, I mean, I've been using it, but is there anything more clinical? Are there other MMP3 inhibitors we could be using? You know, those are all things you could consider. Doxy, we've used it as Buddy implies, as an MMP inhibitor. I think more fundamentally, though, we're missing the boat. I think the issue here is the immune cells, the inflammatory environment, how that interacts with mechanical loading. So yes, doxy may help. Cells may help. This factor may help. Vitamin D may help. I think more fundamentally, it's, you know, recapitulating development is a tall order. The cells, the signals, the mechanical environment are all completely different than what happened during embryologic development. And I don't know how we're going to recapitulate that. So not to give you a negative answer, but I think we need to place our attention on the role of, the complex role of immune cells, macrophages in tissue repair. It's fundamental biology in the injured joint. To your question, yeah, those are all, I think, vitamin D, doxycycline, there's very little clinical data. It's all kind of preclinical animal data. So the other part of it is, Mazaka has shown that the cells now for healing come from the bursa, you know, and a lot of people just obliterate that with a cautery. We've started preserving it and dropping it down and keeping those, and the healing rate seems to be better, at least by ultrasound. So that cell population may be more important or less important, or maybe those are inflammatory cells, because I don't know the answer to that one either. And there's good animal data, or some animal data, demonstrating the bursa has an effect. I agree. It's complex. I'm sure there are, I would think there are also cells derived from marrow. I think there's probably very little from the tendon, although we don't really know that, but I agree, bursa seems to have cells that, you know, synovial cells are very active cells. But again, it's a different phenotype than an enthesis cell, an enthesial fibroconocyte, a tendon fibroblast. And yes, I think there are fundamental biology questions that we need to get our arms around. John. Thanks, Brian. It's a great session. John Ticker from New York. Just a thought, or what are your impressions of the local environment? You mentioned the inflammatory environment that's there already. My impression, although I haven't seen specific work, for the people who get really stiff postoperatively, those are the ones who have no problem healing. So what can we do about understanding that environment and avoid the stiffness? So is there something that's in that local environment that promotes healing that we want to encourage? And how do we find that? Yeah, probably so that pro-fibrotic response, you have cells that are, you know, making matrix. Problem is you make matrix in the capsule and the other tissues that limit your motion, but you see better healing. George Morel showed that in a study they've published in the past too. So again, so take that model, learn from it. What are the signals that are being turned on there? Probably pro-fibrogenic cytokines, quite simply. How do you use that and leverage that so I can just improve tendon healing but not get the stiffness? Right. JT. Just one basic science question and then a question for you, Brian. So the role of rapamycin, I've been following that and it matches some sort of thought processes with other, you know, cell master control genes that we see in other areas of the body. So are we ready to be talking about rapamycin and the role of cuff repair as an adjunct? Should I be considering doing this on my post-operative patients? I think to Dr. Rodeo's point earlier that, you know, there are so many different pathways involved that rapamycin may affect the mTOR pathway, but it's just one of a few pathways or one of many pathways and while it may decrease fibrotic tissue and fatty infiltration, what are the downsides and what other pathways may actually be more important? So while it may be safe and certainly there could be clinical studies, the question is, is it the main driving factor? Is mTOR the main thing and the reality is that there are many, many others. And you're not ready to conclude that yet. Okay. And then Brian, the second question. Oh, sorry. Go ahead, Scott. Yeah. I was going to echo that. I mean, I think single-factor therapy is probably limited. It's such an evolving milieu. Like back to Buddy's good question about MMP, you know, doxycycline can inhibit MMPs. Well, MMPs are complex. There's different MMPs at different phases. Some are good. Some are bad. We think that all MMPs have an adverse effect. Well, that's probably not the case. At some point they have a role in remodeling. So just knocking everything out is probably a simplistic, naive approach. For sure. That's what's interesting to me about the rapamycin because this concept of a master control gene, no longer single-factor, but really an entire group of processes that this may address. So I'll certainly stay tuned and read your stuff as it comes out. And Brian, a follow-up question for you guys. When Hernigo published his paper in 2014, it shook the world, right? And now five years later, all of us still report back to one study, and you guys thankfully have taken on that question. And so Jason sort of talked and teased us a little bit about your interim results. Can you update us on that and where it's going? Yeah. Thank you. So basically it's a randomized, double-blind study, single tendon tear, multiple surgeons, same technique. So you have to have basically a TOE or double row type technique. Iliac crest, everyone gets a needle stick, half get an aspirate. We do flow cytometry on all aspirates to characterize. We do smears to characterize cell morphology, and then half get the injection in a dry field, which I thought was pretty interesting when Jason showed Hernigo's video. I don't really understand that. But you got to at least dry it out, for God's sakes, instead of washing it away. So we have a little over a one-point difference now. We're about 2,000 enrolled in favor of those who get the concentrate. It's not proper. It's powered for about 110. So that response is not properly powered, but we seem to be showing a difference. But who knows, in the next 40 patients, we may eliminate that difference. Thanks. Congratulations. Thanks. Scott, can I ask a quick question? And then John, come on up. I'm really curious. So I don't know if you've ever read the book, Being Mortal. It's by Atul Gawande. And he has this expression that we're all rotting from the inside out. We just don't know it. Right? And the reality, if you look at natural history data, and this is one of the questions we might want to address. If you look at Ken Yamaguchi's work, and there's a number of them looked at decade by decade, and truth be told, most tears are happening because of degeneration, and just over time. It had probably very little to do with trauma, other than the fact that trauma brings a delight, brings them to a doctor, they get an MRI, oh my goodness, you have a tear, right? So there's probably 6 million people like that running around, and yet only we repair maybe 400,000. So we know there's a lot of tears, and they mostly are occurring decade by decade with increased frequency. So I would think that that's not necessarily an emphasis problem. And so we fix them. And then a year later, we're surprised that they're retorn. And all we really did is just put poor quality tissue back down to bone, and they still have poor quality tissue. We just got it to be there. And you should, you know, you talked about the data at 6, 12 week, we're seeing a lot of re-tears even by six months, right? If they're going to happen, we get a lot of them early. So is it the emphasis, or is it just you got really bad quality tendon, if that's the issue, if you say that's the issue, I'd be interested in your opinion, shouldn't we just be working on getting better collagen, or just a better construct like a hem or something, and do that every time? Because if we don't change the tendon, if we assume that's the reason, how can we even start thinking about the emphasis? Sure. No, point well taken. I mean, I think it's most tears are certainly attritionally, and it's accumulation of microscopic tendon damage early on, it's completely clinically silent, no different than epicondylitis or patellar tendinopathy, and the same underlying biology, that's we need to understand what initiates that process, and what are the cell signals, and I don't know the answer, but certainly you've raised an important point, can we affect the underlying tendon biology? I do think molecular inflammation, I keep going back to inflammation, I think it plays a fundamental role. I think we'll learn a lot from immunologists in this area, honestly. Look at work from, anyway, I think inflammation at the molecular level plays a fundamental role. This idea that tendonitis is not inflammatory, not at the gross histologic level. It is at the molecular level, I think, fundamentally. Just a basic question. You know, Scott, you've done some great work on inflammation, and I think my own bias is that hyperglycemia, silent metabolic syndrome, we know that hyperglycemia, Annie and I did a study in the lab with rats, it's pro-inflammatory, and now that the rapamycin pathway is also related to the sirtuin pathway, which is all the telomere, blah, blah, blah, what I'm getting at is, are you doing any work on metformin? We looked at metformin in our lab as a anti-senescence agent for a hecicapsulitis, we're looking at that now. I'm not going to steer your idea, but are you looking at that for maybe promoting the longevity of cuff tissue? Good thought. We're not, but it's an interesting thought. That's certainly one of many important metabolic pathways, but we're not, it's a neat thought. Gloria, are you good? Okay. So why don't we go...

tendon injuries

repairing tendon injuries

interface between tendon and bone

immune cells and inflammation in tissue repair

rapamycin and metformin for tendon healing