Yeah, so we just encourage everyone to use the mobile app, and I have a question for Dr. Hans. This is, you know, microfracture plus, plus, you know, tell me about your protocol of mobilization of peripheral blood. You know, most orthopedic surgeons don't use GCSF, you know, that's not a typical medication that we prescribe. So tell me, where do you think you're getting the benefit of your cartilage repair? Is it with your mechanical technique with your new device, or is it with the mobilization of peripheral blood to getting CFUs and MSCs? And if it is, have you ever tested how much CFUs and MSCs you're getting with your protocol? Right, so the progenitor cells you mobilize with filgristim, and filgristim makes your bone marrow make more progenitor cells in relation to your peripheral circulation. Then with apheresis, you can harvest a large aliquot, and that process scares us, and we've been presenting this since 2011, and everyone kind of gets scared about it. My brother's a hematologist oncologist, so I'm a little bit biased, and he says I give GCSF every day at him, and it doesn't scare me one bit. The other thing is they give 10 mics per kilogram, so for instance, 700 micrograms per dose for four days, and they harvest on the fifth days. This protocol gives 300 micrograms for three days, and then harvests on the fourth. So it's a lot less of a dose than what they give for bone marrow transplant harvest, and for that reason, it's a lot less scary, or it should be for orthopedic surgeons. The progenitor cell content is a cellular source that has pluripotent potential, and we're going to publish that later this month in arthroscopy, and we presented that at the B.A. Summit yesterday, showing that it is pluripotent. And so some of the cells within this heterogeneous population of cells have pluripotency to them. So I think it's the pluripotency of the cells. I think that it's watering the lawn throughout the whole maturation phase of the tissue, too. It's not just one application. I mean, the cartilage doesn't stop healing at time point zero, so one application doesn't quite make sense, but I think it's the maturation phase and seeding it throughout that whole process. And then I think that there's some principles that Steadman taught us that we shouldn't throw out, and that's the idea of motion, motion, motion, and the idea of static loading of the tissue, and hats off to what the Steadman-Philippon group's doing now with making microfracture plus even better. Question? So a follow-up to that, from the biologic perspective, you're using the micro-drilling, right, which makes sense. My question is, would you want to, from the biology, to use the neupogen before, because the micro-drilling is your primary source of cells, right, for the defect. Is it unsafe to do neupogen and then surgery four days later? What was your decision-making to do the neupogen afterwards? So the decision-making for doing the protocol as it stands today is we have data. We've got phase one data, we've got phase two A data, and we've got phase two B data. This is a phase two B study, and we'll follow it with phase three, but we can't change the protocol now because all the data stands, but there are clinical cases where we've given them the neupogen before the surgery for logistics, i.e., if you're going to do an HTO, you want to harvest them before you do the HTO. And so in terms of, it's flexible in terms of when you give them the neupogen, and the risk of the neupogen is, the risk profile's low. I mean, they're giving neupogen to people who are on chemotherapy and recovering from cancer all the time. And so we get real scared about filgerstem, but to my brother, he's like, Adam, it's candy. We give it out like it's candy. There's nothing to be concerned about when you give it either. That's really interesting. There is a debate in the bone marrow transplant world of a neupogen versus a bone marrow aspirate. So there is two camps in that world, but it's very interesting how hematologists is coming into orthopedics. So that's a really interesting paper. Thank you. Do you have a question? Catherine, great paper. A lot of work, obviously, went into that. Any idea as to the amount of losartan that made it into the blood from that intra-articular injection of the subject? And obviously, these are very low doses overall, so probably not clinically relevant, but as you get thinking to a human model, and it may be clinically relevant for those very few individuals who have an adverse reaction to this drug, will that matter? You know, that was one thing that we did talk about after that we should have actually done analysis of the blood, but we did not include that. So we don't have like a number, you know, that I could sort of, but I think that's really important, especially when we go into the large animal model to include that. That's part of the plan. Mike, we had a couple questions for you on your paper. First, from the audience, what is your post-op pain protocol following outpatient osteotomy? So it's a good question. Obviously, in the hospital, it's multimodal pain management with nerve block, et cetera. Honestly, outpatient, we're relatively simplistic. I mean, we give 30 to 40 percocets. We give them aspirin for DBT prophylaxis for about two to four weeks, surgeon-specific. Change of motion right away, physical therapy as soon as possible. It's not like we're, we're certainly not doing anything out of the ordinary or out of the box regarding our multimodal pain management for these cohorts. And then I had a follow-up question from a safety perspective, particularly for the surgeon who perhaps doesn't do an osteotomy a week or two osteotomies a week, but maybe dabbles and does one a month or one every other month, which hopefully no one's dabbling, but there are some. Is it safe, you didn't have any transfers to the hospital, but any tips or tricks to increase your safety profile of doing an osteotomy, particularly if you're a center that doesn't have a vascular surgeon, if you're not attached to a hospital, any concerns or tips for the audience here? So I think the first thing is that if you are operating in a surgery center that is not directly affiliated with a hospital and you're trying to do surgeries that are a little bit more complicated, then perhaps develop some sort of relationship where if you have a problem where some kind of patient transport is expedited. This doesn't go with just osteotomies, but think about anything in sports medicine, distal biceps repairs, you can hit an artery. You can hit an artery with any kind of surgery, it doesn't need to be an osteotomy. So meticulous surgery technique obviously is the most paramount thing. Take your time, do good work, don't haphazardly start cutting things that you don't know where they are, and then hopefully your outcomes will reflect that. I think the use of TXA, although it hasn't been borne out in the literature, could potentially do something for us because if it truly does limit bleeding, especially in the post-operative setting, maybe there is a role for that. I think the key here is to have an established relationship with the hospital system. And if you don't have one, you can certainly do it. Hospitals are going to be more than happy to establish those relationships because it will only improve patient outcomes as well as their own care. Mike, two questions. One, if you remove the TTOs, do you think you would find any difference? Because a long osteotomy, a femur tibia versus a tubercle are different animals. That's question one. Two, did you ever think about any functional outcomes, obviously? Because if a patient is leaving the same day, maybe has a higher pain threshold, maybe gets stiffer, maybe their functional results versus the patient that's getting their pain controlled and doing PT, do you think, what's your gestalt about that? So I think your second question is a great idea for a second paper, which we haven't really thought about so much. I like that. So thank you. I'll put you on that paper. The first question, again, was what, Anil? If you remove the TTOs. Yeah. I still don't think there's going to be a difference. I mean, if we ran some regressions and we looked at it and there wasn't really a difference. And I think in our outpatient center group, we had about 20 DFOs, maybe 40 HTOs. And again, there was still no readmissions. So that's 60 patients. We can get rid of the TTOs in that cohort and we'll still have zero. So again, I mean, if you wanted to really find a difference in that, we'd probably need like thousands of patients. We did run a post-hoc. It was about 9,000 patients. So I don't think any system is going to develop that unless we do some kind of, you know, Kaiser database search, et cetera. But from our standpoint, we didn't find a difference. And now, Catherine, I have one question for you. I've been hearing Mark present this data for maybe eight years now. And it was always an anti-adhesion mechanism of action. You're now implying a chondroprotective or chondrogenesis mechanism of action. So when it's an ACE inhibitor. So what's the mechanism of action? Because I'm not that smart. So just the same TGF beta pathway. So TGF beta in both those studies with oral losartan was showed to both be an antifibrotic for muscle injury, but also to mediate cartilage repair. So if there's increased TGF beta, that's been shown to be elevated in osteoarthritis. Okay. I think that's it for the session. I want to thank all the authors. Just as a close, can everyone in the audience who does osteotomies raise their hand? If you do them exclusively inpatient, can you please keep your hand in the air? And then if you do them mostly outpatient with the occasional admission. And then if you're somewhere in between. Okay. So for those in the audience who couldn't see the whole audience, the vast majority are doing them mostly outpatient. I think a paper like Mike's is super helpful to prove safety and efficacy, but make sure you're doing it safely. Thank you. Thanks. I'm going to invite Kevin Bonner and his panel to come up. We're going to do a case-based panel discussion in articular cartilage surgery.

orthopedic surgery

GCSF

cartilage repair

osteotomy surgeries

pain management