Next, we have Jason Jagoo from the University of Colorado to talk to us about tendinopathy. All right, good morning, everyone. Well, tendinopathy is tough, and this morning, I wanted to show you why, and maybe taking a step back from the beginning of what really is tendinopathy, and we always thought it was this result of repetitive trauma without adequate healing, or maybe the patient's response is inadequate. But we put that up to the test with our repository system. So we took normal tendons from ACL, bone patellar bone, as well as pathologic tendons from surgery, put them together, and analyzed them all the way to the cell level. This includes genetic data, et cetera, to understand truly what tendinopathy is. And we were really surprised at the results, but here, let me just lay it out for you. The tendon cells can no longer make tendon. If you are a tendinopathy cell, you've lost the cell machinery to synthesize the matrix necessary to regenerate the tendon. Obviously, that's a big problem. If you look at this from a single-cell perspective, these tendon progenitor cells have lost their mechanical responsiveness. They can no longer react to their environment, and that is, again, a hallmark of a tendon cell. The other part of it is that they produce an inflammatory matrix, again, very different than a normal tendon. So we're rethinking what tendinopathy is, and now we think it is a genetic alteration in the affected cells, and these cells can no longer manufacture tendon. Maybe this is good perspective. Right? If you look at Dave Flanagan's article that says, no matter what we do with tendinopathy, we don't do a good job. And for a large extent, that's true. This is a biologics talk, and we have peer P, and he says it's roughly 50% flipping a coin. Well, let's look at this first from the cell model, and if we look at this from a cell model, peer P is true, does not have enough of effect on these cells to turn the genetic code back to normal. Maybe that's why we see the literature like we do. Here's our past three level one randomized trials using peer P for patellar tendinopathy. We didn't see a whole lot of significant results for peer P, and in fact, the only results we really saw was leukocyte-rich peer P plus dry needling at the three-month time point. Lateral epicondylitis, somewhat similar. There's some good studies that do show effect of leukocyte-rich peer P. It's just not a large effect, but it's an effect. To be truthful, the only thing that we have seen to date in our genetic model or cell model that has changed these cells back to normal cell production is BMAC, bone marrow aspirate, and so this is really interesting. I want to be truthful also in that this doesn't work in everyone, and so we're having trouble reproducing our data. Some patients, this works great, and their cells are restored. Some patients, it does not, and so we're trying to figure out why. We're also dealing with the difference of our commercialized systems where they have very disparate outputs, and so we're trying to determine which one is the right call and the right thing that can reprogram our tendinopathy cells. But there is some light at the end of the tunnel, and this is probably the best evidence in the world from Barcelona, Spain, and what they did is they used these bone marrow cells and they cultured them to doses, and they found that the most effective dose is 20 million molecules, and with that, they didn't have overwhelming, again, clinical, you know, similar to PRP, but they had tendon restructuring, and this anatomic tendon restructuring is probably going to be the hallmark of what we need to improve our symptoms long term. Well what about when biologics aren't enough, and I hear a couple of clinical scenarios that I would argue are indeed true. Number one, diffuse affection of the tendon, localized tendon with underlying edema within the fat pad, clinically correlated with positive fat pad symptoms such as Hoffa's test. For these, biologics are probably not enough, and there should be a video rolling in number one, but then the use of arthroscopy to treat the fat pad symptoms from the inside, and then use an outside-in approach for the tendon. We have seen lots of issues with trans-fat pad approaches for patellar tendinopathy, so although not arguing that good results can be attained, we want to avoid these intractable results with pain from retracted fat pad and scarring. It is troublesome, and fat pad transplants have not made these patients feel better. Technique pearl could be the use of tendon scraping for the open procedures, and that scraping the bottom surface of the tendon to remove the neo-vessels and the neo-nerves. This has been done a lot over the years in physical medicine rehab with marked improvement in the results, the single most important thing that's affected my results from an open case. Finally, fenestration. This has been around for a while, but what about this diffuse tendon? How are we going to remodel it? So the use of biologics plus biologic stimulation may be a better choice in that particular scenario. So in summary, this has been a tough one. Biologic therapy at this time has been not sufficient to correct the cellular abnormalities of tendinopathy. However, future dosing of biologics, quite possibly bone marrow cells, may give us the results. Occasionally, surgery is necessary. It's more powerful than our biologics at this time, and each clinical scenario is different, so there's techniques to help with that as well. Thank you very much. Thank you.

tendinopathy

cellular level

tendon regeneration

genetic alteration

biologic therapies