So these are my disclosures. So as way of background, in the animal model, oral intake of lisartan has resulted in high limb-like cartilage healing compared to microfracture alone. Oral lisartan, what we know about it, in the general population, if you have a lower baseline blood pressure, it does have some side effects. The effects of locally injected lisartan in the normal joint are unknown, however. So we all do know that cartilage repair by microfracture alone produces fibrocartilage, and there's been a lot of effort to look at inhibition of growth factors to produce a better outcome. There's been many studies done by Dr. Johnny Heward. This one basically highlights oral lisartan blocking TGF-beta, which resulted in excellent healing. Similarly, he's looked at muscle injury models as an antifibrotic, so blocking TGF-beta with oral intake of lisartan to decrease the fibrosis in this model. So lisartan, we all probably know, is an FDA-approved medication for hypertension. It does have an off-label use for prevention of adhesion formation. So this is Dr. Mark Philippon, who I did this research with. He has routinely used it for multiple years off-label in his post-operative hip arthroscopy protocol. This is some data he presented a few years ago, looking at his rate of revision hip arthroscopy. So before he started using lisartan post-operatively as his protocol, and then post, and looking at his revision and re-revision rates, which were decreased when he started to implement lisartan as his post-operative protocol. So that's led to some more questions based on his historic use of it. He would note that post-operatively, some patients were unable to tolerate lisartan very well orally, specifically in the younger, healthy population with relatively normal blood pressure or low blood pressure. So he started to investigate the idea of intra-articular. So purpose of our work was to determine whether lisartan injected intra-articularly was detrimental to the surrounding joint tissue. And was it also effective for cartilage healing after microfracture? Our hypothesis would be that it did not prove detrimental for the surrounding tissue, and that microfracture would enhance the repair relative to microfracture alone. So for this study, New Zealand rabbits were utilized. There's five groups, microfracture alone, and then microfracture plus varying doses of lisartan, one milliliter. So we used 0.1, 1, 10, and 100 milligrams per that one milliliter. The doses were injected at the day of surgery, at day 14 and day 28. The rabbits were sacrificed six weeks after surgery, and following sacrifice tissue samples for histo and biochemical analysis were collected. So on gross examination, the 0.1, 1, and 10 milligram doses, what we considered the lower doses, all revealed hyaline-like healing and improved articular cartilage healing. This is converse to what we saw at the higher dose. So at 100 milligrams, we saw a lot of detrimental effects to the surrounding cartilage, as well as the soft tissue, and essentially absent repair of the microfracture defect. Micro-CT was also performed, which similarly showed really poor healing of that bony defect at that 100 milligram group, but improving results with 0.1, 1, and 10 relative to microfracture alone. So in our stain analysis, if you're looking at the 100 magnification, what you're generally seeing with microfracture alone, there was a little bit of uneven distribution of the chondrocytes. It improves at 0.1, and then there's a nice distribution at 1 and 10 of the chondrocytes at that cartilage layer. At 100, you're really seeing an absence, at the 100 dose, you're seeing essentially an absence of those chondrocytes. Also, everything was scored with odryscal scoring. The best scores were seen at the 1 milligram dose, the worst at 100 milligrams, indicating really detrimental impact of that high dose. So certainly the study has several limitations. The observation period was only six weeks, so quite short. Also, this needs to really be applied in a larger animal. These were just rabbits at that point. We haven't done any large animal studies, and certainly this hasn't been performed in humans yet in a study application. We also have no comparison. There is no prior data of the use of intraarticular injection of Losarin available for us to review. So intraarticular injection of Losarin at doses 0.1, 1, and 10 are effective for enhancing that microfracture-mediated cartilage repair, whereas 100 was really detrimental to that surrounding cartilage as well as the cartilage repair itself. In summary, our study demonstrates that low-dose intraarticular injection after microfracture improved articular cartilage healing. High dose was quite detrimental, but certainly further investigation in large animal models is needed before we start to put this in a clinical application. And finally, just acknowledgments. Certainly this was a complex study that required the assistance of multiple scientists, both at the University of Texas as well as the Stedman Clinic. Thank you.

Dr. Mark Philippon

intra-articular injection

lisinopril

microfracture surgery

cartilage healing