Thank you for being here. These are my disclosures relevant to this talk, and they're also listed in the program. So when we think about history of ACL surgery, really we started off with primary repair, had high failure rates for that, and since then have gone through a lot of different innovations on how to treat ACLs, with tendon augmented primary repairs, then tendon reconstruction only, tendon and extra articular ligament augments, now we're talking about bigger grafts, but really all of these things have worked to increase the mechanical strength of what we're replacing the ACL with. So we thought, well, what if instead of changing the grafts, what if we address the biologic environment that surrounds the torn ACL? So we know when you tear your MCL, you get this blood clot that forms between the torn ends, and there's all kinds of good growth factors in there, like TGF-beta, PDGF, FGF-2, but in the ACL, when it tears, it's in this degradative environment, and so it has things like MMP-1, MMP-13, things that actually break down collagen, and so those torn ends really can't heal. So what if instead of that environment, we put a different environment around those torn ends? So we put something that had those same growth factors that we see in the MCL. Could we create a healing environment? And maybe if we did that, then maybe the same thing that happens in the MCL, as that blood clot resolves and it's replaced by healing tissue, maybe we could make the same thing happen for the ACL. So we tested this idea in animal models first. So in an animal model, this is a pig's knee, where we've cut the ACL 15 weeks earlier and then go to see what happens at three months. And here you can see that the notch is empty, that our suture repair has failed, the ends have resorbed, and all we have left in the notch is the PCL. For bridge-enhanced ACL restoration, we can take a soft, porous implant, and we can actually load the blood onto that implant and put it in the notch between the torn ends of the ACL. And when we do that in animal models, what we see is that the ACL actually heals and turns back into something that looks very much like an ACL. And in those large animal models, we've shown that that tissue not only looks like an ACL, actually it looks like an ACL under the microscope as well, and that the restored ACL strength is actually better than a simple repair in these models and is equivalent to an ACL graft. Also, we note that in these animal models, if we cut the ACL and either don't do any further surgery or we do an ACL reconstruction, at about a year, these animals start to break down that cartilage around the medial femoral condyle. However, when we do bridge-enhanced ACL restoration, we don't see that cartilage breakdown. So with that data in hand from the large animal models, we got approval from the FDA as well as our IRB to run a first-in-man study. This was a small study of two cohorts, 10 patients undergoing the BARE procedure, 10 undergoing ACL reconstruction with the hamstring autograft. These were for patients with a complete mid-substance tear. The results of this study showed that we had no infection, rejection, or failure in these patients at two years, and note that these were all patients over the age of 18. We also had good clinical outcomes in terms of patient-reported outcomes as well as instrumented AP laxity. So once we had that safety study underway, we thought, what about our adolescents? So we've heard in multiple talks today that adolescents are at higher risk for re-tearing their ACL for graft failure. They're also at higher risk for post-traumatic osteoarthritis and for that affecting their lives for a long period of time. So with that in mind, we opened the BARE 2 trial. This was a 100-patient randomized control trial of BARE versus autograft ACL reconstruction. These were also for patients with a complete mid-substance tear. The median age in this study was 17 years of age, and the median preoperative marks activity score was 16 out of 16, so young, active patients for this study. We were able to obtain two-year follow-up on 99 percent of the patients. And the outcome measures that we chose, the primary outcome measures were we wanted to show non-inferiority to an ACL graft in terms of patient-reported outcomes at two years as well as the AP laxity of the knee as measured by KT1000 instrumented testing. Secondary outcomes that we looked at were hamstring strength as well as safety measures, and we're planning to look at osteoarthritis at six and 10 years. The BARE 2 trial demographics, again, showed the two groups were very similar in age, agenda, and preoperative activity as one would expect from a randomized control trial. The results of this study showed in terms of safety there were no infections, no immune responses or allergic reactions, and none of the BARE implants needed to be removed. In terms of six-month results, so we know in age-matched norms the IKDC subjective score has a mean of 88 points. In our study at, sorry, this should say, the graph should say at six months. At six months, the ACL reconstructed patients had a score of 78. BARE patients came in almost back to normal at 86 at six months. In addition, we found the AP knee laxity of the two groups at six months, there was no difference, and the hamstring strength was better in BARE. The vast majority of the patients in this study that underwent autograft ACL reconstruction had a hamstring autograft. In terms of results at two years, again, the IKDC age-matched norms mean it's 88 points. The ACL reconstruction group came in very respectably at 85 points, BARE group came in at 89 points, and thus was found to be non-inferior to ACL graft. KT1000 testing at two years showed in most, in uninjured patients we would expect less than one millimeter of difference in side-to-side. Other trials for ACL reconstruction show a range from one to three millimeters. In this study, the mean side-to-side difference for the reconstructed patients was 1.8 millimeters, mean for BARE was 1.6. ACL restoration was, again, found to be not inferior to ACL reconstruction for the second primary outcome. Hamstring strength at two years, the BARE patients continued to have better hamstring strength, again, at the two-year time point, and this was statistically significant. How about re-tear rates? We know that re-tear rates in adolescents are high. We've heard today in Dr. DeFelice's study, as well as prior literature, showing failure rates are as high as 49 percent with primary repair alone. Autographed ACL reconstruction rates range somewhere between 15 and 20 percent, a two-year follow-up. In this study, the ACL reconstructed patients had a re-tear rate of 6 percent, and the ACL restoration patients had a re-tear rate of 14 percent, which was similar to that seen historically for ACL reconstruction, and was not statistically significantly different from the ACL reconstruction group in this trial, likely due to underpowering of the ACL reconstruction group. How about what happens to those patients that do re-tear, though, after a BARE procedure? So the patients that converted to ACL reconstruction, we looked at their outcomes at the two-year time point. Their IKDC score was a mean of 85 points, very similar to those patients that had an ACL reconstruction alone. Also patients that had a BARE that was then converted to an ACL reconstruction had a mean of 1.4 millimeter side-to-side difference at the two-year time point on instrumented apulaxity testing. So again, the results for BARE converting to an ACL reconstruction were very similar to those patients who had an ACL reconstruction alone. So in terms of our summary results to date, the comparable results between ridge-enhanced ACL restoration and ACL reconstruction, they're similar in terms of patient-reported outcomes at two years, knee stability is measured by instrumented KT1000 testing, revision ACL recovery rate, but where ACL restoration does better than ACL reconstruction so far is in restoring the ACL anatomy, so it does a better job of restoring the sagittal angle of the ligament as well as its cross-sectional area, and early patient-reported outcomes. So recovery is much easier for these patients. In addition, hamstring muscle strength is preserved in the ridge-enhanced ACL restoration patients. So as far as a final word on the status update, so the BARE scaffold recently got FDA de novo clearance and manufacturing is in progress to try to get more of these scaffolds made so we can do more of these studies. The next studies we're hoping to open is the BARE Moon trial, which is going to be a study of ridge-enhanced ACL restoration versus bone patellar tendon bone to try to understand what the – how those two procedures compare. And then we also are planning the long-term follow-up in the BARE 1 and 2 trials to start looking at the osteoarthritis question to see if BARE can actually help with osteoarthritis in humans as well. And we'll continue to collect data on this novel alternative treatment for ACL injury. Thank you very much for your attention. Thank you.

Bridge-Enhanced ACL Restoration

BARE procedure

torn ACL

healing environment

ACL reconstruction