So, ironically, I actually titled this Damage or Dogma, but Damage of Dogma came out in the program, and it might be appropriate. You can decide at the end how you feel about that, so I have no relevant disclosures. As a bit of a background, we all know in the field of orthopedics, of course, that meniscal injuries are common and can lead to post-traumatic arthritis, and also that these are often concomitant with other traumatic injuries that induce hemarthrosis, such as ACL tears, which is a very common combination. And we also know that traumatic injuries that result in these hemarthroses can be implicated in degeneration of joint tissue. We know that vascularity is very important in terms of healing potential of meniscal tears, and meniscal tear location in terms of how peripheral it is and type can certainly influence healing rates. But when we think about vascularity, we're specifically thinking about blood supply to that part of the tissue, not necessarily blood exposure to the tissue. And we know from Dr. Arnosky's work, of course, about the location of vascular penetration when we're speaking of vascularity of the tissue, that this is largely at the outer third of the menisci, with slightly more penetration of the medial meniscus than portion of the lateral meniscus. And otherwise, those non-vascularized areas do depend on nutrition via diffusion or intermittent synovial fluid flow through the meniscal tissue. And also from Dr. Arnosky's work, of course, we know that when there is a peripheral tear and there is some local bleeding, a fibrin clot forms, vascular proliferation and cellular infiltration occurs, and ultimately, a fibrovascular scar fills at that defect. And most of us, I think, leave our training and go out into our practices, wanting, of course, to maximize our healing rates in our patients and have these general constructs in mind, I think, when we're trying to do our best by our patients, especially those patients that have an isolated meniscal tear. We've learned that meniscus tears repaired in the setting of ACL reconstruction have potentially higher healing rate than those that are repaired in isolation. That blood in the joint from the ACL tear and reconstruction potentially provides healing factors and biological response that aids in meniscal healing that might potentially be absent in the isolated meniscal tear. And we've learned or been taught in some circumstances that microfracture of the notch and other techniques that induce healing, as are induced blood in the joint, are then effective methods to increase meniscal healing. Thus, this concept that, you know, if you believe these tenets, then we would tend to say, well, blood in the joint is probably a good thing for meniscus healing. But is it? So I think in order to get to the bottom of that question, we sort of need to look at these three, you know, concepts or dogma, I'll call them. Number one, meniscus repairs with ACL reconstruction have higher healing rates. When you really dig deep and look into literature, I would say it's not as clear as you think it is. This article from 2019 in arthroscopy showed 75% rate of meniscal healing with ACL reconstruction on second look arthroscopy at one year. The Moon Group, 2014, 14% of meniscus repairs failed, resulting in reoperation at six years in those knees that had concomitant ACL reconstruction. And then here, this article from JOT in 2015 that showed 14% failure in the combined meniscus repair with acute ACL reconstruction, 27% with delayed, and 16% with the isolated meniscus repair. So it doesn't look so drastically different. And then this article from 2017 showing a very low failure rate when you're looking at the traumatic isolated tears in young athletes, average age 22. So this is a number perhaps lower than those that we saw in the concomitant ACL reconstructed meniscus repairs. And then some data in favor of the other concept, a meta-analysis of specifically looking at second look arthroscopies did favor a higher healing rate with concomitant ACL reconstruction. And this 2013 article that attempted to take more into account the age, sex, when you're comparing isolated repairs versus those repaired in the setting of an ACL reconstruction, and did show, again, favor of the combined meniscus repair ACL reconstruction having a better healing rate. So on this dogma, I would say it's a little bit less clear perhaps than I thought when I went into practice. Dogma number two, microfracture of the notch improves meniscal healing. When I started practice, I thought for sure it was an obvious thing. But when you look back at what's out there about this, it's really not as potentially well supported as I thought. This 2017 publication looked at meniscus healing with ACL reconstruction, showed an 8% failure rate, and then compared to isolated meniscus repairs that had microfracture of the notch to sort of simulate that ACL reconstruction environment, and showed no difference in healing rates. We really lack that comparison of the isolated meniscus repair that did not have the microfracture of the notch. And when you look at animal studies on this, specifically rabbit studies show when you compare meniscus repair with and without microfracture of the notch, there is certainly a contribution to post-traumatic arthritis with an inflammatory response, chondral degeneration, and a catabolic response in the meniscal tissue with drilling of the notch. So it may not be as helpful as we think or have learned. So document number three, blood in the joint is good for meniscal healing. My question is, but is it? We do know that blood in the joint is harmful to articular cartilage. It's less clear what is the exact effect on meniscal tissue in the joint, so that is something that we've been exploring with my collaborators at Duke. And I'll share some of that towards the end of this talk. But some of our lessons learned from blood in the joint, of course, come from hemophilic arthropathy, which is the extreme example of recurring bouts of blood in the joint. And there are really a couple of destructive mechanisms that lead to joint degradation, including the inflammatory cytokine cascade that results with activation of the synovium and with the exposure to the blood, but also the development of hydroxyl radical-induced the presence of hydroxyl radicals, which essentially induce apoptosis of the chondrocytes. So this schematic is a sort of a, it's a complex summary. But when you have blood in the joint, certainly in a joint that is exposed recurrently, they're going to develop this process quite rapidly. But even in the setting of a single hemarthrosis, this process is occurring. So we know that the synovium responds with an inflammatory response. We see elevated levels of IL-1, IL-6, TNF-alpha. And these are actually comparable to some, you know, other long-term and severe diseases like RA and OA. The monocytes are activated directly by phagocytosis of red blood cells. They secrete IL-1. This triggers cartilage to produce essentially hydrogen peroxide, which is then released into the synovium. This then is combined with catalytically active iron that comes from the broken down red blood cells and the presence of the hydroxyl radicals then stimulates the chondrocytes to have apoptosis. So it's a multi-pronged attack on the cartilage. And we've all seen these knees that look a little unhappy. This is just a 13-year-old who had a hemarthrosis for one week, and the cartilage just doesn't look nice and shiny. And you probe it, and it's a little soft, and it just doesn't look nice and healthy. So what does this same process do to the meniscus? Are there similar effects on meniscal tissue? Maybe blood isn't as good for the meniscus as we think, potentially with sort of gross exposure to it. And to that end, we've explored that in our lab at Duke, and these are collaborators of mine who've been instrumental in this work. We've done some pig studies, essentially, with these punch biopsies of meniscal tissue, which are placed in a meniscal culture medium and exposed to different fractions of blood to study the effects of whole blood and monocytes and lymphocytes with and without lyse-red blood cells to better understand the potential catabolic effects of blood on meniscal tissue. And essentially, we utilize centrifuge technique to separate out the buffy coat and therefore isolate monocytes and lymphocytes, and then separate those out with an adhesion method. And then we have our red blood cells, which can be either lysed or not lysed in various experimental conditions. And the first sort of set of data I'll show you, it's looking at whole blood versus lymphocyte versus monocyte versus control exposure. And essentially, these meniscal plugs are placed in these culture mediums with different fractions of blood exposed for three days to those fractions. And then after three days of exposure, these are then placed in the media, removed from those blood components, but followed for out to 16 and 14 days to look at the lingering or persistent catabolic effects from that exposure. And some of the outcomes are MMP activity both within the media as well as the tissue, gag content within the media and the tissue. Also looking at DNA collagen content and nitric oxide production as a measure of the catabolic effect. Of course, elevated nitric oxide and elevated MMP activity are an indicator of catabolic effect, whereas depression or lesser amount of the gag content also a measure of catabolism. And what we found, and this is without the lysed red blood cells, so without that catalytically active iron, we see that MMP activity is elevated with exposure to whole blood to monocytes to lymphocytes. Nitric oxide really quite elevated with exposure to lymphocytes and gag content suppressed with exposure to lymphocytes. So overall, we're seeing that these mononuclear cells seem to be the part of the blood that is contributing to meniscal catabolism and nitric oxide production. And then when we repeat this study in the next phase, including groups with lysed red blood cells to provide that catalytically active iron to contribute to that sort of apoptosis effect that we see in cartilage, we don't know what occurs in meniscal tissue, we see these results. I would just call your attention to the tall green bars to simplify for you. But at day 6 and 14, we see elevations of MMP activity with exposure to lymphocytes and monocytes. The green bars are those that are also combined with the lysed red blood cells versus oranges without the lysed red blood cells. So sort of the worst response in sort of meniscal catabolism with exposure to blood is with monocytes and lymphocytes combined with the lysed red blood cells. And then when we look at the gag content, for instance, in the tissue, we see suppression of the gag content at day 6, also at day 14, but the levels are lowest when combined with the lysed red blood cells. So we see that this 3-day exposure of lymphocytes or monocytes to the meniscal tissue result in sustained meniscal catabolism at 14 days. This is exacerbated with exposure to lysed red blood cells. And I think this then leads me to our question and potential discussion at the end of the session, but where do we go from here? I think that we need to be more considerate about when we utilize techniques that increase gross bleeding within the joint. I think we should minimize the use of microfracture in the notch when you have a meniscal tear that's at a location that already has good vascularity. So that peripheral tear that isn't combined with an ACL reconstruction probably doesn't mean microfracture of the notch, which contributes to that inflammatory response in the joint. You know, for now, is blood in the joint a necessary evil to produce substrate for a fibrin clot in some tear patterns that are not vascular? Possibly. Future directions of our research, we're repeating these studies with a low white cell ACP, so more to come on that. And I just presented this data to you all to help you question dogma and dig deeper. These are some of our funding sources, and these are my collaborators who aren't here today, but I thank them very much. Thank you.

meniscal injuries

healing rates

meniscus repairs

blood in the joint

catabolic effects