Hi, everyone. This is Jason Dragoo talking to you from Colorado here on a talk on biologics, the use of adipose tissue and the use of bone marrow concentrate and other modalities in our practice of orthopedic surgery. Disclosures are on the board here but really nothing germane to the talk today. So let's start with adipose tissue. Why would you choose fat tissue as a biologic? The simple answer is that there's many more of these MSCs or cells that we would like to harvest in comparison to bone marrow. 100 to 500 times more than bone marrow, 5,000 more than amniotic products, and 25,000 more than peripheral blood. Here you see one of our trials that we had on harvesting these MSC cells from the fat pad in the knee and you see that wherever you look it's 15 to 20 percent of the total cells. So it's really a good population to harvest bioactive cells. Well, what do these cells do in our body? And I think here is the best evidence today showing that these cells consistently relieve pain. Well, how do they do that? Well, it's by activating the mu opioid receptors. We also know that they're very strongly anti-inflammatory and they tend to perform this benefit by modulating our immune response. And I'm going to show you some data which is some emerging evidence that they may also rebuild tissue and of course that would be the fountain of use that we're looking for with our quote stem cells. Well, what are the main uses of adipose tissue technologies? And I will show you the trials using tissue for articular cervix defects as well as osteoarthritis. If you're going to harvest adipose tissue, it's important to know where the cells are located. And the cells are located near the blood vessels within fat. And because fat is so vascular, there's tons of cells. But recognizing that fat needs to be processed for these cells to be harvested is a real important issue when using adipose tissue. If we look at the two main ways of harvesting adipose tissue, on the right we have a harvest from the abdomen. This is tumescent liposuction. You see that the wires being placed in some local anesthetic and saline are placed in the subcutaneous layers. And then the fat is harvested after 20 minutes. To the left side, you see arthroscopic harvesting of the adipose tissue with a shaver system and a special FDA vessel where you can have, house the adipose tissue and then it will allow you to use them for further processing. There are two main ways then to fractionate the fat or to make it more bioactive after you harvest it. To the right is a ball bearing based system. This breaks down the fat and also washes it and puts it through a series of meshes to decrease its size. To the left is syringe emulsification. This is forcing the fat through a small aperture. As these apertures are decreased in size, then it blows apart the fat, so to speak, and then the cells fall out after treatment. I'll go over both of these techniques and maybe some of the benefits of them. The first is, what is this MFAT, the ball bearing system, what does it actually do to the fat? Pretty clear evidence that it decreases the cluster size. It does not isolate out the actual cells, but it decreases the size of the fat clusters. It also washes it, as we talked about, so mark a decrease in the red blood cell contamination. Certainly red blood cells are something that we don't want to have as part of our biologics. What about the evidence? Here's one of the best studies that shows this MFAT's anti-inflammatory effect. Lipopolysaccharide, of course, is a polysaccharide that causes a lot of inflammation when exposed to cells. Here we see that the lipopolysaccharide was exposed to these cells and it created a big inflammatory reaction. But when these micronized fat particles were given at the same time, you see that they prevented the onset of inflammation. This is one of the most striking indicators, again, of the elution of anti-inflammatory mediators. We feel that the same thing is going on in the human body when this is injected. What about the evidence of this micronized fat and pain inhibition? Here is a meta-analysis of all the studies that use this technology. Really, what they have in common is all of them show a marked decrease in pain. We think, again, this is occupation of the mu opioid receptors, but it's pretty clear across the board. Another question that you may have is, well, what's its relative efficacy in comparison to other biologics? Here's a study that uses leukocyte-poor PRP and repeated doses of the PRP plus hyaluronic acid. This is compared to a single dose of micronized fat. This shows that the micronized fat performs better than multiple doses of leukocyte-poor PRP plus hyaluronic acid. This is at the six and the 12-month mark with regard to activities, and certainly symptom reduction at six months better, again, than PRP and hyaluronic acid. Well, what about the other way of processing? This is through the small apertures, breaking apart the fat, and then this fat is then placed in a centrifuge. Then you can see that although they're not specifically all MSCs, it's a more cellular type of product at the end. This can then be applied clinically. Here's how the clinical trials are performed. You see here, this is a chondral defect of the knee. Then you're going to see that we have taken out the saline, taken out the calcified cartilage layer below the area of the cartilage. Now we're putting fiber and glue. Here is a combination of these cells that I just showed in the centrifuge tube along with a non-cellular cartilage matrix. You see how just from time zero, this creates a resolution of the chondral defect. Then we create a little cocoon for this biologic using another layer of fiber and glue. The question then is, well, how does this do over time? Here are some of our preliminary studies. You can see that on the left at eight weeks, you see that this looks very abnormal. You can see the graft in place, but it doesn't look at all like cartilage. Look at its transition over a two-year period of time. These MSC-driven cells within the product here tend to change into very close to the articular cartilage cells next door. The way we can look into this further is that we can actually measure the behavior of cartilage through physiologic MRI scanning. This is T2 mapping. We take the area which is now in the pink color, and that is our regenerate cartilage. We're measuring how does it perform on these functional MRIs in comparison to the normal cartilage, both in the front and the back of the area of the graft. What we see is that the cartilage here is closer to actual cartilage of its neighbor. This is in contrast to micro-drilling, previously known as micro-fracture. You can see that this is turning this layer of cartilage into a more normal physiologic consistency than micro-drilling. Certainly exciting preliminary data. If you look at how these adipose cells do with regards to treatment of arthritis, here's some of the strongest data from around the world. This is a double-blind randomized trial of giving adipose cells or saline. You see that pain is decreased. Function is improved. Here, with the MRI analysis, a marked increase in cartilage regeneration in osteoarthritis. Very promising data. Here's another Chinese trial. You see the same thing, that there's decreased pain and improved function across the board. Again, they saw significant improvements in cartilage thickness. This is some of the first evidence that suggests there's actually growth of tissue with adipose-derived treatments. Finally, here's another randomized controlled trial. This is from Korea. This shows marked decrease in pain and improved function. For them, they did not see thickening of cartilage. The jury is still out if these cells can really produce an improvement in the thickness of cartilage with osteoarthritis. In summary, across the board, these adipose-derived cells improve pain and function. There's some evidence to suggest that cartilage regeneration occurs. The best evidence is in osteoarthritis studies, but our studies of chondral defect treatment are going to be out shortly. That may give us some additional clues that these cells can be used for the treatment of chondral defects. What about bone marrow aspirate? The key to understanding the use of bone marrow tissue is technique. It has to be specific. Bone marrow aspirate is harvested from the iliac crest. It is aspirated in a very quick way by really pulling back and creating a lot of negative pressure. The key to the technique is using small little areas of aspirate at each different area in the iliac crest. That is the key to performing good bone marrow aspirate. You cannot just put your needle at one location and take out a bunch of bone marrow. That just doesn't work. There is clear evidence to suggest that the bone marrow should be harvested from the iliac crest and not the proximal tibia and the proximal humerus. Bone marrow concentration has been shown in many studies to be beneficial. It roughly doubles the amount of bioactive cells within the bone marrow concentrate. However, please be careful because the different manufacturers produce different bone marrow concentrating technologies. This leads to a study showing that in the same patient, the output of these machines are very different. Therefore, we need to know what machine we are using and what sort of output we are really asking for when we are using this bone marrow technology. The other thing is that there is a problem with bone marrow concentration. These MSCs that we are looking for are located in bone marrow right next to the white blood cells. Now, we don't really have any good technology to separate the two. When we have increased numbers of MSCs, we have increased numbers of white blood cells. Of course, that can decrease their efficiency. Where do you want to use bone marrow cells in the practice of orthopedic surgery? Here is the best data. The best data shows that if you have a problematic rotator cuff patient and you want to do your best to improve your rotator cuff repair, it is reasonable to use bone marrow concentrate. This is a famous study from Philippe Hernegau showing 45 patients in each group. The one group that had the bone marrow concentrate basically doubled the healing of it. Here is a picture of his technique underneath the rotator cuff. You can see he is injecting it below there. Also, this is a new study from Brian Cole. This is a randomized trial again after rotator cuff repair and showed improved tendon healing in the bone marrow concentrate plus rotator cuff group. That is in comparison to the rotator cuff group alone. The other worldwide indication of this is for the treatment of tendinopathy. Here is the best data to date from Spain. This shows specific cell dosing of the bone marrow drive cells. 20 million cells in this particular study really has been the best data to show that it remodels the actual tendon from tendinopathy into normal tendon. Pretty striking data. This article also represents really the beginning of our cell dosing or the future of biologics when we are not just putting in random numbers of cells but we will be much more specific as time goes by. The final topic is the birth products. This is the amniotic fluid, warden's jelly, and cord blood. Long story short, as of June 3, 2021, these technologies are illegal and cannot be used in orthopedic surgery unless they are part of a study. This is an FDA IND study, not an IRB study. Otherwise, they are illegal. I want you all to know that because there are still some distributors trying to get rid of their products on the shelf and claiming that they are FDA approved, but it's just not true. There are no approved products in this category. In summary, adipose tissue technologies have shown to be beneficial for the symptoms of osteoarthritis to decrease pain and inflammation. The bone marrow concentrate cells have been shown to be beneficial in improving the rotator cuff healing rate after rotator cuff repair and the treatment of tendonopathy. Thank you very much. I hope you guys have a wonderful course and look forward to seeing you soon.

adipose tissue

bone marrow concentrate

orthopedic surgery

mesenchymal stem cells

treatment