Okay, so the final talk before pizza and beer is from our co-chair, Rachel Frank. She has also been really thoughtfully looking at the orthobiologics and how they could be incorporated into cartilage repair and will certainly give us a big understanding of this from the current research as well. So thank you, Rachel. Okay, I don't want to hold us too much from pizza and beer, so I'll try to be brief. Again, thank you all for attending this course, terrific turnout, and thank you for taking the time out of your schedule. And thank you to our co-chairs. And with that, I have still no disclosures over the last hour. As we know, cartilage pathology is common. When we do diagnostic arthroscopy, there's multiple authors that have shown that up to two-thirds of patients have cartilage lesions at the time of their diagnostic arthroscopy. The question that we have to ask ourselves is, do all cartilage lesions require treatment? And the answer most certainly is no. The difficult decision is which ones do and which ones don't. And where do some of our less invasive technologies and techniques come into play, such as orthobiologics? Here's a case example. This is an arthroscopy of the knee of a 24-year-old male with a focal chondral defect and meniscus deficiency. That's the problem, and the solution is certainly joint preservation. But the question is, what does that mean, and how do we do it, and where do orthobiologics play into that scenario? As I mentioned in the first talk, the role of biologics in chondrosis and focal cartilage defects includes disease modification, prevention of further cartilage deterioration or the progression of that knee to arthritis. They play a role in the non-surgical treatment of osteoarthritis. They can serve a role as an adjunct to cartilage restoration, and I'll highlight some evidence that shows their purpose in that regard. And then they can act as the surgical intervention, such as with a scaffold, as opposed to doing a traditional cartilage transplantation technique. Why bother? Cartilage repair techniques are pretty good. We have pretty good outcomes. But they're not perfect. In fact, our reported failure rates can go up to 30 percent, depending on the paper that you read. Reoperation rates can be up to 30, 40 percent, depending on the paper that you read. And so there are opportunities for improvement, and this may be where orthobiologics come into play. In 2001, and this is almost 20-year-old data, the direct and indirect cost of osteoarthritis in the United States was $65 billion a year. And by 2030, our joint replacement epidemic is going to be substantial for every joint in the body, namely the knee, shoulder, and hip. And so we do need some solutions, and ideally solutions that are less invasive and easy to do. So the questions we ask ourselves with cartilage problems are, can biologics help to improve the outcomes for chondral defects, and can they change the natural history of osteoarthritis progression so that that chondral defect does not become full-blown arthritis? Which biologics are typically used for cartilage repair? We've heard a lot today already about PRP, bone marrow-derived MSCs. I'm not going to use the word stem cell for the rest of today, or my life. Adipose-derived MSCs, and other innovative tools and technologies that we've heard about and hot off the press with our industry. With regard to PRP, I'm going to highlight just a few of the technologies with orthobiologics that we use for cartilage repair. With regard to PRP, PRP results in increases in all of these things that I'm mentioning here, and this has been well-described in the literature. The question is, when do we do this? What patient do we put this in with regard to cartilage defects, and how do we put this in? What concentration, what dose, what time of the day? So PRP can help with focal cartilage defects, but we just don't know who that patient is that would benefit the most. Some studies have looked at this in an animal setting. So this was a paper looking at a sheep model with a medial femoral condyle focal chondral defect, and the authors divided their subjects into treatment with either microfracture alone for that focal chondral defect, microfracture with a PRP fibrin gel, and microfracture with a PRP liquid. And they assessed outcomes at six months with regard to gross macroscopic viewing, stiffness, and histology. And what they found, and to not go into too much detail, but what they found is that the microfracture with the PRP gel group, which had the fibrin glue, performed better in all three regards compared to the microfracture with the PRP liquid and the microfracture alone. So this is one take-home point that maybe the way we use PRP or the type of PRP can be beneficial for focal cartilage defects. This study was another animal study looking at rabbits in this regard, and they created a chondral defect in their femoral patellar groove, and they had three treatment arms, either no treatment for this defect, PRP, and a PLGA substrate, or PLGA alone. And they looked at outcomes at three months, again, gross outcomes, micro-CT, and histology. And they found that the PRP in PLGA improved their osteochondral healing compared to the other two groups. So here's some translational research that might show a purpose for PRP in the setting of a focal chondral defect. What about in humans? Well, the literature is challenging with regard to PRP and focal chondral defects in the surgical setting. There's really only technique papers with regard to augmenting a surgical procedure for focal chondral defects. This was a technique paper written by Dr. Cole and his team looking at an allograft cartilage matrix. And basically, this product is a dehydrated and micronized cartilage scaffold that can be stored on the shelf, and you mix it into a paste with your biologic product of choice, most often PRP, but also can be BMAC. And there's some good early anecdotal evidence and some early results that show promise for these lesions compared to microfracture alone. And so microfracture plus for a focal chondral defect in the setting of this technique may be helpful, but we need more clinical data to help show us the benefits of this potential product. What about after surgery? So this has been given some recent attention and has really peaked my interest a little bit. Is there something that we can do to patients after we treat them for a cartilage defect to augment their repair even more? There's some preclinical data in this study from 2014 looking at rats, where the authors looked at control groups, microfracture groups, and then microfracture groups that got PRP after surgery. And they found improved outcomes with regard to their call to staining with the PRP group. So again, preclinical animal evidence, but maybe some potential for the future. There was a clinical study published in 2013, a randomized trial of microfracture with or without postoperative PRP. In this cohort, there were 49 patients aged greater than 40 years. And the authors performed an arthroscopic microfracture of a small focal chondral defect in the knee. And they did second look biopsies in 10 patients in each group. And they found significantly better cartilage in the patients who had the PRP after their microfracture surgery. So again, potentially some early evidence to support that adding orthobiologics, and in this case PRP, may be beneficial and augment our cartilage restoration surgery techniques. What does the literature say about PRP? Well, this is just a few different studies. And there's been hundreds more that have published. As I showed you in my first lecture, there's over 10,000 hits just on PRP alone when you look at PubMed as of a few hours ago. The bottom line is it's very heterogeneous, as we've heard today. Lots of low levels of evidence. And one of the key things we have to understand is many of the PRP articles for cartilage problems are actually for osteoarthritis. And those results, those findings, may not be extrapolatable. I think I might have just made up that word. They may not be able to be extrapolated to focal chondral defects. And so we have to be careful when we're reading abstracts or reading titles of papers and really make sure we read the nitty gritty details to be sure that what you're reading is something that you can apply to your patient. Because arthritis or full-blown arthritis may not have the same potential to benefit from PRP as a focal chondral defect. Or it may. We just don't know yet. The bottom line is early outcomes are promising. Let's switch to MSCs for focal chondral defects. There's a couple studies that I'd like to highlight. This one was a level three cohort study where the authors performed this observational study of 36 patients undergoing either cartilage repair with first generation ACI or no cartilage repair but scopes with injections of cultured BMSCs. What did they find? Significant clinical outcomes in both, significant clinical improvements in both groups with no differences in their patient reported outcomes or in their MRI findings. And so they concluded in this so-called negative study, meaning no improvement in one versus another but improvements in both, that the BMSCs were as effective as the chondrocytes from the ACI study or ACI procedure, but only one operation was required. Because as we know, ACI or MACI now is a two-staged procedure. And so this may be an option to help give us cartilage that's as good as ACI gives us but in a single stage. This was another animal study looking at microfracture with or without bone marrow derived, I'm just going to say MSCs, with hyaluronic acid versus microfracture with hyaluronic acid alone versus microfracture alone. This was a horse study. The authors created a focal chondral defect to the medial femoral condyle of the equivalent to the horse knee. And both knees underwent microfracture. And then at one month post-op, the intervention was performed either the mesenchymal MSCs with HA or the HA alone or none. And then the contralateral leg was used as a control. What did they find? They found no clinical or histological differences between the groups. But the immunohistochemistry showed significantly greater levels of aggrecan within the BMSC group, again, suggesting the potential biologic benefit of adding this biologic agent. This was another horse study looking at trochlear focal chondral defects in 12 specimens. And the authors performed microfracture with or without BMAC at the time of surgery. And they looked at outcomes both gross and on MRI. And they found that in both of these outcomes, both in gross macroscopic inspection as well as on MRI findings and looking at T2 mapping as well as T1 weighted row scoring, that the BMAC performed better than microfracture alone. And so, again, this provides us some translational evidence to potentially apply to our clinical setting and stimulate some human randomized clinical trials looking at this exact situation. This was a clinical study, a level 4 evidence, where 15 patients with an average age of 48 years with an average defect size of 9.2 centimeters squared, which is very big. Many of these patients had multiple different defects. And those were pooled into an average size. And these authors performed a single-stage surgery to treat their focal chondral defects, or in this case, multiple chondral defects, with BMAC and collagen type 1 slash 3 matrix. And they found significant improvements in all patient-reported outcomes at final follow-up, which was at 24 months. They did note that patients with single lesions and smaller lesions had better improvements. And they found, when they looked at their MRI, that there was coverage of the lesion with hyaline-like tissue as best as we can evaluate with current MRI techniques. They were able to do a second look arthroscopy in four patients and a biopsy in three of those patients. And they noted in those three patients that the biopsy resulted in hyaline-like cartilage. Again, potentially supporting this opportunity to use orthobiologics with our standard cartilage surgery techniques. Another study published just recently looked at nine patients, again, average of 43 years, for a focal chondral defect of the femoral condyle, a slightly smaller, more realistic size here of an average of 2.5 centimeters squared. And these authors performed a microfracture and then covered that microfracture with a collagen membrane immersed in BMAC. And they followed these patients for just over two years. And they found that the vast majority of patients, eight out of nine, had significantly clinical improvements in their patient-reported outcome scores. And at a second look arthroscopy at 12 months, the authors noted, and I quote, all repairs appeared almost normal. That was verbatim from their article. So we take that for what it's worth. It looked like the cartilage appeared normal at the time of arthroscopy. So again, BMAC in this setting may be helpful after microfracture. What about after surgery? Just like the previous study that I discussed with regard to PRP, certain authors have attempted to use MSCs after cartilage restoration surgery. So this was a study of eight patients. And this is very interesting. So preoperatively, all these patients had peripheral blood MSCs harvested and cryopreserved. They underwent their surgery, which included drilling, abrasion, chondroplasty, and a high tibial osteotomy to offload that compartment. Postoperatively, and I highlight this because this is important, the patients underwent CPM and then had partial to full weight bearing at three to six months following surgery, which is a little atypical for the vast majority of us performing these surgeries. In their postoperative period, they underwent injections weekly for five weeks postoperatively of those peripheral blood MSCs with a hyaluronic acid injection, and then additional injections at six, 12, and 18 months. And then they underwent a second look arthroscopy with removal of hardware and a biopsy of their cartilage at the time of removal of hardware. What did they find? They found good ICRS-2 histology scores and excellent cartilage findings on their biopsy results. Here's some clinical and MRI findings of what they showed. But here's my question, so it's multiple choice question time. Are these improved outcomes from the high tibial osteotomy? Are they from the extended partial weight bearing restrictions for three to six months? Are they from the MSCs? Or is it D, all of the above? It's probably D, all of the above, and the question is what do we need to get these results? And I don't think we necessarily know the answer. And then finally, looking at adipose-derived cells, this was the only clinical study I could find for focal chondral defects. The vast majority of adipose cells are focusing on arthritis. But for focal chondral defects, this was a study of 80 patients, 40 in each group, with a focal chondral defect of at least three centimeters squared. And the authors used the technique of microfracture with adipose-derived cells with fiber and glue versus microfracture alone. There was no blinding, of course, for the patients as those patients who got the cells had those cells harvested from their abdomen. And there was an average 27-month follow-up. And the authors found significantly better pain and symptom subscale scores in the group that underwent the orthobiologic augmentation, and significantly better MRI signal intensity in that group as well. Again, providing potentially some early evidence, not randomized, but some early evidence to say that these patients may—sorry, it is randomized but not blinded—some evidence to say that adding an orthobiologic to a standard cartilage repair or restoration technique may be beneficial. So these are some of the studies talking about adipose-derived cells for osteoarthritis. And I would recommend reading these. But again, we have to read these differently than we might read these same studies for focal chondral defects. Putting it all together, this was a recent systematic review published in AJSM looking at stem cell therapy for articular cartilage repair. I said stem cell. I said I wasn't going to say it, but it's in the title here. And they reviewed 46 studies, the vast majority of them looking at bone marrow-derived MSCs. As well as adipose-derived MSCs. But they noted that these studies were mostly case reports and case series, and there were many errors in terminology. And I think we've highlighted here today some of the confusion with the nomenclature, even amongst all of us. And they looked at their level of evidence, and as you can see here circled in red, the poor— It's interesting. There was a poor level of evidence in 33 of these studies, nearly three-fourths of them. And so the authors found that all the studies reported favorable outcomes and or cartilage repair findings on MRI, but they advised care in terminology in terms of stem cells versus cell populations containing a portion of stem cells, and advised caution due to the overall low quality and low level of evidence in all of these studies. My strategy and my practice for biologics and focal chondral defects, I apply a standard cartilage restoration algorithm. If these patients have a focal chondral defect, I need to decide, number one, do they need surgery or do they not? If we're going along the surgical route, we have to remember not just to treat the cartilage, but to treat the knee as an organ. Remember alignment, meniscus status, ligament status, and overall biology of the joint, as well as patient-specific factors, including BMI, age, and sex. And then we have to see, should we incorporate the use of biologics? I can say with some of this evidence and with the anecdotal experience that I had when I was back training in Chicago, I think that we can be a little bit more liberal with our use of biologics, but we need to be very honest and open and transparent with our patients about the experimental nature and the fact that they're not covered by insurance due to the FDA not approving them just yet. But I use them a little bit more and more as I grow in my practice, and I'm excited to see the potential for them. But again, we have to pick the right patient with the right technology. Take-home points, the current literature for orthobiologics and the setting of focal chondral defects is limited by relatively low levels of evidence. Most of the literature focuses on arthritis, and we don't know that arthritis and focal chondral defects are similar with regard to their ability to improve with orthobiologics. Terminology can be confusing and often is, but early outcomes to date are encouraging. Thank you all very much.

orthobiologics

cartilage repair

disease modification

platelet-rich plasma

mesenchymal stem cells