Sheldon Lynn just flew in from Utah to be here. He's from New Jersey. He's the chief of Foot & Ankle over there. He's on our board. He knows a whole lot about a lot, much smarter than I am. That's why he's here. And just like all of my speakers are smarter than I am, that's why I invited them. Sheldon, thank you very much for being here. Thank you very much. Appreciate it. The people I want to thank, let's be honest, folks. It's Saturday, and we're here. I want to thank the audience, because truly, you sacrificed something, which is your time for education. I mean, as a representative of the board, I want to thank Dr. Roberts and the speakers. This is an excellent course. And I apologize. Maybe the ghost of this whatever is going to keep on coming, but we'll see. We'll see. First thing we've got to do, of course, is disclose. I do have a few things here, but they're for research and research purposes. But when I was first asked to give this talk, I said to myself, we should talk about two key words, osteoconductive, osteoinductive. Then I realized, my god, this is boring. Let's see what the internet says. I mean, we're that generation. So I went to Google. I typed in the phrase osteoconductive. And sure enough, it refers to any structure that facilitates the formation of bone. And you think about it, there are many substances, calcium phosphate, sulfates, these various collagen composites, DBM, that are osteoconductive. Then I went back and I said, hmm, let's see what osteoinductive is. Because, you know, I mean, it's Google. It's got to be right. Well, it's something, any substance that stimulates the formation of bone. And now, in my mind, the classic is BMP. But of course, there's autologous bone graft, allogenic bone, bone marrow aspirates. Well, these are things to think about. And of course, classic questions asked on the OITE. But for ankle surgery, we know, as surgeons, that arthrodesis of the hindfoot and midfoot remains really the preferred method of managing arthritis and deformities. And given the mechanical role of the foot during gait, that these are better tolerated. But there are problems. If you look at the classic article, Carol Fry, back in 1994, she reported in ankle arthrodesis a non-union rate of 41%. Now, it was, you know, in post-traumatic patients. It was in patients who had a plafon and talus fracture. But that was very high. I looked at this study by my good friend, Mark Easley. Large series. These are really all of Lushom's and Mark Meyerson's patients for isolated subtalar fusion, 184. And sure enough, non-union rate, 16%. What it means, like, if that back row back there, one, two, three, four, five, six, non-union right there. And think about it. It was higher in smokers. It was higher in those with redo as well. And this is pretty humbling, especially if you're sitting there and you're looking at the patient, and you go, why is it not healed? And finally, the diabetic population. I'll be honest with you. My family has a history of diabetes. Papa Meyerson, Stuart, Tisdale, Graves. 15 to 30% non-union. So, you know what my chairman used to say down at the Rothman Institute? What's worse than taking care of a complication is treating your own. This is one of my own patients. The subtalar never healed. And what it tells you, the kernel interest is the overall non-union rate is about 15%. Higher in certain subsets, like smokers, redos, and those people with AVN and diabetes. And in spite of good surgical technique, it's still a problem. And that really asks the questions, what can we do through our available orthobiologics to help this problem? Because we know that as surgeons, we prepare the fusion site, we minimize the soft tissue stripping, we expose all the cartilage, and we really perforate the bone to create this raw, bleeding, bony bed. And we're perfect, right? Because we're surgeons. But despite all of this, in order to achieve this picture that we want to see here, with rigid internal fixation to achieve compression, that we still don't really get what we want. There are certain subsets, the smokers, people who have redos, people with AVN, they just don't succeed. And so the question I want to throw to you is that in the concept of tissue engineering, can we, in order to achieve that picture right there on the far left, working with the cells, working with the scaffold, working with the environment in the appropriate time, certain growth factors, can we achieve tissue regeneration? In this case, bone formation. So I want to go over this now in several concepts. One is we know there's autograft, we know there's alternatives like allograft, DBM, some synthetics. But I want to first talk about autograft. You know, the classic, when I was a resident, I don't know if D. Giovanni still does this, but you know, or Ben, you know, does this. Iliac crest, it has the stem cells, it has the matrix, it has the growth factors, and about 340,000 patients undergo this annually. But with it comes a price. Pain, scarring, increased overtime, blood loss, infections. You know, it's very humbling when you see this. This is one of my own pictures where the, you know, the iliac crest was a herniation after my operation that required a mesh, or heaven forbid this, where just oozing out and you're like, oh my God, what happened to you? And that requires, you know, multiple washouts, skin grafting, drains, and of course, long-term antibiotics. And if you look at the literature, Gupta et al. describes top patient rates at 31%, and even worse, while the foot and ankle may feel great, 27% of the patients, up to two years after surgery, still has pain. Recently, I was involved in an FDA trial, and we've shown, even with the proximal tibia, distal ankle, or even the calcaneus, they have this percentage of pain at the donor site. So, let's go back, just jump back. What are the growth factors that are commercially available to you as an orthopedic surgeon? Well, first, in my mind, one is autologous platelet concentrates. We know this is PRP. The other ones is this recombinant BMPs, whether it be infused BMP2 and OP1 BMP7. What is autologous platelet concentrates? Simply, it's a system, whether we do through centrifugation, whether through filtration, to concentrate the patient's own blood, the platelets, at the point of care. And if you type into Google, and I just want to see exactly, you know, I want to point out one, this is not regulated by the FDA. So, the FDA does not regulate blood and blood products. That's minimally manipulated. That's the key word. It says here, PRP is the practical application for tissue engineering. And then it said further, a concentrated source of platelets that provides various growth factors, cytokines that stimulate soft tissue and bony healing. I go, hmm, interesting. And you think about it, it has a potpourri, whether from PDGF, TGF-beta, VEGF, IGF to EGF. And these platelets, when they activate, due to hitting some type of stimuli, they release these growth factors into the sites. Whether you cut a tendon, break a bone, or have like a bad, you know, scratch, this is what you get, the scab, the platelets releasing these growth factors. In contrast, BMP, we can really thank Marshall Urs, was from, originally, the Atomic Energy Program, which he tried to understand how to get bone to heal, to remineralize bone in the face of a nuclear event. And they discovered that DBM placed even in extra skeletal sites can induce new bone formation, as shown here. You see that thigh mass is really bone that he has induced. And you type in bone morphogenic protein into Google, and I apologize, sometimes I can't type that fast. And sometimes I can't type that accurately, too. But BMP is described as a family or group of growth factors and cytokines known for their ability to induce bone and cartilage. I think there's right now up to 17 BMPs, the ones that we have utilized in the commercial arena is one, BMP2, the other one is BMP7. There are others that are in middle trials. Now, I'm not here to talk to you about love. It's data, folks. Data, data, data. In regards to clinical trials of PRP, very few published studies, I'm not gonna talk about our little case series. The one that I think in my mind is Chris Kosia out of Minnesota. He looked at patients that underwent TIB-FIB syndesmosis fusion after an agility total ankle. And he looked at patients that had bone grafting alone versus PRP with bone grafting. And he showed me this data and I was like, wow, impressive. Patients who had bone grafting alone, various time points, eight, 12, six months, ultimately went to a 15% non-union. And by adding PRP, this rate dropped to 3%. Now, let's be honest. It's a level three comparative cohort study, but it's very fascinating. There are very, very few clinical papers of PRP, platelet gel, platelet-rich plasma. There's one article by Dalari and JBGS on enhanced tibial osteotomy. This was patients undergoing high tibial osteotomies for genuvarum. They had three groups, bone chips with platelet gels, platelet gels, bone chips with bone marrow, and finally, those with bone chips alone. I mean, the results show that group A and group B did better than group C. My whole point in bringing this out is there are very few studies and therefore we need data. I mean, I saw this article recently in JLT. I said, okay, that's interesting. Then I read the conclusion. This study failed to show the clinical usefulness of isolated percutaneous platelet gel supplementation in long bone nonunits. We need data, and I really ask you, the audience, because you're the future generation, to provide that data for us to read. Bone marrow aspirate, and actually I went in here and I decided to type in mesenchymal stem cell or cell-mediated therapy because I thought it was a little easier to type, MSCs, and actually what it defined according to Google was multi-potent stem cells that can differentiate into various types of cells or tissues. I thought, okay, I can get into that, and we know that autograft is the gold standard for an ankle surgery. We know that a recent study in JBGS by Heyer et al showed that these osteoblastic progenitor cells exist, iliac crest, tibia, calcaneus, with a little higher number at the iliac crest site. Recent article back by Hernegut, JBGS 2006, it showed that percutaneous injection of bone marrow appeared to work for tibial nonunions in which they took these patients who had a tibial nonunion and all they did was inject bone marrow, 60 patients. The result, union was achieved in 53 out of 60. They actually showed that the seven that did not heal had a very low number, below 20,000 per one million cells. So they showed there's a critical number that exists in order to get a successful union. Now in contrast, the BMP, the growth factors, we know this is made from CHO cells, sterile, purified, placent vials, and available for your use. The clinical trial started in 1997. It has three FDA labels, one alif, two open tibia, three oral maxillofacial. What does that mean to us if we're into foot and ankle? Well, it means that we're really doing this off-label. And I think the key point is this, the article by Chris Bibble, FAI 2009, 112 fusion sites, we mean high-risk population, a lot of smokers, a lot of AVM, a lot of diabetics. He demonstrated only a 4% nonunion. But you notice the first three words in there, non-FDA label. You have to tell your patient this is off-label. But this study concluded that recombinant BMP2 was effective adjunct for high-risk ankle and hind foot fusions. So let us step back. What is the current FDA indications? Well, clearly PRP, bone marrow, are not regulated by the FDA because this is classified such as blood or autograft. Infuse has label for open tibia fractures, spine, oral maxillofacial. OP1, BMP7 is really an HDE requiring IRB for long bone nonunions. I did throw in exogen, I don't know why, but they have approval for fresh fractures and nonunions. But the point is this, you have to disclose to the patient. One of the things that's always testable is people get mechanisms. We know that bone marrow, what it does is provide to the site osteogenic progenitor cells. BMP2 is a differentiating agent that causes the local undifferentiated cells to multiply and become osteoblasts. PRP is a concentration of the body's own growth factors to stimulate healing. And I think there are many new candidates. I'm really excited because if I was in your shoes, it's like, whoa, this is what's coming down the pike. There are multiple candidates that are coming down in the orthobiologic realm to help you and more importantly, your patients, but they're not approved yet by the FDA. And therefore, the question asked me most commonly is who should we treat? In my opinion, the high-risk subset, smokers, diabetics, people on steroid, the extreme of age, elderly, or chemo, patients with a history of delayed union or non-union and those with a high-risk fracture. The key word, I think, is you got to tell your patients, you got to tell your patients what the FDA label is because they need to know and you need to know and disclose that appropriately. And thank you very much. Thank you.

orthobiologics

ankle surgery

fusion

tissue engineering

clinical data