Good morning on Sunday to everybody. My disclosures are listed in the academy book, my research has been supported by the Wilton Webster Foundation. To overview talking about placenta and specifically about amniotic tissue today, the cells and the tissue lines we're talking about are amniotic fluid, amnion, chorion, umbilical cord tissue and umbilical cord cells. But why the placenta is readily available tissue, it's off the shelf and it has plasticity and by that I mean it has higher proliferative and differentiation potential, it's more plastic. Placenta tissue has tissue that's rich with extracellular membrane growth factors and cytokines. Wharton's jelly and amniotic tissue in particular have been noted to have the highest concentrations of MSC. In this review of the literature, umbilical cord, 2% of the nucleated cells are MSC, stromal stem cells, about up to 8% of the amniotic membrane are MSCs. If we take the placenta and process it, we're going to micronize it and put it for injection, we're going to micronize it, take those cells and then culture expand them and isolate the stem cells for injection or we're going to use amniotic sheets as an allograft for coverage of wounds and plastic surgery and cornea stuff. We're not talking about the allografts today, it's just more of the cellular components. The FDA's concerned with safety, they say you cannot, you have to use minimal manipulation, you cannot sterilize, decellularize, enzymatically digest, culture, expand or preserve tissue. That's more involved, that's more than minimal manipulation, classifying it as a 351 and that requires an IND. Investigational new drug applications are very complex, very expensive, therefore there are no human placenta-derived biologic drugs or device marketed in the United States right now. In particular, there's no stromal or stem cell drug for musculoskeletal disorders in the United States right now. You cannot do expanded stromal stem cell injections in the United States. There's only one approved drug in the United States and that's for hematopoietic reconstruction. Now the FDA recently, last month, came out with a statement early in June, they're concerned about the safety issues, all the problems with tumor formation, infections. And they have these reported and so now they look at all these biologics that we're talking about this morning and they said, well, these are bad actors, they call them bad actors and they said we'll get rid of them. They allowed you to sell these products in such time that you could create an IND, they gave an expended period of time for companies to do that and they said the discretion with the COVID ended on 5-31-21 recently. So as of June 1, no other companies are selling these legally in the United States. So you can't get these products right now. If we look at the next point of the literature, it's a lot of confusion. Nomenclature is difficult, study design is difficult, they lack control, small numbers, the passages, how they biologically treat these drugs, if you will, is not listed well and of course none of these have dosing, PRP, none of these have any dosing in any of these studies. Nomenclature is very difficult, very confusing, all these different names, it's probably best to call them stromal cells right now, it's very confusing in the literature. Arnie Kaplan, who is the godfather, talks about medicinal signaling cells, well clearly that's what's going on around his periocytes. It's a lot of confusion. If we look just now at the amniotic tissue, which is the charge today, in this study out of Brian Cole's group, they found 14 companies, about three of them involved in orthopedics and this continues to evolve. Amniotic fluid products, in this study they took three companies, looked at the growth factors in the cells, found that there were no MSCs in the amniotic fluid products. So that's not a great source for cells, but it's a great source for all these other good things such as growth factors and cytokines. On the left you can see in this chart the most commonly promoted products out there right now, but the data is limited, limited animals, and of course we need more level one studies for amniotic products. This study by Gomel and Jack Farr's terrific, 200 patients, a good randomized clinical trial, where they compared it to HA and saline and their suspended allograft of fluid and amniotic membrane micronized beat most of the pain reported. They improved with patient reported outcomes across the study for activity and pain and things like that. So that's really exciting. They have another study coming out that's in press right now. So that's kind of where we're at and it's really exciting for these types of tissues. Other placental cells I should talk about before coming off the stage for plantar fascia, necrosis, you know, cuff in the back. So there's other smaller studies coming out with other biologics in the placenta. And finally, had to talk about cord blood banking, huge billion dollar business for saving cells for the future. That's very common, not the purpose of this talk today, but big part of this placenta as a biologic. Last thing I want to talk about, exosomes. Exosomes are the new biology. These very small nanometers, 100 nanometers of bilipid layer. And in them, they have micro RNA, growth factors, and mRNA. So they're really the intelligentsia, the communication of cells to cells. The FDA just got them on their website in 2020. So the FDA will say this is a 351-2. But this is the drug. This is how cells communicate. And if we take them from stem cells, we have all these different factors of RNA and micro RNA and growth factors. It's very exciting that if we can corral these exosomes, that's how these drugs or these cells work. Clinical trials around the world, amnion up to 605, placenta 109. But across the world, there's about 8,400 in clinicaltrials.gov, a majority of them in the United States. So the evidence is coming down the road with good trials. So in summary, if we talk about factor fiction, factor fiction for the biologic injections, there are going to be a lot more clinics. We'll get improvement in the definition and the science of MSCs, stromal cells, and exosomes. The FDA will always monitor us. Insurance companies will not pay for it until we get evidence. It's a cash business. For the many studies that have been published to date, even if they're small, safety is probably there. We'll have to look at that some more. There's always a call for level one studies. Costs will come down. That's terrific. I'm really excited because there's several of these products that are in the phase three trials, and they're going to come off the shelf for another injection product that is going to be excellent, similar to a hyaluronic acid. Thank you very much. Thank you.

placenta

amniotic tissue

medical treatments

FDA regulations

exosomes