This week we are excited about our exclusive interview with Dr. Janice Smiell, CMO at Alliqua BioMedical, Inc. Dr. Smiell and her team have been doing some groundbreaking work on battling chronic wounds using placental biomaterials.
Steve Freed: Welcome, Dr. Janice Smiell. Let’s begin by having you tell us a little bit about yourself. What do you do and how did you get involved?
Dr. Janice Smiell: Presently, I’m chief medical officer at Alliqua BioMedical, Inc. Alliqua is a relatively new company aimed at helping healthcare professionals take care of their patients’ chronic wounds, such as diabetic foot ulcers. As for myself, I started off as a general surgeon and had a general surgery practice. I became interested in wound healing and ended up running the wound care center for my hospital. Once my family came along, I decided I needed to make a change in my career so I could help raise my children. I looked toward industry to see what was going on with wound healing products. I saw that Johnson & Johnson was working hard to come up with advanced therapy that would be beneficial for diabetes patients with ulcers, and I became involved with that. From there, I went to other companies that were working on chronic wound management and healing. Eventually, I came to Alliqua. One of those other companies was Celgene Cellular Therapeutics, which had a division that was working with placentas. During my tenure there, I started developing products from placental biomaterials. The company was also working on stem cells from cord blood and placental origins that they are putting into ischemic diabetic foot ulcers, to see if they can simulate healing there.
During my time there, we took the amnion, and did minimal processing to come up with a membrane product that could be used on wounds. We tested in a number of wounds—all different types of chronic wounds and some acute wounds—and found that it could be beneficial as long as it was used along with good wound care for the patient. That product is Biovance. Because Celgene was focused on its stem cell initiatives, progress on bringing Biovance to the market was shelved until Alliqua came along. Alliqua licensed Biovance from Celgene so that we could distribute it to sectors of the wound care community where it is needed.
Dr. S: Biovance is a very simple, pure, amniotic membrane that has had the cells removed from it. Amnion is, typically, avascular, and the non-cellular layer of placental membrane. It does have a layer of epithelium that sits on top of it. The amniotic membranes are created from the same layer of the developing fetus, so it is an extension of fetal skin. It covers the entire interior of the uterus, and around the umbilical cord, and then extends as the fetal skin. The amniotic layer is the one closest internally to the baby. It keeps the baby from sticking inside the womb. Then, beneath that top layer is the chorion, which is more collagen-laden, but not as strong—this tissue that has more cells within it. Beneath that is the layer that is right up against the uterine wall that is from maternal origin—it is called the decidua. That maternal layer and the chorion layer, in effect, have fingers projecting into one another, and that’s where exchange of nutrients can happen between mother and fetal membranes. After birth of the baby, the placenta is delivered. It is typically a waste product, but these are now being harvested from healthy, normal-term deliveries. The amnion is very easy to strip apart from the chorion and the other parts of the membrane. Then, very gently, amnion is processed by scraping off the epithelium and rinsing it, which removes the cells from it. Then it is slowly dried to a dehydrated state and cut into a variety of sizes of sheets, so that doctors have a choice of which to use depending on the wound size. So it is simply providing a very thin, very pure amnion. It’s almost like plastic wrap, or tissue-paper thin—but inside, it’s a powerhouse. This is because it gives you a basement membrane, which is important since cells will attach to that membrane and create the epithelium you need for the outer of layer skin and it has an extracellular matrix that is mainly collagen. (Most of our body’s structural parts include collagen.) It involves different types of collagen that have with them other proteins, and glycogen-type molecules. There are also proteoglycans, your glycosaminoglycans, as well as other proteins that cells get attracted to. While it comes with no cells, it does allow for cells to infiltrate it. Once they sit there in the extracellular matrix, they will release whatever cytokines and growth factors are needed to keep the process going toward wound healing. There are structural collagen proteins to use, and it attracts the cells that are needed. We’ve actually done some recent benchtop research to show that it can wake up the cells that are senescent, which is a problem specifically with diabetes patients. They tend to have senescent cells, and therefore healing stalls. You need to do something to wake those cells up. This is something that benchtop research with models seems to show is happening.
Dr. S: We’ve done a study where we’ve treated all types. We’ve treated acute wounds and burns, we’ve treated diabetic pressure ulcers, venous stasis ulcers, those with collagen vascular disease, and those with ischemia. We found that there is some benefit across the board. Every wound needs to have new tissue built into it, and then the epithelium covers over it in order for the wound to be healed. If you allow the wound to do it on its own, and have the cells do all the building work, you end up with a scar. The scar tends to be a different color and a different texture than the skin around it. It continues to change in color and vascularity as it remodels over six months to a year’s time. It’s never quite as strong as normal skin. However, if you can provide some building blocks for that healing wound that look very much like native tissue should, then these will be welcomed and used by the wound, and cut short the process of cells having to rebuild everything from scratch. That is called regenerative healing. Regenerative healing actually cuts down on inflammation, which prolongs the vicious cycle of stalled wounds. It keeps it moving along. When you cut down on inflammation and provide the native-looking structural proteins that are needed, you end up with a wound that has minimal scarring, much softer and more functional tissue. I don’t have the data, if you will, to say that the strength returns to normal, but for all purposes it appears to be like normal tissue should be in the area. You can minimize scarring, and minimize the negative effect of having fibrosis by delayed healing.
SF: What about rejections? If you take a placenta from one individual and use it in an individual from a different racial background, what does that do?
Dr. S: Those two are not the same things. Under the skin, color is not there, so there’s no concern about any of that. The interesting thing about amnion is that it is immunologically inert. It has to be, or mothers would be rejecting their fetuses. It has this HLA class that is unique and that doesn’t allow for that specific kind of rejection. There are no foreign markers so that it is not seen as foreign. As long as you do nothing to rearrange its structure, like cross-link it or damage it in some way, then the body sees it as itself, and it doesn’t matter who you are. Now, if you have a product that will introduce maternal cells, which is possible if you include the chorion, then you may also include maternal cells if you don’t decellularize it; you may see some mild kind of reaction that happened. It is typically self-limited. It is inflammation. That was one of the reasons why, when Biovance was produced about 15 years ago, it was decided to only go with the amnion and not to use the chorion, and to remove all cells so that you wouldn’t have a cell marker issue. You just have the purest, most beneficial, and least risky layer of tissue.
SF: How long has it been in research and development? I assume it is FDA-approved—how long has that been the case?
Dr. S: The FDA does not require that human tissue allografts be approved. What they do is regulate how they are processed and advertised. It is treated just as a unit of blood would be: you don’t have to get it approved to use it for someone who needs the unit of blood. This is true as long as you’re using human tissue in a homologous way, meaning that where you are going to use it requires knowing its function in the donor. Because this is an extension of fetal skin, the FDA states that you can use it on a wound as a homologous function to provide a barrier from the outside world. It keeps moisture in, provides a structural component like it did in utero for the fetus, and offers protection. The other beautiful thing is that in utero, this was a tissue used to a highly hostile environment, because it didn’t have its own vascular supply—so it tends to tolerate some ischemia well whenever it is placed in wounds. It also has a native ability to protect from infection. We see that these chronic wounds are clean. There’s always a concern when you have any bio-burden that you are going to have proteases that will simply chew up whatever tissue product you put on them; but it’s able to withstand a pretty good amount, certainly not something you want to put into an infected situation. That’s true of any product. You want to take care of infection before you try to actively treat anyone.
Dr. S: Presently, Biovance has Medicare coverage in one U.S. region. We’re going to the Medicare providers in the rest of the country and attempting to get on their approval lists. Commercial insurances have not denied its coverage. Those with diabetes who get ulcers typically tend to be older, and so Medicare coverage is very important. That is what we’re working toward at this point.
Dr. S: It hasn’t been so far. It’s interesting, isn’t it? There is certainly a lot of placental product out there now, but it doesn’t seem to be an issue. We have a five-year shelf life. There are babies born every day, so harvesting it hasn’t been a problem. We hope we won’t ever run into that shortage situation. There is no issue from an ethical standpoint.
SF: How do you get your placenta product? A woman goes into hospital, gives birth. There is a placenta…
Dr. S: The company that produces this product for us is one of the divisions of Celgene. You may know Celgene from its work in cancer drugs. They have a cord blood bank. They are in hospitals for people who want to store their cord blood. They also accept donations for the research, as well as develop some of their stem cell products. These placentas come from voluntary donors who were willing to undergo the testing that is necessary, just like when you donate blood. You have certain tests that are run on your blood. These folks have blood tests done to look for viruses that are of concern. The product itself is tested for bacteria and fungi, and just like all other human tissue product, goes through a very rigorous schedule test that it has to pass. The donors also go through social screening. They are asked a lot of questions, just like you do when you give a unit of blood. You have to pass the social history and medical history to be a donor. It is a very hands-on kind of processing, so you have all this testing that has to occur. In the meantime, you’ve got the processing going on—because it takes a while to get all that medical and social history, the history of the birth, and all the blood testing that takes place at the same time that the product is being physically processed. The FDA mandates that with human tissues, each donor is one lot. The one placenta makes up only one lot. You can only process one lot at a time. It is all hand-processed, and tracked very carefully from the manufacturer all the way through to the patient, so that if any issue comes up, even after it’s been cleared for use, you know exactly who used what placenta where.
Next week, Part 2 of our Exclusive Interview with Dr. Janice Smiell.
Dr. Janice M. Smiell, M.D., Chief Medical Officer, brings more than 20 years of wound care, regenerative medicine, and clinical development experience to Alliqua BioMedical. She is the former VP of Medical Affairs at LifeCell Corporation, where she oversaw clinical development and product safety programs from 2007 to 2011. LifeCell develops and markets tissue repair products for use in reconstructive, urogynecologic and orthopedic surgical procedures. Prior to joining LifeCell, Dr. Smiell was the Executive Director of Global Clinical R&D at Celgene, where she led the clinical development of biomaterials and stem cells at the Company’s Cellular Therapeutics Division. From 1994 to 2003, Dr. Smiell was the Senior Director of Global Clinical R&D at Johnson and Johnson where she was awarded the prestigious Johnson Medal in recognition of her development work on Regranex, a growth factor for wound healing. Before joining Johnson and Johnson, Dr. Smiell served as the Medical Director of the Wound Care Center at Morristown Memorial Hospital. Dr. Smiell received her M.D. from the Medical College of Pennsylvania in Philadelphia (now Drexel University School of Medicine).