Section: CME Category: Surgery

Regenerative Medicine in the Foot and Ankle

Patrick Agnew, DPM

Patrick Agnew, DPM discusses the basics of regenerative medicine, the principles of optimization of healing, product material modifications that may impact efficacy, as well as discussing the basics of fetal derived products.

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Goals and Objectives
  1. Explain the basics of regenerative medicine
  2. List the principles of optimization of healing
  3. Describe product material characteristics modifications and their impact on efficacy
  4. Review fetal derived products
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  • CPME (Credits: 0.75)

    PRESENT e-Learning Systems is approved by the Council on Podiatric Medical Education as a provider of continuing education in podiatric medicine. PRESENT e-Learning Systems has approved this activity for a maximum of 0.75 continuing education contact hours

    Release Date: 12/19/2018 Expiration Date: 12/31/2020

  • Author
  • Patrick Agnew, DPM

    Eastern Virginia Medical School
    Podiatry Education
    Virginia Beach, VA

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    Patrick Agnew has disclosed that he is a speaker for Mimedx.

  • Lecture Transcript
  • TAPE STARTS – [00:00]

    Speaker: Our next speaker for this afternoon is Patrick Agnew. Dr. Agnew is a fellow of the American College of Foot and Ankle Surgeons. He is an associate professor and director of Eastern Virginia Medical Schools Podiatric Surgery Residency Program. And this afternoon, he is going to talk about variable in regenerative medicine technologies.

    Patrick Agnew: Afternoon. [Indecipherable] [00:36] from Virginia. It was 80 degrees there today. I don’t know why. That was very unexpected. I am afraid this is going to leave you with more questions than answers, but I do want to raise those questions to help guide our future in employing some of these potentially viable methodologies. So I deliberately obscure the faces of the couple of these Navy SEAL special operators that are in my family, but that one is my son and he is not and my daughter painted her face just because they were at Busch Gardens. She isn't a SEAL. I bring greeting from Eastern Virginia Medical School, Children's Hospital of King's Daughters. This is Sentara Princess Anne Hospital, one of the six training sites of our residency program. So disclosures, previous research to me are the same thing. These, I don't have any financial connections with any of these companies except that they have funded research that I have been site principal investigator on. You will notice a broad variety of different companies and I think that should tell us something about my voracity. This is my youngest son, Mathew. He is a cadet at Virginia Military Institute.


    And this is my daughter again. Remember, she is married to SEAL sniper, so no matter how cute she is, just don't even think about it. My interest in all of this came out of my interest in connective tissue disorders in collagen. That predated my interest in wound care research. Actually, I didn't even go looking for wound care research. I am a surgeon. I have never really tried to be a wound care specialist, but hey, I make sounds and sometimes I have complicated wounds to deal with and particularly when dealing with people with connective tissue disorders, which I have been doing for a very long time about 30 years. So they do have some special problems and we will just touch on this real briefly. Some common problems may present with uncommon manifestations like the bunion. On that side, it doesn't look quite normal, does it? That's because it has become a pseudotumor sort of like a ganglionic cyst. Someone did a more traditional bunion operation, wound closure deep failed and joint fluid continued to leak and created this bizarre sort of phenomenon. I would just go through this part very fast, but there are a number of different connective tissue disorders. This is my oldest son who was on the US Surf Team and he is very flexible but doesn't have a connective tissue disorder that I know of unless you count his brain. Some special considerations you have to think about when you are dealing with people with connective tissue disorders are handling their soft tissue. It has been described for example classic type Ehlers-Danlos syndrome as sewing wet tissue paper together and I can tell you it's very much like that. Also, in vascular type of Ehlers-Danlos syndrome, also Marfan syndrome, vascular fragility can be not only annoying, but also life threatening. And bones are sometimes fragile not necessarily because of collagen disease, but may be because of disuse atrophy, osteopenia, although the classic type of connective tissue disorder is osteogenesis imperfecta affecting type 1 collagen, and therefore affecting bone also.


    Let me see if I can this thing to play. Can you double tap that, AV guy? Is there a way to double tap the top left? Don't worry about it. It's just a little video of somebody's finger dislocating in a really revolting way. This is what my son does for fun at his college, my youngest son. When we think about using advanced wound healing technologies, I think we have to think about a lot of things about wounds in general and I am also going to blow through this pretty fast because everybody here I am sure is very familiar with these concepts. But boiling them down to different material states is something I haven't seen done a lot and I think it's interesting. So we want the base of the wound, substrate of the wound to be of appropriate density as a solid or gel of some sort that's going to support healing almost like a Petri dishes that our previous speaker was talking about. You want to optimize any liquids that are present. Generally, we think that the moist wounds heal better than dry wounds and it's probably true, but how much liquid is enough and how much is too much. You want to optimize gases something really hasn't been talked about very much, but right there at that interface have any optimal mixture of gases in amounts is important. So in terms of optimizing the substrate, some types of advanced wound healing products might have inherent strength, which may be desirable with certain wounds. Thickness is often talked about and sometimes I think of it is maybe a good thing because you might have a wound that has some depth to it or wound that might be vulnerable to traumas as you are trying to get it to heal and so a thicker material may be more desirable, but also I wonder about its ability to deliver its healing properties if it's too thick. And no more than once I have gone back after using a thicker type of graft and remove my dressing and there is basically a dead body there both the way it looks and smells and my whole office smells like that and it's not good.


    Solubility may be a desirable thing, but maybe not too fast or too much. So all these are variables that we ought to consider. And Matthew in class again out in a nature walk with telephone pulse. Optimizing the milieu is desirable in terms of having the right growth factors present. It's nice to have a material that's not going to necessarily regenerate too much inflammation, although a little inflammation may be desirable. Sterility, I think, is important. It's not always -- some of the advanced wound products are certainly not sterile that may or may not be clinically relevant though. Optimization of perfusion, getting enough oxygen, for example, to the wound but not too much oxygen because oxygen is an oxidizer and you can overshoot in that direction too. So an appropriate gas mixture is desirable and the amount of time that those gases are present. All cells go through respiratory cycle, right? Sometimes it might want some carbon dioxide, sometimes it might want some oxygen. They are not going to want some turnover in those gases and the exchange rate is part of that formula that hasn't been elucidated to my knowledge. So historically, we know wounds need to be debrided and probably want them clean at least if not sterilized. Substrate modifiers, we talked about, milieu modifiers and perfusion modifiers, we will talk about in a little bit more detail now. That's a surfing trophy by the way in my backward, Michael is very happy about. So why we do we debride? Of course because chronic doesn't tend to heal, so we want to create a fresh wound.


    We might want to remove some things that can build up there, scar, bioburden, metalloproteinase, other substances that will get there and interfere with healing. Debridement of an open wound, you might use a blade, scalpel. You might use other things listed there. Deeper tissues that are closed in, you don’t' necessarily have to open to debride but you might still want to debride. So, for example, things like dry needling. Sometimes we inadvertently make a fresh wound by doing something simple as injecting. You know when fluid comes out of the tip of the hypodermic needle, it comes out fast and hard and appropriate size of the needle, the pressure that's supplied, the size of the syringe behind it can all influence how fast that stuff comes out and how hard it hits the tissue that you are trying to deposit or certain substance in and you can do harm with that. You can also maybe do some good by again creating that fresh wound. Electromagnetic RF, we use Topaz for example in some our sports medicine type applications of advanced products. Cautery, similarly you might want to limit bleeding and certain more bloody substances as you are debriding. Shockwave therapy probably creates a certain amount of that fresh wound environment to simulate healing and of course chemical and enzymatic debrider can sometimes very precisely target a particular substance. So some enzymes, their use commonly in wound care, I call it like my Green Beret, different special forces. If you want like one guy killed, you send in a Delta guy. If you want a village built and teach the locals how to fight, you bring Green Beret. If you want to basically kill all the people in the village, you send SEALs.


    So Green Beret are enzymes, they go in there and maybe just kill the bad stuff and leave the good stuff behind. Sterility is really a spectrum. To absolutely get rid of every single microorganism is very, very difficult and rarely done even on our surgical instruments or at least components of them. You might still have pro-ons [phonetic] if you are using neurologic instruments, YK or Yakov Smirnoff or whatever that disease, it's bad and can survive on surgical instruments after neurosurgery. So when you have an open wound and there has been tissue injury, you are going to have to address any necrotic tissue and contaminated tissue, you're going to have to debride. Super infection is certainly something not desirable. If you keep using certain types of antimicrobials, for example, you might favor the overgrowth of other microorganisms that are equally harmful. A sterile site, for example, Achilles tendon, plantar fascia, something you might be injecting advanced product into is a situation where you want the material you are injecting there probably to be as close to sterile as possible. And you worry about things that maybe we have not tested for before or maybe we don't know exactly how you use it as to kill or not kill like Zika. So you might think about where is a particular advanced product manufactured? Where are they acquiring the material? Is it a Zika infested area? So material characteristics, the actual physics of it. If you take a material -- this by the way is Wave Warriors Surf Project. We have people that have been injured in military and we bring them down to Virginia Beach every summer and get them up surf boards. So best day of the year.


    So does meshing kill living cells? Probably, a certain number. It certainly got a long history and split-thickness and partial-thickness grafting, but you know you're certainly going to kill something by crushing it. When you fenestrate, you are getting the holes in the right distribution to get the right fluid turnover and gas exchange as we have talked about a little bit earlier? Those negative pressures maybe take away something from the wound but then give you the positive wound contact. These are all variables that research is really very lacking in but there are questions that I want you to ask yourself as you are looking at these new wound healing products and decide what might be best in a particular case you are dealing with. I don't think it's an easy black and white, I am going to use this on every wound decision. When we modify the milieu, we may want to acquire optimal pH. Certainly an infected wound is going to have in most cases a lower pH. Cleansing agents and things sometimes can have very low or very high pH, which may be counterproductive to tissue healing or they may just get it right where you want it. They may buffer it to that neutral zone that's desirable. Surfactants to remove bioburdens are often desirable but may take away more than you want. That glicocalix, that's on certain organism you want to probably find a way to get rid of, but you don't want to take away living cells along with it. So like I said, lot more questions than answers in this talk. Just want to stimulate thought. So optimizing perfusion of gases, hyperbaric medicine may be a way to do that. Certainly, systemic hyperbaric medicine is, I think, shown to be superior to topical but that having been said, I don't think again there has been enough research.


    So physical modalities might impart oxygen at a desirable concentration to wound are being investigated and will probably be more available on the market very soon. The size of a dressing matters a bit and maybe the shape also because people are paying attention on how much you throw away. Why? Well, if they can find a way to show that you are being wasteful or that they can avoid having to pay for a full graft when you are losing part of the graft, they are going to do that. People are always collecting data, they are always going to use it to their own benefit and people who have most of the data are the people who also have the money. So you pay attention to how much material you are using. When you are thinking about using different products, you might want to use something that's appropriate to size if that's an option. Results, so Dr. Jacobs talks about the fact that just about all these advanced wound healing products have been tested on not really real world patients. Some of the patients in the studies that you will see published and the studies that I participated in are going to be sicker than others, but we see of course the sickest of the sick. When I am taking these cases in and I called the anesthesiologist and I said, “yes, so I got to amputate this toe, can I do it tonight?” He will say, “well, how is the patient?” I will say, “well, they are elderly, they are hypertensive, they have heart disease, diabetes poorly controlled and they aren't very bright, but other than that, they are fine.” Anesthesiologist will say, “we are operating on the sickest people in the hospital.” Good news is that you don’t always have to use any kind of general anesthetic because often the foot is so numb. So the physical and emotional stability of the patient has a lot to do with how things turn out.


    We have published not long ago a study looking at angiogenesis particular wound healing product using fluorescence angiography. This is maybe already passe, it showed up, we used it a little bit, we published some data and now we can cosmic radiation to take pictures of perfusion. So just talk to David Armstrong. He will tell you whatever is noticed. He is the Elon Musk of Podiatry. So what's out there, what's our future, what are we looking for? Well, maybe dressing to deliver oxygen. Super Band-Aid of sort, maybe a dressing that delivers growth factors, maybe a dressing that's anti-inflammatory, antimicrobial, the right size, the right shape, the right cost. That's kind of a goal. Any questions so far. Is it good to place to pause? So again, we are looking for that super Band-Aid for people like special operators in our general patients. The things that I would like to talk about and again potential conflicts I think of more as [indecipherable] [17:15] experiences. But I would like to talk a little about fetal derived products and again I don't know if that video will run but not important. Just my first and only grandchild who thinks the word butt is hilarious. And my daughter and we are getting her to laugh a lot. But certainly, we could talk at length about Xenografts, allografts whether cellular, acellular or otherwise. But I just want to talk for the moment about some fetal derived products, mostly because that's what I have had the most experience in the research. Oh it did play. Here we go. I don’t know if it has sound. So what do we think they can do.


    We think they can deliver growth factors, we think they can potentially attract or deliver stem cells in particular. We believe they are immunoprivileged. We know they are designed not to be rejected by the mother or the baby. We have found data suggesting that they are to certain degree anti-inflammatory. Certainly, there is clinical evidence that they can minimize scarring. They may be somewhat anti-microbial at very least by providing physical barrier but may be by other mechanisms that are not well understood yet. And they can, in many cases, provide a matrix or scaffold for healing. So pretty good. Lot of things we are looking for and a lot of history. It's far back as 1920s. Fetal membranes were used in ophthalmologic surgery for the repair of pterygiums for those same reasons, low inflammation, not a lot of scarring. Currently used in neurosurgery, frequently in spine surgery. In urology, if you have nerve sparing prostatectomy because you have prostate cancer, which is endemic to my part of the country, be incidence of things like impotence and incontinence can be decreased by about half. So that's pretty cool. We try to classify wounds. We will talk about diabetic foot ulcers, venous leg ulcers, pressure ulcers, but let's face it a lot of them have a lot of the similar characteristics and you could certainly call this a pressure ulcer but if it happens to be a diabetic, it's also interesting. It's not a typical venous leg ulcer but that there is venous congestion. You can see the changes on the leg. So, is this all three? And talking about diabetic foot ulcers, we want to provide a wound environment that is may be anti-microbial or at least a barrier to new bacteria getting in.


    We may want to deliver growth factors. We may want to attract or delivery stem cells to try and actually reconstruct the tissue or regenerate it as the topic of the discussion. We may want a matrix or scaffold for tissue to grow over. So I have highlighted this characteristics a little bit brighter for a diabetic foot ulcer. It's nice that they are immunoprivileged, although a lot of our diabetic patients don't have a whole lot of immune system going on already. It's nice that they are anti-inflammatory, although the same patients are probably not going to be complaining much pain or inflammation. And as far as scarring, in my experience, most of our diabetic foot ulcer patients that's not high on their agenda of concerns. They just want to keep their leg. Venous leg ulcers, we might want to lead more towards the anti-inflammatory characteristics of a product that we were applying. Anti-microbial, certainly, these things can very easily become infected. We may again want to provide a matrix for tissue healing. Whether or not stem cells are going to accelerate or optimize that healing, I have always thought of this as more of a mechanical hydrostatic pressure problem really than a lack of desire to heal. These things are very inflamed. There are lots of ingrowth of vegetative angiogenesis, so I am not sure that we need a whole lot of stimulation in healing, which is I want to protect it from making it worse. Again, immunoprivileged, I probably should have highlighted here because if something is inflammatory and creates a host response, it might create more pain and certainly these things cannot be very painful. Scarring, again probably not the highest priority to the patient with the lesion like this. And growth factors, again I think if you get the environment right, these wound really want to heal, but it's more of a mechanical problem than a problem of inadequate growth factors.


    Pressure wounds and also happen to be a diabetic in this case and also has some lymphangitis. So again, these wounds overlap quite a lot, but matrix might be particularly desirable on a wound on weightbearing surface. Minimizing scarring may be desirable for functional reasons, not so much for cosmetic but a thick ropey scar in the sole of the foot can interfere with function. You probably don’t want to get infected although these things may be a little bit less prone to infection once you get them off weighted and cleaned up. You may want to track or deliver some stem cells, but again, I think they want to heal. They are being kept from healing because of primarily physical problems. Inflammation, most people might develop a pressure sore like this one are often insensate or may be just not able to tell us how it feels but again not the highest priority. And again growth factors may be not that critical of a thing to deliver to a wound like this because once you get it off weighted, once you get it cleaned up, it really does want to heal. So putting these different characteristics into some boxes and seeing where they might overlap, thick or thin can be desirable or undesirable depending on what kind of wound you are talking about and what you want out of the thing you are putting on it. Whether they are life stem cells or stem cells from the host is certainly a place for investigations necessary and not yet to my satisfaction answered. And most of these things will provide a certain number of growth factors, some more than others, but these are the characteristics that you can look at in deciding what sort of product might be appropriate for your particular patient.


    The re-application of different advanced wound healing products is maybe good, maybe bad. You know, certainly, it's nice if you had something that was magical and powerful enough to give it one-and-done sort of healing. I have not seen that yet, although some products are sold in exactly that manner. And in fact a global period may ensue after application of certain events of wound healing products and then you really can't get paid to do anything for a period of time. In other cases, repeated applications are recommended, which may add to cost quite a bit but also gives you opportunity to see the patient repeatedly. So probably somewhere in between there is desirable not because of income but because of monitoring, you want to see the patient. The availability of a product can affect your decision making or may enter into it. Something might have to be shipped to you, you might have to plan in advance to use something that you might prefer to use immediately. So whether something is refrigerated or frozen could be a good thing in terms of preserving live cells or preserving the integrity of the matrix of the material, but also can be a delaying thing that might interfere with you putting it on when you actually want to put it on. Shelf life is probably of greater interest to your materials manager at your institution than it might be to you but something that last a few weeks might be considered inferior to something that might last a few years or five years. And on one product, they put a backpacks and I'd to cross Afghanistan and got up to about 140 degrees inside of the backpacks and would still had all of its original characteristics when it was retested.


    This is one of the Navy SEAL who died in helicopter, which was shot down in Afghanistan in an incident known as Extortion 17. Again sterility, we talked about earlier whether or not that's essential or necessary but also what kind of organisms are we testing for. Are we eliminating everything that might concern you? When we talk about sports injuries, which we are doing a lot of researching right now, slight different characteristics might be desirable, so we may want more matrix, for example. We might want the stem cells to get in to tissue that they don’t have a lot of living tissue in them like ligaments and tendons. These things are mostly matrix. Plantar fascia ligaments, tendons don't have a whole lot of living cells there, so bringing living cells to them by one method or another might be desirable. Cartilage is also good example of that. In the sophistication of the tissue that you are working with, this is nerve-sparing surgery with prostate resection and of course nerve and muscle are more sophisticated materials. So you want to maybe try to regenerate more of the original tissues as opposed to just generating the quick scar and getting something to heal fast. Maybe a place where stem cells are desirable. So this is actually a long video. It was end of the day but you can pause that one. Thank you. So what are we desiring? Do we want to get -- do we went to put something on the wound that's going to take like a patient's own tissue and directly repair tissues? Sometimes yes.


    Do we want characteristics of something we put on a wound that's going to encourage healing? Pretty much always yes. But sometimes the emphasis on one of those two factors is going to vary depending on the type of wound we are talking about, location, type of tissues. So all these characteristics like antimicrobial capabilities, attracting or delivering stem cells, being immunoprivileged, being anti-inflammatory, delivering growth factors, minimizing scar, providing matrix for tissue healing like we talked about very early in the talk are all probably desirable characteristics and indifferent of quantities depending on which wound we are talking about. And that's the end of my talk. Thank you all very much for your attention.

    TAPE ENDS - [28:52]