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Speaker: We are going to start this afternoon by inviting up Dr. Michael Troiano. Dr. Troiano is an adjunct clinical professor at the University of Pennsylvania at the Penn Wound Care Center. He is a nationally and internationally recognized lecturer. He has spoken at this meeting and other present meeting several times. He has also authored several journals, articles and book chapters published in various peer reviewed journals and books. And this afternoon Dr. Troiano is going to be discussing eliminating the biofilm structure and upgrade to the standard of care and he will be coming up now. So please welcome Dr. Troiano.
Dr. Michael Troiano: Alright, good afternoon. With that said, this is an industry-sponsored lecture. So anything that I say are my own thoughts and ideas and not necessarily reflective of the company, but we will stick to the slide deck largely. So biofilm, we hear a lot about biofilm as a new concerning wound care. Some people say it doesn't exist, some people say it does exist, but I can tell you that there is an electron microscopy identifying biofilm and it's border and bacteria housing, which we are going to discuss and we are going to discuss why this is important in wound care. This is obviously wound care conference. So we are not going to go through the facts and figures of infections other than to note that there was approximately two million hospitals acquired infections with an annual cost of 30.5 billion dollars in 2014. That continues to rise.
Annual cost of Medicare readmission is 26 billion dollars. So these -- you know initially when I looked at this PowerPoint, I said what am I trying to say here. In other words, we are talking how is this wound care product going to stop readmission and stop infections and the answer is it's two-fold. There is two wound care products developed into one and one is post-surgical wound care product that we are going to discuss as well. So the idea is you suture the patient up, you put this on wound and then it mitigates the chance of infection developing. The other is the wounds developed and recalcitrant to healing and instead we are going to put this product on and get the wound to advance. There are greater than 6.5 million people suffering from chronic wounds and it will cost 25 billion. So these are bullet points for this afternoon. The barriers to wound healing, identifying what the biofilm actually is, strength is in structure of the biofilm and how it needs to be degraded, goal of a comprehensive approach, current trends in biofilm treatment and then a science-driven treatment. So beginning with barriers to wound healing. We learned day one of wound care, the phases of healing and the time of healing. So hemostasis is seconds to hours, inflammation is hours to days, proliferation -- this is the surgeon showing the fibroblast. The important guy is there and then finally remodeling, which is our end point and our goal. What we find is hemostasis happens just about regularly in everybody provided they have platelets of some sort. But where wound really can get into some trouble is in the inflammation stage. This inflammation stage ideally takes hours to days but in a chronic wound, inflammation is stalled and self-perpetuating. Many of the wound care products that we have on the market, amniotic grafts, small intestinal submucosa, they all target a defunct either scaffold or bacterial bioburden or what have you.
So we are finding that more and more wounds get stuck in this inflammation phase and this is a phase that we need to seriously look at. In the inflammation phase, ideally there is bacterial clearance, right? So there is phagocytosis that occurs that eat the bacteria away and then release cytokines and growth factors to get to that entrance of the fibroblast cell. They need to be modulated into the wound bed at that point and cannot obviously if the bacteria are eating them as they enter. So there are four pillars to chronic wounds. Number one is hypoxia, number two ischemia, number three the intrinsic host factors and number four is biofilm. There is no excuse for good wound care. Everyone needs good wound care. Hypoxia obviously with the -- you want to get with your vascular surgeon, your interventional radiologist or cardiologist, consider your hyperbaric oxygen with your nitric oxide and oxygen concentration. Same for ischemia as well. Remember ABI, PVRs are essential but kind of an archaic test. You definitely want to look at your TCOM and see what the skin is doing at the wound bed. And then you are looking at the host factors. What's nutrition? You know what's their albumin and prealbumin. Are they taking the food and converting it into albumin from prealbumin? Hemoglobin A1c above 7 of the red blood cells begin to kind of crash into the walls of the vessels instead of march along the line that they are designed to. So make sure their hemoglobin A1c is adequate. And then after that, then we need to consider the biofilm and not just the bacterial colonization or contamination of wound but the actual biofilm. So this is Chris Attinger, his opinion on biofilm defense. This is couple-page paper but the pertinent parts are biofilm becomes resistance to therapeutic maneuvers at 48 hours to 96 hours after formation. By repeatedly attacking it on a regular schedule, one forces biofilm to reattach and reform.
Biofilm perpetuates the inflammatory phase of wound healing. Biofilm is present only 6% of acute wound but over 90% of chronic wounds. So biofilm is a self-serving prophecy and that it's kind of a nice design. 90% of bacteria exists in biofilm. So they are basically existing, housed on the wound bed and living with the protective cover over them, 90%. The 10% that are not are free floating or planktonic and actually dispersing throughout the wound site actually planting and recolonizing and recreating more bacteria. So it's akin to a dandelion. You take the dandelion, you blow on the seeds and the seeds fly everywhere and they land. Once they land, they sprout new dandelions and the dandelions then evolve and hatch and fly again. And that's basically what biofilms do. So we need a product that's actually going to target the biofilm as it's living in vivo and then of course we need to target those that are free floating to get rid of them. If we are to look at the pathogenesis of the biofilm and where the bacteria enters, first we see colonization by free floating planktonic pathogen in stage 1 here. The pathogens begin to attach irreversibly to the wound bed. Then here comes the biofilm growth in division to actually secure them into place and create a nice stable house. Micro colonies mature and then you develop three dimensional protective layer, here becomes the biofilm with single molecules and then you see chemoattraction into multi species, dispersion and cascade just repeat itself.
So this is where biofilms need to be eliminated so that by eliminating the biofilm, the bacteria that are housed in is also eliminated. Biofilm begins to arrest the inflammatory processes. Dr. Attinger said there is a reason why that occurs. Inflammation becomes ineffective for the host. There develops a reactive oxygen species and proteus off-target effects. The biofilm formation releases small molecules, which trigger more inflammation and then this is a key one that is important. The increased exudate from inflammation incorporates into the biofilm and provides nutrition for the biofilm. So it actually not only hijacks inflammatory responses but then it uses that inflammatory response to get even stronger. So the exudate is key to controlling as well. Ultimately, the ineffective inflammatory response prevents wound healing and makes the body susceptible to other infection. So biofilm provides protection for the bacteria and for itself. Nutrition for the bacteria and for itself, water, so it stays alive and then a place for the pathogens to flourish as well as resist host immune responses. What that basically means is big polymers that need to get through the antibiotics are protected by the biofilm so well that they can't disperse through the biofilm and into the microbes. Biofilm has been described for quite some time. What is biofilm? It has been described as a sticky layer protective, infection, extracellular polymeric substance. Biofilm driven in soluble film, slime, all of these have been used in literature describe what a biofilm is. But in actuality, the best definition that we can come up with is biofilm is a community of pathogens enveloped within a complex structure of entangled polymers strengthened with metallic bonds.
So pictures worth a thousand words. This is an actual biofilm. What you are seeing is you are seeing these long chain polymers, which look like steel rods here and they are connected by the metal, metallic bonds, binding the two together and the metallic bonds literally glues these polymers together and now you have structure and on top of that inside the structure are these little green guys here, which are the bacteria. So you can see the bacteria nestled in that structure and living very comfortably and protected. Strength is in the structure. Robust bacteria inside this protected power house use the extra polymeric substance or biofilm AKA biofilm to protect them. So the extracellular polymeric substance is defined because of each integral words and its part. Extracellular meaning non-cellular sticky gel, so when people describes sticky gel and gel, they are not wrong. It's secreted by the bacteria to provide a physical barrier of protection while encased within the gel. Polymeric meaning the scaffolding structure, the steel rod structure of long chain polysaccharides beginning in simple organic molecules, polymers in the gel become linked with metallic bonds giving height and strength to the structure and then substance obviously is once metallic bonds become established, the substance converts to an insoluble capsular environment interacting with a host for bacterial growth, mutation and proliferation. So once the biofilm is formed, then the substance begins to evolve and repeat itself at another location. Mature biofilm forms in 24 to 48 hours. So 90% of bacteria in an infected wound or in a wound are enveloped within the structure.
Free floating bacteria only 10% of the wound. Moreover, for antibiotics to work period of bacteria needs to be active. It cannot be laying dormant. So there is bacteria laying in the biofilm dormant as well that cannot be attacked by traditional antibiotic therapy. The structure is designed by nature to be mechanically resistant. These are very much self-sustained and self-living because of these metallically bonded polymers. This metallically bonded polymer anchors the structures and gives it strength, prevents it from being washed off or eradicated by treatment protocols. Forget about it if you have hardware. It's very, very difficult to penetrate the biofilm of exposed hardware but wounds in compromised host, I mean people who develop wounds, long-term wounds, chronic wounds are not usually in the best of health in first place. So you can imagine how this biofilm just takes over and begins to control the wound environment. Pathogens are structurally protected by the EPS. They block large molecules such that the large molecule anti-microbial, antibodies, inflammatory cells. There is mutual protection in that the biofilms protects itself. The wound protects the biofilm and the bacteria and then quiescent bacteria develop and hide in the biofilm. So even if you can't find an antibiotic to penetrate the biofilm and kill the microbes that are living there, unfortunately those are the dormant are still alive and those bacteria are going to redevelop or recreate a biofilm and go forward. The goal of the comprehensive biofilm treatment approach is to target the structure. First, the structure needs to be dismantled. You need to blow away those long chain and the ties that bind them. After you do that, then you need to go after the bacteria itself. So there are some ways to target the structure that are mechanical and first is local debridement.
The problem with local debridement is when you locally debride, you don't know exactly what you are removing. So you are removing some biofilm, you are removing some slough, you are removing fibroblast as well. You are removing normal rim of subcutaneous tissue and when we debride all of our dictations have to say for Medicare to pay for the debridement. The wound was debrided down to normal healthy rim of subcutaneous tissue. However, in that subcutaneous tissue, you are also taking out some of the good stuff and actually setting the wound back before you advance it forward. So we need something that's really going to target the pathogens and kill newly exposed pathogens protected within the EPS or biofilm without cytotoxicity. We can't put products on the wound that's going to destroy the wound and the fibroblast and the bacteria at the same time because that's just biting you nose despite your face as they say. So prevent reformation without damaging new tissue is important. You have to create a physical environment that binds detachment of planktonic organisms, biofilm formation is supporting pro-healing processes. So current trends in biofilm treatment. Number one I alluded to is debridement. Debridement has some pitfalls in addition to not knowing what's good and what's bad no matter how good you are at debridement or what tool you are using whether it's scalpel or ring curette or Misonix or reversal jet or what have you. None of these can really tell so, so well what's good and what's bad. And more over the debridement breaks the biofilm into smaller colonies and those colonies can spread to other areas of the wound and other areas of body and then restart the cascade there. So it can actually amplify the biofilm making spreading more aggressive and reformation faster. So I am not saying for a second that debridement should not be performed and should be performed on a weekly basis but it's not the end all and be all to cleaning up this wound.
And we look at traditional antimicrobial and anti-septic therapy. So we are talking about our Polymyxin B powders, our triple antibiotics or silver things, they are non-selective. They can impact all wounds, not just pathogens. They are not designed for use in all phases of wound healing and they are unable to penetrate the EPS or the biofilm layer matrix. Why? Because as I alluded to before, they are big compounds that oftentimes have difficulty entering through the biofilm and at their effective strengths, they are oftentimes cytotoxic. And of course, more antibiotics you use, more resistance you create and you get into trouble there. So there is some pitfalls with debridement and topical antimicrobial therapies. So what we need to do, it sounds like to create a wound care product that will have a broad antimicrobial spectrum. Biofilm is oftentimes polymicrobial. We need something with no antibiotic resistance. High tissue compatibility, so we don't destroy the good stuff as we are getting rid of the bad stuff and sustained barrier effect, meaning that once we have killed all of this, it doesn't allow it to reperpetuate. And that's what we are here to talk about today is this product blastics that targets that biofilm structure. If you look the new technologies what we're referring to is this blastics. It dissolves the biofilm structure, has a broad antimicrobial spectrum, high tissue compatibility, no microbial resistance and then sustained biofilm reformation barrier effects. Each of the others that we referenced here today have some pitfalls. Some of them have check marks, some do not, but this product blastics, the new technology that we are referring of right now is one that satisfies all of our algorithm. So science-driven treatment, simultaneous actions are the target to structure the pathogens and control the environment.
So what is in blastics? Blastics is made of four principal ingredients. The first is citric acid. What citric acid does is it chelates those metal ions. So it binds to the metal. It separates that metal, attaches to it, sacrifices it as a molecule and then allow a long chain sugars of polysaccharides to divide. Once they divide, the structure is well on its way to falling. The tie that binds these structures is eliminated and everything falls like a house of cards but that's just a citric acid. Sodium citrate acts as a buffer agent and actually will go after those long chain polysaccharides and then benzalkonium chloride comes in and attacks the actual microbe. The actual bacteria becomes surfactant and antimicrobial within the gel. Finally, you have PEG, which is polyethylene glycol and that gel is superhydrophilic. And what that allows is that that allows a diffusion gradient for the wound such that you take a wound that's macerated and this will kind of dry it up a little bit. If it's a little dry, it will put into a stage where it's moist enough as we all know wounds heal best in the moist environment but too moist you are going to start to see maceration and what the PEG gel does is it keeps a nice environment for the wound from a hydration standpoint. So step by step, citric acid is going to bind to the metallic bonds and what you see here is the orange is the citric acid, the first ingredient of blastics and it's binding to the metallic bond here the blue. Now, once it binds to the metallic bond, you are going to start to see separation of these long chains. The polymers are released from one another. But what's to stop another metallic ion to go in and reattach them? Enter the sodium citrate. What the sodium citrate does, it buffers these metallic ions from reattaching onto the long chain polysaccharides by capping them off.
So no more of the metallic ions get stick back together and reform the biofilm. Next, after that enters the benzalkonium chloride. What this does is it begins to change the osmotic pressure of the bacteria cell wall, distends it, makes it wet, makes it friable and then attaches to the protein in the cell wall and removes it causing apoptosis lysis or what have you program cell death. So now you are killing the actual structure and then the bacteria. Final thing, it does is it defends from recolonization by creating a physical environment that prevents the attachment of planktonic organism or the biofilm regrowth and supports the prohealing process by reducing the rate of bacterial and biofilm regrowth 100 times, 100 folds. If one compares blastic -- in all fairness, these are in vitro studies not in vivo studies but if one compares blastics with particular pseudomonas aeruginosa and staphylococcus aureus to some of the other products on the market, we see the killing power of blastics of pseudomonas in the blue and staphylococcus aureus in the orange is much higher log reduction from the control in each of wound care products compared to. So some of these we probably use them on everyday basis. Mepilex silver, SilvaSorb, Microcyn compared to blastics and you can see that they don't even touch the product in vitro. Texas Tech in vivo murine model or mouse model, again use pseudomonas and staphylococcus aureus and in the control, you begin to see full-thickness ulceration down the subcutaneous tissue is initiated and inoculated with pseudomonas on the top and staphylococcus aureus on the bottom and same is done in the experimental mouse and then the blastic is applied.
And by 24 hours after the first blastic treatment, one sees full removal of the pseudomonas aeruginosa and staphylococcus aureus from the wound and by 48 hours that murine model is totally finished with any bacterial, which was cultured out pseudomonas or staphylococcus. So what this basically means is again sprout back to wound healing 24 to 48 hours is when the inflammatory phase happens, you know that this blastic is acting in that inflammatory phase to allow the fibroblastic phase to take over and move forward. There have been two randomized control trials on biofilm that published key wound healing parameters. Yesterday, if you were here, you heard Dr. Lavery say that he was not a fan of this first study. First study is done by Kim and it assesses the biofilm destructing agent for the management of chronic wounds compared to standard wound care and then Walcott is the second one and that's an interesting story. So to go through each, the first one Kim study is done at the mayo clinic and the objective was to study the use of biofilm destructing wound get blastics to determine if disrupting chronic wound film would be therapeutically efficacious. So what they did was it was a 12-week perspective study. The wound ages ranged from four weeks to more than 20 years in duration and two categories were made. The first category had the wound applied triple antibiotic, literally Neosporin, the second with the blastics and the triple antibiotic was considered the controller of the standard of care group. What this showed was at about week four, you see the blastics wining here. But by week 12, the blastics continues to rise and really outdo the triple antibiotic and in fact the triple antibiotic begins to take it downward curve at week 12.
At week four, those that were recalcitrant to healing in the controlled group were eligible to be switched to the blastics group. So some of the data is a little higher actually than what this shows. But as a clinician, this shows two things. Number one, it is not a product that you are going to put on your wound care center on Monday and see results on Tuesday. It takes a solid four weeks of this use before you really start to see it take off. The second thing is we need to consider that topical antibiotics that we use longer than about a month, especially Neosporin and things like that. Triple antibiotics, you know, the bacteria becomes resistant after a while, so you are actually have degraded pose in your long-term patients that are still using your Bactroban on or triple antibiotic or what have you. So what this identified was a relative wound closure, relative increase of 205% versus the control at week 12. The second study that we are going to get into is the Walcott study. Walcott study was done in Texas and basically for each patient with each wound, there were two controls. The standard of care in this study was DNA gel. I don't know if you have used these DNA gels but I certainly have in my practice. They made things vastly better in wound care. Basically, what you do is you swab the patient, you sent it to a lab. That lab takes the bacteria that's grown out, creates DNA gel for that particular bacterium. Sometimes at concentrated levels if the patient was taking orally or what have you would be detrimental to the kidneys, liver or what have you. And then you take DNA gel and you apply it to the wound on a daily basis. It takes a little while for the DNA gel to be made but when it comes back, it by and large works pretty well and I have had great success with my recalcitrant wounds. So it took this DNA gels in one category and it took second category with blastics and compared the two.
What was found is in the standard of care, the DNA gel alone 53% went on to subrogate healing and when I say that, study was only conducted for four weeks. So the end point was reduction in size of the wound not full healing if you look at this wound in all fairness. The blastics had an 80% effectiveness -- effective rate. And then when you combine the two, 93%. So you are looking at 13% higher by adding the blastics in the DNA gel. So you can kind of see where this is going to go in the future. Right now, we have the DNA gel that we know works. We have the blastics that we know works a little bit better and then we have the two combined, which seem to be additive. Clinical use of blastics, it's indications are vast. Every ulcer that we would see in our clinic; pressure ulcer, partial and full thickness wounds, diabetic foot and leg ulcers, postsurgical wounds, first-to-second-degree burns, not third degree burns, why? The only thing it's indicated for that is a Weck knife and grafted and donor sites. Blastics is available in quarter ounce tubes and one ounce tubes. The one ounce tube is what you can keep in your wound care center. The quarter ounce tube can be sent home with the patient to be used on every other day basis. We in our wound care center have used blastics underneath the Coban 2 or Profore wraps and I have left it in place for a week at a time and it's done its job very nicely. How do you use it? You apply a nickel thick layer, very similar to Santyl to the wound in the thickness of the wound and you spread it out. And then you have to cover it with an appropriate dressing and that's based on the amount of exudate that the wound has. So you want to use exudate absorbers for high exudate or petroleum based contact layers for low exudate. The only thing that you cannot put on with this are silver, why? Because it's going to bind to the silver ions and degrades the silver product.
And then you should not use any of the calcium alginate for the same reason. It will break down those long polysaccharides of that particular dressing. It can be used before applying negative pressure therapy and you change it every one to three days, which makes compliance for the patient pretty easy and home care application pretty easy for your nurse who, he or she, is going to this patient every other day. Blastic should not be used if there is a history of allergy to any of the ingredients. In all fairness, the one that I see people react to the most is benzalkonium. You should not use with other antimicrobial. It's not necessary but I think that there is going to be some research coming out soon, which we will show it in comparison with the DNA or I hope there is with the DNA gel additive and again don't use with alginates with blastics. So in closing wound healing is interrupted with biofilm causing prolonged inflammation and halts of the wound healing. Biofilm is a community of pathogens protected by the polymeric structure. Current trends in the treatment, identify combination of debridement, topical dressings and all of those are not fully effective. So consider this product as part of your armamentarium or bag of tricks, so to speak. And it is new science. It's elegant chemistry to dismantle the EPS of the biofilm, destroy pathogen and defend against reformation. Thank you very much for your time.
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