Interview with Dr. Gregory Schultz: Mānuka Honey Benefits in Wound Care
Dr. Gregory Schultz, PhD, is Professor of Obstetrics and Gynecology and Director of the Institute for Wound Research at the University of Florida. A major area of his research focuses on defining the role of bacterial biofilms in stimulating chronic inflammation, and proteases that impair healing in chronic wounds.
Dr. Schultz has co-authored over 400 scientific publications that have been cited over 26,000 times, has received $38 million in grant support as Principal Investigator or Co-investigator, is an inventor on 36 patents, was elected a Fellow of the National Academy of Inventors in 2021, and is a co-founder of two biotech companies in the areas of antimicrobial coatings and anti-scarring drugs. He served as President of the Wound Healing Society (1999-2001) and as a member of the National Pressure Ulcer Advisory Panel (2007-2010).
First Honey founder Sarah Scarlet speaks with Dr. Schultz about Mānuka honey benefits in wound care.
Sarah: Thanks so much for being here. We’re glad to have an opportunity to speak with you.
Dr. Schultz: Well, I'm glad to be here. I think this is an important educational effort for the wound healing community to really understand more about medical honey, what the data are, and how people can incorporate it into their wound care practice.
Sarah: Can you explain the process of wound healing and what is happening at each stage?
Dr. Schultz: In general, we think of wound healing and acute wounds as going through four distinct but somewhat overlapping phases.
1. The first is the hemostasis phase, which is when the clotting sequence initiates, fibrinogen is converted into fibrin molecules that spontaneously associate into a stable net (called the fibrin clot) that entraps red blood cells and restricts the blood flow to keep us from hemorrhaging. Another important process that occurs during the hemostasis phase is the platelets (a component of blood) aggregate (stick together) and release the contents of their granules (degranulate,) which contain multiple active cytokines and growth factors. Those key regulatory molecules released right at the site of the injury are really the first important step in helping to draw in the neutrophils and macrophages (our normal white blood cells) that come into the wound bed to start taking the wound into the next phase.
2. The second phase is the inflammatory phase. Neutrophils and macrophages start migrating into the wound bed within the first 24 to 48 hours, and they provide very critical activities. The first is they will engulf and kill contaminating bacteria and fungi by engulfing and internalizing the microbes into vesicles that contain unique enzymes in the membrane walls of the endocytic vesicles that generate and secrete reactive oxygen molecules into the vesicles. The neutrophiles and macrophages also synthesize and secrete proteases that help remove extracellular matrix proteins that were damaged by the injury. Once the neutrophils and macrophages have killed the contaminating microbes and the proteases have removed damaged matrix components, the wound moves out of the inflammatory phase into the third phase.
3. In the repair/proliferation phase, the fibroblasts (which support and connect other tissues or organs in the body) adjacent to the wound area, migrate into the initial provisional matrix of fibrin, they activate, and in response, produce locally-produced growth factors and cytokines, start synthesizing and secreting new collagen that converts the provisional fibrin matrix into the initial the scar matrix. If the wound bed is kept in a moist environment, which is something honey provides, epithelial cells at the edge of the wound will begin to proliferate and migrate over the initial scar matrix and eventually re-epithelialize the wound.
4. The wound then moves into the final fourth phase, which is the remodeling phase. This is when, over the next six months to a year, the initial irregular scar matrix that was generated as fast as the fibroblasts can make, begins to be slowly broken down by the highly regulated actions of proteases. The irregular scar matrix gets remodeled to be much more like the normal extracellular matrix in the dermis before it was injured. Now it's never perfect, it does not regenerate the original skin matrix - it repairs it, but usually the repaired scar matrix is close enough in structure and function to normal skin that the scar tissue doesn't seriously impair the functioning of the surrounding skin and the wound area.
Sarah: Can you talk to me about some of the factors that can impact wound healing?
Dr. Schultz: There are multiple factors that can influence wound healing. Probably the most significant are comorbidities, which happen when a patient has two or more medical conditions, like diabetes. This can lead to impaired vasculature and impaired immune function if they have underlying vascular diseases like arterial or venous insufficiency.
Age is also another major factor. As we age, many of our cells are not as metabolically able to proliferate and generate the repaired tissue. So, the overall rate of healing and the quality of healing is usually worse as we get older.
The final most common and most frankly serious effect is infection. Wounds are never sterile when they're initially made. Even in an operating room, you can't perfectly sterilize everything. So, there are almost always, especially outside of the operating room, high levels of bioburden bacteria and fungi that get deposited in the wound. Unless those contaminating and colonizing bacteria and fungi are removed and prevented from expanding into an infection, then the wound will never heal appropriately - and can lead to severe consequences; including, systemic sepsis and death if the infection is not controlled.
Sarah: We talked about the inflammatory phase, and we know that it's a necessary part of wound healing. So, when does this become a problem for wound resolution?
Dr. Schultz: The normal inflammatory phase starts within hours after an acute injury in skin and normally will extend to a maximum of about five and six days. Now, as we can talk a little bit later, when the bacterial bioburden in a wound—both planktonic and especially biofilm—increases to significant levels, then the stimulus to bring in more and more neutrophils and macrophages continues. And so, the wound gets stuck in this inflammatory phase. If the patient has a normal functioning immune system, most of these injuries will never lead to a bioburden problem and infection. But, if the patient's immune system is compromised or if there's a huge influx of contamination and the patient doesn't get good wound bed preparation, the bioburden will continue and cause chronic inflammation.
As we talked before, proteases and reactive oxygen species do very good things when they are in the right time, at the right place, and at the right amount. But when they are at hundreds of times the concentrations in the healing wound fluid (as found in most chronic wound fluids), those proteases begin to have off-target effects and destroy good growth factors, receptors, and extracellular matrix proteins. The destruction of these proteins that are essential for healing causes the wound to just stop. And that's what leads to a chronic wound that is out of balance in terms of the proteases, reactive oxygen and the proteins that are needed for healing.
Sarah: Can you explain how a burn wound differs from other wound types?
Dr. Schultz: A burn wound is a thermal injury whereas a ‘trauma’ in most cases results from a sharp type of implement injury. Now, not always. I mean, you can have blunt trauma that rips the tissue apart or will cause substantial injury to structures around the wound bed. But the biggest and most obvious difference between an incisional injury from trauma or surgery and a burn wound is the collateral thermal damage that occurs in the tissue that was exposed to the heat.
Sarah: And how do these wound types differ in healing?
Dr. Schultz: When it comes to a burn wound, the tissue adjacent to where a burn occurs is also frequently damaged. And because the vasculature (arrangement of blood vessels), is damaged much more effectively from a thermal injury than an incisional or sharp injury, the initial burn wound can progress into more severe stages. Over the next several days, the wound can become so deficient of blood supply that the wound increases in depth and severity compared to something like a sharp implement injury.
Sarah: Can you explain, in your opinion, what the role of medical grade Mānuka honey can play in the treatment of burn wounds?
Dr. Schultz: The Mānuka honey is a unique product because when it is applied to injuries like burn wounds or other types of incision or trauma, it can have multiple effects. The first is that it acts as an effective barrier that prevents bacteria from penetrating the wound bed. In addition to providing a physical bacterial barrier, the Mānuka honey also has antimicrobial activities due to the glucose oxidase enzyme that the bees add to the honey when they make it from plant nectar. The glucose oxidase enzyme converts glucose into hydrogen peroxide, which is a well-recognized antimicrobial chemical.
Many of the medical grade honeys also contain a molecule called methylglyoxal which is found in the nectar of some plants like tea tree flowers, and it is a very effective antimicrobial agent. The Mānuka honey benefits on a burn have at least three phases: it's a bacterial barrier, it's an antimicrobial effect, and it has an ability to maintain the right moisture balance within the wound. Because of Mānuka honey’s very high osmotic (solute) concentration, it can absorb a large amount of wound fluid caused by inflammation. Also, the low pH of Mānuka honey is the most effective for healing of wounds as well, for the activity of the neutrophils and macrophages as they generate their reactive oxygen molecules. So, there are many benefits of Mānuka honey to promote a better wound healing environment.
Sarah: What do you believe is the optimal wound healing environment?
Dr. Schultz: It is unquestioned in both animal studies as well as in controlled patient studies that wound healing occurs almost twice as fast when there is a proper moisture balance in the wound bed. Now, what does that really mean at a cell level? Well, once a burn wound or an incisional wound has formed, the initial provisional fibrin matrix slowly gets modified by addition of new collagen. If the wound bed is not kept moist as the tissue begins to repair, they will die from desiccation because new epithelial cells won’t have keratin at that point.
If this happens, then instead of rapidly moving across the surface of the wound bed when there's moisture, the epithelial cells must penetrate into the dermal layer and burrow under the surface of the wound bed where the moisture level is sufficient to prevent them from desiccating and dying. That's why moist healing is twice as fast as dry healing because the cells take much more time and energy and effort to move under the surface of the wound bed.
Sarah: So why do you think that there is still this misunderstanding about a dry wound? Where does it come from?
Dr. Schultz: Well, I think part of it is people don't understand how the new epithelial cells (or tissue that forms the covering on all internal and external surfaces of the body) proliferate and migrate and new epithelial cells are not resistant to desiccation. The other issue, I think, is that when we have an injury, say, for example, a partial thickness burn or a partial thickness traumatic injury we form a scab which is dried wound fluid and 50% plasma and dried desiccated dermis. Now, that scab is a bacterial barrier— it has almost no antimicrobial activity itself, but it helps to prevent bacteria from being able to rapidly penetrate into the deeper layers of the wound bed. So, in one sense, our evolution of forming a scab on a wound was an advantage before we had advanced wound care, because the scab basically provided a dry “skin bandage” that helped to prevent bacteria penetrating, colonizing, and infecting the wounds.
Sarah: There seems to be a huge gap in understanding and a lot of debate around the protocol for cleaning a wound. Can you speak to this?
Dr. Schultz: The concept that we need to cleanse the wound is correct. If we go back to this concept that when there is an acute wound, whether it's a burn wound or a trauma or especially if there's a chronic wound, then the bacteria will always be present and continually contaminate wounds. To prevent bacteria from finding an area to attach and grow and proliferate and cause an infection, we must create an optimal wound environment. Wound cleansing is an effective method to help remove necrotic tissue, help remove wound slough, which is similar to plasma - so that the bioburden in the wound is reduced and that new tissue can effectively interact with new wound cells.
Sarah: What’s the ideal cleansing protocol for minor wounds then?
Dr. Schultz: The cleansing needs to be able to help remove the necrotic tissue and bacteria but not be so cytotoxic that it will kill a significant amount of these very susceptible new wound cells. The pharmacology terminology is called the “therapeutic index” of a wound cleanser. Breaking this down, it means how low a concentration of the agent is required to effectively kill bacteria and how high a concentration of the agent can you use before it starts killing wound cells. That ratio is called the therapeutic index and honey has a very high therapeutic index - it's one of the unique advantages that medical honey has in treating a wide range of wounds.
Sarah: Can you talk a little bit about why wounds are slow to heal for people who are elderly, or those with immunocompromised conditions, like diabetes?
Dr. Schultz: Typical type two diabetic patients have systemic impairment of many critical systems. When glucose molecules interact, especially with protein or DNA, they can make a chemical bond, a covalent bond to the amino acid or nucleotide side groups. When you add glucose covalently onto these molecules, it usually inactivates them. That's why when the patient's A1C levels get very high the red blood cells don't work well. Age also impairs the function of those critical biological systems symptoms. So, if they do get an injury, then their immune systems don't work well. Their vascular supply is impaired due to the impairment of the vessel dilation. Their tissue elasticity becomes reduced because the collagen and elastin molecules' biological functions are impaired. It's just a whole combination of effects from chronically elevated levels of glucose.
Sarah: Could you address the issue of topical antimicrobial use and the idea that wounds should not be treated with these agents unless they are clinically infected?
Dr. Schultz: This goes back to a constant ongoing discussion about whether a wound is able to heal without any additional antimicrobial interventions. Now we're going to assume that the wound is kept moist, but in many patients, as we just talked about, in terms of the type two diabetics or in patients that have other impaired immune function, their immune system frequently gets overwhelmed. And that puts them at a huge risk for developing acute infections, or systemic infections that can lead to bacterial biofilms that our immune systems and our antibiotics are not effective at clearing.
Should acute wounds always have a treatment with an antimicrobial wound dressing? Not necessarily, but it depends upon the conditions of the patient and the wound. If the patient has significant comorbidities, that increases the risk of their acute wound becoming infected with these terrible consequences, including death - then yes, those patients do need the standard of antimicrobials to prevent this severe progression of the bioburden.
Now in Europe, the trend is to try to minimize use of systemic or topical antibiotics because of the risk of developing antibiotic resistance. One of the advantages of medical honey is that it has multiple activities that impair bacteria from advancing into infections. What that means is it's very, very difficult for a bacterium to develop genetic resistance against the multiple factors and actions of honey compared to using a single antibiotic that affects one essential protein activity within a bacteria. So, it's very unlikely that a wound contaminated with typical commensal bacteria that's treated with honey will suddenly develop and evolve out a honey resistant bacteria.
Sarah: So, what role do you think medical grade Mānuka honey can play in terms of this overall area of antibiotic-resistant bacteria?
Dr. Schultz: Well, to say it just slightly differently, if you have a methicillin-resistant Staph aureus (MRSA) and in the lab or in patients you apply adequate amounts of medical grade honey, it doesn't matter if the bacteria has developed a genetic resistance to ampicillin or to vancomycin because honey doesn't act the same way. It uses an entirely different mechanism of action to work. So, a medical honey used appropriately can prevent infections from antibiotic-sensitive as well as antibiotic-resistant bacteria.
Sarah: Can you explain a little bit more about why the pH is important to wound healing and a little more about why, in your opinion, medical grade honey can play a role in maintaining an ideal pH within a wound bed?
Dr. Schultz: That's an important point, because normally we think of the skin in the dermis at an uninjured area of being 7.2 pH or something like that when there's an acute injury and the neutrophils and macrophages begin to come into the wound bed. One of the things that happens is the neutrophils and macrophages begin to generate these reactive oxygen molecules inside their endocytic vessels, and they also secrete reactive oxygen molecules into the surrounding tissue.
The hydrochloric acid and hydrogen peroxide are two major reactive oxygen species that our immune cells make. They are much more effective at a pH of about 5 than at a pH of 7 or 10. The reason is that the hydrochloric acid has a much higher oxidation reduction potential at pH 5 than 7, where half of the protons are already gone at pH 7.
Many pathogenic bacteria tend to not grow well at acidic pH. So, when you measure the pH in an acute healing wound, it's usually about 5 during the early inflammatory phase and will slowly migrate up to about 7 in the final stages of repair. If you measure the pH in a chronic wound, it is usually 9, 10 or 11, because the bacteria have been able to attach and proliferate for biofilms, and they tend to secrete molecules that raise the pH because it impairs the function of the neutrophils and macrophages that need low pH to effectively kill them.
Sarah: Could you explain what biofilm is in simple terms?
Dr. Schultz: To form a biofilm, single planktonic bacteria adhere to a surface and then generate a polysaccharide matrix that also sequesters different minerals that are available. Within a biofilm, one or more types of bacteria and/or fungi share nutrients and DNA and undergo changes to evade the immune system. Extracellular bacterial DNA can attach very tightly to a surrounding environment, whether it's the enamel of your tooth, (because the plaque on your tooth is a bacterial biofilm), or whether it's on an orthopedic implant on that titanium surface or on your bone periosteum, or in the soft tissue of a skin wound. Those biofilm communities then are encased in this dense protective matrix that tightly attaches them to the surrounding structures. Most importantly, from our perspective, it provides incredible tolerance against our normal immune cells, our antibodies, and unfortunately against most of our antiseptics and antibiotics.
Sarah: And what’s the history of why bacteria developed this biofilm?
Dr. Schultz: About 1.2 billion years ago in the evolution of bacteria, the bacteria came under threat from their natural predators that were also evolving—those are the big amoebas, those big single cell organisms that eat bacteria. So, what did the bacteria do? They evolved the ability to protect themselves against being eaten by the amoebas or infected and killed through proliferation of the viruses that infect bacterial cells that are called bacteriophages. Now, unfortunately, the evolutionary defense that bacteria generated a billion years ago to protect them against their natural predators also protects them against our neutrophils, macrophages, and our antibodies.
Sarah: Fascinating. So how do we fight that?
Dr. Schultz: In biofilm wound care, we don't kill biofilm-based bacteria effectively with our normal immune system. Also, the antibiotics that we typically would give for an acute planktonic infection don't work effectively against mature biofilm bacteria because the matrix can substantially reduce the penetration of the antibiotic molecules into the middle of the biofilm.
The most important point is that a huge percentage of the biofilm bacteria that form these big, mature, massive biofilm structures are not metabolically active. The oxygen can’t diffuse into them. Other nutrients can't come in, so they become dormant bacteria. Antibiotics only kill metabolically active bacteria. They kill them by interfering with these essential bacterial protein systems like protein synthesis, rRNA, DNA synthesis, cell wall synthesis, etc. So, if a planktonic bacteria that is sensitive to penicillin gets converted into the biofilm phenotype and develops a mature biofilm community and you hit them with antibiotics you may kill the outer layer of the metabolically active bacteria in the biofilm, but you're not killing the bacteria that are metabolically dormant in the middle of that biofilm. That's why infections can become highly chronic when the bacteria convert into the biofilm phenotype, because our immune system doesn't kill it.
Sarah: Wow. And where does medical grade honey come into play with this?
Dr. Schultz: Medical grade honey is able to provide some very effective reduction of planktonic bacteria. That's well established. What the field probably doesn't appreciate is that medical honeys, when they're used correctly and following instructions for use, can significantly begin to reduce this biofilm mass through multiple actions. First, the hydrogen peroxide and the methylglyoxal can penetrate into the biofilm matrix. Also, the honey desiccates and helps to remove a lot of the water and the nutritional components that the bugs need to form a biofilm - so it also helps to prevent biofilm formation.
Sarah: Can you explain what debridement is, first, and when it is necessary in a wound?
Dr. Schultz: In the early 2000s we knew that chronic wounds that were not healing well would begin to heal much better when they had frequent debridement (the removal of damaged tissue or foreign objects from a wound). What we didn't understand in 2003 and 2005 well enough, was that a benefit that's provided from the debridement of the wound bed, was removal of the planktonic bacteria, but especially removal of the biofilm. Because that was what was causing the chronic inflammation that led to the hugely elevated levels of proteases and reactive oxygen that were destroying the proteins essential for healing.
Debridement became much more important in the overall management of a chronic wound. When we began to understand the problem of biofilms and how that was a major factor impairing healing in these chronic wounds, debridement became incorporated into the international consensus guidelines on wound infection.
Sarah: So, what’s the process for removing the biofilm?
Dr. Schultz: To put it in very simple terms since we don't kill biofilm bacteria well and our immune system is unable to get rid of it (and our antibiotics and many antiseptics are also not very effective at killing and removing biofilm). The best, most effective way to rapidly convert a non-healing chronic wound into a healing wound is to remove the bioburden -especially the biofilm that's causing this initiation of the cascade that destroys the proteins needed for healing.
Now, there are multiple ways to do the treatment. The most effective and fastest is sharp treatment by a scalpel etc. But there are other ways that can effectively remove the necrotic tissue, and especially the biofilm. Aggressive debridement in the earliest stages of treatment of an established chronic wound is the first major way. Getting rid of the biofilm will get rid of the inflammatory stimulus, will reduce the proteases and damaging reactive oxygen molecules. The wound can then move out of that chronic inflammatory phase into the repair phase.
Sarah: I've got one last question, which was based on a quote that I read from A.C. Matin, who is a professor of microbiology and immunology at Stanford University. Dr. Matin said that “Biofilm resistance combined with a general increase in antibiotic resistance among bacteria is a double whammy and a major challenge to treating infections.” Can you speak to this?
Dr. Schultz: Sure. And I totally agree with Dr. Matin. We need to just clarify the terminology here. There's permanent genetic resistance to antibiotics. A patient can have a permanent genetic alteration which means the antibiotics can't effectively kill that bug because of the way they change their proteins or the things they secrete. Then there's temporary tolerance to antibiotics or antiseptics based on the conditions that the bacteria are in at the time. For example, you can take a methicillin-sensitive Staph aureus that you can kill 6-logs after 4 hours of exposure of a culture of planktonic rapidly growing Staph aureus. And if you allow them to form a mature biofilm over a couple or three days and then you treat them with that same concentration of antibiotics that previously killed all the planktonic bacteria in 4 hours, after four days, it's killed less than one log. And that's because of these principles.
We talked about how the bacteria in the biofilm develop tolerance to the antibiotics or the antiseptics. Now, here's the key. If we take those antibiotic tolerant bacteria in the biofilm and we disperse them through ultrasound dispersal back to single planktonic bacteria and hit them with the antibiotic, it kills every one of them just like it did before. So, this biofilm phenotype provides a temporary tolerance to the agents that normally would kill them when they're in the planktonic form.
What Dr. Matin is talking about is, if you have an antibiotic resistant bacterium, like MRSA, and they're in planktonic form, they're going to have a very good ability to survive in the presence of the antibiotic because they've had gene mutations that prevent the antibiotic from killing them. However, if you take those and you put them into a biofilm, they have even more tolerance to the antibiotic that they have already developed permanent genetic resistance to.
Sarah: Thank you Dr. Schultz, it's been a pleasure speaking with you.
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