Porous foam – How to dress wounds with glass

– What was a breakthrough moment in your career?

– It is difficult to clearly define a breakthrough, it seems to me that the entirety of my work may have been decisive, the importance of what I am working on. I specialise in bioactive glasses which are particular biomaterials that cause a specific, desired effect after being planted in the body – they stimulate the body to regenerate. These glasses are components of composites which we aim to apply in diabetic foot treatment. This is one of the most frequent and most serious complications of diabetes. It is also one of the most costly ones to treat. Meanwhile, diabetes is recognised by the WHO as the first non-infectious disease which is a 21st-century epidemic with an estimated nearly 50 percent incidence  increase by 2045. Thus, the diabetic foot syndrome is a big issue. We are trying to develop a dressing which could be easily accessible, meaning cheap, and at the same time very effective, so designed specifically for treating the diabetic foot syndrome.

– How does such a diabetic foot wound differ from other wounds? Why should the dressing have some special properties?

– Due to numerous reasons these are often deep, hard-to-heal wounds. If they occur, they will not heal without proper care, they will only grow and get infected. The biggest issue is that these are not only skin-deep wounds, they go into the subcutaneous tissue, i.e. muscles, ligaments, fascia, and often also bones. Inflammation may lead to osteolysis, so bone loss. The second thing is that there is a problem with vascularisation in the diabetic foot syndrome. Very often, peripheral blood micro vessels that directly vascularise specific tissues get damaged. Vascularisation is essential for regeneration, to supply with nutrients, collect metabolic products, provide oxygen. This is a vicious circle, for if one does not have a restored structure of blood vessels, they will not regenerate, and without regeneration there is no restoration of the structure of blood vessels. On the market there is solely one dressing which induces regeneration of the vessels which vascularise tissues and it is a dressing made of bioactive borate glass. But it is not accessible at all in Europe and it is truly expensive. Besides, it is a glass in the form of fibres, not a composite, so despite its high effectiveness, its use has some limitations. The wound healing process in diabetics is also hindered by chronic inflammation. Diabetes involves chronic inflammation in the organism, so the inflammation in the wound is also heightened. If we want to lead to tissue regeneration, we need to alleviate it. Lastly, in case of diabetes, the production of reactive forms of oxygen as well as free radicals is extensive, which also prevents healing. That is why we want the dressing to limit the production of free radicals.

– So the main difference is that in diabetic wounds the regeneration processes that work well in other wounds fail?

– Exactly. Other wounds which do not result from a systemic disease usually are not that difficult to heal.

– You mentioned the use of glass in dressings. Glass is typically associated with glasses, jars, bottles, something hard but easily breakable. How much in common does the glass you are talking about have with the glass used for example in windows? 

– Quite a lot as glass is a specific state of matter, so in this case what makes it glass is the lack of long range structure order. Of course, such glasses, various types of bioactive glass for implanting, are much less chemically resistant. The truth is that regular glass, the one used in windows, is there for a long time and nothing happens to it, it is very stable, resistant to numerous factors, the atmosphere, humidity, pollution, and so on. The glass we implant is much more chemically reactive, less chemically resistant, so it is able to restructure, to dissolve. When it dissolves, it releases desirable ions from its structure, such that are responsible for biological activity, the restoration activity of bioactive glasses.

– The dressing for the diabetic foot treatment you are developing is to consist of such a type of glass.

– Of milk proteins, plant extracts, and bioactive borate glass. In medical applications, there are a few types of bioactive glasses, depending on the basic component of the structure. We have three basic components of glass, i.e. vitrifiable oxides: silicon oxide, boric oxide, and phosphorus oxide. Based on their main component, these glasses mostly differ in chemical reactivity. Silicon glasses are the most stable because they are most like the window glasses due to their basic component being silica, i.e. silicon oxide. Various chemical modifications make them more reactive than window glasses, but they are the most stable, the most known. The fact that the right chemical composition of the glass is able to induce regeneration of bone tissue and, as it later turned out, also of other tissues, was noticed in 1969. So it has been a while since the discovery of the first bioactive glasses, but it is still a relatively new material. Later, we were dealing with borate glasses, that is, precisely those in which silicon oxide is replaced by boric oxide. These glasses are definitely more reactive, bioactive, dissolvable and thus we can use them for soft tissue regeneration, including skin regeneration, for example in these diabetic wounds.

– And what was the rationale behind using milk proteins in the dressing?

– In general, milk proteins are used orally because they  are de facto able to provide all the essential amino acids that later build proteins in our body. Our tissues are mostly made of different types of proteins, so by providing these amino acids, the basic building blocks of proteins, we encourage the body to rebuild proteins. The body cuts the proteins delivered by us into bricks, into amino acids, and rebuilds our tissues from these blocks. So, in fact, if we provide the raw material, our body is able to rebuild this tissue that has been damaged. This, of course, is a gross oversimplification, but proteins, i.e. amino acids, are needed and milk proteins are capable of providing all these amino acids. Moreover, they exhibit a number of other properties, also antioxidant ones, hence orally administered wound-healing supplements are used. And this brings very good results when it comes to burn wounds, chronic wounds, pressure sores and wounds in the diabetic foot syndrome. By following the thread, if we are able to deliver these amino acids orally, by means of proper nutrition, why not deliver these beneficial components topically, directly to the place where the amino acids are supposed to act? Preliminary results indicate that it actually works that way, that the cells are able to use milk proteins precisely to rebuild, to produce proteins that are later to build the tissue.

– So, beginning the project, you did not know whether this would work?

– Absolutely. There were only preliminary reports... In fact, this work is done in collaboration with a colleague from the UK, Dr. Timothy Douglas. And it was he who started to deal with milk proteins precisely in the context of biomaterials in the broadest sense, that is, in various applications. At the beginning, we were mainly targeting bone tissue, but then we started using milk proteins in the context of soft tissues, in this case of those wounds.

– And what is the contribution of the plant extracts in the dressing?

– Above all antioxidant and anti-inflammatory properties. Continuous, chronic inflammation and overproduction of active forms of oxygen and other free radicals are also a big problem. Why are these extracts so fun, so to speak? Because they are of natural origin, so it is very difficult to overdose them, they have a very high biocompatibility, that is, compatibility with our body, and they are readily available. There are reports that in addition to these antioxidant, antibacterial, and anti-inflammatory properties, the plant extracts themselves are able to promote tissue regeneration. Of course, the effect of plant extracts, in general of what comes from plants, is much weaker than of other preparations, but these plant extracts are supposed to mainly support those main ingredients, namely milk proteins and borate bioactive glasses.

– Are they also cheaper and thus this dressing will be able to be cheaper?

– That’s right. We are dealing here with waste, with waste raw material. Hundreds of hectolitres of milk are processed in the world every day, so it is the whole cheese industry, the whole dairy industry. In fact, some milk proteins are treated simply as waste, so they are cheap. We use such plants which, first of all, are widely available in our climate, you can buy them in any herb store or grow them in your garden.

– You mentioned implanting bioactive glasses. How is it done?

– In a variety of ways. These glasses are cool in that they can be a base of some biomaterials or they can be implanted on their own. Bioactive glasses are primarily used in bone tissue engineering, especially in oral surgery. If we have a defect that is unable to regenerate itself, this is where such biomaterials come to the rescue, including bioactive glass, one of the most effective biomaterials. We can apply bioactive glass into the defect in the form of granules or powder, or we can use bioactive glass to create various types of scaffolding so these porous constructs designed to fill in the tissue and provide a base for the living tissue that is to outgrow them. We can also use such bioactive glasses as components of other materials, such as injectables, so we can use them in minimally invasive medicine. If we have a defect in the jaw, for example, we can inject such bioactive glass in the form of some kind of paste or hydrogel without opening the integument. This way we can avoid additional damage to the body.

– And what form will the dressing you are working on take?

– It is supposed to be a porous foam. We were talking about these deep wounds in the diabetic foot, but this foam is not supposed to be the kind of typical flat bandage we associate with a bandage or a patch. This is supposed to be a roomy, porous foam that we are able to cut, compress, and stuff into a deep wound. It is to fill the wound, as diabetic wounds are really ugly and deep. If we completely fill this wound, we will prevent infections, for the reason that we will isolate the wound from the external environment. It is not that there will not be any gas exchange, but by filling it in, there will be no niche for these bacteria to grow in. In addition, the advantage is that direct contact between the biomaterial and the tissue will promote tissue regeneration.

– At what stage are you with the dressing?

– We are at the stage of cell research. We are now seeking to extend this research and obtain money for animal studies. We are expecting the results of the competition. This is a very early stage, although, as I say, we also use ingredients that are proven to work, whether by us or in the literature. Borate glass is already in commercial use. Plant extracts are such an extensive topic, they are actually folk medicine. Now, there is a huge return to nature, to the study of natural ingredients, and in recent years a great deal of scientific research has confirmed the effects of plants previously observed in folk medicine. And the milk protein – all studies, especially ours, indicate that the protein will greatly promote the regeneration of skin tissue and other tissues that are damaged in the diabetic foot syndrome.

– As for this project, I guess the biggest challenge was just coming up with it?

– Inventing it, yes. But when it comes to any materials for medical applications, research adversity is also funding. Unfortunately. At our own expense, we can do a lot of research, but it means nothing without confirmation of the biological activity of the materials. Because the fact that we come up with the composition of this material, its form, produce it in the right form and shape, with the right ingredients that we think should work, is really just the beginning of the journey. Only in vitro environment, that is, using cell lines, will allow us to confirm the initial properties. Later, animal studies are required and the third and final phase is human studies, clinical research. This is the part that every biomaterial researcher would like to get to, but it is actually very difficult to achieve.

– I understand that this dressing is now your main focus of research, are you involved in anything else?

– This is not the only thing our research group is concerned with. Bioactive glasses, especially borate glasses, are a fresh new material and their interaction with the system is not fully explored. We know it works. But how does it work? What is responsible for this process? It has not been fully investigated yet. So now one of our research directions is to learn about the molecular and biological mechanisms of borate bioactive glasses. The second direction is the use of glasses – silicate and borate – for various types of composite materials but also for hydrogel materials, primarily injectables. We are also completing a major project which involves the use of bioactive glasses and plant extracts to create composites for bone tissue regeneration but from synthetic polymers.

– Did we miss anything important?

– I do not think so. I think we may add that this is a fascinating field, because we are doing something that we all need here and now, as we are an aging society and we are all experiencing injuries. We need all this to live in good health for as long as possible, to replace various parts, to force the body to regenerate. I must also mention that this is truly a dream job. The subject matter is great, the research team is great, what more could you want? These are the important things. That you can simply do what you like.

The newest information on research on functional (bio) materials are available at: nbf-ktsipa.agh.edu.pl.

The interview with Dr Michał Dziadek was conducted by Katarzyna Dziadowicz from the Centre for Communication and Marketing of the AGH University.