Engineering Health – Day 2 – Pt. 1– 09:00 10:15
Good morning everyone and welcome back to RunAn the auditorium at Chalmers University of Technology in Gothenburg Sweden and to the first initiative seminar of the area of advanced Engineering Health. That's quite a mouthful, isn't it? Yeah, So, I'm saying welcome back because we had a fully packed day yesterday with really interesting talks on the theme of Engineering Health and the theme of the whole conference or seminar is joining forces in Healthcare Solutions. So we're talking about all the fascinating opportunities for collaboration that have already been realized between the realms of technological development and health care. Now, as when we say health care, of course, we also mean not just what happens within a hospital but also what happens when we try to safeguard our health outside of the hospital context. So today we will be tackling two themes that are central to this more proactive perspective, I guess you could say.
So, just to give you a kind of idea of the whole frame of the day, we will be, we will be presenting a program from 9 o'clock until 5 o'clock with a lunch break at 12 o'clock for one hour, so you're ready for that. And I want to encourage our viewers and I was about to say listeners, but depends on if you're doing something else while you watch, I guess really not too much. Yes, so we are broadcasting on YouTube and there is a chat there.
Your thoughts are very, welcome there and we also have an email address which is health.engineering@chalmers.se and we also have a phone number and I have to admit that I can't actually read it right now because I'm not wearing glasses. So Martin could you help me out there? Yes. If you're outside Sweden, it's +46 723 77 34 22. Thank you.
So that's the general structure for the whole day. The two themes that we will be covering are, oops, sorry that went a little too quickly, the two themes are. First of all prevention, keep out of the hospital. Basically how can we offload the strain on ongoing Health Care organizations and personnel and the second thing will be restoring health, new solutions for rehabilitation. And our speakers in the first block prevention, keep out of the hospital will be presented by Martin. Yes, But before we do that, what did you think about yesterday? Oh yeah, it was a very thought-provoking day.
It was a lot of very diverse and fascinating presentations on very specific things. But I was kind of zooming out a bit and thinking about this collaborative aspect that for many of these successful collaborations, it becomes a generational thing that if you make sure that not just the one researcher travels alone on that path, but brings new people into the mix over time, such as bringing in a PhD student, or two, or maybe a master thesis student, that that kind of gives them the purpose, and job of staying in the realm in between, and if they can focus on that, that's when we can get really far with developing the combined technology and Healthcare kind of solution realm. Yeah. And I think, I think that's what we will see more about today also, people have starting maybe with the master thesis like Max mentioned yesterday. I think their presentation was amazing.
What you can achieve with transplants of hands or, or sort of repair or restoring function with bionic prosthises. That was something that stuck to me, but also that we had, I mean, we can show a lot of great inventions and a lot of advanced technologies and and fruitful Innovations. If we collaborate here in the Gothenburg area and I think that's something that we should all be very happy about and something that we should try to do even more or foster, even more. Another thing that I brought with me from yesterday was Tom's stressing Tom stressing or dr. Tom Krummel stressing that the mindset really matters, if you really want to change the world, maybe you have to live on water noodles for or five years because you will not have enough money to both expensive dinners and pursue your tasks in life. Maybe develop some new technologies.
Bringing to that also, money matters, of course, if we wanted to achieve these things, Just speaking of water and noodles, I wonder what our researcher Rikard Landberg would say about that, he's going to talk about gut health and the microbiome. Yeah, I hope he doesn't look back or know what I was eating when I was a student here at Chalmers that's something we keep from from him, from now on I think. Well, I think that was my main reactions from yesterday. There's much more to say, and there is much more to view also today, Actually, one more reflection I have on that, is that it seems like we have really good opportunities to develop Health Care technology, not just within or on the body, but also surrounding it and outside it. So yesterday, we also had Mattias Wahde presenting the robots Isolde it, which is supposed to offload the tasks from Healthcare Personnel within the hospital context and provide some more opportunities for social distancing. And we also had a lot of present presenters talking about digital solutions. For example, Minna Pikkarainen, and
people who are working towards how the exchange of data and information can benefit Health Care in both the more informative way for the patient and also so that the staff can work from a larger basis of decision support. Yeah, and when you say it, I mean also I think the presentation or discussion with I had with the Sara and Andreas about having patients in the center or maybe even having patience leading, our research and Innovation as a complement to all the great research that is done. That's also something that I will bring with me.
It's not something that comes first to mind when I think about it, but it will, from now on. So that's something I've learned at least. I just realized that I forgot to tell new viewers today, who we are. So, my name is Cecilia Berlin and I do research in production ergonomics and I'm at the department division of design and human factors at Industrial and Material Sciences. So for me, it really stuck with the co-creation idea that was discussed yesterday. How do you bring in users and get their input into what works for them? But also to draw conclusions about how do we deliver value to the people who are in great need of decision support and health care support.
My name is Martin Fagerström, I work as an associate professor in Solid Mechanics here at Chalmers. And I just recently or maybe a year ago or something, I started more adressing my research more towards sport injuries. So, and that got me thinking when we talked about trust yesterday, I have a started a collaboration with sports medicine at Sahlgrenska Academy and we can really see that we are different, but at the same time we have a lot of things in common. And as we are meeting more and more, we really having fun, and I really feel that building trust takes time but we really on that track. Now, it's just about starting those amazing projects also. So, that comes next, Hopefully,
I just want to point out at the that, of course, all the exciting stuff isn't just going on at Chalmers, we are very focused on the technology, and we have the Techno Joy as Eddie Izzard likes to call it, but we do need to always match it with where are the needs? And where are the problems to solve so are clinically oriented colleagues at Sahlgrenska University, and Gothenburg University, and Sahlgrenska Academy are a very major driving force in making this happen, but also our industrial partners and other organizations around primarily the west of Sweden. So we have, for example, MedTech West, and we have GoCo. And I'm afraid that now that I've started mentioning, I may forget someone.
That's a risky business. Yeah. But speaking of that, we should also emphasize those, although this is an initiative seminar from the area of Advance here at Chalmers, this is a series of seminars that has been running.
This is the third edition of Engineering Health and it's done in great collaboration with the organizations that you just mentioned. The University Hospital, Sahlgrenska Academy and the Faculty of Science at Gothenburg University. So, again, a great thanks to everyone who contributed with ideas and bringing people to this fantastic schedule that we have had for one day and now we are continuing it for for a second day.
Absolutely, and it's beginning to be time to start this first theme. Which is Prevention, keep out of the hospital. So Martin go ahead and introduce our first speakers. I will do my best. So we actually have four speakers now and then we will have a joint discussion afterwards. So the first two comes in pair it's Jonatan Tillander, medical doctor and PhD at the department of Infectious Diseases at Sahlgrenska Academy at the University of Gothenburg together with Martin Andersson professor at the Department of Chemistry and Chemical Engineering at Chalmers And their title is Challenges and Opportunities for Implant Associated Orthopedic Infections and I will introduce the second two speakers after Martin´s finished with his presentation.
So by that Jonatan I give you the floor or the virtual floor to start your presentation. Thank you very much for being introduced and thanks for the opportunity to shed some light on the current clinical situation of Orthopedic implant infection. This presentation is setting the table for Martin Anderson, really. And I fear that his self-sterilizing implants will make me obsolete in the future, but let's see what I have for you.
All right. Orthopedic implants are inserted by the millions, every year, they are in this absolute necessity in modern medicine, But they also the root cause of many of the infections we see associated to these implants. The incidence rate of infection is somewhere between 0.92 and 1.3 in hip and knee prosthesis and about 5% in implants used to mend broken bones, such a nail's, plates or screws. So the absolute numbers of infections are very high even though the incidents are not that high.
As you see in the graph to the right and in the u.s. the infection rates numbers are in the tens of thousand and they are gradually increasing since there are more implants in place. Ones you developed an infection it´s even a higher risk in developing a second infection and further infections beyond that, because of course, that there is a pretty selective risk factors in the patient, renewed tissue trauma and via exposure to the hospital flora and this is of course in taken together, means longer hospital stays and prolonged antibiotic treatments.
Secondary infections are also more prone to be caused by the gut flora and in the gut flora, enteric flora, many of the most rapidly emerging multi resistant strains can be found and I'm sure Joakim Larsson will talk about that later. We do not know the true consumption of antibiotics in Bone and Joint infections, but if you look at transactional data like this one, at Point-Prevalence studies performed every once in a while in Europe, we see that Bone and Joint infections receive a lot of antibiotic treatment and it's also important to know every started treatment in a Joint or a Bone infection is seldom shorter than six weeks, so the total burden is very high. How is the prosthetic joint really infected? Or what, 90 to 95 percent of all infections are probably caused by microbes inserted into the surgical wound at the time of joint replacement or intra medullary named placement. For instance, At that from that time point and on through the entire lifetime of the implant, there's of course, the risk of blood bones eating if you have a distant infection or microbes in the blood.
So the risk is never zero. These infections there are mainly caused by microbes that originated from the skin mainly aesthetic oxide species, but also other species and they may have a very low, very lens but the high capacity to cling to the implant and be very hard to eradicate. Later blood-borne infections tends to be caused by just one microbe of higher virulence. So it's very important to keep in mind that there's high number of opportunistic microbes that normally do not cause infection in the uncompromised tissues. And if you design implants,
it's very important also to, take height for this wide variety of bacteria. Why is the implan infected? Why is anything infected really? But specifically talking about implants, it's important to appreciate that the effective dose is very much reduced in the vicinity of an implant and this is true even though if you get a thorn in your finger but even so even more so if their implant is very large. And also was even more troublesome is that the key leukocytes, white blood cells, killing microbes they are severely hampered by the presence of an implant and in the long run, the poor bio-integration or fusion between to host tissues and the implant surface.
The normally goes with the zone of scar tissue that's vulnerable to later seeding of bacteria from the bloodstream. So if you all, would design, a complete protection, in a smart implant, this must have a sterilizing capacity throughout the entire use of the implant not just for a brief period. What are we currently doing to prevent infection? All right, we try to deny bacteria entry by special drapes, clothing of the surgeon, laminar airflow, skinny cleaning procedures, Etc. And this in place for many decades.
And despite this we not seeing a significant decrease in the rate of infections, we're also trying to prevent the bacteria from colonizing the wound, once they are there. And we can do this by a prophylactic antibiotics. That's a Mainstay in orthopedic surgery, especially with prosthetic surgery.
And we can also optimize the patient before the treatment which is very important. For instance, smoking is doubling the risk for prosthetic joint infection and obesity and poor bloodsuger, sugar control is also identified with the tractors. We can not talk about biomaterial infections without mentioning the biofilm. It's not to be considered just a a community of
or a claustrum of bacteria but the more semi intelligence community rather and the protected matrix which the bacteria grows produced themselves and they also communicate when in the biofilm. And mature biofilm has more big channels for nutrients etcetera In the clinical setting this is problem. Because the biofilm could be vastly resistant to antimicrobial more than 10,000 folds for different antibiotics has been shown. And furthermore, the close proximity of these microbes makes it easy for them to transmit, gene cassettes, and gene elements that may contain resistance genes. Our group has found poor outcomes and implant infections caused by so-called strong biofilm microbes producing a lot of biofilm with a high antibiotic resistance.
So this is something we need to address like an intelligent implant, possibly to. Well, as I said, the cell proximity in the biofilm might cause an ultimate result of a treatment failure in the individual patient or at the hospital unit, where there might be a clonal spread of a resistant strain. But on the global scale, of course, this ultimately may cause the driver resistance in more virulent microbes also leading to higher septic deaths. And furthermore, there is a problem with some of the antibiotics we use, we have no way of measuring the concentration of antibiotics that in the implant tissue interface. At least not in the clinical setting. And there are many studies showing that sub-therapeutic antibiotics dosing, really promotes biofilm production, instead of eradicating it.
So there could be a problem using our conventional antibiotics from this perspective as well. All right, so just briefly on how we treat these infections. As I indicated earlier, there's really not enough just giving antibiotics or relying on the immune cells eradicate, these infections in the vicinity of an implant but we need to remove the implant, either and it's entirely or components there of and then we can use biofilm effective antibiotics and the cure rates are somewhere between 60 to 90% depending on the method. So we're not succeeding completely here either. You can augment systemic antibiotics by local antibiotics, but this is understudied and has its own drawbacks. Unfortunately.
We should prevent rather than treat. That's obvious to prevent morbidity in excess mortality loss of function Etc. And, not least to prevent antimicrobial resistance drives. Alright into do this of course, collaboration with the research department there is key and I would also like to stress that we should never underestimate the bugs and hand over the presentation to Martin Andersson.
Thank you. Okay, so good morning. See if I can get my shared screen to work as well.
So, thank you, Jonatan for setting the stage. So my name is Martin Andersson and I'm a professor here at Chalmers. I work at the Department of Chemistry and Chemical Engineering.
And in our research, we develop materials specifically we design surfaces for materials, that will be implanted as medical devices such as implants. And I have historically mainly focused on materials to improve integration for instance, of osseointegration of bone integrating implants but as Jonatan just showed you, we have a big challenge when it comes to infections and that these infections can be caused by artificial surface such as an implant. So we try to develop ideas and techniques in our lab to prevent these infections to occur.
And we are focusing on Material Science and we're focusing on the surface of our materials. So, to give you some insights into the different strategies that we are working on, we can work with non-adhesive surfaces. So these are surfaces that avoid spectral attachment. We can focus on the integration part. So this is what we refer to as winning the race for the surface. So you get a eukaryotic tissue cells.
Forming cells on the surface. Instead of bacteria, we can work with selective contact killing surfaces. So these are surfaces that can actively kill bacteria, but stay unharmful for human cells. We can introduce drugs so here we can have drug-eluting implants, for instance. So you get a very high concentration locally that could eradicate these biofilms being formed on the surface.
And we can also, then combine these different strategies into multifunctional surfaces. So, in the end, the question that we ask ourselves is, is it possible to design a surface that has good integrating properties? And at the same time, being selectively, avoiding bacterial infections. So I would like to share with you three concepts that we are working on to give you some insights into what material science can bring to the table here. So I will start by giving you an idea of how we can use nanostructured gold materials in combination with photons or near infrared light, we can use this concept to have a contact killing surface as well as inducing a drug release from an implant. Then, I will also share with you some of our work that we are performing on something called antimicrobial peptides. So this is kind of a possible antibiotics for the future for the future.
So this is part of our own innate immune system. And I will show you some ideas of how we can implement that together with materials. First, I like to share with you these two beautiful, beautiful photos. So, pre Corona you been traveling around the world and maybe visiting some chapels and old churches.
And these chapels and churches often have old nice windows that are of vivid colors. And as you may know, this can be very, very old but still they have this very, very shiny and bright appearance. So how can that be? How can you make a color that is so sustainable for hundreds and hundreds of years? Well, the reason for this is that these colors they contain small tiny particles, nanoparticles of various metals. And when light are interacting with these nanoparticles, some of the wavelengths of that light is being absorbed.
This is due to a property called localized surface plasmons. So depending on the size of these nanoparticles and their shape. They absorb different types of wave length. Hence, they give rise to different colors. So by design, the size and shape you can then select which colors that will will be given from the window. So this is a concept that we will bring to implant then into an implant surface.
And the reason for this is that as these nanoparticles, absorb light this energy will be translated into heat. So you can actually locally heat up this nanoparticles using this incoming light. So this is the property that we are after this very localized heating. So if you have any bacteria that is attached to the surface, we can kill it by this heating effects.
The first challenge though, is that as you saw from the church windows I mean, we are not transparent. So we cannot use the same types of particles. The same sizes, as in church windows, because we are not transparent for the light.
So we need to work with a light which are, which our teaches more transparent for, and that is what why we using this near infrared light. So, near infrared light is in what we call the biological window. So this is the wavelength of light that can penetrate deeply into our tissue.
So we are designing nanoparticles or non rods of gold. That absorbs this near-infrared light, we deposit them onto the implant surface. And the concept here is that you can eradicate the implant site. This can be done during the surgery for instance. So this would be like an in vivo sterilization of the implant surface.
So even though as Jonatan mentioned I mean you have drapes and you have a laminated air flow and so on. There will always be bacteria present and some of these bacteria will be on the surface of the implant and will be dragged along the implant and will be on the implant surface as the implant is being installed. So this could be a possible way of preventing any bacteria, present on the surface To give you some ideas of how well it works I can share with you, this, in vitro study here. These are Green Dots. The green dots represent living bacteria onto surfaces. So, here we have three control surfaces, we have glass, we have glass with near-infrared light and a glass surface with these gold nanoparticles.
But when you combine the gold nanoparticles together with the near infrared light, they turn red in step and this means that you have eradicated the bacteria that is present on the surface. You can still see some green dots appearing and these are bacteria that is laying on top of the dead bacteria. So this really shows that this is a very, very local effect, of only the bacteria that is present on the surface. I can also emphasize that these studies, of course, using a lots and lots of bacteria. Hopefully we don't have this much bacteria in our surgical operating theaters but it is a possible material that can then be used to prevent these types of infection. Using the same concept of heating up this gold nanorods.
We can also indusea drug release from an implant. So here we use this gold nanorods and we embed them in a thermo-responsive polymer and by initiating this or originating with the light. You can then heat up the particles.
Get this transformation in the polymer and then you can get a release and local release of the antibiotics. So this is a conceptual study as I present here. So these are auger plates onto which we have bacteria and it's only in the combination where we have a loaded implant with an antibiotic together with the gold nanorods and the near infrared light that you can eradicate the bacteria in the nearby surrounding. So here you can visualize that you can have these coatings that have antibiotics within them.
You then do the surgery procedure and then if you expect an infection to occur later on, you can then initiate a localized drug release from the implant surface. And by doing it from the surface, you might get a very high local concentration of the antibiotics. That might eradicate the biofilm.
The last example I like to share with you is on our work with so called antimicrobial peptides. So these are very short proteins that is being part of our own innate system. They have a very broad spectrum of activity and their mode of action is to function as destroying the outer membrane of the bacteria. So we have designed implant surfaces utilizing this antimicrobial peptides combined with cell adhesive parts. So here the concept is to have a surface that is nice and kind so to save for tissue forming cells and at the same time can contact kill the bacteria that might be present. That the contact killing works fine, you can see here you go from green to red.
Using these antimicrobial peptides, but at the same time, you have a surface, that is also a nice bed or nice surface for a eukaryotic human cells to thrive and form tissue. So again, we can then have this selectivity of the surface. So you have nice tissue integration at the same time, as you can kill the bacteria. This technology, we have taken also further developed developing wound dressings for wound care applications. First Jonatan mentioned many of or the thought here is that many of the bacteria that is causing these inplant associated infections comes from the skin. But these are part of the normal skin flora, then when it comes in contact with the implant surface, might form a biofilm causing in the infection.
So using these materials also for wound dressings, we can then prevent any bacteria, that's on the skin to enter into the world and then they may end up on the surface. So again, it's a contact killing mechanism here. So if you don't have these peptides on the wound dressing, you can get biofilm being formed causing maybe an infection and then you can eradicate them locally. So to summarize a little bit on the strategies that we are working on here at Chalmers to prevent these infections. So we use these Gold nanorods causing or making a contact killing surface, or by local release of drugs.
And I show you also, how we can use these antimicrobial peptides in combination, with bioactive modifications, to form selective surfaces. So, I post a question in the beginning and it is then possible to design a surface that has good integrating properties. And, at the same time, selectively avoid bacterial adhesion reducing the need of future antibiotics. So with this, I like to thank all my students and collaborators to making this research happen. So thank you for listening and now I will turn to the next couple of presenters. Thank you.
Thank you. Thank you very much Martin. And thank you also to Jonatan, I think this was a very nice introduction to understand the complexity of osseointegration when it comes to the risk of forming biofilms for instance.
And also then suggesting a few ways on how we can treat them, I will not spend more time on that or any questions now, I would rather like to introduce the next two speakers. It's Joakim Larsson, professor and director of the center for Antibiotic Resistance Research called CARe. At Sahlgrenska Academy at the University of Gothenburg. And following him, Johan Bengtsson-Palme, assistant professor who is also at the same department. I didn't mention that, department of Infectious Diseases at Sahlgrenska Academy at the University of Gothenburg.
And the title of your combined talk is Antibiotic resistance as a health and research challenge. So please, Joakim. I will give the floor to you. Thank you very much and thank you very much for inviting us to talk to you today. So, let's see if I can share screen here to you.
And from beginning. Hope you can see this. So I will continue on what previous speakers talked about and actually go back a bit and talk about some more general aspects of antibiotic resistance as both a health and research challenge. Here in Sweden, we might not realize how big a challenge antibiotic resistance really can be but it's actually enough if you just travel across the Baltic Sea. Then you face considerably bigger problems with antibiotic resistant infections. This is just one example of one particular resistant bacteria and it is quite typical pattern with low prevalence up here in the north and considerably higher prevalence, south in Europe and even more in other parts of the world.
And this is to a large extent driven by higher use of antibiotics in other in other regions than Sweden. We have been very good at keeping down our use of antibiotics and to the right you see an example of one group of antibiotics cephalosporins and and their use in different European countries and you can see there's a striking difference. Also of course we know that hygiene matters a lot for this. Now the challenge is that bacteria. They don't stay put they move they move with us as we travel across the world and also with goods and food, Etc.
So, the resistant problems really becomes a global challenge for everyone and we need to deal with the emergence of new forms of resistance regardless of where they emerge because it will be other our problem, at the end of the day. So, the reason why we have this health crisis really is because of the failure to discover new antibiotics for gram-negative bacteria, Particularly. For several decades, as you can see on this slide, it was a long time ago since we got a truly new type of antibiotic on the market that was good for treating Gram-negative bacteria.
So, we're running out one by one of treatment options as the bacteria, accumulate more and more types of resistances. And we're already facing today, some bacteria that are pan-resistant, where there is no antibiotic discovered, that could kill them. So to solve the health crisis or to address, the health crisis, there's really two pathways, either you develop new antibiotics, or new treatments. Or, you reduce the need for new antibiotics.
And as we know that the new antibiotics pathway has been very difficult, we need to work a lot on, reducing the need for new antibiotics As we also had before limiting infections in the first place is perhaps the very best option if that's possible. And if that cannot be done, it's also about reducing. resistance development as much as possible, both the emergence of new forms of resistance and the spread of these resistances, once they have formed, It's also, recognized more and more that bacteria, they move between different compartments.
They move between humans between an animal's and external environments and they change genes with each other. So, an overall solution to the antibiotic resistance challenge needs to deal with all these three compartments. Both humans domestic animals and the environment as well. A few years ago, the, it was Pam Fredman, the former vice-chancellor of the University of Gothenburg initiated something, what's called you got challenges.
An initiative to address global societal challenges in an interdisciplinary fashion at University of Gothenburg. So 300 million Swedish Crowns was invested from 2016 to 2022, and one of these six centra that were funded, was CARe, the Center of Antibiotic Resistance research at the University of Gothenburg. So, we are about 120 researchers that work on different aspects on antibiotics and antibiotic resistance with an overall vision to limit mortality and morbidity and costs related to antibiotic resistance through research. We have divided or structured our work, according to six different themes. We use the same themes as the joint programming initiative on antimicrobial resistance, chose for their strategic research agenda.
And this JPI, they are coordinating directing much of the research funding that goes on in particularly Europe, but also some other parts of the world. And we did that partly to be able to meet upcoming opportunities for funding. But it also makes some sense to structure ourselves in this way.
So, we work with, for example, transmission of genes and bacteria. We work on surveillance different types of surveillance. I will show one, slide, on this later on. We work with diagnostics quite a lot here together with researchers at Chalmers actually also.
We work on therapeutics not that we have developed any new antibiotics yet but we're working on early drug discovery processes. We work with societal interventions different ways, particularly social scientists and scientists from the humanities are working here. And we also work on the environmental dimensions of antibiotic resistance.
That's my personal focus area and I'll give you a few examples of what we working on on here. Now antibiotic resistance in the environment. That's that's nothing new. bacteria have been able to withstand exposure to antibiotics for a long time. If you like this guy, go out and dig up, thirty thousand year-old permafrost and isolate DNA and sequence it.
You find DNA from creatures like this side by side with genes, that provide resistance to Vancomycin or beta-lactam, to tetracycline. No, we didn't have much intensive care in those days that we use in these antibiotics. But of course, there was competition among microorganisms and many microorganisms produce antibiotics or antibiotic like molecules. And therefore, we also have these defensive systems around, But as long as these defenses stay in what I should call environmental bacteria or harmless bacteria, it's not a big problem. The big problem is when they make the move into pathogens, that's when we have the real problem and that happens all the time and it's actually sufficient that this happens once for a certain resistance factors anywhere, then we have to live with it.
We can't really turn back the clock. So then it's more about preventing transmission after those unfortunate events. So environmental dimensions has become high on the agenda. This is highlight a couple years ago from United Nations that says that antibiotic resistance from environmental pollution is one of the biggest emerging health threats.
They focus particularly on discharges from manufacturing, which we have worked on for a number of years. This is a picture from India, where lots of our drugs are produced. This is a treatment plant where they try to treat the wastewater that comes out from the many, many factories that are located here. The concentrations of drugs that we find in the released water here are enormous, we found up to 30 milligrams per liter of ciprofloxacin, that's way higher than what you have in the blood as a patient, that can be compared to what we find in, for example, normal sewage in Sweden, it's like 13 nanograms. And this is how big the differences is.
I don't say this because show this because 13 nanograms is very little. It actually might even have an effect, but because 30 milligrams is absolutely unacceptable, and something needs to be done about this. And indeed there is things done about it now it has taken quite a few years but there are a multitude of actions going on in the world now.
For example, India has proposed new laws to regulate antibiotic emission's based on discharge limits that myself and Johan proposed a few years ago. Also, most antibiotic producing Industries in the world are also implementing voluntary limits as we speak also which is also good initiative, of course. But it also needs to be Technical Solutions to manage this.
And that's also where we have to work together with the technological expertise, to figure out how to deal with these challenges. Now, we learned just a few months ago here that they could be challenges, even closer to us. We showed that in the sewer systems from the Sahlgrenska University Hospital we have a strong selection for antibiotic-resistant bacteria. Most likely by antibiotic residues in here. There's comes another technical challenge. How could we prevent this from happening? How do we reduce the risk of allowing these bacteria to be selected for and and to be transported further downstream to the the sewage treatment plant into to the external environment? So we have been involved in some collaborative work with technologists.
And we actually buildt Sweden's first ozonation step for sewage treatment in Knivsta that some years ago. And this was an experience to see and here we could remove basically all the pharmaceuticals from the effluent, we did like that. But of course, in other parts of the world, there might be very different technological challenges because lots of parts of the world's have no sewage treatment whatsoever.
And here we need to have very different solutions in place that works, of course. Before finishing I also want to mention one thing that is not really dealing with the environments role in antibiotic resistance. But how we use sewage to study antibiotic resistant and to do surveillance for about antibiotic-resistance.
So we use sewage because it's basically pooled fecal material from from many many thousands of individuals and of that reason if we have smart strategies, we can actually discover very rare and new emerging resistance factors which we have done in the recent past. We've also shown that we study the bacteria in the sewage, we can use their resistance patterns to predict the clinical resistant situation. And we have calibrated that across Europe for isolates and we're now trying to implement that in Africa where there is basically no clinical surveillance. We also done similar work, using meter genomics and sequencing, a DNA code of bacterial communities in sewage and I'll let Johan talk a bit more about those types of technologies and challenges relating to do that.
So, I think there's lots of opportunities to work together or not only on the environment, which I spoke about here. But also many of these other areas with expertise in in other fields of science than those that we are experts on in the University of Gothenburg. I think that and I know that there are a number of very good scientist at Chalmers, who are interested in joining forces in this. I think that this will be an interesting discussion for the future to see how we could work together on these types of challenges. So, with that, I want like to thank for the opportunity and I leave the word to Johan Bengtsson-Palme.
Thank you, Joakim. I hope that everyone can see and hear me now or at least see my slides. So I will talk a little bit now, connecting to what Joakim just said and connecting to how we can use bioinformatics to really the resistance crisis. One reason why this is important is that you might have seen a figure like this before, this is the price over time of sequencing, a billion bases of DNA. And if you multiply that by say a factor of ten year proximately have the cost of sequencing, a human genome as you can see over the past 20 years, this capacity or the price of sequencing has dropped by at least a factor, 100,000 maybe a factor of a million. The problem is that at the same time computer development has not kept up so computer development has increased in a slightly more linear fashion and it's actually tapered off a little bit in the past couple years.
So what that means is that to handle all this data that we now can generate very cheaply through sequencing. We need better analysis solutions. And this is an area where there is substantial collaboration, between the University of Gothenburg, and Chalmers University of Technology. And I will try to highlight a few of those instances here.
So we can get sequencing data and to solve the recistance crisis, or not solve it, but alliviate it a little bit in a few different ways. And one obvious way is to use it within hospitals, for resistance typing. And the reason why this is smart is that you can very easily get both an insight into what species you have in your sample, if it's a particularly troublesome strain that causes more severe infections and you can at the same same time also look at the antibiotic resistance profile of this bacterium that you've isolated or in a mixed sample actually like a urine sample. And what's really smart about this compared to just doing classical culturing of bacteria is the time. Sequencing allows you to do things much faster than just a couple hours you will have being through DNA extraction and preparing your libraries and you can start doing the sequencing on one of these modern sequencing machines. And, even in the first hour, you will get a good picture of what species you have and if it's a particularly worrisome isolate, you've you have in your sample, The antibiotic resistance profiling, take a little bit longer, but still just within hours, you have a good picture of what antibiotics might work on this bug, which is much quicker than you would get from culturing in most cases.
And this is the entire premise behind the company, 1928 Diagnostic, and that was founded on based, on research from Chalmers University of Technology in collaboration, with the University of Gothenburg. So this is a very good example of this innovation potential that there is within this field. So the entire idé here is to provide a bioinformatics platform to do these kind of really quick diagnostics based on sequencing. As Joakim mentioned, we can also use bioinformatics and sequencing to do surveillance for resistance.
And one smart point of doing surveillance is, as Joakim mentioned, is in sewage. And that's simply because sewage is a mix of poo and other things that come out in the sewers and can be from hospitals, it can be from households, and there's probably a little bit of industry material in there as well. So this provides a pretty good mixed picture of the risk system situation in for example a city And this has been used, well and what we're doing here in metagenomics is that you're taking your sample from say sewage and you isolate DNA from it and just isolate all the DNA you don't care about but there is a particular bacteria or anything. You just isolate all the DNA you can get from there and you sequence it randomly. So you will have a little bit of that and a little bit of this in this sample. And then you analyze the data and try to tease that apart, looking for, for example, resistance factors.
And if you do that, you can start stratifying trends. So for example, in this study and they have been looking at the resistance gene content in sewage in different parts of the world. So not surprisingly can see that you have higher resistance gene loads in for example, Africa and lower in Europe and North America. And what's interesting there is that you can then as you work, Joakim mentioned, you can use this as a surveillance tool and also predict what's going on in in the general population in terms of the resistance situation.
Furthermore, you can also look at specific gene categories or even specific genes like we did in this study. Where we looked at how efficiently different kinds of resistances are reduced in the wastewater treatment process and this is also something that you can compare globally, of course, and look at the efficiency of different treatment processes in different treatment plans. And this is also work that was performed in collaboration with researchers at Chalmers. Furthermore.
Knowing that we can we can do this. We can also start looking at environments that would be particularly risky environment for resistance development. So this is a study where we were looking at resistance gene abundance and resistance gene diversity.
Like, how many different kinds of resistance genes are there in different environments? And interestingly as Joakim talked about, samples from antibiotic plume from antibiotic. Samples has been exposed to antibiotic pollution from manufacturing are among the samples where you have the absolute highest abundances of antibiotic resistance genes. But if you look at diversity resistance genes, something like, air has a really high abundance of high diversity of different resistance genes, which is probably a reflection of that air is, I mean, what you sample here is a filter and that filter gets exposed to a number of different kinds of bacteria. Many of those will not be alive but still the resistance genes are there in a very diverse way. Also, we can start looking at how resistance genes are related to other factors. So in this study we looked at soil thousands of soil samples and we looked at antibiotic producing fungi and related the abundance of those fungi to the antibiotic resistance geno abundance.
As we can see that we have the pretty strong correlation between those two. So in this way, you can start teasing apart, what kind of factors that actually drives antibiotic resistance in different environments. Which is a way of sort of pointing to if there are certain risk environments again with the aim to keep particularly notable resistance genes out of the clinic. And this is the premise behind the EMBARK program that I'm coordinating, which is a JPI-AMR funded program, that has three goals.
One of them is to establish the baseline for how how common resistance is in the environment naturally or in a normal situation so that we can see deviations from this baseline. The other one is to standardize different methods for monitoring resistance in the environment. Sequencing is one of those but maybe culturing is a cheaper way to get the same kind of data.
And we also want to identify high-priority targets for monitoring so that we know what would be most what would be the highest priority to look for Finally, I also want to just briefly touch upon one more cool thing that you can do with sequence data, related to antibiotic resistance. And that is that you can actually use statistical modeling to predict how novel resistance gene looks. And this is something that colleagues have Chalmers has been working on particularly Fanny Berglund and Erik Christiansson, and I've been a little bit involved in this work, and the cool thing here is that you can predict novel resistance genes, that has a pretty low sequence similarity to known genes. But at the same time, when you express them in E.coli, they actually provide resistance to the antibiotic. So this is a way of discovering resistance genes before they are present in disease-causing bacteria so that we could actually perform proactive monitoring of these genes to see if they are getting into sewage, for example, maybe that's something that we should worry about, try to take care about.
So just briefly. What we are using here in terms of collaboration with Chalmers is, for example, shared resources, we share a lot of our computational infrastructure with researchers from Chalmers. Both on local servers but also as part of this C3Se, high performance, computing cluster. There is also a lot of the bioinformatic method development going on in collaboration with Chalmers.
And, one thing that I don't know, so much about perfect personally, but I think is really exciting is the Chalmers AI Research Center which is also starting to be integrated into a more research. And I think that's a very exciting development for the future because I think this might actually be the solution to this bioinformatic problem that we get more and more data to get more artificial intelligence in there. And that was what I had to say.
This is my little lab that has done some of the some of the analysis that I've been showing. We I have a website, microbiology.se and we also run a podcast if you want to hear more about research, that's called Microbiology Lab Pod and with that I am finished. Thank you, Joakim and thank you Johan.
I think all four speakers have have made very interesting contribution. Maybe Joakim and Johantan, pointing out how serious this really is. I mean, I was going to say painting and rather pessimistic picture.
But I chose not to I think we have a lot of opportunities also that we see from from both Martin´s and Johan´s presentations. But obviously there is a lot of work that still needs to be done. So, I'm thinking start with you, Joakim You've been leading CARe for some time now, which is a very impressive investment from the University of Gothenburg and it ends next year. So what's next and how can how can Chalmers and maybe other parts in the Gothenburg area contribute or be part of what's coming next.
Do you have any any thoughts on that? I think that We haven't made any final plans, of course it's a matter also about funding at the end of the day, What we have expressed both from Chalmers side and from the GU side is that we have an interest in collaborating. And we actually plan seminar, workshop, meeting a two-day meeting in September. Hopefully, a physical meeting Together with Chalmers scientists to see what collaborative opportunities are there and how could we build something together in the future? And I also think that we already have partly in the region as part of this at the Sahlgrenska University hospital. But I think that could also contribute to such a center in some form or the other in the future, The investment has been rather big now, for the first six years, after these first six years, there's a lot of researchers that have sort of gained speed and started to attract their own funding. So I think that there's a good possibility to run a center on a more moderate budget, also in the years to come, Okay.
I think that would be a good investment. Yeah, that sounds sounds promising, and I think this workshop in September is a good first step In these discussions. We're running a little bit out of time, but I also wanted to address sorry, Martin and Jonatan´s collaborative presentation. I'm curious Martin, with these technologies for disposing, drugs or heating up bacteria, so they kill what how What steps are necessary until we see them in the first implants, in our bodies? Where are you now? And, and sort of what are the steps ahead? That's a very good question.
It's little bit depending on which of the different technologies that we are referring to. I mean we have a regulatory framework that we need to take into consideration and these different surface technologies that we're working on, which do not include drugs, those are quicker and easier to get implemented in the clinical setting. Still, though, it takes time, I would say it's about 10 years before you can show that actually works, before it can actually be used in the clinic. Of course, it could be speeded up to some extent, but you have a first of all regulatory framework that you need to obay and and show that it's safe to use and that's not cause any harm. We also have a big challenge here and Jonatan pointed out that, it's a relatively low percentage of patients that actually get infections, though, there are high in numbers. So if you want to prove that these technologies works in the clinical setting, if you do the power analysis, you will see that, Oh, that's a lot of patients, you need a lot of patients in these clinical studies and clinical studies with lots of patience cost lots of money.
So that is, a little bit, one of the challenges that we're working on right now. So I will say that. You have to show that it's safe.
It doesn't impact the functionality in any way. And then combine that with other techniques to show that you can avoid bacterial attachment on the surfaces and so on and make things together to work out. So, I cannot give you a clear answer. I can tell you that we are now together with the department of Orthopedics at Sahlgrenska hospital, we are planning for a clinical study on these softer antimicrobial peptide based materials for for a wound healing. We have a higher number of patients getting infected wounds, I mean in the skin, compared to the biomaterial associate infections.
I think that's a good start. So as you can see, I mean, this really we need to collaborate, of course, make materials, make them safe and work together with the conditions such as Jonatan here that knows the real problem and what can be used and what materials that might I work out. Yeah. So I'm curious maybe addressing, Jonatan then. So how did you find each other? I mean, it sounds like this is some some technologies that have a lot of potential but it's not always easy to find the match with the need.
Maybe sometimes we don't even know the need, but sometimes, we don't just don't find the right person or the right person. We cannot attract that person interest. So so in your case, how did that happen and sort of, how do you foresee your future collaboration? Well I think there has been title tracks on biomaterials and infection control. And me and Martin has not collaborated before but as you mentioned it with this antimicrobial peptide project, there is a collaboration happening soon. The so I think over the last maybe five or six years has been much much more intersection between these departments of Orthopedics, and in fact, clinical infectious diseases, biomaterials, and and the Chalmers as well.
And I'm, I have a great hope that we would produce something that's really tangible in the clinical setting, since we both appreciate the magnitude of the problem and the challenges of designing studies to address this but, we'll see what happens. I mean it's a challenge is finding the right person. It's finding the right competence and also somehow establishing a good connection on the personal level. If this is going to work, that's my experience. And it is not always easy, but it seems like you're starting off on a very good foot. We also have some questions now from the audience, one question for Martin and Jonatan about bone implants, is there a difference in the bacteria level? If the implant has been sterilized by ETO or radiation? I cannot answer that question I'm afraid.
Okay. Oh, I think that would be tricky. When it comes to sterilization procedures, they're highly linked to the type of material that you want to use.
If you want to use a polymer for a certain type of implant, or if you, if you have metals, which is also most frequent for Orthopedic implants, I mean autoclavation, we know that that's very, very, very powerful tool to eradicate the bacteria, but the, the issue that I was highlighting a little bit, is that I think that when they come sterilized and packaged, I think we can, we can trust the kind of technologies there. So I think there's no bacteria, should be no bacteria, on the implants when they are packaged and delivered but when you have to open the package you have to touch them. You have to insert them and there's a kind of a time there where they might be bacteria, adding onto the surface and Jonatan you mentioned this with the skin where is typically are coming from. I don't know if you can mention something about that.
Well that would be the logical conclusion since in the clinical setting when we isolate microbes from these infections they originate from the skin floor and there are a few studies linking a specifically to certain patients and even surgeons some. So, it's unlikely that the the implant will come contaminated, but it's, of course, it's not be ruled out in every instance. And you also mentioned this with the blood supply, so it could basically approach in the later stages, I understand it.
Absolutely. Even though that's just a few percent of all the infections but I mean for a normal joint implant, the patient should have been able to use it for at least 15 years before the need for revision. So I mean, the community to me the cumulative risk is, of course, maybe one or two percent for the lifetime of the implant. I will come to Johan and Joakim in a second, but it is one more question for Martin about the use of nearly infrared radiation for eradication in the clinical setting, if you use will use and infrared or nearly infrared laser then, or is it any specific excitation wavelength that are sort of relevant? Yeah exactly.
So I mean, for this to work, you need to have a wavelength that can go through tissue, right? So this is what they refer to as the biological window. So this is in the area of 850-900 nanometers, maybe up to fourteen hundred or so. So, this is within that region.
So what we do is that we can tailor make these nanorods to a specific wavelength. So the ones that we are working with now is 859 nanometers. So then we have a diode lasers that are in that wavelength specifically.
So, so that, that that's the idea, right? So you can think of this as, as I mentioned that if you have the light on, shining onto the surgical site and onto the during the procedure, the light itself does not cause any harm it doesn't heat up or the tissue or so. So it would be to prevent these attachments and during the procedure, so to say. We don't know if you can be used for treatment, Jonatan showing me the biofilm problem here that you have something on the surface of the implant.
You want to eradicate it with antibiotics. We know that they are very, very difficult to eradicate with antibiotic as such. But if you also give a systemic kind of treatment you need extremely high concentrations of the antibiotic at the interface. And how do you get the antibiotics to get only to the interface without hurting any other parts of the body? That is the tricky part.
So, I think getting back to your question. Yes, it is specific wailing. Yeah, Thank you.
Johan and Joakim. I don't know who's best equipped to answer this question. Maybe you, you both are But there was a question also from the audience if there is any International collaboration ongoing to fight the antibiotic resistance? Especially then in the countries where we have this high amount of antibiotic resistance as you showed in the beginning, Joakim.
Are there any big efforts on the international scene? If I can say something up. Yes there is of course there is action on the on the highest level. I would say. So both WHO and United Nation, I was advising the G7 actually just a few weeks ago on bringing up the also the environmental aspects of the agenda for the all the world leaders.
Many other countries have much severe problems than we. So they really recognize how it impacts their society and their health, there are hundreds of thousands of people that are dying from resistant infections yearly. It was one report that projected that there would be many millions dying in a not too distant future. So, I think there's quite a lot of actions.
There's investment also from from industry Etc. A major problem is of course the lack of a the good economical solution for developing new antibiotics because it's not worth while to develop antibiotics today, many companies thinks because it takes, maybe a decade to develop them and then you get resistance in a few years and then they can become useless, and the ideal antibiotic to get a really good one, you should actually save it and how then do you get revenue? So, we need a new economic system also, But this is also something you lifted in your presentation that we haven't seen new gram-negative antibiotics for quite a while. So what does it mean, that it's gram-negative? And is that sort of a dead end or is that still a path that we also need to pursue? To think about new antibiotic drugs, as well as preventing infection and finding other ways? Definitely. Because it's antibiotics are extremely valuable and Jonatan would probably agree with that without them we would really have a big problems in healthcare overall. Yes, we do need to continue the quest to find new drugs also for gram-negative infections.
Absolutely. But we cannot rely on that. We need to work on both sides. That was my point with this two paths. Where we need to walk on both over, there is actually much more money invested in new drugs than it is in in preventing resistance.
And if I can, if you can just connect to that, I think one of the important lessons that we've learned from our from the resistance development is that we have to take care of this as a precious resource and I think the see part of what we're building up now would like resistance surveillance, I'm looking for novel types of resistance, genes is something that we can use to avoid quick resistance development for novel antibiotics. So I think there's, I mean, we can take a lot of the lessons that we learned from the resistance crisis and try to do better on the next generation of antibiotics. Now the that, that makes it certainly sence.
So maybe my question about whether we need new antibiotics was a bit stupid, but I think you gave a very kind answer, not not revealing my potential ignorance. I don't know. Anyway, Martin, you want to say something? Yeah, I can comment on that, also, because I talked about using antibiotics for local release and this antimicrobial peptides, for instance, I think it's very interesting. So these antimicrobial peptides are it's been known for quite many years and there's lots of research on it, but it has been challenges with their stability, with enzymes in the blood, so on so. But I think that hopefully we can see that material science, can maybe bring something helpful into this because when we use this antimicrobial peptides combined with material, so this is a contact killing all of the of the bacteria. And that is something that can be clinically implemented relatively soon.
So we are excited. We actually have products that are being developed with spin-off companies. We have a company called Amferia that are developing these soft hydrogels, as a preventive wound care plaster you can say. So you can use that to collect any bacteria in the wound, both gram-negative and gram-positive with this, this kind of electrostatic interaction. So these are fundamental physics, you can say. And not based on biological impact, you don't need to reach the core of the of the bug.
So to say players interact with its outer skin and eradicated with plants. So they are ideas. Sound quite efficiant.
I see that Joakim also, wants to add on this? Yes, I think I think antimicrobial peptides are all quite quite interesting, but I also have a slight, slight fear here. I mean, we now for all without any exception, for all antibiotics that are coming to market, they have been met by resistance. You mentioned Martin that they have low, that the peptides have low propensity for antibiotic resistance. Let's say that same thing happened as for all other antibiotics that have come into massive use that you get resistance to it, then you don't just get resistance to a compound that is produced by some fungi. Where you actually get resistance to our own innate defense. That's very different than getting resistance to a drug that we are.
You get resistance to the defense that we every one of us use every day to fight resistance. So I really would like to see much more research going into. What are the possible resistance mechanisms towards antimicrobial peptides? Because if there is, if we get them in there as a result of massive use of antimicrobial peptides in the clinics. We could face a very different and challenge than the one we have now and it may be even worse.
I think I'm afraid we have to leave that as a very important cliffhanger for your discussions in September because I already let you I already asked you too many questions but it's time for a break. Thank you so much for the discussion and the presentations. We will be back here again at the 10:30. Thank you. Thank you.
2021-05-17 20:11
