Periodic Reporting for period 1 - STIMULUS (Stimuli Responsive Materials for the Rapid Detection and Treatment of Healthcare Associated Infections)
Reporting period: 2020-10-01 to 2022-09-30
Healthcare-Associated Infections (HAIs) are bacterial infections obtained as a result of clinical treatment, e.g. following medical intervention. HAIs are a problem of tremendous proportion as more than 4 million EC citizens get infected annually. The ECDC estimates 147,000 HAI-related deaths in Europe each year, largely stemming from wound infections. These alarming facts motivate the urgent need to develop novel medical devices, particularly wound dressings, which rapidly signal and prevent or eradicate invasive bacterial colonization following a stimulus. Current antimicrobial coatings rely on slow, passive diffusion of antimicrobials. Hence the antimicrobial may not be sufficiently concentrated to eradicate the infection; such low-concentration zones promote the evolution of resistance.
The research focus of STIMULUS is to develop new solutions for wound dressings that greatly reduce the risk of bacterial infection in the wound. New materials will be invented and tested that help clinicians and patients identify if an infection is beginning and which can be used for targeted treatments that avoid an increase in antibiotic resistance. Further, we aim to improve methods to test medical devices for wound dressings and to implement our solutions in wound dressing platforms that can be scaled for production by leading industrial partners.
Integrated with this research, we will create a lasting and comprehensive training program for young researchers, making them suitable for leading research on advanced materials for medical devices.
The research focus of STIMULUS is to develop new solutions for wound dressings that greatly reduce the risk of bacterial infection in the wound. New materials will be invented and tested that help clinicians and patients identify if an infection is beginning and which can be used for targeted treatments that avoid an increase in antibiotic resistance. Further, we aim to improve methods to test medical devices for wound dressings and to implement our solutions in wound dressing platforms that can be scaled for production by leading industrial partners.
Integrated with this research, we will create a lasting and comprehensive training program for young researchers, making them suitable for leading research on advanced materials for medical devices.
After being impaired in recruitment, training, and mobility interactions during the COVID pandemic, STIMULUS has made rapid progress toward its goals in 2022.
We have developed two novel dyes, which are stable in a wound environment but change their color when a bacterial infection starts. Bacteria will change the pH in the wound from a healthy pH to one that suits their development. These dyes are precisely tuned to change color when this occurs. A doctor can visually inspect a wound dressing that has these dyes incorporated to decide on a proper cause of action without opening the wound unnecessarily and risking infection or impairing the healing process.
In a theranostic approach, i.e. combining automatic diagnosis and treatment of a disease in one material, we have demonstrated several wound dressing materials that can store molecular drugs but release them as pathogens multiply.
In one approach, a soft wet matrix provides a good protective environment for wound healing and stores drugs entrapped within. It becomes a liquid to release the stored drugs when enzymes secreted specifically by bacterial pathogens cut linkers within the material. In an alternative approach that could be optimized with any similar wound dressing, we demonstrated that we could make containers small as viruses, which release their contents when enzymes degrade them.
Building on previous work from the consortium, we have already developed one test built on lipid vesicles dedicated to point-of-care detection of Group B Streptococcus (GBS) infection. These are small containers similar to parts of cells that release their contents when GBS is present. The result is an easy optical readout that tells whether these bacteria are present. GBS infections are a severe health risk for neonates, and lacking a fast, accurate, and easy-to-use point-of-care test for mothers before birth.
STIMULUS researchers have also developed tools for how to kill bacteria inside a wound dressing without opening it. Small nanoparticles, either made of carbon or of inorganic materials, so-called quantum dots, were synthesized that can absorb light and create reactive oxygen species with the energy input from the light. Reactive oxygen species are especially dangerous to bacteria, destroying them at high concentrations. We showed that these nanoparticles could be incorporated into polymer coatings that are antimicrobial, and by varying the light intensity, up to 100% of the bacteria in proximity to the coating were killed. This approach has the advantage of killing bacteria by a physical effect that circumvents the rapidly increasing problem of causing antibiotic resistance. This approach has the advantage that a doctor can trigger the treatment at his or her discretion.
In an additional approach to finding antimicrobial therapies for wound dressings that will not risk triggering antimicrobial resistance, we have developed several leads to make antimicrobial peptides that do not exist in nature. These mimic properties of the innate immune system of many animals, which attack bacterial membranes and destroy them by secreting small molecules that insert specifically into material membranes. In STIMULUS, we have developed several such leads, showing very high efficacy in killing bacteria, including then incorporated into wound dressing materials from the consortium.
Finally, we have developed new models of biofilms relevant to wound healing, which could increase the predictability when antibiotic wound dressing therapies are tested in the lab. These take into account that a complex community of mutually competing and supporting microbes adhering to the surface protected by secreted matrix develop in a wound, which can be more difficult to kill than what is realized in standard tests on the killing of single types of bacteria that are free in solution.
We have developed two novel dyes, which are stable in a wound environment but change their color when a bacterial infection starts. Bacteria will change the pH in the wound from a healthy pH to one that suits their development. These dyes are precisely tuned to change color when this occurs. A doctor can visually inspect a wound dressing that has these dyes incorporated to decide on a proper cause of action without opening the wound unnecessarily and risking infection or impairing the healing process.
In a theranostic approach, i.e. combining automatic diagnosis and treatment of a disease in one material, we have demonstrated several wound dressing materials that can store molecular drugs but release them as pathogens multiply.
In one approach, a soft wet matrix provides a good protective environment for wound healing and stores drugs entrapped within. It becomes a liquid to release the stored drugs when enzymes secreted specifically by bacterial pathogens cut linkers within the material. In an alternative approach that could be optimized with any similar wound dressing, we demonstrated that we could make containers small as viruses, which release their contents when enzymes degrade them.
Building on previous work from the consortium, we have already developed one test built on lipid vesicles dedicated to point-of-care detection of Group B Streptococcus (GBS) infection. These are small containers similar to parts of cells that release their contents when GBS is present. The result is an easy optical readout that tells whether these bacteria are present. GBS infections are a severe health risk for neonates, and lacking a fast, accurate, and easy-to-use point-of-care test for mothers before birth.
STIMULUS researchers have also developed tools for how to kill bacteria inside a wound dressing without opening it. Small nanoparticles, either made of carbon or of inorganic materials, so-called quantum dots, were synthesized that can absorb light and create reactive oxygen species with the energy input from the light. Reactive oxygen species are especially dangerous to bacteria, destroying them at high concentrations. We showed that these nanoparticles could be incorporated into polymer coatings that are antimicrobial, and by varying the light intensity, up to 100% of the bacteria in proximity to the coating were killed. This approach has the advantage of killing bacteria by a physical effect that circumvents the rapidly increasing problem of causing antibiotic resistance. This approach has the advantage that a doctor can trigger the treatment at his or her discretion.
In an additional approach to finding antimicrobial therapies for wound dressings that will not risk triggering antimicrobial resistance, we have developed several leads to make antimicrobial peptides that do not exist in nature. These mimic properties of the innate immune system of many animals, which attack bacterial membranes and destroy them by secreting small molecules that insert specifically into material membranes. In STIMULUS, we have developed several such leads, showing very high efficacy in killing bacteria, including then incorporated into wound dressing materials from the consortium.
Finally, we have developed new models of biofilms relevant to wound healing, which could increase the predictability when antibiotic wound dressing therapies are tested in the lab. These take into account that a complex community of mutually competing and supporting microbes adhering to the surface protected by secreted matrix develop in a wound, which can be more difficult to kill than what is realized in standard tests on the killing of single types of bacteria that are free in solution.
STIMULUS has progressed beyond the state-of-the-art by adapting materials to the specific problem of treating bacterial infections in wound dressings while avoiding the critical problems of using antibiotics unnecessarily (when there is no infection), targeting the pathogens, or having to open the wound (dressing) to inspect if an infection is present. We have accomplished that by creating polymer materials that degrade in response to environmental changes caused by pathogens or the release of substances from these bacteria. The degradation is used to either create a change of color of the wound dressing, which can easily be identified by a clinician and lead to action or to directly release antimicrobial compounds at a sufficiently high concentration to kill the infection. We have also broken new ground in using nanoparticles incorporated into wound dressing materials that can destroy bacteria in their vicinity using light to activate the destruction. These demonstrators have been shown in lab experiments on model systems developed by STIMULUS, which should improve the predictability of the testing of wound dressing materials.
Until the end of the project, we expect to launch more successful platforms building on the same principles. We expect to have demonstrated all platforms in vitro and in vivo on improved models for predicting clinical success. Further, we aim to have implemented the most successful materials in a scalable format compatible with industrial production.
First and foremost, at the end of this project, we will have trained 15 transdisciplinary scientists to lead the development of antimicrobial medical devices, specifically in the area of wound dresses, to take up a career in either academia or industry.
In the extension, we will have contributed greatly to reducing patient suffering from wound infections, which also reduces large costs in the European healthcare system.
Until the end of the project, we expect to launch more successful platforms building on the same principles. We expect to have demonstrated all platforms in vitro and in vivo on improved models for predicting clinical success. Further, we aim to have implemented the most successful materials in a scalable format compatible with industrial production.
First and foremost, at the end of this project, we will have trained 15 transdisciplinary scientists to lead the development of antimicrobial medical devices, specifically in the area of wound dresses, to take up a career in either academia or industry.
In the extension, we will have contributed greatly to reducing patient suffering from wound infections, which also reduces large costs in the European healthcare system.