The 12+ 1 innovations of MEDUWA

In MEDUWA-Vecht(e) 12+1 innovations have been developed:

Innovation 1: Watershed Information System (WIS)

Innovation 2: Grey Water Footprint

Innovation 3: Regional Risk Assessment

Innovation 4: Nanofiltration

Innovation 5: Mobile Water Analysis Device

Innovation 6: Herbal Antibiotic Replacement

Innovation 7: Wireless Groundwater Monitoring

Innovation 8: Farm Animal Monitoring

Innovation 9: Plasma Activated Water

Innovation 10: Phytoremediation

Innovation 11: Biopharmaceuticals

Innovation 12: Algal Antibiotic Replacement

Innovation 12+1: Product Chain Approach

Innovation 1: Watershed Information System (WIS)

Partners: Geoplex GIS GmbH, University of Osnabrück IUSF, Wetsus, Radboud University, University of Twente

The Institute of Environmental Systems Research of Osnabrück University, Geoplex GIS GmbH, Wetsus, Radboud University, and University of Twente, pooled their efforts and experience to set up a digital platform for risk assessment for a wider audience, the Watershed Information System (WIS). The basis of the WIS is the Geographyreferenced Regional Exposure Assessment Tool for European Rivers, or GREAT-ER model.

The aim of the WIS is to visualise and evaluate the complex behaviour of medicines and their potential effects on ecology and the health of local communities with regard to water. This has been assessed under both wet and dry weather conditions. Wetsus analysed the medicines and resistant bacteria (ESBL E. coli) in the entire case study area. The model-calculated concentrations of medicines and bacteria were compared with values measured in the samples in order to improve the model. Waterschap Zuiderzeeland (the regional water authority in the Dutch province of Flevoland) provided data on the efficiency of removal by sewage treatment plants.
The results of the modelled scenarios formed an important basis for the risk assessment carried out by Radboud University. In the WIS, the predicted concentration and the ecological risk of 15 medicines for each segment of the Vecht(e) river basin can be retrieved. The selection pressure of antibiotics can also be retrieved for any location.

The digital platform is also used by other project partners in the MEDUWA-Vecht(e) consortium to visualise and evaluate the effectiveness of their innovations. The WIS can be used to simulate the potential contribution of each developed measure to reducing the emission of medicines and multi-resistant bacteria for the entire watershed. In this way, the platform is also suitable for communication and decisionmaking on measures to reduce pollution from medicines.

Wetsus, European knowledge centre for sustainable water technology in Leeuwarden, together with Osnabrück University, analysed and modelled Escherichia coli (E. coli) bacteria as well as antibioticresistant E. coli, in the entire Vecht(e) watershed as an indicator of faecal pollution. Insights into the fate of bacteria in a catchment area can help predict human exposure to (multi-resistant) bacteria, for example during recreational activities in water or via drinking water and irrigation of food crops.

At 25 locations, the surface water of the Vecht(e) and its tributaries was sampled repeatedly. In addition, samples from the outflow of sewage treatment plants and ditches in agricultural areas were taken throughout the basin. The samples were analysed for the presence of E. coli by means of cultures. The proportion of the E. coli that can produce ESBL or carbapenemase enzymes is also determined. At seven locations, both E. coli and the resistant variants were isolated from each sample taken at that location. Concentrations were highest in winter. The GREAT-ER model was used to model concentrations in the various locations.

Based on the E. coli concentrations found and modelled, it was concluded that the Vecht(e) watershed does not have water quality that is safe for swimming everywhere. At a number of these bacterially-contaminated locations, bathing takes place on summer days. What this means for public health has not yet been investigated.

The results obtained have been incorporated in the Watershed Information System (WIS).

Innovation 2: Grey Water Footprint

Partners: University Twente Water Management, Geoplex GIS GmbH, Osnabrück University

The Water Footprint is a well known indicator of the volume of water consumed for the production of goods and services. The Water Footprint is suitable for demonstrating water use issues to the general public, the commercial sector, policy makers and decision makers. In addition to the Water Footprint, a tool called the ‘Grey Water Footprint’ has now been developed. This new concept provides a measure of how much water is needed to reduce the concentration of a pollutant in water to a level that is no longer toxic according to water quality standards. This amount of water depends on the amount and toxicity of a given pollutant in the water.

In the MEDUWA-Vecht(e) project,the University of Twente’s Multidisciplinary Water Management research group calculated the Grey Water Footprint of various human and veterinary medicines for the German-Dutch Vecht(e) watershed. The largest Grey Water Footprint from human medicine use in the area was found for the hormone ethinylestradiol, commonly used in the birth control pill: amounting to 16 billion cubic metres of water per year. In other words, it would take 16 billion cubic metres of water per year to reduce the concentration of this substance in the Vecht(e) Basin to non-toxic levels. This hormone originates exclusively from households and 95% for this hormone comes from the Dutch part of the catchment area, due to the higher number of inhabitants and higher usage.

The largest Grey Water Footprint originating from hospitals was found for the antibiotic, ciprofloxacin.

The largest Grey Water Footprint from livestock farming in the catchment area was found for the antibiotic amoxicillin. The results also show that a considerable amount of manure produced in the Vecht(e) region is exported. This means that pollution from veterinary medicines takes place outside the region: 35% of the German and 55% of the Dutch share of pollution is outside the catchment area.

The results of the Grey Water Footprint analysis are visualised in the Watershed Information System (WIS) developed by project partners Geoplex GIS GmbH and Osnabrück University. Interactive maps show the footprint of medicines per municipality, region, hospital or livestock product (dairy products, beef, pork, chicken and eggs).

Innovation 3: Regional Risk Assessment

Partners: Radboud University Environmental Sciences, University Osnabrück, Wetsus

The Human and Ecological Risk Assessment Group of the Radboud University Nijmegen uses large data sets, advanced computer techniques and statistical models to assess the environmental risks of hazardous substances.

The main objective of this research group in MEDUWA was to optimise the environmental risk assessment of pharmaceuticals so that water managers and policy makers are better able to protect the environment and public health. The studies carried out for the Vecht(e) watershed serve as a model for future international risk assessments of medicines in the environment.

In cooperation with the Institute of Environmental Systems Research of Osnabrück University and Wetsus, the group mapped the risks of some medicines in the Vecht(e) River.

For aquatic plants and aquatic animals, the concentrations of some medicines in Vecht(e) water are sometimes too high.

On the basis of current knowledge, the public health risks for people who come into contact with the water of the Vecht(e) via drinking water, sport fishing and swimming are small.

In addition, a literature study has been conducted into the relationship between the antibiotic resistance levels of microbes and antibiotic concentrations in water. The degree of antibiotic resistance of bacteria in surface water is related, among other factors, to the presence of antibiotics in sewage, surface water and sediment. Follow-up research will focus, among other things, on the risks associated with combinations of medicines and biologically active transformation products of medicines.

The results obtained were partially incorporated in the Watershed Information System (WIS).

Innovation 4: Nanofiltration

Partners: NXFiltration BV, Weil Wasseraufbereitung GmbH, Saxion AUS

NX Filtration BV and Saxion University of Applied Sciences in Enschede together with Weil Wasseraufbereitung GmbH from Osnabrück, three partners in the MEDUWA-Vecht(e) project, combined of “brains, passion and skills” for fruitful cross-border cooperation. Together, they took a big step towards introducing a nanofiltration product that removes micro-pollutants from the effluent of sewage treatment plants.

The nanofiltration membrane is a new and specialised membrane developed by NX Filtration. This membrane has an extremely thin selective layer. Water and minerals can pass through this layer, but the pores of the layer are too small for most micro-pollutants. The result is that the micro-pollutants that are still present in the current effluent are trapped by the filter, resulting in clean and safe water. In addition to pharmaceuticals, the nanofiltration process also removes other components of concern such as microplastics and nanoparticles, such as titanium dioxide in paint and sunscreen, that cannot be filtered out or broken down by other treatment technologies such as UV, ozone and activated carbon. Potential applications include not only the treatment of effluent for direct reuse or replenishment of groundwater, but also the direct treatment of surface water to produce water suitable for drinking.

In the MEDUWA-Vecht(e) project, the partners demonstrated the efficiency and effectiveness of this technique at a number of locations in both the Netherlands and Germany. They started at the level of one-day laboratory experiments and progressed to a test bed at the Glanerbrug sewage treatment plant (NL). There, tests were carried out to demonstrate the stable, long-term operation of nano filtration. In the last phase of the project, long-term tests were performed with several versions of the nanofiltration membrane under different process conditions at various sewage plants in the Vecht(e) catchment area. Follow-up research focuses on optimising the processing of the remaining concentrate.

Innovation 5: Mobile Water Analysis Device

Partners: InProSens UG

The start-up InProSens UG develops innovative sensors based on optical measurement technology. These devices can be used to gain direct insights into the composition of both liquid substances and solid materials.

Until now, water samples had to be sent to a laboratory to determine the level of medicines in water, soil and food. There, these samples are prepared using complex methods and then analysed with ordinary laboratory instruments. Analysis results are therefore usually only available a few days after sampling. This also makes the analyses expensive. Moreover, these are only samples. Direct intervention, for example, to adjust the wastewater flows on the basis of the analysis results, is therefore not possible.

In the MEDUWA-Vecht(e) project, InProSens has focused on developing a measuring device with which liquid samples can be analysed continuously and within a few seconds on site, for example in a sewage treatment plant. In this way, the concentration of pollutants can be observed over a longer period of time.

The sensor system developed is based on the non-destructive, chemical-free principle of optical radiation. The sample to be measured is irradiated by a sensor using light in the nearinfrared range. The sample absorbs a characteristic part of the light. The part of the light that is not absorbed by the sample, is reflected back to the sensor, which receives an individual absorption spectrum from each substance, as characteristic as a person’s fingerprint.

The sensor will be ready for use in the chemical industry from 2021. The component of the sensor for measuring very low concentrations of medicines still needs further optimisation. In cooperation with the partners in the MEDUWA consortium, InProSens has already been able to test the sensor in a realistic pilot sewage treatment plant.

Innovation 6: Herbal Antibiotic Replacement

Partners: Europa Ayurveda Centre (EAC) in Witharen (NL), the institutes of Hygiene and Medical Microbiology of the Münster University Medical Centre (UKM) and Wetsus, Leeuwarden (NL)

These partners carried out research into the antimicrobial properties of plants. According to Ayurvedic health science, plant extracts also have a bacterial-inhibiting effect. The EAC cultivated 15 different water plants (the Bhima Choorna formula) for this purpose, for which the antibiotic effect on spore-forming, skin, environmental and waterborne bacteria could be clearly demonstrated.

According to the UKM, the use of the extracts as a substitute for antibiotics in veterinary and human medicine is therefore conceivable and will now be tested in further studies and projects. In the next phase, randomised, doubleblind experiments will be conducted.

The Bhima Choorna formula will be further developed as a natural antibiotic for animals and humans. With this, the Europe Ayurveda Centre hopes to provide an effective solution to the huge problem of antibiotic resistance and the many side effects of current antibiotics. The product is expected to be on the market in 2024.

For the MEDUWA study on the antibiotic effect of ayurvedic plants, classical microbiological methods as well as new culture-independent techniques and procedures at cellular and molecular levels, including flow cytometry and polymerase chain reaction (PCR), were applied and further developed by UKM.

Innovation 7: Wireless Groundwater Monitoring

Partners: Novaris Orbit Technology BV

Gaining insight into the hydrological regime in soil is not only important for agriculture in order to support green meadows and good yields. Data on soil permeability and groundwater levels are also useful for mapping the distribution of underground water flows containing contaminants such as salts, fertilisers, medicines and pesticides. These data for soils are not easy to obtain. Existing measuring systems are not only expensive, but also difficult to install and the data difficult to interpret.

With the aim of gaining better insight into the hydrological regime in soil, Novaris Orbit Technology BV in Saasveld has developed a new wireless and energy-efficient underground measuring system as part of the MEDUWA-Vecht(e) project. The sensors are entirely buried in the soil and data are transmitted from these. The meadow or field can therefore continue to be used normally; there is no equipment or antenna above the ground. This also makes it possible to place sufficient sensors in a meadow so that an accurate measurement can be obtained for the management of water for an entire plot. All the information from the sensors is transmitted via an underground wireless network to a central point, usually at the farm itself.

Depending on the availability of suitable sensors, data on groundwater quality can be collected in addition to water quantity. The farmer or the water authority can thus determine almost continuously whether there is sufficient water in the soil, whether the permeability of the soil and the quality of the water are good, and also where the groundwater flows to. Irrigation and fertiliser applications can then be better adjusted to soil conditions, and groundwater managers gain better insight into the spread of contamination.

In the MEDUWA project, this wireless measuring system has been tested in several test fields and will be further developed in the coming years.

Innovation 8: Farm Animal Monitoring

Partners: Noldus Information Technology BV, Demcon BV, Ubisense GmbH

Noldus Information Technology from Wageningen has been developing integrated systems for animal behaviour research since 1989, with the aim of improving animal health and welfare.

With the trend towards larger stalls for groups of farm animals, it is becoming increasingly important to be able to monitor the behaviour, health and welfare of individual animals in those groups. Individual monitoring allows for early detection of disease and rapid targeted responses, thus contributing to a reduction in excessive applications of medication. Individual monitoring also helps to identify animals exhibiting undesirable behaviour, such as feather pecking in poultry and tail-biting in pigs.

Traditional methods of monitoring, such as live observation and video-based manual scoring of behaviour, are subjective and time-consuming. In the MEDUWA-project, a robust and accurate system for automated observation of animals was further developed, allowing multiple types of animal data to be collected. Using ultra-wideband radio technology, the TrackLab™ system allows real-time individual tracking of large numbers of animals over large areas with high spatial accuracy and a sufficient number of readings.

The next step was to increase the system’s ability to automatically detect specific behaviours. This worked well: eating behaviour (eating and ruminating) can now be recognised with 95% accuracy. Locomotion including lying down and standing up can be detected with respectively 87% and 81% accuracy.

The ultra-wide-band sensors were developed by project partner Ubisense GmbH in Düsseldorf. Demcon BV, project partner in Enschede, developed a prototype of a body temperature sensor, based on subcutaneous measurement and wireless data transmission. Noldus IT focused on developing the software: a versatile and userfriendly tool for data collection, storage, visualisation and analysis. Together with the sensors and data processing hardware, this has resulted in an integrated solution for livestock research and precision agriculture.

Innovation 9: Plasma Activated Water

Partners: VitalFluid, University Hospital of Münster (UKM) IfMM, Radboud University Medical Centre

VitalFluid BV from Eindhoven is specialised in plasma technology, an oxidation process that makes exclusive use of air and electricity. Air is brought into a plasma state using electricity and then brought into contact with the water to be treated. Reactive oxygen and reactive nitrogen from the air dissolve in the water and break down the contaminants.

The MEDUWA-Vecht(e) project investigated whether plasma technology could be used to render medicines and micro-organisms harmless at the source before they are discharged into the sewage system. Since the concentration of pollutants is highest here, this is the most energy-efficient means of reducing or eliminating harmful substances. By developing the plasma oxidation technology on a small scale and in modular form, it can be used flexibly at the source for many water purification applications, for example, mobile units that patients can connect to the toilet during treatment with medication at home.

The disinfecting effect of this technique was investigated by the Institutes of Hygiene and Medical Microbiology of the University Hospital in Münster (UKM). The plasma-activated water demonstrated a strong bacterial-suppressing effect in numerous test series and the quantity of living bacteria was minimised. Waterbacteria and physiologically stable bacteria were also killed. According to UKM, the oxidation technique can therefore be used in hygiene processes such as toilet flushing or surface cleaning.

The Molecular Epidemiology Research Lab at the Radboud University Medical Centre in Nijmegen has investigated whether medicines can be removed from water using this technique. On a laboratory scale, it appears to be possible to use plasma-activated water to break down medicines such as cyclophosphamide, diclofenac, metoprolol and paracetamol into a cocktail of hundreds of smaller molecules with reduced toxicity. The remaining level of toxicity is subject of further research. In any case, degradation by plasmaactivated water appears more effective than by conventional techniques, such as UV. The technique has already been tested on a small scale with urine from patients. This has given rise to the idea of purifying urine from day care patients before it is flushed into the sewer system. The Radboudumc will install a test unit in the hospital for this purpose.

Innovation 10: Phytoremediation

Partners: Europa Ayurveda Centre (EAC) in Witharen (NL), the institutes of Hygiene and Medical Microbiology of the Münster University Medical Centre (UKM) and Wetsus

These partners carried out research into the purifying properties of ayurvedic plants (phytoremediation). In this context, it was investigated whether these plants can purify water contaminated by medicines.

It was demonstrated that a set of five water plants is capable of reducing concentrations of medicines such as tetracycline, metformin and erythromycin in the water. What exactly happens to the medicines needs to be investigated further. For example, other variables that can influence the fate of medicines, including natural UV radiation, should be excluded in follow-up research.

Innovation 11: Biopharmaceuticals

Partners: Amrif BV, Alloksys BV, TDI BV, Aix Scientifics CRO

Alloksys Life Sciences BV, AMRIF BV and TDI BV based in Wageningen (NL) are companies developing medicines based on alkaline phosphatase (AP), a non-toxic biodegradable enzyme. AP has the potential to both prevent complications and avoid the use of various side-effects-causing and environmentallyharmful and -persistent anti-inflammatory agents as well as antibiotics.

The companies have been working on the use of AP during major surgical procedures to prevent complications, such as renal failure due to the release of inflammatory substances during and after surgery. AP also prevents the need for longterm reliance on of large amounts of various post-operative medicines.

Supported by the MEDUWA-Vecht(e) project, a clinical study with 1250 cardiac surgery patients was started. In addition, clinical studies were started for the use of AP in kidney transplants and for burn patients, which are also situations where large amounts of medicines are used. Furthermore, a study with COVID-19 patients was initiated, aimed at avoiding the need for ICU admission and the associated need for large amounts of medicines. Aix Scientifics, an experienced clinical research organisation based in Aachen, has supported the Dutch partners in carrying out these trials in various hospitals.

In addition, AP is being targeted at reducing chronic inflammation, which is thought to contribute to conditions such as diabetes, obesity, and neurodegenerative diseases such as Parkinson’s disease. In the case of diabetes, the enzyme may prevent use of the environmentally harmful metformin.

The companies have also conducted a study to reduce antibiotic use in piglets. Disruption of the intestinal barrier system, accompanied by indigestion and diarrhoea, is a common condition in piglets for which antibiotics are commonly used. The use of AP in piglets is expected to remedy this post-weaning syndrome.

Finally, the development of oral applications (pills or capsules) was a major hurdle in making AP treatment possible. AP, if administered orally, needs to be protected from stomach acid. New sources of AP have also been sought. Currently AP is extracted from the intestines of cows. AP production from genetically-engineered plants is a less expensive alternative which may be applied in the near future.

Innovation 12: Algal Antibiotic Replacement

Partners: Microganic GmbH, University Hospital of Münster IfH, Wetsus a.o.

The use of medicines plays a major role in modern animal husbandry. The animals themselves, the quality of the food they provide and the environment suffer from the overuse of medicines, especially antibiotics. Micro-algae can reduce the unnecessary reliance of medicines. Scientific studies show that microalgae have positive properties and can make a valuable contribution to a healthy diet for humans and animals. Micro-algae are edible, and although they have been on the menu in Asia for centuries, they are still not well-known as a food to Europeans.

The Melle-based company, Microganic GmbH, is a partner in the MEDUWA-Vecht(e) project and a specialist in the production of micro-algae as an ingredient for animal feed and food. Their idea is to use the positive effects of micro-algae to prevent or mitigate the development of diseases using a sustainably-cultivated raw material that is natural and entirely plant-based – a clear advantage over reliance on environmentallypersistent medicines. Micro-algae can be used advantageously in the feed sector for farm animals or pets, but also as food supplements for human consumption. The technical processing of micro-algae in a wide variety of existing standard feeds is generally possible without any problems. In this way, the health of animals and humans can be promoted naturally and easily, and excessive use of medicines can be avoided.

The MEDUWA-Vecht(e) project investigated whether and which micro-algae can positively influence the health of pigs. To this end, selected micro-algae were incorporated into pig feed and fed to the animals over a period of time. German and Dutch scientific institutions and companies were involved in the research to study the effects in the laboratory and in practice. The results of the feeding trial showed that the selected algae indeed had positive effects on the health and growth of the pigs. Further research is needed to find out more precisely how and in which situations the microalgae can best fulfil their potential to promote animal health.

Innovation 13: Product Chain Approach

The 13th innovation is the product chain approach. Measures have be developed along the entire life cycle of the medicine (the so called medicine, product or responsibility chain), with emphasis on the beginning of this chain.

The aim of MEDUWA-Vecht(e) was to show that a complex and dynamic issue with an ecological and societal impact of global proportions, such as the medicinal environmental cycle, can be addressed in multiple phases of the life cycle of the medicine by multiple sectors (i.e. human health care, veterinary medicine, environmental management, government, industry, civil society initiatives) in a coherent manner.

The solution to this problem depends not only on innovation in knowledge and technology. The way in which (semi-)governmental bodies, universities, innovators and other actors communicate and cooperate is also decisive. In practice, this requires inclusive transdisciplinary, cross-sector and cross-border cooperation. Each actor has the knowledge, influence and ability to develop solutions and change processes at their own specific level in the product chain.

The concept for the MEDUWA-Vecht(e) project was designed by Stichting Huize Aarde. The practical implementation of the MEDUWA-concept could be brought to a successful conclusion thanks to the close cooperation of Osnabrück University, The Integrated Assessment Society (TIAS) and EUREGIO.