Innovation
Innovation examples
HealthToxicologyInnovationIn vitro
Development of 3D liver spheroids
Human-based in vitro models are increasingly being used in the hepatology field. And in addition to the obvious ethical arguments, they offer several advantages over the classical animal models. One of them is the ability to perform mechanistic research at the molecular level in a well-controlled setting and reduce species differences. These liver-based in vitro models can range from simple monolayer cultures of hepatocytes to the liver-on-chips systems in which all liver cells are cultured in a 3D configuration on a microfluidic platform. Liver-based in vitro models must be selected on a case-by-case basis and should fit the purpose of the research, which might go from fundamental to translational research.
Innovation examples
HealthToxicologyInnovationIn vitro
Platform for in vitro airborne inhalation testing
The air-liquid interface (ALI) technique uses lung cells cultured on a tiny polymer membrane in a cup. On one side of the membrane is a liquid containing the medium necessary for the cells to survive, while the other side is in contact with air. This is similar to the situation in the human lung. The compound to be tested is administered via an aerosol, vapor, or gas to mimic the situation in human lungs. By monitoring different parameters in the cell model before and after the compound is added, it is possible to measure the effects on lung cells. Depending on the test to be carried out, the lung cells can come from different regions in the respiratory tract and even from a variety of people, including individuals who smoke a lot or have specific diseases such as chronic obstructive pulmonary disease or asthma.
In vitro ALI inhalation testing (https://doi.org/10.1021/acs.est.7b00493) adds value for e.g. pre-clinical trials and research in the pharmaceutical industry and testing (new) compounds for the chemical sector and beyond. The advantages of ALI inhalation testing are that it is a non-animal method, it reduces the use of in vivo experiments, pre-clinical testing with human-derived cell models is more realistic and limits clinical trial failures and it provides faster and more efficient testing of compound
Innovation examples
HealthInnovationIn vitro
Using skin and mucosa models to replace animal testing
The skin and mucosa are important tissues that differ between species in health and disease. The group of Sue Gibbs works on the development of advanced in vitro models that mimic these two tissues, specialising in immunity models and organ-on-a-chip technologies. They use skin models to study for example melanoma, skin allergies, eczema, burns and healing wounds. Dental models are used for the safety of materials used in dentistry, for example to test the quality of the implant and false tooth when it comes to attaching to the soft tissue. Their ambition is to expand into the field of multi-organ technology to make even more relevant models for the human skin and mucosa.
Click on the link in the video to watch more or read the interview with Sue he[https://vu.nl/en/research/more-about/using-skin-and-mucosa-models-to-replace-animal-testing]re.
Innovation examples
HealthInnovationData
Using data and computational modelling in biomedical research
Bioinformatics and systems biology hold great promise to translate the wealth of biological data into meaningful knowledge about human health and disease. The group of Bas Teusink helps biologists to deal with high throughput data, for example metabolomics (how cell metabolism works) and proteomics (how protein networks work) from patient material or cell cultures. This can help to better understand disease mechanisms and aid drug targeting or personalised medicine. In the future, combining data from different models (in vitro, in vivo and human data) could become a digital model of humans, or a “ digital twin”.
Click on the link in the video to watch more or read the interview with Bas (and Jaap Heringa) he[https://vu.nl/en/research/more-about/using-data-and-computational-modelling-in-biomedical-research]re.
Innovation examples
HealthInnovationIn vitro
Treating genetic heart disease using engineered heart tissue
Some heart disease are caused by a gene mutation in the cardiac muscle cells. People with this genetic disease are affected it between the ages of 20 and 40, and there is no preventative treatment for this. The group of Jolanda van der Velden works on the development of engineered heart tissue made from human stem cells to unravel disease mechanisms and test drugs to treat the disease. They use different kinds of stem-cell-based cultures. 2D cell cultures are useful to test a large number of candidate drugs, while patient-derived stem cells that are differentiated in heart cells can help to get detailed understanding of the disease and test the most promising treatments.
Click on the link in the video to watch more or read the interview with Jolanda here (https://vu.nl/en/research/more-about/treating-genetic-heart-disease-using-engineered-heart-tissue).
Innovation examples
HealthInnovationIn vitro
Using human organoid technology to treat viral infections in children
Viral infection in (very young) children can be detrimental to their neurological health. The mechanisms of some viruses work very differently in children compared with adults, which is not well understood yet. The research group of Dasja Pajkrt studies viral infections in children from the clinic by using human-derived organoids. They focus on three groups of viruses that can severely affect children: picornaviruses (responsible for illnesses like meningo-encephalitis and sepsis), cytomegalovirus (which can cause severe disabilities in children born with this virus) and HIV. The human-derived organoids or multi-organ systems allow for detailed mechanistic analysis of the disease and possible treatments that can be brought back to the clinic.
Click on the link in the video to watch more or read the interview with Dasja here (https://vu.nl/en/research/more-about/using-human-organoid-technology-to-treat-viral-infections-in-children).
Innovation examples
HealthInnovationIn vitro
Tumor-on-chips to study delivery of protein therapeutics
Valentina is a PhD candidate at the Department of Biochemistry at Radboudumc. Her research focuses on developing and applying organ-on-chip technologies, such as tumor-on-a-chip systems, to study the tissue-specific and cytosolic delivery of protein therapeutics. Valentina's research has also aimed at bridging the gap between engineers and biologists, promoting the use of microfluidic organ-on-chip technologies to answer more relevant biological questions. One example of this is the development of a mathematical model that could be applied to study drug delivery and diffusion in a tumor-on-a-chip system and to extrapolate possible outcomes of the delivery of therapeutic proteins to tumors in the human body. Another collaboration led to the development of a tumor-on-a-chip where hypoxic conditions can be replicated and investigated, and where the targeting of specific hypoxia markers in tumor cells can be investigated.
Innovation examples
ToxicologyInnovationIn vitro
Stem cell differentiation assays for animal-free developmental neurotoxicity assessment
Victoria de Leeuw was a PhD candidate in the research group of prof. dr. Aldert Piersma at the RIVM and Institute for Risk Assessment Sciences at Utrecht University. Piersma's lab studies the effects of compounds on development of the embryo during pregnancy with, among other techniques, stem cell cultures. The project of Victoria was aimed to differentiate embryonic stem cells of mouse and human origin into neuronal and glial cells, which could mimic parts of differentiation as seen during embryonic brain development. These models were able to show some of the known toxic mechanisms induced by these compounds, congruent with what they we hypothesised to mimic. This provides mechanistic information into how chemical compounds can be toxic to brain development. Therefore, these two stem cell assays make a useful contribution to the animal-free assessment of developmental neurotoxicity potential of compounds.
Victoria is nominated for the Hugo van Poelgeest prize 2022 for excellent research to replace animal testing.
Innovation examples
HealthInnovationIn vitro
Immortalized human cells to model atrial fibrillation in vitro
Niels Harlaar is a PhD Candidate at the Laboratory of Experimental Cardiology at the Leiden University Medical Center. Here, under the supervison of prof. dr. D.A. Pijnappels and dr. A.A.F. de Vries, he focusses on the conditional immortalization of human atrial cardiomyocytes for (among many other applications) in vitro modelling of atrial fibrillation. He has successfully generated, characterized and applied this technique of these conditionally immortalized human atrial myocyte lines to model atrial fibrillation in vitro.
Niels is nominated for the Hugo van Poelgeest prize 2022 for excellent research to replace animal testing.
Click here (https://hartlongcentrum.nl/research/laboratory-of-experimental-cardiology/) for more information on the Laboratory of Experimental Cardiology.
Innovation examples
Animal-free computational modelling for prevention of human chemical-induced neural tube defects
Animal-free methods for human chemical safety assessment are promising tools for the reduction of animal testing. However, these methods only measure a small aspect of biology compared to an in vivo test. The reductionist nature of these methods thus limits their individual application in the regulatory arena of chemical risk assessment. Ontologies can be used to describe human biology, and delineate the basis of adverse outcome pathway networks that describe how chemical exposures may lead to adverse health effects. This pathway description can then help to select animal-free in vitro and in silico methods, comprehensively covering the network. The comprehensiveness of this approach, firmly rooted in human biology, is expected to facilitate regulatory acceptance of animal-free methods. As an example, this video zooms in on the development of a computational model for neural tube development, an aspect of human development that is especially vulnerable to chemical disruption.
This research is part of the ONTOX project (https://www.ontox-project.eu).
For more information on the concept of the Virtual Human, click here (https://doi.org/10.1016/j.cotox.2019.03.009.).
Innovation examples
Developmental neurotoxicity testing using stem cells
Children should grow up in a safe and healthy environment. Disruption of brain development may have enormous impact on future life and might result in disorders such as ADHD or cognitive decline. The effect of compound exposure on the developing brain is largely unknown, since in the current regulatory test procedures in experimental animals effects on the brain are rarely investigated and human relevance of these animal models is under debate.
Researchers at RIVM are developing a cell model based on human stem cells that mimics a small part of the developing brain. This method is human-relevant, animal-free, and based on mechanistic knowledge of human biology and physiology of brain development. The model can be an important component in a testing strategy to test the safety of chemicals and pharmaceuticals on the developing brain.
Innovation examples
Understanding implant safety in vitro
Each year, millions of people receive an implant. The function of damaged tissues or organs is successfully restored in most people, however, some do develop complications. The safety of medical devices is indicated for legislation using international regulations. In the relevant standards, tests mainly focus on the chemical nature of the implants using classical toxicological end-points. However, more recently we have learned that the mechanical forces from an implant on the host-tissue can have significant effects on the host-response as well. At RIVM we want to develop an animal-free model that better resembles the interface between the implant and the host-tissue, and by updating the testing strategies contribute to implant safety on the long term.