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.
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.
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.
FirstbaseBIO - human brain organoids for studying neurological diseases
Human neurological diseases are still poorly understood, amongst others because animals are used as a model for the human brain. A way to overcome this problem is to mimic human brain functioning in a dish with organoids. FirstbaseBIO is developing off-the-shelf brain organoids on which neurological diseases can be studied. This 3D platform will be formed by reprogrammed human cells from easily accessible sources, for example urine, skin, or mucosa. The proof of-concept brain organoids will be those from patients who are suffering from adrenoleukodystrophy (ALD), a rare, incurable brain disease that occurs primarily in young boys and is often fatal. With the brain organoid platform, possible medicinal treatments for ALD can be effectively optimised. FirstbaseBIO was nominated for the Venture Challenge 2021 for their development of human brain organoids to study neurological diseases.
GUTS BV - small intestine-on-a-chip and advanced computational analysis for compound and protein screening
GUTS BV is a contract research organization offering its 3-dimensional state-of-the-art small intestinal in vitro model in combination with custom computational analysis approaches. The small intestinal model was developed during Dr. Paul Jochems PhD research at Utrecht University in the group of Prof. Roos Masereeuw. In comparison to the current gold standard (Transwell model), they show improvement in cell differentiation (all major specialized cell types present), physiological structure (3D tube- and villi-like structures) and a functional epithelial barrier. After acquiring experimental data from this model computational analysis approaches are used to score and compare measured compounds for all tested biological parameters at once. The combined effort of improved in vitro modelling and data analysis is believed to result in an enhanced preclinical predictability. GUTS BV was nominated for the Venture Challenge 2021 for their development of an intestinal model combined with advanced computational analysis for protein and chemical compound screening. Research papers: https://www.sciencedirect.com/science/article/pii/S0887233318307811 https://www.mdpi.com/2072-6643/12/9/2782/htm https://www.nature.com/articles/s41538-020-00082-z LinkedIn: https://www.linkedin.com/company/71016128/
Projects and initiatives
SMART OoC platform
The SMART Organ-on-Chip project aims to bring Organ-on-Chip technology to the next level, out of the pioneering labs to industrial applications. NWO awarded 4.8 million euro to a large and diverse consortium of universities, companies, research institutes and foundations, brought together by hDMT (Dutch Organ-on-Chip Consortium), that will together develop standardized Organ-on-Chip models. These models will be made to fit the scale and quality that pharmaceutical companies need to use them for development of novel drugs, with better science and less animal use as a result. The project will kick off in autumn 2021. More information on the project will follow in the course of 2021.
Human neuronal cell models for in vitro neurotoxicity screening and seizure liability assessment
Anke Tukker was a PhD candidate in the Neurotoxicology Research group of Dr. Remco Westerink at the Institute for Risk Assessment Sciences at Utrecht University. Dr Westerink’s research group investigates the mechanisms of action of toxic substances on a cellular and molecular level using in vitro systems. Anke's project aimed to develop a human induced pluripotent stem cell (hiPSC)-derived neuronal model for in vitro neurotoxicity screening and seizure liability assessment. Using micro-electrode arrays (MEAs), she showed that these models mimic in vivo neuronal network activity. When these hiPSC-derived neurons are mixed with hiPSC-derived astrocytes, they can be used for in vitro seizure liability assessment. Comparing these data with data obtained from the current used model of ex vivo rodent cortical cultures, she found that these human cells outperform the rodent model. Here research thus contributes towards animal-free neurotoxicity testing. Anke Tukker has won the public vote of the Hugo van Poelgeest prize 2020 for her research on human neuronal cell models for in vitro neurotoxicity screening and seizure liability assessment. Neurotoxicology Research Group, IRAS, Utrecht University: https://ntx.iras.uu.nl/NTXatIras
Human pluripotent stem cell derived cardiomyocytes for disease modelling and drug discovery
Berend van Meer did his PhD research in the research group of prof. Christine Mummery at the department of Anatomy and Embryology of the Leiden University Medical Center. In this group, human pluripotent stem cell derived (Organ-on-Chip) models are being developed, mostly cardiovascular models. The work of Berend aimed to understand how well these stem cell based cardiac models can predict the effect of (well-known) drug therapies in patients. Importantly, the outcomes of the experiments were compared to very similar measurements in rabbit heart muscle cells. And while animal models predicted less than 70% correctly, the human stem cell based models predicted almost 80% of the expected effects correctly. The research contributes to understanding the relevance of stem cell based models and strengthens the confidence regulators and pharmaceutical companies have in such models as animal alternatives in the drug development pipeline. Berend van Meer has won the Hugo van Poelgeest prize 2020 for his research on human pluripotent stem cell derived cardiomyocytes for disease modelling and drug discovery. Christine Mummery's lab on Heart on Chip, Disease modeling and toxicity: https://www.lumc.nl/org/anatomie-embryologie/research/902040935402533/
Cartilage-on-a-chip for studying joint degenerative diseases
Carlo Alberto Paggi is currently a PhD candidate at the University of Twente in the research group of Prof. Marcel Karperien and Prof. Séverine Le Gac. Karperien’s lab focus on the biological aspects of osteoarthritic research while Le Gac’s specialize in organ-on-chip development. The project of Carlo Alberto is developing a joint-on-chip platform to create a reliable in vitro model to study disease progression in osteo- or rheumatoid arthritis. The model combines different organ-on-chips aimed at replicating each a tissue around the joint such as cartilage, bone and ligaments. This new technology focuses on better reproducing human models and at substituting the use of animal models for drug research. If you want to know something more about the project and the groups, you can follow the link in the video. Carlo Paggi was nominated for the Hugo van Poelgeest prize for his research on a cartilage-on-a-chip model to study joint degenerative diseases Karperien’s lab of Developmental Bioengineering: https://www.utwente.nl/en/tnw/dbe/ Le Gac’s lab of Applied Microfluidics for BioEngineering Research: http://www.severinelegac.com/ Linkedin: https://www.linkedin.com/in/carlo-alberto-paggi-76500b135/
Helpathon #4 - can you help Raissa?
Can you help Raissa find a more complex organoid-like brain and immune model based on rhesus microglia to study aging in relation to neuroinflammation and neurodegenerative diseases? Join Helpathon #4, look at www.tpihelpathon.nl/coming-up ! Raissa Timmerman is a PhD student at the alternative unit at the Biomedical Primate Research Center. A better understanding of aging of the brain is key to studying neuroinflammation and neurodegenerative diseases. We believe there is a potential for breakthrough in using our existing live macaque data obtained from past aging experiments to develop more complex in vitro rhesus brain-like models and then to correlate all this data with data from human in vitro models and human live data.
Helpathon #4 - can you help Anne-Marie?
Can you help Anne-Marie develop a more organ-like Rhesus 3D liver model in which she can study the dormancy and the waking up of malaria parasites? Join Helpathon #4, look at www.tpihelpathon.nl/coming-up ! Anne- Marie Zeeman is a researcher at the Biomedical Primate Research Center (BPRC). Anne-Marie studies recurrent malaria ( P. vivax). She successfully developed a single cell layer in vitro model to study compounds affecting dormant and active malaria parasites in the liver of Rhesus monkeys. We believe that the cross correlation between in vitro Rhesus and in vitro human models will provide the missing link required to improve the drug development process and aid transition. A more refined Rhesus in vitro model can reduce the number of monkeys currently used for testing drugs. The data from in vivo monkeys combined with new in vitro models could help validate and develop reliable human in vitro models making testing on monkeys unnecessary detours.
Erwin Roggen (ToxGenSolutions)
ToxGenSolutions provides a cutting-edge patchwork of test methods required for modern testing and assessment of compounds and products. It builds on a virtual generic platform of leading test and technology developers providing novel technologies addressing key events in outcome pathways. ToxGenSolutions products are proprietary mechanism-based gene signatures for identification and classification of toxicants during screening, product development and safety assessment. More information on https://toxgensolutions.eu/ .