To improve the predictive capability of pre-clinical models and reduce the use of animal models in drug discovery and disease modelling, advanced in vitro models are being developed. These... Show moreTo improve the predictive capability of pre-clinical models and reduce the use of animal models in drug discovery and disease modelling, advanced in vitro models are being developed. These microphysiological systems (MPS) or “Organs-on-Chip” (OoC) are being developed to include all aspects of the human physiology to improve the in vitro cellular response. OoCs combined with differentiated human induced pluripotent stem cells (hiPSC) allow the use of cells with patient specific genotypes and aid the development of personalized and precision medicine.In this thesis, the development of tractable models of the vasculature is described. These models allow for the combination of hiPSC-derived vascular and tissue specific cells with haemodynamics to recapitulate essential stimuli of blood vessels. Show less
Due to the steep rise of the prevalence of osteoarthritis in the world's population in recent years, it has been of great interest to search for the best way to relieve symptoms and consequences of... Show moreDue to the steep rise of the prevalence of osteoarthritis in the world's population in recent years, it has been of great interest to search for the best way to relieve symptoms and consequences of OA like pain and inflammation. For that reason, the tissue engineering using a porous tri-layer scaffold is a great alternative for patients with this illness.In this way, it was designed, developed and improved a novel chitosan/collagen-based tri-layer porous scaffold with similar chemical composition and structure to the articular cartilage. One of these layers included hydroxyapatite, to promote the integration of growing tissue next to subchondral bone.The biomaterial was physic-chemical characterized, in vitro and in vivo tested obtaining promising results. Later, the scaffold was crosslinked to promote rheological properties that bear the knee cyclic charges while walking. The anti-inflammatory effect was enhanced by the incorporation of a TNF-α blocking drug, which was released in a controlled manner from the material in the damaged tissue over time. The scaffold was non-cytotoxic against chondrocytes and osteoblasts, had great rheological properties and promoted the growth of new cartilage tissue after four weeks after grafted into the osteoarthritic mice knee. Show less
Velden, J. van der; Asselbergs, F.W.; Bakkers, J.; Batkai, S.; Bertrand, L.; Bezzina, C.R.; ... ; Thum, T. 2022
Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of... Show moreCardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and co-morbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models cannot provide a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on a organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and improved current animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction and refinement (3R) as a guiding concept. Show less
Corneal transplantation still represents the elected method for the treatment of corneal endothelial pathologies. However, the worldwide shortage of donor corneas induced the exploration of... Show moreCorneal transplantation still represents the elected method for the treatment of corneal endothelial pathologies. However, the worldwide shortage of donor corneas induced the exploration of approaches to use the donor tissue more efficiently or to be more independent from donor tissue. This thesis will illustrate the improvements of new strategies for cell-based corneal endothelial regeneration, alternative to corneal endothelial surgical transplantation, by bridging the gap between in vitro experiments and clinical models. In the studies described, we first address the establishment of a GMP-compliant protocol for in vitro hCEC culture for clinical application and then we focus on endothelial cell sheet transplantation, describing both in vitro and in vivo applications of expanded CEC-carriers constructs made by biocompatible materials. Show less
Man, S.; Duffhues, G.S.; Dijke, P. ten; Baker, D. 2019
Pathologies of the respiratory system such as lung infections, chronic inflammatory lung diseases, and lung cancer are among the leading causes of morbidity and mortality, killing one in six people... Show morePathologies of the respiratory system such as lung infections, chronic inflammatory lung diseases, and lung cancer are among the leading causes of morbidity and mortality, killing one in six people worldwide. Development of more effective treatments is hindered by the lack of preclinical models of the human lung that can capture the disease complexity, highly heterogeneous disease phenotypes, and pharmacokinetics and pharmacodynamics observed in patients. The merger of two novel technologies, Organs-on-Chips and human stem cell engineering, has the potential to deliver such urgently needed models. Organs-on-Chips, which are microengineered bioinspired tissue systems, recapitulate the mechanochemical environment and physiological functions of human organs while concurrent advances in generating and differentiating human stem cells promise a renewable supply of patient-specific cells for personalized and precision medicine. Here, we discuss the challenges of modeling human lung pathophysiology in vitro, evaluate past and current models including Organs-on-Chips, review the current status of lung tissue modeling using human pluripotent stem cells, explore in depth how stem cell based Lung-on-Chips may advance disease modeling and drug testing, and summarize practical consideration for the design of Lung-on-Chips for academic and industry applications. (C) 2018 Elsevier B.V. All rights reserved. Show less
The general introduction in Chapter 1 of this thesis provides an overview of the emerging field of regenerative medicine, and its different areas of technology. Contemporary approaches to heart... Show moreThe general introduction in Chapter 1 of this thesis provides an overview of the emerging field of regenerative medicine, and its different areas of technology. Contemporary approaches to heart valve repair and replacement by mechanical and biological prosthesis, as well as their limitations are discussed. Furthermore, the novel approach of (stem)cell-based therapy in ischemic heart disease and a variety of potential cell types are described. In Part I of the thesis different methods to produce completely acellular porcine and rat aortic valve scaffolds for the purpose of creating a biological substitute that can restore, maintain, or improve normal function. In addition, the in vivo behavior of these valves was studied in a rat model. Subsequently, Part II of the thesis studied the in vivo behavior and functional improvement after transplantation of different human cell types in an animal model of acute myocardial infarction. Furthermore, the feasibility of combining cell therapy with gene-therapy was studied in this same model. Finally, in Part III different methods for cardiac phenotyping in mice were assessed and compared. Show less