VICs remain physiologically dispersed in ECM, VECs surround the leaflet and the MPS enables the application of adjustable biomechanical force to achieve physiological model parameters . In case of diseased AVs, mostly from human origin, the intermediate scaling provides the opportunity of choosing macroscopically healthy AV regions instead of applying the entire degenerated valve. The applied tissue of only 15 mm 2 allows several cuttings from the same AV to be incubated in parallel as technical replicates. In contrast to previous bioreactors, this novel system allows incubation of integer porcine AV (pAV) and hAV tissue cuttings of intermediate scale. The presented study introduces an innovative MPS consisting of a pneumatic pump chip in conjunction with a tissue incubation chamber (TIC). Tissue stretch, culture medium pressure, shear forces with side-specificity, varying oxygen supply and dynamic incubation of aortic valve cuttings or entire aortic roots were modelled and performed for incubation periods of up to 56 days (Table 1). In succession, tissue culturing in MPSs was realized to model appropriate cell–cell and cell–matrix interaction as well as biomechanical and -chemical simulation. 2D-tissue cultures in microphysiological systems (MPSs) were established to elucidate calcification pathways including miRNAs or to investigate the effect of hypoxic environment. Diverse ex vivo bioreactors were introduced to bridge in vitro and in vivo approaches by reflecting diverse microenvironmental parameters. Animal models are used but the in vivo approach held aberrant microanatomy, physiology and calcification potential that impede result interpretation and transferability to the human system. Nonetheless, cell–cell communication, ECM, biomechanical and -chemical emulation were not represented physiologically. ĢD-cell culture models of human and porcine VECs and VICs were conducted. after cellular apoptosis, in between collagen fibres augments pathogenesis. In parallel, passive hydroxyapatite intercalation, e.g. These modified VICs actively deposit bone substrate. CAVD is caused by active processes in which VICs experience pathological differentiation to myofibroblasts or osteoblast-like cells. VICs are responsible for tissue maintenance. ![]() ![]() Valvular endothelial cells (VEC) are located at the surface of the valve, while valvular interstitial cells (VIC) are dispersed in extracellular matrix (ECM). The calcification process most frequently initiates at the fibrosa side adjacent to the aorta. The human aortic valve (hAV) consists of three distinct layers: the lamina ventricularis, the lamina spongiosa and the lamina fibrosa (Fig. Conservative treatment options are not available and the only therapy remains surgical aortic valve replacement. In 2019, 9.4 million patients worldwide were diagnosed with CAVD. The calcific aortic valve disease (CAVD) characterizes a degenerative obstruction of the aortic valve. The bimodal viability assessment and ECM analyses approve reliability of ex vivo CAVD investigation and comparability of parallel tissue segments with different treatment strategies regarding the AV (patho)physiology. The presented ex vivo MPS allows long-term AV tissue incubation and will be adopted for future investigation of CAVD pathophysiology, also implementing human tissues. Glycosaminoglycans remained stable, no significant alterations of α-SMA or CD31 epitopes and no accumulation of calciumhydroxyapatite were observed after 14 days of incubation. ![]() ECM changes such as an increase of collagen fibre content in line with tissue contraction and mass reduction, also observed in early CAVD, were detected in MPS-TIC culture, as well as an increase of collagen fibre content. An increased metabolic rate was detected for pulsatile dynamic MPS culture compared to static condition indicated by increased LDH intensity. The MPS-TIC conjunction proved applicable for incubation periods of 14–26 days. Tissue cultures in two different MPS setups were compared and validated by a bimodal viability analysis and extracellular matrix transformation assessment. This study introduces a novel MPS comprising different micropumps in conjunction with a tissue-incubation-chamber (TIC) for long-term porcine and human AV incubation (pAV, hAV). Microphysiological systems (MPSs), also known as organ-on-chip or lab-on-a-chip systems, proved promising in bridging in vitro and in vivo approaches by applying integer AV tissue and modelling biomechanical microenvironment. The complex pathophysiology remains to be understood to develop novel prevention and treatment strategies. Calcific aortic valve disease (CAVD) causes an increasing health burden in the 21 st century due to aging population.
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