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Irregular hemodynamics affects the progression of various vascular diseases, such atherosclerosis or aneurysms. Despite the extensive hemodynamics studies on animal models, the inter-species differences between humans and animals hamper the translation of such findings. Recent advances in vascular tissue engineering and the suitability of in vitro models for interim analysis have increased the use of in vitro human vascular tissue models. Although the effect of flow on endothelial cell (EC) pathophysiology and EC-flow interactions have been vastly studied in two-dimensional systems, they cannot be used to understand the effect of other micro- and macro-environmental parameters associated with vessel wall diseases. To generate an ideal in vitro model of the vascular system, essential criteria should be included: 1) the presence of smooth muscle cells or perivascular cells underneath an EC monolayer, 2) an elastic mechanical response of tissue to pulsatile flow pressure, 3) flow conditions that accurately mimic the hemodynamics of diseases, and 4) geometrical features required for pathophysiological flow. In this paper, we review currently available in vitro models that include flow dynamics and discuss studies that have tried to address the criteria mentioned above. Finally, we critically review in vitro fluidic models of atherosclerosis, aneurysm, and thrombosis.

Fast and minimally invasive approaches for early, preclinical diagnosis of neurodegenerative Alzheimer’s disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β-amyloidosis, one of the pathological hallmarks of AD, has raised the question of whether immune markers could be used as proxies for β-amyloid accumulation in the brain. Here, we deploy multidimensional mass cytometry combined with unbiased machine learning techniques to immunophenotype peripheral blood mononuclear cells from study participants in cross-sectional and longitudinal cohorts. We show that increases in antigen-experienced T and B cell subpopulations in blood are associated with early accumulation of β-amyloid in still cognitively healthy human brains. Our results suggest that preclinical AD pathology stages are associated with systemic alterations of the adaptive immune system. These β-amyloid-induced immunophenotype changes may be exploited in the future to identify and develop novel diagnostic tools for early AD detection and prediction of clinical outcomes. Funding Information: This work was supported by grants from the Synapsis Foundation – Alzheimer Research Switzerland ARS (No. 2019-PI06 to R.M.N., C.G., and A.G.), the Swiss National Science Foundation (SNF 33CM30-124111, SNF 320030-125387/1 to C.H.), the Maxi Foundation (to C.H.) and the Velux Foundation (to L.K.). Declaration of Interests: T.K. is currently an employee of Biogen, Switzerland; L.K. and V.Tosevski are employees of Roche, Switzerland; C.H. and R.M.N. are members of the board of directors and shareholders of Neurimmune AG, Switzerland; M.T.F. is co-founder and CSO of the Women’s Brain Project. Ethics Approval Statement: All participants gave written informed consent. The studies were conducted in concordance with the guidelines of the local ethics committee (Kantonale Ethikkommission Zurich) and the Declaration of Helsinki (World Medical Association, 2013). The current analyses were conducted with permission of the ethics committee for further use of data and samples.

Atherosclerosis is an arterial disease characterized by intravascular plaques. Disease hallmarks are vessel stenosis and hyperplasia, eventually escalating into plaque rupture and acute clinical presentations. Innate immune cells and local flow variations are core players in the pathology, but their combined effects have never been investigated before in human vessel replicas due to the lack of modeling systems with adequate degree of complexity. Here, we combined computational fluid dynamics and tissue-engineering to achieve full human atherosclerotic plaque development on-a-chip. Our model incorporates induced pluripotent stem cell-derived populations into small-caliber arteries that are cultured in atheroprone conditions. Using machine-learning-aided immunophenotyping, as well as molecular and nanoprobe-based tensile analyses, we found that immune cells and extracellular matrix were comparable between in vitro and ex vivo human plaques. Our results provide further insights into the relation between disturbed flow dynamics and vascular inflammation, introducing a versatile, scalable modeling tool to study atherosclerosis onset and progression.

Atherosclerosis is an arterial disease characterized by intravascular plaques. Disease hallmarks are vessel stenosis and hyperplasia, eventually escalating into plaque rupture and acute clinical presentations. Innate immune cells and local variations in hemodynamics are core players in the pathology, but their mutual relationship has never been investigated before due to the lack of modeling systems with adequate degree of complexity. Here, we combined computational fluid dynamics and tissue-engineering to achieve, for the first time in vitro, full atherosclerotic plaque development. Our model incorporates induced pluripotent stem cell-derived populations into small-caliber arteries that are cultured in atheroprone conditions. Using machine-learning-aided immunophenotyping, molecular and nanoprobe-based tensile analyses, we found that immune cells, extracellular matrix components and tensional state were comparable between in vitro and ex vivo human lesions. Our results provide further insights into the relation between hemodynamics and inflammation, introducing a versatile, scalable modeling tool to study atherosclerosis onset and progression.

Summary: This study showed that bone marrow mononuclear cell pre-seeding had detrimental effects on functionality and in situ remodeling of bioresorbable bisurea-modified polycarbonate (PC-BU)-based tissue-engineered heart valves (TEHVs) used as transcatheter pulmonary valve replacement in sheep. We also showed heterogeneous valve and leaflet remodeling, which affects PC-BU TEHV safety, challenging their potential for clinical translation. We suggest that bone marrow mononuclear cell pre-seeding should not be used in combination with PC-BU TEHVs. A better understanding of cell–scaffold interaction and in situ remodeling processes is needed to improve transcatheter valve design and polymer absorption rates for a safe and clinically relevant translation of this approach. Key Words: cardiovascular regenerative medicine, endogenous tissue regeneration, in situ tissue engineering, supramolecular polymer, tissue-engineered heart valve

Atherosclerotic plaques are cholesterol-induced inflammatory niches accumulating in the vascular sub-endothelial space. Cellular and extracellular composition of human plaques is maneuvered by local inflammation that leads to alterations in the original vascular microenvironment and to the recruitment of an invading fibrous layer (fibroatharoma). In the present study we introduce a bioengineered three-dimensional model of human fibroatheroma (ps-plaque) assembled with a tailored hanging-drop protocol. Using vi-SNE based multidimensional flow cytometry data analysis we compared the myeloid cell-populations in ps-plaques to those in plaques isolated from human carotid arteries. We observed that plasmacytoid and activated dendritic cells are the main myeloid components of human carotid plaques and that both cell types are present in the biofabricated model. We found that low-density lipoproteins affect cell viability and contribute to population polarization in ps-plaques. The current work describes the first human bioengineered in vitro model of late atherosclerotic lesion for the investigation of atherosclerosis aetiopathogenesis.