Organs-on-Chips in Drug Development: The Importance of Involving Stakeholders in Early Health Technology Assessment

Organs-on-chips are three-dimensional, microfluidic cell culture systems that simulate the function of tissues and organ subunits. Organ-on-chip systems are expected to contribute to drug candidate screening and the reduction of animal tests in preclinical drug development and may increase efficiency of these processes. To maximize the future impact of the technology on drug development, it is important to make informed decisions regarding the attributes and features of organs-on-chips even though the technology is still in a stage of early development. It is likely that different stakeholders in organ-on-chip development, such as engineers, biologists, regulatory scientists, and pharmaceutical researchers, will have different perspectives on how to maximize the future impact of the technology. Various aspects of organ-on-chip development, such as cost, materials, features, cell source, read-out technology, types of data, and compatibility with existing technology, will likely be judged differently by different stakeholders. Early health technology assessment (HTA) is needed in order to facilitate the essential integration of such potentially conflicting views in the process of technology development. In this critical review we discuss the potential impact of organs-on-chips on the drug development process, and we use a pilot study to give examples of how different stakeholders have different perspectives on attributes of organ-on-chip technology. As a future tool in early HTA of organs-on-chips, we suggest the use of multicriteria decision analysis (MCDA), which is a formal method to deal with multiple and conflicting criteria in technology development. We argue that it is essential to design and perform a comprehensive MCDA for organ-on-chip development, and so the future impact of this technology in the pharmaceutical industry can be maximized

Human induced pluripotent stem cell-derived endothelial cells in thrombosis-on-a-chip devices

A microfluidic thrombosis-on-a-chip platform was developed to compare the pro-thrombotic response of healthy and inflamed monolayers of human umbilical vein endothelial cells (HUVECs) and human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs). Inflammation was induced by exposing the endothelial cells (ECs) to an inflammatory cytokine Tumor Necrosis Factor-α (TNF-α). After human whole blood perfusion at an arterial shear rate, the platelet coverage and average clot size were determined. Healthy endothelium showed a lower platelet coverage than inflamed endothelium. A minor difference was measured for both platelet coverage and average clot sizes on inflamed HUVECs versus hiPSC-ECs

3D Blood Vessels-on-Chip for atherosclerosis modelling

More than 25% of all deaths worldwide have a direct vascular cause, with coronary artery disease and stroke being two leading causes of death. These two diseases are the direct result of the acute rupture of atherosclerotic plaques in the arterial wall that contain dysfunctional tissue, fats and extracellular matrix. The disease processes in early atherosclerosis are hard to study due to the lack of realistic in vitro models. In this paper we present a 3D blood vessel-on-a-chip model for early atherosclerosis, which includes vascular tissue, cholesterol and immune cells in a patterned extracellular matrix. For the first time, we demonstrate that human iPSC-derived vascular cells take up oxidized LDL (‘bad cholesterol’) in a 3D microfluidic vessel on chip

Mimicking arterial thrombosis in a 3D-printed microfluidic : In vitro vascular model based on computed tomography angiography data

Arterial thrombosis is the main instigating factor of heart attacks and strokes, which result in over 14 million deaths worldwide every year. The mechanism of thrombosis involves factors from the blood and the vessel wall, and it also relies strongly on 3D vessel geometry and local blood flow patterns. Microfluidic chip-based vascular models allow controlled in vitro studies of the interaction between vessel wall and blood in thrombosis, but until now, they could not fully recapitulate the 3D geometry and blood flow patterns of real-life healthy or diseased arteries. Here we present a method for fabricating microfluidic chips containing miniaturized vascular structures that closely mimic architectures found in both healthy and stenotic blood vessels. By applying stereolithography (SLA) 3D printing of computed tomography angiography (CTA) data, 3D vessel constructs were produced with diameters of 400 μm, and resolution as low as 25 μm. The 3D-printed templates in turn were used as moulds for polydimethylsiloxane (PDMS)-based soft lithography to create microfluidic chips containing miniaturized replicates of in vivo vessel geometries. By applying computational fluid dynamics (CFD) modeling a correlation in terms of flow fields and local wall shear rate was found between the original and miniaturized artery. The walls of the microfluidic chips were coated with human umbilical vein endothelial cells (HUVECs) which formed a confluent monolayer as confirmed by confocal fluorescence microscopy. The endothelialised microfluidic devices, with healthy and stenotic geometries, were perfused with human whole blood with fluorescently labeled platelets at physiologically relevant shear rates. After 15 minutes of perfusion the healthy geometries showed no sign of thrombosis, while the stenotic geometries did induce thrombosis at and downstream of the stenotic area. Overall, the novel methodology reported here, overcomes important design limitations found in typical 2D wafer-based soft lithography microfabrication techniques and shows great potential for controlled studies of the role of 3D vessel geometries and blood flow patterns in arterial thrombosis

Mimicking arterial thrombosis in a 3D-printed microfluidic in vitro vascular model based on computed tomography angiography data

Arterial thrombosis is the main instigating factor of heart attacks and strokes, which result in over 14 million deaths worldwide every year. The mechanism of thrombosis involves factors from the blood and the vessel wall, and it also relies strongly on 3D vessel geometry and local blood flow patterns. Microfluidic chip-based vascular models allow controlled in vitro studies of the interaction between vessel wall and blood in thrombosis, but until now, they could not fully recapitulate the 3D geometry and blood flow patterns of real-life healthy or diseased arteries. Here we present a method for fabricating microfluidic chips containing miniaturized vascular structures that closely mimic architectures found in both healthy and stenotic blood vessels. By applying stereolithography (SLA) 3D printing of computed tomography angiography (CTA) data, 3D vessel constructs were produced with diameters of 400 μm, and resolution as low as 25 μm. The 3D-printed templates in turn were used as moulds for polydimethylsiloxane (PDMS)-based soft lithography to create microfluidic chips containing miniaturized replicates of in vivo vessel geometries. By applying computational fluid dynamics (CFD) modeling a correlation in terms of flow fields and local wall shear rate was found between the original and miniaturized artery. The walls of the microfluidic chips were coated with human umbilical vein endothelial cells (HUVECs) which formed a confluent monolayer as confirmed by confocal fluorescence microscopy. The endothelialised microfluidic devices, with healthy and stenotic geometries, were perfused with human whole blood with fluorescently labeled platelets at physiologically relevant shear rates. After 15 minutes of perfusion the healthy geometries showed no sign of thrombosis, while the stenotic geometries did induce thrombosis at and downstream of the stenotic area. Overall, the novel methodology reported here, overcomes important design limitations found in typical 2D wafer-based soft lithography microfabrication techniques and shows great potential for controlled studies of the role of 3D vessel geometries and blood flow patterns in arterial thrombosis