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Vascular Engineering on chip using differentiated Stem Cells

Periodic Reporting for period 4 - VESCEL (Vascular Engineering on chip using differentiated Stem Cells)

Reporting period: 2020-04-01 to 2020-09-30

In the VESCEL program we aimed to develop innovative technologies enabling the use of differentiated human induced pluripotent stemcells (hiPSC) to engineer blood vessels in microfluidic chips that constitute realistic disease models for thrombosis and neurodegenerative (ND) diseases.

There were 6 sub-aims to be addressed for this overall aim to be achieved.

(1) Differentiating hiPSC into blood vessel tissue; (2) optimizing the culture conditions of hiPSC-derived vascular cells; (3) controlled engineering of blood vessel networks by culturing vascular cells in microfluidic chips; (4) integration of biosensors to monitor the state of the on-chip blood vessels; (5) applying the blood vessels on-chip in studying thrombosis; (6) applying the blood vessels on-chip in studying blood-brain barrier function.

The development of these complex and realistic disease models while having the potential to refine, reduce and (partly) replace existing animal models. Moreover, they will contribute significantly to our understanding of important vascular and neurological diseases.

The main conclusions of the project are that (1) microfluidic technology is of great added value in the development of laboratory models of human tissues, and (2) that such microfluidic models are superior in capturing the morphology and function of human tissues compared to their conventional counterparts based on well plates.
Work on all sub-aims has been completed and has led to successful results in line with the proposed action. The key achievements in the sub-aims are listed below:

We achieved differentiation of endothelial cells from hiPSC, as well as their long-term culture inside microfluidic culture systems (sub-aim 1). We developed a modular, automated microfluidic cell culture platform, and demonstrated its use in long-term culture of vascular tissues (sub-aim 2). We demonstrated the formation of microvascular networks in microfluidic chips with a superior degree of control due to the microfluidic patterning of hydrogels (sub-aim 3). We developed electrical sensors for pH and used them to track the metabolic activity of human stem cell-derived tissues (sub-aim 4). We systematically studied the formation of blood clots in 3D-printed microfluidic cultures ('vessels-on-chips') and demonstrated that hiPSC-derived cells are capable of inducing platelet aggregation and fibrin formation in vitro (sub-aim 5). And finally, we studied how human brain microvascular endothelial cells can be cultured in microfluidic chips, and how this affects their barrier function when compared to conventional culture systems (sub-aim 6).

This substantial scientific progress has led to multiple publications (see 'Publications' in report) in scientific journals, as well as accepted abstracts for major conferences in the field (e.g. microTAS, NanoBioTech, International Organ-on-Chip Sympsosium, Micro and Nanotechnology in Medicine Conference, European Organ-on-Chip Society Annual Meeting).

The development of the modular automated microfluidic culture platform in sub-aim 2 was used as a basis for applying for an ERC Proof-of-Concept funding. This funding was granted, and the platform is now being further developed for use in the field of organs-on-chips as an 'open platform' that can control multiple microfluidic chips via a standardized interface.
The results of the project have demonstrated convincingly that hiPSC-derived cells can be used to engineer well-controlled vascular structures in microfluidic chips. hiPSC-derived vascular cells are person-specific, as well as a reproducible and indefinite source for cells of one specific donor, their integration in chips is a major accomplishment that will open the possibilities to apply the vessels-on-chips in biomedical and pharmaceutical science.

Moreover, the project has already led to significant technical innovation in the development of organ-on-chip systems in general, with highlights being the controlled 3D printing of vascular geometries, integration of on-line electrical biosensors for vascular barrier function, and a high level of control over 3D microvessel network formation by on-chip patterning of hydrogels.

Overall, the project has led to significant advances in the emerging field of 'organs-on-chips', and this technology is expected to have a major impact on biomedical and pharmaceutical science in the coming decade.