Development of a microfluidic system for modelling the heart-kidney interaction in vitro

Abstract

Cardiorenal Syndrome (CRS) is a multi-organ disease characterized by a reciprocal pathological interaction between the heart and kidneys during acute or chronic injury. Yet, a complete understanding of the underlying bi-directional pathophysiological mechanisms is lacking, hence obscuring effective diagnostic strategies, patient stratification and adequate administering of intervention therapies. Thus far, CRS has only been modelled in in vivo animal models, which are inherently limited in terms of experimental control and translatability of results to humans physiology. This underlines the need to develop more advanced in vitro models that accurately recapitulate the complex inter-organ cross talk responsible for the onset and progression of CRS. However, to date no such disease model system has been reported.

This project set out to design, develop and validate a microfluidic set-up, which would then enable the investigation of CRS in a three-dimensional environment. To that end, a theoretical framework covering all aspects related to Multi-Organ-On-Chip (MOoC) design was developed. This framework then formed the foundation for an extensive list of requirements to establish an ideal microfluidic set-up for a heart-kidney disease model. Various conceptual circuit designs were proposed and evaluated on the basis of the set requirements and their associated priority.

By executing feasibility studies, simulating computational fluid dynamics, designing specific organoid inserts and eventually setting-up the proposed microfluidic circuits, a better understanding of the technological and biological challenges to be addressed was obtained. Proof-of-principle experiments were promising, but more experimental iterations with a focus on in-depth biological tissue characterization are required to further evolve and fully validate the
proposed cardiorenal model. Pressing issues entail establishing physiologically relevant scaling ratios, reducing required medium volume and identifying the exact disease models to incorporate once the physiological organoid system is functional and has been validated.