Cardiovascular disease is the leading cause of deaths worldwide. In the US, heart diseases account for nearly 800,000 of deaths per year. Most heart disease cases involve cardiac fibrosis characterized by excessive deposition of extracellular matrix (ECM) proteins by myofibroblasts, which are activated form of cardiac fibroblasts (CFs). It causes stiffening of the heart wall (myocardium), which reduces pumping capability of the heart and accelerates the progression to heart failure. However,
the CF as a cell type and the pathological development of fibrosis are still poorly understood. As a result, there are currently limited clinical interventions that effectively target CF and its pathological contributions to disease progression.
One key change that lead to cardiac fibrosis is the upregulation of α‐smooth muscle actin (aSMA) expression, a contractile protein, by activated myofibroblasts. This event coexists with the increase of stiffness and structure of myocardium, loss of contraction and pumping capability of the heart.
We have previously built a pneumatically controlled Heart‐on‐Chip (HoC) platform capable of applying well controlled and physiologically relevant strain to cells imbedded in hydrogel. (Fig. 1) The system is being used to study mechanotransduction of cardiac fibroblasts on morphological as well as molecular level. Some initial result confirmed the biocompatibility, robustness and functional capability of the system. However, much more can be harnessed from the system as a platform, and more improvement/extension can be made to accommodate more complex requirements. These further developments and explorations are included in this project.
Figure 1: Heart‐on‐Chip platform.
First, initial study shows the effect of applying deformation on cell construct in HoC platform leads to upregulation of aSMA expression. More detailed studies need to be performed to pinpoint the onset of strain condition that triggers this event, and to investigate the effect of strain in gene expression in CF in general. We can also modify HoC for stiffness/tensile strength measurement of the cell construct. Idea is to put micropillars on top of the film. And by either a) pneumatic actuation of the film or b) automatic contraction by the cardiomyocyte construct we can measure the stiffness by measuring the deflection of the pillars. Extend the modes of deformation can be applied on HoC. Besides biaxial stretching from spherically confined membrane, other modes such as radial stretching mimicking vasculature dealation can be applied by designing proper shape of the wells. Cell response to different modes of actuation then will be studied. Also, microfluidic systems can be integrated to study the effect of stress on cell development/behavior. Perfusion/waste removal can be done automatically with precision with an external pumping system connected to each wells through microfluidic accessories and accommodating design of the chip. Fluid flow results in shear stress, which has influence in cell differentiation and maturation. Design of a proper microfluidic system, taken into account of the long‐term robustness, ease of use as well as stress/pressure requirement that is physiologically relevant.
The PhD student will be mainly supervised by Dr. Ye Wang from the Microsystems group. Microsystems group is a part of the Institute of Complex Molecular Systems (ICMS). The Microsystems group manages the Microfab lab, a state‐of‐the‐art micro fabrication facility that houses a range of micro manufacturing technologies - microfluidics technology is one of the main research pillars of the group. The candidate will also work closely with experts from Biomedical department from TU/e, and work in their state‐of‐the‐art cell lab.
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