Project
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.

• A research oriented attitude, ambitious, self‐motivated and proactive;
• Experience in working in multidisciplinary projects, preferably combining mechanical, physical and/or biological disciplines;
• Experience or interest in doing hands‐on laboratory work in microfabrication;
• Knowledge and experience in cell biology, biochemistry and/or biophysics;
• Good communication skills in written and spoken English;
• Willing to contribute to education activities, like supervising BSc and MSc projects.

Embedding

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.

We offer you:

• A meaningful job in a dynamic and ambitious university with the possibility to present your work at international conferences.
• A full-time employment for four years, with an intermediate evaluation after one year.
• To support you during your PhD and to prepare you for the rest of your career, you will have free access to a personal development program for PhD students (PROOF program).
• A gross monthly salary and benefits in accordance with the Collective Labor Agreement for Dutch Universities.
• Additionally, an annual holiday allowance of 8% of the yearly salary, plus a year-end allowance of 8.3% of the annual salary.
• A broad package of fringe benefits, including an excellent technical infrastructure, moving expenses, and savings schemes.
• Family-friendly initiatives are in place, such as an international spouse program, and excellent on-campus children day care and sports facilities.