Job description
Effective cancer management requires precise imaging, but current methods are not sufficiently accurate. Tumor vasculature abnormalities, such as increased permeability and tortuosity, challenge traditional imaging techniques. Contrast-enhanced ultrasound (CEUS) using microbubbles can map microvascular dynamics but is limited to assessing intravascular flow and structure. Nanobubbles, capable of penetrating the tumor microvasculature and targeting cancer-specific biomarkers, offer enhanced imaging potential. However, their clinical translation is hindered by insufficient understanding of nanobubble acoustic behavior and flow kinetics in the microvasculature. In this collaborative project, we will develop a comprehensive strategy combining (1) vasculature-on-chip models, (2) in-depth nanobubble characterization, and (3) tailored imaging solutions to advance cancer diagnostics by nanobubble ultrasound imaging. The research on these three topics will be carried out by 2 PhD students and a postdoc at Eindhoven University of Technology and the University of Twente. The whole consortium also includes industrial and clinical partners.
This particular PhD project aims to develop the in-vitro vasculature-on-chip models, microfluidic chips in which controllable and physiologically relevant representations of the tumor microvasculature are created. These cm-sized chips are then used by the other researchers in the overall project for US imaging experiments. The models should fulfil several critical requirements: first, the geometry and size of the vascular network should be representative of real (tumor) microvasculature, i.e. consisting of 3-dimensional networks of perfusable lumens with circular cross section, ranging from a hundreds of microns down to a few microns in diameter; second, the model should include relevant biology, i.e. lumens should be endothelialized, it should allow the inclusion of tumor cells, and the cells should be embedded in a relevant extracellular matrix (ECM); third, the chips must be acoustically transparent to allow transmission of ultrasound, i.e. the materials have optimal acoustic impedance and attenuation characteristics; additionally, a desirable characteristic is optical transparency to allow for validation testing by optical imaging.
Information
The overall project aims at enabling new imaging methods for cost-effective and accurate detection and diagnosis of prostate cancer, as well as several other forms of cancer for which angiogenesis plays a role, using nanobubble-based CEUS. This will be achieved by extending fundamental knowledge on nanobubble acoustic response in relevant conditions, on nanobubble kinetics in the microcirculation and extravasation into tissue, and by jointly optimizing nanobubble formulation and image acquisition, analysis and interpretation methods.
As it is the most common and second-most lethal cancer in the western world, our primary focus is prostate cancer. With the project, we will tackle the challenges described above through a multidisciplinary approach which combines our expertise in bubble physics, bio-mimicking microfluidics, ultrasound modeling and signal analysis. Three junior researchers will work synergistically to achieve a framework for improved image-based cancer diagnostics, consisting of an experimental model of (cancer) microvasculature, nanobubble theoretical and experimental characterization, and dedicated US signal analysis methods.
As a PhD student in this project, you will design, realize, and experimentally characterize in-vitro vasculature-on-chip models. To create the vascular networks, we will use a proven concept of 3D printing and angiogenesis. With our previously developed sugar 3D printing technique, we can create sacrificial templates consisting of complex networks of fibers with circular cross sections and diameters from tens to hundreds of microns. These fiber templates can be embedded in hydrogel mimicking ECM and subsequently selectively dissolved leaving a hollow network in the hydrogel. Then, endothelial cells are seeded in the luminal network to create a biologically relevant vessel network that can be connected to a micropump to perfuse them with liquid and injecting with contrast agents. The diameter of the blood vessels created with this printing technique is limited to tens of micron in diameter, but the vessel diameters in the real (tumor) microvasculature may be as small as a few microns. We will achieve such small vessels by combining our 3D printing technique with directed angiogenesis, thus achieving a vascular model with a broad range of (relevant) dimensions. To connect the chips to a perfusion pump, it must be contained in a small casing which should be made from materials that are acoustically transparent. We will characterize the flow characteristics and the biological characteristics using (live) microscopy of relevant cell characteristics.
Building on this first-generation model, we will develop a second-generation model in which we will modulate and characterize the permeability of the endothelium. This is deemed important for the quantification of nanobubble extravasation. Different concentrations of inflammatory agents are known to affect endothelial permeability, mimicking the characteristic leakiness of the tumor vasculature. Such agents will be administered to the model, and the permeability will be characterized using fluorescent microscopy, combined with optical characterization of the cells like for the first-generation model. This will provide a range of vsaculature models with different permeabilities for the US nanobubble experiments. After full fluidic and biological characterization, these second-generation chips form a representative model for the US experiments carried out by our project partners, and will be compared with in-vivo models.
Embedding
The PhD student will be embedded in the Microsystems research section at the Department of Mechanical Engineering, headed by prof.dr.ir. Jaap den Toonder, and they will be supervised by prof.dr.ir. Jaap den Toonder. 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 and organ-on-chip research are main research pillars of the group. The project is a collaboration between two groups at Eindhoven University of Technology (at Mechanical Engineering and Electrical Engineering), one group at the University of Twente, and several industrial and clinical partners.
Requirements
We are looking for enthusiastic PhD candidates with a background in mechanical or biomedical engineering. The ideal candidate would have experience in microfluidics, microfabrication, organ-on-chip, cell culture, and cell and tissue characterization, but excellent candidates with a background in one area (and an interest to master the other) will also be considered. We are looking for a motivated candidate who enjoys working in a multidisciplinary academic environment and has interest in applied research. Our dream candidate is skilled at practical work in the microfabrication and biology labs and is also able to use and develop theoretical skills needed to develop a fundamental understanding of the subject matter. Other important personal skills include fluent spoken and written English, a proven ability to manage a project, to be able to collaborate with a multidisciplinary team, and to be self-driven.