Our research focuses on investigating how the engineered microenvironments direct cell function and tissue regeneration. In particular, we are exploring extracellular matrix (topology, rigidity, dimensionality, etc) regulation of cell fate and function in developmental, physiological and pathological process. Several specific thrusts of the current research program include: microscale cardiovascular tissue engineering, BioMEMS for stem/progenitor cell niche engineering, microengineered platforms for cell-matrix mechanobiology, and mechanical regulation of cancer cell invasion and collective cell migration. Here is a summary of our current research projects.
Technological: Development of biomimetic cell/tissue microenvironments using micro/nano/molecular engineering techniques
Our current research focuses on engineering combinatorial cellular microenvironment through use of variable nano-patterns, and soluble and matrix-bound cell guidance cues in a single experiment, which better mimics the in vivo microenvironment under physiological conditions. For example, we are developing a microfluidics-based on chip assay integrated with complex nanoscale topographic features to enable the analysis of concerted cell responses to composite gradients of precisely generated and aligned surface-bound ECM molecules and diffusible guidance cues or topographic guidance cues. Using these tools, we strive to systematically characterize live cells to wide spectra of dynamically changing combination of mechanical and chemical stimuli (e.g. ECM proteins, topographic, growth factors and signal transduction pathway inhibitors). The proposed measurements are highly resolved in time and space, using a variety of live cell probes and highly defined extracellular conditions. Using UV-assisted nanomolding and 3D nanofabrication techniques, we are developing nanotopographically-defined cell culture models and biomaterial tissue scaffolds for cell biology and tissue engineering. For high-throughput quantitative analysis, we are also working to combine a large area nanopatterned substrate with a traditional multi-well tissue culture plate. We aim to use these tools to gain new mechanistic insights into cell signaling and function, to design new therapies or diagnostic tests for cancer progression and cardiovascular diseases, and to establish organizing principles for development of precisely defined scaffolds for advanced tissue engineering applications.
Micro- and nanoengineering for stem cell biology: the promise with a caution (Trends Biotechnol.29(8), 399-408 [2011])
Fundamental: Mechanobiology and mechanotransduction in engineered tissue models
Mechanotransduction - from how cells sense mechanical forces in different tissues to how these mechanical forces are transduced into biochemical signals - is an essential biological process in development, normal physiology and disease. In this exciting area, we are particularly interested in investigating the role of mechano-biological processes associated with cell-cell and cell-matrix adhesions (e.g. topography and rigidity of the extracellular matrix) in the regulation of collective and directed cell migration and tissue morphogenesis. Using a combination of various techniques, from molecular biology to nanotechnology and live cell imaging, for example, we have been accumulating interesting data suggesting that one of the most important factors distinguishing metastatic from non-metastatic cells could be their ability to collectively invade and migrate towards blood vessels by physically interacting with the surrounding extracellular matrices. By experimenting with the nanotopographically-defined cell adhesion substratum (i.e. quasi 3D cell culture system) and 3D natural/synthetic extracellular matrices, we are investigating the biophysical and signaling mechanisms of collective cell migration driven by the hypothesis that the physical interaction of migrating cells with the surrounding ECM has a crucial role in the collective guidance of cell migration in the context of cancer invasion and wound healing. To test this hypothesis, we recently developed a micro/nanofabricated collective migration assay as an enabling tool for analysis and control of cancer cell invasion and epithelial/endothelial wound healing in a high-throughput, controlled manner. Using these tools, we also explore the potential role of mechanical guidance in the regulation of collective cell migration and tissue morphogenesis under the presence/absence of growth factor-induced signals, and test their biomedical implication by screening cytoskeletal and signal transduction pathways.
Translational: Stem cell niche engineering and functional tissue engineering
With advances in nanofabrication and biomaterials, scaffolding materials can be designed to integrate biomimetic structural and mechanical cues present in the in vivo ECM environment. Based on ultrastructural analyses of the native heart tissue, we are developing a bio-inspired model cardiac tissue to better understand cardiac tissue structure-function relationships, and to seek applications in stem cell-based therapies for cardiac tissue repair and regeneration. The ultimate goal of this project is to develop nanopatterned functional cardiac patches for treating the damaged heart tissue (e.g. myocardial infarction). The working hypothesis is that cultivation of cardiac cells and/or stem cells on novel biomaterials scaffolds integrated with nanotopographic cues promotes biomimetic anisotropic assembly of uniformly contractile engineered muscle, while simultaneously enabling control over local cell alignment. We further envision that integrating the transplantable stem cells with the proposed nano-grafting techniques have therapeutic potential in repairing cardiac tissue damage and may prevent the onset of heart failure. In order to test these hypotheses, our research focuses on elucidating the relationships between scaffold-mediated nanostructural cues and tissue engineered cardiac graft contractility and function. In addition, the therapeutic potential of a nanopatterned cardiac stem cell graft will be studied in vitro and in vivo (implantation onto the left ventricle in an adult rat model of myocardial infarction). Tissue structure and function will be characterized at various hierarchical scales (molecular, structural, functional) and the obtained experimental data will be used to tailor the conditions and duration of cultivation, leading to engineering implantable grafts.
Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs (PNAS107, 565-570 [2010])
Funding Sources:
Our research would not be possible without the the generous support of the following public and private organizations.
