>> Zhang Lab: Biological/biomedical Micro/nanosystem (homepage)

We have applied micro/nanosystem approaches to the development of technology platforms aimed at understanding functional behavior at the cellular and subcellular levels. Beginning with my NSF Career Award in 2003, my group has developed and applied a moire-based optomechanical approach to mapping cellular forces. Through the combination of an optical system with precisely engineered microstructured polymeric substrates, we developed a cellular force mapping approach which leverages the magnification capacity inherent in the moire phenomenon to yield ultra-sensitive and high-throughput analyses. Underscoring our focus on understanding fundamental principles in micro/nanosystem, during our development of the moire-based cellular force mapping platform, we developed a deep understanding of the materials properties of the polymer transducers employed in the microfabricated substrates of this platform. An understanding of the fundamental principles of our micro/nanosystem, in this case, led to increasingly accurate derivations of cellular force. Subsequent to its development, the moire platform was applied to the analysis of cellular contraction forces in cardiomyocytes and vascular smooth muscle cells which play fundamental roles in cardiovascular disease.

Currently, our focus is on optimizing and further developing the moire platform, extending its unique advantages towards high-throughput, microenvironment microarray-based assays and working towards three-dimensional polymeric substrates which more closely model the in vivo cellular environment. To this end, we are developing microfabricated substrates for use with the moire approach using materials beyond poly(dimethylsiloxane) in order to realize the capacity to precisely pattern three-dimensional polymeric arrays with cell adhesive proteins. In addition, using a recently developed double-sided micropillar substrate which features both a cell substrate layer and a reference layer for generation of the moire patterns in a single structure, we are developing cell culture microenvironments which yield the capacity to exert dynamic stretch on cultured cells in parallel to cellular force measurements. We are currently engaged in tailoring the moire technology platform towards the study of primary hepatic stellate cells which represent a primary effector cell in chronic liver disease. With a deeper understanding of hepatic stellate cell biology and force generation, we seek to identify novel therapeutic targets for patients with chronic liver disease and hepatic fibrosis.

In parallel to the development of the optomechanical technology featuring moire readout for cellular force mapping, we developed impedance sensing approaches to analyze a variety of cellular functions in culture. With an initial aim towards a deep understanding of the fundamental principles and a focus on cardiovascular disease, we derived an equivalent circuit model of cardiomyocyte cell-related impedance using electrochemical impedance spectroscopy (ECIS). Using our equivalent circuit model enabled the capacity to derive a continuous, real-time, noninvasive assessment of cell-substrate distance which we employed to monitor cardiomyocyte adhesion. Furthermore, using the cell-substrate distance as a biomarker, we employed impedance sensing to study cardiomyocyte apoptosis and cell death in real time in response to proinflammatory cytokines.

Similar to the optomechanical technology, we are currently focused on applying impedance sensing to a high-throughput paradigm, integrating microelectrode arrays for microenvironment microarray assays. While numerous applications are envisioned, we initially aim to employ this high-throughput approach in hepatocellular carcinoma cells to enable a highly parallel study of the effects of the cellular microenvironment on cancer development and progression. In addition, we are integrating impedance technology as a readout approach in microfabricated cell culture environments which model the physiology and cytoarchitecture of the liver ('liver-on-a-chip'). Compared to conventional microscopy and biochemical end-point analyses, impedance sensing offers distinct advantages which we aim to bring to bear on toxicology analyses using physiologically accurate models of primary liver cells in culture.

Project Examples/Representative Publications (Listed based on Ph.D. dissertations)
Miniaturized biomechanosensors for cardiomechanical studies
Flexible fabrication of 3D multi-layered microstructures using a scanning laser system
Impedance sensing for cellular response studies
Microsystem based opto-mechano platform for cardiovascular cell contraction study
Viscoelastic characterization of PDMS micropillars for cell force measurement applications

Selected Recent Publications:
D.W. Sutherland, et al, Water Infused Surface Protection as an Active Mechanism for Fibrin Sheath Prevention in Central Venous Catheters. Artificial Organs, 2017. DOI: 10.1111/aor.12916 [DOI]
A. Li, et al, Towards uniformly oriented diatom frustule monolayers: experimental and theoretical analyses. Microsystems & Nanoengineering - Nature, 2016, 2: 16064(4pp). [DOI]
J. Cai, et al, Biologically enabled micro- and nanostencil lithography using diatoms. Extreme Mechanics Letters, 2015, 4: 186-192. [DOI]
Y. Qiu, et al, A role for matrix stiffness in the regulation of cardiac side population cell function. AJP-Heart and Circulatory Physiology, 2015, 308(9): H990-H997. [DOI]
F. Zhang, et al, Cell force mapping using a double-sided micropillar array based on the moire fringe method. Applied Physics Letters, 2014, 105(3): 033702(5pp). [DOI]
C. Wang, et al, Biocompatible, micro- and nano-fabricated magnetic cylinders for potential use as contrast agents for magnetic resonance imaging. Sensors and Actuators B: Chemical, 2014, 196: 670-675. [DOI]
C. Wang, et al, Fabrication and characterization of composite hydrogel particles with x-ray attenuating payloads. Journal of Vacuum Science & Technology B, 2014, 32(3): 032001(7pp). [DOI]
X. Wang, et al, Microfabricated iron oxide particles for tunable, multispectral magnetic resonance imaging. Materials Letters, 2013, 110: 122-126. [DOI]
E.M. Frohlich, et al, Topographically-patterned porous membranes in a microfluidic device as an in vitro model of renal reabsorptive barriers. Lab on a Chip, 2013, 13(12): 2311-2319. [DOI]
P. Du, et al, Tunable electrical and mechanical responses of PDMS and polypyrrole nanowire composites. Journal of Physics D: Applied Physics, 2013, 46(19): 195303(8pp). [DOI]
P. Du, et al, Investigation of cellular contraction forces in the frequency domain using a PDMS micropillar-based force transducer. Journal of Microelectromechanical Systems, 2013, 22(1): 44-53. [DOI]
E.M. Frohlich, et al, The use of controlled surface topography and flow-induced shear stress to influence renal epithelial cell function. Integrative Biology, 2012, 4(1): 75-83. [DOI]

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