Laboratory for Biomeasurement

In our research projects, we aim at utilizing microtechnology and applied mathematics to create new forums that can transfer the unique physical/chemical phenomenon into platforms for biomedical applications such as tissue engineering, disease diagnostics or therapeutics.

Microfluidic Bead Trap is a dipstick-type bar visible by naked eyes for simple and quantitative detection of oligonucleotides. In recent years, visual detection, as a simple, direct and rapid method, has been developed in many platforms. However, while convenient, current platforms for visual detections are mostly limited to qualitative results (yes or no signal). For quantitative measurement, the visual signal needs to be converted into optical/fluorescence intensity measured by lateral flow strip reader, or spectral absorbance read by UV-Vis spectrometer. As a result, cumbersome, bulky instruments and power supply are inevitable, which creates technical hurdles for detection and analysis in resource-limited settings. Thus, we use magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) that are connected and form MMPs-targets-PMPs when target oligonucleotides are present, leaving free PMPs with a number inversely proportional to the amount of targets. Using a capillary flow-driven microfluidic circuitry consisting of a magnetic separator to remove the MMPs-targets-PMPs, the free PMPs can be trapped at the narrowing nozzle in downstream, forming a visual bar quantifiable based on the length of PMP accumulation (Zhao, Lab Chip, 2017). We anticipate that this method can provide a simple, sensitive approach achieving visual detection and direct quantification of lead contamination on a power-free and instrumental-free platform.

Bead based biosensor is to provide a rapid and simple approach for detection of biomolecules such as nucleic acid or protein biomarkers. Recently, many biomarkers present in the blood stream were recently found to show  promise for cancer classification and prognostication. However, the complex environment of blood has created significant challenge for on-site detection. Using functionalized microparticles, we explore the possiblity of visual detection of nucleic acids. With the use of magnetic microparticles and polystyrene microparticles, the visual readouts have been resorted to Mie scattering (Zhao, Analyst, 2015), which provide greatly enhanced extinction coefficient based on the magnetic extraction and the stability of mono-dispersion, enabling sensitive, multiplexed assays and ability for handling complex fluids, such as whole blood, in a single assay. Thus, by satisfying many of the requirements of point-of-care detection, we envision that this method will be applicable to healthcare and environmental monitoring in resource-limited settings in the future.

Microtechology is an essential tool allowing spatial modulations such as physical stimuli or diffusion gradient of chemicals to control the biological systems. With the enhanced efficiency and efficacy, it has been used to optimize the design principle in electrochemical sensor (Garcia, Chen, JALA, 2009). The dominance of surface tension in microscale can also be exploited in the droplet based fluidic systems (Chen, et al, J. Micromech. Microeng., 2007), or a separation mechanism for biological entities (Wong, Chen, et al, Anal. Chem., 2011). Integrating with cell biology, the interface between cell-adhesive and non-adhesive substrate also play as an powerful stimulus to direct this intrinsic motility of cells (Chen, et.al, Circ Res, 2012; Chen, et.al, Biomaterials, 2012). Overall, it creates a new venue with great flexibility and versatile application for a variety of experimental scenarios. 

Cell mechanics plays a central role in regulating cell proliferation, differentiation, and morphogenesis.a central role in regulating cell proliferation, differentiation, and morphogenesis. How does cell mechanics regulate cellular behavior? To probe this question, we cultured cells on microengineered substrate which defines alternating stripes of cell adhesive and non-adhesive substrate. We found that cellular mechanical stress accumulated at the substrate interfaces triggers an inherent left-right asymmetry of cells. Based on it, cells preferentially turn right on migration across the interfaces, eventually leading to multicellular structures with left-right asymmetry (Chen, et.al, Circ Res, 2012). Importantly, this finding is the first demonstration that tissue morphology with left-right asymmetry can be formed from single-cell organizer which has left-right preference. Also, although cells have been cultured for decades, left-right biased migration in cultured adult cells is rarely seen. Given that mechanical inductions are generally absent in the conventional cultures, our findings suggest that it is because cytoskeletal remodeling like those in our experiments was not activated in the traditional way.

Tissue formation is the central core in many biological organizations, with implications for many diseases such as spinal cord injury or heart diseases. However, how can we guide the cells to rebuild the damage or missing tissue? When rebuilding a tissue replacement, self-organization also creates inherent challenge that may frustrate and disorganize the artificial attempts. To work in concert with self-organization rather than against it, we use mathematical models that formulate the Turing's reaction-diffusion mechanism as observed in many developmental process. By modeling the kinetics of a pair of growth factor, slowly-diffusing activator and its rapidly-diffusing inhibitor, together with cellular activity, we can reproduce the nonlinear dynamics that results in specific pattern formations representing the tissue development.  Importantly, small difference in the initial cell distribution (Chen, et.al, Biomaterials, 2012) and cellular motility (Chen, et.al, Interface Focus, 2012) can be integrated and amplified into changes in global tissue morphology, shows a completely different route for designing and reconstructing tissue with minimum engineering efforts.