Browsing by Author "Zhao, Yang"

Optical imaging techniques generally offer shallow penetration depths due to high scattering in biological tissue. We have recently developed frequency domain multispectral multiple scattering low coherence interferometry (ms2/LCI) for deep tissue imaging. The ms2/LCI system offers unique spatial and angular rejection of out-of-focus photons by utilizing an off-axis interferometric setup. Multiply forward scattered light is preferentially detected for imaging at extended depths. Using tissue-mimicking phantoms that match the full scattering phase function of human dermal tissue, we demonstrate that the ms2/LCI system can provide a signal/noise ratio (SNR) improvement of 15.4 dB over conventional OCT at an imaging depth of 1 mm.

In vivo imaging is challenging for the ms2/LCI system due to its slow acquisition speed. To enable fast image acquisition, we have developed dual-axis optical coherence tomography (DA-OCT), which offers a 100-fold speed increase compared to the ms2/LCI system. Two DA-OCT systems were designed and constructed, operating at a center wavelength of 800 nm and 1300 nm respectively. The 1300 nm DA-OCT system offers up to 2 mm depth penetration in skin imaging, which is unprecedented for an OCT system. This significant improvement in penetration depth opens the door for various exciting applications in fields where conventional OCT imaging was limited by poor penetration depths.

Deep features revealed by DA-OCT can be confounded by speckle noise. Speckle is an intrinsic noise of interferometric signals which reduces contrast and degrades the quality of images. A novel frequency compounding speckle reduction technique using the Dual Window (DW) method was recently presented. Using the DW method, speckle noise is reduced without the need to acquire multiple frames. A ~25% improvement in the contrast-to-noise ratio (CNR) was achieved using the DW speckle reduction method with only minimal loss in resolution. The DW speckle reduction method can work on any existing OCT instrument without further system modification or extra components. This makes it applicable both in real-time imaging systems and during post-processing.

Finally, functional information was extracted from the raw interferometric data for diagnostic purposes. Depth-resolved spectra were calculated by a time-frequency analysis, which carry valuable localized tissue information. The spectroscopic information was first used to objectively evaluate burn injuries in an in vivo mouse model. Significant spectral differences were observed and correlated with the depth of the injury as determined by histopathology. Later, spectroscopic DA-OCT was used for the assessment of flap viability in an in vivo Macfarlane rat flap model, which exhibited a gradient in tissue perfusion along the length of the flap. These results suggest that the DA-OCT system can be used for objective evaluation of skin injuries at extended depths.

Digital microfluidics is an emerging technology that provides fluid-handling capability on a chip. Biochips based on digital microfluidics have therefore enabled the automation of laboratory procedures in biochemistry. By reducing the rate of sample and reagent consumption, digital microfluidic biochips allow continuous sampling and analysis for real-time biochemical analysis, with application to clinical diagnostics, immunoassays, and DNA sequencing. Recent advances in technology and applications serve as a powerful driver for research on computer-aided design (CAD) tools for biochips.

This thesis research is focused on a design automation framework that addresses chip synthesis, droplet routing, control-pin mapping, testing and diagnosis, and error recovery. In contrast to prior work on automated design techniques for digital microfluidics, the emphasis here is on practical CAD optimization methods that can target different design problems in a unified manner. Constraints arising from the underlying technology and the application domain are directly incorporated in the optimization framework.

The avoidance of cross-contamination during droplet routing is a key design challenge for biochips. As a first step in this thesis research, a droplet-routing method based on disjoint droplet routes has been developed to avoid cross-contamination during the design of droplet flow paths. A wash-operation synchronization method has been developed to synchronize wash-droplet routing steps with sample/reagent droplet-routing steps by controlling the order of arrival of droplets at cross-contamination sites.

In pin-constrained digital microfluidic biochips, concurrently-implemented fluidic operations may involve pin-actuation conflicts if they are not carefully synchronized. A two-phase optimization method has been proposed to identify and synchronize these fluidic operations. The goal is to implement these fluidic operations without pin-actuation conflict, and minimize the duration of implementing the outcome sequence after synchronization.

Due to the interdependence between droplet routing and pin-count reduction, this thesis presents two optimization methods to concurrently solve the droplet-routing and the pin-mapping design problems. First, an integer linear programming (ILP)-based optimization method has been developed to minimize the number of control pins. Next an efficient heuristic approach has been developed to tackle the co-optimization problem.

Dependability is an important system attribute for microfluidic biochips. Robust testing methods are therefore needed to ensure correct results. This thesis presents a built-in self-test (BIST) method for digital microfluidic biochips. This method utilizes digital microfluidic logic gates to implement the BIST architecture. A cost-effective fault diagnosis method has also been proposed to locate a single defective cell, multiple

rows/columns with defective cells, as well as an unknown number of rows/columns-under-test with defective cells. A BIST method for on-line testing of digital microfluidic biochips has been proposed. An automatic test pattern generation (ATPG) method has been proposed for non-regular digital microfluidic chips. A pin-count-aware online testing method has been developed for pin-constrained designs to support the execution of both fault testing and the target bioassay protocol.

To better monitor and manage the execution of bioassays, control flow has been incorporated in the design and optimization framework. A synthesis method has been developed to incorporate control paths and an error-recovery mechanism during chip design. This method addresses the problem of recovering from fluidic errors that occur

during on-chip bioassay execution.

In summary, this thesis research has led to a set of unified design tools for digital microfluidics. This work is expected to reduce human effort during biochip design and biochip usage, and enable low-cost manufacture and more widespread adoption for laboratory procedures.