Microfluidic very large-scale integration for biochips: Technology, testing and fault-tolerant design

Microfluidic biochips are replacing the conventional biochemical analyzers by integrating all the necessary functions for biochemical analysis using microfluidics. Biochips are used in many application areas, such as, in vitro diagnostics, drug discovery, biotech and ecology. The focus of this paper is on continuous-flow biochips, where the basic building block is a microvalve. By combining these microvalves, more complex units such as mixers, switches, multiplexers can be built, hence the name of the technology, “microfluidic Very Large-Scale Integration” (mVLSI). A roadblock in the deployment of microfluidic biochips is their low reliability and lack of test techniques to screen defective devices before they are used for biochemical analysis. Defective chips lead to repetition of experiments, which is undesirable due to high reagent cost and limited availability of samples. This paper presents the state-of-the-art in the mVLSI platforms and emerging research challenges in the area of continuous-flow microfluidics, focusing on testing techniques and fault-tolerant design

Directed Placement for mVLSI Devices

Continuous-flow microfluidic devices based on integrated channel networks are becoming increasingly prevalent in research in the biological sciences. At present, these devices are physically laid out by hand by domain experts who understand both the underlying technology and the biological functions that will execute on fabricated devices. The lack of a design science that is specific to microfluidic technology creates a substantial barrier to entry. To address this concern, this article introduces Directed Placement, a physical design algorithm that leverages the natural "directedness" in most modern microfluidic designs: fluid enters at designated inputs, flows through a linear or tree-based network of channels and fluidic components, and exits the device at dedicated outputs. Directed placement creates physical layouts that share many principle similarities to those created by domain experts. Directed placement allows components to be placed closer to their neighbors compared to existing layout algorithms based on planar graph embedding or simulated annealing, leading to an average reduction in laid-out fluid channel length of 91% while improving area utilization by 8% on average. Directed placement is compatible with both passive and active microfluidic devices and is compatible with a variety of mainstream manufacturing technologies

Scheduling and Fluid Routing for Flow-Based Microfluidic Laboratories-on-a-Chip

Microfluidic laboratories-on-a-chip (LoCs) are replacing the conventional biochemical analyzers and are able to integrate the necessary functions for biochemical analysis on-chip. There are several types of LoCs, each having its advantages and limitations. In this paper we are interested in flow-based LoCs, in which a continuous flow of liquid is manipulated using integrated microvalves. By combining several microvalves, more complex units, such as micropumps, switches, mixers, and multiplexers, can be built. We consider that the architecture of the LoC is given, and we are interested in synthesizing an implementation, consisting of the binding of operations in the application to the functional units of the architecture, the scheduling of operations and the routing and scheduling of the fluid flows, such that the application completion time is minimized. To solve this problem, we propose a list scheduling-based application mapping (LSAM) framework and evaluate it by using real-life as well as synthetic benchmarks. When biochemical applications contain fluids that may adsorb on the substrate on which they are transported, the solution is to use rinsing operations for contamination avoidance. Hence, we also propose a rinsing heuristic, which has been integrated in the LSAM framework

Membrane Deflection-based Fabrication and Design Automation for Integrated Acoustofluidics

Continuous-flow microfluidic large-scale integration (mLSI) is a developing field first introduced in the early 2000s, that continues to offer promising solutions to many biochemical, biophysical and biomedical problems. In his seminal paper, Thorsen et al. 2002 demonstrated the fabrication of high-density microfluidic systems capable of complex fluidic routing in combinatory arrays of multiplexors, mixers, and storage assemblies integrated with micromechanical valves. mLSI has been a powerful tool for scientific research by allowing for dramatic reduction in the volume of reagent needed for experimentation and offering highly parallelizable and dynamic process flows. These systems have since been the focus of strong interdisciplinary academic research efforts. Despite the success in scientific applications, the mLSI technologies have not found widespread use in commercial environments. One critical issue preventing mLSI to realize its full potential is the need for specialized fabrication techniques that are scalable and more suitable for the unique requirements of biology. The work presented here demonstrates an mLSI integrated acoustofluidic platform that offers versatility while maintaining a robust fabrication process. In particular, conductive liquid metal-based acoustic transducers integrated with micromechanical valves to facilitate dynamic switching of the resonant frequency of the device and generated surface acoustic waves (SAWs) is demonstrated. Shortcomings in the fabrication of fluidic channels for mLSI integrated acoustofluidic applications are examined, and solutions to these problems are presented. A novel and scalable soft-lithographic method is introduced, that allows for the fabrication of large valvable channels with tunable height that exceeds practical limitations dictated by previous photolithographic techniques. A thorough characterization of this method and demonstration of its robustness are included here as a promising data to promote further exploration of the technique as a viable commercial solution for the fabrication of many classes of mLSI bio-devices. The testing of a computeraided design software, Columba, is briefly discussed