BioScript: programming safe chemistry on laboratories-on-a-chip

This paper introduces BioScript, a domain-specific language (DSL) for programmable biochemistry which executes on emerging microfluidic platforms. The goal of this research is to provide a simple, intuitive, and type-safe DSL that is accessible to life science practitioners. The novel feature of the language is its syntax, which aims to optimize human readability; the technical contributions of the paper include the BioScript type system and relevant portions of its compiler. The type system ensures that certain types of errors, specific to biochemistry, do not occur, including the interaction of chemicals that may be unsafe. The compiler includes novel optimizations that place biochemical operations to execute concurrently on a spatial 2D array platform on the granularity of a control flow graph, as opposed to individual basic blocks. Results are obtained using both a cycle-accurate microfluidic simulator and a software interface to a real-world platform

A Microfluidic Platform for Precision Small-volume Sample Processing and Its Use to Size Separate Biological Particles with an Acoustic Microdevice.

A major advantage of microfluidic devices is the ability to manipulate small sample volumes, thus reducing reagent waste and preserving precious sample. However, to achieve robust sample manipulation it is necessary to address device integration with the macroscale environment. To realize repeatable, sensitive particle separation with microfluidic devices, this protocol presents a complete automated and integrated microfluidic platform that enables precise processing of 0.15-1.5 ml samples using microfluidic devices. Important aspects of this system include modular device layout and robust fixtures resulting in reliable and flexible world to chip connections, and fully-automated fluid handling which accomplishes closed-loop sample collection, system cleaning and priming steps to ensure repeatable operation. Different microfluidic devices can be used interchangeably with this architecture. Here we incorporate an acoustofluidic device, detail its characterization, performance optimization, and demonstrate its use for size-separation of biological samples. By using real-time feedback during separation experiments, sample collection is optimized to conserve and concentrate sample. Although requiring the integration of multiple pieces of equipment, advantages of this architecture include the ability to process unknown samples with no additional system optimization, ease of device replacement, and precise, robust sample processing

Synthesis of biochemical applications on digital microfluidic biochips with operation variability

Abstract—Microfluidic-based biochips are replacing the con-ventional biochemical analyzers, and are able to integrate on-chip all the necessary functions for biochemical analysis using microfluidics. The digital microfluidic biochips are based on the manipulation of liquids not as a continuous flow, but as discrete droplets. Researchers have presented approaches for the synthesis of digital microfluidic biochips, which, starting from a biochemical application and a given biochip architecture, determine the allocation, resource binding, scheduling and place-ment of the operations in the application. Existing approaches consider that on-chip operations, such as splitting a droplet of liquid, are perfect. However, these operations have variability margins, which can impact the correctness of the biochemical application. We consider that a split operation, which goes beyond specified variability bounds, is faulty. The fault is detected using on-chip volume sensors. We have proposed an abstract model for a biochemical application, consisting of a sequencing graph, which can capture all the fault scenarios in the application. Starting from this model, we have proposed a synthesis approach that, for a given chip area and number of sensors, can derive a fault-tolerant implementation. Two fault-tolerant scheduling techniques have been proposed and compared. We show that, by taking into account fault-occurrence information, we can derive better quality implementations, which leads to shorter application completion times, even in the case of faults. The proposed synthesis approach under operation variability has been evaluated using several benchmarks. I

Microfluidics: A Groundbreaking Technology for PET Tracer Production?

Application of microfluidics to Positron Emission Tomography ( PET) tracer synthesis has attracted increasing interest within the last decade. The technical advantages of microfluidics, in particular the high surface to volume ratio and resulting fast thermal heating and cooling rates of reagents can lead to reduced reaction times, increased synthesis yields and reduced by-products. In addition automated reaction optimization, reduced consumption of expensive reagents and a path towards a reduced system footprint have been successfully demonstrated. The processing of radioactivity levels required for routine production, use of microfluidic-produced PET tracer doses in preclinical and clinical imaging as well as feasibility studies on autoradiolytic decomposition have all given promising results. However, the number of microfluidic synthesizers utilized for commercial routine production of PET tracers is very limited. This study reviews the state of the art in microfluidic PET tracer synthesis, highlighting critical design aspects, strengths, weaknesses and presenting several characteristics of the diverse PET market space which are thought to have a significant impact on research, development and engineering of microfluidic devices in this field. Furthermore, the topics of batch- and single-dose production, cyclotron to quality control integration as well as centralized versus de-centralized market distribution models are addressed

A Framework for Automated Correctness Checking of Biochemical Protocol Realizations on Digital Microfluidic Biochips

Recent advances in digital microfluidic (DMF) technologies offer a promising platform for a wide variety of biochemical applications, such as DNA analysis, automated drug discovery, and toxicity monitoring. For on-chip implementation of complex bioassays, automated synthesis tools have been developed to meet the design challenges. Currently, the synthesis tools pass through a number of complex design steps to realize a given biochemical protocol on a target DMF architecture. Thus, design errors can arise during the synthesis steps. Before deploying a DMF biochip on a safety critical system, it is necessary to ensure that the desired biochemical protocol has been correctly implemented, i.e., the synthesized output (actuation sequences for the biochip) is free from any design or realization errors. We propose a symbolic constraint-based analysis framework for checking the correctness of a synthesized biochemical protocol with respect to the original design specification. The verification scheme based on this framework can detect several post-synthesis fluidic violations and realization errors in 2D-array based or pin-constrained biochips as well as in cyberphysical systems. It further generates diagnostic feedback for error localization. We present experimental results on the polymerase chain reaction (PCR) and in-vitro multiplexed bioassays to demonstrate the proposed verification approach

Microfluidic PCR with plasmonic imaging for rapid multiplexed characterization of DNA from microbial pathogens

Bloodstream infections (BSIs) are a critical concern in modern medicine due to their continued prevalence in modern hospitals, along with high costs and attributable mortality, particularly among those who are immunocompromised. The current gold standard for detection and characterization of causative pathogens involves cell culture, which can take 24-48 hours to complete, increasing time to adequate treatment and thus mortality. The rise of antimicrobial resistance in hospital acquired infections has reduced the effectiveness of broad spectrum antimicrobial treatments, resulting in a clear need for a rapid, sensitive technique for characterization of resistance markers in microbial pathogens without cell culture. Here we present the development of a microfluidic platform for polymerase chain reaction (PCR) mediated amplification of microbial gene targets in a continuous flow system for potential coupling with sample preparation systems to reduce time to diagnosis from days to within two hours. This culminated in a thermoelectric cooler mediated fluidic thermocycler with a recirculating assay region for real-time hybridization measurements to minimize assay time. We subsequently demonstrated development of a low-cost optical system for localized surface plasmon resonance imaging using a digital micromirror device and tuned nanoprism monolayers for DNA hybridization with a spectral resolution of 2nm. This LSPR imaging system was integrated in-flow into the microfluidic thermocycler, enabling detection of input E. coli DNA samples at a minimum concentration of 5fg/ [microliter]. We further demonstrated multiplex detection of target markers, indicating potential for assaying target panels for characterization of pathogens. Overall, the studies in this dissertation demonstrate a microfluidic PCR system with built-in sensitive LSPR detection of DNA hybridization. It should serve as a starting point for exploration of and expansion with fluidic sample preparation with a focus on rapid characterization of pathogens.Biomedical Engineerin