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

Establishment of a fully automatized microfluidic platform for the screening and characterization of novel Hepatitis B virus capsid assembly modulators

El procés de descobriment de fàrmacs s'enfronta a importants desafiaments a causa de la constant disminució dels guanys per medicament atesa la disminució en les noves aprovacions de la FDA combinada amb el constant augment dels costos i el temps de desenvolupament. Les plataformes integrades de detecció usant microfluídica van sorgir com a possibles solucions per accelerar el desenvolupament de molècules actives i reduir els requisits de temps i costos. El projecte VIRO-FLOW té com a objectiu identificar nous agents curatius per al virus de l'hepatitis B (VHB), integrant els avantatges de la química de flux continu amb tecnologies de bioassaigs in vitro en microfluídica. Durant aquesta tesi es va construir un sistema microfluídic aplicant dispositius modulars automatitzats. Es van redactar protocols d'avaluació per a les dades de fluorescència i reflexió, permetent el càlcul del factor Z, les desviacions estàndard, les corbes de dilució i els valors de concentracions efectives mitjanes màximes (EC50). La proteïna central del VHB (HBc) es va seleccionar com a objectiu principalEl proceso de descubrimiento de fármacos se enfrenta a importantes desafíos debido a la constante disminución de las ganancias por medicamento dada la disminución en las nuevas aprobaciones de la FDA combinada con el constante aumento de los costes y el tiempo de desarrollo. Las plataformas integradas de detección usando microfluídica surgieron como posibles soluciones para acelerar el desarrollo de moléculas activas y reducir los requisitos de tiempo y costes. El proyecto VIRO-FLOW tiene como objetivo la identificación de nuevos agentes curativos para el virus de la hepatitis B (VHB), integrando las ventajas de la química de flujo continuo con tecnologías de bioensayos in vitro en microfluídica. Durante la presente tesis se construyó un sistema microfluídico aplicando dispositivos modulares automatizados. Se redactaron protocolos de evaluación para los datos de fluorescencia y reflexión, permitiendo el cálculo del factor Z, desviaciones estándar, curvas de dilución y valores de concentraciones efectivas medias máximas (EC50). La proteína central del VHB (HBc) se seleccionó como objetivo principal.Drug Discovery as known today faces major challenges due to the constant decrease of earnings per drug given the decrease in new FDA approvements combined with the steadily rising development costs and time. Integrated microfluidic screening platforms emerged as possible solutions by accelerating the hit-to-lead development cycle and reducing time and cost requirements. The VIRO-FLOW project aims at the fast and efficient identification of novel curative agents for the Hepatitis B Virus (HBV), integrating the advantages of continuous flow chemistry with in vitro microfluidic bioassay technologies. During the present thesis a microfluidic system was built, applying automatized modular devices. Evaluation protocols were written for the fluorescence and reflection data, allowing the Z´-factor calculation, standard deviations, dilution curves, and half‐maximal effective concentrations (EC50) values. HBV core protein (HBc) was selected as primary target due to the ongoing demand for a functional cure to reduce the economic and social challenges imposed by the chronic diseas

Optical Printing of Multiscale Hydrogel Structures

Hydrogel has been a promising candidate to recapitulate the chemical, physical and mechanical properties of natural extracellular matrix (ECM), and they have been widely used for tissue engineering, lab on a chip and biophotonics applications. A range of optical fabrication technologies such as photolithography, digital projection stereolithography and laser direct writing have been used to shape hydrogels into structurally complex functional devices and constructs. However, it is still greatly challenging for researchers to design and fabricate multiscale hydrogel structures using a single fabrication technology. To address this challenge, the goal of this work is the design and develop novel multimode optical 3D printing technology capable of printing hydrogels with multiscale features ranging from centimeter to micrometer sizes and in the process transforming simple hydrogels into functional devices for many biomedical applications. Chapter 2 presents a new multimode optical printing technology that synergistically combined large-scale additive manufacturing with small-scale additive/subtractive manufacturing. This multiscale fabrication capability was used to (i) align cells using laser induced densification in Chapter 3, (ii) develop diffractive optics based on changes in refractive indices in Chapter 4, (iii) print diffractive optical elements in Chapter 5, and (iv) digitally print complex microfluidic devices and other 3D constructs in Chapter 6. Overall, this work open doors to a new world of fabrication where multiscale functional hydrogel structures are possible for a range biomedical application

Velocity-independent thermal conductivity and volumetric heat capacity measurement of binary gas mixtures

In this paper, we present a single hot wire suspended over a V-groove cavity that is used to measure the thermal conductivity ($k$) and volumetric heat capacity ($\rho c_p$) for both pure gases and binary gas mixtures through DC and AC excitation, respectively. The working principle and measurement results are discussed

Microfabrication Technology for Isolated Silicon Sidewall Electrodes and Heaters

This paper presents a novel microfabricationtechnology for highly doped silicon sidewall electrodesparallel to – and isolated from – the microchannel. Thesidewall electrodes can be utilised for both electricaland thermal actuation of sensor systems. Thetechnology is scalable to a wide range of channelgeometries, simplifies the release etch, and allows forfurther integration with other Surface ChannelTechnology-based systems. Furthermore, thefabrication technology is demonstrated through thefabrication of a relative permittivity sensor. The sensormeasures relative permittivity values ranging from 1 to80, within 3% accuracy of full scale, including waterand water-containing mixtures

Plasmonic metal nanoparticles, synthesis and applications

Previously restricted to Strathclyde users from 1 June 2017 until 1 June 2022Plasmonic metal nanoparticles are widely exploited in academia and industry for use in various assay types. In collaboration with an industrial partner, BBI Solutions, the work here details investigations into the production and use of the plasmonic nanoparticles. The work was split into two themes. The first of these was flow chemistry of nanoparticles, covering a microfluidic assay platform and continuous colloid production.;In chapter one, a novel microfluidic assay platform was developed which facilitated the transfer of multiple, sequential bench-top procedures into a single device. This allowed the rapid detection of a sugar binding protein to be demonstrated. The microfluidic system included all pre-detection steps involved in employing the specific aggregation of functionalised silver nanoparticles. Straightforward detection of the protein was demonstrated at concentrations lower than those achieved using comparable methods in the literature.;In the second chapter, a novel bench-top scale continuous reactor for the production of gold nanoparticles was developed. It was found that the continuous stirred tank reactor was generally unsuitable for this synthesis. A laminar tubular reactor was more successful but fouling of the reactor material was a significant obstacle to production of good quality colloid. In both cases, nanoparticles produced in a batch synthesis were of more consistent quality. This suggested that further work was needed to develop a competitive continuous production method.;The second research theme was development of a novel nanoparticle assembly assay, based on DNA assembly. In chapter three it was found that current tools for the understanding of dynamic DNA structure were limited. This led to the first use of an existing coarse grain model to determine thermodynamic properties of DNA assembly. Analysis showed that the results were comparable with the best simulation models shown in the literature, while being generated much more quickly and at less computational expense.Plasmonic metal nanoparticles are widely exploited in academia and industry for use in various assay types. In collaboration with an industrial partner, BBI Solutions, the work here details investigations into the production and use of the plasmonic nanoparticles. The work was split into two themes. The first of these was flow chemistry of nanoparticles, covering a microfluidic assay platform and continuous colloid production.;In chapter one, a novel microfluidic assay platform was developed which facilitated the transfer of multiple, sequential bench-top procedures into a single device. This allowed the rapid detection of a sugar binding protein to be demonstrated. The microfluidic system included all pre-detection steps involved in employing the specific aggregation of functionalised silver nanoparticles. Straightforward detection of the protein was demonstrated at concentrations lower than those achieved using comparable methods in the literature.;In the second chapter, a novel bench-top scale continuous reactor for the production of gold nanoparticles was developed. It was found that the continuous stirred tank reactor was generally unsuitable for this synthesis. A laminar tubular reactor was more successful but fouling of the reactor material was a significant obstacle to production of good quality colloid. In both cases, nanoparticles produced in a batch synthesis were of more consistent quality. This suggested that further work was needed to develop a competitive continuous production method.;The second research theme was development of a novel nanoparticle assembly assay, based on DNA assembly. In chapter three it was found that current tools for the understanding of dynamic DNA structure were limited. This led to the first use of an existing coarse grain model to determine thermodynamic properties of DNA assembly. Analysis showed that the results were comparable with the best simulation models shown in the literature, while being generated much more quickly and at less computational expense

Capillary Microfluidic Chips for Point-of-Care Testing:from Research Tools to Decentralized Medical Diagnostics

Research on microfluidic devices for biological analysis has progressed sufficiently to be developed into point-of-care diagnostics products. The goal of this thesis is to improve multiple aspects of capillary-driven microfluidic devices. In particular, the objective is to provide devices with a fast time to result, that are simple to use (one-step), that can be portable, that accept a variety of samples, that operate reliably, that provide a range of detection signals, that are mass manufacturable at lost cost, and that are able to detect medically relevant biological molecules. First, we survey the evolution of microfluidic research into portable medical diagnostic devices. By looking at several gaps and opportunities in current medical diagnostics, we provide an overview of research topics that have the potential to shape the next generation of point-of-care diagnostics. Specifically we explain technologies in the order of sample interacting with different components of a device. We investigate the materials, surface treatments, sample processing, microfluidic elements (such as valves, pumps and mixers), receptors and analytes and the integration of these components into a device that might conceivably leave the laboratory for the hands of consumers. The knowledge of what is important in a point-of-care diagnostics device was used to develop a proof of concept. One of the main challenges is to make microfluidics easy to use by incorporating reagents and microfluidic elements. We integrated a number of functional elements on a chip such as a sample collector, delay valves, flow resistors, a deposition zone for detection antibodies (dAbs), a reaction chamber sealed with a polydimethylsiloxane (PDMS) substrate, and a capillary pump and vents. We further incorporated capture antibodies (cAbs), detection antibodies (dAbs) and analyte molecules for making one-step immunoassays. The integrated microfluidic chip requires only the addition of sample to trigger a sequence of events controlled by capillary forces to detect C-reactive protein (CRP), a general inflammation and cardiac marker, at a concentration of 1 ng mL-1 within 14 min using only 5 µL of human serum. The proof-of-concept is extended to easily modify several assay parameters such as the flow rates and the volumes of samples for tests, and the type of reagents and receptors for analytes. The multiparametric microfluidic chip is capable of analyzing 20 µL of human serum in 6 parallel flow paths in a range of flow rates with filling times from 10 minutes to 72 minutes. The asymmetric release of dAbs in a stream of human serum is compensated by a Dean flow mixer. Sample is equally split into 6 reaction chambers connected to flow resistances that vary flow rates, and the kinetics of capture of analyte-dAb complexes. The increased incubation time leads to a fourfold increase in detection signal in the reaction chamber with the longer incubation time. Furthermore, integrating reagents and controlling their release is essential for simple and accurate point-of-care diagnostic devices. We developed reagent integrators (RIs) to release small amounts of dried reagents (ng quantities and less) into microliters of sample. Typical RIs are composed of an inlet splitting into a central reagent channel, with a high hydraulic resistance, and two diluter channels. Reagents spotted in the central channel reconstitute in sample during filling and merge at the end of the RI with a dilution factor corresponding to the relative hydraulic resistance of the channels forming the RI. RIs are simple to integrate in lateral flow assays and provide a great degree of control over reagent integration and dissolution. Finally, the one-step capillary-driven microfluidic chips have the ability to not only detect a variety of proteins, but also to detect nucleic acids for molecular diagnostics. These devices, especially if manufactured in low cost plastic and used with portable fluorescence readers, have the potential to identify a wide variety of health conditions and to enable truly decentralized medical diagnostics

The Design and Optimization of Jet-in-Cross-Flow (JICF) for Engineering Applications: Thermal Uniformity in Gas-turbines and Cavitation Treatment in Hydro-turbines

Jet-in-cross-flow (JICF) is a well-known term in thermal flows field. Ranging from the normal phenomenon like the volcano ash and dust plumes to the designed film cooling and air fuel mixing for combustion, JICF is always studied to understand its nature at different conditions. Realizing the behavior of interacting flows and importance of many variables lead to the process of reiterating the shapes and running conditions for better outcomes or minimizing the losses. Summarizing the process under the name of optimization, two JICF applications are analyzed based on the principles of thermodynamics and fluid mechanics, then some redesigns are proposed to reach the optimal statuses for the goals sought. Correlations and recommendations are given between the input variables and the outputs. In the first application, annular thermal mixing chamber, the cold stream penetrates the axial hot flow as circumferential inward jets. Thermal uniformity of the exit mixture is the target to maximize, and accordingly, a streamlined body is firstly suggested to be placed at the center of the chamber to divert the hot stream towards the cold one. Following the idea, the shape and dimensions (length and maximum diameter) are tested experimentally with four 3-D printed bodies expressing different aspect, blockage, and profile ratios. Later, an Analysis LED Design stage (numerical then experimental) checked the effect of adding swirlers on the best streamlined shape. Swirlers shape, number, and height are examined for the relation with the uniformity and pressure drop. By defining a decision-making variable (useful efficiency), the two contradicting variables were consolidated into one, and the swirlers performance was easier to be quantified and the most efficient one was nominated. At the final stage, a numerical study searched the optimal design(s) using design of experiment and optimization (Global and Hybrid) algorithms. The study sought the optimality of the dimensional aspects (diameter, length, and position) of the swirling streamlined body based on minimizing the contradicting objectives. The results were represented by Pareto curve, correlation matrix, parallel axes, and response surface model. It was understood that the optimization can offer improvement of 68% and 15% to the uniformity number and the pressure drop respectively. On the other hand, aeration treatment for cavitating flow in axial Kaplan turbine was considered for the second engineering application. Using CFD models of a 7.5-cm hydro-turbine, cavitation situation was simulated, then air is injected from the housing to redistribute around the blades of the rotor. The value of the vapor fraction is tracked over the blades and the hub areas throughout the time of turbine cycles. Comparison is achieved by evaluating an average value for the vapor fraction at each case. Air mass flowrate and ports distribution are found to be effective in reducing the cavitation phenomena. Proposed linear aeration distributor on the housing presented a promising technology for spreading the air over the blade chord in a better way than the circumferential distribution. The study allowed the understanding of the flow behavior (in terms of air flow, liquid pressure, and cavitation formations) and turbine performance (i.e. mechanical power) at different air injection locations and turbine rotational speeds. A broader view of research investigated the functionality of linear aeration distributor on the hub with an air supply going through a hollow shaft. The invention of the hub air injection targets the marine industry (i.e. propellers) where the housing/shrouds do not exist, but it also can be a competitor to the housing air injection technology as well. For the two aeration approaches (housing and hub), the conducted numerical investigations were based on the vapor mitigation and power regain in the Kaplan turbine, meanwhile the experimentation looked for the vapor and motor power reduction for the propeller operation. A good agreement (qualitatively and quantitatively) was found between matching cases created for such purpose using tools for high-speed imaging, statistical analysis for turbulent flow, image processing and power measurements. Finally, the dissertation sets some recommendations for the continuation of the researches on the two applications (thermal uniformity and aeration treatments) for better jets interaction with the cross flow by the consideration of the addition/orientation of guide vanes and the relocation of the jets on the turbine blades respectively

Microfluidics and Nanofluidics Handbook

The Microfluidics and Nanofluidics Handbook: Two-Volume Set comprehensively captures the cross-disciplinary breadth of the fields of micro- and nanofluidics, which encompass the biological sciences, chemistry, physics and engineering applications. To fill the knowledge gap between engineering and the basic sciences, the editors pulled together key individuals, well known in their respective areas, to author chapters that help graduate students, scientists, and practicing engineers understand the overall area of microfluidics and nanofluidics. Topics covered include Finite Volume Method for Numerical Simulation Lattice Boltzmann Method and Its Applications in Microfluidics Microparticle and Nanoparticle Manipulation Methane Solubility Enhancement in Water Confined to Nanoscale Pores Volume Two: Fabrication, Implementation, and Applications focuses on topics related to experimental and numerical methods. It also covers fabrication and applications in a variety of areas, from aerospace to biological systems. Reflecting the inherent nature of microfluidics and nanofluidics, the book includes as much interdisciplinary knowledge as possible. It provides the fundamental science background for newcomers and advanced techniques and concepts for experienced researchers and professionals