Academic literature on the topic 'Microfluidic method'

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2011.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (p. 145-149).<br>The field of microfluidics has powerful applications in low-cost healthcare diagnostics, DNA analysis, and fuel cells, among others. As the field moves towards commercialization, the ability to robustly manufacture these devices at low cost is becoming more important. One of the many challenges in microfluidic manufacturing is the reliable sealing of the microfluidic chips once the channels have been generated. This work was an investigation of innovative ways to robustly heat the substrate-cover plate interface of a microfluidic device for the purpose of bonding and sealing the microfluidic channels. An extensive literature review revealed the benefits of interfacial heating, and both simulations and experimental investigations were used to evaluate a few different methods. Ultimately, a unique method was established that uses light to provide both the bonding energy and the illumination for an in-process vision system for real-time viewing and control of the bonding process. The process results in the generation of a homogenous and optically clear bond, and preliminary tests show that when properly controlled, a bond with minimal microchannel deformation can be created.<br>by Michelle E. Lustrino.<br>S.M.

Controlled drug delivery devices provide numerous advantages such as reduced side effects, higher therapeutic efficiency and improved patient compliance. Biodegradable polymer has become the most important material for controlled drug delivery device because of the excellent biocompatibility and tunable physicochemical properties. Biodegradable polymeric drug delivery devices are usually processed into various types of micro-particles due to the ease of fabrication and administration. However, controlling the drug release kinetics of these microparticles is still a challenge. One important reason is that drug release kinetics is significantly influenced by the microstructure of drug delivery devices, which is difficult to control. 　Microfluidic method is a group of technologies involved in the manipulation of fluids using channels in the scale of micrometers. Microfluidic method is particularly useful in controlling the structure of micro-droplets and generating homogeneous droplets. Therefore, microfluidics suggests great potential in controlling microstructures of drug delivery devices and drug release kinetics. 　In this study, biodegradable polymer based controlled drug delivery devices were fabricated using microfluidic method. Various types of microstructures were developed such as microspheres, core-shell microspheres, hollow microspheres and hydrogel microspheres. The results showed that microstructures were well controlled by fluid flow rates and geometries of capillary microfluidic devices. Both hydrophobic and hydrophilic drugs could be delivered by choosing drug delivery devices with suitable microstructures. 　Drug release kinetics of biodegradable polymeric microspheres has been studies a lot, yet complete understanding is still to be achieved. The diameter is an important factor which contributes to the drug release kinetics. However, the influence of diameter has not been systemically studied because monodisperse microspheres are difficult to obtain. Using microfluidic method, monodisperse PLGA microspheres with different diameters were fabricated to study the influence of diameter on drug release kinetics. It was found that diameter only influence the duration of the first phase (lag phase) in drug release process and smaller microspheres exhibited shorter lag phase. The relatively faster expansion of smaller microspheres was found to be responsible for the size effect by monitoring physicochemical changes during drug release. 　Rifampicin, a broad-spectrum antibiotic, was encapsulated by PLGA microspheres and PLGA-alginate core-shell microspheres. The long-term antimicrobial effects of drug loaded microspheres were investigated by drug release test and antimicrobial test against Staphylococcus aureus. The results showed that drug delivery devices could provide antimicrobial effect for more than one month. These drug delivery devices show potential in applications of controlled drug delivery and long-term antimicrobial therapy. 　In conclusion, drug delivery devices with different microstructures were fabricated using microfluidic method. The diameter of PLGA microspheres only influence the first phase of drug release profile (lag phase) and smaller microspheres exhibited shorter lag phase. The size effect is due to the relatively faster expansion rate of smaller microspheres. Rifampicin loaded PLGA microspheres and PLGA-alginate core-shell microspheres could provide sustained release of rifampicin for more than one month. The released rifampicin was able to inhibit the growth of Staphylococcus aureus. The controlled drug delivery devices presented showed great potential in long-term antimicrobial applications.<br>published_or_final_version<br>Orthopaedics and Traumatology<br>Doctoral<br>Doctor of Philosophy

The doctoral research summarized in this thesis has focused on the study of microflows in Tissue Engineering (TE) scaffolds and microdevices. The thesis is organized in two parts. In the first part, the properties influencing mass transport through scaffold are investigated both experimentally and in silico. In detail: (1) an acoustic measurement system suitable for the evaluation of TE porous scaffolds and based on a single (pressure) transducer is developed; (2) realistic models of irregular porous scaffolds were reconstructed from micro-CT images and fluid transport through them is simulated by applying the Lattice Boltzmann method. In the second part, the issue of mixing of species in microdevices is investigated in depth and a novel low-cost passive microfluidic mixer design is proposed and its performance evaluated both in silico and in vitro. PART I: The performance of porous scaffold for tissue engineering (TE) applications are generally evaluated in terms of porosity, pore size and distribution, and pore tortuosity. However these descriptors are often confounding when they are applied to characterize the mass transport within porous scaffolds. On the contrary, permeability is a more effective parameter in (1) estimating mass and species transport through the scaffold and (2) describing its topological features. Therefore, this first part has focused on the study of TE porous scaffold permeability and on its dependence on the microscopic features of the scaffold. Firstly, an overview of methods applied to evaluate TE scaffold permeability is provided, with an emphasis on both experimental and computational approaches. In detail, after a discussion on the most relevant scaffolds features to be considered in the evaluation of the permeability, the presentation of the theoretical background and the introduction of semi-empirical models relating scaffolds features to permeability, the most widely applied experimental setup for the direct measurement of tissue engineered scaffold permeability are presented. Then, the focus is put on the application of computational methods, useful to verify and compare the experimental measurements of permeability, and to integrate experimental data with a more quantitative analysis which is very effective in supporting the design process of TE porous scaffolds. In conclusion, limitations of the methods and future challenges are pointed out. Successively, an acoustic permeability measurement system to quantify the inter-pore connectivity structure of tissue-engineering scaffolds by using a single (pressure) transducer is presented. The proposed method has been developed keeping in mind the limitations of the permeability measurement system in TE field. Technically, this system uses a slow alternating airflow as a fluid medium and allows at the same time a simple and accurate measurement procedure. The intrinsic permeability has been determined in the linear Darcy’s region, and deviation from linearity due to inertial losses has been also quantified. The structural parameters of a scaffold, such as effective porosity, tortuosity and effective length of cylindrical pores, have been estimated using the modified Ergun’s equation. From this relation, it is possible to achieve a well-defined range of data and associated uncertainties for characterizing the structure/architecture of tissue-engineering scaffolds. This quantitative analysis is of paramount importance in tissue engineering, where scaffold topological features are strongly related to their biological performance. In the last investigation of this part, the permeability of three bioactive glass/polymer composite scaffolds for bone tissue regeneration is evaluated. Structural features such as porosity, specific surface area and tortuosity, and lacunarity have been measured as well. Concerning lacunarity analysis, results confirmed its potential in providing insights into (i) self-similarity, (ii) random structure at some scale (i.e. heterogeneity) and (iii) Representative Elementary Volume (REV) identification. Permeability is evaluated both experimentally and computationally using the novel acoustic permeability system and Lattice Boltzmann Method (LBM), respectively. The advantage of LBM approach is due to their geometric versatility in simulating flows in irregular porous media. Results of the LBM models are in good agreement with the experimental results, even if the permeability values estimated in silico overestimate experimental data. This discrepancy is due to the influence of grid resolution and sample size on permeability calculations. In addition, the lower permeability values obtained in this study than the permeability data of different bone tissue reported in literature confirms the need to optimize the design of these scaffolds in terms of mass transport. PART II: Microfluidic deals with the control and manipulation of fluids at the microscale. A typical microfluidic platform is characterized by several components. One of the most important is the micromixer. Mixing of species is often critical to be achieved, since microfluidics is characterized mainly by very low Reynolds flows, and cannot take advantage of turbulence in order to enhance mixing. A good understanding of the dynamic of mixing becomes crucial to i) improve the effectiveness of and ii) speed up chemical reactions. In order to enhance mixing, several techniques have been developed. In general, mixing strategies can be classified as either active or passive, according to the operational mechanism. Active mixers employ external forces in order to perform mixing, so that actuation system must be embedded into the microchips. On the contrary, passive mixers avoid resorting to external electrical or mechanical sources by exploiting characteristics of specific flow fields in microchannel geometries to mix species, offering the advantage to be easy to be produced and integrated. The aim of this investigation was to develop a new low-cost passive microfluidic mixer design. First, a survey of the passive micromixing solutions currently adopted is provided. In detail, the most widely used microchannel geometries and the metrics used to quantify mixing effectiveness in microfluidic applications has been discussed. Then, a new low-cost passive microfluidic mixer design, based on a replication of identical mixing units composed of microchannels with variable curvature (clothoid) geometry, is shown. The micromixer presents a compact and modular architecture that can be easily fabricated using a simple and reliable fabrication process. The particular clothoid-based geometry enhances the mixing by inducing transversal secondary flows and recirculation effects. The role of the relevant fluid mechanics mechanisms promoting the mixing in this geometry have been analysed using computational fluid dynamics (CFD) for Reynolds numbers ranging from 1 to 110. A measure of mixing potency has been quantitatively evaluated by calculating mixing efficiency, while a measure of particle dispersion has been assessed through the lacunarity index. The results showed that the secondary flow arrangement and recirculation effects are able to provide a mixing efficiency equal to 80% at Reynolds number above 70. In addition, the analysis of particles distribution promotes the lacunarity as powerful tool to quantify the dispersion of fluid particles and, in turn, the overall mixing. On fabricated micromixer prototypes the microscopic-Laser-Induced-Fluorescence (µLIF) technique has been applied to characterize mixing. The experimental results confirmed the mixing potency of the microdevice. In conclusion, the proposed design (i) assures a good mixing efficiency (i.e. comparable, if not superior, to other passive micromixer, (ii) is easy to fabricate (i.e. single layer microfluidic devices) and (iii) is easy to integrate (i.e. high modularity).

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2010.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (p. 48-51).<br>A microfluidic system has been developed for studying the factors inducing different responses of cells in vascular system using a three-dimensional microenvironment. The devices have been transferred from PDMS to a platform in cyclic olefin copolymer (COC) which has advantages in terms of hydrophobicity, production by the more commercially-viable hot embossing technique, and amenability to surface treatments. Here the fabrication process is described and the new systems are characterized. Surface wettability, bond strength between the system body and a covering plastic film, and cell viability data are presented and compared to systems fabricated in PDMS.<br>by Jessie Sungyun Jeon.<br>S.M.

Three-dimensional analysis of particles in flows within microfluidic devices is a necessary technique in the majority of current microfluidics research. One method that allows for accurate determination of particle positions in channels is defocusing-based optical detection. This thesis investigates the use of the defocusing method for particles ranging in size from 2-18 μm without the use of a three-hole aperture. Using a calibration-based analysis motivated by previous work, we were able to relate the particle position in space to its apparent size in an image. This defocusing method was then employed in several studies in order to validate its effectiveness in a wide range of particle/flow profiles. An initial study of gravitational effects on particles in low Reynolds number flows was conducted, showing that the method is accurate for particles with sizes equal to or greater than approximately 2 μm. We also found that the resolution of particle position accuracy was within 1 μm of expected theoretical results. Further studies were conducted in inertial focusing conditions, where viscous drag and inertial lift forces balance to create unique particle focusing positions in straight channels. Steady-state inertial studies in both rectangular and cylindrical channel geometries showed focusing of particles to positions similar to previous work, further verifying the defocusing method. A new regime of inertial focusing, coined transient flow, was also investigated with the use of the 3D defocusing method. This study established new regimes of particle focusing due to the effects of a transient flow on inertial forces. Within the transient study, the effects of fluid and particle density on particle focusing positions were also investigated. Finally, we provide recommendations for future work on the defocusing method and transient flows, including potential applications.<br>Applied Science, Faculty of<br>Graduate

The rapid advancement of drug delivery systems (DDS) has raised the possibility of using functional engineered nano/micro-particles as drug carriers for the administration of active pharmaceutical ingredients (APIs) to the affected area. The major goals in designing these functional particles are to control the particle size, the surface properties and the pharmacologically active agents release in order to achieve the site-specification of the drug at the therapeutically optimal rate and dose regimen. Two different equipment (i.e. glass capillary microfluidic device and micro-engineered membrane dispersion cell) were utilised in this study for the formation of functional nano/micro-particles by antisolvent precipitation method. This method is based on micromixing/direct precipitation of two miscible liquids, which appear as a straightforward method, rapid and easy to perform, does not require high stirring rates, sonication, elevated temperatures, surfactants and Class 1 solvents can be avoided. Theoretical selection of a good solvent and physicochemical interaction between solvent-water-polymer with the aid of Bagley s two-dimensional graph were successfully elucidated the nature of anti-solvent precipitation method for the formation of desired properties of functional pharmaceutical nano/micro-engineered particles. For the glass capillary microfluidic experiment, the organic phase (a mixture of polymer and tetrahydrofuran/acetone) was injected through the inner glass capillary with a tapered cross section culminated in a narrow orifice. The size of nanoparticles was precisely controlled by controlling phase flow rates, orifice size and flow configuration (two- phase co-flow or counter-current flow focusing). The locations at which the nanoparticles would form were determined by using the solubility criteria of the polymer and the concentration profiles found by numerical modelling. This valuable results appeared as the first computational and experimental study dealing with the formation of polylactide (PLA) and poly(ε-caprolactone) (PCL) nanoparticles by nanoprecipitation in a co-flow glass capillary device. The optimum formulations and parameters interactions involved in the preparation of paracetamol encapsulated nanoparticles (PCM-PCL NPs) using a co-flow microfluidic device was successfully simulated using a 25-full factorial design for five different parameters (i.e. PCL concentration, orifice size, flow rate ratios, surfactant concentration and paracetamol amount) with encapsulation efficiency and drug loading percentage as the responses. PCM-loaded composite NPs composed of a biodegradable poly(D,L-lactide) (PLA) polymer matrix filled with organically modified montmorillonite (MMT) nanoparticles were also successfully formulated by antisolvent nanoprecipitation in a microfluidic co-flow glass capillary device. The incorporation of MMT in the polymer matrix improved the drug encapsulation efficiency and drug loading, and extended the rate of drug release in simulated intestinal fluid (pH 7.4). The encapsulation of MMT and PCM in the NPs were well verified using transmission electron microscopy (TEM), energy dispersive x-ray spectroscopy (EDS), x-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). PCL drug-carrier nanoparticles were also produced by rapid membrane micromixing combined with nanoprecipitation in a stirred cell employing novel membrane dispersion. The size of the NPs was precisely controlled by changing the aqueous-to-organic volumetric ratio, stirring rate, transmembrane flux, the polymer content in the organic phase, membrane type and pore morphologies. The particle size decreased by increasing the stirring rate and the aqueous-to-organic volumetric ratio, and by decreasing the polymer concentration in the aqueous phase and the transmembrane flux. The existence of the shear stress peak within a transitional radius and a rapid decline of the shear stress away from the membrane surface were revealed by numerical modelling. Further investigation on the PCL nanoparticles loaded immunosuppressive rapamycin (RAPA) drug were successfully synthesised by anti-solvent nanoprecipitation method using stainless steel (SS) ringed micro-engineered membrane. Less than 10 μm size of monohydrate piroxicam (PRX) micro-crystals also was successfully formed with the application of anti-solvent precipitation method combined with membrane dispersion cell that has been utilised in the formation of functional engineered nanoparticles. This study is believed to be a new insight into the development of integrated membrane crystallisation system.

A growing number of pollutants are being shown to have a large environmental and health impact resulting in stricter legislative limits. Increased environmental monitoring is forcing analytical chemists to consider automating and miniaturizing current standard methods. Instrumentation and sample handling techniques for centrifugal microfluidic devices in motion have been developed with the objective of integrating multi-step reactions into a single device for the analysis of environmental solid samples.In order to study and optimize centrifugal microfluidic devices in motion, motorized stages integrating a camera, strobe and a variety of other peripheral components were developed. These allowed precise control of the devices throughout the methods' spin sequences and simultaneous acquisition of a series of stop action photographs of the devices.Non-contact methodologies for sample introduction, preparation and extraction on centrifugal microfluidic devices in motion are presented. To achieve this, hybrid fabrication techniques including the use of 3D printers were investigated and a World-to-Disk interface permitting the introduction of a solution gradient to a spinning device was developed. The interaction of integrated mobile magnets with a series of fixed magnets placed below the spinning devices was also investigated resulting in the development of both a magnetically actuated solid sample preparation and a magnetically actuated liquid-solid extraction technique. New automated and miniaturized methods for the analysis of environmentally important species such as polycyclic aromatic hydrocarbons and pesticides in solid samples are presented.<br>Les polluants ont des impacts importants sur la santé et l'environnement résultant à des restrictions accrues des limites législatives. Cette surveillance environnementale accrue pousse les chimistes analytiques vers l'automatisation et la miniaturisation des méthodes de référence actuelles. L'analyse d'échantillons environnementaux solides bénéficiera de cette envolée par le développement de nouveaux instruments et techniques de manipulation d'échantillon via des dispositifs microfluidiques centrifuges qui intègrent des réactions à étapes multiples sur un dispositif unique.Afin d'étudier et d'optimiser les dispositifs microfluidiques centrifuges en mouvement, des plateformes motorisées qui incluent une caméra, une lumière stroboscopique et une variété d'autres composantes périphériques ont été développées. Celles-ci ont permis le contrôle efficace des dispositifs tout au long des séquences giratoires et l'acquisition simultanée de séries de photographies en arrêt sur image.Des méthodologies sont présentées pour l'introduction, la préparation et l'extraction d'échantillons sur des dispositifs microfluidiques centrifuges en mouvement. Ceci fut réalisé grâce à la recherche de techniques de fabrication hybrides incluant l'utilisation d'imprimantes 3D menant au développement d'une interface permettant l'introduction de solutés à concentrations variables aux dispositifs en mouvement. De plus, l'interaction d'aimants mobiles intégrés avec une série d'aimants fixes placée sous les dispositifs en mouvement a mené au développement des techniques de préparation d'échantillons solides par force magnétique et d'extraction liquide-solide d'échantillons par force magnétique. De nouvelles méthodes automatisées et miniaturisées ont été développées pour l'analyse d'espèces environnementales importantes telles que les hydrocarbures polycycliques aromatisés et les pesticides dans des échantillons solides.

Theoretical and numerical studies of chaotic mixing are performed to circumvent the difficulties of efficient mixing, which come from the lack of turbulence in microfluidic devices. In order to carry out efficient and accurate parametric studies and to identify a fully chaotic state, a spectral element algorithm for solution of the incompressible Navier-Stokes and species transport equations is developed. Using Taylor series expansions in time marching, the new algorithm employs an algebraic factorization scheme on multi-dimensional staggered spectral element grids, and extends classical conforming Galerkin formulations to nonconforming spectral elements. Lagrangian particle tracking methods are utilized to study particle dispersion in the mixing device using spectral element and fourth order Runge-Kutta discretizations in space and time, respectively. Comparative studies of five different techniques commonly employed to identify the chaotic strength and mixing efficiency in microfluidic systems are presented to demonstrate the competitive advantages and shortcomings of each method. These are the stirring index based on the box counting method, Poincare sections, finite time Lyapunov exponents, the probability density function of the stretching field, and mixing index inverse, based on the standard deviation of scalar species distribution. Series of numerical simulations are performed by varying the Peclet number (Pe) at fixed kinematic conditions. The mixing length (lm) is characterized as function of the Pe number, and lm ∝ ln(Pe) scaling is demonstrated for fully chaotic cases. Employing the aforementioned techniques, optimum kinematic conditions and the actuation frequency of the stirrer that result in the highest mixing/stirring efficiency are identified in a zeta potential patterned straight micro channel, where a continuous flow is generated by superposition of a steady pressure driven flow and time periodic electroosmotic flow induced by a stream-wise AC electric field. Finally, it is shown that the invariant manifold of hyperbolic periodic point determines the geometry of fast mixing zones in oscillatory flows in two-dimensional cavity.