Industrial lab-on-a-chip: Design, applications and scale-up for drug discovery and delivery

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Abstract

Microfluidics is an emerging and promising interdisciplinary technology which offers powerful platforms for precise production of novel functional materials (e.g., emulsion droplets, microcapsules, and nanoparticles as drug delivery vehicles- and drug molecules) as well as high-throughput analyses (e.g., bioassays, detection, and diagnostics). In particular, multiphase microfluidics is a rapidly growing technology and has beneficial applications in various fields including biomedicals, chemicals, and foods. In this review, we first describe the fundamentals and latest developments in multiphase microfluidics for producing biocompatible materials that are precisely controlled in size, shape, internal morphology and composition. We next describe some microfluidic applications that synthesize drug molecules, handle biological substances and biological units, and imitate biological organs. We also highlight and discuss design, applications and scale up of droplet- and flow-based microfluidic devices used for drug discovery and delivery.

Introduction

Microfluidics is the science and technology of manipulating and processing fluids in microchannels (MCs) that have at least one dimension (e.g., channel depth, width or diameter) smaller than 1 mm [1]. The early applications of current microfluidic technology include blood rheology [2], [3] and chemical analysis [4], which were prompted by the capability of microfluidic devices to use very small volumes of samples and reagents, to carry out analysis in a short time due to short diffusion distances and to achieve high levels of compactness due to process integration. The rapid progress in silicon microfabrication technology, which started in the 1980s, enabled the development of these silicon-based microfluidic devices. A number of recent microfluidic devices have been fabricated using transparent polydimethylsiloxane (PDMS) elastomer [1]. Microfluidic device (also referred to as lab-on-a-chip device) allows for single unit operation (e.g., mixing, separation, droplet generation, particle manipulation, heating, and detection) or incorporates multiple unit operations [5], [6], [7], [8]. Microfluidic technology is a rapidly growing interdisciplinary field and has received a great deal of attention in a broad spectrum of fields from fluid physics to biomedicine within the past two decades. Promising applications of microfluidic devices also include drug discovery, drug development, and drug synthesis [9], [10], [11].

In microfluidic technology, continuous and multiphase fluidic systems are usually used for various applications including biomedicals, chemicals, and foods. Multiphase fluid flows in microfluidic devices can be classified into droplet-based flows and parallel (coaxial) flows. Droplet-based microfluidic devices have at least one droplet generation unit (e.g., T-, X-, and Y-junctions, flow focusing, co-flow, and comb geometry) and have droplet splitting/merging unit for some applications [11], [12], [13], [14]. At a droplet generation unit, a dispersed phase fluid is compartmentalized into numerous droplets that are surrounded by a continuous phase fluid in a channel. The growth of microfluidic drop generation processes in the past decade was driven by a rising number of applications that can take advantage of precision generation and manipulation of droplets on a microscale [15]. For instance, the generated monodisperse droplets are useful templates for producing monodisperse microcapsules and microparticles for delivering drugs and functional nutrients as well as for encapsulating living cells [11], [13]. Moreover, monodisperse droplets that range in volume from picoliter to nanoliter can function as numerous individual microvessels for fast mixing and reaction [11], [13]. Wetting of a dispersed phase fluid and droplets to the channel wall is usually prevented by a thin wetting layer of a continuous phase, which is required for successful droplet generation/manipulation. It is also noteworthy that surfactant must be appropriately selected for successfully generating droplets [14], [16].

The scale-up of droplet-based microfluidic devices is a challenging field. A single microfluidic device usually produces emulsions at a droplet throughput of tens to hundreds of microliters per minute, while much greater throughputs are needed, even for very expensive pharmaceutical and biomedical applications [17], [18]. Several research groups have increased the throughput capacity of droplet-based microfluidic devices by parallelizing droplet generation units and/or such devices [17], [19], [20], [21], [22], [23]. Kobayashi et al. [23] recently achieved the production of monodisperse emulsions at a droplet throughput higher than 1 L h 1 by MC emulsification using asymmetric straight-through MC arrays. Spontaneous-transformation-based droplet generation for MC emulsification [24] is basically insensitive to the flow rates of two phases, making the scale-up and parallelization of MC emulsification device easier. Although the robust scale-up of the other droplet-based microfluidic devices is still quite challenging, these devices are promising for producing compound droplets with precisely controlled inner structure and morphology [20], [25].

Continuous and parallel multiphase flows in a microfluidic device are formed downstream Y-, T-, and Ψ-junctions [5], [9], [26]. Flows in a straight MC are laminar due to low Reynolds number; e.g., pure water that flows in a 10-μm diameter MC at its flow velocity of 10 3 m s 1 has a Reynolds number of ~ 10 3. Since it is difficult to stabilize immiscible multiphase flows in an MC with homogeneous hydrophilic/hydrophobic surface, several selective surface modification methods have been proposed to realize stable parallel multiphase flows consisting of immiscible fluids [5]. Continuous and parallel-flow-based microfluidic devices can be applied to unit operations, such as mixing, reaction, extraction, and separation. These devices have also been used for forming self-assembled nanoparticles as drug delivery vehicles and for fabricating drug-loaded microfibers [8], [27]. Integrated microfluidic devices have been used in research labs for almost two decades.

The scale-up of these microfluidic devices through integration techniques increases their popularity in diagnostic and medical sciences [28]. The integration of nanoparticle and microreaction technologies also offers enormous opportunities for the further development of smart drug delivery systems and microreactors for drug development and other biochemical synthesis [29]. Microfluidic integration technology, referred to the development of microfluidic devices with thousands of integrated micromechanical valves, enables hundreds of assays to be performed in parallel with multiple reagents in an automated manner [30]. This technology has been used for protein crystallization [6], cell chemotaxis and morphogenesis [31], genetic and amino acid assays [32], [33], high-throughput screening [25], neurobiology [34], bioreactors [35], chemical and material processing and synthesis [36], three-dimensional (3D) cell cultures [37] and single cell analysis [38]. Integrated microfluidic systems can be readily extended to solar-fuel generators, fuel-cell devices [27], organ-on-a-chip, human-on-a-chip, and point-of-care (POC) devices [39]. The commercialization of these scaled-up devices would revolutionize the world.

This review primarily focuses on multiphase microfluidics for producing biocompatible materials that are precisely controlled in size, shape, internal morphology and composition. The applications of continuous and multiphase microfluidics for bioassays, screening, detection systems, and diagnostics are in detail discussed in other review articles [10], [40], [41], [42], whereas their scale-up strategies have not yet been comprehensively evaluated. In the following sections, we first provide an overview of materials and fabrication techniques for existing microfluidic (lab-on-a-chip) devices, as well as of on-chip unit operations (droplet generation, droplet splitting/merging/loading, and formation of parallel multiphase flows). We then describe recent applications of microfluidic devices for producing functional biocompatible materials including drugs as well as drug delivery vehicles, bioassays, diagnostics, screening and detection techniques. We further discuss the scale-up strategies of microfluidic devices together with large scale microfluidic integration techniques that aim at materials processing at industrial scales.

Section snippets

Chip materials and fabrication

The most common materials used for fabrication of microfluidic devices along with fabrication methods are listed in Table 1.

Generation of simple droplets and bubbles

The most common microfluidic strategies for generation of liquid–liquid or gas–liquid dispersions (droplets and bubbles) are shown in Fig. 3.1.1.

Fabrication of microparticles and nanoparticles

Numerous chemical and physicochemical processes have been used to microengineer particles including ionotropic gelation [68], cold-set gelation [236], polymerisation [20], self-assembly [175] and nanoprecipitation. These processes can be triggered by rapid mixing (Fig. 4.1.1a), solvent evaporation (Fig. 4.1.1b), UV irradiation (Fig. 4.1.1d, e, and f), and temperature gradient (Fig. 4.1.1h). Non-spherical particles (discoid, cylindrical, rod-like, and square prisms) can be generated using

Microchannel array devices

Although the frequency of droplet generation in flow focusing devices can reach 1000 Hz for oil-in-water droplets and 12,000 Hz for water-in-oil droplets [348], the volume flow rate of dispersed phase is very low, because there is typically only one droplet generation unit (DGU). Note that when 10 μm diameter droplets are produced at 12,000 Hz frequency, the flow rate of dispersed phase flow is just 0.02 mL h 1. In microchannel (MC) array devices, droplets are formed simultaneously from hundreds or

Conclusions and outlook

Microfluidic technology offers an unprecedented level of control over size, shape, morphology, and composition of emulsion droplets, enabling production and manipulation (sorting, splitting, merging, single cell encapsulation, incubation, etc.) of highly uniform single and compound droplets with a typical variation of droplet diameters of less than 5%. Microfluidic devices can only be industrialized if they meet the following two requirements: scalability and versatility. High throughput

References (408)

  • V. Lecault et al.

    Microfluidic single cell analysis: from promise to practice

    Curr. Opin. Chem. Biol.

    (2012)
  • W.G. Lee et al.

    Nano/microfluidics for diagnosis of infectious diseases in developing countries

    Adv. Drug Deliv. Rev.

    (2010)
  • T. Nisisako et al.

    Novel microreactors for functional polymer beads

    Chem. Eng. J.

    (2004)
  • J.A. Plaza et al.

    Definition of high aspect ratio glass columns

    Sens. Actuators A

    (2003)
  • S. Kuiper et al.

    Development and applications of very high flux microfiltration membranes

    J. Membr. Sci.

    (1998)
  • J. Tong et al.

    Production of oil-in-water microspheres using a stainless steel microchannel

    J. Colloid Interface Sci.

    (2001)
  • T. Kawakatsu et al.

    The effect of the hydrophobicity of microchannels and components in water and oil phases on droplet formation in microchannel water-in-oil emulsification

    Colloids Surf. A

    (2001)
  • S. Sugiura et al.

    Size control of calcium alginate beads containing living cells using micro-nozzle array

    Biomaterials

    (2005)
  • D.S. Zhao et al.

    Rapid fabrication of a poly(dimethylsiloxane) microfluidic capillary gel electrophoresis system utilizing high precision machining

    Lab Chip

    (2003)
  • M. Bu et al.

    A new masking technology for deep glass etching and its microfluidic application

    Sens. Actuators A

    (2004)
  • X. Li et al.

    Deep reactive ion etching of Pyrex glass using SF6 plasma

    Sens. Actuators A

    (2001)
  • A. Utada et al.

    Monodisperse double emulsions generated from a microcapillary device

    Science

    (2005)
  • H. Hotomi, Inkjet Printing Head and Inkjet Printing Head Manufacturing Method, in: US (Ed.),...
  • B. Jiang et al.

    Research on microchannel of PMMA microfluidic chip under various injection molding parameters

    Adv. Mater. Res.

    (2010)
  • H. Ge et al.

    Gas phase catalytic partial oxidation of toluene in a microchannel reactor

    Catal. Today

    (2005)
  • G.M. Whitesides

    The origins and the future of microfluidics

    Nature

    (2006)
  • Y. Kikuchi et al.

    Microchannels made on silicon wafer for measurement of flow properties of blood cells

    Biorheology

    (1989)
  • A. Aota et al.

    Parallel multiphase microflows: fundamental physics, stabilization methods and applications

    Lab Chip

    (2009)
  • L. Li et al.

    Protein crystallization using microfluidic technologies based on valves, droplets, and slipchip

    Annu. Rev. Biophys.

    (2010)
  • J.W. Chung et al.

    Photoresponsive coumarin-stabilized polymeric nanoparticles as a detectable drug carrier

    Small

    (2012)
  • S.Y. Teh et al.

    Droplet microfluidics

    Lab Chip

    (2008)
  • C.N. Baroud et al.

    Dynamics of microfluidic droplets

    Lab Chip

    (2010)
  • R. Seemann et al.

    Droplet based microfluidics

    Rep. Prog. Phys.

    (2012)
  • G.T. Vladisavljević et al.

    Production of uniform droplets using membrane, microchannel and microfluidic emulsification devices

    Microfluid. Nanofluid.

    (2012)
  • J. Atencia et al.

    Controlled microfluidic interfaces

    Nature

    (2005)
  • I. Kobayashi et al.

    Controlled generation of monodisperse discoid droplets using microchannel arrays

    Langmuir

    (2006)
  • V. Barbier et al.

    Producing droplets in parallel microfluidic systems

    Phys. Rev. E

    (2006)
  • C. Holtze

    Large-scale droplet production in microfluidic devices — an industrial perspective

    J. Phys. D Appl. Phys.

    (2013)
  • W. Li et al.

    Simultaneous generation of droplets with different dimensions in parallel integrated microfluidic droplet generators

    Soft Matter

    (2008)
  • T. Nisisako et al.

    Microfluidic large-scale integration on a chip for mass production of monodisperse droplets and particles

    Lab Chip

    (2008)
  • K. van Dijke et al.

    Parallelized edge-based droplet generation (EDGE) devices

    Lab Chip

    (2009)
  • I. Kobayashi et al.

    Microchannel emulsification for mass production of uniform fine droplets: integration of microchannel arrays on a chip

    Microfluid. Nanofluid.

    (2010)
  • I. Kobayashi et al.

    Large microchannel emulsification device for mass producing uniformly sized droplets on a liter per hour scale

    Green Process. Sci.

    (2012)
  • S. Sugiura et al.

    Interfacial tension driven monodispersed droplet formation from microfabricated channel array

    Langmuir

    (2001)
  • M.B. Romanowsky et al.

    High throughput production of single core double emulsions in a parallelized microfluidic device

    Lab Chip

    (2012)
  • F.S. Majedi et al.

    Microfluidic synthesis of chitosan-based nanoparticles for fuel cell applications

    Chem. Commun.

    (2012)
  • A.M. Streets et al.

    Chip in a lab: microfluidics for next generation life science research

    Biomicrofluidics

    (2013)
  • J. Melin et al.

    Microfluidic large-scale integration: the evolution of design rules for biological automation

    Annu. Rev. Biophys. Biomol. Struct.

    (2007)
  • S. Kim et al.

    Biological applications of microfluidic gradient devices

    Integr. Biol.

    (2010)
  • A.M. Skelley et al.

    Development and evaluation of a microdevice for amino acid biomarker detection and analysis on Mars

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Design, production and characterization of drug delivery systems by Lab-On-A-Chip technology”.

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