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Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Molecular Liquids".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 46537

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Dr. Goran T. Vladisavljević

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Guest Editor

Department of Chemical Engineering, Loughborough University, Loughborough LE11 3TU, UK
Interests: particle generation and manipulation in microfluidic (lab-on-a-chip) devices; microencapsulation; micromixing and chemical synthesis in microreactors; polymer synthesis; healthcare engineering (drug-eluting balloon catheters, controlled drug release, antimicrobial resistance); energy and environment (carbon capture; biodiesel production; membrane separations)
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Dr. Guido Bolognesi

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Department of Chemical Engineering, Loughborough University, Loughborough LE11 3TU, UK
Interests: optical tweezers; microfluidics; interfacial transport phenomena; synthetic biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Droplet microfluidics is a branch of fluid mechanics, soft condensed matter physics, and microtechnology dealing with droplet generation and manipulation in micrometre-sized structures. Droplets can be generated in microfluidic systems using a variety of different geometries and methods, such as on-demand droplet dispensing, electrowetting processes, microfluidic junctions, flow focusing channels, terrace and edge-based structures, air nozzles, and membrane emulsification. Applications of droplet microfluidics benefit from the ability of microfluidic systems to generate and manipulate droplets in a highly controllable fashion and to incorporate, integrate and synchronise numerous operations and processes within a single microfabricated entity, including droplet generation, indexing, splitting, merging, reagent dosing, encapsulating, incubating, analysing, sorting and manipulating under various fields (electric, acoustic, magnetic, optical, temperature, etc.) either in closed or open systems. Further, droplets can serve as microreactors for chemical and biochemical synthesis, analysis and diagnostics or templates for the synthesis of advanced and functional materials and bio-materials.

The main aims of the Special Issue “Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering” is to be an open forum where researchers may share their investigations and findings in this promising field and, thanks to the open access platform, increase their visibility and the chances to interact with industries and academics. Contributions to this issue, both in the form of original research or review articles, may cover all aspects of droplet generation and manipulation in microfluidic systems ranging from fundamental aspects and modelling of droplet generation and manipulation to various applications in chemistry, biology and physics such as (but not limited to) chemical synthesis and micromixing within droplets, imaging, high-throughput screening, in vitro compartmentalisation and digestion, single-cell encapsulation, production of nanoparticles and microparticles, synthesis of cell and tissue mimics and drug delivery systems. Contributions may also deal with droplet microfluidic methods and microfabrication of droplet microfluidic systems. Multidisciplinary studies offering new methodologies or insights and emerging applications such as digital microfluidics and synthetic biology applications are particularly welcome.

Dr. Goran T. Vladisavljević
Dr. Guido Bolognesi
Guest Editors

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Keywords

Microfluidics
Microengineering
Microfabricated channels
Lab on a chip
Droplet generation
Droplet manipulation
Particle synthesis
Micromixing
High-throughput screening
Drug synthesis and discovery
Drug delivery
Small-molecule detection
Single-cell encapsulation
Lipid membranes
Surfactants

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Published Papers (10 papers)

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Research

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13 pages, 1881 KiB

Open AccessArticle

Hammett Correlation in the Accelerated Formation of 2,3-Diphenylquinoxalines in Nebulizer Microdroplets

by Nathan W. Fenwick, Richard Telford, Amie Saidykhan, William H. C. Martin and Richard D. Bowen

Molecules 2021, 26(16), 5077; https://doi.org/10.3390/molecules26165077 - 21 Aug 2021

Cited by 3 | Viewed by 2350

Abstract

The accelerated formation of 2,3-diphenylquinoxalines in microdroplets generated in a nebulizer has been investigated by competition experiments in which equimolar quantities of 1,2-phenylenediamine, C₆H₄(NH₂)₂, and a 4-substituted homologue, XC₆H₃(NH₂)₂ [X = F, Cl, Br, CH₃, CH₃O, CO₂CH₃, CF₃, CN or NO₂], or a 4,5-disubstituted homologue, X₂C₆H₂(NH₂)₂ [X = F, Cl, Br, or CH₃], compete to condense with benzil, (C₆H₅CO)₂. Electron-donating substituents (X = CH₃ and CH₃O) accelerate the reaction; in contrast, electron-attracting substituents (X = F, Cl, Br and particularly CO₂CH₃, CN, CF₃ and NO₂) retard it. A structure–reactivity relationship in the form of a Hammett correlation has been found by analyzing the ratio of 2,3-diphenylquinoxaline and the corresponding substituted-2,3-diphenylquinoxaline, giving a ρ value of −0.96, thus confirming that the electron density in the aromatic ring of the phenylenediamine component is reduced in the rate-limiting step in this accelerated condensation. This correlation shows that the phenylenediamine acts as a nucleophile in the reaction. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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9 pages, 2340 KiB

Open AccessArticle

Efficient Generation of Microdroplets Using Tail Breakup Induced with Multi-Branch Channels

by Daiki Tanaka, Satsuki Kajiya, Seito Shijo, Dong Hyun Yoon, Masahiro Furuya, Yoshito Nozaki, Hiroyuki Fujita, Tetsushi Sekiguchi and Shuichi Shoji

Molecules 2021, 26(12), 3707; https://doi.org/10.3390/molecules26123707 - 17 Jun 2021

Cited by 2 | Viewed by 2577

Abstract

In recent years, research on the application of microdroplets in the fields of biotechnology and chemistry has made remarkable progress, but the technology for the stable generation of single-micrometer-scale microdroplets has not yet been established. In this paper, we developed an efficient and stable single-micrometer-scale droplet generation device based on the fragmentation of droplet tails, called “tail thread mode”, that appears under moderate flow conditions. This method can efficiently encapsulate microbeads that mimic cells and chemical products in passively generated single-micrometer-scale microdroplets. The device has a simple 2D structure; a T-junction is used for droplet generation; and in the downstream, multi-branch channels are designed for droplet deformation into the tail. Several 1–2 µm droplets were successfully produced by the tail’s fragmentation; this continuous splitting was induced by the branch channels. We examined a wide range of experimental conditions and found the optimal flow rate condition can be reduced to one-tenth compared to the conventional tip-streaming method. A mold was fabricated by simple soft lithography, and a polydimethylsiloxane (PDMS) device was fabricated using the mold. Based on the 15 patterns of experimental conditions and the results, the key factors for the generation of microdroplets in this device were examined. In the most efficient condition, 61.1% of the total droplets generated were smaller than 2 μm. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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15 pages, 1974 KiB

Open AccessArticle

Droplet Microfluidic Optimisation Using Micropipette Characterisation of Bio-Instructive Polymeric Surfactants

by Charlotte A. Henshaw, Adam A. Dundas, Valentina Cuzzucoli Crucitti, Morgan R. Alexander, Ricky Wildman, Felicity R. A. J. Rose, Derek J. Irvine and Philip M. Williams

Molecules 2021, 26(11), 3302; https://doi.org/10.3390/molecules26113302 - 31 May 2021

Cited by 4 | Viewed by 3979

Abstract

Droplet microfluidics can produce highly tailored microparticles whilst retaining monodispersity. However, these systems often require lengthy optimisation, commonly based on a trial-and-error approach, particularly when using bio-instructive, polymeric surfactants. Here, micropipette manipulation methods were used to optimise the concentration of bespoke polymeric surfactants to produce biodegradable (poly(d,l-lactic acid) (PDLLA)) microparticles with unique, bio-instructive surface chemistries. The effect of these three-dimensional surfactants on the interfacial tension of the system was analysed. It was determined that to provide adequate stabilisation, a low level (0.1% (w/v)) of poly(vinyl acetate-co-alcohol) (PVA) was required. Optimisation of the PVA concentration was informed by micropipette manipulation. As a result, successful, monodisperse particles were produced that maintained the desired bio-instructive surface chemistry. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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9 pages, 1336 KiB

Open AccessArticle

Compressed Air-Driven Continuous-Flow Thermocycled Digital PCR for HBV Diagnosis in Clinical-Level Serum Sample Based on Single Hot Plate

by Kangning Wang, Bin Li and Wenming Wu

Molecules 2020, 25(23), 5646; https://doi.org/10.3390/molecules25235646 - 30 Nov 2020

Cited by 6 | Viewed by 2769

Abstract

We report a novel compressed air-driven continuous-flow digital PCR (dPCR) system based on a 3D microfluidic chip and self-developed software system to realize real-time monitoring. The system can ensure the steady transmission of droplets in long tubing without an external power source and generate stable droplets of suitable size for dPCR by two needles and a narrowed Teflon tube. The stable thermal cycle required by dPCR can be achieved by using only one constant temperature heater. In addition, our system has realized the real-time detection of droplet fluorescence in each thermal cycle, which makes up for the drawbacks of the end-point detection method used in traditional continuous-flow dPCR. This continuous-flow digital PCR by the compressed air-driven method can meet the requirements of droplet thermal cycle and diagnosis in a clinical-level serum sample. Comparing the detection results of clinical samples (hepatitis B virus serum) with commercial instruments (CFX Connect; Bio Rad, Hercules, CA, USA), the linear correlation reached 0.9995. Because the system greatly simplified the traditional dPCR process, this system is stable and user-friendly. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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15 pages, 3804 KiB

Open AccessArticle

Protein-Stabilized Palm-Oil-in-Water Emulsification Using Microchannel Array Devices under Controlled Temperature

by Takashi Kuroiwa, Miki Ito, Yaeko Okuyama, Kanna Yamashita and Akihiko Kanazawa

Molecules 2020, 25(20), 4805; https://doi.org/10.3390/molecules25204805 - 19 Oct 2020

Cited by 4 | Viewed by 3541

Abstract

Microchannel (MC) emulsification for the preparation of monodisperse oil-in-water (O/W) and water-in-oil-in-water (W/O/W) emulsions containing palm oil as the oil phase was investigated for application as basic material solid/semi-solid lipid microspheres for delivery carriers of nutrients and drugs. Emulsification was characterized by direct observation of droplet generation under various operation conditions, as such, the effects of type and concentration of emulsifiers, emulsification temperature, MC structure, and flow rate of to-be-dispersed phase on droplet generation via MC were investigated. Sodium caseinate (SC) was confirmed as the most suitable emulsifier among the examined emulsifiers, and monodisperse O/W and W/O/W emulsions stabilized by it were successfully obtained with 20 to 40 µm mean diameter (d_m) using different types of MCs. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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12 pages, 2799 KiB

Open AccessArticle

A High-Throughput Screening System Based on Droplet Microfluidics for Glucose Oxidase Gene Libraries

by Radivoje Prodanović, W. Lloyd Ung, Karla Ilić Đurđić, Rainer Fischer, David A. Weitz and Raluca Ostafe

Molecules 2020, 25(10), 2418; https://doi.org/10.3390/molecules25102418 - 22 May 2020

Cited by 20 | Viewed by 4561

Abstract

Glucose oxidase (GOx) is an important industrial enzyme that can be optimized for specific applications by mutagenesis and activity-based screening. To increase the efficiency of this approach, we have developed a new ultrahigh-throughput screening platform based on a microfluidic lab-on-chip device that allows the sorting of GOx mutants from a saturation mutagenesis library expressed on the surface of yeast cells. GOx activity was measured by monitoring the fluorescence of water microdroplets dispersed in perfluorinated oil. The signal was generated via a series of coupled enzyme reactions leading to the formation of fluorescein. Using this new method, we were able to enrich the yeast cell population by more than 35-fold for GOx mutants with higher than wild-type activity after two rounds of sorting, almost double the efficiency of our previously described flow cytometry platform. We identified and characterized novel GOx mutants, the most promising of which (M6) contained a combination of six point mutations that increased the catalytic constant k_cat by 2.1-fold compared to wild-type GOx and by 1.4-fold compared to a parental GOx variant. The new microfluidic platform for GOx was therefore more sensitive than flow cytometry and supports comprehensive screens of gene libraries containing multiple mutations per gene. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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11 pages, 5519 KiB

Open AccessCommunication

Versatile Tool for Droplet Generation in Standard Reaction Tubes by Centrifugal Step Emulsification

by Martin Schulz, Sophia Probst, Silvia Calabrese, Ana R. Homann, Nadine Borst, Marian Weiss, Felix von Stetten, Roland Zengerle and Nils Paust

Molecules 2020, 25(8), 1914; https://doi.org/10.3390/molecules25081914 - 21 Apr 2020

Cited by 21 | Viewed by 6896

Abstract

We present a versatile tool for the generation of monodisperse water-in-fluorinated-oil droplets in standard reaction tubes by centrifugal step emulsification. The microfluidic cartridge is designed as an insert into a standard 2 mL reaction tube and can be processed in standard laboratory centrifuges. It allows for droplet generation and subsequent transfer for any downstream analysis or further use, does not need any specialized device, and manufacturing is simple because it consists of two parts only: A structured substrate and a sealing foil. The design of the structured substrate is compatible to injection molding to allow manufacturing at large scale. Droplets are generated in fluorinated oil and collected in the reaction tube for subsequent analysis. For sample sizes up to 100 µL with a viscosity range of 1 mPa·s–4 mPa·s, we demonstrate stable droplet generation and transfer of more than 6 × 10⁵ monodisperse droplets (droplet diameter 66 µm ± 3 µm, CV ≤ 4%) in less than 10 min. With two application examples, a digital droplet polymerase chain reaction (ddPCR) and digital droplet loop mediated isothermal amplification (ddLAMP), we demonstrate the compatibility of the droplet production for two main amplification techniques. Both applications show a high degree of linearity (ddPCR: R² ≥ 0.994; ddLAMP: R² ≥ 0.998), which demonstrates that the cartridge and the droplet generation method do not compromise assay performance. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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Review

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19 pages, 3389 KiB

Open AccessReview

A Review on Microfluidics: An Aid to Assisted Reproductive Technology

by Anand Baby Alias, Hong-Yuan Huang and Da-Jeng Yao

Molecules 2021, 26(14), 4354; https://doi.org/10.3390/molecules26144354 - 19 Jul 2021

Cited by 23 | Viewed by 5880

Abstract

Infertility is a state of the male or female reproductive system that is defined as the failure to achieve pregnancy even after 12 or more months of regular unprotected sexual intercourse. Assisted reproductive technology (ART) plays a crucial role in addressing infertility. Various ART are now available for infertile couples. Fertilization in vitro (IVF), intracytoplasmic sperm injection (ICSI) and intrauterine insemination (IUI) are the most common techniques in this regard. Various microfluidic technologies can incorporate various ART procedures such as embryo and gamete (sperm and oocyte) analysis, sorting, manipulation, culture and monitoring. Hence, this review intends to summarize the current knowledge about the application of this approach towards cell biology to enhance ART. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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32 pages, 14796 KiB

Open AccessReview

Crosslinking Strategies for the Microfluidic Production of Microgels

by Minjun Chen, Guido Bolognesi and Goran T. Vladisavljević

Molecules 2021, 26(12), 3752; https://doi.org/10.3390/molecules26123752 - 20 Jun 2021

Cited by 28 | Viewed by 8046

Abstract

This article provides a systematic review of the crosslinking strategies used to produce microgel particles in microfluidic chips. Various ionic crosslinking methods for the gelation of charged polymers are discussed, including external gelation via crosslinkers dissolved or dispersed in the oil phase; internal gelation methods using crosslinkers added to the dispersed phase in their non-active forms, such as chelating agents, photo-acid generators, sparingly soluble or slowly hydrolyzing compounds, and methods involving competitive ligand exchange; rapid mixing of polymer and crosslinking streams; and merging polymer and crosslinker droplets. Covalent crosslinking methods using enzymatic oxidation of modified biopolymers, photo-polymerization of crosslinkable monomers or polymers, and thiol-ene “click” reactions are also discussed, as well as methods based on the sol−gel transitions of stimuli responsive polymers triggered by pH or temperature change. In addition to homogeneous microgel particles, the production of structurally heterogeneous particles such as composite hydrogel particles entrapping droplet interface bilayers, core−shell particles, organoids, and Janus particles are also discussed. Microfluidics offers the ability to precisely tune the chemical composition, size, shape, surface morphology, and internal structure of microgels by bringing multiple fluid streams in contact in a highly controlled fashion using versatile channel geometries and flow configurations, and allowing for controlled crosslinking. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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27 pages, 8002 KiB

Open AccessReview

Fabrication of Microfluidic Devices for Emulsion Formation by Microstereolithography

by Max J. Männel, Elif Baysak and Julian Thiele

Molecules 2021, 26(9), 2817; https://doi.org/10.3390/molecules26092817 - 10 May 2021

Cited by 11 | Viewed by 4117

Abstract

Droplet microfluidics—the art and science of forming droplets—has been revolutionary for high-throughput screening, directed evolution, single-cell sequencing, and material design. However, traditional fabrication techniques for microfluidic devices suffer from several disadvantages, including multistep processing, expensive facilities, and limited three-dimensional (3D) design flexibility. High-resolution additive manufacturing—and in particular, projection micro-stereolithography (PµSL)—provides a promising path for overcoming these drawbacks. Similar to polydimethylsiloxane-based microfluidics 20 years ago, 3D printing methods, such as PµSL, have provided a path toward a new era of microfluidic device design. PµSL greatly simplifies the device fabrication process, especially the access to truly 3D geometries, is cost-effective, and it enables multimaterial processing. In this review, we discuss both the basics and recent innovations in PµSL; the material basis with emphasis on custom-made photopolymer formulations; multimaterial 3D printing; and, 3D-printed microfluidic devices for emulsion formation as our focus application. Our goal is to support researchers in setting up their own PµSL system to fabricate tailor-made microfluidics. Full article

(This article belongs to the Special Issue Droplet Microfluidics: A Tool for Biology, Chemistry and Materials Engineering)

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