Magnetic digital microfluidics – a review

TLDR: Various methods of droplet manipulation using magnetic forces are discussed, ranging from conventional magnetic particle-based actuation to the recent development of ferrofluids and magnetic liquid marbles.

Abstract: A digital microfluidic platform manipulates droplets on an open surface. Magnetic digital microfluidics utilizes magnetic forces for actuation and offers unique advantages compared to other digital microfluidic platforms. First, the magnetic particles used in magnetic digital microfluidics have multiple functions. In addition to serving as actuators, they also provide a functional solid substrate for molecule binding, which enables a wide range of applications in molecular diagnostics and immunodiagnostics. Second, magnetic digital microfluidics can be manually operated in a “power-free” manner, which allows for operation in low-resource environments for point-of-care diagnostics where even batteries are considered a luxury item. This review covers research areas related to magnetic digital microfluidics. This paper first summarizes the current development of magnetic digital microfluidics. Various methods of droplet manipulation using magnetic forces are discussed, ranging from conventional magnetic particle-based actuation to the recent development of ferrofluids and magnetic liquid marbles. This paper also discusses several new approaches that use magnetically controlled flexible substrates for droplet manipulation. In addition, we emphasize applications of magnetic digital microfluidics in biosensing and medical diagnostics, and identify the current limitations of magnetic digital microfluidics. We provide a perspective on possible solutions to close these gaps. Finally, the paper discusses the future improvement of magnetic digital microfluidics to explore potential new research directions.

Figures

Fig. 3 A magnetic digital microfluidic platform integrated with automated magnetic control, a miniaturized thermal cycler and a fluorescence-based real-time detection system. a) A permanent magnet fixed on a rotational motor controls the droplet motion in a circular path. Droplet 1 − functional magnetic particles, Droplet 2 − sample in binding buffer, Droplets 3 and 4 − washing buffer, Droplet 5 – PCR buffer. b) H1, H2, H3 and H4 are four temperature zones. The PCR buffer droplet is magnetically driven between the four temperature zones for thermal cycling. c) Real-time PCR results. Reproduced from Ref. 13 with permission from Wiley.

Fig. 11 A magnetic gyromixer in magnetic digital microfluidics. Reproduced from Ref. 93 with permission from Springer.

Fig. 6 Physical structure-assisted magnetic digital microfluidics. a) Physical structure-assisted magnetic digital microfluidic platform using a permanent magnet. b) Physical structure-assisted magnetic digital microfluidic platform using an electromagnet. Reproduced from Ref. 12 with permission from the Royal Society of Chemistry and from Ref. 9 with permission from Elsevier.

Fig. 1 An overview of magnetic digital microfluidics. Inset images reproduced from Ref. 12, 25, 45-48 with permission from the Royal Society of Chemistry, from Ref. 13, 49, 50 with permission from Wiley, and from Ref. 18, 50, 51 with permission from the American Chemical Society.

Fig. 2 Conventional magnetic digital microfluidics. a) Principle of conventional magnetic digital microfluidic actuation. b) Serial images of droplets actuated by magnetic particles and a permanent magnet. c) Phase diagram of magnetic digital microfluidic actuation. Reproduced from Ref. 45 with permission from the Royal Society of Chemistry.

Fig. 5 Magnetic droplet manipulation using a ferrofluid for pH sensing. FF – ferrofluid, PR – phenol red. Reproduced from Ref. 71 with permission from the American Society of Mechanical Engineering.

Full text

Magnetic digital microfluidics - a review
Author
Zhang, Yi, Nam-Trung, Nguyen
Published
2017
Journal Title
Lab on a Chip
Version
Accepted Manuscript (AM)
DOI
https://doi.org/10.1039/c7lc00025a
Copyright Statement
© 2017 Royal Society of Chemistry. This is the author-manuscript version of this paper.
Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal
website for access to the definitive, published version.
Downloaded from
http://hdl.handle.net/10072/344389
Griffith Research Online
https://research-repository.griffith.edu.au

Magnetic Digital Microfluidics – A Review
Yi Zhang
1
* and Nam-Trung Nguyen
2
1
School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
2
Queensland Micro- and Nanotechnology Centre, Griffith University, Brisbane, QLD 4111, Australia
*Correspondence should be addressed to Y. Zhang: yi_zhang@ntu.edu.sg.

Page 1
Abstract
A digital microfluidic platform manipulates droplets on an open surface. Magnetic digital
microfluidics utilizes magnetic forces for actuation and offers unique advantages compared to other
digital microfluidic platforms. First, the magnetic particles used in magnetic digital microfluidics have
multiple functions. In addition to serving as actuators, they also provide a functional solid substrate
for molecule binding, which enables a wide range of applications in molecular diagnostics and
immunodiagnostics. Second, magnetic digital microfluidics can be manually operated in a "power-
free" manner, which allows for operation in low-resource environments for point-of-care diagnostics
where even batteries are considered a luxury item. This review covers research areas related to
magnetic digital microfluidics. This paper first summarizes the current development of magnetic
digital microfluidics. Various methods of droplet manipulation using magnetic forces are discussed,
ranging from conventional magnetic particle-based actuation to the recent development of
ferrofluids and magnetic liquid marbles. This paper also discusses several new approaches that use
magnetically controlled flexible substrates for droplet manipulation. In addition, we emphasize
applications of magnetic digital microfluidics in biosensing and medical diagnostics, and the current
limitations of magnetic digital microfluidics are identified. We provide a perspective on possible
solutions to close these gaps. Finally, the paper discusses the future improvement of magnetic digital
microfluidics to explore potential new research directions.

Page 2
Introduction
Digital microfluidics has been established as a research field of its own for a decade. Together with
continuous-flow droplet microfluidics, digital microfluidics lays the foundation for droplet-based
microfluidics. Continuous-flow droplet-based microfluidics, also known as emulsion microfluidics,
deals with pico- to nanolitre droplets that are continuously generated in a closed microfluidic
network. These droplets are primarily manipulated in closed microchannels. Usually, many droplets
are generated that are not manipulated individually.
1-4
Continuous-flow droplet-based microfluidics
has been adopted for high-throughput parallel reactions such as digital polymerase chain reaction
(PCR) and sequencing library preparation. In contrast, digital microfluidics deals with discrete nano-
to microlitre droplets.
5-8
The droplets are manipulated on a plain surface with no confinement or in
an open channel or well with partial confinement. These discrete droplets on an open-surface
platform are usually individually controlled and act as virtual reaction chambers. This approach is
often used in point-of-care diagnostics that require complex sample preparation
9-17
or in on-demand
synthesis of hazardous materials.
18-20
In this review, we refer to the open-surface droplet platform as
digital microfluidics.
Based on the actuation mechanism, digital microfluidics can be further categorized into
electrowetting on dielectric (EWOD),
5, 7, 21-23
magnetic,
9, 12, 13, 24-26
surface acoustic wave (SAW)
27-30
and other types
31-34
. Currently, EWOD is the most popular actuation concept, followed by magnetic
and SAW. EWOD is very beneficial for droplet manipulation and offers automated and precise
droplet control. Most importantly, EWOD is able to split and dispense droplets with great ease.
Many recent advances have overcome earlier limitations of the EWOD platform. EWOD-based digital
microfluidic platforms can now be applied for more complex operations and more intricate
bioassays. To date, several reviews have covered various aspects of EWOD-based digital
microfluidics.
5, 7, 22, 23
Magnetic actuation is less popular than EWOD but its unique advantages should not be
overlooked. Tab. 1 summarizes and compares the features of magnetic digital microfluidics and
EWOD-based digital microfluidics. Conventionally, magnetic digital microfluidics manipulates
droplets by controlling magnetic particles in the droplet using permanent magnets or
electromagnets. The magnetic particles in turn drag the droplet along. The most unique feature of
magnetic digital microfluidics is the dual functionality of magnetic particles. In addition to their role
as the droplet actuator, the magnetic particles also provide a functional solid substrate for molecule
adsorption. Several papers have demonstrated that silica-functionalized magnetic particles can
control droplet motion and bind DNA molecules for solid phase DNA extraction.
10-13
The chemical
function of magnetic particles makes magnetic digital microfluidics very attractive for droplet-based

Page 3
bioassays. EWOD-based digital microfluidic platforms often employ functional magnetic particles for
complex bioassays,
35-37
thus requiring the introduction of magnetic control or other separation
mechanisms
38, 39
in addition to the primary droplet actuation mechanism. In contrast, magnetic
digital microfluidics uses particles for both actuation and biochemical assays, which greatly reduces
the complexity of the platform.
In a two-plate EWOD system, the droplets are sandwiched between two flat surfaces separated
by a small distance. Therefore, the droplet size is limited to several picolitres to hundreds of
nanolitres. A magnetic digital microfluidic platform handles droplets of submicrolitres to tens of
microlitres, which is larger than those employed in the two-plate EWOD. When testing clinical
samples, targets of interest are usually present at low concentrations, and there is a mismatch
between the required sample volume and the volume that a microfluidic system can handle.
40-42
The
magnetic digital microfluidic platform allows for a larger sample volume and can potentially achieve
a higher detection sensitivity. Single-plate EWOD system
43, 44
is capable of handling droplets of a
relatively large volume comparable to that of magnetic digital microfluidics. Nonetheless, single-
plate EWOD cannot perform liquid dispensing and droplet splitting,
5
thereby losing tremendous
advantages of the EWOD-based system. The liquid volume handled by a magnetic digital microfluidic
platform is highly scalable. The same platform could operate with droplet from submicrolitre to tens
of microlitres. Even a large volume would be possible except the fact that the liquid forms a puddle
at such large volumes because the gravity becomes dominant over the capillary force. Nevertheless,
one may still use magnetic particles to manipulate this large liquid puddle.
Both magnetic digital microfluidics and EWOD-based digital microfluidics use a hydrophobic low-
friction substrate for droplet manipulation, but the substrate used by magnetic digital microfluidics
has a much simpler structure. Conventional magnetic digital microfluidics only needs a plain surface
coated with a hydrophobic material such as Teflon AF. More advanced magnetic digital microfluidic
platform with assistive features may have additional physical structures or chemical modifications.
However, these features only add one additional layer to the substrate. The basic EWOD substrate is
more complex and requires multiple layers of structures. Let’s take a two-plate EWOD system for
example, the bottom plate has a dielectric layer to cover the electrodes, and the hydrophobic layer
is coated on top of the dielectric layer. On the top plate, a transparent indium tin oxide (ITO) layer is
coated on the substrate followed by another hydrophobic layer on top. Despite the fact that the use
of printed circuit board (PCB) as the EWOD substrate greatly simplifies the fabrication process, the
EWOD substrate is still considerably costlier than a plain substrate used in magnetic digital
microfluidics.

Frequently asked questions

Q1. What are the contributions in this paper?

In this paper, the authors compare the features of magnetic digital microfluidics and electrowetting on dielectric ( EWOD ) based digital micro-fluidic platforms. 

Q2. What are the future works in this paper?

In the last section of the review, the authors probed several problems associated with magnetic digital microfluidics such as liquid dispensing, evaporation prevention, multiplexing and automation and discussed potential solutions and future research directions. Despite recent advances in magnetic droplet manipulation, further work is needed to achieve better droplet control for fluidic operation. Although magnetic digital microfluidics is not as well established as EWOD-based digital microfluidics, this emerging field has tremendous potential for bioanalytical and preparative assays due to its simple operation and the unique dual functionality of magnetic particles. 

Q3. What is the important aspect of magnetic digital microfluidics?

One important aspect of magnetic digital microfluidics is the substrate with low surface tension and adhesion, allowing droplets to move with minimum friction. 

Q4. What was the effect of the external magnetic field on the nanostructures?

When an external magnetic field was applied, the magnetic nanostructures collapsed, reducing the surface roughness and the apparent contact angle. 

Q5. Why is the magnetic force often adjusted by different amounts of particles?

Due to a limited selection of magnetic particles, the magnetic force is often adjusted by using different amounts of magnetic particles or applying magnetic fields of various strengths. 

Q6. What is the main limitation of digital microfluidics for point-of-care applications?

One major limitation of digital microfluidics for point-of-care applications is the lack of a wellestablished strategy for reagent storage. 

Q7. how can surface-functionalized magnetic particles be introduced for molecule binding?

85 Nonetheless, the authors believe that surface-functionalized magnetic particles can be introduced for molecule binding without interfering with the liquid marble operation because these particles are hydrophilic and will stay within the liquid portion of the marble. 

Q8. What is the way to store reagents in a liquid marble?

Due to the stability of liquid marbles, reagents may be packed in the form of liquid marble on the substrate withPage 17a relatively simple physical confinement. 

Q9. What is the role of the ferrofluid in biochemical reactions?

The ferrofluid is used only as the actuator to move the droplet cargo for liquid phase reactions; it does not participate in the solid phase biochemical reactions (Fig. 5).71 

Q10. What is the common type of fluid used for magnetic digital microfluidics?

Another type of fluid used for magnetic digital microfluidics is a solution containing a relatively high concentration of iron ions. 

Q11. What are the assistive features for a droplet?

These assistive features generally fall into two categories: physical structures that constrain the droplet and chemical modifications that change the surface properties of the substrate. 

Q12. How do you store reagents for digital microfluidics?

Unlike in a closed-chamber system where reagents can be easily sealed within the device, reagents for digital microfluidics are often stored off-chip in vials. 

Q13. How did Chiou and his team keep the temperature below 30°C?

Chiou et al. added an active cooling device below the electromagnet and managed to keep the temperature below 30°C during the entire operation.