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Chapter

A Microfluidic Device as a Drug

Carrier
Fikadu Ejeta

Abstract

The development of nanomedicine or medical nanotechnology, has brought

important new ways to the development of medicines and biotechnology products.
As a result of groundbreaking discoveries in the use of nanoscale materials significant
commercialization initiatives have been launched and are at the forefront of the
rapidly expanding field of nanotechnology by using smart particles. Microfluidic
technologies use nano-and micro-scale manufacturing technologies to develop
controlled and reproducible liquid microenvironments. Lead compounds with
controlled physicochemical properties can be obtained using microfluidics, charac-
terized by high productivity, and evaluated by biomimetic methods. Microfluidics,
for example, can not only produce nanoparticles in a well-controlled, reproducible,
and high-throughput manner, but it can also continuously create three-dimensional
environments to mimic physiological and/or pathological processes. Materials with
smart properties can be manipulated to respond in a controllable and reversible way,
modifying some of their properties as a result of external stimuli such as mechanical
stress or a certain temperature. All in all, microfluidic technology offers a potential
platform for the rapid synthesis of various novel drug delivery systems. Therefore,
these smart particles are equally necessary as the drug in drug delivery.

Keywords: smart materials, nanomedicine, microfluidic devices, drug delivery,

nanocarriers

1. Introduction

Nanomedicine is a branch of medicine. Its goal is to use nanotechnology—

manipulation and manufacturing of materials and devices with diameters of 1–100
nanometers—to prevent diseases and imaging, diagnose, monitor, treat, repair, and
regenerate biological systems [1]. The development of nanomedicine or medical
nanotechnology, has brought important new ways to the development of medicines
and biotechnology products [2]. As a result of groundbreaking discoveries in the use
of nanoscale materials significant commercialization, initiatives have been launched
and are at the forefront of the rapidly expanding field of nanotechnology [3, 4], and
they are expected to overcome the continuing challenges of ineffective drug delivery
systems [5].

1
Drug Carriers

Materials with smart properties can be manipulated to respond in a controllable

and reversible way, modifying some of their properties as a result of external stimuli
such as mechanical stress or a certain temperature. Because of their small size,
customizable chemical surface qualities, high volume-to-surface ratio, and, funda-
mentally, the ability to load active medicinal components and imaging agents, nano-
particulate drug delivery has been discovered to successfully affect nanomedicine
[6]. In addition, nano-drug delivery media have been proven to improve beneficial
results or effects, and reduce the side effects associated with drugs that have already
been approved on the market, enabling new treatment methods and inspiring further
improvements in the undesirable drug properties of active biological products.
Research that was previously considered undeveloped [7].
Microfluidic technologies use nano-and micro-scale manufacturing technologies
to develop controlled and reproducible liquid microenvironments [8, 9]. Lead com-
pounds with controlled physicochemical properties can be obtained using microfluid-
ics, characterized by high productivity, and evaluated by the biomimetic method in
vitro for a human organ on a chip [8, 10]. The microfluidic generation has become
an efficient device for the manufacture of microparticles with controlled morphol-
ogy and preferred properties due to its ability to precisely control the emulsification
procedure and generate droplets of monodisperse compounds in microchannels
[11]. Microfluidics’ ability to produce double emulsions having one, two, three, or
more numbers of droplets with remarkable precision displays the degree of control
it provides [12]. Since the size of the particles has a substantial influence on carrier
release profile [13], it’s crucial to place together polymer matrix with appropriate sizes
and size distributions to accurately regulate the release of payloads. The loading of
medicines onto the polymeric matrix and the release of payloads can both be con-
trolled by changing their interior structures [14]. Multiple medication delivery can
be achieved by altering the size and number of interior partitions [14, 15]. Another
way to control the release of the payload is to synthesize polymer fragments by using
stimulus-responsive substances [16]. After the environmental triggers (including pH,
temperature, or ionic strength) are disclosed, the fragments will pass through physi-
cochemical alternatives and then release the payload [17, 18].
Microfluidic technology has advantages in terms of small particle size distribu-
tion, lower polydispersity index, higher packaging and loading efficiency, better
batch-to-batch uniformity, and the possibility of easy scaling [19]. Interestingly, the
preparation of microfluidic chips is simple and easy to implement, thus realizing the
economical production of nanocarriers [20]. Various microfluidic chips have been
manufactured to synthesize organic, inorganic, polymer, lipid-based vesicular and
hybrid nanocarriers [21]. All in all, microfluidic technology offers a potential plat-
form for the rapid synthesis of various novel drug delivery systems [22].
The manufacturing processes for polymer microparticles are becoming increas-
ingly important for applications such as the controlled release of active ingredients,
medical-diagnostic tests, the achievement of superhydrophobic surfaces, the optimal
design of impact-resistant polymer composites, and food technology [23].
Polymer microparticles are produced using a variety of processes, including sus-
pension or emulsion polymerization, solvent evaporation, spray drying, small-hole
spraying of polymer solution and the Shirasu porous glass membrane (SPG) emulsifi-
cation method. On the other hand, traditional manufacturing processes have several
disadvantages, including the fact that they take time, cause particle coalescence, and
lead to non-uniform particle sizes and shape irregularities [24]. To work around these
limitations, you can use the electrospray method. Furthermore, the electrospray
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A Microfluidic Device as a Drug Carrier
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technique offers many benefits over earlier approaches, including minimal residue,
the use of very few solvents, low cost, and the use of high molecular weight polymers
[25]. The microdevices are made up of two flow-focusing pads that work together
in a two-step procedure to make double emulsions. As a result, at low flow rates, the
aqueous phase is symmetrically restricted at the initial connection point as a result of
which monodisperse aqueous monomer plugs are formed. The oil phase encapsulates
liquids 1 and 2 at the second connection point and creates double droplets of aqueous
and monomeric phases. The composite droplets then reach a third junction where the
channel cross-section is enlarged, whereby they assume spherical shapes. In the large
section, conservation of mass forces the droplets to slow down significantly, thereby
decreasing the spacing between successive droplets and thus decreasing the spac-
ing between successive droplets, thereby decreasing the spacing between successive
droplets [26].
Advances in drug delivery technology can improve pharmacological factors,
including efficacy and bioavailability, to discover and develop more effective drugs to
improve the treatment effects and quality of life of patients. Manufacturing quality
control, fluctuations between product batches, and the inability to obtain physiologi-
cally relevant test results in traditional in vitro prescreening platforms are all obstacles
to nanoparticle drug delivery [10]. Microfluidics has evolved from microliter fluid
processing to nanoliter fluid processing, including multidisciplinary methods that
can be used in a wide range of applications [27, 28]. Microfluidics (a method of
fabrication) provides a mechanism for making highly controllable, reproducible, and
scalable methods to produce nanoparticles. When compared to traditional in vitro
culture methods, the organ-on-chip microfluidic technology provides highly relevant
organ-specific testing platforms capable of biologically relevant experimental time
scales while employing a fraction of the sample and media volumes [29, 30].
Microfluidic technologies provide low-cost, simple-to-use platforms to control the
flow of fluids. Emulsions produced in microfluidic devices have been used in a variety
of scientific applications, comprising biomedical field, chemical synthesis, fluid flow,
and controlled drugs delivery. T-junctions and flow-focusing nozzles are two types of
microfluidic platform devices that are used to make emulsions [31, 32]. Both proce-
dures allow for the production of monodisperse particles as well as a wide range of
emulsion sizes. Flow-focusing devices are commonly used to produce monodisperse
polymer particles, both spherical and non-spherical. FF devices have been proven to
generate photo-curable polymeric particles, ion-cross-linkable thermosensitive gels,
polymer-encapsulated cells, and other particles in some situations [33, 34], polymer-
encapsulated cells [35, 36], and other particles [21, 37]. Microfluidics can be applied
to polylactide particles to make the production of novel drugs easier.

2. Microfluidic devices

There are two main types of microfluidic devices for particle production: micro-
channels and microcapillaries [38]. Microchannel-based devices are commonly
manufactured through processes such as micro-milling, micro-machining, lithogra-
phy, and shape replication. In such devices, minimizing the interfacial environment
causes spontaneous droplet formation, and therefore the droplet size is best depen-
dent on the microchannel geometry while maintaining the oil phase flow rate within
an optimal range. Total devices based entirely on microchannels are costly and time-
consuming to manufacture, but they enable microsystems to be manufactured with
3
Drug Carriers

a particle size of only a few tens of micrometers. In addition, the microchannels in

such devices can be properly aligned and, in addition to the uniform flow and strong
liquefaction of certain droplets or the splitting of droplets to a uniform size, they can
serve their equipment, and the systems can be expanded to produce a large number
of products. In addition, structures mainly based on capillaries are usually made
of low-cost components available on the market and can become microchannels in
particle manufacturing. Importantly, these systems can be manufactured in a shorter
time and can operate under harsh process conditions [39]. In a complete device based
on microchannels, the dispersed phase is very close to the tool wall before being
emulsified by the continuous phase, which may cause phase inversion [40]. Although,
the affinity of the dispersed relative substance is greater than that of the continuous
phase, the dispersed phase preferentially wets the partitions of the tool. This makes
the selection of materials produced by the equipment more important than all other
materials. However, phase inversion can be avoided by deciding which equipment
is suitable for water droplets or organic droplets [41]. On the other hand, capillary-
primarily based devices are tremendous for such terms. Here, the droplets are stopped
from assembling the device’s partitions. Capillary-specific devices allow for the
manufacture of oil-in-water or water-in-oil emulsions with a single microsystem [42].
Using a variety of materials and shapes in microfluidic devices to allow future and
desirable sort of physical activity and features. Each layer of a laminated microfluidic
device is cut separately. The cutting process has a considerable impact on the device’s
dimensions and functionality. For prototyping and laboratory settings, due to the
speed and simplicity each tool offers, cutting is usually done with a knife plotter
(i.e., xurography) or laser cutter. A knife plotter works by precisely cutting material
with a blade to create the geometry, while a laser cutter uses a focused beam (tradition-
ally, CO2 lasers are used) [43, 44]. Under these conditions, the droplet diameter can
be reduced by increasing the flow rate, density ratio, and viscosity [45]. Bottom-up

In vitro Advantages Disadvantages Reference

culture

2D cell Cell cultures are laboratory dishes that are used Limit the simulation of [48–51]
culture to grow cells. They are flat and are usually made complex cell-cell and
out of plastic. By sticking cells onto these dishes, cell-matrix interactions to
scientists are able to study cell behavior using study cell behavior
cheap materials. There are several protocols and
extensive literature available to analyze data and
understand cell behavior.

3D cell Increasing the cell's ability to organize tissue, to The cells in the in vivo [10, 52]
culture express different functions, and improving live system are in the body,
imaging. so the in vitro system is
not exactly like the in vivo
system when testing cells
in a dish.

(Organ- Physiological effects of different tissue types This experiment is very [29, 53]
on-a- and structures, such as cells and blood vessels, difficult to do and will
chip) are recreated in a system of fluid and particles to likely yield inconclusive
generate forces. results, because different
humans react differently
to the same stimuli.

Table 1.
Advantages and disadvantages of the methods used in invitro drug screening by microfluidics.

4
A Microfluidic Device as a Drug Carrier
DOI: http://dx.doi.org/10.5772/intechopen.102052

technologies that rely on emulsion or self-assembly on the shape of the equipment

used do not always provide fine, pre-designed control over particle geometry (shape,
aspect ratio) and composition [46]. A microchannel flow-focusing system (EDCl)
was used to study the manufacture of HANP cross-linked with adipic acid hydrazide
(ADH) and chlorinated carbodiimide. The focus of this work is to analyze the process
parameters of this unique method, which is a continuous nanoprecipitation at the
water-organic solvent interface. The influence of the type of organic solvent used, the
flow rate of the non-solvent, and the content of hyaluronic acid (HA) on the HANP
characteristics of (hyaluronic acid nanoparticles) [47]. Several studies have found that
the affinity between water and organic solvents influences the average diameter of
nanoparticles (NPs) via water diffusion and the rate of nanoprecipitation. When the
non-solvent shows a moderate affinity for water, the polydispersity becomes narrower.
In addition, since the process is regulated by convection, lower HA concentrations and
higher isopropanol flow rates will produce smaller particles. Regardless of the organic
solvent, flow rate, or HA concentration, some stable NPs are formed. The process was
found to be simple, repeatable, and fast. This process is expected to be used in the
manufacture of oil-free HANP, which is important for medical, pharmacological, and
cosmetic applications, as shown in Table 1 [45, 47].

3. Synthesis of microfluidic nanocarriers

Beyond that, it seems that pharmaceutical formulators have been more interested
in using synthetic nanocarriers than natural nanocarriers and colloidal systems,
which have not been of much interest. Scientists have recently paid a lot of atten-
tion to the production of organic nano-carriers, particularly in pharmaceuticals, as
pharmaceutical scientists have begun to recognize the important properties they
confer on nano-carriers by microfluidic methods [21, 54]. Nano-carriers are created
by spreading premade polymers or inducing polymers to develop through monomer
reactions. These nanocarriers can be advanced in a variety of ways, and they are
divided into classes based on the processes involved. In the primary group, materi-
als are emulsified, but not necessarily in the other categories. As a result, it gives
a straightforward and straightforward synthesis process. When those tactics are
applied in typical devices, there is a lack of control over uniform blending, forma-
tion, and better impacts on formulation ingredients, and few goods have an excessive
particle size dispersion as a result. Microfluidic control structures, on the other hand,
can provide control over the aforementioned elements due to their equally sized par-
ticles [55]. Lipid polymer hybrid nanoparticles have been merged into high-capacity
nanocarriers.
The microfluidic co-flow nanoprecipitation technology has been used to make a
large number of LPHNPs. With the help of dissolving poly (lactic-co-glycolic acid)
(2 mg/ml) into acetonitrile as a natural phase, the internal fluid changed its ordered
state. The outer fluid had a two-to-three mass ratio of lecithin and Distearoyl-
sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000 dissolved in 4 percent
ethanol and responded in water. These characteristics define a drug’s potential to be a
good choice for treating breast cancer [21, 22, 55].
Water-to-oil emulsification in a paper-based microfluidic drug carrier results
in unique open-channel microfluidics with the capacity to manage the flotation of
both adequate and inadequate surface tension liquids. The open channel devices are
shown to be effective in limiting a variety of lower surface tension oils at high and low
5
Drug Carriers

flow rates, allowing for microfluidic emulsification of water in oil in an open chan-
nel instrument. The droplets should be formed inside the channel with the aid of an
adjustable speed of the continuous phases of the emulsified water and oil. Finally,
an instrument has been turned to being used efficiently to synthesize remarkably
monodisperse hydrogel microparticles that might contain a drug molecule.
Additional research into the drug delivery properties of manufactured products
has yielded promising results. Open channel microfluidic devices have the potential
to achieve a high level of fluid manipulation with fast and low-cost production [56].
Dopamine is used as a model drug to quantify electrochemical flow on paper-based
devices in a dynamic microfluidic method. Combining electrochemical methods with
microfluidic devices to achieve time-resolved detection of neuron-like PC12 cells
cultured on filter paper Dopamine [57, 58]. After investigating the attachment of cells
to the outside of the paper with a fluorescence microscope; dopamine drug delivery
after stimulation with acetylcholine was investigated. As a result, the data collected
by the device is consistent with single-cell statistics, demonstrating the effectiveness
of the technique for high-throughput quantification of tissues or chemical targets on
tissues [59] for higher-throughput quantification of chemical targets on tissues or
organs-on-a-chip [58].
In general, microfluidic devices maintain many qualities in pharmaceutical
science, consisting of appropriate doses, ideal drug delivery, site-targeted delivery,
sustained release and controlled release, reduced repeated doses, and minimal side
effects. To do so, these advantages are the key quality of the drug delivery system.
Microfluidic technology has been routinely used in many active moiety carriers,
direct drug delivery systems, high-throughput screening, and the production of
polymers as superior carriers for additives and drugs. Cheaper and easily produced
paper-based materials are good substrates that do solve several problems associated
with transportation, filtration and storage, concentrators, valves, and multiplex-
ing [59]. Going forward, creating microfluids on paper in controlled drug delivery
programs can offer exciting opportunities to broaden the scope of the subject matter
and support improved the scientific translation of drug delivery systems. A device for
the controlled release of vinblastine (VBL) drug responsive to stimuli from magneto-
sensitive chitosan capsules, which is a magnetically sensitive device for controlled
drug delivery, was developed by embedding superparamagnetic iron oxide (SPIO)
nanoparticles (NPs) into a chitosan matrix and external magnet. Thus, the release
rate, time, and dose of VBL released have become controlled by an exterior magnet.
The prepared VBL and SPIO NPs-loaded chitosan microparticles were character-
ized and showed individual and distinctive controlled release patterns. In addition,
droplet microfluidics, which is a unique technique for producing polymer spheres,
has grown to be used for the manufacturing of monodispersed chitosan micropar-
ticles [60]. Because of their distinct physicochemical behavior and synergistic effects
in the prevention and inhibition of colorectal cancer progression, atorvastatin and
celecoxib were chosen as the version dosage form. For precisely controlled multi-
drug delivery, a microfluidic collection of monodisperse multistage pH-responsive
polymer/porous silicone composites were developed [61]. Fabrication incorporating
hypromerose succinate acetate, which does not dissolve in acidic conditions but
incredibly dissolves in basic (alkaline) pH environments, is effective in preventing
and suppressing the acceleration of colon and rectal cancers. Microcomposite [62] of
Atorvastatin, which benefits from the larger pore volume of porous silicon (PSi), is
first loaded into the PSi matrix and then encapsulated via microfluidics into pH-
responsive polymer microparticles containing celecoxib, a multidrug obtained Road
6
A Microfluidic Device as a Drug Carrier
DOI: http://dx.doi.org/10.5772/intechopen.102052

Polymer/PSi microcomposite. The manufactured microcomposites were confirmed

to have a monodisperse size distribution, multistage pH-response, a particular
ratiometric controllable loading extent closer to the concurrently loaded drug
molecules, and tailored-made drug release kinetics. This attractive microcomposite
technology prevents payloads from being released at low pH values and promotes
medicine delivery at higher pH values, and could be used to prevent and treat colon
and rectum cancers in the future. Overall, the pH-responsive polymer/PSi-based
fully micro composite [63] might be employed as a common platform for combining
drug delivery systems for multiple drug compounds [61].
The preparation of monodisperse microparticles of a biodegradable polymer was
carried out using an instrument for focusing a microfluidic flow for controlled drug
delivery. The manufacture of monodisperse microparticles containing a drug from
biodegradable polymers, the use of devices for focusing a microfluidic flow, and the
drug delivery properties of these particles have been described [64]. The particle
size ranges from 10 to 50 mm. These particles are practically monodispersed with a
polydispersity index of 3.9% [65]. Bupivacaine (amphiphilic) is included in a biode-
gradable debris matrix to characterize the formulation as a model drug [65–67]. The
kinetic evaluation suggests that drug release from these monodisperse microparticles
is slower than conventional strategies with the same average size, but reveals a larger
particle size distribution and, more importantly, a significant reduction in a primary
burst than that found with traditional methods, as shown in Figure 1 [65, 67]. The
difference in the preliminary kinetics of drug release is explained by the even distri-
bution of the drug within the particles created using microfluidic strategies. These
results demonstrated the application of microfluidic flow-focusing to homogeneous
particle system technology for drug delivery [65].
Recently, thermosensitive liposome-controlled release using a disposable micro-
fluidic instrument was developed, with the release of the encapsulated drug from
the liposome nanocarrier expected to increase local drug delivery while reducing the
toxic effects of increased temperature. High Intensity Focused Ultrasound (HIFU)
[68–71], microfluidic devices with micro-HIFU (MHIFU), allow simulation of the
bulky HIFU transmission instrument with lower energy consumption and to control
of the release of the investigated low-temperature liposomes (LTSL) [52, 72]. In
addition, when transitioning to a local temperature of 41–43°C, the structure changes
from a gel to a liquid crystal phase, and the encapsulated drug is released by an
external hyperthermia source (such as a microwave or infrared radiation laser). The

Figure 1.
A strategy for producing dispersed drugs using microfluidic techniques.

7
Drug Carriers

lipid membrane structure of low temperature-sensitive liposomes (LTSL) [73]. The

era of microfluidics may also provide a promising method for studying ultrasound
and the complex dynamics of organisms at the ultramicro level [74]. The main task
of improving polymer nanoparticles for many procedures is to specifically engineer
preferred physicochemical properties in a repeatable manner [67].
Microfluid self-assembly [9, 75] of polymer nanoparticles with adjustable com-
pactness for controlled drug delivery is predominantly self-assembled hydrophobi-
cally modified chitosan (HMC) biopolymer-based nanos. The particle compactness
can be determined by adjustable high-speed blending with hydrodynamic flow
focusing on microfluidic channels. It has been demonstrated that the self-organizing
properties of the chain can be controlled by optimizing the size and compactness of
the species, as well as the more restricted particle size distribution, through various
flow rates as well as the hydrophobicity of the chitosan chain of nanoparticles [67, 76].
The particle size of the formulation components increased with increasing blending
time, while the chitosan produced smaller and more compact nanoparticles with a
much smaller variety of aggregated chains and a higher degree of hydrophobicity.
The scientists found that nanoparticles with nearly equal forms of hydrophobic
adhesion were formed by blending the two liquids. The scientists found that the lack
of affinity for the aqueous medium and the blending times longer than the time of
aggregation hindered the formation of nanoparticles with different forms of hydro-
phobic adhesion.
Moreover, researchers investigating the effectiveness of microfluidics for assembling
HMCs and enclosing paclitaxel, a typical anticancer medication, showed that it has a
significantly greater encapsulation efficiency and overall quality than the traditional
bulk technique. The impact of the components of the synthetic medication on the
parameters of the release of paclitaxel from nanoparticles was investigated. [31]. The
predicted 50% paclitaxel diffusion coefficient upon drug release meant sustainability in
controlling drug release for nanoparticle compactness and superior results compared to
traditional bulk blending methods [31, 77]. These results show an excess of microfluidic
methods for specific bottom-up control of the physicochemical properties of polymer
nanoparticles in many programs [78], including controlled drug delivery [31, 67, 77].
An electrokinetic microfluidic device for rapid, low-power drug delivery in
self-sustaining microcontrollers evolved as a low-power, powerful, electrically active

Figure 2.
Fluid-handling systems for the microfabrication of smart materials, including pumps, valves, and flow channels.

8
A Microfluidic Device as a Drug Carrier
DOI: http://dx.doi.org/10.5772/intechopen.102052

microwell intended for use in self-sustaining microcontrollers. The tool features a sili-
con primary base shape at the top that represents the drug storage location and PDMS
(polydimethylsiloxane) that is electrically functionalized as a polymer. The drug
release mechanism evolved here utilizes local electrokinetic results of controlled drug
release times and compound velocities stored in appropriate, unbiased storage areas
[79, 80]. This proves that the dose time can be reduced from hours to seconds over
the preceding diffusion, primarily based on the use of low intensities of 20 mJ for the
dose. Release techniques are completed in less than 2 minutes or with the use of low
energy of 20 mJ. Each of these has an advantage over the state of the artwork subsys-
tem [79]. A version of the electrokinetic delivery involved in the release technique
used detailed 3D numerical simulations. The simulated model showed that a large
part of the content is released by this technology at an early stage. It also provides a
physical view of the delivery process [20, 79]. Such microfabrication is illustrated [81]
in Figure 2.

4. Conclusions

In conclusion, microfluidic technology allows for incredibly accurate fluid

delivery. It could be coupled to an actuator system that delivers drugs on demand or
continuously. Microfluidics has revolutionized the design of devices for direct drug
delivery in general, as well as the manufacturing of drug carriers. Microfluidic tech-
nology is required for the manufacture of drug carriers with a reproducible release
profile as well as the controlled release of several substances with varied release
characteristics. Materials with smart properties can be manipulated to respond in
a controllable and reversible way, modifying some of their properties as a result of
external stimuli such as mechanical stress or a certain temperature.

Conflict of interest

The author declares no conflict of interest.

Author details

Fikadu Ejeta
Department of Pharmaceutics and Social Pharmacy, School of Pharmacy, College of
Medicine and Health Sciences, Mizan-Tepi University, Ethiopia

*Address all correspondence to: [email protected]

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of
the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
9
Drug Carriers

References

[1] Viseu A. Nanomedicine. Encyclopedia [9] Shamsi M, Zahedi P,

Britannica. 2020. Available from: Ghourchian H, Minaeian S. Microfluidic-
https://www.britannica.com/science/ aided fabrication of nanoparticles blend
nanomedicine. [Accessed: 31 July 2021] based on chitosan for a transdermal
multidrug delivery application.
[2] Farokhzad OC, Langer R. Impact International Journal of Biological
of nanotechnology on drug delivery. Macromolecules. 2017;99:433-442.
ACS Nano. 2009;3(1):1-7. DOI: 10.1021/ DOI: 10.1016/j.ijbiomac.2017.03.013
nn900002m
[10] Ahn J, Ko J, Lee S, Yu J, Kim YT,
[3] Juliano R. Nanomedicine: Is the Jeon NL. Microfluidics in nanoparticle
wave cresting? Nature Reviews. Drug drug delivery: From synthesis to pre-
Discovery. 2013;12(3):171-172. clinical screening. Advanced Drug
DOI: 10.1038/nrd3958 Delivery Reviews. 2018;128:29-53.
DOI: 10.1016/j.addr.2018.04.001
[4] Wagner V, Dullaart A, Bock AK,
Zweck A. The emerging nanomedicine [11] Zhao X et al. Hierarchically
landscape. Nature Biotechnology. porous composite microparticles from
2006;24(10):1211-1217. DOI: 10.1038/ microfluidics for controllable drug
nbt1006-1211 delivery. Nanoscale. 2018;10(26):12595-
12604. DOI: 10.1039/c8nr03728k
[5] Park K. Facing the truth about
nanotechnology in drug delivery. ACS
[12] Liu D, Zhang H, Fontana F,
Nano. 2013;7(9):7442-7447. DOI: 10.1021/
Hirvonen JT, Santos HA. Microfluidic-
nn404501g
assisted fabrication of carriers for
controlled drug delivery. Lab on a Chip.
[6] Tomeh MA, Zhao X. Recent
2017;17(11):1856-1883. DOI: 10.1039/
advances in microfluidics for the
c7lc00242d
preparation of drug and gene delivery
systems. Molecular Pharmaceutics.
[13] Berkland C, King M, Cox A,
2020;17(12):4421-4434. DOI: 10.1021/
Kim K, Pack DW. Precise control of PLG
acs.molpharmaceut.0c00913
microsphere size provides enhanced
[7] Riahi R, Tamayol A, Shaegh SAM, control of drug release rate. Journal of
Ghaemmaghami AM, Dokmeci MR, Controlled Release. 2002;82(1):137-147.
Khademshosseini A. Microfluidics for DOI: 10.1016/S0168-3659(02)00136-0
advanced drug delivery systems. Current
Opinion in Chemical Engineering. [14] Duncanson WJ, Lin T,
2015;7:101-112. DOI: 10.1016/j. Abate AR, Seiffert S, Shah RK, Weitz DA.
coche.2014.12.001 Microfluidic synthesis of advanced
microparticles for encapsulation and
[8] Kwak B, Ozcelikkale A, Shin CS, controlled release. Lab on a Chip.
Park K, Han B. Simulation of complex 2012;12(12):2135-2145. DOI: 10.1039/
transport of nanoparticles around a c2lc21164e
tumor using tumor-microenvironment-
on-chip. Journal of Controlled Release. [15] Araújo F et al. Microfluidic assembly
2014;194:157-167. DOI: 10.1016/j. of a multifunctional tailorable composite
jconrel.2014.08.027 system designed for site specific
10
A Microfluidic Device as a Drug Carrier
DOI: http://dx.doi.org/10.5772/intechopen.102052

combined oral delivery of peptide drugs. polylactic acid microparticles using

ACS Nano. 2015;9(8):8291-8302. electrospray with porous structure.
DOI: 10.1021/acsnano.5b02762 Applied Sciences. 2021;11(11):1-13.
DOI: 10.3390/app11115090
[16] Stuart MAC et al. Emerging
applications of stimuli-responsive [24] Fantini D, Zanetti M, Costa L.
polymer materials. Nature Materials. Polystyrene microspheres and
2010;9(2):101-113. DOI: 10.1038/ nanospheres produced by electrospray.
nmat2614 Macromolecular Rapid Communications.
2006;27(23):2038-2042. DOI: 10.1002/
[17] Zhao CX. Multiphase flow marc.200600532
microfluidics for the production of single
or multiple emulsions for drug delivery. [25] Xu Y, Hanna MA. Electrospray
Advanced Drug Delivery Reviews. encapsulation of water-soluble protein
2013;65(11-12):1420-1446. with polylactide: Effects of formulations
DOI: 10.1016/j.addr.2013.05.009 on morphology, encapsulation efficiency
and release profile of particles.
[18] Mura S, Nicolas J, Couvreur P. International Journal of Pharmaceutics.
Stimuli-responsive nanocarriers for 2006;320(1):30-36. DOI: 10.1016/j.
drug delivery. Nature Materials. ijpharm.2006.03.046
2013;12(11):991-1003. DOI: 10.1038/
nmat3776 [26] Hennequin Y et al. Synthesizing
microcapsules with controlled
[19] Huang X et al. Microfluidic geometrical and mechanical properties
hydrodynamic focusing synthesis of with microfluidic double emulsion
polymer-lipid nanoparticles for siRNA technology. Langmuir. 2009;25(14):7857-
delivery. Oncotarget. 2017;8(57):96826- 7861. DOI: 10.1021/la9004449
96836. DOI: 10.18632/oncotarget.18281
[27] Whitesides GM. The origins and
[20] Lin YS et al. Microfluidic synthesis the future of microfluidics. Nature.
of microfibers for magnetic-responsive 2006;442(7101):368-373. DOI: 10.1038/
controlled drug release and cell culture. nature05058
PLoS One. 2012;7(3):4-11. DOI: 10.1371/
journal.pone.0033184 [28] Tokeshi M, Sato K. Micro/
nano devices for chemical analysis.
[21] Karnik R et al. Microfluidic Micromachines. 2016;7(9):6-8.
platform for controlled synthesis of DOI: 10.3390/mi7090164
polymeric nanoparticles. Nano Letters.
2008;8(9):60-75 [29] Huh D, Matthews BD,
Mammoto A, Montoya-Zavala M,
[22] Tahir N et al. Microfluidic fabrication Hsin HY, Ingber DE. Reconstituting
and characterization of Sorafenib-loaded organ-level lung functions on a chip.
lipid-polymer hybrid nanoparticles Science (80-). 2010;328(5986):1662-
for controlled drug delivery. 1668. DOI: 10.1126/science.1188302
International Journal of Pharmaceutics.
2020;581(March):119275. DOI: 10.1016/j. [30] Bhise NS et al. Organ-on-a-chip
ijpharm.2020.119275 platforms for studying drug delivery
systems. Journal of Controlled Release.
[23] Tasci ME et al. Production, 2014;190:82-93. DOI: 10.1016/j.
optimization and characterization of jconrel.2014.05.004
11
Drug Carriers

[31] Thorsen T, Roberts RW, Arnold FH, [38] Zhao X, Bian F, Sun L, Cai L,
Quake SR. Dynamic pattern formation Li L, Zhao Y. Microfluidic generation
in a vesicle-generating microfluidic of nanomaterials for biomedical
device. Physical Review Letters. applications. Small. 2020;16(9):1-19.
2001;86(18):4163-4166. DOI: 10.1103/ DOI: 10.1002/smll.201901943
PhysRevLett.86.4163
[39] Herranz-Blanco B, Ginestar E,
[32] Nisisako T, Torii T, Higuchi T. Zhang H, Hirvonen J, Santos HA.
Droplet formation in a microchannel Microfluidics platform for glass
network. Lab on a Chip. 2002;2(1):24-26. capillaries and its application in
DOI: 10.1039/b108740c droplet and nanoparticle fabrication.
International Journal of Pharmaceutics.
[33] Kim JW, Fernández-Nieves A, 2017;516(1-2):100-105. DOI: 10.1016/j.
Dan N, Utada AS, Marquez M, and ijpharm.2016.11.024
Weitz DA. “Colloidal assembly route
for responsive colloidosomes with [40] J. Pessi, H. A. Santos, I. Miroshnyk,
tunable permeability,” Nano Letters. Joukoyliruusi, D. A. Weitz, and S. Mirza,
2007;7(9):2876-2880. DOI: 10.1021/ “Microfluidics-assisted engineering
nl0715948 of polymeric microcapsules with high
encapsulation efficiency for protein
drug delivery,” International Journal of
[34] De Geest BG, Urbanski JP,
Pharmaceutics. 2014;472(1-2):82-87.
Thorsen T, Demeester J, and De
DOI: 10.1016/j. ijpharm.2014.06.012
Smedt SC. “Synthesis of monodisperse
biodegradable microgels in microfluidic
[41] Olanrewaju A, Beaugrand M,
devices,” Langmuir. 2005;21(23):10275-
Yafia M, Juncker D. Capillary
10279. DOI: 10.1021/la051527y
microfluidics in microchannels: From
microfluidic networks to capillaric
[35] Tan WH, Takeuchi S. Monodisperse circuits. Lab on a Chip. 2018;18(16):2323-
alginate hydrogel microbeads for cell 2347. DOI: 10.1039/c8lc00458g
encapsulation. Advanced Materials.
2007;19(18):2696-2701. DOI: 10.1002/ [42] Martins JP, Torrieri G, Santos HA.
adma.200700433 The importance of microfluidics for the
preparation of nanoparticles as advanced
[36] Clausell-Tormos J et al. Droplet- drug delivery systems. Expert Opinion
based microfluidic platforms for on Drug Delivery. 2018;15(5):469-479.
the encapsulation and screening of DOI: 10.1080/17425247.2018.1446936
mammalian cells and multicellular
organisms. Chemistry & Biology. [43] Gale BK et al. A review of
2008;15(5):427-437. DOI: 10.1016/j. current methods in microfluidic
chembiol.2008.04.004 device fabrication and future
commercialization prospects.
[37] Chang J-Y, Yang C-H, Huang K-S. Inventions. 2018;3(3):60-75. DOI:
Microfluidic assisted preparation of 10.3390/inventions3030060
CdSe/ZnS nanocrystals encapsulated
into poly(DL-lactide-co-glycolide) [44] Niculescu AG, Chircov C, Bîrcă AC,
microcapsules. Nanotechnology. Grumezescu AM. Fabrication and
2007;18(30):305305. DOI: 10.1088/ applications of microfluidic devices:
0957-4484/18/30/305305 A review. International Journal of

12
A Microfluidic Device as a Drug Carrier
DOI: http://dx.doi.org/10.5772/intechopen.102052

Molecular Sciences. 2021;22(4):1-26. Engineering. 2019;208(January):14-28.

DOI: 10.3390/ijms22042011 DOI: 10.1016/j.mee.2019.01.004

[45] Chiesa E et al. The microfluidic [52] Grüll H, Langereis S. Hyperthermia-

technique and the manufacturing triggered drug delivery from
of polysaccharide nanoparticles. temperature-sensitive liposomes using
Pharmaceutics. 2018;10(4):267-290. MRI-guided high intensity focused
DOI: 10.3390/pharmaceutics10040267 ultrasound. Journal of Controlled
Release. 2012;161(2):317-327.
[46] Caldorera-Moore M, Guimard N, DOI: 10.1016/j.jconrel.2012.04.041
Shi L, Roy K. Designer nanoparticles:
Incorporating size, shape and triggered [53] Kim HJ, Huh D, Hamilton G,
release into nanoscale drug carriers. Ingber DE. Human gut-on-a-chip
Expert Opinion on Drug Delivery. inhabited by microbial flora that
2010;7(4):479-495. DOI: 10.1517/ experiences intestinal peristalsis-like
17425240903579971 motions and flow. Lab on a Chip.
2012;12(12):2165-2174. DOI: 10.1039/
[47] R. C. S. Bicudo and M. H. A. Santana, c2lc40074j
“Production of hyaluronic acid (HA)
nanoparticles by a continuous process [54] Le TN, Nguyen VA, Bach GL, Tran LD,
inside microchannels: Effects of non- Cao HH. Design and fabrication of a
solvents, organic phase flow rate, and HA PDMS-based manual micro-valve system
concentration,” Chemical Engineering for microfluidic applications. Advances in
Science. 2012;84:134-141.DOI: 10.1016/j. Polymer Technology. 2020;2020:1-8. DOI:
ces.2012.08.010 10.1155/2020/2460212

[48] Arduino I et al. Preparation of cetyl [55] Khan IU, Serra CA, Anton N,
palmitate-based PEGylated solid lipid Vandamme TF. Production of
nanoparticles by microfluidic technique. nanoparticle drug delivery systems
Acta Biomaterialia. 2021;121(xxxx):566- with microfluidics tools. Expert
578. DOI: 10.1016/j.actbio.2020.12.024 Opinion on Drug Delivery.
2015;12(4):547-562. DOI: 10.1517/
[49] Damiati S, Kompella UB, Damiati SA, 17425247.2015.974547
Kodzius R. Microfluidic devices for drug
delivery systems and drug screening. [56] Kim DY, Jin SH, Jeong SG,
Genes (Basel). 2018;9(2):103-127. DOI: Lee B, Kang KK, Lee CS. Microfluidic
10.3390/genes9020103 preparation of monodisperse
polymeric microspheres coated
[50] Laity P, Cassidy A, Skepper J, with silica nanoparticles. Scientific
Jones B, Cameron R. Investigation into the Reports. 2018;8(1):1-11. DOI: 10.1038/
intragranular structures of microcrystalline s41598-018-26829-z
cellulose and pre-gelatinised starch.
European Journal of Pharmaceutics and [57] Zhou W, Feng M, Valadez A,
Biopharmaceutics. 2010;74(2):377-387. Li XJ. One-step surface modification
DOI: 10.1016/j.ejpb.2009.10.006 to graft dna codes on paper: The
method, mechanism, and its
[51] Coluccio ML et al. Microfluidic application. Analytical Chemistry.
platforms for cell cultures and 2020;92(10):7045-7053. DOI: 10.1021/
investigations. Microelectronic acs.analchem.0c00317

13
Drug Carriers

[58] Trouillon R, Gijs MAM. Dynamic microparticles using a microfluidic

electrochemical quantitation of flow-focusing device for controlled drug
dopamine release from a cells- delivery. Small. 2009;5(13):1575-1581.
on-paper system. RSC Advances. DOI: 10.1002/smll.200801855
2016;6(37):31069-31073. DOI: 10.1039/
c6ra02487d [66] Maher S et al. Multifunctional
microspherical magnetic and pH
[59] Mao K et al. Paper-based responsive carriers for combination
microfluidics for rapid diagnostics and anticancer therapy engineered by
drug delivery. Journal of Controlled droplet-based microfluidics. Journal of
Release. 2020;322(March):187-199. Materials Chemistry B. 2017;5(22):4097-
DOI: 10.1016/j.jconrel.2020.03.010 4109. DOI: 10.1039/c7tb00588a

[60] Huang KS, Yang CH, Wang YC, [67] Dashtimoghadam E, Mirzadeh H,
Wang WT, Lu YY. Microfluidic synthesis Taromi FA, Nyström B. Microfluidic
of vinblastine-loaded multifunctional self-assembly of polymeric nanoparticles
particles for magnetically responsive with tunable compactness for controlled
controlled drug release. Pharmaceutics. drug delivery. Polymer (Guildf).
2019;11(5);212-226. DOI: 10.3390/ 2013;54(18):4972-4979. DOI: 10.1016/j.
pharmaceutics11050212 polymer.2013.07.022

[61] Liu D et al. Microfluidic assembly of [68] Mu X, Gan S, Wang Y, Li H,

monodisperse multistage pH-responsive Zhou G. Stimulus-responsive vesicular
polymer/porous silicon composites for polymer nano-integrators for drug and
precisely controlled multi-drug gene delivery. International Journal of
delivery. Small. 2014;10(10):2029-2038. Nanomedicine. 2019;14:5415-5434.
DOI: 10.1002/smll.201303740 DOI: 10.2147/IJN.S203555

[62] Amoyav B, Benny O. Microfluidic [69] Chen W, Meng F, Cheng R, Zhong Z.

based fabrication and characterization pH-Sensitive degradable polymersomes
of highly porous polymeric microspheres. for triggered release of anticancer
Polymers (Basel). 2019;11:419. drugs: A comparative study with
DOI: 10.3390/polym11030419 micelles. Journal of Controlled Release.
2010;142(1):40-46. DOI: 10.1016/j.
[63] Vasiliauskas R et al. Simple jconrel.2009.09.023
microfluidic approach to fabricate
monodisperse hollow microparticles [70] Paasonen L, Laaksonen T, Johans C,
for multidrug delivery. ACS Applied Yliperttula M, Kontturi K, Urtti A.
Materials & Interfaces. 2015;7(27):14822- Gold nanoparticles enable selective
14832. DOI: 10.1021/acsami.5b04824 light-induced contents release from
liposomes. Journal of Controlled Release.
[64] Zhang L, Chen Q, Ma Y, Sun J. 2007;122(1):86-93. DOI: 10.1016/j.
Microfluidic methods for fabrication jconrel.2007.06.009
and engineering of nanoparticle drug
delivery systems. ACS Applied Bio [71] Ganta S, Devalapally H, Shahiwala A,
Materials. 2019;3(1):107-120. Amiji M. A review of stimuli-responsive
DOI: 10.1021/acsabm.9b00853 nanocarriers for drug and gene
delivery. Journal of Controlled Release.
[65] Xu Q et al. Preparation of 2008;126(3):187-204. DOI: 10.1016/j.
monodisperse biodegradable polymer jconrel.2007.12.017
14
A Microfluidic Device as a Drug Carrier
DOI: http://dx.doi.org/10.5772/intechopen.102052

[72] Ranjan A et al. Image-guided drug efficient protein delivery. Langmuir.

delivery with magnetic resonance guided 2016;32(19):4996-5003. DOI: 10.1021/
high intensity focused ultrasound and acs.langmuir.5b04645
temperature sensitive liposomes in a
rabbit Vx2 tumor model. Journal of [79] Chung AJ, And DK, Erickson D.
Controlled Release. 2012;158(3):487-494. Electrokinetic microfluidic devices
DOI: 10.1016/j.jconrel.2011.12.011 for rapid, low power drug delivery in
autonomous microsystems. Lab on a
[73] Meng L, Deng Z, Niu L, Cai F, Chip. 2008;8(2):330-338. DOI: 10.1039/
Zheng H. Controlled thermal-sensitive b713325a
liposomes release on a disposable
microfluidic device. Proceedings Under [80] Santini JT, Richards AC,
Annual International Conference of Scheidt R, Cima MJ, Langer R.
the IEEE Engineering in Medicine Microchips as controlled drug-delivery
and Biology Society (EMBC). devices. Angewandte Chemie,
2015;2015(November):5912-5915. International Edition. 2000;39(14):2396-
DOI: 10.1109/EMBC.2015.7319737 2407. DOI: 10.1002/1521-3773(20000717)
39:14<2396::AID-ANIE2396>3.0.CO;2-U
[74] Meng L et al. A disposable
microfluidic device for controlled drug [81] Ejeta F. Recent advances of
release from thermal-sensitive liposomes microfluidic platforms for controlled
by high intensity focused ultrasound. drug delivery in nanomedicine. Drug
Theranostics. 2015;5(11):1203-1213. Design, Development and Therapy.
DOI: 10.7150/thno.12295 2021;15:3881-3891. DOI: 10.2147/DDDT.
S324580
[75] Liu D et al. “Core/Shell
Nanocomposites Produced by
Superfast Sequential Microfluidic
Nanoprecipitation.” Nano Letters. 2017

[76] Morikawa Y, Tagami T,

Hoshikawa A, Ozeki T. The use of an
efficient microfluidic mixing system
for generating stabilized polymeric
nanoparticles for controlled drug release.
Biological & Pharmaceutical Bulletin.
2018;41(6):899-907. DOI: 10.1248/bpb.
b17-01036

[77] Wang J et al. A microfluidic tubing

method and its application for controlled
synthesis of polymeric nanoparticles.
Lab on a Chip. 2014;14(10):1673-1677.
DOI: 10.1039/c4lc00080c

[78] Bazban-Shotorbani S,
Dashtimoghadam E, Karkhaneh A,
Hasani-Sadrabadi MM, Jacob KI.
Microfluidic directed synthesis of alginate
nanogels with tunable pore size for
15