P&O: Chemische Technologie Review article

Microfluidic production of pharmaceutical lipid nanocar-

riers for light-controlled release of active molecules

Jacobs A., Markey P., Martens B., Melis W., Mortiers A., Muyllaert M., Van Strydonck M., Kaya Özkiper K.,
Bolze H.

Department of Chemical Engineering, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium

Abstract

Microreactors pave the way to more intensified processes, and this is largely attributed to their small scale. It’s biggest features
are safety, controllability, high mixing capabilities and the improved heat and mass transfer, all surpassing that of the current
technology used in macro scale reactors. The properties of microreactors depend both on the structure and amount of microchan-
nels. However, the reactants determine which microreactor is optimal for mixing and the production of lipid nanoparticles. Lipid
nanoparticles have several good properties, one of their main features is the capability of encapsulating a chosen set of molecules
and forming a carrier for drugs. These sort of carriers can be customized to have a trigger mechanisms for controlled drug deliv-
ery. A possible trigger mechanism is the formation of a singlet oxygen after irradiation with light of certain wavelengths. This
mechanism makes for a controlled release of an otherwise poorly administrable substance.

1 Introduction leading to improved efficacy and reduced side effects [5].

The study of microfluidic systems has increased over
the past two decades [1]. The first application of
microfluidic systems dates back to 1950 where it was
used for the production of inkjet printers [1]. From
1980 onward the use of microfluidics began, due to the
advent of micro-valves and micro-pumps. Experiments
with these micron methods led to a better control
and precision of the devices when the volume of the
fluid was reduced [1]. Some typical characteristics of
microfluidic technology are the small-scale particle flow,
rapid response time and the low cost [2].
One application of microfluidics is the production
of pharmaceutical lipid nanocarriers. These carriers
encapsulate drugs and consist of specific types of lipids
such as liposomes, ethosomes, etc [3]. One madvantage
of using lipid nanocarriers is the ability to regulate
the release of drugs through exposure to specific types
of light (UV, visible light,..). This could be achieved
by incorporating photosensitive molecules into the
lipid nanocarriers, which would allow the release
of the drug to be triggered by exposure to specific
wavelengths of light [4]. This approach could allow
for more precise and targeted drug delivery, potentially
This review paper researches the state-of-the-art of
microreactors and it’s utilization within the manufac-
turing of carriers. A definition of microreactors is
given followed by a comparison between active and
passive microreactors. Afterwards, lipids are described
with some applications. Finally, the release of drugs
involving light is explained.
2 Batch Reactor vs. microreactor
2.1 Batch Process
Typically nanoparticles for research are prepared in
batch reactors as these allow manageable lab scale ex-
periments. However, batch reactors experience limita-
tions due to inefficient mass and heat transfer [6, 7]. In-
adequate heat transfer can hinder the control of highly
exothermic, fast kinetic reactions, leading to potentially
adverse consequences [8]. To prevent overheating, the
feedstock in a batch reactor can be diluted therefore low-
ering the over-all reaction intensity but decreasing the re-
action rate and altering the yield and selectivity of the de-
sired product [7, 9]. Hence, a batch reactor is not optimal
for highly exothermic reactions [9, 10]. For fast kinetic
reactions, the reaction time may be comparable to the

1
2.2 Microreactor
mixing time. As a result, concentration gradients within
the reaction volume can impact the nucleation rate, lead-
ing to the formation and growth of inconsistent nuclei
[7]. These inconsistent nuclei result in a polydisperse
particle size distributions and large batch-to-batch varia-
tions [11, 12]. However, more recent studies found that
the use of a microfluidic batch reactor significantly im-
proves the efficiency of mass and heat transfer compared
to traditional batch reactors as a resumt of a smaller re-
actor size and high surface-to-volume ratio [12–14].
2.2 Microreactor
A microreactor is a small-scale mixing device specifi-
cally designed to handle and facilitate chemical reactions
between at least two different phases, such as solids,
liquids, or gases [15]. Micromixers are characterized
by channel sizes in the sub-millimeter range, typically
between 100-500 µm. The overall volume of these
mixing devices can range from a few microliters to
several milliliters [15, 16]. The ability to handle small
fluid volumes makes microsystems an attractive option
for drug development and production, particularly
when the drug substance is rare or in low demand,
or if it is very expensive [17, 18]. However, larger
quantities of the drug substance may be needed for
clinical trials or commercial purposes, and production
at this scale can be achieved using microsystems as
well. Microsystems enable a continuous production
with a higher product yield and enhanced product space
time yield as a common batch reactor which means
that the reaction time can be reduced from hours in a
batch to minutes or even seconds [19–21]. This constant
quality is largely attributed to the reduced nanoparticle
dispersity obtained by a micromixer in comparison to a
conventional discontinuous batch reactor [22, 23].
Microreactors are also suitable for fast hydrogena-
tion reactions with short half-lives, as the mass transfer
coefficients in these small-scale mixing devices have
been found to be two orders of magnitude higher than
in traditional batch reactors. This enables more efficient
and consistent reactions, making microreactors an
attractive choice for this application [24, 25]. While
microsystems have many advantages, there are also
challenges to be considered. For example, scaling up
to multiple microreactors can be difficult, as achieving
uniform flow towards each reactor from a single inlet
stream can be challenging [26]. However, various
approaches have been developed to address this issue
and enable the successful operation of multiple microre-
2
Microfluidic production of pharmaceutical nanocarriers
actors in parallel or special geometries [27–29].
Microreactors can be categorized as active and passive
microreactors. In active microreactors, an external field
induces the disturbance whereas passive microreactors
rely entirely on diffusion or chaotic advection for the
mixing process [1, 15]. The need for external power
sources makes the design of active micromixers both
challenging and expensive. In contrast, passive mi-
cromixers are easily integrable in more complex system
as they are stable in operation and can be robust [15].
In the subsequent sections, only passive microreactors
are discussed. As for active types, examples are acoustic
wave-assisted and magnetic-field driven microreactors
[15, 30, 31].
2.2.1 High-pressure microreactor
Initially, the high-pressure microreactor (seen in Figure
1) was designed to produce solid lipid nanoparticles by
splitting an oil phase with high-velocity water jets during
a preemulsification step. [13, 32] Later, it has been uti-
lized to rapidly blend ethanolic and fluid arrangements
in a violent stream system for the development of med-
ication nanoparticles through antisolvent precipitation
[32, 33]. This type of micromixer commonly consists of
steel microparts. Two pressure intensifiers, connected to
the microreactor, control the inflow of the solutions[13].
Figure 1: High-pressure microreactor [13]
2.2.2 Staggered Herringbone microreactor
A staggered herringbone microreactor (SHM), shown in
Figure 2, is a so called chaotic advection microreactor,
designed for both higher flow rates and an increased mix-
ing efficiency. By placing grooves in the microchannel
and creating chaotic advection, mixing in the laminar
flow regime is intensified by multiple orders of magni-
tude compared to simple molecular diffusion [34]. As
a result, ta reduction in the required channel length for
complete mixing is attained [34]. Regarding the direc-
tion of the grooves, a positive groove pattern with a for-
ward flow is more efficient for mixing than the conven-
tionally used negative pattern. This is primarily a result
of the convex shape at the entrance of the positive SHM
structure that enhances mixing. [35].

Figure 2: Staggered herringbone micromixer [36]
2.2.3 Segmented Gas-Liquid Flow Microreactor
In addition to the liquid phases to be mixed, in this type
of microreactor a gas phase is injected into the mixing
channel, as seen in Figure 3. As a consequence of the
narrowness of the mixing-channels, the gas bubbles are
of the same diameter as the channel resulting in a Tay-
lor flow, a dominant flow pattern in gas-liquid channels.
This type of pattern consists of elongated bubbles sepa-
rated by liquid slugs [36, 37]. The bubbles can almost
completely fill the cross-section of the channel leaving
only a thin liquid film between the bubbles and the chan-
nel wall [37]. Shear stress in the individual parts cre-
ates a backflow, limiting the stability in the Taylor flow
[13, 37]. As a stable Taylor flow is desirable, opti-
mal volume flows are essential [37, 38]. Some studies
have demonstrated that the use of a segmented-flow mi-
cromixer can be more effective than a herringbone mixer
in certain conditions [39, 40]. This can be attributed to
the shear-induced crystallization induced by the presence
of an air-water interface, leading to the formation of di-
verse particle morphologies [39]. These findings suggest
that the chemical composition of the samples may signif-
icantly influence the superiority of a given microsystem
over batch setups or alternative microsystems [13].
Figure 3: Segmented Gas-Liquid Flow Microreactor [13]
2.2.4 Hydrodynamic Flow-Focusing Microreactor
A hydrodynamic flow-focusing type is a microreactor
containing three inlet streams with a cross-shaped geom-
etry, shown in Figure 4. In this micromixing method,
lipid nanostructures are formed at the stream interface
due to the mixing of an aqueous solution and a liquid
3
Microfluidic production of pharmaceutical nanocarriers
like ethanol, resulting in diffusive mixing and local dilu-
tion of the organic phase [36]. Despite the limited-flow
rate hindering a scale-up possibility and high through-
put, this technique is frequently used in the production
of lipid nanoparticles because of the high mixture level
and encapsulation efficiency [36].
Figure 4: Hydrodynamic flow-focusing [36]
3 Lipids
3.1 Definition
A lipid is a type of organic compound that is com-
posed primarily of hydrocarbons and is insoluble in wa-
ter. Lipids are a diverse group of molecules that include
fats, waxes, and certain hormones and vitamins. They
play a number of important roles in the body, including
providing a source of energy, insulation, and structural
support [41]. There are three main types of lipids: fatty
acids, glycerides (also known as lipids), and phospho-
lipids [42]. Fatty acids are long-chain carboxylic acids
that are the primary components of fats [43], while glyc-
erides are esters of fatty acids and glycerol [44]. Phos-
pholipids are a type of lipid that contains a phosphate
group and are an important component of cell mem-
branes [45].
3.2 Liposomes
A liposome is a type of drug delivery system that uses
a spherical vesicle made up of one or more lipid bilay-
ers [36, 46]. Liposomes are similar to lipid nanoparti-
cles (LNPs) in that they both use lipids to deliver drugs
to the body. However, liposomes are often larger than
LNPs, with diameters ranging from 20 to 1,000 nanome-
ters [36]. Liposomes can be used to deliver a wide range
of drugs, including nucleic acids, proteins, and small
molecules. Because they are composed of lipids, they
can be easily taken up by cells, making them an effec-
tive drug delivery system. Like LNPs, liposomes can be
designed to release their drug payload over a controlled
period of time [36, 46].
3.3 Lipid Nanoparticles
3.3 Lipid Nanoparticles
A lipid nanoparticle (LNP) is a type of drug delivery
system that uses lipids, to deliver drugs to the body.
LNPs are small, typically measuring between 10 and
100 nanometers in diameter, and can be designed to
release their drug payload over a controlled period of
time [36]. They are often used to deliver nucleic acids,
such as DNA or RNA, which can be difficult to deliver to
the body using traditional methods [36]. One advantage
of LNPs is that they can be easily taken up by cells,
allowing for the efficient delivery of drugs to specific
areas of the body [4, 36].
Liposomes and lipid nanoparticles (LNPs) are both
drug delivery systems that use lipids to deliver drugs
to the body. However, there are some key differences
between the two. Liposomes are typically larger than
LNPs. This size difference can affect their behavior in
the body, with larger liposomes being more susceptible
to recognition and uptake by the immune system, while
smaller LNPs can circulate in the body for longer
periods of time [36, 47]. Additionally, liposomes can
be used to deliver a wider range of drugs than LNPs,
which are primarily used for delivering nucleic acids
[36]. Liposomes can carry polar and apolar molecules
or aqueous solutions due to their bilayer structure. Con-
versely, LNPs can carry apolar molecules like proteins
or large organic molecules due to their single layer
structure [36]. These structures are shown in Figure 5.
Figure 5: different types of lipid nanostructures [36]
4
Microfluidic production of pharmaceutical nanocarriers
3.4 Applications
3.4.1 Drug Delivery
Lipid nanoparticles are a potential drug delivery system
because their hydrophobic interior allows them to encap-
sulate hydrophobic drugs, and their hydrophilic exterior
allows them to be transported in water. In addition, lipid
nanoparticles can be engineered to target specific cells or
tissues in the body, making them a potentially effective
way to deliver drugs to specific locations [36]. There are
several different types of lipid nanoparticles that are be-
ing developed for drug delivery, including liposomes and
solid lipid nanoparticles. These nanoparticles are cur-
rently being studied for their potential to deliver a wide
range of drugs, including anticancer agents, antibiotics,
and vaccines [4].
3.4.2 Gene Therapy
Lipid nanoparticles have also been studied for their po-
tential use in gene therapy. Gene therapy involves de-
livering therapeutic genes to cells in order to treat ge-
netic diseases [48]. One of the challenges of gene ther-
apy is delivering the therapeutic genes to the right cells
in the body. Lipid nanoparticles are attractive as a de-
livery system because they can be engineered to tar-
get specific cells or tissues, and their hydrophobic in-
terior allows them to encapsulate the therapeutic genes
[49].There are several different types of lipid nanopar-
ticles that are being studied for gene therapy includ-
ing liposomes and solid lipid nanoparticles [48].These
nanoparticles are currently being studied for their poten-
tial to deliver a wide range of therapeutic genes, includ-
ing genes that can correct genetic defects or stimulate
the body’s immune response to fight cancer and other
diseases [13].
3.4.3 Cosmetics
Lipid nanoparticles are also used in some cosmetics
products [50, 51]. Lipid nanoparticles can be used to
deliver active ingredients, such as moisturizers or anti-
aging agents, to the skin. Because lipid nanoparticles are
made up of lipids, which are similar to the lipids found
in the skin, they can be easily absorbed into it and can
help to improve the effectiveness of the active ingredi-
ents [50]. In addition, lipid nanoparticles can be engi-
neered to release the active ingredients over a period of
time, which can help to extend the effects of the prod-
uct. There are several different types of lipid nanopar-
ticles that are used in cosmetics, including liposomes,
niosomes and solid lipid nanoparticles. These nanoparti-
cles are commonly used in moisturizers, sunscreens, and
other skin care products [50, 51].

4 Drug release from lipid based carriers
As mentioned above, lipids are frequently used to con-
struct organic carriers [52]. Due to their structure, they
can form multiple different structures which can act as
carriers, e.g. liposomes, lipid nanoparticles, oily suspen-
sions, lipid emulsions, lipid microbubbles, etc [53]. Each
structure has its own advantages and disadvantages for
different types of payloads that need to be encapsulated
by a carrier, this in order to stabilize or to deliver them at
their desired destination [54, 55]. Drug delivery in bod-
ies (e.g. humans, animals, ...etc.) is one of the primary
uses for lipid based carriers [53].
4.1 Triggered drug release
Lipid based carriers are frequently used for drug deliv-
ery to specific sites in the body. One of the more promi-
nent research fields where these carriers are frequently
used are cancer treatments [55]. Due to the strong cohe-
sive nature of liposomes and lipid based nanoparticles,
these carriers can survive long in the human body with-
out dissolving [56]. This could leak the anticancer drugs
at wrong sites in the body or at the wrong pace. This
is why triggered release is considered a significant ben-
efit in this practice [57]. By modifying the carriers, they
become susceptible to different parameters which trigger
drug release [55]. When they are triggered, these mod-
ifications have an effect on the formed lipids structure.
Triggers can be the presence of ions at certain concen-
trations, e.g. Fe2+ , pH-environment, light [58, 59]. For
the scope of this paper, only light triggered release will
be covered as primary source of trigger factors.
4.2 Light triggered drug release
Light is the most prominent source to trigger drug
release at different sites [55, 60]. Light can be seen
as a bundle of electromagnetic waves, each with their
specific wavelength, which can be relatively easy
controlled and changed when compared to the pH-
environment and the ions-concentration [61]. Light
itself doesn’t have an effect on the release aspect of
nonmodified lipid based carriers, only on the size of
the particles may vary due to exposure [62]. In order
to make light triggered drug release possible, red-light
photoswitchable-phosphatidylcholine analogs (AzoPC
and redAzoPC) can be added to liposomes in order to
create photoactivatable LNPs (paLNP) [55, 63]. AzoPC
has two forms: a trans- and a cis-form. In trans form,
AzoPC is stable and doesn’t affect the drug release [64].
”When stimulated to adopt the cis-form, the AzoPC
containing liposomes exhibit triggered release properties
5
Microfluidic production of pharmaceutical nanocarriers
resulting in enhanced cytotoxic effects in vitro. The
responsiveness of photoactivatable LNPs (paLNPs) to
a different wavelength is easily tuned by substituting
AzoPC with a red-shifted variant red-AzoPC.” [55]
AzoPC does not stay in his cis-form infinitely: the
molecule transforms back to its stable state over time
[64]. In order to keep the drug leakage going for longer
periods of time, pulsed irradiation of the carriers can
be used. Pulsed irradiation significantly improves the
drug release while also preventing any side-effects long
exposure to wavelengths may have on the site where the
drug is released [55].
4.3 Singlet Oxygen
Singlet oxygen is a dioxygen molecule which has been
brought to one of its excited states. The lowest excited
state has a long decay time and the highest excited
state has a short decay time to the ground state or the
triplet state[65, 66]. It also contains several unpaired
electrons which makes the singlet oxygen molecule
very reactive when interacting with organic species.
Because of this, the decay time is very easily influenced
by the interaction with other species, mostly organic
species. Contact and reaction with these species can
result in the molecule being quenched and returning to
its groundstate much faster [65, 66].
The easiest method of producing singlet oxygen is
photosensitized generation[65, 67]. This method
requires only light, ground state oxygen and a photosyn-
thesizers. During this process, two different mechanisms
can occur; a type one and type two photosensitization
process. Every process starts with photosensitization
which involves the irradiation of a photosensitizer
molecule like organic dyes and transition metal com-
plexes to its singlet excited state. Afterwards these
molecules are converTed from their singlet to their
triplet excited state. This all happens in the presence of
oxygen. In the final step the combination of photosen-
sitizers and oxygen results in the formation of singlet
oxygen in two possible chemical reactions; a radical
reaction and a superoxide formation [65, 67].
Singlet oxygen has several characteristics like its
extremely high reactivity which makes the use of this
molecule interesting for drug release and in medical
applications like cancer treatments [68, 69]. One inter-
esting characteristic is the fact that It inflicts significant
damage to organic molecules in biological systems like

for example the human body [68, 69]. One way of
using this to this project is by using it in photodynamic
therapy or light therapy for curing cancer. It is possible
to inject a patient with photosynthesizers to produce
singlet oxygen. Using an external light source of
inserted fiber optic light, these photosynthesizers and
the oxygen molecules in our body can produce singlet
oxygen. When this molecule gets in contact with cancer
molecules, it can shrink or even kill them. This therapy
has the large advantage that it involves only non-toxic
substances [68, 69].
Another application of singlet oxygen is its use in
the control and increased release of drugs in nanocarri-
ers [70]. As mentioned earlier in this paper, nanocarriers
are often produced using lipids, an organic substance,
that surround the drug. In this application, the drug is
released when the lipid carrier leaks. In order to control
the release, adding photosensitizers to the drugcarriers
and emitting light on the drugcarriers will result in the
formation of singlet oxygen. Singlet oxygen will react
with these lipids and cause leakage which results in
drugrelease [70].
5 Conclusion
In this review article the state-of-the-art of microreactors
was highlighted. It’s usefulness for toxic, expensive
or explosive chemicals leads to safer experiments and
higher yields then batch reactors for small volumes. The
limited flow rate and the problems of up-scaling however
prove a difficulty for the industrial use of microreactors.
A selection of microreactors is briefly introduced and
it’s features explained.
The making of photoactivatable liquid nanoparti-
cles was discussed in its facets regarding the making
of carriers inside a microreactor, the high solubility of
liposomes and the addition of molecules for the singlet
oxygen production. The effect of the singlet oxygen
and the importance and workings of drug release from
carriers is explained and supported. The excitation of
these molecules with light allows for highly localized
deposit of the drugs.
Acknowledgements
The authors would like to thank KU Leuven, which ini-
tiated and sponsored this project, and H. Bolze and K.
Özkiper for their experimental assistance.
6
Microfluidic production of pharmaceutical nanocarriers
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