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280 I. Chiesa et al.
the breakage of the chemical bonds, thus leading to a fast and tunable release profile
of the drug.
Shape memory effect: Shape memory materials (SMMs) are an important class of
responsive materials, highly used in pharmaceuticals (Melocchi et al.
exhibit shape memory effect (SME), which could be triggered by different stimuli
(e.g., temperature, which is the wider used, magnetic field, pH). SMM can be forced
to assume a secondary (also referred to as temporary) shape by the application of
external stress, starting from an initial (also referred to as permanent) one. The
temporary shape is maintained until the material is exposed to its specific stimulus,
thus recovering its initial shape.
Shape memory alloys (SMAs), such as nitinol, have been used for their
temperature-triggered shape memory effect, for example for the fabrication of
drug-eluting temperature-expandable stents for urethra and biliary ducts. Here, the
responsiveness of the SMA is used to allow the drug to easily reach the target
area and to retain its position. In this context, Lee et al. (Lee and Cima
exploited nitinol (a nickel-titanium alloy) for the development of a lidocainereleasing intravesical system (Fig.
silicon tube hosting a drug-containing formulation. The nitinol wire has a “pretzel”like final shape to prevent its escaping from the bladder, thus allowing the DDS
to retain its position. To allow a minimally invasive accommodation of the system
in the bladder, the nitinol wire was forced into a temporarily elongated shape and
was able to recover its final “pretzel”-like shape once in position due to the body
temperature. Thus, the SMA was exploited to both easily reach the target area and
keep the correct position.
Shape memory polymers have also been highly implemented in the drug delivery
field. Thermo-, chemo-, and light-responsive SMPs were mainly exploited for both
reaching and retaining the correct positions as well as for triggering the release
of the drugs. For example, Li et al. (Zainal et al.
methacrylate-co-butylacrylate) (P(MMA-BA)), a shape memory polymer with a low
LCST, to fabricate a DDS triggered by high-intensity focused ultrasound (HIFU).
More in detail, the authors embedded copper sulfide in the polymer, as a drug model,
and studied its release from the polymer when it is heated up above its LCST by
HIFU. Indeed, the HIFU controlled the shape recovery of the cross-linked P(MMABA) and, consequently, the release of copper sulfate due to polymer network
swelling, water penetration, and drug dissolution and diffusion associated with the
polymer shape recovery. Moreover, the authors showed the ability to synchronize
the shape memory of the polymer and the consequent drug release with the HIFU
exposure time and intensity.
8.1c). Briefly, a nitinol wire was inserted into a
2017) exploited poly(methyl
2021). SMMs
2011)
8.3 Applications of 4D Printing in Pharmaceuticals
As already stated above, the exploiting of 4D printing in pharmaceuticals is still at
its infancy, although several studies on the use of smart materials can be found in
literature. Nowadays, the main applications of 4D printing in pharmaceuticals can
8 4D Printing in Pharmaceuticals 281
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be classified into three distinct groups: (i) triggering the drug release, (ii) retention
of the DDS in the target area, and (iii) reaching and releasing in the target area.
In the following sections, a detailed descriptions of these research topics will be
provided, with a focus on most relevant literature examples. A summary of the main
examples is reported in Table
8.1, alongside with details over the smart materials
used, manufactured methods, and applications in drug delivery.
8.3.1 4D Printing for Triggering Release
Thanks to their ability of changing properties by an external stimulus, 4D printing
structures offer multiple ways to trigger the drug release from the DDSs. One of the
most used triggering stimuli is the temperature variation. Research has been carried
out to optimize the smart materials for 4D printing to have an activation temperature
around that of the human body so that the drug is released after the DDSs enter the
patient body. In this context, Zu et al. used an extrusion-based system to print a
core-shell structure for temperature-triggered drug delivery. The core of the device
contained one or more model drugs, in powder form and loaded inside a Carbopolbased hydrogel, while the outer shell was composed of a PNIPAAm hydrogel,
cross-linked after printing using UV light (Fig.
dependent PNIPAAm swelling behavior, the authors showed that the printed device
could sustain delivery in vitro over a prolonged period (order of tens of hours), with
a release kinetic that depends on temperature and can be tuned by varying the outer
shell thickness (Zu et al.
2022a), as well as by modifying the PNIPAAm outer shell
with a pore-forming agent (i.e., PEG) (Zu et al.
Interestingly, Dai et al. produced a smart double-network hydrogel, which exhibited shape memory behavior, starting from Pluronic F127 diacrylate macromer,
poly(lactide-co-glycolide) (PLGA) (as a second network to increase the mechanical
stability), and graphene oxide (GO, for remote activation using NIR) which were
dissolved together in acetone. The resulting ink was printed through EBP with the
addition of a UV cross-linking step. The printed structure showed an SME with
a recovery temperature lower than 37
◦
C, making the ink a good candidate for
biomedical applications. Moreover, the authors incorporated a model drug inside
the hydrogel and showed that the drug release rate could be controlled via NIR
activation depending on the state of the printed shape (i.e., temporary or fixed shape)
(Dai et al.
2019).
Besides temperature, pH is another well-studied external stimulus, which has
important applications for example in localized cancer treatment, as the tumor
environment is more acidic than the healthy tissue (Larush et al.
al. demonstrated the use of digital light processing (DLP) printing (i.e., a lightbased AM technology which consists of the layer-by-layer photopolymerization
of a monomer resin contained in a vat using a projected light pattern (Ding
et al.
2022)) to develop drug-loaded formulation with a pH-responsive swelling
ratio. The authors used a mixture of acrylic acid monomer, a polyethylene glycol
diacrylate (PEGDA) crosslinker, and a photo-initiator (2,4,6-trimethylbenzoyl-
8.2a). Thanks to the temperature-
2022b).
2017). Larush et
282 I. Chiesa et al.
Dai et al. (2019)
depending on the shape of the SMP
Larush et al.
(2017)
(i.e., temporary, permanent)
depending on the pH/swelling ratio
Zhao et al. (2021)
drug-containing device in which the
drug release is modulated by water
diffusion in the folded shape
Rivera-Tarazona
et al. (2022)
“valve” made of genetically modified
Melocchi et al.
yeast, which opens in the presence of a
specific biomolecule
(2019a)
SME to anchor in a specific site
Han et al. (2020)
adhesion for drug delivery through skin
Hu et al. (2022)
Smart device which can be moved
through an external magnetic field. The
use of PNIPAAM reduces the drug
leakage until the target site is reached
and magnetic shaking is applied
Bozuyuk et al.
(2018)
and light-triggered drug release
Tab le 8 .1 Summary of the main examples available in literature on the application of 4D printing for fabrication of smart DDSs
Application Employed material(s) AM technology Triggering stimulus Brief description Ref
PNIPAAm EBP Temperature Core-shell drug-releasing device Zu et al. (2022a)
Triggering drug
EBP Temperature/SME Device for controlled drug releasing
Pluronic
F127–PLGA–GO
rele ase
DLP pH Device for controlled drug release
Acrylic
acid–PEGDA–TPO
GelMA EBP Humidity Bilayer, self-folding, and
EBB Biomolecule Composite capsule with a smart
Yeast-containing
acrylamide ink
PVA FDM Temperature/SME Drug-releasing device which uses the
Retention in the
EBP Temperature/magnetic
PCL EBP Temperature/SME Drug-eluting shape memory stent Zhou et al. (2021)
PEGDA DLP Rinsing and drying Microneedle array with enhanced tissue
PNIPAAm–Laponite
nanoclay–NdFeB
magnetic
nanoparticles
Chitosan–SPIONs 2PP Light Micro-swimmer with magnetic control
target area
Reaching the
target area
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284 I. Chiesa et al.
diphenylphosphine oxide, TPO, nanoparticles) as ink, while a pH-insensitive fluorescent dye was added to the ink as a model drug. The printed structures (i.e.,
hive-like, boxlike, and a hemisphere) demonstrated a swelling ratio and, as a result,
a cumulative drug release, which were dependent on the pH of the solution in which
they were immersed. In particular, these structures showed a decreased release in
acidic medium at pH 1.4, which corresponded to a lower swelling ratio, with respect
to pH 7.4 (Larush et al. 2017).
Differential swelling behavior due to water absorption can also be used to trigger
drug
delivery from a 4D printed DDS. For example, Zhao et al. processed heparinloaded gelatin methacryloyl (GelMA) hydrogels by EBP (Fig. 8.2a). In particular,
the
authors first printed a solid layer (i.e., with no porosity) of GelMA, which was
UV-cured after printing, and then a second layer (composed of multiple strips) was
printed on top. The whole structure was UV-cured again at the end of the printing
process. Thanks to the introduced cross-linking degree gradient, the structure folded
from a flat sheet to a tubular structure (diameter in the order of millimeters) once
swelled in water. In vitro studies showed that the heparin loaded inside the GelMA
ink was released from the tubelike structure over 30 h, with a fast initial release
due to the heparin contained on the outside of the tube and a slower release due to
degradation of the less cross-linked GelMA on the inside of the tube (Zhao et al.
2021).
The presence of specific molecules/biomolecules is the fourth stimulus that has
been
investigated (Wang et al. 2018). Very recently, Rivera-Tarazona showed how
li
ving materials could be exploited to create smart drug-delivering capsules (Fig.
8.2a), through a bioprinting process (Bonatti et al. 2022).
The authors employed hydrogel inks (containing (i) cellulose nanocrystals to
enhance the printability of the final ink; (ii) acrylamide; (iii) bisacrylamide as
crosslinker; (iv) lithium phenyl-2,4,6-trimethylbenzoylphosphinate, LAP as photoinitiator) with/without the inclusion of yeast, which were genetically modified to
react to a specific biomolecule. Employing this system, they printed a capsule
Fig. 8.2 Summary of the main examples of 4D printing for the fabrication of DDSs. (a) Examples
of three main external stimuli used for triggering drug release from 4D printed systems. In
particular, the temperature-triggered example reports a method to fabricate drug-loasded devices
with an external shell based on PNIPAAm and an internal, drug-loaded core based on a Carbopol
hydrogel (image adapted with permission from (Zu et al. 2022b)). In the humidity-triggered
xample, the fabrication process for a heparin-containing GelMA-based device, which folds in
e
a tubular shape when exposed to water (image adapted with permission from (Rivera-Tarazona et
al. 2022)). Finally, for the biomolecule-triggered example, AM fabrication of capsule with a valve
of genetically modified yeast. When exposed to a specific biomolecule, the valve opens and
made
so triggers the release of the drug contained in the device core (image adapted with permission
from (Rivera-Tarazona et al. 2022)). (b) An example of a drug-releasing shape-memory device,
is triggered by the temperature variation once inside the body to expand and anchor in
which
the gastrointestinal tract (image adapted with permission from (Melocchi et al. 2019a)). (c)An
xample of a remotely controlled drug-loaded micro-gripper, which can be moved along complex
e
paths through external magnetic stirring and can be triggered for releasing drug once the target site
is reached (image adapted with permission from (Hu et al. 2022))
8 4D Printing in Pharmaceuticals 285
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composed of (i) a hydrogel outer shell, (ii) a drug-containing core, and (iii) a layer
of genetically modified yeast-laden hydrogel, which acted as a valve for the device.
The release was achieved by exposing the yeast portion to a biomolecule, triggering
the rapid release of the drug contained inside the capsule (Rivera-Tarazona et al.
2022).
8.3.2 4D Printing for Retention in the Target Area
Retention of the DDS in the target area and prolonged drug release over time
have multiple advantages when compared to systemic administration, as it can help
reduce the dose and the number of administrations thanks to the localized delivery,
thus increasing patient compliance to the treatment (Melocchi et al.
context, Melocchi et al. employed 4D printing to create expandable gastroretentive
devices (Fig.
8.2b). In particular, the authors investigated fused deposition modeling
(FDM) printing technology (i.e., extrusion of a thermoplastic material in filament
form, which is heated above its fusion temperature and deposited in continuous
strands onto the printing bed (Gibson et al.
2021)) to provide the material (i.e.,
polyvinyl alcohol, PVA) with an initial shape. Then, the printed sample was
manually deformed into a temporary shape so that it could fit inside a capsule.
Finally, the device was immersed in a solution at 37
◦
C to recover the original,
bulky shape. Furthermore, the authors coated the material with a drug and showed a
controlled release over time (Melocchi et al. 2019a; Uboldi et al. 2021). In another
recent example, Zhou et al. developed a novel PCL-based ink for 4D printing
of a vascular stent. The ink was composed of both PCL, which is known for its
biocompatibility and can enhance the mechanical properties of the device, and betacyclodextrin, to provide both the cross-linking points and the host–guest site for
drug loading/delivering. The composite ink was optimized for EBP on a rotating
axis and UV cross-linking after printing. The printed stent could be temporarily
deformed at relatively low temperatures (around 60
shape around body temperature (above 28
◦
C) and could regain its original
◦
C). Finally, the release kinetic was
studied in vitro, showing a prolonged release over time (order of hundreds of hours),
with the final aim to solve restenosis problems caused by commercial metal stents
(Zhou et al.
2021).
Finally, Han et al. used DLP printing of microneedle arrays for enhanced
tissue adhesion and drug delivery. In particular, 4D printing was employed by
first fabricating the microneedle barbs horizontally, which were then “actuated”
using ethanol to change their shape to a curved shape that would be difficult
to print otherwise. The curved shape substantially increased the adhesion force
when compared to the barbless needle array. The drug loaded inside the array
demonstrated a fast in vitro release of the drug in the first minutes, followed by
medium release for up to 2.5 h, and a slow release up to 3 h. The drug release
from the array was also tested on a chicken breast skin-barrier model, showing the
potential of the proposed system for transdermal drug delivery applications (Han et
al.
2020).
2019b). In this
286 I. Chiesa et al.
8.3.3 4D Printing for Reaching the Target Area
Interestingly, the incorporation of magnetic nanoparticles in the DDS opens to the
possibility of remotely guiding the 4D printed structure to the target area and then
releasing the drug following the application of an external stimulus, avoiding an
invasive insertion (Breger et al.
to fabricate complex millirobots with applications in localized drug delivery (Fig.
8.2c). The authors developed a novel composite ink of PNIPAAm (for the thermal
actuation), laponite nanoclay (to increase the mechanical properties and provide
better extrusion behavior), and magnetic nanoparticles (for guidance to the target
area and for the external trigger). Bilayer structures, where the upper layer contains
the nanoparticles and the lower does not, were fabricated using a two-tool head
extrusion-based printer. During printing, a permanent magnet positioned under the
printing plate was used to align the magnetic nanoparticles, while UV light was
applied both during and after printing to cross-link the whole structure. Using this
procedure, areas with different magnetization orientation were produced to control
the final movement of the microrobot. The authors printed a gripper and showed
how the magnetic field can be used to move it over complex paths and then opened
to release a cargo. Moreover, drugs could be loaded inside the hydrogel at room
temperature. At body temperature, the hydrogel contracted to limit leakage, and
once the DDS reached the target site, drug release was accelerated by applying a
rotating magnetic field (Hu et al.
Furthermore, 4D printing can enable the fabrication of smart micro-swimmers
which, thanks to their small size, can enable deep tissue penetration for minimally
invasive localized drug delivery (Bozuyuk et al.
interesting recent example, Bozuyuk et al. developed a micro-swimmer (6 μm
diameter, 20 μm length) for localized drug delivery through light activation. In
particular, the authors employed two-photon polymerization (2PP) (i.e., a novel
light-assisted AM technology in which two laser sources are focused on the same
point to photopolymerize the material, creating features at the micro/nanoscale
(Bonatti et al.
2022)) to print the micro-swimmer using chitosan, which was
chemically modified to be photopolymerizable. Chitosan was chosen as the main
material since it is a biocompatible and biodegradable hydrogel. Superparamagnetic
iron oxide nanoparticles (SPIONs) were included in the ink during printing to enable
magnetic control and stirring in the final micro-swimmer. Moreover, photocleavable
linkers which could bind to a model drug (i.e., Dox) were included in the final
formulations to impart the structure with light-triggered chemical modifications.
The results from the experiments showed that the printed micro-swimmers could be
easily controlled through an external magnetic field and that the UV could be used
for controlled release, which could be switched on and off on demand depending
on the light pattern. Finally, under physiologically relevant conditions, substantial
nontoxic degradation of the micro-swimmers was shown in 204 h (Bozuyuk et al.
2018).
2015). In this context, Hu et al. used 4D printing
2022).
2018; Ceylan et al. 2019). In an
8 4D Printing in Pharmaceuticals 287
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8.4 Conclusions and Future Perspectives
In this chapter, possible applications of 4D printing in pharmaceuticals were
comprehensively analyzed. In particular, we first discussed different smart materials
that have been used for fabrication of drug delivery systems. Each smart material
class was presented according to the triggering stimulus or phenomenon, and the
main characteristics of each class was discussed, reporting meaningful examples
from literature. These studies were discussed in view of their possible processability
with AM technologies with the aim of expanding the library of smart materials to
be used in 4D printing for pharmaceutic applications.
Although smart materials have been used in several examples for pharmaceuti-
cals,
the
use of 4D printing in the same field is still at its infancy and it is currently
mainly exploited in three different research topics: (i) triggering the release, (ii)
retaining the target position, and (iii) reaching the target area. In this chapter, we
do not consider the chemical degradation of the structure as a smart property of the
materials; thus, the studies that leveraged this mechanism for drug release are not
discussed.
4D printing represents a disruptive technology in the biomedical field and, in the
conte
xt
of pharmaceutics, promises to drastically improve the way drug delivery
systems are designed and manufactured. 4D printing will enable highly controllable
drug release in space and time and a more sophisticated approach for reaching the
target area, where the drug is retained, boosted by the on-demand fabrication and
customized production provided by AM technologies.
To be able to translate these tools to the clinical practice, different aspects should
be
taken into consideration for future research. Firstly, the library of currently
available materials for 4D printing pharmaceutics formulations is limited. Moreover,
quality control strategies able to guarantee high reproducibility and accuracy of
the printing process should be implemented, as well as the use of simulations and
mathematical modeling to support the design phase. Then, ethical and regulatory
barriers should also be taken into account.
Acknowledgements This research received funding from the Italian Ministry of Education,
University and Research (MUR) under the PRIN Project “Development and promotion of levulinic
acid and carboxylate platforms by the formulation of novel and advanced PHA-based biomaterials
and their exploitation for 3D-printed green-electronics applications” grant 2017FWC3WC. All
authors acknowledge the support of the CrossLab Additive Manufacturing Department of Information Engineering of the University of Pisa.
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