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4D Printing in Pharmaceuticals
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Irene Chiesa, Amedeo Franco Bonatti, Aurora De Acutis,
Gabriele Maria Fortunato, Giovanni Vozzi, and Carmelo De Maria
Abstract
The term four-dimensional (4D) printing refers to the fabrication via additive
manufacturing (AM) of structures with the capability to shape transform over
time under a predefined stimulus (e.g., temperature, pH, electric field, humidity).
Since its introduction in 2013, 4D printing has been in rapid expansion in
several fields, including smart textiles, autonomous and soft robotics, biomedical
devices, electronics, and tissue engineering. Shape-changing, self-repairing,
and self-assembly are some of the characteristics usually associated with 4D
printing, highlighting that 4D printed s tructures are no longer static objects
but programmable active structures that accomplish their function through a
change in their physical and/or chemical properties over time when exposed to
a predetermined stimulus. Here, AM acts as an enabling technology by allowing
a precise arrangement of an exact amount of one or more stimulus-responsive
materials in predefined positions, without any constraints on the geometric
complexity.
In the last few years, 4D printing has been exploited to develop increasingly sophisticated pharmaceutical and drug delivery systems, providing several
advantages when compared with conventional fabrication approaches, such as
(i) obtaining a highly controllable kinetic thanks to the smart properties and
patterning of the involved stimulus-responsive material(s), (ii) achieving a time-
8
Irene Chiesa and Amedeo Franco Bonatti are co-first authors.
I. Chiesa ·A.F.Bonatti·A. De Acutis ·G.M.Fortunato ·G.Vozzi ·C.DeMaria ()
Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa,
Italy
e-mail:
carmelo.demaria@unipi.it
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals,
https://doi.org/10.1007/978-981-99-2404- 2_8
271
272 I. Chiesa et al.
and/or site-dependent drug release according to the shape-shifting of the structure
after the sensing of a defined stimulus (e.g., change in pH or temperature, nearinfrared lighting), and (iii) increasing the freedom to design systems able to
settle, adapt, or remain and then release the conveyed drug in the target districts
or move away from them.
In this chapter, we aim to provide the reader with an overview of 4D
printing, as an emerging and breakthrough fabrication technology. Then, relevant
examples from the recent literature regarding the use of 4D printing for the
development of pharmaceutical and drug delivery systems are presented and
deeply discussed.
Keywords
4D printing · Drug delivery · Responsive material · Pharmaceutics
8.1 Introduction
As comprehensively introduced in the previous chapters, in the last decades,
additive manufacturing (AM) technologies (also known as three-dimensional (3D)
printing) have been extensively used in several interdisciplinary research areas
(e.g., automotive, soft electronics, and personalized healthcare) for their ability to
fabricate complex structures with a fine control on the geometry and for their high
repeatability (Khoo et al.
In 2013, Dr. Skylar Tibbits (Tibbits 2014) introduced the term “four-dimensional
(4D) printing” to denote the fabrication via AM of structures with the capability
to shape transform over time under a predefined environmental stimulus (e.g.,
temperature, pH, electric field). Nowadays, the common properties connected with
4D printed structures are shape-changing, self-repairing, and self-assembly, emphasizing that they are no longer static objects but programmable active structures
that accomplish their function t hrough a change in their physical and/or chemical
properties over time when exposed to a predetermined stimulus (Tofail et al.
Kuang et al.
2019; Bodaghi et al. 2019; Agarwal et al. 2021).
Several 4D printing studies make use of active materials (usually referred to
as smart or responsive materials), namely substances that change in meaningful,
predictable, reproducible, and macroscopic ways as a result of environmental
changes (Lui et al.
material classes (i.e., metals, polymers, ceramics), but smart polymers (such as
shape memory polymers and liquid crystal elastomers) have been favored for 4D
printing due to their ease of processing and wide variety of stimuli that they can
respond to (Khoo et al.
4D printing is characterized by three main pillars: (i) active materials or a combi-
nation of materials that react differently to the same stimulus; (ii) environmental
stimuli; and (iii) AM technologies that act as enabling technologies allowing a
2015; Moroni et al. 2018; Bonatti et al. 2022).
2018;
2019; Shafranek et al. 2019). There are active materials in all
2015; Kuang et al. 2019; Miao et al. 2017).
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precise arrangement of an exact amount of one or more materials in predefined
4D printing has an incredible potential to develop sophisticated pharmaceutical
and drug delivery systems (DDSs) thanks to its advantages, over conventional
fabrication methods, such as direct tableting and capsule filling (Firth et al.
2018).
As a matter of fact, in addition to its overarching advantages (e.g., an easier
fabrication of complex structures, which are usually printed flat and reach their 3D
conformation upon actuation, and the capability to accomplish a task without the use
of external actuation but relying on contactless approaches), 4D printing enables
several added values specifically for pharmaceuticals and for DDS development,
such as (i) obtaining a highly controllable kinetic thanks to the smart properties
and patterning of the involved stimulus-responsive material(s); (ii) achieving a
time- and/or site-dependent drug release according to the shape-shifting or property
modification of the structure after the sensing of a defined stimulus (e.g., change in
pH or temperature, near-infrared (NIR) irradiation); and (iii) increasing the freedom
to design systems able t o settle, adapt, or remain and then release the conveyed drug
in the target districts (e.g., by folding and unfolding depending on local temperature,
pH, or concentration of relevant molecules) or move away from the delivery location
(Firth et al.
2018; Melocchi et al. 2021; Osouli-Bostanabad et al. 2022).
In this scenario, the shape-shifting, which a 4D printed object can be programmed to achieve, may influence the drug release kinetic. Thus, it is important
to precisely design both the initial and final configuration of the DDS, to finely tune
the drug release. As a consequence, novel tools based on mathematical modeling
(e.g., finite element modeling, spring mass modeling) should be developed to define
a priori the final shape and so more efficiently design the 4D printed DDS (Roy et
al.
2020).
Although responsive materials have been extensively used in the last years, the
exploitation of 4D printing in pharmaceuticals is still at its infancy (Willemen et al.
2022; Karavasili and Fatouros 2016). Currently, the main applications of 4D printing
in pharmaceuticals can be classified into the following research topics: (i) triggering
the drug release, (ii) retention of the DDS in the target area, and (iii) reaching and
releasing the DDS in the target area.
In this context, it is important to stress out that several studies refer as 4D
printing the mere degradation of a drug-embedded structure in the human body.
However, in the context of this chapter, we will not consider chemical degradation
as a “smart” property of the structure, and consequently this research field will not
be investigated.
The following paragraphs aim at providing a survey of 4D printing in pharmaceuticals. After an overview on responsive materials, classified according to
the triggering stimulus or phenomenon, the main applications of 4D printing in
pharmaceuticals will be discussed, exploiting relevant examples from the recent
literature.
274 I. Chiesa et al.
8.2 Responsive Materials for 4D Printing Applications
in Pharmaceutical
Several cases of study can be found in literature in which r esponsive materials
are exploited in pharmaceutical for their ability to sense and respond to an
environmental stimulus. Those materials could be translated towards 4D printing
application in the next future, increasing the potential of the technology, by the
combination of the responsiveness of the materials with the design freedom of AM.
Here, after a brief introduction on the requirements that materials must present
to be used in 4D printing for pharmaceutical, the most widely used responsive
materials in the field will be described according to the stimulus that activates them.
Accordingly, a selection of relevant case studies from literature will be discussed.
8.2.1 Key Material Requirements to Take into Considerations
When selecting a smart material for the 4D printing of DDSs, multiple aspects
should be considered, which dictate different requirements to which these materials
must comply.
Firstly, they must be biocompatible, since they need to interface and interact with
the human body and must be responsive to a stimulus which is not cytotoxic. For
example, several studies exploit the use of temperature-dependent smart materials
with a triggering temperature of around 37
Moreover, employed materials should also present adequate mechanical stability
(demonstrated also in the presence of water) and should not be degraded by the
inclusion of the drug. In this scenario, the chemistry of the material must be carefully
tuned to be compatible with the different drugs that will be embedded, and the
interaction between the polymer and the drug should be taken into consideration
during DDS design and material selection (Tran et al.
Then, the materials and the chosen geometry must be printable with the desired
AM technology. As a matter of fact, different AM technologies possess different
requirements related to printability, and thus the materials should present adequate
physical properties (e.g., viscosity, yield stress, surface tension) to be processable
with the specific AM technology. For example, in extrusion-based printing (EBP,
i.e., AM technology in which a material, usually contained in a syringe, is extruded
in continuous strands onto a printing bed to create a 3D object in a layer-by-layer
fashion), a shear thinning material with high yield stress is required (Bonatti et al.
2021). Differently, when processing a material using inkjet-based techniques (i.e.,
AM technologies relying on the on-demand deposition of droplets of liquid material
onto the printing bed), a balance between surface tension (slightly lower than water)
and material viscosity (liquid-like material with an upper limit on viscosity of
around 10 mPa*s) should be sought, as indicated by the a-dimensional Ohnesorge
number (which should be in the range of 0.1–1 for a successful inkjet printing
process) (Saunders and Derby
2014).
◦
C (Sponchioni et al. 2019).
2022).
8 4D Printing in Pharmaceuticals 275
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Finally, issues regarding sterilization and shipping must be addressed in the
perspective of clinical applications and wide distributions.
8.2.2 Classification Through Stimulus
Several couples of “active material – stimulus” could be enumerated spanning from
metals to ceramics and polymers, which can be activated by different types of
environmental stimuli, including electric field and heating. Among them, active
polymers are the mainly used materials in pharmaceuticals (Wang and Kohane
2017). They could be activated by a variety of external stimuli (including tem-
perature, pH, and light) or activated by the human body itself, through its internal
temperature or the pH gradient that characterizes the digestive system.
In the following paragraphs, the responsive materials mostly used in pharmaceuticals will be analyzed and classified in relation to the involved stimulus.
Temperature-responsive materials: Nowadays, temperature responsiveness is
one of the most investigated mechanisms to achieve shape-changing in 4D printing
for pharmaceuticals. Changes in temperature can induce variations in wettability
and solubility alterations of materials (Klouda and Mikos
In this context, poly(N-isopropylacrylamide) (PNIPAAm) is one of the most wellknown and used hydrogel. It has a lower critical solution temperature (LCST)
of 32–35
◦
C in aqueous solution. Therefore, when PNIPAAm is dipped in water
above its LCST, it undergoes a coil-to-globule transition, changing its wettability,
from hydrophilic to hydrophobic, thus expelling water and decreasing in volume
in the process (Bakarich et al.
2015; Wu and Wang 1998). Similarly, poly(methyl
vinyl ether), poly(N,N-dimethylaminoethyl methacrylate), poly(poly(ethylene glycol) methacrylate, and polyhydroxyethylmethacrylate exhibit a soluble-to-insoluble
transition when heated, thus representing the most used thermo-responsive materials
(Plamper et al.
2007; Longenecker et al. 2011;Lutz 2011).
The heat that is required to control the drug release or modify the properties/shape of the 4D printed device can be applied from the outside (i.e., thermal
heating, microwave irradiation or photo-illumination), and the human body temperature (approximately equal to 37
◦
C) or the temperature gradients that are naturally
associated with pathological conditions, such as inflammation, can be exploited to
trigger the material response (Sponchioni et al.
2019).
One of the most studied applications of thermo-responsive polymers in pharmaceutical is the synthesis of active micelles in which a drug can be encapsulated and
then its release in space and time can be controlled via temperature increase, thus
enhancing drug therapeutic efficiency.
In this context, Chang et al. (2008) developed a thermosensitive triblock
poly(e-caprolactone)-bpoly(N-isopropylacrylamide)-b-poly(e-caprolactone) (PCLPNIPAAm-PCL) copolymer, in which prednisone acetate, a widely used
anti-inflammation drug, was dissolved. More in detail, the hydrophobic nature
of the PCL allows the encapsulation of the drug, whereas the PNIPAAm provides
the temperature responsiveness that is used to release the drug. The cumulative
2011;Lietal. 2002).
276 I. Chiesa et al.
release of the drug was investigated at 15 ◦C and 37 ◦C, i.e., body temperature. As
expected, when the temperature arises and the PNIPAAm turns hydrophobic, the
drug release dramatically increases, being expelled from the materials thanks to the
contraction of the materials, moved from approximately 39.8% to approximately
77.9% in 120 h.
Humidity-responsive materials: The humidity responsiveness is a simple mechanism that promotes the time shape transformation of 4D printed structures. This
property refers to the intrinsic swelling characteristic of natural and synthetic
hydrogels (i.e., 3D cross-linked polymer networks, which can absorb and retain
large amount of water (Malda et al.
2013; Wang et al. 2020)) (Castro et al.
2017). Hydrogel swelling behavior can be defined as their ability to absorb water
without dissolving in a thermodynamically good solvent due to their chemically or
physically cross-linked network that undergoes a reversible volume change when
dipped in the proper solution (Quesada-Pérez et al.
2011). In swelling-controlled
DDSs, the amount of water that is taken up by the hydrogel determines the quantity
of the released drug. Several hydrophilic natural polymers (e.g., gelatin, collagen)
as well as synthetic polymers (e.g., polyethylene glycol (PEG)) have been used as
humidity-responsive materials in 4D printing (Jamal et al.
2013).
For example, Khan et al. (Khan et al. 2016) investigated and tuned the swelling
behavior of genipin-cross-linked gelatin nanoparticles for the controlled release
of cytarabine, a commonly used chemotherapy drug. More in detail, the authors
showed that when the drug-loaded gelatin nanoparticles encountered water, the
gelatin became softer and its chains underwent a relaxation, thus allowing the water
molecules to enter its network. The entered water dissolved the drug molecules that
in turn came out from the matrix into the released medium. The authors studied this
phenomenon according to different parameters, such as the drug concentration, the
physiological fluids, and the type of gelatin. They found that the cytarabine release
profile was positively influenced by % loading of cytarabine and genipin content
and negatively influenced by the gelatin concentration.
PH-responsive materials: pH-responsive polymers are a class of active materials
able to swell, shrink, or modify their rheological properties (e.g., viscosity, shear
modulus) upon change in environmental pH or ion concentration (Lui et al.
Shafranek et al.
2019; Chiesa et al. 2020). This phenomenon can be attributed either
2019;
to the protonation of ionizable groups or to the degradation of acid cleavable bonds.
More in detail, when there is a change in pH, the polymeric chains of those materials
can stretch to a coil form due to electrostatic repulsion of charged functional
groups or form globule structure when the charge of the functional groups is
neutralized (Dai et al.
2008). In nature, there are several natural proteins displaying
pH responsiveness, such as collagen, gelatin, chitosan, and keratin, that undergo
different swelling/shrinkage profile when responding to different pH environments
(Lui et al.
2019; Peralta Ramos et al. 2017). Similarly, pH can be used to trigger
the self-assembly of peptide hydrogels made of the alternation of natural amino
acids, thus promoting the formation of intramolecular β-sheets or α-helices that
increase the mechanical and rheological properties of the material (Banwell et al.
2009; Ligorio et al. 2022). In addition, a wide variety of synthetic polymers, such as
8 4D Printing in Pharmaceuticals 277
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acrylic acid-based hydrogels, exhibit a pH-responsive behavior and have been used
for drug release applications (Okwuosa et al.
2017; Larush et al. 2017).
In the context of DDSs, since oral drug delivery represents the main route for
delivery therapeutic, the pH gradient that can be found along the gastrointestinal
tract (i.e., salivary pH around 6.7–7.5 in the mouth, acidic pH of the stomach around
1.0–3.0, and alkaline pH of the intestine around 5.0–8.0) can trigger the specific
space-dependent activation of the drug release (Rizwan et al.
2017). Moreover, some
diseases imply an altered pH (e.g., chronic wounds range between 5.4 and 7.4 and
acid pH of extracellular matrix in cancer tissue) that can be exploited to activate the
DDS only in the affected regions of the body (Schmaljohann
2006).
For example, El-Mahrouk et al. (El-Mahrouk et al. 2016) developed a pH-
responsive chitosan hydrogel containing metronidazole for the treatment of a
Helicobacter pylori infection in the stomach. The authors showed that the swelling
ratio of the hydrogel, and consequently the drug release, was higher and faster in
gastric pH when compared to the intestinal one. In vivo tests in a dog model revealed
that the use of this pH-responsive hydrogel allows the retention of the DDS in the
stomach for at least 48 h, with a more effective treatment of the infection than the
commercially available oral metronidazole tablets (Flagyl
®
).
Interestingly, some studies also exploited the capabilities of certain natural
hydrogel to respond to both the temperature and the pH with a differential
swelling. For example, Constantin et al. (Constantin et al.
2017) designed and
synthesized a temperature- and pH-sensitive DDS by incorporation of chitosanbased microspheres into poly(N-isopropylacrylamide-co-hydroxyethylacrylamide)
hydrogel (Fig.
8.1a). Salicylic acid was used to mimic an anionic drug and loaded
into the chitosan microspheres. The authors were able to tune the release profile of
the drug according to the environmental pH and temperature, due to the swelling
ratio of the hydrogel, which changed according to those environmental stimuli.
Light-responsive materials: Light-sensitive materials may convert externally
applied optical stimulation (e.g., visible, ultraviolet (UV), and NIR light) into other
responses, usually mechanical ones (Lima et al.
2012). A light-responsive behavior
can be either reversible or irreversible, depending on the chromophore that is
added to the polymer. Most commonly used chromophores include photochromic
molecules (e.g., azobenzene, spiropyran, salicylideneaniline) that undergo isomerization and polarity changes upon irradiation (Dai et al.
2009; Jochum and Theato
2013). Differently from other stimuli, light provides unique advantages, such as
spatially controlled activation by the use of a photomask or a focused light source,
and an instant activation that is easy to stop, pause, and resume (Mu et al.
2015).
Recently, carbon nanotubes and graphene-based materials have been used as lightsensitive elements, due to their excellent optical responsiveness (Li et al.
2011). It is
important to highlight that in several studies, light is used as an alternative method
to heat up the 4D structure in spatially defined locations. Thus, in these cases, the
real stimulus that triggers the shape-shifting is the increase in temperature due to
light irradiation (Nishiguchi et al.
2020; Jeong et al. 2020).
An interesting example of light-responsive materials for DDSs is provided by
Li et al. (
2012). Here, the authors fabricated a UV-responsive amphiphilic diblock
278 I. Chiesa et al.
Fig. 8.1 Summary of meaningful examples of applications of responsive materials in pharmaceuticals. (a) A pH- and temperature-responsive system developed by Constantin et al.: (i) Schematic
representation of the synthesis steps of smart composite hydrogels; (ii) swelling kinetic curves
of smart composite hydrogels at 23
standard acidic solution at pH 1.2 (image adapted with permission from (Constantin et al.
◦
C and 37 ◦C in phosphate buffer solution at pH 7.4 and in
2017)).
(b) A light-sensitive system developed by Li et al.: (i) schematic illustration of the fabrication
of the light-responsive polymeric micelles; (ii) cumulative Dox release profile from the drugloaded micelles at different pHs without and with UV irradiation for 30 min (image adapted with
permission from (Li et al.
2012)). (c) Shape memory device developed by Lee et al. for lidocaine
intravesical release: (i) a fabricated device consisting of a drug reservoir unit and a nitinol retention
frame; (ii) the sequence of deployment of the device by a catheter. The body temperature triggers
the shape recovery of the nitinol wire, thus allowing the retention of the device in the bladder; (iii)
in vitro release profile of lidocaine from the device immersed in water at 37
with permission from (Lee and Cima
2011))
◦
C (image adapted
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POEGMA-b-P(NIPAM-co-NBA-co-Gd) for controlled drug release (Fig. 8.1b).
Doxorubicin (Dox), a model chemotherapeutic drug, was loaded into the hydrogel
micellar nanoparticles. Then, upon UV irradiation, the photocleavage of NBA
moieties led to a hydrophobic-hydrophilic transition for the micellar cores, which
was associated with the core swelling. This core swelling was exploited to increase
the Dox release. As a matter of fact, the ∼65% of Dox was released in 12 h upon
UV irradiation versus ∼47% Dox release in 25 h for the nonirradiated samples.
Electric field-responsive materials: Electrical responsive materials (e.g., polythiophene, poly(2-hydroxyethyl methacrylate) possess intrinsic electrically conductive characteristic. Their shape and size can be regulated by the intensity and
direction of an external electric field (Palza et al.
2019; Borisova et al. 2015).
Electric field responsiveness is a combination of several electrical interactions
occurring in the material, including coulombic, electrophoretic, electroosmotic, and
piezoelectric phenomena (Morouço et al.
2020). Moreover, electrical responsive
materials can be obtained combining passive polymers with electro-responsive
particles, such as dielectric polarizable particles, which polarize when exposed
to an electric field, thus changing the structure of the material (Zhang and Choi
2014). In this scenario, electric field could provide a wireless and on-demand
activation of the drug release from the DDS (Mirvakili and Langer
example, Ge et al. (
2012) exploited polypyrrole, a conductive material, to develop
2021). For
a system for the programmed drug delivery under electric field by the simultaneous
electrochemical reduction/oxidation process and electric field-driven movements
of charged drug. More in detail, polypyrrole nanoparticles were loaded with
daunorubicin, a positively charged chemotherapy medication, and resuspended into
a poly[(
D,L-lactic acid)-co-(glycolic acid)]-b-poly(ethylene oxide)-b-poly-[(D,L-
lactic acid)-co-(glycolic acid)] hydrogel. The authors analyzed the ability of the
hybrid material to release the drug according to the intensity of the electric field
(ranging between 0.5 and 1.5 V) and the duty cycle of the stimulus (i.e., 10 s every
5 min or 20 s everyday), thus being able to obtain a fine dosage-controlled release
of the drug.
Magnetic field-responsive materials: Besides electrical field, magnetic field is
broadly used to induce material modifications for pharmaceutical applications (Price
et al.
2018). Magnetic field offers effective and safe manipulation via noncontact
remote mode, which can be easily started and stopped (Lui et al.
2019). Similarly
to electrical responsive materials, magnetic responsive materials usually are made
of magnetic responsive particles (e.g., cobalt ferrite, iron platinum, iron oxide) that
are uniformly dispersed in a carrier medium (Morouço et al.
2020; Zhang and Choi
2014).
For example, Chen et al. (Chen et al. 2011) developed magnetically controllable
DDS by the use of iron (II, III) oxide (Fe
). Briefly, Fe3O4 was used to
3O4
cap mesoporous silica nanoparticles, in which an anticancer drug was dispersed.
Without magnetic stimulus, a negligible amount of the drug is released from the
construct. However, when it is subjected to an external magnetic field (magnetic
power equal to 2 kW for 1, 3, and 5 min), some of the Fe
caps were removed by
3O4
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