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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5427_Библиотеки_им_академика_М_И_Перельмана
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7 4D Printing: The Next Dimension of Healthcare in Cancer Research 239
MCF-7 Michigan Cancer Foundation-7
MNPs Magnetic nanoparticles
MMP-2 Metalloproteinase-2
NIR Near-infrared
NLC26 Nano-lantern colon26
NSs Nanosheets
PCL Polycaprolactone
PDA Polydopamine
PDO Patient-derived organoid
PEG Polyethylene glycol
PEG-b-PAEMA Poly(ethylene glycol)-block-poly(2-azepane ethyl methacrylate)
PEGDA Poly(ethylene glycol) diacrylate
PLA Polylactic acid
PLGA Poly(lactic-co-glycolic acid)
PNIPAM Poly(N-isopropylacrylamide)
PTX Paclitaxel
PU Polyurethane
PμSL Projection micro-stereolithography
PVA Poly(vinyl alcohol)
P(DLLA-TMC) Poly(lactic acid-co-trimethylene carbonate)
SA Stearic acid
SA-MA Methacrylated alginate
siRNA Small interfering RNAs
SOL Soluplus
SPIONs Superparamagnetic iron oxide nanoparticle
TED Technology, Entertainment, and Design
TEMED N,N,N
TDIW Two-photon direct laser writing
T
g
T
trans
UV Ultraviolet
WHO World Health Organization
,N
-tetramethylethylenediamine
Glass transition temperature
Transition temperatures
7.1 Introduction
Cancer is recognized as a serious issue, leading to a large number of worldwide
deaths and post-treatment trauma. Cancer mortality in 2020 was considered to be
around 52% of all cancer patients reported by an international agency for cancer
research, the World Health Organization (WHO), and the cancer deaths are almost
one-sixth of worldwide deaths (Sung et al.
continue to increase until 2040, and cancer deaths will reach 13.1 million cases
in 2030 (Sung et al.
2021; Anirudhan and Mohan 2014). Literally, most cancer
patients could survive with medicines and therapeutics if there are early diagnoses
and treatments. It is well known that a one-size-fits-all treatment is not effective
in cancer treatments (Li et al.
2021). This is because cancer cells mostly originate
from mutated epithelial cells in any organ or tissue that abnormally grow and spread
to others, which make cancer heterogeneous between patients and is considered a
variability factor in treatment. Therein, a precise diagnosis and a specific treatment
2021). Cancer cases are expected to
240 A. Chinnakorn et al.
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during the early stage of the cancer are highly desirable to cure it and prevent its
mortality.
With capabilities of individual formation, unlimited design and various useable
materials, additive manufacturing (AM), particularly three-dimensional (3D) printing, has attracted considerable interest in cancer treatments because it is able to
provide personalized 3D models which enhance cancer treatments like surgery, and
benefit to produce personal medicines (Haleem et al.
Chen et al.
2020b). 3D printed structures have also provided precise positioning and
2020; Bhuskute et al. 2021;
porous texture, both of which are advantageous in medical applications (Luo et al.
2019b). In addition, another advancement in 3D printing is the combination of 3D
printing and live cells to print medical parts, known as “bioprinting.” It is proposed
as a proper tool to understand the complexity of the cancer microenvironment that
is necessary for aspects of diagnosis and prognosis (Germain et al.
et al.
2021). Even though 3D printing has facilitated advanced manufacturing, it is
2022; Augustine
still faced with limitations of static structures that cannot react or adjust according
to environment (Agarwal et al. 2021). To address these challenges, dynamic 3D
constructs that respond to environmental stimuli have emerged as a new pathway
to enhance diagnosis, prognosis, and treatment strategies in cancer therapies. Certainly, the fabrications of dynamic constructers use smart materials in manufacturing
to allow printed constructs to respond to stimuli such as heat, light, magnetic field,
pH value, or enzyme, resulting in a transformation in shape, properties, or function
over time. This time variable has become the fourth dimension in manufacturing
as four-dimensional (4D) printing which was firstly revealed by Skylar Tibbits at
Technology, Entertainment, and Design (TED) conference and in a journal article in
2013 (Tibbits
various cancer treatments, including hyperthermia (Tang et al.
therapy (Deng et al.
2014). 4D printing has immensely emerged as an advanced method in
2021), photothermal
2022), drug delivery systems for chemotherapy (Liu et al.
2021a;Huetal. 2022; Xin et al. 2021), surgery resection (Deng et al. 2022; Chen
et al.
2022), organ models (Chadwick et al. 2020; Bodaghi and Zolfagharian 2022),
and devices (Osawa et al.
2020).
Herein, various smart materials used in the 4D printing technique for healthcare
will be presented as responding to different stimuli, including physical, chemical,
and biological stimuli. The significant role of 4D printing in cancer treatment will
be further detailed through improved applications from 3D to 4D printing with the
current progress of 3D printing, bioprinting, and 4D printing in each therapy such
as hyperthermia, chemotherapy with anticancer/antitumor drug delivery systems,
and pharmaceutical models. Future perspectives are finally proposed, along with a
conclusion.
7.1.1 Smart Materials
4D printing is not a straightforward method that uses only manufacturing processes.
It is based on the existing 3D printing technologies and requires smart materials in
the production of dynamic architectures (Khalid et al.
2022). In 4D printing, smart
7 4D Printing: The Next Dimension of Healthcare in Cancer Research 241
materials enable printed architectures responding to specific stimuli, and they play
essential roles to obtain desired shapes, functions, or property changes (Naniz et
al.
2022), such as shape transformation (Kim and Lee 2018; Wang et al. 2021),
self-heating (Tang et al.
or properties (Ceylan et al.
2021; Deng et al. 2022), self-clamping (Hu et al. 2022),
2019). With the potentials of smart materials integrated
into 3D printing, the dynamic structures play great alternatives in cancer treatments.
This topic focuses on the stimulus responsiveness of smart materials in healthcare
that are represented in the term “stimuli-responsive materials” as following physical
(temperature, light, magnetic field), chemical (pH value, ion concentration), and
biological (enzyme) stimuli. The next section explains how these smart materials
are employed in cancer treatment will be considered in the next topic.
7.1.1.1 Physical Stimuli
Physical stimuli, including temperature, light, humidity, magnetic field, electrical
field, pressure force, and water have often induced changes to an object by physical
arrangements (Sahafnejad-Mohammadi et al.
2022). We will present current details
of temperature, light, and magnetic field stimuli since they have been considerably
applied in 4D printing for cancer treatments.
Temperature-Responsive Materials
Temperature-responsive materials have been commonly used in 4D printing
and have gained widespread applications in healthcare. These materials can be
activated by temperature, which is used to achieve shape transformation by directly
heating above their transition temperatures (T
), resulting in an increase in
trans
the entropy (Zhou et al. 2020; Moroni et al. 2022). Temperature-driven dynamic
architectures can be found in both internal and external environments (Arif et al.
2022). Common thermo-responsive materials mentioned in healthcare are poly(N-
isopropylacrylamide) (PNIPAM), gelatin (Gel), polyethylene glycols (PEGs),
polyurethane (PU), poly(lactic acid-co-trimethylene carbonate) (P(DLLA-TMC)),
and poly(vinyl alcohol) (PVA) (Arif et al.
2022; Wang et al. 2020). Among these
materials, PNIPAM is commonly used in biomedical applications (Wang et al.
2022). For example, Zu et al. (2022) demonstrated the fabrication of PNIPAM-
based drug capsules enabling multidrug encapsulation. The drug capsules were
inspired by a plant stoma and produced using an extrusion-based printer with
ultraviolet (UV)-cross-linking curing. The shape morphing of capsules was operated
by shrinking/swelling properties (Fig.
sensitivity at around 34.9
◦
C. Besides, Lee and Jho (2018) employed PNIPAM
7.1a) and provided excellent temperature
crosslinking with PVA to fabricate grippers that were capable of catching, lifting,
and releasing objects that were heavier than them at 25
◦
C and 37 ◦C of water
temperature with swelling properties. The shape transformation driven by thermoresponsive materials also enhances advances of artificial implants or devices with
the functions of switchable shapes and adjustable sizes to pass through a tight
pathway. Kim and Lee (
2018) printed a bifurcated stent with a kirigami structure
based on shape memory PU, which provides a switchable shape between a thin
sheet and an expanded form under temperature changes, as seen in Fig. 7.1b.
242 A. Chinnakorn et al.
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Fig. 7.1 (a) Schematic images of (i) an opening/closing response of stomatal leaves upon suitable
and high temperature, (ii) a schematic fabrication of 4D hydrogel capsule inspired by the stomatal
leaves, (iii) the printed capsule based on poly(N-isopropylacrylamide) (PNIPAM), (iv) the capsule
encapsulating single, and (v) multiple drugs (Zu et al.
smart stent which (i) can control shape transformation under temperature stimulus and (ii) can be
inserted into a branched mock like vessels in the human body (Agarwal et al.
sol–gel transition of gelatin with 70% of the concentration between 37
2020)
2022), (b) demonstration images of a printed
2021), and (c)a
◦
C and 50 ◦C(Weietal.
In addition, Gel is another material widely applied in pharmaceutical and
biomedical fields because of its biocompatibility and biodegradability (Anirudhan
and Mohan
2014; Omer et al. 2021). It is able to induce dynamic structures
through reversible gel-sol transitions, such as the sol-gel transformation of 70% gel
concentration in Fig.
(PDA), which provided a potential photothermal conversion (Wei et al.
7.1c. To more illustrate, gel was combined with polydopamine
2020). Core-
shell fiber hydrogels, which contained PDA/alginate (Alg) with concentrations of
15.3%wt Alg as the shell layer and 70%w/v of gel as the core layer, presented
excellent responsive performance with a photothermal effect. The temperature was
rapidly raised to 53
infrared (NIR) laser irradiation of 0.6 and 0.8 Wcm
◦
C and 60 ◦C when the hydrogel was exposed to 808 nm near-
−2
, respectively, within 1 min.
Many temperature-responsive materials have been employed in combination with
other smart materials to receive multifunctional structures through a magnetothermal or photothermal effect. To illustrate, PNIPAM incorporated with iron oxide
nanoparticles (Fe
facilitates local cancer treatment with hyperthermia (Tang et al.
) was fabricated to present the magnetothermal effect that
3O4
2021). Similarly,
PU incorporated with metal nanoparticles was used to perform the photothermal
effect (Deng et al.
2022).
Light-Responsive Materials
Light-responsive materials in 4D printing play a crucial role in healthcare because
they provide exposure location and minimal invasiveness for individual treatments.
These materials, which consist of stilbene, derivatives of nitrobenzene, azobenzene,
fulgide, spiropyran, or photosensitive-nanometals, have been triggered by light
with different wavelengths, including UV, infrared (IR), NIR, leading to change
the shapes and also generating heat through the photothermal effect (Arif et
al.
2022). The NIR has been immensely interested in applications in healthcare
7 4D Printing: The Next Dimension of Healthcare in Cancer Research 243
because of tissue penetration depth and lower self-heating in tissue, especially in
a region of the second NIR (He et al.
2021; Zhang et al. 2021). PDA is a main
component of melanin (Mel) that is biocompatible and biodegradable, and it enables
light absorption in the NIR region of 700–1100 nm, which gains photothermal
conversion reaching 40% (Sun et al.
2021). For instance, Luo et al. (2019a)
fabricated programmable cell-laden scaffolds comprising of Alg/PDA and cellladen hydrogels based on gelatin methacryloyl (GelMA). The shape-morphing of
scaffolds was induced by 808 nm NIR irradiation without significant damage to the
cells. Besides, Mel has been presented as one of the light-responsive materials. In
recent years, Mel has been employed in on-demand drug delivery for transporting
insulin via the photothermal performance (Kim et al.
2022). 3D-printed multiunit
scaffolds were designed as a rectangular matrix consisting of multi-subunit sectors
segregated by the polycaprolactone (PCL) axis, and each subunit was fabricated
from PCL, lauric acid (LA), and Mel. Human insulin (hIn) was loaded into each
unit, and it could be released from scaffolds because LA/PCL was melted by
heat generated from Mel upon the light exposure on the subunit, as illustrated
in Fig.
performance upon 808 nm NIR irradiation at 1.5 W/cm
from 21.9 ± 1.1
7.2a-(ii). The scaffolds based on PCL, LA, and Mel showed responsive
2
◦
C to 45.4 ± 1.2 ◦C. In contrast, scaffolds without Mel did
by increasing temperature
not raise heat and the lack of Mel or LA did not show the photothermal effect
as shown in Fig.
7.2a-(iii). Rarely, Egyptian blue (EB, CaCuSi4O10), known as
a synthetic pigment, has been reported to have excellent NIR absorption in a
range of 1000–1350 nm, which enhances its photothermal effect. For example,
100 ppm of CaCuSi
almost 55
◦
C within 300 seconds, and the temperature was raised as a result of
the increased content of CaCuSi
absorption filler but also encourages bone formation as well (He et al.
Another group, Wang et al. (
in the CaCO3/PCL platform raised the temperature to
4O10
. EB has been considered not only a NIR
4O10
2020) embedded black phosphorus (BP) recommended
2021).
as an excellent photothermal agent in biomedical applications in P(DLLA-TMC)
matrix to fabricate scaffolds. A 95:5 ratio of DLLA/TMC provided a glass transition
temperature (T
)of45◦C that became a critical point of shape change. The scaffolds
g
performed the photothermal effect incorporating with shape memory abilities to
achieve the on-demand deformation/recovery performance.
Metal nanoparticles are photosensitive because of excellent light absorption that
is almost originated by excited electron-hole pairs (Hartland et al.
metal nanoparticles such as Pt, TiO
localized heat for cancer treatments (Zhou et al.
al. (
2022) fabricated sheet-like scaffolds comprising shape memory PU polymer
, and Au have been widely used in generating
2
2020). For example, Deng et
2017). The
and gold nanoparticles (AuNPs), which provided high photothermal conversion
efficiency (Sun et al.
2021) and were still biocompatible. Under light irradiation, the
surfaces of AuNPs generated heat by the plasma resonance effect and increased the
temperature of the PU matrix. As seen in Fig.
7.2b, the shape of PU/AuNPs scaffolds
had completely changed from a tightened claw to a flat claw by light illustration with
a wavelength of 520 nm and an intensity of 2 W/cm
2
within 78 s.
244 A. Chinnakorn et al.
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2022)and(b) shape memory polyurethane
containing of polycaprolactone (PCL), melanin (Mel) lauric acid (LA), and human insulin (hIn), (ii) a procedure of on-demand drug release induced by NIR
irradiation, (iii) results of different four types of implants upon NIR irradiation (scale bar = 0.5 cm) (Kim et al.
Fig. 7.2 (a) Images of on-demand human insulin (hIn) delivery triggered by NIR irradiation including (i) printing processes of insulin delivery platform
(PU)/gold nanoparticles (AuNPs) structures including (i) shape recovery process induced by light illustration with 520 nm wavelength and (ii) shape recovery
2022)
results of intraluminal scaffold that can used in the defect healing (Deng et al.
7 4D Printing: The Next Dimension of Healthcare in Cancer Research 245
Although light-responsive materials are always required to have photosensitive
elements, some polymers can be modified to have photosensitive characterizations
(Arif et al.
2022). For instance, chitosan that is biocompatible, biodegradable,
antimicrobial, and antitumor was chemically modified in a photosensitive methacrylamide without changes of polysaccharide chain, which its amino group (–NH2)
was transferred with methacrylamide (Bozuyuk et al.
2018). This methacrylamide
chitosan (ChMA) was composed of 70% photosensitive methacrylamide groups and
was presented as a photoinitiator in the 350 nm range of UV light.
Magnetic-Responsive Materials
Magnetic-responsive materials are essentially useful in 4D printing, which are used
for various purposes including controllable locomotion (Hu et al.
2022; Ceylan et al.
2019), controllable shape transformation (Zhao et al. 2019; Wang et al. 2021), on-
demand drug release (Hu et al.
for cancer treatment (Ganguly and Margel
2022; Shi et al. 2020a), and magnetic hyperthermia
2022; Tang et al. 2021). On the subject
of locomotion, these magnetic-responsive materials have allowed for safe and
effective locomotion because of the use of external magnetic fields that provide
accurate positioning and depth penetration. To be more specific, soft millirobots
consisting of PNIPAM, NdFeB had achieved practical mobility through obstacles
in stomach model (Hu et al.
symmetrically three pairs which present symmetrical magnetic moments [M
formed by magnetic field of external permanent magnet and generate M
2022). The starfish-like millirobots were designed as
x,My
moments
z
caused by thermal expansion. This magnitude of magnetic moments was used in
driving the robots, as seen in Fig.
7.3a. In fact, the amount of magnetic nanoparticle
relates to magnitude of magnetization, resulting in application efficiencies like
the maximum speed of mobile robots. Certainly, higher amount will result in
increasing swimming speeds; however, the higher amount resulted in inefficient
3D printability. It was reported that the threshold concentration of Fe
3O4
in helical
microrobots providing homogeneously printed structures without any aggregation
was at 5 mg/mL (Bozuyuk et al.
2018). Another purpose of the magnetic-responsive
applications is the control of shape transformation. For example, Zhao et al.
(
2019) designed bioinspired tracheal scaffolds of shape memory polylactic acid
(PLA)/Fe
composites. The shape transformation of scaffolds was induced under
3O4
an alternating magnetic field (AMF) that appeared shape recovery within 35 seconds
upon 30 kHz frequency of the magnetic field with an intensity of 4 kAm
in Fig.
7.3b. Additionally, the ability of controllable shape transformation under a
−1
as shown
magnetic field has been used to achieve on-demand drug delivery by controlling
only the opening/closing ends of hollow tube/fiber scaffolds (Wang et al.
2021).
These magnetic-responsive materials have always been incorporated with mag-
netic materials (Bodaghi and Zolfagharian
2022), especially magnetic nanoparticles.
The magnetic nanoparticles have been widely used in cancer therapies because of
heat generation source in hyperthermia (Ganguly and Margel
2022). The magnetic
materials generate heat through energy conversions with different mechanisms
from the dissipation of magnetic energy into thermal energy upon exposure to
an AMF (Shaterabadi et al.
2018). To illustrate, a voltage induced in materials
]
246 A. Chinnakorn et al.
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Fig. 7.3 (a) A magnetic-driven mechanism of millirobot including (i) a schematic image showing
the control of magnetic-responsive hydrogel with magnetic moments, and (ii) different locomotion
patterns of the starfish-like millirobot (scale bars are 5 mm) (Hu et al.
transformation of bioinspired tracheal scaffolds induced by the magnetic field (Zhao et al.
2022), and (b) shape
by a magnetic field produces circular currents that leads to the formation of the
opposite magnetic field and then loss magnetic energy as heat. Besides, heat can
be generated by hysteresis lose and relaxation of magnetic moment alignment,
like Brownian and Neel relaxation. Among these materials, superparamagnetic
nanoparticles like Fe
are popular because of excellent magnetic interactions,
3O4
possibly leading to potential the magnetothermal effect, and abilities as good drug
carriers at high concentration (Materón et al.
2021). Currently, Fe3O4 embedded in
PNIPAM hydrogel that placed on a printed elastomer layer was used to generate
heat to kill cancer cells for hyperthermia (Tang et al.
2021). This Fe3O4/PNIPAM
composite hydrogel provided rapid and excellent performance of magnetic response
reached to 86.5
◦
C in 100 s with 20% content of Fe3O4 nanoparticles. The uses of
2019)
7 4D Printing: The Next Dimension of Healthcare in Cancer Research 247
magnetic-responsive materials in hyperthermia will be more thoroughly discussed
in the topic of hyperthermia.
7.1.1.2 Chemical Stimuli
Chemical stimuli induce conversions under the action of chemicals and generally
consist of pH changes and ionic concentrations (Chu et al.
2020). pH-responsive
materials respond to the pH variation with a swelling-shrinkage behavior, mostly
occurring from protonation-deprotonation reaction (Yang et al.
2021). There are
two classes of functional groups in pH-responsive materials, including an acidic
group containing –COOH and –SO
H bonds and a basic group containing a –NH
3
bond (Arif et al. 2022). Indeed, abnormal activities in body could be revealed by
pH level. To be more specific, cancer tissue, including tumors, possesses a special
surrounding because unnormal proliferation and metabolism of cancer cells make
intra- and extracellular pH different from that of normal cells. Extracellular and
intracellular environments of cancer cells exist with weak acidity (pH = 6.5–7.2)
and lower acidity (pH = 4.5–6.5), respectively, while the pH level of normal cells
is commonly maintained between 7.2 and 7.4, resulting in a pH gradient between
cancer and normal sites (Yang et al.
2021). The pH gradient becomes an effective
variable for cancer detection in drug delivery and makes pH-sensitive materials
desirable in a study of 4D printing in cancer treatments. Recently, Xin et al. (
2021)
fabricated pH-responsive hydrogels, which were inspired by the natural behaviors
of fish, crabs, and butterflies, by using a one-step rapid process of femtosecond
direct laser writing. The main components of pH-responsive hydrogels contained
acrylic acid (AAc), dipentaerythritol pentaacrylate (DPEPA) as a crosslinker, and
4,4
-bis(diethylamino) benzophenone (EMK) as a photoinitiator (Fig. 7.4a). These
hydrogel networks would be expanded in a pH > 9 environment by the deprotonation
of the carboxyl group, and the shrinkage would happen because of protonation in
a pH < 9. To achieve a programmable pH response, morphological changes were
driven with a different expansion rate by a determination of porosity in each part of
the microstructures as illustrated in Fig.
7.4b.
Another mechanism of chemical stimuli is equilibrium ion displacement, such
as that of zinc (Zn
2+
), iron (Fe2+), and calcium (Ca2+) ions (Chu et al. 2020). Lai
2
Fig. 7.4 (a) Main components and a mechanism of expansion/contraction of pH-responsive
hydrogel, (b) a designable point density in various parts used to fabricate fish-like microrobot,
and (c) optical images of fish-like and crap-like demonstrating response which providing opening/closing of fins and claws under pH variables (Xin et al.
2021)
248 A. Chinnakorn et al.
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Fig. 7.5 (a) A schematic diagram showing a fabrication with different alginate/methylcellulose
(Alg/MC) patterns that affected to different deformation after immersing in CaCl
et al.
2021)and(b) images of a step-wise deformation that provided volume a contraction of
methacrylated alginate with a 5/1 molar ratio of methacrylic anhydride/-OH (SA-MA
after immersed in Ca
2+
and chitosan solution (scale bar is 10 mm) (Cao et al. 2021)
solution (Lai
2
) hydrogels
5
2021) exhibited Alg/methylcellulose (Alg/MC) hydrogels with the optimal
et al. (
concentration of 3%w/v and 9%w/v, respectively, provided shape transformation
with swelling/shrinking abilities after immersion in a calcium solution and controlled the transformation with the orientation of patterned structures in Fig.
Similarly, Cao et al. (
2021) demonstrated the volume contraction ability of a
methacrylated alginate (SA-MA)-based hydrogel. The volume change was caused
by an anisotropic shape change from increasing crosslinking density and modulus
through the Ca
shown in Fig.
2+
ion exchange and ionotropic reaction with chitosan solution as
7.5b.
Moreover, many researchers reported material developments like gel that is well
known as a thermo-responsive material and able to achieve pH-responsive gel-based
materials (Omer et al.
Shi et al. (
2020b) presented cross-linked Gel and chitosan to fabricate Schiff base
2021; Anirudhan and Mohan 2014). To be more specific,
complexes which have a formation of imine bond (–N == C) that is pH-responsive.
In crosslinking strategy, glutaraldehyde was used to add in a mixed solution of 5%
gel in water and 2.5% chitosan in critic acid with 10% concentration by a volume
ratio of 2:1, respectively. This gel-chitosan (GC) gels were applied in controlling
7.5a.
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