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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 249
drug release for antitumor by hydrolysis, and it found that the pH-responsive GC
generated from Schiff base response to acid environment and rapidly release drug
including doxorubicin (DOX) and 5-fluorouracil (FLU) from network under pH 5,
compared to pH 7 (Shi et al.
enable not only materials to be pH-responsive owing to reversible covalent bond
between amino and carbonyl groups, but the Schiff of crosslinked-b sed hydrogels
also perform a self-healing property (Shi et al.
2020b; Sahajpal et al. 2022). The Schiff base reaction
2020b, Sahajpal et al. 2022).
7.1.1.3 Biological Stimuli
Biological molecules in human body, such as enzymes and glucose, can cause
changes in dynamic structures. Enzyme-responsive materials use enzymatic environments as stimuli causing responses in materials and have a growing demand for
cancer treatment and medical applications (Naniz et al.
and tumor treatments, the use of enzyme-responsive materials has gained interest
because some enzymes are highly expressed (Liu et al.
metalloproteinase-2 (MMP-2) enzyme can degrade various types of collagen which
is a component of various stimuli-responsive materials. The MMP-2 was used to
control drug release with a swelling property and degrade GelMA-based doublehelical hydrogels as seen in Fig.
enzyme was employed in the degradation process of chitosan-based hydrogel
because the lysozyme could cut off the glycosidic bonds, resulting to smaller chains.
Moreover, no toxic products were found after the entire degradation (Ceylan et al.
2019; Bozuyuk et al. 2018).
7.6 (Ceylan et al. 2019). Similarly, lysozyme
2022; Ulijn 2006). In cancer
2021b). For example, the
7.2 Application Developments from 3D to 4D Printing
in Cancer Therapies
Here, we would like to present how 3D printing has been applied in cancer treatment
and how it has been evaluated with 4D printing through three categories: hyperthermia, including photothermal therapy, drug delivery systems for chemotherapy; and
models in pharmaceutical fields.
7.2.1 Hyperthermia and Photothermal Therapy
Both hyperthermia and photothermal therapy have attracted attention in cancer
treatments because of minimal invasiveness with little or no harm to normal tissue,
accurate spatial-temporal mapping, and high specificities (He et al.
fore, they are particularly helpful in the personalized and localized cancer treatments
that are highly desired for cancer patients. Hyperthermia is a cancer treatment that
employs an increase of heat that is higher than the normal body temperature from
a rearrangement of cellular components and functions for damaging and killing
abnormal cells (Musielak et al.
type of hyperthermia that the heat that is used to induce cancer death is generated
2019). Similarly, photothermal therapy is a specific
2021). There-
250 A. Chinnakorn et al.
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Fig. 7.6 (a) A schematic concept of drug delivery that use an enzyme to control drug release and
a magnetic material to propel movement and (b) potential biodegradation of gelatin methacryloyl
(GelMA)-based double-helical hydrogels in 4 μgmL
al.
2019)
−1
metalloproteinase-2 (MMP-2) (Ceylan et
from light (Gellci and Mehrmohammadi 2014). There were reported that cancer
cells can be damaged with the heat in a range of 42–45
without any injury of normal tissue (Shaterabadi et al.
◦
C or 109.4–113.0 ◦F
2018; Musielak et al. 2019).
For instance, tumors in mice induced by nano-lantern colon26 (NLC26) had started
to be cured at 42
were completely dead at 43
o
C with the photothermal therapy using NIR light irritation, and all
o
C (Nomura et al. 2020).
3D printing has been used for producing scaffolds that can generate heat on the
scaffolds, and the scaffolds are used as implants in the required areas via surgery.
For example, He et al. (
-PCL (CaP) scaffolds, which their surface was painted with nanosheets
CaCO
3
2021) fabricated CaPCu scaffolds incorporating 3D-printed
7 4D Printing: The Next Dimension of Healthcare in Cancer Research 251
Fig. 7.7 An overview image of CaPCu scaffolds used in the photothermal therapy including (a)
photographs and SEM images of CaP scaffolds (upper row) and CaPCu scaffolds (lower row), (b)
a schematic image of CaP and CaPCu-based scaffolds used to kill osteosarcoma with photothermal
therapy, and (c) an in vivo results of osteosarcoma elimination (He et al.
2021)
(NSs) containing CaCuSi4O10. The scaffolds could intercept cancer metabolism
because of raised heat from the excellent NIR adsorption of EB, resulting in cancer
cell death. The scaffolds were in vivo tested by being implanted in mice, which were
induced by 143B cells. The temperature of CaPCu scaffolds was raised to 48
◦
C
within 4 min upon 1064 nm NIR irritation, which resulted in a decrease in tumor
size and eventually damaged all tumors, as seen in Fig.
7.7. Apart from 3D printed
scaffolds used in photothermal therapy, there are their applications in magnetic
hyperthermia that generate raised heat with magnetic nanoparticles (MNPs). For
instance, Yang et al. (
2018) showed a fabrication of PCL/Fe3O4 scaffolds using
an electrohydrodynamic jet (E-jet) printer combining extruder-based printing and
electrospinning methods. PCL mat with 6 mmol/L of Fe3O4 reached a temperature
of around 45
◦
C within 45 minutes under AMF and induced obvious reductions in
in vivo tumor sizes.
To overcome the limitations of static printed structures, 4D printing has emerged
in hyperthermia to obtain multifunctional performances, enhancing potential applications in hyperthermia as seen in Fig.
7.8a and shown in Table 7.1. The current
dynamic structures by 4D printing have been reported to have advantages for the
photothermal therapy in various aspects, including (1) controllable shape morphing
that prevents side effects on normal tissue and provides reduced incision (Tang et al.
2021; Chen et al. 2022) and (2) on-demand transformations include a healing ability
of any defect (Deng et al.
2022).
Tang et al. (2021) reported an advanced strategy using smart magnetic robots
with controllable shape transformation for hyperthermia. The robots were comprised of magnetic hydrogel and elastomer to perform magnetothermal responses.
This strategy employed the magnetic nanoparticle as a heat generator to kill
cancer cells and urged programmable shape transformation with thermo-responsive
materials to wrap the cancer cells. These composite structures were designed
as a multi-arm structure and produced in two parts: top and bottom layers,
using an extrusion-based direct ink writing (DIW) printer. The magnetic hydrogel
incorporating PNIPAM, Fe
nanoparticles, and nanoclay was printed as the top
3O4
252 A. Chinnakorn et al.
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Fig. 7.8 (a) A schematic diagram of current applications in hyperthermia, which driving from (i) 3D to (ii) 4D technologies, (b)theuseof4Dprintedmulti-
arm scaffolds in a magnetic hyperthermia including (i) a schematic illustration showing the application of scaffold which heat can be generated by a magnetic
induction and the deformation of scaffolds was induced by an alternating magnetic field, resulting to kill cancer at a localized site and (ii) a photograph showing
2021), and (c) a schematic performance of self-expandable tracheal stent used in tracheal support for
raised heat on the scaffold (scale bar is 1 cm) (Tang et al.
2022)
hyperthermia and drug release (Chen et al.
7 4D Printing: The Next Dimension of Healthcare in Cancer Research 253
143B Bone He et al. (2021)
4T1 Breast Luo et al. (2019b)
Saos-2 Bone Pan et al. (2020)
HCT-116 Colon Yang et al. (2018)
A375 Cancer Tang et al. (2021)
MDA-MB-231 Breast Deng et al. (2022)
Franz cells Tracheal stents Chen et al. (2022)
Extruder-based printer – Photothermal
,PCL,
3
Materials AM type 4D printing mechanism Therapeutics Cells Tissue/Organ Ref.
CaCo
Tab le 7 .1 Applications of 3D and 4D printing technologies in hyperthermia
therapy
therapy
10
O
4
Alg, PDA Extruder-based printer – Photothermal
CaCuSi
therapy
hyperthermia
– Magnetic
Extruder-based printer – Photothermal
Electrohydrodynamic jet
(E-jet) printer
2
C
,
3
4
O
3
3
Bioactive glass
(Si/ca/P), Ti
PCL, Fe
POCl
Magnetic
hyperthermia
Magnetothermal
performance
Extruder-based direct ink
writing (DIW) printer
,
4
O
3
PNIPAM, Fe
silicone
elastomer, APS,
TEMED
Photothermal
PU, AuNPs Extruder-based bioplotter Photothermal
therapy
Magnetic
hyperthermia
performance
performance
Pneumatic-based printer Magnetothermal
,EVA
4
O
3
PCL, Fe
copolymer,
1-hexadacanol
254 A. Chinnakorn et al.
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layer by placing it on the previously printed elastomer part incorporating commercial silicone elastomer, nanosilica, and benzophenone. The printed structures
of magnetic hydrogel and elastomer were connected by covalent interlinks. The
potential of hyperthermia was examined in vitro with human malignant melanoma
cells (A375 cells), which were prepared by being cultured in GelMA hydrogel and
placed on the center of printed multi-arm structures. When applying an AMF, the
arm was heated and folded to encase the GelMA hydrogel. The A375 cells were
concurrently killed by raised heat of magnetic hydrogel, obliviously decreasing to
50% when heat temperature was reached above 50
with 230 A of AMF, as illustrated in Fig.
7.8b.
◦
C for 20 min by inducing them
Furthermore, both hyperthermia and photothermal therapy have often been
combined with other cancer treatments, such as hyperthermia-chemotherapy (Zhang
et al.
2014; Lai et al. 2021), photothermal-chemotherapy (Liu et al. 2021a;Wei
et al.
2020), photodynamic-chemotherapy (Sunil et al. 2021) to enhance potential
outcomes of the cancer treatment. For example, Chen et al. (
2022) fabricated a self-
expandable tracheal stent consisting of three layers as follows: an inner PCL layer,
a middle Fe
blended with PCL layer, and an outer paclitaxel (PTX) drug loaded
3O4
in an ethylene-vinyl acetate-based layer. The external magnetic field was used to
generate heat and then activate the thermo-responsive PCL layer to release the PTX
drug, as seen in Fig.
7.8c.
7.2.2 Drug Delivery System (DDS) for Chemotherapy
7.2.2.1 3D Printing
Chemotherapy is a cancer treatment that cures cancer cells with drugs, and
traditional chemotherapy is almost used as an auxiliary treatment because drug
resistance, drug delivery problems, and side effects on normal tissue are still
concerned (Hu et al.
2016). To address these concerns, drug delivery systems (DDS)
have been introduced as efficient ways to achieve controllable drug release on
localized and specific sites, which also reduces side effects for patients.
Normally, 3D printing has been used to fabricate static scaffolds that enable
drug loading and intergrading other functions. For example, Zhang et al. (
2014)
reported a multifunctional platform with apatite-forming bioactivity and hyperthermia for local anticancer drug delivery and bone tissue engineering. The platform
was fabricated as hierarchically meso-macropore scaffolds by containing Fe
3O4
nanoparticles, mesoporous bioactive glass in a Si/Ca/P molar ratio of 80/15/5,
and PCL (Fe
/MBG/PCL), and DOX hydrochloride (DOX-HCL) was loaded in
3O4
MBG powders before the printing process. The drug loading capability in MBG
powder was limited at around 84.8 ± 5.0%, and 30% of DOX in the scaffolds
was rapidly released within 24 hours. It was continuously conducted with a slower
release up to 60% in 10 days. In addition, Shi et al. (
2019) presented the fabrication
of an anticancer drug using a drop-on-powder (DoP) 3D printer for personalized
medicines. The anticancer drug was printed as an oral tablet by composing of
CaSO
-based powder, which was a mixture of CaSO4 hydrates (<90%), vinyl
4
7 4D Printing: The Next Dimension of Healthcare in Cancer Research 255
Fig. 7.9 Schematic diagram showing the roadmapping applications from 3D to 4D printing
techniques for drug delivery systems (DDS) in cancer treatments as following: (a) drug-loaded
scaffolds using 3D printing techniques, (b) triggerable drug-loaded scaffolds, and (c) milli- and
microrobots with capabilities of drug loading and controllable locomotion
polymer (<20%) and carbohydrate (<10%), and FLU drug loaded into the tablets by
dropping onto the surface of tablets. 100% of the loaded drug was released within
2 h, and the drug release rate could be slightly slower by preparing FLU solution
with hydrophilic polymers like soluplus (SOL) and PEG because of amphiphilic
attribution.
Most control of drug release in 3D-printed scaffolds has been determined by
studying drug release behavior via diffusion; however, these scaffolds didn’t break
through the challenges of on-demand drug release and controllable dose. Dynamic
structures using 4D printing have gained tremendous interest for anticancer/tumor
drug delivery. Not only does the on-demand drug delivery system improve the
potential for driving drug delivery systems to specific areas, but it can also provide
highly desired controllable dose capabilities. It helps to prevent causes toxic effects
because of higher concentration in the body (Liu et al.
2021b). In Fig. 7.9 a
roadmapping diagram of drug delivery development used in chemotherapy via 3D
and 4D printing technologies is shown as summarized in Table
7.2 starting from
drug-loaded scaffolds to mobile drug carriers with abilities of on-demand releases
and controllable doses.
7.2.2.2 Triggerable Scaffolds
To enhance the potential of localized cancer treatment, the use of smart materials
such as pH-responsive, temperature-responsive, light-responsive, and magneticresponsive materials has emerged in drug delivery systems to achieve on-demand
release in specific areas. For example, Shi et al. (
2020b) explored multifunctional
scaffolds which releasing drug on tumor environment by responding to pH value.
The intelligent scaffolds (IS) incorporating poly(lactic-co-glycolic acid) (PLGA),
Gel, and chitosan were fabricated for breast cancer. Anticancer drugs including
FLU and DOX were loaded into scaffolds. The Gel and chitosan were modified
by crosslinking to form the imine bond, resulting in hydrolysis in an acidic
environment. These GC scaffolds would only respond to an acidic environment,
which as previously stated is a tumor or cancer environment, and release drugs into
the only cancer area.
256 A. Chinnakorn et al.
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– h-BMSCs Bone Zhang et al.
(2014)
– – Oral Shietal.
(2019)
– – Cancer Liu et al.
(2020)
Chen et al.
(2015)
Lung,
bone
H1299, HeLa,
U251
– hMSCs,
(2020b)
Breast Shietal.
NIH3T3,
HUVEC,
MDA-MB-
pH-responsive
performance
231
(2020)
4T1 Breast We i et al .
Photothermal effect
with sol-gel transition
(2021a)
4T1 Breast Liu et al.
Photothermal effect
with sol-gel transition
printer
DOX-HCL Extruder-based 3D
,
4
20
O
3
EO
70
PO
20
(Si/ca/P), Fe
EO
Platform Materials Drugs AM type 4D printing mechanisms Cells Tissue/organ Ref.
Scaffolds PCL, MBG
Tab le 7 .2 The summarization of 3D and 4D printing in drug delivery systems for chemotherapy
3D printer
FLU Drop-on-powder (DoP)
,vinyl
4
polymer,
copolymer
Scaffolds CaSO
Extruder-based 3D
printer
PEGylated liposomal
DOX
DOX, other siRNAs Extruder-based 3D
Carbohydrate
Scaffolds F-GelMA, CMC, DOX-HCL,
Scaffolds PCL, chitosan,
printer
acetic acid,
montmorillonite
clay, tricalcium
phosphate
(E-jet) 3D printing
DOX-HCL, FLU Electrohydrodynamic jet
chitosan,
Scaffolds PLGA, gel,
system
glutaraldehyde
DOX-HCL Extruder-based 3D
Scaffolds Gel, PDA, Alg,
printer using co-axis
core/shell nozzles
2
CaCl
DOX-HCL, DEX Extruder-based 3D
Scaffolds Gel, Alg, PCL,
printer
2
PDA, CaCl
7 4D Printing: The Next Dimension of Healthcare in Cancer Research 257
(continued)
(2021)
(2022)
al. (2018)
(2019)
(2021)
– Cancer Wang et al.
Magnetothermal
performance
Extruder-
based 3D
printer using
co-axis
core/shell
nozzles
DOX-HCL, BSA
protein
,
4
O
3
2
CaCl
MCF-7 Breast Hu et al.
Thermal-magnetic
performance
Extruder-
based printer
with pho-
tolithography
and
two-photon
Levofloxacin
(L830182)
8
Si
0.66
]
4
Li
), 1-
5.34
(OH)
0.66
20
nanoclay
([Mg
O
hydroxycyclohexyl
Na
SKBR3 Breast Bozuyuk et
Magnetic control and
light-trigger
performance
polymerization
direct laser
writing
(TDIW)
DOX Two-photon
,
4
O
3
LAP
phenyl ketone
SKBR3 Breast Ceylan et al.
Magnetic control and
enzyme-
Responsive
Performance
Two-photon
direct laser
writing
(TDIW)
Dextran-FITC,
ErbB 2 antibody
,
4
O
3
LAP
HeLa Cancer Xin et al.
Magnetic control and
pH-responsive
performance
direct laser
writing
(Fe-DIW)
DOX Femtosecond
,
4
O
3
DPEPA, EMK,
AAc, Fe
PEG-b-PAEMA
Scaffolds Alg, Fe
Millirobot PNIPAM, NdFeB,
Microrobot ChMA, Fe
Microrobot GelMA, Fe
Microrobot PNIPAM,
258 A. Chinnakorn et al.
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Han et al.
(2022)
(2018)
(2022)
cancer
L929, CT26 Colorectal
Photothermal
HeLa Cancer Xu et al.
Performance
Magnetic
fabrication
(FFF) printer
DOX-HCL 3D laser
Franz cells Tracheal Chen et al.
Performance
Magnetothermal
performance
lithography
based 3D
PTX Extruder-
,EVA
4
O
3
printer
negative
photoresist, Fe, Ti
copolymer,
1-hexadacanol
Tab le 7.2 (continued)
Platform Materials Drugs AM type 4D printing mechanisms Cells Tissue/organ Ref.
Microrobot PLA, Ti, SA, LA Nile red, Cyanine7 Fused filament
Microrobot Sperm cells, SU-8
Stent PCL, Fe
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