December 30, 2020

Archives • 2020 • vol.3 • 292-302

PROSPECTS OF 4D PRINTING IN PHARMACEUTICALS

Arpita Roy1 , Md. Sakhawat Hossain2, Aditi Bhowmick3 Nisarat Nizhum4, Shadhan Kumar
Mondal 4, Tushar Saha 4*
1
Department of Pharmaceutical Technology, University of Dhaka, Bangladesh
2
Department of Pharmacy, Daffodil International University, Dhaka-1207, Bangladesh.
3
Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh.
4
Department of Pharmacy, World University of Bangladesh, Dhaka, Bangladesh.

tushar.saha21@yahoo.com

Abstract

4D printing is a fledgling technology with enormous potential that may bring revolution to the future
manufacturing industry along with pharmaceuticals. MIT’s Self Assembly Lab and Stratasys education
and R&D department first developed this concept jointly in 2013. 3D printing has already proved its
competence and achieved wide acceptance after being invented in 1984. 4D printing is an up-gradation
of 3D printing technology. 4D printing adopts time as the 4th dimension. It allows the fabrication of
stimuli-responsive 3D structures that can independently change its morphology over time. External
stimuli such as light, pH, magnetic field, moisture content, etc. can trigger the shape-changing event.
4D printing technology can be applied to develop site-specific, controlled release as well as a
customized drug delivery system. Researchers are also optimistic about its application in the
biomedical sector. This paper presents a comprehensive review of the basic mechanism of 4D printing
technology and its possible future application and prospects in the pharmaceuticals and biomedical
fields.

Keywords: 4D printing, stimuli, pharmaceutical, biomedical.

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materials, digital design software, and the 3D

Introduction printer.
4D printing technology is an up to the minute On the other hand, 4D printing technology relies on
concept, which will substantially influence the appropriately combining ‘smart materials’ in three-
modern manufacturing industries. It is an up- dimensional space according to a very sophisticated
gradation of the novel 3D printing technology. 3D mathematical model [8]. The end product possesses
printing, one of the revolutionary advancements of a dynamic conformation with adjustable shape,
the 20th century, has allowed us to fabricate objects property, and functionality. Both 3D and 4D printing
in three dimensions according to a digital model. technology are an additive manufacturing process
The idea of 4D printing embraces time as a fourth which results in the formation of a new product. The
dimension and allows the printed structure to only difference is ‘time’, which is an extra dimension
change its structural morphology upon any external in the case of 4D printing.
stimuli [1]. Advantages of 4D printing technology [6]:
The idea of printing objects considering four 1. 4D printing allows the fabrication of
dimensions was first conceptualized by a research programmed products with self-actuation
group of MIT [2]. 4D printing deals with structural as and sensing property.
well as functional development of 3D printed 2. It allows the manufacturing of smart
objects. So, 4D printing is the incorporation of time products that do not rely on external
as a fourth dimension in the 3D printing technology. devices or any electromechanical system for
[3]. activation.
4D printing technology allows fabrication of 3. Requires the use of minimum components
structures that are not static and fixed rather for developing a product or system.
capable of altering their shape, property, and 4. Requires the least time for post-fabrication
functionality with time [4].4D printed objects have assembly.
some brilliant features which include self-assembly, 5. Cost-efficient and time-efficient.
self-repair, and capability of multitasking. Moreover, 6. Reduces the number of error-prone
time dependency and printer independence made products.
the technology more rational. 7. High productivity and sensitivity.
Programmable activity and intellectual sensitivity Building Blocks for 4D printed products
allow 4D printed materials to respond against Stimulus Responsive Smart Materials. Stimulus
stimuli like heat, pH, light, magnetic field, etc. [5]. responsive smart materials are the most critical
The foundation of this new technology relies on component of 4D printing technology. External
three pillars- smart material, smart machine, and the stimuli such as water, pH, light irradiation, magnetic
geometric ‘program’ [6]. field, etc. are supposed to act as a driving force of
3D printing has already proved its intelligence in distortion of these responsive materials. These are
various engineering and biomedical fields. Although the feedstock of 4D printing technology.
4D printing is now in its infancy, it has the potential Hydrogels. Hydrogels are mostly used smart
of changing the face of the future manufacturing materials in 4D printing. Several types of hydrogels
industry. The application of 4D printing may open like peptide hydrogels, natural polymeric hydrogels,
the way for personalized ‘smart’ formulation of 4D and synthetic polymeric hydrogels with their
printing may open the way for personalized ‘smart’ responsive properties can be applied in formulating
formulation. 4D products for biomedical purposes [9].
Basic of 4D Printing Technology Hydrogels have some brilliant characteristics that
United States Government Accountability Office make them one of the most important candidates
(GAO) defines 3D printing as a procedure that for 4D printing materials. For example,
produces a 3D object according to a digital model in 1. Hydrogels are a network of polymeric chains
a layer-by-layer fabrication manner [7]. 3D printing that are hydrophilic in nature. Diffusion of
requires mainly three building blocks: Raw water into the scaffold of hydrogel results in
specific and localized swelling. As a result,

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the morphology of the structure is distorted can solve this issue by fabricating stents in a time
in a predicted manner [1]. and cost-efficient manner.
2. Viscous matrix and high water content of Again, shape memory alloy, for example, ‘Nitinol’
soft hydrogels make them able to respond that is an alloy of nickel and titanium has potential
against external stimuli like temperature, applications in the biomechanical sector. Having a
light, pH, etc. [10]. corrosion resistance similar to stainless steel it can
3. Interconnectivity and porosity of the be used in manufacturing stents for veins [24].
polymeric network allow controlled Smart Model. The success of 4D printing technology
permeation of gas and nutrition to cells in depends on appropriate mathematical modeling
the case of 4D bioprinting [11]. [25]. The necessity of a mathematical model in 4D
4. Hydrogels also exhibit unique self-healing printing:
properties [12, 13].  To predict the shape evolution of the final
5. Self-assembly is also observed in stimuli- product.
responsive hydrogels [14].  To smoothen self-assembly function
The researchers of MIT has printed a linear product  To manipulate the design of the structure
by combining rigid waterproof material and and orientation of the smart materials.
hydrogel. Hydrogels were placed at the hinges of  To customize the deposition of materials
the structure. The structure when immersed in and their anisotropic behaviour.
water, contorted to create a 3D structure. Water  To reduce the number of trial and error
absorption into the hinge Shape Memory experiments.
Polymers. Shape memory polymers (SMPs) or alloys Problems associated with 4D printing mathematics
are thermo-responsive materials that can transform can be divided into two categories [25]:
into different shapes at various temperatures. Upon Forward problem: to determine the final desired
exposure to an external stimulus, they can hold on a shape of the final product when material structures,
temporary structure and are capable of recovering material properties, and stimulus properties are
their permanent shape when they return to the given.
original environment [1]. Inverse problem: To determine the structure of the
An interaction mechanism is generally required to materials/print paths/nozzle sizes when the desired
make shape-memory polymers appropriate to use in shape of the final product, materials properties, and
4D technology. For instance, constrained-thermos- stimulus properties are given.
mechanics is one of the most used interaction
mechanisms. In this mechanism, at first, an external Several mathematical models developed by
load at a high temperature deforms the shape researchers like [26, 27, 28, 29, 30] can be applied in
memory material. Next, the temperature is lowered 4D printing technology.
but the external load remains the same. Then, the Along with the sophisticated mathematical model,
external load is removed at the low temperature an appropriate theoretical model is also important
and the desired shape of the material is achieved. for 4D printing technology. The theoretical model
This desired shape is actually a temporary should include information about four major
morphology of the polymer. This is because; the components [3]:
original shape can be recovered after heating the 1. The desired shape of the final product
material again. Thus shape memory effect is including bending angle, twisting angle,
achieved which can be used in 4D technology [3]. length, the volume of the structure.
SMPs have already been used to make stents for 2. Material structure including filament size,
cardiovascular patients, which can change its shape orientation, interfilamentous spacing,
in response to changing temperature. Because of its anisotropy.
sophisticated geometrical structure, it is very time 3. Material properties including shear modulus,
consuming and expensive to manufacture stents by Young`s modulus, glass transition
conventional manufacturing methods. 4D printing temperature, and swelling ratio, etc.

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system and 4D printing has the capability to offer

4. Stimulus properties such as temperature that novelty.
value and light intensity. pH guided drug delivery system. Using smart
By applying the theoretical model and some materials that respond specifically to pH change, it is
mathematical computation, the desired shape of possible to fabricate 4D printed pH guided
the final product can be predicted more accurately controlled release drug delivery system. He et al.
and quickly for a given material structure, material designed a mucoadhesive drug delivery device using
properties, and stimulus properties. pH-sensitive hydrogel that contorts its shape when
Printing machine reaches to the small intestine (pH 6.5) and grip on to
Initially, researchers used a 3D printing facility to the gut wall. This self-folding device demonstrated
create 4D printed structure. longer residence time, minimum drug exposure to
Stratasy’s Connex multi-material printer allows intestinal fluid and increased drug absorption
printing of static as well as dynamic structures using through the mucosal epithelium [33].
smart materials. It can work with a variety of Self-deformation property of 4D printed products
materials ranging from rigid to a soft plastic or can be utilized for biomedical applications also. For
transparent materials. It has high-resolution control instance, 4D printed microcapsules can be
over dot deposition. Again, it can be used to developed to treat the gastric ulcerous condition
fabricate Digital Materials (DMs) that hold distinct that will deform itself upon exposure to gastric acid
combinations of both components in different and thus will cover the wound and prevent further
proportions and spatial arrangements [6]. damage [34].
However, researchers faced some problems while Magnetically activated drug delivery
constructing a 4D structure using smart materials in system. Magneto-restrictive materials that are
a 3D printing machine. Feedstocks can get stimulated by an external magnetic field can be used
agglomerated and cause clogging of the nozzle. As to fabricate a 4D printed device, which may aid in
a result, productivity could significantly be targeted drug delivery ensuring the least side effect
hampered. To solve this issue, many research and optimal dosing.
groups have developed specific 4D printers. For For example, Li et al. developed a micro-robot by a
example, Choi has introduced a smart printer with a conventional lithographic technique that has a
significantly longer nozzle, coated with hydrogel bilayer. One of the layers exhibited pH-
polytetrafluoroethylene to reduce friction. This responsive properties and aided in drug release by
machine can be used to print smart materials like changing its morphology upon exposure to specific
thermal polyurethane (TPU) [31]. pH [18]. On the other hand, another layer with iron
Again, Ge Q has developed another specific 4D oxide particles in it enabled the device to be guided
printer, which is an upgraded version of micro SLA magnetically and ensured site-specific drug delivery.
printer, capable of creating structure up to 1µm This particular finding can be utilized in the targeted
resolution [32]. delivery of anti-cancer drugs. Tumor tissue
Opportunities of 4D printing in pharmaceutics and microenvironment, low oxygen partial pressure, and
healthcare specific pH of tumor tissue can act as stimuli for
Although the 4D printing concept is at its infancy, it drug release [35, 36].
has a huge potential for future manufacturing Such a device can maximize the therapeutic efficacy
revolution. However, there is still much research of drugs whilst minimizing the associated side
required to proceed from proof-of-concept to real- effects. However, this device needs more advanced
life applications. 4D printing is a promising research before clinical application.
technology that may add a new dimension in the Micro-grippers. Micro-grippers are microsystem
field of personalized medication manufacturing as devices developed by researchers using smart
well as site-specific drug delivery. It may take micro- feedstock materials. Based on actuation stimuli like
robotics and bio printing to the next level and make thermal, electrostatic, electromagnetic, or
our health care system smarter. Scientists over the piezoelectric there can be several types of micro-
world are concerned about novel drug delivery grippers. This 4D printed micro-device can be used

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for localized cell probing, measurement as well as 4D bioprinting. 4D printing allows the formation of
site-specific drug delivery. products with self-assembly and self-healing
Thera-grippers are a kind of micro-grippers that are properties which makes it an important emerging
responsive to temperature change. It is a multi- technology in the biomedical field. Hydrogels are
tipped drug delivery device, which grips onto tissue preferred for 4D bioprinting and been used to
when exposed to a temperature above 32°C. The create a scaffold-free bio-printed structure. It is now
porous layer of thera-gripper then allows sustained possible to print nature mimicking cell-based
release of the drug following first-order kinetics for structures without any scaffold, mold support, or
up to 7 days. For example, in vitro study of liquid delivery medium by 4D printing technology
doxorubicin thera-grippers exhibited an enhanced [1].
sustained-release property than control [37]. A study has displayed the deposition of
Magnetically responsive smart materials can be chondrocytes inside a hydrogel cylinder. The latticed
used to fabricate micro-grippers that can be guided tissue strand exhibited post-printing maturation and
by an external magnetic field. Incorporation of iron created a patch containing viable tissue, which
oxide nanoparticles onto a porous hydrogel layer could be used for implantation [41]. The
makes them able to respond against magnetic proliferating nature of the depositing cells makes
stimuli [20]. Such micro-grippers has potential them able to act as smart feedstock material for
application in surgical invasions. Researchers have bioprinting.
already proved its capability by excising cells from a Researchers have already developed tissues that
fibroblast cell clump. demonstrate muscle-like movements by using ion
Encapsulation devices. 4D printing offers a responsive smart hydrogels. Muscle contraction was
formulation of a product that has self-folding or noticed in such tissues upon the influx of Ca2+ ion
unfolding capacity. This unique feature can be like natural muscles [41].
utilized to create encapsulation devices for Tissue engineering using 4D printing technology is
controlled drug delivery. showing signs of future success in the field of
For example, researchers have printed a multi some, vascular treatment. Artificial vascularization can be
consisting of a mixture of DOPE and oleic acid, achieved by using this technology. For example,
which encapsulated a droplet containing Ca2+ and researchers have embedded multiple cell types (like
dextran-conjugated-fluo-4. Upon exposure to a fibroblasts, ECs, MSCs, etc) in a hydrogel matrix and
certain pH, the multi some released its inner content thus printed a cylinder-shaped structure in a layer-
and the signal was measured by fluorescence by-layer manner [42, 43]. This cylindrical structure
microscope [38]. resembles natural blood vessels. Upon activation of
Such a multi-compartmental structure can also be the maturation factors, vascular cells can get
programmed to fold/unfold their complex matured and form an integral vascular structure.
framework upon a change in osmolarity gradients, 4D printing can also be used to fabricate artificial
temperature, ionic environment, etc. Furthermore, hard tissues e.g. bone graft. Scientists have printed
surface modification of multisomes can be done by a grid-patterned polymeric bone graft and coated it
attaching membrane proteins with them. This may with human nasal inferior turbinate tissue-derived
allow rapid electrical communication between MSCs to facilitate graft mineralization. The printed
multisomes [39]. Again, such functionalization may bone graft exhibited post-printing maturation after
enhance the circulatory time of multisomes, cell a short culture period. In vitro as well as in vivo
tracking property as well as targeted drug delivery. investigation demonstrated improved
Not only pharmaceutical ingredients but also living osteoconductive and osteoinductive property of the
cells can be enclosed within a 4D printed structure. graft. However, the mechanical strength of the
For example, researchers have encapsulated synthetic graft was less than the natural bones.
fibroblast and pancreatic beta-cell onto such Therefore, this creation requires more improvisation
structure, and cells were reported to display viability before a real-life application [44].
even after 7 days of encapsulation [40]. 4D bioprinting can be used to prepare mini tissues,
which integrate and develop onto larger tissue over

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time. Shortly, this technology may be promoted to a 4. Tibbits S. 2014. 4D printing: multi‐material
level, where it would be possible to print mature shape change. Architectural Design, 84 (1):
tissue and complex organs like physiological organs 116-121.
[45]. 5. Das AK, Jadhav RG (2017) Four dimensional
printing in healthcare. 3D Printing in
Conclusion Medicine, 207-218.
4D printing is a novel concept, which allows the 6. Tibbits S, McKnelly C, Olguin C, Dikovsky D,
advancement of 3D printing technology to Hirsch S (2014) 4D Printing and universal
formulate smart time-dependent products. This transformation. Acadia, 539-548.
concept aims to produce products with features like 7. Norman J, Madurawe RD, Moore CM, Khan
self-assembly, self-repair, and multi-functionality. It MA, Khairuzzaman A (2017) A new chapter in
has greater potential applications in the field of pharmaceutical manufacturing: 3D-printed
pharmaceutical and biomedical sectors. It is possible drug products. Advanced drug delivery
to fabricate customized smart pharmaceutical reviews, 108: 39-50.
formulation using this technology. However, it is still 8. Gladman AS, Matsumoto EA, Nuzzo RG,
in its dawning phase and requires more research Mahadevan L, Lewis JA (2016) Biomimetic
regarding software, mathematical modeling, 4D printing. Nature materials, 15 (4): 413-418.
mechanical and chemical issues. A few numbers of 9. Kopeček J, Yang J (2012) Smart
self-assembling and multi-responsive materials have self‐assembled hybrid hydrogel biomaterials.
been investigated for 4D printing technology. More Angewandte Chemie International Edition,
extensive research should be done to enlist raw 51 (30): 7396-7417.
materials that meet the requirements to be 10. Peppasa NA, Buresa P, Leobandunga W,
feedstock of 4D printing technology. Ichikawab H (2000) Hydrogels in
Biodegradability and biocompatibility of the printed pharmaceutical formulations. European
product as well as in vivo microenvironment should Journal of Pharmaceutics and
be considered in case of biomedical use. Biopharmaceutics, 50 (1): 27-46.
Researchers are working hard to make 4D printed 11. Koetting, MC, Peters JT, Steichen SD,
biomedical products to be clinically applicable. We Peppas NA (2015) Stimulus-responsive
can certainly expect that 4D printing will bring hydrogels: Theory modern advances and
revolution to the manufacturing industry and will applications. Materials Science and
open a plethora of unexplored dimensions that will Engineering: R: Reports, 93: 1-49.
make our future smarter. 12. Biswas S, Dnyaneshwar B, Apurba KD (2016)
Blue light emitting self-healable graphene
References quantum dot embedded hydrogels. RSC
1. Firth J, Gaisford S, Basit AW (2018) A New Advances, 6: 54793-54800.
Dimension: 4D Printing Opportunities 13. Highley CB, Rodell CB, Burdick JA (2015)
in Pharmaceutics. In: Basit AW, Gaisford (ed) Direct 3D printing of shear‐thinning
3D Printing of Pharmaceuticals, Springer hydrogels into self‐healing hydrogels.
Cham, Switzerland. Advanced Materials, 27 (34): 5075-5079.
2. Zhang Z, Demir KG, Gu GX (2019) 14. Apurba KD, Maity I, Parmar HS, McDonald
Developments in 4D-printing: a review on TO, Konda M (2015) Lipase-Catalyzed
current smart materials, technologies, and Dissipative Self-Assembly of a Thixotropic
applications. International Journal of Smart Peptide Bolaamphiphile Hydrogel for Human
and Nano Materials, 10(3): 205-224. Umbilical Cord Stem-Cell Proliferation.
3. Momeni F, Hassani SMM, Liu NX, Ni J (2017) Biomacromolecules, 16 (4): 1157-1168.
A review of 4D printing Materials & Design, 15. Li G, Yan Q, Xia H, Zhao Y (2015) Therapeutic-
122: 42-79. doi::10.1016/j.matdes.2017.02.068. ultrasound-triggered shape memory of a
melamine-enhanced poly vinyl alcohol

http://pharmacologyonline.silae.it
ISSN: 1827-8620
 PhOL Roy, et al. 298 (pag 292-302)

physical hydrogel. ACS applied materials & 25. Gladman AS, Matsumoto EA, Nuzzo RG,
interfaces, 7 (22): 12067-12073. Mahadevan L, Lewis JA (2016) Biomimetic
16. Li YK, Guo CG, Wang L, Xu Y, Liu CY, Wang 4D printing. Nature materials, 15 (4): 413-418.
CQ (2014) A self-healing and multi- 26. Raviv D, Zhao W, McKnelly C, Papadopoulou
responsive hydrogel based on A, Kadambi A, Shi B, Raskar R (2014) Active
biodegradable ferrocene-modified chitosan. printed materials for complex self-evolving
RSC advances, 4 (98): 55133-55138. deformations. Scientific reports, 7422.
17. Yao C, Liu Z, Yang C, Wang W, Ju XJ, Xie R, 27. Sun L, Huang WM, Ding Z, Zhao Y, Wang CC,
Chu LY (2016) Smart hydrogels with Purnawali H, Tang C (2012) Stimulus-
inhomogeneous structures assembled using responsive shape memory materials: a
nanoclay-cross-linked hydrogel subunits as review. Materials & Design, 33: 577-640.
building blocks. ACS applied materials & 28. Yu K, Xie T, Leng J, Ding Y, Qi HJ (2012)
interfaces, 8 (33): 21721-21730. Mechanisms of multi-shape memory effects
18. Li H, Go G, Ko SY, Park JO, Park S (2016) and associated energy release in shape
Magnetic actuated pH-responsive hydrogel- memory polymers. Soft Matter, 8 (20): 5687-
based soft micro-robot for targeted drug 5695.
delivery. Smart Materials and Structures, 25 29. Sun L, Huang WM (2010) Mechanisms of the
(2): 027001. multi-shape memory effect and temperature
19. Naficy S, Gately R, Gorkin III R, Xin H, Spinks memory effect in shape memory polymers.
GM (2017) 4D printing of reversible shape Soft Matter, 6 (18): 4403-4406.
morphing hydrogel structures 30. Tobushi H, Hashimoto T, Hayashi S &
Macromolecular Materials and Engineering, Yamada E (1997) Thermomechanical
302 (1): 1600212. constitutive modeling in shape memory
20. Breger JC, Yoon C, Xiao R, Kwag HR, Wang polymer of polyurethane series. Journal of
MO, Fisher JP, Gracias DH (2015) Self-folding intelligent material systems and structures,
thermo-magnetically responsive soft 8 (8): 711-718.
microgrippers ACS applied materials & 31. Choi J, Kwon OC, Jo W, Lee HJ, Moon MW
interfaces, 7 (5): 3398-3405. (2015) 4D printing technology A review. 3D
21. Gargava A, Arya C, Raghavan SR (2016) Printing and Additive Manufacturing, 2 (4):
Smart hydrogel-based valves inspired by the 159-167.
stomata in plants ACS. applied materials & 32. Ge Q, Sakhaei AH, Lee H, Dunn CK, Fang NX,
interfaces, 8 (28): 18430-18438. Dunn ML (2016) Multimaterial 4D printing
22. Ren Z, Zhang Y, Li Y, Xu B, Liu W (2015) with tailorable shape memory polymers.
Hydrogen bonded and ionically crosslinked Scientific reports, 6: 31110.
high strength hydrogels exhibiting Ca 2+- 33. He H, Guan J, Lee JL (2006) An oral delivery
triggered shape memory properties and device based on self-folding hydrogels.
volume shrinkage for cell detachment. Journal of Controlled Release, 110 (2): 339-
Journal of Materials Chemistry B, 3 (30): 346.
6347-6354. 34. Gao B, Yang Q, Zhao X, Jin G, Ma Y, Xu F
23. Ter SJ, Coleman S, Stumpel JE, Azouz AB, (2016) 4D bioprinting for biomedical
Diamond D, Schenning AP (2015) Molecular applications. Trends in biotechnology, 34
design of light-responsive hydrogels for in (9): 746-756.
situ generation of fast and reversible valves 35. Manchun S, Dass CR, Sriamornsak P (2012)
for microfluidic applications. Chemistry of Targeted therapy for cancer using pH-
Materials, 27 (17): 5925-5931. responsive nanocarrier systems. Life
24. Kamila, Susmita (2013) Introduction, sciences, 90 (11-12): 381-387.
Classification and Applications of Smart 36. Tong Z, Luo W, Wang Y, Yang F, Han Y, Li H,
Materials: An Overview. American Journal of Tan H (2010) Tumor tissue-derived
Applied Sciences, 10 (8): 876-880. formaldehyde and acidic microenvironment

http://pharmacologyonline.silae.it
ISSN: 1827-8620
 PhOL Roy, et al. 299 (pag 292-302)

synergistically induce bone cancer pain. PloS 44. Pati F, Song TH, Rijal G, Jang J, Kim SW, Cho
one, 5 (4): e10234. DW (2015) Ornamenting 3D printed scaffolds
37. Malachowski K, Breger J, Kwag HR, Wang with cell-laid extracellular matrix for bone
MO, Fisher JP, Selaru FM, Gracias DH (2014) tissue regeneration Biomaterials, 37: 230-
Stimuli‐responsive theragrippers for 241.
chemomechanical controlled release 45. Mironov V, Visconti RP, Kasyanov V, Forgacs
Angewandte Chemie International Edition, G, Drake CJ, Markwald RR (2009) Organ
53 (31): 8045-8049. printing: tissue spheroids as building blocks
38. Villar G, Heron AJ, Bayley H. (2011) Formation Biomaterials, 30 (12): 2164-2174.
of droplet networks that function in
aqueous environments. Nature
nanotechnology, 6 (12): 803-808.
39. Villar G, Graham AD, Bayley H (2013) A tissue-
like printed material. Science 340 (6128): 48-
52.
40. Azam A, Laflin KE, Jamal M, Fernandes R,
Gracias DH (2011) Self-folding
micropatterned polymeric containers
Biomedical microdevices, 13 (1): 51-58.
41. Yu Y, Moncal KK, Li J, Peng W, Rivero I,
Martin JA, Ozbolat IT (2016) Three-
dimensional bioprinting using self-
assembling scalable scaffold-free tissue
strands as a new bioink Scientific reports, 6:
28714.
42. Norotte C, Marga FS, Niklason LE, Forgacs G
(2009) Scaffold-free vascular tissue
engineering using bioprinting Biomaterials,
30 (30): 5910-5917.
43. Hong S, Song SJ, Lee JY, Jang H, Choi J, Sun
K, Park Y (2013) Cellular behavior in
micropatterned hydrogels by bioprinting
system depended on the cell types and
cellular interaction Journal of bioscience and
bioengineering, 116 (2): 224-230.

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Table 1: List of potential stimuli responsive hydrogels.

Composition of Hydrogels Stimuli Observation Possibility Reference

Melamine and poly(vinyl Ultrasound Change in shape Useful for therapeutic and [15]
alcohol) diagnostic purpose
Ferrocene-modified chitosan pH Change in Useful for controlled [16]
hydrogel physical phase release dosage form
Poly(N-isopropylacrylamide- Temperature Change in shape Useful for soft robotics [17]
co-acrylamide) and nanoclay
Hydroxyethyl methacrylate pH, magnetic Exhibit self- Useful for controlled [18]
and poly (ethylene glycol) field folding property release dosage form
acrylate with Fe3O4
N, N′-methylenebisacrylamide, Temperature Change in shape [19]
N-isopropylacrylamide and
polyether-based polyurethane
Poly(N-isopropylacrylamide- Temperature, Change in shape Useful for site specific [20]
co-acrylic acid), polypropylene magnetic field drug delivery
fumarate, PPF), and Fe2O3
nanoparticles
N-isopropylacrylamide and Temperature Change in gel Useful for bioprinting [21]
N,N-dimethylacrylamide structure
Ionic dimethylacrylamide and pH Change in gel Useful for bioprinting [21]
dimethylacrylamide structure
2-vinyl-4,6-diamino-1,3,5- Change in Ion Change in gel Useful for nondestructive [22]
triazine, acrylic acid, concentration volume cell harvesting
polyethylene glycol diacrylate
Acrylamide +Irgacure 819, Light Change in gel [23]
spiropyran and lightresponsive structure
poly(N-isopropylacrylamide)

Table 2: Other promising smart materials for 4D printing technology [24].

Material type External stimuli Output Application

Piezoelectric material Stress, electric field Electric charge, Optical tracking device, dot matrix
mechanical strain printer.
Magneto-restrictive Magnetic field Mechanical strain Site specific drug delivery
material
pH-sensitive material Change in H+ conc. Change in color and Diagnostic purpose, controlled
structure release dosage form
Electrochromic Voltage change Change in color Diagnostic purpose
material and opacity
Photochromic material Change in light Change in color Diagnostic purpose
Optical fiber Temperature, Change in opto- Diagnostic purpose, useful as
pressure, mechanical electronic signal sensor
strain

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Fig. 1: Basic mechanism of 3D printing.

Fig. 2: Basic mechanism of 4D printing.

Fig. 3: One way and two way shape memory effect.

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Fig. 4: Mathematical model of 4D printing.

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