Materials and Design 194 (2020) 108940

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Materials and Design

journal homepage: www.elsevier.com/locate/matdes

The role of three-dimensional printing in healthcare and medicine

Saeideh Kholgh Eshkalak a,⁎, Erfan Rezvani Ghomi a, Yunqian Dai b,⁎,
Deepak Choudhury c, Seeram Ramakrishna a
a
Department of Mechanical Engineering, Center for Nanofibers and Nanotechnology, National University of Singapore, 119260, Singapore
b
School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 211189, PR China
c
Bio-Manufacturing Technology, Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, 138668, Singapore

H I G H L I G H T S G R A P H I C A L A B S T R A C T

• The contributions of Three-dimensional

Printing in Healthcare and Medicine.
• A comprehensive review of technolo-
gies types used in 3D printing.
• Discussing the foremost applications
and approaches to Bio-materials-based
Additive Manufacturing technology.
• Addressing the advantages of three-
dimensional printing in relation to med-
ical implants.

a r t i c l e i n f o a b s t r a c t

Article history: Different three-dimensional (3D) printing techniques are being increasingly used to produce medical apparatus
Received 29 March 2020 due to their ability to print intended designs with high dimensional accuracy. Indeed, the major credit for the
Received in revised form 23 June 2020 broad use of 3D printing techniques in medical fields stems from the ability of this method to prepare patient-
Accepted 3 July 2020
matched devices due to the conventional manufacturing methods limitations such as economically inefficiency
Available online 10 July 2020
and multiple steps processing for complex geometries. This review manuscript aims to present brief insights of
Keywords:
various 3D printing concepts and technologies used in the medical field. Biomaterials and bioprinting are
Three-dimensional (3D) printing pinpointed. Finally, the pharmaceutical potentials of 3D printing are discussed.
Additive manufacturing (AM) © 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
Bioprinting creativecommons.org/licenses/by/4.0/).
Healthcare

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Biomaterials in 3D printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. 3D printing/additive manufacturing (AM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

⁎ Corresponding authors.
E-mail addresses: [email protected] (S. Kholgh Eshkalak), [email protected] (Y. Dai).

https://doi.org/10.1016/j.matdes.2020.108940
0264-1275/© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
2 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940

3.1. AM - a disruptive technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

4. 3D printing technologies in healthcare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4.1. Fused deposition modeling (FDM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4.2. Inkjet printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4.3. Stereolithography (SLA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.4. Powder bed fusion (PBF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.5. Digital light processing (DLP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.6. Multiphoton polymerization (MPP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.7. 3D slurry printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.8. Core-shell printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4.9. Four-dimensional printing (4D printing) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5. 3D bioprinting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1. Bioinks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2. Ideal material characteristics for bioprinting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
6. Implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
6.1. Advantages of 3D printing in relation to medical implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
7. Pharmaceutical potentials of 3D printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
8. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

1. Introduction modeling software. Reverse engineering and 3D scanning of an avail-

able part can be also used in some cases. The second step is to create
Three-dimensional printing (3D printing) includes a set of processes an STL model file. The model has to be converted to a format that can
that link controlled materials together to build a 3D object. This process be readable to the printer. To this end, the file needs to be converted
is typically performed layer by layer [1]. In another definition, 3D print- to STL. The 3D printing and OBJ formats are less popular in comparison
ing refers to any process by which 3D objects are formed when layers to other formats. STL format uses polygons or triangles to introduce a
are fused in a row in a two-dimensional cross-section. This process is model to the printer. The STL file is imported to a program that slices
much similar to an event during which ink spraying on paper is per- file layers and is called slicer [8]. The slicer receives the model and con-
formed in other types of printing as we know it, except that this hap- verts it to a G-code that contains instructions for CNC machines and 3D
pens in 3D printing by crystallizing, solidifying, or joining a liquid printers. The third step is related to model printing. There are a variety
material or powder at any point in the contact of the object that we of machines that each utilizes a different mechanism to print a model
want to print it. The presence of a computer is a necessity in this process, piece. Regarding step four which is about removing the printed parts,
because it relies on “computer-aided design” (CAD) [2–4]. it should be noted that in some devices, removing parts is fairly simple
The early technology of 3D printing was observed in 1980. Dr. and without any problem. However, in more industrialized models, this
Kodama from Japan [5] invented this technology in his name for the process is quite technical and precise. The final step, step five is post-
first time. During this time, this technology was called rapid prototyping processing which varies in different technologies. In some cases, a part
(RP). This title was given because the technology was designed for rapid has to be processed by UV rays [9,10]. Fig. 1 summarizes the aforemen-
and frugal construction of a prototype for mass production. Following tioned common stages of the process of 3D printing.
this, Chuck Hull patented the invention of stereolithography (SLT) de- The term ‘additive manufacturing’ (AM), generally called 3D print-
vice in his name in 1986. Needless to say, Hull invented his device in ing, is described by ISO/ASTM standards as the process of materials
1983, and in the meantime he was busy establishing 3D Systems Com- connecting for creating parts from 3D model data, often layer upon
pany which was then known as RP Systems and is now one of the largest layer, as contrary to formative manufacturing and subtractive
enterprises in the field of 3D printing, where he built the early prototype manufacturing methods [11,12]. The common ground between all
of this device under the name of SLA-1 and introduced it in 1987, which methods of 3D printing, referred to as AM, is their sequential or step-
underwent its first successful test in 1988. At the same time, Carl by-step processing. Unlike casting or forging that requires a single-
Deckard who was studying at the University of Texas performed the step or solidifying process, or what is obtained from a cubic mass in
process of RP with selective laser sintering (SLS) in his name in 1987. shear sheet metal or machining—which follows a subtractive process,
The patent for this invention was issued in 1989, and was then awarded creation based on 3D printing methods have significant advantages
to DTM Inc., and was later on purchased by 3D Systems. In the same and disadvantages over previous conventional methods. Table 1 sum-
year, 1989, Scott Crump, a co-founder of Stratasys Inc., announced the marizes some advantages and drawbacks of AM in comparison to tradi-
patenting of his melting layer modeling machine and assigned it to the tional methods.
company. so, the technology as a RepRap open-source model is very
functional. The term “3D printing” was initially dedicated to a specified 2. Biomaterials in 3D printing
process patented by scholars at the University of MIT in 1993, and its li-
cense was then granted under contract to many manufacturers. Today, Biomaterials refer to natural or synthetic materials interacting bio-
this term is used as a general title for plenty of related processes [6,7]. logically with human liquids and are utilized to prepare products for re-
The matters discussed above are part of the most important activi- placing any organ or compensating injured tissues in the body in a
ties in the history of 3D printing, which helped this technology reach secure and physiologically approved way [17]. Biomaterials could effec-
its current point. Apart from what has been discussed above, there are tively address many health-related problems by using new materials
other events in this field such as an early desktop printer, an early [18]. Thay are applicable in controlled drug delivery systems as well as
cheap printer, etc. Although there are various methods for 3D printing, engineering and culturing both soft and hard tissues [19] and organs
their main stages are common The first step in 3D printing is to create [20] . Moreover, biomaterials can enable clinicians in custimization of
a 3D model for it on a computer. This is carried out with a 3D or CAD the products for individuals via 3D printing [21].
 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940 3

Fig. 1. Schematic of common stages in 3D printed format.

superior mechachanical properties along with great wettability, wear-

Table 1
resistance, and biocompatibility. In contradiction to most of the metals,
Some advantages and drawbacks of AM vs traditional methods.
ceramics are stable at high temperatures [18]. The advantages of poly-
Advantages Drawbacks Ref. meric biomaterials are acceptable mechanical properties, stability, and
No need for expensive equipment The possibility of producing in low [13] elacticity. Polymers have been widely used in different biomedical ap-
used in metal smelting plants and number and speed plications such as prosthetics, implants, controlled drug delivery and
for milling process
so on [22].
The ability to build parts with The lower strength, accuracy, and [14]
complicated and customized gloss of the surface
unconventional structure in a
short time
The less waste production and The relatively limited materials that [15]
process of eco-friendly can be processed and constitute the
3. 3D printing/additive manufacturing (AM)
type of output products
Cost-effective for manufacturing of The high limitation on structural [16]
low volume and small batch dimensions It should be noted that there are various subtypes of AM such as
three-dimensional printing, direct digital manufacturing (DDM), and
RP. The term “subtractive manufacturing” (SM) points out traditional
manufacturing approaches like machining, casting, molding, and
Based on the chemical nature of the biomaterials, they are catego- forming. These approaches commonly are equivalent to complicated
rized into four different types including metals, ceramics, polymers, processes, which need machinery, tooling, robots, and computers, etc.
and composites, as presented in Table 2. Due to excellent mechanical for developing 3D parts. AM significant decreases or totally escapes
properties of metallic biomaterials, they are mostly used in dentistry the use of tools, allowing full customization designs by just modification
or orthopedic applications [20]. In addition to the crucial role of metallic of the 3D model in the software, which causes a reduction of the cost in
biomaterials in reconstructive surgery, they are also used in non- the prototyping stage.
osseous tissues recently. Moreover, ceramic biomaterials can afford

Table 2
Biomaterials classification with their advantages, disadvantages, and applications [23].

Type Advantages Disadvantages Applications Ref.

Metals and metal alloys ⁎ High material ⁎ Corrosive ⁎ Orthopedic implants, [24,25]
strength screws, pins, and plates
E.g.,: gold, platinum, titanium, steel, chromium, cobalt ⁎ Easy to fabricate and ⁎ Aseptic loosening
sterilize ⁎ Excessive elastic
modulus
Ceramics and carbon compounds ⁎ High material ⁎ Difficult to mold ⁎ Bioactive orthopedic [26,27]
strength implants
E.g.,: calcium phosphate salts (HA), glass, oxides of aluminum and titanium ⁎ Biocompatibility ⁎ Excessive elastic Dental Implants
⁎ Corrosion resistance modulus ⁎ Artificial hearing aids
Polymers ⁎ Biodegradable ⁎ Leachable in body ⁎ Orthopedic and dental [28–30]
fluids implants
⁎ Biocompatible ⁎ Tissue engineering
scaffolds
⁎ Easily moldable and ⁎ Hard to sterilize ⁎ Drug delivery systems
readily available
E.g.,: PMMA, Polycaprolactone(PCL), PLA, polycarbonates, polyurethanes ⁎ Suitable mechanical ⁎ Prostheses
strength
Composites ⁎ Excellent mechanical ⁎ Expensive ⁎ Porous orthopedic implants [31,32]
properties
E.g.,: Dental filling composites, carbon fiber reinforced methyl methacrylate bone ⁎ Corrosive resistant ⁎ Laborious ⁎ Dental fillings
cement + ultra-high molecular weight polyethylene manufacturing ⁎ Rubber catheters and
methods gloves
⁎ PMMA—poly (methyl methacrylate).
4 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940

Fig. 2. Common martials used for bio-applications by 3D printing.

3.1. AM - a disruptive technology considerable developments of 3D printing technologies enabled sur-

geons to address most of the shortcomings associated with the conven-
New applications are appearing as new materials, and AM ap- tional manufacturing methods of medical devices such as several
proaches are frequently developing. One of the major drivers for higher manufacturing steps and expensive tooling, and can help with fabricat-
accessibility of this technology is due to the expiration of the earlier pat- ing patient-specific devices [40]. In the following, different types of 3D
ents that allows manufacturers to create new 3D printing systems. The printing process used in medical applications will be discussed [44].
cost of 3D printers has been reduced by recent developments. Thus their
applications have been expanded in homes, schools, laboratories, and li- 4.1. Fused deposition modeling (FDM)
braries. The growing general agreement on the adaption of the 3D
manufacturing system over traditional methods is due to some benefits In the fused deposition modeling (FDM) approach, a continuous fil-
such as highly precise construction of complex geometry, flexible de- ament of a thermoplastic polymer is utilized in 3D print layers of mate-
sign, personal customization, and maximal material savings. An exten- rials. For reaching a semi-liquid state, the filament is heated at the
sive range of materials is used in 3D printing such as polymers, nozzle, and then it is extruded on top of the layers that previously
metals, concrete, and ceramics [2,5,33–35]. Acrylonitrile butadiene sty- have been printed or on the platform [4,45]. An important feature for
rene (ABS) and Polylactic acid (PLA) are the major polymers that are this approach is the thermoplasticity of the polymer filament allowing
utilized in the 3D printing of composites. Fig. 2. Shows common mate- fusing the filaments when printing and solidifying at ambient after
rials used in the 3D printing process for biomedical applications [2,36]. printing [46]. The thickness of the layer, orientation, and width of fila-
Advanced alloys and metals are usually used in the aerospace sector ments as well as air gap (between layers or in the same layer) are the
as traditional procedures are more expensive, difficult, and slow. Ce- primary processing factors affecting the mechanical characteristics of
ramics are primarily utilized in medical 3D printed platforms, and con- printed parts. The main reason of mechanical weakness is inter-layer
crete is the major material that is used in the AM of buildings. distortion [47–49]. The major advantages of fused deposition modeling
Nevertheless, the inferior mechanical characteristics, as well as aniso- include acceptable speed, low cost, and process simplicity. Its major
tropic behavior of 3D, printed components yet confine the large-scale drawbacks include weak mechanical characteristics, poor quality of sur-
printing potential. Thus, for controlling anisotropic behavior and flaw face, layer-by-layer appearance, and a confined number of thermoplas-
sensitivity, it is crucial to have an optimal pattern of 3D printing [37,38]. tic materials [50]. The development of fiber-reinforced composites by
fused deposition modeling can improve the mechanical characteristics
4. 3D printing technologies in healthcare of 3D printed parts [51]. Nevertheless, bonding between the matrix,
fiber, and void formation, and fiber orientation are the major objections
3D printing technology has been used by clinicians to fulfill a wide arising in three-dimensional printed composite parts. Fig. 3 summerizes
range of applications in healthcare and medical requirements [39]. the pros and cosn of FDM method.
The custimiztion of the medical products for individuals is one of the Regarding the healthcare field, the future of medical devices and
most notable features of this technology in biomedical applications medicines is going to be personalized for different patients which ex-
[40]. In addition, fabrication of complex designs of implants, prosthesis, ploits AM features for imaging of patients and outlining matched de-
surgical aids and models is another advantage of 3D printing in medical vices [52]. According to literature, FDM is the only used method for
applications. In most of the 3D printing processes, the raw material is ei- designing personalized catheters with promising results [53]. FDM is a
ther composed of soft plastic or metal powder. The powder is typically potential method for manufacturing of surgical instruments, implants,
contained in cartridges or beds as it is distributed in very small quanti- orthoses, and prostheses [54].
ties and fed by a roller or blade fitted in the bed where the part of a
model is being made. The thickness of these layers put together is as 4.2. Inkjet printing
slim as the size of the powder particles of the raw material, which can
be up to 5 μm. [41–43]. One of the major approaches for AM of ceramics is inkjet printing
Early 3D printers were mostly able to create relatively rough sculp- [52]. It is employed for printing advanced and complicated ceramic
tures made with plastic, ceramic, and sometimes plaster; but over structures for such applications as scaffolds for tissue engineering. In
time, more advanced printers were manufactured that were able to pro- this approach, a fixed ceramic suspension like zirconium oxide powder
duce metal volumes with greater accuracy and durability. Currently, 3D in water is pumped, and it is accumulated as droplets through the injec-
printers are caple of printing polymers, ceramics, and metals in different tion nozzle onto the substrate [4]. A continuous pattern is then formed
feedstock forms including, powder, filament, and bioinks. The by the droplets that are solidified in sufficient strength for holding the
 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940 5

Fig. 3. Pros and cons of the FDM method.

next layers of printed materials. It is an efficient and quick approach that include the energy of the light source and exposure. SLA can be
provides flexibility for printing and designing complicated structures employed for AM of complex nanocomposites in an effective manner
[55]. Liquid suspensions and wax-based inks are two major types of ce- [23,61].
ramic inks. For solidification, wax-based inks are heated and deposited Regarding the capability of SLA to produce large-sized objects with
on a cold substrate, while liquid evaporation is used for solidification submillimetre errors, several patients' products have been successfully
of liquid suspensions. The factors determining the quality of inkjet- prepared so far such as Invisalign®, which is an orthodontic device,
printed parts include ceramics' particle size distribution, the extrusion and hearing aid tools. Moreover, due to resolution development, broad-
rate, the ink viscosity, and solid content, printing speed, and size of ening of the applicable materials, controlling the porosity, and produc-
the nozzle [56,57]. The major drawbacks of this approach include coarse ing patient-specific devices, SLA has proved its capability to be used as
resolution, maintaining workability, and absence of adhesion between a potential manufacturing technique for tissue engineering [2,64]. An
layers. overview of the SLA process is shown in Fig. 4 [61].
Inkjet printing is a complex technique that requires various time and Due to the ability of SLA in creating crosslinked polymeric structures
length scales. Hence, in case of different materials used for inkjet print- via photopolymerization, it is a potential method in the fabrication of
ing [58], different scales and assumptions are used which are summa- high resolution with low temperature [65]. These features of SLA
rized in Table 3. methos make it an excellent candidate method for controlled drug
Inkjet printing is applicable for both polymer and ceramic bio- realease biomanufacturing, tissue engineering (TE) and regenerative
materials such as polyethylene glycol (PEG), hydroxyl aprtite medicine (RM).
(HA), bioglasses, polycaprolactone (PCL), polylactic acid (PLA).
There is a wide range of applications of inkjet printing in healthcare
such as controlled drug delivery, personalized medicine, and pros- 4.4. Powder bed fusion (PBF)
theses [60].
The PBF processes are composed of thin layers of fine powders that
are dispersed and packed closely on a platform. The powders are fused
4.3. Stereolithography (SLA) in each layer with a binder or a laser beam. The next layers of powders
are joined on top of previous layers, and they are fused so that the last
SLA is one of the primary approaches of AM that was created in 1986 3D part is constructed [66]. Then, the excess powder is eliminated by a
[4,61]. UV light (or electron beam) is used in this approach for initiating vacuum. Further detailing and processing like infiltration, sintering, or
a chain reaction on a resin layer or monomer solution. The monomers coating are performed if required. The most important factors affecting
(primarily epoxy-based or acrylic) are UV-active, and they are immedi- the efficacy of this approach include powder size distribution and pack-
ately converted into polymer chains following they are activated (radi- ing that specify the printed part's density [2,9,67]. It is possible to use the
calization) [62]. A pattern is solidified inside the resin layer after laser just for powders with a low sintering/ melting temperature, while
polymerization for holding the subsequent layers. When the printing a liquid binder should otherwise be employed. For various polymers,
is completed, the unreacted resin is eliminated. A post-process treat- alloy powders, and metals, SLS is utilized, while selective laser melting
ment like photo-curing or heating can be used for some printed parts (SLM) is utilized just for specific metals like aluminum and steel. The
so that the optimal mechanical performance can be achieved. It is possi- powders are not completely melted in laser scanning in SLS, and the in-
ble to use a dispersion of ceramic particles in monomers for printing creased local temperature on the grains' surface leads to the powders'
ceramic-polymer composites or polymer-derived certifiable monomers fusion at the molecular level. In addition, the powders are completely
such as silicon oxycarbide [63]. SLA provides printing high-quality parts melted and fused in selective laser sintering after laser scanning,
at a good resolution as low as 10 μm. However, it should be mentioned which leads to better mechanical characteristics [68]. provides a detailed
that it is costly, relatively slow and there is a very limited range of ma- description of various applications and materials that use SLS.
terials for printing. Moreover, the curing process and reaction kinetics PBF showed great potential to be used as manufacturing methods for
are complicated. The major factors that control the layers' thickness tissue engineering and bio-devices [69]. It has been utilized to fabricate
6 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940

Table 3
Inkjet printing assumption and scales for different materials [59].

Inkjet printing

Newtonian Particle suspensions Viscoelastic fluids Reactive materials Biological samples

fluids

Ohnesorge No continuum assumption Weissenberg and Requiring further time scales To get higher location accuracy and consistency, cell durability
number When the size of the particles is near Deborah numbers relating to heat transfer and in the printing process must be considered importantly.
the diameter of the liquid thread reaction

Fig. 4. The SLA production process. Source: Reprinted with permission from Biomaterials 31 (2010). Copyright 2019, The Biomaterials journal [61].

metallic scaffolds with desired porosity for bone grafting [70]. Fig. 5 4.6. Multiphoton polymerization (MPP)
represents the characteristics of the PBF technique [71].
The MPP is with the same high-resolution of SLA method. Micro-
scale and less-than-micron-scale 3D printing, which has recently
4.5. Digital light processing (DLP) attracted a lot of attention, is a process based on the polymerization
of multiphotons using a super short-pulse laser [2]. This nonlinear
This technology works with a photopolymer just like SLA. The major optical process occurs by polymerizing a light-sensitive material
difference between these two methods lies in their source of radiation. by simultaneously absorbing several photons at a wavelength of
In DLP, a typical light source is used together with a Liquid Crystal Dis- higher which is in range of 780–820 nm [64]. Usually, the parts
plays (LCD) or Digital Micromirror Device (DMD) screen that affects made by the MPP method are significantly smaller. Therefore, are
the entire surface of the tank containing photopolymer resin at a single not suitable for constructive tissue scaffolding of implants. But on
instant; and indeed it fabricates each layer at a moment, which is why it the other hand, it is used for understanding the interactions of
is generally faster than stereo lithography technology [16,64,72]. As cell scaffolding.
with SLA, DLP technology creates parts with great accuracy, though it Photobioprinting is a newly emerged AM method, which is highly
has similar problems. One of the advantages of this method over SLA applicable in TE and RM. MPP is considered one of the most important
is that a tank containing very low depth resin is required in light pro- bioprinting methods due to excellent cell viability as there is no external
cessing. This reduces cost and provides saving in expensive raw bioma- force while printing the product [75]. However, MPP is associated with
terials. Compared to other 3D printing technologies used in healthcare, low speed and expensive tooling, which hinders its applications in some
DLP technology has a high resolution, speed and efficiency [73]. The use cases.
of this technology began in 2006 and due to its outstanding features, it
has received a lot of attention in the field of medicine. Its applications 4.7. 3D slurry printing
in the various fields include, medical devices (medical models, implants,
functionalized devices), tissue engineering (liver, lung, bone, heart, spi- One of the newest 3D printing methods used in healthcare applica-
nal cord, etc), and pharmaceutics (drug discovery and development, tions is 3D slurry printing [76,77]. This method is can be conducted via
drug delivery) [74]. both SLA and sintering. In this method, a photo curable matrix as the
 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940 7

Fig. 5. PBF technical features.

binder can be incorporated with different ceramics powders for forming schematically represents the 3D slurry printing process related to
slurries. Then the slurry is photocured using a light source to shape the zirconia printing.
3D final shape to be used for the intended applications. Regarding
sintering process, the lasr is used to heat the slurry and then sodifidy, 4.8. Core-shell printing
while in SLA the slurry is cured via light [78].
This technique has been mostly used for dental implants Core-shell printing uses a co-axial nozzle and can provide the oppor-
[76,79]. Lee et al. used 3D slurry printing to fabricate dental im- tunity to print two different materials simultaneously [82]. One of the
plants using zirconia (ZrO2 ) [80]. The slurry was consisted of a materials is considered as the inner part or core and the other one
photocurable resin, methanol solvent, and ZrO 2 powder. Fig. 6 which is covering the core is called shell. So far, coaxial printing has

Fig. 6. The illustration of 3D slurry printing of zirconia [81].

8 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940

Fig. 7. The schematic of the A) main nozzle parts, B) nozzle in a close up scale [85].

been exploited to manufacture core-shells and hollow strands. How- this reason, recent advances in this field show the focus on smart mate-
ever, none of them was successful to afford good mechanical properties rials, as presented in Fig. 8.
along with cell viability. It is of great importance that using of two bio- 4D bioprinting is the application of 4D printing in medical sciences
materials in core-shell printing can help with optimizing mechnical and technologies and is directly associated with the maturation of the
properties of the 3D printed objects. Regarding scaffold fabrication by incorporated cells [91]. The process of the maturation of cells is carried
this method, by selecting a crosslinking agent as the core, and a bioma- out via self-organization using the fourth dimension that is a the exter-
terial as the shell, it would be able to creat a hallow tube thorugh just nal stimuli. Various materials such as lipids, biopolymers, and hydrogels
one fabrication step. This one step fabrication is considered as the have been printed via 4D printing for biomedical applications [92]. One
most cost-efficient fabrication method [83]. of the most applicable material in 4D printing process is stimuli-
The core-shell printed scaffolds are applicable in TE applications responsive hydrogels including synthetic and natural. The benefites of
such as vascular structures. Nozzles are made of metal to prevent any exploiting hydrogels in 4D printing stem from their excellent intercon-
deformation during 3D printing process and can provide prompt nectivity and adjustable porosity [93].
crosslinking of the feedstock, which leads to one step hallow filament
fabrication. This method is used for fabrication of microchannels
5. 3D bioprinting
where hollow filaments are the supporting structures affording the me-
chanical stability of the product while microchannels are serving as the
Guillemot et al. (2010) described bioprinting as ‘using computer-
nutrient delivery path to cells [84].
aided transfer processes for the purpose of assembling and patterning
In a recent study conducte by Milojević et al., they designed a core-
non-living as well as living materials by a prescribed 3D or 2D organiza-
shell printing for woodpile structures fabrication using a two coaxial
tion for producing bioengineered structures that serve in pharmacoki-
G27 needles as the nozzle [85]. Fig. 7 shows the schmatic of the coaxial
netic, regenerative medicine, and basic cell biology studies [94]. To
nozzle. Their atudy developed a simple fabrication method that was
achieve a three-dimensional structure of human tissue and organs, it
personalizable for a wide range of applications.
is necessary to use precise and well-controlled methods of fabrication
for suitable biomaterials and living cells. Considering the aforemen-
tioned requirments, four types of 3D bioprinting techniques have been
4.9. Four-dimensional printing (4D printing) developed that can print based on the principle of biological release.
These techniques include bioprinting systems of extrusion-based, Ink-
4D printing is a subset of 3D printing. When functional and intelli- Jet, Laser-Assisted, and Stereolithography-Based [95,96]. Fig. 9 illus-
gent materials are used in the 3D printing process which is able to func- trates the classification of different types of the 3D bioprinting tech-
tion by external stimuli such as heat, change in pH and so on, the niques with a simple view of the overall shape of the 3D bioprinter.
process is called 4D printing [41]. It has high potential of applicability Apart from the normal 3D printing challenges, 3D bioprinting chal-
in biomedical field such as organ regeneration, tissue enginnering, im- lenges include the cell incorporation issues. On the on hand, In case of
plants, and drug delivery [15]. 4D printing was first regarded as a meth- the 3D printing challenges, the bioinks must be biocompaticle, and pro-
odology connecting AM with time. Actually, in the early studies in 2013, vide good structrul stability [97]. On the the other hand, cell-related is-
the strategy suggested includes the design of a 3D printed part that suf- sues consist of cytocompatiblity of the bioinks and viability of cells. The
fers a controllable shape change. Momeni et al. [86–88] reported a defi- most important parameters in further development of 3D bioprinting
nition of 4D printing. They described this process as an intended are cytocompatibility and good printability [98]. In addition to the
evolvement of the 3D printed structures, in terms of functionality, char- afformentioned challenges, a successful 3D bioprinting process requires
acteristics, and shape [89]. As reported by the Atlantic Council of the a sterilized environment with a constant temperature adjusted on 37 °C.
United States, 4D printing is described as “AM of objects with the ability Furthermore, shear stress is the other important factor affecting the
of self-transformation in function or form when exposed to a cells in higher amounts. At present, there are limited successful ap-
prespecified stimulus like heat, osmotic pressure, ultraviolet light, cur- proaches fulfilling all the 3D bioprinting requiremnts such as partial
rent, or other energy sources”. Therefore, 4D printing is the programma- gel cross-linking.
ble aspect of a 3D printed area with the capability of changing the 3D bioprinting had developed considerably during the past decade
functionality of available material or material hybrids that are and is progressing rapidly. One the promising achivements of this
engineered for self-assembly at accurate shapes and locations [90]. For method is organ printing. Organs are defines as a complicated
 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940 9

Fig. 8. 4D printing technology considerading on materials and type of stimulus.

combination of tissues. The term ‘organ printing’ was firstly observed in of material coating, cells encapsulated in tailored colloidal microen-
2003, which is described as ‘a quick prototyping computer-aided 3D vironments, or cells seeded onto microcarriers. Moreover, bioinks
printing technology, based on the use of layer-by-layer deposition of may include bioactive molecules like DNA, growth factors, miRNA,
cells and/or cell aggregates into a 3D gel with sequential maturation of cytokines, biomaterials, and exosomes, but they do not have to be
the printed construct into vascularized and perfused living organs or tis- so [41,94,103,104]. Fig. 11 shows differences between bioinks and
sue’. ‘Organ printing’ is yet used frequently; especially it is frequently biomaterial inks. Moreover, Table 4 shows the comparison of com-
used in popular literature [4,44,99]. Nevertheless, it is currently broader mon bioprinting technologies. According to recent literature, re-
than its relatively narrow original definition. searchers are working to modification FDM 3D printing and turns
Further progress in biofabrication facilitates and make it more feasi- them into modified-extrusion which leads to improve features, es-
ble to creating products with higher mimicking percentage to natural pecially costs reduction [105]. Recently, a new study was conducted
tissues and organs. Biofabrication is described as ‘the automatic on using bioinks for patient-matched applications by Faramarzi et al.
manufacturing of biologically functional products with the structural [104] According to their new approach, it was confirmed that
organization from bioactive molecules, living cells, cell aggregates like patient-matched tissues can be provided by bioprinting.
micro-tissues, biomaterials, or hybrid cell-material constructs, through
bioassembly or bioprinting and subsequent processes of tissue matura- 5.2. Ideal material characteristics for bioprinting
tion [6,100,101]. It is used to describe natural processes such as biomin-
eralization and technological processes in various disciplines such as The choice of proper materials for application in bioprinting as well
catalysis, biotechnology, sensing, synthetic biology, and especially TE as the performance of these materials in a specific application are de-
and RM. This concept is pinpointed in Fig. 10. 3D printing of multi- pendent on various factors, which are given in the following [109].
materials instead of just a single one allows for cutimizing of growth fac-
tors and cell adhesion along with better structural stability of the final a) Printability- the characteristics facilitating deposition and handling
product. by the bioprinter include rheological properties, viscosity, and gela-
tion approaches.
b) Biocompatibility- Materials should not stimulate unwanted sys-
5.1. Bioinks temic or local responses from the host, and they should have an ac-
tive and controllable contribution to the construct's functional and
Bioinks are the formulation of the cells that are appropriate for biological elements.
processing by an automated biofabrication technology. It may also c) Byproducts and kinetics of degradation- Rates of degradation
include the biomaterials and components that are active biologi- should have a match to the cells' ability for producing their
cally’ [102]. Bioinks may contain cells in various forms and environ- own ECM; byproducts of degradation should not be toxic; ma-
ments like single cells, cellular rods, cells aggregated in spheroids, terials should represent appropriate contractile or swelling
cells organized in organoids or mini tissues, cells with a thin layer properties.
10 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940

Fig. 9. Classification of the different types of 3D bioprinting with a schematic illustration a simple view of the overall shape of the 3D biprinter.

Fig. 10. Describing biofabrication process and relevant applications [6].

d) Mechanical and structural characteristics- Materials are selected rigid thermoplastic polymer fibers for strength.
on the basis of needed mechanical characteristics of the con- e) Material biomimicry- Engineering of optimal dynamic, func-
struct, which range from soft hydrogels for cell compatibility to tional, and structural material characteristics should be based
 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940 11

Fig. 11. Distinction between a bioink (left side), where cells are a mandatory component of the printing formulation in the form of single cells, coated cells and cell aggregates (of one or
several cell types), or also in combination with materials (for example seeded onto microcarriers, embedded in microgels, formulated in a physical hydrogel, or formulated with hydrogel
precursors), and a biomaterial ink (right side), where a biomaterial is used for printing and cell-contact occurs post-fabrication. The images in this scheme are not displayed in scale [103].

Table 4
Comparison of bioprinting approaches [98,103,105–108].

Parameters Bioprinting Approaches

Microextruson Inkjet Laser-assisted Stereolithography

Material Viscosity 30 to N6*107 mPa/S 3.5–12 mPa/S 1–300 mPa/S No limitation

Crosslinking Strategy Photocuring, thermal, Chemical Photocuring, Chemical Photocuring, Chemical Photocuring, Chemical also
Cell viability 40%–80% N85% N95% N85%
Cell density High Low Medium Medium
Printing Speed Slow Fast Moderate Fast
Printing resolution Medium High High High
Cost of printer Low Low High Low

on the knowledge about tissue-specific endogenous material biomaterials, which are placed, either partially or totally, within the
compositions. body [12,23,112,113].

6.1. Advantages of 3D printing in relation to medical implants

6. Implants a) Reduced duration of surgery: The surgery duration is shortened with

the planning and changes of implants based on the pathology pre-
Implants are one the useful product of 3D printing in healthcare, hand, and the surgeon and the surgery team precisely knows the ac-
which has been widely developed with different 3D printing techniques curate steps of surgery.
and materials. The term ‘implant’ is described as a device that is grafted b) Reduced intraoperative bleeding: With pre-hand knowledge on steps
or inserted by surgery, either permanently or temporarily, within the of surgery and reduction in surgery time, the overall per-operative
body for improving, assisting, or maintaining a function or enhance- bleeding would be reduced. Thus, the return to normal conditions
ment/alteration of a contour [18,110]. The implants can be made from occurs faster than conventional.
synthetic materials like hip prosthesis or from soft tissues like blood c) Higher precision: The surgeons would be able to have better planning
vessel grafts, which are mostly inert [111]. The following definition is for surgery when there is an exact model available. According to the
the most recent definition given in the 2018 conference that with the bone shape and size, the implants can be molded in advance. Thus,
consensus over it: It is a medical tool that is made from one or more precision is increased, and surgery duration is reduced.
12 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940

d) Education of Patient: Explaining the pathology and the procedure of approach for altering the size and shape of the dosage form.
the surgery to the patients is easier now with increasing knowledge b) Creating complex shapes: With 3D printing, the complex shapes
and awareness of patients with the availability of a 3D print model. It can be formed, with a precise medication dose or active pharma-
is helpful for informing the patients, and they will be aware of the ceutical ingredients, even as low as 10–12 mol per tablets that is
expectations from the procedure of the surgery. helpful in the reduction of the adverse effects observed because
e) Medicolegal litigations: The patients will be better informed about of excessive doses. In comparison with the conventional ap-
the expectations with the guide of models. Hence, the communica- proaches, where complicated geometries were not possible, it
tion between the patients and doctor is improved, and subsequently, can be achieved easily by 3D printing. Also, varying sizes and
the cases of medical litigations are reduced. shapes lead to a different release profile. Complicated shapes re-
f) Instruments and jigs specific to the patient: The human beings are dif- sult in a modified release, adjusted drug loading, and masking
ferent, so the sizes of bones are also different. Using this technology, the medication taste.
implants can be customized according to the exact dimensions of the c) Sustained-release: 3D printing allows easily controlling and
patient, and the jigs can be prepared. targeting drug release. By printing a binder in the layers of the
matrix powder, it can be adopted. Thus, a barrier is created be-
Some recent development in healthcare and medical implants for tween the API layers allowing variation in the release profile.
different applications obtained in recent works literature [114,115]. d) Unique dosage form: 3D printing can be employed in the phar-
Some of the relative applications in this field are Dentistry, Orthopedics, maceutical production process for creating limitless and unique
Cardiovascular, Pharmaceutics, Neurosurgery, Engineered Tissue dosage forms. For creating a new dosage form, 3D printing is
Models, Medical Devices, and Anatomical Models. utilized.
e) Mini dispenser unit: The 3D printer setup requires minimal
7. Pharmaceutical potentials of 3D printing space that allows these printers to fit in any environment and it
is economical. Three-dimensional printing is a computer-aided
The traditional processes like milling, granulation, compression, and design. It means that 3D printing can be controllable by the use
mixing used by pharmaceutical industries sometimes lead to irregular of computer software and network. Besides, 3D printing technol-
qualities of the end products, which depend on such factors as drug re- ogies provide the opportunity for medication individualization.
lease, drug loading, drug stability, and pharmaceutical dosage. Three- Based on these properties, the 3D printer works as a mini-
dimensional printing, as a robust tool technology, possesses such com- dispenser for potentially bringing tablet manufacturing closer
petitive advantages as improved safety, enhanced R and D productivity, to patients.
medicine accessibility, and efficacy. Followings are the main advantages f) Integration with Health Care Network: Pharmacists and physi-
of three- dimensional printing making it more attractive [60,116–118]: cians can make modifications to the next dose or drug combina-
tions based on the needs of the patient. 3D printers are controlled
a) Personalization remotely. Thus, patients can easily access 3D printing. Therefore,
✓ Personalized medicine: Personalized medicine contains ac- the patients' compliance is improved, and the time of clinical re-
commodation of medical treatments to the properties, prefer- sponse to the needs of the patient is shortened.
ences, and needs of every individual patient. It involves g) Quick Disintegration: There is a great difference between 3D
purposeful diagnosis, treatment, and follow-up. The concept printing and powder compression in terms of the disintegration
of Personalized medicine can be extended so that it covers process. The powder aggregation has a different pattern in both
pre-emptive medicine intended to the reduction of the risk of the newer and conventional approaches. In 3D printing powder,
diseases a patient has shown susceptibility to, by altering the there is higher binding strength in the periphery, and lower
patient's diet, habits, and lifestyle, and by advising the use of binding strength in the center resulting in accelerated rapid dis-
particular drugs or supplements. integration of tablets. It has been found that Aprecia's Zip Dose®
✓ Personalized therapy: 3D printing in the medicine was origi- can disintegrate in below 10s while it contains a high dose of pir-
nally utilized by surgeons as an aiding tool in the creation of acetam (1000 mg).
3D models of patients for better visualization of their anat- h) Tool-Less: The tool production need can be eliminated by 3D
omy, especially in the case of patients with particular anom- printing. Thus, the costs, lead time, and the associated labor is re-
alies or structures that need complicated surgeries. More duced.
established approaches (for example, particulate leaching i) Sustainable/ecofriendly: 3D printing as an emerging and novel
and solvent casting, molding, and membrane lamination) technology is efficient in terms of energy, and it presents efficien-
have been replaced by this approach partially because it al- cies in terms of the environment. It uses up to 90% standard ma-
lows fabrication (beginning with biocompatible substances) terials, and, thus, fewer wastes are created. It has a more
of items with perfect fitting the anatomical properties of powerful design imposing a decreased carbon footprint com-
the patient as shown by diagnostic imaging tools (for exam- pared with the products that are manufactured traditionally.
ple, computed tomography, nuclear magnetic resonance, X- j) Short production time: 3D printers are efficient in terms of time
ray). The intention for the construction of scaffolds includes that shortens the duration of product development design cycles.
space-filling, 3D structures organizing proliferation of cells k) Manufacturing process: There is a cost-effective and easier
into the respective tissue, in situ vehicles for the delivery of manufacturing process. The processing time is shorter because
active molecules (for example, anti-inflammatory or antibi- of improved tools, fewer wastes are created, and fewer steps
otic drugs, growth factors). are required for assembling the setup, and lead time is reduced
through functional integration of parts.
a) Tailored medication: Three-dimensional printing as 3D food l) Maintenance and Engineering: there are more flexible setup and
printing is helpful in medication production according to the maintenance processes in 3D printers. It is a cost-effective indus-
patient's needs or based on the medication required. This ap- trial engineering.
proach can be used in the case of a pediatrics dose, where there m) Logistic: 3D printing is an auspicious means by which products
are varying ranges of doses. Similarlyway, the dosage form can be produced upon needs and places where required, which
shape can be changed for the patients suffering from swallowing decreases the logistics handling and inventory as well as the
problems. 3D printing is simple as well as a very flexible transportation cost and related costs.
 S. Kholgh Eshkalak et al. / Materials and Design 194 (2020) 108940 13

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