3D printing promotes the development of drugs

Abstract

3D printing is an emerging field that can be found in medicine, electronics, aviation and other fields. 3D printing, with its personalized and highly customized characteristics, has great potential in the pharmaceutical industry. We were interested in how 3D printing can be used in drug fields. To find out 3D printing’s application in drug fields, we collected the literature by combining the keywords "3D printing"/"additive manufacturing" and "drug"/"tablet". We found that 3D printing technology has the following applications in medicine: firstly, it can print pills on demand according to the individual condition of the patient, making the dosage more suitable for each patient's own physical condition; secondly, it can print tablets with specific shape and structure to control the release rate; thirdly, it can precisely control the distribution of cells, extracellular matrix and biomaterials to build organs or organ-on-a-chip for drug testing; finally, it could print loose porous pills to reduce swallowing difficulties, or be used to make transdermal microneedle patches to reduce pain of patients.

Full text

Biomedicine & Pharmacotherapy 131 (2020) 110644
Available online 24 August 2020
0753-3322/© 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Review
3D printing promotes the development of drugs
Xiao Zhu
a
,
b
,
c
,
d
,
1
, Hongjian Li
a
,
b
,
1
, Lianfang Huang
a
,
b
,
c
,
1
, Ming Zhang
e
,
*, Wenguo Fan
f
,
***,
Liao Cui
a
,
b
,
**
a
Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang
524023, China
b
The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang 524023, China
c
The Key Lab of Zhanjiang for R&D Marine Microbial Resources in the Beibu Gulf Rim, Guangdong Medical University, Zhanjiang 524023, China
d
Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524023, China
e
Department of Physical Medicine and Rehabilitation, Zibo Central Hospital, Shandong University, Zibo 255000, China
f
Department of Anesthesiology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
ARTICLE INFO
Keywords:
3D printing
drug development
drug delivery
precise pharmaceutical technology
review
ABSTRACT
3D printing is an emerging eld that can be found in medicine, electronics, aviation and other elds. 3D printing,
with its personalized and highly customized characteristics, has great potential in the pharmaceutical industry.
We were interested in how 3D printing can be used in drug elds. To nd out 3D printing’s application in drug
elds, we collected the literature by combining the keywords "3D printing"/"additive manufacturing" and "drug"/
"tablet". We found that 3D printing technology has the following applications in medicine: rstly, it can print pills
on demand according to the individual condition of the patient, making the dosage more suitable for each pa-
tient’s own physical condition; secondly, it can print tablets with specic shape and structure to control the
release rate; thirdly, it can precisely control the distribution of cells, extracellular matrix and biomaterials to
build organs or organ-on-a-chip for drug testing; nally, it could print loose porous pills to reduce swallowing
difculties, or be used to make transdermal microneedle patches to reduce pain of patients.
1. Introduction
3D printing, also called additive manufacturing, was rst proposed
by engineer Charles Hull in the early 1980s [1]. 3D printing is a
manufacturing process in which materials are deposited layer by layer to
form an entity. Based on a pre-designed 3D digital model, it accumulates
the printed layers layer by layer to complete the construction of a 3D
object. 3D printing is extremely exible, allowing local control of ma-
terial composition and microstructure. Compared with traditional pro-
cesses, 3D printing has great advantages in producing highly complex
and custom-designed products, so it is more economical and time-saving
[2–4]. Currently, the 3D printing technologies applied in the pharma-
ceutical preparation eld mainly include fused deposition modeling
(FDM), stereo lithography appearance (SLA) and binder extrusion
printing, etc. 3D printing can be used to make molds to produce pills, or
to print pills directly using drug powders as raw materials. Researchers
or doctors can use computer-aided design (CAD) to create instructions
for the printing trajectory of the nozzle. With this instruction, the printer
nozzle stacks the ink that contains the binder and the powder of the APIs
(active pharmaceutical ingredients) layer upon layer to print out a 3D
Abbreviations: 3D printing, three-dimensional printing; APAP, acute acetaminophen; API(s), Active Pharmaceutical Ingredient(s); CAD, computer-aided design;
dECM, decellularized extracellular matrix; ECM, extracellular matrix; FDM, fused deposition modeling; FFF, fused lament fabrication; HME, hot-melt extrusion;
GAMs, Glioblastoma-associated macrophages; GBM, glioblastoma multiform; HPMC, hydroxypropyl methylcellulose; iPSCs, induced pluripotent stem cells; IM,
injection molding; IR, immediate release; PEGDA, poly real (ethylene glycol) diacrylate; PVA, polyvinyl alcohol; SLA, stereo lithography appearance; SR, sustained
release; vWF, von willebrand factor.
* Corresponding author at: Department of Physical Medicine and Rehabilitation, Zibo Central Hospital, Shandong University, Zibo 255000, China.
** Corresponding author at: Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong
Medical University, Zhanjiang 524023, China.
*** Corresponding author at: Department of Anesthesiology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China.
E-mail addresses: signname@163.com (M. Zhang), fanweng@mail.sysu.edu.cn (W. Fan), cuiliao@163.com (L. Cui).
1
These authors contributed equally to this work.
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
https://doi.org/10.1016/j.biopha.2020.110644
Received 25 May 2020; Received in revised form 13 August 2020; Accepted 16 August 2020

Biomedicine & Pharmacotherapy 131 (2020) 110644
2
product. For example, Goyanes et al. incubated PVA (polyvinyl alcohol)
laments in a solvent solution of aminosalicylates, and then used PVA
laments as raw material to print tablets with different lling percent-
ages by FDM 3D printing technology [5]. Therefore, 3D printing has
enormous potential in personalized medicine. Because it can make
tablets with different shapes, sizes or APIs-percentages. 3D printing has
the ability of precise micro-controlling, and can obtain different release
proles by controlling the external shape and internal structure of tab-
lets. In addition, high precision of 3D bioprinting technology enables it
to build "organs" or organ-on-a-chip that mimic the normal physiological
functions of the human body. These "organs" or organ-on-a-chip can be
utilized to drug testing. Besides, 3D printing can also be used to prepare
painless microneedle patches, which can improve patient compliance,
due to its advantage of one-step construction of complex structures in
details (Table 1).
Some commonly used 3D printing technologies for pharmaceutical
preparations are introduced as follows: (1) FDM [6] is to heat the la-
mentous material to the critical state and make it liquid. The material is
then extruded and solidied quickly along the designed track through
the print nozzle, and layered into the desired product. FDM has ad-
vantages such as safe operating environment and low cost, but it also has
disadvantages such as low accuracy and slow speed. (2) SLA [7] is to use
a laser beam of specic intensity and wavelength to focus on the
photosensitive material and solidify it. Then the lifting platform drops
for a certain distance, and a new layer of photosensitive material is
covered on the solidied layer, and so on to build a 3D object. SLA has
the advantages of fast forming speed, stable operation and high preci-
sion, but the equipment cost is high and the photosensitive resin has a
little pollution to the environment. (3) Selective laser sintering (SLS)
[8–12]: based on the principle of sintering of powdered materials under
laser irradiation, selective sintering is carried out according to the
computer-controlled interface contour information, and layer by layer
stacking is formed. SLS can use a variety of materials with a simple
manufacturing process and high precision, but SLS has shortcomings of
rough product surface and the long processing time.
2. 3D printed customed tablets
Since the United States began implementing the precision medicine
program in 2015, people have paid more and more attention to the
individualization of therapeutic services [13–16]. There are individual
differences between people, including heredity, gure, living environ-
ment and dietary habit, etc [17]. Even for the same disease, different
patients have different requirements of drugs. Traditional pharmaceu-
tical processes strictly limit the parameters of the drug, including its
shape, size and type of release, it can only produce drugs in batches of a
certain specication, based on the formulation that most people achieve
the appropriate effect. This can cause a very common problem in the use
of drugs that the pills may be effective in some patients but less effective
in others. This is because each patient’s condition, genetic characteris-
tics and constitution are different, and one specication cannot be
applied to all patients [18–20]. For example, most drugs are produced
based on the dosage of adults, and pediatricians can only cut up the pills
and give them to children’ patients. 3D printing drug is an innovative
preparation processing technology [21,22]. 3D printing is a highly
exible process [23] that allows you to design the size of the pill or
lling percentage to precisely control the dosage [5,24], meeting each
patient’s individual needs. When 3D printing’ cost is no longer high in
the future, doctors may be able to print pills on the spot, depending on
how much dosage each patient needs, if they have personal desktop
3D-printers (Fig. 1). Some studies have demonstrated the feasibility of
3D-printed pills in humans. Goyanes et al. [25] used FDM 3D printing
technology to produce 10 different printlets shapes, and proved that
these printlets could improve the acceptability of patients to solid oral
drugs. In addition, Goyanes et al. printed chewable isoleucine printlets
for patients with Maple Syrup urine disease, and showed good accept-
ability [26].
3. 3D printing and controlled release drug
Drug delivery system is the control system that comprehensively
regulates the distribution of drugs in the body in terms of time and
space. 3D printing can adjust the shape and internal structure of the
tablet by selecting materials, setting parameters and designing models.
It can control the release rate or the time of the drug [27] because the
printed tablets’ release curve is linked to the shape of drugs. According
to pharmacokinetics, drug release rates are related to the geometry of
the drug, and changing the geometry of the drug may affect drug release
[28]. The customed shape created by 3D printing changes the surface
area of the pill, which can control the strength and time of the drug
release. For example, Yu et al.’s doughnut-shaped drug delivery devices
allowed linear drug release based on the concentration gradient of the
sustained-release polymer [29]. And there is a mathematical model have
shown that the central hole in the doughnut-like pill gives it a linear
release capacity [30]. Tan et al. [31] developed a capsule with three
parts: a surface-eroding matrix containing the drug, a surface-eroding
matrix without the drug, and a coating with an open side. They made
the three parts from 3D printing molds and assembled them. The drug
was degraded layer by layer on the open side, and the release curve was
consistent with the shape of the surface-eroding matrix. So, in theory,
they can get all kinds of release proles by manufacturing different
surface-eroding matrixes. Liang et al. [32] used 3D printing technology
to manufacture oral drug delivery device with adjustable release rate,
and the device appeared in the form of dental braces. They then eval-
uated the device’s performance in local environments, demonstrating
the feasibility of a 3D-printed drug delivery system in humans.
In addition to the above controlling methods, another one is to
combine multiple drugs in a single pill[33–36]. It is benecial for pa-
tients who need multiple medications to cope with multiple diseases
[37,38], and avoid the trouble of taking the drug many times in one day
to improve patient compliance. Current tablet preparation techniques
can only guarantee the release of a single drug or a combination of
drugs, but not the independent release of different drugs at different
sites. And 3D printing solves the problem of having multiple drugs
compatible with multiple polymers in a single formulation, ensuring
Table 1
3D printing’s applications in drugs
Applications Examples Feature
Customed
tablets
Design the size of the pill; the
feasibility of 3D-printed pills:
FDM 3D printing technology
Personalized, printing on
demand
Controlled
released
tablets
Doughnut-shaped drug
delivery devices;
mathematical model;
Released independently at
different sites; different surface-
eroding matrixes; different sites
and at different time; solid
dosage forms;
Drug testing
Eudragit®RL sustained
release layer; customized double-layer tablet
fused lament fabrication
(FFF);
Screening drugs by mimicking
organs
Polypill Reducing difculty swallowing;
one-step fabrication
Organ-on-a-ship;
ink-jet; microextrusion bioprinting;
organ-on-a-chip; manufacturing complex
structures and
liver-on-a-ship; induced a hepatotoxic reaction
heart-on-a-chip iPSCs
Action
manners of a
drug
Spritam; Painless;
Microneedle; transdermal drug injections
ZipDose; porous water solubility;
nanouids;’ immunotherapy;
MucoJet new non-invasive vaccine
delivery
X. Zhu et al.

Biomedicine & Pharmacotherapy 131 (2020) 110644
3
that different drugs are released independently at different sites and at
different time[39–41]. Gioumouxouzis et al.[42] embedded metformin
and glimepirea into Eudragit®RL sustained release layer and polyvinyl
alcohol (PVA) release layer respectively to produce a double-layer
dosage form for anti-diabetes. Their study results highlight the poten-
tial of 3D printing for solid dosage forms to combined drug therapy.
Fuenmayor et al. combined the two technologies: fused lament fabri-
cation (FFF) and injection molding (IM) to produce a customized
double-layer tablet [43]: FFF layer loaded with hydrochlorothiazide, a
drug for the treatment of hypertension and edema, and IM layer loaded
with lovastatin, a drug for the treatment of cardiovascular diseases,
demonstrating a feasible method for mass customization of oral tablets.
Khaled et al. used 3D extrusion printing to create a ve-in-one polypill
[44]. The shape of the tablet was designed by a 3D drawing package. It
included immediate release (IR) layer and sustained release (SR) layer.
Aspirin and hydrochlorothiazide were located in the IR layer, while
pravastatin, atenolol and ramipril were separated in three SR chambers,
ensuring the unique release of each drug. The polypill makes it easier for
patients with multiple conditions, such as high blood pressure, diabetes,
or chronic kidney failure, to take the pill and allows each drug to be
released independently.
4. 3D bioprinting helps drug development and testing
3D bioprinting could help drug trials. Each new drug is approved
through two-dimensional cytology, animal testing, and clinical trials.
Organ-on-a-chip [45] (e.g. liver [46], heart [47]) can imitate the
physiological characteristics of living organs, and perform drug tests on
behalf of animals [48]. According to the ink-jet method, 3D bioprinting
can be divided into laser-assisted bioprinting, stereolithography
(SLA)-based bioprinting, jetting-based bioprinting, and microextrusion
bioprinting [49,50]. Among these technologies, microextrusion
bioprinting maybe the most potential technology. Researchers often use
gelatin, hyaluronic acid, alginate and decellularized extracellular matrix
(dECM) as bioinks to encapsulate cells, because they are very well
simulate the natural physical and chemical characteristics of extracel-
lular matrix (ECM), and have good biocompatibility, printability, me-
chanical and structural integrity and biodegradability. Cells used in 3D
bio-printing are mainly stem cells, which are divided into differentiated
types (such as mesenchymal stem cells, adipose-derived stem cells and
neural stem cells) and pluripotent types [51]. 3D bio-printing technol-
ogy can exibly and accurately locate cells [52] to recapitulate human
tissues through intelligent design, advanced bio-inks and polymeriza-
tion technologies [53]. Therefore, researchers can create different tis-
sues using a bio-3D printer and bio-ink containing different cells, and
then transfer these tissues to organ-on-chips. 3D printing enables auto-
mated and high-throughput manufacturing of the microbioreactor
[54–56], the main component of the organ-on-a-chip, which consists of
fresh primary cells, gels for packaging and other components. This is
because 3D bioprinting technology has the advantages of manufacturing
complex structures and one-step fabrication [48]. So that it can precisely
control the distribution of cells, extracellular matrix and biological
materials and create microuidic devices in the organ-on-a-chip.
Nupura et al. [46] developed a liver-on-a-ship platform for evalu-
ating drug toxicity by 3D bioprinting and HepG2/C3A cells. The secre-
tion rates of four biomarkers (albumin, alpha-1 antitrypsin, transferrin,
and ceruloplasmin) increased steadily during culture, the number of
cells increased from 4 ±0.5 ×10
5
on day 1 to 4 ±0.2 ×10
6
on day 30,
indicating the good function of the liver construct. Then they induced a
hepatotoxic reaction with acute acetaminophen (APAP): in a bioreactor
without APAP treatment, metabolic activity increased by 78 ±4%; In
the APAP-treated bioreactor, the metabolic activity decreased by 63 ±
2%. This suggests that liver-on-a-chip is responsive to acute toxic drugs
and can be used for drug screening. Zhang et al.[47] constructed
Fig. 1. Based on the diagnosis, treatment and treatment plan, the doctors print the drug on the spot on need to adapt to the specic situation of each patient. The
printed drugs have a precisely measured API (Active Pharmaceutical Ingredient).
X. Zhu et al.

Biomedicine & Pharmacotherapy 131 (2020) 110644
4
endothelialized heart-on-a-chip by using induced pluripotent stem cells
(iPSCs) and 3D bioprinting technology. Cardiomyocytes grew on the
printed scaffold strongly expressed the protein sarcomeric
α
-actinin for
contraction and connexin-43 for conductivity, and the cardiomyocytes
beat strongly. Then they tested the cardiac toxicity of doxorubicin: the
beating rates of cardiomyocytes exposed to 10
μ
M and 100
μ
M dropped
to 70.5% and 1.62%, respectively. The levels of vWF (von willebrand
factor) secretion were reduced to 76.0% and 35.3%, respectively. It
shows that the heart-on-a-chip has the potential of drug screening.
And some researchers used 3D-printed organ models to test drugs.
Organovo (a bioprinting company) and Roche (a pharmaceuticals
company) used 3D-printed “livers” to test different drug toxicity levels
and detect liver damage caused by trovaoxacin [57].
Glioblastoma-associated macrophages (GAMs) play an important role in
the development of glioblastoma multiform (GBM). Heinrich et al.
created a 3D-printed mini-model of the brain that contains both GBM
and GAMs to simulate the interactions between the two cell types and
test the efcacy of anti-tumor drugs [58].
5. 3D printing improves the way patients take medicine
3D printing technology can make loose and porous tablets to reduce
swallowing difculties[59]. Yu et al. used 3D printing to make fast
disintegrating tablets with a highly porous mesh structure, and proved
the feasibility of 3D printing[60]. Aprecia pharma, inc, using “ZipDose”
3D printing, made Spritam [61,62] with porous water solubility, which
can hydrolyze rapidly and reduce the risk of swallowing difculty in
epileptic patients.
3D printing can also be used to make microneedles. Microneedle
technology is a painless technique for delivering a drug through the skin
[63]. It is because the microneedle penetrates the skin and releases the
drug in the dermis without stimulating the pain nerve. Conventional
techniques for making microneedles involve a series of time-consuming
and difcult to extend processes, and coating techniques do not entirely
guarantee that the active coated layers are laid evenly and accurately.
3D printing technology can make microneedles with different structures
through one-step fabrication, and the high resolution of the 3D printer
guarantees good details of the array[64], so that it can be applied to
produce microneedles. Goyanes et al. used 3D scanning and SLA 3D
printing to create a transdermal patch that ts the shape of a patient’s
nose[65]. The shape of the device is very suitable for individual patients.
Cristiane et al. used 3D printed microneedles for transdermal insulin
delivery, and proved the feasibility of 3D printing technology for pre-
paring microneedle patches[64]. Lu et al.’s 3D-printed microneedles
may allow painless, transdermal drug injections [66]. They created an
array of twenty-ve microneedles made of fumaric acid that resists the
pressure of piercing the skin and keep the patients from feeling painful.
In addition, some scholars have developed some new ways to take
drugs by 3D printing technology. The team, led by Priya Jain, designed
an implantable delivery device with nanouids for topical immuno-
therapy of tumors [67]. 3D printing technology determines the
personalized structure, and the implant’s small holes to control the drug
release rate. In this device, drug diffusion is controlled by physical and
electrostatic nanometers, enabling continuous immunotherapy [68].
Using 3D printing technology, Aran et al. invented the oral vaccine in-
jection capsule MucoJet, which can produce gas after extrusion, launch
the vaccine and penetrate the mucous membrane of the mouth to acti-
vate the immune system of the oral mucosa [69]. It has been successfully
tested in the oral cavity of rabbits, which is a new non-invasive vaccine
delivery method.
6. Conclusion and perspectives
Although the traditional pharmaceutical industry can meet most of
the needs of medicine, it still has some limitations: it cannot produce
personalized/customized tablets or create different/targeted release
tablets. 3D printing allows for the creation of specic geometric shapes
to realize the high degree of customization of the pill (and its dose). 3D
printing overcomes the limitations of conventional formulation tech-
niques in tailoring the tablet’s microstructure and changing composition
in different regions, making it possible to print tablets with different
release responses [5,65,70]. And the "organ"/organ-on-a-chip for drug
testing also requires 3D bioprinting to achieve a perfect distribution of
cells, extracellular matrix, biomaterials and circulatory devices within it
[70–72]. Combined with 3D printing technology, the drug delivery de-
vice can improve the effect of drugs. At present, cutting-edge papers on
3D printing are published every day, illustrating the innite possibilities
of 3D printing. The commercial viability of 3D printing has been proved
by Spritam manufactured by Aprecia pharma, inc. Although 3D printing
technology still has shortcomings in technologies and materials, we
believe that these problems will be solved by the progress of technology.
We envisage that in the future, the effect of patients’ medication and
drug testing will be greatly improved. We believe that more and more
pharmacies and hospitals will have 3D printing facilities to enable
on-demand printing.
Authors’ contributions
HL and XZ wrote the manuscript. XZ, MZ, WF and LH discussed and
edited the manuscript. WF, MZ and XZ designed the concept. LC, WF and
XZ supported the fundings. All authors read and approved the nal
manuscript.
Consent for publication
All authors consent for publication.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
This work was supported partly by National Natural Science Foun-
dation of China (81771098); Guangdong Science and Technology
Department(2016B030309002 and 2019B090905011); The Fund of
Southern Marine Science and Engineering GuangdongLaboratory
(Zhanjiang) (ZJW-2019-007); The Public Service Platform of South
China for R&D Marine Biomedicine Resources (GDMUK201808);
Zhanjiang Science and Technology Plan(2017A06012). The funders had
no role in the design of the study; the collection, analysis, and inter-
pretation of the data; the writing of the manuscript; and the decision to
submit the manuscript for publication.
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