The Shape of Things to Come: Emerging Applications of 3D Printing in Healthcare

Abstract

We now stand on the brink of a fourth industrial revolution. By the remarkable technological advancements of the twenty-first century, manufacturing is now becoming digitalised. In the last decade, the rise of rapid prototyping has provided individual patient care, acted as an educational and training tool and contributed to research. Innovative technologies such as three-dimensional printing (3DP), have the potential to cause a paradigm shift in medicine design, manufacture and use. Instead of using conventional large batch processes, customised printlets (3D printed tablets) with a tailored dose, shape, size and release characteristics could be produced on-demand. Arguably, never before has the pharmaceutical industry experienced such a transformative technology in medicines manufacture. Indeed, this technology could be utilised throughout the drug development process, ranging from pre-clinical development and first-in-human clinical trials through to front-line medical care (personalized medicines). This chapter aims to discuss the current and future potential applications of 3DP in healthcare and, ultimately, the power of 3DP in pharmaceuticals.

Full text

Translating 3D printed pharmaceuticals: From hype to real-world
clinical applications
Iria Seoane-Viaño
a,1
, Sarah J. Trenfield
b,1
, Abdul W. Basit
b,c,
⇑
, Alvaro Goyanes
b,c,d,
⇑
a
Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Paraquasil Group, Faculty of Pharmacy, and Health Research Institute of Santiago de Compostela
(IDIS), University of Santiago de Compostela (USC), Santiago de Compostela 15782, Spain
b
Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK
c
FabRx Ltd., 3 Romney Road, Ashford, Kent TN24 0RW, UK
d
Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma Group (GI-1645), Facultad de Farmacia, and Health Research Institute of Santiago de
Compostela (IDIS), Universidade de Santiago de Compostela (USC), Santiago de Compostela 15782, Spain
article info
Article history:
Received 10 January 2021
Revised 4 April 2021
Accepted 4 May 2021
Available online 20 May 2021
Keywords:
Additive manufacturing
3D printing formulations
Personalized drug products and
translational pharmaceutics
Printed oral drug delivery systems
Mass customization and personalization
Early phase therapeutics development and
computational modeling
Artificial intelligence and industry 4.0
Biomedical engineering and medical devices
abstract
Three-dimensional (3D) printing is a revolutionary technology that is disrupting pharmaceutical develop-
ment by enabling the production of personalised printlets (3D printed drug products) on demand. By cre-
ating small batches of dose flexible medicines, this versatile technology offers significant advantages for
clinical practice and drug development, namely the ability to personalise medicines to individual patient
needs, as well as expedite drug development timelines within preclinical studies through to first-in-
human (FIH) and Phase I/II clinical trials. Despite the widely demonstrated benefits of 3D printing phar-
maceuticals, the clinical potential of the technology is yet to be realised. In this timely review, we provide
an overview of the latest cutting-edge investigations in 3D printing pharmaceuticals in the pre-clinical
and clinical arena and offer a forward-looking approach towards strategies to further aid the translation
of 3D printing into the clinic.
!2021 The Authors. Published by Elsevier B.V. This is an open access articleunder the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
Contents
1. Introduction......................................................................................................... 554
2. 3Dprintingtechnologies............................................................................................... 555
2.1. Binderjetting....... ...................................................................................... ...... 555
2.2. VATphotopolymerization............................................................. ............................ 555
2.3. Powderbedfusion................................ ............................................................... 555
2.4. Materialjetting............................ ..................................................................... 556
2.5. Materialextrusion............................................................................ ................... 556
2.5.1. Fused deposition modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556
2.5.2. Semi-solidextrusion...................................................................................... 557
2.5.3. Direct powder extrusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
3. Pre-clinicalapplications................................................................................................ 557
3.1. Immediate and modified release oral drug products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
3.2. Rectalformulations.................................................. ............................................ 560
3.3. Gastrointestinal fluid sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
4. Clinicalopportunities.................................................................................................. 561
https://doi.org/10.1016/j.addr.2021.05.003
0169-409X/!2021 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
⇑
Corresponding authors at: Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
E-mail addresses: a.basit@ucl.ac.uk (A.W. Basit), a.goyanes@fabrx.co.uk (A. Goyanes).
1
The authors contributed equally to this work.
Advanced Drug Delivery Reviews 174 (2021) 553–575
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/adr

4.1. Personalisedmedicine................... ......................................................................... 561
4.2. Improved medicine acceptability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
4.2.1. Paediatrics.............................................................................................. 567
4.2.2. Adult and geriatric populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
4.3. Massmanufacture...................................................................... ......................... 569
4.4. On-demand printing in hard-to-reach areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
4.5. Veterinaryapplications........................................................................................... 570
5. Challenges and future directions of 3D printing in pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
6. Conclusions.......................................................................................................... 572
References .......................................... ................................................................ 572
1. Introduction
Three-dimensional (3D) printing offers the potential to revolu-
tionise the production of pharmaceuticals targeted to the gastroin-
testinal (GI) tract by offering a flexible drug product manufacturing
platform that can adapt readily to changing market and patient
needs [1]. By using digital computer-aided design software to pro-
duce medicines in a layer-by-layer manner, 3D printing enables
the on-demand production of drug products with personalised
dosages [2,3], drug combinations [4–6], geometries [7,8] and
release characteristics [9–12]; a concept which is currently
unattainable and cost inefficient with conventional manufacturing
technologies (e.g. tabletting and encapsulation). This technology
has been forecast to disrupt a wide range of pharmaceutical appli-
cations, ranging from expediting the drug development process
and providing benefits for pharmaceutical manufacture, to on
demand printing of personalised medicines on the front-line and
in hard-to-reach areas (Fig. 1).
Due to the potential to readily adapt dosages, 3D printing can
provide many benefits for early phase drug development (e.g.
pre-clinical, as well as first-in-human through to Phase I/II clinical
trials). These early phase studies involve the in vivo administration
of a new drug candidate across a wide dosage range [13–15], with
the aim to gain an initial understanding of parameters including
efficacy, toxicology, tolerability, safety and pharmacokinetic (PK)
behaviour in animal models (pre-clinical studies) and humans
(clinical trials) [16]. Conventional large-scale manufacturing pro-
cesses (e.g. tabletting and encapsulation) do not provide a dose
flexible or dose-sparing platform, with smaller scale manufactur-
ing processes (manual filling of capsules, or solutions and suspen-
sions) coming alongside challenges with high labour and solubility
issues. 3D printing has the potential to overcome these challenges
and streamline, automate and accelerate the manufacturing of
dosage forms for pre-clinical and clinical studies, while saving time
and reducing costs [17,18]. By implementing 3D printers into a
clinical setting, small batches of printlets with the desired dose
could be manufactured on demand and immediately before admin-
istration, thus avoiding the need for long term stability studies
[19,20].
3D printing also has benefits for formulation optimisation, by
enabling the production of patient-friendly formulations to aid
medication adherence, such as personalised chewable and fla-
voured drug products for paediatrics and geriatric patients
[21,22]. Printed drug products with fully customisable drug
release profiles have also been produced, ranging from immediate
and controlled release, through to targeted drug delivery systems
to different regions of the gastrointestinal tract [23,24]. 3D print-
ing has also been highlighted as a promising enabling technology
to improve the solubility of BCS II and IV drug compounds
through the production of solid dispersions. Such opportunities
not only provide benefits for new drugs coming into the fore,
but also existing drugs which have known formulation challenges
that could be improved by using a flexible production platform
[25,26].
Fig. 1. Pharmaceutical Applications of 3D Printing.
I. Seoane-Viaño, S.J. Trenfield, A.W. Basit et al. Advanced Drug Delivery Reviews 174 (2021) 553–575
554

This technology has also been indicated in providing an alterna-
tive for pharmaceutical mass manufacture [27]. Indeed, in 2015,
the world’s first 3D printed medicine (Spritam
"
) was approved
by the Food and Drug Administration (FDA), which for the first
time enabled the production of a unique drug product which had
both high drug loading (up to 1000 mg) and rapid disintegration.
The 3D printing method used was a scaled-up binder jet printer,
which offered four different fixed-dose strengths. As the system
was an alternative mass manufacturing process, FDA approval
was achieved via conventional regulatory pathways. Another
potential application for 3D printed dosage forms is for the mass
customisation of drug products, a process which is being used
almost exclusively for the manufacture of hearing aids to date,
with 10 million hearing aids currently in circulation globally
[23]. Due to the high level of design freedom as well as the on-
demand capability offered by 3D printing, this technology has been
forecast to disrupt the way that we treat patients, away from mass
manufacture towards personalised therapies (e.g., with tailored
shapes, sizes, dosages and dose combinations) [28,29], including
on the front-line (e.g. in hospital or community pharmacies). Via
decentralisation of the manufacturing process, this novel treat-
ment pathway could enable patients to have an easier access to
medicines within their community and reduce waiting times for
those medicines that require extemporaneous preparation or com-
pounding by a pharmacist [30,31]. 3D printing has also been indi-
cated in producing personalised drug products in hard-to-reach
areas, such as within disaster areas, for military operations, low-
or middle-income countries, and even for space missions. Due to
being digitised in nature, 3DP is well placed to be connected to
other digital health technologies, including artificial intelligence
and remote diagnostic tools including smart monitors and point-
of-care tests, which could be sent to a clinician for data review
and generation of a personalised prescription, enabling the easy
review and modification of treatments or dosages.
Significant progress has been made over the last 5 years to
advance and translate this technology from a theoretical benefit
into a realistic prospect in pharmaceutical production [32–34].
Indeed, the benefits of 3D printing in pharmaceuticals has been
well documented, with the evidence-base and investment into
the research of 3D printing growing every day. Since 2016, over
3,700 academic papers have been published in this field according
to PubMed (search criteria ‘3D printed medicines’ [All fields]),
demonstrating the benefits that 3D printing can bring to the phar-
maceutical industry and patients alike. However, despite this
growing support for printing technologies, regulatory and techni-
cal challenges still remain before the widespread adoption of this
technology into the pharmaceutical industry will occur.
This review will provide a timely update on the latest innova-
tions in 3D printed medicines, firstly by discussing the five most
promising 3D printing technologies within pharmaceuticals, as
well as providing an overview on the latest, cutting-edge pre-
clinical and clinical research using 3D printed medicines in the
clinic. Finally, we will provide an opinion on the remaining barriers
to entry of 3D printing technologies in pharmaceuticals, as well as
provide a forward-looking approach towards the widespread adop-
tion of 3D printing in clinical practice.
2. 3D printing technologies
3D printing is an umbrella term that include several technolo-
gies; according to the American Society of Testing Materials
(ASTM) classification there are seven main categories [35]: binder
jetting, VAT polymerisation, powder bed fusion, material jetting,
material extrusion, direct energy deposition and sheet lamination
(Fig. 2) that can be divided into different subcategories [36]. Within
pharmaceuticals, five main 3D printing technologies can be distin-
guished: binder jetting, VAT polymerisation, powder bed fusion,
material jetting, material extrusion. These 3D printing technologies
and their applications have been extensively reviewed elsewhere
[37,38], and so only a brief description of each technology will be
provided in this review.
2.1. Binder jetting
Binder jetting is a form of additive manufacturing where a liq-
uid binding solution is selectively deposited with a printer nozzle
over a powder bed. The wetted powder particles adhere together
causing layer solidification [40]. This technology was adapted in
2015 as an alternative mass manufacturing process called ZipDose
technology to produce the first FDA approved 3D printed tablet
(Spritam
"
by Aprecia Pharmaceuticals) [41]. Binder jetting is suit-
able to produce highly porous, fast dissolving tablets with high
drug loadings of drugs showing appropriate properties [42]. Spri-
tam
"
dissolves in the mouth in 11 s needing only small amount
of saliva and can incorporate a dose of up to 1000 mg. However,
this technology is also applicable to the production of complex for-
mulations such as near zero-order release dosage forms [43]. To
avoid the use of organic solvents, pharmaceutical binders could
be dissolved in aqueous inks [3].
2.2. VAT photopolymerization
Vat photopolymerization uses a laser to induce the solidifica-
tion of a liquid resin by photopolymerization [44]. This process
encompasses stereolithography (SLA), digital light processing
(DLP), and continuous liquid interface production (CLIP) technolo-
gies, being SLA the most used for pharmaceutical purposes [45].
SLA has a high degree of resolution necessary to fabricate drug
delivery devices with complex structures, such as microneedles
for skin delivery [46,47], bladder devices for intravesical drug
delivery [48], hearing aids [49], anti-acne masks personalised to
the patient’s anatomy [50] or drug loaded scaffolds [51]. More
recently, this technology was applied to the field of dosage form
manufacturing, where it has been employed to produce polypills
containing up to six different drugs [6] and reservoir devices for
oral drug delivery [52]. However, the compatibility of photocurable
resins and drugs should be ensured to avoid unwanted chemical
reactions between the drugs and the resins [53]. Also, the toxicity
of photosensitive polymeric materials has hindered their applica-
tion for biomedical purposes. The selection of biocompatible com-
pounds or improved curing procedures could help improve resin
compositions to mitigate potential toxicity [54].
2.3. Powder bed fusion
Powder bed fusion uses a laser to draw a specific pattern on a
powder bed, melting the powder particles together to form the
3D object [55,56]. It includes selective laser sintering (SLS), multi-
jet fusion (MJF), direct metal laser sintering/selective laser melting
(DMLS/SLM) and electron beam melting (EBM). SLS is the main
technology employed in the production of medicines and medical
devices [57]. In the past, due to the high localised temperatures
required to sinter powder materials which may cause drug degra-
dation, this technique has been mostly restricted to the production
of medical devices, such as scaffolds [58]. However, in 2017, Fina
et al. [59] described the use of an alternative diode laser 3D printer
to manufacture tablets using SLS without degradation of the drug.
Due to the high resolution and precision of the laser, since then,
SLS has also been exploited to fabricate printlets with complex
gyroid lattice structures [60] and orally disintegrating printlets
with Braille and Moon patterns suitable for patients with visual
impairment [61].
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555

2.4. Material jetting
Material jetting involves the deposition of liquid droplets of
materials on a surface. This surface could be a substrate made,
for example, of edible paper (2D printing), or the building plate
(3D printing) [62–64]. This process includes the drop-on-demand
(DOD) technique, in which the drops could spontaneously solidify,
and the nanoparticle jetting (NPJ) and material jetting (MJ) tech-
niques, in which the drops are cured or fused using a heat source
or by UV light [65–67]. Some examples of the application of these
technologies are found in the production of oral films [68], nano-
and microparticles with arbitrary geometries [69] and controlled-
release tablets [70–72].
2.5. Material extrusion
2.5.1. Fused deposition modeling
Fused deposition modelling (FDM) is a form of material extru-
sion in which a polymer filament is heated and extruded through
a heated nozzle creating an object layer by layer [73,74]. The drug
Fig. 2. Graphical representation of the different 3DP technologies. Binder jetting; VAT polymerisation (stereolithography, direct light processing and continuous liquid
interface production); powder bed fusion (selective laser sintering, direct metal laser sintering/selective laser melting, material jet fusion and electron beam melting);
material jetting (nanoparticle jetting, material jetting and drop-on-demand); material extrusion (fused deposition modelling, semi-solid extrusion and direct powder
extrusion); direct energy deposition (laser engineering net shape and electron beam additive manufacturing); sheet lamination (laminated object manufacturing and
ultrasonic additive manufacturing). Adapted with permission from [39].
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556

loaded filaments are usually fabricated by hot melt extrusion
(HME) [75–78]. FDM 3D printing allows the manufacture of objects
with geometrical shapes not obtainable with powder compaction,
such as hollow structures and tablets with different shapes
(sphere, torus, cube, pyramid) [79–81]. Moreover, it is also possible
to modify the drug release patterns varying the infill percentage
[26,82] to obtain controlled release [83–86] and immediate release
[87–90] dosage forms. One of the initial limitations of FDM was the
high printing temperatures required for extrusion and printing,
which caused a risk of drug degradation [91]. However, nowadays
the used of new materials has allowed printing at much lower tem-
peratures to overcome this issue [92,93].
2.5.2. Semi-solid extrusion
Semi-solid extrusion (SSE) is another technology under the
material extrusion umbrella. Instead of extruding a filament, SSE
employs a syringe-like system to extrude a gel or paste in sequen-
tial layers to create the 3D object [94–96]. An advantage of this
technique compared to FDM is the lower temperature required
for printing, which makes SSE more adequate for thermolabile
drugs [97,98]. This technology has been employed to prepare rapid
release tablets [99] and gastro-floating tablets [100], as well as
polypills with compartmentalised drugs to obtain both immediate
and sustained release profiles [5] and orodispersible films
[101,102]. Moreover, using SSE it was also possible to print lipid-
based dosage forms with different geometries, either to be admin-
istered orally [103,104] or rectally in the form of suppositories
[31].
2.5.3. Direct powder extrusion
Direct powder extrusion (DPE) is another type of material
extrusion in which powdered material is directly printed using a
small hot melt extruder within a printhead nozzle. The main differ-
ence of DPE with FDM is that the filament production step is
avoided, reducing optimisation and drug development timelines
and making this technology more accessible for clinicians and
researchers. Another advantage of DPE is that only small amounts
of drug and excipients are needed, making this technique espe-
cially suited for preparing formulations for preclinical and clinical
studies [105,106]. Since the appearance of this technology in the
pharmaceutical field is recent, only a few studies have described
the use of DPE to produce dosage forms. However, medicines incor-
porating tramadol with abuse-deterrent and alcohol-resistant
properties were prepared using this technique [107]. Recently,
the company Triastek, Inc. developed a technology platform called
melt extrusion deposition [108] that could also be considered a
type of DPE.
3. Pre-clinical applications
During the drug development process, pre-clinical studies are
used to test the safety, efficacy and pharmacokinetic behaviour (in-
cluding absorption, bioavailability, metabolism and excretion) of
new drug candidates using experimental and animal models [16].
The data collected crucially aids in deciding which drug candidates
to take forward into first-in-human (FIH) clinical trials and pro-
vides information such as dosing schedules and expected adverse
effects [109,110]. The most common animal model used in preclin-
ical study are rodents which are low cost, easy to handle and have
been shown to have physiological similarities with humans [111].
Small formulations (e.g. size 9 capsules or mini-tablets), as well as
liquid formulations, are typically employed in pre-clinical work as
these formulations have geometries that can be administered to
small rodents. However, traditional manufacturing processes often
hinder the rapid progress through pre-clinical studies, due to being
dose inflexible, high cost and causing high waste.
3D printing technologies have been indicated in providing
unique benefits for pre-clinical studies over conventional manufac-
turing processes, including high degree of dose and design flexibil-
ity. Due to the high degree of design freedom offered by 3D
printing technologies, the production of dosage forms of appropri-
ate geometry and size that contains the exact dosage adapted to
the pre-clinical animal model can be achieved. To date, SLS 3D
printing has been used to prepare small capsule-shaped devices
and 3D printed pellets (miniprintlets of 0.5 mm and 1 mm diame-
ter) that, due to their small size, have potential for administration
to rodents and small animals in preclinical studies [112,113]. In
recent years, the reduction in the price of 3D printers, as well as
miniaturisation and development of user-friendly interfaces, has
made it an affordable and accessible technology which is easy to
integrate and use in a laboratory setting. Indeed, researchers and
laboratory staff can manufacture small batches of printlets in a
rapid and on-demand manner ready for use in preclinical studies.
The increasing number of published studies from all over the
world using 3D printing in preclinical studies has highlighted the
versatility of this technology (Table 1). This section will provide
an overview on the types of 3D printed formulations that have
been evaluated in preclinical animal models, including oral imme-
diate release drug products, modified release preparations, suppos-
itories, as well as latest advances in regional gastrointestinal
targeting and fluid sampling using orally administered 3D printed
devices.
3.1. Immediate and modified release oral drug products
Several studies have tested 3D printed formulations in animal
models to evaluate the pharmacokinetic behaviour of the dosage
forms. FDM 3D printing has previously been used to prepare a
dual-compartmental dosage unit to physically isolate and control
the release of two anti-tuberculosis drugs; rifampicin and isoniazid
(Fig. 3A, B and C). The drugs were compartmentalised to prevent
their simultaneous release into the stomach, avoiding a drug-
drug interaction. The in vivo evaluation in rats confirmed the abil-
ity for the device to release rifampicin first and the delayed and
slower release of isoniazid from the dosage unit (Fig. 3D and E)
[114].
FDM technology has also been used to manufacture 3D printed
tablets with different doses of warfarin, a narrow therapeutic index
drug which conventionally requires splitting of commercially
available tablets to achieve the correct dosage (Fig. 4A and B)
[118]. After administration to rats, the 3D printed tablets showed
a more desirable pharmacokinetic behaviour due to a more sus-
tained drug release compared to the warfarin administered as a
solution (Fig. 4C).
Drug-free and drug-impregnated filaments for FDM printing
have also been prepared using a single-screw HME using diltiazem
as model drug. The study showed that by modifying process
parameters including the infill percentage and the number of
shells, both sustained and immediate-release tablets were
obtained. The fabrication of both pulsatile and chrono controlled-
release tablets was also achieved by alternating the use of the pla-
cebo and drug-loaded filaments (Fig. 5). The in vivo release profiles
obtained from administration of the tablets to rats were consistent
with those obtained in vitro [119].
In one study, FDM printing was used to print four different
polymer-based capsules containing a radiotracer to evaluate
intestinal behaviour after administration to rats. The transit of
the capsules through the gastrointestinal tract was assessed using
PET/CT imaging [116])(Fig. 6. Although the capsules were fabri-
cated with the recommended sizes for rodent administration, the
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Table 1
Examples of studies that used 3DP in preclinical research.
Formulation 3DP technology Drug Animal Aim Ref.
Capsule FDM Lamivudine Beagle dog Fabrication of capsules with different wall thicknesses to
modulate drug release and evaluate the regional absorption of the
drug in the gastrointestinal tract of dogs.
[115]
Capsule FDM Radiotracer [
18
F]FDG Rat Fabrication of capsule-shaped devices filled with [
18
F]FDG to track
the device through the gastrointestinal tract of rats using medical
imaging.
[116]
Capsule FDM Octreotide, sodium caprate and
paracetamol
Beagle dog Fabrication of a pressure sensitive capsule for the local release of
drugs in the upper gastrointestinal tract.
[117]
Tablet FDM Isoniazid and rifampicin B Rat Preparation of a dual-compartmental dosage unit to physically
isolate and prevent the simultaneous release of two anti-
tuberculosis drugs.
[114]
Tablet FDM Sodium warfarin Rat Manufacture of tablets with different doses of an anti-coagulant
drug as an alternative to splitting marketed tablets.
[118]
Tablet FDM Diltiazem Rat Preparation of pulsatile and chrono controlled-release tablets
using drug-free and drug-impregnated filaments.
[119]
Tablet SSE Efavirenz, tenofovir and
emtricitabine
Pig Preparation of controlled release tablets containing three drugs
for HIV treatment.
[120]
Gastro-floating
tablet
FDM Domperidone Rabbit Fabrication of floating tablets with different shell numbers and
infill percentages and determination of their gastric residence
time by X-ray imaging.
[121]
Gastro-floating
device
FDM Amoxicillin Rabbit Fabrication of a floating device to prolong the gastric residence
time of a commercial capsule of amoxicillin and determination of
the residence time by X-ray imaging.
[122]
Gastro-floating
device
FDM Acyclovir Beagle dog Fabrication of a gastroretentive system to prolong the release of a
conventional acyclovir tablet and determination of the residence
time by X-ray imaging.
[123]
Gastric resident
device
FDM Doxycycline and levonorgestrel Pig Development of a gastric resident electronic device capable of
delivering drugs and maintaining in vivo wireless communication.
[124]
Gastric resident
device
VAT
photopolymerisation
Ivermectin Pig Development of a gastric resident dosage forms for ultra–long-
acting drug delivery.
[125]
Pill SLA None Pig and
primate
Manufacturing of a pill with an integrated osmotic sampler and
microfluidic channels for in vivo sampling in the gut.
[126]
Suppository SSE Tacrolimus Rat Evaluation of the therapeutic activity of lipid-based tacrolimus
suppositories in an experimental animal model of colitis.
[20]
Fig. 3. Schematic representation of isoniazid and rifampicin hot-melt extruded drug filaments (A) and the dual-compartmental dosage units (B). In (C) it can be seen a
photograph of the final 3D printed dual-compartmental dosage units. On the right, in vivo drug release profiles of isoniazid (D) and rifampicin (E) in fasted rats after oral
administration of free filaments and dual compartmental dosage units with and without sealing [114].
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558

devices did not empty from the stomach of the animals; an incon-
sistency previously reported by other authors [127]. Subsequent
studies found that the size of the device and the use of anaesthetic
agents influence the gastric emptying of dosage forms [112]. The
findings highlighted in this study highlight the critical importance
to evaluate the impact of a number of variables (including dosage
form suitability and anaesthetisation) on the performance of the
chosen pre-clinical formulation prior to the study being initiated.
SSE has also been employed within preclinical research for the
fabrication of controlled release tablets containing three drugs
(efavirenz, tenofovir disoproxil fumarate and emtricitabine) for
HIV treatment (Fig. 7). The 3D printed tablets were administered
to pigs, and the results of the study showed an enhanced bioavail-
ability of the drugs formulated in the 3D printed tablet compared
to the marketed formulation [120].
Gastroretentive systems are used to prolong the formulation
gastric residence time. 3D printing has also been employed to pro-
duce these types of formulations and some have also been tested in
animal models. For instance, a conventional acyclovir sustained-
release tablet was inserted into a gastroretentive system prepared
by FDM and administered to Beagle dogs (Fig. 8A). X-ray imaging
showed that the device stayed in the stomach for more than
12 h, it was present in the small intestine at 24 h, and finally dis-
appear at 48 h (Fig. 8B), and the in vivo pharmacokinetic analysis
confirmed the prolonged release and absorption of acyclovir
(Fig. 8C) [123]. The same approach has been used in another study
[122] to prolong the release of amoxicillin in the stomach for the
treatment of H. Pylori infection. The gastroretentive device was also
fabricated by FDM and a commercial capsule of amoxicillin was
inserted into the printed device. The capsule in the floating 3D
printed device was administered to rabbits and the residence time
in the stomach was evaluated by X-ray imaging, which showed
that the gastroretentive system remained in the stomach for 10 h
until it disappeared at 12 h as tablet opacity fades. In another
study, FDM was used to print intragastric floating tablets for the
sustained release of domperidone [121]. Unlike the works men-
tioned above, in this study the drug was loaded into the filaments
which were then printed on hollow tablets with different shell
numbers and infill percentages. The floating tablets were given to
rabbits and their stomach residence time was determined by X-
ray imaging. The images showed that the devices remained in
the stomach for at least 10 h until they finally disappear at 12 h,
and the results from pharmacokinetic studies indicated that the
floating tablets exhibited a prolonged release when compared with
commercial tablets of domperidone.
In another study, capsule shells were printed and filled with a
drug-loaded vehicle containing lamivudine (Fig. 9). By controlling
the wall thickness of the capsules it was possible to obtain differ-
ent release profiles, with the final aim of delaying the release of the
drug from the formulation, which allowed the evaluation of regio-
nal drug absorption in Beagle dogs [115].
3D printing also has applications beyond small molecules
towards large molecules and biologics. The growing interest in oral
delivery of peptides and other biological drugs has led to the devel-
opment of alternative strategies to conventional enteric coating.
Targeting the upper part of the GI tract is especially challenging
using enteric coatings due to the high variability that enteric
coated dosage forms exhibit in the time of drug release. To over-
come this challenge, one group devised 3D printed pressure sensi-
tive capsules that were capable of breaking in a specific section of
the GI tract [117]. The devices were manufactured by FDM using
filaments produced by extrusion of Eudragit RS powder. The cap-
sules were loaded with the octapeptide octreotide and the perme-
ation enhancer sodium caprate (C10) and administered orally to
beagle dogs. Paracetamol, which is completely absorbed in dogs,
was also included in the formulations to help with the evaluation
of the capsule performance. Moreover, drug delivery from the 3D
printed capsules were compared with traditionally enteric coated
gelatin capsules and enteric coated tablets. The results showed that
the pressure sensitive capsules released the drug in 50% of the dogs
and had a similar performance in terms of octreotide bioavailabil-
ity or C
max
compared to the enteric coated dosage forms. This study
demonstrated, for the first time, a novel strategy for delivering bio-
logics orally using 3D printing.
The combination of biomedical electronics with 3D printing
represents another innovative approach to achieve advanced per-
sonalised diagnostics and therapeutic functionalities [1]. Most
long-term resident electronic devices need to be implanted by
invasive procedures or require complex equipment for communi-
cation. However, the delivery of electronics through ingestion rep-
resents a feasible approach with a myriad of functionalities, such
as measuring pH or temperature or even administering medica-
tions. Using 3D printing technology, it was possible to fabricate a
wireless gastro-retentive electronic device with a residence time
in a porcine stomach of 36 days while maintaining in vivo wireless
communication for at least half the time (Fig. 10)[124]. The device
included a drug delivery module with a two-arm gastric residence
architecture made of polylactic acid (PLA) and a thermoplastic
polyurethane that expands to a diameter larger than the diameter
of the pylorus and enables the simultaneous controlled-release of
drugs. The passive disintegration of the device allowed its passage
through the pylorus and gastrointestinal tract to be finally excreted
(Fig. 10).
Fig. 4. Rendered image (A) and photograph (B) of 3D printed tablets adapted in size
for oral gavage administration in rats. Figure (C) shows the in vivo drug release
profiles of warfarin in rats after oral dosing of 200 or 400
l
g from warfarin solution
and warfarin loaded 3D printed tablets [118].
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These gastro-retentive devices are especially useful when an
extended release of drugs is desired. An example of the possible
application of these long-acting devices is in the malaria treatment,
where the efficacy of the therapies depends on obtaining sufficient
drug blood levels over a long period of time. Since malaria is more
prevalent in resource-limited and less-developed areas, adherence
to the treatment is hampered. To overcome these limitations, an
ultra-long-acting drug delivery device was developed that can
achieve a sustained release of ivermectin, an antimalarial drug,
for at least one week [125]. The star-shaped devices were created
using a PCL matrix containing a crosslinking agent. The mixture
was added to PDMS (Dow Corning Sylgard 184 RTV silicone)
moulds and cured for 48 h. The moulds with the desired star-
shaped geometry were fabricated using 3DP. The devices contained
degradable linkers made from Eudragit L100-55 and an adhesive
plasticiser on the arms to facilitate the dissociation and passage
of the dosage form through the intestine. The dosage forms were
administered to pigs folded inside 00 capsules, and once in the
stomach, the gelatin capsule dissolves and releases the device that
unfolds its arms. X-ray images showed that the star-shaped device
remained in the stomach for up to 10 days without affecting the
passage of food.
3.2. Rectal formulations
The first attempts to prepare rectal or vaginal formulations
using 3DP focused mainly on creating moulds that were used to
cast suppositories. Using FDM, it was possible to create moulds
using different materials, such as PVA [128–130] and resins
[131]. However, this work did not print the suppositories directly.
More recently, a new approach to prepare self-supporting suppos-
itories without the need for moulds has been described [31]. Using
SSE technology, lipid-based suppositories loaded with tacrolimus
were successfully prepared (Fig. 11A) in different sizes and with
different dosages as an example of how 3DP could aid medicine
personalisation. Blends of Gelucire and coconut oil were employed
as excipients due to their self-emulsifying properties, which helped
to solubilise the drug once the suppositories began to melt at
human body temperature. As tacrolimus is an immunosuppressant
drug used in a variety of conditions, such as therapy-resistant
ulcerative colitis, in a subsequent study, the suppositories were
adapted in size and dose for its administration to rats with exper-
imental colitis (Fig. 11B) [20]. PET/CT imaging [132] was used to
monitor the evolution of the disease before and after the adminis-
tration of the treatment. PET/CT images showed a remission of the
disease from day 7 compared to the control group (Fig. 11C), which
confirmed the efficacy of this approach in ameliorating colitis.
In other study, self-nanoemulsifying suppositories loaded with
lidocaine were prepared for the topical pain relief in conditions
such as haemorrhoids [133]. The suppositories were prepared
using blends of lipid excipients and surfactants (Geloil, Gelucire
and Kolliphor) selected to form a nanoemulsion to provide a larger
surface for drug solubilisation. This work provides another exam-
ple of suppository personalisation.
3.3. Gastrointestinal fluid sampling
The development of technological devices capable of noninva-
sively sampling different locations of the GI tract could provide
new insights into the relationship between the microbiome and
Fig. 5. (A) Design of chrono controlled-release (A1) and pulsatile (A2) tablets. Drug-free layers are coloured in grey and drug-loaded layers in red. (B) Photographs of printlets
with varying infill density and infill patterns, as well as chrono and pulsatile printlets. (C) Drug absorption profiles after oral administration of (C1) immediate-, (C2)
extended-, (C3) chrono- and (C4) pulsatile-release tablets [119]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of
this article.)
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560

human health. Medical analysis often relies on easily accessible
samples (e.g., faeces) that are inadequate for identifying abnormal
conditions as the gut microbiome changes as intestinal contents
moves through the GI tract. Recently, 3D printing has been used
to fabricate a miniaturised biocompatible pill with an integrated
osmotic sampler and microfluidic channels for in vivo capable of
sampling in different locations in the gut (Fig. 12)[126]. The pill
was composed of three main parts: top sampling head, a semiper-
meable membrane in the middle and a bottom salt chamber. The
membrane was made of cellulose acetate and the pill casing was
fabricated using a biocompatible photocurable polymer and cov-
ered with a pH-sensitive enteric coating. Also, a magnet was placed
inside the salt chamber to enable the pill to sample from a targeted
region of the intestine. The pill sampling head and the bottom salt
chamber were manufactured using an SLA 3D printer. Briefly, a
pressure differential was created across the semipermeable mem-
brane that facilitates the flow of water from the microfluidic chan-
nels towards the salt chamber. The porosity of the membrane
allowed larger particles, such as microorganisms, to get trapped
in the channels. The pill was administered to pigs and non-
human primates and the bacterial populations recovered from
the channels closely resemble the bacterial populations present
in the areas to which the pill was exposed, also demonstrating
its ability to take microbiome samples from upper parts of the gut.
4. Clinical opportunities
4.1. Personalised medicine
In recent years, several studies involving humans have been
carried out to evaluate the use of 3D printing to prepare medicines
tailored to each patient’s needs (Table 2). 3D printing could help to
drive the field of personalised medicine due to its capabilities of
Fig. 6. (A) Above, from left to right pictures of 3D printed capsules made of (A1) Kollicoat IR, (A2) Klucel EF, (A3) Aqualon N7 and (A4) Aquasolve-LG. Bellow, micro-CT images
of the same 3D printed capsules. (B) Fused PET/CT images prior to the administration of the Klucel device and 10, 120 and 360 min post-administration [116].
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producing individualised printlets in small or ‘one-off’ batches,
directly at the point of care. The dosage form could be designed
to contain an appropriate dosage, drug combinations, formulation
type and/or aesthetics that are tailored to suit the patient. This pro-
cess could benefit a number of different situations and patient
groups in the clinic, which will be discussed in turn.
A particularly promising application of 3D printed medicines is
for the formulation of medicines that require exact tailoring and
personalisation. For example, formulation of an exact dose of nar-
row therapeutic index drugs (i.e. those which have a narrow gap
between the therapeutic and toxic dose) is of paramount impor-
tance to ensure drug efficacy and safety [142]. Furthermore, paedi-
atric and geriatric populations often require different dosing and
formulation requirements compared with the standard adult. As
an example, the elderly may have visual or swallowing impair-
ments which may require consideration in the development of
Fig. 7. (A) Photograph of two designs for the 3D printed controlled release fixed dose combination tablets. (B) In vivo plasma drug concentrations for (B1) efavirenz, (B2)
tenofovir and (B3) emtricitabine [120].
Fig. 8. (A) Photograph of a gastroretentive system composed of a 3D printed gastro-floating device and acyclovir tablet inside the device. (B) Abdominal X-ray images
indicating the positions of the gastroretentive system (device from photograph A, indicated with a circle) in the gastrointestinal tract of a beagle dog following oral
administration for 48 h. (C) In vivo pharmacokinetics of acyclovir in the dogs after oral administration of immediate-release (IR) and sustained-release (SR) tablets alone or
included into the gastroretentive system (GR) [123].
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new drug products and packaging. Furthermore, children com-
monly require smaller and tailored dosages of medicines based
on physical characteristics, for example body weight, or body sur-
face area [143,144]. Formulation of personalised drug products
with tailored dosages can be problematic due to the vast majority
of medicines being commercially available as limited dose
strengths and formulation types. In order to achieve the correct
dosage, it is common practice for patients to manually adjust the
dose by tablet splitting or crushing. This practice carries a series
of risks, such as inaccurate dosing and human error [145,146] as
well as the risk of drug product failure for enteric coated tablets,
leading to severe therapeutic consequences for patients
[147,148]. Extemporaneous preparation (also known as com-
pounding) can be used to prepare patient-specific drug products
with tailored dosages, e.g. at facilities that hold a manufacturing
license, such as within hospitals or external specials manufacturing
units. However, it is worth noting that preparation of these drug
products can be a time-consuming and labour-intensive task.
In this instance, 3D printing has been suggested as an alterna-
tive automatic technology which is capable of formulating drug
products containing an exact dosage in a flexible manner. For
example, subdivided tablets of spironolactone and hydrochloroth-
iazide were fabricated using SSE technology as a substitute for the
subdivided tablets obtained by pharmacists’ splitting (Fig. 13)[17].
The comparison between 3D printed and splitted tablets in terms
of mass variation, drug content and content uniformity yielded
improved parameters for the 3D printed tablets, which were found
to meet the requirements of the European Pharmacopoeia. More-
over, the 3D printed tablets had better appearance, improving
the patient compliance and being especially convenient for young
patients.
The first clinical study that used 3D printing for the preparation
of personalised therapies in a hospital pharmacy setting was pub-
lished in 2019 [22]). Chewable isoleucine printlets with different
flavours [22] and colours were prepared by SSE to treat children
with a severe metabolic disease; maple syrup urine disease
(MSUD) (Fig. 14A). The printed formulations were compared with
the conventional capsules prepared by manual compounding in
terms of isoleucine blood levels and medicine acceptability after
six months of treatment. Isoleucine printlets showed mean drug
concentration levels closer to the target value and with less vari-
ability, which was attributed to the consistency in formulation
compared with manually filled capsules, which were often opened
onto food-stuff for administration into children (Fig. 14B and C).
Fig. 9. (A) Images of CAD drawings for 1-, 3- and 5-wall PVA capsule shells and (B) photographs of the 3D-printed PVA capsules (the 3-wall capsule on top of a U.S. dime). (C)
In vivo drug release profiles in blood in Beagle dogs for the reference formulation of lamivudine (50 mg immediate release tablet) and 40 mg 3- and 7-wall drug filled 3D
printed capsules [115].
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Fig. 10. (A) CAD model of the gastric-resident electronic device showing a Bluetooth wireless-microcontroller, antenna, batteries, and drug delivery modules. (B) Photograph
of the electronic device showing it dimensions and (C) X-ray image of the device in a porcine stomach. (D) Photographs showing the expansion of the 3D printed device
before, during and after expansion [124].
Fig. 11. (A) 3D printed self-supporting suppositories in different sizes [31]. (B) 3D printed suppositories adapted in size and dose for administration to rats. (C) PET/CT images
over time of rats treated with the 3D printed tacrolimus suppositories and non-treated. Experimental colitis was induced on day 3. The metabolic activity is coded on a colour
scale ranging from blue (low [
18
F]FDG uptake) to red (high [
18
F]FDG uptake). A lower [
18
F]FDG uptake in the colon can be observed from day 7, which means that the illness is
in remission [20]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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Moreover, all of the different flavours and colours of the printlets
were in general well accepted by patients, although each patient
had different preferences. Research is also ongoing at Alder Hey
Hospital in Liverpool for the production of personalised 3D printed
hydrocortisone preparations for paediatrics [149].
Personalised medicine has been especially linked to genetic
testing, whereby drugs are selected based on the genetic makeup
of an individual patient. It can be envisioned that, in the future,
3DP is used as a small-scale personalised drug manufacturing tool
which is linked to enable the patient’s medicine and dosage to be
produced directly at the point of care, which would be a current
challenge for centralised manufacturing processes.
In addition to the production of oral dosage forms, 3D printing
has also been used to manufacture drug delivery devices with
Fig. 12. On the left, schematic representation and photograph of the 3D printed osmotic pill samplers. On the right, schematic hypothetical drawing of the passage of the
osmotic pill in an enteric capsule through the gastrointestinal tract of a human [126].
Table 2
Examples of studies that used 3DP in clinical research.
Formulation 3DP technology Drug Aim Ref.
Printlets FDM None Investigation of the influence of the shape, size and colour of different
placebo printlets on end-user acceptability.
[134]
Printlets FDM None To evaluate the preferences and perceptions of polypharmacy patients
regarding 3D-printed medicines.
[135]
Chewable printlets SSE Isoleucine Preparation of chewable isoleucine printlets in a hospital setting with
different flavours and colours to treat children with a rare metabolic
disease.
[22]
Candy-like printlets FDM Indomethacin Preparation of candy-like formulations for paediatric patients with
enhanced palatability.
[79]
Subdivided tablets SSE Spironolactone and
hydrochlorothiazide
Preparation of subdivided spironolactone tablets to be administered to
patients instead of the conventional tablets subdivided by splitting.
[17]
Polypills FDM Lisinopril, amlodipine,
indapamide and
rosuvastatin
Fabrication of polypills with bespoke release patterns for multiple
drugs.
[136]
Rapidly disintegrating
tablets
Binder jetting Levetiracetam Clinical study to determine and compare drug plasma concentrations
following the administration of the 3D printed tablet and the reference
formulation in healthy volunteers and to evaluate the effect of food
consumption on the PK profile of the 3D printed tablet.
[137]
Printlets with braille and
moon patterns
SLS Paracetamol Preparation of orally disintegrating printlets suited for patients with
visual impairment.
[61]
Oral films FDM Ketoprofen Haptic evaluation study to assess the readability of 3D-printed Braille
oral films.
[138]
Mouthguards FDM Vanillic acid Manufacture of a tailored oral drug delivery device in the form of a
mouthguard with tuneable release rates and evaluation of it
performance in human volunteers.
[139]
Orthodontic retainers FDM Clonidine hydrochloride Fabrication of wearable personalised 3D printed orthodontic retainers
for local sustained-release of drugs.
[140]
Printlets DLP, SLS, SSE and FDM None Visual evaluation of printlets produced using different 3DP
technologies by children.
[141]
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customised designs and drug release rates. For example, in one
study it was possible to fabricate a customisable oral delivery
device in the form of a mouthguard, which was loaded with clobe-
tasol propionate (CBS) as a model drug, which was replaced by
vanillic acid for human release studies (Fig. 15)[139]. A sustained
release of vanillic acid was achieved through the duration of use.
However, the release rate was faster compared with in vitro
release, perhaps due to disturbances generated by tongue move-
ments and salivation. Volunteers only reported some minor dis-
comfort due to imperfect fitting and speech impediment,
problems that could be partially overcome with the use of a 3D
printer with better resolution to obtain mouthguards with well-
defined walls. In another study, personalised orthodontic retainers
loaded with clonidine hydrochloride were prepared for the local
sustained-release of the drug [140]. The PK profiles of clonidine
hydrochloride after dosing were simulated using pharmacokinetic
modelling (Gastroplus
"
). The simulated release profiles showed a
burst release followed by a sustained-release for more than 3 days,
but when the retainers were washed to remove the clonidine
hydrochloride present on the surface of the device, the burst
release and also the possible adverse effects derived from the burst
release were avoided.
4.2. Improved medicine acceptability
3D printing has demonstrated the potential to produce medici-
nes with a desirable geometry or formulation characteristics,
enabling an improvement in medicine acceptability. To date, a
number of different patient-friendly formulations have been devel-
oped, including rapidly dispersing tablets [150,151], chewable for-
mulations and rapidly dissolving oro-dispersible films [68,152]. In
all cases, these formulations could ease administration in patients
with dysphagia, commonly demonstrated in paediatric and geri-
atric populations.
Fig. 13. Photographs of 3D printed spironolactone tablets (2 and 4 mg) (A) and
hydrochlorothiazide tablets (5 mg) (B) compared to tablets with the same dose
obtained by splitting commercial tablets. (C) Mass variation for subdivided tablets
obtained by 3D printing and by splitting commercial tablets [17].
Fig. 14. (A) Chewable printlets in different flavours, colours and with different
doses of isoleucine. (B) Isoleucine blood levels of the patients during the study and
(C), isoleucine blood levels and mean values for printlets and capsules during the
study [22].
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4.2.1. Paediatrics
One of the benefits of implementing 3D printing in healthcare
and early human studies is the possibility to produce dosage forms
with personalised colours and flavours, which paediatric patients
could especially benefit from. Among these patients, the main rea-
son for refusal of medication is taste adversity [153]. Thus, the
development of dosage forms using taste-masking strategies and
with attractive shapes and colours could improve patient compli-
ance and treatment adherence. In this regard, a study used FDM
to prepare candy-like chewable printlets with enhanced palatabil-
ity that can be easily consumed by children [79]. Indomethacin
was used as model drug and hypromellose acetate succinate
(HPMCAS) and polyethylene glycol (PEG) were used as the thermo-
plastic carrier and plasticiser, respectively. The preparation of drug
filaments using HME helped to improve the taste due to the drug-
polymer interactions during the HME process. Printlets imitating
Starmix
"
sweets were printed in the form of a heart, bottle ring,
bear, ring, and lion. The taste masking ability of the Starmix
"
print-
lets was evaluated by giving the formulations to healthy volun-
teers. The printlets showed adequate taste masking and the
volunteers did not report any bitterness or aftertaste, which is of
the utmost importance in paediatric medicine. Other works have
proposed interesting approaches taking advantage of the versatil-
ity of 3D printing, such as the manufacture of chocolate-based
dosage forms with customised designs [154] and chewable
gelatin-based LegoTM-like bricks [155].
In another study, the preference of children aged 4–11 years for
different printlets was assessed based on visual inspection of the
printlets [141]. Placebo printlets were prepared using four differ-
ent 3D printing technologies: DLP, SLS, SSE and FDM (Fig. 16A).
The results of the survey showed that 61.7% of children consider
DLP printlets to be the most visually appealing, followed by SLS
printlets, and with both FDM and SSE printlets scoring the lowest
(Fig. 16B). However, when the children were informed that the
Fig. 15. Photograph of the 3D printed mouthguard comprising a clobetasol propionate (CBS) free zone (red) and a CBS-containing zone (off-white). On the left, another
mouthguard comprising a drug laden area (off-white) and a drug-free area (white) where CBS was substituted by vanillic acid for human testing [139]. (For interpretation of
the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 16. Above, placebo printlets fabricated by (A1) digital light processing (DLP), (A2) selective laser sintering (SLS), (A3) semi-solid extrusion (SSE) and (A4) fused deposition
modelling (FDM). Bellow, summary of visual description data for the printlets manufactured by the different 3DP technologies based on their familiarity, appearance,
perceived taste and texture (DLP, n = 244; SLS, n = 170; SSE, n = 125; FDM, n = 92) [141].
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SSE printlet is chewable, most of them changed their original
choice highlighting children’s preference for chewable dosage
forms.
4.2.2. Adult and geriatric populations
To date, several studies have evaluated the potential for 3D
printing to create patient-friendly formulations that would be
otherwise impossible to produce with conventional mass manufac-
turing processes. Goyanes et al. [134] published the first study
which evaluated acceptability of 3D printed medicines. A wide
variety of printlets were produced using FDM printing, with differ-
ing geometries and colours, which were evaluated for ease of swal-
lowing and picking (Fig. 17). It was noted that printlets with a
similar physical appearance to conventional formulations (e.g.,
caplets and discs) were favoured. Interestingly, and somewhat
unexpectedly, the formulation that scored the highest in ease of
swallowing and picking were the torus-shaped printlets, which
highlights the need to consider alternative shapes and sizes despite
conventional practice.
The preferences and perceptions of polypharmacy patients
regarding 3D printed medicines were evaluated in another study
[135]. As in the previous study, the patients tended to prefer
shapes similar to conventional forms. Also, the easy to handle
and most importantly easy to swallow shapes were the most
appealing to them.
In another interesting study, SLS 3D printing was employed to
prepare orally disintegrating printlets (ODPs) with Braille and
Moon patterns to enable visually impaired patients to identify
medications (Fig. 18A and B) [61]. The printlets were also pro-
duced in different shapes to offer additional information, such
as the dosing regimen, and their readability was verified by a
blind person. Using FDM, it was also possible to fabricate intrao-
ral films with Braille dots of 0.2 mm height to comply with the
Marburg Medium spacing convention for pharmaceutical Braille
on packaging (Fig. 18C). The films were subjected to a haptic eval-
uation by visually impaired volunteers, which reported an excel-
lent readability of the Braille texts. Moreover, the intensive
handling derived from the haptic evaluation did not affect the
height of the dot, a crucial factor to guarantee the readability
and safety of the films [138].
Although not tested in humans, orodispersible warfarin films
were prepared using SSE [21] as an alternative to oral powders in
unit dose sachets prepared by manual compounding used to treat
the patients. Moreover, a QR code was printed onto them by inkjet
printing to avoid medication errors. The administration of the films
through a nasogastric tube was mimicked to ensure that the for-
mulations could be administered to the hospital patients. The films
displayed improved drug content compared to the conventional
formulation with the added advantage of easier administration,
as they are intended to be administered directly into the patient’s
mouth without the need of water.
Polypharmacy, which involves the use of more than one medi-
cine at a time is an increasing reality in geriatric populations that
can cause challenges in medication adherence [156,157]. For
example, patients who have multiple co-morbidities (for examples
those with heart disease, diabetes, or HIV) are often affected by a
high tablet burden which requires patients to have a good under-
standing of and discipline with their treatment regime to ensure
treatment efficacy and safety [158]. To overcome a high tablet bur-
den and reduce complexity in the treatment pathway, pharmaceu-
tical companies have developed polypills, which combine multiple
drugs and/or dosages into a single formulation. It is worth noting
that the conventional production of polypills does not currently
support personalisation, and instead uses mass production to pro-
duce fixed-dose combinations. Whilst this can reduce the pill bur-
den for patients who are on maintenance (and unchanging
dosages) it does not support the ability to individualise dosages
based on the changing needs of the patient.
As an alternative solution, a number of papers have demon-
strated the potential for 3D printing to produce 3D printed polyp-
ills (termed polyprintlets) using a range of printing technologies
due to its ability to flexibly adapt dosages and drug combinations
on demand [4,10,159]. A previous study prepared highly modular
3D printed polyprintlet capsules using FDM printing combined
with hot-fill technology [136]. The multi-drug systems contained
four drugs used in the management of cardiovascular diseases
(lisinopril, amlodipine, indapamide and rosuvastatin) separated
into four different compartments with two different spatial distri-
butions; concentric and parallel. The parallel format was intended
to obtain an immediate release profile, whereas the concentric
Fig. 17. (A) Capsule-shaped printlets in different colours and printlets with different geometries (disc, torus, sphere, titled diamond, capsule, pentagon, heart, diamond,
triangle and cube) presented in four different sizes [134].
I. Seoane-Viaño, S.J. Trenfield, A.W. Basit et al. Advanced Drug Delivery Reviews 174 (2021) 553–575
568

format was designed to achieve a more delayed release of the drug.
Drug release control was achieved by manipulating shell thickness
and pore sizes in the concentric and parallel formats, respectively.
In silico simulation of pharmacokinetics was performed using Gas-
troplus
"
to provide an approximate in vitro plasma profile that
could help to design a polypill suited to individual patient needs.
4.3. Mass manufacture
3D printing has also been explored as an alternative tool for
mass production. Indeed, in 2015, the world’s first 3D printed oral
drug product received regulatory approval from the FDA (Spri-
tam
"
, Aprecia Pharmaceuticals) and was commercialised for
patient use [41]. The Spritam
"
manufacturing system involves a
scaled-up binder jet printing system enabling tablets containing
the anti-epileptic drug, levetiracetam, to be mass produced in a
fixed dose. The ability of binder jet 3D printing to produce highly
porous and rapidly disintegrating oral formulations was exploited
to produce high drug-loaded (1000 mg) rapidly disintegrating
tablets. This product was approved following a study published
in 2016 which tested the first 3D printed medications in humans
[137]. The study aimed to compare drug plasma concentrations
following the administration of the 3D printed tablet and the refer-
ence formulation (an immediate-release tablet) in healthy volun-
teers. In addition, the effect of food consumption on the
pharmacokinetic profile of levetiracetam 3D printed tablet was
also evaluated. The results showed that the rate and extent of drug
absorption obtained with the 3D printed tablet was equivalent to
the conventional immediate-release tablet. A delay and a reduced
absorption profile were only observed in volunteers under fed con-
Fig. 18. (A) Photograph of printlets containing the Braille alphabet and (B), printlets with Braille and Moon patterns printed in different shapes [61]. (C) Images of the Braille
dots onto the surface of films with different dosage strengths [138].
I. Seoane-Viaño, S.J. Trenfield, A.W. Basit et al. Advanced Drug Delivery Reviews 174 (2021) 553–575
569

ditions, and most participants agreed that the 3D printed tablet
was acceptable and easy to take and swallow.
4.4. On-demand printing in hard-to-reach areas
Due to the potential for portable and decentralised manufac-
ture, 3D printing could have numerous benefits for hard-to-reach
locations to improve medicines access, such as within low- and
middle-income countries [160], disaster zones or even in space.
In 2017, the very first medical supplies were 3D printed in space,
whereby custom-fitted hand splint models were both designed
and printed in orbit [161]. In 2019, NASA funded the evaluation
of 3D printed prosthetics for treating space injuries such as mallet
finger [162]. In-space 3D printed manufacturing could also be
applied to oral medicines and medical devices, enabling astronauts
to better design and produce medicines on demand based on the
unexpected clinical needs of crew members within deep space-
crewed missions.
4.5. Veterinary applications
As demonstrated in Section 3, due to the potential for 3D print-
ing to produce animal-appropriate medicines in a wide range of
dosages, there is a natural extension of this technology into the
veterinary medicine sector. Domestic animals, such as dogs, cats,
guinea pigs and rabbits, typically require dosing by age or body
weight, depending on the drug and indication. Conventionally, this
requires the owners to split commercially available dosage forms
or administer an appropriate dosage via a syringe directly onto
the animal’s food or into their mouth. Such practices come with
a high risk of human error, as well as a risk of the animal rejecting
the medicine if the formulation is not palatable. Dogs, for example,
have an acute sense of smell and hence if the formulation is not
desirable or palatable, there is a risk that the drug may not be
administered or rejected. Owners typically attempt to overcome
this issue via masking the medicine in the animal’s food, however
there is a risk of drug-food interactions, or the animal eating only a
small part of the food and not gaining the appropriate dosage
[163,164].
It could be envisioned that, in the future, personalised animal
formulations with a suitable dose and palatability could be 3D
printed in the veterinary clinic or at home, to ensure pet safety
in medicines administration [165].
5. Challenges and future directions of 3D printing in
pharmaceuticals
The integration of 3D printing, alongside other innovative tech-
nologies, into pharmaceuticals has been forecast to give rise to a
new digital pharmacy era (Fig. 19). With the integration of
non-invasive diagnostics or drug monitoring strategies (e.g., via
artificial intelligence and point-of-care testing) and electronic pre-
scriptions, 3D printing could provide a digital and decentralised
platform for the production of tailored medicines in response to
these monitored outputs [166]. Indeed, numerous researchers
around the world hold this vision for 3D printing, with new
research papers being published every day to further evidence
the potential of 3D printing technologies in formulation develop-
ment and patient care. However, as discussed in the previous sec-
tions, only a limited number of studies have been performed in
pre-clinical and clinical settings. This hesitation around testing for-
mulations in vivo is likely due to a combination of reasons, ranging
from regulatory, quality and technical concerns through to a need
for a shift in mindset and culture for the acceptance of digital tech-
nologies in Pharma.
It is widely regarded that the most pressing obstacle for the
integration of 3D printing in pharmaceuticals is the lack of clear
regulatory guidance and advice from regulatory agencies. In
2017, the Food and Drug Administration (FDA) published a techni-
cal guidance on 3D printed medical devices and prosthetics [167],
however, although the FDA has already approved some additively
manufactured medical devices, none of these have a drug delivery
function [168]. To date, the only 3D printed drug product approved
for commercialisation is Spritam
"
, by Aprecia Pharmaceuticals,
Fig. 19. The virtuous cycle of personalised medicine.
I. Seoane-Viaño, S.J. Trenfield, A.W. Basit et al. Advanced Drug Delivery Reviews 174 (2021) 553–575
570

which is an alternative scaled-up manufacturing process and hence
falls under the standard regulations for dosage form production.
For the on-demand production of personalised medicines using
3D printing, standard regulations could not apply due to the need
for flexible and adaptative manufacture based on real-time market
demands.
The debate of whether 3D printing should be considered a man-
ufacturing process or extemporaneous production (compounding)
is still ongoing, with strong arguments in favour of the latter.
Extemporaneous compounding involves the preparation of an unli-
censed medicine for an individual patient in response to an identi-
fied need. Conventionally, extemporaneous formulations are
produced in hospital pharmacies, community pharmacies, and spe-
cials manufacturing units, with the pharmacist producing a per-
sonalised drug product for the patient. Indeed, on the one hand,
3D printing technologies can be viewed as ‘automatic com-
pounders’, whereby a drug-loaded feedstock is inserted into the
printer and the dosage controlled via the amount of material
deposited onto the build plate. This vision is similar in concept to
an automatic liquid dispenser, whereby the correct dose is auto-
matically calculated and dispensed by the machine.
Two potential implementation models could be applied here.
One strategy could involve a ‘Nespresso’ style system, whereby
the 3D printer is analogous to the coffee machine and the drug-
loaded feedstock is analogous to the interchangeable coffee pods.
This model would involve the drug-loaded feedstock cartridges
being premade by a facility holding a manufacturing license,
involving the feedstock being manufactured, quality and safety
approved and delivered to local pharmacies for on-demand dis-
pensing. Alternatively, another strategy could involve the feed-
stock being prepared in the hospital or pharmacy via
extemporaneous preparation (pharmaceutical compounding);
whereby the pharmacist could either mix the required drug and
excipient powders or crush commercialised preparations and mix
with additional excipients. The potential to use marketed formula-
tions would avoid the risk of patent infringement as it would fol-
low the general process of extemporaneous preparation.
However, depending on the 3D printing technology used, exter-
nal factors such as the application of heat or light may be required
and hence it would be important to ensure the quality of the for-
mulation post-printing. It is clear that for the application of 3D
printing within personalised medicines and drug development, it
is vital that regulatory guidance and support is developed to best
guide and support stakeholders looking to innovate the sector
and to aid the integration of this technology into the pharma space.
Another key consideration for the application of 3D printing
into clinical trials involves ensuring the quality of the dosage forms
produced to ensure participant safety. Conventional quality control
(QC) tests used within large-scale manufacturing processes are
inherently destructive, laborious and expensive, which would be
unsuitable for on-demand production at the trial site using 3D
printing. Several studies have described the implementation of
reliable and non-destructive analytical techniques for real time
drug quantification [169,170]. In this sense, near infrared (NIR)
and Raman spectroscopy have shown to be capable of performing
QC measures of 3D printed medicines in a non-destructive manner
in studies performed by University College London in collaboration
with Pfizer [171,172]. Other studies have suggested using track-
and-trace measures by including QR codes and data matrices on
formulations to ensure drug product quality and safety
[173,174]. Such innovative strategies could provide a real-time
assurance of drug product quality, facilitating the use of the tech-
nology in the clinic.
Aside from regulatory and QC issues, commercially available 3D
printers were previously not standardised or fit-for-purpose (per-
taining to Good Manufacturing Practice; GMP) for the production
of pharmaceutical products. As discussed previously, there are a
wide range of different 3D printing technologies available, many
of which have been explored for the production of pharmaceuticals
in academic research papers. However, certain technologies are
more amenable to pharmaceutical production than others. Vat
photopolymerization methods, for example, have widely recog-
nised technical challenges surrounding the use of non-GRAS (Gen-
erally Recognized As Safe) certified materials with potential
cytotoxic effects in vivo. Indeed, the ideal 3D printer for pharma-
ceuticals will be compact, low cost, easy-to-use, produce medici-
nes safely and with a high quality, and have an acceptable
production speed. With the aim of attaining this goal, companies
have been focussed on developing pharmaceutical 3D printers that
meet GMP and QC requirements. For example, FabRx Ltd., a com-
pany specialised in the manufacture of 3D printed drug products,
has recently developed the M3DIMAKER
TM
3D printer which has
multiple exchangeable extrusion-based nozzles that is intended
for use in hospital pharmacies, specials manufacturing units or
clinical trial settings [175]. This is the first 3D printer especially
developed for the production of personalised medicines that can
be fully validated to GMP regulations, achieving a significant mile-
stone in the history of 3D printed pharmaceuticals. Other compa-
nies, including DiHeSys [176], Vitae Industries [177] Craft Health
[178] and Merck [179] are also working towards producing GMP-
compliant pharmaceutical printers, but there is no published
research using these printing systems. Examples of other 3D print-
ers commercialised for pharmaceutical or bioprinting purposes are
Ultimaker [180], Regemat [181], RegenHu (3DDiscovery) [182] and
Cellink (Bio X) [183]. However, it is not clear if these 3D printers
are currently adapted to comply with GMP regulations for
medicines.
From a Big Pharma business perspective, one concern around
digitalised 3D printing technologies for decentralised production
may be the need for protection of formulation and process details
which are widely regarded as business-critical trade secrets. Due to
the requirement for digital transfer of computer aided designs and
printing conditions, issues surrounding data security and accessi-
bility needs to be well controlled and maintained. Another techni-
cal challenge for pharmaceuticals during drug development and
clinical trials is the potential for scale-up of 3D printing processes.
Phase II and III clinical trials generally recruit a higher number of
participants compared to first-in-human (FIH) trials and hence
pose a higher demand on dosage form production. Strategies to
enable the effective scale up for Phase II and III trials could involve
use of multiple 3D printers running in tandem or using a 3D printer
with multiple nozzles enabling a higher throughput.
A final, and somewhat harder to tackle, challenge hindering the
adoption of 3D printing is the need for a mindset and culture shift
within the pharmaceutical industry. Indeed, the industry has well
established manufacturing procedures that were developed over
200 years ago to enable the safe and effective production of med-
icines. However, with the increasing demand for personalised oral
therapies, it is likely that the adoption of alternative flexible man-
ufacturing technologies may be needed in order to meet these
changing market and patient needs. Whilst the evidence-base for
the benefits of 3D printing in pharmaceuticals is extensive, it is
clear that there is still more work to be done before all stakehold-
ers will have full confidence in the technology. To date, the major-
ity of published research in the area has had limited involvement
from more than one key stakeholder. To increase receptiveness
in the community, it will be critical to move towards a more mul-
tidisciplinary approach to 3D printing research, inviting other
major stakeholders (including clinicians, patients, and Big Pharma)
to come together to discuss a way forward for this technology in
the sector and to evaluate more streamlined routes into animal
and human studies. By taking these initiatives, 3D printing will
I. Seoane-Viaño, S.J. Trenfield, A.W. Basit et al. Advanced Drug Delivery Reviews 174 (2021) 553–575
571

be translated from a theoretical prospect to a realistic and revolu-
tionary manufacturing tool to benefit the pharmaceutical industry
and patients alike.
6. Conclusions
This review article summarises the current investigations on
the applications of 3D printing technology in the field of preclinical
and clinical research. Both preclinical studies and FIH trials require
a platform that enables rapid, on demand manufacturing of dosage
forms with flexible doses; requirements that conventional manu-
facturing techniques cannot meet. It is in this sense that 3D print-
ing can revolutionise the way medicines are designed and
produced, expediting the drug development process. This innova-
tive technology is capable of producing dosage forms of virtually
any shape and size and with the exact dose necessary to meet
the requirements of the preclinical or clinical study. The affordable
cost of 3D printers makes it possible to implement them in
research laboratories and hospital settings, where small batches
of printlets can be produced on demand with flavours, colours
and shapes customised to the patients. The continued advances
within the research community will enable the translation of 3D
printing technologies towards a revolutionary manufacturing tool
within preclinical and clinical drug development.
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