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Bioprinting in Pharmaceuticals
Mansi Dixit, Nidhi Singh, Priyanka Das, and Pallab Datta
Abstract
Commercial launch of a pharmaceutical new chemical entity is an outcome
of extensive financial and time commitments. Failure of drugs at late stage of
clinical trials causes immense loss to the developer. Technological innovations
that can provide reliable prediction of efficacy and safety of the molecules
in the early phases of discovery process are of extreme importance for the
pharmaceutical industry. Due to their potential to better resemble composition
and anatomical characteristics of tissues over conventional two-dimensional
monolayer cultures, three-dimensional (3D) models are increasingly proving
beneficial. Successful development of such 3D models is expected to provide
better physiological correlation compared to 2D culture and may be used as a
replacement for animal models. Amongst various other fabrication techniques,
bioprinting has advanced technique to fulfill the purpose of development of
biomimetic constructs.
The chapter presents the fundamental aspects of bioprinting and discusses
their application in different stages of drug discovery like high-throughput
screening and predictive in vitro safety.
9
Keywords
Bioprinting · HTS · 3D models · ADME · Microarrays
M. Dixit
Department of Medical Devices, National Institute of Pharmaceutical Education and Research
Kolkata, Kolkata, India
N. Singh ·P.Das ·P.Datta (
Department of Pharmaceutics, Polymer-based Medical Devices, and Complex Drug Delivery
Laboratory, National Institute of Pharmaceutical Education and Research Kolkata, Kolkata, India
e-mail:
pd@niperkolkata.edu.in
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals,
https://doi.org/10.1007/978-981-99-2404-2_9
)
293
294 M.Dixitetal.
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Abbreviations
2D Two-dimensional
3D Three-dimensional
ASCs Adipose-derived stem cells
BCA Bovine serum albumin
Bio-MEMS Biological microelectromechanical system
BMP-2 Bone morphogenic protein
CBD Collagen-binding domain
CCD Charge-coupled devices
CT Computed tomography
DBB Droplet-based bioprinting
dECM Decellularized extracellular matrix
EBB Extrusion-based bioprinting
EBs Embryonic bodies
ECFCs Endothelial colony-forming cells
ECM Extracellular matrix
EGF Epidermal growth factor
EHS Engelbreth-Holm-Swarm
FGF-2 Fibroblast growth factor-2
HTS High-throughput screening
HUVECs Human umbilical vein endothelial cells
IGF-II Insulin-like growth factor-II
LAB Laser-assisted bioprinting
LBB Laser-based bioprinting
LDW Laser direct-write
LVT Levofloxacin
mESC Mouse embryonic stem cell line
MMP Matrix metalloproteinase
MPS Microphysiological systems
MRI Magnetic resonance imaging
MSCs Multipotent stromal cells
OCN Osteocalcin
PDLSC Periodontal ligament stem cells
PDMS Polydimethylsiloxane
PEGDA Poly(ethylene glycol) dimethacrylate
ROS Reactive oxygen species
SB Scaffold based
SBB Scaffold-based bioprinting
SF Scaffold free
SFB Scaffold-free bioprinting
STRs Structure-toxicity relationship
TGF Transforming growth factor
VEGF Vascular endothelial growth factor
VTD Veratridine
9 Bioprinting in Pharmaceuticals 295
9.1 Introduction
Drug discovery in the preclinical and drug development through the clinical development are the two primary stages involved in the approval of a new drug molecule
(Amir-Aslani and Mangematin
with high affinity, a suitable chemical moiety is screened first from a vast pool
of probable chemical entities (Tiwari et al.
iterations are needed to understand how the molecule interacts with the target. In this
context, trials are conducted in four phases both before and after market approval
to ensure the efficacy and safety of the candidates. Apart from binding to the target,
successful drug candidates are also required to possess stable physicochemical
properties (lipophilicity and solubility) to achieve adequate bioavailability at the
target site. Therefore, the assimilation of drug delivery approach with drug discovery
is increasingly calling for the need of models that predict their future druglikeness early in the pipeline (Zhang et al.
Despite enormous improvements in pharmaceutical research, new drug development
is prolonged and expensive accompanied by a high attrition rate (Waring et al.
2015). In the primary stages of drug development, one to four competitors are
selected from a wide pool of lead molecules. The most significant challenge and
opportunity for therapeutic research and development are to reduce the attrition
rate of drug candidates in the clinical phase—primarily in II and III because
clinical development accounts for almost 61% of the total cost (Paul et al.
According to a review of cumulative data from 2000 to 2011 collected from four
large pharmaceutical corporations, which led to 605 withdrawn compounds from
808 proposed compounds, nonclinical toxicology accounted for approximately 40%
failures. The higher proportion of nonclinical toxicological failures arises due to
processes that are more challenging to deduce from in vitro data, which necessitates
more models to predict toxicological properties. The creation of new techniques to
raise the value of in vitro research can minimize the price of preclinical trials and
greatly enhance the initial detection of a compound’s toxicity (Jovic et al.
During drug discovery, the in vitro efficacy tests are performed to identify the
lead molecules directly from hits. In vitro toxicity assessments exclude substances
with undesirable toxicities and help in the selection of leads with highest safety
profile. These in vitro tests minimize the number of compounds that need to be
validated in the successive trials. Despite the simplicity and speed of these studies,
a nonmimetic in vitro test may fail to recognize active substances and provide
invalid leads for further stages, which undoubtedly increases attrition and cost. Most
common in vitro drug discovery assays are carried out in 2D single-layered cell
culture systems in order to precisely analyze cellular responses to treatments. These
approaches, however, do not perfectly recreate the in vivo conditions (Wrzesinski
et al.
2015). In 2D cell culture systems, the effects of drugs show variations
from in vivo effects, leading to unexpected outcomes. Therefore, it is crucial to
develop in vitro cell-based systems that can accurately mimic the physiological 3D
environment and predict in vivo efficacy and safety.
2010). In order to bind the pharmacological target
2021). Several processes and testing
2019a; Rosen and Abribat 2005).
2010).
2020).
296 M.Dixitetal.
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9.2 3D Models in Pharmaceutics
The 2D single-layer culture technique, in which cells adhere to a smooth or stiff
substrate made of glass or polystyrene, is employed for a majority of cell-based
drug studies. In these studies, rapid cell division results in confluency which
resembles a sheet of paper. Due to the fact that in vivo cells exist in a 3D
microenvironment surrounded by other cells and the extracellular matrix (ECM),
the standard 2D monolayer culture technique has been proven inadequate for these
applications (Rimann and Graf-Hausner
not successfully mimicked an in vivo cell environment. In order to improve the
results of cell assays and overcome these limitations, two key 3D culture systems,
3D scaffold-based and scaffold-free systems, have been developed in the past two
decades (Seoane-Viaño et al.
2021). Cells are embedded in ECM-like matrixes
prior to polymerization or solidification, and cells or cell aggregate is seeded on
a prefabricated matrix cell. Alternatively, cell sheets are used to fabricate layered
scaffold-based models. Scaffold materials include natural or synthetic polymers
or decellularized extracellular matrix (dECM) with varying mechanical properties,
biocompatibility, and toxicities (Blehm et al.
cells are able to grow on their own without the aid of any supporting polymer by
cellular self-assembly generated through cadherin-mediated adhesion (Wang et al.
2022).
Several techniques have been established to create in vitro 3D tissue models, such as bioprinting, hydrogel culture, micro-well, hanging drop, miniature
designed lattice, microfluidics-based methods, acoustic method, and attractive
forces (Ruedinger et al.
2015). Spheroids are the most fundamental and frequently
used 3D tissue models (Beauchamp et al.
surface modification, hanging drop strategy, rotating wall vessels, or impulsive
creation (Achilli et al.
2012). High-throughput microarrays can also micro-fabricate
3D models using various techniques, such as cell printing, micro-wells, surface
patterning, and microfluidics (Li et al.
pharmaceutical products, numerous 3D models or microarrays of biological organs,
including the heart (Mirdamadi et al.
et al.
2022), kidney (Wragg et al. 2019), and lung (Galliger et al. 2019), as
well as disease models, including lung edema (Barros et al. 2021) and carcinoma
(Theodoraki et al.
2015), have been developed.
Furthermore, numerous 3D culture systems, with different ECM compositions,
have been developed for pharmaceutical testing, including drug effectiveness,
targeted drug delivery or toxicity studies, and high-throughput screening (HTS) (Lee
et al.
2014). However, fabricating a biomimetic scaffold with suitable topologic
and mechanical simulation remains a crucial step due to the complication and
specificity of 3D cellular niches. Additionally, due to the complexity required for
the production of 3D models, not all 3D tissue culture models are ideal for reliable
drug testing. There are currently very few mammalian 3D co-culture models that
can be used for commercial drug screening (Chameettachal et al.
2012). Thus, 2D culture techniques have
2015). In systems lacking scaffolds,
2015). Spheroids can be created through
2014). For the analysis of cosmetic and
2020), skin (Sun et al. 2022), liver (Guagliano
2019).
9 Bioprinting in Pharmaceuticals 297
Despite their benefits, 3D models still have certain drawbacks (Eglen and Randle
2015; Liu et al. 2018). One of the major limitations arises from the consolidation of
various cell types, which results in more heterogeneity and inconsistent comparison
of data to 2D models. Furthermore, 3D models do not adhere to any volume or
size standards (Zhang et al.
to-batch differences in vivo, which have shown inconsistent experimental results.
Although synthetic matrices exhibit more consistent performance, their applicability
is limited due to low biocompatibility (Peng et al.
using high-throughput microarray systems or standardized microfluidics-based
technologies have discovered discrepancies between natural scaffolds and specific ECM components (Rothbauer et al.
or high-throughput analysis, 3D culture is more expensive and time-consuming
than traditional 2D culture. Moreover, 3D tissue models generated from in vitrocultivated cells cannot be hierarchical, controlled designs and structures of native
tissue.
According to a recent study, 3D systems primarily rely on cell-to-cell and
cell-to-ECM transport networks to communicate information between cells and to
distinguish between various 2D and 3D systems (Abaci and Guvendiren
overcome the constraints of 3D models, this cellular t ransport network has to be
set up in a biomimetic manner, giving mammalian cells the appropriate topological
signals with the precise niche, and inducing mechanical stress, similar to those found
in vivo (Kjar and Huang
culture systems, bioprinting has the greatest potential since it may closely imitate in
vivo cell-to-cell and cell-to-matrix communication (Ozbolat et al.
2018). Natural ECM lattices exhibit significant batch-
2017). A few investigations
2016). For large-scale investigations
2020). To
2019). Amongst the different methods used to create 3D
2016).
9.3 Bioprinting in Pharmaceuticals
Bioprinting has received a lot of attention in recent years on a global scale and
has made a significant impact on biomedical sciences (Ozbolat
involves the simultaneous placement of scaffold and cell lines in a layer-by-layer
manner (Ozbolat
arrangement of genetic materials, proteins, living cells, drugs, growth regulators,
and other biologically active substances in order to regulate tissue development
and synthesis. The biomaterial arrangement utilized in bioprinting is referred to as
“bioink.” The main bioink components utilized in bioprinting technology include
cell mass (including tissue spheroids, tissue strand, and cell pellets) (Hospodiuk et
al.
2017), hydrogels, micro transporters, and decellularized network compartments
(Decante et al.
two methods that can be used to perform bioprinting (Ozbolat
first, cells are bioprinted onto exogenic biomaterial matrices such as hydrogels or
dECM. Cell granules or pre-aggregates of cells are sparsely contained in printable or
molding structures during self-assembly. The bioprinting procedure typically entails
bioink sampling, bioprinting, and usage of bioprinted scaffolds in vitro or in vivo.
2015a). It entails high accuracy in the spatial and temporal
2021). Scaffold-based bioprinting and scaffold-free bioprinting are
2016). Bioprinting
2015b). In the
298 M.Dixitetal.
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Imaging methods and analysis of proposed designs with computer assistance are
additional steps (Jose et al.
2016).
9.4 Types of Bioprinting
On the basis of biological material deposition and printing methodologies, bioprinting is classified into three subcategories, extrusion based, droplet based, and laser
based (Ozbolat and Gudapati
drug discovery and development (Peng et al.
2016), and their applications in tissue construction for
2017)are showninFig. 9.1a, b.
9.5 Extrusion-Based Bioprinting (EBB)
Extrusion-based bioprinting technique is based on the extrusion of fibers made up
of bioinks and is being utilized widely for bioprinting of living cells (Tian et al.
2021). It features automated three-axis robotic extrusion, material management,
and a fluid dispensing system. This widely used method of extruding biological
materials depends on pneumatic or machine-driven extrusion (cylindrical or screwaided) dispensing processes (Hospodiuk et al.
deposition of different natural materials with diverse rheological characteristics.
The majority of cell support materials have been shown to work with this system
when arranged as hydrogels with viscosities that vary from 31 mPa to >108 mPa
(Yu et al.
2013). Additional advantage of EBB is its capacity to accommodate
cells at extremely high concentrations, such as spheroids. Mechanical driven
2016). The driving forces enable the
Fig. 9.1 Fundamental principles involved in (a) different modalities of 3D bioprinting, reprinted
with permission from (Peng et al.
pharmaceutical research, reprinted from (Vernetti et al.
2017), and (b) the principal application areas of bioprinting in
2017)
9 Bioprinting in Pharmaceuticals 299
extrusion systems are the most popular technique for bioprinting tissue spheroids.
On the contrary, viability of cells is decreased by high shear stress induced by the
dispensing pressure onto liquids. This hindrance may be addressed to some extent,
but it results in loss of precision and speed in bioprinting. Cell functionalization and
survival are higher in EBB as it employs more compatible bioinks with different
degrees of cross-linking of hydrogels (Jacob et al.
2022).
9.6 Droplet-Based Bioprinting (DBB)
DBB, now developed, has formed the basis for the development of bioprinting
(Gudapati et al.
printers, are the most commonly employed DBB. DBB uses bioinks that are
integrated into the cartridges resembling the cartridge used in normal inkjet printing.
Ejection of bioink droplets is followed by chemical and physical cross-linking.
The minimal cell viability in DBB is close to 70%, and in some technologies,
such as acoustic or micro-valve bioprinting and electrohydrodynamic jetting, it
can even reach up to 90%. The advantages of inkjet bioprinting are lower cost,
rapid bioprinting, and compatibility with many biopolymers. On the other hand,
uncontrolled particle diameters and clogging of nozzles in case of bioinks with
excessive cell densities are the major drawbacks of DBB printing (Badr et al.
2016). Inkjet printers, often known as drop-on-demand (DOD)
2022).
9.7 Laser-Based Bioprinting (LBB)
The terms laser-based bioprinting modalities and laser-assisted bioprinting (LAB)
are also called as laser direct-write (LDW). In 1999, a laser-based technology
was used for the first time to conduct two-dimensional cell printing (Odde and
Renn
1999). Despite being less common than DBB or EBB, LAB technique is
more frequently utilized in tissue engineering. The donor slide of a laser-assisted
printer comprises layers of biological material and energy-absorbing material and a
collector substrate slide. In DBB, droplets are ejected due to one amongst thermal,
piezoelectric, or acoustic mechanism. Bioinks are contained in a donor slide made
of gold or titanium (Guillotin et al.
of gold or titanium and then transferred to the collector substrate after absorbing
of laser energy by the donor slide. Various parameters such as wettability of
the substrate layer, distance between the donor and collector slides, thickness,
irradiation energy, and consistency of the organic layer affect the resolution in
laser bioprinting. LBB does not involve any nozzle and thus no clogging issues
are encountered, and it is compatible with viscosity ranging from 1 to 300 mPas.
Despite enormous advantages, LBB possesses some limitations such as increased
cost, tedious planning, and accurate cell deposition (Yang et al.
2014). Bioinks are placed in donor slide made
2021).
300 M.Dixitetal.
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9.8 Bioprinting over Traditional Bio-Fabrication Techniques
In comparison to conventional bio-fabrication methods, bioprinting offers several
advantages, such as increased accuracy and precision, elevated cellular resolution accumulation, high-throughput potential, co-fabrication of cells in a layered
arrangement, and low toxicity (Meenambigai and Kumari
fabricate anatomically precise 3D tissue models from magnetic resonance imaging
(MRI) or computed tomography (CT) images is the primary benefit of bioprinting.
Secondarily, bioprinting enables the fabrication of porous construct with ample
space for transfer of oxygen, cell growth, and nutrients to living cells. Thirdly,
bioprinting enables the simultaneous co-culture and printing of one or more
types of cells to mimic the in vivo anatomical structure (Ozbolat and Yu
Furthermore, bioprinting makes it simple to control the transfer of protein sequence
and growth factors, which is crucial while keeping the engineered structure in
culture for a prolonged period. In contrast to other methods (like soft lithography,
mathematical surface examples, and microfluidic-based control), bioprinting offers
a promising way to produce tissue analogs mimicking native structure (Huang et
al.
2014). Contrary to 3D bioprinted organ replacements for organ transplants,
pharmaceutical-grade bioprinted tissue models are not subject to the same strict
regulatory controls. As a result, pharmaceutical companies have expressed interest
in marketable products such as liver models, kidney arrays, and bioprinted, which
have led to better results in preliminary tests (Faulkner-Jones et al.
has approved the following models like 3D printed liver model (Neff
model, blood-brain barrier model, intestinal tissue model, and placenta model.
Fransen and his team fabricated the in vitro model of kidney using sacrificial 3D
printing technique with gelatin-fibrin extracellular matrix hydrogel shown in Fig.
9.2a, b (Fransen et al. 2021). Madden’s team established an intestinal tissue model
for ADME analysis by utilizing human intestinal epithelial cells. 3D experiments
were performed simultaneously with Caco-2 monolayer (Madden et al.
Janani’s group has established the in vitro model with parenchymal and nonparenchymal cells, which mimic liver lobule microarchitecture using silk fibroin
(Janani et al.
ECM interaction analysis by utilizing 3D bioprinted monoculture glioblastoma
model (GBM). Studies were conducted using gelatin-alginate-fibrinogen hydrogel
by extrusion-based bioprinter (Tang et al.
2022). Tang and his group established a glioblastoma model for tumor-
2021).
2021). The ability to
2013).
2015a). The FDA
2017), kidney
2018).
9.9 Generation of Tissue Constructs Using Bioprinting
9.9.1 Selection of Bioink
Bioinks contain additives, polymers, and cells in a medium to generate a cell
suspension. As already stated, the significant difference between scaffold-based
bioprinting (SBB) and scaffold-free bioprinting (SFB) (Ovsianikov et al.
the formulation of bioinks with or without polymers as the scaffold. The primary
2018)is
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