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9 Bioprinting in Pharmaceuticals 311
Fig. 9.5 (a) Bioprinting and evaluation of monoculture of glioblastoma cells; (b) increased
morphological properties of glioma cells, reprinted with permission from (Tang et al.
2021)
9.11 Crucial Factors for Bioprinting in Drug Discovery
and Development
9.11.1 Target Selection
Reducing Phase II and III attrition is essential for enhancing R&D productivity and
cost-effectiveness. The first step should be chosen as the most authentic and specific
targets, while establishing proof of concept (POC) as soon as expected during the
progress sequence should be the second step (preferably in Phase I). To make the
initial “go/no-go” decisions, this stage also needs crucial therapeutic targeting which
association with the disease may be verified by a biomarker and clinically relevant
and surrogate endpoints. According to the survey, these clinical specialties are more
affected by attrition rates, with Phase II and Phase III dropouts being 70% and 59%,
respectively. This is because some drug targets are only partially predictable, and no
models can accurately predict human physiology (Kola and Landis
2004).
The hereditary indication originating in individuals through gain or loss of
functional state, knockout rat models, and natural effects observed in f ollowing
pharmaceutical intervention in in vivo preclinical models and selection of target
needs to be confirmed. Pharmacologic variation of targets in animal models recurrently produces outcomes that are different from human reactions. Additionally,
frequent in vitro studies by means of mammalian cell line could not accurately
mimic the anthropological in vivo response (Monie and Bhatia
2015). The ability
of bioprinting to mimic complex and clinically relevant human pathophysiological
states can help with the specification and validation of possible targets. Investigations on the relationship between the target and biomarkers or substitute endpoints
have looked quite possible. As already revealed, in the near future, two research
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Fig. 9.6 Comparative diagram showing native intestine, 3D printed intestinal tissue, and Caco-2 monolayers reprinted from (Madden et al. 2018)
9 Bioprinting in Pharmaceuticals 313
have demonstrated that 3D bioprinted models are more effective than 2D models
for screening ROCK as a molecular target for angiogenesis. However, more indepth evidence of 3D bioprinted stages on biological or pathophysiological rationale
with genetic evidence and in vivo analyses is required for target identification and
validation (Roth and Singer
2014).
9.11.2 Efficiency Screening
For in vitro efficiency testing at the hit-to-lead (HTL) phase, bioprinting can be
helpful to mimic the 3D models. Bioprinted scaffolds can be used as substitutes
or replacements for lead optimization in vivo. To achieve these goals, mammalian
cell lines or stem cells can be utilized. A suitable ECM can also be chosen
to replicate in vivo environments. To generate reproducible and reliable data,
bioprinted pathological or physiological tissue construct must be stable. The
objective of successful bioprinting is to create an efficient research framework for
the production of a model that captures the essential traits of a specific disease.
For instance, chemotherapy models can be efficiently fabricated via bioprinting
because cell-to-cell and cell-to-ECM exchanges serve a vital role in cancer growth
and metastasis. Complex co-culture models have been bioprinted to examine the
growth and local immunological responses, which ultimately helps to enhance the
accuracy of prediction of chemoresistance or cytotoxicity of test samples (Zhang et
al.
2016).
On the other hand, bioprinting of infection models is rare (Zhao et al. 2014).
However, for the lead optimization phase, bioprinted models are very affordable
and effective alternatives to traditional in vivo disease testing. The main benefits
comprise decreased costs of testing, minimized ethical issues related to using
animals, shorter expression times for disease progression, and being better than
animal models that could not accurately reproduce data variation (King et al.
2014).
9.11.3 Toxicity Analysis
Lead molecules have traditionally undergone minimal preclinical safety evaluation
beyond the most fundamental in vitro toxicity assays as from drug discovery to
development stage. Nevertheless, the increased percentage of preclinical and clinical
failure highlights the significance of applying toxicology assessments in the initial
stages of the drug development. As a result, higher rate of systemic toxicity analyses
should be conducted before the candidate molecules are subjected to preclinical
GLP toxicity studies. Prospective in vitro toxicological testing (predictive in vitro
assays), in vivo signal pathway, and retrospective in vitro toxicological tests are all
components of early toxicological assays (mechanistic in vitro assays) (Roth and
Singer
2014).
The primary objective of in vitro toxicological assays is to identify toxicities that
are likely to limit the development process (no histological association in short-
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term in vivo analysis). These tests comprise common or cell-specific cytotoxic
effects, blocking the human epithelial related gene (hERG) network, genotoxic
effects, drug-drug interactions, and metabolite-related toxicity (Kramer et al.
2007).
Toxicities of the targeted organs are dose-limiting and elucidated by in vivo signal
pathway analysis. The majority of the dose-limiting target organ toxicities may
be predicted by a well-conducted short-term repeated-dose in vivo toxicity assay.
The safety margin is established after dose-limiting toxicities have been identified,
and assumptions about whether or not the results are development-restricting are
drawn. Target organ-specific reviewing in vitro toxicological assays are used after
target organ identification to screen out toxicities that could limit development,
comprehend structure-toxicity relationships (STRs), enhance leads with minimal
side effects, and ultimately carry a more significant lead molecule to the next
phase. The data from four major pharmaceutical companies between 2000 and 2010
presented a similarity in the preclinical toxicology rates in the pre- and post-2005
periods, despite substantial industry investment in in vitro toxicology screening.
This suggests that it is still challenging to assess in vitro organ toxicity (Waring
et al.
2015). Employing a multitude of endpoint as of cellular function over a
single endpoint can increase the relevance of such arrays. These can be achieved
by applying high-content imaging, transcriptomics, metabolomics, proteomics, and
genomics to in vitro assay (Heijne et al.
2005). Even though genomics, also known
as “toxicogenomic,” has proven to be extremely helpful and highly prognostic at an
in vivo level (Steiner et al. 2004), developing “-omics” skills for organ function or
toxicity prediction at an in vitro level remains a challenging task. Improved statistics
and systems are essential, but the models that produce the in vitro data are also
crucial for predicting enhanced drug toxicity. More biomimetic toxicities to drugs
have been found in in vitro 3D models than in conventional 2D prototypes (KirschVolders et al.
2011).
As a result, 3D bioprinted massive models should be preferred over 2D or other
3D prototypes for in vitro toxicology assay. A 3D model is necessary for all in
vitro toxicity assays to increase predictability. The capacity for early rejection
of compounds due to common adverse toxicity (such as phospholipidosis) can
be significantly minimized by early extrapolative in vitro toxicological screening
(such as genotoxicity and hERG inhibition). Micronucleus testing, comet assay,
teratogenic potential, and Ames testing are few examples of genotoxicity assays.
These traditional in vitro tests utilize single-cell modeling and a clearly defined
endpoint, enabling scientists to produce additional informed choices (Roth and
Singer
2014). Instead of native tissues, t he majority of models for the prediction in
vitro toxicity assays are exploited well-defined endpoints, such as the hERG-binding
assay, which uses patch clamp analysis and human KCNH
potassium channel gene
2
to identify compounds that may be at risk of causing cardiac arrhythmias. Moreover,
embryonic stem cell testing (EST) is done to check for teratogenic potential. Briefly,
the differentiation of cardiomyocytes and embryonic toxicity is studied using 3D
EBs created by hanging drops of the mouse embryonic stem cell line (mESC line
D3). In a high-throughput bioprinting, the 3D spheroid-like EBs form spontaneously
followed by their manipulation to EBs of desired sizes (Xu et al.
2011b).
9 Bioprinting in Pharmaceuticals 315
The key to reviewing in vitro toxicological assay models, as opposed to predictive
ones, is an advanced level of biomimetic characteristics at the organ level of
organization. The primary drawback of existing prototypes for reviewing an in vitro
toxic assay in drug safety is that they do not adequately capture the intricate physiology of a target organ due to their short duration of culture and straightforward
monolayer cell culture systems. The pharmaceutical industry continues to struggle
with the lack of in vitro methods for accurately identifying organ toxicity. It is well
recognized that liver toxicity is the primary factor in drug rejection. Published data
predominantly uses primary hepatocytes or transformed cell lines such as HepG2
in monolayer and monotype cultures as hepatic surrogates in hepatotoxicologic
analysis. Everyone is aware that interactions between the different cell types found
in the liver cause drug-induced hepatic injury. Determining a lethal and acute hepatic
toxicity cannot be made by means of single-layer and mono-type cell cultures;
currently, a couple of human 3D co-culture liver substitute structures can be used
in drug safety assays; these systems exhibit more precise predictive ability than 2D
single-layer system (Skardal et al.
2015).
Additionally, 3D prototypes as primary specific organs for drug-induced side
effects—the heart, kidneys, and skin—have been generated (Esch et al.
2015). In
addition to having biological mimicry that has been independently verified, 3D
models must support testing at an industrial level and include automation, usability,
and reproducibility. Retrospective use of bioprinted 3D models in relation to in vitro
toxicity testing of compounds may fully address these problems. Approximately all
bioprinting businesses have created bioprinted tissue prototypes so far being used in
toxic research (Astashkina et al.
2012; Homan et al. 2016).
9.11.4 Absorption, Distribution, Metabolism, and Excretion (ADME)
Adverse pharmacokinetic characteristics and oral absorption, which remained unanticipated by preclinical ADME studies and thus led to highly toxic concentrations,
are responsible for the increased rate of Phase I and Phase II letdowns (Paul et al.
2010; Homan et al. 2016). Recent years have seen a significant decline in attrition
due to subpar pharmacokinetic profiles, partly because of continual improvement
in preclinical ADME understanding. Pharmacologists can rapidly anticipate the
effectiveness or toxicity of candidate molecules and its metabolites using artificial
in vitro tissues that mimic human tissues. According to a few research data, in 3D
bioprinting, various metabolism-related cells in their natural topological characters
effectively envisage the effect of pharmacokinetic activities of specific organs.
Moreover, “organs-on-a-chip” or “humans-on-a-chip” made of bioprinted organs
are credibly attached to a chip and used to predict the overall effects of chemicals
and their metabolic products (Knowlton and Tasoglu
2016; Knowlton et al. 2016).
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9.11.5 Traditional High-Throughput Screening (HTS)
HTS refers to parallel screening of several compounds on recombinant or petrified
targets, and compounds are evaluated based on binding capability with the enzymes,
receptors, and ion channels (Pereira and Williams
ate for this goal because this procedure i s typically high throughput with a primary
focus on a particular target molecule endpoint, which is different from a global
cellular functional endpoint. High-throughput processes, however, operate in the
same controlled environment on a micro-tissue or micro-organ array inside microwell plates or chips, leading to increased efficiency.
In addition, miniature structures only need a tiny quantity of the test substance,
which can be advantageous in the initial stage of development. Throughput, analysis
indices, and fidelity can affect HTS effectiveness. Low affinity to a model could
provide misleading information (Mazzocchi et al.
drug screening platform is microarrays implemented on a 2D cell culture system
(Gidrol et al.
2009). However, because of the advanced dependability of the
3D designs, it is anticipated that 3D microarrays will displace 2D microarrays.
Processes like micro-well, geometric surface patterns, and microfluidic techniques,
amongst others, can be used to create 3D microarrays. High resolutions are not
a significant cause of concern unlike issues with dimensional accuracy and cell
densities. Microarrays that are bioprinted should contribute to the possibilities to
overcome these drawbacks (Engel et al.
2022).
Organoids, also known as bioprinted organ-like structures, can be composed in
a microarray or micro-organ for micro-engineering (Rawal et al.
cross-contamination, media or medications should be added to each well being
studied in microarrays. Numerous procedures have been developed for the delivery
of drugs onto cell microarrays, including drug color and pattern, aerosol spraying,
and microfluidic drug loading. Each part in a microarray or micro-organ array
should be linked to a self-determining stream constructed on the bioreactor to
analyze the enduring effects of various drugs or contaminants in a high-throughput
manner (Ren et al.
2021).
2007). Bioprinting is inappropri-
2019). The most popular HTS
2021). Without
9.11.6 Phenotypic Screening
In drug discovery, phenotypical screening is a form of screening that looks for
compounds that alter a cell or organism phenotype in a preferred way. Refocusing
on discovery and research assumes significance in the era of “me-too” or “slightly
me-better” drugs to one of the enormously advanced drugs that deliver enhanced
therapeutic conclusions. Drug phenotypical screening primarily relies on endpoint
feedback in animal or cell models. An efficient in vitro phenotypic screening
requires using in vitro models that capture essential disease features while being
compatible with high throughput (Kang et al.
2020).
9 Bioprinting in Pharmaceuticals 317
9.12 Upcoming Perspective
9.12.1 Microphysiological Systems (MPS) and Organ-on-a-Chip
Tissue arrays could be made smaller using bioprinting technologies. 3D bioprinting
can precisely tailor multi-organoids to produce micro-organs, which can unite
within a microfluidic chip to create “organs-on-a-chip” (Ramadan et al.
in vitro “organ-on-a-chip” or “micro-organ” device can be employed in investigating
the pharmacological and toxicological effects of the drugs (Huh et al.
A promising in vitro testing platform for drug discovery is made possible by
combining bioprinting and microfluidic techniques.
Reported literature (Esch et al. 2015) with information on these systems is
available, which states that diverse organ models, such as heart-on-a-chip, liver-ona-chip, and kidney-on-a-chip, should be connected to generate different prognostic
human-on-chip platforms to assess drug responses to tested compounds comprehensively. Bioprinting can simultaneously fabricate several organoids at various
positions on a chip to create a body-on-a-chip or a human-on-a-chip, which
miniaturizes the entire human body. Direct bioprinting of vessels or interconnected
vascularization can be used to connect organoids (Wu et al.
network can mimic physiological flow environments to maintain systemic condition
and evaluate whole-body reactions to drugs. Vascularization in 3D prototypes is
essential for drug delivery, tissue growth, and survival. Bioprinting of vascular
networks is made possible by the elevated fabrication of tissue micro-surroundings
with vascularization (Datta et al.
using currently available methods, such as biological emergent vessels through coculturing endothelial cells and forming conjugation amongst organoids or applying
bioink perfusion channels (Peng et al.
Fluorescence, colorimetry, and enzyme reporter techniques can be used to
observe the effect of medications on bioprinted constructs. The fluorescence
method typically uses in situ imaging, particularly in micro-organs or microarrays.
Bioprinted human-on-a-chip devices must provide, in high resolution, real-time
information because different organoids possess unique and specific physiological responses over time. Development of advanced biosensors that work with
bioprinting technologies, such as microelectrodes and charge-coupled devices
(CCD) without lenses, is ongoing (Dias et al.
boundary cell inspection framework that combines intracellular coarseness with an
electrochemical resistance technique to check for cell-cell communication and count
the number of cells.
For this reason, at least two or more than two biosensing systems are combined
together (Charwat et al.
organ, organ-on-a-chip, or human-on-chips, are supposed to be realized by MPS,
there is still need of more in-depth research to understand the benefits of the human
system miniaturization fully. It is impossible to manufacture MPS efficiently at the
microscale by merely ascending down the macrosystem. MPS calls for focused
knowledge. However, given its adaptability, bioprinting can be an efficient method
2013). Even though the entire organs, like tiny tissue and
2017). Vascular construction connections are made
2016; Richards et al. 2017).
2014). One concept is a twofold
2020). The vascular
2021). The
2011).
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for fabricating complex MPS on its own or in combination with other approaches
(Wikswo
2014).
9.12.2 Personalized Pharmaceutics
Customized treatment in light of individual digestion potential and reaction to a
specific medication is gaining more attention, benefiting and nullifying harmful
impacts from a drug treatment. A customized pharmaceutics stage ought to be a
body-on-a-chip made of organoids of the critical body parts that are drug sensitive,
like the heart, liver, and kidneys, as well as target organs. With minimal wellbeing concerns, bioprinting of patient-determined essential cells has the chance to
deliver customized screening models. Various cells from a single patient can be
separated by induced pluripotent immature microorganisms (iPS) and multipotent
undifferentiated organisms (Faulkner-Jones et al.
substantial number of cells from the patient into iPS, which can then be bioprinted
in specific environment to separate into different organ cells. Normal mammalian
skin cells were transformed at GSK into iPS cells, which can differentiate into any
body cell. To predict the cardiac toxicity of experimental drugs, these iPS cells can
be distinguished into cardiac muscle cells (Theodosiou et al.
most effective active ingredients, iPS from humans can be bioprinted and committed
to various organs in MPS.
2015b). It is feasible to obtain a
2014). To choose the
9.12.3 Commercial Prospective
In addition to the standard procedures utilized in drug discovery and advancement,
bioprinted 3D structures, DNA analysis, and miniature structures are currently
used for existing drug assessment. However, it is still too early to conclude the
viability of replacing animal models with bioprinted models. Recognition of the
system should be approved utilizing standard drugs based on sizable sets of welldocumented experiments for a 3D bioprinted process, ensuring a target organ
for drug screening. The 3D skin models employed to test cosmetics significantly
illustrate an innovative human-relevant in vitro system that is getting acceptance
[160]. It has been conclusively demonstrated to be a strong indicator of drug
outcomes in persons, thus lowering the necessity for animal trials. The model was
validated by employing a set of trial substances using an identified mode of action
over the skin. 3D epidermis modeling can be appropriately adapted for broader
applications to create disease layouts and HTS (Gatenholm et al.
2015).
9 Bioprinting in Pharmaceuticals 319
9.13 Conclusion
Besides the higher worthiness than 2D layered system, the primary consideration
for applying bioprinting to drug R&D ought to strike an equilibrium between
the expense and cost of bioprinting in research and advancement (Seoane-Viaño
et al.
2021). Even though more convincing evidence and commercially available
customized bioprinted product lines are still lacking, pharmaceutics has begun to
see the benefits of bioprinting. Before regulations consider bioprinted structures
as quality control and regulatory equipment for drug delivery, the benefits of
bioprinting should be shown. The bioprinted constructs needs more proof of concept
before broader deployment. Additional research is necessary to demonstrate similar
drug efficiency or toxic effect in 3D bioprinted structure in vivo. Moreover, the
3D bioprinted models are combined with excellent assay methods. Genomic or
proteomic expression analyses of biomarkers via pharmacoinformatic analysis kits
will produce enormous information that will accelerate the drug discovery and
delivery.
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