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Review Information technology (IT) is ubiquitous in recent human existence. The aim of this article is to present some basic concepts and specific demands that biofabrication may place on IT. Some of these technologies are already available, with a need for improvement, while others will need to be newly developed. Technologies that clearly, precisely and unambiguously specify a tissue or organ are unavailable. A move from expensive in vitro and in vivo assays toward in silico technologies will allow for exhaustive tests and optimization of human substitutes by means of computer biological systems. To complete this substitution, biofabrication lines shall be established; integrating what was planned and designed into physical processes executed by automatic machines. Biofabrication will impose great challenges, since many tools will need to be developed by engineers together with biologists. Many other concerns and challenges will be faced in the path to an autonomous biofabrication line, including cybernetic and biological safety issues. Therefore, the main aim of this paper is to shed some light and establish a primary nexus between the present and future applications of IT in biofabrication.
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63J. 3D Print. Med . (2017) 1(1), 63–74 ISSN 2059-4755
10.2217/3dp-2016-0005 © 2017 Future Medicine Ltd
part of
Review
J. 3D Print. Med.
Review 2017/ 01/30
1
1
2017
Information technology (IT) is ubiquitous in recent human existence. The aim of this
article is to present some basic concepts and specific demands that biofabrication
may place on IT. Some of these technologies are already available, with a need for
improvement, while others will need to be newly developed. Technologies that
clearly, precisely and unambiguously specif y a tissue or organ are unavailable.
A move from expensive in vitro and in vivo assays toward in silico technologies
will allow for exhaustive tests and optimization of human substitutes by means of
computer biological systems. To complete this substitution, biofabrication lines shall
be established; integrating what was planned and designed into physical processes
executed by automatic machines. Biofabrication will impose great challenges,
since many tools will need to be developed by engineers together with biologists.
Many other concerns and challenges will be faced in the path to an autonomous
biofabrication line, including cybernetic and biological safety issues. Therefore, the
main aim of this paper is to shed some light and establish a primary nexus between
the present and future applications of IT in biofabrication.
First draft submitted: 5 August 2016; Accepted for publication: 18 November 2016;
Published online: 9 January 2017
Keywords:  3D bioprinting • Bio-CAD • Bio-CAE • Bio-CAM • biofabrication • information 
technology • organ printing • systems biology
Arguably, information technology (IT) has
played a fundamental role in different areas
of human activity since the first electronic
computer, electronic numerical integrator
and computer, was created in 1946 using vac-
uum tubes. The end of the 1950s witnessed
the popularization of the transistor, based
on doped semiconducting materials, which
was a major game changer and heralded the
rise of the digital era based on binary logic.
Computer programming became flexible
and the next two decades consolidated the
use of digital technologies in many fields.
From the 1980s to date, software engineer-
ing has become well established, hardware
has evolved beyond expectations and com-
munication has undergone a great evolu-
tion, mainly with the advent of the internet
from the mid-1980s and more strongly in the
1990s. There are many nonconflicting defi-
nitions of the acronym ‘IT.’ Probably the first
IT definition was coined in 1958 by Leavitt
and Whisler [1] , as a technique for processing
large amounts of information; the applica-
tion of statistical and mathematical meth-
ods to decision-making problems; and the
simulation of higher order thinking through
c omputer programs.
According to Gartner, IT is a myriad of
technologies for information processing,
including software, hardware, communica-
tions technologies and related services, not
including embedded technologies that do not
generate data for use in general [2]. This same
company explicitly defines 3D printing and
bioprinting as branches of IT [3].
The role of information technology in the
future of 3D biofabrication
Janaina de Andréa
Dernowsek*,1, Rodrigo
Alvarenga Rezende1 & Jorge
Vicente Lopes da Silva1
1Three-Dimensional Technologies 
Division – DT3D, Renato Archer 
Information Technology Center – CTI, 
Rodovia Dom Pedro I (SP-65) , Km 143,6, 
13069–901 Campinas – SP, Brazil
*Author for correspondence: 
anaina.dernowsek@ cti.gov.br
For reprint orders, please contact: reprints@futuremedicine.com
64 J. 3D Print. M ed. (2017) 1(1) future science group
Review Dernowsek, Rezende & Lopes da Silva
IT has become an intrinsic part of the healthcare
ecosystem in recent years [4] . Since the term ‘medical
informatics’ was first coined [5] , experts working at the
intersection of IT a nd medicine have developed a nd bet-
tered computer approaches aiming to improve health-
care. Considerable progress in medicine, biology and
informatics has contributed to the emergence of health
information technology, which is a technology applied
to improve the overall quality, safety and efficiency of
the health system [6]. Better knowledge regarding the
evolution of IT can improve understanding of how this
tool is needed in all fields of knowledge. No one can
argue how much IT has changed, and keeps changing,
the way medical and biological sciences are practiced.
Emergent technologies such as healthcare systems,
clinical information systems, regenerative medicine,
tissue engineering, systems pharmacology, system biol-
ogy, among many are highly dependent on IT. Natu-
rally, the IT revolution is already affecting strongly and
will continue to shape the future of the promising area
of biofabrication and bioprinting of organs.
Computers have allowed better studies to be con-
ducted around the world to understand systems biol-
ogy. However, this field requires extensive support from
mathematical modeling, molecular biology and engi-
neering [7] . The emergence of platforms to study bio-
logical systems in multi-scales will enable understand-
ing, creation and optimization of biological structures
for biofabrication. These systems will become key for
important steps in medical science, systems biology,
tissue engineering and, consequently, biofabrication.
In recent years, an in silico approach has been prac-
ticed in several fields, and offers new opportunities
for medical discovery and investigation, helping and
improving the storage, organization and classification
of the large datasets of digital biological information
that are available [8,9] . Additionally, ongoing evolu-
tion has led to the emergence of new computational
approaches in medical science and the results have
improved the analysis, organization, classification and
processing of data.
Biofabrication technology is evolving into a complex
system composed of many processes, including com-
puter-aided design (Bio-CAD), computer-aided engi-
neering (BioCAE), computer-aided manufacturing
(Bio-CAM) and biological processes, which depend on
the combination of different inter-related components
such as molecules, genes, regulatory networks, cells,
organoids and tissues, integrated with computational
approaches such as design, modeling, simulation and
optimization, among others, as depicted in Figure 1.
As a reference, a systematic search on Medline was
performed via the PubMed and Embase platforms,
identifying 860 and 549 publications, respectively.
The terms applied in the search were ‘bioprinting/bio-
fabrication/organ printing’ and of the papers found,
only 11 publications included the words ‘information
technology’ linked to those three words. This search
indicates the need for computational methods devel-
opment and in silico applications to aid understanding
and development of tissue spheroids, tissues, organs
and all necessary hardware [10 –15 ] .
The purpose of this search was to review the
approaches and methods for using IT in the biofab-
rication process. This article discusses the challenges
and prospects for databanks, imaging, data mining,
modeling, simulation, interoperability, optimization,
design and the effects of changes on cell behavior
during biofabrication, and the role of an integrated
p latform to integrate and analyze information.
Biofabrication strategies
According to Mironov et al. the combination of an
engineering approach with the developmental biol-
ogy concept of embryonic and tissue fluidity enables
the creation of a new, feasible technology for organ
printing, which will dramatically accelerate and opti-
mize tissue and organ assembly [16] . More recently,
Mironov et al. defined biofabrication technology as the
production of complex living and nonliving biological
microtissues from raw materials such as living cells,
molecules, extracellular matrices and biomaterials [10] .
Biofabrication is an area of tissue engineering where
many solutions can be developed using additive manu-
facturing (AM). AM is also known as 3D printing and
involves a layer-by-layer material deposition paradigm.
This includes the use of different AM techniques,
materials, cell types and applications. Figure 2 shows
the relationship between tissue engineering, biofabri-
cation and the embracing role of IT.
Tissue engineering presents different potential
alternatives for the replacement and restoration of
live tissues and organs. Figure 3 shows the possibilities
together with an indication of how ‘natural’ a solution
is and its related complexity. Included in Figure 3 are
the current prostheses solutions made of biomateri-
als, which are classified as less complicated and con-
sequently less natural to the human body. Biofabrica-
tion, a branch of tissue engineering, is represented by
scaffolds, bioprinting and in the future, in vivo tissue
printing. Three different biofabrication approaches are
presented: scaffold-based tissue engineering, scaffold-
free tissue engineering or bioprinting, and a mixture
of both methods.
Scaffold-based tissue engineering
This first approach is based on the use of 3D structures
known as scaffolds, which are biocompatible and con-
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Figure 1. The role of information technology in the biofabrication of
tissues and organs.
Figure 2. Relationship between tissue engineering, biofabrication, bioprinting and information technology.
• Cells
• Biomolecules
• Biomaterials
First (scaffolds)
• Second (tissue spheroids)
• Third – hybrid (TS + S)
• Imaging
Data mining
• Modeling
• Simulation
Tissue spheroids • Cells
• Cell selection
Proliferation
• Differentiation
• Hanging drop
• Cell sorter
• Encapsulator
• Bioprinter
• Bioreactor
• Microfluidics devices
• Optimization
• Interoperability
• Design and blueprint
Additive manufacturing
(3D printing)
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The role of information technology in the future of 3D biofabrication Review
trollably biodegradable via control of the number of
pores and porosity of the material. Cells can be seeded
inside a scaffold so that they can adhere, proliferate
and grow, originating a new tissue. Many biomaterials
can be used for scaffolds, such as ceramics and poly-
mers. Polymers can be natural or synthesized and must
be nontoxic. Examples of natural polymers include col-
lagen, chitosan, agarose, alginate and hyaluronic acid.
Examples of synthesized polymers include polylactide,
polyglycolide, poly(ε-caprolactone), PEG, polyure-
thane, polydimethylsiloxane and polymethylmetracry-
late, among others. Figure 4 depicts the layer-by-layer
fabrication of a scaffold.
Tissue spheroid approach for tissue
engineering
A second approach is based on the use of tissue spher-
oids [17] . As with transistors in electronics, tissue spher-
oids are fundamental building blocks in bioprinting.
Tissue spheroids are 3D structures composed of pre-
sorted autologous cells as aggregates in some type of
hydrogel. Figure 5 illustrates the formation of one tissue
spheroid.
The essential biophysical principle of organ printing
technology is the natural capacity of tissue spheroids for
tissue fusion – which is a ubiquitous phenomenon dur-
ing the embryonic development stage – driven by surface
tension forces. Implementation of organ printing is not
possible without the development of technology for the
large-scale production of living tissue spheroids [17,18].
Hybrid approach for tissue engineering
A third approach is a mixture of the best features of
the two approaches mentioned above. This hybrid
approach, utilizing the higher mechanical strength of
scaffolds and the greater similarity of tissue spheroids
to the natural materials, can assure optimal character-
istics from both a mechanical and biological viewpoint.
One example is the use of lockyballs – microspheres
with hooks and loops – as microscaffolds involv-
ing tissue spheroids, thus offering higher mechanical
protection for the cells and saving time in such way
that the cells can advance the fusion process [15 ,19].
The design and the computational modeling of new
66 J. 3D Print. M ed. (20 17) 1(1)
Figure 3. Biofabrication and the relationship between complexity and
‘naturalness’ of the solution.
Figure 4. Virtual fabrication of a scaffold layer-by-layer by additive
manufacturing.
More natural solution
Complexity of the solution
Needs
for research
future science group
Review Dernowsek, Rezende & Lopes da Silva
microscaffolds have been described [20,21] and open up
new o pportunities for tissue engineering, as shown in
Figure 6.
IT for biofabrication
Imaging
Medical imaging is used as a noninvasive technique
for the acquisition and interpretation of images for
medical diagnosis, treatment and the development of
medical devices, among many other purposes. Images
of different parts of the human body can be generated
and analyzed to supply digital and visual information
of organs and tissues, which are of high value for phy-
sicians as clinical information about patients’ health
conditions [22] .
A wide variety of medical imaging modalities are
currently available for medical diagnosis, such as
c omputed tomography, MRI, ultrasonography, mam-
mography and photon emission tomography, among
others. One of many tools available for medical appli-
cations is InVesalius [2 3], an open-source framework
with a set of functionalities for processing, analysis,
visualization and 3D printing support for medical
images.
3D visualization of anatomical structures allows
for more accurate surgical planning, avoiding poten-
tial medical errors, reducing interventions and, in the
near future, will provide support for anatomical reverse
engineering for biofabrication in terms of micro and
macro structures.
Design & blueprint
The most logical approach to construct a complex
organ such as a kidney, for example, will be first to
specify it virtually and conduct in silico simulations.
Obviously it will not be possible to bioprint physi-
cal organs without a digital model and biological
and p rocessing data and information [2 4]. It will be
necessary to develop a new computational field that
can support designing, modeling, prediction, optimi-
zation, integration and decision-making, and which
can assist in all the steps of the biofabrication process.
There are many research groups around the world
attempting to develop tools utilizing IT to under-
stand biological systems in order to construct func-
tional tissues. In particular, from an anatomical per-
spective, the new tools must be capable of integrating
micro and macro details of the desired tissue or organ
to be bioprinted.
Computer simulation & optimization
Advances in biological research require the use of
computational tools, researchers with a background in
both the life and physical sciences, and knowledge of
computational, mathematical and engineering tools to
solve biological problems [25] . These are useful to deter-
mine a model, which can be defined as a representation
of reality that embodies some essential and interest-
ing aspects of that reality [26] , and whether a complex
system is robust. A robust biological system is one
that maintains its state and functions when exposed
to external and internal perturbations [27] , which may
enhance understanding, and facilitate prediction of a
biological system.
The outcome of a bioprinting process depends on
both the deposition of the discrete bioink units (cells or
tissue spheroids) and their ability to self-assemble [17] ,
besides biomolecules and its interaction with the cells.
Postprinting structure formation is an autonomous
process governed by fundamental biology and bioprint-
ing remains largely a trial and error approach [28] . In
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Figure 5. Hanging drop cells aggregate to form tissue spheroids.
Figure 6. Five lockyballs were modeled for improving diffusion kinetics. (A & B) Solid microscaffold without
internal structure [15] . (C , D & E) Solid microscaffolds with internal structures to improve the oxygenation of
cells [20,21] .
ABC D E
High LowOxygen gradient
future science group
The role of information technology in the future of 3D biofabrication Review
order to overcome this barrier, it is necessary to know
how to use existing computational tools such as com-
puter simulations and to develop new computational
approaches.
Computer modeling and simulations are an effec-
tive computational strategy for understanding and
describing many biological behaviors in different envi-
ronments and systems. For example, tissue and organ
bioprinting, composed of cells, tissue spheroids, organ-
oids and, in the future, complex organs and organisms.
There is a range of methods and software for model-
ing and simulation. Some models and strategies are
described in Ta bl e 1.
These simulations not only explore the feasibility
of bioprinting 3D constructs using tissue spheroids,
but also demonstrate the potential to aid engineering
design in all steps of the biofabrication process.
In the mid-1990s a new discipline emerged called
‘systems biology,’ with the aim of understanding bio-
logical systems from the population level through to
the molecular and atomic level [44] , utilizing a wide
variety of biological, mathematical and computational
approaches [2 7,45, 46]. These approaches have generated
a huge amount of data that has to be managed properly
to feed simulation tools; useful for biofabrication opti-
mization and design. Therefore, integrated platforms
and computational tools are paramount to manage and
deal with databanks, data mining, network inference,
design inference, dynamical simulation and intensive
analysis [7,9] .
The emergence of integrated software platforms
to understand complex biological systems in multi-
scale levels will enable the creation and optimization
of biological structures. These integrated platforms
can be called Bio-CAE and will likely become key for
i mportant steps of the biofabrication processes.
System interoperability
The interoperability of information systems is based
on open international standards capable of automati-
cally transmitting and interpreting data and informa-
tion. This includes in terms of syntax – data format
and communication protocols; and semantic – ensur-
ing information is exchanged in a meaningful and
accurate way. In this context, current representation
of AM (3D printing) does not suffice for precise data
68 J. 3D Print. M ed. (20 17) 1(1) future science group
Review Dernowsek, Rezende & Lopes da Silva
and information representation for biofabrication
products and processes. The most recent standard for
AM product representation is the Additive Manufac-
turing File Format (AMF), an initiative of the Ameri-
can Society for Testing and Materials (ASTM). Since
2013, AMF has been adopted by the International
Standardization Organization (ISO) as the inter-
national standard ISO/ASTM 52915 [47] to replace
the STereoLitography standard created 30 years ago.
More recently, a consortium composed of many com-
panies in the area of AM, software and design systems
created the open format called the 3D Manufactur-
ing Format with the purpose to improve on AMF [48] .
However, none of the current proposals meet the
needs for biofabrication in terms of complexity and
ability to represent both micro and macro anatomi-
cal details. It is therefore mandatory to develop new
standards for biofabrication data and information in
terms of syntax and semantics. A future standard for
biofabrication interoperability will include data and
information not only about micro and macro geom-
etries of the tissue and organs, but also the right posi-
tion of each material, the cellular fate and the required
biomolecules, besides their processing parameters.
Hardware for biofabrication
In the general IT universe, hardware is the physical
aspect of computers, telecommunications and other
devices. Focusing the spotlight on biofabrication, this
relates to the equipment or devices that are employed in
a biofabrication line for producing a tissue or an organ.
The biofabrication line includes mainly the follow-
ing equipment: cell sorters, microfluidic devices, tis-
sue spheroid fabricators and e ncapsulators, b ioprinters,
bioreactors and microfluidic devices, among o thers [49] ,
as can be seen in the Figure 7 and discussed in the
f ollowing sections.
Cell sorter
A cell sorter device is one of the first classes of equipment
employed in the production of new tissues and organs.
High numbers and a high quality of cells must be guar-
anteed during biofabrication. It is then necessary that
cells with different phenotypes are available. Preferen-
tially the cells should be autologous [5 0] . Cell sorters uti-
lize cells from the patient and selects them individually
for storage in a suitable environment for later use.
Tissue spheroid fabricators & encapsulators
Scalability in tissue spheroid biofabrication must
be considered as a critically important technology
enabling organ printing. Currently, there are three
basic ways of producing tissue spheroids: using
n onadhesive hydrogels as molds, hanging-drop or
microfluidics [51] . In summary, nonadhesive molds
involve the use of microdevices (negative mold),
which can be filled with a nonadhesive hydrogel, cre-
ating the positive mold. This positive mold is then
used as a substrate for pipetting cells that will origi-
nate tissue spheroids after some days. The mold is geo-
metrically settable and allows variety in the number
and shape of the recessions [52] . These molds can be
bought commercially or can be home made using AM
for biological tests, for example, as has been done at
Renato Archer Information Technology Center, Bra-
zil (Figure 8). It is worth mentioning that AM is only
possible because of IT integrating other knowledge
fields such as chemistry, mechanics and so on.
The hanging-drop method is a simple and classi-
cal way adopted by many companies and researchers
worldwide for fabricating tissue spheroids. The prin-
ciple is based on gravity-induced cell aggregation [53 ] .
Initially, this method did not assure homogeneity in
spheroid size which could, potentially, form undesir-
able satellite tissue, resulting in tissue spheroids with
an irregular shape [5 4] . However, the redesign of the
top geometry of recessions in hexagonal shape has
helped avoid large numbers of cells being lost by not
falling into the recession.
A high level of scalability of tissue spheroids cannot
be guaranteed using molds or hanging-drop fabrication.
Therefore, microfluidics looks to be the fastest manner
to reach a high level of tissue spheroid production.
Bioprinter
The bioprinter is responsible for materializing the design
of the organ or of the scaffold. Tissue spheroid (second
approach) deposition is related to digital d eposition
Table 1. Computational strategies to study biological behavior
and other biofabrication processes.
Study Strategy Ref.
Fusion of multicellular aggregates CPM; MMC; KMC [29–37]
Cell shape evolution CPDs; Surface Evolver [17, 38]
Extrusion bioprinting CPDs [38]
Interstitial flow in 3D tissue construct CFD [39]
Cell migration CC3D [20,40]
Optimization of microscaffolds for
tissue spheroid
FEM [15,20]
Diffusion in tissue spheroid CFD [21]
Cell differentiation CC3D [4 1]
Tissue morphogenesis CC3D [4 2]
Bioreactor CFD [39, 43]
CC3D: CompuCell3D; CFD: Computational uid dynamic; CPD: Cellular particle dynamics ; 
CPM: Cellular Potts model; FEM : Finite element modeling; KMC: Kinetic Monte Carlo; 
MMC: Metropolis Monte Carlo.
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Figure 7. Digital plan of a biofabrication room.
Figure 8. 3D molds made by additive manufacturing for the formation of tissue spheroids.
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The role of information technology in the future of 3D biofabrication Review
since spheroid-by-spheroid is taken into right place. IT
is directly involved in this stage, with a wide range of
data being generated and controlled. There is a set of
parameters inserted in this context and the c ontrol of
each variable requires real-time management.
A supervisory system integrating functionalities and
subsystems is required in such way that operations
and interventions as setup of parameters, calibrations,
monitoring by sensors, alarms and log report of all
events are assured. Moreover, an important resource is
a real-time monitoring system, which enables online
check-up and feedback about the quality and normal-
ity of the bioprinting process; detecting and report-
ing any failure or error during the digital deposition
of tissue spheroids layer by layer. Figure 9 shows a 3D
bioprinter currently under development at the Renato
Archer Information Technology Center.
Bioreactor
One important aspect for the development of a new tis-
sue or organ is to offer suitable conditions for the cells to
grow and mature. In this sense, many physical param-
eters must be controlled. For example, the internal envi-
ronmental temperature must be constant. In addition,
the fluid flow inlet and outlet of nutrients and oxygen
must be supervised and controlled. Mass transfer inside
the scaffold or inside a 3D structure assembled by tissue
spheroids is another critical factor. In tissue culture, the
maximum cell layer thickness for which oxygen can be
supplied by diffusion alone is about 100–200 μm [55] . In
these conditions, an insufficient amount of oxygen feeds
the new tissue under formation and it can induce necro-
sis. This is one important motivation for the controlling
and monitoring of bioreactors.
Figure 10 illustrates a virtual perfusion bioreactor
composed of needles, which allows the entrance of flu-
ids and removal of excretions. The needles are porous
and each pore is 40 μm diameter. Tissue spheroids are
100–200 μm diameter.
IT has been employed in this context by means of
computer simulations. The in silico development of a
perfusion bioreactor for maturing a construct formed
by tissue spheroids has been carried out at the Renato
Archer Information Technology Center. Effects of dif-
fusion, temperature, pressure and aspects related to
needle geometry (number of pores, pore sizes, length,
etc.) have been analyzed [3 9]. A supervisory system
must store essential information of events (lifetime his-
tory) that have occurred in the bioreactor during the
organ maturation period. Moreover, the bioreactor
must contain sensing devices to follow the organ mat-
uration level and to indicate the moment the organ is
mature and ready to be implanted into the patient. For
instance, some sensors are able to detect pH level alter-
ations or even the presence of certain types of proteins
or biological factors as evidence of maturation.
Microfluidic devices
Microfluidics has been adopted as a tool and technique
for biofabrication. In particular, microfluidics can be
applied to the fabrication of a huge number of tissue
spheroids. Scalability is a challenge to be addressed,
70 J. 3D Print. M ed. (20 17) 1(1)
Figure 9. The bioprinter under construction at the Renato Archer
Information Technology Center. The supervisory system controls and
integrates functionalities and subsystems of the bioprinter.
Figure 10. Model of a bioreactor compounded by needles for the perfusion
and consequent maturation of organs.
future science group
Review Dernowsek, Rezende & Lopes da Silva
since the fabrication of an entire organ requires hun-
dreds of millions of spheroids to be ready in advance.
Microfluidic devices allow biofabrication of 10,000
droplets per second, allowing higher scalability [5 6] .
In addition, a new class of microfluidic device called
organs-on-chips has recently been introduced in tissue
engine ering, pha rmaceutic al biology a nd several k nowl-
edge fields. These devices are microenvironments that
are engineered in such a way that it better replicates the
in vivo microphysiology of living organs [57 ] . A more
likely scenario is the increasing convergence of systems
in organ-on-chip devices, with a range of integrated
methods onto this interface, such as a microfluidic
phase, microelectronics circuits, mechanical processes,
software and hardware. The convergence toward an
integrated microenvironment will contribute to the
development of new platforms of modeling, simulation
and testing, which can be called lab-on-a-chip. A new
class of AM systems for micro- and nano-structures
is available. These machines are based on two-photon
polymerization technology [15, 19] being potentially able
to produce complex 3D m icrofluidic devices.
Biofabrication & Industry 4.0
There is a world movement led by Germany to intro-
duce the concept of Industry 4.0 as a high-tech strategy
for industry of the 21st Century [5 8] . This is a refer-
ence to the previous three industrial revolutions. The
first revolution started in Britain circa 1760 when the
concept of the manufacturing plant was introduced,
with the help of hydro and steam power to take the
place of the hand manual production processes. The
second industrial revolution took place circa 1870
with the first assembly line and use of electricity as a
power source. The third industrial revolution started
more recently, at the end of the 1960s, with the use
of computer systems and IT to control machines and
automation of production lines. Industry 4.0 or the so-
called fourth industrial revolution is based on cyber-
physical systems in order to reach a high level of mass
customization in decentralized production with high
flexibility and resource efficiency. Cyber-physical sys-
tems are the integration of networking and IT with ele-
ments of the physical world that creates smart or intel-
ligent systems to improve physical processes in many
domains of human activities enabling functions never
seen before [59 ] . This is as an emerging area that refers
to the next generation of engineered systems [60, 61] . We
expect that one of these revolutionary systems will be
the new paradigm of biofabrication. The major reason
is the clear demand for a complex, integrated, efficient
and safe system to deliver engineered human parts,
overcoming organ shortage problems. With the rapid
development of the industry, mainly concerning the
intelligent system, which includes advances in software
and hardware, more sophisticated tools for biofabrica-
tion will be created or even updated such as b ioprinters,
bioreactors, microfluidic devices and others.
Conclusion
Biofabrication as an interdisciplinary area is fostering
new knowledge and integration of areas such as nano-
technology, chemistry, materials science, control sys-
tems, among many others, necessary to accomplish the
challenge of more complex tissue and organ produc-
tion outside the human body. Undoubtedly, current
biofabrication initiatives are possible because of the
set of above-cited technologies that are supported and
integrated through IT. The supervisory and control
systems of bioprinters, in terms of their positioning,
deposition rate and process parameters depending on
biomaterials and biological materials, environmental
control, user-friendly interface, data log, among many
71
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Figure 11. Analogy between Industry 4.0 and Medicine 4.0.
future science group
The role of information technology in the future of 3D biofabrication Review
others, are possible only because of the digital tech-
nology that permits the implementation, integration
and automation of complex tasks with repeatability
and minimum human intervention. This is the factor
that makes biofabrication promising for the automated
production of human tissues and organs. Moreover,
standalone bioprinters cannot be the solution for the
more complex task of a biofabrication production line.
Higher-level control systems optimizing and integrat-
ing many bioprinters – and complimentary devices of
a biofabrication line – in production lines, data log-
ging and recording for the lifetime of the production
processes parameters and variables, and design support
tolls – Bio-CAE, Bio-CAD integrated with a Bio-
CAM – shall be mandatory for a consistent tissue and
organ industry. As a cybernetic system, the prevention
of faults, errors, failures and risk situations, as well as
the security of sensitive data and information, is of
great importance.
Future perspective
The future of biofabrication should comply with the
paradigm of Medicine 4.0, which alludes to Indus-
try 4.0, whose intelligent systems and personaliza-
tion will open up new opportunities for health treat-
ments. Medicine 4.0, as we envision it, refers to the
progress toward digitalization, simulations and process
o ptimization, and the production of organs and tissues
in a safe and productive way. In the wake of modern
medicine, biofabrication will need and bring a myriad
of new techniques, methods and significant improve-
ments in existing processes. From an educational and
training perspective, students will dive into anatomy
and physiologic studies not only on virtual dissec-
tion tables but also using biofabricated organs. From
the perspective of drug development, biofabrication
is closer to realization, opening up the possibility to
have a set of microtissues or organoids that can be used
as a combinatory analysis to screen the best drug and
the real amount for a specific disease in a combinatory
patient-specific solution.
Bioreactors are essential for maturating the fresh
organ. However, currently, the bioprinting and matu-
ration steps are separate. This means that the organ
is first 3D printed using a bioink and then moved to
an adequate chamber to evolve the organ to later be
implanted into the patient. In the future, these two
devices will likely be integrated into one, which will
decrease the risk of contamination and avoid manipu-
lation and transference of live constructs between two
pieces of equipment.
Regarding computational biology, the ‘omics tech-
nologies already allow us to envision an era of per-
sonalized biofabrication in which patients receive
72 J. 3D Print. M ed. (20 17) 1(1) future science group
Review Dernowsek, Rezende & Lopes da Silva
c ustomized therapy and customized dosages to prevent
and cure diseases, when it is used wisely and carefully.
In addition, the ‘omics technologies integrated with
data mining, machine learning, smart devices and oth-
ers intelligent systems, could build automated produc-
tion systems of tissues and organs ( Figure 11) . These
p latforms can be called ‘biofabrication lines.
A biofabrication line will first be created digitally,
for simulation, and then physically. The biofabrica-
tion line is set by a layout with the spatial distribution
of devices and for the incorporation of mathematical,
physical and biological models. These characteristics
will allow training and attraction of new students and
researchers, prediction of phenomena and processes,
calculation of the raw material needed for getting a
new organ, estimation of costs, control of logistics of
organ production and supply, improvement of the pro-
cess and other issues. The biofabrication line will be
installed in hospitals.
Acknowledgements
Our sincere thanks to OHJ Amorim for his cooperation and his 
special digital arts skills.
Financial & competing interests disclosure
The  authors  ar e  grateful  to  CNPq  and  FAPESP  for  the  Bra-
zilian  Institute  of  Biofabrication  (INCT-BIOFABRIS  process 
2008 /57860–3 )  for  nancial  suppor t.  The  authors  are  also 
thankful to CNPq for the ‘Regenerative Medicine’ grant (pro-
cess 467643/2014–8 ). The authors are thankful to FAPESP for 
the Brazilian Research Institute  for Neuroscience and Neuro-
technology - BRAINN (CEPID process 2013/07559–3),  for the 
Thematic Project (Grant 2011/ 22749- 8). The authors have no 
other  relevant  af liations  or  nancial  involvement  with  any 
organization  or entity with  a nancial interest  in or  nancial 
conict with the subject matter or materials discussed  in the 
manuscript apart from those disclosed.
No writing assistance was utilized in the production of this 
manuscript.
Executive summary
• This article discusses the potential of information technology (IT) in the future of the 3D biofabrication field.
• This work provides a discussion of the challenges and prospects for databanks, imaging, data mining,
modeling, simulation, interoperability, optimization, design and the ef fects of changes on cell behavior during
the biofabrication steps.
• IT has contributed in several areas of knowledge, over the past decades and it is clear that the emergence and
advancement of medicine, biofabrication and modern industry is only possible due to IT revolution.
• The most logical approach to produce (Bio-CAM) a complex organ will be first to specify it virtually (Bio -CAD)
and promote in silico simulations (Bio-CAE).
• The emergence of integrated software platforms for understanding complex biological systems in multiscale
levels will enable the creation and optimization of biological structures and it will become key for important
steps of the biofabrication processes.
• Cyber-physical systems and complex systems engineering will play a key role in healthcare, translational
medicine, biological and cyber security, and all other enabling technologies for the success of biofabrication.
• Industry 4.0 is the new paradigm for an advanced industry. We believe that as an analogous movement,
medicine 4.0, which strongly encompasses biofabrication, will be based on a myriad of new techniques,
methods and significant improvements in existing processes , especially in the field of clinical trials, with
bioprinting, imaging, computer simulation, microfluidics and so on.
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... Commercially available materials include acrylate-based photopolymers such as Veroclear TM , MED610 TM , MED625FLX TM (all produced by Stratasys) and iSQUARED TM , a generic compatible photopolymer, among variations based on rubber-like and polypropylene-like materials available on the market. The photopolymer materials can assume the mold shape by means of instant reticulation under ultraviolet light exposure during 3D printing [126]. ...
... Indeed, the use of this type of technology offers a considerable distinctive feature compared to other spheroid production techniques: refined geometric control of the spheroids to be produced [26,59,60,126]. Greater spheroid uniformity is thus achieved when compared to processes that depend solely on collisions between cells and fluid flow. Micromolding is therefore characterized as a robust and reproducible manufacturing strategy [124], of great applicability in the generation of macroscopic 3D constructions. ...
... Mathematical and computational modeling have increasingly proven to be key methods for the simulation, analysis and prediction of complex and multiscale biological phenomena [152][153][154]. Analogously to simulation of industrial processes, these tools can be used to reduce time and costs for the understanding, design and mass production of spheroid and tissues in the near future [126]. Table 2 summarizes examples of studies involving spheroids in which these tools have been employed, directly relating them to the engineering aspects exploited in each case. ...
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This work presents InVesalius, an open-source software for analysis and visualization of medical images. The tool has supported several surgeries in hospitals and has been downloaded from more than a hundred countries around the world. Its main characteristics, aspects of implementation, and applications in areas such as image segmentation, mesh generation, volume rendering, and 3D printing of anatomic models are described.
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Aggregates of pre-sorted cells form structures called tissue spheroids that have been widely used in the field of tissue engineering. The greater contact of the cells with the culture medium is directly related to cell viability and to the increase of proliferation rate. Due to the characteristics of a 3D environment, at some zones within the tissue spheroids some cells are not equally exposed to the environment, impacting in the formation of microenvironments with decreased oxygen, nutrients and soluble factors produced by cellular metabolism leading to the formation of low proliferation areas and consequently necrosis (cell death). The fusion of cells also changes the catabolites flow, generating a very heterogeneous diffusion. The idea of this project is to develop and improve a microscaffold based on the concept of lockyballs that have cell support function for tissue engineering. Lockyballs have hooks and loops which attach each other assuring a 3D cellularized mesh. The model has a spherical outer structure and inner hollow microsphere constituted by pores with diameters smaller than the cell ones, whose function would be to prevent cell entry and provide an environment suitable to diffusion gradient necessary for the cell viability of the spheroid avoiding necrosis. The first stage of the work consisted in the generation of different three dimensional models by Computer Aided Design (CAD) software Rhinoceros 5.0. At the second stage, the CAD model was imported into finite element method (FEM) software (ANSYS R16 Static) to perform computational simulation, which consisted of structural analyses. Computational simulations were essential to predict the diffusion phenomenon inside the whole 3D structure. The development of new microscaffolds models can enhance the regenerative capacity and 3D tissues construction.
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The outcome of a bioprinting process depends on both the deposition of the discrete bioink units and their ability to self-assemble into the desired structure following deposition. Post-printing structure formation is an autonomous process governed by fundamental biological organizing principles. As the quantitative formulation of such principles is notoriously difficult, bioprinting remains largely a trial and error approach. To address this problem, specifically in extrusion bioprinting, we have recently developed an effective computational method, the cellular particle dynamics (CPDs). We have demonstrated the predictive power of CPD in cases of simple printed constructs prepared with spherical multicellular bioink units. Here we generalize CPD to the important practical case of tubular grafts printed with cylindrical bioink units by taking into account the realistic experimental situation in which the length and the volume of the cylinders decrease post-printing. Based on our results, we provide a set of instructions for the use of CPD simulations to directly predict tubular graft formation without the need to carry out the corresponding complex and expensive control experiments. Using these instructions allows the efficient and timely biofabrication of tubular organ structures. A particularly instructive outcome of our analysis is that building tubular organ structures, such as vascular grafts by bioprinting can be done considerably faster by using cylindrical rather than spherical bionk units. Work supported by NSF [PHY-0957914]. The computations were performed on the HPC resources at the University of Missouri Bioinformatics Consortium (UMBC).
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Aggregates of pre-sorted cells form structures called tissue spheroids that have been widely used in the field of tissue engineering. The greater contact of the cells with the culture medium is directly related to cell viability and to the increase of proliferation rate. Due to the characteristics of a 3D environment, at some zones within the tissue spheroids some cells are not equally exposed to the environment, impacting in the formation of microenvironments with decreased oxygen, nutrients and soluble factors produced by cellular metabolism leading to the formation of low proliferation areas and consequently necrosis (cell death). The fusion of cells also changes the catabolites flow, generating a very heterogeneous diffusion. The idea of this project is to develop and improve a microscaffold based on the concept of lockyballs that have cell support function for tissue engineering. Lockyballs have hooks and loops which attach each other assuring a 3D cellularized mesh. The model has a spherical outer structure and inner hollow microsphere constituted by pores with diameters smaller than the cell ones, whose function would be to prevent cell entry and provide an environment suitable to diffusion gradient necessary for the cell viability of the spheroid avoiding necrosis. The first stage of the work consisted in the generation of different three dimensional models by Computer Aided Design (CAD) software Rhinoceros 5.0. At the second stage, the CAD model was imported into finite element method (FEM) software (ANSYS R16 Static) to perform computational simulation, which consisted of structural analyses. Computational simulations were essential to predict the diffusion phenomenon inside the whole 3D structure. The development of new microscaffolds models can enhance the regenerative capacity and 3D tissues construction.
Chapter
Organ printing is defined as a layer-by-layer, additive, robotic, and computer-aided biofabrication of functional three-dimensional (3D) organ constructs using self-assembling tissue spheroids according to a digital model. Information technology and computer-aided design software are instrumental in the transformation of virtual 3D bioimaging information about human tissue and organs into living biological reality during 3D bioprinting. Information technology enables design blueprints for bioprinting of human organs as well as predictive computer simulation of both printing and postprinting processes. 3D bioprinting is now considered an emerging information technology, and the effective application of existing information technology tools and development of new technological platforms, such as human tissue and organ informatics, design automation, virtual human organs, virtual organ biofabrication line, mathematical modeling, and predictive computer simulations of bioprinted tissue fusion and maturation is important for advancing organ bioprinting.
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