IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO.

3, MARCH 2013 691

Bioprinting Toward Organ Fabrication: Challenges

and Future Trends
Ibrahim T. Ozbolat and Yin Yu

AbstractTissue engineering has been a promising field of re-

search, offering hope for bridging the gap between organ shortage
and transplantation needs. However, building three-dimensional
(3-D) vascularized organs remains the main technological barrier
to be overcome. Organ printing, which is defined as computer-
aided additive biofabrication of 3-D cellular tissue constructs, has
shed light on advancing this field into a new era. Organ print-
ing takes advantage of rapid prototyping (RP) technology to print
cells, biomaterials, and cell-laden biomaterials individually or in
tandem, layer by layer, directly creating 3-D tissue-like structures.
Here, we overview RP-based bioprinting approaches and discuss
the current challenges and trends toward fabricating living organs
for transplant in the near future.
Index TermsBioadditive manufacturing, bioprinting, organ
fabrication, tissue engineering.

I. INTRODUCTION Fig. 1. Organ printing concept: 3-D functional organs are printed from the bot-
RGAN shortage has become more problematic in spite tom up using living cells in a supportive medium (image courtesy of Christopher

O of an increase in willing donors. From July 2000 to July

2001, for example, approximately 80 000 people in the United
Barnatt [8]).

States awaited an organ transplant, with less than a third receiv-

ing it [1]. The solution to this problem, as with the solutions
to other grand engineering challenges, requires long-term so-
lutions by building or manufacturing living organs from a per-
sons own cells. For the past three decades, tissue engineering
has emerged as a multidisciplinary field involving scientists, en-
gineers, and physicians, for the purpose of creating biological
substitutes mimicking native tissue to replace damaged tissues
or restore malfunctioning organs [2]. The traditional tissue engi-
neering strategy is to seed cells onto scaffolds, which can then di-
rect cell proliferation and differentiation into three-dimensional
(3-D) functioning tissues. Both synthetic and natural polymers
have been used to engineer various tissue grafts like skin, car-
tilage, bone, and bladder [3][6]. To be successfully used for
tissue engineering, these materials must be biocompatible and
biodegradable, with the mechanical strength to support cell
Manuscript received December 12, 2012; revised January 20, 2013 and
January 23, 2013; accepted January 24, 2013. Date of publication January 30,
2013; date of current version March 7, 2013. This research was supported by
the National Institutes of Health and the Institute for Clinical and Translational
Science under Grant ULIRR024979. Asterisk indicates corresponding author.
I. T. Ozbolat is with the Mechanical and Industrial Engineering Department
and Biomanufacturing Laboratory, The University of Iowa, Iowa City, IA 52242
USA (e-mail: Ibrahim-ozbolat@uiowa.edu).
Y. Yin is with the Biomedical Engineering Department and Biomanufacturing
Laboratory, The University of Iowa, Iowa City, IA 52242 USA (e-mail: yin-yu@
uiowa.edu).
Digital Object Identifier 10.1109/TBME.2013.2243912
0018-9294/$31.00 2013 IEEE
attachment, proliferation, and direct cell differentiation toward
certain lineages. Although significant success has been achieved
in the past decades both in research and clinical applications [7],
it is obvious that complex 3-D organs require more precise mul-
ticellular structures with vascular network integration, which
cannot be fulfilled by traditional methods.
A computer-aided bioadditive manufacturing process has
emerged to deposit living cells together with hydrogel-based
scaffolds for 3-D tissue and organ fabrication. Bioprinting or
direct cell printing is an extension of tissue engineering, as it
intends to create de novo organs. It uses bioadditive manufactur-
ing technologies, including laser-based writing [9], inkjet-based
printing [10], and extrusion-based deposition [11]. Bioprinting
offers great precision on spatial placement of the cells them-
selves, rather than providing scaffold support alone [12]. Al-
though still in its infancy, this technology appears to be more
promising for advancing tissue engineering toward organ fab-
rication, ultimately mitigating organ shortage and saving lives.
Fig. 1 demonstrates the concept of futuristic 3-D direct organ
printing technology, where multiple living cells with the sup-
portive media stored in cartridges are printed layer by layer
using inkjet printing technology. It offers a controllable fabri-
cation process, which allows precise placement of various bio-
material and/or cell types simultaneously according to the nat-
ural compartments of the target tissue or organs. Multiple cell
types, including organ-specific cells and blood vessel cells, i.e.,
smooth muscle and endothelial cells (ECs), constitute the en-
tire organ. Although the concept seems to be trivial considering
692
Fig. 2. Bioprinting techniques including (a) laser-based writing of cells,
(b) inkjet-based systems, and (c) extrusion-based deposition.
the complexity and functionality of the parts that can be man-
ufactured using contemporary rapid prototyping (RP) technol-
ogy [13], several challenges impede the evolution of organ print-
ing. This paper discusses the current state of the art in bioprinting
technology, its advantages and limitations, and grand challenges
and future trends toward fabrication of living organs in both re-
search and clinical scenarios.
II. BIOPRINTING: CURRENT STATE OF THE ART
Bioprinting, where living cells are precisely printed in a cer-
tain pattern, has great potential and promise for fabricating en-
gineered living organs. Based on their working principles, bio-
printing systems can be primarily classified as: 1) laser based,
2) inkjet based, or 3) extrusion based.
Laser technology has recently been applied in the cell print-
ing process, in which laser energy is used to excite the cells
and give patterns to control spatially the cellular environment.
A laser-based system was first introduced in 1999 by Odde et al.
to process 2-D cell patterning [14]. Laser direct-write (LDW) is
a biofabrication method capable of rapidly creating precise pat-
terns of viable cells on petri dishes. In LDW, cells suspended in a
solution in donor slides are transferred to a collector slide using
laser energy. A laser pulse creates a bubble, and shock waves
are generated by the bubble formation, which eventually propel
cells toward the collector substrate [see Fig. 2(a)]. Microscale
cell patterning can be achieved through optimizing viscosity
of biological material (bioink), laser printing speed, laser en-
ergy, and pulse frequency [15]. Writing of multiple cell types
is also feasible by selectively propelling different cells to the
collector substrate. Laser printing technology is also integrated
with scaffold printing, where LDW is performed in tandem with
photopolymerization of hydrogels. It basically deposits cells in a
certain pattern onto a substrate by a laser beam. This is followed
by deposition of hydrogel on top of each layer of cells, and the
process is repeated for multiple cycles to get a 3-D structure.
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013
Nahmias et al. successfully performed hepatocytes patterning in
collagen and Matrigel using laser-guided 3-D cell writing [16].
In their study, three layers of cells and hydrogels were alter-
nately deposited on top of each other, forming a 3-D cellular
structure. Cell viability and proliferation was well-maintained
post-deposition.
Inkjet-based bioprinting was introduced in the early 2000s
and built a great foundation for future organ printing technolo-
gies. In this technique, living cells are printed in the form of
droplets through cartridges instead of seeding them on scaffolds
[see Fig. 2(b)]. It uses a noncontact reprographic technique that
takes digital data from a computer representing tissue or organs,
and reproduces it onto a substrate using bioink made of cells
and biomaterials [10]. Boland et al. used a thermal inkjet printer
to successfully fabricate 3-D cellular assemblies of bovine aor-
tal ECs with thermosensitive gels [10]. Post-incubation, printed
structures showed high cell viability and maintained cell pheno-
type. Cui and his coworkers [17] applied inkjet printing technol-
ogy to repair human articular cartilage, showing its promising
potential for high-efficiency direct tissue regeneration. Huang
and his coworkers [18] developed a bipolar wave-based drop-
on-demand jetting. In their studies, cell-encapsulated alginate
microspheres were jetted and assembled to create vertically ori-
ented, short, tubular structures [19]. Inkjet-based system allows
printing single cells or cell aggregates [20], [21] by controlling
process parameters such as cell concentration, drop volume,
resolution, nozzle diameter and average diameter of printed
cells [22]. Weiss and his coworkers [23] developed a multihead
inkjet-based bioprinting platform for fabricating heterogeneous
structures with a concentration gradient changing from the bot-
tom up. Multiple growth factors such as fibrinogen and thrombin
and cells were printed with spatial precision in a functionally
graded manner into rat calvarial defect in-situ [24]. They demon-
strated the feasibility of in-situ printing; however, this technique
did not seem to be a practical approach for clinicians due to
complex nature of the process in their study [24].
Another bioprinting technique has been introduced for print-
ing living cells and is based on the extrusion of continuous
filaments made of biomaterials. It is a combination of a fluid-
dispensing system and an automated three-axis robotic system
for extrusion and printing, respectively [11]. During printing,
biomaterial is dispensed by a pressure-assisted system, under the
control of robots, resulting in precise deposition of cells en-
capsulated in the cylindrical filaments of desired 3-D structures
[see Fig. 2(c)]. Wang et al. used a 3-D syringe-based bioprint-
ing system to deposit different cells with various biocompati-
ble hydrogels [25], [26]. They used hepatocytes and adipose-
derived stromal cells (ADSCs) together with gelatin/chitosan
hydrogels to engineer an artificial liver. Sun and his cowork-
ers [27][29] built a multinozzle bioprinting system with the
capacity to simultaneously deposit cells and multiple biomate-
rials. Their rheology study and cell viability assay were per-
formed to investigate mechanical-stress-induced cell damage
during the printing process [30]. The results showed that cell
viability was influenced by material flow rate, material concen-
tration, dispensing pressure, and nozzle geometry. Their findings
can serve as a guideline for future studies and optimization of
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013
the deposition system. Kachouie et al. proposed a method using
hydrogel-encapsulated cells as tissue units to make a construct
with geometric patterns specific to target tissue types [31].
Although bioprinting is a promising way as a methodical in-
terface between tissue and engineering, each technique has its
own limitations. Laser-based systems have high resolution and
enable precise patterning of living cells, where cells can main-
tain registry within 5.6 2.5 m to the initial pattern [32]. This
resolution, certainly, cannot be achieved by other bioprinting
techniques that makes laser-based cell writing as a great po-
tential for microcellular features in organs and tissues i.e., mi-
crovascularate. In the authors opinion, prolonged fabrication
time, laser shock related thermally and mechanically induced
cell deformation, interactions of cell components with light,
gravitational and random setting of cells in the precursor solu-
tion, limitations in printing in third dimension and the need for
photo-crosslinkable biomaterials should be overcome for future
developments in laser-based systems [15], [33], [34]. In order
to improve resolution further and increase throughput, param-
eters related to laser pulse characteristics (i.e., pulse duration,
wavelength, repetition rate, energy, and beam focus diameter),
precursor solution properties such as viscosity, thickness, sur-
face tension, and substrate properties should be optimized [34].
One-directional propulsion of cells toward the collector sub-
strate (top to bottom) certainly limits development of 3-D struc-
tures with complex heterocellular architectures. In order to ex-
pand this technology in the third dimension, a rotating donor-
side carousel leveling system with rotational and linear stages
can be developed that allows printing multiple cells in different
layers for the development of heterocellular structures. Similar
technology has been recently demonstrated with multimaterial
stereolithography process [35]. In addition, the fabrication speed
can be improved by increasing the laser pulse rate or integrating
multiple laser beams [36].
Inkjet-based systems are versatile and affordable that favors
cells encapsulation. For instance, Xu et al. [37] developed a
fabrication platform with a different working principle as op-
posed to traditional inkjet printers, where droplets of crosslinker
chemical were deposited onto a suspension of cardiomyocytes
and alginate for 3-D cardiac pseudo tissue fabrication. In ad-
dition, the traditional setup allows integrating multiple print
heads easily to deposit multiple cell types, which is one of the
pivotal steps in fabricating heterocellular tissues and organs.
The other advantage of inkjet printing is that surfaces where
the cells are printed and patterned do not have to be flat that
favors cell printing in situ [38]. In general, all other techniques
require gentle handling of a flat deposition surface that limits
their direct applicability in surgery rooms. Despite their great
advantages, inkjet printers suffer from drawbacks including sig-
nificant cell damage and death as well as cell sedimentation and
aggregation due to small orifice diameter that restricts printing
cells in high densities (<5 106 cell/ml) [22], [39], [40]. In
addition, structural integrity of the printed structures is another
obstacle, where the droplets do not fuse into each other easily
and the shape of droplets cannot be controlled precisely. Ade-
quate structural integrity is crucial to retain the designed and the
fabricated shape.
693
Extrusion-based systems provide relatively better structural
integrity due to continuous deposition of cylindrical struts. It is
the most convenient technique in rapidly fabricating 3-D porous
cellular structures [12]. Although this technology lays founda-
tion for cell patterning for scale-up tissue and organ fabrication
technologies, it constitutes several limitations such as shear-
stress-induced cell deformation and limited material selection
due to need for rapid encapsulation of cells via gelation. Shear
stress on nozzle tip wall induces significant drop in the number
of living cells when the cell density is high; however, this can be
partially alleviated using optimum process parameters such as
biomaterial concentration, nozzle pressure (ideally minimum),
nozzle diameter, and loaded cell density [41]. Restricted bioma-
terial selection and low resolution and accuracy brings limited
applicability of extrusion-based systems [12], [42]. Besides,
sufficiently high viscosity is essential for the biomaterial sus-
pension to overcome surface tension-driven droplet formation
and be drawn in the form of straight filaments. High viscosity,
on the other hand, triggers clogging inside the nozzle tip and
should be optimized considering the diameter of the nozzle tip.
Considering prolonged fabrication time for printing scale-up
tissues and organs, one of the important disadvantages of en-
capsulating living cells in biomaterials is that cell-biomaterial
suspension needs to be stored for a considerable period of time
in the material reservoir that compromises cell viability and
limits their bioactivity. Thus, a more automated way of loading
and ejecting cell-biomaterial suspension is required for scale-
up tissue and organ fabrication. Recently, Novogen MMX Bio-
printer [43] developed the technology where the printer head has
both suction and ejection capability enabling automatic loading
of suspension through the nozzle tip occasionally instead of
loading it manually prior to fabrication. Mechanical strength
and structural integrity of the fabricated structures is a com-
mon drawback among bioprinting techniques, which mainly
use hydrogels due to high water content and biocompatibil-
ity that allows permeation of nutrients into and cellular prod-
ucts out of the gel [44]. Water content increases their biocom-
patibility; however, it deteriorates mechanical properties and
processability significantly. Although hydrogels possess unique
properties, they are intrinsically weak due to high water con-
tent and do not withstand mechanical loading during and after
gelation process. Gelation of cell-encapsulated hydrogels is a
crosslinking reaction initiated by a light, a chemical, or thermal
transitions [45]. Photo-crosslinking processes compromise cell
viability and pose significant limitations on encapsulation of
cells within hydrogels [33]. Crosslinking through thermal tran-
sitions limits the applicability of hydrogels. Thermal transition
initiated crosslinking is not easy to handle after the process,
while temperature changes can result in rapid degradation of
the printed thermogel that does not support cell viability in
cell media culture [46]. Chemical crosslinking can compromise
cell viability if any abrupt pH changes are observed; however,
nonacid involved crosslinking, i.e., sodium alginate, occurs gen-
tly under mild conditions and at room temperature without pro-
ducing any toxic components, which has a great potential for
tissue engineering [47]. So, new hydrogels should be tailored to
enhance mechanical properties and processability for specific
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Fig. 3. (a) Hanging drop cultures with 20 000 chondrocytes showing
(b) spheroid fusion seven days after harvesting, creating a larger scale tissue.
bioprinting techniques toward advanced tissue and organ fab-
rication. In addition, these materials should have the ability to
withstand sterilization while sterile conditions certainly need to
be acquired for process safety.
In general, cell encapsulation in biomaterial allows cell pat-
terning that has a great potential for direct organ printing; how-
ever, subsequent extracellular matrix (ECM) formation, diges-
tion, and degradation of biomaterial matrix and proliferation of
encapsulated cells are not trivial to control. There are still intrin-
sic limitations for bioprinting due to limited cell proliferation
and colonization while cells are immobilized within hydrogels,
and do not spread, stretch, and migrate to generate the new tis-
sue. Most recently, a new concept was introduced by Mironov
and his coworkers [48], bioprinting and assembling them in
hydrogel media has brought a significant potential for tissue
engineering.
Cell aggregates or cell-laden hydrogels as building blocks
at the microscale are selectively deposited to create larger tis-
sues [48], [50], [51]. In this approach, these minitissues are
considered as a biomaterial with certain measurable and con-
trollable properties and are assembled into tissues with specific
features through layer-by-layer stacking [52] or direct assem-
bly [48], [53]. Fig. 3 shows hanging drop cultures, where each
spheroid contains 20 000 chondrocytes, and fusion between
spheroids was observed seven days after harvesting, resulting in
a larger scale cartilage tissue. This shows a great promise in ob-
taining larger scale cartilage formation, where researchers have
already demonstrated regeneration of cartilage tissue on rabbit
knees with comparable properties with that of natural cartilage
tissue [42]. Tissue spheroids in that study eliminated or mini-
mized inclusion of biomaterials and hence tissue regeneration
achieved without the need of scaffolds. In general, this also re-
duces complications related with degradation of biomaterials
and resulted toxic byproducts. In addition, large-scale tissues
can be easily obtained by fusion process, where cells in cell-
laden hydrogels cannot easily fuse [48]. By taking advantage
of tissue spheroids, the time needed for tissue maturation can
be significantly reduced, since each tissue spheroid contains a
large number of cells that can be printed at once. Moreover, cell
viability is enhanced due to the large cell seeding density and
less mechanical stress experienced compared with direct cell
manipulation [48]. Researchers have been investigating means
to reduce the actual size of tissue spheroids which is around
500 m because the current size restricts biomanufacturing of
smaller scale features considering the average size of tissue
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013
Fig. 4. Tissue spheroids for blood vessel printing: (a) Deposition of straight
filaments containing a string of tissue spheroids (stained in white) with agarose
filaments as support material (stained in blue) both around cellular filaments and
inside the core, (b) design for multicellular assembly with (c) printed samples
with human umbilical vein smooth muscle cells and human skin fibroblast cells
(reproduced from [55], image courtesy of Elsevier).
spheroid as the resolution of the fabrication technology. In ad-
dition, more efficient and economical ways of fabricating tissue
spheroids are also under investigation. Iwasaki et al. introduced
a new technique using micropatterned tissue culture plates for
mass fabrication of spheroids that has the potential for rapid
scale-up organ fabrication technology [54].
By using tissue spheroids, Forgacs and his coworkers at the
University of Missouri, Columbia, MO, USA, used RP-based
bioprinting together with multicellular spheroids made from
smooth muscle cells and fibroblasts, producing scaffold-free
vascular constructs [55]. Fig. 4 illustrates vascular construct
printing, where tissue spheroids are printed sequentially in
cylindrical filaments from the bottom up. Upon fusion of tis-
sue spheroids followed by a tissue maturation process of three
days post-printing, the support material is pulled away manu-
ally to generate the lumen. Multiple cell types, including human
umbilical vein smooth muscle cells and human skin fibroblast
cells, were printed together to fabricate multicellular constructs.
The bioprinting platform used in this study, the Novogen MMX
Bioprinter [43], has been recently commercialized and special-
izes in developing bioprinting across a broad array of cell types
to create functional 3-D tissues. When building large-scale or-
gan structures, the mechanical integrity of the printed structures
as well as the integration of the vascular network with the rest
of the organ seems to be the major challenges to expanding the
technology for further applications.
III. ORGAN PRINTING AND ITS CHALLENGES
Organ printing is a computer-aided process in which cells
and/or cell-laden biomaterials are placed in the form of aggre-
gates, which then serve as building blocks and are further assem-
bled into a 3-D functional organ. It is an automated approach
that offers a pathway for scalable, reproducible mass produc-
tion of engineered living organs where multiple cell types can
be positioned precisely to mimic their natural counterparts. De-
veloping a functional organ requires advances in and integration
of three types of technology [56]: 1) cell technology, which ad-
dresses the procurement of functional cells at the level needed
for clinical applications, 2) biomanufacturing technology, which
involves combining the cells with biomaterials in a functional
3-D configuration, and 3) technologies for in vivo integration,
which addresses the issue of biomanufactured construct im-
mune acceptance, in vivo safety and efficacy, and monitoring
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013
of construct integrity and function post-implantation. Success
in fabrication of functional organs highly depends on advance-
ments in stem cell technology. Stem cells, which are found in
several tissues in the human body [57], can self-renew to pro-
duce more stem cells and differentiate into diverse specialized
cell types to form various organs [58]. A variety of cell types
can be used for this application, such as embryonic stem cells
(ESCs) [57], adult stem cells (ASCs) [59], most recently, in-
duced pluripotent stem (iPS) cells [60], and tissue-specific cell
lines [61], [62]. Although a patients stem cells can be differenti-
ated into organ-specific cells for organ printing, there is still risk
of tissue rejection by the receiver [56]. Stem cell behaviors can
even change during the bioprinting process. In addition, organ
fabrication necessitates various types of organ-specific cells,
which is not currently feasible considering the current isolation
and differentiation technologies. Although stem cells offer great
promise as an unlimited source of cells, a greater understand-
ing of and control over the differentiation process is required
in order to generate expandable organ-specific cells in consis-
tent quality with the desired phenotype. In this way, rejection
by the recipient side will be minimized post-transplantation.
Moreover, imaging modalities such as computed tomography
(CT), positron emission tomography (PET), and nuclear mag-
netic resonance (NMR) imaging should be used to monitor the
transplanted organ noninvasively; NMR offers a unique advan-
tage in monitoring organ integrity and function without the need
to modify the cells genetically [63]. Although cell and transplan-
tation technology plays a crucial role in organ fabrication, this
review focuses on biomanufacturing technology, and the rest of
the paper discusses major challenges in the context of bioprint-
ing toward organ fabrication.
Despite the progress in tissue engineering, several challenges
must be addressed for organ printing to become a reality. The
most critical challenge in organ printing is the integration of a
vascular network, which is also a problem that majority of tissue
engineering technologies are facing. Without vascularization,
the engineered 3-D thick tissue or organs cannot get enough
nutrients, gas exchange, and waste removal, all of which are
needed for maturation during perfusion. This results in low cell
viability and malfunction of artificial organs. Systems must be
developed to transport nutrients, growth factors, and oxygen to
cells while extracting metabolic waste products such as lactic
acid, carbon dioxide, and hydrogen ions so the cells can grow
and fuse together, forming the organ. Cells in a large 3-D organ
structure cannot maintain their metabolic functions without vas-
cularization, which is traditionally provided by blood vessels.
Bioprinting technology, on the other hand, currently does not
allow multiscale tissue fabrication where bifurcated vessels are
required to be manufactured with capillaries to mimic natural
vascular anatomy. Although several researchers have investi-
gated developing vascular trees using computer models [64],
only a few attempts have been made toward fabricating bifur-
cated or branched channels [55]. Successful maturation toward
functional mechanically integrated bifurcated vessels is still a
challenge.
In order to closely mimic natural organs, 3-D vascularized
organs need to be fabricated using heterocellular aggregates,
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Fig. 5. Concept of 3-D organ-printing technology where vessel-like microflu-
idic channels are printed in tandem with tissue spheroids layer by layer. The
printed structure can be then connected to a bioreactor for media perfusion
(figures are not to scale).
which was discussed extensively in the literature [48]. In that
study, intraorgan vascular branched networks are envisioned to
be printed and maturated with the rest of the organ. Instead of
biomimetically designing and fabricating a vascular tree, which
seems to be one of the impediments down the road for organ
printing, we alternatively propose printable semipermeable mi-
crofluidic channels to mimic a vascular network in perfusing
media and facilitating oxygenation for cell viability, coaxing
tissue maturation and formation.
Fig. 5 illustrates our conceptual model of organ printing
through integration of vessel-like microfluidic channels with
cellular assembly, which has been featured in the literature [1],
[65]. The concept allows constructing structures with microflu-
idic channels acting like blood vessels, allowing media perfusion
through an extracellular matrix that can support cell viability in
3-D. In Fig. 5, vessel-like microfluidic channels are printed in a
0 90 lay-down pattern to develop 3-D structures. Oxygenized
perfusion media can be pumped into channels for circulation
purposes. Round ends are considered for the zigzag deposition
pattern to prevent blockage of media flow. After parallel printing
of each microfluidic channel layer, cellular spheroids, i.e., tissue
spheroids or cell-encapsulated microspheres, can be deposited
between fluidic channels in the form of droplets using another
robotic arm; semipermeable fluidic channels allow transport and
diffusion of media to the cellular environment. The proposed
strategy enables printing semi-permeable microfluidic channels
in tandem with printing cellular assembly. Concurrent printing
has the potential to reduce the fabrication time, which is crucial
for the development of scale-up technologies [see Fig. 7(c)].
Advantages of tissue spheroids have already been discussed in
Section II; spheroids significantly enhance cell viability of stem-
cell-derived organ-specific cells, allowing the development of
further organ fabrication techniques in the near future. Printing
encapsulated cells in spheroids also greatly reduces shear-stress-
induced cell damage compared to printing cells directly loaded
within biomaterial media. In general, cells are subjected to shear
stress during the printing process, and cell injury and DNA
damage should be minimized. The proposed concept can also
allow inclusion of multiple cell types in a spatially organized
696
Fig. 6. Printed cellular microfluidic channels. (a) Perfusion of oxygenized cell
type media. (b) Media flow with intentionally generated air bubbles. (c) Laser
confocal image of the mid-plane showing single lumen channel with live/dead
staining where CPCs are labeled with calcein AM and ethidium homodimer.
way by integrating another printer unit mounted on the robotic
arm to print a secondary type of spheroids precisely.
Fig. 6 illustrates oxygenized media perfusion through a
printed cellular microfluidic channel 44 cm in length and 1 mm
wide with a 500-m lumen diameter. The cell media is circulated
through the channel without any blockage or swirling, which
shows a great potential for developing embedded channels and
serving as a vascular network for thick tissue fabrication. Di-
rect printing of these channels allows them to be integrated
within a hybrid bioprinting platform and also facilitates pat-
terning them into very complex shapes. Currently, mechanobi-
ological properties of printed channels are under investigation,
and electrospun nanofiber reinforcement is performed to match
the mechanical properties with that of blood vessels. Elasticity
and tensile strength are essential to be biomimetically medi-
ated. Viability of cartilage progenitor cells (CPCs) encapsulated
within printed microfluidic channels showed 97.6 1.2% one
day post-printing and maintained high cell viability on day 4,
with a percentage of 95.8 1.2 where living cells are shown
around the lumen on the cut-away view [see Fig. 6(c)].
It should be ensured that the printed organ functions correctly.
For example, a bioprinted pancreatic organ must be able to pro-
duce and secrete insulin just like its natural counterpart. Thus,
multiple organ-specific cell types are required to be spatially
organized to form the complex architecture of an organ. Ad-
vancements in bioprinting processes to precisely and selectively
place cells, are promising when it comes to achieving heterocel-
lular architectures. Fig. 7 illustrates some of the bioprinters that
can facilitate printing heterocellular structures, including Envi-
sionTEC 3-D Bioplotter (where solid filaments are printed in a
secondary plotting media), Novogen MMX Bioprinter (which
allows printing heterocellular tissue aggregates and hydrogels
as support material), and the Multi-Arm BioPrinter (MABP)
(which can print tissue spheroids in tandem with vessel-like
microfluidic channels). These technologies can be applied for
cellular aggregate biofabrication in such a way as to facilitate
self-assembly of the tissue spheroids to mimic the natural pro-
cess of tissue and organ morphogenesis.
In order to fabricate scalable organs such as a mouse liver
which has 1.3 108 cells per gram [67], the bioprinter needs to
run for several hours considering the resolution of the system as
in microscale. During prolonged fabrication time, it should de-
liver biological substances through micronozzle or other means
without clogging problems or collision issues between the noz-
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013
Fig. 7. Bioprinters. (a) 3-D BioplotterR
(designed by envisionTEC GmbH,
Gladbeck, Germany [66]). (b) Novogen MMX Bioprinter (designed by
Organovo, San Diego, CA, USA [43]). (c) Multi-Arm BioprinterMABP
(designed by the University of Iowa, Iowa City, USA).
zle tip and the printed structure. In addition, sterilization is
also crucial during bioprinting and necessitates construction of
bioprinters on a small scale to fit in standard biosafety cabi-
nets. In general, commercial bioprinters can cost substantially
high around $100200k depending on their unique capabilities,
where home-made bioprinters on the other hand roughly cost
less than quarter of their commercial counterparts.
Another challenging site for organ printing technology is the
rapid or accelerated tissue maturation process, where printed
organ constructs should be rapidly fused, remodeled, and mat-
urated toward a solid construct, ensuring mechanical rigidity
for transplantation. Collagen and elastin are some of the pro-
teins in the extracellular matrix of human organs, and they are
abundant in the connective tissue stromal of parenchymal or-
gans [68], [69]. Thus, production and deposition of these pro-
teins during tissue maturation are essential to enhancing the
mechanical properties of the printed organs. After the organ-
printing process, the fabricated structure needs to be transferred
to the bioreactor. Bioreactors such as an irrigation dripping per-
fusion bioreactor can be used to expedite the tissue maturation
and organ formation process, providing an optimal environ-
ment. The transfer of a printed organ to the bioreactor should
be performed gently without inducing any vibration that can
degenerate the integrity of fragile gel-based structures. Thus,
future bioprinters can be enclosed in a bioreactor system that
will allow direct and rapid connection of printed structures to
perfusion channels.
IV. PROPOSED ENVISIONED FUTURE
Considering the pathway from isolation of stem cells to trans-
plantation into a human, seamlessly automated protocols and
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013
systems are essential for customized functional organ fabrica-
tion. This pathway includes 1) blueprint modeling of an organ
with its vascular architecture, 2) generation of a process plan
for bioprinting, 3) isolation of stem cells, 4) differentiation of
stem cells into organ-specific cells, 5) preparation and loading
of organ-specific cells and blood vessel cells as well as support
medium, and 6) bioprinting process followed by organogenesis
in a bioreactor for transplantation. In order to accelerate the en-
tire process, one can envision a bioreactor enclosing a bioprinter
that will immediately facilitate fusion of tissues and keep the
printed organ until desired maturation is achieved. In this way,
a customized and automated system will facilitate delivering
artificial organs to transplant patients in a reasonable amount of
time, preferably at earlier stages of their diseases when patients
are healthier so that they are better able to withstand surgical
interventions.
Miniature organs can be considered a future trend in organ
printing and might be a transition toward fully functioning or-
gans. Miniature organs, which can also be called a factory in
the human body, can be built in smaller scale than their natural
counterparts and closely perform the most vital function of the
associated organ, such as a pancreatic organ that can produce
and secrete insulin in substantial amounts to regulate the glu-
cose level to normoglycemia in the human body. The miniature
organ can be transplanted and placed in less immune-responsive
sites in the human body as an extravascular device or attached
to blood vessels as an intravascular device to secrete insulin
to the bloodstream. Although the pancreas serves two func-
tions, which are carried out by two different cell groups within
the organ, a patient with diabetes will be interested in correct-
ing hyperglycemia through fabrication and transplantation of a
pancreatic organ that can restore the function of the endocrine
portions of the pancreas, which makes only about 2% of pan-
creas cells. The endocrine portion is made of approximately a
million cell clusters called islets of Langerhans [70]. Four main
cell types exist in the islets. , , delta, and gamma cells secrete
glucagon, insulin, somatostatin (regulates/stops and cells),
and pancreatic polypeptide, respectively. Miniature organs can
also be designed and fabricated to bring new functionalities
and superiorities in the human body rather than restoring the
functionality of their natural counterparts, such as living organs
that can continuously generate electricity to eliminate the use of
batteries for internal devices such as peace makers.
Another future trend in organ printing is in-situ printing,
where living organs can be printed in the human body dur-
ing operations. Currently, in-situ bioprinting has already been
tested for repairing external organs such as skin [38], where the
wounded section is filled with multiple cells, including human
keratinocytes and fibroblast, with stratified zones throughout
the wound bed. A transitional approach seems to be logical to
advance the state of the art through printing and repairing par-
tially damaged, diseased, or malfunctioning internal organs that
do not have self-repair characteristics, such as the liver. With
the recent advancements in robot-assisted surgery, computer-
controlled robotic bioprinters will lead the evolution of this
technology in the very near future.
697
V. CONCLUSION
This paper discusses the current state of the art in bioprinting
with recent trends in organ printing technology toward fabri-
cation of living organs for transplant, where prototype organs
can be developed using layer-by-layer technology in the very
near future. Although the technology shows a great deal of
promise, there is still a long way to go to practically realize
this ambitious vision. Overcoming current impediments in cell
technology, biomanufacturing technology, and technologies for
in-vivo integration is essential for developing seamlessly auto-
mated technology from stem cell isolation to transplantation.
ACKNOWLEDGMENT
The authors would like to thank A. Lehman from the Ignacio
Ponseti Orthopaedic Cell Biology Lab (The University of Iowa)
for the fabrication of chondrocyte spheroids.
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IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 60, NO. 3, MARCH 2013 699

Ibrahim T. Ozbolat received dual B.S. degrees in Yin Yu received the M.D. degree from Medical Col-
industrial engineering and mechanical engineering lege of Nantong University, China, in 2010, and the
from the Middle East Technical University, Ankara, M.S. degree in biomedical engineering from The Uni-
Turkey, in 2006 and 2007, respectively, and the Ph.D. versity of Iowa, Iowa City, USA.
degree in industrial engineering from University at His research mainly focuses on stem cell biology,
Buffalo, New York, USA, in 2011. tissue engineering, and biomanufacturing.
He is an Assistant Professor of the Department Prof. Yu is a member of ASME, TERMIS, BMES,
of Mechanical and Industrial Engineering and a Re- and ICMRS.
search Faculty at the Center for Computer-Aided De-
sign at The University of Iowa, Iowa City, USA. His
research interests are biomanufacturing, tissue en-
gineering, manufacturing and design, virtual manufacturing, computer-aided
design, and electronics manufacturing.
Prof. Ozbolat is a member of IIE, ASME, APM and TERMIS.