PERSPECTIVE
Creation of a vascular system for organ manufacturing
Libiao Liu and Xiaohong Wang*
Center of Organ Manufacturing, Department of Mechanical Engineering, Tsinghua University, Beijing 100084, China
Abstract: The creation of a vascular system is considered to be the main object for complex organ manufacturing. In
this short review, we demonstrate two approaches to generate a branched vascular system which can be printed using
rapid prototyping or bioprinting techniques. One approach is constructing mathematical tree models on the basis of human physiological characteristics and calculating the model using constrained constructive optimization to obtain
three-dimensional (3D) geometrical structures. The rules of the branching of the vessel tree were extracted from the
literature. Another approach is using computer-aided design models to build a multi-scale vascular network including
arteries, veins, and capillaries. A 3D vascular template with both synthetic scaffold polymer and cell/hydrogel was
created in our group, using a double-nozzle, low-temperature deposition technique. Each of the approaches holds promise in producing a vascular system.
Keywords: vascular system, three-dimensional (3D) modeling, branching rule, constrained constructive optimization,
hybrid architecture
*Correspondence to: Xiaohong Wang, Center of Organ Manufacturing, Department of Mechanical Engineering, Tsinghua University,
Beijing 100084, China; Email: [email protected]
Received: April 30, 2015; Accepted: June 21, 2015; Published Online: July 2, 2015
Citation: Liu L B and Wang X H, 2015, Creation of a vascular system for organ manufacturing. International Journal of Bioprinting,
vol.1(1): 77–86. http://dx.doi.org/10.18063/IJB.2015.01.009.
1. Introduction
C
omplex organ failures are the first cause of
mortality all over the world despite advances
in interventional, pharmacological, and surgical therapies[1]. Clinically, orthotopic organ transplantation is greatly limited by the issues of donor
shortage and immune rejections[2]. Over the last two
decades, the creation of branched vascular systems has
attracted significant attention, both from the scientific
and clinical areas. However, it is still a formidable
challenge to build a three-dimensional (3D) branched
vascular system, mimicking the native vascular
systems in complex organs, such as the liver, the heart,
and the kidney, with traditional or existing
manufacturing techniques[3–11]. For example, cell sheet
techniques face problems of rescuing tissues with increased thicknesses above 80 µm[12]. Cell encapsulation techniques encounter problems of capsule loss,
low stability, and poor efficiency[13]. Decellularized
matrices are hard to repopulate with multiple cell
types[14]. Rapid prototyping (RP) techniques, also
named as additive manufacturing (AM), solid
freeform fabrication (SFF), or 3D printing (3DP)
cannot solve all the difficulties in generating a
vascular network with all the multi-scale features of
large arteries, arterioles, capillaries, venules, and large
veins.
Currently, RP (AM, or 3DP) techniques are the
prevailing tools for defining macro- or microenvironment for cell cultures[15–20]. There is an increasing interest in the use of RP techniques for cell-laden hydrogel or solution manipulation. However, most of the
existing RP techniques are mainly used for the manipulation and analysis of one or two cell types in a
construct, which are machine dependent and significantly time consuming[15–20]. The least progress made
in complex organ manufacturing is the development
Creation of a vascular system for organ manufacturing. © 2015 Libiao Liu, Xiaohong Wang. This is an Open Access article distributed under the
terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting
all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Creation of a vascular system for organ manufacturing
of a vascular network that can mimic the native counterparts[21,22]. For example, Kaihara and Borenstein
used RP technology to generate a vascular system on
silicon and Pyrex surfaces[23]. Although this approach
is useful in creating a layer of endothelial tissue, it has
not been successfully used to build a vascular network
with multiple cell types.
The design and manufacture of biocompatible
branched vascular systems is a key factor in successful
organ manufacturing. Besides providing nutrients and
excluding metabolites, branched systems also serve as
a 3D template for initial cell accommodation and subsequent tissue/organ regeneration[21–23]. To meet the
metabolic needs of nutrients, oxygen delivery, and
waste removal, transport by diffusion is no longer sufficient; it also requires a convective pathway, i.e., a
vasculature, among the transplanted cells. Two ambitious approaches that aim to form a fully vascularised
system with multi-scale blood vessels of sufficient
size for implantation have been introduced. The vascular systems are designed to be connected with the
patient’s own blood vessels during surgery[24].
In this perspective, we describe the two basic strategies for producing a complex vascular system with a
predefined hierarchical architecture. Firstly, the hypothesis of the branching of a vessel tree, extracted from
the literature including the law of diameter of the bifurcation segments and the relation between the diameter and the branching angles, was introduced. An
algorithm, constrained constructive optimization
(CCO) method, was used to produce a vascular tree[25].
Secondly, a novel approach for engineering as vasculature in vitro has been developed. The strategy is
based on RP techniques which translate the tissue’s
3D structure into 2D layers using computer modeling
to organize millions of cells into a 3D structure[26].
Each of the two strategies can be used to create a
whole spectrum of vascular tissues, including arteries,
arterioles, veins, venules, and capillaries.
2. Constrained Constructive Optimization
(CCO) Method
2.1 The Basic Assumptions for Establishment of a
Vascular Tree
The algorithm to generate a vessel tree automatically
is a fractal and CCO method. To make the calculation
convenient, Schreiner et al. have made a series of
simplifications for generating a vascular tree based on
the following assumptions[27].
78
(i) The part of the living tissue to be supplied with
blood by the vascular tree can be modeled as a convex
area (polygon for 2D and polyhedron for 3D)[27].
(ii) The blood vessel can be regarded as a rigid cylindrical tube (segment) with a stable laminar blood
flow. From capillaries (the root segments), the
vascular tree successively bifurcates down to the
larger diameter level, where the vascular tree is
truncated in the form of terminal segment[28].
(iii) Blood is supposed to be a homogeneous incompressible Newtonian fluid and the hydrodynamic
resistance Rj of each segment j is given by Poiseuille’s
law[29]:
 8η  l j
(1)
Rj =   4
 π  rj
Where lj and rj represent the length and the internal
radius of the segment j.
(iv) The radii of parent and two daughter segments
at bifurcations (left and right) obey a power law (bifurcation law)[30,31] of the form:
γ
γ
γ
= rleft
+ rright
rparent
(2)
Where pterm denotes the pressure at the distal ends of
the terminal segments.
(1) Optimized arterial trees around a hollow organ
Using the above hypotheses and the algorithm of CCO,
various vascular tree models can be created with
different bifurcation angles and segment numbers
(Figure 1). For example, Schreiner et al. confined an
arterial tree model to some part of an elliptical shell,
representing the free wall of the left ventricle of the
heart (Figure 1(C))[32]. In this model, the coronary
arteries supply the left ventricular wall and the spatial
information was utilized to regulate optimization. The
rules of the branching of the vessel tree were extracted
accordingly, including the law of the diameter of the
bifurcation segments and the relation between the diameter and the branching angles. In a living organ, the
information is usually obtained from the intercellular
signaling pathways.
In our own group, we have developed an extension
to the computational method of the CCO for our 3DP
purposes. Within the framework of the CCO model, a
model tree is represented as a series of dichotomouslybranched, straight, cylindrical tubes. The tree is grown
by successively adding new terminal segments from
randomly selected points, while optimizing the geometric location and the topological site of each new
connection with respect to the minimum intra-vascular
International Journal of Bioprinting (2015)–Volume 1, Issue 1
Libiao Liu and Xiaohong Wang
Figure 1. (A), (B) A vascular tree containing 12 segments designed with the constrained constructive optimization method.
(C) A vascular tree in the anterior ventricular wall, regarding
branching patterns and other statistical and functional properties of vessel segments. An elliptical shell of 1 cm thickness
was represented by approximately 1000 triangles each and then
restricted by two cut-off planes. The perfusion volume was
used to grow a CCO tree to 2000 terminal segments for minimum intravascular volume. The location of the inlet was prescribed while all other segments’ locations are determined by
the algorithm. The models also used ‘staged-growth’ and a
‘spatially regulated optimization target’[32]. (D) A vascular tree
model of kidney made of plastic[33].
volume. An example result of a compute-program is
shown in Figure 1(A) and (B). In this example, there
are a total of 12 segments in the model tree. In another
group, a plastic vascular tree model of kidney was
built using bioprinting techniques (Figure 1(D)).
2.2 Some Details of the Vascular Tree Based on the
CCO Method
In the algorithm of CCO, the connective structure and
the segment locations depend on the sequence of
pseudorandom numbers chosen for a particular realization of the model. Especially, the locations chosen
for the first few terminal segments determine the final
appearance of the vascular tree[34]. Consequently, optimization of the tree can only be achieved within each
given random number sequence. The uncertainty thus
induced can be estimated from the standard deviations
of the mean segment radii. These quantify the sensitivity of the tree’s morphometric properties to changes
in a random number sequence[35]. It was found that the
branched vascular systems of human organs are
mainly two branches, with only a few branches that
are trigeminal. It is very hard for the CCO method to
mimic the natural vascular systems completely. The
dichotomous branching can be determined as the basic
structure of biomimetic vessel. Based on the physical
laws and conditions to establish the corresponding
model tree, as shown in Figure 1, the optimization
principle is to make sure the vascular system
throughout the entire organ as far as possible and
reduce the length of the vessels to improve its
efficiency. In the optimization design, the first step is
mainly to build a larger trunk, and based on it,
increase new blood vessels as a subordinate branch; at
the same time, the start and the end of each segment of
the vessel and its vessel diameter are determined. After a series of deduction, an entire vascular system can
be built.
The key idea of CCO is the stepwise growth of the
vascular tree, during which geometric and structural
optimization are performed. It is the locations of the
very first terminal segments that determine the coarse
structure of the fully developed vascular tree. The
segments, originating from early stages of development, become mainstream vessels when the tree
grows to its final size[27].
Most of the previous computer models used to consider a whole arterial tree, follow a compartment or
lumped parameter approach, and thereby ignore the
details of the geometric structure[36,37]. In some models, several features of geometric structure are introduced on a statistical basis only, by generating segment lengths and diameters randomly, according to
distributions suggested by morphometry of real blood
vessels. However, a similarity in the distribution of
segment parameters does not guarantee functional
similarity[38,39].
3. Bioprinting of a Vascular Template
3.1 Introduction of Several Bioprinting Techniques
in Tsinghua University
RP technology is a set of manufacturing processes,
which can deposit materials layer-by-layer until a
complete computer-aided design (CAD) with freeform
geometry is built. Over the last decade, a series of 3D
RP-based approaches have been developed in our
group, the Center of Organ Manufacturing,
Department of Mechanical Engineering, Tsinghua
University (Figure 2)[8–11, 40–63]. Various complex vascular systems for different complex organ manufac-
International Journal of Bioprinting (2015)–Volume 1, Issue 1
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Creation of a vascular system for organ manufacturing
Figure 2. Several bioprinters made in Tsinghua Unversity, Prof. X Wang’s group. (A) Hepatocyte and adipose-derived stem cell
–
(ADSC) assembling based on the first generation of cell assembling technique [40 51]. (B) Cell assembling based on a two syringe RP
,
technique.Two different cell types in the gelatin-based hydrogels can be assembled simultaneously into a construct[52 53]. (C) A
double-nozzle, low-temperature deposition manufacturing (DLDM) technique. An elliptical hybrid hierarchical polyurethane and
–
cell/hydrogel construct was fabricated using the DLDM system[56 63]. (D) A schematic description of the modeling and manufacturing
processes of four liver lobe-like constructs with a four-nozzle low-temperature deposition manufacturing (FLDM) bioprinting system[10].
turing, such as the heart, the liver, and breast, have
been successfully designed and printed (Figure 2(D)).
We have published more than 110 research articles
and 40 patents with these bioprinting techniques. In
addition, the first combined multi-nozzle 3D printer
has also been developed in our group and a viable liver substitute with various branching functional channels has been printed. These RP techniques have become the most convenient and reliable techniques for
the manufacturing of complex organs, including the
vascular trees, in the coming years.
3.2 A Low-Temperature Deposition Manufacturing
(LDM) Technology
Particularly, in order to generate complex organs with
adequately strong mechanical properties and hierarchical structures, we have developed a series of LDM
technologies to process various biomaterials under a
temperature ~ –20℃. Both synthetic and natural polymers, including cells, can be designed and fabricated
into complex 3D objects with an intrinsic network of
interconnected channels (Figure 2(C) and 2(D)). A
80
building block approach was used to print multichannel 3D organ regenerative scaffolds[56–63]. With
this technique, a specific model was selected via CAD
and solid free form fabrication processes were conducted under computer’s directions.
Hybrid hierarchical polyurethane (PU)-cell/hydrogel constructs were automatically created using a
double-nozzle, low-temperature deposition device based
on the layer-by-layer manufacturing principle[62,63]. The
elastomeric PU, mainly based on polycaprolactone
and poly(ethylene glycol) with excellent biocompatibility and tunable biodegradation properties, was used
as a supportive template for cell/hydrogel accommodation, growth, immigration and proliferation. Bioreactors can be applied for pulsatile cultures of the 3D
vascular templates with the principal axis. Further
researches are carried out for stem cell engagement in
the construct for a real vascular system.
3.3 Several Examples Made from the LDM
Technology
A primary branched vascular template, made of syn-
International Journal of Bioprinting (2015)–Volume 1, Issue 1
Libiao Liu and Xiaohong Wang
thetic biodegraded PU, was firstly built in our group
based on the simulation principles of the hepatic lobe
structure. This structure was printed according to a
CAD model using a one nozzle LDM technology. As
shown in Figure 3, the outer layer of the structure is
an ellipsoidal protective shell. The internal room is
isolated into multiple independent branch channels by
a series of division plates. The branching channels are
arranged around a central axis uniformly and can
transport nutrients to each part of the structure.
Through the branched channels, the surface area/ volume ratio is greatly expanded. This is beneficial for
the exchange of gas and nutrients inside the construct[56].
Figure 4. A branched tri-channel liver regeneration scaffold
made of poly (lactic-co-glycolic acid) (PLGA)[63]: (A and B)
CAD models of the branched tri-channel liver regeneration
scaffold; (C) and (D) the fabrication stages of a branched
tri-channel hemisphere scaffold.
Figure 3. (A) branched polyurethane (PU) vascular template
made by a low-temperature deposition manufacturing system[56].
(A) A computer-aided design (CAD) model. (B) A
three-dimensional (3D) construct made from PU. (C) A
cross-section of the PU construct in (B). (D) A scanning electronic microscope picture of the outer wall in (B).
Later on, using the same LDM printer, a more
complex vascular regeneration template was constructed in our group. As shown in Figure 4, this
structure is made of poly(lactic-co-glycolic acid)
(PLGA). Much smaller channels are produced with
the grid PLGA fibers. Compared with Figure 3, the
advantage of this structure is that the surface
area/volume ratio is greatly increased and can further
improve gas and nutrient exchange efficiency when
cells are incorporated inside the structure[63].
With the two nozzle LDM printer, much more
complex vascular networks with two material systems
have been generated (Figure 5)[60–62]. For example, a
Figure 5. Illustration of the hybrid hierarchical construct made
by the double-nozzle low-temperature deposition (DLDM)
bioprinting system: (A) a digital CAD model with an outlook
(the inset image) and an internal branched network; (B) a
common layer interface (CLI) file and a cross-sectional view
(the inset image) of the CAD model; (C) a DLDM product with
a PU outcoat; the inset image shows the scanning electron microscope result of the in vitro cultured sample with porous PU
and cell/hydrogel layers; (D) the middle part of (C) with
branched/grid internal cell/gelatin/alginate/fibrinogen hydrogel
channels; the inset image shows the PI staining result of the
–
cell/hydrogel section[60 63].
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Creation of a vascular system for organ manufacturing
PU encapsulated adipose-derived stem cell (ADSC)/
gelatin/alginate/fibrin construct with a multi-branched
vascular network has been produced. ADSCs encapsulated in the natural gelatin/alginate/fibrinogen hydrogel can be simultaneously printed with synthetic
polymers. The outer PU layer can provide the internal
cells with excellent mechanical support and biological
protection. Both the optimized PU overcoat and internal gelatin/alginate/fibrin provided the ADSCs with a
stable and comfortable accommodation to grow, proliferate, and differentiate. The axial branched channels
can be directly connected to a pulsatile culture system
to supply the internal cells with sufficient nutrients
and oxygen. With the elaborate branched channels, the
internal flow and permeation efficiency can be greatly
improved. Thus, the exchange rate of nutrients and
oxygenin the flow fluid can be enhanced greatly.
3.4 Advantages of the LDM Technologies in Creating Branched Vascular Systems
The afore mentioned three forms of LDM technologies are based on the functional simulation of the natural vascular systems in complex organs, such as the
liver[56–77]. Though the morphologies of the vascular
systems are different from those of the CCO calculation methods and far from the natural vascular systems, several distinguished advantages of this model
can be obtained. Firstly, the CAD models can be easily built and practiced with the LDM printers. Secondly,
the central axial channels are designed to simulate the
central veins or arteries of complex organs, which can
be connected directly to the pulsatile culture systems
or host vascular systems. The surrounding branched
channels can increase the surface area/volume ratio
and take roles to distribute the fluids. Thirdly, the
constructed size and branched channels can be easily
scaled up to accommodate more cells and adapt to
intricate environments. Fourthly, the mechanical
properties of the synthetic polymers are essential for
the anti-suture in vivo implantation of the vascular
systems or complex organs. Overall, this technique
holds the promise to be used widely in the areas of
future complex organ manufacturing and regenerative
medicine.
Conflict of Interest and Funding: No conflict of
interest is reported by the authors. The work was
supported by grants from the Cross-Strait Tsinghua
Cooperation Basic Research (No. 2012THZ02-3),
Beijing Municipal Natural Science Foundation (No.
3152015), National Natural Science Foundation of
China (NSFC) (No. 81271665 & 30970748),
International Cooperation and Exchanges NSFC and
Japanese Society for the Promotion of Science (JSPS)
(No. 81411140040), State Key Laboratory of
Materials Processing and Die & Mold Technology,
Huazhong University of Science and Technology (No.
2012-P03), and the National High Tech 863 Grant (No.
2009AA043801).
References
1.
2.
3.
4. Conclusions
One of the key challenges in the regeneration of vital
organs, such as the liver and heart, concerns the
82
transport requirements for transplanted cells. In order
to create branched vascular systems that mimic human
organs, we have introduced two approaches to design
and manufacture complex 3D objects with an intrinsic
network of interconnected branching channels. Methodologies such as CCO and CAD were used to
create a branched vascular tree for bioprinting. Within
the framework of the CCO model, a model vascular
tree, such as the kidney, is represented as a series of
dichotomously-branched, straight, cylindrical tubes.
Several 3D vascular templates with synthetic polymers or both synthetic polymer PLGA and natural
cell/hydrogel were created using a low-temperature
deposition technique in our own group. The design
and methodological strategies described in this article
for the creation of a branched vascular system directly
from CCO and CAD represent a promising route for
complex organ manufacturing.
Walther G, Gekas J and Bertrand O F, 2009, Amniotic
stem cells for cellular cardiomyoplasty: promises and
Premises. Catheterization and Cardiovascular Interventions, vol.73(1): 917–924.
http://dx.doi.org/10.1002/ccd.22016.
Aikawa E, Nahrendorf M, Sosnovik D, et al. 2007,
Multimodality molecular imaging identifies proteolytic
and osteogenic activities in early aortic valve disease.
Circulation, vol.115(3): 377–386.
http://dx.doi.org/10.1161/circulationaha.106.654913.
Wang X, Tuomi J, Mäkitie A A, et al. 2013, The Integrations of biomaterials and rapid prototyping techniques
for intelligent manufacturing of complex organs, in Advances in Biomaterials Science and Biomedical Appli-
International Journal of Bioprinting (2015)–Volume 1, Issue 1
Libiao Liu and Xiaohong Wang
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
cations. R Lazinica ed, Intech, Rijeka, 437–463.
http://dx.doi.org/10.5772/53114.
Wang X, 2013, Overview on biocompatibilities of implantable biomaterials, in Advances in Biomaterials
Science and Biomedical Applications. R Lazinica ed,
Intech, Rijeka, 111–155.
http://dx.doi.org/10.5772/53461.
Wang X, Yan Y and Zhang R, 2010, Gelatin-based hydrogels for controlled cell assembly, in Biomedical Applications of Hydrogels Handbook. RM Ottenbrite ed,
Springer, New York, 269–284.
http://dx.doi.org/10.1007/978-1-4419-5919-5_14.
Wang X, 2015, 3D printing of tissue/organ scaffolds for
regenerative medicine, In Handbook of Intelligent Scaffolds for Regenerative Medicine. G Khang ed, the
Second Edition, Pan Stanford Publishing, Singapore, in
press.
Liu L, Wang X 2015, Organ manufacturing. In Organ
Manufacturing. X Wang ed, Nova Science Publishers
Inc, New York, in press.
Wang X, Yan Y and Zhang R, 2007, Rapid prototyping
as a tool for manufacturing bioartificial livers. Trends in
Biotechnology, vol.25(11): 505–513.
http://dx.doi.org/10.1016/j.tibtech.2007.08.010.
Wang X, Yan Y and Zhang R, 2010, Recent trends and
challenges in complex organ manufacturing. Tissue Engineering Part B-Reviews, vol.16(2): 189–197.
http://dx.doi.org/10.1089/ten.teb.2009.0576.
Wang X, 2012, Intelligent freeform manufacturing of
complex organs. Artificial Organs, vol.36(11): 951–961.
http://dx.doi.org/10.1111/j.1525-1594.2012.01499.x.
Wang X, 2014, Spatial effects of stem cell engagement
in 3D printing constructs. Journal of Stem Cells Research Review & Report, vol.1(1): 5–9.
Orive G, Hernández R M, Gascón A R, et al. 2004, History, challenges and perspectives of cell microencapsulation. Trends in Biotechnology, vol.22(2): 87–92.
http://dx.doi.org/10.1016/j.tibtech.2003.11.004.
Sekine H, Shimizu T, Yang J, et al. 2006, Pulsatile
myocardial tubes fabricated with cell sheet engineering.
Circulation, vol.114: I87–I93.
http://dx.doi.org/10.1161/circulationaha.105.000273.
Moniaux N and Faivre J, 2011, A reengineered liver for
transplantation. Journal of Hepatology, vol.54(2): 386–
387.
http://dx.doi.org/10.1016/j.jhep.2010.07.053.
Xu Y and Wang X, 2015, Application of 3D biomimetic
models in drug delivery and regenerative medicine.
Current Pharmaceutical Design, vol.21(12): 1618–
1626.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
http://dx.doi.org/10.2174/1381612821666150115154059.
Liu L, Zhou X, Xu Y, et al. 2015, Controlled release of
growth factors for regenerative medicine, Current
Pharmaceutical Design, vol.21: 1627–1632.
Zhao X, Liu L, Wang J, et al. 2014, In vitro vascularization of a combined system based on a 3D printing technique. Journal of Tissue Engineering and Regenerative
Medicine.
http://dx.doi.org/10.1002/term.1863.
Zhao X and Wang X, 2013, Preparation of an adipose-derived stem cell/fibrin–poly(d,l-lactic-co-glycolic
acid) construct based on a rapid prototyping technique.
Journal of Bioactive and Compatible Polymers,
vol.28(3): 191–203.
http://dx.doi.org/10.1177/0883911513481892.
Wang X, He K and Zhang W, 2013, Optimizing the fabrication processes for manufacturing a hybrid hierarchical polyurethane-cell/hydrogel construct. Journal of
Bioactive and Compatible Polymers, vol.28(4): 303–
319.
http://dx.doi.org/10.1177/0883911513491359.
Wang X and Zhang Q, 2011, Overview on "Chinese-Finnish Workshop on Biomanufacturing and Evaluation Techniques", Artificial Organs, vol.35(10):
E191–E193.
http://dx.doi.org/10.1111/j.1525-1594.2011.01341.x.
Wang X and Wang J, 2015, Vascularization and adipogenesis of a spindle hierarchical adipose-derived stem
cell/collagen/alginate-PLGA construct for breast manufacturing. International Journal of Innovative Technology and Exploring Engineering, vol.4(8): 1–8.
Wang X, Huang Y and Liu C, 2015, A combined rotational mold for manufacturing a functional liver system.
Journal of Bioactive and Compatible Polymers: Biomedical Applications, vol.30: 436–451.
http://dx.doi.org/10.1177/0883911515578872.
Kaihara S, Borenstein J, Koka R, et al. 2000, Silicon
micromachining to tissue engineer branched vascular
channels for liver fabrication. Tissue Engineering,
vol.6(2): 105–117.
http://dx.doi.org/10.1089/107632700320739.
Borenstein J T, Terai H, King K R, et al. 2002, Microfabrication technology for vascularized tissue engineering.
Biomedical Microdevices, vol.4(3): 167–175.
http://dx.doi.org/10.1023/a:1016040212127.
Karch R, Neumann F, Neumann M, et al. 1999, A
three-dimensional model for arterial tree representation,
generated by constrained constructive optimization.
Computers in Biology and Medicine, vol.29(1): 19–38.
http://dx.doi.org/10.1016/s0010-4825(98)00045-6.
International Journal of Bioprinting (2015)–Volume 1, Issue 1
83
Creation of a vascular system for organ manufacturing
26. Xu W, Wang X, Yan Y, et al. 2008, Rapid prototyping of
polyurethane for the creation of vascular systems.
Journal of Bioactive and Compatible Polymers,
vol.23(2): 103–114.
http://dx.doi.org/10.1177/0883911507088271.
27. Schreiner W and Buxbaum P F, 1993, Computeroptimization of vascular trees, Biomedical Engineering,
IEEE Transactions on, vol.40(5): 482–491.
http://dx.doi.org/10.1109/10.243413.
28. Schreiner W, Neumann M, Neumann F, et al. 1994, The
branching angles in computer-generated optimized
models of arterial trees. Journal of General Physiology,
vol.103(6): 975–989.
http://dx.doi.org/10.1085/jgp.103.6.975.
29. Chen J, Yao B and Zhang Y, 1994, Anatomical textual
research and analysis of vascular branche mathematical
model. Chinese Journal of Anatomy, vol.17(3): 228–
230.
30. Sherman T F, 1981, On connecting large vessels to small.
The meaning of Murray's law. The Journal of General
Physiology, vol.78(4): 431–453.
http://dx.doi.org/10.1085/jgp.78.4.431.
31. Karch R, Neumann F, Neumann M, et al. 2000, Staged
growth of optimized arterial model trees. Annals of
Biomedical Engineering, vol.28(5): 495–511.
http://dx.doi.org/10.1114/1.290.
32. Schreiner W, Karch R, Neumann M, et al. 2006, Optimized arterial trees supplying hollow organs. Medical
Engineering & Physics, vol.28(5): 416–429.
http://dx.doi.org/10.1016/j.medengphy.2005.07.019.
33. Little T S, Mironov V, Mehesz A N, et al. 2011, Engineering a 3D, biological construct: representative research in the South Carolina Project for Organ Biofabrication. Biofabrication, vol.3(3).
http://dx.doi.org/10.1088/1758-5082/3/3/030202.
34. Karch R, Neumann F, Neumann M, et al. 2003, Voronoi
polyhedra analysis of optimized arterial tree models.
Annals of Biomedical Engineering, vol.31(5): 548–563.
http://dx.doi.org/10.1114/1.1566444.
35. Zamir M, 1978, Nonsymmetrical bifurcations in arterial
branching. Journal of General Physiology, vol.72(6):
837–845.
http://dx.doi.org/10.1085/jgp.72.6.837.
36. Van Beek J H, Roger S A and Bassingthwaighte J B,
1989, Regional myocardial flow heterogeneity explained with fractal networks. American Journal of
Physiology, vol.257(5): H1670–H1680.
37. Hahn H K, Georg M and Peitgen H-O, 2003, Fractal
properties, segment anatomy, and interdependence of
the human portal vein and the hepatic vein in 3D. Frac84
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
tals-Complex Geometry Patterns and Scaling in Nature
and Society, vol.11(1): 53–62.
http://dx.doi.org/10.1142/s0218348x03001422.
Yeong W-Y, Chua C-K, Leong K-F, et al. 2006, Indirect
fabrication of collagen scaffold based on inkjet printing
technique. Rapid Prototyping Journal, vol.12(4):
229–237.
http://dx.doi.org/10.1108/13552540610682741.
Pati F, Jang J, Ha D-H, et al. 2014, Printing threedimensional tissue analogues with decellularized extracellular matrix bioink. Nature Communications,
vol.5(11): 11.
http://dx.doi.org/10.1038/ncomms4935.
Yan Y, Wang X, Xiong Z, et al. 2005, Direct construction of a three-dimensional structure with cells and hydrogel. Journal of Bioactive and Compatible Polymers,
vol.20(3): 259–269.
http://dx.doi.org/10.1177/0883911505053658.
Yan Y, Wang X, Pan Y, et al. 2005, Fabrication of viable
tissue-engineered constructs with 3D cell-assembly
technique. Biomaterials, vol.26(29): 5864–5871.
http://dx.doi.org/10.1016/j.biomaterials.2005.02.027.
Wang X, Yan Y, Pan Y, et al. 2006, Generation of
three-dimensional hepatocyte/gelatin structures with
rapid prototyping system. Tissue Engineering, vol.12(1):
83–90.
http://dx.doi.org/10.1089/ten.2006.12.83.
Xu W, Wang X, Yan Y, et al. 2007, Rapid prototyping
three-dimensional cell/gelatin/fibrinogen constructs for
medical regeneration. Journal of Bioactive and Compatible Polymers, vol.22(4): 363–377.
http://dx.doi.org/10.1177/0883911507079451.
Zhang T, Yan Y, Wang X, et al. 2007, Three-dimensional
gelatin and gelatin/hyaluronan hydrogel structures for
traumatic brain injury. Journal of Bioactive and Compatible Polymers, vol.22(1): 19–29.
http://dx.doi.org/10.1177/0883911506074025.
Sui S, Wang X, Liu P, et al. 2009, Cryopreservation of
Cells in 3D constructs based on controlled cell assembly
processes. Journal of Bioactive and Compatible Polymers, vol.24(5): 473–487.
http://dx.doi.org/10.1177/0883911509338990.
Wang X and Xu H, 2010, Incorporation of DMSO and
dextran-40 into a gelatin/alginate hydrogel for controlled assembled cell cryopreservation. Cryobiology,
vol.61(3): 345–351.
http://dx.doi.org/10.1016/j.cryobiol.2010.10.161.
Wang X, Paloheimo K-S, Xu H, et al. 2010, Cryopreservation of cell/hydrogel constructs based on a new
cell-assembling technique. Journal of Bioactive and
International Journal of Bioprinting (2015)–Volume 1, Issue 1
Libiao Liu and Xiaohong Wang
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
Compatible Polymers, vol.25(6): 634–653.
http://dx.doi.org/10.1177/0883911510382571.
Yao R, Zhang R, Yan Y, et al. 2009, In vitro angiogenesis of 3D tissue engineered adipose tissue. Journal of
Bioactive and Compatible Polymers, vol.24(1): 5–24.
http://dx.doi.org/10.1177/0883911508099367.
Yao R, Zhang R and Wang X, 2009, Design and evaluation of a cell microencapsulating device for cell assembly technology. Journal of Bioactive and Compatible
Polymers, vol.24: 48–62.
http://dx.doi.org/10.1177/0883911509103329.
Xu M, Wang X, Yan Y, et al. 2010, An cell-assembly
derived physiological 3D model of the metabolic syndrome, based on adipose-derived stromal cells and a gelatin/alginate/fibrinogen matrix. Biomaterials, vol.31
(14): 3868–3877.
http://dx.doi.org/10.1016/j.biomaterials.2010.01.111.
Xu M, Yan Y, Liu H, et al. 2009, Controlled adipose-derived stromal cells differentiation into adipose
and endothelial cells in a 3D structure established by
cell-assembly technique. Journal of Bioactive and
Compatible Polymers, vol.24(S1): 31–47.
http://dx.doi.org/10.1177/0883911509102794.
Li S, Yan Y, Xiong Z, et al. 2009, Gradient hydrogel
construct based on an improved cell assembling system.
Journal of Bioactive and Compatible Polymers, vol.24:
84–99.
http://dx.doi.org/10.1177/0883911509103357.
Li S, Xiong Z, Wang X, et al. 2009, Direct fabrication
of a hybrid cell/hydrogel construct by a double-nozzle
assembling technology. Journal of Bioactive and Compatible Polymers, vol.24(3): 249–265.
http://dx.doi.org/10.1177/0883911509104094.
Xu Y and Wang X, 2015, Fluid and cell behaviors along
a 3D printed alginate/gelatin/fibrin channel. Biotechnology and Bioengineering, vol.112(8): 1683–1695.
http://dx.doi.org/10.1002/bit.25579.
Zhao X, Du S, Chai L, et al. 2015, Anti-cancer drug
screening based on a adipose-derived stem cell/hepatocyte 3D printing technique. Journal of Stem Cell Research and Therapies, vol.5(4).
http://dx.doi.org/10.4172/2157-7633.1000273.
Xu W, Wang X, Yan Y, et al. 2008, A polyurethanegelatin hybrid construct for manufacturing implantable
bioartificial livers. Journal of Bioactive and Compatible
Polymers, vol.23(5): 409–422.
http://dx.doi.org/10.1177/0883911508095517.
Cui T K, Yan Y, Zhang R, et al. 2009, Rapid prototyping
of a double-layer polyurethane-collagen conduit for peripheral nerve regeneration. Tissue Engineering Part
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
C-Methods, vol.15(1): 1–9.
http://dx.doi.org/10.1089/ten.tec.2008.0354
Cui T, Wang X, Yan Y, et al. 2009, Rapid prototyping a
new polyurethane-collagen conduit and its Schwann cell
compatibility. Journal of Bioactive Compatible Polymers, vol. 24(S1): 5–7.
http://dx.doi.org/10.1177/0883911509102349.
Wang X, Cui T, Yan Y, et al. 2009, Peroneal nerve regeneration using a unique bilayer polyurethane-collagen
guide conduit, Journal of Bioactive and Compatible
Polymers, vol.24(2): 109–127.
http://dx.doi.org/10.1177/0883911508101183.
He K, Wang X, Madhukar K S, et al. 2009, Fabrication
of a two-level tumor bone repair biomaterial based on a
rapid prototyping technique, Biofabrication, vol.1(2):
025003.
http://dx.doi.org/10.1088/1758-5082/1/2/025003.
He K and Wang X, 2011, Rapid prototyping of tubular
polyurethane and cell/hydrogel constructs, Journal of
Bioactive and Compatible Polymers, vol.26(4): 363–
374.
http://dx.doi.org/10.1177/0883911511412553.
Huang Y, He K and Wang X, 2013, Rapid prototyping of
a hybrid hierarchical polyurethane-cell/hydrogel construct for regenerative medicine, Materials Science and
Engineering: C, vol.33(6): 3220–3229.
http://dx.doi.org/10.1016/j.msec.2013.03.048.
Wang X, Rijff B and Khang G, 2015, A building block
approach into 3D printing a multi-channel organ regenerative scaffold, Journal of Tissue Engineering Regenerative Medicine
http://dx.doi.org/10.1002/term.2038.
Lei M and Wang X, 2015, Rapid prototyping of artificial
stomachs, in Organ Manufacturing. X Wang ed, Nova
Science Publishers Inc, New York, in press.
Xu Y, Li D and Wang X, 2015, The construction of vascularized pancreas based on 3D printing techniques, in
Organ Manufacturing. X Wang ed, Nova Science Publishers Inc, New York, in press.
Xu Y, Li D and Wang X, 2015, Liver manufacturing approaches: the thresholds of cell manipulation with
bio-friendly materials for multifunctional organ regeneration, in Organ Manufacturing. X Wang ed, Nova
Science Publishers Inc, New York, in press.
Xu Y, Li D and Wang X, 2015, Current trends and challenges for producing artificial hearts, in Organ Manufacturing. X Wang ed, Nova Science Publishers Inc,
New York, in press.
Liu L and Wang X, 2015, Artificial blood vessels and
International Journal of Bioprinting (2015)–Volume 1, Issue 1
85
Creation of a vascular system for organ manufacturing
69.
70.
71.
72.
73.
86
vascular systems, in Organ Manufacturing. X Wang ed,
Nova Science Publishers Inc, New York, in press.
Zhou X and Wang X, 2015, Artificial lung manufacturing, in Organ Manufacturing. X Wang ed, Nova
Science Publishers Inc, New York, in press.
Zhou X and Wang X, 2015, Breast Engineering, in Organ Manufacturing. X Wang ed, Nova Science Publishers Inc, New York, in press.
Lei M and Wang X, 2015, Uterus bioprinting, in Organ
Manufacturing. X Wang ed, Nova Science Publishers
Inc, New York, in press.
Zhou X and Wang X, 2015, Skin substitute manufacturing, in Organ Manufacturing. X Wang ed, Nova
Science Publishers Inc, New York, in press.
Zhou X and Wang X, 2015, Artificial kidney manufacturing, in Organ Manufacturing. X Wang ed, Nova
Science Publishers Inc, New York, in press.
74. Schrepfer I and Wang X, 2015, Progress in 3D printing
technology in health care, in Organ Manufacturing. X
Wang ed, Nova Science Publishers Inc, New York, in
press.
75. Henzler T, Chai L and Wang X, 2015, Integrated model
for organ manufacturing: a systematic approach from
medical imaging to rapid prototyping, in Organ Manufacturing. X Wang ed, Nova Science Publishers Inc,
New York, in press.
76. Leonard JF, Chai L and Wang X, 2015, Application of
gelatin and glucose as sacrificial structures in organ
manufacturing, in Organ Manufacturing. X Wang ed,
Nova Science Publishers Inc, New York, in press.
77. Zimmermann S, Chai L and Wang X, 2015, Progress of
electrospinning in organ manufacturing, in Organ Manufacturing. X Wang ed, Nova Science Publishers Inc,
New York, in press.
International Journal of Bioprinting (2015)–Volume 1, Issue 1