Cent. Eur. J. Eng. • 2(3) • 2012 • 325-335
DOI: 10.2478/s13531-012-0016-2
Central European Journal of Engineering
Scaffolds for tissue engineering produced by inkjet
printing
Review article
Yi Zhang, Christopher Tse, Davood Rouholamin, Patrick J. Smith∗
Kroto Research Institute, Department of Mechanical Engineering, University of Sheffield, Broad lane, Sheffield, England, S3 7HQ
Received 31 January 2011; accepted 15 May 2012
Abstract: This review discusses the use of scaffolds in tissue engineering and summarises the means by which they might
be fabricated. The review identifies the main features a scaffold should have, and discusses the progress that
has been made towards obtaining these targets. In particular, the review focuses on inkjet printing as a viable
production route and discusses why this additive manufacturing technique holds considerable appeal and promise.
The article concludes with an overview of the current challenges in this field and reviews the different types of
material that can be used for scaffolds.
Keywords: Tissue engineering • Inkjet printing • Scaffolds • Materials
© Versita sp. z o.o.
1.
Introduction
Tissue engineering is a multidisciplinary field which combines the basic principles of life sciences and materials
engineering to overcome the shortage of organs and tissues
from donors. It aims to produce biological substitutes to
mimic the behaviours of natural tissues in vitro or in vivo
[1, 2] that will enable researchers to repair, regenerate and
replace damaged tissue with fabricated cellular constructs
[3]. The potential and scope of tissue engineering is vast; it
encompasses a broad range of knowledge. A combination
of cell biology, biomaterial chemistry and physiology are
essential for understanding cell viability, influence with
biomaterials, biocompatible support, material strength and
structure and understanding the organ-specific environment respectively [4].
∗
A biological scaffold ideally provides a supporting backbone for cells to proliferate, and to resorb at the same rate
as tissue regenerates inside the wound; it breaks down into
non-toxic byproducts that are readily excreted out of the
body [5]. It is vital that scaffolds possess excellent biocompatibility and bioresorbability, controllable biodegradability, and sufficient mechanical properties such as strength,
hardness and elasticity [6]. Additionally, scaffolds need
to possess suitable surface chemistry and morphology for
cells’ physical actions such as attachment, proliferation and
differentiation [1]. Typically, scaffolds should have threedimensional structures with suitable porosity (> 90%) and
suitable pore sizes for cell proliferation, blood vessel infiltration, metabolic waste diffusion, oxygen diffusion which
are pivotal to the success of the implant integrating with
the body [7]. Cells respond better in a 3D structure, as
opposed to 2D, since it mimics native tissue due to the
inherent spatial properties [8]. The porous structure of a
biodegradable scaffold is presented in Figure 1. Cells and
E-mail: [email protected]
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Scaffolds for tissue engineering produced by inkjet printing
Figure 1.
A schematic diagram of a porous biodegradable scaffold
with cells and proteins incorporated to the structure.
proteins which have been incorporated in to the structure
are shown in the magnified image.
There are many types of tissue in the human body, with
examples being bone, skin, tendon and cartilage. All of
these tissue types have their own internal structures and
functions; similarly the constituent cells vary in terms of
size and behaviour. Therefore, fabricated scaffolds should
match the structural parameters of their target tissues. For
example, in bone tissue engineering, the optimal pore size
range is 200–400 µm [9]; for skin tissues, the optimal size
range is 100–200 µm [10]; for cardiac tissues, the optimal
pore sizes range from 40–100 µm [11]. If pore size is too
small or too large the functions of the target tissues cannot
be met, and stress is induced in the cells, which reduces
viability.
The ability to fabricate scaffolds reliably and consistently
with controllable accuracy of pore sizes, geometry and
safety for biomaterials are key points in tissue engineering.
And there are many conventional strategies for fabricating scaffolds, such as freeze-drying [10, 12, 13], electrospinning [14–17], gas forming [18, 19], gas forming and
particulate leaching [20], solvent casting and particulate
leaching [21, 22]. However, such techniques lack the ability
to control the pore sizes and geometry of pores consistently [23].
In order to achieve better control, researchers have investigated: stereolithography [24, 25], fused deposition
modelling [26, 27], selective laser sintering [28, 29] and
inkjet printing [30–34]. All of these techniques can be
grouped under the term, solid freeform fabrication, which
allow ideal internal structures to be built since they are
all computer aided strategies that build layer by layer.
Table 1 compares several techniques used for fabricating
scaffolds for tissue engineering. Brian Derby [35] reviewed
the use of bio-printing, in which an inkjet printer directly
deposits proteins and living cells and Delaney et al. [36]
considered several other applications of using inkjet printing to print proteins, such as in the preparation of sensors
and diagnostic devices. Inkjet printing builds structures
droplet by droplet, allowing the fabrication of scaffolds
with ideal internal structures for tissue engineering. This
review will focus on scaffolds for tissue engineering fabricated by inkjet printing and discuss the range of materials
that can be used with this technique.
Inkjet printing offers three significant advantages: a threedimensional structure can be produced with a single procedure, droplets can be deposited within a few microns
of accuracy, and because both the scaffold and the cells
can be deposited at the same time no cell seeding step
is required. Circumventing the cell-seeding step is important as conventional seeding may not fully penetrate thick
scaffolds leading to cell-sparse regions in the bulk.
2.
Inkjet printing
Inkjet printing is a computer-aided technique in which
picolitre volume droplets, of solution or suspension, are
precisely placed at pre-determined locations on a substrate [35]. Droplets can be placed side by side to form
lines and other two-dimensional structures. Droplets can
also be stacked, to form three-dimensional structures, although, obviously some form of morphological control is
needed. Typically, this control is achieved by using a
phase change approach, for example molten wax quickly
solidifies upon contact with a room temperature substrate.
Other approaches are discussed further in this review.
Inkjet printing directly prints a pattern that researchers
design before printing via computer, so there is no need
to prepare a pre-mask. This reduction in process steps
reduces costs and simplifies the overall procedure [37, 38].
As inkjet printing is also a non- contact technique it minimises the risk of contamination of the final product [36].
There are two main inkjet printing systems: a) continuous
inkjet printing (CIJ) and b) drop-on- demand inkjet printing
(DOD) [35], with DOD further divided into: 1) thermal
and 2) piezoelectric. In CIJ a continuous stream of fluid
is ejected out of the printhead orifice. This stream breaks
up into small droplets, due to Rayleigh instability. An
electric charge is imparted to the droplets to control their
direction. Droplets can either be directed towards the
substrate – to form a print, or directed towards a gutter, to
be subsequently recycled. CIJ has a very fast deposition
rate, but due to the recycling, contamination can occur.
Inks also need to be capable of carrying an electric charge
in order to be deflected by the plates.
DOD printing allows finer control of the deposition of
the droplets. Droplets can be spatially and temporally
controlled by positioning the printhead over the substrate
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Y. Zhang, C. Tse, D. Rouholamin, P.J. Smith
Table 1.
Comparison of the main fabrication techniques used for tissue engineering [10, 12–22, 24–34].
Technique
Freeze-drying
Electrospinning
Pore sizes ( µm) &
Porosity (%)
Advantages
Disadvantages
References
< 200
< 99
Simple processing steps
Limited control of pore size
and geometry
[10, 12, 13]
0.01–900
70–92
High porosity
High pore interconnectivity
Wide range of materials
can be used
30–40,
ave. max = 140
< 90
Simple processing steps
Gas forming and
particulate leaching
< 200
88–94
High porosity
Solvent casting
particulate leaching
< 300
82–92
Gas forming
Solvent free
Time-consuming
Use of solvent
[14–17]
Uncontrollable pore geometry
Uncontrollable pore sizes
and geometry
[18, 19]
Limited pore interconnectivity
Uncontrollable pore geometry
[20]
Solvent free
High porosity
Use of solvent
[20–22]
Simple processing steps
Limited to thin structures
Solvent free
Limited pore interconnectivity
Liquid photo-crosslinkable resin
required
[24, 25]
High processing temperature
[26, 27]
Time-consuming
Stereolithography
Fused deposition
modelling
170–500 ∼ 70
160–700
< 80
Selected laser
sintering
Customer-based
Inkjet printing
Customer-based
Controllable geometry of scaffold
and porosity
Controllable porosity
Good structural integrity
Thermoplastic materials only
Good mechanical properties
(limited materials can be used)
Solvent free
Controllable shapes and
structural isotropy
(limited materials can be used)
Solvent free
Controllable porosity and pore
geometry
Can integrate with cells and
growth factors
before ejection. The formation of droplets in a piezoelectric
DOD inkjet printing is due to a pressure wave propagating
in the ink chamber. This pressure wave forms due to an
increase in the voltage applied across the piezoelectric
actuator which surrounds the ink chamber [39]. Both the
velocity and the size of an ejected droplet can be controlled
by modulating the voltage [38], larger voltage values result
in larger droplets. In a thermal DOD inkjet printing system,
a resistor within the printhead heats up, causing a localised
area to increase in temperature. This increase generates a
bubble of gas, which generates a pressure difference large
enough to eject a droplet out of the printhead [35, 40].
In the current study, piezoelectric and thermal DOD are
discussed in more detail since they are the main techniques
that have been used.
The rheological nature of the ink also needs to be considered. If the viscosity of an ink is too high, droplets
cannot be formed due to the damping of the pressure wave
[38]. Although, the viscosity of an ink can be modified by
High processing temperature
Use of solvent
[28, 29]
[30–34]
Limited materials can be used
the addition of co-solvents and viscosity modifiers such
additions may negatively affect the final function of the
generated scaffold.
Examples where inkjet printing has been used in a biological context include the work of Wiktor et al. at the
Biodesign Institute at Arizona State University who have
used the technique to miniaturise proteomic assays [41].
This miniaturisation is possible due to the higher resolutions that can be obtained by inkjet printing. Being a
non-contact and highly scalable technique, research has
been made to apply inkjet technology for medical adhesives and sealants [42]. This has shown to reduce bond
lines between tissues, reduce toxicity, be low cost with
minimal wastage and improve bond strength that is easily
transferable into a clinical environment.
With the ability to print a versatile range of inks, this technology has also been shown to be successful on the field
of fabricating biosensors. It is able to produce biosensors
that have significantly higher resolution than convention-
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Scaffolds for tissue engineering produced by inkjet printing
Figure 2.
SEM images of the PU scaffold made by inkjet printing. A and B show the primary structures. C shows the secondary structure [37].
ally made biosensors in a non-contact method. Its ability
to deposit multiple biological reagents at high resolutions,
form uniform layers, low cost, high throughput capacity and
print in an accurate manner has shown to be promising [43].
3. Synthetic biodegradable polymers printing
Many synthetic biodegradable polymers have been extensively explored to fabricate tissues to date, because they
can be tailored to give a wide range of predictable properties. For example, poly(lactic acid), poly(L-lactic acid),
poly(glycolic acid), poly(lactic-co-glycolic acid), poly(εcaprolactone) and polyurethanes. Zhang et al. [37] successfully used inkjet printing to fabricate water-soluble
polyurethane elastomers. These scaffolds possess good
hierarchical structures, which is good for cell proliferation,
diffusion of metabolic waste and nutrients. Figure 2 shows
the primary and secondary structures of these scaffolds,
the pore sizes range from 10 µm to 30 µm in the primary
structure while the pore sizes are less than 100 nm in the
secondary structure. Additionally, they have a relatively
uniform interconnected pore distribution. This promotes
cell proliferation and metabolic waste diffusion. Therefore,
it is a promising candidate for vascular tissue engineering. Hydrogels are a promising set of materials for tissue
engineering. However their relatively poor mechanical
properties limit their application. Delaney, et al. [44]
successfully used both piezoelectric DOD and CIJ systems
and fabricated numerous open pore structured macroporous matrices with reversible calcium alginate porogens
(beads). The differences between using these two inkjet
printing techniques are the droplet size and distribution.
The droplets generated by DOD are more uniform and
smaller than those generated by CIJ: DOD: 44–52 µm; CIJ:
206–290 µm. Figure 3 shows the difference between using
DOD and CIJ and shows clearly that DOD produces beads
of smaller size and smaller variance.
However, CIJ is two times order of magnitude quicker at
producing beads than DOD, and this must be taken into
consideration when deciding the optimum technique in a
lab experiment. Limem et al. [45] demonstrated that selfassembling polyelectrolyte hydrogels, which are good at
mimicking native extracellular matrix, can be inkjet printed.
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Y. Zhang, C. Tse, D. Rouholamin, P.J. Smith
(a)
(b)
Figure 3.
Microscopy images of using DOD (A) and CIJ (B) printed reversible calcium alginate porogens. These were fabricated
by jetting sodium alginate into a bath of calcium chloride
solution [44].
A variety of properties such as susceptibility to swelling
and rheological properties of the gels can be controlled
by varying their composition and deposition rate.
Biase, et al. [32] used a piezoelectric DOD printer to
fabricate thermo-reversible photocurable gel structures
at room temperature. By printing layer-by-layer, they
obtained simple 3-D square well structures which are
stable in an aqueous environment after photo-crosslinking.
They also successfully delivered human fibroblast cells onto
these structures by using inkjet printing. However, more
post treatment was needed to functionalize the surface of
the substrates in order to promote the adhesion of cells.
4.
Natural polymers printing
Natural polymers are another type of biological materials
used to fabricate scaffolds for tissue engineering. Recently,
more and more research has focussed on simultaneously
printing biomaterials and living cells in order to reduce the
risk of contamination during cell seeding afterwards. However, synthetic biopolymers usually need organic solvents
to dissolve them before use; and these organic solvents can
have detrimental effects on cells. Therefore, using natural
biopolymers is a promising choice. Collagen, nucleic acids,
starch, chitosan and fibrin have been investigated for producing a variety of scaffolds using inkjet printing. Xu et al.
[46] used modified thermal inkjet printing to print 3D structures by printing fibrin gel and neurons layer-by-layer.
They demonstrated the potential for inkjet printing in the
Figure 4.
Photography of a 3D structure fabricated with fibrin by inkjet
printing cultured in medium at day 1. The gross dimension
of the 3D structure was 25 mm × 5 mm × 1 mm [46].
field of neural tissue engineering. Figure 4 shows the
3D structure fabricated by printing fibrin gel and neurons
alternately.
Cui and Boland [31] also reported the use of thermal DOD
to print thrombin solution onto fibrinogen to form a fibrin
gel substrate for subsequent cell printing. Figure 5 shows
the printed fibrin scaffold. It can be seen that the scaffold
has some minor deformation. From SEM images (Figure 6),
hierarchical structures can be observed, which is good for
cell attachment and proliferation.
These two examples show the potential of fabricating 3D
scaffolds by using natural gelatine polymers like fibrin.
Since organic solvents are not used, researchers can print
living cells and materials in one step with little or no
damage to cells.
5.
Bioceramics printing
Many forms of bio-ceramic are very similar to natural bone
which make them good candidates for fabricating scaffolds
that mimic natural bone [47]. These particular types of
bioceramic have osteo- conductivity, which means they encourage comprehensive bone growth and osteo-inductivity
which means they initiate bone formation [48]. Hydroxyapatite, calcium phosphate and tri-calcium phosphate are
commonly used for fabricating bone tissues. Non toxicity,
biocompatibility and excellent osteoconductive properties
of these materials have made them popular choices for
bone regeneration applications [49].
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Scaffolds for tissue engineering produced by inkjet printing
Figure 5.
Images of printed fibrin scaffold seen under light microscope [31].
In the past few years, ceramic/polymer composites have
been produced and used in various tissue engineering
applications. Better cell seeding, mechanical properties,
flexibility and structural integrity are expected from the
composites compared to neat ceramic or polymer [50]. Several groups have used powder bed printing to produce
scaffolds. In powder bed printing, an inkjet printer is used
to selectively dispense a liquid binder onto a powder bed.
Structures are built up layer by layer following the process depicted in Figure 7. The reaction of the powder
and liquid generates the scaffolds with the desired shape
and internal structures, Figure 8 shows example of actual
printing [51]. Powder-based 3D printing has many advantages: 1) many powder materials can be used as long as
the powder can react with appropriate binder; 2) using
computer design, scaffolds with various shapes and sizes
can be attained. Butscher et. al [52] used this technique
to manufacture scaffolds using calcium phosphate powder
(Figure 9), and investigated size distribution on the final
scaffolds. They demonstrated that both powder size and
droplet size had affected the size and internal structures
of designed scaffolds.
6.
Proteins printing
In native tissue, the natural scaffold which provides support
to the cells is called the extracellular matrix (ECM), which
is itself a highly complicated construct. The ECM con-
tains a large variety of proteins, inorganic matter, growth
factors and enzymes all of which regulate and define tissue identity, governing cell orientation and differentiation.
Through research, it has been identified that there are
proteins that are essential to the correct differentiation
and maturation of cells that act as cues throughout a cell’s
life cycle [53, 54].
Different gradients of each substance can be printed at
a controllable and simple way via inkjet printing. The
substance can be diluted and then multiple layers can be
printed to increase the concentration at the user’s discretion [55]. Inkjet printing has been successfully used for
printing proteins with a wide array of materials, demonstrating [36] that it is feasible to deliver a protein gradient
by using inkjet printing [30].
Inkjet printing has been used to determine the minimum
concentration of substances that can cause a change in
cells that are in contact, either through a change in phenotype or cellular alignment. For example, through the
addition of spatially defined patterns of fibroblast growth
factor −2, or bone morphogenic protein −2 to undifferentiated progenitor cells, their fate can be promoted to
differentiate to tendon and bone respectively [56]. With
the use of printed laminin gradients, endothelial cells orientated strongly to higher concentrations of laminin [30].
Although many publications state that the inkjet delivery
of proteins and growth factors can be easily accomplished
without any detrimental effects [36], Derby et al found that
glucose oxidase showed decreased activity after printing.
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(a)
(a)
(b)
Figure 8.
Powder-based 3D printing using inkjet printer, whereby the
binder is ejected from the print head, onto a powder bed
where it reacts and hardens to form a solid layer [51].
(b)
Figure 6.
SEM images of printed fibrin scaffold with different amplification to highlight nano-sized fibrin fibres [31].
Figure 7.
Procedures of 3D printing. A thin powder layer is rolled
onto a platform (steps 1 and 2); Inkjet printer dispense
binder onto this thin powder layer selectively (step 3); The
roller placed a new thin powder layer onto the platform then
repeat step 3 (step 4). After repeating these steps for a
period of time, a 3D structure can be obtained [51].
With further investigation using standard characterisation
methods, no significant changes were detected by the inkjet
process [57].
Material ejected out of an inkjet printhead nozzle is affected
by a shear force, which can be characterised with the shear
rate. Shear is a problem which can cause the denaturing
of proteins. Research groups around the world have made
progress to reduce the inhibition of activity through the
addition of stabilizing additives Nishioka et al. studied the
effects which could cause damage to proteins and found
the displacement rate affects the nature of protein. The
addition of simple sugars such as trehalose and glucose
promotes the stability of the enzymes and reduced the
decreased efficacy of enzymes after printing [58]. The
biological reasoning for what was observed is not clear
and this will need to be further investigated. Once a
sufficient understanding of the damage mechanisms to
proteins, enzymes and cells has been accumulated, then
better and more reliable materials can be fabricated in
the future. Limem et al. [36] demonstrated that when
the viscosity of an ink is high, increasing the temperature
of the printer can reduce the viscosity to allow better
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Scaffolds for tissue engineering produced by inkjet printing
develop blood vessels, as without it, normal tissue and cancerous tissue cannot develop. This is why Raf-1 research
can lead to future developments in cancer treatment, and
also to be utilised to promote angiogenesis [60].
However, the stability of cell suspension in the printer
reservoir needs to be taken into consideration. The stability can be enhanced by using strategies like stirring to
prevent the aggregation of cells. However, this strategy
increases the risk of cell damage and contamination of
suspensions. Additionally, better understanding of the
interaction between cell behaviours and three dimensional
environments is needed for better design of artificial structures.
Figure 9.
3D calcium phosphate scaffold fabricated by using powderbased 3D printing [52].
printing. However, if the ink contains proteins, very high
temperatures can obviously denature the proteins.
7.
Cell printing
Cells have also been deposited using inkjet printing. Saunders et al. [40] successfully printed human fibroblasts
(HT1080 fibrosarcoma) suspensions using piezoelectric
DOD and found that survivability reached 98%, compared
to controls. The group of Boland have been active in
this area. In 2005, they used thermal DOD to print a
Chinese Hamster Ovary cells suspension and found that
cell viability was 97% [59]. These data indicate that mammalian cells can be delivered via inkjet printing without
significant damage to the vast majority of cells. In 2009,
Boland et al. [31] utilised a modified thermal DOD inkjet
printer to precisely print tubular structures using fibrin
as a matrix. They then successively seeded human microvascular endothelial cells onto this structure using the
same technique. They found that printing both scaffold
and cells simultaneously promoted the viability of the cells
and microvasculature formation. Boland et al. [46] have
also successfully used inkjet technology to print neural
cell suspensions and, through the use of fibrin, been able
to build a 3D structure in a layer-by-layer process, which
can be used in neural tissue engineering.
Vasculature is required for any development of tissue that
is thicker than a few mm. This is because the tissue requires a steady and sufficient supply of nutrients and to
facilitate the removal of waste from each cell within the
scaffold. This is done naturally through the development of
new blood vessels through angiogenesis, which is vital for
tissue regeneration in adults. Raf-1 needs to be present to
It has been shown that cells develop transient pores on
their permeable cell membranes through inkjet printing.
This has been advantageous as a method to incorporate
plasmids into cells. During this study, cell viability has
been analysed to be typically above 90%, with transfection
rates of plasmid integration below 30% [61].Through the
addition of varying known sizes of fluorescently labelled
molecules after cell, Boland showed with Chinese Hamster
Ovary cells the creation of pores of around 15 Å in size after
printing, which were repaired after 2 hours [62]. Forgacs
et. al [63] use the cell’s innate ability to self-organise to
build structures. They used an inkjet printer, or bioprinter,
to deposit hollow spheres of gel that contained thousands
of cells, which clump together and form structures with the
correct cell types at the correct places.
8. Remaining challenges and conclusion
The scale of tissue engineering has diversified. Many
researchers have focussed on tissue engineering at the
micron scale but produced tissue that varies in thickness
from a few mm to a cm. This has been done so that a
detailed analysis of the tissue can be undertaken to understand cellular mechanisms and behaviour. However, the
generation of tissues greater than a few mm in thickness
is problematic due to the associated vasculature. Oxygen
and nutrients cannot traverse freely enough to supply all
cells, and waste cannot readily be eliminated to keep the
tissue viable for long if the vasculature is either absent or
too small in the bulk of the scaffold [64]. It is this barrier
that has been a significant difficulty for researchers and
has been slowing the advancement of this field. Angiogenesis is essential and this is still a key problem – as
in most cases, the fabrication of cells and the scaffold
together would involve a process that would either cause
significant harm to the cells, or would alter the scaffold
so that it becomes inappropriate for its use when both
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cells and the scaffold are combined together. However,
once this has been solved, it would result in a vast range
of new possibilities and/or allow access to develop many
theoretical applications for tissue engineering. Examples
include the ability to be able to keep vast quantities of
readily available soft tissue in tissue banks, be able to
open up the field of regenerative medicine and ultimately
improve the quality of life of everyone that has access to
this marvel.
As inkjet printing has been accepted as a mask-free, additive manufacturing 3D structure methodology, more researches about wetting processes, surface chemistry have
to be done to fabricate more suitable structures for targets
in the future [38]. Moreover, since ink is the key to inkjet
printing, and there are limited materials that can be used
for this technique due to the specific requirements such
as viscosity and surface tension for inks, a better understanding of the printability of various inks needs to be
achieved.
Boland’s group has developed a technique which can print
cells onto thermoreversible gel [65]. They demonstrated
this technique has potential to directly print organs. Since
inkjet printing is computer-aided technology, researchers
can use up-to-date software to design statistic organs, then
use an inkjet printer to deliver different cell types according
to different requirements of the target organs onto actually
print an organ such as skin or bone [66, 67]. Finally, the
recent work of Brugger et. al may be of interest [68]. They
used alginate as a model system, and show that a suitable
bioink with an adapted 3D printing strategy can be used to
print viable cells and branched microvasculature suitable
for physiologically relevant flow. They also demonstrate
how this strategy can also be applied to other hydrogel
systems and could open up new avenues for generating
tissue models.
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