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 Biomed. Mater. 10 (2015) 034002 doi:10.1088/1748-6041/10/3/034002

Special SECTION TOPICAL REVIEW

Current progress in 3D printing for cardiovascular tissue

engineering
received
16 December 2014
re vised
28 January 2015
accep ted for publication
Bobak Mosadegh, Guanglei Xiong, Simon Dunham and James K Min
9 February 2015 Dalio Institute of Cardiovascular Imaging, Department of Radiology, Weill Cornell Medical College, New York, NY 10021, USA
published Email: bom2008@med.cornell.edu
16 March 2015
Keywords: 3D printing, bioprinting, cardiovascular, tissue engineering, cardiology

Abstract
3D printing is a technology that allows the fabrication of structures with arbitrary geometries and
heterogeneous material properties. The application of this technology to biological structures that
match the complexity of native tissue is of great interest to researchers. This mini-review highlights
the current progress of 3D printing for fabricating artificial tissues of the cardiovascular system,
specifically the myocardium, heart valves, and coronary arteries. In addition, how 3D printed sensors
and actuators can play a role in tissue engineering is discussed. To date, all the work with building 3D
cardiac tissues have been proof-of-principle demonstrations, and in most cases, yielded products less
effective than other traditional tissue engineering strategies. However, this technology is in its infancy
and therefore there is much promise that through collaboration between biologists, engineers and
material scientists, 3D bioprinting can make a significant impact on the field of cardiovascular tissue
engineering.

1. Introduction a­ ccommodate biopolymers, which are typically used

Tissue engineering comprises the optimization of three
primary components: (i) the type or types of cells be-
ing implanted (e.g. somatic, embryonic stem cells, adult
stem cells, or induced-pluripotent stem cells) [1], (ii)
type of scaffolds supporting the cells (i.e. the mechani-
cal cues provided to the cells), and (iii) type of drugs,
extra-cellular matrix (ECM), and growth factors con-
ditioning the cells, (i.e. the chemical cues provided to
the cells). In addition, the conditions (e.g. fluid flow,
oxygenation, temperature) in which the construct is
cultured can have a significant impact on its matura-
tion, making the development of novel bioreactors a
major part of tissue engineering [2]. Typically these
constructs are fabricated using manual procedures
and are therefore limited in the complexity by which
materials of varying properties and dimensions can be
interfaced. 3D printing provides a means to meet this
technological challenge by automating the fabrication
process of these materials. 3D printing is an additive
manufacturing technique that builds structures, based
on a computer-aided design (CAD), by depositing
material in a layer-by-layer manner. There are several
methods to accomplish the layer-by-layer fabrication
depending on the type of material printed [3, 4]. There
are four methods of 3D printing that most readily
for providing the scaffolding and/or ECM for tissue
engineering applications: (i) selective laser sintering
(SLS) [5], (ii) stereolithography (SLA) [6], (iii) fused
deposition modeling (FDM) [7], and (iv) pressure-
based extrusion (PBE) [8, 9].
SLS uses a CO2 laser to locally raise the tempera-
ture of a thin layer of powder so the particles fuse to
form a solid object (figure 1(a)). SLA uses UV or vis-
ible light to polymerize a thin layer of a solution con-
taining a photocrosslinkable resin (figure 1(b)). FDM
melts and extrudes a polymer through a nozzle onto a
flat substrate to build up a 3D structure (figure 1(c)).
PBE uses a differential pressure, generated by a pres-
sure reservoir upstream or a syringe pump, to drive the
material through a nozzle (figure 1(c)). While SLS and
SLA are typically faster than FDM and PBE, they both
require lasers and optics. SLS is ideal for materials such
as ceramics or metals that might require higher tem-
peratures, but the temperatures required for printing
can be prohibitive. SLA can be both fast and straight-
forward, however materials must be available in photo-
curable chemistries (typically plastics). Both FDM and
PBE can be much simpler systems, However, they can be
quite slow compared to other methods. FDM is limited
to thermally extruded materials (typically thermoplas-
tics), but can be simple, high resolution and produce

© 2015 IOP Publishing Ltd

Biomed. Mater. 10 (2015) 034002
Figure 1.  Schematic illustration of various modes of 3D
printing: (a) SLS: focused CO2 laser heats loose powder of
print material to sinter into solid traces, (b) SLA: focused UV
light induces chemical change from liquid to solid in bath
of precursor liquid, (c) extrusion methods: both heating of
molten solids extruded via FDM or pressure based extrusion
of viscous liquids.
dense parts. Finally, PBE offers the advantage that most
materials with appropriate viscocities for printing can
be achieved including hydrogels and direct printing of
cells, however, like FDM, it can be quite slow. We refer
readers to other reviews regarding which 3D printing
methods are useful for different biopolymers [8, 10].
Here, we focus on the use of these techniques specifi-
cally for 3D printing for cardiac tissue engineering.
For tissue engineering applications, 3D printing
serves two main purposes: (i) scaffolds of complex
geometries are directly fabricated using biocompat-
ible materials, which may or may not be seeded with
cells, and (ii) artificial tissues are directly fabricated
with cells encapsulated within the ink, or ‘bioink’, dur-
ing the printing process [10, 11]. The first purpose of
3D printing uses routine methods for industrial appli-
cations, thus allowing the use of commercial printers
without any modifications. The second purpose of 3D
printing for tissue engineering, however, requires the
use of materials not currently used by most industrial
users, and therefore custom printers are typically built.
Two commercially available bioprinters and services
are the 3D-Bioplotter from envision TEC [12] (http://
envisiontec.com/3d-printers/3d-bioplotter/) and the
NovoGen MMX Bioprinter from Organovo [13]. The
impact of 3D printing on the field of tissue engineering
has been most prevalent in applications involving hard
2
B Mosadegh et al
tissues with limited cellular involvement (e.g. bone)
[14, 15]. This outcome is reasonable since 3D printing
is inherently a technique developed for structural fab-
rication of rigid materials. Furthermore, the complex
cues needed to facilitate desired cellular phenotypes
are still not well understood. The promise of 3D print-
ing, however, is that once those cues are discovered, this
technology will enable such a microenvironment to
be built. Already, 3D printing has been shown to build
structures at both the nano-scale [16] and macro-scale
[17]. There currently, however, is not a single system
that can build artificial tissues that span the full range
of hierarchical structures observed in vivo. For example,
muscle comprises protein filaments, myofibrils, muscle
fibers, and fascicles, all of which are well organized and
span several orders of magnitude in length. To bridge
this gap, novel methods of 3D printing and new classes
of bioinks are being developed [3, 4, 18, 19]. In general,
bioinks require three characteristics to be useable: (i)
biocompatible (i.e. will not induce harm to the host
after implantation), (ii) non-cytotoxic (i.e. will not kill
or damage cells during printing due to chemical, ther-
mal, or mechanical issues) (iii) printable (i.e. has the
proper rheological properties to be extruded or assem-
bled effectively during printing), and (iv) robust (i.e.
able to withstand the physical forces of the environment
into which it is applied) [3, 4].
According to the Centers for Disease Control and
Prevention (CDC) and World Health Organization,
cardiovascular disease (CVD) is the number one cause
of death for both men and women, and is responsible
for killing nearly 30% of people world-wide [20, 21].
CVD is a broad term that refers to disorders of the
heart and blood vessels, including coronary heart dis-
ease, peripheral arterial disease, rheumatic heart dis-
ease, heart failure, arrhythmia, myocardial infarction,
and even stroke [22]. Often these diseases are linked
to atherosclerosis, a disease in which a build-up of
plaque causes inflammation, but other congestive and
congenital diseases exist as well [22]. Medications can
be effective if administered early, but if the disease
progresses, surgical intervention that aims to repair or
replace the damaged tissue is often required. Due to a
lack of organ donors and adequate synthetic solutions,
tissue-engineering approaches are being developed.
This review focuses on the use of 3D printing to fab-
ricate tissue-engineered cardiac tissue, but we refer the
reader to the following reviews that survey cardiac tissue
engineering using other fabrication methods [23–28].
For cardiovascular applications, 3D printing has
already been used in a clinical setting to visualize ana-
tomical structures for surgeons [29–31]. For this rea-
son, the NIH has already begun a public resource for
the exchange of CAD files, medical images, tutorials
and software [32]. These surgical models are made of
solid plastic that are not directly useful for tissue engi-
neering purposes. Bioinks, which typically comprise of
cells suspended in hydrogels that serve as the ECM, are
beginning to be developed and printed directly to form
Biomed. Mater. 10 (2015) 034002
tissues that can be implanted for cardiovascular tissue
engineering [8, 10, 17, 33–35], specifically in the form
of myocardial tissue, heart valves, and coronary arteries.
Furthermore, 3D printing has the ability to integrate
electronics into tissue-engineered constructs to provide
additional functionality, such as sensing and actuation.
Although currently there is no clinical impact of 3D
printed tissues, as techniques are refined and the tech-
nology improved in resolution and scale, this technol-
ogy should yield an unprecedented ability to integrate
artificial tissues with native cardiac tissue seamlessly
with respect to geometry, mechanical properties, elec-
trical properties, and ability to remodel.
2.  3D printing for myocardial tissue
When heart tissue undergoes damage, the heart pumps
blood inefficiently due to the loss of contractile muscle
tissue (primarily cardiomyocytes) and the formation
of stiff scar tissue (due to activated fibroblasts) [36].
The resulting decrease in cardiac output often results
in ischemia that can lead to death [37]. One approach
to repair the heart is to implant cells at the site of the
damaged tissue, a treatment option referred to as cel-
lular therapy [1]. The effectiveness of cellular therapy
depends on the ability of the cells to survive the im-
plantation and properly integrate into the heart tissue
in a manner that increases cardiac output. Due to the
demanding constraints of the heart, cell therapy alone
has not been able to cause sufficient regeneration, and
therefore techniques of tissue engineering are being
explored [37]. There are many combinations of strate-
gies being explored for cardiac tissue engineering, and
we refer the readers to the following reviews [36–40].
One of the main limitations to survival of the
implanted cells is the immediate availability of oxy-
gen [41]. During in vitro culture, the effective trans-
port of oxygen to cells is facilitated by either, (i) limit-
ing the thickness of the construct of cells to thin slices
(<200 µm) [38], and/or, (ii) integrating open pores or
channels to allow oxygen to more easily reach the mid-
dle regions of the construct either by diffusion or con-
vective mass transport. The disadvantage of limiting
the thickness of the construct in vitro, is that multiple
constructs will need to be implanted in vivo, a process
that requires repeated surgeries to obtain useful clini-
cal outcomes since proper vascularization by the host
takes days [42]. Currently, strategies to build thicker
multi-layered tissues are being pursued by integrating
a vascular system prior to implantation. So far, only tis-
sues on the order of 100 µm thick have been produced,
and still suffer from cell death [43]. The second method
of integrating pores or channels into the scaffold allows
larger constructs to be built in vitro, but currently all
methods use cellular densities at least 100 ×  less than
that of in vivo tissue, which yields limited improve-
ment in heart function [44]. Simply increasing the cell
density, however, is not trivial since (i) current meth-
ods to provide proper vascularization have not met the
3
B Mosadegh et al
Figure 2.  SLS fabricated scaffolds. (a) CAD drawing of the
unit cell and final geometry of the scaffold made from PCL.
(b) SEM image (scale bar: 100 µm) and optical image of the
PCL scaffold (scale bar: 4 mm). (c) Merged fluorescence
image of DAPI (blue) and F-actin (red) expression of C2C12
cells 6 d after seeding in the PCL scaffold (scale bar: 100 µm).
­ etabolic requirements of tissues at those high densi-
m
ties, and therefore will result in significant cell death,
and (ii) cardiomyocytes do not proliferate, so the use of
stem cells is needed if sufficient densities of cardiomyo-
cytes are not seeded initially.
3D printing holds promise to overcome the above
limitation by enabling the direct fabrication of thick
3D constructs of a defined geometry of arbitrary com-
plexity, with uniformly dispersed cells. For example,
Yeong et al used the additive manufacturing technique
of SLS to produce structures that were porous on both
the micron and millimeter scale, ensuring efficient
mass transport throughout the structure (figure 2).
SLS uses a CO2 laser to sinter a specific pattern of a thin
layer of power, based on a CAD model, and similar to
other 3D printing methods, builds up the structure
layer-by-layer. The power used in this study was poly-
caprolactone (PCL), which yields sintered structures
with ~48% porosity, ~34 µm surface roughness, a ten-
sile stiffness of ~0.43 MPa, and a yield strain of ~89%.
Viable C2C12 cells were maintained for three weeks in
culture and formed multi-nucleated myotubes after
11 d. The authors did not conduct any further studies
to characterize the performance of this construct for
therapeutic use. This method of additive manufactur-
ing also prevents the direct printing of cells due to the
high temperatures needed to sinter the power.
Gaetani et al used 3D bioprinting (using pressure-
based extrusion) to create a construct containing
human cardiac-derived cardiomyocyte progenitor
cells (hCMPCs) and RGD-modified sodium alginate
as the ECM (figure 4) [45]. This construct was shown to
Biomed. Mater. 10 (2015) 034002 B Mosadegh et al

maintain the viability of the hCMPCs in vitro, promote

the differentiation of hCMPCs into cardiomyocyte-like
cells, and allow the migration of the hCMPCs out of
the construct when cultured in a Matrigel migration
assay. The use of hCMPCs as a cell source is attractive
since they are already committed to the cardiac line-
age, able to differentiate into cardiomyocytes, and able
to proliferate in vitro. The authors show that hCMPCs
have a greater potential to differentiate in the 3D bio-
printed construct than when cultured in 2D, as shown
by the increased expression of the transcription factors
Nkx2.5, GATA-4, Mef-2c, and TnT. The hCMPCs, how-
ever, did not display the striated phenotype of cardio-
myocytes, suggesting that additional factors (i.e. chemi-
cal, mechanical) are needed to fully differentiate this
population of cells in vitro. The authors, however, do
show that these progenitor cells are able to migrate from
the construct in a Matrigel invasion assay, suggesting
the therapeutic potential of this population of cells to
integrate into damaged heart tissue if implanted.
Another avenue in 3D bioprinting being pursued
by the Cho group is the use of bioinks generated from
decellularized ECM (dECM) for extrusion-based
printing [19]. dECM of whole organs have been shown
to provide instructional cues to cells that better main-
tain a proper phenotype [46–50]. A drawback of the
Figure 3.  Decellulrized ECM bioprinting. (a) Images that
top-down approach of decellularized organs is that pat-
compare native heart tissue to decellularized ECM in bulk
terning of multiple types of cells is difficult, and not all and histological form (scale bar: 100 µm). (b) Schematic of
applications of tissue engineering require whole organ extrusion printing of the dECM bioink into a 3D porous
replacement. Using similar methods for decellularizing tissue construct (scale bar: 5 mm). (c) Microscopic images of
bioprinted construct (scale bar: 400 µm).
whole organs, tissue from the heart, fat, and cartilage
were made into bioinks and printed to form porous
tissue-like structures, similar to those by Gaetani et ­ recisely patterned and oriented on scales ranging three
p
al (figure 3(b)). Due to the limited sources of human orders of magnitude (microns to millimeters), and (iii)
cardiomyocytes, the Cho group encapsulated rat myo- materials that induce and maintain proper phenotype
blast cells into the heart-derived bioink. As compared of the cells and that do not illicit a negative reaction
to collagen constructs, the bioink increased expression from the host.
cardiac-specific genes (Myh6 and Actn1) after 4 d in
culture, and the increased expression was maintained 3.  3D printing for heart valves
for at least 14 d. Furthermore, the bioink constructs
induced higher expression of cardiac myosin heavy Currently, two options currently exist for heart valve
chain (β-MHC) than the collagen construct. replacement surgery: (i) using a mechanical heart valve,
Although 3D bioprinting is useful for building and (ii) using a biological heart valve [51]. The advan-
porous constructs that can maintain the viability of tage of prosthetic valves is that they are mechanically
cells, as shown in the described examples, to date this robust and have a long lifetime before a subsequent
technology has not successfully printed tissue that has replacement surgery is needed (relative to biological
clinical relevance. Similar to standard tissue engineer- valves) [52]. Their disadvantage is they require the pa-
ing approaches, 3D printing of myocardial tissue is pri- tient to take anticoagulants for life. Biological valves,
marily limited by: (i) the source of human cardiac cells made from either an allographic or xenographic source
able to be implanted, and (ii) the limited resolution by of tissue, do not require the patient to take anticoagu-
which complex structures can be built. The promise lants for life, but have a significantly shorter lifetime
of iPS cells and cardiac progenitor cells will hopefully (10–20 years) than prosthetic valves [53].
address the issues associated with the first limitation, a Tissue engineered heart valves have the promise
feat more likely to be solved by biologists. Tissue engi- of using a patient’s own cells, mitigating the need for
neers, however, have the responsibility to address the long-term drug use, improving hemocapability of
second limitation by building tissues that, at a mini- the replacement valve, and adding the capacity for the
mum, possess the following features: (i) a functional replacement heart valve to repair itself, and even grow
vascular system that can easily be integrated with a with the patient (a major attribute for younger patients)
host, (ii) a hierarchical structure that enables cells to be [51, 52, 54, 55]. The desired qualities for any heart valve

4
Biomed. Mater. 10 (2015) 034002 B Mosadegh et al

are that they: (i) have minimal regurgitation of blood

upstream, (ii) have a low transvalvular pressure gradi-
ent, (iii) have minimal thrombogenetic response, and
(iv) have a high capacity to repair damage [56].
3D printing has the potential to improve the clinical
outcome of tissue engineered heart valves by allowing
their fabrication to better match: (i) the patient-­specific
geometries of the heart valve, (ii) the spatial heterogene-
ity of the mechanical properties of the heart valve, and
(iii) the spatial heterogeneity of the cell types seeded
within and on the surface of the heart valve.
Currently, Jonathon Butcher’s lab has been lead-
ing the front for 3D printing of tissue engineered heart
valves [56–58]. In 2012 the Butcher group developed an
extrusion-based 3D printer, which deposited two types
of photocrosslinkable hydrogels, one rigid (~75 kPa)
hydrogel for the root and another soft (~5 kPa) hydro-
gel for the leaflets (figure 4) [56]. This artificial valve
demonstrated that 3D printing easily allowed arbitrary
geometries, which ranged between 12 mm (average
size of a 6 month old heart valve) and 22 mm (aver-
age size of an adult) in diameter. The heart valves were
3D printed within 45 min and with an accuracy up to
93% (when compared to the desired geometries). The
ability to print two materials simultaneously with dis-
tinct mechanical properties allowed the fabrication of
heart valves that better mimicked the varying stiffness
in native heart valves between the leaflets and the root
(figure 4(b)). Since this work was a proof of principle
for the use of 3D printing for the fabrication of tissue
engineered heart valves, no functional testing was per-
formed. The authors did, however, demonstrate that Figure 4.  3D printed heart valve. (a) Schematic of 3D
porcine aortic valve interstitial cells (PAVIC) could be printer system, including two extrusion systems with
seeded into the 3D printed heart valves and survive for integrated UV light source to crosslink the hydrogel.
(b) CAD model and image of a heart valve with a geometry
up to three weeks (figure 4(c)). In another study, the obtained from microCT images. The red regions are the
Butcher group used 3D printing to directly fabricate leaflets and the blue regions are the roof of the heart valve.
a heart valve with two types of cells, aortic root sinus (c) Microscopic images of the PAVIC cells in the root/
annulus of the heart valve after being stained with a live
smooth muscle cells (SMCs) and aortic valve leaflet (green) and dead (red) stain (scale bar: 2 mm).
interstitial cells (VICs), encapsulated into the root and
leaflet regions, respectively. The results showed that the
cells maintained the mechanical properties of the algi- and (iii) have a relatively lower contribution of cellular
nate/gelatin mixture over 7 d but that an acellular heart activity, such that complex differentiation pathways
valve of the same material would lose its mechanical and need for highly ordered vascular networks are not
properties [57]. Most recently, the Butcher group dem- required for the successful development of a heart valve.
onstrated that methacrylated hydrogels (mixtures of With that said, thorough testing of 3D printed tissue
gelatin and hyaluorinc acid) could be printed with sus- engineered heart valves has yet to be done, and only by
pensions of human aortic valvular interstitial (HAVIC) doing so can their improved functionality be tested.
cells [58]. The HAVIC cells could remodel the printed
hydrogels by depositing their own ECM (collagen and 4.  3D printing for coronary arteries
glycosaminoglycans), and furthermore would undergo
changes in their phenotype based on the stiffness of the Despite improvements in therapies targeted at reduc-
printed hydrogels (a softer hydrogel better maintained ing disease burden, coronary artery disease continues
the fibroblastic behavior of the HAVIC cells). to afflict more than 16 million US adults, accounting
As shown by the work of the Butcher group, 3D for more than 1/3 of all deaths and is responsible for
printing is particularly suited for developing heart approximately 1.2 million hospitalizations annually.
valves because: (i) they are of a sufficiently complex Depending on the stage of coronary artery disease,
geometry that normal fabrication methods ca not eas- its symptoms are managed through lifestyle modi-
ily address, (ii) require heterogeneity in stiffness, that is fications, medical therapy, coronary angioplasty, or
easily achieved by incorporating multiple print heads, coronary artery bypass grafting (CABG) surgery. For

5
Biomed. Mater. 10 (2015) 034002
complex multivessel coronary artery disease, CABG
is often recommended in clinical practice. This pro-
cedure involves diverting blood around a section of
severely narrowed or blocked artery using grafts har-
vested from other parts of the body. About 400 000
CABG operations are performed annually in the US.
In a typical CABG surgery, one or more conduits,
typically internal thoracic arteries, radial arteries, or
saphenous veins harvested from the rest of the body,
are placed to ­supply additional blood flow to the distal
coronary arteries blocked by stenosis. While CABG can
alleviate the symptoms and improve the survival rate
of patients with coronary artery disease, approximately
30% of patients are not eligible for this procedure due
to the lack of suitable autologous vessels. Even if one of
these vessels is available for harvest, a number of draw-
backs are associated with CABG, including accidental
graft damage during harvest, relatively poor long-term
patency, and morbidity at donor sites after surgery [59].
Consequently, it has long been hoped that artificial
coronary bypass grafts can satisfy this unmet clinical
need. The ideal vascular graft should be biocompatible,
anti-thrombogenic, durable, and have similar compli-
ance and density to native vessels [60]. Early attempts
to synthesize coronary grafts used expanded polyte-
trafluoroethylene (ePTFE, also known as Gortex) and
woven polyethylene terephthalate (PET, also known
as Dacron)—both of which are frequently used for
aorta and peripheral vascular territories. The results of
using these conventional materials for making small-
diameter low-flow coronary grafts are, however, disap-
pointing. At least two major limitations are attributed
to the poor outcome of these synthesized grafts: (i)
improper mechanical characteristics and (ii) undesir-
able biochemical properties. In spite of their strength,
both ePTFE and PET are stiff and lack the flexibility
to stay in the proximity of the heart with its complex
geometry and cyclic deformation. In addition, inflam-
matory responses are activated by exposure of these
materials to the blood and causes poor patency due
to thrombogenesis. A shift in research has been made
to favor the exploration of more compliant materials
as well as the combination with pharmaceutical and
tissue-engineered modifications [61]. Polyurethane
grafts, although more compliant than ePTFE grafts,
have yielded higher rates of thrombosis and infection
[62] and aneurysm formation [63]. With the promise
of creating living conduits for restoring hemodynamic
function, vascular tissue engineering has been hoped
to become a new avenue to make artificial coronary
bypass grafts. The ideal tissue-engineered graft should
be endothelialized, non-thrombogenic, and have com-
parable biomechanical properties to the native blood
vessel.
There are two main approaches in engineering
biomimetic blood vessels [64]: (i) scaffold-guided, in
which scaffolds using natural, synthetic biomaterials,
or decellularized matrix are developed to support cell
attachment, infiltration and proliferation during the in
6
B Mosadegh et al
vitro tissue development, and (ii) cell-sheet-based, in
which a monolayer of cells is cultured and then rolled
on a mandrel to produce a tubular conduit mimick-
ing the media and adventitia of an artery. Despite these
recent efforts, few artificial coronary bypass grafts have
matched the long-term performance of autologous
grafts and thus none is commercially available for clini-
cal use to date.
3D printing is a promising tool to facilitate in both
tissue engineering approaches by: (i) generation of
scaffolds, whose paths conform to the patient-specific
geometry and printing using synthetic biomaterials,
and (ii) directly printing using differentiated endothe-
lial cells, fibroblasts and SMCs, or mesenchymal and
hematopoietic stem cells in biocompatible materials
(e.g. hydrogel). However, 3D printing has not been
directly applied to the creation of patient-specific coro-
nary bypass graft. Current research has been focused on
the in-vitro generation of vascular models and lining
with endothelial cells in the inner surface, particularly
for the formation of microvascular networks to study
angiogenesis and thrombosis or supply of nutrients and
oxygen to engineered tissue.
Wu et al demonstrated omnidirectional printing of
3D biomimetic microvascular networks by direct-write
assembly of fugitive ink filaments within a photocur-
able gel reservoir (figure 5). This method broadens the
network design space and removes the need for tradi-
tional layer-by-layer patterning [65]. The ink can be
subsequently removed by liquefaction under a mod-
est vacuum to yield the desired microvascular network
within the solidified gel matrix. However, this study
does not discuss the integration of cells into the con-
structed networks.
Miller et al [66] printed rigid 3D filament networks
for rapid casting of patterned vascular networks in
engineered tissues using extrusion through a syringe
mounted on a custom-modified RepRap Mendel 3D
printer (figure 6). For this purpose, they developed a
biocompatible sacrificial material based on carbohy-
drates. To show the flexibility of the approach, they pat-
terned vascular channels in the presence of living cells
in a wide range of natural and synthetic ECM mate-
rials. In particular, they also demonstrated three key
compartments of vascularized solid tissues (i.e. lumen,
endothelial cells, and the matrix and cells residing in the
interstitial zone).
Li et al fabricated a hybrid cell/hydrogel vascular-
like network using a double-nozzle assembling tech-
nique [67]. Adipose-derived stromal cells (ADSCs)
were combined within a gelatin/alginate/fibrinogen
hydrogel to form the network construct and hepato-
cytes combined gelatin/alginate/chitosan were placed
around it. After assembly, the printed construct was
stabilized and the ADSCs were induced to differenti-
ate into endothelial-like cells with endothelial growth
factor. Interestingly, the ADSCs at the periphery of the
vascular-like network demonstrated some endothelial-
like cell properties.
Biomed. Mater. 10 (2015) 034002 B Mosadegh et al

Figure 5.  Omnidirectional printing of 3D microvascular networks. (a) Deposition of a fugitive ink into a physical gel reservoir
to pattern hierarchical, branching networks. (b) Photopolymerization of the reservoir yields a chemically cross-linked, hydrogel
matrix. (c) After the ink is liquefied, it is removed by a vacuum to expose the microvascular channels. (d) Fluorescent image of a 3D
microvascular network fabricated via omnidirectional printing of a fugitive ink (dyed red) within the photopolymerized matrix.
Reprinted from [65].

Figure 6.  3D printing of filament networks with carbohydrate glass and generation cylindrical channels lined with endothelial
cells (expressing mCherry, shown as red) and perfused with blood to support 10T1/2 cells (expressing enhanced green fluorescent
protein, shown as green) in the interstitial space. (a) Top view (scale bar: 1 mm) of printed multiscale carbohydrate-glass lattice
and magnified interfilament melt fusions in side view (scale bar: 200 µm). (b) Multilayered lattices are fabricated with precise
lateral and axial positioning resolution (scale bar: 1 mm). (c) After 9 d in culture, cross-section imaging showed the endothelial
monolayer lining the vascular lumen became surrounded by 10T1/2 cells (scale bar: 200 µm). D) Endothelial cells formed single and
multicellular sprouts (arrowheads) from patterned vasculature. Reprinted from [66].

Cui and Boland simultaneously deposited human aqueous processes that were shown to induce ­minimal
microvascular endothelial cells (HMVECs) and fibrin damage to cells. When printing HMVECs in con-
to form the microvasculature using a modified ther- junction with the fibrin, the cells were found to align
mal inkjet printer [68]. This printing technique used ­themselves inside the channels, and proliferated within

7
Biomed. Mater. 10 (2015) 034002
7 d to form a confluent lining. The authors concluded
that simultaneous cell and scaffold printing promoted
HMVEC proliferation and microvasculature forma-
tion. Despite the promising results, the risk of exposing
cells and materials to thermal and mechanical stress,
low droplet directionality, imprecise droplet size and
shape, frequent clogging of the nozzle and unreliable
cell encapsulation pose considerable challenges for the
use of ink-jet printers.
These important results have demonstrated the
potential to generate tubular structures in small scales
using 3D printing methods. In the meantime, it is clear
that several challenges still exist to translate the early
successes in microvascular 3D printing to the ultimate
goal of making an ideal artificial coronary bypass graft.
First, autologous blood vessels have three layers and
each has different cellular components, stiffness, and
functions. It is difficult for scaffold printing and sub-
sequent cell seeding to mimic such layered structures,
given the current limitations of resolution and scale.
Second, almost all of tissue-engineered vasculature by
3D printing is microscale. It remains unclear how to
seed cells of multiple types in the printed tubular scaf-
folds of a few millimeters in diameter. Finally, the cells
within the coronary bypass graft should be kept alive
by continuous supply of oxygen and other nutrients.
In normal coronary arteries, nutrients come from the
vasa vasorum (capillaries in the vessel wall). Therefore,
future tissue-engineered grafts may require creation
of both microvascular and macrovascular structures;
further emphasizing the need to build systems that can
span the large range of scales associated with biological
tissues.
5.  3D printing for cardiac sensors and
electrodes
Whether fabricated from synthetic material or biologi-
cal tissue, a wide variety of cardiovascular implants and
surgical tools either require or benefit greatly from the
incorporation of sensing or actuation elements that al-
low the implant or tool to collect information about the
surrounding conditions and apply a response. Today,
a variety of clinically relevant surgical and diagnostic
tools utilize individual sensor elements, made from
small but complex rigid elements mounted on cath-
eters or guidewires. Guidewires with embedded flow
[69] and pressure sensors [70] as well as catheters with
complex imaging functionality such as optical coher-
ence tomography and ultrasound are common tools in
interventional medicine [71, 72]. These are robust tech-
nologies and reviews of them can be found elsewhere,
however, they demonstrate the existing utility of these
types of sensors.
Recently, new classes of devices that incorpo-
rate arrays of similar (although in most cases, much
simpler) sensing or actuation elements into mate-
rials and surfaces have been seamlessly integrated
with biological systems or surgical tools to create
8
B Mosadegh et al
Figure 7.  (a) Image of an array of stretchable sensors on
a Langendorff-perfused rabbit heart. Sensors can detect,
electrocardiogram, pH, temperature, and strain. µLEDs are
also integrated to allow for optical mapping. Scale bar: 6 mm.
Reprinted from [82]. (b) Image of a strain and pressure
sensor, comprising three layers of 3D printed conductive
ink in a silicone elastomer. Scale bar: 10 mm. Reprinted
from [99]. (c) Stretchable display of organic LEDs folded
in half. Reprinted from [101]. (d) Image of a 3  ×  4 array of
capacitive sensors connected to electrochemical transistors
that control an electrochromic display. Reprinted from [88].
e­ lectronic sensing [73–77], artificial skins [78–81],
heart shaped membranes [82, 83], and balloon
catheters [84]. These devices suggest the potential
for cardiovascular implants or surgical tools that
implement multifunctional sensing and actuation.
A critical aspect of all of these devices is the need
for geometries, form factors and material properties
(especially stiffness and biocompatibility) that can
match and allow for seamless integration or interfac-
ing with biological tissue.
3D printing is an optimal technology for these
types of devices. It provides the ability to create geom-
etries that are highly complex and patient specific
(based on conventional imaging techniques) [83]. Xu
et al, demonstrated this by creating a patient-specific
thin flexible membrane to surround the heart with
embedded electronic sensors and actuators to moni-
tor cardiac function based on a 3D printed mold [82].
Figure 7 shows an image of this device conforming to
a rabbit heart. Here, microtransfer printing was used
to fabricate electronics on this complex 3D mem-
brane based on electronics fabricated on a 2D wafer
(via traditional microfabrication). This suggests a
general methodology for fabricating 3D patient spe-
cific sensing devices based on fabrication of soft and
flexible 2D arrays or sensors and actuators which
can then be transferred or bonded to complex 3D
implants or tools.
Biomed. Mater. 10 (2015) 034002
To date, there are several approaches that allow for
precision printing of 2D patterns of these soft func-
tional materials. Examples include inkjet printing
[85], ejet printing [86], roll-to-roll techniques [87],
and flexible printed circuit board technologies. A few
noteworthy examples include flexible arrays of pres-
sure sensors and flexible displays shown in figures 7(b)
and (c). These approaches typically (but not always)
utilize conducting, semiconducting, or piezoelectric
polymers, which are flexible and, when utilized prop-
erly, can impart a wide range of sensing modalities.
For cardiovascular applications, those which can
measure pressure [75, 76, 80, 88] and flow [74, 89] are
particularly useful. Furthermore, for devices that aim
to mimic biological systems (pumps, valves, etc), sen-
sors and actuators are particularly important to create
or detect mechanical motion [90–94] and electrical
signals [95]. Other potentially useful sensors include
temperature [74, 80], pH [73] and chemical [96] or
biological sensors [97], which can detect particular
markers of various CVDs or dysfunctions. Also note-
worthy are approaches that allow for 2D arrays of
functional inorganic components to be assembled and
integrated with soft substrates, whereby flexible and
stretchable configurations can be achieved with the
excellent performance of inorganic materials [77, 98].
For applications where limited flexibility is sufficient,
simple solutions such as flex printed circuit board
technology can be sufficient. When true stretchabil-
ity is required, approaches that utilize microtransfer
printing and advanced geometries with serpentine
interconnects and neutral mechanical plane designs
should be used.
To date, there are very few demonstrations of direct
3D printing of soft functional sensors or actuators,
however several examples exist that utilize printing of
conductive liquids or greases that can be utilized for
basic strain sensors [99, 100]. Figure 7(d) shows a 3D
flexible trace of conductive carbon grease, which was
printed in a flexible elastomer matrix. Development
of materials and methods for direct printing of 3D
sensors and actuators opens the door for cardiovascu-
lar implants with even greater complexity that could
mimic the functionality observed in many existing
biological systems. However, this is challenging: tech-
niques common in 2D printing of such as solvent based
deposition of functional polymers are limited by the
need to create viscous spanning and supportive features
during 3D complex drying dynamics make it difficult
to control morphology and resulting properties. New
innovations are required.
3D printing, as a template or mold for integrated
electronic sensing or for direct printing of sensors,
opens the door for a wide range of implants and surgi-
cal tools such as balloon catheters or stents with inte-
grated sensing capabilities or grafts, valves and artificial
hearts that integrate mechanical pumping and/or sens-
ing and feedback. For all of these devices, biocompat-
ibility and/or encapsulation will be critical challenges
9
B Mosadegh et al
to overcome. While these types of integrated sensing
implant and tools are still an emerging technology, they
provide great potential to solve a wide variety of clinical
challenges.
6.  Future perspective
3D printing holds much promise for the development
of cardiac tissues because of its inherent ability to
build structures with arbitrary geometry and material
properties. Despite its promise, it appears that most
examples of 3D printed tissues for cardiac applications
are behind those of traditional tissue engineering ap-
proaches. Several limitations prevent this technology
from reaching fruition since the promise of arbitrary
features is not actually achievable with current print-
ing systems and bioinks. Although nanoscale struc-
tures can be built using two-photon lithography, this
high resolution 3D printing system does not trans-
late into tissue engineering since cells are not easily
incorporated into these systems, and if they were, they
still are not able to build structures large enough to
be useful for tissue engineering purposes. Therefore,
a major need for 3D printing is the development of
Hierarchical structures that can span the entire range
of scales associated with tissues (i.e. nearly 7 orders of
magnitude). In addition, development of printers that
can easily accommodate multiple materials within a
given job need to be built, so that a sufficient variety
of cell types and ECM proteins can be used to build
complex tissues.
An ideal bioprinter could switch between laying
down ECM at the nanoscale resolution, then switch
to printing single cells at the microscale, in a seamless
fashion that allows truly arbitrary features to be printed.
For example, the formation of a basement membrane
in both planar and cylindrical geometries would allow
printed endothelial and epithelial cells to be printed
with a proper orientation to form vasculature and tis-
sue boundaries, respectively. Furthermore, the ability
to print ECM with an orientation would allow polarity
to be given to cells, such as cardiomyocytes, as is done
with electrospinning. An ideal bioprinter would also
integrate components that allow actuation, electrical
stimulation, and sensing to of the tissue to (i) opti-
mize maturation by providing additional mechano/
eletrical cues, (ii) provide quantitative data to assess
performance pre-implantation, (iii) provide quantita-
tive data to monitor performance of the tissue post-
implantation.
Despite the limitations of current 3D printers, which
will undoubtedly improve, some of the major limita-
tions of cardiac tissue engineering are not related to
fabrication but are rooted in much more fundamentals
issues, such as sources of human stem cells, protocols
for proper differentiation, and methodologies for effi-
cient conditioning of the formed tissues. Nonetheless,
it is likely that advances in all these areas of research will
synergistically improve the entire field, suggesting that
Biomed. Mater. 10 (2015) 034002
direct communication and collaboration between biol-
ogists, engineers, and material scientists will expedite
such progress.
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