Advances in melt electrowriting for cardiovascular applications

Abstract

Melt electrowriting (MEW) is an electric-field-assisted additive biofabrication technique that has brought significant advancements to bioinspired scaffold design for soft tissue engineering and beyond. Owing to its targeted microfiber placement, MEW has become a powerful platform technology for the fabrication of in vitro disease models up to functional biohybrid constructs that are investigated in vivo to reach clinical translation soon. This work provides a concise overview of this rapidly evolving field by highlighting the key contributions of MEW to cardiovascular tissue engineering. Specifically, we i) pinpoint the methods to introduce microvascular networks in thick 3D constructs benefitting from (sacrificial) MEW microfibers, ii) report MEW-based concepts for small-diameter vascular grafts and stents, iii) showcase how contracting cardiac tissues can profit from the tunable structure–property relationship of MEW scaffolds, and iv) address how complete regenerative heart valves can be built on complex fiber scaffold architectures that recapitulate J-shaped tensile properties and tissue heterogeneity. Lastly, we touch on novel biomaterial advancements and discuss the technological challenges of MEW to unlock the full potential of this transformative technology.

Full text

Advances in melt electrowriting
for cardiovascular applications
Kilian Maria Arthur Mueller
1
, Salma Mansi
1
,
Elena M. De-Juan-Pardo
2
,
3
,
4
and Petra Mela
1
*
1
Technical University of Munich, TUM School of Engineering and Design, Department of Mechanical
Engineering, Chair of Medical Materials and Implants, Munich Institute of Biomedical Engineering (MIBE),
Munich Institute of Integrated Materials, Energy and Process Engineering (MEP), Munich, Germany,
2
T3mPLATE, Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre and
University of Western Australia Centre for Medical Research, The University of Western Australia, Perth,
WA, Australia,
3
School of Engineering, The University of Western Australia, Perth, WA, Australia,
4
Curtin
Medical School, Curtin University, Perth, WA, Australia
Melt electrowriting (MEW) is an electric-field-assisted additive biofabrication
technique that has brought significant advancements to bioinspired scaffold
design for soft tissue engineering and beyond. Owing to its targeted
microfiber placement, MEW has become a powerful platform technology for
the fabrication of in vitro disease models up to functional biohybrid constructs
that are investigated in vivo to reach clinical translation soon. This work provides a
concise overview of this rapidly evolving field by highlighting the key
contributions of MEW to cardiovascular tissue engineering. Specifically, we i)
pinpoint the methods to introduce microvascular networks in thick 3D constructs
benefitting from (sacrificial) MEW microfibers, ii) report MEW-based concepts for
small-diameter vascular grafts and stents, iii) showcase how contracting cardiac
tissues can profit from the tunable structure–property relationship of MEW
scaffolds, and iv) address how complete regenerative heart valves can be built
on complex fiber scaffold architectures that recapitulate J-shaped tensile
properties and tissue heterogeneity. Lastly, we touch on novel biomaterial
advancements and discuss the technological challenges of MEW to unlock the
full potential of this transformative technology.
KEYWORDS
melt electrowriting, tissue engineering, heart valve, cardiac patch, vascular graft,
capillary network, cardiovascular
1 Introduction
Melt electrowriting (MEW) is a powerful fiber-forming biofabrication strategy that
combines electrically driven fiber jet formation with digitally controlled jet deposition to
form highly ordered microfibrous architectures following the layer-by-layer paradigm of
additive manufacturing.
In MEW, a polymer melt is extruded pneumatically from a syringe through a metal
nozzle (Eichholz et al., 2022;Lanaro et al., 2021;Mieszczanek et al., 2021b)(Figure 1A) or, as
recently proposed, via a filament-based system (Luposchainsky et al., 2022;Mueller et al.,
2023a;Reizabal et al., 2023). An electric potential applied to the nozzle transforms the
extruded melt into a Taylor cone from which a fiber jet emerges that travels to the oppositely
charged collector. The electric field stabilizes the fiber during the flight phase and leads to a
significant reduction of its diameter. Collecting the fiber jet onto a flat or tubular target that
moves with a speed matching the flight speed of the jet enables fiber deposition in a direct-
writing mode along computer-controlled paths so that a three-dimensional structure is
OPEN ACCESS
EDITED BY
Wojciech Swieszkowski,
Warsaw University of Technology, Poland
REVIEWED BY
David Dean,
The Ohio State University, United States
*CORRESPONDENCE
Petra Mela,
petra.mela@tum.de
RECEIVED 29 April 2024
ACCEPTED 26 August 2024
PUBLISHED 17 September 2024
CITATION
Mueller KMA, Mansi S, De-Juan-Pardo EM and
Mela P (2024) Advances in melt electrowriting
for cardiovascular applications.
Front. Bioeng. Biotechnol. 12:1425073.
doi: 10.3389/fbioe.2024.1425073
COPYRIGHT
© 2024 Mueller, Mansi, De-Juan-Pardo and
Mela. This is an open-access article distributed
under the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other forums is
permitted, provided the original author(s) and
the copyright owner(s) are credited and that the
original publication in this journal is cited, in
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No use, distribution or reproduction is
permitted which does not comply with these
terms.
Frontiers in Bioengineering and Biotechnology frontiersin.org01
TYPE Mini Review
PUBLISHED 17 September 2024
DOI 10.3389/fbioe.2024.1425073

FIGURE 1
Microchannels and cardiac patches obtained via MEW. (A) In MEW, a polymer melt is extruded via a charged nozzle and transforms into a fiber jet that
undergoes significant thinning in diameter while traveling towards the collector, where it is deposited in direct writing mode according to computer-
coded paths. A wide range of fiber pattern architectures has been established and realized onto various collector geometries to result in flat, tubular, or
out-of-plane scaffolds. (B) Examples of bifurcating channel networks. i-iii) time-lapse of the dissolution of PcycloPrOx fibers and iv-ix) progressing
perfusion of the branching channels. (C) Multiphoton image of an endothelialized microchannel. Cytoskeleton: Alexa Fluor 488 Phalloidin; nuclei:
Hoechst 33342. (D) Microchannels from dissolved isomalt in PDMS. The channel diameter was controlled via the fiber diameter from 200 µm (region 1) to
30 µm (region 3). Perfusion was demonstrated via polystyrene (PS) microparticles. (E) Detailed image of the as-fabricated hexagonal scaffold and in vivo
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formed by repeatedly stacking fiber layers (Robinson et al., 2019). To
date, a wide range of fiber architectures have been melt-
electrowritten onto flat and tubular collector geometries
(Robinson et al., 2019), and some examples of out-of-plane
designs have been reported (Brooks-Richards et al., 2022;
Luposchainsky et al., 2022;Mueller et al., 2023a;O’Connell et al.,
2021;Peiffer et al., 2020;Saha et al., 2021;Saidy et al.,
2020)(Figure 1A).
Since its conceptualization (Brown et al., 2011;Dalton et al.,
2008;2007), MEW has been employed to produce scaffolds in a vast
array of studies on engineering inter alia bone, neural, and cartilage
tissue (Robinson et al., 2019). This review specifically addresses
MEW as a versatile technology platform to solve challenges in tissue
engineering (TE) and regenerative medicine for the cardiovascular
system, including capillary networks, vascular grafts, cardiac
patches, and heart valves.
2 Capillary networks
Cell-laden constructs with a thickness larger than the diffusion
limit of oxygen suffer from inadequate nutrient supply and waste
removal and hence require microvascularization to avoid necrosis.
To this end, various approaches to templating microchannels within
hydrogels have been explored based on precisely deposited sacrificial
MEW fibers.
Ryma et al. (2022) reported a print-and-fuse strategy via MEW
of poly(2-cyclopropyl-2-oxazoline) (PcycloPrOx) to form
microchannels in various hydrogels, including gelatin-methacrylol
(GelMA), agarose, alginate, and gelatin. PcycloPrOx fibers
(87–275 µm diameter) were deposited as multilayered network
template, fused via water-induced plasticity, and subsequently
dissolved to result in bifurcating channels that follow Murray’s
law. A functional endothelial monolayer was obtained within
3 days by static seeding followed by fluid perfusion (Figures 1B,C).
Wang et al. (2020) embedded PCL MEW microfibers
(50–220 µm diameter) in poly(ethylene glycol) (PEG) hydrogels
as sacrificial channel templates. Dissolving the fibers with 90%
acetone resulted in the creation of microchannels, which were
then decorated with cell adhesion peptides to guide cell growth
into the channels. Physical removal of PCL microfibers embedded in
GelMA has also been shown, with the added benefit of obtaining a
perfusable channel network within a fiber-reinforced hydrogel when
fibers were selectively removed (Liu et al., 2023).
Nadernezhad et al. (2021) pioneered MEW of the water-soluble
sugar isomalt as a fugitive channel template (30–200 μm diameter)
in polydimethylsiloxane (PDMS) molds for microfluidic model
systems (Figure 1D).
A different approach to induce vascularization was undertaken
by Bertlein et al. (2018), who leveraged the preferential adhesion of
human umbilical vein endothelial cells (HUVECs) along PCL fibers
to provide initial orientation for the formation of capillary-like
structures in a fibronectin and gelatin matrix with HUVECs and
human dermal fibroblasts. When the pore size of the fibrous scaffold
exceeded 350 µm, additional neovascular-like structures formed
within 7 days to counteract the hypoxic conditions in the
pore center.
3 Cardiac patches
Cardiac patches are a promising strategy to restore myocardial
contractility of infarcted tissue. A clinically successful patch must
fulfill very stringent requirements: support the large multiaxial
strains of the myocardium, comply with its electroconductivity,
and provide the potential to deliver cells along with growth factors to
the host tissue. In this context, multiple MEW fiber architectures
have been investigated to profit from both cell guidance via
geometrical cues and a tunable mechanical structure-property
relationship.
Zhang et al. (2023) manufactured box-pore scaffolds (fiber
spacing 60–100 µm) from polylactic acid (PLA) and seeded them
with human induced pluripotent stem cell-derived cardiomyocytes
(iPSC-CM). The MEW scaffold guided the sarcomere formation
along its fibers, leading to ordered engineered tissues with
synchronous calcium transients.
Castilho et al. (2018) exploited the potential of hexagonal pore
scaffold designs for large elastic deformations. These hexagonal
scaffolds were able to undergo 35%–40% strain before plastic
deformation and to store elastic strain energy ≈20–40 times
higher than box-pore scaffolds. However, the hexagonal scaffolds
were still stiffer than native cardiac tissue (10–20 kPa at early
diastole and 200–500 kPa at late diastole) (Nakano et al., 1990).
After 7 days of culture of iPSC-CM encapsulated in a scaffold
consisting of collagen-based hydrogel combined with a MEW
mesh with hexagonal pores, synchronous contraction was
observed along with enhanced cell alignment and sarcomere
content, as well as an increase in cardiac maturation-related
markers when compared to boxed scaffolds. The patches
successfully recovered their shape after epicardial delivery on a
beating porcine heart via a catheter-like 1.5 mm diameter tube
owing to their superior elastic compliance (Figure 1E). In a follow-
up study, the MEW mesh was filled with two different hydrogels via
extrusion-based bioprinting: first, a myocardial bioink containing
iPSC-CM + human fetal cardiac fibroblasts (hfCFs) and second, a
vascular bioink with HUVECs + hfCFs that was patterned according
to the shape of the left anterior descending artery to serve as pre-
vascular pathway (Ainsworth et al., 2023). However, when straining
such hexagonal scaffolds in the axial direction, they suffer from
contraction in the transversal direction (Castilho et al., 2018).
Auxetic scaffold designs, such as a missing-rib model, are
characterized by a negative Poisson’s ratio and, therefore, allow
FIGURE 1 (Continued)
placement of the patch onto a porcine heart. (F) Auxetic scaffold design before (white PCL fibers) and after coating with electroconductive PPy
(black appearance). (B, C) Adapted with permission from Ryma et al. (2022), CC BY-NC 4.0. (D) Adapted with permission from Nadernezha d et al. (2021),
CC BY-NC 4.0. (E) Adapted with permission from Castilho et al. (2018), Wiley. (F) Adapted with permission from Olvera et al. (2020), Wiley.
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FIGURE 2
Vascular grafts and heart valves based on MEW scaffolds. (A) A bilayered heterotypic scaffold architecture consisting of electrospun nanofibers and
aligned MEW fibers. (B) While endothelial colony-forming cells (CD31
+
) were cultured on the luminal side of the graft, vSMCs (αSMC
+
) colonized the wall.
(C) Completely endothelialized electrospun lumen with (D) tight cell–cell connections (black arrows). (E) Nitric oxide (NO) production from endothelial
cells. (F) The MEW structures were covered by vSMCs, which (G) were oriented along the MEW fibers. (H) Microporous scaffold architecture that
supports efficient infiltration of smooth muscle cells (scale bars 500 µm, 100 µm, and 20 µm) and (I) enables tailored anisotropy. (J, K) The design strategy
can be translated to seamless tubular scaffolds and (L) used to produce covere d stents (scale bars 1 mm, inset 100 µm). (M) Aortic root model with sinuses
of Valsalva and a wall architecture inspired by the native collagen fiber distribution (scale bars 200 µm). (N, O) A serpentine fiber architecture with tunable
curvature degree enabled tailored mechanical properties. Compared to (P) box pore scaffolds, (Q, R) serpentine scaffolds outperformed in mimicking the
(Continued )
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large biaxial strains as needed for cardiac patches (Figure 1F)
(Olvera et al., 2020). Furthermore, by tuning the geometrical
features of the repeating cell unit, an anisotropy ratio of effective
stiffness close to that reported for human myocardium (1.9–3.9) was
obtained while still presenting sufficient elasticity (Engelmayr et al.,
2008;Montgomery et al., 2017;Neal et al., 2013;Park et al., 2011). In
the second step, these PCL scaffolds were coated with polypyrrole
(PPy) to result in an electroconductive, acellular patch.
Han et al. (2022) studied the efficacy of cardiac patches of co-
cultured rat aortic endothelial cells and cardiomyocytes in fibrin
reinforced by MEW scaffolds with stacked fiber walls oriented at 0°,
60°, and 120°. This fiber architecture was inspired by the transition of
cellular orientations within the thickness of the myocardium. In an
infarcted myocardium in vivo rat model, the patches increased the
survival to 90% compared to the control group (sham operation),
and improved myocardial contractile activity was shown via
M-mode echocardiographs.
Montero-Calle et al. (2022) built a computational model to
predict the evolution of cardiac patches by correlating cell alignment
and functional performance. Their model was informed by cardiac
minitissues consisting of iPSC-CM embedded in a hybrid matrix of
matrigel reinforced with a box-pore MEW scaffold. In agreement
with the model’s predictions, the minitissues displayed advanced
maturation and functionality after 28 days, together with a
substantial expression of cardiac genes.
4 Vascular grafts
Vascular grafts are an important tool of vascular surgery.
However, autologous grafts are not always available, and
synthetic ones perform poorly in small-diameter settings. Tissue-
engineered grafts that build on the MEW platform to provide
biomimetic solutions could help tackle this issue.
Jungst et al. (2019) presented an integral scaffold design (inner
diameter 3 mm) that permits the formation of an intraluminal
endothelial cell monolayer surrounded by an outer layer of oriented
vascular smooth muscle cells (vSMCs). This was enabled via a
bilayered tubular scaffold, comprising an inner layer of randomly
oriented electrospun fibers and an outer layer of melt-electrowritten
linear microfibers with controlled winding angle (Figure 2A). The
heterotypic architecture directed physiological cell organization
without the need for soluble factors or bioactivation of the
scaffold (Figures 2B–G). Building on this work, Bartolf-Kopp
et al. (2024) tuned the ratio of PCL to poly(ester-urethane)
during the electrospinning process step of the hybrid constructs
to recapitulate the natural J-shaped stress–strain response in native
vessels (Young’s modulus of 0.9 ± 0.7 kPa for the cell-seeded hybrid
scaffolds, 0.5 ± 0.6 kPa for the internal mammary artery (IMA)).
Federici et al. (2023) also investigated the effects of fiber winding
angle inspired by the extracellular matrix orientation in the tunica
media using a MEW scaffold alone. This biomimetic fiber
arrangement promoted neo-tissue formation along the MEW
fibers with extracellular matrix deposition preferentially oriented
along the pore’s long axis and enabled a biomimetic stress–strain
characteristic in the physiological range (up to 10% strain).
Following the in vivo tissue engineering approach, Zhi et al.
(2022) embedded melt-electrowritten tubular scaffolds
subcutaneously in rats to exploit the foreign body response
resulting in fibrous encapsulation. These biohybrid constructs
performed well in in vitro assessments and as abdominal artery
replacements in rats. Successful translation to larger animal models
(canines and sheep) underlines this as a promising approach for a
future alternative to autologous vessel replacements. While in these
studies (Bartolf-Kopp et al., 2024;Federici et al., 2023;Jungst et al.,
2019;Pickering et al., 2022;Zhi et al., 2022) the MEW fiber
architecture was a simple diamond 172 pattern, others reported
the design of tubular auxetic (Paxton et al., 2020a) and nonlinear
(McCosker et al., 2022) designs that could potentially allow for
combined longitudinal and radial growth. Also, serpentine fiber
patterns have been demonstrated to enable tubular scaffolds with
compliance of 12.9 ± 0.6% (100 mmHg)
−1
(Weekes et al., 2023),
which is the physiological range of the IMA, 11.5 ± 3.9%
(100 mmHg)
−1
(Konig et al., 2009). Performing the fiber
deposition process on patient-specific water-soluble polyvinyl
alcohol (PVA) molds will lead to further anatomically relevant
tubular constructs (Brooks-Richards et al., 2022).
MEW scaffolds have been mainly macroporous due to
entrapped charge carriers in the fibers that prevent accurate fiber
placement below a fiber diameter-dependent interfiber distance
(Ding et al., 2019;Kim et al., 2021;Tourlomousis et al., 2017).
Therefore, MEW scaffolds have been used as mechanical
reinforcement that must be combined with a secondary
biomaterial that provides the microporosity required for cellular
infiltration following the in situ TE paradigm. To overcome this,
Mueller et al. (2023b) developed a design strategy that results
directly in microporous MEW scaffolds and allows tailoring the
directional anisotropy to a wide range of cardiovascular tissues such
as the IMA and the aortic valve leaflets (Figures 2H–K).
Furthermore, this approach decouples fiber diameter from pore
size (in contrast to electrospinning, where they correlate) and can be
applied to both flat and tubular scaffold architectures. Also, covered
stents can be fabricated with this approach (Figure 2L). First
attempts towards purely melt-electrowritten stents were
fabricated from PCL mechanically reinforced with reduced
graphene oxide to increase their flexural stiffness (Somszor et al.,
2020). How the mechanical properties would evolve with
progressing PCL degradation remains to be investigated.
FIGURE 2 (Continued)
J-shaped stress–strain response of leaflet tissue. (S, T) Spatially heterogeneous scaffold with serpentine fiber architecture at the leaflets and
diamonds at the interleaflet triangles (scale bars 5 mm). (U, V) Composite construct after embedding the scaffold in an ELR hydrogel and suturing it into a
silicone aortic root (scale bars 5 mm). (W) Salt leaching/gas foaming technique resulted in micropores in the ELR hydrogel for in situ TE (scale bar 50 µm).
(A–G) Scale bars represent 100 µm unless otherwise stated. Adapted with permission from Jungst et al. (2019), CC BY-NC 4.0. (H–L) Adapted with
permission from Mueller et al. (2023b), CC BY-NC 4.0. (M) Adapted with permission from Saidy et al. (2020), CC BY 4.0. (N–R) Adapted with permission
from Saidy et al. (2019), Wiley. (S–W) Adapted with permission from Saidy et al. (2022), CC BY-NC-ND 4.0.
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Moving to larger vessel diameters, Saidy et al. (2020) presented a
melt-electrowritten aortic root featuring sinuses of Valsalva with a
triphasic fiber architecture inspired by the collagen fiber distribution
in the intima (50°), media (65°), and adventitia (40°)(Figure 2M). As
the aortic roots were also fabricated onto a 3D-printed target
obtained from the patient’s data, the scaffolds could potentially
be used in personalized external aortic root support (PEARS)
procedures.
5 Heart valves
Heart valves are characterized by mechanical anisotropy, a
nonlinear stress–strain relationship, viscoelasticity, and spatial
heterogeneity, and, therefore, they particularly benefit from the
capabilities of MEW for complex scaffold designs.
Inspired by the wavy collagen fibers in the extracellular matrix,
Saidy et al. (2019) fabricated scaffolds with a serpentine fiber
architecture to recapitulate the J-shaped stress–strain response of
native leaflet tissue (e.g., high tensile modulus 1 MPa (radial) and
5 MPa (circumferential) for the MEW scaffolds and 2.3 MPa (radial)
and 9.9 MPa (circumferential) for native aortic valve tissue (Pham
et al., 2017)) (Figures 2N–R). Tuning the curvature degree, interfiber
spacing, and layer number enabled tailored mechanical characteristics,
anisotropy, out-of-plane flexibility, and viscoelastic behavior closely
matching human tissue. The scaffolds’suitability for heart valve
engineering was tested by embedding them in fibrin and suturing
them as single leaflets to form a trileaflet valve in a silicone aortic root
model. The valve complied with ISO 5840 standards under aortic
conditions (International Organization for Standardization, 2021).
Similarly, Mirani et al. (2023) exploited computational modeling
and design of experiments to produce sinusoidal fiber patterns with
prescribed biaxial mechanics mimicking the tissue characteristics of an
adult aortic valve, a pediatric pulmonary valve, and the pediatric
pericardium. Embedding the MEW scaffolds in a cell-laden fibrin
hydrogel resulted in tissue sheets that were sutured into trileaflet valves
that performed well under pulmonary pressure conditions in a pulse
duplicator bioreactor (Mirani et al., 2023).
With the motivation of fabricating a tubular trileaflet valve,
Saidy et al. (2022) presented a spatially heterogeneous tubular
scaffold design that featured the established serpentine
architecture in the leaflet regions, while the interleaflet triangles
and annulus region showed a diamond architecture (±25°linear
fibers) to allow for diameter changes according to the dynamic
circulatory pressure conditions (Figures 2S,T). Subsequently, the
macroporous scaffolds were embedded in an elastin-like
recombinamer (ELR) hydrogel containing a porogen so that a
microporous composite for in situ TE was obtained by salt
leaching/gas foaming technique (Figures 2U–W). These valves
were sutured in a silicone aortic root using the single point
attachment commissure (SPAC) technique and were in
accordance with ISO 5840 requirements when tested in a flow-
loop system under aortic conditions.
Vernon et al. (2022) focused on interfaces in melt-electrowritten
heart valve scaffolds, specifically on the interleaflet triangle to leaflet
region. Compared to an overlapping or suture-like regional link, the
authors advocate for continuous fiber transitions and gradient
porosities, as this will result in superior tensile and flexural
properties while better mimicking the collagen orientation,
density, and recruitment in native valves.
This body of work impressively demonstrates the potential of
engineering heart valves based on MEW scaffolds.
6 Technological and material
advancements
Mimicking native tissues often requires scaffold design using
multiple scales and materials (Castilho et al., 2020). Therefore,
converging biofabrication techniques have led to the hybridization
of MEW with multiple technologies. Examples of hybrid MEW + X
approaches include those where MEW has been combined with
molding (Saidy et al., 2022;2019) and extrusion-based bioprinting
of hydrogels (Ainsworth et al., 2023;de Ruijter et al., 2019)tofill the
macropores of MEW scaffolds and to introduce cells as living
components. In other cases, MEW has been hybridized with
volumetric bioprinting (Größbacher et al., 2023), solution
electrospinning (Bartolf-Kopp et al., 2024;Jungst et al., 2019), and
melt electrospinning (Großhaus et al., 2020). Recently, translating the
electric-field driven fiber formation to the widely established filament-
based additive manufacturing technology (fused filament fabrication,
FFF) enabled the fabrication of multi-scale scaffolds by combining
macroscale FFF prints with microfibrous MEW scaffolds
manufactured by a single print head (Mueller et al., 2023a). This
approach also had the motivation of making MEW more accessible by
astraightforwardmodification of commercially available FFF printers.
Given the technological progress and increasing number of in
vivo studies with MEW scaffolds, clinical translation of MEW
products is within reach, yet it will be accompanied by the need
for high throughput fabrication with excellent quality. In this
context, MEW setups with multiple print heads working in
parallel (Wunner et al., 2019), in situ process monitoring (Collier
et al., 2022;Mieszczanek et al., 2021a) and, consequently, the ability
to self-correct process parameters based on machine learning
(Mieszczanek et al., 2021b) will be of great importance.
MEW is an AM technology and, as such, holds the potential to
produce highly complex, patient-specific scaffold geometries.
However, MEW is inherently bound to deposit the fibers onto a
collector, which limits design freedom and poses significant
challenges when depositing fibers on curving surfaces that stray
from a single plane of deposition (i.e., “out-of-plane”fiber
deposition). Recent attempts to perform MEW onto out-of-plane
geometries point to the difficulty of controlling process parameters
such as the electric field and the print speed on complex collector
geometries (Brooks-Richards et al., 2022;Luposchainsky et al., 2022;
Mueller et al., 2023a;O’Connell et al., 2021;Peiffer et al., 2020;Saha
et al., 2021;Saidy et al., 2020). Solving these challenges will require
specific advancements in both hardware and software components,
including versatile toolpath generators (Paxton et al., 2020b).
In parallel, the biomaterial library accessible to MEW is also quickly
expanding. In addition to PCL as the undoubted gold standard material,
researchers are introducing new polymers, composites, and bioactive
coatings for MEW scaffolds. This progress has been extensively
reviewed elsewhere (Kade and Dalton, 2021;Saiz et al., 2024).
Incorporating ultrasmall superparamagnetic iron oxide nanoparticles
as contrast agents into the PCL microfibers added the option for non-
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invasive magnetic resonance imaging of MEW scaffolds (Mueller
et al., 2021). This approach was further exploited by using metal-
organic frameworks (MOFs) as additives that can provide multiple
combined functions (Mansi et al., 2023). Like this, MEW scaffolds that
were simultaneously MRI visible, antimicrobial, and drug-loaded were
obtained with only one additive. Alternative approaches for
introducing imaging capabilities to MEW scaffolds exploited PCL
labeled with fluorophores or near-infrared region II dyes (Hall et al.,
2024;Jing et al., 2021).
Of particular interest for cardiovascular applications is the use of
the electroactive polymer poly(vinylidene fluoride) (PVDF) with
incorporated carbonyl iron particles, which offers the potential for
magnetoactive cell stimulation (Kade et al., 2022). Resistance against
bacterial infection and biofilm formation is particularly important
for successful clinical translation and has been tackled by loading
antibiotics (Bai et al., 2020;Mathew et al., 2023) or silver
nanoparticles (Du et al., 2022) into the polymers or by coating
calcium phosphate nanoparticles onto melt-electrowritten fibers
(Abdal-hay et al., 2023). Ainsworth et al. (2022) coated PCL
scaffolds covalently with TGF-β1 after (reagent-free) plasma
treatment to enhance hydrophilicity and enable cytokine loading
for improved tissue regeneration, while thiol and carbodiimide
chemistry was also used to conjugate peptides to MEW PCL
scaffolds (Mirzaei et al., 2023). Ryma et al. (2021) combined
flow-directed polymer phase separation during MEW with the
selective dissolution of the matrix polymer to obtain nanofiber
bundles with structural similarity to native collagen I from PCL/
poly(vinylacetate) blends. These fibrillar structures were capable of
highly efficient topographic immunomodulation. Furthermore, the
potential of drug-loaded MEW scaffolds was demonstrated with
water-soluble indomethacin loaded in a poly(2-oxazoline)-based
triblock copolymer for sublingual drug delivery (Keßler et al., 2022).
7 Conclusion
Given MEW’s capability for precise control over fiber diameter
and deposition, we see great potential to further drive TE research
towards functional regenerative implants by employing complex fiber-
based scaffold architectures with tailored properties and also
opportunities for future in vitro models. Vascular constructs have
been realized from the scale of capillary networks by exploiting
sacrificial MEW fibers embedded in various matrices to small-
diameter vascular grafts via tubular MEW constructs. Both cardiac
patches and heart valve scaffolds have been designed to exploit
application-specific structure-function relationships of MEW scaffolds.
Although a plethora of MEW scaffold microarchitectures have
been investigated, MEW has yet to demonstrate its full potential
toward complex scaffold macrogeometries, such as bifurcating
vessels and multicurvature heart valves. Reaching these
milestones will open new avenues for the development of a
broad range of tissues beyond the cardiovascular field. MEW is a
powerful technique that provides access to a previously unavailable
design space. Intriguing new opportunities are presented in this
review, including hybrid biofabrication approaches (i.e., MEW + X)
that synergistically provide novel solutions to achieve the ultimate
goal: improved therapies that benefit patients.
Author contributions
KM: conceptualization, data curation, investigation, methodology,
visualization, writing–original draft, writing–review and editing. SM:
writing–review and editing. ED-J-P: writing–review and editing. PM:
funding acquisition, project administration, resources, supervision,
writing–review and editing, conceptualization.
Funding
The author(s) declare that financial support was received for the
research, authorship, and/or publication of this article. This work
was supported by Deutsche Forschungsgemeinschaft (DFG) Grant
403170227 - ArchiTissue and by the TUM Innovation Network
project ARTEMIS of the Technical University of Munich.
Acknowledgments
The authors gratefully acknowledge the contribution of Paulina
Kraus to Figure 1.
Conflict of interest
ED-J-P is cofounder and director of CoraMetix Pty Ltd., which
holds two patent applications related to 3D-printed heart valves.
The remaining authors declare that the research was conducted
in the absence of any commercial or financial relationships that
could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board
member of Frontiers, at the time of submission.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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