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Biomaterials
journal homepage: www.elsevier.com/locate/biomaterials
Review
Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha 2713, Qatar
Department of Mechanical Engineering, Faculty of Engineering and Architecture, American University of Beirut, Beirut 1107 2020, Lebanon
c
Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical
School, Cambridge, MA 02139, USA
d
BioMEMS and Bioinspired Microuidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, Canada
e
Center for BioEngineering Research and Education, University of Calgary, Calgary, Canada
f
Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California Berkeley, 208A Stanley Hall,
Berkeley, CA 94720-1762, USA
g
Physical Biosciences Division, Lawrence Berkeley National Lab, Berkeley, CA 94720, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2016
Received in revised form
26 June 2016
Accepted 1 July 2016
Available online 2 July 2016
Due to the increased morbidity and mortality resulting from heart valve diseases, there is a growing
demand for off-the-shelf implantable tissue engineered heart valves (TEHVs). Despite the signicant
progress in recent years in improving the design and performance of TEHV constructs, viable and
functional human implantable TEHV constructs have remained elusive. The recent advances in micro and
nanoscale technologies including the microfabrication, nano-microber based scaffolds preparation, 3D
cell encapsulated hydrogels preparation, microuidic, micro-bioreactors, nano-microscale biosensors as
well as the computational methods and models for simulation of biological tissues have increased the
potential for realizing viable, functional and implantable TEHV constructs. In this review, we aim to
present an overview of the importance and recent advances in micro and nano-scale technologies for the
development of TEHV constructs.
2016 Elsevier Ltd. All rights reserved.
Keywords:
Heart valves
Tissue engineering
Nanotechnologies
Microtechnologies
Scaffolds
Hydrogels
1. Introduction
Nearly 300,000 valve replacement surgeries are performed
every year due to heart valve diseases [1e3]. Replacement surgeries
are often required due to severe valve damages that render valve
repair not feasible. Replacements valves can be mechanical or
bioprosthetic, each having its set of severe limitations. Mechanical
valves may result in thrombosis or blood clotting and hence, they
require the patient to be on anti-blood clotting drugs for the rest of
their life. Bioprosthetic valves, on the other hand, lack longevity and
are known to calcify, which leads to stiffening and thickening of the
valve cusps and eventually insufcient closure, resulting in leakages. Additionally, these valves neither allow for somatic growth
nor remodeling after implantation. The lack of remodeling proves
to be a major problem for children as they would require repeated
replacements every few years to accommodate physical growth [4].
Tissue engineering promises to overcome these challenges and to
provide suitable replacement valves helping both growth and selfremodeling capabilities in vivo [5e10].
Various approaches have been developed to synthesize TEHVs
heart valves for clinical uses, including: 1) the use of regenerative
capability of the body (in-situ) to recruit circulating cells into
implanted decellularized or preshaped biodegradable synthetic
scaffolds, 2) hybrid approaches via modication of decellularized
scaffolds using biomaterials and hydrogels to improve cell seeding
onto scaffold, and 3) development of the valve substitutes in vitro
using prolonged tissue culture prior to implantation [11,12]. The
method of generating implantable TEHVs starts with seeding
appropriate cells on biodegradable scaffolds and culturing them
under appropriate environmental cues in bioreactors, controlling
279
The aortic and pulmonary valves are composed of three semilunar leaets (or cusps) along with sinus complexes called valve
roots as shown in Fig. 1(b) and (c). These valve leaets are
composed of four main components, namely the commissural region, the belly of the leaets, the lannula with the noduli of Arantii,
and the coapting surface [20]. The leaets are thin, exible and trilayered structures that are composed of collagen, elastin, and glycosaminoglycans (GAGs). The three sublayers are the brosa, the
spongiosa, and the ventricularis [21], as shown in Fig. 1(d). The
intricate structure of the valves results in strong mechanical
properties necessary to withstand the high trans-valvular pressures, and the low exural stiffness required for regular valve
operation. The annulus of the heart valves consists of a dense
elastin and collagen meshwork. The collagenous bers in the
corrugated brosa layer are shown in Fig. 1(e) [20].
The thickest layer, the brosa, consists mainly of a dense
network of corrugated type-I collagen bers arranged in the
circumferential direction. The highly organized collagen of the
brosa provides the primary load-bearing properties of the heart
valve [20]. The collagen bers form sheets in the brosa which
allows expansion of the leaet during closure of the heart valve
[24]. The middle layer, the spongiosa, is composed of highly hydrated GAGs and proteoglycans (PGs) as well as loosely arranged
collagen and elastin. The spongiosa acts as a cushion between the
brosa and the ventricularis and enables shearing between the two
layers during loading and unloading, and absorb the load by
transferring it to the elastic aortic wall, resulting in minimal stress
on the leaet itself. In addition, the tissue is nearly incompressible
due to the physical properties of bound water molecules that
comprise almost 70% of the natural weight. It is believed that the
viscoelastic and mechanical-force damping properties of the tissue
is due to water retained by GAGs [25].
Below the inow surface is the thinnest layer, the ventricularis,
which is comprised of a dense network of collagen bers and
elastin sheets, Fig. 1(d) and (e). The collagen in ventricularis is less
Fig. 1. Heart valve structure and composition: a) structure of heart valves, the schematics of the 2D position of the four valves on valvular basal plane of heart where P: pulmonary
valve, AO: aortic valve, M: mitral valve, and T: tricuspid valve, bee) Composition of the heart valves: b) the schematic cross section of an aortic valve leaet, c) histology of the cross
section of a valve leaet showing the three main layers, brosa, spongiosa and ventricularis, d) The schematic of the elastin and collagen microstructures in different layers during
systolic and diastolic cycles, e) Arrangement of collagen bers as well as distribution of elastin and GAG's. Figures adapted and reprinted from Ref. [6,22,23], with permissions from
the Royal Society of Chemistry and Elsevier Science.
280
281
Fig. 2. Tissue engineering of heart valves: In-situ, in vitro, and hybrid approaches: a) Macroscopic picture of cell-populated (i), mesenchymal stem cells (MSCs) differentiation and
reseeding of in-situ TEHV. MSCs were differentiated into osteogenic (red) and chondrogenic (blue) cell lineages (ii), b) Photographs of decellularized whole rat heart included heart
valves (i). Staining of MHC, vWF, and connexin-43 showing small channels and gap junctions in recellularized heart (ii and iiii), c) The engineered hybrid leaet with stainless with
steel mesh core (left), and Nitinol mesh embedded within layers of cells (right). Fig (a) is reproduced from Ref. [41] and (c) from Ref. [51] with permission from Elsevier Science, and
(b) from Ref. [57] with permission from Nature Publishing Group. (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this
article.)
282
Table 1
Summary of the major natural and synthetic polymers used to develop heart valves.
Biodegradable
electrospun bers
Model system
Ref
Chitosan
[67]
PGA:PLLA
Pulmonary valve
PEUU
Cardiovascular
tissue sheet
transannular patch
Scaffold reinforced with chitosan bers offered biocompatibility and enhanced mechanical properties,
but were weaker compared to native valve leaets
Scaffold provided mechanical support for cells and allows deposition of ECM but loses mechanical
integrity
Achieved high cell density by concurrent electrospraying of cells and electrospinning of PEUU polymer
Patch completely degraded and was replaced with a viable endothelialized tissue and ECM. The
substituted tissue showed low brosis, low calcications and no thrombus
Tri-layered scaffold supported cell growth, ECM deposition, and anisotropic mechanical properties
[72]
PDO
[40]
[71]
PGS/PCL
Tri-layered scaffold
for heart valves
Cell-seeded hydrogels
Model system
Ref
Fibrin gel
Trileaet and
bileaet valves
Vi-layered scaffold
Aortic heart
valve leaet
Heart valve leaet
Native aortic valve-like geometry and aligned patterns but poor mechanical properties
[68]
Anisotropic bending of the scaffold and control over the cell distribution throughout the scaffold
Biocompatible, easily modied physical properties, and induced elastin synthesis
[77]
[59]
High biostability and resistance to platelet adhesion for use as TEHV material
[66]
Collagen, elastin
Hyaluronan gel
POSS-PCU
[74]
283
Fig. 3. Micro and nano-technologies for tissue engineering of the heart valves, a) Porous chitosan tri-leaet heart valve scaffold including chitosan hydrogel ber, b) SEM image of
VICs and VECs on electrospun scaffolds, c) The brin-based valves with exible tissue consist of three leaets continuous with a conduit wall, d) Microstructures of the fabricated
PGS scaffold with and without aligned brous layer and the cross-section of tri-layered scaffolds comprised of a PGS layer and bers. Fig (a) is reproduced from Ref. [67], (b) from
Ref. [73], (c) from Ref. [15], and (d) from Ref. [74] with permission from Elsevier Science.
284
Fig. 4. Application of micro and nano-composites and gene delivery techniques for the synthesis of TEHVs. Examples of TEHVs: a) Fibrin-based bi-leaet valve construct after one
month incubation, with cusp-like leaets attached to a cylindrical root, b) Bioprinting a heart valve conduit with the encapsulation of HAVIC within the leaets after 7-day incubation in culture tube, c) The prototype of POSSePCU nanocomposite heart valve, d) Adenovirus-encapsulated bers for the controlled gene delivery in tissue engineered
scaffolds, e) Heart valve leaet gene delivery using polyurethane (PU) pulmonary replacement cusps with antibody-tethered AdGFP. Fig (a) is reproduced from Ref. [68] with
permission from Mary Ann Liebert. Fig (b) is reproduced from Ref. [90], (c) from Ref. [83], (d) from Ref. [91] with permission from Elsevier Science. Fig (e) is reproduced from
Ref. [92] with permission from Nature Publishing Group.
were used to fabricate tri-leaet heart valve leaet with a high cell
viability and matrix remodeling ability [97]. 3D printing was also
used to print aortic valve PEG-DA scaffolds seeded with interstitial
cells and cultured for up to 21 days with 100% cells viability [98].
Synthetic living alginate/gelatin hydrogel-based valve conduits
were developed with anatomical architecture and incorporation of
dual cell types of aortic root sinus smooth muscle cells (SMCs) and
aortic leaet VICs. Aortic valve conduits were successfully bioprinted with direct encapsulation of SMC in the valve root and VIC
in the leaets, resulted in 3D heart valves made by self-assembly of
cell types constituting the valve [97]. Despite a slight drop in the
ultimate strength and peak strain of 3D bioprinted hydrogel in 7
days culture, the tensile biomechanical properties were preserved,
and a robust living tri-leaet heart valve with multiple cell populations, high cell viability, and reasonable phenotypes in culture
was developed. The cells used in bioprinted cell-laden hydrogels
need a better migration into the inner structure of the polymeric
layer [99]. In spite of potential application of bioprinting approaches for the synthesis of TEHVs, the applicability of printable
and biocompatible hydrogel materials and certainty on human
valve's cell response under heavy biomechanical loading are still
questionable. The achievement of anisotropic mechanical properties of native valve is a challenge for 3D bioprinting techniques.
However, the combination of 3D bioprinters and electrospinning
has a unique advantage to improve the anisotropy of 3D hydrogels.
The fabrication of alternative layers of electrospun PCL and
chondrocyte-laden brin/collagen hydrogel layer is an example of
using this combinatory technique [100].
4.3. Gene delivery, growth factors, and biomolecules in HVTE
Micro and nano-technologies can play signicant roles to the
synthesis of TEHVs in many ways including controlled delivery of
growth factors as well as gene therapy for regaining functional
heart valve tissues.
285
used to coat the decellularized aortic heart valves with the purpose
of acting as antithrombotic agent, whereas a-SMA expression using
growth factor-h1 (TGF-h1) on valvular interstitial cells induced the
migration of endothelial progenitor cells on decellularized valves
[89].
The modication of nanoscale morphology of the scaffold surface increases the surface area to volume and provides nanoscale
drug carrier coatings for the use in TEHVs [90]. Also a majority of
TEHVs perform satisfactorily within an in vitro microenvironment,
but they do not depict a strong function upon implantation.
Microfabricated organ-on-chip technology has recently been
introduced to provide platforms for modeling the in vivo microenvironment of different organs and particularly to assess the inuence of drugs, genes, and biomolecules on the function of cells
and tissues. Microuidics was used to provide a pulsatile ow of
physiologic systole and diastolic phase within bioreactors and to
supply transvalvular pressure and ow conditions [183]. Cells
seeded within a microuidic bioreactor for the synthesis of a trileaet construct showed an improved cell proliferation, ECM synthesis, and led to enhanced tensile properties with respect to the
native pulmonary valves [184]. Also a microuidic-based heart
valve-on-chip was developed to investigate the impact of shear
stress-regulated paracrine interactions between VECs and VICs as
well as studying the diverse aspects of gene delivery mechanism
and vascular/valvular biology for modeling the in vivo performance
of heart valves [185].
5. Application of computational modeling in heart valve
tissue engineering
The recent advances in high-performance computing and
noninvasive imaging have made possible the numerical simulation
of complex biological systems, such as heart valves. As a result,
researchers have gained a better understanding of the heart valves'
biomechanics via designing effective prosthetic valves, and developing novel diagnostic tools, treatment modalities, and surgical
procedures for heart valve diseases [186e188].
Despite the ubiquity of computation in many disciplines, its
application in tissue engineering is still relatively nascent
[189e192], particularly for heart valves. This is partly due to a fast
progress in technologies that have outpaced computational
research. Numerical simulations (referred herein as simulation) of
biological systems, whether at the organ, tissue, cellular or molecular scales, can be extremely computationally intensive. Therefore, development of techniques that take advantage of modern
hardware are required both at the algorithmic and scientic levels
(e.g., novel mathematical formulations).
Simulation of tissue-engineered heart valves as a complement
to the experimental models can be categorized as 1) macroscale
computation and 2) molecular/nanomicroscale computation. The
former is concerned with the mechanical, thermal, and electrical
properties of valve tissues, whereas the latter is concerned with
properties and composition of valve tissues at the micro and nanostructure level [193]. Continuum modeling (nite element analysis
(FEA) [194], computational uid dynamics (CFD) [195]), and molecular dynamics (MD)-based models are the models typically used
in these simulations [196].
5.1. Macroscale modeling: tissue mechanical properties and design/
evaluation of bioprosthetic valves
Macroscale models of heart valves in general use uid-structure
interaction (FSI), which have been developed extensively over the
years for heart valve systems [197] and applied to bioprosthetic
valves [198e204]. Such models allow researchers to simulate
286
287
Fig. 5. Computational modeling of TEHVs, a) Representative volume element (RVE) of valve tissue [225], b) RVE of scaffold model [229], c) Leaet stresses with ber orientation of
engineered tissue with orthotropic scaffold [230], d) Nanoscale poroelastic indentation. Fig (a) is reproduced from Ref. [225] with permission from American Society of Mechanical
Engineering. Fig (b) is reproduced from Ref. [229], (c) from Ref. [230], (d) from Ref. [230] with permission from Elsevier Science.
respect to the decellularized tissues given the fact that they are
synthesized from materials that are essential for cell adhesion and
function with minimally induced immune response. However,
technological restrains in fabrication of 3D biomimetic scaffolds
limits their translation to the clinical use. There are evident challenges associated with the storage and establishment of quality
control standards. Incorporation of bioactive materials for the
controlled recruitment of cells and regulating the biochemical
properties of ECM can also lead to new challenges for biosafety,
inammation, thrombosis, angiogenesis, and efcacy performance.
A key strategy for the TEHVs studies should be identifying specic
signaling pathways that are able to regulate post-infarction
inammation, limit scaffold degradation, and manage tissue
remodeling and scarring.
When considering tissue-engineering applications, it is of
utmost importance to consider the micro and nanoscale mechanics
and features. Even with the rapidly increasing technology, experimentation at the micro-and nanoscales is costly, difcult, and often
impractical. Computational techniques provide a very powerful
method to circumvent these limitations. Although the high cost and
unavailability of fresh human heart valves is an obstacle in
obtaining extensive biomechanical data of heart valves, a combined
experimental-computational modeling approach can provide
extensive insights into structure-biomechanical response relationships from a small number of heart valve samples. Specifically, extensive parametric studies using computational models
that have been validated against simple experimental test data will
288
7. Conclusion
Tissue-engineered heart valves are currently the sole technology to create physiologically relevant tissues analogous to native
human valves with fewer side effects and longer sustainability for
future valve replacement. The challenges of strength and durability
under hemodynamic mechanical loading and rejection of explanted valves due to the inammatory response of host tissue are the
bottleneck of these engineering heart valves and yet to be tackled.
In this review, we addressed the advantages of micro and nanotechnology for self-organizing the cells behavior according to the
guidance cues provided by the ECM and for recapitulating the
structure and function of in vitro and in-situ tissue engineered heart
valves. Micro and nano-technologies have signicantly helped to
engineer topography of scaffolds, delivery of molecules and cells to
the specic site of tissues, and complex geometries and multidirectional anisotropic properties of valve scaffolds. This technology can be further linked to novel bioreactors to advance biomechanical properties of engineered valves as a key step for
translating the TEHVs to implantable valves, speeding up the process of treatment and allowing patients to receive cardiac
treatment.
Selection of appropriate scaffolds, choice of cell seeding method,
understanding remodeling of the scaffold seeded with cells, design
of biomimetic bioreactors for process conditioning and testing
synthesized valves for further scale-up operation, incorporation of
effective anti-inammatory drugs modulating the immune
response, and adjustment of waiting time for seeding the cells onto
scaffolds to provide of the shelf TEHVs, accommodating patientto-patient heterogeneity via considering the design aspects, and
predicting function of explanted valves as early as possible are
critical future steps for successful development of long-lasting, selfrepairing, functional, and implantable heart valves.
Acknowledgement
The authors acknowledge the Natural Sciences and Engineering
Research of Canada, NPRP9-144-3-021 from Qatar Foundation,
QUUG-CENG-MIE-15/16-7 and QUST-CENG-FALL-15/16-20 from
Qatar University, the Farouk Jabre interdisciplinary research award
from American University of Beirut, and the CNRS grant from National Council for Scientic Research, Lebanon, for the support for
this paper.
References
[1] D.T. Simionescu, J. Chen, M. Jaeggli, B. Wang, J. Liao, Form follows function:
advances in trilayered structure replication for aortic heart valve tissue engineering, J. Healthc. Eng. 3 (2012) 179e202.
[2] M.K.S. Loftin, Y.W. Chun, A. Khademhosseini, W.D. Merryman, EMT-inducing
biomaterials for heart valve engineering: taking cues from developmental
biology, J. Cardiovasc. Trans. Res. 4 (2011) 658e671.
[3] M.H. Yacoub, J.J.M. Takkenberg, Will heart valve tissue engineering change
the world? Nat. Clin. Pract. Cardiovasc. Med. 2 (2005) 60e61.
[4] J.M. Reimer, Z.H. Syedain, B.H. Haynie, R.T. Tranquillo, Pediatric tubular
pulmonary heart valve from decellularized engineered tissue tubes, Biomaterials 62 (2015) 88e94.
[5] C.A. Durst, M.P. Cuchiara, E.G. Manseld, J.L. West, K.J. Grande-Allen, Flexural
characterization of cell encapsulated PEGDA hydrogels with applications for
tissue engineered heart valves, Acta Biomater. 7 (2011) 2467e2476.
[6] I. Vesely, Heart valve tissue engineering, Circulat. Res. 97 (2005) 743e755.
[7] A. Khademhosseini, J.P. Vacanti, R. Langer, Progress in tissue engineering, Sci.
Am. Mag. 2009 (May 2009).
[8] Y. Du, E. Lo, S. Ali, A. Khademhosseini, Directed assembly of cell-laden
microgels for fabrication of 3D tissue constructs, PNAS 105 (2008)
9522e9527.
[9] T.C. Flanagan, A. Pandit, Living articial heart valve alternatives: a review,
Eur. Cells Mater. 6 (2003) 28e45.
[10] R. Gauvin, M. Guillemette, R. Langer, A. Khademhosseini, Emerging trends in
tissue engineering, in: Zhanfeng Cui (Ed.), Comprehensive Biotechnology,
Elsevier Ltd, 2011.
n, A. Driessen-Mol, C. Bouten, F. Baaijens, J.L. de la
[11] D. MacGrogan, G. Luxa
Pompa, How to make a heart valve: from embryonic development to
bioengineering of living valve substitutes, Cold Spring Harb. Perspect. Med. 4
(2014) a013912.
[12] C.V. Bouten, A. Driessen-Mol, F.P. Baaijens, In situ heart valve tissue engineering: simple devices, smart materials, complex knowledge, Expert Rev.
Med. Devices 9 (2012) 453e455.
[13] N.J.B. Driessen, A. Mol, C.V.C. Bouten, F.P.T. Baaijens, Modeling the mechanics
of tissue-engineered human heart valve leaets, J. Biomech. 40 (2007)
325e334.
[14] J.-H. Chen, C.A. Simmons, Cellematrix interactions in the pathobiology of
calcic aortic valve disease critical roles for matricellular, matricrine, and
matrix mechanics cues, Circulat. Res. 108 (2011) 1510e1524.
[15] T.C. Flanagan, C. Cornelissen, S. Koch, B. Tschoeke, J.S. Sachweh, T. SchmitzRode, et al., The in vitro development of autologous brin-based tissueengineered heart valves through optimised dynamic conditioning, Biomaterials 28 (2007) 3388e3397.
[16] H. Hong, N. Dong, J. Shi, S. Chen, C. Guo, P. Hu, et al., Fabrication of a novel
hybrid scaffold for tissue engineered heart valve, J. Huazhong Univ. Sci.
Technol. Med. Sci. 29 (2009) 599e603.
[17] P.M. Dohmen, W. Konertz, Tissue-engineered heart valve scaffolds, Ann.
Thorac. Cardiovasc. Surg. Off. J. Assoc. Thorac. Cardiovasc. Surg. Asia 15
(2009) 362e367.
[18] M. Van Lieshout, C. Vaz, M. Rutten, G. Peters, F. Baaijens, Electrospinning
versus knitting: two scaffolds for tissue engineering of the aortic valve,
J. Biomaterials Sci. Polym. Ed. 17 (2006) 77e89.
[19] H. Onoe, T. Okitsu, A. Itou, M. Kato-Negishi, R. Gojo, D. Kiriya, et al., Metrelong cell-laden microbres exhibit tissue morphologies and functions, Nat.
Mater. 12 (2013) 584e590.
[20] M. Misfeld, H.H. Sievers, Heart valve macro- and microstructure, Philos.
Trans. R. Soc. B Biol. Sci. 362 (2007) 1421e1436.
[21] M.A.J. Cox, Local Mechanical Properties of Tissue Engineered Heart Valves,
Technische Universiteit Eindhoven/Eindhoven University of Technology,
2009.
[22] E.O. Carew, J. Patel, A. Garg, P. Houghtaling, E. Blackstone, I. Vesely, Effect of
specimen size and aspect ratio on the tensile properties of porcine aortic
valve tissues, Ann. Biomed. Eng. 31 (2003) 526e535.
[23] J.T. Butcher, G.J. Mahler, L.A. Hockaday, Aortic valve disease and treatment:
the need for naturally engineered solutions, Adv. Drug Deliv. Rev. 63 (2011)
242e268.
[24] T.C. Flanagan, A. Pandit, Living articial heart valve alternatives: a review,
Eur. Cells Mater. 6 (2003) 28e45.
[25] M.S. Sacks, W.D. Merryman, D.E. Schmidt, On the biomechanics of heart
valve function, J. Biomech. 42 (2009) 1804e1824.
289
290
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]
[111]
[112]
291
292
[195] C. Hirsch, Numerical Computation of Internal and External Flows: the Fundamentals of Computational Fluid Dynamics: the Fundamentals of Computational Fluid Dynamics, Butterworth-Heinemann, 2007.
[196] K. Burke, J. Werschnik, E. Gross, Time-dependent density functional theory:
past, present, and future, J. Chem. Phys. 123 (2005) 062206.
[197] S.C. Vigmostad, H.S. Udaykumar, J. Lu, K.B. Chandran, Fluid-structure interaction methods in biological ows with special emphasis on heart valve
dynamics, Int. J. Numer. Methods Biomed. Eng. 26 (2010) 435e470.
[198] R. Haj-Ali, L.P. Dasi, H.S. Kim, J. Choi, H.W. Leo, A.P. Yoganathan, Structural
simulations of prosthetic tri-leaet aortic heart valves, J. Biomech. 41 (2008)
1510e1519.
[199] G. Querzoli, S. Fortini, A. Cenedese, Effect of the prosthetic mitral valve on
vortex dynamics and turbulence of the left ventricular ow, Phys. Fluids 22
(2010) 041901.
[200] W. Sun, K. Li, E. Sirois, Simulated elliptical bioprosthetic valve deformation:
implications for asymmetric transcatheter valve deployment, J. Biomech. 43
(2010) 3085e3090.
[201] M.D. de Tullio, G. Pascazio, L. Weltert, R. De Paulis, R. Verzicco, Evaluation of
prosthetic-valved devices by means of numerical simulations, Philos. Trans.
Ser. A Math. Phys. Eng. Sci. 369 (2011) 2502e2509.
[202] T.B. Le, F. Sotiropoulos, Fluid-structure interaction of an aortic heart valve
prosthesis driven by an animated anatomic left ventricle, J. Comput. Phys.
244 (2013) 41e62.
[203] C. Capelli, G. Biglino, L. Petrini, F. Migliavacca, D. Cosentino, P. Bonhoeffer, et
al., Finite element strategies to satisfy clinical and engineering requirements
in the eld of percutaneous valves, Ann. Biomed. Eng. 40 (2012) 2663e2673.
[204] C. Guivier-Curien, V. Deplano, E. Bertrand, Validation of a numerical 3-D
uid-structure interaction model for a prosthetic valve based on experimental PIV measurements, Med. Eng. Phys. 31 (2009) 986e993.
[205] C. Martin, W. Sun, Simulation of long-term fatigue damage in bioprosthetic
heart valves: effects of leaet and stent elastic properties, Biomech. Model.
Mechanobiol. 13 (2014) 759e770.
[206] F. Sotiropoulos, I. Borazjani, A review of state-of-the-art numerical methods
for simulating ow through mechanical heart valves, Med. Biol. Eng. Comput. 47 (2009) 245e256.
[207] D. Bluestein, Y. Li, I. Krukenkamp, Free emboli formation in the wake of bileaet mechanical heart valves and the effects of implantation techniques,
J. Biomech. 35 (2002) 1533e1540.
[208] D. Bluestein, E. Rambod, M. Gharib, Vortex shedding as a mechanism for free
emboli formation in mechanical heart valves, J. Biomech. Eng. 122 (2000)
125e134.
[209] M.S. Sacks, A. Mirnaja, W. Sun, P. Schmidt, Bioprosthetic Heart Valve Heterograft Biomaterials: Structure, Mechanical Behavior and Computational
Simulation, 2006.
[210] Y. Alemu, D. Bluestein, Flow-induced platelet activation and damage accumulation in a mechanical heart valve: numerical studies, Artif. Organs 31
(2007) 677e688.
[211] U. Morbiducci, R. Ponzini, M. Nobili, D. Massai, F.M. Montevecchi,
D. Bluestein, et al., Blood damage safety of prosthetic heart valves. Shearinduced platelet activation and local ow dynamics: a uid-structure
interaction approach, J. Biomech. 42 (2009) 1952e1960.
[212] S. Shahriari, H. Maleki, I. Hassan, L. Kadem, Evaluation of shear stress accumulation on blood components in normal and dysfunctional bileaet mechanical heart valves using smoothed particle hydrodynamics, J. Biomech. 45
(2012) 2637e2644.
[213] M.S. Sacks, Incorporation of experimentally-derived ber orientation into a
structural constitutive model for planar collagenous tissues, J. Biomech. Eng.
125 (2003) 280e287.
[214] J.L. Tan, J. Tien, D.M. Pirone, D.S. Gray, K. Bhadriraju, C.S. Chen, Cells lying on a
bed of microneedles: an approach to isolate mechanical force, Proc. Natl.
Acad. Sci. 100 (2003) 1484e1489.
[215] D. Vader, A. Kabla, D. Weitz, L. Mahadevan, Strain-induced alignment in
collagen gels, PLoS One 4 (2009) e5902.
[216] Z. Yang, J.-S. Lin, J. Chen, J.H. Wang, Determining substrate displacement and
cell traction eldsda new approach, J. Theor. Biol. 242 (2006) 607e616.
[217] J. Friedrichs, A. Taubenberger, C.M. Franz, D.J. Muller, Cellular remodelling of
individual collagen brils visualized by time-lapse AFM, J. Mol. Biol. 372
(2007) 594e607.
[218] N.J. Driessen, M.A. Cox, C.V. Bouten, F.P. Baaijens, Remodelling of the angular
collagen ber distribution in cardiovascular tissues, Biomech. Model.