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Bopaya Bidanda
Paulo Jorge Bártolo Editors
Virtual
Prototyping & Bio
Manufacturing
in Medical
Applications
Second Edition
Virtual Prototyping & Bio Manufacturing
in Medical Applications
Bopaya Bidanda • Paulo Jorge Bártolo
Editors
This Springer imprint is published by the registered company Springer Nature Switzerland AG.
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
This book is dedicated to our parents
Lucilia Pinto Dias and Antonio Dias (late)
Neena and Monapa Bidanda (late)
Claudina Coelho da Rocha and Arlindo
Terreira Galha (late)
Maria Alice and Francisco Bartolo
And our families
Helena and Pedro
Louella, Maya, and Rahul
For their constant support throughout this
project
We are especially pleased to present the second edition of our edited book
in an area that is quickly emerging as one of the most active research areas
that integrates both engineering and medicine. Research in this area is growing
by leaps and bounds. Preliminary research results show significant potential in
effecting major breakthroughs ranging from a reduction in the number of corrective
surgeries needed to the “scientific miracle” of generating tissue growth. Billions
of dollars/euros/pounds have been invested in tissue engineering over the past
decade—a large and significant component of this is in the area of virtual and
physical prototyping. As a result, we have made significant changes to this edition
as you will see from our summary of chapters below.
Virtual and physical prototyping can broadly be divided into three categories:
modeling, manufacturing, and materials. This book focuses on the first part and
some areas of the second. The second book in this series will focus on the areas
in the second and third categories. As you will see from this book, the princi-
ples utilized draw heavily from the more traditional engineering fields including
mechanical engineering, industrial engineering, civil engineering (structures), and
bioengineering.
The first chapter by Ekinci et al. provides insights into the essentials and efficient
methods to design and fabricate optimal vascular network for tissue engineering.
The physiological considerations in design, the advantages, and in vitro studies of
the fabricated optimal vascular vessels are described and explored.
In Chap. 2, Ming Leu and his group of researchers review the use of virtual
reality technology for a virtual bone surgery simulation system, which can be used
for training in orthopedic surgery and planning of bone surgery procedures. Then,
they discuss the basic methods and techniques used to develop these systems.
Amorim et al. present fundamental aspects related to the generation and visu-
alization of models for three-dimensional printing in Chap. 3. Concepts including
medical imaging, preprocessing, segmentation, volume rendering, image data rep-
resentation, 3D printing, and biofabrication are present.
In Chap. 4, Naing et al. present a system of CAD structures based on convex
polyhedral for use with rapid prototyping (RP) technology in tissue engineering
vii
viii Preface
applications that allows the designer (given the unit cell and the required dimen-
sions) to automatically generate a structure that is suitable for the intended tissue
engineering application.
Scaffolds are key structures in tissue engineering as they provide an initial
biochemical substrate for the novel tissue until cells can produce their own
extracellular matrix. Therefore, scaffolds not only define the 3D space for the
formation of new tissues but also serve to provide tissues with appropriate functions.
Several techniques have been developed to produce scaffolds. In Chap. 5, Huang et
al. review the current state of the art of additive manufacturing techniques used
for tissue engineering. Different additive techniques are described, and their main
advantages and disadvantages are analyzed. Antman-Passig and Shefi, in Chap. 6,
present and describe the tissue engineering techniques and advanced fabrication
strategies for oriented scaffolds and nerve conduit for nerve repair.
Bioengineering strategies strongly depend on both material and manufacturing
processes. It is difficult for a single fabrication technique currently to meet
the requirements of all scale tissue regeneration. Many advanced biofabrication
techniques have been developed to produce tissue constructs with improved prop-
erties in both mechanical and biological aspects for broad biomedical engineering
applications. The seventh chapter by Aslan et al. reviews and discusses the use of
different developed electrospinning techniques and hybrid electrospinning and melt-
extrusion techniques to produce polymer and polymer composite nanofiber meshes
for skin repair and regeneration. In Chap. 8, Liu et al. describe and discuss different
types of bioprinting techniques and classify into three main categories: basic, semi-
hybrid, and fully hybrid additive systems. The main advantages and disadvantages
of the systems are analyzed.
In Chap. 9, Guardado and Cooper review the various attempts to use rapid
prototyping techniques to directly or indirectly produce scaffolds with a defined
architecture from various materials for intervertebral disc components, the nucleus
pulposus, and annulus fibrosus replacement.
In Chap. 10, Al-Tamimi et al. describe recent work on power bed fusion for
making tissue engineering metallic fixation implants. A general overview about the
fundamentals of bone characteristics, metallic biomaterials, and metallic powder
bed fusion techniques are provided as well as models of heat, mass, and momentum
transport phenomena associated with melting and solidification of metallic powders.
The chapter also provides in-depth information about powder bed fusion of titanium
and titanium alloys, cobalt-based alloys, and stainless steel for making bone tissue
engineering fixation implants. Examples of internal implants produced by EBM
or SLM discussing their mechanical and biological performance, stress shielding,
personalization, and the reduction of the total surgical procedure are presented.
The last chapter by Xu and Bártolo introduces the structure and the regeneration
process of the nerve tissue and explains the current strategies used to treat nerve
injury. A review on the current state of the art in the scaffold design requirements
and additive manufacturing techniques for nerve scaffold fabrication within the
tissue engineering context is provided. The techniques focus on the extrusion-
Preface ix
xi
xii Contents
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Chapter 1
Optimised Vascular Network for Skin
Tissue Engineering by Additive
Manufacturing
1.1 Introduction
Many clinical therapies utilise autologous and allografts to repair skin defects
resulting from genetic disorders, acute trauma, chronic wounds or surgical inter-
ventions. Tissue engineering (TE) of skin is an emerging technology that offers
many potential advantages in repairing skin defects over conventional autologous
grafts [1]. It overcomes the shortage of donor organs and reduces the added cost
and complications of tissue harvesting. Tissue-engineered skin can also be used
as a skin equivalent for pharmaceutical or cosmetics testing, eliminating the need
for animal testing [2]. A major issue in tissue engineering is that the artificial skin
may not develop adequate vascularisation for long-term survival [3]. An artificial
vascular system can be pre-embedded in a skin equivalent before it is implanted.
The embedded network has three primary functions: (1) to supply nutrients and
other soluble factors and to remove waste products from the surrounding cells,
(2) to act as scaffolds for culturing vascular endothelial cells and (3) to develop
A. Ekinci
Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough
University, Loughborough, UK
e-mail: [email protected]
X. Han ()
HNU College of Mechanical and Vehicle Engineering, Hunan University, Changsha, China
e-mail: [email protected]
R. Bibb
Design School, Loughborough University, Loughborough, UK
e-mail: [email protected]
R. Harris
Mechanical Engineering, University of Leeds, Leeds, UK
e-mail: [email protected]
small sprouting capillaries that can be connected with existing blood vessels, also
known as angiogenesis [1, 4–6]. Nutrition supply in the human body is realised by
a very complex blood vessel network. It consists of vessels in dimensions between
several millimetres down to several micrometres in diameter. To mimic the system,
flexible structuring processes are needed. Traditional manufacturing technologies,
such as spinning, dip-coating or extrusion, can produce linear tubes with different
inner-diameters [7]. However, it is not possible to generate branched vessels, with
decreasing or increasing internal diameters to mimic the natural changes in blood
vessel networks.
Additive manufacturing (AM) technologies have made it possible for the first
time to manufacture artificial blood vessels and their networks of any sophisticated
geometry and connections. With AM, three-dimensional (3D) objects can be
produced from 3D computer-aided design (CAD) data by joining materials together
using a layer-by-layer manner. There are many AM technologies classified as
bioprinting systems, based on microvalve deposition, ink-jetting, material extrusion
and stereolithography (SLA) techniques [8, 9]. SLA has advantages in 3D printing
microvascular vessel networks due to (1) its high resolution, (2) its ability to
produce flexible materials and (3) excellent process control. The use of these AM
technologies will enable the generation and mimicking of complex blood vessel
networks under controlled conditions. Currently, various research groups have
successfully 3D printed and tested such vascular vessels [4, 10–13]. Wu et al. [13]
used transient inks to print a solid template within the substrate and then removed
the ink to create microchannels. Hinton et al. [14] invented a freeform reversible
embedding of suspended hydrogels method (called FRESH in their paper) to
print hydrated materials that enable the printing of complex vascular architectures.
However, in their work, vascular networks were printed with little understanding of
the physiological demands. Therefore, general design guidance is missing. Design
parameters such as branch levels, a branching point, branch angles, vessel diameter,
the daughter vessel asymmetry ratio, wall shear stress (WSS) and recirculation areas
should be considered carefully in the design of vascular vessels. Based on these
parameters, this chapter presents guidance on the design optimisation of a vascular
network manufactured by SLA for skin tissue engineering.
Fig. 1.1 The macro-scale (a) and the micro-scale (b) parameter definitions [15]
In Fig. 1.1a, branch levels and branching point are illustrated, while Fig. 1.1b
demonstrates parent diameter Rp , daughter diameters Rd1 and Rd2 , total branching
angle, WSS and the recirculation areas.
Fig. 1.2 Distributed configuration of the vascular network with different branching levels: (a) 2
levels, (b) 3 levels, (c) 4 levels [15]
The WSS is a critical haemodynamic indicator that affects endothelial cell develop-
ment [17–20]. Many researchers have found that branching angles have a significant
effect on WSS in the bifurcation of a branch vessel [21–24]. The maximum
curvature of the junction is the most important factor that influences WSS. High
curvature also leads to stress concentration, which weakens the system mechanically
[18, 19, 25, 26]. The volume (V) of the junction is another important factor in
haemodynamics [27, 28]. A large volume leads to local recirculation of the blood
[27, 28]. Another physiological requirement at the micro-scale is to ensure minimal
recirculation areas where nutrient and oxygen may be trapped.
Design approaches to optimise a vascular network have been based on the minimi-
sation of the sum of the energy required for pumping blood through the network and
the energy required for the metabolic supply of the blood volume. To minimise the
energy, Murray’s law given in Eq. (1.1) is applied [29, 30]:
Rp3 = Rd1
3
+ Rd2
3
(1.1)
Using Murray’s law, the radii of daughter vessels (Rd1 and Rd2 ) can be obtained
based on the radius of their parent vessels (Rp ). It has been confirmed that most
natural vascular systems follow Murray’s law [31]. It is widely recognised that local
geometries of a vascular bifurcation, such as bifurcation angles, junction curvatures
and branching, are major features of the arterial system [20, 25].
The basic principle for a good junction design is therefore to ensure that the
volume of the junction remains in a desired narrow range while limiting the
maximum curvature. The exact range and limit depend on specific applications. Han
et al. [32] developed a mathematical model using parameters such as bifurcation
angles, and diameters of parent and daughter vessels. All the parameters in the
model influence the junction volume V and the maximum curvature Cmax . In their
paper, a systematic parametric study was carried out to establish a set of simple
design rules to achieve a balance between V and Cmax . A parametric map, which
can be used as a guide for designers, is provided based on the parametric study. The
parametric study shown in Fig. 1.4 calculated Cmax and V for bifurcation angle of
30◦ , 50◦ and 85◦ and more detailed information can be found in the study completed
by Han et al. [32].
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