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Optimized vascular network by stereolithography for tissue engineered skin

needs to develop adequate vascularisation for long-term critical hemodynamic indicator that affects endothelial
[3]
survival . Without a functional vascular network, the cell development [20–23] . WSS outside the normal
diffusion of oxygen is limited to a distance of 100–200 range between 1Pa to 7Pa [24] is considered harmful to
[4]
microns . This can be addressed by pre-embedding vessel development and may lead to cardiovascular
an artificial vascular network into the skin scaffolds. diseases [20,25,26] . Many researchers have found that the
The embedded network has two primary functions: branching angles have a significant effect on WSS
1) to supply nutrients and other soluble factors and in the bifurcation of a branch vessel [27–31] . Another
remove waste products from the surrounding cells and physiological requirement at the micro-scale is to ensure
2) to develop small sprouting capillaries that can be minimal recirculation areas where nutrient and oxygen
connected with existing blood vessels, also known as may be trapped. At the macro-scale, the main objective
angiogenesis [5-8] . Nutrition supply in the human body of the design is to maximise the nutrient supply and the
is realized by a very complex blood vessel network. waste exchange to surrounding tissues and cells. This
It consists of vessels in dimensions between several can be achieved in two ways: firstly, the blood resistance
millimetres down to several micrometres in diameter. needs to be minimized to use minimal energy supplying
To mimic this system, flexible structuring processes are surrounding cells; secondly, the artificial network needs
needed. Traditional manufacturing technologies, such to cover the greatest area of the skin patch to achieve
as spinning, dip-coating or extrusion, can produce linear a satisfactory and uniform nutrient supply. While
[9]
tubes with different inner-diameters . However, it is not the final design will be limited to a two-dimensional
possible to generate branched vessels, with decreasing geometry; it could be converted to enable 3D structures
or increasing internal diameters to mimic the natural by stacking repeated copies. The optimized vascular
changes in blood vessel networks. network will be then constructed using SLA. SLA has
With Additive Manufacturing (AM), three-dimensional advantages in printing micro vascular vessel networks
(3D) objects can be produced from 3D computer-aided due to 1) its high resolution, 2) its ability to produce
design (CAD) data by joining materials together using flexible materials and 3) its easy to control ability. The
a layer-by layer manner. It is been employed widely photocurable resin used in the project has advantages
in fabricating scaffolds and complete constructions of elasticity, biocompatibility and surface readiness for
for tissue engineering applications. There are many “bio-coatability”. Preliminarily physical validations
AM techniques served as bioprinting systems, such as were carried out in vitro to show that the optimised
microvalve-based, ink-jetting based, extrusion-based artificial vascular network can support cells in an adipose
and stereolithography (SLA)-based techniques [10,11] . The scaffold. Though further in vitro investigation is needed
use of these AM technologies will enable the generation to provide systematic results, the work presented in this
and mimicking of complex blood vessel networks under paper provides significant results to tissue engineering
controlled conditions. It offers the freedom to design a researchers. Together with previous studies, a complete
vascular network. Currently, some research groups have design methodology for 3D printing an artificial vascular
successfully constructed and tested branched vascular network has been fully developed and preliminarily
[14]
vessels [5,12–16] . Wu et al. used fugitive inks to print solid tested.
template within the substrate and then removed the ink to 2. Design Rules of Vascular Network
create microchannels. Hinton et al. [17] invented a freeform
reversible embedding of suspended hydrogels method Previous design approaches to optimise a vascular
(called FRESH in their paper) to print hydrated materials network have been based on the minimisation of the
which enable printing of complex vascular architectures. sum of the energy required for pumping blood through
However, in their work, vascular networks were printed the network and the energy required for the metabolic
with little understanding of the physiological demands. supply of the blood volume. To minimize the energy,
There is currently a lack of detailed and validated Murray’s law is applied [32,33] :
guidance for the design of artificial vascular networks of (1)
skin scaffolds. Using Murray’s law, the radii of daughter vessels
In our previous work [18,19] , a set of design rules were (Rd1 and Rd2) can be obtained based on the radius of
developed for designing one single artificial vascular their parent vessels (Rp). It has been confirmed that
[34]
branch made by 3D printing. This paper focuses on most natural vascular systems follow Murray’s law . A
further development of design rules for complex artificial volume minimisation routine was applied in the design
vascular networks based on multiscale physiological method to determine the position of the branching point.
demands. At the microscale, the local bifurcation design These technologies were used recently by researchers
needs to ensure that the shear stress on the vessel wall to generate different vascular systems [35,36] . However,
is in the healthy range. The wall shear stress (WSS) is a several issues were not considered in their research due

2 International Journal of Bioprinting (2018)–Volume 4, Issue 2