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Fibrin-based Bioinks
3.2 Angiogenesis that causes the heterogeneity in local ECM
stiffness and changes in its bulk structure .
[72]
As mentioned above, fibrin has intrinsic Among the MMP variety, the MMP2, MMP9,
angiogenic properties and provides relevant and MT1-MMP are considered to play the most
microenvironment determined by structure- important role. In endothelial cells, VEGF, well-
depended chemical, physical, and biochemical known angiogenic factor, is proven to induce the
cues. Its fibrillar structure serves as a scaffold for MMP9 and MT1-MMP expression through Notch
invading cells which bind to its fibers through signaling that regulates cell morphogenesis . It
[73]
cellular receptors and form capillaries. It was was observed that initial stages of capillarogenesis
showed that the fiber network morphology can by endothelial cells corresponds with the rise of
be significantly influenced by fibrinogen and proenzyme proMMP-2 and drop of proMMP-9;
thrombin concentrations [65-67] , pH , buffers , however, MMP-2 was not revealed and MMP-9
[5]
[68]
incorporation of extra molecules , etc. was low . MT1-MMP was proven to regulate
[27]
[74]
On invading cells, receptors bind to specific vessel formation by both EC and MSC and more
sites on fibrin fibers that not only ensures cell strongly affected it than MMP-2 and MMP-9 [75,76] .
adhesion but also triggers various intracellular Interestingly, compared to fibroblast-assisted one,
pathways due to their biochemical interaction MSC-induced vessel formation is totally controlled
and formed tensional forces. Such cues determine by MT-MMP . Hence, by tuning fibrin gel
[77]
position-assisted cell response to the external properties through its modification that changes its
stimulation by cytokines and growth factors. The mechanical properties and degradability the tissue
cell adhesion to fibrin is mainly ensured by two engineers can significantly influence angiogenesis
arginylglycylaspartic acid (RGD) sites located on in vitro . Moreover, fibrin ensures the synthesis
[78]
the α-chain through integrins (αvβ3, α5β1, etc.). of extracellular matrix (ECM) proteins such as
Integrin αvβ3 and integrin α5β1 were proven laminin, and collagen type IV [66,79,80] that stabilizes
to control vacuolation and lumen formation by the formed microvasculature.
endothelial cells . Interestingly, the insertion of Angiogenesis can be also promoted by
[69]
additional selective binding sites for αvβ3 integrin fibrin degradation products. It was showed that
(the sixth immunoglobulin-like (Ig-like) domain of fibrin fragment E undergone thrombin-assisted
the cell adhesion molecule L1 (L1Ig6)) provided proteolytic cleavage led to the increase in the
the increase in vessel formation by them . Except endothelial cell proliferation, migration an
[68]
RGD sites, endothelial cells interact with β15–42 differentiation in vitro and in the vessel number
[81]
sequence of fibrin where VE-cadherin serves as while applied on the chorioallantoic membrane
a specific cell receptor . The adhesion of MSC (CAM) model .
[70]
[82]
used to stabilize the newly forming vessels and To increase its angiogenic properties, several
induce their formation is ensured through the structural modifications which can be divided
interaction with another type of integrins – α6β1 into two main groups: Inert or active substance
– to fibrin fibers [71]. loading/binding were offered. For instance, it was
However, in angiogenesis, fibrin is not a showed that the PEGylation of fibrin can ensure the
stable scaffold for migrating cells; it is a highly enhanced endothelial and mesenchymal stromal
responsive system that remodels providing the cells’ migration and spreading followed with the
required environment for forming vessels. Its formation of cell extensions and intercellular
degradation and remodeling are critical in the new junctions and expression of specific MMP [66,79] .
vessel formation and mainly orchestrated by matrix Moreover, compared to the native fibrin gel, the
metalloproteinases (MMP), including membrane- PEGylated fibrin promoted the increased growth
type MMP (MT-MMP). When cells migrate within rate, branching, and length of tubules formed by
a fibrin network, they degrade it facilitating their encapsulated spheroids from adipose-derived
invasion and making space for lumenogenesis MSC (Figure 1). However, the most trivial
[58]
32 International Journal of Bioprinting (2020)–Volume 6, Issue 3