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Fibrin-based Bioinks
bioprinting, and their development should ensure in hepatocytes and modulates gene expression
both precise deposition and tissue specificity. For through various transcription factors .
[13]
the last decade, there is a bioink boom, and the efforts
of many research teams focus on not inventing 2.2 Fibrinogenesis
new set-ups, but creating new bioink formulations. Fibrin formation from fibrinogen is one of the
New tissue-specific bioinks with good printability, essential steps in the enzymatic cascade of blood
shape fidelity, and biocompatibility can be based coagulation pathway to stop bleeding. This process
on “old” biomaterials. Among their huge variety, can be divided into two stages: Enzymatic and non-
fibrin is of particular interest. enzymatic. In the first stage, thrombin (Factor II)
Despite its long history of use, fibrin is still highly induces proteolytic cleavage and fibrinopeptide
in demand that is ensured by its unique properties. release from Aα and Bβ chains. Hence, two
Except its biocompatibility, it is biodegradable, polymerization regions, α and β, are formed
and the degradation products are not toxic. and spontaneously interact with complementary
Moreover, compared to other biomaterials, fibrin polymerization centers a- and b- in γC and βC
properties (fiber morphology, stability, mechanics, regions on the D knot of another fibrin monomer.
etc.) can be simply tuned by varying component This leads to the gradual formation of protofibrils.
concentrations, buffers, etc. [5-9] While the interest Protofibrils’ aggregation in lateral and longitudinal
in fibrin-based bioinks is constantly growing, it directions ensures the formation of fibers, which
is essential to provide a framework of material’ branch and form a fibrin network providing
properties and trends. This review focuses on structural stability [12,14] . Transglutaminase (Factor
describing the fibrin properties and application in XIIIa) stabilizes this fibrillar network.
3D bioprinting and providing a view on further
development of fibrin-based bioinks. 2.3 Fibrinolysis

2 Fibrin overview Fibrinolysis is controlled by various cofactors,
inhibitors, and receptors . The main enzyme
[15]
2.1 Classification and structure which lyses fibrin to fragments known as D-
[16]
Fibrin is a fibrillar protein formed from fibrinogen dimers is plasmin activated by plasminogen .
circulating in blood. It may have different origin Plasminogen is a physiological substrate for
and can be derived from salmon, bovine, porcine, two serine proteases, tissue-type plasminogen
and human blood plasma. Fibrinogen is an activator (tPA) and urokinase-type plasminogen
elongated dimeric glycoprotein (inactive fibrin activator (uPA). The first one is synthetized and
monomer) which consists of two-dimensional released by endothelial cells; the second one by
[17]
domains bound by a coiled-coil segment to the monocytes, macrophages, and urothelial cells .
central E domain. The fibrinogen molecule is Both activators have a short half-life period
formed by three polypeptide chains Aα, Bβ, and (4 – 8 min) because of high concentrations of
γ connected to each other in the N-terminal E inhibitors (e.g. plasminogen activator inhibitor-1
domain by disulfide bridges [10,11] . It is synthetized (PAI-1)) in blood plasma. Compared to tPA, uPA
by hepatocytes that makes the liver to be the has low affinity to plasminogen and does not
[12]
main source of fibrinogen. Fibrinogen is mostly require fibrin as a cofactor; normally, it functions
distributed in circulating blood plasma; however, in extravascular regions . Both tPA and uPA
[17]
it can also be found in platelets, lymph, and are eliminated by the liver after the formation of
interstitial fluid. Fibrinogen synthesis can be a complex with low density lipoprotein (LDL)-
stimulated by injury and/or inflammation which receptor-like protein . Moreover, fibrin can
[18]
causes a ten-fold increase in concentration . be easily lysed by other proteolytic enzymes,
[7]
Such activation is induced by interleukin-6 (IL-6) for example, proteinase K, collagenase, trypsin,
which triggers intercellular signaling pathways accutase, and metalloproteinases.

28 International Journal of Bioprinting (2020)–Volume 6, Issue 3