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Fibrin-based Bioinks
The main parameter that controls the gel potential are physiologically determined, and it is not
stiffness appears to be fibrinogen concentration. surprising that fibrin is widely applied in vascular
By varying it in a range from 1 to 50 mg/mL, tissue engineering and improvement of wound
the elastic modulus of the resulted gel from healing.
several Pa to several hundred Pa might be Due to its tunable properties that can guide
achieved [27-29] . Another important modulator is cells and determine substance release kinetics,
Factor XIII, its addition substantially increases fibrin is commonly used in skin equivalent
the elastic modulus of the gel by incorporating design or cell/bioactive substance delivery
fibrin covalent crosslinking and compacting for the defect site treatment [40] . Even only by
fibers . The cell embedded into the gel might also adjusting, for example, its mechanical properties,
[6]
induce its stiffening through myosin-driven cell one can tailor its biological properties. For
contraction . instance, Murphy et al. [41] varied the component
[30]
The low viscosity of pure fibrinogen solution concentrations to reveal their correlation with
makes it suitable for inkjet bioprinting methods . gel stiffness, degradation rate, and vascular
[31]
However, shape fidelity and mechanical properties endothelial growth factor (VEGF), and
of such gels are relatively poor. Due to irreversible prostaglandin (PGE2) secretion by encapsulated
and fast fibrin gelation at physiological mesenchymal stromal cell (MSC) spheroids.
temperatures, bioprinting with fibrinogen/ They showed that the secretion of both factors
thrombin mixture might be performed at low was the highest in hydrogels with medium values
temperatures, or thrombin can be added to the of compressive and storage moduli.
construct after bioprinting . The gelated fibrin To improve its innate healing potential, fibrin can
[32]
cannot be printed with standard extrusion-based be combined with cells, functionalized particles, or
techniques without damaging its structure. To bioactive compounds (Table 2). In the first case,
improve or modify the mechanical properties of various cell types, for example, keratinocytes ,
[42]
the gel construct, the composite bioinks of fibrin fibroblasts , bone-marrow derived, and adipose-
[43]
[44]
with other components were used. Combinations derived MSC, have already been tested. In the
[45]
with gelatin , alginate , collagen , hyaluronic second case, for instance, platelet-like particles
[34]
[33]
[35]
acid , or more complex formulations prepared from functionalized ultralow crosslinked
[37]
[36]
were used for different applications. Some poly (N-isopropylacrylamide-co-acrylic acid)
biochemical modifications were also introduced microgels were offered to improve wound healing.
to the fibrinogen to modulate the structural and In the third case, growth factors are usually applied,
mechanical properties of the gel [27,29,38] . which can be physically entrapped within a fibrin
mesh or affinely or covalently bonded. For instance,
3 Biological properties and their tuning fibrin can be mixed with growth factor-loaded
3.1 Wound healing nanoparticles that promoted wound healing. Losi
et al. tested poly(lactic-co-glycolic acid) (PLGA)
[46]
The formation of fibrin which is known as nanoparticles loaded with VEGF and bFGF and
fibrinogenesis is associated with hemostasis, one of showed that they can significantly promote wound
the main stages in wound healing. By forming an closure and facilitate the re-epithelialization and
interconnected porous network, fibrin fibers act as granulation tissue formation. Growth factors can be
a temporary scaffold for migrating and proliferating linked to fibrin, for example, by transglutaminase-
cells. Fibrin provides an angiogenic environment assisted binding of their recombinant
that enables the growth of capillaries’ sprouts. modifications that ensures their prolonged release.
Together with fibroblasts and macrophages, they Mittermayr et al. showed the efficacy of such
[47]
form the mature granulation tissue, essential for the approach. In their study, they achieved a controllable
following re-epithelialization. Hence, its angiogenic release of platelet-derived growth factor AB (PDGF.
(will be discussed in the next section) and healing AB) from fibrin that enabled the acceleration and

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