Page 290 - IJB-9-5

International Journal of Bioprinting Blood components for tissue graft bioprinting

plasma-based hydrogels. The concentration and the process physically and chemically crosslinked polymers. They
temperature directly affect the rheological properties, i.e., possess a high water content, which provides a suitable
viscosity. From a rheological point of view, plasma as a microenvironment for soluble protein retention (growth
liquid material presents a complex shear modulus (G*) factors, chemokines, and cytokines), gradient formation,
close to zero, increasing in consistency when it is mixed and diffusion to influence cell behavior and tissue
with activators such as thrombin or calcium solutions. repair/regeneration. When mixing biomaterials with
The clotting of plasma occurs with the conversion of blood-derived products, the retention/release of healing
fibrinogen into fibrin. Plasma hydrogels present a non- factors depends on the plasma formulation and specific
linear viscoelastic response under shear deformation. characteristics (functional groups) and processing of the
hydrogel, i.e., sterilization for clinical translation and
2.4. Fibrinogen/fibrin crosslinking reactions to maintain the stability of the tissue
Fibrinogen is an abundant blood glycoprotein constructs.
(concentration 2.0–4.0 g/L), produced by hepatocytes in
the liver. It is involved in hemostasis and clot formation. Knowledge about the anatomy and physiology of the
Briefly, upon platelet activation, plasma prothrombin target tissue guides the functionalization strategy and
converts into thrombin (in the presence of Ca ) and the choice of inductive tissue components, specific cell
2+
cleaves soluble fibrinogen, releasing fibrinopeptides A and phenotypes, or cell aggregates to be loaded within the
B. In doing so, thrombin transforms plasmatic fibrinogen hydrogels. This systematic review reveals that some blood
into insoluble fibrin networks with large pores and high biomaterials, such as fibrinogen, are used as inductive
permeability. Fibrinogen/fibrin is a crucial component elements and to enhance printability, while others are used
of most blood-derived products but removed in serum- for printable hydrogel functionalization. In some instances,
converted fresh-frozen plasma and serum-converted blood-derived biomaterials are included in the bioink
platelet lysates (Figure 2). formulation, used as a cell carrier in the bioprinting system,
or added to the bioprinted scaffold. Table 1 summarizes
Alternatively, purified fibrinogen is prepared by
cryoprecipitation or chemical precipitation and embodies research organized by target tissue, and Table 2 lists studies
involving multipurpose bioinks.
commercial preparations of fibrin glue or fibrinogen
adhesives. The latter also includes thrombin and CaCl In any case, the use of blood-derived biomaterials in
2
to be mixed at the point of care for tissue sealing. The bioprinting platforms has been preliminarily explored to
resulting fibrin networks are composed of highly branched meet the specific demands of both soft and hard tissues,
fibers and are less prone to lysis than plasma clots. but these approaches are still in the early stages of research
and far from providing therapeutic solutions. In fact,
3. Progress in plasma-functionalized most of the research is in technology readiness level 2–3
(TRL 2–3), and only one study includes a proof of concept
bioinks (TRL4) (reviewed in Perez-Valle, Del Amo and Andia,
The use of 3D printing/bioprinting in tissue grafting 2020). In vivo studies are needed to assess the integration
will only grow as new bioinks match the complexity and function of the construct in animal models mimicking
and dynamic nature of healing mechanisms. In this the clinical problem.
section, we will discuss how SBE printing/bioprinting Several additives should be included in bioink
platforms can benefit from the broad family of blood- formulations to fulfill printability requirements and
derived products and how these products, depending on match the mechanical properties of the target tissue.
the specific formulation, can influence printability and For example, alginate is an anionic polysaccharide and a
rheology and confer biologically relevant properties on common ingredient in many bioinks because of its low
the construct. Thus, the ideal bioink should have several immunological profile. It is often combined with other
properties: (i) good printability, (ii) non-toxicity and no hydrophilic polymers (11 out of 21 studies, 52%), such
immunological reactions, (iii) good mechanical stability as poly(ethylene glycol) (PEG) for cartilage , gelatin
[43]
after curing, (iv) good biodegradability, (v) mimicry (protein) for dermal tissue , methacrylated gelatin
[44]
of the in vivo microenvironment, and (vi) the support (GelMA) for islet organoids , or agarose (polysaccharide)
[45]
and promotion of cellular activities (i.e., proliferation, for cardiac tissue (Table 1). However, these bioinert
[46]
migration, or differentiation).
hydrogels cannot create biomimetic tissue unless they
The main bioink component for solvent extrusion is a are provided with RGD domains for cell attachment and
shear-thinning hydrogel that can flow during extrusion and functionalized with cytokines and growth factors to boost
protect cells from shear stresses. Hydrogels are hydrophilic cell activities.

Volume 9 Issue 5 (2023) 282 https://doi.org/10.18063/ijb.762