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González, et al.
4.3. Composite hydrogels in bioinks For the other composite hydrogels, manufacturability

Figure 7 presents the most frequently reported composite and biological functionality are also the main guidelines
for bioink design. Other criteria are often considered,
hydrogels used in bioink formulations: Hydrogel blends such as the use of reinforcers or sacrificial matrices
and hydrogels enhanced with functional additives. From that leave hollow spaces within the hydrogels to mimic
the pool of 393 articles analyzed, 263 mention the use of vascular networks [191-193] .
composite or hybrid bioinks. We identified 102 materials Bioink formulations may also include other
combined in different ways in bioink formulations. A total functional additives, such as biomolecules [194,195] ,
of 213 documents reported the use of hydrogel blends particles [151,196] , and drugs [197,198] (Table 3). A larger version
(i.e., hybrid matrices containing more than one hydrogel) of these correlation maps is presented as supplementary
(Figure 8A), while 54 reported the use of functional
additives (other than hydrogels) within the bioinks Table 2. The most frequently used hydrogel blends categorized by
(Figure 8B). From the group of hydrogel blends, 170 of the number of matrices involved
the 213 (80%) were composed of two hydrogels [181,182] , Ranking Two Three Four
36 (17%) of three hydrogels [183,184] , and 7 (3%) of four hydrogels hydrogels hydrogels
hydrogels [185,186] (Figure 8).
Figure 9 shows the correlation maps corresponding 1° Alginate Fibrin Gelatin
to all hydrogel blends (Figure 9A), and 2–4 hydrogel Gelatin Gelatin GelMA
blends (Figures 9B‑D). Table 2 lists the most frequently HA HA
used hydrogel blends, categorized by the number of HAMA
matrices involved. Not surprisingly, the main components 2° Alginate Alginate Alginate
in all the correlation maps are alginate and GelMA, GelMA Chitosan CS-AEMA
which is consistent with the top ten hydrogels reported Fibrin GelMA
in Figure 7A. Evident reasons for combining these HAMA
two hydrogels are the facile and rapid cross-linking of 3° Alginate Alginate PEGDA
alginate and the presence of cell-anchoring motifs in Collagen GelMA PEGOA
GelMA. GelMA hydrogels are somewhat recalcitrant type 1 PEGDA Thiolated
to cross-linking immediately after extrusion from Gelatin
the bioprinting nozzle, and the use of alginate easily Thiolated HA
overcomes this challenge. Very often, alginate is used as 4° Gelatin Alginate Collagen
a temporary template and GelMA as the permanent cell Silk Carboxymethyl type 1
scaffolding. [187–190] A filament of an alginate-GelMA blend Fibroin cellulose GelMA
can be ionically cross-linked immediately after extrusion Collagen type 1 Gellan Gum
to preserve its 3D shape. GelMA can then be covalently PLA
cross-linked by exposed to light. Finally, the alginate 5° Agarose Alginate Alginate
matrix can be removed using a Ca -chelating agent, such Collagen Collagen type 1 dECM
2+
as EDTA. [133] This methodology and minor variations of type 1 Gelatin PLGA
it were reported in 22 of the 393 analyzed manuscripts. PVA
A B

Figure 8. The most frequently reported hydrogel blends. (A) Distribution and (B) number of documents of hydrogel blends according to
the number of matrices used.
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