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International Journal of Bioprinting Bioprinted tumor immune microenvironment

Table 2. Summary of hydrogels for bioprinted tumor immune microenvironment.
Hydrogel Source Key properties Immune response
Alginate Brown seaweed Biocompatible, gelation with Triggers innate immune responses through macrophage
divalent cations receptors, activates macrophages via the NF-κB pathway,
produces IL-6, IL-12, IL-1β, and TNF-α 58,59
Gelatin Derived from collagen Biocompatible, biodegradable, easy Minimal immune response, suitable for bioinks with
to use in bioprinting minimal immune interaction; requires crosslinking with
other polymers 60,61
HA Connective tissues Excellent hydration, supports cell Interacts with HA-binding receptors (TLR-2, TLR-4);
proliferation and migration triggers pro-inflammatory responses; modulates
immune environment; regulates T cell recruitment 62–65
Collagen The most abundant protein in Supports cell adhesion, migration, Immune response varies by species; high density
humans and differentiation reduces T cell proliferation and infiltration, affecting
immunomodulation 66–68
Chitosan Exoskeletons of crustaceans Biodegradable, biocompatible, Activates macrophages (anti-inflammatory) and
antimicrobial dendritic cells (pro-inflammatory), influences cytokine
secretion (TNF-α, IL-12/23) 69–71
dECM Derived from tissue/organ Preserving organ-specific ECM Immune response can be varied depending on the
properties decellularization method 72
Abbreviations: dECM, decellularized extracellular matrix; ECM, extracellular matrix; HA, hyaluronic acid; IL, interleukin; NF-κB, nuclear factor kappa
B; TLR, toll-like receptor; TNF-α, tumor necrosis factor alpha.

Alginate is a naturally occurring polysaccharide Collagen is the most abundant protein in the human
derived from brown seaweed, which is known for its body and a key component of the ECM, providing support
biocompatibility and gelation capabilities in the presence for cell adhesion, migration, and differentiation. The
66
of divalent cations like calcium ions. Alginate can trigger immune response to collagen varies depending on the
58
innate immune responses through macrophage receptors. species from which the collagen is derived and the species
59
Yang et al. showed that alginate activated macrophage- of cells being cultured with it. Tumors tend to remodel the
67
59
like cells via the nuclear factor kappa B (NF-κB) pathway, surrounding ECM, resulting in a collagen-rich structure
leading to the production of pro-inflammatory cytokines with increased stiffness. Kuczek et al. showed that a high
68
such as interleukin (IL)-6, IL-12, IL-1β, and TNF-α. density of collagen matrices reduced T cell proliferation and
infiltrating CD8+ T cells indicating an immunomodulatory
Gelatin is derived from collagen and is widely used due
to its excellent biocompatibility, biodegradability, and ease effect depending on collagen matrix density. This property
is crucial for designing bioinks that aim to study immune
of use in bioprinting applications. Pure gelatin does not cell interactions within a controlled environment .
60
elicit a significant immune response, making it a suitable
material for bioinks where minimal immune interaction is Chitosan, derived from chitin found in the exoskeletons
desired. However, since gelatin does not crosslink, it is of crustaceans, is known for its biodegradability,
61
difficult to create a 3D structure on its own when making biocompatibility, and antimicrobial properties. Chitosan
69
bioink. Therefore, it is necessary to mix polymers that can activates both macrophages and DCs, eliciting different
be crosslinked or made to crosslink through additional responses. Oliveira et al. showed that macrophages
70
chemical bonding. tend towards an anti-inflammatory phenotype, while
DCs exhibit pro-inflammatory attributes. Additionally,
Hyaluronic acid (HA) is a naturally occurring
62
glycosaminoglycan present in connective tissues. It has the cytokine secretion profile of human monocytes/
macrophages cultured on chitosan scaffolds indicates
excellent hydration properties and the ability to support enhanced TNF-α secretion, with scaffold geometry
cell proliferation and migration. HA can interact with influencing the quantities of TNF-α and IL-12/23 released,
HA-binding receptors, such as toll-like receptor (TLR)- which is particularly relevant for applications requiring
2 and TLR-4, recognizing HA fragments that trigger specific immune responses. 71
pro-inflammatory responses and thus contribute to the
modulation of the immune environment. HA also GelMA is a modified form of gelatin with methacryloyl
63
serves as a ligand for cell surface receptors such as CD44, groups that allow photo-crosslinking. It combines the
73
which can regulate the recruitment of T cells, neutrophils, biocompatibility of gelatin with the tunable mechanical
and monocytes. 64,65 properties of synthetic polymers. GelMA, like gelatin,
Volume 10 Issue 5 (2024) 35 doi: 10.36922/ijb.3988