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International Journal of Bioprinting Bioprinted tissue-on-a-chip in drug screening

as a support and delivery foundation for mimicking protease to adjust the ECM activity. The fibroblasts around
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the physical properties and biomimetic behaviors in healing wounds and under some pathological conditions
TMEs or organs. These strategies used to imitate other have stronger proliferation ability and secrete more ECM
tissue microenvironments are similar to those employed than counterparts in normal tissues. This phenomenon is
for tumors, which are also relevant to the study of known as fibroblast activation.
their cell compositions and physical properties. Since Activated fibroblasts relevant to tumor
the characteristics of TMEs are well-established and microenvironment were discovered as CAFs in 2006.
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extensively researched, we selected TMEs as representative CAFs that were defined by Kobayashi et al. locate in or
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examples for different disease and tissue environments to around TME, encompassing both natural fibroblasts and
avoid unnecessary and redundant descriptions.
fibroblasts that activate, proliferate, and gather in response
A comprehensive study of the components and to cancer stimulation. However, the novel definition and
behaviors in TMEs is essential for creating realistic and biomarkers to represent CAFs are still evolving due to their
vibrant artificial tissues. Furthermore, TMEs encompass high heterogeneity and variation. ECM is modulated by
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various cells, non-cellular components, and even CAFs to control tumor stromal properties and secrete
microorganisms. 16,17 growth factors, thereby regulating the formation of vessels
that provide nutrients for tumors. Simultaneously, CAFs
2.1. Cell components are implicated in tumor invasion, metastasis, and drug
Cell selection is the starting point in the fabrication of resistance.
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in vitro 3D construct. Target lesion cells and the cells
they interact with are selected to ensure better maturity 2.1.2. Tumor-associated macrophages
in subsequent cell culture and higher expression of Tumor-associated macrophages (TAMs), which are derived
tissue-like or organ-like molecules. TME is composed of from the marrow and affiliated to immunomodulatory
immunocytes such as thymus-dependent lymphocytes/ cells, are divided into anti-tumor M1 and pro-tumor M2
bursa-dependent lymphocytes (T/B lymphocytes), phenotypes. The definition and mutual transformations of
tumor-associated macrophages (TAMs), natural killer the two phenotypes depend on environmental signaling
cells (NK cells), and stroma cells, including cancer- stimulation from immunocytes and ECM. The M2
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associated fibroblasts (CAFs), pericytes, and mesenchymal phenotype is constantly differentiated into other subtypes
stromal cells. These cells interact with the ECM and upon the stimulation of different cytokines. TAMs
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interconnect with other secretory molecules, including with the M2 phenotype contribute to tissue remodeling,
growth factors and chemotactic factors, contributing to angiogenesis, and immune responses. TAMs cannot
the complex mechanisms of TMEs. The maturity of 3D activate NK and T cells but release relevant factors and
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constructs that precisely recapitulate the physiological and enzymes to control immune response. TAM-induced
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pathological processes of tissues of interest is dependent inflammation also affects tumor growth. 28
on cell proliferation and differentiation. Moreover, the
cell introduction is not limited to tumor cells but involves 2.1.3. Immune cells
cells with various functions. Fibroblasts, macrophages, and Innate immune cells contain monocytes, neutrophils,
other immunocytes are research hotspots in the realm of eosinophils, basophils, and NK cells, all of which restrict
3D bioprinting. tumor progression. However, the proliferation and
maturation of immune cells are negatively regulated by
2.1.1. Cancer-associated fibroblasts soluble modulators in TME. This explains why immune
Mesothelial cells covering the entire coelom are cells are not abundant in TME. Tumor cells exert a
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differentiated into fibroblasts or other cells for promoting significant inhibitory effect on immunocytes. Tumor
organ development through epithelial–mesenchymal cells compete with immunocytes for essential nutrients
transition (EMT) during embryonic growth. A motif and glucose uptake, which are heavily relied on by tumor
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enrichment analysis by Huang et al. for up-regulated genes cells and necessary for immunocyte growth and function
in antigen-presenting CAF demonstrated that the signaling activity. More research on immunocytes in 3D constructs
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pathways of interleukin (IL)-1 and transforming growth is needed.
factor beta (TGF-β) induced the transformation from
mesothelial cells into fibroblasts. Furthermore, fibroblasts 2.2. Physiological characteristics
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regulate epithelial cell differentiation, participate in wound Tissues under an oxygen partial pressure of less than 10–15
healing, and excrete growth factors to maintain the mmHg are defined as hypoxic tissues. Hypoxia-inducible
stability of the epithelial microenvironment. Fibroblasts factor (HIF) is a transcription factor that binds to DNA
also control the synthesis of the ECM and its degrading and triggers reactions to reduce oxygen partial pressure.
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Volume 10 Issue 3 (2024) 175 doi: 10.36922/ijb.1951