Page 185 - IJB-10-3

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

development. Moreover, proteases, especially matrix autoimmunogenicity of immune cells. Moreover,
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metalloproteases (MMPs), acting as an indispensable metabolic characteristics of tumor cells help impel
contributor in tumor metastasis, not only degrade ECM immune escape. Lactate, the metabolic reprogramming
to provide transfer channels for migrating cells but also product, impairs the capability of immune cells to produce
release factors relevant to metastasis during degradation. cytokines and hinders their activation and killing ability.
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Telomere, a protein complex, controls cell survival and
2.3.2. Vascularization and co-culture accelerates cell aging until cell death caused by injury.
Vascularization is the generation of vascular system for Telomerase, abundant in tumor cells, allows the cells to
tumor growth, under the influence of vascular regulators proliferate infinitely.
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from host cells and tumor cells. The endothelial cell
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(EC)–TME interaction and angiogenin contribute to 2.3.4. Drug resistance
vascularization. A review illustrates that the progress of The refractory nature after chemotherapy stems from the
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vascularization cannot rely only on vessel induction. The tumor metastasis and drug resistance. Drug resistance
two mechanisms of vascularization are: (i) occupation is manifested by inadequate drug response at the site of
of pre-existing blood vessels by tumor cells; and (ii) treatment during early administration or prolonged drug
formation of vessel-like structures made of tumor cells to exposure. Persistent exposure to drugs engenders drug
enable bloodstream passage. resistance in various tumor cells, thereby circumventing
TME with cell–cell and cell–matrix interactions has drug-induced apoptosis and reducing the clinical efficacy
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a collective influence on tumor growth. 3D constructs of drugs. Drug resistance stemming from TME is caused
featuring interactions of components in the TME, rather by ECM reconstruction and vessel generation, which alter
than single cell type, assure greater in vivo relevance than drug distribution and metabolism. Furthermore, Taylor
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2D models. Co-culture models that recapitulate crosstalks et al. proved that weak alkaline drugs to neutralize the
among components in TME are superior to single tumor acidity in the TME served as an effective and well-tolerated
cell models due to the existence of interactions between therapy to reverse acquired resistance to chemotherapeutic
components within the TME. There are some instances drugs, insinuating that acidity in the TME is one of the
of co-culture: the communication between cancer stem crucial factors contributing to drug resistance. Although
cells (CSCs) and ECM enhances the performance of stem TME is not the leading cause of drug resistance in tumors,
cells; immunocytes and tumor cells inhibit each other; the it directly affects the treatment effect. In non-small cell lung
matrix metalloproteinase secreted by CAFs creates room carcinoma (NSCLC), carbon materials are metabolized
for abnormal vessels to grow; TAMs and ECs both have through the Embden-Meyerhof-Parnas pathway,
effect on the tumor growth and vasculogenesis. Tumor producing metabolites that activate RAS proteins. On this
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cells activate CAFs to release factors that induce tumor basis, PI3K/AKT and MAPK/ERK signaling pathways are
progression, and apoptotic cancer cells influence the triggered to contribute to drug resistance, which indirectly
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invasion of CAFs. Jeong et al. demonstrated that tumor restricts drug efficiency. Therefore, research on TME-
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cells co-cultured with CAFs were much larger than those driven resistance in 3D constructs for drug screening is
in monocultures, and they could also activate CAFs. necessary. 51,52
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TAMs that exchange more with tumor cells may contribute
to chemotherapeutic resistance and tumor recurrence. 3. Simulating components in
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3D bioprinting
2.3.3. Immune evasion and limitless proliferation
Anti-tumor immunity encompasses three stages: clearance, 3.1. Bio-based polymers as bioinks
balance, and escape. The congenital immune system is Bioinks, whose rheological and mechanical properties
the initial coping mechanism of our body encountering resemble those of internal tissues, refer to the printed stock
tumors, namely the stage of immune clearance with the solutions that are compatible with cell culture. Generally,
cooperation between congenital and acquired immune cell-laden bioinks are used to print tissue-like structures
cells. There is no obvious clinical manifestation in this stage. directly, while cell-free bioinks are employed in structure
When the immunity is at a balanced state, tumor cells and printing prior to cell inoculation. Bioink materials, derived
the immune system do not significantly affect each other. from natural and synthetic polymers, can fuse functional
However, surviving tumor cells with good proliferative proteins and genes. Bioinks with excellent properties,
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capacity and viability may escape the recognition of the such as non-toxicity, biocompatibility, and biomechanic
immune system, producing manifestations that can be properties, can be applied in tissue engineering. In
clinically detected during the balance stage. Immune addition, compared with 2D culture and animal models,
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escape occurs in malignant tumors because of the declining 3D culture models that are dependent on the abilities of

Volume 10 Issue 3 (2024) 177 doi: 10.36922/ijb.1951