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Fang, et al.
drug candidates suggest the development of more bioprinting can capture the entire complexity of the
effective preclinical platforms for screening anticancer TME . Integration of the vascular network with cancer
[12]
compounds will potentially increase their success rate in cells can be performed by techniques, such as sacrificial
the clinical phase pipeline . bioprinting, microfluidics, and stereolithography
[9]
Conventionally, cancer drug discovery and bioprinting [22-24] . Bioprinting may be used to develop
preclinical screening have relied on animal models tumor-on-a-chip systems that combine additive
and monolayer cell cultures (two-dimensional or 2D manufacturing, tissue engineering, and biomaterials to
models) which most often cannot recapitulate the mimic the physiological dynamic properties of a tumor.
physiological properties and dynamics of the human These systems hold a lot of potential for low-cost, high-
tumor microenvironment (TME) . Due to a lack of throughput anticancer drug screening [25-27] .
[10]
biological and mechanical stimuli that cancer cells would Among additive manufacturing, melt electrowriting
ordinarily encounter in vivo, planar 2D cell cultures (MEW) is an emerging method that can increases
have some constraints. The TME is complicated, with the resolution of fabrication and hence, enhance the
malignant cells interacting with one another and various function. MEW applies a potential difference between
types of cells entrenched in a three-dimensional (3D) the nozzle and the collector when the jet is direct-written,
extracellular matrix (ECM) [11-13] . In addition to the ethical to maintain a molten fluid column at low flow rates. In
considerations and time-consuming nature of animal trials, this case, MEW has its advantage in adapting to various
the success rate of translating animal models to cancer manufacturing requirements, with well-defined fibers that
[28]
clinical trials is about 8%. This indicates the inability of range from 820 nm to 130 µm in length .
animal trials to replicate human responses accurately in This paper comprehensively reviews the tumor-
complex processes, such as human carcinogenesis and on-a-chip technology fabricated by bioprinting for its
progression, and capture interspecies differences [14,15] . application in anticancer drug screening. The TME,
Three-dimensional models allow for the evolution of cell cultures in cancer research, advantages
reconstruction of the complex TME and are therefore and techniques of bioprinting, and development of tumor-
significant in the advancement of anticancer treatments. on-a-chip platforms by bioprinting are discussed.
Cell-cell and cell-ECM interactions, carcinogenesis,
drug discovery, gene expression, metabolic profiling, and 2. Tumor microenvironment
protein profiling of cells may all be studied using 3D cell The experimental gap that exists between in vitro models
culture [16,17] . The interaction of cells and biomaterials is for screening anticancer drugs and in the efficacy of
mainly based on the biomaterials’ structural and physical treatments largely contributes to their limited success.
properties, such as pore size feature, material size feature, Understanding the cellular and molecular composition of
mechanical, and surface properties. For example, porous tumors is important to developing models that recapitulate
constructs of biomaterials promote the cell migration, the TME. These models will then most accurately predict
viability, morphology, and alignment . the success rate of potential drug candidates.
[18]
Tumors can be effectively cultivated in a 3D In addition to understanding malignant tumor cells,
microenvironment or ECM, allowing cells to be exposed a thorough exploration of the TME and complicated
to oxygen and nutritional gradients, resulting in disparities interactions that occur between cells is necessary . Cells
[12]
in cell proliferation. These features of tumors cannot within the tumor, stromal TME, and ECM, which provide
be recreated in 2D models, making 3D models better structural support for cells in the extracellular space,
equipped for drug screening [19,20] . For 3D modeling of the affect the tumor’s behaviour [12,29-31] . Proteins, extracellular
TME, several techniques have been developed, including vesicles, cytokines, growth factors, and hormones are
spheroid culture, organoid culture, biopolymer scaffolds, all found in the ECM, which is fed through a vascular
and tumor-on-a-chip platforms . Three-dimensional network. Endothelial cells, fibroblasts, and mesenchymal
[21]
cancer models can potentially reduce the costs associated stem/stromal cells (MSCs) are all examples of stromal
with the drug development phase by decreasing the cells [32,33] . Immune cells (T-lymphocytes, B-lymphocytes,
number of animals needed for preclinical studies and natural killer [NK] cells, and macrophages), adipocytes,
allowing for more accurate predictions of drug candidates and pericytes are among the other biological components
in the clinical study phase. found in the TME. Communication between cells,
The advancement of printing from 2D to 3D cell-ECM, and the network of cytokines, proteins,
approach has resulted in the creation of 3D tumor tissue and chemokines affects tumor behavior, such as
constructs that may be utilized to study cancer biology tumorigenesis, angiogenesis, metastasis, and resistance to
and evaluate prospective drug candidates. By permitting drugs . Another important feature of the TME is leaky
[34]
the construction of numerous distinct types of cells and vasculature caused by altered endothelial cell junctions
biomaterials with great precision and repeatability, 3D that compromise the vascular barrier function. Further,

International Journal of Bioprinting (2022)–Volume 8, Issue 4 47