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International Journal of Bioprinting Biomimetic biofabrication of tumors volume

nutrients, and signaling molecules to the tumor, as well as pathways which lead to the dissemination of tumor
(ii) facilitating the removal of waste products. However, cells from the primary tumor site to a secondary site [105] .
in a pathological scenario such as cancer progression, the Metastasis consists of a complex succession of cell-
angiogenetic process is radically upregulated and sustained biological events, which can be divided into three major
to maximize the tumor survival and spreading ratio. events, including (i) tumor cells exiting their primary
Typically, the oxygen diffusion within a 3D-bioprinted sites of growth (EMT of cancerous cells, local invasion,
construct is slower than its consumption . Thus, the intravasation) [106] , (ii) tumor cells translocating from
[99]
gaseous and nutrition kinetics is a limiting factor for their primary site (survival in the circulation, arrest at a
cancer maturation in vitro and often fails to replicate the secondary site, extravasation) [107,108] , and (iii) tumor cells
highly vascularized tumor mass that is present in vivo. To adapting to survive in distant sites (micro-metastasis
study and recapitulate complex dynamics happening as a formation, metastatic colonization) [109-111] .
consequence of the intense angiogenic kinetic within the In particular, angiogenesis and vascularization have a
tumor mass, new studies are exploring 3D bioprinting to critical role to play in events associated with tumor growth
engineer customizable vessels within the biofabricated and metastasis [112,113] . The tumor vasculature is structurally
cancer tissue. The importance of such models has been immature, leaky, chaotically organized, and poorly
recently highlighted elsewhere [100] . perfused. Blood vessel leakiness along with interstitial
The incorporation of vascular networks in 3D-bioprinted fibrosis and stromal fibroblast-mediated interstitial matrix
cancer models holds great promise for advancing the contraction elevates interstitial fluid pressure (IFP) and
understanding of tumor angiogenesis and impact on tumor induces hypoxic environment [114] . Metastatic models are
growth and ultimate response to therapeutic agents. Kim et challenging to 3D-print, due to a superior architectural
al. [101] have recently demonstrated the possibility to engineer complexity and culturing methodology. In a pioneering
3D-bioprinted cancer-vascular model by in situ cell printing work by Lee et al. [115] to engineer a biomimetic metastatic
technology. The impact of vascular supply to cancer model, a microfluidic bioprinting system was used to
spheroids was investigated in three dimensions, finding that deposit GB cells to model the GBM TME via accurate
the close proximity of new vessels stimulates epithelial-to- deposition and use of ad-hoc designed biomaterial ink.
mesenchymal transition (EMT), while affecting vascular Indeed, the printed GBM cells were found to be able to
physiology by driving inflammation. The latest study spontaneously assemble into spheroids post-printing and
from Franca et al. [102] revealed the supporting effect of express significantly elevated levels of CD133 proteins
pericytes to guide the maturation of new vessel sprouting and DCX markers, demonstrating the ability to replicate
in 3D-bioprinted models. This approach might hold the metastatic invasiveness and niche.
potential to closely mimic pathological angiogenesis Secondary metastatic sites often act as a cancer
in vitro. These models may provide a functional platform reservoir, enhancing dramatically the chances of tumor-
to investigate how the spatial arrangement and functional driven death. Bone is among the most common metastatic
properties of blood vessels influence the behavior of cancer site in patients with advanced cancer. Once tumor cells
cells, the formation of metastases, and the efficacy of anti- reach the skeleton, the disease is generally declared
cancer treatments [103] . Furthermore, the ability to engineer incurable, and treatment is only palliative. The majority
customizable vessels within the biofabricated cancer tissue (70%) of breast, prostate, and lung carcinomas form
opens to new avenues for drug testing and anti-angiogenic deadly metastases in the bone tissue [116] . More than half
therapies. of the patients affected by skeletal metastasis experience
New engineering approaches are harnessing artificial at least a skeletal-related events within 24 months from
intelligence (AI) technologies to aid the development of diagnosis [117] . Besides having a significant impact on
biomimetic vascularized cancer models [104] . The use of novel patients, these skeletal-related events are associated with
AI tools can be applied to the investigation of angiogenic substantial costs for the health care system [118] . Therefore,
potential in ex vivo models (such as chicken chorioallantoic new bioinspired models that can closely recapitulate
membrane [CAM]) to elucidate new ways of disrupting the the intricate metastatic process from a primary tumor
tumor vascularization. In turn, these new ways of modeling site to the skeletal tissue are urgently needed. Thus, 3D
tumor angiogenesis might be harnessed to explore the bioprinting holds the potential to generate complex shapes
untapped potential for the study of metastasis. with precise spatially defined cell distribution, to better
represent both early and late events in the development
4.6. Engineering models for the metastatic niche and the formation of the metastasis. Recently, Meng
Tumor metastasis is believed to be the main cause of et al. [119] engineered a 3D-bioprinted in vitro tumor model
cancer-related deaths, consisting of a series of complex mimicking the metastatic dissemination of primary

Volume 9 Issue 6 (2023) 383 https://doi.org/10.36922/ijb.1022