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Bioinformatics of the Brain

For instance, agarose in collagen gels is reported to increase stiffness and cre-

ate an intercalating matrix accompanied with significant retardation of cell

invasion suggesting critical result of sterical hinderance and loss of cell binding

sites in collagen [188].

In tumor environment, stromal cells interact with CSCs by cell-cell interac-

tions and soluble factors. In an effort to confirm this, McCoy et al. previously

described that endothelial cells encapsulated with GSC spheroids stimulated

stemness markers, limited the loss of Nestin+ cells and advanced the migration

distance of these cells through contribution of endothelial signal of IL-8 [189].

Additionally, various gene expressions were enriched in a bioprinted tetra-

culture of GSCs, macrophages, astrocytes, and neural progenitor cells. This

system promoted invasion, polarized macrophages into TAM and partially

differentiated neural progenitor cells to retaliate against immune suppression

[190] highlighting the requirement of dynamic interplay between CSCs, tissue-

resident, and immune system cells in a unique microenvironment.

As one of the final aspects of tumor biology, angiogenesis is a key for

survival of tumor mass, to direct migration of immune system cells to the

brain as well as to establish metastatic niche. In literature, scaffold-based and

microfluidic systems are constructed to investigate role and mechanisms be-

hind for in vitro presence of pericytes and astrocytes with angiogenesis. In one

of such applications, endothelial cells in gelation hydrogels increased average

branch and total network length, as well as production of laminin, ZO-1 and

GLUT1 featuring onset of intact BBB formation. Co-encapsulation of GBM

spheroids with brain vascular cells enhanced outgrowth area and number of

invasion distance, promoted expression of certain GBM signature proteins

(e.g., MMP9, PGDFAA, OPN, IL-8), yet no significant advancement was ob-

served when only endothelial cells were used in GBM spheroids addressing the

requirement of supporting cells for the stability of vessels [159].

3.4.2

Drug Response

Today’s clinics is overcome by drugs mainly failing due to incompatibility

in transition from bench to bedside. So far, many drug candidates offered

limited clinical success heavily depending on 2D cell culture of immortalized

cell lines such as U87 as first-line approach [191]. Later, pharmacokinetics

and pharmacodynamics are investigated on mainly ectopically or orthotopi-

cally transplanted or genetically engineered murine models. However, lifespan,

anatomical, physiological, and metabolic differences between humans and es-

pecially mice are main shortcomings for in vivo modeling. Further, mutation

mechanism, possible lack of immune cell-tumor cell interaction in immuno-

compromised mice, inability to provide communications between tumor cell-

stromal cells of primary tumors in mouse xenograft models adversely affect

the utilization of these animals as pre-clinical models. Large animal models

such as primates, canine, and pigs are also under research to shorten the gap