Tissue Engineered Models of Brain Tumors and Their Applications

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preparation of magnetic particles is essential before levitation and the number

of cells produced will be limited [142].

Alternatively, single cell suspensions can be encapsulated in synthetic or

natural porous scaffolds such as matrigel which allow cell-matrix and/or cell-

cell interaction, and emergence of spheroids (Figure 3.3E). These systems can

be altered on application basis, but diffusion limitation and confinement can

amplify cell death [142, 154, 155]. For survival and clonal expansion of cells,

growth factor supplement such as EGF and bFGF can also be added to the

medium for patient-derived cells/tissues [156, 157].

Given those facts, spheroids/organoids are remarkable to reproduce certain

features of GBM. Through this strategy, they can offer an alternative route

for the development of tumor substitutes to minimize animal experiments and

cost, time, and labor-related issues to discover new treatments or improve

current therapeutic efficacy. But they should be modified to incorporate bio-

logical and chemical criteria such as cell composition and ECM, biochemical

and biophysical cues related to drug resistance, malignancy and perivascular

niche. These drawbacks led to the emergence of biocompatible natural and/or

synthetic biomaterial scaffold-based models with tunable properties and di-

verse cell composition. Scaffold-based methods not only create GBM models

to study disease and therapy but also are ideal alternatives to certain assays

such as scratch assay [151, 158–160]. Finally, a combination of scaffold-based

and scaffold-free strategies offer a unique platform for GBM in macro-scale

and in micro-scale changes, as non-cellular and cellular environment can be

reshaped accordingly [159, 161–165].

Currently, microfluidic devices stand as one of recent techniques estab-

lished for various applications in biomedical sciences from diagnosis to molec-

ular studies. In GBM applications, modeling of a wide range of aspects includ-

ing tumor biology, drug discovery, on-site analysis and real-time monitoring

of therapeutic efficiency can be devised on microfluidic devices (Figure 3.3F).

Polydimethylsiloxane (PDMS) is the most common material to design diverse

shapes, chambers and channels, and it can be modified with natural or syn-

thetic materials such as collagen I and decellularized ECM [172–176].

Organotypic brain slice culture experiments have been successfully prac-

ticed in neuroscience and are adapted to GBM modeling as well. These plat-

forms offer access to in vivo brain sections to manipulate and study ex vivo.

These slices are 200-350 µm in thickness and can be derived from mouse, rat

and human biopsies. The sections can carry tumor or cells (patient-derived,

commercially available)/spheroids associated with the tumor which can be

cultured on/injected into healthy slices. This technique is promising to fill

the experimental gap between in vivo and in vitro in cell behavior analysis,

drug screening, and cell therapy and to study the impact of tumor mass on

healthy regions [177–181]. Although brain slice culture decreases study du-

ration from months to weeks compared to animal models, major limitations

include the cost, source of slices, inability to recapitulate effect of BBB and

hypoxia [182, 183].