Rational Design of Artificial Cellular Niches for Tissue Engineering - Tissue Engineering: Computer Modeling, Biofabrication and Cell Behavior - page 131

terials, during the last decade novel bio-AFM equipments have been developed (e.g.
Asylum Research MFP-3D-BIO Atomic Force Microscope System; Nanonics Hy-
dra BioAFM; JPK Instruments NanoWizard 3 BioAFM; Bruker BioScope Catalyst
AFM) to work with living cells at physiological conditions and even under flow con-
ditions, while the mechanical testing is performed. Consequently, their application
is not restricted to hard materials anymore, opening a new field for the analysis of
mechanical properties of cells themselves [ 19 , 20 ].
3 In Vitro Biomimetic Models: From Tissues to Models
The manufacture of physiologically relevant in vitro biomimetic models is critical
for both the development and validation of novel products in Tissue Engineering.
3.1 Controlling Cell-Cell and Cell-Matrix Interactions
In the previous section, we have highlighted the importance of a thorough charac-
terization of the natural tissue that wants to be replaced. In this section, we want
to emphasize the importance of studying the key cell-cell and cell-matrix interac-
tions that will take part during the regeneration process: i.e., how a particular cell
type will respond to the design parameters of a certain scaffold, such as rigidity,
microstructural arrangement, surface chemistry, etc., and how it will interact with
other neighbor cells present.
3.1.1 Cellular Response to Mechanical and Topographical Cues
As we have already described, organs are formed by tissues, which are mainly com-
posed of cells and the ECM. Certain mechanical properties are associated to every
healthy tissue, and every tissue cell is adapted to it, ensuring homeostasis [ 21 , 22 ].
For instance, tissues such as brain or adipose tissue are more compliant than bone or
cartilage. In the case of epithelial cancers, tumors are stiffer than the surrounding tis-
sue and might be detected through physical palpation, as a rigid mass residing within
a compliant tissue. Monitoring of tumors based on rigidity maps is widespread, but
the relationship between tissue rigidity and tumor behavior at the molecular level is
still unclear [ 23 ]. It has been observed that tumor rigidity could influence treatment
efficacy, enhancing tumor metastasis. In addition, cells adhere more strongly and
migrate faster on stiffer substrates [ 24 ]. Tumor progression leads to variations in the
ECM organization and stiffness of the tumor mass itself; moreover, it also induces
changes in the viscoelastic properties of the stromal cells associated with the tumor
[ 25 , 26 ].
Many studies have been performed in order to define the effect that matrix stiff-
ness has in the differentiation of stem cells towards specific phenotypes [ 27 , 28 ].