Page 258 - Advances in Biomechanics and Tissue Regeneration

13.2 PRINCIPLES FOR ELECTRIC AND MECHANICAL CLUES 255

goes to depolarization from resting state, followed by repolarization to the resting state, reversing its polarity for a
short period of time. In this way, by changing the electric potential of a nerve cell, an action potential can be produced.
Electric fields ranging from 0.1 to 10V/cm have been shown to influence the direction of neurite growth and increase
the neurite initiation [39]. Moreover, these electric fields can also influence the rate and orientation of neurite out-
growth in vitro [11].
In this way, electroactive materials and, particularly, piezoelectric ones show a huge potential for tissue engineering
applications. These materials vary their surface polarization under mechanical loading and influence cell morphology,
adhesion, proliferation, and differentiation [40], mimicking the stimuli present under many physiological conditions.
When compared with nonpiezoelectric controls, a higher cell growth and differentiation are observed for piezoelectric
materials [11, 41]. Moreover the use of these active scaffolds has proved to promote neurite extension and neuronal
differentiation [42]. The use of piezoelectric materials, with mechanically induced variations of surface charge, leads to
enhanced osteogenic differentiation of human adipose stem cells [43]. Positively charged surfaces have been also
reported to promote higher adhesion [44] and spreading [43, 45].
Moreover, for tissues such as bone, which are subjected to mechanoelectrical solicitations during movement, tissue
reparation when immobilized is more complex as the natural stimuli are absent [46]. Thus the use of smart materials
able to induce mechanical or electrical stimulation to the tissue during damage repair or in cell cultures within bio-
reactors shows great potential as an alternative to the already existing tissue engineering strategies.

13.2 PRINCIPLES FOR ELECTRIC AND MECHANICAL CLUES

The tissue development, repair, and/or regeneration of cells and organs and also the cell behavior and function
require multiple physiological clues, not only the (bio)chemical ones but also the physical signals, which may be elec-
trical and mechanical [47, 48].
With respect to the mechanical forces, cells are constantly exposed to them (depending on the tissue, they can be
shear, compressive, or tensile forces) [49], which in turn exert forces to their environment, modulating their behavior
(cell migration, proliferation, and differentiation) [47, 50]. Also, they play a key role in diverse cellular processes, rang-
ing from proliferation to transcription to organogenesis [51], due, for example, to the focal adhesion complexes and the
internal remodeling of the cytoskeletal architecture, to the signalization of the second messenger (such as the intracel-
2+
lular Ca ), or to the gene expression changes. So, cells are constantly monitoring the extracellular parameters of the
surrounding microenvironment to respond to these changes appropriately and modify their behavior, through a pro-
cess termed mechanotransduction [52]. Basically, each cellular process must begin with mechanotransduction, which
is the conversion of the mechanical forces into biochemical or electrical signals that will remodel the cells and tissues at
the structural and functional levels [53].
The microenvironment found is dependent on the tissue and can be highly distinct. For example, skeletal muscle
cells are found embedded in a 3-D tissue undergoing mechanical stretching and compression, while endothelial cells
are found in a 2-D interface in contact with the fluid, exposed also not only to stretching and compression during pul-
satile blood flow but also to fluid shear stress [51, 54]. In this way, for the design of the mechanical platforms, it must be
taken into consideration the mechanobiological niche of each tissue.
The bioelectric fields are generated by specific ion channels and pumps within cell membranes, which guide the
development and regeneration of many tissues, such as cartilage, nervous system, and vascular endothelial cells
[55, 56].
The knowledge that cells and tissues are able to receive from physical stimuli to translate them into biochemical and
biological responses has been paving the way for the development of novel smart materials to be applied in regener-
ative medicine [57–60].
One such example is the development of electrically and magnetically active materials/scaffolds for tissue engineer-
ing purposes. These materials are able to efficiently induce cell seeding, growth, and differentiation, taking advantage
of the mechanotransduction properties of the cells [4]. Living cells show many properties that are typical of electrical
systems. They generate electromotive force, use varying resistances in series or in parallel, regulate the potential dif-
ferences whenever needed, switch on and off, control and rectify current flow, and store charge. Across the plasma
membrane, in the presence of electrical voltage, the environment inside the cell remains more negative than outside [4].
Due to all these properties the application of small electric fields on different cells such as corneal [6, 7] and epithelial [9]
has been described to guide them to move and migrate in culture. Electric fields have also been reported to modulate
phenotypes of vascular endothelial cells [10] and to enhance nerve fiber outgrowth in vitro [11] and have been widely
used in bone and cartilage regeneration [12, 56, 61].

II. MECHANOBIOLOGY AND TISSUE REGENERATION