Biomedical Engineering Reference
In-Depth Information
factors important for neural repair will be reviewed. In the second section, the effect of
physico-mechanical cues will be summarized in terms of micro-/nanotopography,
mechanics, and piezoelectricity of natural and synthetic substrates. We believe that this
extensive overview of studies that examine the relation of cells to their physical and
chemical microenvironment will identify some key bioengineering milestones necessary
for successful nerve regeneration.
The Role of ECM Components/Engineering
ECM Signals into Biomaterials
The interplay between CNS cells and their surrounding ECM influences most aspects of
nervous system development and function such as adhesion, survival, migration, proliferation,
and differentiation of cells by providing a physical and biochemical cellular microenvironment
[14-17]. The CNS microenvironment is primarily composed of a complex blend of glycopro-
teins, proteoglycans (such as collagens, laminins, and fibronectins), glycosaminoglycan (GAG)
hydrated gel, other link proteins, and a stack of signaling molecules, growth factors, and
morphogens [14, 18, 19]. This framework is dynamically created, secreted, transported, and
depleted by CNS cells (e.g., glia cells), hence acellular allografts can be used as ideal scaffolds
[19]. However, variations in biochemical and mechanical properties following the extraction
process should be taken into consideration in order to prevent immunogenic responses and
incomplete repair in foreign hosts, allograft-limited sources, imperfections in the chemical
processes for removing epitopes/globular proteins and immune stimulating factors [20].
Potentially, a scaffold can be supplemented with ECM in the hope of generating neural-like
constructs and providing structural stability. By doing so, desirable bioactivity that can induce
a neural stem/progenitor's fate toward lineages of interest is applied. Thus, three-dimensional
ECM-based synthetic or natural implants with robust biomechanical properties and biocom-
patibility can be promising alternatives to allografts and autografts [20].
Natural scaffolds composed of collagen, Matrigel, laminin, or fibronectin have been fabricated
to enhance neuron survival and neurite outgrowth in response to signals [20]. Interaction of
fibronectin and laminin as the most important CNS basement-membrane components with
specific cell-surface molecules (integrin receptors) initiates a cascade of signal transduction that
lead to varied cellular responses [21]. The concentration and type of these components can
affect neuronal cell behavior. For example, embryonic motor neurons (MNs) require laminin
2/4/8 to improve their neurite outgrowth. Additionally, implants made of natural materials have
been shown to exert neuroprotective effects on an injured CNS and provide a favorable bridge
for the regenerating axons [22, 23].
The CNS native environment is mainly composed of GAGs. Some GAGs such as chon-
droitin sulfate (CSPG) and heparin sulfate (HSPG) inhibit axonal outgrowth at the injury
site [24, 25]. However, HSPGs such as syndecan-1 and glypican-1 participate in neural
survival and regeneration via controlling the IGF-I interaction with their binding proteins
on the neural surface [25, 26].
In addition to the above-mentioned materials, other ECM proteins such as growth-factor-
reduced Matrigel (gfrMG) have been shown to support neural cell survival, migration, and
neurite outgrowth both
in vitro
and
in vivo
. This can promote proliferation of grafted cells
and increase the number of tyrosine hydroxylase (TH)-positive dopaminergic neurons. The
gfrMG increases the number of TH-positive cells by suppressing the inhibitory effects of the
host-brain microenvironment on neural differentiation [27].
Thus, scaffolds based on natural materials that depend on the desired microenvironmental
cues can be fine-tuned to properly mimic the particular neuronal-niche's biophysical and
