SC
Schwann cell
SEM
Scanning electron microscopy
1 Introduction
The central nervous system (CNS) is crucial for performing motor, sensory, and
autonomic functions, including somatic injury repair. Unfortunately, the CNS has
limited capacity for regeneration, resulting in the formation of glial scars and cysts.
This makes the effects of neurotrauma, ischemia, hemorrhage, or neurodegenerative
diseases displeasing and, very often, irreversible [1]. This is mainly due to the
intrinsic properties of neural parenchyma (i.e., insufficiency of progenitor neural
cells in the adult nervous system and slow ability of mature neural cells to regenerate, proliferate, and migrate [2]) and the heterogeneous microenvironment generated
by the damage. This can lead to destruction of the blood-brain barrier (BBB),
cytotoxicity (e.g., due to release of proteases and free radicals from necrotic cells),
and trophic and oxygen deprivation.
Many therapeutic strategies designed for enhancing endogenous repair mechanisms
of the nervous system have become unsuccessful due to the short half-life and systemic
effects of injectable growth factors, as well as the poor survival, differentiation, and
migration of transplanted stem cells. One of the most promising approaches to overcome these issues is the use of three-dimensional (3D) hydrogel networks with tunable
physical and chemical properties [3]. In the context of brain tissue regeneration, such
hydrogels must support both viscous flow under shear stress (shear-thinning during
injection) and time-dependent recovery upon relaxation (self-healing after injection at
the injury site) in order to achieve a minimally invasive surgery [4]. Moreover, many
other features such as biocompatibility, biodegradability, porosity, cell adhesion ability, low cytotoxicity and immunogenicity, lack of mutagenicity, and lack of swelling,
are also critical aspects that should be considered to develop hydrogel scaffolds suitable
for clinical applications in neuroregeneration [5].
Hydrogels can serve as local transport systems for the delivery of drugs and signaling
molecules specifically to the injury site and as 3D scaffolds providing appropriate
physical support, substrates for cell adhesion, optimal nutrient and oxygen exchange,
and protection to host and graft cells, thus facilitating extracellular matrix (ECM)
formation [6]. Within this context, the main role of hydrogels in neuroregeneration is
to exert control over the host neural tissue and grafted cell fate by sustaining attachment,
neurite outgrowth, proliferation, migration, differentiation, and viability. Among many
types of hydrogels, biohydrogels derived from preexisting components of body tissues,
such as collagen, constitute promising biomaterials for brain injury therapy due to their
biocompatibility, noncytotoxic properties, self-healing ability, and intrinsic content of
cell-signaling domains that can efficiently promote cell growth [7].
Usually, biological materials such as collagen are turned into mechanically stable
hydrogels by either cross-linking processes (i.e., chemical cross-linking, photochemical cross-linking, enzymatic cross-linking, thermal cross-linking) or mixing with other
Self-Healing Collagen-Based Hydrogel for Brain Injury Therapy
357
Schwann cell
SEM
Scanning electron microscopy
1 Introduction
The central nervous system (CNS) is crucial for performing motor, sensory, and
autonomic functions, including somatic injury repair. Unfortunately, the CNS has
limited capacity for regeneration, resulting in the formation of glial scars and cysts.
This makes the effects of neurotrauma, ischemia, hemorrhage, or neurodegenerative
diseases displeasing and, very often, irreversible [1]. This is mainly due to the
intrinsic properties of neural parenchyma (i.e., insufficiency of progenitor neural
cells in the adult nervous system and slow ability of mature neural cells to regenerate, proliferate, and migrate [2]) and the heterogeneous microenvironment generated
by the damage. This can lead to destruction of the blood-brain barrier (BBB),
cytotoxicity (e.g., due to release of proteases and free radicals from necrotic cells),
and trophic and oxygen deprivation.
Many therapeutic strategies designed for enhancing endogenous repair mechanisms
of the nervous system have become unsuccessful due to the short half-life and systemic
effects of injectable growth factors, as well as the poor survival, differentiation, and
migration of transplanted stem cells. One of the most promising approaches to overcome these issues is the use of three-dimensional (3D) hydrogel networks with tunable
physical and chemical properties [3]. In the context of brain tissue regeneration, such
hydrogels must support both viscous flow under shear stress (shear-thinning during
injection) and time-dependent recovery upon relaxation (self-healing after injection at
the injury site) in order to achieve a minimally invasive surgery [4]. Moreover, many
other features such as biocompatibility, biodegradability, porosity, cell adhesion ability, low cytotoxicity and immunogenicity, lack of mutagenicity, and lack of swelling,
are also critical aspects that should be considered to develop hydrogel scaffolds suitable
for clinical applications in neuroregeneration [5].
Hydrogels can serve as local transport systems for the delivery of drugs and signaling
molecules specifically to the injury site and as 3D scaffolds providing appropriate
physical support, substrates for cell adhesion, optimal nutrient and oxygen exchange,
and protection to host and graft cells, thus facilitating extracellular matrix (ECM)
formation [6]. Within this context, the main role of hydrogels in neuroregeneration is
to exert control over the host neural tissue and grafted cell fate by sustaining attachment,
neurite outgrowth, proliferation, migration, differentiation, and viability. Among many
types of hydrogels, biohydrogels derived from preexisting components of body tissues,
such as collagen, constitute promising biomaterials for brain injury therapy due to their
biocompatibility, noncytotoxic properties, self-healing ability, and intrinsic content of
cell-signaling domains that can efficiently promote cell growth [7].
Usually, biological materials such as collagen are turned into mechanically stable
hydrogels by either cross-linking processes (i.e., chemical cross-linking, photochemical cross-linking, enzymatic cross-linking, thermal cross-linking) or mixing with other
Self-Healing Collagen-Based Hydrogel for Brain Injury Therapy
357