neurodegenerative disorders. Although collagen does not naturally occur in the
brain, it has been proved that collagen I, which resides in the basal lamina of the
subventricular zone in adults, supports neural cell attachment, axonal growth,
proliferation, and guidance in neural development [15]. Collagen I also forms the
dura mater (i.e., the thick membrane that surrounds the brain and spinal cord) and
leptomeninges [16].
Collagen I is routinely obtained from rat tails, porcine, and bovine skin, and
several research groups have demonstrated that the collagen source influences
significantly the properties of the hydrogels that can be formed [17]. Due to its
role in CNS development, as well as the self-healing capacity of its hydrogels,
collagen I is considered to be a good candidate for brain tissue regeneration
[15]. For instance, neural progenitor cells isolated from the rat embryonic CNS
have been found proliferate and differentiated rapidly into both neurons and astrocytes in collagen I hydrogels [8]. Furthermore, the neurons in these hydrogels were
found to develop neuronal features, including neuronal polarity, neurotransmitters,
ion channels/receptors, and excitability. Several reviews have been reported in the
literature regarding the use of different biopolymers to repair nerve injuries [9, 18].
3 In Vitro Studies
In 2007, Brannvall and co-workers developed a two-component collagen I-HA
scaffold (1:1 volume mix) matrix to enhance the differentiation of mouse embryonic,
postnatal, and adult NSCs and PCs (progenitor cells) [19]. The gel formation of the
scaffold used in this study takes place during physiological conditions and is caused
by the physical aggregation of collagen. The resulting network was found to retain
hyaluronan and provided the stability required for culturing cells in 3D. It is worth
noting that the formation of mature neural cells from NSC/PC depends on its
intrinsic machinery but also on external factors and signals derived from the ECM.
Both components of the 3D matrix, when used separately, were found to be
compatible with culture of cells from the nervous system. The authors demonstrated
that their combination constitutes a favorable condition for neuronal differentiation
of NSC/PC. By raising the temperature to 37
C, gel formation of the collagen
scaffold can be induced, and such property would be advantageous for tissue
replacement after traumatic brain injury, where a cavity in the brain parenchyma is
formed. By mixing cells with the scaffold at temperatures below 37
C, the cellmatrix mixture may fill the cavity with ECM components and new cells. Specifically, stem cells isolated from different ages of CNS tissue were seeded in the
presence of the 3D bio-scaffold and cultured in medium containing the mitogens
epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2), a condition
that stimulates NSC/PC proliferation. In general, the results showed that progenitor
cells from the embryonic brain had the highest proliferation rate, and adult cells the
lowest, indicating a difference in mitogenic responsiveness. NSC/PC from postnatal
stages downregulated nestin expression more rapidly than both embryonic and adult
Self-Healing Collagen-Based Hydrogel for Brain Injury Therapy
359
brain, it has been proved that collagen I, which resides in the basal lamina of the
subventricular zone in adults, supports neural cell attachment, axonal growth,
proliferation, and guidance in neural development [15]. Collagen I also forms the
dura mater (i.e., the thick membrane that surrounds the brain and spinal cord) and
leptomeninges [16].
Collagen I is routinely obtained from rat tails, porcine, and bovine skin, and
several research groups have demonstrated that the collagen source influences
significantly the properties of the hydrogels that can be formed [17]. Due to its
role in CNS development, as well as the self-healing capacity of its hydrogels,
collagen I is considered to be a good candidate for brain tissue regeneration
[15]. For instance, neural progenitor cells isolated from the rat embryonic CNS
have been found proliferate and differentiated rapidly into both neurons and astrocytes in collagen I hydrogels [8]. Furthermore, the neurons in these hydrogels were
found to develop neuronal features, including neuronal polarity, neurotransmitters,
ion channels/receptors, and excitability. Several reviews have been reported in the
literature regarding the use of different biopolymers to repair nerve injuries [9, 18].
3 In Vitro Studies
In 2007, Brannvall and co-workers developed a two-component collagen I-HA
scaffold (1:1 volume mix) matrix to enhance the differentiation of mouse embryonic,
postnatal, and adult NSCs and PCs (progenitor cells) [19]. The gel formation of the
scaffold used in this study takes place during physiological conditions and is caused
by the physical aggregation of collagen. The resulting network was found to retain
hyaluronan and provided the stability required for culturing cells in 3D. It is worth
noting that the formation of mature neural cells from NSC/PC depends on its
intrinsic machinery but also on external factors and signals derived from the ECM.
Both components of the 3D matrix, when used separately, were found to be
compatible with culture of cells from the nervous system. The authors demonstrated
that their combination constitutes a favorable condition for neuronal differentiation
of NSC/PC. By raising the temperature to 37
C, gel formation of the collagen
scaffold can be induced, and such property would be advantageous for tissue
replacement after traumatic brain injury, where a cavity in the brain parenchyma is
formed. By mixing cells with the scaffold at temperatures below 37
C, the cellmatrix mixture may fill the cavity with ECM components and new cells. Specifically, stem cells isolated from different ages of CNS tissue were seeded in the
presence of the 3D bio-scaffold and cultured in medium containing the mitogens
epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2), a condition
that stimulates NSC/PC proliferation. In general, the results showed that progenitor
cells from the embryonic brain had the highest proliferation rate, and adult cells the
lowest, indicating a difference in mitogenic responsiveness. NSC/PC from postnatal
stages downregulated nestin expression more rapidly than both embryonic and adult
Self-Healing Collagen-Based Hydrogel for Brain Injury Therapy
359