Growing neurites are guided through their environment during development and regeneration via different cellular and extracellular matrix (ECM) molecular cues. To mimic cell-matrix interactions, a three-dimensional (3D) hydrogel-based ECM equivalent containing a covalently immobilized laminin oligopeptide sequence was designed to facilitate nerve regeneration. This study illustrates that the oligopeptide domain CDPGYIGSR covalently linked to an agarose gel as a bioartificial 3D substrate successfully supports neurite outgrowth from dorsal root ganglia (DRG) in vitro. The specificity of the neurite promoting activity was illustrated through the inhibition of neurite outgrowth from DRG in a CDPGYIGSR-derivatized gel in the presence of solubilized CDPGYIGSR peptide. Gels derivatized with CDPGYIGSK and CDPGRGSYI peptides stimulated a smaller increase of neurite outgrowth. In vivo experiments revealed the capability of a CDPGYIGSR-derivatized gel to enhance nerve regeneration in a transected rat dorsal root model compared to an underivatized gel, a CDPGRGSYI gel, and saline-filled nerve guidance channels. These data suggest the feasibility of a 3D hydrogel-based ECM equivalent capable of enhancing neurite outgrowth in vitro and in vivo.
Growing neurites are guided through their environment during development and regeneration via different cellular and extracellular matrix (ECM) molecular cues. To mimic cell-matrix interactions, a three-dimensional (3D) hydrogel-based ECM equivalent containing a covalently immobilized laminin oligopeptide sequence was designed to facilitate nerve regeneration. This study illustrates that the oligopeptide domain CDPGYIGSR covalently linked to an agarose gel as a bioartificial 3D substrate successfully supports neurite outgrowth from dorsal root ganglia (DRG) in vitro. The specificity of the neurite promoting activity was illustrated through the inhibition of neurite outgrowth from DRG in a CDPGYIGSR-derivatized gel in the presence of solubilized CDPGYIGSR peptide. Gels derivatized with CDPGYIGSK and CDPGRGSYI peptides stimulated a smaller increase of neurite outgrowth. In vivo experiments revealed the capability of a CDPGYIGSR-derivatized gel to enhance nerve regeneration in a transected rat dorsal root model compared to an underivatized gel, a CDPGRGSYI gel, and saline-filled nerve guidance channels. These data suggest the feasibility of a 3D hydrogel-based ECM equivalent capable of enhancing neurite outgrowth in vitro and in vivo.
The nervous system of the human body can be divided into two parts: the central and the peripheral nervous system. While the central nervous system (CNS) includes the brain and the spinal cord, the peripheral nervous system (PNS) consists of all the nerve branches exiting the spinal cord or brain stem that process information from our environment to the CNS and vice versa. The main extension that passes all incoming information to the next neuron or a peripheral target is called an axon. Axons can be as long as 1 meter, as in the case of axons sending electrical signals to the toes. All incoming information is received by smaller structures called dendrites. Axons are wrapped with glial cells, Schwann cells in the PNS, and oligodendrocytes in the CNS. These cells are responsible for the deposition of myelin, a powerful insulator. Each glial cell is covering an axonal segment of about 1-2 mm. An unmyelinated gap separates two glial cells. Action potentials are generated at those gaps. This electrical signal jumps from one unmyelinated gap to the next, giving rise to conduction velocities as fast as 1 m/s. In the PNS, axons are grouped together into fascicles, consisting of a layer of connective tissue surrounding bundles of axons. Several of these fascicles form a peripheral nerve surrounded by another connective tissue layer named epineurium. The epineurium is responsible for the integrity of the overall structure of a peripheral nerve. While the PNS shows regenerative capabilities, this is in general not the case for the CNS. The mechanisms explaining the poor regeneration capabilities of the CNS have started to be elucidated. The expression of inhibitory molecules in the mammalian-adult nervous system seems to be an essential component in the inherent lack of CNS regeneration. Examples for possible applications of materials systems addressing certain issues of PNS and CNS regeneration are presented in the following sections.
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