Effects of an injectable functionalized self-assembling nanopeptide hydrogel on angiogenesis and neurogenesis for regeneration of the central nervous system

Abstract

Brain injury is a devastating medical condition and represents a major health problem. Tissue and organ reconstruction have been regarded as promising therapeutic strategies. Here, we propose a regenerative methodology focusing on the provision of functionalized nanopeptide scaffolds to facilitate angiogenesis and neurogenesis at the brain injury site. The peptide RADA16-SVVYGLR undergoes self-assembly to construct an interconnected network with intertwining nanofibers, and can be controlled to display various physicochemical properties by the adjustment of microenvironmental factors such as pH and ion concentration. Such scaffolds can support endothelial cells to form tube-like structures and neural stem cells to survive and proliferate. In an in vivo zebrafish brain injury model, sprouting angiogenesis and developmental neurogenesis were achieved, and functional recovery of the severed optic tectum was enhanced in RADA16-SVVYGLR hydrogel-implanted zebrafish. This nanopeptide hydrogel was non-toxic to zebrafish embryos during early developmental stages. This angiogenic self-assembling peptide hydrogel had programmable physical properties, good biocompatibility, and regenerative ability for functional recovery in the injured brain. We suggest that functionalized self-assembling peptides encapsulated with neural stem cells or used alone could be an attractive and effective therapeutic modality for brain injury and diseases (e.g., trauma, stroke, tumor, degenerative neurological disorders, etc.).

Biomaterial Scaffolds in Regenerative Therapy of the Central Nervous System

“…PHPMA-RGD hydrogels containing brain-derived neurotrophic factors have been tested in a rat TBI model, with results showing the occurrence of axon regeneration and cell infiltration [ 157 ]. Self-assembling hydrogels, such as the RADA16-I hydrogel, also show the ability to promote regeneration of brain tissue and angiogenesis [ 158 , 159 ]. Hydrogels made from synthetic materials can be combined with the scaffold to increase its strength.…”

Regenerative Medicine Therapies for Targeting Neuroinflammation After Stroke

“…Therefore, crosslinking dictates the administration technique used for delivering hydrogel to the site of injury, with injectable hydrogels requiring crosslinking (gelation) to occur under physiological conditions [Figure 2 ; ( 109 , 110 )], whereas implanted hydrogels can be crosslinked in a controlled in vitro situation. Hydrogel injection has been achieved with both synthetic ( 43 , 111 , 112 ) and natural biopolymer hydrogels ( 109 , 113 – 115 ) for stroke and other CNS applications.…”

“…The interactions between implanted hydrogel and endogenous brain cells have the potential to induce many different reparative and anti-inflammatory cellular pathways, through binding of CAPs (including RGD, IKVAV, and YISGR motifs) to specific cell surface receptors ( 101 ). Anti-inflammatory targets of CAPs include; cell adhesion molecules (CAMs), which are involved in the recruitment and trafficking of leukocytes ( 51 , 116 ); integrin receptors, which in addition to having anti-inflammatory effects can have proangiogenic properties ( 115 , 117 , 118 ), reduce reactive gliosis ( 43 , 119 ) and promote the infiltration of neural progenitor cells to the site of injury ( 43 , 111 ); and growth factor receptors that can initiate similar anti-inflammatory effects ( 120 ). CAPs can also be used to mimic growth factors and initiate preferential cellular pathways.…”

A self-assembling peptide hydrogel for ultrarapid 3D bioassays

“…[28][29][30][31][32] The spontaneous bottom-up assembly of monomer peptide motifs can drive the formation of ordered supramolecular architectures in a tuneable and controlled manner, that can easily generate new functional so materials, including peptide hydrogels. [33][34][35][36] These materials are usually formed by entangled self-assembled nanobers that bundle to form a stable network that entraps water within it. Ordered noncovalent interactions are the key driving force for the assembly process, and they can confer stunning robustness to these brillar nanostructures.…”