Self-Assembling Hydrogel Structures for Neural Tissue Repair

Abstract

Hydrogel materials have been employed as biological scaffolds for tissue regeneration across a wide range of applications. Their versatility and biomimetic properties make them an optimal choice for treating the complex and delicate milieu of neural tissue damage. Aside from finely tailored hydrogel properties, which aim to mimic healthy physiological tissue, a minimally invasive delivery method is essential to prevent off-target and surgery-related complications. The specific class of injectable hydrogels termed self-assembling peptides (SAPs), provide an ideal combination of in situ polymerization combined with versatility for biofunctionlization, tunable physicochemical properties, and high cytocompatibility. This review identifies design criteria for neural scaffolds based upon key cellular interactions with the neural extracellular matrix (ECM), with emphasis on aspects that are reproducible in a biomaterial environment. Examples of the most recent SAPs and modification methods are presented, with a focus on biological, mechanical, and topographical cues. Furthermore, SAP electrical properties and methods to provide appropriate electrical and electrochemical cues are widely discussed, in light of the endogenous electrical activity of neural tissue as well as the clinical effectiveness of stimulation treatments. Recent applications of SAP materials in neural repair and electrical stimulation therapies are highlighted, identifying research gaps in the field of hydrogels for neural regeneration.

Keywords: bioactive; conductive biomaterials; neuroengineering; neuroregeneration; peptide synthesis; review; scaffold; self-assembling peptides; tissue engineering.

Figure 1

Effect of material stiffness on neural stem cell fate in vitro. A stiffness of around 1 kPa allows the presence of a mixed neural population, whereas excessively high or low values decrease cell survival. Reproduced with permission from ref (18). Copyright 2012 Elsevier.

Figure 2

Design criteria for a neural scaffold can be divided into four categories: biological cues, mechanical properties, architecture and topography, and conductive properties.

Figure 3

Possible self-assembled structures secondary and tertiary structures of (a) linear peptides and (b) cyclical peptides Adapted with permission from ref (212). Copyright 2010 Royal Society of Chemistry.

Figure 4

Schematic illustrations of self-assembled structures formed from various building blocks. (a) Amphiphilic building blocks adopting different morphologies. Reprinted with permission from ref (240). Copyright 2014 Royal Society of Chemistry. (b) Trigonal building blocks yielding different structures and morphologies. Reprinted with permission from ref (209). Copyright 2013 Royal Society of Chemistry.

Figure 5

Effect of pH and concentration on self-assembly. (a) pH-dependent micellar, fibrillar, or dispersed topography. Reprinted with permission from ref (233). Copyright 2012 American Chemical Society. (b) Schematic illustration of pH change leading to the formation of nanobelts and varying concentration leading to a change in morphology from plaques to nanoribbons; (c) schematic illustration of morphology changes due to change in concentration. Reprinted with permission from ref (235). Copyright 2009 American Chemical Society.

Figure 6

SAP PA-IKVAV. (A) Molecular structure composed of four functional regions dedicated to different functions, highlighting the versatility and multifunctionality of SAP systems. (B) Molecular graphics of the PA-IKVAV molecules, also assembled into a nanofiber. (C, D) Scanning electron microscopy and transmission electron microscopy (respectively) of self-assembled PA-IKVAV nanofibers. Reproduced with permission from refs (276) and (273). Copyright 2004 The American Association for the Advancement of Science and 2010 John Wiley and Sons.

Figure 7

In vivo effect of a SAP biofunctionalized with the adhesive molecule IKVAV and the growth factor GDNF in a Parkinson’s disease murine model. (a, b) The effect of the functionalized hydrogel is more pronounced than the cell implanted alone, as shown by the GFP+ cell density 10 weeks post-transplantation. The transplant has different outcomes in vivo, where (c) the cell line alone showed a lower graft survival than (d) the cells with the SAP N-fluorenylmethyloxycarbonyl (Fmoc)-DIKVAV and (e) the SAP combined with the GDNF growth factor. Reproduced with permission from ref (282). Copyright 2017 John Wiley and Sons.

Figure 8

Alignment of π-conjugated peptide hydrogel using shear flow assembly. Reproduced with permission from ref (368). Copyright Advanced Materials 2011.

Figure 9

Methods for increasing conductivity of π-conjugated self-assembling systems. (a) SEM of self-doping PPy-TB and (c) Molecular structure of PPy-TB. Reprinted with permission from ref (374). Copyright 2019 American Chemical Society. (b) Schematic of EDOT–OH polymerization along the fiber axis. Reprinted with permission from ref (372). Copyright 2013 American Chemical Society.