Gelator Length Precisely Tunes Supramolecular Hydrogel Stiffness and Neuronal Phenotype in 3D Culture

Abstract

The brain is one of the softest tissues in the body with storage moduli (G') that range from hundreds to thousands of pascals (Pa) depending upon the anatomic region. Furthermore, pathological processes such as injury, aging and disease can cause subtle changes in the mechanical properties throughout the central nervous system. However, these changes in mechanical properties lie within an extremely narrow range of moduli and there is great interest in understanding their effect on neuron biology. We report here the design of supramolecular hydrogels based on anionic peptide amphiphile nanofibers using oligo-L-lysines of different molecular lengths to precisely tune gel stiffness over the range of interest and found that G' increases by 10.5 Pa for each additional lysine monomer in the oligo-L-lysine chain. We found that small changes in storage modulus on the order of 70 Pa significantly affect survival, neurite growth and tyrosine hydroxylase-positive population in dopaminergic neurons derived from induced pluripotent stem cells. The work reported here offers a strategy to tune mechanical stiffness of hydrogels for use in 3D neuronal cell cultures and transplantation matrices for neural regeneration.

Manipulation of Stem Cells Fates: The Master and Multifaceted Roles of Biophysical Cues of Biomaterials

“…Most recent studies have focused on the simulation of ECM stiffness in 2D or 3D biomaterials. Commonly used hydrogels such as hyaluronic acid (HA), [ 23 ] polyacrylamide, [ 17b ] polyethylene glycol (PEG), [ 24 ] and poly l ‐lactide (PLLA), [ 25 ] as well as natural compounds such as collagen, [ 26 ] fibrin, [ 27 ] and peptide amphiphiles, [ 28 ] have been utilized to rebuild ECM‐like properties.…”

“…Generally, biomaterial stiffness can be dynamically manipulated via stimulation with a magnet, [ 24a ] temperature, [ 18 ] crosslinking density, [ 28 ] ion concentration, [ 30 ] and pH. [ 31 ] For example, Wei et al.…”

Controlling Structure with Injectable Biomaterials to Better Mimic Tissue Heterogeneity and Anisotropy

“…[82] Further, these gels are degraded within a month in vivo with the degradation products being naturally occurring amino acids and lipids allowing for fast clearance [83] and their modulus can be tuned precisely by varying the chain length of oligo-llysines, which acts to crosslink the fibers. [84] Growth factors can be bound to the supramolecular assemblies as well for enhanced tissue regeneration. [83] Moreover, the hierarchical structure of the gels can be controlled much like the native ECM by modifying the cohesive forces between the peptide assemblies.…”

Recent Progress in the Design and Application of Supramolecular Peptide Hydrogels in Cancer Therapy

“…[105] Given that the concentration of salts must be limited within a tolerable range for biomedical application, Stupp and coworkers used oligo-L-lysines of different molecular lengths to precisely tune anionic gel stiffness and found that G′ increased by 10.5 Pa for each additional lysine monomer in the oligo-L-lysine chain. [106] In addition to these small molecular crosslinkers, macromolecules and even nanoparticles could be used to modulate the mechanical property of the hydrogels through non-specific or specific intermolecular interactions. Huang and coworkers demonstrated that mixing ovalbumin (OVA) protein with Nap-HHFF peptides can enhance the mechanical property up to 15-fold.…”