Fibrillar Hydrogels Research Articles

Long-Lived and Thermoresponsive Emulsion Foams Stabilized by Self-Assembled Saponin Nanofibrils and Fibrillar Network.

Nanofibrils from the self-assembly of the naturally occurring saponin glycyrrhizic acid (GA) can be used to produce an oil-in-water emulsion foam with a long-term stability. Through homogenization and aeration followed by rapid cooling, stable emulsion foams can be produced from the mixtures of sunflower oil and saponin nanofibrils. At high temperatures, the GA fibrils form a multilayer assembly at the interface, creating an interfacial fibrillar network to stabilize the oil droplets and air bubbles generated during homogenization. A subsequent rapid cooling can trigger the self-assembly of free GA fibrils in the continuous phase, forming a fibrillar hydrogel and thus trapping the oil droplets and air bubbles. The viscoelastic bulk hydrogel showed a high yield stress and storage modulus, which lead to a complete arrest of the liquid drainage and a strong slowdown of the bubble coarsening in emulsion foams. The jamming of the emulsion droplets in the liquid channels as well as around the bubbles was also found to be able to enhance the foam stability. We show that such stable foam systems can be destroyed rapidly and on demand by heating because of the melting of the bulk hydrogel. The reversible gel-sol phase transition of the GA hydrogel leads to thermoresponsive emulsion foams, for which the foam stability can be switched from stable to unstable states by simply raising the temperature. The emulsion foams can be further developed to be photoresponsive by incorporating internal heat sources such as carbon black particles, which can absorb UV irradiation and convert the absorbed light energy into heat. This new class of smart responsive emulsion foams stabilized by the natural, sustainable saponin nanofibrils has potential applications in the food, pharmaceutical, and personal care industries.

Human-based fibrillar nanocomposite hydrogels as bioinstructive matrices to tune stem cell behavior.

The extracellular matrix (ECM)-biomimetic fibrillar structure of platelet lysate (PL) gels along with their enriched milieu of biomolecules has drawn significant interest in regenerative medicine applications. However, PL-based gels have poor structural stability, which severely limits their performance as a bioinstructive biomaterial. Here, rod-shaped cellulose nanocrystals (CNC) are used as a novel approach to modulate the physical and biochemical microenvironment of PL gels enabling their effective use as injectable human-based cell scaffolds with a level of biomimicry that is difficult to recreate with synthetic biomaterials. The incorporation of CNC (0 to 0.61 wt%) into the PL fibrillar network during the coagulation cascade leads to decreased fiber branching, increased interfiber porosity (from 66 to 83%) and modulates fiber (from 1.4 ± 0.7 to 27 ± 12 kPa) and bulk hydrogel (from 18 ± 4 to 1256 ± 82 Pa) mechanical properties. As a result of these physicochemical alterations, nanocomposite PL hydrogels resist the typical extensive clot retraction (from 76 ± 1 to 24 ± 3 at day 7) and show favored retention of PL bioactive molecules. The feedback of these cues on the fate of human adipose-derived stem cells is evaluated, showing how it can be explored to modulate the commitment of encapsulated stem cells toward different genetic phenotypes without the need for additional external biological stimuli. These fibrillar nanocomposite hydrogels allow therefore the exploration of the outstanding biological properties of human-based PL as an efficient engineered ECM which can be tailored to trigger specific regenerative pathways in minimal invasive strategies.

A thermoreversible, photocrosslinkable collagen bio-ink for free-form fabrication of scaffolds for regenerative medicine.

As a biomaterial, collagen has been used throughout tissue engineering and regenerative medicine. Collagen is native to the body, is highly biocompatible, and naturally promotes cell adhesion and regeneration. However, collagen fibers and the inherent weak mechanical properties of collagen hydrogels interfere with further development of collagen as a bio-ink. Herein, we demonstrate the use of a modified type-I collagen, collagen methacrylamide (CMA), as a fibril-forming bio-ink for free-form fabrication of scaffolds. Like collagen, CMA can self-assemble into a fibrillar hydrogel at physiological conditions. In contrast, CMA is photocrosslinkable and thermoreversible, and photocrosslinking eliminates thermoreversibility. Free-form fabrication of CMA was performed through self-assembly of the CMA hydrogel, photocrosslinking the structure of interest using a photomask, and cooling the entire hydrogel, which results in cold-melting of unphotocrosslinked regions. Printed hydrogels had a resolution on the order of ~350 μm, and can be fabricated with or without cells and maintain viability or be further processed into freeze-dried sponges, all while retaining pattern fidelity. A subcutaneous implant study confirmed the biocompatibility of CMA in comparison to collagen. Free-form fabrication of CMA allows for printing of macroscale, customized scaffolds with good pattern fidelity and can be implemented with relative ease for continued research and development of collagen-based scaffolds in tissue engineering.

Multiple Water-in-Oil-in-Water Emulsion Gels Based on Self-Assembled Saponin Fibrillar Network for Photosensitive Cargo Protection.

A gelled multiple water-in-oil-in-water (W1/O/W2) emulsion was successfully developed by the unique combination of emulsifying and gelation properties of natural glycyrrhizic acid (GA) nanofibrils, assembling into a fibrillar hydrogel network in the continuous phase. The multiple emulsion gels had relatively homogeneous size distribution, high yield (85.6-92.5%), and superior storage stability. The multilayer interfacial fibril shell and the GA fibrillar hydrogel in bulk can effectively protect the double emulsion droplets against flocculation, creaming, and coalescence, thus contributing to the multiple emulsion stability. Particularly, the highly viscoelastic bulk hydrogel had a high storage modulus, which was found to be able to strongly prevent the osmotic-driven water diffusion from the internal water droplets to the external water phase. We show that these multicompartmentalized emulsion gels can be used to encapsulate and protect photosensitive water-soluble cargos by loading them into the internal water droplets. These stable multiple emulsion gels based on natural, sustainable saponin nanofibrils have potential applications in the food, pharmaceutical, and personal care industries.

Rational Design of Short Peptide-Based Hydrogels with MMP-2 Responsiveness for Controlled Anticancer Peptide Delivery.

Molecular self-assembly makes it feasible to harness the structures and properties of advanced materials via initial molecular design. To develop short peptide-based hydrogels with stimuli responsiveness, we designed here short amphiphilic peptides by engineering protease cleavage site motifs into self-assembling peptide sequences. We demonstrated that the designed Ac-I3SLKG-NH2 and Ac-I3SLGK-NH2 self-assembled into fibrillar hydrogels and that the Ac-I3SLKG-NH2 hydrogel showed degradation in response to MMP-2 but the Ac-I3SLGK-NH2 hydrogel did not. The cleavage of Ac-I3SLKG-NH2 into Ac-I3S and LKG-NH2 was found to be mechanistically responsible for the enzymatic degradation. Finally, when an anticancer peptide G(IIKK)3I-NH2 (G3) was entrapped into Ac-I3SLKG-NH2 hydrogels, its release was revealed to occur in a "cell-demanded" way in the presence of HeLa cells that overexpress MMP-2, therefore leading to a marked inhibitory effect on their growth on the gels.

Triggered Formation of Anionic Hydrogels from Self-Assembling Acidic Peptide Amphiphiles

Peptide amphiphiles represent a growing class of self-assemblers capable of forming a wide array of superstructures that can display targeted function. The electrostatic charge of the amphiphile is an important design attribute that can greatly influence the physical, mechanical, and biological properties of the resultant self-assembled material in which the peptide is contained in high copy number. We have previously reported the design of cationic amphiphiles that assemble into highly positively charged hydrogels. Herein, we report a new class of anionic β-hairpin peptide amphiphiles that undergo pH- and temperature-triggered folding and self-assembly into negatively charged fibrillar hydrogels capable of shear-thin/recovery mechanical behavior. The influence of amino acid composition on material formation, local fibril morphology, and mechanical properties is defined and allowed the iterative design of gels capable of three-dimensional encapsulation of mesenchymal stem cells under physiological conditions.

A Note on the Role of Spatial Scale in Imaging Collagen Hydrogels

Fibrillar collagen hydrogels have been used widely as bioactive scaffolds for multiple applications in biomedical and tissue engineering. The physical functions of collagen fibrils are regulated by their underlying microstructure—represented by fibrillar density and orientation. The extent to which characterization techniques are used for imaging collagen fibrillar networks has significantly reduced the usefulness of published data for biomedical engineers. This short communication explains the level of uncertainty surrounding fibrillar orientation measurements. It is discussed how a correlation between the orientation of collagen fibrils and normal distribution function can provide a robust baseline for comparative research in imaging collagen.

Molecular, Local, and Network-Level Basis for the Enhanced Stiffness of Hydrogel Networks Formed from Coassembled Racemic Peptides: Predictions from Pauling and Corey.

Hydrogels prepared from self-assembling peptides are promising materials for medical applications, and using both l- and d-peptide isomers in a gel’s formulation provides an intuitive way to control the proteolytic degradation of an implanted material. In the course of developing gels for delivery applications, we discovered that a racemic mixture of the mirror-image β-hairpin peptides, named MAX1 and DMAX1, provides a fibrillar hydrogel that is four times more rigid than gels formed by either peptide alone—a puzzling observation. Herein, we use transmission electron microscopy, small angle neutron scattering, solid state NMR, diffusing wave, infrared, and fluorescence spectroscopies, and modeling to determine the molecular basis for the increased mechanical rigidity of the racemic gel. We find that enantiomeric peptides coassemble in an alternating fashion along the fibril long axis, forming an extended heterochiral pleat-like β-sheet, a structure predicted by Pauling and Corey in 1953. Hydrogen bonding between enantiomers within the sheet dictates the placement of hydrophobic valine side chains in the fibrils’ dry interior in a manner that allows the formation of nested hydrophobic interactions between enantiomers, interactions not accessible within enantiomerically pure fibrils. Importantly, this unique molecular arrangement of valine side chains maximizes inter-residue contacts within the core of the fibrils resulting in their local stiffening, which in turn, gives rise to the significant increase in bulk mechanical rigidity observed for the racemic hydrogel.

Cross-Linking and Bundling of Self-Assembled Protein-Based Polymer Fibrils via Heterodimeric Coiled Coils.

Previously, we developed triblock protein polymers that form fibrillar hydrogels at low protein polymer concentrations (denoted C2-SH48-C2). We here demonstrate that the structure of these hydrogels can be tuned via heterodimeric coiled coils that cross-link and bundle the self-assembled protein polymer fibrils. We fused well-characterized, 47 amino acids-long heterodimeric coiled coil "linkers" (DA or DB) to the C-terminus of the triblock polymer. The resulting C2-SH48-C2-DA and C2-SH48-C2-DB polymers, were successfully produced as secreted proteins in Pichia pastoris, with titers of purified protein in the order of g L-1 of clarified broth. Atomic force microscopy showed that fibrils formed by either C2-SH48-C2-DA or C2-SH48-C2-DB alone already displayed extensive bundling, apparently as a result of homotypic (DA/DA and DB/DB) interactions. For fibrils prepared from protein polymers having no linkers, plus a small fraction of polymers containing either DA or DB linkers, no cross-linking and bundling was observed. At these same low concentrations of linkers, fibrils containing both the DA and the DB linkers did show cross-linking and bundling as a consequence of heterodimer formation. This work shows that we can control the extent of bundling and cross-linking of supramolecular fibrils by varying the density of heterodimerizing coiled coils in the fibrils, which is promising for the further development of materials that mimic the extracellular matrix.

Fibrin structural and diffusional analysis suggests that fibers are permeable to solute transport.

Fibrin is a natural biopolymer that has drawn much interest as a biomimetic carrier in tissue engineering applications. We hereby use a novel combined approach for the structural characterization of fibrin networks based on optical microscopy and light scattering methods that can also be applied to other fibrillar hydrogels, like collagen. Furthermore, our findings on the relation between solute transport and fibrin structural properties can lead to the optimized design of fibrin hydrogel constructs for controlled release applications. Finally, we provide new evidence for the fact that fibrin fibers may be permeable for solutes with a molecular weight comparable to that of growth factors. This finding may open new avenues for tailoring mass transport properties of fibrin carriers.

Abstract 2171: Beta-hairpin peptide hydrogels as scaffolds for 3D high-throughput cancer drug discovery

Abstract High-throughput screening (HTS) remains a promising initial step in discovering novel lead compounds for cancer therapy, but its value is limited by the poor predictability of clinical effectiveness of candidate compounds. One compelling reason for this lack of reliability to predict in vivo efficacy is the fact that most HTS is done using traditional two-dimensional (2D) cell cultures. While 2D cultures are convenient and can easily be automated, compelling evidence suggests that cells cultured in these non-physiological conditions differ from cells grown in the more in vivo like three-dimensional (3D) systems that better mimic microenvironments. Thus, a 3D culture model is expected to be a better platform for cancer drug discovery. Here we demonstrate the feasibility of a beta-hairpin hydrogel as a novel platform for 3D HTS. MAX8 forms a bonded fibrillar hydrogel network under physiological conditions and moreover, due to its unique shear-thinning abilities can be incorporated into standard HTS equipment. MAX8 is biocompatible with a variety of cancer cell lines, can be tuned for porosity, permeability and stiffness, and can be functionalized with common and cell-type specific ligands to more closely resemble an in vivo-like tumor environment. Using medulloblastoma cells that are known to display more immature, tumor-like features in 3D and that were automatically dispensed onto 384-well plates we have developed a robust assay to measure cell viability on a HTS platform that will have broad applicability for other cancers for which 3D HTS is desirable. Citation Format: Peter Worthington, Katherine M. Drake, Andrew D. Napper, Darrin J. Pochan, Sigrid A. Langhans. Beta-hairpin peptide hydrogels as scaffolds for 3D high-throughput cancer drug discovery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2171.

Preparation of 3D Collagen Gels and Microchannels for the Study of 3D Interactions <em>In Vivo</em>

Historically, most cellular processes have been studied in only 2 dimensions. While these studies have been informative about general cell signaling mechanisms, they neglect important cellular cues received from the structural and mechanical properties of the local microenvironment and extracellular matrix (ECM). To understand how cells interact within a physiological ECM, it is important to study them in the context of 3 dimensional assays. Cell migration, cell differentiation, and cell proliferation are only a few processes that have been shown to be impacted by local changes in the mechanical properties of a 3-dimensional ECM. Collagen I, a core fibrillar component of the ECM, is more than a simple structural element of a tissue. Under normal conditions, mechanical cues from the collagen network direct morphogenesis and maintain cellular structures. In diseased microenvironments, such as the tumor microenvironment, the collagen network is often dramatically remodeled, demonstrating altered composition, enhanced deposition and altered fiber organization. In breast cancer, the degree of fiber alignment is important, as an increase in aligned fibers perpendicular to the tumor boundary has been correlated to poorer patient prognosis1. Aligned collagen matrices result in increased dissemination of tumor cells via persistent migration2,3. The following is a simple protocol for embedding cells within a 3-dimensional, fibrillar collagen hydrogel. This protocol is readily adaptable to many platforms, and can reproducibly generate both aligned and random collagen matrices for investigation of cell migration, cell division, and other cellular processes in a tunable, 3-dimensional, physiological microenvironment.

Preparation of 3D Collagen Gels and Microchannels for the Study of 3D Interactions In Vivo.

Historically, most cellular processes have been studied in only 2 dimensions. While these studies have been informative about general cell signaling mechanisms, they neglect important cellular cues received from the structural and mechanical properties of the local microenvironment and extracellular matrix (ECM). To understand how cells interact within a physiological ECM, it is important to study them in the context of 3 dimensional assays. Cell migration, cell differentiation, and cell proliferation are only a few processes that have been shown to be impacted by local changes in the mechanical properties of a 3-dimensional ECM. Collagen I, a core fibrillar component of the ECM, is more than a simple structural element of a tissue. Under normal conditions, mechanical cues from the collagen network direct morphogenesis and maintain cellular structures. In diseased microenvironments, such as the tumor microenvironment, the collagen network is often dramatically remodeled, demonstrating altered composition, enhanced deposition and altered fiber organization. In breast cancer, the degree of fiber alignment is important, as an increase in aligned fibers perpendicular to the tumor boundary has been correlated to poorer patient prognosis(1). Aligned collagen matrices result in increased dissemination of tumor cells via persistent migration(2,3). The following is a simple protocol for embedding cells within a 3-dimensional, fibrillar collagen hydrogel. This protocol is readily adaptable to many platforms, and can reproducibly generate both aligned and random collagen matrices for investigation of cell migration, cell division, and other cellular processes in a tunable, 3-dimensional, physiological microenvironment.

Production of Highly Aligned Collagen Scaffolds by Freeze-drying of Self-assembled, Fibrillar Collagen Gels.

Matrix and cellular alignment are critical factors in the native function of many tissues, including muscle, nerve, and ligaments. Collagen is frequently a component of these aligned tissues, and collagen biomaterials are widely used in tissue engineering applications. However, the generation of aligned collagen scaffolds that maintain the native architecture of collagen fibrils has not been straightforward, with many methods requiring specialized equipment or technical procedures, extensive incubation times, or denaturing of the collagen. Herein, we present a simple, rapid method for fabrication of highly aligned collagen scaffolds. Collagen was assembled to form a fibrillar hydrogel in a cylindrical conduit with high aspect ratio and then frozen and lyophilized. The resulting collagen scaffolds demonstrated highly aligned topographical features along the scaffold surface. This presence of an initial fibrillar network and the high-aspect ratio vessel were both required to generate alignment. The diameter of fabricated scaffolds was found to vary significantly with both the collagen concentration of the hydrogel suspension and the diameter of conduits used for fabrication. Additionally, the size of individual aligned topographical features was significantly dependent on the conduit diameter and the freezing temperature. When cultured on aligned collagen scaffolds, both rat dermal fibroblasts and axons emerging from chick dorsal root ganglia explants demonstrated elongated, aligned morphology and growth on the aligned topographical features. Overall, this method presents a simple means for generating aligned collagen scaffolds that can be applied to a wide variety of tissue types, particularly those where such alignment is critical to native function.

Hierarchically aligned fibrillar fibrin hydrogel designed for spinal cord injury repair

Event Abstract Back to Event Hierarchically aligned fibrillar fibrin hydrogel designed for spinal cord injury repair Xiumei Wang1* and Shenglian Yao1* 1 Tsinghua University, School of Materials Science and Engineering, China Biomaterial-based strategies for nerve regeneration have attracted extensive attentions in recent years. In this study, a hierarchical aligned fibrillar fibrin hydrogel was prepared through electrospinning technique and the concurrent molecular self-assembly process at the moment of collection. The aligned fibrin hydrogel that simulated the elasticity and oriented structures of nerve tissue simultaneously provided biomimetically biophysical cues to direct in vivo or in vitro cells thus constructing nerve-like microtissues rapidly. In vitro studies showed that human umbilical cord mesenchymal stem cells could “feel” the cues afforded by aligned fibrin gels and extend along the long axis of the fibers soon after cell attachment and undergo strong neural differentiation after two weeks cell culture in regular growth medium without any soluble growth factors. More interestingly, the rat dorsal root ganglion neurons also could follow the fiber structure in a highly oriented longitudinal manner with three-dimensionally neurite elongation to total 3.92 mm just in 3 days basic culture. In rat T9 dorsal hemisection spinal cord injury. the host neural cells with β-tubulin III-positive migrated into the aligned fibrin hydrogels very quickly. And the axon reconstruction and locomotor performance was improved starting from 2 weeks after the surgery in the aligned fibrin hydrogel group. Our study suggested that the hierarchically aligned fibrillar fibrin hydrogels will not only have great promising for directing stem cells towards nerve lineage, but also may have great potential applications in spinal cord regeneration. Tsinghua University Initiative Scientific Research Program (20121087982, 20131089199); 973 Program (No. 2011CB606205)

Co-effects of matrix low elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth

The development of novel biomaterials that deliver precise regulatory signals to direct stem cell fate for nerve regeneration is the focus of current intensive research efforts. In this study, a hierarchically aligned fibrillar fibrin hydrogel (AFG) that was fabricated through electrospinning and the concurrent molecular self-assembly process mimics both the soft and oriented features of nerve tissue, thus providing hybrid biophysical cues to instruct cell behavior in vitro and in vivo. The electrospun hydrogels were examined by scanning electron microscopy (SEM), polarized light microscopy, small angle X-ray scattering assay and atomic force microscopy (AFM), showing a hierarchically linear-ordered structure from the nanoscale to the macroscale with a soft elastic character (elasticity ∼1 kPa). We found that this low elasticity and aligned topography of AFG exhibit co-effects on promoting the neurogenic differentiation of human umbilical cord mesenchymal stem cells (hUMSCs) in comparison to random fibrin hydrogel (RFG) and tissue culture plate (TCP) control after two week cell culture in growth medium lacking supplementation with soluble neurogenic induction factors. In addition, AFG also induces dorsal root ganglion (DRG) neurons to rapidly project numerous long neurite outgrowths longitudinally along the AFG fibers for a total neurite extension distance of 1.96 mm in three days in the absence of neurotrophic factor supplementation. Moreover, the AFG implanted in a rat T9 dorsal hemisection spinal cord injury model was found to promote endogenous neural cell fast migration and axonal invasion along AFG fibers, resulting in aligned tissue cables in vivo. Our results suggest that matrix stiffness and aligned topography may instruct stem cell neurogenic differentiation and rapid neurite outgrowth, providing great promise for biomaterial design for applications in nerve regeneration.

Osteogenic differentiation of human mesenchymal stem cells promotes mineralization within a biodegradable peptide hydrogel

An attractive strategy for the regeneration of tissues has been the use of extracellular matrix analogous biomaterials. Peptide-based fibrillar hydrogels have been shown to mimic the structure of extracellular matrix offering cells a niche to undertake their physiological functions. In this study, the capability of an ionic-complementary peptide FEFEFKFK (F, E, and K are phenylalanine, glutamic acid, and lysine, respectively) hydrogel to host human mesenchymal stem cells in three dimensions and induce their osteogenic differentiation is demonstrated. Assays showed sustained cell viability and proliferation throughout the hydrogel over 12 days of culture and these human mesenchymal stem cells differentiated into osteoblasts simply upon addition of osteogenic stimulation. Differentiated osteoblasts synthesized key bone proteins, including collagen-1 (Col-1), osteocalcin, and alkaline phosphatase. Moreover, mineralization occurred within the hydrogel. The peptide hydrogel is a naturally biodegradable material as shown by oscillatory rheology and reversed-phase high-performance liquid chromatography, where both viscoelastic properties and the degradation of the hydrogel were monitored over time, respectively. These findings demonstrate that a biodegradable octapeptide hydrogel can host and induce the differentiation of stem cells and has the potential for the regeneration of hard tissues such as alveolar bone.

Hierarchical Structure of the Fibrillar Hydrogel Network of a Self‐Assembled Synthetic Peptide Revealed by X‐ray Scattering and Atmospheric Scanning Electron Microscopy

SummaryWe herein developed a self‐assembling peptide with the ability to form a gel in water at pH ∼7 (SPG‐178 (a self‐assembling peptide gel with the amino acid sequence #178; [CH3CO]‐RLDLRLALRLDLR‐[NH2]; R = arginine, L = leucine, D = aspartic acid, and A = alanine). Leucine residues were employed to increase the hydrophobic interaction of SPG‐178 in water, which was one of the important driving forces of self‐assembly, and stabilize fibrillar hydrogel formation. The hierarchical structure of the fibrillar hydrogel of the peptide was analyzed using small/wide angle X‐ray scattering measurements (SAXS and WAXS), atomic force microscopy (AFM), transmission electron microscopy (TEM), and atmospheric scanning electron microscopy (ASEM). SAXS, AFM, and TEM measurements revealed the fibril nano‐structure of the self‐assembled peptide; the width of the fibril was ∼5 nm, which coincided with the length of one molecule in the β‐sheet structure revealed by FT‐IR and WAXS in water. ASEM permitted in situ observations, even in water, without freezing. The fibrillar network structure of the gel (micrometer scale) was directly visualized using ASEM measurements.

Hierarchical Structure of the Fibrillar Hydrogel Network of a Self‐Assembled Synthetic Peptide Revealed by X‐ray Scattering and Atmospheric Scanning Electron Microscopy

Hierarchical Structure of the Fibrillar Hydrogel Network of a Self‐Assembled Synthetic Peptide Revealed by X‐ray Scattering and Atmospheric Scanning Electron Microscopy

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

SummaryThe mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.