We have developed a class of self-assembling peptides that undergo triggered hydrogelation in response to physiological conditions to afford mechanically rigid, viscoelastic hydrogels. These gels display shear-thin recovery behavior that allows them to be syringe delivered. Peptides that comprise a given gel are small (20 residues), de novo designed beta-hairpins composed of two beta-strands of alternating hydrophobic and hydrophobic residues. A tetrapeptide (-VdPPT-) sequence with a high propensity to form a type II beta-turn centrally connects the two strands. In low ionic strength, aqueous solutions, peptides are freely soluble and remain unfolded due to electrostatic repulsions between the hydrophilic residues. Increasing the ionic strength of the solution by adjusting the NaCl concentration to 150 mM (physiologically relevant salt concentration) screens some of this charge and promotes the folding of the peptides into facially amphiphilic beta-hairpin structures. In addition to adjusting the ionic strength, increasing the temperature also triggers folding by driving the hydrophobic effect. Folded hairpins subsequently self assemble to form a physically cross-linked network of fibrils. Although discussed as separate events, biophysical analysis suggests that the folding and self-assembly events are linked equilibria. Small angle neutron scattering and transmission electron microscopy data show that the hairpins self-assemble laterally by forming a network of intermolecular hydrogen bonds that define the long axis of a given fibril;all the beta-strands of the assembled hairpins are in register affording fibrils of distinct diameter ( 3 nm). Peptides also assemble in a facial manner by burying their hydrophobic residues to form a bilayer that defines the thickness of a given fibril as demonstrated by AFM. Along the long axis of a given fibril, bilayer formation occurs in a regular fashion with one hairpin docked, and in register, with its partner. This arrangement shields the maximal amount of hydrophobic surface area from water. However, as shown by cryo-TEM and oscillatory rheology, imperfections in this mechanism occur where the face of one hairpin is rotated relative to its partner in the bilayer. This results in a site for nascent fibril growth in a new three-dimensional direction and constitutes the formation of an inter-fibril crosslink. These inter-fibril crosslinks, in addition to fibril entanglements, are physical crosslinks that define the mechanical rigidity of a given gel. By linking the triggered folding event to self-assembly, hydrogel materials can be made with temporal and spatial resolution. We have shown that peptide folding and assembly can be triggered in the presence of small molecules and proteins to directly encapsulate these molecules within the resulting hydrogel network. The resulting loaded gel can be easily delivered to a secondary site via syringe where it can subsequently release its payload. Hydrogel materials are promising vehicles for the delivery of protein therapeutics. Proteins can impart physical interactions, both steric and electrostatic in nature, that influence their release from a given gel network. For example, model proteins of varying hydrodynamic diameter and charge can be directly encapsulated and their release studied from electropositive fibrillar hydrogels prepared from the self assembling peptide, MAX8. Hydrogelation of MAX8 can be triggered in the presence of proteins for their direct encapsulation with no effect on protein structure nor the hydrogels mechanical properties. Bulk release of the encapsulated proteins from the hydrogels was assessed for a month time period at 37 degrees Celsius before and after syringe delivery of the loaded gels to determine the influence of protein structure on release. Release of positively charged and neutral proteins was largely governed by the sterics imposed by the network. Conversely, negatively charged proteins interacted strongly with the positively charged fibrillar network, greatly restricting their release to 200 nm) hydrogel domains during flow. After cessation of flow the large hydrogel domains are immediately percolated which immediately reforms the solid hydrogel. In addition to the work outlined above, we have also published manuscripts describing how we: 1) Developed a family of peptide gels whose rate of degradation can be controlled by metalloproteinase-13 enzymatic action;2) Developed new synthetic chemistry that allows the preparation of non-natural amino acids. Here, we designed and prepared a Cu(II) chiral auxiliary that enables enhanced stereoselectivity;3) Developed new photopolymerization chemistry that allows chemical crosslinking of the peptide-based gels after shear thin delivery;4) We have designed novel protein-based hydrogels that take advantage of domain-swapping events during their formulation;5) In collaboration, we have extended the design of the hairpin hydrogels to enable biomineraliztion;6) We have demonstrated that silica networks can be grown using the gel network as a nano-scaffold;basic science toward hard tissue engineering. This basic science ultimately leads to the discovery of novel materials for biomedical use.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Yamada, Yuji; Chowdhury, Ananda; Schneider, Joel P et al. (2018) Macromolecule-Network Electrostatics Controlling Delivery of the Biotherapeutic Cell Modulator TIMP-2. Biomacromolecules 19:1285-1293
Shi, Junfeng; Fichman, Galit; Schneider, Joel P (2018) Enzymatic Control of the Conformational Landscape of Self-Assembling Peptides. Angew Chem Int Ed Engl 57:11188-11192
Nagarkar, Radhika P; Miller, Stephen E; Zhong, Sheng et al. (2018) Dynamic protein folding at the surface of stimuli-responsive peptide fibrils. Protein Sci 27:1243-1251
Medina, Scott H; Michie, Megan S; Miller, Stephen E et al. (2017) Fluorous Phase-Directed Peptide Assembly Affords Nano-Peptisomes Capable of Ultrasound-Triggered Cellular Delivery. Angew Chem Int Ed Engl 56:11404-11408
Nagy-Smith, Katelyn; Beltramo, Peter J; Moore, Eric et al. (2017) Molecular, Local, and Network-Level Basis for the Enhanced Stiffness of Hydrogel Networks Formed from Coassembled Racemic Peptides: Predictions from Pauling and Corey. ACS Cent Sci 3:586-597
Schneider, Joel (2016) Towards peptide vaccines for influenza. Biopolymers :
Yamada, Yuji; Schneider, Joel P (2016) Fragmentation of Injectable Bioadhesive Hydrogels Affords Chemotherapeutic Macromolecules. Biomacromolecules 17:2634-41
Schneider, Joel (2016) Pulsed electron-electron double resonance, peptaibols and chlorotoxin in review. Biopolymers 106:5
Smith, Daniel J; Brat, Gabriel A; Medina, Scott H et al. (2016) A multiphase transitioning peptide hydrogel for suturing ultrasmall vessels. Nat Nanotechnol 11:95-102
Schneider, Joel (2016) Synthesis, peptoids and yellow pseudo peptides. Biopolymers 106:632-3

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