We have developed a class of hydrogels for the direct encapsulation of therapeutics and their subsequent localized delivery via syringe/catheter. Hydrogels have been formulated using beta-hairpin 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. 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. When gelation is triggered in the presence of small molecules, other peptides, proteins or cells, these potential therapeutics are directly encapsulated. The shear thin-recovery property of the loaded gel allows it direct delivery by syringe.To understand how the gel responds to shear force during delivery, we studied hydrogel behavior during flow in a cylindrical capillary geometry that mimicked the actual situation of injection through a syringe needle. This also allowed us to quantify effects of shear-thin injection delivery on encapsulated cell payloads. Hydrogels investigated displayed a promising flow profile for injectable cell delivery: a central wide plug flow region where gel material and cell payloads experienced little or no shear rate, and a narrow shear zone close to the capillary wall where gel and cells were subject to shear deformation. The width of the plug flow region was found to be weakly dependent on hydrogel rigidity and flow rate. Live-dead assays were performed on encapsulated MG63 cells 3 h after injection flow and revealed that shear-thin delivery through the capillary had little impact on cell viability and the spatial distribution of encapsulated cell payloads. These observations help us to fundamentally understand how the gels flow during injection through a thin catheter and how they immediately restore mechanically and morphologically relative to preflow, static gels.In addition to exploring the potential clinical applications of these materials, we are also interested in studying their mechanical/rheological properties and network structures. 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). Chirality can be used as a design tool to control the mechanical rigidity of hydrogels formed from self-assembling peptides. In the course of our studies, we have discovered that hydrogels prepared from enantiomeric mixtures of self-assembling beta-hairpins show non-additive, synergistic, enhancement in material rigidity compared to gels prepared from either pure enantiomer, with the racemic hydrogel showing the greatest effect. CD spectroscopy, TEM, and AFM indicate that this enhancement is defined by nanoscale interactions between enantiomers in the self-assembled state. We are currently working towards a molecular and network level understanding of the structure and the interactions responsible for the enhancement in material rigidity. In addition to the beta hairpin peptides, we also developed a class of linear peptides that undergo triggered gelation. Under non-gelling aqueous conditions, these peptides exist in a random coil conformation and peptide solutions have the viscosity of water. On the addition of a buffered saline solution, the peptides assemble into a beta-sheet rich network of fibrils ultimately leading to hydrogelation. A family of nine peptides was prepared to study the influence of peptide length and amino acid composition on the rate of self-assembly and hydrogel material properties. The amino acid composition is modulated by varying residue hydrophobicity and hydrophilicity on the two opposing faces of the amphiphile. One weight percent gels formed under physiological conditions have moduli values that vary from 20 to 800 Pa, with sequence length and hydrophobic character playing a dominate roll in defining hydrogel rigidity. Based on the structural and functional data provided by the nine-peptide family members, an optimal sequence, namely LK13, was evolved. LK13 (LKLKLKLKLKLKL-NH2) undergoes triggered self-assembly, affording the most rigid gel of those studied (storage modulus =797 +/- 105). It displays shear thin-recovery behavior, allowing its delivery by syringe and is cytocompatibile as assessed with murine C3H10t1/2 mesenchymal stem cells. The shear thinning-self healing properties of both the linear and beta-hairpin gels allow their local delivery.In addition to the work outlined above, we have also published manuscripts describing how we: 1) Developed a class of peptide hydrogels whose gelation is triggered by heavy metal ion complexation. 2) Developed a family of peptide gels whose rate of degradation can be controlled by metalloproteinase-13 enzymatic action. 3) Demonstrated that circumin, an anticancer small molecule, can be controllably released from specifically formulated gels. 4) Accomplished the total synthesis of Fmoc-L-gamma-carboxyglutamic Acid via the newly developed stereoselective Cu(II) complex chiral auxiliary. 5) Developed a new class of zinc-triggered hydrogels.This basic science ultimately leads to the discovery of novel materials for biomedical use.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
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
Sun, Jessie E P; Stewart, Brandon; Litan, Alisa et al. (2016) Sustained release of active chemotherapeutics from injectable-solid ?-hairpin peptide hydrogel. Biomater Sci 4:839-48
Medina, Scott H; Schneider, Joel P (2015) Cancer cell surface induced peptide folding allows intracellular translocation of drug. J Control Release 209:317-26
Lindsey, Stephan; Piatt, Joseph H; Worthington, Peter et al. (2015) Beta Hairpin Peptide Hydrogels as an Injectable Solid Vehicle for Neurotrophic Growth Factor Delivery. Biomacromolecules 16:2672-83
Medina, Scott H; Li, Sandra; Howard, O M Zack et al. (2015) Enhanced immunostimulatory effects of DNA-encapsulated peptide hydrogels. Biomaterials 53:545-53

Showing the most recent 10 out of 34 publications