Self-Assembling Multidomain Peptide Nanofibers for Delivery of Bioactive Molecules and Tissue Regeneration

Abstract

ConspectusMultidomain peptides (MDPs) are a class of self-assembling peptides that are organized in a β-sheet motif, resulting in a nanofibrous architecture. This structure is stabilized by hydrophobic packing in the fiber core and a hydrogen-bonding network down the fiber long axis. Under easily controllable conditions, regulated by electrostatic interactions between the peptides and the pH and salt composition of the solvent, the nanofiber length can be dramatically extended, resulting in fiber entanglement and hydrogel formation. One of the chief strengths of this supramolecular material is that the design criteria governing its structure and assembly are robust and permit a wide range of modifications without disruption. This allows the MDPs to be tailored to suit a wide range of applications, particularly in biomedical engineering. For example, delivery of small molecules, proteins, and cells is easily achievable. These materials can be trapped within the matrices of the hydrogel or trapped within the hydrophobic core of the nanofiber, depending on the cargo and the design of the MDP. Interactions between the nanofibers and their cargo can be tailored to alter the release profile, and in the most sophisticated cases, different cargos can be released in a cascading time-dependent fashion. The MDP hydrogel and its cargo can be targeted to specific locations, as the thixotropic nature of the hydrogel allows it to be easily aspirated into a syringe and then delivered from a narrow-bore needle. The sequence of amino acids making up the MDP can also be modified to permit cross-linking or enzymatic degradation. Selection of sequences with or without these modifications allows one to control the rate of degradation in vivo from as rapidly as 1 week to well over 6 weeks as the MDP nanofibers are degraded to their amino acid components. MDP sequences can also be modified to add biomimetic sequences derived from growth factors and other signaling proteins. These chemical signals are displayed at a very high density on the fibers’ surface, where they contribute to the modification of cellular behavior. We have used this approach to drive blood vessel formation, which is critical for tissue regeneration generally and more specifically for the treatment of diseases related to poor blood flow. MDPs represent an ideal case of bottom-up design where control of chemical structure leads to control of self-assembly and nanostructure and thereby control of material properties that collectively can control biological function.

Extracellular Matrix‐Based Strategies for Immunomodulatory Biomaterials Engineering

“…Multiple different ECM‐derived peptides can also be incorporated into the central and terminal regions of the A–B–A block motif. The assembly and material properties of MDPs have been extensively reviewed by others …”

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

“…Functional motif can be displayed at a very high density on the nanofiber's surface to influence cellular behaviors, including new blood vessel formation. [ 122 ] So far, 29 MDP sequences are previously identified in biomedical fields. These MDP hydrogels currently orient the aligned and multilayered bioactive architecture in 3D tissue or cell constructs to reconstruct the complex stratified tissues in regenerative medicine and tissue engineering.…”

Multicomponent self-assembly as a tool to harness new properties from peptides and proteins in material design

“…10 Peptides on the other hand provide a simpler structure allowing easier manipulation, a higher degree of control, and predictable assembly. Examples such as aromatic peptides, 11 peptide amphiphiles, 12 self-assembling peptides, 13 hair-pin peptides, 14 or multidomain peptides 15 have been used to generate nanostructures with the capacity to recreate elaborate quaternary structures, 3a,16 promote mineralization, 17 adhesiveness, 18 enzyme-mediated tunability, 19 or cell growth. 20 Despite the increasing precision with which we are able to engineer these materials using self-assembly strategies, the level of complexity that has been achieved with molecular self-assembly is no way near the highly sophisticated and functional structures found in nature.…”