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Translational Supramolecular Design of Peptide Amphiphile Materials for Cartilage Regeneration /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Translational Supramolecular Design of Peptide Amphiphile Materials for Cartilage Regeneration // Shelby C Yuan.
Author:	Yuan, Shelby C.,
Description:	1 electronic resource (340 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Biomedical engineering. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31840052
ISBN:	9798315798804

Translational Supramolecular Design of Peptide Amphiphile Materials for Cartilage Regeneration /
Yuan, Shelby C.,

Translational Supramolecular Design of Peptide Amphiphile Materials for Cartilage Regeneration /Shelby C Yuan. - 1 electronic resource (340 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Articular cartilage degeneration is a leading cause of morbidity worldwide, often due to injury, disease, and age. This connective tissue provides load bearing, lubrication, and shock absorption in joints, and its deterioration causes painful functional impairment, known as osteoarthritis (OA). Unlike many other tissues, cartilage is unable to self-repair, and existing treatments are temporary and palliative, focusing on slowing disease progression rather than regeneration. Currently, there are no disease-modifying OA drugs, and therapies based on exogenous protein delivery face issues of uncontrolled release and instability. Tissue-engineered cartilage products remain challenging due to the tissue's low density of cells, lack of blood vessels, lymphatics, and nerve tissue, along with its rigorous mechanical demands. This work describes the development of peptide amphiphile (PA) biomaterials to address these challenges. PAs are a class of molecules that self-assemble under physiological conditions into filamentous nanostructures displaying high densities of bioactive epitopes, making them versatile building blocks for a variety of biomaterials.To understand how basic molecular design can define the structure and function of PA materials, the first project investigated two constitutionally isomeric PA molecules and the effects of supramolecular polymerization pathway on self-assembly and bioactivity. In this work, two isomeric PA monomers with amino acid sequences AAEE and AEAE were subjected to five different pathways that varied the order the monomers were exposed to electrostatic screening and thermal annealing. It was revealed that electrostatic screening of the charged E residues before annealing led to ordered packing of AAEE monomers. This screening decreased intermolecular repulsion among AAEE monomers and promoted internal order within the supramolecular polymers, while subsequent annealing brought them closer to thermodynamic equilibrium with enhanced β-sheet secondary structure. This increased pathway sensitivity and β-sheet enhancement in AAEE monomers was attributed to their hydrogen bonding-driven self-assembly. In contrast, supramolecular polymerization of AEAE monomers was less pathway dependent, which was attributed to side-chain dimerization. Regardless of the pathway, the internal structure of AEAE nanostructures had limited internal order and β-sheet structure. These supramolecular polymers generated hydrogels with lower porosity and greater bulk mechanical strength than those formed by the AAEE polymers. These mechanical properties of AEAE materials may have been due to the more homogeneous morphologies and less rigid AEAE nanostructures that packed into denser gel networks, and the lower internal order that withstood higher strains before collapse of the gel network. The combination of low β-sheet content and high mechanical integrity of AEAE networks promoted strong cell-material interactions in adherent epithelial-like cells from the ATDC5 cell line, evidenced by increased cytoskeletal remodeling and cell spreading. These enhanced cellular interactions were likely a result of the optimal combination of the AEAE matrix's high storage modulus, needed for cellular adhesion, and the supramolecular dynamics enabled by the low internal order. The supramolecular motion also likely promoted integrin signaling by extracellular matrix proteins adhered to the dynamic PA nanofibers. The highly ordered AAEE nanostructures formed more porous hydrogels with weaker cell-material interactions. Overall, it was discovered that pathway sensitivity in supramolecular synthesis, and therefore structure and function, are highly dependent on the nature of dominant interactions driving supramolecular polymerization.The insights into supramolecular self-assembly and molecular design gleaned from the first project informed the strategy behind the second project, the development of PA nanostructures mimicking the critical chondrogenic growth factor transforming growth factor (TGF)-β1. Two isomeric systems of supramolecular PA coassemblies were investigated based on the tetrapeptides investigated in the first project. Each nanostructure system contained PA molecules displaying a cyclic mimetic peptide of TGF-β1 coassembled with non-bioactive PA comonomers. Human articular chondrocytes were used to examine the bioactivity of the supramolecular copolymers of each isomer displaying either the previously reported linear form of the mimetic peptide or the novel cyclic analogue developed here. Cells were treated with solutions of each supramolecular assembly, and protein production and gene expression were measured using western blot and immunocytochemistry. The highest bioactivity was observed in assemblies of molecules containing the tetrapeptide isomer with enhanced supramolecular motion, based on fluorescence depolarization and 1H NMR spin-spin relaxation times. In the more dynamic of the two isomeric systems, PA nanostructures containing a low molar fraction of the cyclic mimetic peptide activated intracellular signaling pathways associated with TGF-β1-mediated chondrogenesis and cartilage matrix production. These nanostructures containing AAEE PA backbones and non-bioactive comonomers exhibited greater supramolecular dynamics, which was surprising given their strong β-sheet propensity and internal order identified in the first chapter of this work. These seemingly counterintuitive results led to the hypothesis that steric hindrance from epitope-bearing molecules. (Abstract shortened by ProQuest).

English

ISBN: 9798315798804Subjects--Topical Terms:

535387
Biomedical engineering.
Subjects--Index Terms:

Cartilage

Translational Supramolecular Design of Peptide Amphiphile Materials for Cartilage Regeneration /
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520 $a Articular cartilage degeneration is a leading cause of morbidity worldwide, often due to injury, disease, and age. This connective tissue provides load bearing, lubrication, and shock absorption in joints, and its deterioration causes painful functional impairment, known as osteoarthritis (OA). Unlike many other tissues, cartilage is unable to self-repair, and existing treatments are temporary and palliative, focusing on slowing disease progression rather than regeneration. Currently, there are no disease-modifying OA drugs, and therapies based on exogenous protein delivery face issues of uncontrolled release and instability. Tissue-engineered cartilage products remain challenging due to the tissue's low density of cells, lack of blood vessels, lymphatics, and nerve tissue, along with its rigorous mechanical demands. This work describes the development of peptide amphiphile (PA) biomaterials to address these challenges. PAs are a class of molecules that self-assemble under physiological conditions into filamentous nanostructures displaying high densities of bioactive epitopes, making them versatile building blocks for a variety of biomaterials.To understand how basic molecular design can define the structure and function of PA materials, the first project investigated two constitutionally isomeric PA molecules and the effects of supramolecular polymerization pathway on self-assembly and bioactivity. In this work, two isomeric PA monomers with amino acid sequences AAEE and AEAE were subjected to five different pathways that varied the order the monomers were exposed to electrostatic screening and thermal annealing. It was revealed that electrostatic screening of the charged E residues before annealing led to ordered packing of AAEE monomers. This screening decreased intermolecular repulsion among AAEE monomers and promoted internal order within the supramolecular polymers, while subsequent annealing brought them closer to thermodynamic equilibrium with enhanced β-sheet secondary structure. This increased pathway sensitivity and β-sheet enhancement in AAEE monomers was attributed to their hydrogen bonding-driven self-assembly. In contrast, supramolecular polymerization of AEAE monomers was less pathway dependent, which was attributed to side-chain dimerization. Regardless of the pathway, the internal structure of AEAE nanostructures had limited internal order and β-sheet structure. These supramolecular polymers generated hydrogels with lower porosity and greater bulk mechanical strength than those formed by the AAEE polymers. These mechanical properties of AEAE materials may have been due to the more homogeneous morphologies and less rigid AEAE nanostructures that packed into denser gel networks, and the lower internal order that withstood higher strains before collapse of the gel network. The combination of low β-sheet content and high mechanical integrity of AEAE networks promoted strong cell-material interactions in adherent epithelial-like cells from the ATDC5 cell line, evidenced by increased cytoskeletal remodeling and cell spreading. These enhanced cellular interactions were likely a result of the optimal combination of the AEAE matrix's high storage modulus, needed for cellular adhesion, and the supramolecular dynamics enabled by the low internal order. The supramolecular motion also likely promoted integrin signaling by extracellular matrix proteins adhered to the dynamic PA nanofibers. The highly ordered AAEE nanostructures formed more porous hydrogels with weaker cell-material interactions. Overall, it was discovered that pathway sensitivity in supramolecular synthesis, and therefore structure and function, are highly dependent on the nature of dominant interactions driving supramolecular polymerization.The insights into supramolecular self-assembly and molecular design gleaned from the first project informed the strategy behind the second project, the development of PA nanostructures mimicking the critical chondrogenic growth factor transforming growth factor (TGF)-β1. Two isomeric systems of supramolecular PA coassemblies were investigated based on the tetrapeptides investigated in the first project. Each nanostructure system contained PA molecules displaying a cyclic mimetic peptide of TGF-β1 coassembled with non-bioactive PA comonomers. Human articular chondrocytes were used to examine the bioactivity of the supramolecular copolymers of each isomer displaying either the previously reported linear form of the mimetic peptide or the novel cyclic analogue developed here. Cells were treated with solutions of each supramolecular assembly, and protein production and gene expression were measured using western blot and immunocytochemistry. The highest bioactivity was observed in assemblies of molecules containing the tetrapeptide isomer with enhanced supramolecular motion, based on fluorescence depolarization and 1H NMR spin-spin relaxation times. In the more dynamic of the two isomeric systems, PA nanostructures containing a low molar fraction of the cyclic mimetic peptide activated intracellular signaling pathways associated with TGF-β1-mediated chondrogenesis and cartilage matrix production. These nanostructures containing AAEE PA backbones and non-bioactive comonomers exhibited greater supramolecular dynamics, which was surprising given their strong β-sheet propensity and internal order identified in the first chapter of this work. These seemingly counterintuitive results led to the hypothesis that steric hindrance from epitope-bearing molecules. (Abstract shortened by ProQuest).
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650 4 $a Nanotechnology. $3 526235
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653 $a Cartilage
653 $a Peptide amphiphile
653 $a Regenerative medicine
653 $a Self-assembly
653 $a Transforming growth factor
653 $a Tissue engineering
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710 2 $a Northwestern University. $b Biomedical Engineering. $e degree granting institution. $3 3824913
720 1 $a Stupp, Samuel I. $e degree supervisor.
720 1 $a Kamat, Neha P. $e degree supervisor.
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