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Peptide Amphiphiles as a Supramolecular and Biomimetic Platform for Tissue Regeneration
Peptide Amphiphiles as a Supramolecular and Biomimetic Platform for Tissue Regeneration
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103202
- ISBN
- 9798315799900
- DDC
- 540
- 저자명
- Lin, Xinyi.
- 서명/저자
- Peptide Amphiphiles as a Supramolecular and Biomimetic Platform for Tissue Regeneration
- 발행사항
- [Sl] : Northwestern University, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 173 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Stupp, Samuel.
- 학위논문주기
- Thesis (Ph.D.)--Northwestern University, 2025.
- 초록/해제
- 요약Regenerative medicine holds transformative potential for addressing tissue degeneration caused by injury, disease, or aging. However, clinical translation remains hindered by the limitations of conventional biomaterials, which often lack dynamic adaptability, bioactivity, and mechanical resilience. Peptide amphiphiles (PAs), a class of supramolecular polymers, offer a versatile solution through their ability to self-assemble into bioactive nanostructures that mimic the extracellular matrix (ECM), enabling precise control over cellular behavior and tissue repair. This work leveraged PA-based platforms to advance regenerative strategies across multiple applications. In Chapter 2, a BMP-2 mimetic PA system was developed to address the challenges of recombinant BMP-2 (rhBMP-2) growth factor therapies, including high dose requirements and associated adverse effects. The PA system incorporated bioactive peptide sequences derived from the so called "knuckle" and "wrist" epitopes of BMP-2, targeting receptor binding and activation by supramolecular assemblies. Co-assembly of epitope-containing PA molecules with the β-sheet-forming molecule E2-PA backbone lacking an epitope ensured nanofiber formation. Structural characterization using transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), and wide-angle X-ray scattering (WAXS) revealed that a 10% knuckle PA co-assembly formed well-defined supramolecular nanofibers with strong β-sheet character, while higher knuckle PA content disrupted fiber integrity and led to the formation of small micellar aggregates. In vitro studies using human mesenchymal stem cells (hMSCs), multipotent progenitor cells capable of osteogenic differentiation, demonstrated that 10% knuckle PA assemblies significantly upregulated alkaline phosphatase (ALP) expression compared to E2-PA assemblies or knuckle peptide. Western blot (WB) was conducted to investigate activation of BMP signaling pathways in response to PA treatment. BMP signaling proceeds through two primary branches: the canonical pathway, mediated by Smad1/5/8 phosphorylation (p-Smad), and the non-canonical pathway, involving downstream effectors such as p38 mitogen-activated protein kinase (MAPK). Pathway activation depends on receptor complex formation: initial activation of BMP type II receptors followed by recruitment of type I receptors can lead to non-canonical signaling, whereas engagement of a pre-formed hetero-oligomeric complex of type I and type II receptors typically triggers canonical Smad signaling. Treatment with 10% knuckle PA, which displays the knuckle epitope, resulted in strong p38 phosphorylation with minimal p-Smad activation, indicating preferential activation of the non-canonical pathway. In contrast, 10% wrist PA, designed to present the wrist epitope of BMP-2, promoted Smad1/5 phosphorylation, consistent with activation of the canonical BMP signaling pathway. However, it did not significantly affect downstream osteogenic markers due to its limited bioactivity on its own. To better mimic native BMP-2, wrist and knuckle PAs were combined to form a co-assembled wrist-knuckle PA supramolecular system. After characterization, a 10% total bioactive epitope ratio was selected as the optimal condition. Interestingly, the resultant PA assembly simultaneously activated p38 and p-Smad phosphorylation, mimicking native BMP-2 signaling. Further analysis of downstream osteogenic markers indicated that this PA promoted Runx2 activation, COL1A1 production, and ALP elevation, along with increased gene expression of osteogenic markers OPN and OCN. Additionally, it significantly enhanced calcium deposition. In all assays, the wrist-knuckle PA assemblies outperformed either wrist PA or knuckle PA alone, demonstrating a cooperative effect of the two epitopes on osteogenic differentiation. This finding suggests that the supramolecular assembly enables a spatial organization in which both bioactive sequences are effectively presented. It is inferred that the translational dynamics of monomers within the nanofiber may permit sufficient lateral mobility or molecular exchange, allowing type I and type II BMP receptors to engage with their respective epitopes within the same local domain. Such dynamic presentation could facilitate receptor clustering and formation of the oligomeric complexes required for full BMP-2 signaling, ultimately enabling concurrent activation of both canonical and non-canonical pathways. Finally, in vivo data revealed some preliminary data that the wrist-knuckle PA supramolecular system exhibited chemo-attractive properties, effectively recruiting stem cells in a manner similar to native BMP-2; this observation will have to be confirmed by future experiments. In a rat posterolateral fusion (PLF) model, implantation of the wrist-knuckle PA led to successful fusion in 1 out of 6 animals. Co-treatment with the wrist-knuckle PA and a BMP-2-binding PA further improved the fusion outcome, achieving fusion in 2 out of 6 animals. Although the fusion rate is modest, the result suggests the potential of the system to promote bone formation in vivo without requiring exogenous BMP-2, highlighting its promise as a safer alternative for bone regeneration and informing future strategies involving optimized dosing or delivery approaches.In Chapter 3, a distinct class of bioactive supramolecular system was developed to investigate therapeutic strategies for osteoarthritis (OA), a degenerative joint disease characterized by cartilage degradation, inflammation, and disrupted. (Abstract shortened by ProQuest).
- 일반주제명
- Chemistry
- 일반주제명
- Biomedical engineering
- 일반주제명
- Biochemistry
- 일반주제명
- Molecular chemistry
- 기타저자
- Northwestern University Chemistry
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■1001 ▼aLin, Xinyi.▼0(orcid)0009-0002-9033-9616
■24510▼aPeptide Amphiphiles as a Supramolecular and Biomimetic Platform for Tissue Regeneration
■260 ▼a[Sl]▼bNorthwestern University▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a173 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Stupp, Samuel.
■5021 ▼aThesis (Ph.D.)--Northwestern University, 2025.
■520 ▼aRegenerative medicine holds transformative potential for addressing tissue degeneration caused by injury, disease, or aging. However, clinical translation remains hindered by the limitations of conventional biomaterials, which often lack dynamic adaptability, bioactivity, and mechanical resilience. Peptide amphiphiles (PAs), a class of supramolecular polymers, offer a versatile solution through their ability to self-assemble into bioactive nanostructures that mimic the extracellular matrix (ECM), enabling precise control over cellular behavior and tissue repair. This work leveraged PA-based platforms to advance regenerative strategies across multiple applications. In Chapter 2, a BMP-2 mimetic PA system was developed to address the challenges of recombinant BMP-2 (rhBMP-2) growth factor therapies, including high dose requirements and associated adverse effects. The PA system incorporated bioactive peptide sequences derived from the so called "knuckle" and "wrist" epitopes of BMP-2, targeting receptor binding and activation by supramolecular assemblies. Co-assembly of epitope-containing PA molecules with the β-sheet-forming molecule E2-PA backbone lacking an epitope ensured nanofiber formation. Structural characterization using transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), and wide-angle X-ray scattering (WAXS) revealed that a 10% knuckle PA co-assembly formed well-defined supramolecular nanofibers with strong β-sheet character, while higher knuckle PA content disrupted fiber integrity and led to the formation of small micellar aggregates. In vitro studies using human mesenchymal stem cells (hMSCs), multipotent progenitor cells capable of osteogenic differentiation, demonstrated that 10% knuckle PA assemblies significantly upregulated alkaline phosphatase (ALP) expression compared to E2-PA assemblies or knuckle peptide. Western blot (WB) was conducted to investigate activation of BMP signaling pathways in response to PA treatment. BMP signaling proceeds through two primary branches: the canonical pathway, mediated by Smad1/5/8 phosphorylation (p-Smad), and the non-canonical pathway, involving downstream effectors such as p38 mitogen-activated protein kinase (MAPK). Pathway activation depends on receptor complex formation: initial activation of BMP type II receptors followed by recruitment of type I receptors can lead to non-canonical signaling, whereas engagement of a pre-formed hetero-oligomeric complex of type I and type II receptors typically triggers canonical Smad signaling. Treatment with 10% knuckle PA, which displays the knuckle epitope, resulted in strong p38 phosphorylation with minimal p-Smad activation, indicating preferential activation of the non-canonical pathway. In contrast, 10% wrist PA, designed to present the wrist epitope of BMP-2, promoted Smad1/5 phosphorylation, consistent with activation of the canonical BMP signaling pathway. However, it did not significantly affect downstream osteogenic markers due to its limited bioactivity on its own. To better mimic native BMP-2, wrist and knuckle PAs were combined to form a co-assembled wrist-knuckle PA supramolecular system. After characterization, a 10% total bioactive epitope ratio was selected as the optimal condition. Interestingly, the resultant PA assembly simultaneously activated p38 and p-Smad phosphorylation, mimicking native BMP-2 signaling. Further analysis of downstream osteogenic markers indicated that this PA promoted Runx2 activation, COL1A1 production, and ALP elevation, along with increased gene expression of osteogenic markers OPN and OCN. Additionally, it significantly enhanced calcium deposition. In all assays, the wrist-knuckle PA assemblies outperformed either wrist PA or knuckle PA alone, demonstrating a cooperative effect of the two epitopes on osteogenic differentiation. This finding suggests that the supramolecular assembly enables a spatial organization in which both bioactive sequences are effectively presented. It is inferred that the translational dynamics of monomers within the nanofiber may permit sufficient lateral mobility or molecular exchange, allowing type I and type II BMP receptors to engage with their respective epitopes within the same local domain. Such dynamic presentation could facilitate receptor clustering and formation of the oligomeric complexes required for full BMP-2 signaling, ultimately enabling concurrent activation of both canonical and non-canonical pathways. Finally, in vivo data revealed some preliminary data that the wrist-knuckle PA supramolecular system exhibited chemo-attractive properties, effectively recruiting stem cells in a manner similar to native BMP-2; this observation will have to be confirmed by future experiments. In a rat posterolateral fusion (PLF) model, implantation of the wrist-knuckle PA led to successful fusion in 1 out of 6 animals. Co-treatment with the wrist-knuckle PA and a BMP-2-binding PA further improved the fusion outcome, achieving fusion in 2 out of 6 animals. Although the fusion rate is modest, the result suggests the potential of the system to promote bone formation in vivo without requiring exogenous BMP-2, highlighting its promise as a safer alternative for bone regeneration and informing future strategies involving optimized dosing or delivery approaches.In Chapter 3, a distinct class of bioactive supramolecular system was developed to investigate therapeutic strategies for osteoarthritis (OA), a degenerative joint disease characterized by cartilage degradation, inflammation, and disrupted. (Abstract shortened by ProQuest).
■590 ▼aSchool code: 0163.
■650 4▼aChemistry
■650 4▼aBiomedical engineering
■650 4▼aBiochemistry
■650 4▼aMolecular chemistry
■653 ▼aPeptide amphiphiles
■653 ▼aRegenerative medicine
■653 ▼aExtracellular matrix
■653 ▼aTransmission electron microscopy
■653 ▼aWide-angle X-ray scattering
■690 ▼a0485
■690 ▼a0431
■690 ▼a0541
■690 ▼a0487
■71020▼aNorthwestern University▼bChemistry.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0163
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357290▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
