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Targeting Cell Signaling Pathways to Modulate the Foreign Body Response for Medical Device and Tissue Engineering Applications
Targeting Cell Signaling Pathways to Modulate the Foreign Body Response for Medical Device and Tissue Engineering Applications
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152653
- ISBN
- 9798384050551
- DDC
- 616.079
- 서명/저자
- Targeting Cell Signaling Pathways to Modulate the Foreign Body Response for Medical Device and Tissue Engineering Applications
- 발행사항
- [Sl] : University of Colorado at Boulder, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 141 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Advisor: Bryant, Stephanie J.
- 학위논문주기
- Thesis (Ph.D.)--University of Colorado at Boulder, 2024.
- 초록/해제
- 요약The foreign body response (FBR) is an innate immune response that wreaks havoc on implanted biomaterials in the form of chronic inflammation and fibrous encapsulation. The FBR impacts a wide range of biomaterials, and thus, a wide range of applications, such as structural, cosmetic, prosthesis implants, biosensors, and tissue regeneration scaffolds. This thesis identifies prostaglandin E2 receptors EP2 and EP4, and toll-like receptors (TLR) 2 and 4 in the cell signaling cascades driving the FBR and demonstrates the manipulation of these receptors and their downstream pathways as viable therapeutic targets. A variety of material properties were chosen to study, including FDA approved poly(ether etherketone) (PEEK) and medical grade silicone (MGS), and non-FDA approved poly(ethylene glycol) (PEG)-norbornene, PEG diacrylate, and a cartilage mimetic PEG-norbornene, to understand material dependent signaling differences in the FBR. Herein we demonstrate that EP2 modulates the FBR in a material dependent manner through non-myeloid cells, while ablation of both TLR 2 and 4 remove the materials dependencies in the FBR as observed in immune competent mice. Macrophages are considered the drivers of the FBR, and this work focuses on macrophage driven chronic inflammation, macrophage plasticity, and macrophage fusion in vitro to better understand these functions. Our findings demonstrate that macrophages drive chronic inflammation through recognition of damage associated molecular patterns (DAMPs) via TLR 2 and 4, the pro-inflammatory macrophage state is dampened by EP2 and EP4, and macrophage fusion is modulated by a combination of EP2 and EP4. Additionally, in the FBR to a highly inflammatory biomaterial, PEG diacrylate, we demonstrate that TLRs only partially contribute to the macrophage driven FBR. Applying this knowledge to a cartilage-mimetic hydrogel, we demonstrate that use of a MyD88 inhibitor, a pathway downstream of TLR 2 and 4, tethered into a cartilage-mimetic hydrogel via a degradable linker could improve tissue repair and shows evidence for increased early-stage chondrogenesis in an osteochondral defect rat model. Generating a promising therapeutic option for the treatment of osteochondral defects associated with osteoarthritis. Overall, this dissertation identifies therapeutic targets for many applications impacted by the FBR, including the regeneration of tissues using PEG scaffolds.
- 일반주제명
- Immunology
- 일반주제명
- Biology
- 일반주제명
- Materials science
- 키워드
- EP receptors
- 키워드
- Macrophages
- 키워드
- Neutrophils
- 기타저자
- University of Colorado at Boulder Materials Science and Engineering
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
008250123s2024 us c eng d■001000017163325
■00520250211152653
■006m o d
■007cr#unu||||||||
■020 ▼a9798384050551
■035 ▼a(MiAaPQ)AAI31487196
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.079
■1001 ▼aThompson, Brittany J.
■24510▼aTargeting Cell Signaling Pathways to Modulate the Foreign Body Response for Medical Device and Tissue Engineering Applications
■260 ▼a[Sl]▼bUniversity of Colorado at Boulder▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a141 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aAdvisor: Bryant, Stephanie J.
■5021 ▼aThesis (Ph.D.)--University of Colorado at Boulder, 2024.
■520 ▼aThe foreign body response (FBR) is an innate immune response that wreaks havoc on implanted biomaterials in the form of chronic inflammation and fibrous encapsulation. The FBR impacts a wide range of biomaterials, and thus, a wide range of applications, such as structural, cosmetic, prosthesis implants, biosensors, and tissue regeneration scaffolds. This thesis identifies prostaglandin E2 receptors EP2 and EP4, and toll-like receptors (TLR) 2 and 4 in the cell signaling cascades driving the FBR and demonstrates the manipulation of these receptors and their downstream pathways as viable therapeutic targets. A variety of material properties were chosen to study, including FDA approved poly(ether etherketone) (PEEK) and medical grade silicone (MGS), and non-FDA approved poly(ethylene glycol) (PEG)-norbornene, PEG diacrylate, and a cartilage mimetic PEG-norbornene, to understand material dependent signaling differences in the FBR. Herein we demonstrate that EP2 modulates the FBR in a material dependent manner through non-myeloid cells, while ablation of both TLR 2 and 4 remove the materials dependencies in the FBR as observed in immune competent mice. Macrophages are considered the drivers of the FBR, and this work focuses on macrophage driven chronic inflammation, macrophage plasticity, and macrophage fusion in vitro to better understand these functions. Our findings demonstrate that macrophages drive chronic inflammation through recognition of damage associated molecular patterns (DAMPs) via TLR 2 and 4, the pro-inflammatory macrophage state is dampened by EP2 and EP4, and macrophage fusion is modulated by a combination of EP2 and EP4. Additionally, in the FBR to a highly inflammatory biomaterial, PEG diacrylate, we demonstrate that TLRs only partially contribute to the macrophage driven FBR. Applying this knowledge to a cartilage-mimetic hydrogel, we demonstrate that use of a MyD88 inhibitor, a pathway downstream of TLR 2 and 4, tethered into a cartilage-mimetic hydrogel via a degradable linker could improve tissue repair and shows evidence for increased early-stage chondrogenesis in an osteochondral defect rat model. Generating a promising therapeutic option for the treatment of osteochondral defects associated with osteoarthritis. Overall, this dissertation identifies therapeutic targets for many applications impacted by the FBR, including the regeneration of tissues using PEG scaffolds.
■590 ▼aSchool code: 0051.
■650 4▼aImmunology
■650 4▼aBiology
■650 4▼aMaterials science
■653 ▼aEP receptors
■653 ▼aMacrophages
■653 ▼aNeutrophils
■653 ▼aToll-like receptors
■690 ▼a0794
■690 ▼a0982
■690 ▼a0306
■71020▼aUniversity of Colorado at Boulder▼bMaterials Science and Engineering.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0051
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17163325▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
