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Spatiotemporal Control of Tendon Healing Through Modular, Injectable Hydrogel Composites
Spatiotemporal Control of Tendon Healing Through Modular, Injectable Hydrogel Composites
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152058
- ISBN
- 9798382739427
- DDC
- 610
- 서명/저자
- Spatiotemporal Control of Tendon Healing Through Modular, Injectable Hydrogel Composites
- 발행사항
- [Sl] : University of Michigan, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 250 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
- 주기사항
- Advisor: Baker, Brendon M.
- 학위논문주기
- Thesis (Ph.D.)--University of Michigan, 2024.
- 초록/해제
- 요약Biomaterials providing control over microenvironmental cues pose an effective strategy for augmenting the repair of tendon, injury of which involves aberrant scar formation, chronic pain, diminished function, and heightened risk of re-injury in adults. The unknown mechanisms driving this natural, maladaptive repair process pose a major hurdle to full tendon regeneration. While adult tendons heal by scar formation, neonatal mouse tendons possess a greater regenerative capacity. As such, emulating this regenerative healing response through biomaterial-mediated, spatiotemporal control of cell recruitment, differentiation, and matrix remodeling following injury may provide an effective route toward improved tendon regeneration in adults.Fiber-reinforced hydrogel composites are promising biomaterials for augmenting tendon regeneration that imbue the wound microenvironment with fibrous topographical cues and can be localized to an internal wound defect through minimally invasive administration. Typically composed of polymer chains crosslinked into a solid bulk by protease-responsive segments, these materials also benefit from tunable and modular inclusion of biochemical moieties in addition to tailorable mechanical properties. These synthetic scaffolds are also attractive from a manufacturing perspective because polymer and peptide synthesis are readily scalable. Positing that the microenvironmental cues defined by the natural healing response fail to properly differentiate tendon progenitor cells (TPCs) recruited to the wound site, this thesis pursued novel strategies to significantly improve the therapeutic potential of synthetic hydrogels through a fibrous, composite material approach and temporal release of biomolecules.In this thesis, a synthetic, fiber-reinforced hydrogel composite was used to assess whether the recruitment of tendon progenitor cells can be enhanced via combined mechanical, topographical, and microparticle-delivered soluble cues. Composites were fabricated by encapsulating electrospun fiber segments in a bulk hydrogel formed from dextran vinyl sulfone crosslinked with an MMP-labile peptide. Monodisperse populations of hybrid microgels with covalently incorporated heparin were then fabricated to release platelet-derived growth factor-BB, a chemokine that potently induces TPC migration. In this material platform, recruitment of murine tendon progenitor cells into synthetic hydrogels was enhanced by fibrous topographical cues and microgel-delivered platelet-derived growth factor-BB. These cues translated effectively to an ex vivo model of progenitor cell recruitment from the epitenon of explanted murine Achilles tendons.The thesis then applied 2D, and 3D engineered culture platforms to identify critical microenvironmental determinants of tenogenesis. TGF-β3 and Rho/Rho-kinase inhibition led to increased Scleraxis expression in murine tendon progenitor cells across 2D and 3D settings. Interestingly, the pro-tenogenic effect of aligned fibrous topography was unique to 2D cultures. Although fiber alignment did not increase Scleraxis expression in 3D, it drove deposition and organization of type I collagen, thereby defining mechanical anisotropy and function of regenerated tissue.Lastly, this thesis studied the influence of fibrous topography on a tenogenic vs. fibrochondrogenic fate switch, finding that the presence of cell-adhesive fibrous topography biases tendon progenitor cells toward the former. In contrast, Rac1 inhibition and cyclic strain biased tendon progenitor cells toward a fibrochondrogenic phenotype. However, when crosslinked in situ in the gap of a transected murine Achilles tendon, fibers primarily influenced tendon progenitor cell recruitment and had a minimal effect on fibrochondrogenic differentiation.The overall work presented in this dissertation develops an injectable biomaterial that can integrate a combination of physical and soluble cues to temporally orchestrate two critical phases of tendon healing: 1) recruitment of TPC populations and 2) tenogenic differentiation of TPCs leading to synthesis of de novo extracellular matrix with appropriate composition and organization. Moreover, the work provides insight into the microenvironmental cues regulating tenogenesis, information critical to the advancement of biomaterial therapeutics geared toward connective tissue regeneration.
- 일반주제명
- Biomedical engineering
- 일반주제명
- Materials science
- 일반주제명
- Bioengineering
- 키워드
- Tendon healing
- 키워드
- Fiber-reinforced
- 키워드
- Biomaterials
- 기타저자
- University of Michigan Biomedical Engineering PhD
- 기본자료저록
- Dissertations Abstracts International. 85-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798382739427
■035 ▼a(MiAaPQ)AAI31348988
■035 ▼a(MiAaPQ)umichrackham005503
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a610
■1001 ▼aKent, Robert N., III.
■24510▼aSpatiotemporal Control of Tendon Healing Through Modular, Injectable Hydrogel Composites
■260 ▼a[Sl]▼bUniversity of Michigan▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a250 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-12, Section: B.
■500 ▼aAdvisor: Baker, Brendon M.
■5021 ▼aThesis (Ph.D.)--University of Michigan, 2024.
■520 ▼aBiomaterials providing control over microenvironmental cues pose an effective strategy for augmenting the repair of tendon, injury of which involves aberrant scar formation, chronic pain, diminished function, and heightened risk of re-injury in adults. The unknown mechanisms driving this natural, maladaptive repair process pose a major hurdle to full tendon regeneration. While adult tendons heal by scar formation, neonatal mouse tendons possess a greater regenerative capacity. As such, emulating this regenerative healing response through biomaterial-mediated, spatiotemporal control of cell recruitment, differentiation, and matrix remodeling following injury may provide an effective route toward improved tendon regeneration in adults.Fiber-reinforced hydrogel composites are promising biomaterials for augmenting tendon regeneration that imbue the wound microenvironment with fibrous topographical cues and can be localized to an internal wound defect through minimally invasive administration. Typically composed of polymer chains crosslinked into a solid bulk by protease-responsive segments, these materials also benefit from tunable and modular inclusion of biochemical moieties in addition to tailorable mechanical properties. These synthetic scaffolds are also attractive from a manufacturing perspective because polymer and peptide synthesis are readily scalable. Positing that the microenvironmental cues defined by the natural healing response fail to properly differentiate tendon progenitor cells (TPCs) recruited to the wound site, this thesis pursued novel strategies to significantly improve the therapeutic potential of synthetic hydrogels through a fibrous, composite material approach and temporal release of biomolecules.In this thesis, a synthetic, fiber-reinforced hydrogel composite was used to assess whether the recruitment of tendon progenitor cells can be enhanced via combined mechanical, topographical, and microparticle-delivered soluble cues. Composites were fabricated by encapsulating electrospun fiber segments in a bulk hydrogel formed from dextran vinyl sulfone crosslinked with an MMP-labile peptide. Monodisperse populations of hybrid microgels with covalently incorporated heparin were then fabricated to release platelet-derived growth factor-BB, a chemokine that potently induces TPC migration. In this material platform, recruitment of murine tendon progenitor cells into synthetic hydrogels was enhanced by fibrous topographical cues and microgel-delivered platelet-derived growth factor-BB. These cues translated effectively to an ex vivo model of progenitor cell recruitment from the epitenon of explanted murine Achilles tendons.The thesis then applied 2D, and 3D engineered culture platforms to identify critical microenvironmental determinants of tenogenesis. TGF-β3 and Rho/Rho-kinase inhibition led to increased Scleraxis expression in murine tendon progenitor cells across 2D and 3D settings. Interestingly, the pro-tenogenic effect of aligned fibrous topography was unique to 2D cultures. Although fiber alignment did not increase Scleraxis expression in 3D, it drove deposition and organization of type I collagen, thereby defining mechanical anisotropy and function of regenerated tissue.Lastly, this thesis studied the influence of fibrous topography on a tenogenic vs. fibrochondrogenic fate switch, finding that the presence of cell-adhesive fibrous topography biases tendon progenitor cells toward the former. In contrast, Rac1 inhibition and cyclic strain biased tendon progenitor cells toward a fibrochondrogenic phenotype. However, when crosslinked in situ in the gap of a transected murine Achilles tendon, fibers primarily influenced tendon progenitor cell recruitment and had a minimal effect on fibrochondrogenic differentiation.The overall work presented in this dissertation develops an injectable biomaterial that can integrate a combination of physical and soluble cues to temporally orchestrate two critical phases of tendon healing: 1) recruitment of TPC populations and 2) tenogenic differentiation of TPCs leading to synthesis of de novo extracellular matrix with appropriate composition and organization. Moreover, the work provides insight into the microenvironmental cues regulating tenogenesis, information critical to the advancement of biomaterial therapeutics geared toward connective tissue regeneration.
■590 ▼aSchool code: 0127.
■650 4▼aBiomedical engineering
■650 4▼aMaterials science
■650 4▼aBioengineering
■653 ▼aTendon healing
■653 ▼aFiber-reinforced
■653 ▼aHydrogel composites
■653 ▼aBiomaterials
■653 ▼aExtracellular matrix
■690 ▼a0541
■690 ▼a0794
■690 ▼a0202
■71020▼aUniversity of Michigan▼bBiomedical Engineering PhD.
■7730 ▼tDissertations Abstracts International▼g85-12B.
■790 ▼a0127
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17162818▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
