자료유형  

 학위논문

Control Number  

0017164489

International Standard Book Number  

9798384044499

Dewey Decimal Classification Number  

610

Main Entry-Personal Name  

Hiraki, Harrison L.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Michigan., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

311 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

General Note  

Advisor: Baker, Brendon M.

Dissertation Note  

Thesis (Ph.D.)--University of Michigan, 2024.

Summary, Etc.  

요약Cell migration is a complex process ubiquitously observed across both physiologic development and disease progression. The phenotype by which cells migrate includes both single cell and multicellular modes, each of which confers cells with unique traits that facilitate survival, differentiation, and tissue-specific functions. However, cells are not rigidly locked into a preprogrammed migration phenotype, and plasticity during migration has been heavily associated with disease progression during development, chronic fibrosis, and cancer. While many external matrix cues and internal cell transcriptomic changes have been identified as determinants of cell migration, how these complex cues work in concert to dictate migration phenotype is not well understood. We therefor aim to develop a model within which both biophysical and biochemical cues can be systematically interrogated to direct cells towards desired migration phenotypes. Fibrous architecture and mechanics of the extracellular matrix (ECM) are known to play a large role in cell migration. Thus, the focus of this dissertation is on the development and use of a tunable fibrous composite biomaterial system to instruct cell migration phenotype and investigate functional consequences of differential phenotypes, specifically in the context of cancer invasion and sprouting angiogenesis.First, this thesis establishes an ECM-mimetic composite biomaterial within which fibrous architecture and bulk mechanics can be orthogonally tuned. To do so, synthetic fiber segments generated via electrospinning of dextran-vinyl sulfone (DexVS) are encapsulated into synthetic amorphous hydrogels of controllable mechanics. Incorporation of magnetic particles into the fiber segments additionally enabled controllable alignment within an external magnetic field. Our results demonstrated how fiber density, degree of fiber alignment, and hydrogel stiffness jointly regulate diverse epithelial cell migration phenotypes spanning amoeboid, single mesenchymal, multicellular cluster, and collective strand. We identified matrix combinations to direct each migration phenotype and found that collective strands best resist drug-induced apoptosis.Next, this thesis develops two methods to generate capillary-scale microvasculature. First, microvascular networks were achieved by printing magnetic poly-caprolactone lattices that could be seeded with magnetized endothelial cells. These rapidly assembled networks supported survival of metabolically demanding induced pluripotent stem cell-derived cardiomyocytes. Second, sprouting angiogenesis from an engineered arteriole-scale endothelium through the aforementioned fibrous hydrogel composite was optimized. Fiber density, hydrogel stiffness, as well as pro-angiogenic ligand presentation within the matrix were orthogonally tuned to direct endothelial cell migration towards a desirable collective strand phenotype. Implantation of composite hydrogels into the fat pad of mice demonstrated robust host endothelial cell ingrowth and vascularization of the constructs.Lastly, this thesis combines migratory epithelial cells with engineered microvasculature to model cancer cell intravasation. Ductal epithelial structures were patterned adjacent to a perfused endothelium within a hydrogel. Invading epithelial cancer cells intravasated into the endothelium, and a pipeline was established to quantitatively assess epithelial invasion and intravasation efficiencies. Patient-derived pancreatic cancer lines were characterized for 2D morphology and epithelial versus mesenchymal traits and then subject to the intravasation microfluidic assay. These quantifiable cell line-specific traits were compared against patient clinical records to identify in vitro markers that may help predict patient outcomes.Overall, the work presented in this dissertation integrates composite biomaterials, microfluidic devices, and custom image analysis codes to investigate biophysical and biochemical contributions to cell migration phenotype. The results presented here will help inform biomaterial design for tissue regeneration applications and disease model development to screen therapeutic drugs.

Subject Added Entry-Topical Term  

Biomedical engineering.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Oncology.

Index Term-Uncontrolled  

Tissue engineering

Index Term-Uncontrolled  

Biomaterials

Index Term-Uncontrolled  

Cell migration

Index Term-Uncontrolled  

Cancer

Index Term-Uncontrolled  

Blood vessels

Index Term-Uncontrolled  

Microfluidic

Added Entry-Corporate Name  

University of Michigan Biomedical Engineering

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

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Control Number  

joongbu:653803