Cellular architects: Harnessing fibroblasts to synthesize highly-aligned, collagen-rich tissue constructs

Wilks, Benjamin Tyler

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Year:: 2020
Contributor:: Wilks, Benjamin Tyler (creator); Morgan, Jeffrey (Advisor); Schell, Jacquelyn (Reader); Fleming, Braden (Reader); Toussaint, Kimani (Reader); Brown University. Biology and Medicine: Biomedical Engineering (sponsor)
Genre:: theses
Subject:: tissue engineering; Fibroblasts; Collagen; Extracellular matrix; Cells--Mechanical properties; Tissues--Mechanical properties; Ligaments; Tendons; Fibrosis
Extent:: xvi, 158 p.
DOI: https://doi.org/10.26300/0638-gq64

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Abstract:: The goal of tissue engineering is to build in vitro models that are predictive of key aspects of human health or disease and to translate the insight we gain from those models into therapeutics with the potential to address some unmet clinical need. Towards that end, this dissertation approached the challenge of building a predictive in vitro model based on the underlying framework that structure determines function; if we can define the normal composition and architecture of a tissue as well as the critical developmental signals that are required to facilitate those structural features to emerge, then the corresponding functional characteristics of the tissue will naturally follow. The embryonic development of connective tissues like ligaments and tendons is characterized by the transformation of mesenchymal fibroblast-like cell aggregates into highly-organized, collagen-rich tissues through a complex coordination of biochemical and biophysical cues. In an attempt to recapitulate some aspects of connective tissue morphogenesis, this dissertation had four primary objectives. (1) To harness primary juvenile human fibroblasts to fabricate collagen-rich, anisotropic 3D tissue constructs in tension via directed self-assembly. (2) To determine whether we could decellularize these 3D tissue constructs while preserving the 3D fibrillar architecture and investigate how newly seeded cells would interact with and respond to the cell-derived matrix. (3) To characterize changes in 3D composition and architecture as a function of maturation and nutrient media by integrating multiple microscopy techniques to compare our constructs to native tissue development. (4) To map compositional and structural changes to tissue function through biochemical and mechanical assessment of “normal” construct development or in response to relevant biological interventions. While this model does not replicate all aspects of native ligaments and tendons, it does mirror critical developmental patterns such as the shift in cellularity towards increased collagen, the maintenance of cell-cell interactions, and an increase in anisotropic organization with time that corresponds to increases in tensile strength and stiffness. Consequently, this relatively straight forward approach to fabricating engineered tissues that mirror the cellular organization and collagen-rich ECM of developing tissues like ligaments and tendons maybe useful for dissecting out the mechanisms of various biochemical or biophysical signals that regulate the transcriptional, post-transcriptional, and post-translational formation or deterioration of ECM-rich connective tissues in health and disease.
Notes:: Thesis (Ph. D.)--Brown University, 2020

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Wilks, Benjamin Tyler, "Cellular architects: Harnessing fibroblasts to synthesize highly-aligned, collagen-rich tissue constructs" (2020). Biomedical Engineering Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.26300/0638-gq64

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Biomedical Engineering Theses and Dissertations

Theses and Dissertations for the Biomedical Engineering department.
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