Dissertation/Thesis Abstract

Clickable, Hybrid Hydrogels as Tissue Culture Platforms for Modeling Fibrotic Pulmonary Diseases in vitro
by Petrou, Cassandra Leah, M.S., University of Colorado at Denver, 2020, 72; 27833295
Abstract (Summary)

Idiopathic pulmonary fibrosis and pulmonary hypertension impact the lives of hundreds of millions of people daily. Despite great efforts to study the cellular and molecular processes underlying these chronic pulmonary diseases, there are currently few effective therapies. Dual-stage polymerization reactions are an innovative tool for recreating heterogeneous increases in extracellular matrix (ECM) modulus, a hallmark of fibrotic diseases in vivo. Here, we present a clickable decellularized ECM (dECM) crosslinker that is incorporated into a dynamically responsive poly(ethylene glycol)-α-methacrylate (PEGαMA) hybrid-hydrogel to recreate ECM remodeling in vitro. An off-stoichiometry thiol-ene Michael addition between PEGαMA (8-arm, 10 kg/mol) and the clickable dECM resulted in hydrogels with an elastic modulus of E = 3.6 ± 0.24 kPa, approximating healthy lung tissue (1-5 kPa). Next, residual αMA groups were reacted via a photo-initiated homopolymerization to increase modulus values to fibrotic levels (E = 13.4 ± 0.82 kPa) in situ. Hydrogels with increased elastic moduli, mimicking fibrotic ECM, induced a significant increase in the expression of myofibroblast transgenes. The proportion of primary fibroblasts from dual-reporter mouse lungs expressing collagen 1a1 and alpha-smooth muscle actin increased by approximately 60% when cultured on stiff and dynamically stiffened hybrid-hydrogels compared to soft. Likewise, fibroblasts expressed significantly increased levels of the collagen 1a1 transgene on stiff regions of spatially patterned hybrid-hydrogels compared to the soft regions. Collectively, these results indicate that hybrid-hydrogels are a new tool that can be implemented to spatiotemporally induce a phenotypic transition in primary murine fibroblasts in vitro.

Indexing (document details)
Advisor: Magin, Chelsea M
Commitee: Jacot, Jeffrey G, Stenmark, Kurt R, Wagner, Darcy E
School: University of Colorado at Denver
Department: Bioengineering
School Location: United States -- Colorado
Source: MAI 81/10(E), Masters Abstracts International
Source Type: DISSERTATION
Subjects: Bioengineering, Materials science, Biomedical engineering
Keywords:
Publication Number: 27833295
ISBN: 9798641782836
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