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MICRO-/NANOTECHNOLOGIES TO ENGINEER MICROENVIRONMENTAL CUES FOR REGENERATIVE HEART VALVE THERAPIES

Xue, Yingfei (2018) MICRO-/NANOTECHNOLOGIES TO ENGINEER MICROENVIRONMENTAL CUES FOR REGENERATIVE HEART VALVE THERAPIES. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Scaffold-based regenerative heart valve therapy represents a promising and innovative approach to address the unmet clinical need in treating valvular heart diseases. However, current tissue-engineered heart valve scaffolds often suffer from issues such as architectural and mechanical mismatch to native valve leaflet, thrombogenicity, and calcification tendency. Our overall goal is to provide effective strategies to improve the design of regenerative heart valve therapies by alleviating these common issues. This dissertation summarizes our efforts to develop micro-/nanotechnology-based strategies in mimicking the fibrous architecture and mechanical properties of the native valves while improving the biocompatibility of tissue-engineered scaffolds.
We first synthesized a novel series of polyethylene glycol (PEG) functionalized biodegradable elastomers. With different molar ratios and molecular weights of PEG in the polymer backbone, these biodegradable and biocompatible elastomers possessed widely tunable mechanical properties and desirable degradation mechanism.
We then fabricated PEGylated biodegradable elastomers into fibrous scaffolds by electrospinning. The introduction of PEG into the polymer backbone led to reduced thrombogenicity of the fibrous scaffolds. Moreover, the uniaxial and cyclic mechanical properties of fibrous scaffolds could be tuned to mimic those of the native valve leaflets.
The electrospinning process was further modified to fabricate anisotropic fibrous scaffolds. By modulating polymer formulation, fibrous scaffolds were produced to possess anisotropic biaxial mechanical properties. The anisotropic nature of scaffold also guided the alignment of human valvular interstitial cells (hVICs) seeded on the scaffolds.
To address the calcification tendency of heart valve substitutes, we developed shape-specific cerium oxide nanoparticles (CNPs), which have unique properties to mitigate oxidative stress. We demonstrated that the oxidative stress exacerbated the calcification in hVICs. We then demonstrated the effectiveness of CNPs in alleviating oxidative stress and preventing calcification in hVICs.
Finally, we combined antioxidant CNPs with anisotropic fibrous scaffolds to obtain nanocomposite scaffolds. These scaffolds possessed antioxidant properties and supported hVIC attachment and proliferation. In an oxidative stress-induced calcification model, hVICs cultured on CNP encapsulated scaffolds displayed reduced calcification tendency.
Collectively, using micro-/nanotechnology-based strategies, we developed novel tissue-engineered heart valve scaffolds with anisotropic mechanical properties and the potential to mitigate the thrombogenicity and calcification frequently observed in current valve replacement therapies.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Xue, Yingfeiyix32@pitt.eduyix320000-0002-4551-3702
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorSant, Shilpashs149@pitt.edushs149
Thesis AdvisorSant, Vinayakvis45@pitt.eduvis45
Committee MemberLi, Songsol4@pitt.edusol4
Committee MemberPhillippi, Juliephillippija@upmc.edu
Committee MemberWang, Yadongyw839@cornell.edu
Date: 16 August 2018
Date Type: Publication
Defense Date: 24 July 2018
Approval Date: 16 August 2018
Submission Date: 15 August 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 219
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: biodegradable elastomer; heart valve tissue engineering; cerium oxide nanoparticle; electrospinning; nanocomposite scaffold; valve calcification
Date Deposited: 16 Aug 2018 13:21
Last Modified: 16 Aug 2018 13:21
URI: http://d-scholarship.pitt.edu/id/eprint/35208

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