Yu, Gary Z.
(2020)
Applications of Ultrasound-targeted Microbubble Cavitation with Sodium Nitrite and Nitro-alkenes.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Microvascular obstruction is a common repercussion of percutaneous coronary intervention in treating acute myocardial infarction, and results from a combination of downstream microembolization, ischemia-reperfusion injury, and inflammation. Ultrasound-targeted microbubble cavitation (UTMC) uses external therapeutic ultrasound pulsation to target intravascularly infused microbubble contrast agents to produce shear stresses which mechanically disrupt obstructing microemboli. This work aims to enhance the therapeutic effects of UTMC through synergistic co-administration of nitrite for enhancement of perfusion and nitric oxide bioavailability (Aim 1) and development of a novel microbubble agent using nitro-alkenes for therapeutic reduction of inflammation after ischemia-reperfusion injury (Aim 2).
For characterization and optimization of nitrite co-therapy with UTMC, a rat gastrocnemius model was used with contrast-enhanced ultrasound imaging. A nitric oxide porphyrinic membrane catheter probe was inserted into the treatment site for real-time measurement of nitric oxide concentration changes. In addition to nitrite co-therapy, effects of administering an endothelial nitric oxide synthase inhibitor as well as varying microbubble concentration and therapeutic ultrasound pressure were studied. Results showed that UTMC and nitrite demonstrated positive synergy for enhancing nitric oxide concentration and perfusion which depended on functional endothelial nitric oxide synthase.
After a novel nitro-alkene microbubble agent was synthesized and characterized, it was applied in both healthy and ischemia-reperfusion injury rat gastrocnemius models. Tissue samples were collected after treatment for quantification of nitro-alkene delivery, changes in inflammatory gene expression, and contrast-enhanced ultrasound imaging was used to quantify changes in hindlimb perfusion after treatment. Results showed that incorporation of the nitro-alkene into a microbubble formulation with UTMC greatly enhanced targeted tissue delivery of the nitro-alkene compared to co-infusion with standard microbubbles and systemic infusion alone. In addition, nitro-alkene microbubble UTMC resulted in greatly enhanced perfusion as well as decreases in inflammatory gene expression.
In all, both of these applications of enhancing UTMC therapy demonstrate significant mechanistic interactions with endogenous nitric oxide metabolism and may serve to enhance nitric oxide bioavailability through different pathways. They may also improve the relevance of UTMC in treating the biological sequelae of microvascular obstruction without compromising its mechanical function in disrupting microemboli.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
3 August 2020 |
| Date Type: |
Publication |
| Defense Date: |
25 March 2020 |
| Approval Date: |
3 August 2020 |
| Submission Date: |
14 April 2020 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
225 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ultrasound, microbubbles, nitrite, nitro-alkenes, nitro-fatty acids |
| Date Deposited: |
03 Aug 2021 05:00 |
| Last Modified: |
03 Aug 2021 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38533 |
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