Awada, Hassan
(2016)
Spatiotemporal Delivery of Complementary Proteins for Repair of the Infarcted Myocardium.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Ischemic heart disease is a leading cause of morbidity and mortality worldwide. After the onset of myocardial infarction, multiple pathologies develop and progress the disease towards heart failure. Pathologies such as ischemia, inflammation, cardiomyocyte death, ventricular remodeling and dilation, and interstitial fibrosis, develop and involve the signaling of many proteins. Therapeutic proteins can play important roles in limiting or countering pathological changes after infarction. However, they typically have low retention rate and short half-lives in vivo in their free form and can benefit from the advantages offered by controlled release systems to overcome their challenges. Protein-based therapies can be more effective when concerns such as spatiotemporal presentation, bioactivity, and retention are addressed. We tested the efficacy of controlled delivery of different combinations of cardiac-implicated proteins such as VEGF, HGF, PDGF, FGF-2, IL-10, TIMP-3, and SDF-1α. The controlled delivery of an optimal combination of proteins per their physiologic spatiotemporal cues to the infarcted myocardium holds great potential to repair and regenerate the damaged heart muscle. To address this issue, we developed a spatiotemporal delivery vehicle comprised of fibrin gel and heparin-based coacervates. Proteins that should be released relatively quickly are embedded in the fibrin gel, while proteins that should be released over a longer period are embedded in the coacervate and distributed in the same gel. This dissertation describes the process of developing the fibrin gel-coacervate composite for spatiotemporal delivery of therapeutic proteins and demonstrates its potential in triggering a significant cardiac repair process. It explores the ability of the coacervate to co-release different proteins, the development of the fibrin gel-coacervate system to achieve sequential delivery of different proteins, and the optimization of protein combinations and doses, paving the way for a potential comprehensive strategy to treat myocardial infarction.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
17 June 2016 |
| Date Type: |
Publication |
| Defense Date: |
22 March 2016 |
| Approval Date: |
17 June 2016 |
| Submission Date: |
29 March 2016 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
217 |
| 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: |
coacervate; fibrin; proteins; myocardial infarction; controlled release; growth factors; cardiac repair; angiogenesis; ecm; remodeling; heart; delivery system; spatiotemporal; fibrosis; cardiomyocyte |
| Date Deposited: |
17 Jun 2017 05:00 |
| Last Modified: |
17 Jun 2017 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/27380 |
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