Nelson, Devin M.
(2013)
Controlled Drug Delivery from Biomaterials used for Cardiac Repair.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The continued risk of death due to heart failure has spurred the advancement of biomaterials-based treatments for cardiac repair, two of which are the application of a cardiac patch or intramyocardial material injection. The inclusion of signaling molecules in these materials can improve the treatment results; however, appropriate molecule delivery is not trivial. This research presents the broad application of therapeutics from both a patch and injectable system to demonstrate how system properties influence drug delivery and how these systems may be engineered to provide added benefit in the desired application.
We demonstrated the ability to release a gene-inducing molecule, Rheoswitch ligand 1 (RSL1), from a biodegradable elastomer that has been used as a cardiac patch. Not only was bioactive RSL1 released over an extended period, the ability to differentially load scaffolds with RSL1 allowed for spatial patterning of gene expression in cells cultured on the scaffold surface, which has implications for creating complex 3D tissues in vitro. This same elastomeric material was able to release bioactive insulin-like growth factor 1 (IGF1) and hepatocyte growth factor (HGF) in vitro. The complex release behavior of IGF1 into saline was replaced by a much simpler release profile during simulated in vivo degradation, demonstrating that the implant environment must be considered when studying drug delivery behavior.
A strong, thermoresponsive and degradable hydrogel was developed for intramyocardial injection. We showed the release rates of a model protein from this gel, or from protein-loaded microparticles inside the gel, could be controlled by changing the material composition. The combination of hydrogel with microparticles delivered two proteins in a sequential manner. We further used this system to release bioactive basic fibroblast growth factor (bFGF) followed by IGF1 in vitro. Injection of the unloaded polymer into infarcted rat hearts was able to improve the remodeling process for at least 16 weeks. While increased tissue bFGF and IGF1 were demonstrated following injection of growth factor-loaded gels, there were no clear benefits seen from protein inclusion. This points to the primary ability of the hydrogel alone to benefit cardiac function and cellular environment and warrants further investigation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
1 February 2013 |
| Date Type: |
Publication |
| Defense Date: |
7 November 2012 |
| Approval Date: |
1 February 2013 |
| Submission Date: |
15 November 2012 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
208 |
| 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: |
cardiac biomaterials, sequential release, controlled release, cardiac patch, myocardial injection, heart failure |
| Date Deposited: |
01 Feb 2013 13:32 |
| Last Modified: |
19 Dec 2016 14:39 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/16430 |
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