Zhu, Yang
(2017)
BIODEGRADABLE, THERMALLY RESPONSIVE HYDROGELS FOR MYOCARDIAL INFARCTION TREATMENT.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Myocardial infarction (MI) is one of the leading causes of human mortality and morbidity. Aimed at preventing post-MI pathological left ventricular remodeling, which leads to end-stage heart failure, intramyocardial biomaterial injection was developed and has been rapidly advancing as a strategy to provide mechanical support to the ventricular wall. Various material candidates have been evaluated in clinical and preclinical trials and have presented promising therapeutic outcomes. This growing body of research has stimulated efforts to optimize material properties, identify key mechanistic factors, and implement safer, more adaptable delivery methods.
We previously invented a series of poly(N-isopropylacrylamide) (polyNIPAAm) based thermally responsive injectable hydrogels which could become hydrophilic and be absorbed in vivo as labile hydrophobic polyester side chains are removed. With advantageous mechanical properties, these hydrogels has shown beneficial effects in small and large animal models of MI. At the same time, there is considerable room for improvement in material design. Hydrogel degradation rates could not be precisely manipulated across a wide range. High viscosity and sol-gel transition of hydrogel solutions below body temperature prohibited catheter based delivery. The bioactivity of the synthetic hydrogels was low, not specifically incorporating activity designed to mitigate adverse responses of MI and the injected hydrogel itself.
Modifications were made on the previous hydrogel platform. We employed the concept of “acid-catalyzed degradation” documented in polyester based scaffold materials and developed an innovative strategy of tailoring the degradation rate of the hydrogel. This allowed tuning hydrogel degradation time from days to months. By copolymerization with more hydrophilic monomers, injectability of the hydrogels through catheters was substantially increased. Patterned subxiphoid transepicardial injections on a beating porcine heart were achieved facilitated by a miniature robotic delivery device. Scavengers for reactive oxygen species were incorporated into the platform design, producing an antioxidant hydrogel which significantly mitigated infarction/reperfusion injury in rat hearts and reduced ventricular cell apoptosis. In a parallel study a connective porous structure was generated in the injected hydrogel and decellularized porcine urinary bladder components were added. Cell infiltration into these hydrogels was greatly increased, and macrophages were polarized towarding a more constructive phenotype.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
14 June 2017 |
| Date Type: |
Publication |
| Defense Date: |
20 February 2017 |
| Approval Date: |
14 June 2017 |
| Submission Date: |
1 March 2017 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
189 |
| 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: |
myocardial infarction; hydrogel; responsive material; injection therapy |
| Date Deposited: |
14 Jun 2018 05:00 |
| Last Modified: |
14 Jun 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/30918 |
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