Heart failure following myocardial infarction (MI) is a leading cause of morbidity and mortality in the United States. MI involves cardiomyocyte death, inflammation, and remodeling of the left ventricle, which results in the formation of scar tissue and long-term loss of heart function. One therapeutic strategy is to selectively replace lost cardiomyocytes; however, there are significant challenges to identifying a cell source and engrafting viable cardiomyocytes in the injured myocardium. An alternative is to induce the proliferation of remaining cardiomyocytes towards the regeneration of functional myocardium. Our collaborators in the Morrisey group recently showed that daily, systemic injections of miR302 mimics leads to cardiomyocyte proliferation and promotes cardiac function post-MI through down-regulation of Hippo signaling in a mouse model. However, the therapy was met with several translational impediments, including off-target accumulation, a limited therapeutic time frame for effective treatment, and the inefficiency and costs associated with systemic delivery of miR302 mimics. The goal of this proposal is to develop an injectable hydrogel system to overcome these limitations by locally delivering miR302 to cardiac tissue after MI. Towards this, the first aim of this proposal is to develop guest-host assembled hydrogels based on cationic polyethyleneimine and neutral polyethylene glycol capable of (i) injection (flow through syringe or catheter), (ii) self-healing (for local deposition and retention at the injection site), and (iii) the encapsulation and release of active miR302 over tunable therapeutic windows.
The second aim of this proposal is to apply this technology in a small animal model of MI to promote healing and improved global cardiac function. The long-term goal of this research is to develop a platform to deliver various forms of RNAi to cardiac tissue post-MI using a catheter-deliverable hydrogel engineered as an effective drug delivery system. In addition to the research proposal, this fellowship includes a training plan through which I will gain clinical experience, expand my scientific background through collaboration with the Atluri and Morrisey groups, and present my research findings both on and off campus.

Public Health Relevance

Heart attack is one of the leading causes of death in the United States. During a heart attack, blood vessels supplying heart tissue are blocked, and heart cells, named cardiomyocytes, are deprived of nutrients and die. This can lead to heart failure. Therapeutic molecules, known as microRNAs, can be delivered to make cardiomyocytes grow to replace the dead cells following a heart attack. We propose using a hydrogel, a drug delivery system, to slowly release these miRNAs over time in the heart to recover cardiomyocytes and promote heart function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL134255-03
Application #
9545847
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Meadows, Tawanna
Project Start
2016-09-16
Project End
2019-09-15
Budget Start
2018-09-16
Budget End
2019-09-15
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wang, Leo L; Chung, Jennifer J; Li, Elizabeth C et al. (2018) Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart. J Control Release 285:152-161
Wang, Leo L; Highley, Christopher B; Yeh, Yi-Cheun et al. (2018) Three-dimensional extrusion bioprinting of single- and double-network hydrogels containing dynamic covalent crosslinks. J Biomed Mater Res A 106:865-875
Chen, Carol W; Wang, Leo L; Zaman, Samir et al. (2018) Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction. Cardiovasc Res 114:1029-1040
Wang, Leo L; Burdick, Jason A (2017) Engineered Hydrogels for Local and Sustained Delivery of RNA-Interference Therapies. Adv Healthc Mater 6:
Chen, Minna H; Wang, Leo L; Chung, Jennifer J et al. (2017) Methods To Assess Shear-Thinning Hydrogels for Application As Injectable Biomaterials. ACS Biomater Sci Eng 3:3146-3160
Wang, Leo L; Liu, Ying; Chung, Jennifer J et al. (2017) Local and sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischemic injury. Nat Biomed Eng 1:983-992