Engineered Anisotropic and Vascularized Human Cardiac Patch Project Summary Currently there are no therapies to effectively reverse cardiac injury following myocardial infarction. Tissue Engineering holds promise for the regeneration of heart tissue through an engineered cardiac patch. Unfortunately, pervious efforts have failed to achieve a cardiac patch with an effective engraftment rate and regenerative efficacy. Human pluripotent stem cell-derived cardiac fibroblasts (hPSCs-CFs) have the potential to provide an unlimited supply of cardiac tissue-specific extracellular matrix (ECM), which could be organized into nanofibers and serve as a universal scaffold to direct the anisotropic orientation of cells and engineered microvessels into a biomimetic hierarchical structure. Human mesenchymal stem cells (hMSCs) are immunomodulatory and effective in promoting myocardial regeneration, and can function as pericytes to mature and stabilize microvessels constructed by endothelial cells. Human pluripotent stem cell-derived cardiomyocytes (hPSCs-CMs) could orchestrate contractile synchrony between the transplanted cardiac tissue and the underlying myocardium. We hypothesize that the combination of hPSCs-CF derived cardiac tissue- specific ECM nanofibers with hMSCs and capillary-like microvessels will significantly enhance the anisotropic cardiac tissue engraftment and effectively promote myocardial regeneration. The objective of the proposed project is to biomimetically engineer an anisotropic cardiac patch containing aligned cardiac tissue-specific nanofibrous ECM, dense and oriented capillary-like microvessels, contractile CMs, and regeneration-promoting hMSCs within a short time. With a strong team comprising of a well-established tissue engineer, a world leading cardiovascular physician-scientist, a very experienced cardiovascular physiologist, an expert in electrophysiology and optical mapping, and an experienced biostatistician, we will pursue the specific aims: I. Derive an aligned and uniform cardiac-specific nanofibrous ECM scaffold from hPSC-CFs. II. Develop an anisotropic, vascularized and contractile cardiac patch representative of native myocardium. III. Evaluate the anastomosis, engraftment and regeneration efficacy of the prevascualrized cardiac patch in a rat MI model.

Public Health Relevance

Currently there are no therapies to effectively reverse cardiac injury following myocardial infarction. This proposed study will allow us to biomimetically engineer a functional anisotropic cardiac patch containing aligned cardiac tissue-specific nanofibrous extracellular matrix, dense and oriented capillary-like microvessels, contractile cardiomyocytes, and regeneration-promoting stem cells within two weeks.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL146652-01A1
Application #
9886725
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lundberg, Martha
Project Start
2020-01-01
Project End
2023-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Michigan Technological University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
065453268
City
Houghton
State
MI
Country
United States
Zip Code
49931