Recent evidence suggests that the delivery of progenitor cells to the infarcted heart improves mechanical function, although the functional mechanism remains equivocal. A major limitation of cell delivery systems for cardiac repair has been ineffective localization and retention of cells in the heart. Recently, we developed new methods for producing biopolymer micro-threads that can be tailored to modulate cell attachment and migration. By attaching these micro-threads to a surgical needle, we have developed a novel biological suture that can be seeded with cells. This method efficiently delivers cells to the heart with a 63.6 ? 10.6 % engraftment rate, which is significantly higher than the 11.8 ? 6.2 % engraftment rate determined for intramyocardial injection. Based on these observations, we hypothesize that fibrin micro-thread-based delivery of progenitor cells can efficiently deliver cells to infarcted regions of the heart, resulting in improved mechanical function. In the first aim, we will determine how strategically enhancing cell adhesion to micro-threads with ECM proteins prior to implantation improves cell engraftment in the beating rat heart. As multiple cell types have been shown to improve mechanical function in the infarcted heart, we will investigate the delivery of two different types of cells: pre-differentiated induced pluripotent stem (iPS) cell-derived cardiomyocytes and mesenchymal stem cells (MSCs). We will also determine how extending cell incubation time increasing cell adhesion strength to micro-threads.
The second aim will determine the therapeutic effects of micro-thread-mediated progenitor cell delivery on promoting myocardial regeneration and mechanical function in the infarct zone and border zone. Cell delivery as a function of viability status of myocardial tissue will be assessed by concurrently delivering cells to healthy, infarcted and border zone tissue. Cell engraftment rates and regional mechanical function will be evaluated. Expression of cardiac specific markers will also be evaluated.
The final aim will analyze how combining progenitor cell types with endothelial progenitor cells (EPCs) increases regeneration of myocardium in the infarcted rat heart. Individual micro-threads will be seeded with EPCs and combined with micro-threads seeded with iPS cell- derived cardiomyocytes or MSCs. We will also evaluate the ability of these cells to engraft and differentiate in the rat heart. Development of this innovative technology will improve cell delivery to the heart while providing targeted delivery and concise placement of cells in the region of interest.

Public Health Relevance

Cell therapy is a promising treatment option for millions of Americans suffering from myocardial infarction. However, cell therapy is limited by low cell engraftment rates. The innovative use of biological sutures for cell delivery may overcome cell engraftment issues, bringing cell therapy closer to becoming a viable therapy for many Americans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL115282-02
Application #
8710337
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Lundberg, Martha
Project Start
2013-08-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$380,808
Indirect Cost
$104,377
Name
Worcester Polytechnic Institute
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
041508581
City
Worcester
State
MA
Country
United States
Zip Code
01609
Adamski, Michal; Fontana, Gianluca; Gershlak, Joshua R et al. (2018) Two Methods for Decellularization of Plant Tissues for Tissue Engineering Applications. J Vis Exp :
Hansen, Katrina J; Laflamme, Michael A; Gaudette, Glenn R (2018) Development of a Contractile Cardiac Fiber From Pluripotent Stem Cell Derived Cardiomyocytes. Front Cardiovasc Med 5:52
Gershlak, Joshua R; Hernandez, Sarah; Fontana, Gianluca et al. (2017) Crossing kingdoms: Using decellularized plants as perfusable tissue engineering scaffolds. Biomaterials 125:13-22
Grasman, Jonathan M; Page, Raymond L; Pins, George D (2017) * Design of an In Vitro Model of Cell Recruitment for Skeletal Muscle Regeneration Using Hepatocyte Growth Factor-Loaded Fibrin Microthreads. Tissue Eng Part A 23:773-783
Hansen, Katrina J; Favreau, John T; Gershlak, Joshua R et al. (2017) Optical Method to Quantify Mechanical Contraction and Calcium Transients of Human Pluripotent Stem Cell-Derived Cardiomyocytes. Tissue Eng Part C Methods 23:445-454
Tao, Ze-Wei; Favreau, John T; Guyette, Jacques P et al. (2017) Delivering stem cells to the healthy heart on biological sutures: effects on regional mechanical function. J Tissue Eng Regen Med 11:220-230
Grasman, Jonathan M; O'Brien, Megan P; Ackerman, Kevin et al. (2016) The Effect of Sterilization Methods on the Structural and Chemical Properties of Fibrin Microthread Scaffolds. Macromol Biosci 16:836-46
Coffin, Spencer T; Gaudette, Glenn R (2016) Aprotinin extends mechanical integrity time of cell-seeded fibrin sutures. J Biomed Mater Res A 104:2271-9
O'Brien, Megan P; Carnes, Meagan E; Page, Raymond L et al. (2016) Designing Biopolymer Microthreads for Tissue Engineering and Regenerative Medicine. Curr Stem Cell Rep 2:147-157
Guyette, Jacques P; Charest, Jonathan M; Mills, Robert W et al. (2016) Bioengineering Human Myocardium on Native Extracellular Matrix. Circ Res 118:56-72

Showing the most recent 10 out of 14 publications