Myocardial infarction leads to millions of deaths per year. Clinical strategies to address this heart muscle destruction are essentially palliative or ineffective. For phase 2 (years 6-10) of this Bioengineering Research Partnership, we take knowledge gained in years 1-5 and apply this to developing an engineering system for clinical repair of damaged heart muscle. Specifically, we use proliferating human cardiomyocytes and a novel pro-angiogenic porous scaffold (both developed in years 1-5 of this program) to engineer 300?m diameter rods of cardiac muscle (RCM) or particles of cardiac muscle (PCM) that can be injected into a heart infarct zone and facilitate functional repair of cardiac muscle. The in vitro tissue engineering of cardiac muscle by itself, though an important step, is insufficient - this new muscle must survive, grow, integrate into the heart and, ultimately, enhance systolic function. Our engineering systems approach will evolve an integrated therapeutic strategy addressing these issues. We envision that, as early as possible after a myocardial infarction, a series of minimally invasive interventions will be implemented to reduce fibrosis, promote angiogenesis and limit further heart damage. RCM or PCM then will be implanted in this """"""""primed"""""""" infarct. Ischemic death of these myocardial constructs will be minimized via the geometry of the implant, strategies to """"""""harden"""""""" cardiomyocytes to ischemic injury, and novel approaches to induce rapid angiogenesis. Electrical integration of the implant is essential, and therefore we will optimize the electrophysiologic properties of the construct. The partnership's efforts to develop this heart muscle repair system are centered around four broad aims: (1) the tissue engineering of heart muscle rods and particles using rationally designed porous scaffolds and proliferating cardiomyocytes derived from human embryonic stem cells (approved lines GEO01.07; WA01, 07, 14), (2) priming the infarct site to prepare the tissue bed to accept the implant by controlling extracellular matrix components and inducing blood vessel formation, (3) developing surgical approaches to deliver the tissue-engineered rods or particles into the infarct and molecular approaches to promote implant survival, and (4) assessing structural and functional benefit to the infarcted heart. This comprehensive approach to heart muscle repair will be implemented by a collaborative, multidisciplinary team closely integrating engineers, scientists and clinicians. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064387-07
Application #
7284157
Study Section
Special Emphasis Panel (ZRG1-SBIB-N (50))
Program Officer
Lundberg, Martha
Project Start
2000-05-15
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
7
Fiscal Year
2007
Total Cost
$2,001,635
Indirect Cost
Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wight, Thomas N (2018) A role for proteoglycans in vascular disease. Matrix Biol 71-72:396-420
Hartman, Matthew E; Dai, Dao-Fu; Laflamme, Michael A (2016) Human pluripotent stem cells: Prospects and challenges as a source of cardiomyocytes for in vitro modeling and cell-based cardiac repair. Adv Drug Deliv Rev 96:3-17
Järveläinen, Hannu; Sainio, Annele; Wight, Thomas N (2015) Pivotal role for decorin in angiogenesis. Matrix Biol 43:15-26
Luo, Jun; Weaver, Matthew S; Cao, Baohong et al. (2014) Cobalt protoporphyrin pretreatment protects human embryonic stem cell-derived cardiomyocytes from hypoxia/reoxygenation injury in vitro and increases graft size and vascularization in vivo. Stem Cells Transl Med 3:734-44
Obika, Masanari; Vernon, Robert B; Gooden, Michel D et al. (2014) ADAMTS-4 and biglycan are expressed at high levels and co-localize to podosomes during endothelial cell tubulogenesis in vitro. J Histochem Cytochem 62:34-49
Thomson, Kassandra S; Dupras, Sarah K; Murry, Charles E et al. (2014) Proangiogenic microtemplated fibrin scaffolds containing aprotinin promote improved wound healing responses. Angiogenesis 17:195-205
Luo, Jun; Weaver, Matthew S; Dennis, James E et al. (2014) Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell-derived cardiomyocytes. J Thorac Cardiovasc Surg 148:3180-8.e1
Shiba, Yuji; Filice, Dominic; Fernandes, Sarah et al. (2014) Electrical Integration of Human Embryonic Stem Cell-Derived Cardiomyocytes in a Guinea Pig Chronic Infarct Model. J Cardiovasc Pharmacol Ther 19:368-381
Zhu, Wei-Zhong; Filice, Dominic; Palpant, Nathan J et al. (2014) Methods for assessing the electromechanical integration of human pluripotent stem cell-derived cardiomyocyte grafts. Methods Mol Biol 1181:229-47
Lundy, Scott D; Murphy, Sean A; Dupras, Sarah K et al. (2014) Cell-based delivery of dATP via gap junctions enhances cardiac contractility. J Mol Cell Cardiol 72:350-9

Showing the most recent 10 out of 59 publications