Congenital and surgically-induced block of cardiac atrioventricular (AV) node conduction is a serious long-term clinical problem in pediatric patients. Currently, the permanent implantation of a cardiac pacemaker device is the only therapy available for the treatment of congenital complete heart block and AV block subsequent to surgical repair of inborn heart abnormalities such as ventricular septal defect, AV canal defect, and tetralogy of Fallot. Despite the technological advancements in cardiac pacemaker design and function, permanent pacemaker therapy in infants and children continues to be problematic. Since the survival rate for children that undergo complex surgical procedures to repair congential cardiovascular defects has greatly increased, the need for improved long-term pacing solutions in the pediatric patient population has provided the rationale for this project. The primary goal of the project is to engineer tissue that would act as an electrical conduit from the atrium to the ventricle of the heart for use in patience that lack normal AV node function. The engineered tissue will be comprised of skeletal muscle progenitor cells (myoblasts) or mesenchymal stem cells (bone marrow stromal cells) that can be autologously derived. The cells will be cast in a three dimensional tissue construct using natural polymers, such as collagen, in order to efficiently deliver cells to the AV groove of the heart. Accordingly, in the present proposal, we will address the following specific aims; (a) engineer electrically conductive tissue suitable for cardiac implementation (b) characterize the electromechanical properties of engineered tissue constructs in vitro, (c) determine the practicality of implanting tissue constructs in the cardiac AV groove, and (d) evaluate electrical conduction in hearts implanted with engineered tissue constructs. This is a conceptually simple research project that requires extensive expertise in a number of fields including cell biology, tissue engineering, and electrophysiology. The success of the research depends on a multidisciplinary group of individuals that will apply their knowledge to specific components of the project with the intention of developing a therapy to alleviate a substantial clinical problem. Ultimately, these experiments are intended to provide an alternative or adjunct treatment to conventional cardiac pacemaker therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068915-04
Application #
6832237
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Lathrop, David A
Project Start
2002-01-18
Project End
2006-08-31
Budget Start
2005-01-01
Budget End
2006-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$315,537
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Treskes, Philipp; Neef, Klaus; Perumal Srinivasan, Sureshkumar et al. (2015) Preconditioning of skeletal myoblast-based engineered tissue constructs enables functional coupling to myocardium in vivo. J Thorac Cardiovasc Surg 149:348-56
Neef, Klaus; Treskes, Philipp; Xu, Guoxing et al. (2015) Dynamic Support Culture of Murine Skeletal Muscle-Derived Stem Cells Improves Their Cardiogenic Potential In Vitro. Stem Cells Int 2015:247091
Pacak, Christina A; Hammer, Peter E; MacKay, Allison A et al. (2014) Superparamagnetic iron oxide nanoparticles function as a long-term, multi-modal imaging label for non-invasive tracking of implanted progenitor cells. PLoS One 9:e108695
Pacak, Christina A; MacKay, Allison A; Cowan, Douglas B (2014) An improved method for the preparation of type I collagen from skin. J Vis Exp :e51011
Friehs, Ingeborg; Cowan, Douglas B; Choi, Yeong-Hoon et al. (2013) Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium. Am J Physiol Heart Circ Physiol 304:H697-708
Neef, Klaus; Choi, Yeong-Hoon; Srinivasan, Sureshkumar Perumal et al. (2012) Mechanical preconditioning enables electrophysiologic coupling of skeletal myoblast cells to myocardium. J Thorac Cardiovasc Surg 144:1176-1184.e1
Srinivasan, Sureshkumar Perumal; Neef, Klaus; Treskes, Philipp et al. (2012) Enhanced gap junction expression in myoblast-containing engineered tissue. Biochem Biophys Res Commun 422:462-468
Pacak, Christina A; Powers, Jared M; Cowan, Douglas B (2011) Ultrarapid purification of collagen type I for tissue engineering applications. Tissue Eng Part C Methods 17:879-85
Sill, Bjoern; Roy, Nathalie; Hammer, Peter E et al. (2011) Development of an ovine model of pediatric complete heart block. J Surg Res 166:e103-8
Choi, Yeong-Hoon; Cowan, Douglas B; Wahlers, Thorsten C W et al. (2010) Calcium sensitisation impairs diastolic relaxation in post-ischaemic myocardium: implications for the use of Ca(2+) sensitising inotropes after cardiac surgery. Eur J Cardiothorac Surg 37:376-83

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