Hydrogel-based Engineered Skeletal Muscle Grafts Normalize Heart Function Early After Myocardial Infarction *Marie-Noëlle Giraud, *Erick Ayuni, †Stéphane Cook, ‡Matthias Siepe, *Thierry P. Carrel, and *Hendrik T. Tevaearai *Department of Cardiovascular Surgery, Inselspital; †Department of Cardiology, Inselspital, Berne, Switzerland; and ‡Department for Cardiovascular Surgery, University Medical Center, Freiburg, Germany Abstract: Tissue engineering represents an attractive approach for the treatment of congestive heart failure.The influence of the differentiation of myogenic graft for func- tional recovery is not defined. We engineered a biodegrad- able skeletal muscle graft (ESMG) tissue and investigated its functional effect after implantation on the epicardium of an infarcted heart segment. ESMGs were synthesized by mixing collagen (2 mg/mL), Matrigel (2 mg/mL), and rat skeletal muscle cells (10 6 ). Qualitative and quantitative aspects of ESMGs were optimized. Two weeks following coronary ligation, the animals were randomized in three groups: ESMG glued to the epicardial surface with fibrin (ESMG, n = 7), fibrin alone (fibrin, n = 5), or sham opera- tion (sham, n = 4). Echocardiography, histology, and immu- nostaining were performed 4 weeks later. A cohesive three-dimensional tissular structure formed in vitro within 1 week. Myoblasts differentiated into randomly oriented myotubes. Four weeks postimplantation, ESMGs were vas- cularized and invaded by granulation tissue. Mean frac- tional shortening (FS) was, however, significantly increased in the ESMG group as compared with preimplantation values (42  6 vs. 33  5%, P < 0.05) and reached the values of controlled noninfarcted animals (control, n = 5; 45  3%; not significant). Pre- and postimplantation FS did not change over these 4 weeks in the sham group and the fibrin-treated animals. This study showed that it is possible to improve systolic heart function following myocardial infarction through implantation of differentiated muscle fibers seeded on a gel-type scaffold despite a low rate of survival. Key Words: Tissue engineering—Myocardial infarction—Cell therapy—Myoblasts. Due to limited capacity for self-repair or regenera- tion, the myocardial tissue represents a challenging target for regenerative medicine. One of the most recent strategies is to provide viable cells to the damaged area of the heart in order to promote neovascularization and myogenesis that may lead to functional improvement. Cell and engineered tissue therapies have been investigated for the past decade (1). However, beneficial effects on heart function and regeneration, observed after cell therapy in animal models, were not always followed by convincing clini- cal outcomes (2). The modest or absent improvement of heart function may be the result of poor cell speci- ficity and quality as well as technical pitfalls during implantation. Important questions such as the mechanism of action, the optimal cell type, delivery mode, and time of implantation remain major issues that have to be experimentally investigated. The hypothesis that increased number of survival cells would increase the beneficial effect of cell therapy has led to the search for different cell deliv- ery strategies (3). The remodeling process of the injured myocardium includes immunologic and inflammatory reactions, which represent hostile con- ditions for the integration and differentiation of embedded cells. In this respect, the implantation of an engineered muscle graft may provide a better microenvironment for cell engraftment as it provides a biominetic extracellular matrix. In addition, it allows in vitro preconditioning with the control of cell survival and differentiation as well as the doi:10.1111/j.1525-1594.2008.00595.x Received September 2007; revised November 2007. Address correspondence and reprint requests to Dr. Marie- Noëlle Giraud, Department of Cardiovascular Surgery, Murten- strasse 35 MEM C812, CH-3010 Berne, Switzerland. E-mail: giraud@dkf.unibe.ch Artificial Organs 32(9):692–700, Wiley Periodicals, Inc. © 2008, Copyright the Authors Journal compilation © 2008, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc. 692