Novel regenerative therapy combined with transphrenic peritoneoscopy-assisted omentopexy (original) (raw)
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Objective: A key challenge to applying cell transplantation to treat severely damaged myocardium is in delivering large numbers of cells with minimum cell loss. We developed a new implantation method using skeletal myoblast (SMB) sheets, wrapped with an omentum flap as a blood supply to deliver huge numbers of SMBs to the damaged heart. We examined whether this method could be used to deliver a large amount of cells to deteriorated porcine myocardium. Methods: Cell sheets were obtained by culturing mini-pig autologous SMB cells on temperature-responsive culture dishes. Myocardial infarction was induced by placing an ameroid constrictor around the left anterior descending artery. The mini-pigs were divided into 4 treatment groups (n ¼ 6 in each): cell sheets with omentum, cell sheets only, omentum only, and sham operation. Each animal implant consisted of 30 cell sheets (1.5 3 10 7 cells per sheet). Six 5-layer constructs were each placed on a different area, immediately adjacent to but not overlapping one another, to cover the infarct and border regions. Results: The new regenerative cell delivery system using SMB sheets covered and wrapped with omentum resulted in (1) a significantly reduced infarct size causing, at least in part, a thin scar with thick well-vascularized cardiac tissue; (2) increased angiogenesis, as determined by a significantly higher vascular density; and (3) improved cardiac function, as determined by echocardiography, compared with the conventional method (SMB sheet implantation). Conclusions: This cell delivery system shows potential for repairing the severely failed heart. (J Thorac Cardiovasc Surg 2011;142:1188-96) Heart failure is a frequent and life-threatening disorder, despite recent medical and surgical advances. Myocardial re-generative therapy is gaining interest as a means for improving left ventricular (LV) function in patients with end-stage heart disease. 1-3 However, a recent clinical trial of cell transplantation by needle injection reported slightly disappointing results. 2-4 The main drawbacks of cell transplantation by needle injection appear to be poor retention and survival of the injected cells, local mechanical myocardial damage owing to injury by the needle itself, and the potential for lethal arrhythmias. We have been investigating cell-sheet techniques for delivering cells to severely damaged myocardium more efficiently, without damaging the myocardium, and, consequently, more effectively. This technique provides better improvement of cardiac function than obtained with the needle cell-injection method. 5-7 The greatest advantage of the cell-sheet technique is that the sheet consists only of cells, which produce an extracel-lular matrix without requiring an artificial scaffold. The cell sheet has a high ability to integrate with native tissues, because the adhesion molecules on its surface are preserved. 5-7 The layered grafts must be carefully prepared to avoid tearing, but they themselves are strong, flexible, and easy to work with. It has been suggested that an increased number of implanted skeletal myoblast (SMB) sheets is related to better results, such as improved cardiac function and angiogene-sis, less fibrosis, and less hypertrophy, with the amounts of secreted cytokines dependent on the number of cell sheets used. 7 However, cell sheets with more than 5 layers show areas with disorganized vasculature, presumably because of insufficient supplies of blood, oxygen, and nutritients. 7,8 Thus, in applying cell transplantation to the severely damaged myocardium, a key challenge is in improving the blood perfusion of the implanted cells so
Cell Transplantation, 2009
Tissue engineering holds the promise of providing new solutions for heart transplant shortages and pediatric heart transplantation. The aim of this study was to evaluate the ability of a peritoneal-generated, tissue-engineered cardiac patch to replace damaged myocardium in a heterotopic heart transplant model. Fetal cardiac cells (1 × 106/scaffold) from syngeneic Lewis rats were seeded into highly porous alginate scaffolds. The cell constructs were cultured in vitro for 4 days and then they were implanted into the rat peritoneal cavity for 1 week. During this time the peritoneal-implanted patches were vascularized and populated with myofibroblasts. They were harvested and their performance in an infrarenal heterotopic abdominal heart transplantation model was examined ( n = 15). After transplantation and before reperfusion of the donor heart, a 5-mm left ( n = 6) or right ( n = 9) ventriculotomy was performed and the patch was sutured onto the donor heart to repair the defect. Echoc...
Myoblast transplantation in the porcine model: A potential technique for myocardial repair
The Journal of Thoracic and Cardiovascular Surgery, 1995
The use of transgenic cells transplanted in syngeneic rodents has shown modest success, but allogeneic and xenogeneic transplants have not been uniformly successful. To assess the feasibility of xenogeneic and allogeneic myoblast transplantation, we subjected seven adult swine to transplantation of murine atrial tumor cells (xenogeneic), neonatal porcine myocytes (allogeneic), and human fetal cardiomyocytes into the left ventricular wall. After general anesthesia, isolated cells were injected along the anterior and posterior walls of the porcine left ventricle. All the animals were immunosuppressed and observed for 1 month after injection, at which time they were killed and analyzed. This report will present results primarily concerned with the success of human cell transfers. In all injected sites examined, the transplanted cells thrived within the host myocardium with no significant rejection. Transplant cells formed close associations with host myocytes that resembled nascent intercalated disks on electron microscopy. These cells also contained myofibrils and other cell architecture resembling the transplanted cell lines. Additionally, these cells appeared to produce an angiogenic influence resulting in the proliferation of the surrounding microvasculature. We believe that these findings indicate successful xenogeneic and allogeneic myoblast cell transplantation in a large animal model. These experiments set the stage for future studies to assess the ability of these cells to form a syncytium, contract, and potentially repair failed myocardium. (J THORAC CARDIOVASC SURG 1995;
Molecular therapy : the journal of the American Society of Gene Therapy, 2015
Cell-sheet transplantation induces angiogenesis for chronic myocardial infarction (MI), though insufficient capillary maturation and paucity of arteriogenesis may limit its therapeutic effects. Omentum has been used clinically to promote revascularization and healing of ischemic tissues. We hypothesized that cell-sheet transplantation covered with an omentum-flap would effectively establish mature blood vessels and improve coronary microcirculation physiology, enhancing the therapeutic effects of cell-sheet therapy. Rats were divided into four groups after coronary ligation; skeletal myoblast cell-sheet plus omentum-flap (combined), cell-sheet only, omentum-flap only, and sham operation. At 4 weeks after the treatment, the combined group showed attenuated cardiac hypertrophy and fibrosis, and a greater amount of functionally (CD31(+)/lectin(+)) and structurally (CD31(+)/α-SMA(+)) mature blood vessels, along with myocardial upregulation of relevant genes. Synchrotron-based microangiog...
Video-assisted thoracoscopic transplantation of myoblasts into the heart
The Annals of Thoracic Surgery, 2004
Video-assisted thoracoscopic transplantation of myoblasts into the heart I n contrast to what is happening with other cardiac diseases, the incidence of congestive cardiac insufficiency is not decreasing despite significant progress in pharmacologic treatment, and that is likely due to the increased longevity of the population. Cardiac transplantation is the elective therapy, but the limit set by organ donors seems to have been reached all over the world. In the future, xenotransplants could offer a solution to the problem, even though such an approach would still carry the risk of zoonotic viral infections. Mechanical circulatory support has also been studied as a viable option, but many more studies are needed before considering it the final solution.
Autologous porcine heart cell transplantation improved heart function after a myocardial infarction
The Journal of Thoracic and Cardiovascular Surgery, 2000
Fetal cardiomyocyte transplantation improved heart function after cardiac injury. However, cellular allografts were rejected despite cyclosporine (INN: ciclosporin) therapy. We therefore evaluated autologous heart cell transplantation in an adult swine model of a myocardial infarction. Methods: In 16 adult swine a myocardial infarction was created by occlusion of the distal left anterior descending coronary artery by an intraluminal coil. Four weeks after infarction, technetium 99m-sestamibi single photon emission tomography showed minimal perfusion and viability in the infarcted region. Porcine heart cells were isolated and cultured from the interventricular septum at the time of infarction and grown in vitro for 4 weeks. Through a left thoracotomy, either cells (N = 8) or culture medium (N = 8) was injected into the infarct zone. Results: Four weeks after cell transplantation, technetium 99m-sestamibi single photon emission tomography demonstrated greater wall motion scores in the pigs receiving transplantation than in control animals (P = .01). Pigs receiving transplantation were more likely to have an improvement in perfusion scores (P = .03). Preload recruitable stroke work (P = .009) and end-systolic elastance (P = .02) were greater in the pigs receiving transplantation than in control animals. Scar areas were not different, but scar thickness was greater (P = .02) in pigs receiving transplantation. Cells labeled with bromodeoxyuridine in vitro could be identified in the infarct zone 4 weeks after transplantation. Swine receiving transplantation gained more weight than control animals (P = .02). Conclusion: Autologous porcine heart cell transplantation improved regional perfusion and global ventricular function after a myocardial infarction. (