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In the early 1990's our team developed and patented one of the first percutaneous heart valve systems working with Dr. Ivan Casagrande and Dr. Domingos Moraes in Brazil. We learned in this experience that a patient is nearly always better off keeping their own heart valve it they can. The aim of

La regeneración cardíaca requiere una cascada compleja de acontecimientos con numerosos factores, la mayoría aún no clarificados, que limitan la terapia celular y su traslación a la práctica clínica. Las células tienen que injertarse, sobrevivir e integrarse funcionalmente en el órgano para restaurar su función. De la misma manera que en los tejidos originales, un sistema complejo de señales bien definidas, muchas de ellas generadas desde la matriz extracelular, son necesarias para desarrollar una fisiología celular normal. El planteamiento de combinar conocimientos de biología celular e ingeniería con materiales biocompatibles para restaurar tejidos biológicos y mejorar su función es el fundamento de la ingeniería tisular que define un nuevo abordaje de la regeneración cardíaca.La investigación y desarrollo de un miocardio bioartificial tiene gran interés clínico. La estrategia es el uso de biomateriales para desarrollar una microatmósfera que proporcione a las células endógenas y exógenas un ambiente óptimo para la reparación de tejidos. Los conocimientos adquiridos en el desarrollo de biomateriales aportan las bases para desarrollar matrices 3D que ofrecen el ambiente idóneo para la liberación de células y genes que dirijan las células terapéuticas hacia el fenotipo funcional. La descelularización de órganos para construir nuevas matrices es un nuevo concepto de investigación, desarrollado gracias al desarrollo de nanomateriales que aseguran un nicho celular apropiado para la diferenciación celular y la terapia génica o farmacológica.Cardiac regeneration requires a complex cascade of events. There are many factors, most of them still no clarified, that limit the effectiveness of the stem cell therapy and their translation to the clinic. Cells should graft, survive and functionally integrate to the target organ in order to have a chance to restore its function. As in original tissues, a complex and well defined set of signals, many of them coming from the extracellular matrix, is required for normal cell physiology. The idea of combining principles from cell biology and engineering of biocompatible materials in order to create biologic replacement structures that restore, maintain, or improve tissue function, is at the basis of the tissue engineering and defines a different approach to the cardiac regeneration.Research and development of bioartificial myocardium is of great clinical interest. The rationale for the use of specific biomaterials is to allow the creation of a microatmosphere where the exogenous and endogenous cells find the microenvironment optimal for repair. Biomaterials science gives us important tools to build this extracellular matrix. Functionalized 3D systems can provide the correct environment and act as a delivery system for cells and genes, guiding the therapeutic cells to the functional phenotype. Organ decellularization for bioscaffolds fabrication is a new investigated concept. nanomaterials are emerging as the main candidates to ensure the achievement of a proper instructive cellular niche with good drug release/ administration properties.

Stem cell therapy is a major field of research worldwide, with increasing clinical application, especially in cardiovascular pathology. However, the best stem cell source and type with optimal safety for functional engraftment remains unclear. An intermediate cardiac precommitted phenotype expressing some of the key proteins of a mature cardiomyocyte would permit better integration into the cardiac environment. The predifferentiated cells would receive signals from the environment, thus achieving gradual and complete differentiation. In cell transplantation, survival and engraftment within the environment of the ischemic myocardium represents a challenge for all types of cells, regardless of their state of differentiation. An alternative strategy is to embed cells in a 3-dimensional structure replicating the extracellular matrix, which is crucial for full tissue restoration and prevention of ventricular remodeling. The clinical translation of cell therapy requires avoidance of potentially harmful drugs and cytokines, and rapid off-the-shelf availability of cells. The combination of predifferentiated cells with a functionalized scaffold, locally releasing molecules tailored to promote in-situ completion of differentiation and improve homing, survival, and function, could be an exciting approach that might circumvent the potential undesired effects of growth factor administration and improve tissue restoration.

Heart disease and atherosclerosis are the leading causes of morbidity and mortality worldwide. The lack of suitable autologous grafts has produced a need for artificial grafts; however, current artificial grafts carry significant limitations, including thrombosis, infection, limited durability and the inability to grow. Tissue engineering of blood vessels, cardiovascular structures and whole organs is a promising approach for creating replacement tissues to repair congenital defects and/or diseased tissues. In an attempt to surmount the shortcomings of artificial grafts, tissue-engineered cardiovascular graft (TECVG), constructs obtained using cultured autologous vascular cells seeded onto a synthetic biodegradable polymer scaffold, have been developed. Autologous TECVGs have the potential advantages of growth, durability, resistance to infection, and freedom from problems of rejection, thrombogenicity and donor scarcity. Moreover polymers engrafted with growth factors, cytokines, drugs have been developed allowing drug-releasing systems capable of focused and localized delivery of molecules depending on the environmental requirements and the milieu in which the scaffold is placed. A broad range of applications for compound-releasing, tissue-engineered grafts have been suggested ranging from drug delivery to gene therapy. This review will describe advances in the development of drug-delivery systems for cardiovascular applications focusing on the manufacturing techniques and on the compounds delivered by these systems to date.

Congestive heart failure is a complex clinical syndrome resulting from myocardial dysfunction that impairs the cardiovascular system's function. Medical and surgical therapy both still result in a large number of patients with very few options and persistent ventricular dysfunction. The major process to reverse ventricular remodeling would be the enhancement of regeneration of cardiac myocytes, as well as the stimulation of neovascularization within the affected area of the myocardium. This can be achieved by introducing progenitor cells that are capable of differentiating into cardiac myocytes, or that promote neovascularization and restore the normal characteristics of myocardium environment. A number of issues remain as to the type of cells, delivery, timing, and mechanisms involved, however.There have been a number of clinical trials in patients with heart failure that have been based on animal data related to stem cell therapy. Most have utilized whole bone marrow cells or myoblasts. The majority of the studies demonstrate an improvement in ventricular function, reduction in scarring, and improvement in symptoms. Some trials have shown no improvement at all.This review examines the bench-to-bedside developments of stem cell therapy related to congestive heart failure.

Electrostimulation represents a well-known trophic factor for different tissues. In vitro electrostimulation of non-stem and stem cells induces myogenic predifferentiation and may be a powerful tool to generate cells with the capacity to respond to local areas of injury. We evaluated the effects of in vivo electrostimulation on infarcted myocardium using a miniaturized multiparameter implantable stimulator in rats. Parameters of electrostimulation were organized to avoid a direct driving or pacing of native heart rhythm. Electrical stimuli were delivered for 14 days across the scar site. In situ electrostimulation used as a cell-free, cytokine-free stimulation system, improved myocardial function, and increased angiogenesis through endothelial progenitor cell migration and production of vascular endothelial growth factor (VEGF). In situ electrostimulation represents a novel means to stimulate repair of the heart and other organs, as well as to precondition tissues for treatment with cell-based therapies.

Myocardial repair using stem-cell therapy has become a promising therapeutic tool. However, many questions concerning a precise functional integration of injected cells remain unanswered. The use of cardiac pre-committed cells may improve integration, as these cells may complete their differentiation in the myocardium reducing fibrosis and restoring muscle function. We have previously demonstrated that electrostimulation (ES) induces cardiomyocyte pre-commitment of fibroblasts in vitro and is an effective alternative to cytokine-induced differentiation. In this study, we evaluated the effects of long term electrostimulation on human mesenchymal stem cells (hMSCs). ES induced both morphological and biochemical changes in hMSCs resulting in a shift toward a striated muscle cell phenotype expressing cardiac specific markers. This partially differentiated phenotype might allow a gradual, ongoing differentiation within the cardiac environment, providing time for both myocardial regeneration and electro-mechanical integration, and convey potential advantages in clinical applications.

Angiogenesis and vasculogenesis are fundamental processes in embryonic development enabling multiorgan characteristics. Through the capillary net, the nutrient diffusion process is successfully achieved in complex cellular organisms. In adults the establishment, maintenance, and renewal of an efficient vascular net are required for the maintenance of normal, viable tissues. This requirement is especially important in the cardiovascular system, where vascular supply efficiency and endothelium normal function are affected in many different pathological entities. Impaired angiogenesis and endothelial dysfunction are the bases of many cardiovascular diseases such as hypertension, coronary artery disease, myocardial infarction, and chronic heart failure.

The objective of cellular cardiomyoplasty is to regenerate the myocardium using implantation of living cells. Because the extracellular myocardial matrix is deeply altered in ischemic cardiomyopathies, it could be important to create a procedure aiming at regenerating both myocardial cells and the extracellular matrix. We evaluated the potential of a collagen matrix seeded with cells and grafted onto infarcted ventricles. A myocardial infarction was created in 45 mice using coronary artery ligation. Animals were randomly assigned to 4 local myocardial treatment groups. Group I underwent sham treatment (injection of cell culture medium). Group II underwent injection of human umbilical cord blood mononuclear cells (HUCBCs). Group III underwent injection of HUCBCs and fixation onto the epicardium of a collagen matrix seeded with HUCBCs. Group IV underwent fixation of collagen matrix (without cells) onto the infarct. Echocardiography was performed on postoperative days 7 and 45, followed by histological studies. Echocardiography showed that the association between the cell-loaded matrix and the intrainfarct cell implants was the most efficient approach to limiting postischemic ventricular dilation and remodeling. Ejection fraction improved in both cell-treated groups. The collagen matrix alone did not improve left ventricular (LV) function and remodeling. Histology in Group III showed fragments of the collagen matrix thickening and protecting the infarct scars. Segments of the matrix were consistently aligned along the LV wall, and cells were assembled within the collagen fibers in large populations. Intramyocardial injection of HUCBCs preserves LV function following infarction. The use of a cell-seeded matrix combined with cell injections prevents ventricular wall thinning and limits postischemic remodeling. This tissue engineering approach seems to improve the efficiency of cellular cardiomyoplasty and could emerge as a new therapeutic tool for the prevention of adverse remodeling and progressive heart failure.

Ischemic myocardial disease, the main cause of heart failure, is a major public health and economic problem. Given the aging population, heart failure is becoming an increasing clinical issue and a substantial financial burden. Thus, research in heart failure is of relevant interest and importance, involving specialties such as cellular and molecular biology, tissue engineering, genetics, biophysics and electrophysiology. Stem cell-based regenerative therapy is undergoing experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles following myocardial infarction or in patients presenting non-ischemic dilated cardiomyopathies. This biological approach is particularly attractive due to the potential for myocardial regeneration with a variety of myogenic and angiogenic cell types. The development of a bio-artificial myocardium using biological or synthetic matrix is a new challenge.

Background: Current clinical experience with cellular cardiomyoplasty (using serum bovine-cultivated myoblasts) has demonstrated significant malignant ventricular arrhythmias and sudden deaths in patients. In some ongoing clinical trials the implantation of cardioverterdefibrillator is mandatory. We have hypothesized that contact of human cells with fetal bovine serum results after 3-week fixation of animal proteins on the cell surface, representing an antigenic substrate for immunological and inflammatory adverse events. Methods and Results: Autologous myoblasts were transplanted into infarcted LV in 20 patients (90% males, mean age 62±8 years). Cells were cultivated in a complete human medium during 3 weeks, using the patients' own serum obtained from a blood sample or from plasmapheresis. Injections were performed during CABG (2.1 grafts/pt). All patients had an uneventful recovery. At a mean follow-up of 14±5 months without mortality, no malignant cardiac arrhythmias are reported. LV ejection fraction improved from 28±3% to 52:k4.7% (p = 0.03), and regional wall motion score index (WMSI) from 3.1 to 1.4 (p = 0.04) in the cell-treated segments. Myocardial viability tests showed areas of regeneration. Patients moved from mean NYHA class 2.5 to class 1.2. Conclusions: A total autologous cell culture procedure was used in cellular cardiomyoplasty reducing the risk of arrhythmia. Human-autologous-serum cell expansion avoids the risk of prion, viral or zoonoses contamination. Since patients treated with noncultivated bone marrow cells are free of arrhythmia, the bovine-culture medium seems to be responsible for this complication. Cellular cardiomyoplasty may be efficient to avoid progression of ventricular remodeling and subsequent heart failure in ischemic heart disease.

In vitro, in vivo animal, and human clinical data show a broad field of application for mesenchymal stem cells (MSCs). There is overwhelming evidence of the usefulness of MSCs in regenerative medicine, tissue engineering, and immune therapy. At present, there are a significant number of clinical trials exploring the use of MSCs for the treatment of various diseases, including myocardial infarction and stroke, in which oxygen suppression causes widespread cell death, and others with clear involvement of the immune system, such as graft-versus-host disease, Crohn’s disease, and diabetes. With no less impact, MSCs have been used as cell therapy to treat defects in bone and cartilage and to help in wound healing, or in combination with biomaterials in tissue engineering development. Among the MSCs, allogeneic MSCs have been associated with a regenerative capacity due to their unique immune modulatory properties. Their immunosuppressive capability without evidence of immunosuppressive toxicity at a global level define their application in the treatment of diseases with a pathogenesis involving uncontrolled activity of the immune system. Until now, the limitation in the number of totally characterized autologous MSCs available represents a major obstacle to their use for adult stem cell therapy. The use of premanufactured allogeneic MSCs from controlled donors under optimal conditions and their application in highly standardized clinical trials would lead to a better understanding of their real applications and reduce the time to clinical translation.

La terapia celular con células madre, como estrategia para regenerar tejidos dañados, es una de las áreas más prometedoras en el tratamiento de enfermedades con escasas o nulas expectativas de curación. La insuficiencia cardíaca, principalmente de origen isquémico, es una de las enfermedades que más se pueden beneficiar de esta estrategia. El objetivo es regenerar el músculo, reducir la apoptosis, aumentar la expresión del colágeno intersticial e inducir la generación de nuevos vasos. la terapia celular cardíaca ha sido propuesta con una gran variedad de células angiogénicas y miogénicas: mioblastos esqueléticos, células mononucleares y mesenquimales de médula ósea, progenitores endoteliales circulantes, células derivadas del estroma de la grasa o del endometrio, células mesoteliales y pluripotenciales (induced pluripotent stem cells [iPS]). las indicaciones incluyen a pacientes con miocardiopatía isquémica o dilatada, enfermedad de Chagas, insuficiencia mitral isquémica y miocardiopatía diabética. Los abordajes son quirúrgicos, con inyección periinfarto, intracoronario y endoventricular percutáneo. Los mecanismos de acción propuestos son la reducción del tamaño de la cicatriz del infarto, el aumento de la viabilidad miocárdica, la limitación del remodelado ventricular y los efectos paracrinos. Sin embargo, los resultados clínicos muestran sólo mejoras muy limitadas de la función sistólica y del remodelado ventricular. El desarrollo de estrategias que mejoren la supervivencia y la diferenciación celular deben ser prioritarias, tales como el preacondicionamiento con electroestimulación o la ingeniería tisular con el objetivo de desarrollar un miocardio bioartificial.Stem cell therapy, as a strategy to regenerate injured tissues, has emerged as one of the most promising areas for the treatment of illnesses with low possibilities of treatment. The heart failure, mainly of ischemic ethiology, is one of the diseases that more can benefit from this therapeutic strategy. The aim is to regenerate the muscle, reduce apoptosis, increase the expression of the collagen and get an effective production of new vessels. This approach is undergoing with a variety of myogenic and angiogenic cells: skeletal myoblasts, mononuclear and mesenchymal bone marrow cells, circulating blood-derived progenitors, endometrial or adipose-derived stromal cells, mesothelial cells and induced pluripotent stem cells (iPS). The indications concern patients with ischemic cardiomyopathy, idiopathic dilated cardiomyopathies, Chagas heart disease, ischemic mitral regurgitation and diabetic cardiomyopathy. The approaches for cell delivery are surgical performing in the periinfarct area, intracoronary and endoventricular catheter-based cell delivery. The proposed mechanisms of action are reduction of the size and fibrosis of infarct scars, improvement of myocardial viability, limitation of ventricular remodeling, improvement of ventricular compliance and paracrine effects. However, the clinical results have reported only limited improvement in systolic function and remodeling. The development of strategies for improving cell survival and differentiation should be encouraged, such as preconditioning procedures with cell electrostimulation or by using tissue engineering in order to create a bioartificial myocardium.