[Frontiers in Bioscience 13, 2421-2434, January 1, 2008] Cellular cardiomyoplasty: routes of cell delivery and retention Adil Al Kindi1, Yin Ge1, Dominique Shum-Tim1, Ray C-J Chiu1 1Divisions of Cardiac Surgery and Experimental Surgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Cell delivery 3.1. Intramyocardial injection 3.2. Intracoronary injection 3.3. Retrograde coronary venous injection 3.4. Systemic intravenous injection 4. Cellular Retention and Engraftment 4.1. Cell loss due to “washout” 4.2. Factors affecting cell survival and engraftment 4.3. Comparative studies on cell delivery techniques 5. On enhancing cell retention and survival 6. Summary and conclusions 7. References 1. ABSTRACT 2. INTRODUCTION Experimental and clinical studies have proven the During the past several years, there have been feasibility of cellular cardiomyoplasty in treating the many experimental and clinical studies on progenitor/stem damaged myocardium following ischemic injury. Over the cell therapies for myocardial damage and heart failure. In years, this field has exploded with different investigators view of continuous and forceful contraction of the heart, trying different routes of cell delivery ranging from direct effective delivery of the therapeutic cells effectively into cell injection into the heart to peripheral intravenous the target tissue has been quite challenging. Here, we will delivery utilizing the various signaling mechanisms known. review the routes of cell delivery to the heart and explore These different routes have resulted in a wide range of the advantages and limitations of each mode of delivery. retention and engraftment of cells in the target tissues. In This will be followed by evidence of cell retention and this review, we will explore the different modalities of cell engraftment and methods of improvement of the delivery, the pros and cons of each route and the cellular methodologies used. Finally, we will look at factors that retention and therapeutic efficacy of these routes. We will decrease cell retention and how they could be inhibited. then look into the different theories that try to explain the observed retention and engraftment of cells in the target 3. CELL DELIVERY tissues. Finally, we will discuss various methods that can improve cellular retention and engraftment and hence better Physiological mobilization of bone marrow stem improvement in myocardial function. cells (BMSCs) occurs after Acute Myocardial Infarction 2421 Cellular cardiomyoplasty: routes of cell delivery and retention (AMI) (1-3). This mobilization, although limited, is a proven very beneficial in cases of chronic ischemia, when natural process by which the body attempts to heal the dead the patient is excluded from any revascularization (5, 6), or cardiac cells by replacing them with multipotent BMSCs in diffuse pathology of the myocardium such as in viral that are capable of differentiating into cardiac cells. cardiomyopathy, where diffuse cell delivery into the entire Therefore, attempts to deliver more cells to the heart would ventricular wall is desirable. Transcatheter techniques augment this natural process and, in theory, amplify the require mapping of the ischemic areas in order to achieve healing response. Thus, different methods were developed accurate delivery. Thus, this approach results in prolonged in order to deliver the cells to the heart in a more controlled procedure times that may not be tolerated by sick patients fashion. The optimal route of cell delivery is currently still (5, 6). under investigation. It should be able to deliver the maximum cell quantity with the best precision to the As in the development of other biotherapeutics, targeted site. It should also be easily reproducible, safe to early studies in cardiac cell therapy were conducted in the patient, with minimal unwanted adverse effects. animal models. These animal studies have examined extensively the different aspects of the epicardial route and 3.1. Intramyocardial injection have become the foundation for subsequent studies using Direct Intramyocardial injection (IM) is one of other methods (4, 7, 10-17). The ease of delivering cells the earliest routes of cell delivery that have been developed. using this route in animals is probably why it initially It can be achieved either through direct injection into the gained great popularity. These studies have proven the epicardium or endocardium (4-7). feasibility of this route, possible clinical safety and benefit and have led to subsequent use in phase I and II clinical This route has a number of advantages. It allows trials (18-21). This was also true for the endocardial route the delivery of large number of cells to the targeted in which animal studies have also been applied to clinical myocardium. Large cells such as Marrow Stromal Cells trials (4-7, 22). (MSCs) and myoblasts can be delivered without fear of coronary occlusion. Direct epicardial injection allows the In a small clinical trial by Tse et al. (6), eight visualization of the myocardium and targets the cell patient with stable angina refractory to maximum medical delivery precisely to scar areas and border zone of infarct therapy and not candidates for any revascularization areas. This visualization also allows avoiding damage to procedure were enrolled in the study. Mononuclear bone structures such as the coronary arteries whereas some of the marrow cells were first harvested from the BM. Using an other methods are blind to this point. When coupled with electromechanical mapping of the left ventricle for other planned open surgical procedures, this route has ischemic areas, the cells were delivered through direct proven to be very useful with negligible added risk to the injection into the endocardium using a catheter. There were patient. no procedure related complications such as ventricular or atrial arrhythmias, myocardial ischemia, pericardial However, such a procedure is not without any effusion or bleeding. Although there was no improvement limitations and disadvantages. Direct injection into in the ventricular function of the treated patients, patients ischemic and scarred myocardium creates islands of cells reported improvement in the anginal class and reduction in with limited blood supply that may lead to poor survival of the use of antianginal treatment. Areas injected with BM the cells (5). This technique may not be safe in acute cells showed significant improvement in target wall myocardial ischemia, where the myocardium is fragile and thickness, perfusion, and motion as assessed by MRI. sensitive; thus direct injection may result in ventricular arrhythmias or perforation of the myocardium. In addition, These results were supported in another study by epicardial injection may be difficult in reaching all areas of Fuchs et al. (5), who studied ten patients with chronic the heart, the septum being an important example. Also, ischemic heart disease all not candidates for any direct IM route by itself causes mechanical damage of the revascularization procedure. Fuchs used a cell delivery cells and this subsequently provokes an acute inflammatory technique similar to Tse et al. There were no procedure response in the host tissue that may translate into lower cell related complications and at three months treated patients survival (8). showed improved Canadian Cardiovascular Society angina score, as well as reduction in the stress induced ischemia Due to the limitations of the direct epicardial within the injected areas. injections in this population; namely the high risk of performing an open procedure in the absence of the need Catheter endocardial technique has been proven for concomitant cardiac surgical procedure, catheter based to be clinically safe and feasible. Although the studies were techniques were developed for cell delivery via the phase I trials only, there was subjective and objective endocardium. This route, compared with the direct evidence of improvement. However, it is important to note epicardial injection, has a number of advantages. It allows that these studies were carried out on no-option patients. the delivery of large number of cells specifically into the Further studies, with more liberal selection criteria, are myocardium without the need for a major surgical needed in order to be able to generalize the results to wider procedure. It also allows the delivery of multiple injections patient population. over time as it carries low procedure related risks. This route has proven very useful in no-option patients with The catheters that have been developed for cell advanced coronary artery disease. This method has also delivery try to simulate the direct surgical injection 2422 Cellular cardiomyoplasty: routes of cell delivery and retention techniques. There are currently different catheters available be a problem in freshly purified bone marrow cells, the risk in the market but all have the same basic components (23). of coronary occlusion is more likely when infusing ex vivo There is a core element, which is dedicated for the transport expanded cells that are larger in size and often more of cells. This terminates in the beveled injection needle adhesive. Animal studies have demonstrated rising distally. The rest of the catheter is composed of elements Troponin levels, markers of myocardial damage, and EKG that are designed to support the core element and direct it changes (ST-segment elevation and T-wave inversion) after towards