injections are most frequently made into the left ventricle by a direct epicardial approach or using a catheter - based transendocardial approach . epicardial injection is considered the most reliable method of delivery , which also results in higher cell retention within the myocardium [ 2 , 3 , 911 ] . in previous clinical trials of epicardial injection , cell transplant was performed using a minimally invasive surgical approach via a left anterior mini - thoracotomy   or combined with coronary artery bypass graft or other open heart procedures [ 911 ] . surgical exposure of the heart provides direct access and visualization of the epicardium . location of the injection sites are identified prior to surgery using non - invasive methods including nuclear imaging and echocardiography . during surgery , injection sites are located by direct visualization and therapy is administered to the external surface of the heart via a standard syringe . this procedure also limits access to certain areas of the left ventricle such as the septum . there is also a risk of perforation at the injection sites inside the left ventricle ( lv ) , as well as systemic embolization . tissue inflammation may also increase the risk of cardiac arrhythmias or require the use of corticosteroids or other anti - arrhythmic agents [ 2 , 13 ] . there are varieties of catheters currently undergoing phases i and ii clinical trials which use either a fluoroscopic 2-dimensional ( 2d ) guidance system or a 3-dimensional ( 3d ) system . the helix infusion catheter ( biocardia , inc . , south san francisco , ca ) and the myocath(bioheart inc . , sunrise , fl ) , the myostar injection catheter is combined with a 3d guidance system noga xp ( biologics delivery systems , diamond bar , ca ) [ 46 , 14 , 15 ] . unlike the surgical method , this procedure can be extended to the high - risk population and be repeated if needed . preclinical evidence indicates that this approach achieves better myocardial cell retention when compared to intravascular infusion possibly resulting in greater therapeutic effects [ 3 , 12 ] . the 3d - guided system also avoids local toxicity by distributing the injections across the infarct area , border area of the infarct , and ischemic area . as with all forms of endocardial injection , the risk of perforation , tissue irritation , and arrhythmia still remains . biocardia 's helical infusion catheter is a catheter with a small , hollow , distal corkscrew needle , which is rotated into tissue to provide active fixation during drug delivery similar to the active fixation electrodes used in cardiac pacing . this system provides a means for fixation to the beating heart wall , uses fluoroscopic imaging , crosses the aortic arch and valve over a guide wire with biocardia 's morph deflectable steerable guide , and allows 3 of freedom to maximize operator control . the morph deflectable guide catheter can be used to steer a guide wire through the aortic valve for transendocardial delivery from within the lv . for transendocardial delivery , the morph deflectable guide catheter is advanced over the wire , and the wire is removed to allow for advancement and navigation of the helical infusion catheter [ 46 ] . this catheter is under investigational use in multiple ongoing clinical trials [ 46 , 14 ] . the myocath system utilizes a 115-cm - long deflectable injection catheter that contains a single core 25-gauge needle which is advanced and retracted from the tip of the catheter and provides for multiple injections to a pre - determined needle insertion depth . the myostar is a steerable catheter equipped with a location sensor and a retractable , hollow 27-gauge needle . the catheter interfaces with the noga 3d electromagnetic cardiac mapping system for local agent delivery into the myocardium . the noga map is a 3d reconstruction of the lv from electromechanical points obtained by the mapping catheter . the noga map discriminates between areas of mi , the border zone of the mi , and normal myocardium . the precise areas intended for injection can be identified when used in combination with imaging techniques such as echocardiography to measure wall thickness and single - photon emission computed tomography to assess myocardial perfusion . this information provides increased accuracy and homogeneous distribution of injections [ 8 , 15 , 17 , 2022 ] . intracoronary administration is the preferred technique following acute myocardial infarction and has been previously described extensively [ 2 , 2326 ] . similar to balloon angioplasty , treatments commonly performed for coronary artery occlusions , ic transfer is the most practiced technique of coronary cell transfer . cells are injected through the delivery catheter at slow or high flow rates while maintaining coronary flow ( non - occlusive ) or interrupting it with balloon occlusion (  stop - flow a balloon catheter or specialty catheters are used for the sub - selective injection in the coronary vessel . method uses a temporary balloon inflation to reduce cell loss due to speed of blood flow . potential advantages may include homogenous distribution of the cells in the targeted myocardium and can be applied in studies for chronic myocardial ischemia or ischemic lv dysfunction . this procedure requires cell migration which is partially guided by a phenomenon called stem cell homing . cells migrate preferentially toward damaged myocardium and retention is largely dependent on adhesion to the endothelial layer of the vasculature [ 2 , 2327 ] . issues to consider regarding this method include post - infusion blood flow in the target artery , timing of cell delivery , type of cell and cell preparation . total occlusion of the coronary artery from the balloon inflation may lead to decreased blood flow which could cause ischemia leading to arrhythmia . the movement of large cells or particularly viscous suspensions may pose risk of occlusion or emboli which may also reduce accuracy of targeting and retention [ 24 , 28 ] . the coronary sinus ( cs ) and coronary veins have been utilized in applications for several therapeutic interventions . the retrograde coronary sinus delivery method provides access to the target ischemic and infarcted regions of the heart . details of this procedure have been previously described [ 2 , 26 , 29 , 30 ] . a small number of preclinical and early clinical studies demonstrated safety and feasibility of delivering stem cells via the coronary sinus . coronary sinus delivery is the preferred option in cases of severe subtotal stenosis of one or more coronary arteries or severe aortic stenosis . this approach provides safe and accurate access to most of the myocardium creating more homogenous delivery . potential limitations and complications of this technique include variability in coronary sinus anatomy and coronary sinus rupture . the movement of large cells or particularly viscous suspensions may pose risk of occlusion or emboli . also important there is insufficient evidence to determine whether or not homing is effective with all forms of heart damage including chronic disease or remodeling as a result of previous mi [ 2 , 26 , 29 , 30 ] . this delivery method depends heavily stem cell homing signals to the area of injury following an acute myocardial infarction . preclinical studies indicate low cell retention within the heart following iv infusion and that a significant number are trapped in the lungs . intramyocardial , epicardial , and transendocardial delivery approaches are shown to be accurate and reliable . the epicardial approach provides direct visualization of the heart allowing for more accurate administration , but is high risk due to its invasive nature . the intracoronary method is preferred post - acute mi and is similar to balloon angioplasty , a commonly performed procedure . it is dependent on cell retention and additional factors such as timing of delivery , cell adhesion and homing . coronary sinus delivery is considered lower risk and is a potentially effective method . limitations of this procedure include the variability in coronary sinus anatomy and risk of coronary sinus rupture . intravenous biologics delivery is the easiest and least invasive of all discussed methods , but relies heavily on cell homing . optimizing the safety and accuracy of these procedures by establishing training guidelines can significantly affect the outcomes of these therapies . initial recommendations have been published for training on these methods of delivery by the task force for the international society for cardiovascular translational research . controversies and challenges that still remain in the field of cell - based therapies include optimal cell type , delivery route , timing , therapeutic dose , cell survival and retention . current preclinical investigations aimed at enhancing cell survival and retention includes genetic modifications , combining stem cells with gene products or biomaterials such as collagen matrix . ongoing and future clinical studies can address these challenges through randomized , double - blind , placebo - controlled study designs [ 33 , 34 ] .
the field of myocardial regeneration utilizing novel cell - based therapies , gene transfer , and growth factors may prove to play an important role in the future management of ischemic heart disease and cardiomyopathy . 
 phases i and ii clinical trials have been published for a variety of biologics utilizing four methods of delivery : systemic infusion , intracoronary infusion , transvenous coronary sinus , and intramyocardial . 
 this review discusses the advantages and disadvantages of the delivery approaches above .