710 M ajor advances in the understanding of stem cells as reparative biotherapeutics have been achieved during the past decade, yet regenerative procedures remain limited by the low retention rates after transplantation. To date, vari- ous routes of cell administration have been explored, with the average retention typically <10% of the injected dose. 1–4 A surgical approach was originally used with delivery of stem cells via an epicardial route. 5,6 A transition to percuta- neous approaches, including intracoronary infusion with an over-the-wire balloon catheter, has enabled cell therapy at the time of myocardial infarction. 7–9 Intracoronary adminis- tration of stem cells is thought to amplify endogenous repair processes at site of injury but requires efficient transendothe- lial migration of progenitors within the coronary bed. 2,10–13 To circumvent the need for transendothelial homing, endo- myocardial injection has more recently been used to deliver cells directly into the region of interest. 1,11–13 Although endomyocardial injection has been suggested to improve delivery, overall retention rates remain limited, potentially compromising adequate stem cell dosing. 1–3 Accordingly, optimized myocardial delivery of stem cells is a priority to advance regenerative procedures. To date, straight and helical needle designs have been used for endomyocardial delivery in the clinical setting. 14–18 The straight needle design has been extensively used in the delivery of myoblasts and mesenchymal stem cells (MSC), demonstrat- ing an excellent safety profile. 19–23 Yet, reported retention rates are typically in the single digits. 4,20 Helical needles are thought to provide a better fixation during delivery and have also been associated with safe clinical outcome, 11,24 although retention rate analysis has yet to be reported. Regardless of the design, the high pressure generated by the end-hole feature of all avail- able needles has been suggested as a culprit in compromising reliable delivery of a desired viable and potent cell dose. 1 The present bioengineering study is based on the hypoth- esis that uniform distribution of cells over the length of the Background—Regenerative cell-based therapies are associated with limited myocardial retention of delivered stem cells. The objective of this study is to develop an endocardial delivery system for enhanced cell retention. Methods and Results—Stem cell retention was simulated in silico using 1- and 3-dimensional models of tissue distortion and compliance associated with delivery. Needle designs, predicted to be optimal, were accordingly engineered using nitinol, a nickel and titanium alloy displaying shape memory and superelasticity. Biocompatibility was tested with human mesenchymal stem cells. Experimental validation was performed with species-matched cells directly delivered into Langendorff-perfused porcine hearts or administered percutaneously into the endocardium of infarcted pigs. Cell retention was quantified by flow cytometry and real-time quantitative polymerase chain reaction methodology. Models, computing optimal distribution of distortion calibrated to favor tissue compliance, predicted that a 75°-curved needle featuring small-to-large graded side holes would ensure the highest cell retention profile. In isolated hearts, the nitinol curved needle catheter (C-Cath) design ensured 3-fold superior stem cell retention compared with a standard needle. In the setting of chronic infarction, percutaneous delivery of stem cells with C-Cath yielded a 37.7±7.1% versus 10.0±2.8% retention achieved with a traditional needle without effect on biocompatibility or safety. Conclusions—Modeling-guided development of a nitinol-based curved needle delivery system with incremental side holes achieved enhanced myocardial stem cell retention. (Circ Cardiovasc Interv. 2013;6:710-718.) Key Words: catheters ◼ myocardial infarction ◼ regeneration ◼ stem cells © 2013 American Heart Association, Inc. Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.112.000422 Received December 18, 2012; accepted November 11, 2013. From Division of Cardiovascular Diseases and Center for Regenerative Medicine, Mayo Clinic, Rochester, MN (A.B., R.J.C.-D., P.G.S., M.M.R., A.T.); Cardio3 BioSciences, Mont-Saint-Guibert, Belgium (J.-P.L., C.H., D.D., V.S., A.S.); and Cardiovascular Center, OLV Ziekenhuis, Aalst, Belgium (J.B.). The online-only Data Supplement is available at http://circinterventions.ahajournals.org/lookup/suppl/doi:10.1161/CIRCINTERVENTIONS. 112.000422/-/DC1. Correspondence to Atta Behfar, MD, PhD, Center for Regenerative Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail behfar.atta@mayo.edu Optimized Delivery System Achieves Enhanced Endomyocardial Stem Cell Retention Atta Behfar, MD, PhD; Jean-Pierre Latere, PhD; Jozef Bartunek, MD, PhD; Christian Homsy, MD; Dorothee Daro, MS; Ruben J. Crespo-Diaz, PhD; Paul G. Stalboerger, MS; Valerie Steenwinckel, PhD; Aymeric Seron, PhD; Margaret M. Redfield, MD; Andre Terzic, MD, PhD New Techniques Downloaded from http://ahajournals.org by on May 26, 2020