Letter Regarding the Article by Xue et al, “Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes”

Abstract

HomeCirculationVol. 112, No. 6Letter Regarding the Article by Xue et al, “Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter Regarding the Article by Xue et al, “Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes” Richard B. Robinson, PhD and Michael R. Rosen, MD Peter R. Brink, PhD and Ira S. Cohen, MD, PhD Richard B. RobinsonRichard B. Robinson College of Physicians & Surgeons of Columbia University, Department of Pharmacology, Center for Molecular Therapeutics, New York, NY, Search for more papers by this author and Michael R. RosenMichael R. Rosen College of Physicians & Surgeons of Columbia University, Department of Pharmacology, Center for Molecular Therapeutics, New York, NY, Search for more papers by this author Peter R. BrinkPeter R. Brink Department of Physiology and Biophysics, Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY Search for more papers by this author and Ira S. CohenIra S. Cohen Department of Physiology and Biophysics, Institute of Molecular Cardiology, Stony Brook University, Stony Brook, NY Search for more papers by this author Originally published9 Aug 2005https://doi.org/10.1161/CIRCULATIONAHA.104.534214Circulation. 2005;112:e82–e83To the Editor:The article by Xue et al1 on human embryonic stem cell-derived pacemakers illustrates that embryonic stem cells differentiated into spontaneously beating cardiocytes may function as biological pacemakers and mentions a potential limitation: The intrinsic pacemaker rate was slower than desirable. They suggest that incorporating HCN pacemaker channel genes might achieve more desirable rates, an idea consistent with our published results using HCN2 in gene- and adult human mesenchymal stem cell (hMSC)-based therapies.2–4However, certain of the comments by Xue et al misinterpret our own work on HCN-loaded hMSCs. They state that “…these modified, undifferentiated, human mesenchymal stem cells are incapable of pacing quiescent cells because the former are neither electrically active nor genuine cardiac cells” (p 19). This statement suggests a misunderstanding of the rationale and underlying biophysics of the hMSC experiments. In fact, generation of pacemaker activity does not require delivery of an “excitable differentiated cardiac cell,” but only that the delivered cell (1) carry sufficient pacemaker current and (2) make gap junctions; thus, the hMSC-myocyte pair should behave as a pacemaker unit entirely equivalent to a single heart cell with substantial if. We clearly demonstrated both functions for our genetically engineered hMSCs.4,5We further take issue with the statement by Xue et al that biological pacemakers must pace quiescent cells. Extrapolating this to human disease implies that biological pacemakers should initiate activity in non-beating hearts. Yet, this is not what an electronic or a biological pacemaker is expected to do clinically. Rather, both types of pacemaker should initiate activity in hearts beating perilously slowly, putting patients at risk of devastating arrhythmia, syncope, or death. Therefore, although our HCN-load hMSC biological pacemaker can pace quiescent cells, there is much to be said conceptually for a biological pacemaker that increases dangerously slow heart rates.Xue et al also criticize our earliest in situ gene therapy publication.2 They imply a deficiency in this study derived from our use of vagal suppression to eliminate sinoatrial pacemaker function. Given that in the absence of atrioventricular block a physiologically adequate rate generated by gene therapy might be overdriven by the sinoatrial node, the requirement for vagal suppression is not relevant to examination of therapeutic potential. Moreover, in subsequent studies, we showed that during vagal stimulation, an HCN2-based biological pacemaker inserted locally into a bundle branch is functional,3 and that in chronic atrioventricular block and bundle branch insertion of HCN2, physiologically relevant rates are achieved.6In closing, we welcome criticism and discourse but believe it essential that this be based on an accurate interpretation of the subject matter under discussion.1 Xue T, Cho HC, Akar FG, Tsang S-Y, Jones SP. Marban E, Tomaselli GF, Li RA. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes. Circulation. 2005; 111: 11–20.LinkGoogle Scholar2 Qu J, Plotnikov AN, Danilo P, Shlapakova I, Cohen IS, Robinson RB, Rosen MR. Expression and function of a biological pacemaker in canine heart. Circulation. 2003; 107: 1106–1109.LinkGoogle Scholar3 Plotnikov AN, Sosunov EA, Qu J, Shlapakova IN, Anyukhovsky EP, Liu L, Janse MJ, Brink PR, Cohen IS, Robinson RB, Danilo P Jr, Rosen MR. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation. 2004; 109: 506–512.LinkGoogle Scholar4 Potapova I, Plotnikov A, Lu Z, Danilo P, Valiunas V, Qu J, Doronin S, Zuckerman J, Shlapakova I, Gao J, Pan Z, Herron AJ, Robinson RB, Brink PR, Rosen MR, Cohen IS. Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ Res. 2004; 94: 952–959.LinkGoogle Scholar5 Valiunas V, Doronin S, Valiuniene L, Potapova I, Zuckerman J, Walcott B, Robinson RB, Rosen MR, Brink PR, Cohen IS. Human mesenchymal stem cells make cardiac connexins and form functional gap junctions. J Physiol. 2004; 555.3: 617–626.Google Scholar6 Plotnikov AN, Shlapakova IN, Kryukova Y, Danilo P Jr, Cohen IS, Robinson RB, Rosen MR. Biological pacemaker expresses wide range of physiologic rates and compares favorably with electrical pacemaker: a preliminary study in dogs. Circulation. 2004; 110 (suppl III): III-291.Google ScholarcirculationahaCirculationCirculationCirculation0009-73221524-4539Lippincott Williams & WilkinsResponseXue Tian, , PhD and Li Ronald A., , PhD09082005We agree that Rosen et al have elegantly provided extensive proof-of-concept data that HCN2-transduced human mesenchymal stem cells (hMSCs), although otherwise quiescent by themselves, could facilitate pacing. Our approaches and designs for studying and engineering pacemaker activity, however, are different: We differentiate pluripotent human embryonic stem cells (hESCs)1 into an ex vivo sinoatrial (SA) node-like structure, which is capable of generating electrical rhythms on its own accord, for in vivo transplantation and other experiments.2 Unlike native nodal pacemaker cells, transduced hMSCs are indeed neither electrically-active nor genuine cardiac cells. The electrophysiological properties of hMSCs are also somewhat heterogeneous,3 a common property that undifferentiated mouse and hESCs also appear to share.4 It is uncertain over time whether hMSCs after transplantation will further differentiate3 into cardiac or even non-cardiac cells with electrical properties different from those of pre-transplanted cells.Although cardiac derivatives from hESCs, genetically-modified or not, are genuine heart cells,5 we likewise do not yet know how long and to what extent electrically active hESC-derived cardiomyocytes will continue to retain their “nodal-like” phenotype once transplanted into the in vivo ventricular or atrial environment. As Rosen et al correctly pointed out, the induced rate observed in our reported experiment was slow. This could be attributed to the above reason. Alternatively, the graft size, transplantation site, purity of nodal cells in the graft, time course for maturation, etc, are other contributing factors that also need to be considered. Our naïve working hypothesis, which remains to be experimentally tested, is that ex vivo overexpression of particular HCN channels can perhaps somehow compensate for the reduced efficacy after transplantation by (1) boosting the basal firing frequency in vitro6 and/or (2) increasing the percentage of nodal (or nodal-like) cardiomyocytes. This strategy of HCN manipulations, however, is somewhat complicated by the complex molecular identity of native If (as the 4 isoforms, whose expression levels differ depending on the cell type and species, can coassemble with one another7) and the presence of such ionic components as IK1 that can influence the ultimate functional effects of If per se.8 Protein engineering may be useful for custom-tailoring their biophysical properties for achieving specific outcomes.9,10To unleash and study the induced pacing activity of our transplanted human cells, we needed to surgically remove the atria and cryoablate the atrioventricular node because the induced rate by human cells is overridden (by the intrinsically faster native guinea pig SA and atrioventricular nodes).2 Rosen et al chose to perform vagal stimulation in dogs. Although not explicitly stated, we hinted that future in vivo experiments of this kind can perhaps be facilitated by developing a novel animal model that enables the efficacy of cell transplantation or gene transfer approaches be more specifically investigated, free from undesirable effects due to extensive surgical manipulations, escape rhythms, etc.Given that the native SA node is such a complex structure consisting of a gradient of nodal pacemaker cells with a range of phenotypic properties, etc,11 it is likely that all of the above-mentioned factors will need to be carefully taken into consideration for future experiments designed to improve our understanding of the basis of pacing, and to bioengineer a surrogate SA node. Previous Back to top Next FiguresReferencesRelatedDetailsCited By Pushp P and Gupta M (2021) Cardiac Tissue Engineering: A Role for Natural Biomaterials Bioactive Natural Products for Pharmaceutical Applications, 10.1007/978-3-030-54027-2_18, (617-641), . Rafatian N, Vizely K, Al Asafen H, Korolj A and Radisic M (2021) Drawing Inspiration from Developmental Biology for Cardiac Tissue Engineers, Advanced Biology, 10.1002/adbi.202000190, 5:7, (2000190), Online publication date: 1-Jul-2021. Parchehbaf-Kashani M, Sepantafar M, Talkhabi M, Sayahpour F, Baharvand H, Pahlavan S and Rajabi S (2020) Design and characterization of an electroconductive scaffold for cardiomyocytes based biomedical assays, Materials Science and Engineering: C, 10.1016/j.msec.2019.110603, 109, (110603), Online publication date: 1-Apr-2020. Efraim Y, Schoen B, Zahran S, Davidov T, Vasilyev G, Baruch L, Zussman E and Machluf M (2019) 3D Structure and Processing Methods Direct the Biological Attributes of ECM-Based Cardiac Scaffolds, Scientific Reports, 10.1038/s41598-019-41831-9, 9:1, Online publication date: 1-Dec-2019. Spinali K and Schmuck E (2018) Natural Sources of Extracellular Matrix for Cardiac Repair Cardiac Extracellular Matrix, 10.1007/978-3-319-97421-7_6, (115-130), . Kwon T and Moon K (2018) Decellularization Clinical Regenerative Medicine in Urology, 10.1007/978-981-10-2723-9_6, (125-141), . Jurney P, Anderson D, Pohan G, Yim E and Hinds M (2018) Reactive Ion Plasma Modification of Poly(Vinyl‐Alcohol) Increases Primary Endothelial Cell Affinity and Reduces Thrombogenicity, Macromolecular Bioscience, 10.1002/mabi.201800132, 18:11, (1800132), Online publication date: 1-Nov-2018. Roshanbinfar K, Hilborn J, Varghese O and Oommen O (2017) Injectable and thermoresponsive pericardial matrix derived conductive scaffold for cardiac tissue engineering, RSC Advances, 10.1039/C7RA03780E, 7:51, (31980-31988) Srokowski E and Woodhouse K (2017) 2.20 Decellularized Scaffolds Comprehensive Biomaterials II, 10.1016/B978-0-08-100691-7.00055-0, (452-470), . Pok S, Stupin I, Tsao C, Pautler R, Gao Y, Nieto R, Tao Z, Fraser C, Annapragada A and Jacot J (2017) Full-Thickness Heart Repair with an Engineered Multilayered Myocardial Patch in Rat Model, Advanced Healthcare Materials, 10.1002/adhm.201600549, 6:5, (1600549), Online publication date: 1-Mar-2017. Faust A, Kandakatla A, van der Merwe Y, Ren T, Huleihel L, Hussey G, Naranjo J, Johnson S, Badylak S and Steketee M (2017) Urinary bladder extracellular matrix hydrogels and matrix-bound vesicles differentially regulate central nervous system neuron viability and axon growth and branching, Journal of Biomaterials Applications, 10.1177/0885328217698062, 31:9, (1277-1295), Online publication date: 1-Apr-2017. Wan L, Chen Y, Wang Z, Wang W, Schmull S, Dong J, Xue S, Imboden H and Li J (2017) Human heart valve-derived scaffold improves cardiac repair in a murine model of myocardial infarction, Scientific Reports, 10.1038/srep39988, 7:1, Online publication date: 1-Feb-2017. Marinescu K, Uriel N, Mann D and Burkhoff D (2016) Left ventricular assist device-induced reverse remodeling: it’s not just about myocardial recovery, Expert Review of Medical Devices, 10.1080/17434440.2017.1262762, 14:1, (15-26), Online publication date: 2-Jan-2017. Y. Fraint H, E. Richmond M, A. Bacha E and Turner M (2016) Comparison of Extracellular Matrix Patch and Standard Patch Material in the Pulmonary Arteries, Pediatric Cardiology, 10.1007/s00246-016-1413-8, 37:6, (1162-1168), Online publication date: 1-Aug-2016. Wang X, Chang J, Tian T and Ma B (2016) Preparation of calcium silicate/decellularized porcine myocardial matrix crosslinked by procyanidins for cardiac tissue engineering, RSC Advances, 10.1039/C6RA02947G, 6:41, (35091-35101) Lu Y, Jia C, Bi B, Chen L, Zhou Y, Yang P, Guo Y, Zhu J, Zhu N and Liu T (2016) Injectable SVF-loaded porcine extracellular matrix powders for adipose tissue engineering, RSC Advances, 10.1039/C6RA09543G, 6:58, (53034-53042) Domenech M, Polo-Corrales L, Ramirez-Vick J and Freytes D (2016) Tissue Engineering Strategies for Myocardial Regeneration: Acellular Versus Cellular Scaffolds?, Tissue Engineering Part B: Reviews, 10.1089/ten.teb.2015.0523, 22:6, (438-458), Online publication date: 1-Dec-2016. Papalamprou A and Griffiths L (2015) Cardiac Extracellular Matrix Scaffold Generated Using Sarcomeric Disassembly and Antigen Removal, Annals of Biomedical Engineering, 10.1007/s10439-015-1404-6, 44:4, (1047-1060), Online publication date: 1-Apr-2016. Perea-Gil I, Prat-Vidal C and Bayes-Genis A (2015) In vivo experience with natural scaffolds for myocardial infarction: the times they are a-changin’, Stem Cell Research & Therapy, 10.1186/s13287-015-0237-4, 6:1, Online publication date: 1-Dec-2015. Guhathakurta S, Mathapati S, Bishi D, Rallapalli S and Cherian K (2014) Nanofiber-reinforced myocardial tissue-construct as ventricular assist device, Asian Cardiovascular and Thoracic Annals, 10.1177/0218492314523627, 22:8, (935-943), Online publication date: 1-Oct-2014. Kollar E, Dearth C and Badylak S (2014) Biologic Scaffolds Composed of Extracellular Matrix as a Natural Material for Wound Healing Bio-inspired Materials for Biomedical Engineering, 10.1002/9781118843499.ch7, (111-124) Forte G, Pagliari S, Pagliari F, Ebara M, Di Nardo P and Aoyagi T (2011) Towards the Generation of Patient-Specific Patches for Cardiac Repair, Stem Cell Reviews and Reports, 10.1007/s12015-011-9325-8, 9:3, (313-325), Online publication date: 1-Jun-2013. Yanagawa B, Rao V, Yau T and Cusimano R (2013) Initial Experience with Intraventricular Repair Using CorMatrix Extracellular Matrix, Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery, 10.1177/155698451300800505, 8:5, (348-352), Online publication date: 1-Jun-2013. Pereira M, Ouyang B, Sundback C, Lang N, Friehs I, Mureli S, Pomerantseva I, McFadden J, Mochel M, Mwizerwa O, del Nido P, Sarkar D, Masiakos P, Langer R, Ferreira L and Karp J (2012) A Highly Tunable Biocompatible and Multifunctional Biodegradable Elastomer, Advanced Materials, 10.1002/adma.201203824, 25:8, (1209-1215), Online publication date: 25-Feb-2013. Hanson K, Jung J, Tran Q, Hsu S, Iida R, Ajeti V, Campagnola P, Eliceiri K, Squirrell J, Lyons G and Ogle B (2013) Spatial and Temporal Analysis of Extracellular Matrix Proteins in the Developing Murine Heart: A Blueprint for Regeneration, Tissue Engineering Part A, 10.1089/ten.tea.2012.0316, 19:9-10, (1132-1143), Online publication date: 1-May-2013. Yanagawa B, Rao V, Yau T and Cusimano R (2013) Initial Experience with Intraventricular Repair Using CorMatrix Extracellular Matrix, Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery, 10.1097/imi.0000000000000014, 8:5, (348-352), Online publication date: 1-Jun-2013. Remlinger N, Gilbert T, Yoshida M, Guest B, Hashizume R, Weaver M, Wagner W, Brown B, Tobita K and Wearden P (2014) Urinary bladder matrix promotes site appropriate tissue formation following right ventricle outflow tract repair, Organogenesis, 10.4161/org.25394, 9:3, (149-160), Online publication date: 1-Jul-2013. Turner N and Badylak S (2011) Regeneration of skeletal muscle, Cell and Tissue Research, 10.1007/s00441-011-1185-7, 347:3, (759-774), Online publication date: 1-Mar-2012. Sarig U, Au-Yeung G, Wang Y, Bronshtein T, Dahan N, Boey F, Venkatraman S and Machluf M (2012) Thick Acellular Heart Extracellular Matrix with Inherent Vasculature: A Potential Platform for Myocardial Tissue Regeneration, Tissue Engineering Part A, 10.1089/ten.tea.2011.0586, 18:19-20, (2125-2137), Online publication date: 1-Oct-2012. Marçal H, Ahmed T, Badylak S, Tottey S and Foster L (2012) A comprehensive protein expression profile of extracellular matrix biomaterial derived from porcine urinary bladder, Regenerative Medicine, 10.2217/rme.12.6, 7:2, (159-166), Online publication date: 1-Mar-2012. Boyd W, Tyberg J and Cox J (2014) A review of the current status of pericardial closure following cardiac surgery, Expert Review of Cardiovascular Therapy, 10.1586/erc.12.87, 10:9, (1109-1118), Online publication date: 1-Sep-2012. Li R (2012) Gene- and cell-based bio-artificial pacemaker: what basic and translational lessons have we learned?, Gene Therapy, 10.1038/gt.2012.33, 19:6, (588-595), Online publication date: 1-Jun-2012. Godier-Furnémont A, Duan Y, Maidhof R and Vunjak-Novakovic G (2011) Tissue Engineering Strategies for Cardiac Regeneration Regenerating the Heart, 10.1007/978-1-61779-021-8_23, (443-475), . Gao J, Liu J, Gao Y, Wang C, Zhao Y, Chen B, Xiao Z, Miao Q and Dai J (2011) A Myocardial Patch Made of Collagen Membranes Loaded with Collagen-Binding Human Vascular Endothelial Growth Factor Accelerates Healing of the Injured Rabbit Heart, Tissue Engineering Part A, 10.1089/ten.tea.2011.0105, 17:21-22, (2739-2747), Online publication date: 1-Nov-2011. Srokowski E and Woodhouse K (2011) Decellularized Scaffolds Comprehensive Biomaterials, 10.1016/B978-0-08-055294-1.00078-7, (369-386), . Pedron S, van Lierop S, Horstman P, Penterman R, Broer D and Peeters E (2011) Stimuli Responsive Delivery Vehicles for Cardiac Microtissue Transplantation, Advanced Functional Materials, 10.1002/adfm.201002708, 21:9, (1624-1630), Online publication date: 10-May-2011. Sarig U and Machluf M (2011) Engineering cell platforms for myocardial regeneration, Expert Opinion on Biological Therapy, 10.1517/14712598.2011.578574, 11:8, (1055-1077), Online publication date: 1-Aug-2011. Vunjak-Novakovic G, Lui K, Tandon N and Chien K (2011) Bioengineering Heart Muscle: A Paradigm for Regenerative Medicine, Annual Review of Biomedical Engineering, 10.1146/annurev-bioeng-071910-124701, 13:1, (245-267), Online publication date: 15-Aug-2011. Schilling T, Cebotari S, Tudorache I and Haverich A (2011) Tissue Engineering von vaskularisiertem MyokardersatzgewebeTissue engineering of vascularized myocardial prosthetic tissue, Der Chirurg, 10.1007/s00104-010-2032-1, 82:4, (319-324), Online publication date: 1-Apr-2011. Prabhakaran M, Venugopal J, Kai D and Ramakrishna S (2011) Biomimetic material strategies for cardiac tissue engineering, Materials Science and Engineering: C, 10.1016/j.msec.2010.12.017, 31:3, (503-513), Online publication date: 1-Apr-2011. Ravichandran R, Venugopal J, Sundarrajan S, Mukherjee S and Ramakrishna S (2011) Poly(Glycerol Sebacate)/Gelatin Core/Shell Fibrous Structure for Regeneration of Myocardial Infarction, Tissue Engineering Part A, 10.1089/ten.tea.2010.0441, 17:9-10, (1363-1373), Online publication date: 1-May-2011. Duan Y, Liu Z, O’Neill J, Wan L, Freytes D and Vunjak-Novakovic G (2011) Hybrid Gel Composed of Native Heart Matrix and Collagen Induces Cardiac Differentiation of Human Embryonic Stem Cells without Supplemental Growth Factors, Journal of Cardiovascular Translational Research, 10.1007/s12265-011-9304-0, 4:5, (605-615), Online publication date: 1-Oct-2011. Eitan Y, Sarig U, Dahan N and Machluf M (2010) Acellular Cardiac Extracellular Matrix as a Scaffold for Tissue Engineering: In Vitro Cell Support, Remodeling, and Biocompatibility , Tissue Engineering Part C: Methods, 10.1089/ten.tec.2009.0111, 16:4, (671-683), Online publication date: 1-Aug-2010. Seif-Naraghi S, Salvatore M, Schup-Magoffin P, Hu D and Christman K (2010) Design and Characterization of an Injectable Pericardial Matrix Gel: A Potentially Autologous Scaffold for Cardiac Tissue Engineering, Tissue Engineering Part A, 10.1089/ten.tea.2009.0768, 16:6, (2017-2027), Online publication date: 1-Jun-2010. Cheng H, Islam S, Loai Y, Antoon R, Beaumont M and Farhat W (2010) Quantitative Magnetic Resonance Imaging Assessment of Matrix Development in Cell-Seeded Natural Urinary Bladder Smooth Muscle Tissue-Engineered Constructs, Tissue Engineering Part C: Methods, 10.1089/ten.tec.2009.0099, 16:4, (643-651), Online publication date: 1-Aug-2010. Schussler O, Chachques J, Mesana T, Suuronen E, Lecarpentier Y and Ruel M (2010) 3-Dimensional Structures to Enhance Cell Therapy and Engineer Contractile Tissue, Asian Cardiovascular and Thoracic Annals, 10.1177/0218492310361531, 18:2, (188-198), Online publication date: 1-Apr-2010. Merritt E, Hammers D, Tierney M, Suggs L, Walters T and Farrar R (2010) Functional Assessment of Skeletal Muscle Regeneration Utilizing Homologous Extracellular Matrix as Scaffolding, Tissue Engineering Part A, 10.1089/ten.tea.2009.0226, 16:4, (1395-1405), Online publication date: 1-Apr-2010. Hollweck T, Marschmann M, Hartmann I, Akra B, Meiser B, Reichart B, Eblenkamp M, Wintermantel E and Eissner G (2010) Comparative analysis of adherence, viability, proliferation and morphology of umbilical cord tissue-derived mesenchymal stem cells seeded on different titanium-coated expanded polytetrafluoroethylene scaffolds, Biomedical Materials, 10.1088/1748-6041/5/6/065004, 5:6, (065004), Online publication date: 1-Dec-2010. Kelly D, Rosen A, Schuldt A, Kochupura P, Doronin S, Potapova I, Azeloglu E, Badylak S, Brink P, Cohen I and Gaudette G (2009) Increased Myocyte Content and Mechanical Function Within a Tissue-Engineered Myocardial Patch Following Implantation, Tissue Engineering Part A, 10.1089/ten.tea.2008.0430, 15:8, (2189-2201), Online publication date: 1-Aug-2009. Stankus J, Freytes D, Badylak S and Wagner W (2012) Hybrid nanofibrous scaffolds from electrospinning of a synthetic biodegradable elastomer and urinary bladder matrix, Journal of Biomaterials Science, Polymer Edition, 10.1163/156856208784089599, 19:5, (635-652), Online publication date: 1-Jan-2008. Ott H, Matthiesen T, Goh S, Black L, Kren S, Netoff T and Taylor D (2008) Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart, Nature Medicine, 10.1038/nm1684, 14:2, (213-221), Online publication date: 1-Feb-2008. Boink G, Seppen J, de Bakker J and Tan H (2007) Biological pacing by gene and cell therapy, Netherlands Heart Journal, 10.1007/BF03086008, 15:9, (318-322), Online publication date: 1-Sep-2007. Boink G, Seppen J, de Bakker J and Tan H (2007) Gene Therapy to Create Biological Pacemakers Biopacemaking, 10.1007/978-3-540-72110-9_6, (79-93), . Boink G, Seppen J, de Bakker J and Tan H (2006) Gene therapy to create biological pacemakers, Medical & Biological Engineering & Computing, 10.1007/s11517-006-0112-7, 45:2, (167-176), Online publication date: 1-Feb-2007. Jawad H, Ali N, Lyon A, Chen Q, Harding S and Boccaccini A (2007) Myocardial tissue engineering: a review, Journal of Tissue Engineering and Regenerative Medicine, 10.1002/term.46, 1:5, (327-342), Online publication date: 1-Sep-2007. Lallier T, Miner Q, Sonnier J and Spencer A (2007) A simple cell motility assay demonstrates differential motility of human periodontal ligament fibroblasts, gingival fibroblasts, and pre-osteoblasts, Cell and Tissue Research, 10.1007/s00441-006-0372-4, 328:2, (339-354), Online publication date: 1-May-2007. Ott H and Taylor D (2006) From cardiac repair to cardiac regeneration – ready to translate?, Expert Opinion on Biological Therapy, 10.1517/14712598.6.9.867, 6:9, (867-878), Online publication date: 1-Sep-2006. Badylak S, Kochupura P, Cohen I, Doronin S, Saltman A, Gilbert T, Kelly D, Ignotz R and Gaudette G (2017) The Use of Extracellular Matrix as an Inductive Scaffold for the Partial Replacement of Functional Myocardium, Cell Transplantation, 10.3727/000000006783982368, 15:1_suppl, (29-40), Online publication date: 1-Jan-2006. August 9, 2005Vol 112, Issue 6 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.104.534214PMID: 16087804 Originally publishedAugust 9, 2005 PDF download Advertisement SubjectsAnimal Models of Human DiseaseArrhythmiasGene TherapyIon Channels/Membrane TransportPacemakerTransplantation