Electroconductive Biohybrid Hydrogel for Enhanced Maturation and Beating Properties of Engineered Cardiac Tissues

Cardiac tissue engineering is a promising strategy to treat heart failure. Yet, several issues remain to be resolved including the prevention of arrhythmia caused by inefficient electrical coupling within the graft and between graft and host tissue. Here, a biohybrid hydrogel composed of collagen, alginate, and electroconductive poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) is developed that exhibits extracellular matrix–mimetic fibrous structures and enhanced electrical coupling as well and cardiomyocyte maturation. Presence of PEDOT:PSS in the hydrogel improves electrical conductivity and prevents arrhythmia of tissue constructs containing neonatal rat cardiomyocytes. Moreover, it results in increasing beating frequencies reaching more than 200 beats min−1 endogenous frequencies. In addition, cardiomyocytes exhibit increased alignment and density in these constructs, improved sarcomere organization, and enhanced connexin 43 expression, suggesting maturation of the cardiac tissue. Importantly, the here developed electroconductive biohybrid hydrogels also improve maturation and beating properties of human‐induced pluripotent stem cell–derived cardiomyocytes. These cells exhibit 1.9 µm near adult sarcomeric length, enhanced beating frequency, increased speed of contraction, and larger contraction amplitude. Collectively, the data demonstrate the potential of this electroconductive biohybrid hydrogel to improve tissue engineering approaches to treat heart failure and possibly diseases of other electrically sensitive tissues.

[1]  J. Naik,et al.  Ionic conductivity and free volume related microstructural properties of LiClO4/PVA/NaAlg polymer composites: Positron annihilation spectroscopic studies , 2016 .

[2]  A. Hagège,et al.  Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. , 2003, Journal of the American College of Cardiology.

[3]  Dong-Woo Cho,et al.  3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair. , 2017, Biomaterials.

[4]  L. Ferreira,et al.  Restoring heart function and electrical integrity: closing the circuit , 2017, npj Regenerative Medicine.

[5]  Mark A Sussman,et al.  Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth , 2013, Basic Research in Cardiology.

[6]  Horst Fischer,et al.  Controlling Shear Stress in 3D Bioprinting is a Key Factor to Balance Printing Resolution and Stem Cell Integrity , 2016, Advanced healthcare materials.

[7]  A. Erbaş,et al.  Ionic Conductivity in Polyelectrolyte Hydrogels , 2016 .

[8]  Jin-Oh You,et al.  Nanoengineering the heart: conductive scaffolds enhance connexin 43 expression. , 2011, Nano letters.

[9]  Alessandro Giacomello,et al.  Epicardial application of cardiac progenitor cells in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac function after myocardial infarction. , 2015, Biomaterials.

[10]  P. Benzoni,et al.  Human derived cardiomyocytes: A decade of knowledge after the discovery of induced pluripotent stem cells , 2016, Developmental dynamics : an official publication of the American Association of Anatomists.

[11]  Seeram Ramakrishna,et al.  Polypyrrole-contained electrospun conductive nanofibrous membranes for cardiac tissue engineering. , 2011, Journal of biomedical materials research. Part A.

[12]  S. Toyokuni.  Genotoxicity and carcinogenicity risk of carbon nanotubes. , 2013, Advanced drug delivery reviews.

[13]  J. Hilborn,et al.  Injectable and thermoresponsive pericardial matrix derived conductive scaffold for cardiac tissue engineering , 2017 .

[14]  Alexander M Seifalian,et al.  Conductive Polymers: Opportunities and Challenges in Biomedical Applications. , 2018, Chemical reviews.

[15]  Adam E Jakus,et al.  Advancing the field of 3D biomaterial printing , 2016, Biomedical materials.

[16]  Donald O Freytes,et al.  Preparation and rheological characterization of a gel form of the porcine urinary bladder matrix. , 2008, Biomaterials.

[17]  Milica Radisic,et al.  Distilling complexity to advance cardiac tissue engineering , 2016, Science Translational Medicine.

[18]  Stanislav Stříteský,et al.  Printing inks of electroactive polymer PEDOT:PSS: The study of biocompatibility, stability, and electrical properties. , 2018, Journal of biomedical materials research. Part A.

[19]  Zhuang Liu,et al.  Drug delivery with carbon nanotubes for in vivo cancer treatment. , 2008, Cancer research.

[20]  Yang Guo,et al.  Screen-Printed PEDOT:PSS Electrodes on Commercial Finished Textiles for Electrocardiography. , 2017, ACS applied materials & interfaces.

[21]  G. Figtree,et al.  Versatile Fabrication Approach of Conductive Hydrogels via Copolymerization with Vinyl Monomers. , 2017, ACS applied materials & interfaces.

[22]  A. Boccaccini,et al.  Tissue engineering of electrically responsive tissues using polyaniline based polymers: a review. , 2014, Biomaterials.

[23]  A Haverich,et al.  In vitro engineering of heart muscle: artificial myocardial tissue. , 2002, The Journal of thoracic and cardiovascular surgery.

[24]  Ali Khademhosseini,et al.  Layer‐by‐Layer Assembly of 3D Tissue Constructs with Functionalized Graphene , 2014, Advanced functional materials.

[25]  H. Kaji,et al.  Electrodeposition of anchored polypyrrole film on microelectrodes and stimulation of cultured cardiac myocytes. , 2007, Biomaterials.

[26]  P. Menasché.  Stem cell therapy for heart failure: are arrhythmias a real safety concern? , 2009, Circulation.

[27]  M. Los,et al.  Direct Mechanical Stimulation of Stem Cells: A Beating Electromechanically Active Scaffold for Cardiac Tissue Engineering , 2016, Advanced healthcare materials.

[28]  Marjan Gucek,et al.  Contractile Work Contributes to Maturation of Energy Metabolism in hiPSC-Derived Cardiomyocytes , 2018, Stem cell reports.

[29]  Lil Pabon,et al.  Engineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes , 2014, Circulation research.

[30]  G. Seebohm,et al.  Cardiac Subtype-Specific Modeling of Kv1.5 Ion Channel Deficiency Using Human Pluripotent Stem Cells , 2017, Front. Physiol..

[31]  A. Albertsson,et al.  Biodegradable and electrically conducting polymers for biomedical applications , 2013 .

[32]  M. Radisic,et al.  Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. , 2016, Advanced drug delivery reviews.

[33]  Changkai Sun,et al.  Neural stem cell proliferation and differentiation in the conductive PEDOT-HA/Cs/Gel scaffold for neural tissue engineering. , 2017, Biomaterials science.

[34]  Molly M. Stevens,et al.  Highly porous scaffolds of PEDOT:PSS for bone tissue engineering , 2017, Acta biomaterialia.

[35]  M. Vagin,et al.  Electroactive biomimetic collagen-silver nanowire composite scaffolds. , 2016, Nanoscale.

[36]  Feng Xu,et al.  Automated and adaptable quantification of cellular alignment from microscopic images for tissue engineering applications. , 2011, Tissue engineering. Part C, Methods.

[37]  Jessica Ka-Yan Law,et al.  PEDOT:PSS organic electrochemical transistor arrays for extracellular electrophysiological sensing of cardiac cells. , 2017, Biosensors & bioelectronics.

[38]  K. Red-Horse,et al.  Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as an In Vitro Model for Coxsackievirus B3–Induced Myocarditis and Antiviral Drug Screening Platform , 2014, Circulation research.

[39]  Xiaoping Song,et al.  Mussel‐Inspired Conductive Cryogel as Cardiac Tissue Patch to Repair Myocardial Infarction by Migration of Conductive Nanoparticles , 2016 .

[40]  M. Abidian,et al.  Conducting‐Polymer Nanotubes for Controlled Drug Release , 2006, Advanced materials.

[41]  Yen Chang,et al.  Electrical coupling of isolated cardiomyocyte clusters grown on aligned conductive nanofibrous meshes for their synchronized beating. , 2013, Biomaterials.

[42]  N. Gospodinova,et al.  Conducting polymers prepared by oxidative polymerization: polyaniline , 1998 .

[43]  M. Vornanen.  Force-frequency relationship, contraction duration and recirculating fraction of calcium in postnatally developing rat heart ventricles: correlation with heart rate. , 1992, Acta physiologica Scandinavica.

[44]  T. Scheibel,et al.  Recombinant spider silk-based bioinks , 2017, Biofabrication.

[45]  P. Ma,et al.  Electrospun conductive nanofibrous scaffolds for engineering cardiac tissue and 3D bioactuators. , 2017, Acta biomaterialia.

[46]  Christian Mühlfeld,et al.  Silk protein fibroin from Antheraea mylitta for cardiac tissue engineering. , 2012, Biomaterials.

[47]  P. Poulin,et al.  Carbon nanotubes induced gelation of unmodified hyaluronic acid. , 2013, Langmuir : the ACS journal of surfaces and colloids.

[48]  R. Tian,et al.  Mitochondrial Maturation in Human Pluripotent Stem Cell Derived Cardiomyocytes , 2017, Stem cells international.

[49]  Robert Langer,et al.  Bio-Inspired Polymer Composite Actuator and Generator Driven by Water Gradients , 2013, Science.

[50]  David C. Martin,et al.  Polymerization of the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) around living neural cells. , 2007, Biomaterials.

[51]  Ali Khademhosseini,et al.  Gold Nanocomposite Bioink for Printing 3D Cardiac Constructs , 2017, Advanced functional materials.

[52]  Ali Navaei,et al.  Gold nanorod-incorporated gelatin-based conductive hydrogels for engineering cardiac tissue constructs. , 2016, Acta biomaterialia.

[53]  C. Murry,et al.  Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. , 2000 .

[54]  Alessandro Giacomello,et al.  Cardiac tissue engineering using tissue printing technology and human cardiac progenitor cells. , 2012, Biomaterials.

[55]  Gordana Vunjak-Novakovic,et al.  Advanced maturation of human cardiac tissue grown from pluripotent stem cells , 2018, Nature.

[56]  T. Scheibel,et al.  Surface Features of Recombinant Spider Silk Protein eADF4(κ16)‐Made Materials are Well‐Suited for Cardiac Tissue Engineering , 2017 .

[57]  H. Schulz,et al.  Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation. , 2014, Journal of molecular and cellular cardiology.

[58]  M. Soleimani,et al.  Enhanced Cardiac Differentiation of Human Cardiovascular Disease Patient-Specific Induced Pluripotent Stem Cells by Applying Unidirectional Electrical Pulses Using Aligned Electroactive Nanofibrous Scaffolds. , 2017, ACS applied materials & interfaces.

[59]  Charles E. Murry,et al.  Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts , 2014, Nature.