title: Myocardial Tissue Engineering With Cells Derived From Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold.
abstract: BACKGROUND
  Conventional 3-dimensional (3D) printing techniques cannot produce structures of the size at which individual cells interact.
  
  
  OBJECTIVE
  Here, we used multiphoton-excited 3D printing to generate a native-like extracellular matrix scaffold with submicron resolution and then seeded the scaffold with cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human-induced pluripotent stem cells to generate a human-induced pluripotent stem cell-derived cardiac muscle patch (hCMP), which was subsequently evaluated in a murine model of myocardial infarction.
  
  
  RESULTS
  The scaffold was seeded with ≈50 000 human-induced pluripotent stem cell-derived cardiomyocytes, smooth muscle cells, and endothelial cells (in a 2:1:1 ratio) to generate the hCMP, which began generating calcium transients and beating synchronously within 1 day of seeding; the speeds of contraction and relaxation and the peak amplitudes of the calcium transients increased significantly over the next 7 days. When tested in mice with surgically induced myocardial infarction, measurements of cardiac function, infarct size, apoptosis, both vascular and arteriole density, and cell proliferation at week 4 after treatment were significantly better in animals treated with the hCMPs than in animals treated with cell-free scaffolds, and the rate of cell engraftment in hCMP-treated animals was 24.5% at week 1 and 11.2% at week 4.
  
  
  CONCLUSIONS
  Thus, the novel multiphoton-excited 3D printing technique produces extracellular matrix-based scaffolds with exceptional resolution and fidelity, and hCMPs fabricated with these scaffolds may significantly improve recovery from ischemic myocardial injury.
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Molly E
authors.initials: ME
authors.lastname: Kupfer
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Jangwook P
authors.initials: JP
authors.lastname: Jung
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Libang
authors.initials: L
authors.lastname: Yang
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Zhang
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Yong
authors.initials: Y
authors.lastname: Da Sie
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Quyen
authors.initials: Q
authors.lastname: Tran
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Visar
authors.initials: V
authors.lastname: Ajeti
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Brian T
authors.initials: BT
authors.lastname: Freeman
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Vladimir G
authors.initials: VG
authors.lastname: Fast
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.).
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Campagnola
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.). jayzhang@uab.edu ogle@umn.edu.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Ogle
authors.affiliation: From the Department of Biomedical Engineering, School of Medicine, School of Engineering, University of Alabama at Birmingham (L.G., V.G.F., J.Z.); Department of Biomedical Engineering, University of Minnesota, Twin Cities, Minneapolis (M.E.K., J.P.J., L.Y., P.Z., B.T.F., B.M.O.); and Department of Biomedical Engineering, University of Wisconsin, Madison (Y.D.S., Q.T., V.A., P.J.C.). jayzhang@uab.edu ogle@umn.edu.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D006339:Heart Rate; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000637:transplantation; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D010641:Phenotype; D066330:Printing, Three-Dimensional; D020127:Recovery of Function; D012038:Regeneration; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D014162:Transfection; D016277:Ventricular Function, Left
keywords: apoptosis; cardiomyocyte; endothelial cells; heart; myocardial infarction; tissue engineering