Proangiogenic scaffolds as functional templates for cardiac tissue engineering

We demonstrate here a cardiac tissue-engineering strategy addressing multicellular organization, integration into host myocardium, and directional cues to reconstruct the functional architecture of heart muscle. Microtemplating is used to shape poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogel into a tissue-engineering scaffold with architectures driving heart tissue integration. The construct contains parallel channels to organize cardiomyocyte bundles, supported by micrometer-sized, spherical, interconnected pores that enhance angiogenesis while reducing scarring. Surface-modified scaffolds were seeded with human ES cell-derived cardiomyocytes and cultured in vitro. Cardiomyocytes survived and proliferated for 2 wk in scaffolds, reaching adult heart densities. Cardiac implantation of acellular scaffolds with pore diameters of 30–40 μm showed angiogenesis and reduced fibrotic response, coinciding with a shift in macrophage phenotype toward the M2 state. This work establishes a foundation for spatially controlled cardiac tissue engineering by providing discrete compartments for cardiomyocytes and stroma in a scaffold that enhances vascularization and integration while controlling the inflammatory response.

[1]  B D Ratner,et al.  Transport through crosslinked poly(2-hydroxyethyl methacrylate) hydrogel membranes. , 1973, Journal of biomedical materials research.

[2]  D. Hull,et al.  A study of the interface between a fibrous polyurethane arterial prosthesis and natural tissue. , 1982, Journal of biomedical materials research.

[3]  R. White,et al.  Effect of healing on small internal diameter arterial graft compliance. , 1983, Biomaterials, medical devices, and artificial organs.

[4]  J M Anderson,et al.  Inflammatory response to implants. , 1988, ASAIO transactions.

[5]  G Olivetti,et al.  Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. , 1990, Circulation research.

[6]  V. Sukhatme,et al.  Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; Egr-1 induction is primarily an alpha 1-mediated response. , 1990, The Journal of biological chemistry.

[7]  Gordana Vunjak-Novakovic,et al.  Microgravity tissue engineering , 1997, In Vitro Cellular & Developmental Biology - Animal.

[8]  R J Cohen,et al.  Cardiac muscle tissue engineering: toward an in vitro model for electrophysiological studies. , 1999, American journal of physiology. Heart and circulatory physiology.

[9]  R Langer,et al.  Tissue engineering of functional cardiac muscle: molecular, structural, and electrophysiological studies. , 2001, American journal of physiology. Heart and circulatory physiology.

[10]  K Walsh,et al.  Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. , 2001, Journal of molecular and cellular cardiology.

[11]  Larry Kedes,et al.  Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. , 2002, Journal of molecular and cellular cardiology.

[12]  Andreas Hess,et al.  Cardiac Grafting of Engineered Heart Tissue in Syngenic Rats , 2002, Circulation.

[13]  Todd C McDevitt,et al.  In vitro generation of differentiated cardiac myofibers on micropatterned laminin surfaces. , 2002, Journal of biomedical materials research.

[14]  Mitsuo Umezu,et al.  Fabrication of Pulsatile Cardiac Tissue Grafts Using a Novel 3-Dimensional Cell Sheet Manipulation Technique and Temperature-Responsive Cell Culture Surfaces , 2002, Circulation research.

[15]  Gordana Vunjak-Novakovic,et al.  Effects of oxygen on engineered cardiac muscle. , 2002, Biotechnology and bioengineering.

[16]  M. Reddington,et al.  Surface imaging microscopy, an automated method for visualizing whole embryo samples in three dimensions at high resolution , 2002, Developmental dynamics : an official publication of the American Association of Anatomists.

[17]  Todd C McDevitt,et al.  Spatially organized layers of cardiomyocytes on biodegradable polyurethane films for myocardial repair. , 2003, Journal of biomedical materials research. Part A.

[18]  Takehisa Matsuda,et al.  In vivo leukocyte cytokine mRNA responses to biomaterials are dependent on surface chemistry. , 2003, Journal of biomedical materials research. Part A.

[19]  Buddy D. Ratner,et al.  Biomaterials with tightly controlled pore size that promote vascular in-growth , 2004 .

[20]  Y. Rudy,et al.  Basic mechanisms of cardiac impulse propagation and associated arrhythmias. , 2004, Physiological reviews.

[21]  M. Tuszynski,et al.  The fabrication and characterization of linearly oriented nerve guidance scaffolds for spinal cord injury. , 2004, Biomaterials.

[22]  Thomas Eschenhagen,et al.  Engineered heart tissue for regeneration of diseased hearts. , 2004, Biomaterials.

[23]  Silvano Sozzani,et al.  The chemokine system in diverse forms of macrophage activation and polarization. , 2004, Trends in immunology.

[24]  Milica Radisic,et al.  Mathematical model of oxygen distribution in engineered cardiac tissue with parallel channel array perfused with culture medium containing oxygen carriers. , 2005, American journal of physiology. Heart and circulatory physiology.

[25]  T. McDevitt,et al.  Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway. , 2005, Journal of molecular and cellular cardiology.

[26]  Milica Radisic,et al.  Oxygen gradients correlate with cell density and cell viability in engineered cardiac tissue , 2006, Biotechnology and bioengineering.

[27]  Andreas Hess,et al.  Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts , 2006, Nature Medicine.

[28]  Martin Fussenegger,et al.  Tissue-transplant fusion and vascularization of myocardial microtissues and macrotissues implanted into chicken embryos and rats. , 2006, Tissue engineering.

[29]  J. Olerud,et al.  A mouse model to evaluate the interface between skin and a percutaneous device. , 2007, Journal of biomedical materials research. Part A.

[30]  Lila R Collins,et al.  Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts , 2007, Nature Biotechnology.

[31]  P. Allavena,et al.  Macrophage polarization in tumour progression. , 2008, Seminars in cancer biology.

[32]  Stephanie Bryant,et al.  Degradable poly(2-hydroxyethyl methacrylate)-co-polycaprolactone hydrogels for tissue engineering scaffolds. , 2008, Biomacromolecules.

[33]  C. Murry,et al.  Systems approaches to preventing transplanted cell death in cardiac repair. , 2008, Journal of molecular and cellular cardiology.

[34]  S. Badylak,et al.  Macrophage phenotype as a determinant of biologic scaffold remodeling. , 2008, Tissue engineering. Part A.

[35]  James M. Anderson,et al.  Foreign body reaction to biomaterials. , 2008, Seminars in immunology.

[36]  S. Gordon,et al.  Alternative activation of macrophages: an immunologic functional perspective. , 2009, Annual review of immunology.

[37]  Lil Pabon,et al.  Scaffold-free human cardiac tissue patch created from embryonic stem cells. , 2009, Tissue engineering. Part A.

[38]  George P McCabe,et al.  Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. , 2009, Biomaterials.

[39]  Shulamit Levenberg,et al.  Transplantation of a tissue-engineered human vascularized cardiac muscle. , 2010, Tissue engineering. Part A.

[40]  J. Albina,et al.  The phenotype of murine wound macrophages , 2010, Journal of leukocyte biology.

[41]  D. Castrillon,et al.  Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma , 2010, Disease Models & Mechanisms.