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WIREs Nanomed Nanobiotechnol
Impact Factor: 6.14

Biomimetic materials design for cardiac tissue regeneration

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Cardiovascular disease is the leading cause of death worldwide. In the absence of sufficient numbers of organs for heart transplant, alternate approaches for healing or replacing diseased heart tissue are under investigation. Designing biomimetic materials to support these approaches will be essential to their overall success. Strategies for cardiac tissue engineering include injection of cells, implantation of three‐dimensional tissue constructs or patches, injection of acellular materials, and replacement of valves. To replicate physiological function and facilitate engraftment into native tissue, materials used in these approaches should have properties that mimic those of the natural cardiac environment. Multiple aspects of the cardiac microenvironment have been emulated using biomimetic materials including delivery of bioactive factors, presentation of cell‐specific adhesion sites, design of surface topography to guide tissue alignment and dictate cell shape, modulation of mechanical stiffness and electrical conductivity, and fabrication of three‐dimensional structures to guide tissue formation and function. Biomaterials can be engineered to assist in stem cell expansion and differentiation, to protect cells during injection and facilitate their retention and survival in vivo, and to provide mechanical support and guidance for engineered tissue formation. Numerous studies have investigated the use of biomimetic materials for cardiac regeneration. Biomimetic material design will continue to exploit advances in nanotechnology to better recreate the cellular environment and advance cardiac regeneration. Overall, biomimetic materials are moving the field of cardiac regenerative medicine forward and promise to deliver new therapies in combating heart disease. WIREs Nanomed Nanobiotechnol 2014, 6:15–39. doi: 10.1002/wnan.1241 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement

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Cellular and physiological properties are affected by (a) Mechanical stretch. (Reprinted with permission from Ref . Copyright 2002 Elsevier) (b) Surface topography. (Reprinted with permission from Ref . Copyright 2010 National Academy of Sciences) Scale bar 200 nm. (c) Degradable materials. (Reprinted with permission from Ref . Copyright 2003 National Academy of Sciences) (d) Cell‐specific adhesion sites. (Reprinted with permission from Ref . Copyright 2011 Elsevier) (e) Defined shape. Scale bars 10 µm. (Reprinted with permission from Ref . Creative Commons Attribution License 2011 Public Library of Science) (f) Delivery of materials containing bioactive factors. Scale bar 10 µm. (Reprinted with permission from Ref . Copyright 2005 Elsevier) (g) Electrically conducting materials. (Reprinted with permission from Ref . Copyright 2011 American Chemical Society) (h) Three‐dimensional structure. Scale bars 1 mm (left); 200 µm (right). (Reprinted with permission from Ref . Copyright 2008 Nature Publishing Group) (i) Mechanical stiffness and elasticity. Scale bar 20 µm. (Reprinted with permission from Ref . Copyright 2006 Elsevier)
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Heart function can be negatively impacted by diseases and by the presence of congenital heart defects. Biomimetic materials can facilitate development of successful strategies for cardiac regeneration. (a) Myocardial infarction occurs when occlusion of a coronary artery results in ischemia of the area of myocardium fed by the occluded artery. (Reprinted with permission from Ref . Copyright 2006 Nature Publishing Group) (b) Perfusion of a rat heart with detergent (1% SDS) decellularizes the organ leaving only the ECM scaffold. Arrows indicate area where decellularization is incomplete. (Reprinted with permission from Ref . Copyright 2008 Nature Publishing Group) (c) Diseased aortic valve. Note calcified deposits on valve leaflets. (Reprinted with permission from Ref . Copyright 2002 BMJ Publishing Group) (d) Tissue engineered valve replacements with cells grown on a synthetic scaffold. (Reprinted with permission from Ref 169. Copyright 2010 Elsevier)
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Anterior section of normal human heart. RA, Right Atrium; SCV, Superior Vena Cava; TV, Tricuspid Valve; RV, Right Ventricle; IVC, Inferior Vena Cava; MV Mitral Valve; LA, Left Atrium; MPA, Main Pulmonary Artery; PV, Pulmonary Valve; LV, Left Ventricle; Ao, Aorta; AoV, Aortic Valve. (Reprinted with permission from Ref . Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities http://www.cdc.gov/ncbddd/heartdefects/TetralogyOfFallot‐graphic2.html; Public Domain Image)
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Biomimetic materials can be used to advance cardiac tissue regeneration strategies. Properties of biomimetic constructs include presentation of embedded bioactive factors, capacity for enzymatic digestion, inclusion of cell adhesion sites, regulation of patterned nano‐ and micro‐topography for cell attachment, capability to support being mechanically stretched, and the ability to conduct electrical stimuli (Illustration by Brennen Reece).
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Mimicking the nanostructure of native cardiac tissue ECM can play an important role in guiding the formation of engineered cardiac tissue. (a) SEM image of an anisotropically‐patterned PEG‐hydrogel substrate created from a photolithographic mold. (Reprinted with permission from Ref . Copyright 2009 National Academy of Sciences) (b) NRVMs cultured on the patterned surface demonstrated high levels of sarcomere alignment (sarcomeric α‐actinin (red), DAPI (blue)). Scale bar 10 µm. (Reprinted with permission from Ref . Copyright 2009 National Academy of Sciences) (c) Solutions of peptide ampiphiles created highly aligned nanofibers after thermal treatment. (Reprinted with permission from Ref . Copyright 2010 Nature Publishing Group) (d) Calcein‐labeled cells cultured in a string containing nanoscale peptide ampiphile moieites. (Reprinted with permission from Ref . Copyright 2010 Nature Publishing Group) (e) PLA nanofibers created through a rotary jet‐spinning apparatus. (Reprinted with permission from Ref . Copyright 2010 American Chemical Society) (f) NRVMs aligned on PLA nanofibers (sarcomeric α‐actinin (red)). Scale bar 20 µm. (Reprinted with permission from Ref . Copyright 2010 American Chemical Society)
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Biomimetic materials can be used to form cardiac tissue patches and support cells during injection. (a) Polyester urethane urea was used in the creation of a biodegradable cardiac tissue patch. (Reprinted with permission from Ref . Copyright 2007 Elsevier) (b) Patch demonstrates strong engraftment after 8 weeks post‐implantation. (Reprinted with permission from Ref . Copyright 2007 Elsevier) (c) Scaffold‐free cardiac tissue patch formed from hESC‐derived cardiomyocytes in a rotating orbital shaker stains positive for β‐myosin heavy chain. (Reprinted with permission from Ref . Copyright 2009 National Academy of Sciences) (d) Same patch as in (c) engrafted into rat myocardium (Reprinted with permission from Ref . Copyright 2009 National Academy of Sciences) (e) A photo‐crosslinking PEG‐DA hydrogel containing NRVMs was injected into an infarcted rat heart and polymerized in situ. Polymer grafts survived degradation over a 30‐day period. (Reprinted with permission from Ref . Copyright 2011 Elsevier) (f) PEG‐DA with hES‐CMs injected into infarct show wall thickening (arrow) after 30 days. (Reprinted with permission from Ref . Copyright 2011 Elsevier)
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Biomimetic materials can be used in the creation of novel cellular expansion platforms, capable of promoting cell proliferation while directing cardiac differentiation and maturation. Such systems will be necessary to acquire the large numbers of cells required for cardiac regenerative therapy. (a) Mouse ESCs forming aggregates in pLL‐coated alginate beads. (Reprinted with permission from Ref . Copyright 2010 Cognizant Communication Cooperation) (b) Homogenous PLGA microspheres were encapsulated in EBs. (Reprinted with permission from Ref . Copyright 2010 John Wiley and Sons) (c) Surface of collagen sponge structure containing incorporated PGA nanofibers (Reprinted with permission from Ref . Copyright 2009 John Wiley and Sons) (d) Cardiac cell types seeded in channeled scaffolds made from poly(glycerol sebacate). (Reprinted with permission from Ref . Copyright 2010 John Wiley and Sons)
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Biomimetic materials play an important role in expansion and differentiation of cells for cardiac regeneration. (a) Microparticles containing PLGA, agarose, or gelatin were encapsulated in EBs to provide internal cell signaling. (Reprinted with permission from Ref . Copyright 2011 Elsevier) (b) An acrylate surface containing a synthetic peptide was shown to induce cardiomyocyte differentiation (staining: α‐actinin (green), Nkx2.5 (red)). Scale bar 50 µm. (Reprinted with permission from Ref . Copyright 2010 Nature Publishing Group) (c) Maturing cardiomyocytes on modified hyaluronic acid hydrogel showing progressive stages of myofibril development (staining: actin (red), α‐actinin (green), nuclei (blue). Scale bar 25 µm. (Reprinted with permission from Ref . Copyright 2011 Elsevier)
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Replicating the environment provided by the myocardial interstitial ECM is important in fabricating biomimetic materials for myocardial regeneration. (a) SEM images of ECM in adult rat myocardium. Arrow in A2 indicates ECM fibers underlying myocardial surface. Scale bars 5 µm in A1; 10 µm in A2, A3. (Reprinted with permission from Ref . Copyright 2010 National Academy of Sciences) (b) Hematoxylin and eosin stained section of normal human myocardium. Scale bar 30 µm. (Reprinted with permission from Ref . Copyright 2004 BMJ Publishing Group) (c) Three‐dimensional imaging of rat heart by confocal fluorescence laser scanning microscopy. (Reprinted with permission from Ref . Copyright 1998 John Wiley and Sons)
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease
Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement

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