In vitro and in vivo analysis of visible light crosslinkable gelatin methacryloyl (GelMA) hydrogels.

Photocrosslinkable materials have been frequently used for constructing soft and biomimetic hydrogels for tissue engineering. Although ultraviolet (UV) light is commonly used for photocrosslinking such materials, its use has been associated with several biosafety concerns such as DNA damage, accelerated aging of tissues, and cancer. Here we report an injectable visible light crosslinked gelatin-based hydrogel for myocardium regeneration. Mechanical characterization revealed that the compressive moduli of the engineered hydrogels could be tuned in the range of 5-56 kPa by changing the concentrations of the initiator, co-initiator and co-monomer in the precursor formulation. In addition, the average pore sizes (26-103 μm) and swelling ratios (7-13%) were also shown to be tunable by varying the hydrogel formulation. In vitro studies showed that visible light crosslinked GelMA hydrogels supported the growth and function of primary cardiomyocytes (CMs). In addition, the engineered materials were shown to be biocompatible in vivo, and could be successfully delivered to the heart after myocardial infarction in an animal model to promote tissue healing. The developed visible light crosslinked hydrogel could be used for the repair of various soft tissues such as the myocardium and for the treatment of cardiovascular diseases with enhanced therapeutic functionality.

[1]  S. Katiyar,et al.  Crosstalk Among UV‐Induced Inflammatory Mediators, DNA Damage and Epigenetic Regulators Facilitates Suppression of the Immune System , 2017, Photochemistry and photobiology.

[2]  I. Georgakoudi,et al.  Extracellular matrix remodeling following myocardial infarction influences the therapeutic potential of mesenchymal stem cells , 2014, Stem Cell Research & Therapy.

[3]  Brenda Russell,et al.  Cardiac Tissue Engineering , 2009, The Journal of cardiovascular nursing.

[4]  N. Annabi,et al.  The effect of elastin on chondrocyte adhesion and proliferation on poly (ɛ-caprolactone)/elastin composites. , 2011, Biomaterials.

[5]  C. S. Ki,et al.  Thiol-norbornene photo-click hydrogels for tissue engineering applications. , 2015, Journal of applied polymer science.

[6]  Huaping Tan,et al.  Injectable, Biodegradable Hydrogels for Tissue Engineering Applications , 2010, Materials.

[7]  A. Khademhosseini,et al.  A Highly Elastic and Rapidly Crosslinkable Elastin‐Like Polypeptide‐Based Hydrogel for Biomedical Applications , 2015, Advanced functional materials.

[8]  A. DeMaria,et al.  Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction , 2013, Science Translational Medicine.

[9]  Wim E Hennink,et al.  The effect of photopolymerization on stem cells embedded in hydrogels. , 2009, Biomaterials.

[10]  Y. Ullmann,et al.  Aesthetic Applications of Intense Pulsed Light , 2010 .

[11]  Giyoong Tae,et al.  Visible-light-initiated thiol-acrylate photopolymerization of heparin-based hydrogels. , 2015, Biomacromolecules.

[12]  F. Baaijens,et al.  Influence of substrate stiffness on circulating progenitor cell fate. , 2012, Journal of biomechanics.

[13]  J. West,et al.  Visible light photoinitiation of mesenchymal stem cell-laden bioresponsive hydrogels. , 2011, European cells & materials.

[14]  S. Ishiwata,et al.  Sarcomere length nanometry in rat neonatal cardiomyocytes expressed with α-actinin–AcGFP in Z discs , 2014, The Journal of General Physiology.

[15]  M. Moretti,et al.  VA-086 methacrylate gelatine photopolymerizable hydrogels: A parametric study for highly biocompatible 3D cell embedding. , 2015, Journal of biomedical materials research. Part A.

[16]  Ali P Ebrahimi,et al.  Mechanical properties of normal and diseased cerebrovascular system. , 2009, Journal of vascular and interventional neurology.

[17]  A. Metters,et al.  Network formation and degradation behavior of hydrogels formed by Michael-type addition reactions. , 2005, Biomacromolecules.

[18]  H. Song,et al.  Characterizing cutaneous elastic fibers by eosin fluorescence detected by fluorescence microscopy. , 2011, Annals of dermatology.

[19]  A. Khademhosseini,et al.  Cell-laden microengineered gelatin methacrylate hydrogels. , 2010, Biomaterials.

[20]  Ali Khademhosseini,et al.  Engineered cell-laden human protein-based elastomer. , 2013, Biomaterials.

[21]  A. Khademhosseini,et al.  Highly Elastic Micropatterned Hydrogel for Engineering Functional Cardiac Tissue , 2013, Advanced functional materials.

[22]  Ali Khademhosseini,et al.  Hydrogel-coated microfluidic channels for cardiomyocyte culture. , 2013, Lab on a chip.

[23]  Ali Khademhosseini,et al.  Microfabricated Biomaterials for Engineering 3D Tissues , 2012, Advanced materials.

[24]  Hyejin Park,et al.  Visible light crosslinkable chitosan hydrogels for tissue engineering. , 2012, Acta biomaterialia.

[25]  Chien-Chi Lin,et al.  Interfacial thiol-ene photoclick reactions for forming multilayer hydrogels. , 2013, ACS applied materials & interfaces.

[26]  A. Khademhosseini,et al.  Injectable Graphene Oxide/Hydrogel-Based Angiogenic Gene Delivery System for Vasculogenesis and Cardiac Repair , 2014, ACS nano.

[27]  N. Annabi,et al.  Cross-linked open-pore elastic hydrogels based on tropoelastin, elastin and high pressure CO2. , 2010, Biomaterials.

[28]  Mohammad Ariful Islam,et al.  Injectable Hydrogels for Cardiac Tissue Repair after Myocardial Infarction , 2015, Advanced science.

[29]  Aaas News,et al.  Book Reviews , 1893, Buffalo Medical and Surgical Journal.

[30]  A. Khademhosseini,et al.  Transdermal regulation of vascular network bioengineering using a photopolymerizable methacrylated gelatin hydrogel. , 2013, Biomaterials.

[31]  U. Krishnan,et al.  Hydrogel based injectable scaffolds for cardiac tissue regeneration. , 2014, Biotechnology advances.

[32]  Ali Khademhosseini,et al.  Hydrogels for cardiac tissue engineering , 2014 .

[33]  Huaquan Wang,et al.  A facile dip-coating approach to prepare SiO2/fluoropolymer coating for superhydrophobic and superoleophobic fabrics with self-cleaning property , 2015 .

[34]  Ashutosh Chilkoti,et al.  In situ cross-linking of elastin-like polypeptide block copolymers for tissue repair. , 2008, Biomacromolecules.

[35]  Jared P. Stephens,et al.  Comparative analysis of different laser systems to study cellular responses to DNA damage in mammalian cells , 2009, Nucleic acids research.

[36]  Quang Vinh Nguyen,et al.  Injectable polymeric hydrogels for the delivery of therapeutic agents: A review , 2015 .

[37]  D. Seliktar,et al.  The effect of matrix stiffness of injectable hydrogels on the preservation of cardiac function after a heart attack. , 2014, Biomaterials.

[38]  Ali Khademhosseini,et al.  Functional Human Vascular Network Generated in Photocrosslinkable Gelatin Methacrylate Hydrogels , 2012, Advanced functional materials.

[39]  De-Qun Wu,et al.  Injectable Hydrogel Helps Bone Marrow-Derived Mononuclear Cells Restore Infarcted Myocardium , 2010, Cardiology.

[40]  D. J. Goldstein.  The fluorescence of elastic fibres stained with Eosin and excited by visible light , 1969, The Histochemical Journal.

[41]  Mario Miscuglio,et al.  Highly Elastic and Conductive Human‐Based Protein Hybrid Hydrogels , 2016, Advanced materials.

[42]  Chaenyung Cha,et al.  25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine , 2014, Advanced materials.

[43]  S J Bryant,et al.  Cytocompatibility of UV and visible light photoinitiating systems on cultured NIH/3T3 fibroblasts in vitro , 2000, Journal of biomaterials science. Polymer edition.

[44]  B. Epe,et al.  Wavelength dependence of oxidative DNA damage induced by UV and visible light. , 1997, Carcinogenesis.

[45]  Chien-Chi Lin,et al.  Visible light cured thiol-vinyl hydrogels with tunable degradation for 3D cell culture. , 2014, Acta biomaterialia.

[46]  João Rodrigues,et al.  Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. , 2012, Chemical Society reviews.

[47]  W. D. de Lange,et al.  3D engineered cardiac tissue models of human heart disease: learning more from our mice. , 2013, Trends in cardiovascular medicine.

[48]  Ali Khademhosseini,et al.  Controlling the porosity and microarchitecture of hydrogels for tissue engineering. , 2010, Tissue engineering. Part B, Reviews.

[49]  A. Khademhosseini,et al.  Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. , 2015, Biomaterials.

[50]  S. Liang,et al.  Migration of Resident Cardiac Stem Cells in Myocardial Infarction , 2013, Anatomical record.

[51]  Danielle Rockwood,et al.  Three-dimensional culture alters primary cardiac cell phenotype. , 2010, Tissue engineering. Part A.

[52]  W. Marsden.  I and J , 2012 .

[53]  R. Harada,et al.  Theoretical analyses on a flipping mechanism of UV-induced DNA damage , 2016, Biophysics and physicobiology.