Effect of genipin crosslinked chitosan scaffolds containing SDF-1 on wound healing in a rat model.

Prolonged healing is a severe problem for elderly and diabetic patients. Impaired angiogenesis, stem cell differentiation, and migration have been shown to delay wound healing. The chemokine stromal cell-derived factor-1 (SDF-1) plays an essential role in recruiting cells to wound sites and is suggested to be a candidate for tissue engineering. In this study, chitosan (CHI) scaffolds were crosslinked with nontoxic genipin (Gp) and further heparinized for SDF-1 immobilization. Then, the structures were evaluated for their physicochemical properties (porosity, swelling ratio, and water vapor transmission rate (WVTR)). The interaction between SDF-1 and heparin could sustain SDF-1 release, which has been shown to enhance human umbilical vein endothelial cell (HUVEC) 2D/3D migration. The investigation of the wound-healing activity of the SDF-1-loaded CHI scaffolds revealed a better wound recovery rate in vivo in healthy and streptozotocin-induced diabetic Sprague-Dawley (SD) rats. The histological analysis illustrated that the local of SDF-1 treatment scaffold at the wound site enhanced neovascularization. The wounds treated with SDF-1 scaffolds also exhibited higher vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β) expression in Western blot assays. Based on the wound-healing activity and beneficial characteristics, the SDF-1-loaded CHI scaffold demonstrates potential as a material for treating skin wounds.

[1]  D. Buerk,et al.  Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. , 2007, The Journal of clinical investigation.

[2]  A. Minami,et al.  Local upregulation of stromal cell-derived factor-1 after ligament injuries enhances homing rate of bone marrow stromal cells in rats. , 2009, Tissue engineering. Part A.

[3]  A. Ghahary,et al.  Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing. , 2013, Advances in wound care.

[4]  R. Muzzarelli,et al.  Genipin-Crosslinked Chitosan Gels and Scaffolds for Tissue Engineering and Regeneration of Cartilage and Bone , 2015, Marine drugs.

[5]  E. Bernotiene,et al.  Scaffolds and cells for tissue regeneration: different scaffold pore sizes—different cell effects , 2016, Cytotechnology.

[6]  C. Ye,et al.  Combination of stromal-derived factor-1alpha and vascular endothelial growth factor gene-modified endothelial progenitor cells is more effective for ischemic neovascularization. , 2009, Journal of vascular surgery.

[7]  Youbin Wang,et al.  Effects of stromal cell derived factor-1 and CXCR4 on the promotion of neovascularization by hyperbaric oxygen treatment in skin flaps. , 2013, Molecular medicine reports.

[8]  S. T. Lee,et al.  Fabrication and characterization of a sponge-like asymmetric chitosan membrane as a wound dressing. , 2001, Biomaterials.

[9]  T. Kipps,et al.  CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. , 2006, Blood.

[10]  M. Delepierre,et al.  Stromal Cell-derived Factor-1α Associates with Heparan Sulfates through the First β-Strand of the Chemokine* , 1999, The Journal of Biological Chemistry.

[11]  Q. Jin,et al.  SDF-1 Enhances Wound Healing of Critical-Sized Calvarial Defects beyond Self-Repair Capacity , 2014, PloS one.

[12]  A. Ludlow,et al.  Active transforming growth factor-beta in wound repair: determination using a new assay. , 1999, The American journal of pathology.

[13]  Katja Schenke-Layland,et al.  Preserved bioactivity and tunable release of a SDF1-GPVI bi-specific protein using photo-crosslinked PEGda hydrogels. , 2014, Biomaterials.

[14]  A. Salgado,et al.  Adhesion, proliferation, and osteogenic differentiation of a mouse mesenchymal stem cell line (BMC9) seeded on novel melt-based chitosan/polyester 3D porous scaffolds , 2008 .

[15]  L. Gibson,et al.  The effect of pore size on cell adhesion in collagen-GAG scaffolds. , 2005, Biomaterials.

[16]  P. Bainbridge,et al.  Wound healing and the role of fibroblasts. , 2013, Journal of wound care.

[17]  Richard T. Lee,et al.  Local Delivery of Protease-Resistant Stromal Cell Derived Factor-1 for Stem Cell Recruitment After Myocardial Infarction , 2007, Circulation.

[18]  A. Musarò,et al.  A stromal cell-derived factor-1 releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle. , 2011, European cells & materials.

[19]  Esmaiel Jabbari,et al.  Migration of marrow stromal cells in response to sustained release of stromal-derived factor-1alpha from poly(lactide ethylene oxide fumarate) hydrogels. , 2010, International journal of pharmaceutics.

[20]  Yun-yu Hu,et al.  Effects of different cross-linking conditions on the properties of genipin-cross-linked chitosan/collagen scaffolds for cartilage tissue engineering , 2011, Journal of materials science. Materials in medicine.

[21]  Ali Khademhosseini,et al.  Enhancing cell penetration and proliferation in chitosan hydrogels for tissue engineering applications. , 2011, Biomaterials.

[22]  A. Grobbelaar,et al.  The role of the TGF-β family in wound healing, burns and scarring: a review. , 2012, International journal of burns and trauma.

[23]  A. Ludlow,et al.  Active Transforming Growth Factor-β in Wound Repair , 1999 .

[24]  N. Selvamurugan,et al.  Preparation, characterization and antimicrobial activity of a bio-composite scaffold containing chitosan/nano-hydroxyapatite/nano-silver for bone tissue engineering. , 2011, International journal of biological macromolecules.

[25]  M. Ratajczak,et al.  The SDF‐1‐CXCR4 Axis Stimulates VEGF Secretion and Activates Integrins but does not Affect Proliferation and Survival in Lymphohematopoietic Cells , 2001, Stem cells.

[26]  Nai-Jen Harry Chang,et al.  Porous chitosan scaffold cross-linked by chemical and natural procedure applied to investigate cell regeneration , 2012 .

[27]  Anne Imberty,et al.  Characterization of the Stromal Cell-derived Factor-1α-Heparin Complex* , 2001, The Journal of Biological Chemistry.

[28]  R. Sreedharan,et al.  'Genipin' - the natural water soluble cross-linking agent and its importance in the modified drug delivery systems: an overview. , 2014, Current drug delivery.

[29]  Richard T. Lee,et al.  Protease-Resistant Stromal Cell–Derived Factor-1 for the Treatment of Experimental Peripheral Artery Disease , 2011, Circulation.

[30]  Fergal J O'Brien,et al.  The effect of mean pore size on cell attachment, proliferation and migration in collagen-glycosaminoglycan scaffolds for bone tissue engineering. , 2010, Biomaterials.

[31]  R. Salcedo,et al.  Role of Chemokines in Angiogenesis: CXCL12/SDF‐1 and CXCR4 Interaction, a Key Regulator of Endothelial Cell Responses , 2003, Microcirculation.

[32]  J. Lai Biocompatibility of Genipin and Glutaraldehyde Cross-Linked Chitosan Materials in the Anterior Chamber of the Eye , 2012, International journal of molecular sciences.

[33]  Hongbin Fan,et al.  Effects of the controlled-released basic fibroblast growth factor from chitosan-gelatin microspheres on human fibroblasts cultured on a chitosan-gelatin scaffold. , 2007, Biomacromolecules.

[34]  E. Johnston,et al.  Transforming growth factor beta-1 (TGF-β1) stimulates collagen synthesis in cultured rainbow trout cardiac fibroblasts , 2017, Journal of Experimental Biology.

[35]  Liu Yang,et al.  Fabrication and Evaluation of Porous Keratin/chitosan (KCS) Scaffolds for Effectively Accelerating Wound Healing. , 2015, Biomedical and environmental sciences : BES.

[36]  P. Casanova,et al.  Role of the α‐chemokine stromal cell‐derived factor (SDF‐1) in the developing and mature central nervous system , 2003 .

[37]  A. Imberty,et al.  Heparan Sulfate/Heparin Oligosaccharides Protect Stromal Cell-derived Factor-1 (SDF-1)/CXCL12 against Proteolysis Induced by CD26/Dipeptidyl Peptidase IV* , 2004, Journal of Biological Chemistry.

[38]  R. Tan,et al.  Collagen/chitosan based two-compartment and bi-functional dermal scaffolds for skin regeneration. , 2015, Materials science & engineering. C, Materials for biological applications.

[39]  R. Horuk,et al.  Chemokine receptors. , 2001, Cytokine & growth factor reviews.

[40]  A. Zechariah,et al.  SDF-1 restores angiogenesis synergistically with VEGF upon LDL exposure despite CXCR4 internalization and degradation. , 2013, Cardiovascular research.