Vascular Endothelial Growth Factor Improves Physico-Mechanical Properties and Enhances Endothelialization of Poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/Poly(ε-caprolactone) Small-Diameter Vascular Grafts In vivo

Abstract

The combination of a natural polymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and a synthetic hydrophobic polymer poly(ε-caprolactone) (PCL) is promising for the preparation of biodegradable and biocompatible small-diameter vascular grafts for bypass surgery. However, physico-mechanical properties and endothelialization rate of PHBV/PCL grafts are poor. We suggested that incorporation of vascular endothelial growth factor (VEGF) into PHBV/PCL grafts may improve their physico-mechanical properties and enhance endothelialization. Here we compared morphology, physico-mechanical properties, and in vivo performance of electrospun small-diameter vascular grafts prepared from PHBV/PCL with and without VEGF. Structure of the graft surface and physico-mechanical properties were examined by scanning electron microscopy and universal testing machine, respectively. Grafts were implanted into rat abdominal aorta for 1, 3, and 6 months with the further histological, immunohistochemical, and immunofluorescence examination. PHBV/PCL grafts with and without VEGF were highly porous and consisted mostly of nanoscale and microscale fibers, respectively. Mean pore diameter and mean pore area were significantly lower in PHBV/PCL/VEGF compared to PHBV/PCL grafts (1.47 μm and 10.05 μm2; 2.63 μm and 47.13 μm2, respectively). Durability, elasticity, and stiffness of PHBV/PCL grafts with VEGF were more similar to internal mammary artery compared to those without, particularly 6 months postimplantation. Both qualitative examination and quantitative image analysis showed that three-fourths of PHBV/PCL grafts with VEGF were patent and had many CD31-, CD34-, and vWF-positive cells at their inner surface. However, all PHBV/PCL grafts without VEGF were occluded and had no or a few CD31-positive cells at the inner surface. Therefore, VEGF enhanced endothelialization and improved graft patency at all the time points in a rat abdominal aorta replacement model. In conclusion, PHBV/PCL grafts with VEGF have better biocompatibility and physico-mechanical properties compared to those without. Incorporation of VEGF improves graft patency and accelerates formation of endothelial cell monolayer.

Conjugation with RGD Peptides and Incorporation of Vascular Endothelial Growth Factor Are Equally Efficient for Biofunctionalization of Tissue-Engineered Vascular Grafts

“…We previously found that either conjugation with RGD peptides or incorporation of VEGF improve biophysical properties of electrospun PHBV/PCL small-diameter vascular grafts [22,23]. Modification with VEGF reduced mean pore area and mean fiber diameter in comparison with modification with RGD peptides [22,23].…”

“…Modification with VEGF reduced mean pore area and mean fiber diameter in comparison with modification with RGD peptides [22,23]. Grafts with incorporated VEGF consisted mostly of nanofibers; on the contrary, those with RGD were formed mostly of microfibers [22,23].…”

“…Modification with VEGF reduced mean pore area and mean fiber diameter in comparison with modification with RGD peptides [22,23]. Grafts with incorporated VEGF consisted mostly of nanofibers; on the contrary, those with RGD were formed mostly of microfibers [22,23]. As known, nanofibers enhance endothelial cell proliferation and adhesion as opposed to fibers with a larger diameter [29,30,31]; moreover, incorporation of VEGF allowed fabrication of the scaffolds with micro- to nanoscale topography similar to the natural extracellular matrix (ECM) [11,32,33].…”

“…As known, nanofibers enhance endothelial cell proliferation and adhesion as opposed to fibers with a larger diameter [29,30,31]; moreover, incorporation of VEGF allowed fabrication of the scaffolds with micro- to nanoscale topography similar to the natural extracellular matrix (ECM) [11,32,33]. Likewise, stress–strain curve, elasticity, and stiffness of the grafts modified with VEGF were closer to internal mammary artery in comparison with the RGD-modified grafts [22,23]. However, to the best of our knowledge, no studies compared in vivo efficiency of conjugation with RGD peptides and incorporation of VEGF in the same setting.…”

“…The following studies by our group demonstrated that either conjugation with RGD peptides or the incorporation of VEGF improves biocompatibility, physico-mechanical properties, and enhances endothelialization of electrospun PHBV/PCL vascular grafts [22,23]. However, in vivo comparative assessment of the mentioned modifications in either short- or long-term periods is still lacking.…”