VEGF-Loaded Nanoparticle-Modified BAMAs Enhance Angiogenesis and Inhibit Graft Shrinkage in Tissue-Engineered Bladder

Insufficient angiogenesis is a common problem in bladder tissue engineering and is believed to be a major factor responsible for graft shrinkage. In this study, we investigated the use of bladder acellular matrix allografts (BAMAs) modified with vascular endothelial growth factor (VEGF)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for the long-term sustained release of VEGF to enhance blood supply and inhibit graft shrinkage in a rabbit model of bladder reconstruction. Rabbits underwent partial bladder cystectomy using a 2 × 3 cm BAMA modified with VEGF-loaded PLGA NPs in the experimental group, while no modification was used in the control. Histology and immunohistochemical analyses showed that urothelium, smooth muscle fibers and blood vessels were formed in both groups at 4 and 12 weeks postoperatively. The microvessel density in the experiment group was significantly higher than that in control and the contracture rate declined to 27%. In vitro functional experiments indicated that the characteristics of regenerated bladders were similar to native bladders. The VEGF release from BAMA in vivo was almost 83% within 3 months. Our data demonstrated the effectiveness of VEGF-loaded PLGA NPs-modified BAMAs to enhance neovascularization and solve the problems of insufficient angiogenesis and graft shrinkage associated with bladder tissue engineering.

[1]  C. Gleason,et al.  Effect of vascular endothelial growth factor on regeneration of bladder acellular matrix graft: histologic and functional evaluation. , 2005, Urology.

[2]  H. Yeger,et al.  Bladder tissue engineering: tissue regeneration and neovascularization of HA-VEGF-incorporated bladder acellular constructs in mouse and porcine animal models. , 2010, Journal of biomedical materials research. Part A.

[3]  I. Wendt,et al.  Effects of streptozotocin-induced diabetes mellitus on intracellular calcium and contraction of longitudinal smooth muscle from rat urinary bladder. , 2000, The Journal of urology.

[4]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[5]  A Lendlein,et al.  The importance of angiogenesis in the interaction between polymeric biomaterials and surrounding tissue. , 2003, Clinical hemorheology and microcirculation.

[6]  Hua Song,et al.  Sustained release of VEGF from PLGA nanoparticles embedded thermo-sensitive hydrogel in full-thickness porcine bladder acellular matrix , 2011, Nanoscale research letters.

[7]  Stephen F Badylak,et al.  Decellularization of tissues and organs. , 2006, Biomaterials.

[8]  P. Merguerian,et al.  22 week assessment of bladder acellular matrix as a bladder augmentation material in a porcine model. , 2002, Biomaterials.

[9]  K. Fung,et al.  Enhanced angiogenesis of modified porcine small intestinal submucosa with hyaluronic acid-poly(lactide-co-glycolide) nanoparticles: from fabrication to preclinical validation. , 2010, Journal of biomedical materials research. Part A.

[10]  J. Schalkwijk,et al.  Increased angiogenesis and blood vessel maturation in acellular collagen-heparin scaffolds containing both FGF2 and VEGF. , 2007, Biomaterials.

[11]  S. Madihally,et al.  Bladder regeneration in a canine model using hyaluronic acid‐poly(lactic‐co‐glycolic‐acid) nanoparticle modified porcine small intestinal submucosa , 2011, BJU international.

[12]  Yasuhiko Tabata,et al.  Collagenous matrices as release carriers of exogenous growth factors. , 2004, Biomaterials.

[13]  Esther Novosel,et al.  Vascularization is the key challenge in tissue engineering. , 2011, Advanced drug delivery reviews.

[14]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[15]  Alexander M Seifalian,et al.  The roles of tissue engineering and vascularisation in the development of micro-vascular networks: a review. , 2005, Biomaterials.

[16]  D. Bezuidenhout,et al.  Induced chronic hypoxia negates the pro-angiogenic effect of surface immobilized heparin in a polyurethane porous scaffold. , 2011, Journal of biomedical materials research. Part A.

[17]  Jianhua Huang,et al.  A Role for VEGF as a Negative Regulator of Pericyte Function and Vessel Maturation , 2008, Nature.

[18]  Robert J Fisher,et al.  Heparin-regulated release of growth factors in vitro and angiogenic response in vivo to implanted hyaluronan hydrogels containing VEGF and bFGF. , 2006, Biomaterials.

[19]  A. Atala,et al.  Acellular collagen matrix as a possible "off the shelf" biomaterial for urethral repair. , 1999, Urology.

[20]  D. Harrington,et al.  Role of basic fibroblast growth factor in the neuropathic bladder phenotype. , 2005, The Journal of urology.

[21]  Y. Tabata,et al.  Bladder regeneration by bladder acellular matrix combined with sustained release of exogenous growth factor. , 2003, The Journal of urology.

[22]  Ivan Martin,et al.  Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. , 2006, Tissue engineering.

[23]  Wei-Cheng Tian,et al.  Microfluidics for Biological Applications , 2008 .

[24]  C. V. van Blitterswijk,et al.  Engineering vascularised tissues in vitro. , 2008, European cells & materials.

[25]  L. Becker,et al.  Adenovirus-mediated acidic fibroblast growth factor gene transfer induces angiogenesis in the nonischemic rabbit heart. , 1999, Microvascular research.

[26]  A. Khademhosseini,et al.  Building Vascular Networks , 2012, Science Translational Medicine.

[27]  R. Jain,et al.  Small blood vessel engineering. , 2007, Methods in molecular medicine.

[28]  Wei-Chang Tian,et al.  Microfluidic Systems for Engineering Vascularized Tissue Constructs , 2008 .

[29]  P. Merguerian,et al.  Acellular bladder matrix allografts in the regeneration of functional bladders: evaluation of large‐segment (> 24 cm2) substitution in a porcine model , 2000, BJU international.