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

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Abstract

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.

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References

  1. Au, P., J. Tam, D. Fukumura, and R. K. Jain. Small blood vessel engineering. Methods Mol. Med. 140:183–195, 2007.

    Article  CAS  PubMed  Google Scholar 

  2. Bae, H., A. S. Puranik, R. Gauvin, F. Edalat, B. Carrillo-Conde, N. A. Peppas, and A. Khademhosseini. Building vascular networks. Sci. Transl. Med. 4:160ps123, 2012.

    Article  Google Scholar 

  3. Brown, A. L., W. Farhat, P. A. Merguerian, G. J. Wilson, A. E. Khoury, and K. A. Woodhouse. 22 week assessment of bladder acellular matrix as a bladder augmentation material in a porcine model. Biomaterials 23:2179–2190, 2002.

    Article  CAS  PubMed  Google Scholar 

  4. Beqaj, S. H., J. L. Donovan, D. B. Liu, D. A. Harrington, S. A. Alpert, and E. Y. Cheng. Role of basic fibroblast growth factor in the neuropathic bladder phenotype. J. Urol. 174:1699–1703, 2005.

    Article  CAS  PubMed  Google Scholar 

  5. Chen, F., J. J. Yoo, and A. Atala. Acellular collagen matrix as a possible “off the shelf” biomaterial for urethral repair. Urology 54:407–410, 1999.

    Article  CAS  PubMed  Google Scholar 

  6. Du, Y., D. Cropek, M. R. Kaazempur Mofrad, E. J. Weinberg, A. Khademhosseini, and J. Borenstein. Microfluidic systems for engineering vascularized tissue constructs. In: Microfluidics for Biological Applications, edited by W. C. Tian, and E. Finehout. New York: Springer, 2009, pp. 223–240.

    Google Scholar 

  7. Ferrara, N., and T. Davis-Smyth. The biology of vascular endothelial growth factor. Endocr. Rev. 18:4–25, 1997.

    Article  CAS  PubMed  Google Scholar 

  8. Geng, H., H. Song, J. Qi, and D. Cui. Sustained release of VEGF from PLGA nanoparticles embedded thermo-sensitive hydrogel in full-thickness porcine bladder acellular matrix. Nanoscale Res. Lett. 6:312, 2011.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gilbert, T. W., T. L. Sellaro, and S. F. Badylak. Decellularization of tissues and organs. Biomaterials 27:3675–3683, 2006.

    CAS  PubMed  Google Scholar 

  10. Greenberg, J. I., D. J. Shields, S. G. Barillas, L. M. Acevedo, E. Murphy, J. Huang, L. Scheppke, C. Stockmann, R. S. Johnson, N. Angle, and D. A. Cheresh. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456:809–813, 2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kannan, R. Y., H. J. Salacinski, K. Sales, P. Butler, and A. M. Seifalian. The roles of tissue engineering and vascularisation in the development of micro-vascular networks: a review. Biomaterials 26:1857–1875, 2005.

    Article  CAS  PubMed  Google Scholar 

  12. Kanematsu, A., S. Yamamoto, T. Noguchi, M. Ozeki, Y. Tabata, and O. Ogawa. Bladder regeneration by bladder acellular matrix combined with sustained release of exogenous growth factor. J. Urol. 170:1633–1638, 2003.

    Article  CAS  PubMed  Google Scholar 

  13. Kanematsu, A., S. Yamamoto, M. Ozeki, T. Noguchi, I. Kanatani, O. Ogawa, and Y. Tabata. Collagenous matrices as release carriers of exogenous growth factors. Biomaterials 25:4513–4520, 2004.

    Article  CAS  PubMed  Google Scholar 

  14. Laschke, M. W., Y. Harder, M. Amon, I. Martin, J. Farhadi, A. Ring, N. Torio-Padron, R. Schramm, M. Rucker, D. Junker, J. M. Haufel, C. Carvalho, M. Heberer, G. Germann, B. Vollmar, and M. D. Menger. Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. Tissue Eng. 12:2093–2104, 2006.

    Article  CAS  PubMed  Google Scholar 

  15. Loai, Y., H. Yeger, C. Coz, R. Antoon, S. S. Islam, K. Moore, and W. A. Farhat. Bladder tissue engineering: tissue regeneration and neovascularization of ha-vegf-incorporated bladder acellular constructs in mouse and porcine animal models. J. Biomed. Mater. Res. A 94:1205–1215, 2010.

    PubMed  Google Scholar 

  16. Merguerian, P. A., P. P. Reddy, D. J. Barrieras, G. J. Wilson, K. Woodhouse, D. J. Bagli, G. A. McLorie, and A. E. Khoury. Acellular bladder matrix allografts in the regeneration of functional bladders: evaluation of large-segment (>24 cm) substitution in a porcine model. BJU Int. 85:894–898, 2000.

    Article  CAS  PubMed  Google Scholar 

  17. Mondalek, F. G., R. A. Ashley, C. C. Roth, Y. Kibar, N. Shakir, M. A. Ihnat, K. M. Fung, B. P. Grady, B. P. Kropp, and H. K. Lin. Enhanced angiogenesis of modified porcine small intestinal submucosa with hyaluronic acid-poly(lactide-co-glycolide) nanoparticles: from fabrication to preclinical validation. J. Biomed. Mater. Res. A 94:712–719, 2010.

    PubMed  Google Scholar 

  18. Nillesen, S. T., P. J. Geutjes, R. Wismans, J. Schalkwijk, W. F. Daamen, and T. H. van Kuppevelt. Increased angiogenesis and blood vessel maturation in acellular collagen-heparin scaffolds containing both FGF2 and VEGF. Biomaterials 28:1123–1131, 2007.

    Article  CAS  PubMed  Google Scholar 

  19. Novosel, E. C., C. Kleinhans, and P. J. Kluger. Vascularization is the key challenge in tissue engineering. Adv. Drug Deliv. Rev. 63:300–311, 2011.

    Article  CAS  PubMed  Google Scholar 

  20. Pike, D. B., S. Cai, K. R. Pomraning, M. A. Firpo, R. J. Fisher, X. Z. Shu, G. D. Prestwich, and R. A. Peattie. Heparin-regulated release of growth factors in vitro and angiogenic response in vivo to implanted hyaluronan hydrogels containing VEGF and bFGF. Biomaterials 27:5242–5251, 2006.

    Article  CAS  PubMed  Google Scholar 

  21. Rickert, D., M. A. Moses, A. Lendlein, S. Kelch, and R. P. Franke. The importance of angiogenesis in the interaction between polymeric biomaterials and surrounding tissue. Clin. Hemorheol. Microcirc. 28:175–181, 2003.

    CAS  PubMed  Google Scholar 

  22. Roth, C. C., F. G. Mondalek, Y. Kibar, R. A. Ashley, C. H. Bell, J. A. Califano, S. V. Madihally, D. Frimberger, H. K. Lin, and B. P. Kropp. Bladder regeneration in a canine model using hyaluronic acid-poly (lactic-co-glycolic-acid) nanoparticle modified porcine small intestinal submucosa. BJU Int. 108:148–155, 2011.

    Article  PubMed  Google Scholar 

  23. Rivron, N. C., J. J. Liu, J. Rouwkema, J. de Boer, and C. A. van Blitterswijk. Engineering vascularised tissues in vitro. Eur. Cell Mater. 15:27–40, 2008.

    Article  CAS  PubMed  Google Scholar 

  24. Safi, Jr., J., A. F. DiPaula, Jr., T. Riccioni, J. Kajstura, G. Ambrosio, L. C. Becker, P. Anversa, and M. C. Capogrossi. Adenovirus-mediated acidic fibroblast growth factor gene transfer induces angiogenesis in the nonischemic rabbit heart. Microvasc. Res. 58:238–249, 1999.

    Article  CAS  PubMed  Google Scholar 

  25. Schmidt, C., D. Bezuidenhout, L. Higham, P. Zilla, and N. H. Davies. Induced chronic hypoxia negates the pro-angiogenic effect of surface immobilized heparin in a polyurethane porous scaffold. J. Biomed. Mater. Res. A 98:621–628, 2011.

    Article  PubMed  Google Scholar 

  26. Waring, J. V., and I. R. Wendt. Effects of streptozotocin-induced diabetes mellitus on intracellular calcium and contraction of longitudinal smooth muscle from rat urinary bladder. J. Urol. 163:323–330, 2000.

    Article  CAS  PubMed  Google Scholar 

  27. Youssif, M., H. Shiina, S. Urakami, C. Gleason, L. Nunes, M. Igawa, H. Enokida, E. A. Tanagho, and R. Dahiya. Effect of vascular endothelial growth factor on regeneration of bladder acellular matrix graft: histologic and functional evaluation. Urology 66:201–207, 2005.

    Article  PubMed  Google Scholar 

  28. Yancopoulos, G. D., S. Davis, N. W. Gale, J. S. Rudge, S. J. Wiegand, and J. Holash. Vascular-specific growth factors and blood vessel formation. Nature 407:242–248, 2000.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was mainly supported by a grant from the National Nature Science Foundation of China (No. 81170639).

Conflict of interest

The authors have no conflict of interest to disclose.

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    Authors and Affiliations

    1. Department of Pediatric Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China

      Xincheng Jiang, Qianwei Xiong, Guofeng Xu, Houwei Lin, Xiaoliang Fang, Maosheng Xu & Hongquan Geng

    2. Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Bio-Nano Science and Engineering, Institute of Mic-Nano Science and Technology, Shanghai Jiao Tong University, Shanghai, China

      Daxiang Cui

    3. Department of Urology, Children’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China

      Fang Chen

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    1. Xincheng Jiang
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    Correspondence to Hongquan Geng.

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    Associate Editor Mona Kamal Marei oversaw the review of this article.

    Xincheng Jiang and Qianwei Xiong contributed equally to this work.

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    Jiang, X., Xiong, Q., Xu, G. et al. VEGF-Loaded Nanoparticle-Modified BAMAs Enhance Angiogenesis and Inhibit Graft Shrinkage in Tissue-Engineered Bladder. Ann Biomed Eng 43, 2577–2586 (2015). https://doi.org/10.1007/s10439-015-1284-9

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