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An Injectable Nanocomposite Hydrogel for Potential Application of Vascularization and Tissue Repair

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In this contribution, an injectable hydrogel was developed with chitosan, gelatin, β-glycerphosphate and Arg-Gly-Asp (RGD) peptide: this hydrogel is liquid in room temperature and rapidly gels at 37 °C; RGD peptide promises better growth microenvironment for various cells, especially endothelial cells (EC), smooth muscle cells (SMC) and mesenchymal stem cells (MSC). Both stromal cell-derived factor-1 (SDF-1) nanoparticle and vascular endothelial growth factor (VEGF) nanoparticles were loaded in the injectable hydrogel to simulate the natural nanoparticles in the extracellular matrix (ECM) to promote angiogenesis. In vitro EC/SMC and MSC/SMC co-culture experiment indicated that the nanocomposite hydrogel accelerated constructing embryonic form of blood vessels, and chick embryo chorioallantoic membrane model demonstrated its ability of improving cells migration and blood vessel regeneration. We injected this nanocomposite hydrogel into rat myocardial infarction (MI) model and the results indicated that the rats heart function recovered better compared control group. We hope this injectable nanocomposite hydrogel may possess wider application in tissue engineering.

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  1. 1.

    Arai, A. E. Fuzzy or sharp borders of acute myocardial ischemia and infarction? JACC Cardiovasc. Imaging 8(12):1390–1392, 2015.

  2. 2.

    Auerbach, R., L. Kubai, D. Knighton, and J. Folkman. A simple procedure for the long-term cultivation of chicken embryos. Dev. Biol. 41(2):391–394, 1974.

  3. 3.

    Bruzauskaite, I., D. Bironaite, E. Bagdonas, and E. Bernotiene. Scaffolds and cells for tissue regeneration: different scaffold pore sizes-different cell effects. Cytotechnology 68(3):355–369, 2016.

  4. 4.

    Chen, L., J. A. Li, S. Wang, S. J. Zhu, C. Zhu, B. Y. Zheng, G. Yang, and S. K. Guan. Surface modification of the biodegradable cardiovascular stent material Mg–Zn–Y–Nd alloy via conjugating REDV peptide for better endothelialization. J. Mater. Res. 33(23):4123–4133, 2018.

  5. 5.

    Colazzo, F., F. Alrashed, P. Saratchandra, I. Carubelli, A. H. Chester, M. H. Yacoub, P. M. Taylor, and P. Somers. Shear stress and VEGF enhance endothelial differentiation of human adipose-derived stem cells. Growth Factors 32(5):139–149, 2014.

  6. 6.

    Cosme, J., P. P. Liu, and A. O. Gramolini. The cardiovascular exosome: current perspectives and potential. Proteomics 13(10–11):1654–1659, 2013.

  7. 7.

    Drury, J. L., and D. J. Mooney. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials 24(24):4337–4351, 2003.

  8. 8.

    Ekblom, P. Role of extracellular matrix in animal development-an introduction. Experientia 51(9–10):851–852, 1995.

  9. 9.

    Fang, Z., J. F. Wang, X. F. Yang, Q. Sun, Y. Jia, H. R. Liu, T. F. Xi, and S. K. Guan. Adsorption of arginine, glycine and aspartic acid on Mg and Mg-based alloy surfaces: a first-principles study. Appl. Surf. Sci. 409:149–155, 2017.

  10. 10.

    Fang, Z., J. F. Wang, S. J. Zhu, X. F. Yang, Y. Jia, Q. Sun, and S. K. Guan. A DFT study of the adsorption of short peptides on Mg and Mg-based alloy surfaces. Phys. Chem. Chem. Phys. 20(5):3602–3607, 2018.

  11. 11.

    Fish, J. E., and J. D. Wythe. The molecular regulation of arteriovenous specification and maintenance. Dev. Dyn. 244(3):391–409, 2015.

  12. 12.

    Fonarow, G. C. Refining classification of heart failure based on ejection fraction. JACC Heart Fail 5(11):808–809, 2017.

  13. 13.

    Freestone, B., S. Krishnamoorthy, and G. Y. H. Lip. Assessment of endothelial dysfunction. Expert Rev. Cardiovasc. Ther. 8:557–571, 2010.

  14. 14.

    Gao, Y., Z. Lu, C. Chen, X. Cui, Y. Liu, T. Zheng, X. Jiang, C. Zeng, D. Quan, and Q. Wang. Mesenchymal stem cells and endothelial progenitor cells accelerate intra-aneurysmal tissue organization after treatment with SDF-1α-coated coils. Neurol. Res. 38(4):333–341, 2016.

  15. 15.

    He, D., A. S. Zhao, H. Su, Y. Zhang, Y. N. Wang, D. Luo, Y. Gao, J. A. Li, and P. Yang. An Injectable scaffold based on temperature responsive hydrogel and factors loaded nano-particles for potential application of vascularization in tissue engineering. J. Biomed. Mater. Res. Part A 107A:2123–2134, 2019.

  16. 16.

    Hibbert, B., S. Olsen, and E. O’Brien. Involvement of progenitor cells in vascular repair. Trends Cardiovasc. Med. 13(8):322–326, 2003.

  17. 17.

    Kemppainen, J. M., and S. J. Hollister. Tailoring the mechanical properties of 3D-designed poly(glycerol sebacate) scaffolds for cartilage applications. Biomed. Mater. Res. A 94A(1):9–18, 2010.

  18. 18.

    Kuo, K. C., R. Z. Lin, H. W. Tien, P. Y. Wu, Y. C. Li, J. M. Melero-Martin, and Y. C. Chen. Bioengineering vascularized tissue constructs using an injectable cell-laden enzymatically crosslinked collagen hydrogel derived from dermal extracellular matrix. Acta Biomater. 27:151–166, 2015.

  19. 19.

    Kvam, G., H. Dahle, J. E. Nordrehaug, T. I. Randa, and T. Tillung. The shortening fraction of myocardial fibers and its layered distribution, as derived from cine-MR imaged left ventriculograms. An approach for evaluating globar left ventricular function. Acta Radiol. 38(3):391–399, 1997.

  20. 20.

    Leblanc, A. J., L. Krishnan, C. J. Sullivan, S. K. Williams, and J. B. Hoying. Microvascular repair: post-angiogenesis vascular dynamics. Microcirculation 19(8):676–695, 2012.

  21. 21.

    Li, L. Q., and C. Cleo. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng. Part B 19(6):485–502, 2013.

  22. 22.

    Li, J. A., G. C. Li, K. Zhang, Y. Z. Liao, P. Yang, M. F. Maitz, and N. Huang. Co-culture of vascular endothelial cells and smooth muscle cells by hyaluronic acid micro-pattern on titanium surface. Appl. Surf. Sci. 273:24–31, 2013.

  23. 23.

    Li, J. A., K. Zhang, P. Yang, L. L. Wu, J. L. Chen, A. S. Zhao, G. C. Li, and N. Huang. Research of smooth muscle cells response to fluid flow shear stress by hyaluronic acid micro-pattern on a titanium surface. Exp. Cell Res. 319(17):2663–2672, 2013.

  24. 24.

    Li, J. A., K. Zhang, Y. Xu, J. Chen, P. Yang, Y. C. Zhao, A. S. Zhao, and N. Huang. A novel co-culture models of human vascular endothelial cells and smooth muscle cells by hyaluronic acid micro-pattern on titanium surface. J. Biomed. Mater. Res. Part A 102A:1950–1960, 2014.

  25. 25.

    Li, J. A., K. Zhang, H. Q. Chen, T. Liu, P. Yang, Y. C. Zhao, and N. Huang. A novel coating of type IV collagen and hyaluronic acid on stent material-titanium for promoting smooth muscle cells contractile phenotype. Mater. Sci. Eng. C 38:235–243, 2014.

  26. 26.

    Li, J. A., K. Zhang, J. J. Wu, Y. Z. Liao, P. Yang, and N. Huang. Co-culture of endothelial cells and patterned smooth muscle cells on titanium: construction with high density of endothelial cells and low density of smooth muscle cells. Biochem. Biophys. Res. Commun. 456:555–561, 2015.

  27. 27.

    Li, J. A., K. Zhang, W. Y. Ma, F. Wu, P. Yang, Z. K. He, and N. Huang. Investigation of enhanced hemocompatibility and tissue compatibility associated with multi-functional coating based on hyaluronic acid and type IV collagen. Regener. Biomater. 3(3):149–157, 2016.

  28. 28.

    Li, J. A., W. Qin, K. Zhang, F. Wu, P. Yang, Z. K. He, A. S. Zhao, and N. Huang. Controlling mesenchymal stem cells differentiate into contractile smooth muscle cells on a TiO2 micro/nano interface: towards benign pericytes environment for endothelialization. Colloids Surf. B 145:410–419, 2016.

  29. 29.

    Li, J. A., F. Wu, K. Zhang, Z. K. He, D. Zou, X. Luo, Y. H. Fan, P. Yang, A. S. Zhao, and N. Huang. Controlling molecular weight of hyaluronic acid conjugated on amine-rich surface: towards better multifunctional biomaterials for cardiovascular implants. ACS Appl. Mater. Interfaces. 9:30343–30358, 2017.

  30. 30.

    Liu, X., X. M. Wang, A. Horii, X. J. Wang, L. Qiao, S. G. Zhang, and F. Z. Cui. In vivo studies on angiogenic activity of two designer self-assembling peptide scaffold hydrogels in the chicken embryo chorioallantoic membrane. Nanoscale 4:2720–2727, 2012.

  31. 31.

    Liu, Y., F. Luo, B. R. Wang, H. Q. Li, Y. Xu, X. L. Liu, L. Shi, X. L. Lu, W. C. Xu, L. Lu, Y. Qin, Q. Y. Xiang, and Q. Z. Liu. STAT3-regulated exosomal miR-21 promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells. Cancer Lett. 370(1):125–135, 2016.

  32. 32.

    Mathivanan, S., H. Ji, and R. J. Simpson. Exosomes: extracellular organelles important in intercellular communication. J. Proteomics 73(10):1907–1920, 2010.

  33. 33.

    Melchiorri, A. J., B. N. B. Nguyen, and J. P. Fisher. Mesenchymal stem cells: roles and relationships in vascularization. Tissue Eng. Part B 20(3):218–228, 2014.

  34. 34.

    Min, P. K., and G. Sharon. Harnessing developmental processes for vascular engineering and regeneration. Development 141(14):2760–2769, 2014.

  35. 35.

    Mungadi, I. A. Bioengineering tissue for organ repair, regeneration, and renewal. J. Surg. Tech. Case Rep. 4(2):77–78, 2012.

  36. 36.

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

  37. 37.

    Patra, S., M. Remy, A. R. Ray, B. Brouillaud, J. Amedee, B. Gupta, and L. Bordenave. A novel route to polycaprolactone scaffold for vascular tissue engineering. Biomaterials and Tissue Engineering 3:1–10, 2003.

  38. 38.

    Potente, M., H. Gerhardt, and P. Carmeliet. Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887, 2011.

  39. 39.

    Sharma, P., L. Schiapparelli, and H. T. Cline. Exosomes function in cell–cell communication during brain circuit development. Curr. Opin. Neurobiol. 23(6):997–1004, 2013.

  40. 40.

    Simpson, R. J., J. W. E. Lim, R. L. Moritz, and S. Mathivanan. Exosomes: proteomic insights and diagnostic potential. Expert Rev. Proteomics 6(3):267–283, 2009.

  41. 41.

    Sivashanmugam, A., R. A. Kumar, M. V. Priya, S. V. Nair, and R. Jayakumar. An overview of injectable polymeric hydrogels for tissue engineering. Eur. Polym. J. 72:543–565, 2015.

  42. 42.

    Tousoulis, D., M. Koutsogiannis, N. Papageorgiou, G. Siasos, C. Antoniades, E. Tsiamis, and C. Stefanadis. Endothelial dysfunction: potential clinical implications. Minerva Med. 101(4):271–283, 2010.

  43. 43.

    Tseliou, E., W. X. Liu, J. Valle, B. M. Sun, M. Mirotsou, and E. Marban. Newt exosomes are bioactive on mammalian heart, enhancing proliferation of rat cardiomyocytes and improving recovery after myocardial infarction. Circulation 132(S3):15925, 2015.

  44. 44.

    Tu, Q. F., Y. Zhang, D. X. Ge, J. Wu, and H. Q. Chen. Novel tissue-engineered vascular patches based on decellularized canine aortas and their recellularization in vitro. Appl. Surf. Sci. 255(2):282–285, 2008.

  45. 45.

    Wood, J. How cells bind biomaterials determines response: biomaterials. Mater. Today 8(6):16–19, 2005.

  46. 46.

    Wu, F., J. A. Li, K. Zhang, Z. K. He, P. Yang, D. Zou, and N. Huang. Multi-functional coating based on hyaluronic acid and dopamine conjugate for potential application on surface modification of cardiovascular implanted devices. ACS Appl. Mater. Interfaces. 8(1):109–121, 2016.

  47. 47.

    Xu, Q. H., Z. Zhang, C. S. Xiao, C. L. He, and X. S. Chen. Injectable polypeptide hydrogel as biomimetic scaffolds with tunable bioactivity and controllable cell adhesion. Biomacromol 18:1411–1418, 2017.

  48. 48.

    Zhang, K., Z. Q. Shi, J. K. Zhou, Q. Xing, S. S. Ma, Q. H. Li, Y. T. Zhang, M. H. Yao, X. F. Wang, Q. Li, J. A. Li, and F. X. Guan. Potential application of an injectable hydrogel scaffold loaded with mesenchymal stem cells for treating traumatic brain injury. J. Mater. Chem. B 6:2982–2992, 2018.

  49. 49.

    Zhou, J. K., K. Zhang, S. S. Ma, T. F. Liu, M. H. Yao, J. A. Li, X. F. Wang, and F. X. Guan. Preparing an injectable hydrogel with sodium alginate and type I collagen to create better MSCs growth microenvironment. e-Polymer 19:87–91, 2019.

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We appreciated the financial support of the National Natural Science Foundation of China (NSFC 81771988), Key Project and Special Foundation of Research, Development and Promotion in Henan province (No. 182102310076), and Top Doctor Program of Zhengzhou University (No. 32210475).

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The authors declare that they have no conflict of interest.

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Correspondence to An-sha Zhao or Jing-an Li.

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Yilei Ding and An-sha Zhao are joint-first-authors.

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Ding, Y., Zhao, A., Liu, T. et al. An Injectable Nanocomposite Hydrogel for Potential Application of Vascularization and Tissue Repair. Ann Biomed Eng (2020). https://doi.org/10.1007/s10439-020-02471-7

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  • Tissue repair and regeneration
  • Vascularization
  • Injectable nanocomposite hydrogel
  • Nanoparticles