Annals of Biomedical Engineering

, Volume 47, Issue 2, pp 354–365 | Cite as

Harnessing Macrophages for Vascularization in Tissue Engineering

  • Erika M. Moore
  • Jennifer L. WestEmail author


In this review, we explore the roles of macrophages both in vessel development and in vascularization of tissue engineered constructs. Upon the implantation of tissue engineered constructs into the body, macrophages respond, invade and orchestrate the host’s immune response. By altering their phenotype, macrophages can adopt a variety of roles. They can promote inflammation at the site of the implanted construct; they can also promote tissue repair. Macrophages support tissue repair by promoting angiogenesis through the secretion of pro-angiogenic cytokines and by behaving as support cells for nascent vasculature. Thus, the ability to manipulate the macrophage phenotype may yield macrophages capable of supporting vessel development. Moreover, macrophages are an easily isolated autologous cell source. For the generation of vascularized constructs outside of the body, these isolated macrophages can also be skewed to adopt a pro-angiogenic phenotype and enhance blood vessel development in the presence of endothelial cells. To assess the influence of macrophages on vessel development, both in vivo and in vitro models have been developed. Additionally, several groups have demonstrated the pro-angiogenic roles of macrophages in vascularization of tissue engineered constructs through the manipulation of macrophage phenotypes. This review comments on the roles of macrophages in promoting vascularization within these contexts.


Macrophages Vascularization Vessel development Macrophage phenotypes Tissue engineering 



The authors would like to acknowledge Chih-Wei Hsu for the use of his image (Fig. 5). The authors would also like to thank Dr. Botchwey for the use of Fig. 4: Reprinted from Ref. 29. Figure 3, Reprinted from Ref. 39. Funding was provided by National Science Foundation (Grant No. DGE-1644868), Foundation for the National Institutes of Health (Grant No. R01 HL097520).

Conflict of interest

The authors declare no conflicts of interest with regards to this manuscript.


  1. 1.
    Alvarez, M. M., J. C. Liu, G. Trujillo-de Santiago, et al. Delivery strategies to control inflammatory response: modulating M1-M2 polarization in tissue engineering applications. J. Control Release. 1:1–10, 2015. Scholar
  2. 2.
    Ambati, B. K., M. Nozaki, N. Singh, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 443(7114):993–997, 2006. Scholar
  3. 3.
    Armulik, A., A. Abramsson, and C. Betsholtz. Endothelial/pericyte interactions. Circ. Res. 97(6):512–523, 2005. Scholar
  4. 4.
    Arras, M., W. D. Ito, D. Scholz, B. Winkler, J. Schaper, and W. Schaper. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J. Clin. Invest. 101(1):40–50, 1998. Scholar
  5. 5.
    Awojoodu, A. O., M. E. Ogle, L. S. Sefcik, et al. Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis. Proc. Natl. Acad. Sci. USA 110(34):13785–13790, 2013. Scholar
  6. 6.
    Barnett, F. H., M. Rosenfeld, M. Wood, et al. Macrophages form functional vascular mimicry channels in vivo. Sci. Rep. 6:36659, 2016. Scholar
  7. 7.
    Brown, B. N., B. D. Ratner, S. B. Goodman, S. Amar, and S. F. Badylak. Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 33(15):3792–3802, 2012. Scholar
  8. 8.
    Cao, R., E. Brakenhielm, R. Pawliuk, et al. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat. Med. 9(5):548–553, 2003.Google Scholar
  9. 9.
    Daley, J. M., S. K. Brancato, A. A. Thomay, J. S. Reichner, and J. E. Albina. The phenotype of murine wound macrophages. J. Leukoc. Biol. 87(1):59–67, 2010. Scholar
  10. 10.
    Das, A., M. Sinha, S. Datta, et al. Monocyte and macrophage plasticity in tissue repair and regeneration. Am. J. Pathol. 185(10):2596–2606, 2015. Scholar
  11. 11.
    DeFalco, T., I. Bhattacharya, A. V. Williams, D. M. Sams, and B. Capel. Yolk-sac-derived macrophages regulate fetal testis vascularization and morphogenesis. Proc. Natl. Acad. Sci. 111(23):E2384–E2393, 2014. Scholar
  12. 12.
    DiPietro, L. A. Wound healing: the role of the macrophage and other immune cells. Shock. 4(4):233–240, 1995.Google Scholar
  13. 13.
    Dondossola, E., B. M. Holzapfel, S. Alexander, S. Filippini, D. W. Hutmacher, and P. Friedl. Examination of the foreign body response to biomaterials by nonlinear intravital microscopy. Nat. Biomed. Eng. 1(1):1–20, 2017. Scholar
  14. 14.
    Du, R., K. V. Lu, C. Petritsch, et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13(3):206–220, 2008. Scholar
  15. 15.
    Fantin, A., J. M. Vieira, G. Gestri, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116(5):829–840, 2010. Scholar
  16. 16.
    Fournier, G. A., G. A. Lutty, S. Watt, A. Fenselau, and A. Patz. A corneal micropocket assay for angiogenesis in the rat eye. Investig. Ophthalmol. Vis. Sci. 21(2):351–354, 1981.Google Scholar
  17. 17.
    Garash, R., A. Bajpai, B. M. Marcinkiewicz, and K. L. Spiller. Drug delivery strategies to control macrophages for tissue repair and regeneration. Exp. Biol. Med. 2016. Scholar
  18. 18.
    Geissmann, F., S. Jung, and D. R. Littman. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19(1):71–82, 2003. Scholar
  19. 19.
    Gerri, C., R. Marín-Juez, M. Marass, A. Marks, H.-M. Maischein, and D. Y. R. Stainier. Hif-1α regulates macrophage-endothelial interactions during blood vessel development in zebrafish. Nat. Commun. 8(May):15492, 2017. Scholar
  20. 20.
    Gordon, S., and P. R. Taylor. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5(12):953–964, 2005. Scholar
  21. 21.
    Griffith, L. G., and G. Naughton. Tissue engineering–current challenges and expanding opportunities. Science 295(5557):1009–1014, 2002. Scholar
  22. 22.
    Hasan, A., A. Paul, N. E. Vrana, et al. Microfluidic techniques for development of 3D vacularized tissue. Biomaterials 35(1):7308–7325, 2014. Scholar
  23. 23.
    Hibino, N., T. Yi, D. R. Duncan, et al. A critical role for macrophages in neovessel formation and the development of stenosis in tissue-engineered vascular grafts. Faseb J. 25(12):4253–4263, 2011. Scholar
  24. 24.
    Hsieh, J., T. Smith, V. Meli, T. Tran, E. Botvinick, and W. F. Liu. Differential regulation of macrophage inflammatory activation by fibrin and fibrinogen. Acta Biomater. 47:14–24, 2016. Scholar
  25. 25.
    Hsu, C. W., R. A. Poché, J. E. Saik, et al. Improved angiogenesis in response to localized delivery of macrophage-recruiting molecules. PLoS ONE 10(7):1–27, 2015. Scholar
  26. 26.
    Jetten, N., S. Verbruggen, M. J. Gijbels, M. J. Post, M. P. J. De Winther, and M. M. P. C. Donners. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 17(1):109–118, 2014. Scholar
  27. 27.
    Kappel, D. F. Organ donation in the United States—2014. J. Leg. Med. 36(1):7–16, 2015. Scholar
  28. 28.
    Koh, T. J., and L. A. DiPietro. Inflammation and wound healing: the role of the macrophage. Expert Rev. Mol. Med. 13:e23, 2011. Scholar
  29. 29.
    Krieger, J. R., M. E. Ogle, J. McFaline-Figueroa, C. E. Segar, J. S. Temenoff, and E. A. Botchwey. Spatially localized recruitment of anti-inflammatory monocytes by SDF-1α-releasing hydrogels enhances microvascular network remodeling. Biomaterials 77:280–290, 2016. Scholar
  30. 30.
    Kumar, A. H. S., K. Martin, E. C. Turner, et al. Role of CX3CR1 receptor in monocyte/macrophage driven neovascularization. PLoS ONE. 2013. Scholar
  31. 31.
    Lee, K. Y. Alginate: properties and biomedical applications. Prog. Polym. Sci. 37(1):106–126, 2012. Scholar
  32. 32.
    Leibovich, S. J., P. J. Polverini, H. M. Shepard, D. M. Wiseman, V. Shively, and N. Nuseir. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 329(6140):630–632, 1987. Scholar
  33. 33.
    Mantovani, A., S. K. Biswas, M. R. Galdiero, A. Sica, and M. Locati. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229(2):176–185, 2013. Scholar
  34. 34.
    Mantovani, A., S. Sozzani, M. Locati, P. Allavena, and A. Sica. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M 2 mononuclear phagocytes. Trends Immunol. 23(11):549–555, 2002.Google Scholar
  35. 35.
    Martinez, F. O., and S. Gordon. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6:13, 2014. Scholar
  36. 36.
    Moldovan, N. I., P. J. Goldschmidt-Clermont, J. Parker-Thornburg, S. D. Shapiro, and P. E. Kolattukudy. Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium. Circ. Res. 87(5):378–384, 2000. Scholar
  37. 37.
    Moon, J. J., and J. L. West. Vascularization of engineered tissues: approaches to promote angio-genesis in biomaterials. Curr. Top. Med. Chem. 8(4):300–310, 2008. Scholar
  38. 38.
    Moore, E. M., V. Suresh, G. Ying, and J. L. West. M0 and M2 macrophages enhance vascularization of tissue engineering scaffolds. Regen. Eng. Transl. Med. 2018. Scholar
  39. 39.
    Moore, E. M., G. Ying, and J. L. West. Macrophages influence vessel formation in 3D bioactive hydrogels. Adv. Biosyst. 2017. Scholar
  40. 40.
    Murray, P. J., J. E. Allen, S. K. Biswas, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41(1):14–20, 2014. Scholar
  41. 41.
    Nathan, C. F. Secretory products of macrophage. J. Clin. Invest. 79(February):319–326, 1987. Scholar
  42. 42.
    Nomi, M., A. Atala, P. De Coppi, and S. Soker. Principals of neovascularization for tissue engineering. Mol. Aspects Med. 23(6):463–483, 2002. Scholar
  43. 43.
    Novak, M. L., and T. J. Koh. Phenotypic transitions of macrophages orchestrate tissue repair. Am. J. Pathol. 183(5):1352–1363, 2013. Scholar
  44. 44.
    Nsiah, B. A., E. M. Moore, L. C. Roudsari, N. K. Virdone, and J. L. West. Angiogenesis in Hydrogel Biomaterials. Durham: Duke University, 2015. Scholar
  45. 45.
    Nucera, S., D. Biziato, and M. de Palma. The interplay between macrophages and angiogenesis in development, tissue injury and regeneration. Int. J. Dev. Biol. 55(4–5):495–503, 2011. Scholar
  46. 46.
    Okuno, Y., A. Nakamura-Ishizu, K. Kishi, T. Suda, and Y. Kubota. Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing. Blood 117(19):5264–5272, 2011. Scholar
  47. 47.
    Peters, E. B., N. Christoforou, E. Moore, J. L. West, and G. A. Truskey. CD45 + cells present within mesenchymal stem cell populations affect network formation of blood-derived endothelial outgrowth cells. Biores. Open Access. 4:75–88, 2015. Scholar
  48. 48.
    Phelps, E. A., N. Landazuri, P. M. Thule, W. R. Taylor, and A. J. Garcia. Bioartificial matrices for therapeutic vascularization. Proc. Natl. Acad. Sci. 107(8):3323–3328, 2010. Scholar
  49. 49.
    Poché, R. A., J. E. Saik, J. L. West, and M. E. Dickinson. The mouse cornea as a transplantation site for live imaging of engineered tissue constructs. Cold Spring Harb. Protoc. 5(4):1–11, 2010. Scholar
  50. 50.
    Polverini, P. J., P. S. Cotran, M. A. Gimbrone, and E. R. Unanue. Activated macrophages induce vascular proliferation. Nature 269(5631):804–806, 1977. Scholar
  51. 51.
    Przaeres, P., V. Almeida, L. Lousado, et al. Macrophages generate pericytes in the developing brain macrophages generate pericytes in the developing brain. Cell Mol. Neurobiol. 1:1–10, 2017. Scholar
  52. 52.
    Rehman, J., J. Li, C. M. Orschell, and K. L. March. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107(8):1164–1169, 2003. Scholar
  53. 53.
    Richardson, T. P., M. C. Peters, A. B. Ennett, and D. J. Mooney. Access polymeric system for dual growth factor delivery. Nat. Biotechnol. 19:1029–1034, 2001.Google Scholar
  54. 54.
    Rohde, E., C. Malischnik, D. Thaler, et al. Blood monocytes mimic endothelial progenitor cells. Stem Cells. 24(2):357–367, 2006. Scholar
  55. 55.
    Rouwkema, J., N. C. Rivron, and C. A. van Blitterswijk. Vascularization in tissue engineering. Trends Biotechnol. 26(8):434–441, 2008. Scholar
  56. 56.
    Rymo, S. F., H. Gerhardt, F. W. Sand, R. Lang, A. Uv, and C. Betsholtz. A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures. PLoS ONE. 2011. Scholar
  57. 57.
    Sidky, Y. A., and E. C. Borden. Inhibition of angiogenesis by interferons: effects on tumor-and lymphocyte-induced vascular responses. Cancer Res. 47(19):5155–5161, 1987.Google Scholar
  58. 58.
    Spiller, K. L., R. R. Anfang, K. J. Spiller, et al. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials 35(15):4477–4488, 2014. Scholar
  59. 59.
    Spiller, K. L., S. Nassiri, C. E. Witherel, et al. Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds. Biomaterials 37:194–207, 2015. Scholar
  60. 60.
    Sunderkötter, C., M. Goebeler, K. Schulze-Osthoff, R. Bhardwaj, and C. Sorg. Macrophage-derived angiogenesis factors. Pharmacol. Ther. 51(2):195–216, 1991. Scholar
  61. 61.
    Takemura, R., and Z. Werb. Secretory products of macrophages and their physiological functions. Am. J. Physiol. 246(1 Pt 1):C1–C9, 1984.Google Scholar
  62. 62.
    Tang, N., L. Wang, J. Esko, et al. Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6(5):485–495, 2004. Scholar
  63. 63.
    Tattersall, I. W., J. Du, Z. Cong, et al. In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment. Angiogenesis 19(2):201–215, 2016. Scholar
  64. 64.
    Von Tell, D., A. Armulik, and C. Betsholtz. Pericytes and vascular stability. Exp. Cell Res. 312(5):623–629, 2006. Scholar
  65. 65.
    Wynn, T. A. A., and K. M. M. Vannella. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44(3):450–462, 2016. Scholar
  66. 66.
    Yamamoto, S., M. Muramatsu, E. Azuma, et al. A subset of cerebrovascular pericytes originates from mature macrophages in the very early phase of vascular development in CNS. Sci. Rep. 1:1–16, 2017. Scholar

Copyright information

© Biomedical Engineering Society 2018

Authors and Affiliations

  1. 1.Department of Materials Science and EngineeringUniversity of FloridaGainesvilleUSA
  2. 2.Department of Biomedical EngineeringDuke UniversityDurhamUSA

Personalised recommendations