Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Vascularization in 3D printed tissues: emerging technologies to overcome longstanding obstacles

1 Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA
2 Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, MA 02139
† These two authors contributed equally.

Special Issues: 3D Bioprinting

This review paper endeavors to provide insights into the emergence of 3D bioprinting as an alternative to longstanding tissue fabrication techniques primarily through an overview of recent advances in bioprinting vascularized tissues. Bioprinting has promise in resolving many issues that persist within tissue engineering including: insufficient perfusion of nutrients to tissue constructs, high rates of cell necrosis, and lack of cell proliferation and proper differentiation. These issues stem from a lack of proper angiogenesis, a primary challenge that remains to be overcome in tissue engineering. This review will discuss emerging 3D bioprinting techniques (such as inkjet printing, extrusion printing, and stereolithography, among others) that have been specially adapted to enhance and improve the vascularization process. Compatible bioinks are also discussed as they are vital to the 3D bioprinting process by allowing for the building of matrices that encourage vasculature to develop, survive, and prosper under physiological flow rates. Currently, these 3D bioprinting techniques have succeeded in increasing the long-term viability of thick tissues, generated luminal structures needed for vascularization, and allowed for differentiation factors to reach cells deep within thick constructs (~1 cm). While great progress has been made, 3D bioprinting continues to have deficits in high-resolution printing, viability at prolonged time scales and larger thicknesses required for organ transplantation, and the mechanical stability needed for long-term organ functioning. Nonetheless, the recent developments in the vascularization of tissues through bioprinting techniques are paving the way for lab-grown tissues and organs, which could have uses in transplants, in vitro drug testing, and enhancing the current knowledge of organ function.
  Article Metrics

Keywords Vascularization; tissue engineering; 3D bioprinting; scaffolds

Citation: Hannah Grover, Catalina-Paula Spatarelu, Kniya DeDe, Shan Zhao, Kevin Yang, Yu Shrike Zhang, Zi Chen. Vascularization in 3D printed tissues: emerging technologies to overcome longstanding obstacles. AIMS Cell and Tissue Engineering, 2018, 2(3): 163-184. doi: 10.3934/celltissue.2018.3.163


  • 1. Orban JC, Walrave Y, Mongardon N, et al. (2017) Causes and characteristics of death in intensive care units. Anesthesiology 126: 882–889.    
  • 2. Lovett M, Lee K, Edwards A, et al. (2009) Vascularization strategies for tissue engineering. Tissue Eng Part B Rev 15: 353–370.    
  • 3. Griffith CK, Miller C, Sainson RCA, et al. (2005) Diffusion limits of an in vitro thick prevascularized tissue. Tissue Eng 11: 257–266.    
  • 4. Jain RK, Au P, Tam J, et al. (2005) Engineering vascularized tissue. Nat Biotechnol 23: 821–823.    
  • 5. Phelps EA, García AJ (2010) Engineering more than a cell: Vascularization strategies in tissue engineering. Curr Opin Biotechnol 21: 704–709.    
  • 6. Bertassoni LE, Cecconi M, Manoharan V, et al. (2014) Hydrogel bioprinted microchannel networks for vascularization of tissue engineering constructs. Lab Chip 14: 2202–2211.    
  • 7. Rouwkema J, Rivron NC, van Blitterswijk CA (2008) Vascularization in tissue engineering. Trends Biotechnol 26: 434–441.    
  • 8. Ikada Y (2006) Challenges in tissue engineering. J R Soc Interface 3: 589–601.    
  • 9. Griffith LG, Naughton G (2002) Tissue engineering--current challenges and expanding opportunities. Science 295: 1009–1014.    
  • 10. Kang HW, Lee SJ, Ko IK, et al. (2016) A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat Biotechnol 34: 312–319.    
  • 11. Berthiaume F, Maguire TJ, Yarmush ML (2011) CH02CH19-Yarmush. Annu Rev Chem Biomol Eng 2: 403–430.    
  • 12. Hollister SJ (2005) Porous scaffold design for tissue engineering. Nat Mater 4: 518–524.    
  • 13. Chan BP, Leong KW (2008) Scaffolding in tissue engineering: general approaches and tissue-specific considerations. Eur Spine J 17: 467–479.    
  • 14. Novosel EC, Kleinhans C, Kluger PJ (2011) Vascularization is the key challenge in tissue engineering. Adv Drug Deliv Rev 63: 300–311.    
  • 15. Zhao X, Liu L, Wang J, et al. (2016) In vitro vascularization of a combined system based on a 3D printing technique. J Tissue Eng Regen Med 10: 833–842.    
  • 16. Pashneh-Tala S, MacNeil S, Claeyssens F (2015) The tissue-engineered vascular graft-past, present, and future. Tissue Eng Part B Rev 22.
  • 17. O'Brien FJ (2011) Biomaterials & scaffolds for tissue engineering. Mater Today 14: 88–95.    
  • 18. He Y, Lu F (2016) Development of synthetic and natural materials for tissue engineering applications using adipose stem cells. Stem Cells Int 2016: 5786257.
  • 19. Kim JJ, Hou L, Yang G, et al. (2017) Microfibrous scaffolds enhance endothelial differentiation and organization of induced pluripotent stem cells. Cell Mol Bioeng 10: 417–432.    
  • 20. Plunkett N, O'Brien FJ (2010) IV.3. Bioreactors in tissue engineering. Stud Health Technol Inform 152: 214–230.
  • 21. Kolesky DB, Homan KA, Skylar-Scott MA, et al. (2016) Three-dimensional bioprinting of thick vascularized tissues. Proc Natl Acad Sci 113: 3179–3184.    
  • 22. Kolte D, McClung JA, Aronow WS (2016) Vasculogenesis and angiogenesis. Transl Res in Coron Artery Dis 49–65.
  • 23. Risau W (1997) Mechanisms of angiogenesis. Nat 386: 671–674.    
  • 24. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nat 407: 249–257.    
  • 25. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6: 389–395.    
  • 26. Lanza RP, Langer RS, Vacanti J (2014) Principles of Tissue Engineering. Elsevier.
  • 27. Gao Y (2017) Biology of Vascular Smooth Muscle: Vasoconstriction and Dilatation, Singapore: Springer Singapore.
  • 28. Ardalani H, Assadi AH, Murphy WL (2014) Structure, function, and development of blood vessels: lessons for tissue engineering. In, Engineering in Translational Medicine, London: Springer London, 155–182.
  • 29. Rhodin JAG (1980) Architecture of the vessel wall. In, Comprehensive Physiology, Hoboken: John Wiley & Sons, 1–31.
  • 30. Kossmann CE, Palade GE (1961) Blood capillaries of the heart and other organs. Circulation 24: 368–384.    
  • 31. Burton AC (1954) Relation of structure to function of the tissues of the wall of blood vessels. Physiol Rev 34: 619–642.    
  • 32. Yamamoto H, Ehling M, Kato K, et al. (2015) Integrin β1 controls VE-cadherin localization and blood vessel stability. Nat Commun 6: 6429.    
  • 33. Okabe E, Todoki K, Ito H (1990) Microcirculation: function and regulation in microvasculature. In, Dynamic Aspects of Dental Pulp, Dordrecht: Springer Netherlands, pp 151–166.
  • 34. Ji S, Guvendiren M (2017) Recent advances in bioink design for 3D bioprinting of tissues and organs. Front Bioeng Biotechnol 5: 23.
  • 35. Hölzl K, Lin S, Tytgat L, et al. (2016) Bioink properties before, during and after 3D bioprinting. Biofabrication 8: 032002.    
  • 36. Hospodiuk M, Dey M, Sosnoski D, et al. (2017) The bioink: A comprehensive review on bioprintable materials. Biotechnol Adv 35: 217–239.    
  • 37. Smith CM, Stone AL, Parkhill RL, et al. (2004) Three-dimensional bioassembly tool for generating viable tissue-engineered constructs. Tissue Eng 10: 1566–1576.    
  • 38. Chen CY, Barron JA, Ringeisen BR (2006) Cell patterning without chemical surface modification: cell–cell interactions between printed bovine aortic endothelial cells (BAEC) on a homogeneous cell-adherent hydrogel. Appl Surf Sci 252: 8641–8645.    
  • 39. Gao Q, He Y, Fu J, et al. (2015) Coaxial nozzle-assisted 3D bioprinting with built-in microchannels for nutrients delivery. Biomater 61: 203–215.    
  • 40. Norotte C, Marga FS, Niklason LE, et al. (2009) Scaffold-free vascular tissue engineering using bioprinting. Biomaterials 30: 5910–5917.    
  • 41. Zhang YS, Arneri A, Bersini S, et al. (2016) Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomater 110: 45–59.    
  • 42. Lee VK, Kim DY, Ngo H, et al. (2014) Creating perfused functional vascular channels using 3D bio-printing technology. Biomater 35: 8092–8102.    
  • 43. Yin Yu, Ozbolat IT (2014) Tissue strands as "bioink" for scale-up organ printing. Conf Proc IEEE Eng Med Biol Soc 2014: 1428–1431.
  • 44. Wilkens CA, Rivet CJ, Akentjew TL, et al. (2016) Layer-by-layer approach for a uniformed fabrication of a cell patterned vessel-like construct. Biofabrication 9: 015001.    
  • 45. Cui X, Boland T (2009) Human microvasculature fabrication using thermal inkjet printing technology. Biomater 30: 6221–6227.    
  • 46. Darland DC, Massingham LJ, Smith SR, et al. (2003) Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev Biol 264: 275–288.    
  • 47. Korff T, Kimmina S, Martiny-Baron G, et al. (2001) Blood vessel maturation in a 3-dimensional spheroidal coculture model: direct contact with smooth muscle cells regulates endothelial cell quiescence and abrogates VEGF responsiveness. FASEB J 15: 447–457.    
  • 48. Lee VK, Lanzi AM, Ngo H, et al. (2014) Generation of Multi-scale Vascular Network System Within 3D Hydrogel Using 3D Bio-printing Technology. Cell Mol Bioeng 7: 460–472.    
  • 49. Jia W, Gungor-Ozkerim PS, Zhang YS, et al. (2016) Direct 3D bioprinting of perfusable vascular constructs using a blend bioink. Biomater 106: 58–68.    
  • 50. Jang J, Park HJ, Kim SW, et al. (2017) 3D printed complex tissue construct using stem cell-laden decellularized extracellular matrix bioinks for cardiac repair. Biomater 112: 264–274.    
  • 51. Jia J, Richards DJ, Pollard S, et al. (2014) Engineering alginate as bioink for bioprinting. Acta Biomater 10: 4323–4331.    
  • 52. Das S, Pati F, Choi YJ, et al. (2015) Bioprintable, cell-laden silk fibroin–gelatin hydrogel supporting multilineage differentiation of stem cells for fabrication of three-dimensional tissue constructs. Acta Biomater 11: 233–246.    
  • 53. Blaeser A, Duarte Campos DF, Puster U, et al. (2016) Controlling shear stress in 3D bioprinting is a key factor to balance printing resolution and stem cell integrity. Adv Healthc Mater 5: 326–333.    
  • 54. Hipp J, Atala A (2008) Sources of stem cells for regenerative medicine. Stem Cell Rev 4: 3–11.    
  • 55. Wilson KD, Wu JC (2015) Induced pluripotent stem cells. JAMA 313: 1613.    
  • 56. Wong CW, Chen YT, Chien CL, et al. (2018) A simple and efficient feeder-free culture system to up-scale iPSCs on polymeric material surface for use in 3D bioprinting. Mater Sci Eng C 82: 69–79.    
  • 57. Faulkner-Jones A, Fyfe C, Cornelissen DJ, et al. (2015) Bioprinting of human pluripotent stem cells and their directed differentiation into hepatocyte-like cells for the generation of mini-livers in 3D. Biofabrication 7: 044102.    
  • 58. Ma X, Qu X, Zhu W, et al. (2016) Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting. Proc Natl Acad Sci 113: 2206–2211.    
  • 59. Miller JS, Stevens KR, Yang MT, et al. (2012) Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat Mater 11: 768–774.    
  • 60. Kolesky DB, Truby RL, Gladman AS, et al. (2014) 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs. Adv Mater 26: 3124–3130.    
  • 61. Sukmana I (2012) Microvascular guidance: a challenge to support the development of vascularised tissue engineering construct. TheSci World J 2012: 201352.
  • 62. Kim JA, Kim HN, Im SK, et al. (2015) Collagen-based brain microvasculature model in vitro using three-dimensional printed template. Biomicrofluidics 9: 024115.    
  • 63. Muscari C, Giordano E, Bonafè F, et al. (2014) Strategies affording prevascularized cell-based constructs for myocardial tissue engineering. Stem Cells Int 2014: 434169.
  • 64. Bogorad MI, DeStefano J, Karlsson J, et al. (2015) Review: in vitro microvessel models. Lab Chip 15: 4242–4255.    
  • 65. Moon JJ, West JL (2008) Vascularization of engineered tissues: approaches to promote angio-genesis in biomaterials. Curr Top Med Chem 8: 300–310.    
  • 66. Yang P, Huang X, Shen J, et al. (2013) Development of a new pre-vascularized tissue-engineered construct using pre-differentiated rADSCs, arteriovenous vascular bundle and porous nano-hydroxyapatide-polyamide 66 scaffold. BMC Musculoskelet Disord 14: 318.    
  • 67. Zhu W, Qu X, Zhu J, et al. (2017) Direct 3D bioprinting of prevascularized tissue constructs with complex microarchitecture. Biomater 124: 106–115.    
  • 68. Mirabella T, MacArthur JW, Cheng D, et al. (2017) 3D-printed vascular networks direct therapeutic angiogenesis in ischaemia. Nat Biomed Eng 1: 0083.    
  • 69. Gelber MK, Hurst G, Comi TJ, et al. (2018) Model-guided design and characterization of a high-precision 3D printing process for carbohydrate glass. Addit Manuf 22: 38–50.    
  • 70. Xu C, Lee W, Dai G, et al. (2018) Highly elastic biodegradable single-network hydrogel for cell printing. ACS Appl Mater Interfaces 10: 9969–9979.    
  • 71. Hinton TJ, Jallerat Q, Palchesko RN, et al. (2015) Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels. Sci Adv 1: e1500758–e1500758.    
  • 72. Suntornnond R, Tan EYS, An J, et al. (2017) A highly printable and biocompatible hydrogel composite for direct printing of soft and perfusable vasculature-like structures. Sci Rep 7: 1–11.    
  • 73. Lee V, Singh G, Trasatti JP, et al. (2014) Design and Fabrication of Human Skin by Three-Dimensional Bioprinting. Tissue Eng Part C Methods 20: 473–484.    
  • 74. Qilong Z, Juan W, Huanqing C, et al. (2018) Programmed shape‐morphing scaffolds enabling facile 3D endothelialization. Adv Funct Mater 0: 1801027.
  • 75. Yu Y, Moncal KK, Li J, et al. (2016) Three-dimensional bioprinting using self-assembling scalable scaffold-free "tissue strands" as a new bioink. Sci Rep 6: 28714.    
  • 76. Xu C, Chai W, Huang Y, et al. (2012) Scaffold-free inkjet printing of three-dimensional zigzag cellular tubes. Biotechnol Bioeng 109: 3152–3160.    
  • 77. Zhang Y, Yu Y, Chen H, et al. (2013) Characterization of printable cellular micro-fluidic channels for tissue engineering. Biofabrication 5: 25004.    
  • 78. Visser CW, Kamperman T, Karbaat LP, et al. (2018) In-air microfluidics enables rapid fabrication of emulsions, suspensions, and 3D modular (bio)materials. Sci Adv 4: 1–9.
  • 79. Daniel JT, Jessop ZM, Whitaker IS (2017) 3D Bioprinting for Reconstructive Surgery Techniques and Applications. Woodhead Publishing.
  • 80. Mandrycky C, Wang Z, Kim K, et al. (2016) 3D bioprinting for engineering complex tissues. Biotechnol Adv 34: 422–434.    
  • 81. Catros S, Fricain JC, Guillotin B, et al. (2011) Laser-assisted bioprinting for creating on-demand patterns of human osteoprogenitor cells and nano-hydroxyapatite. Biofabrication 3: 025001.    
  • 82. Catros S, Guillotin B, Bačáková M, et al. (2011) Effect of laser energy, substrate film thickness and bioink viscosity on viability of endothelial cells printed by laser-assisted bioprinting. Appl Surf Sci 257: 5142–5147.    
  • 83. Grogan SP, Chung PH, Soman P, et al. (2013) Digital micromirror device projection printing system for meniscus tissue engineering. Acta Biomater 9: 7218–7226.    
  • 84. Sorkio A, Koch L, Koivusalo L, et al. (2018) Human stem cell based corneal tissue mimicking structures using laser-assisted 3D bioprinting and functional bioinks. Biomater 171: 57–71.    
  • 85. Gruene M, Pflaum M, Deiwick A, et al. (2011) Adipogenic differentiation of laser-printed 3D tissue grafts consisting of human adipose-derived stem cells. Biofabrication 3: 015005.    
  • 86. Foyt DA, Norman MDA, Yu TTL, et al. (2018) Exploiting advanced hydrogel technologies to address key challenges in regenerative medicine. Adv Healthc Mater 7: 1700939.    
  • 87. Shanjani Y, Pan CC, Elomaa L, et al. (2015) A novel bioprinting method and system for forming hybrid tissue engineering constructs. Biofabrication 7: 045008.    
  • 88. Aguilar JP, Lipka M, Primo GA, et al. (2018) 3D Electrophoresis-assisted lithography (3DEAL): 3D molecular printing to create functional patterns and anisotropic hydrogels. Adv Funct Mater 28: 1–10.
  • 89. Hribar KC, Meggs K, Liu J, et al. (2015) Three-dimensional direct cell patterning in collagen hydrogels with near-infrared femtosecond laser. Sci Rep 5: 17203.    
  • 90. Wang Z, Jin X, Dai R, et al. (2016) An ultrafast hydrogel photocrosslinking method for direct laser bioprinting. RSC Adv 6: 21099–21104.    
  • 91. Miri AK, Nieto D, Iglesias L, et al. (2018) Microfluidics-enabled multimaterial maskless stereolithographic bioprinting. Adv Mater 30: e1800242.    
  • 92. Mosadegh B, Xiong G, Dunham S, et al. (2015) Current progress in 3D printing for cardiovascular tissue engineering. Biomed Mater 10: 034002.    
  • 93. Ringeisen BR, Pirlo RK, Wu PK, et al. (2013) Cell and organ printing turns 15: Diverse research to commercial transitions. MRS Bull 38: 834–843.    
  • 94. Duan B (2017) State-of-the-art review of 3D bioprinting for cardiovascular tissue engineering. Ann Biomed Eng 45: 195–209.    
  • 95. Gao Q, Liu Z, Lin Z, et al. (2017) 3D bioprinting of vessel-like structures with multilevel fluidic channels. ACS Biomater Sci Eng 3: 399–408.    
  • 96. Khademhosseini A, Camci-Unal G (2018) 3D Bioprinting in Regenerative Engineering: Principles and Applications. CRC Press.
  • 97. Wu Y, Lin ZY (William), Wenger AC, et al. (2018) 3D bioprinting of liver-mimetic construct with alginate/cellulose nanocrystal hybrid bioink. Bioprinting 9: 1–6.    
  • 98. Visconti RP, Kasyanov V, Gentile C, et al. (2010) Towards organ printing: engineering an intra-organ branched vascular tree. Expert Opin Biol Ther 10: 409–420.    
  • 99. Prendergast ME, Montoya G, Pereira T, et al. (2018) Microphysiological systems: automated fabrication via extrusion bioprinting. Microphysiological Syst 2: 1–16.    
  • 100. Charbe N, McCarron PA, Tambuwala MM (2017) Three-dimensional bio-printing: A new frontier in oncology research. World J Clin Oncol 8: 21–36.    
  • 101. Gopinathan J, Noh I (2018) Recent trends in bioinks for 3D printing. Biomater Res 22: 11.    
  • 102. Guvendiren M, Molde J, Soares RMD, et al. (2016) Designing biomaterials for 3d printing. ACS Biomater Sci Eng 2: 1679–1693.    
  • 103. Gu Q, Tomaskovic-Crook E, Wallace GG, et al. (2017) 3D bioprinting human induced pluripotent stem cell constructs for in situ cell proliferation and successive multilineage differentiation. Adv Healthc Mater 6: 1700175.    
  • 104. Ong CS, Fukunishi T, Zhang H, et al. (2017) Biomaterial-free three-dimensional bioprinting of cardiac tissue using human induced pluripotent stem cell derived cardiomyocytes. Sci Rep 7: 4566.    
  • 105. Medvedev SP, Shevchenko AI, Zakian SM (2010) Induced pluripotent stem cells: problems and advantages when applying them in regenerative medicine. Acta Nat 2: 18–28.
  • 106. Wang W, Yang J, Liu H, et al. (2011) Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. Proc Natl Acad Sci 108: 18283–18288.    
  • 107. Tidball AM, Dang LT, Glenn TW, et al. (2017) Rapid generation of human genetic loss-of-function ipsc lines by simultaneous reprogramming and gene editing. Stem Cell Reports 9: 725–731.    
  • 108. Rutz AL, Hyland KE, Jakus AE, et al. (2015) A multi-material bioink method for 3D printing tunable, cell-compatible hydrogels. Adv Mater 27: 1607–1614.    
  • 109. Vatani M, Choi JW (2017) Direct-print photopolymerization for 3D printing. Rapid Prototyp J 23: 337–343.    
  • 110. Tappa K, Jammalamadaka U (2018) Novel biomaterials used in medical 3D printing techniques. J Funct Biomater 9: 17.    
  • 111. Aljohani W, Ullah MW, Zhang X, et al. (2018) Bioprinting and its applications in tissue engineering and regenerative medicine. Int J Biol Macromol 107: 261–275.    


This article has been cited by

  • 1. Margaret E. Prendergast, Jason A. Burdick, Recent Advances in Enabling Technologies in 3D Printing for Precision Medicine, Advanced Materials, 2019, 1902516, 10.1002/adma.201902516
  • 2. Elham Davoodi, Einollah Sarikhani, Hossein Montazerian, Samad Ahadian, Marco Costantini, Wojciech Swieszkowski, Stephanie Michelle Willerth, Konrad Walus, Mohammad Mofidfar, Ehsan Toyserkani, Ali Khademhosseini, Nureddin Ashammakhi, Extrusion and Microfluidic‐Based Bioprinting to Fabricate Biomimetic Tissues and Organs, Advanced Materials Technologies, 2020, 1901044, 10.1002/admt.201901044

Reader Comments

your name: *   your email: *  

© 2018 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved