Bioprinting Approaches to Engineering Vascularized 3D Cardiac Tissues
Purpose of Review
3D bioprinting technologies hold significant promise for the generation of engineered cardiac tissue and translational applications in medicine. To generate a clinically relevant sized tissue, the provisioning of a perfusable vascular network that provides nutrients to cells in the tissue is a major challenge. This review summarizes the recent vascularization strategies for engineering 3D cardiac tissues.
Considerable steps towards the generation of macroscopic sizes for engineered cardiac tissue with efficient vascular networks have been made within the past few years. Achieving a compact tissue with enough cardiomyocytes to provide functionality remains a challenging task. Achieving perfusion in engineered constructs with media that contain oxygen and nutrients at a clinically relevant tissue sizes remains the next frontier in tissue engineering.
The provisioning of a functional vasculature is necessary for maintaining a high cell viability and functionality in engineered cardiac tissues. Several recent studies have shown the ability to generate tissues up to a centimeter scale with a perfusable vascular network. Future challenges include improving cell density and tissue size. This requires the close collaboration of a multidisciplinary teams of investigators to overcome complex challenges in order to achieve success.
Keywords3D printing Cardiac engineered tissue Vascularization Bioprinting Cardiovascular tissue Cardiomyocyte
We thank Mark Skylar-Scott, PhD (Wyss Institute for Biologically Inspired Engineering, Harvard University) for his comments and edits on the manuscript.
Funding for this research was provided by the German Research Foundation/DFG (PU 690/1-1) (N.P.), the NIH Office of Director’s Pioneer Award LM012179-03, the American Heart Association Established Investigator Award 17EIA33410923, the Stanford Cardiovascular Institute, the Hoffmann and Schroepfer Foundation, and the Stanford Division of Cardiovascular Medicine, Department of Medicine (S.M.W). The authors declare no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Compliance with Ethical Standards
Conflict of Interest
Nazan Puluca, Soah Lee, Stephanie Doppler, Andrea Münsterer, Martina Dreßen, Markus Krane, and Sean M. Wu declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 1.Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet Lond Engl. 2006;367(9524):1747–57.Google Scholar
- 2.Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart Disease and Stroke Statistics-2019 update: a report from the American Heart Association. Circulation. 2019;31:CIR0000000000000659.Google Scholar
- 3.Chambers DC, Cherikh WS, Goldfarb SB, Hayes D, Kucheryavaya AY, Toll AE, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; focus theme: multiorgan transplantation. J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2018;37(10):1169–83.Google Scholar
- 4.Zhang YS, Aleman J, Arneri A, Bersini S, Piraino F, Shin SR, et al. From cardiac tissue engineering to heart-on-a-chip: beating challenges. Biomed Mater Bristol Engl. 2015;10(3):034006.Google Scholar
- 17.Ning L, Chen X. A brief review of extrusion-based tissue scaffold bio-printing. Biotechnol J. 2017;12(8).Google Scholar
- 19.Serpooshan V, Mahmoudi M, Hu DA, Hu JB, Wu SM. Bioengineering cardiac constructs using 3D printing. J 3D Print Med. 2017;1(2):123–39.Google Scholar
- 20.Hopp B. Femtosecond laser printing of living cells using absorbing film-assisted laser-induced forward transfer. Opt Eng. 2012;51(1):014302.Google Scholar
- 23.Hölzl K, Lin S, Tytgat L, Van Vlierberghe S, Gu L, Ovsianikov A. Bioink properties before, during and after 3D bioprinting. Biofabrication. 2016;23;8(3):032002.Google Scholar
- 35.Kim JD, Choi JS, Kim BS, Chan Choi Y, Cho YW. Piezoelectric inkjet printing of polymers: stem cell patterning on polymer substrates. Polymer. 2010;51(10):2147–54.Google Scholar
- 37.Khalil S, Sun W. Biopolymer deposition for freeform fabrication of hydrogel tissue constructs. Mater Sci Eng C. 2007;27(3):469–78.Google Scholar
- 39.Turksen K. Bioprinting in regenerative medicine. Cham Heidelberg New York: Springer; 2015. 140 p. (Stem cell biology and regenerative medicine)Google Scholar
- 45.Laronda MM, Rutz AL, Xiao S, Whelan KA, Duncan FE, Roth EW, et al. A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nat Commun. 2017;16;8:15261.Google Scholar
- 50.Panwar A, Tan LP. Current status of bioinks for micro-extrusion-based 3D bioprinting. Mol Basel Switz. 2016;25:21(6).Google Scholar
- 52.Gopinathan J, Noh I. Recent trends in bioinks for 3D printing. Biomater Res [Internet]. 2018 Dec [cited 2019 Feb 28];22(1). Available from: https://doi.org/10.1186/s40824-018-0122-1
- 55.Li S, Xiong Z, Wang X, Yan Y, Liu H, Zhang R. Direct fabrication of a hybrid cell/hydrogel construct by a double-nozzle assembling technology. J Bioact Compat Polym. 2009;24(3):249–65.Google Scholar
- 62.Jose RR, Rodriguez MJ, Dixon TA, Omenetto F, Kaplan DL. Evolution of bioinks and additive manufacturing technologies for 3D bioprinting. ACS Biomater Sci Eng. 2016;2(10):1662–78.Google Scholar
- 66.Ruan J-L, Tulloch NL, Razumova MV, Saiget M, Muskheli V, Pabon L, et al. Mechanical stress conditioning and electrical stimulation promote contractility and force maturation of induced pluripotent stem cell-derived human cardiac tissue. Circulation. 2016;134(20):1557–67.PubMedPubMedCentralGoogle Scholar
- 68.Maiullari F, Costantini M, Milan M, Pace V, Chirivì M, Maiullari S, et al. A multi-cellular 3D bioprinting approach for vascularized heart tissue engineering based on HUVECs and iPSC-derived cardiomyocytes. Sci Rep [Internet]. 2018 Dec [cited 2019 Feb 27];8(1). Available from: http://www.nature.com/articles/s41598-018-31848-x
- 69.•• Redd MA, Zeinstra N, Qin W, Wei W, Martinson A, Wang Y, et al. Patterned human microvascular grafts enable rapid vascularization and increase perfusion in infarcted rat hearts. Nat Commun. 2019;10(1):584. Current state-of-the-art showing vascular remodeling and integration of engineered microchannel networks. PubMedPubMedCentralGoogle Scholar
- 74.Brandenberg N, Lutolf MP. In situ patterning of microfluidic networks in 3D cell-laden hydrogels. Adv Mater Deerfield Beach Fla. 2016;28(34):7450–6.Google Scholar
- 79.Tremblay P-L, Hudon V, Berthod F, Germain L, Auger FA. Inosculation of tissue-engineered capillaries with the host’s vasculature in a reconstructed skin transplanted on mice. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. 2005;5(5):1002–10.Google Scholar
- 81.Schnaper HW, Kleinman HK. Regulation of cell function by extracellular matrix. Pediatr Nephrol Berl Ger. 1993;7(1):96–104.Google Scholar
- 83.Perry L, Flugelman MY, Levenberg S. Elderly patient-derived endothelial cells for vascularization of engineered muscle. Mol Ther J Am Soc Gene Ther. 2017;25(4):935–48.Google Scholar
- 92.Velazquez OC, Snyder R, Liu Z-J, Fairman RM, Herlyn M. Fibroblast-dependent differentiation of human microvascular endothelial cells into capillary-like 3-dimensional networks. FASEB J Off Publ Fed Am Soc Exp Biol. 2002;16(10):1316–8.Google Scholar