Correspondence

Tissue-Engineered Blood Vessel for Adult Arterial Revascularization

N Engl J Med 2007; 357:1451-1453October 4, 2007

Article

To the Editor:

A material that will approach the efficacy of native vein has been widely sought.1 Using autologous cells and a technique termed sheet-based tissue engineering, we were able to produce autologous tissue-engineered blood vessels with physiologic mechanical properties.2 No synthetic or exogenous materials were used; instead, the vessels were created with the use of autologous fibroblasts and endothelial cells harvested from a small biopsy specimen of skin and superficial vein. Here we report on the preliminary use of these tissue-engineered blood vessels in an adult arterial model.

Ten patients receiving hemodialysis whose arteriovenous shunts were failing were enrolled in this study. The subjects had typical risk factors for end-stage renal disease, including previously failed dialysis-access grafts, diabetes, controlled hypertension, and obesity. Patients ranged in age from 29 to 89 years (mean [±SD], 68±17). Vessel patency was evaluated by means of Doppler and angiographic imaging. Mechanically viable vessels were created with autologous cells for each patient. The average burst pressure among 54 vessels was 3340±849 mm Hg, which compares favorably with native veins.3

The primary objective of this study was to demonstrate that a tissue-engineered blood vessel produced in vitro could withstand the challenges of arterial pressure produced by an arteriovenous fistula for at least 3 months. After this observation period, grafts were punctured for hemodialysis access. To date, the first six patients have had vessels implanted and have been followed for up to 13 months.

The tissue-engineered blood vessel in Patient 1 (Figure 1Figure 1The Tissue-Engineered Blood Vessel Preoperatively (Panel A), at 3 Months after Implantation (Panel B, Computed Tomographic Angiography), and at 12 Months after Implantation (Panel C, Doppler Ultrasonography).) was used for more than 13 months, until the patient underwent successful kidney transplantation. At 11.5 months, an aneurysm was noted near an area that had many punctures. A small portion of the vessel wall was resected, and the tissue-engineered blood vessel continued to function until the kidney transplantation. In total, the 14-cm-long graft was punctured more than 200 times.

Patient 2 died at day 39 of unrelated causes with a functioning tissue-engineered blood vessel. The vessel in Patient 3 had a thrombogenic failure at 12 weeks, attributed to a low postoperative flow rate (<500 ml per minute) and a moderate, diffuse dilatation that further reduced flow velocity. At up to 5 months after implantation, Patients 4, 5, and 6 have functioning grafts without complications.

Compliance measurements derived by ultrasonography at 5 months show a 4.8-fold increase for Patient 1 (3.1 to 15.0% per 100 mm Hg) and a 2.7-fold increase for Patient 4 (2.3 to 6.2% per 100 mm Hg) in compliance relative to preoperative values, without concomitant dilatation or evidence of mechanical degradation. This may indicate the formation of an elastic component, which would be consistent with our preclinical results.

Although these are clearly early results, we have demonstrated in 24 patient-months of use that this new approach may be feasible. This transition to human use represents an important milestone for cardiovascular engineering.4

Nicolas L'Heureux, Ph.D.
Todd N. McAllister, Ph.D.
Cytograft Tissue Engineering, Novato, CA 94949
nico@cytograft.com

Luis M. de la Fuente, M.D.
Instituto Argentina de Diagnostico y Tratamiento, 1122 Buenos Aires, Argentina

Drs. L'Heureux and McAllister report holding stock in Cytograft Tissue Engineering.

4 References

1. 1

   Conte MS. The ideal small arterial substitute: a search for the Holy Grail? FASEB J 1998;12:43-45
   Web of Science | Medline

2. 2

   L'Heureux N, Dusserre N, Konig G, et al. Human tissue-engineered blood vessels for adult arterial revascularization. Nat Med 2006;12:361-365
   CrossRef | Web of Science | Medline

3. 3

   Schaner PJ, Martin ND, Tulenko TN, et al. Decellularized vein as a potential scaffold for vascular tissue engineering. J Vasc Surg 2004;40:146-153
   CrossRef | Web of Science | Medline

4. 4

   Weinberg CB, Bell E. A blood vessel model constructed from collagen and cultured vascular cells. Science 1986;231:397-400
   CrossRef | Web of Science | Medline

Citing Articles (67)

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1. 1

   Bo Yang, Gang Chen, Jie Li, Qing Zou, Dan Xie, Yali Chen, Hang Wang, Xiaohui Zheng, Jie Long, Wei Tang, Weihua Guo, Weidong Tian. (2012) Tooth root regeneration using dental follicle cell sheets in combination with a dentin matrix - based scaffold. Biomaterials 33:8, 2449-2461
   CrossRef

2. 2

   Giuseppe Orlando. (2012) Immunosuppression-free transplantation reconsidered from a regenerative medicine perspective. Expert Review of Clinical Immunology 8:2, 179-187
   CrossRef

3. 3

   Sumati Sundaram, Laura E. Niklason. (2012) Smooth Muscle and Other Cell Sources for Human Blood Vessel Engineering. Cells Tissues Organs 195:1-2, 15-25
   CrossRef

4. 4

   Sarra de Valence, Jean-Christophe Tille, Damiano Mugnai, Wojciech Mrowczynski, Robert Gurny, Michael Möller, Beat H. Walpoth. (2012) Long term performance of polycaprolactone vascular grafts in a rat abdominal aorta replacement model. Biomaterials 33:1, 38-47
   CrossRef

5. 5

   Jie Zhao, Liangqi Liu, Jing Wei, Dongyang Ma, Wenxin Geng, Xingrong Yan, Jun Zhu, Huicong Du, Ying Liu, Liwen Li, Fulin Chen. (2012) A Novel Strategy to Engineer Small-Diameter Vascular Grafts From Marrow-Derived Mesenchymal Stem Cells. Artificial Organs 36:1, 93-101
   CrossRef

6. 6

   Marissa Peck, David Gebhart, Nathalie Dusserre, Todd N. McAllister, Nicolas L’Heureux. (2012) The Evolution of Vascular Tissue Engineering and Current State of the Art. Cells Tissues Organs 195:1-2, 144-158
   CrossRef

7. 7

   Christine Cheung, Sanjay Sinha. (2011) Human embryonic stem cell-derived vascular smooth muscle cells in therapeutic neovascularisation. Journal of Molecular and Cellular Cardiology 51:5, 651-664
   CrossRef

8. 8

   Vivek A. Kumar, Luke P. Brewster, Jeffrey M. Caves, Elliot L. Chaikof. (2011) Tissue Engineering of Blood Vessels: Functional Requirements, Progress, and Future Challenges. Cardiovascular Engineering and Technology 2:3, 137-148
   CrossRef

9. 9

   Stephen F. Badylak, Doris Taylor, Korkut Uygun. (2011) Whole-Organ Tissue Engineering: Decellularization and Recellularization of Three-Dimensional Matrix Scaffolds. Annual Review of Biomedical Engineering 13:1, 27-53
   CrossRef

10. 10

    Robert Gauvin, Maxime Guillemette, Todd Galbraith, Jean-Michel Bourget, Danielle Larouche, Hugo Marcoux, David Aubé, Cindy Hayward, François A. Auger, Lucie Germain. (2011) Mechanical Properties of Tissue-Engineered Vascular Constructs Produced Using Arterial or Venous Cells. Tissue Engineering Part A 17:15-16, 2049-2059
    CrossRef

11. 11

    Wei Wu, Robert Allen, Jin Gao, Yadong Wang. (2011) Artificial Niche Combining Elastomeric Substrate and Platelets Guides Vascular Differentiation of Bone Marrow Mononuclear Cells. Tissue Engineering Part A 17:15-16, 1979-1992
    CrossRef

12. 12

    Zeeshan H. Syedain, Matthew T. Lahti, Sandra L. Johnson, Paul S. Robinson, George R. Ruth, Richard W. Bianco, Robert T. Tranquillo. (2011) Implantation of a Tissue-engineered Heart Valve from Human Fibroblasts Exhibiting Short Term Function in the Sheep Pulmonary Artery. Cardiovascular Engineering and Technology 2:2, 101-112
    CrossRef

13. 13

    Giuseppe Orlando, Kathryn J. Wood, Robert J. Stratta, James J. Yoo, Anthony Atala, Shay Soker. (2011) Regenerative Medicine and Organ Transplantation: Past, Present, and Future. Transplantation 91:12, 1310-1317
    CrossRef

14. 14

    Marissa Peck, Nathalie Dusserre, Todd N. McAllister, Nicolas L'Heureux. (2011) Tissue engineering by self-assembly. Materials Today 14:5, 218-224
    CrossRef

15. 15

    Yuji Naito, Toshiharu Shinoka, Daniel Duncan, Narutoshi Hibino, Daniel Solomon, Muriel Cleary, Animesh Rathore, Corey Fein, Spencer Church, Christopher Breuer. (2011) Vascular tissue engineering: Towards the next generation vascular grafts. Advanced Drug Delivery Reviews 63:4-5, 312-323
    CrossRef

16. 16

    Ning Ma, Zhenyu Wang, Hao Chen, Yanjun Sun, Haifa Hong, Qi Sun, Meng Yin, Jinfen Liu. (2011) Development of the novel biotube inserting technique for acceleration of thick-walled autologous tissue-engineered vascular grafts fabrication. Journal of Materials Science: Materials in Medicine 22:4, 1037-1043
    CrossRef

17. 17

    Philippe Levesque, Robert Gauvin, Danielle Larouche, François A. Auger, Lucie Germain. (2011) A Computer-Controlled Apparatus for the Characterization of Mechanical and Viscoelastic Properties of Tissue-Engineered Vascular Constructs. Cardiovascular Engineering and Technology 2:1, 24-34
    CrossRef

18. 18

    Sachiko Sekiya, Tatsuya Shimizu, Masayuki Yamato, Teruo Okano. (2011) “Deep-media culture condition” promoted lumen formation of endothelial cells within engineered three-dimensional tissues in vitro. Journal of Artificial Organs 14:1, 43-51
    CrossRef

19. 19

    Guo You Huang, Li Hong Zhou, Qian Cheng Zhang, Yong Mei Chen, Wei Sun, Feng Xu, Tian Jian Lu. (2011) Microfluidic hydrogels for tissue engineering. Biofabrication 3:1, 012001
    CrossRef

20. 20

    Giuseppe Orlando. (2011) Transplantation as a subfield of regenerative medicine. Expert Review of Clinical Immunology 7:2, 137-141
    CrossRef

21. 21

    Lorenzo Soletti, Alejandro Nieponice, Yi Hong, Sang-Ho Ye, John J. Stankus, William R. Wagner, David A. Vorp. (2011) In vivo performance of a phospholipid-coated bioerodable elastomeric graft for small-diameter vascular applications. Journal of Biomedical Materials Research Part A 96A:2, 436-448
    CrossRef

22. 22

    H. Kerdjoudj, F. Boulmedais, N. Berthelemy, H. Mjahed, H. Louis, P. Schaaf, J. C. Voegel, P. Menu. (2011) Cellularized alginate sheets for blood vessel reconstruction. Soft Matter 7:7, 3621
    CrossRef

23. 23

    D. Chang, T. Okano. 2011. Medical Applications of Cell Sheet Engineering. , 405-419.
    CrossRef

24. 24

    Brett C. Isenberg, Chrysanthi Williams, Robert T. Tranquillo. 2011. Engineering of Small-Diameter Vessels. , 853-875.
    CrossRef

25. 25

    A.A. Ucuzian, H.P. Greisler. 2011. Vascular Grafts. , 449-467.
    CrossRef

26. 26

    Robert Gauvin, Maxime Guillemette, Mehmet Dokmeci, Ali Khademhosseini. (2011) Application of microtechnologies for the vascularization of engineered tissues. Vascular Cell 3:1, 24
    CrossRef

27. 27

    Jennifer L. Olson, Anthony Atala, James J. Yoo. (2011) Tissue Engineering: Current Strategies and Future Directions. Chonnam Medical Journal 47:1, 1
    CrossRef

28. 28

    R. Gauvin, A. Khademhosseini, M. Guillemette, R. Langer. 2011. Emerging Trends in Tissue Engineering. , 251-263.
    CrossRef

29. 29

    R.S. Kellar, J.J. Lancaster, S. Goldman, T.N. McAllister, N. L'Heureux. 2011. Cardiovascular Tissue Engineering. , 361-376.
    CrossRef

30. 30

    Divya Pankajakshan, Devendra K. Agrawal. (2010) Scaffolds in tissue engineering of blood vessels. Canadian Journal of Physiology and Pharmacology 88:9, 855-873
    CrossRef

31. 31

    Jesper Hjortnaes, Danielle Gottlieb, Jose-Luiz Figueiredo, Juan Melero-Martin, Rainer H. Kohler, Joyce Bischoff, Ralph Weissleder, John E. Mayer, Elena Aikawa. (2010) Intravital Molecular Imaging of Small-Diameter Tissue-Engineered Vascular Grafts in Mice: A Feasibility Study. Tissue Engineering Part C: Methods 16:4, 597-607
    CrossRef

32. 32

    Thanh N. Huynh, Robert T. Tranquillo. (2010) Fusion of Concentrically Layered Tubular Tissue Constructs Increases Burst Strength. Annals of Biomedical Engineering 38:6, 2226-2236
    CrossRef

33. 33

    Karoly Jakab, Cyrille Norotte, Francoise Marga, Keith Murphy, Gordana Vunjak-Novakovic, Gabor Forgacs. (2010) Tissue engineering by self-assembly and bio-printing of living cells. Biofabrication 2:2, 022001
    CrossRef

34. 34

    Gustavo A. Villalona, Brooks Udelsman, Daniel R. Duncan, Edward McGillicuddy, Rajendra F. Sawh-Martinez, Narutoshi Hibino, Christopher Painter, Tamar Mirensky, Benjamin Erickson, Toshiharu Shinoka, Christopher K. Breuer. (2010) Cell-Seeding Techniques in Vascular Tissue Engineering. Tissue Engineering Part B: Reviews 16:3, 341-350
    CrossRef

35. 35

    Feng Zhao, Jan J Veldhuis, Yajun Duan, Yong Yang, Nicolas Christoforou, Teng Ma, Kam W Leong. (2010) Low Oxygen Tension and Synthetic Nanogratings Improve the Uniformity and Stemness of Human Mesenchymal Stem Cell Layer. Molecular Therapy 18:5, 1010-1018
    CrossRef

36. 36

    Behnam Zamanian, Mahdokht Masaeli, Jason W. Nichol, Masoud Khabiry, Matthew J. Hancock, Hojae Bae, Ali Khademhosseini. (2010) Interface-Directed Self-Assembly of Cell-Laden Microgels. Small 6:8, 937-944
    CrossRef

37. 37

    Fabien Guillemot, Agnès Souquet, Sylvain Catros, Bertrand Guillotin. (2010) Laser-assisted cell printing: principle, physical parameters versus cell fate and perspectives in tissue engineering. Nanomedicine 5:3, 507-515
    CrossRef

38. 38

    Miguel Alaminos, Bárbara Pérez-Köhler, Ingrid Garzón, Natalio García-Honduvilla, Beatriz Romero, Antonio Campos, Julia Buján. (2010) Transdifferentiation potentiality of human Wharton's jelly stem cells towards vascular endothelial cells. Journal of Cellular Physiologyn/a-n/a
    CrossRef

39. 39

    Stephen E. McIlhenny, Eric S. Hager, Daniel J. Grabo, Christopher DiMatteo, Irving M. Shapiro, Thomas N. Tulenko, Paul J. DiMuzio. (2010) Linear Shear Conditioning Improves Vascular Graft Retention of Adipose-Derived Stem Cells by Upregulation of the α ₅ β ₁ Integrin. Tissue Engineering Part A 16:1, 245-255
    CrossRef

40. 40

    J. I. ROTMANS, J. H. CAMPBELL. 2010. Tissue engineering for small-diameter vascular grafts. , 116-146.
    CrossRef

41. 41

    Bari Murtuza, Jason W. Nichol, Ali Khademhosseini. (2009) Micro- and Nanoscale Control of the Cardiac Stem Cell Niche for Tissue Fabrication. Tissue Engineering Part B: Reviews 15:4, 443-454
    CrossRef

42. 42

    Robert J. Daher, Nadeen O. Chahine, Andrew S. Greenberg, Nicholas A. Sgaglione, Daniel A. Grande. (2009) New methods to diagnose and treat cartilage degeneration. Nature Reviews Rheumatology 5:11, 599-607
    CrossRef

43. 43

    Tomonori Oie, Hisato Suzuki, Toru Fukuda, Yoshinobu Murayama, Sadao Omata, Keiichi Kanda, Yasuhide Nakayama. (2009) Tactile Mapping System. Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery 4:6, 345-350
    CrossRef

44. 44

    Haiying Huang, Yue-Min Zhou, Hatsue Ishibashi-Ueda, Keiichi Takamizawa, Joji Ando, Keiichi Kanda, Hitoshi Yaku, Yasuhide Nakayama. (2009) In vitro maturation of “biotube” vascular grafts induced by a 2-day pulsatile flow loading. Journal of Biomedical Materials Research Part B: Applied Biomaterials 91B:1, 320-328
    CrossRef

45. 45

    Xiaofeng Cui, Thomas Boland. (2009) Human microvasculature fabrication using thermal inkjet printing technology. Biomaterials 30:31, 6221-6227
    CrossRef

46. 46

    Cyrille Norotte, Francois S. Marga, Laura E. Niklason, Gabor Forgacs. (2009) Scaffold-free vascular tissue engineering using bioprinting. Biomaterials 30:30, 5910-5917
    CrossRef

47. 47

    Akihito Muto, Toshiya Nishibe, Herbert Dardik, Alan Dardik. (2009) Patches for carotid artery endarterectomy: Current materials and prospects. Journal of Vascular Surgery 50:1, 206-213
    CrossRef

48. 48

    Jeffrey T. LaCroix, Jinjun Xia, Mark A. Haidekker. (2009) A Fully Automated Approach to Quantitatively Determine Thickness of Tissue-Engineered Cell Sheets. Annals of Biomedical Engineering 37:7, 1348-1357
    CrossRef

49. 49

    Jason W. Nichol, Azeem R. Khan, Mariusz Birbach, J. William Gaynor, Keith J. Gooch. (2009) Hemodynamics and Axial Strain Additively Increase Matrix Remodeling and MMP-9, But Not MMP-2, Expression in Arteries Engineered by Directed Remodeling. Tissue Engineering Part A 15:6, 1282-1290
    CrossRef

50. 50

    V Mironov, T Trusk, V Kasyanov, S Little, R Swaja, R Markwald. (2009) Biofabrication: a 21st century manufacturing paradigm. Biofabrication 1:2, 022001
    CrossRef

51. 51

    Saami K. Yazdani, Benjamin Watts, Masood Machingal, Yagna P.R. Jarajapu, Mark E. Van Dyke, George J. Christ. (2009) Smooth Muscle Cell Seeding of Decellularized Scaffolds: The Importance of Bioreactor Preconditioning to Development of a More Native Architecture for Tissue-Engineered Blood Vessels. Tissue Engineering Part A 15:4, 827-840
    CrossRef

52. 52

    Todd N McAllister, Marcin Maruszewski, Sergio A Garrido, Wojciech Wystrychowski, Nathalie Dusserre, Alicia Marini, Krzysztof Zagalski, Alejandro Fiorillo, Hernan Avila, Ximena Manglano, Jorge Antonelli, Alfred Kocher, Marian Zembala, Lech Cierpka, Luis M de la Fuente, Nicolas L'Heureux. (2009) Effectiveness of haemodialysis access with an autologous tissue-engineered vascular graft: a multicentre cohort study. The Lancet 373:9673, 1440-1446
    CrossRef

53. 53

    Daping Yang, Tiefang Guo, Chunlei Nie, Steven F. Morris. (2009) Tissue-Engineered Blood Vessel Graft Produced by Self-Derived Cells and Allogenic Acellular Matrix. Annals of Plastic Surgery 62:3, 297-303
    CrossRef

54. 54

    Gerhardt Konig, Todd N. McAllister, Nathalie Dusserre, Sergio A. Garrido, Corey Iyican, Alicia Marini, Alex Fiorillo, Hernan Avila, Wojciech Wystrychowski, Krzysztof Zagalski, Marcin Maruszewski, Alyce Linthurst Jones, Lech Cierpka, Luis M. de la Fuente, Nicolas L'Heureux. (2009) Mechanical properties of completely autologous human tissue engineered blood vessels compared to human saphenous vein and mammary artery. Biomaterials 30:8, 1542-1550
    CrossRef

55. 55

    Antonella Rossi, Daniela Pasqui, Rolando Barbucci, Renato Gerli, Elisabetta Weber. (2009) The Topography of Microstructured Surfaces Differently Affects Fibrillin Deposition by Blood and Lymphatic Endothelial Cells in Culture. Tissue Engineering Part A 15:3, 525-533
    CrossRef

56. 56

    Lauren J. Fischer, Stephen McIlhenny, Thomas Tulenko, Negar Golesorkhi, Ping Zhang, Robert Larson, Joseph Lombardi, Irving Shapiro, Paul J. DiMuzio. (2009) Endothelial Differentiation of Adipose-Derived Stem Cells: Effects of Endothelial Cell Growth Supplement and Shear Force. Journal of Surgical Research 152:1, 157-166
    CrossRef

57. 57

    Jason W. Nichol, Ali Khademhosseini. (2009) Modular tissue engineering: engineering biological tissues from the bottom up. Soft Matter 5:7, 1312
    CrossRef

58. 58

    Laura Pandis, Barbara Zavan, Giovanni Abatangelo, Sandro Lepidi, Roberta Cortivo, Vincenzo Vindigni. (2009) Hyaluronan-based scaffold for in vivo regeneration of the rat vena cava: Preliminary results in an animal model. Journal of Biomedical Materials Research Part A 9999A, NA-NA
    CrossRef

59. 59

    Todd N McAllister, Nathalie Dusserre, Marcin Maruszewski, Nicolas L’Heureux. (2008) Cell-based therapeutics from an economic perspective: primed for a commercial success or a research sinkhole?. Regenerative Medicine 3:6, 925-937
    CrossRef

60. 60

    Achala de Mel, Capucine Bolvin, Mohan Edirisinghe, George Hamilton, Alexander M Seifalian. (2008) Development of cardiovascular bypass grafts: endothelialization and applications of nanotechnology. Expert Review of Cardiovascular Therapy 6:9, 1259-1277
    CrossRef

61. 61

    Nicolas L’Heureux, Todd McAllister. (2008) Cytograft Tissue Engineering: a new paradigm in cardiovascular tissue engineering. Regenerative Medicine 3:4, 471-475
    CrossRef

62. 62

    Mi Jin Kim, Ji-Heung Kim, Gijong Yi, Sang-Hyun Lim, You Sun Hong, Dong June Chung. (2008) In vitro andin vivo application of PLGA nanofiber for artificial blood vessel. Macromolecular Research 16:4, 345-352
    CrossRef

63. 63

    Vladimir Mironov, Vladimir Kasyanov, Roger R. Markwald. (2008) Nanotechnology in vascular tissue engineering: from nanoscaffolding towards rapid vessel biofabrication. Trends in Biotechnology 26:6, 338-344
    CrossRef

64. 64

    Brett C. Isenberg, Yukiko Tsuda, Corin Williams, Tatsuya Shimizu, Masayuki Yamato, Teruo Okano, Joyce Y. Wong. (2008) A thermoresponsive, microtextured substrate for cell sheet engineering with defined structural organization. Biomaterials 29:17, 2565-2572
    CrossRef

65. 65

    A. Rodriguez-Morata, I. Garzon, M. Alaminos, N. Garcia-Honduvilla, M.C. Sanchez-Quevedo, J. Bujan, A. Campos. (2008) Cell Viability and Prostacyclin Release in Cultured Human Umbilical Vein Endothelial Cells. Annals of Vascular Surgery 22:3, 440-448
    CrossRef

66. 66

    Laurence Bordenave, Patrick Menu, Charles Baquey. (2008) Developments towards tissue-engineered, small-diameter arterial substitutes. Expert Review of Medical Devices 5:3, 337-347
    CrossRef

67. 67

    Prabir Roy-Chaudhury. (2008) Utility of formaldehyde-fixed arterial allografts for hemodialysis access. Nature Clinical Practice Nephrology 4:2, 74-75
    CrossRef