Vascular anastomosis using controlled phase transitions in poloxamer gels

Abstract

Vascular anastomosis is the cornerstone of vascular, cardiovascular and transplant surgery. Most anastomoses are performed with sutures, which are technically challenging and can lead to failure from intimal hyperplasia and foreign body reaction. Numerous alternatives to sutures have been proposed, but none has proven superior, particularly in small or atherosclerotic vessels. We have developed a new method of sutureless and atraumatic vascular anastomosis that uses US Food and Drug Administration (FDA)-approved thermoreversible tri-block polymers to temporarily maintain an open lumen for precise approximation with commercially available glues. We performed end-to-end anastomoses five times more rapidly than we performed hand-sewn controls, and vessels that were too small (<1.0 mm) to sew were successfully reconstructed with this sutureless approach. Imaging of reconstructed rat aorta confirmed equivalent patency, flow and burst strength, and histological analysis demonstrated decreased inflammation and fibrosis at up to 2 years after the procedure. This new technology has potential for improving efficiency and outcomes in the surgical treatment of cardiovascular disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Thermoreversible properties of poloxamer nanogel.
Figure 2: Thermoreversible poloxamer nanogel and cyanoacrylate glue sutureless anastomoses in vivo.
Figure 3: Poloxamer nanogel anastomoses show long-term patency, flow and equivalent burst strength in vivo.
Figure 4: Poloxamer nanogel anastomoses show less vascular intimal damage.

References

  1. 1

    Moseley, J. Alexis Carrel, the man unknown. Journey of an idea. J. Am. Med. Assoc. 244, 1119–1121 (1980).

  2. 2

    Murray, J.E. The first successful organ transplants in man. J. Am. Coll. Surg. 200, 5–9 (2005).

  3. 3

    Motwani, J.G. & Topol, E.J. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation 97, 916–931 (1998).

  4. 4

    Schwartz, S.M., deBlois, D. & O'Brien, E.R. The intima. Soil for atherosclerosis and restenosis. Circ. Res. 77, 445–465 (1995).

  5. 5

    Zubilewicz, T. Injury in vascular surgery—the intimal hyperplastic response. Med. Sci. Monit. 7, 316–324 (2001).

  6. 6

    Charlson, M.E. & Isom, O.W. Clinical practice. Care after coronary-artery bypass surgery. N. Engl. J. Med. 348, 1456–1463 (2003).

  7. 7

    French, B.N. & Rewcastle, N.B. Recurrent stenosis at site of carotid endarterectomy. Stroke 8, 597–605 (1977).

  8. 8

    Ojha, M., Leask, R.L., Johnston, K.W., David, T.E. & Butany, J. Histology and morphology of 59 internal thoracic artery grafts and their distal anastomoses. Ann. Thorac. Surg. 70, 1338–1344 (2000).

  9. 9

    Ameli, F.M., Provan, J.L., Williamson, C. & Keuchler, P.M. Etiology and management of aorto-femoral bypass graft failure. J. Cardiovasc. Surg. (Torino) 28, 695–700 (1987).

  10. 10

    Beris, A.E. et al. Digit and hand replantation. Arch. Orthop. Trauma Surg. 130, 1141–1147 (2010).

  11. 11

    Erdmann, D. et al. Side-to-side sutureless vascular anastomosis with magnets. J. Vasc. Surg. 40, 505–511 (2004).

  12. 12

    Liu, L., Liu, J., Zhu, M. & Hu, S. Experimental study of one-shot vascular anastomostic device for proximal vein graft anastomoses. Ann. Thorac. Surg. 82, 303–306 (2006).

  13. 13

    Wiklund, L., Bonilla, L.F. & Berglin, E. A new mechanical connector for distal coronary artery anastomoses in coronary artery bypass grafting: a randomized, controlled study. J. Thorac. Cardiovasc. Surg. 129, 146–150 (2005).

  14. 14

    Cho, A.B. et al. Fibrin glue application in microvascular anastomosis: comparative study of two free flap series. Microsurgery 29, 24–28 (2009).

  15. 15

    Grindel, J.M., Jaworski, T., Piraner, O., Emanuele, R.M. & Balasubramanian, M. Distribution, metabolism, and excretion of a novel surface-active agent, purified poloxamer 188, in rats, dogs, and humans. J. Pharm. Sci. 91, 1936–1947 (2002).

  16. 16

    Orringer, E.P. et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. J. Am. Med. Assoc. 286, 2099–2106 (2001).

  17. 17

    Serbest, G., Horwitz, J., Jost, M. & Barbee, K. Mechanisms of cell death and neuroprotection by poloxamer 188 after mechanical trauma. FASEB J. 20, 308–310 (2006).

  18. 18

    Ricci, E.J., Lunardi, L.O., Nanclares, D.M. & Marchetti, J.M. Sustained release of lidocaine from poloxamer 407 gels. In. J. Pharm. 288, 235–244 (2005).

  19. 19

    Escobar-Chávez, J.J. et al. Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations. J. Pharm. Pharm. Sci. 9, 339–358 (2006).

  20. 20

    Grassi, G. et al. Rheological and mechanical properties of pluronic-alginate gels for drug-eluting stent coating. J. Control. Release 116, e85–e87 (2006).

  21. 21

    Kohli, E., Han, H.Y., Zeman, A.D. & Vinogradov, S.V. Formulations of biodegradable Nanogel carriers with 5′-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity. J. Control. Release 121, 19–27 (2007).

  22. 22

    Roques, C., Salmon, A., Fiszman, M.Y., Fattal, E. & Fromes, Y. Intrapericardial administration of novel DNA formulations based on thermosensitive poloxamer 407 gel. Int. J. Pharm. 331, 220–223 (2007).

  23. 23

    Dumortier, G., Grossiord, J.L., Agnely, F. & Chaumeil, J.C. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm. Res. 23, 2709–2728 (2006).

  24. 24

    Xiong, X.Y., Tam, K.C. & Gan, L.H. Polymeric nanostructures for drug delivery applications based on Pluronic copolymer systems. J. Nanosci. Nanotechnol. 6, 2638–2650 (2006).

  25. 25

    Ricci, E.J., Bentley, M.V., Farah, M., Bretas, R.E. & Marchetti, J.M. Rheological characterization of poloxamer 407 lidocaine hydrochloride gels. Eur. J. Pharm. Sci. 17, 161–167 (2002).

  26. 26

    Cogger, V.C. et al. Hyperlipidemia and surfactants: the liver sieve is a link. Atherosclerosis 189, 273–281 (2006).

  27. 27

    Johnston, T.P. et al. Potential downregulation of HMG-CoA reductase after prolonger administration of P-407 in C57BL/6 mice. J. Cardiovasc. Pharmacol. 34, 831–842 (1999).

  28. 28

    Habal, S.M., Fitzpatrick, H.F. & Gree, G.E. Training in microvascular surgery. Surgery 81, 596–598 (1977).

  29. 29

    Hume, S.P., Marigold, J.C. & Michalowski, A. The effect of local hyperthermia on nonproliferative, compared with proliferative, epithelial cells of mouse intestinal mucosa. Radiat. Res. 94, 252–262 (1983).

  30. 30

    Carnero-Alcázar, M. et al. Short-term and mid-term follow-up of sutureless surgery for postinfarction subacute free wall rupture. Interact. Cardiovasc. Thorac. Surg. 8, 619–623 (2009).

  31. 31

    Ong, Y.S. et al. 2-Octylcynanoacrylate-assisted microvascular anastomosis in a rat model: long-term biomechanical properties and histological changes. Microsurgery 24, 304–308 (2004).

  32. 32

    Buijsrogge, M.P., Verlaan, C.W., van Rijen, M.H., Grundeman, P.F. & Borst, C. Coronary end-to-side sleeve anastomosis using adhesive in off-pump bypass grafting in the pig. Ann. Thorac. Surg. 73, 1451–1456 (2002).

  33. 33

    Kachhy, R.G., Kong, D.F., Honeycutt, E., Shaw, L.K. & Davis, R.D. Long-term outcomes of the symmetry vein graft anastomosis device: a matched case-controlled analysis. Circulation 114, I425–I429 (2006).

  34. 34

    Apostolakis, E.E., Leivaditis, V.N. & Anagnostopoulos, C. Sutureless technique to support anastomosis during thoracic aorta replacement. J. Cardiothorac. Surg. 4, 66 (2009).

  35. 35

    Setzen, G. & Williams, E.F. III. Tissue response to suture material implanted subcutaneously in a rabbit model. Plast. Reconstr. Surg. 100, 1788–1795 (1997).

  36. 36

    Claude, O., Gregory, T., Montemagno, S., Bruneval, P. & Masmejean, E.H. Vascular microanastomosis in rat femoral arteries: experimental study comparing non-absorbable and absorbable sutures. J. Reconstr. Microsurg. 23, 87–91 (2007).

  37. 37

    Bettmann, M.A. et al. Atherosclerotic Vascular Disease Conference: Writing Group VI: revascularization. Circulation 109, 2643–2650 (2004).

  38. 38

    Faxon, D.P. et al. Atherosclerotic Vascular Disease Conference: Executive summary: Atherosclerotic Vascular Disease Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 109, 2595–2604 (2004).

  39. 39

    Nabeyama, A. et al. xCT deficiency accelerates chemically induced tumorigenesis. Proc. Natl. Acad. Sci. USA 107, 6436–6441 (2010).

Download references

Acknowledgements

We thank C. Zarins for providing use of his laboratory burst strength apparatus. We also thank T. Doyle for assistance in small-animal imaging (Stanford Center for Innovation in In-Vivo Imaging) and Y. Park for expert technical assistance. This work was supported by a Stanford Bio-X Interdisciplinary Initiatives Research Award (to G.G.F. and G.C.G.).

Author information

E.I.C. was responsible for experimental design and data analysis, and wrote the manuscript. M.G.G. designed experiments, analyzed data and wrote the manuscript. J.P.G. analyzed data and wrote the manuscript. C.D.H. designed experiments and analyzed data. S.E. performed imaging studies and analyzed data. C.T.R. and J.R. designed poloxamer experiments and analyzed data. K.-M.S. designed poloxamer experiments. O.J.A. was responsible for burst strength experimental design and data analysis. G.G.F. supervised poloxamer experiments and data analysis. M.T.L. provided ideas and wrote the manuscript. G.C.G. supervised all aspects of this work and wrote the manuscript.

Correspondence to Geoffrey C Gurtner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 (PDF 435 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chang, E., Galvez, M., Glotzbach, J. et al. Vascular anastomosis using controlled phase transitions in poloxamer gels. Nat Med 17, 1147–1152 (2011). https://doi.org/10.1038/nm.2424

Download citation

Further reading