Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Rapid and coagulation-independent haemostatic sealing by a paste inspired by barnacle glue

Nature Biomedical Engineering volume 5, pages 1131–1142 (2021)Cite this article

Subjects

Abstract

Tissue adhesives do not normally perform well on tissues that are covered with blood or other bodily fluids. Here we report the design, adhesion mechanism and performance of a paste that haemostatically seals tissues in less than 15 s, independently of the blood-coagulation rate. With a design inspired by barnacle glue (which strongly adheres to wet and contaminated surfaces owing to adhesive proteins embedded in a lipid-rich matrix), the paste consists of a blood-repelling hydrophobic oil matrix containing embedded microparticles that covalently crosslink with tissue surfaces on the application of gentle pressure. It slowly resorbs over weeks, sustains large pressures (approximately 350 mm Hg of burst pressure in a sealed porcine aorta), makes tough (interfacial toughness of 150–300 J m−2) and strong (shear and tensile strengths of, respectively, 40–70 kPa and 30–50 kPa) interfaces with blood-covered tissues, and outperforms commercial haemostatic agents in the sealing of bleeding porcine aortas ex vivo and of bleeding heart and liver tissues in live rats and pigs. The paste may aid the treatment of severe bleeding, even in individuals with coagulopathies.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Design and mechanism of the barnacle-glue-inspired paste.
Fig. 2: Effects of matrix materials.
Fig. 3: Adhesion performance.
Fig. 4: In vitro and in vivo biocompatibility.
Fig. 5: In vivo haemostatic sealing of a rat liver.
Fig. 6: In vivo haemostatic sealing of a rat heart.
Fig. 7: In vivo haemostatic sealing of a haemorrhaging liver injury in fully anticoagulated pigs.

Data availability

All data supporting the findings of this study are available within the article and its Supplementary Information. Other raw and analysed data generated during this study are available from the corresponding authors on reasonable request. Source data are provided with this paper.

References

  1. Rodrigues, R. R., Carmona, M. J. C. & Junior, J. O. C. Bleeding and damage control surgery. Curr. Opin. Anesthesiol. 29, 229–233 (2016).

    Article  Google Scholar 

  2. Pfeifer, R., Tarkin, I. S., Rocos, B. & Pape, H.-C. Patterns of mortality and causes of death in polytrauma patients—has anything changed? Injury 40, 907–911 (2009).

    Article  PubMed  Google Scholar 

  3. El Sayad, M. & Noureddine, H. Recent advances of hemorrhage management in severe trauma. Emerg. Med. Int. 2014, 638956 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Reece, T. B., Maxey, T. S. & Kron, I. L. A prospectus on tissue adhesives. Am. J. Surg. 182, S40–S44 (2001).

    Article  Google Scholar 

  5. Coulthard, P. et al. Tissue adhesives for closure of surgical incisions. Cochrane Database Syst. Rev. 5, CD004287 (2010).

    Google Scholar 

  6. Sharma, B. et al. Human cartilage repair with a photoreactive adhesive–hydrogel composite. Sci. Transl. Med. 5, 167ra6 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Annabi, N., Yue, K., Tamayol, A. & Khademhosseini, A. Elastic sealants for surgical applications. Eur. J. Pharm. Biopharm. 95, 27–39 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Roche, E. T. et al. A light-reflecting balloon catheter for atraumatic tissue defect repair. Sci. Transl. Med. 7, 306ra149 (2015).

    Article  PubMed  Google Scholar 

  9. Khoshmohabat, H., Paydar, S., Kazemi, H. M. & Dalfardi, B. Overview of agents used for emergency hemostasis. Trauma Mon. 21, e26023 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  10. King, D. R. Initial care of the severely injured patient. N. Engl. J. Med. 380, 763–770 (2019).

    Article  PubMed  Google Scholar 

  11. Mourão, M. S. F., Cenedezi, J. M., Machado, J. E. P., Ferreira, J. C. D. & Junqueira, D. R. in Vascular Diseases for the Non-Specialist: An Evidence-Based Guide (eds Navarro, T. P. et al.) 47–68 (Springer, 2017).

  12. Lang, N. et al. A blood-resistant surgical glue for minimally invasive repair of vessels and heart defects. Sci. Transl. Med. 6, 218ra6 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Hong, Y. et al. A strongly adhesive hemostatic hydrogel for the repair of arterial and heart bleeds. Nat. Commun. 10, 2060 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Annabi, N. et al. Engineering a highly elastic human protein-based sealant for surgical applications. Sci. Transl. Med. 9, eaai7466 (2017).

    Article  PubMed  CAS  Google Scholar 

  15. Li, J. et al. Tough adhesives for diverse wet surfaces. Science 357, 378–381 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Leonhardt, E. E., Kang, N., Hamad, M. A., Wooley, K. L. & Elsabahy, M. Absorbable hemostatic hydrogels comprising composites of sacrificial templates and honeycomb-like nanofibrous mats of chitosan. Nat. Commun. 10, 1–9 (2019).

    Article  CAS  Google Scholar 

  17. Kim, K. et al. Coagulopathy-independent, bioinspired hemostatic materials: a full research story from preclinical models to a human clinical trial. Sci. Adv. 7, eabc9992 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Khandeparker, L. & Anil, A. C. Underwater adhesion: the barnacle way. Int. J. Adhes. Adhes. 27, 165–172 (2007).

    Article  CAS  Google Scholar 

  19. Kamino, K. Mini-review: barnacle adhesives and adhesion. Biofouling 29, 735–749 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Kamino, K. in Biological Adhesives (eds Smith, A. M. & Callow, J. A.) 153–176 (Springer, 2016).

  21. Essock-Burns, T. et al. Barnacle biology before, during and after settlement and metamorphosis: a study of the interface. J. Exp. Biol. 220, 194–207 (2017).

    PubMed  Google Scholar 

  22. Lee, H., Lee, B. P. & Messersmith, P. B. A reversible wet/dry adhesive inspired by mussels and geckos. Nature 448, 338 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Lee, B. P., Messersmith, P. B., Israelachvili, J. N. & Waite, J. H. Mussel-inspired adhesives and coatings. Annu. Rev. Mater. Res. 41, 99–132 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Maier, G. P., Rapp, M. V., Waite, J. H., Israelachvili, J. N. & Butler, A. Adaptive synergy between catechol and lysine promotes wet adhesion by surface salt displacement. Science 349, 628–632 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Zhao, Q. et al. Underwater contact adhesion and microarchitecture in polyelectrolyte complexes actuated by solvent exchange. Nat. Mater. 15, 407–412 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gohad, N. V. et al. Synergistic roles for lipids and proteins in the permanent adhesive of barnacle larvae. Nat. Commun. 5, 4414 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Fears, K. P., Orihuela, B., Rittschof, D. & Wahl, K. J. Acorn barnacles secrete phase‐separating fluid to clear surfaces ahead of cement deposition. Adv. Sci. 5, 1700762 (2018).

    Article  CAS  Google Scholar 

  28. Nakano, M., Shen, J.-R. & Kamino, K. Self-assembling peptide inspired by a barnacle underwater adhesive protein. Biomacromolecules 8, 1830–1835 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Brubaker, C. E. & Messersmith, P. B. The present and future of biologically inspired adhesive interfaces and materials. Langmuir 28, 2200–2205 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Yuk, H. et al. Dry double-sided tape for adhesion of wet tissues and devices. Nature 575, 169–174 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Yuk, H., Zhang, T., Lin, S., Parada, G. A. & Zhao, X. Tough bonding of hydrogels to diverse non-porous surfaces. Nat. Mater. 15, 190 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Sun, J.-Y. et al. Highly stretchable and tough hydrogels. Nature 489, 133–136 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shastri, V. P. Non-degradable biocompatible polymers in medicine: past, present and future. Curr. Pharm. Biotechnol. 4, 331–337 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Liu, Z. et al. Phosphoester cross-linked vegetable oil to construct a biodegradable and biocompatible elastomer. Soft Matter 8, 5888–5895 (2012).

    Article  CAS  Google Scholar 

  35. Miao, S., Wang, P., Su, Z. & Zhang, S. Vegetable-oil-based polymers as future polymeric biomaterials. Acta Biomater. 10, 1692–1704 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Koos, E. & Willenbacher, N. Capillary forces in suspension rheology. Science 331, 897–900 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Mao, X., Yuk, H. & Zhao, X. Hydration and swelling of dry polymers for wet adhesion. J. Mech. Phys. Solids 137, 103863 (2020).

    Article  CAS  Google Scholar 

  38. Wong, T.-S. et al. Bioinspired self-repairing slippery surfaces with pressure-stable omniphobicity. Nature 477, 443 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Amini, S. et al. Preventing mussel adhesion using lubricant-infused materials. Science 357, 668–673 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Guazzelli, É. & Pouliquen, O. Rheology of dense granular suspensions. J. Fluid Mech. 852, P1 (2018).

    Article  CAS  Google Scholar 

  41. Gan, D. et al. Plant-inspired adhesive and tough hydrogel based on Ag-lignin nanoparticles-triggered dynamic redox catechol chemistry. Nat. Commun. 10, 1487 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Wang, Y. et al. Instant, tough, noncovalent adhesion. ACS Appl. Mater. Interfaces 11, 40749–40757 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Chen, X., Yuk, H., Wu, J., Nabzdyk, C. S. & Zhao, X. Instant tough bioadhesive with triggerable benign detachment. Proc. Natl Acad. Sci. USA 117, 15497–15503 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen, J. et al. An adhesive hydrogel with ‘load‐sharing’ effect as tissue bandages for drug and cell delivery. Adv. Mater. 32, 2001628 (2020).

    Article  CAS  Google Scholar 

  45. Murdock, M. H. et al. Cytocompatibility and mechanical properties of surgical sealants for cardiovascular applications. J. Thorac. Cardiovascular Surg. 157, 176–183 (2019).

    Article  Google Scholar 

  46. Corral, M., Ferko, N., Hollmann, S., Broder, M. S. & Chang, E. Health and economic outcomes associated with uncontrolled surgical bleeding: a retrospective analysis of the Premier Perspectives Database. Clinicoecon. Outcomes Res. 7, 409–421 (2015).

    PubMed  PubMed Central  Google Scholar 

  47. Lee, J. T. et al. Cell culture medium as an alternative to conventional simulated body fluid. Acta Biomater. 7, 2615–2622 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Langley, K. R. & Thoroddsen, S. T. Gliding on a layer of air: impact of a large-viscosity drop on a liquid film. J. Fluid Mech. 878, R2 (2019).

    Article  CAS  Google Scholar 

  49. Walls, D. J., Meiburg, E. & Fuller, G. G. The shape evolution of liquid droplets in miscible environments. J. Fluid Mech. 852, 422–452 (2018).

    Article  CAS  Google Scholar 

  50. Boreyko, J. B., Polizos, G., Datskos, P. G., Sarles, S. A. & Collier, C. P. Air-stable droplet interface bilayers on oil-infused surfaces. Proc. Natl Acad. Sci. USA 111, 7588–7593 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically K. Cormier and the Histology Core for the histological processing, and R. Bronson at Harvard Medical School for the histological evaluations. This work is supported by the MIT Deshpande Center (H.Y., C.S.N., X.Z.), National Institutes of Health (1-R01-HL153857-01, X.Z.), National Science Foundation (EFMA-1935291, X.Z.), the US Army Research Office through the Institute for Soldier Nanotechnologies at MIT (W911NF-13-D-0001) and the ZOLL Foundation (C.S.N.). H.Y. acknowledges financial support from Samsung Scholarship.

Author information

Author notes

  1. These authors contributed equally: Hyunwoo Yuk, Jingjing Wu.

Authors and Affiliations

  1. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Hyunwoo Yuk, Jingjing Wu, Xinyu Mao, Ellen T. Roche & Xuanhe Zhao

  2. Division of Thoracic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA

    Tiffany L. Sarrafian

  3. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Claudia E. Varela & Ellen T. Roche

  4. Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA, USA

    Claudia E. Varela & Ellen T. Roche

  5. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA

    Leigh G. Griffiths

  6. Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA

    Christoph S. Nabzdyk

  7. Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Xuanhe Zhao

Authors
  1. Hyunwoo Yuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingjing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tiffany L. Sarrafian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinyu Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudia E. Varela
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ellen T. Roche
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leigh G. Griffiths
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christoph S. Nabzdyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xuanhe Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.Y., X.M., C.S.N. and X.Z. discussed the initial concept of the barnacle-glue-inspired paste. H.Y. invented the materials and method for the barnacle-glue-inspired paste. H.Y., X.M., J.W., C.S.N. and X.Z. designed the in vitro and ex vivo experiments. H.Y., X.M. and J.W. conducted the in vitro and ex vivo experiments. H.Y., J.W., C.E.V., E.T.R. and C.S.N. designed the in vivo rat studies. J.W., H.Y. and C.E.V. conducted the in vivo rat studies and analysis. C.S.N., T.L.S. and L.G.G. designed and conducted the in vivo pig studies and analysis. H.Y., C.S.N. and X.Z. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Hyunwoo Yuk, Christoph S. Nabzdyk or Xuanhe Zhao.

Ethics declarations

Competing interests

H.Y., X.M., C.S.N. and X.Z. are named as inventors on a patent application (US no. 62/942,874) that covers the design and repel–crosslinking mechanism of the barnacle-glue-inspired paste.

Additional information

Peer review information Nature Biomedical Engineering thanks Nasim Annabi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Overall process of rapid haemostatic tissue sealing by the barnacle-glue-inspired paste.

(Step 1 and 2) The barnacle-glue-inspired paste can be applied directly on bleeding injury without any other preparation process; (Step 3 and 4) On application of gentle pressure, the silicone oil matrix in the barnacle-glue-inspired paste repels and clean blood from the bleeding injury; (Step 5 and 6) Simultaneously, the carboxylic acid groups in the bioadhesive microparticles form temporary physical crosslinks by hydrogen bonds, followed by the covalent crosslinking between the NHS ester groups and the primary amine groups with themselves and the tissue surfaces; (Step 7) the swollen and crosslinked paste provides robust haemostatic tissue sealing.

Extended Data Fig. 2 Adhesion mechanisms of the barnacle-glue-inspired paste.

a, Schematic illustrations for the physical crosslinking-based adhesion between the barnacle-glue-inspired paste and the tissue surface. b, Schematic illustrations for the covalent crosslinking-based adhesion between the barnacle-glue-inspired paste and the tissue surface. c, Interfacial toughness of blood-covered porcine skin adhered by the paste with and without NHS ester over time. Values in c represent the mean and the standard deviation (n = 3; independent samples). Statistical significance and p values are determined by two-sided Student t-test; *** p ≤ 0.001.

Source data

Extended Data Fig. 3 Swelling of the barnacle-glue-inspired paste.

a,b, Images for swelling of a bioadhesive microparticle in DMEM (a) and the corresponding time vs. swelling ratio (b). c, Images of the cross-sectional view of blood-covered porcine heart sealed by the barnacle-glue-inspired paste 5 min and 24 h after haemostatic sealing. L0, thickness of the barnacle-glue-inspired paste 5 min after haemostatic sealing. d, Normalized thickness of the crosslinked barnacle-glue-inspired paste between porcine heart over time. L, thickness of the paste at the current time.

Source data

Extended Data Fig. 4 Additional ex vivo and in vivo haemostatic sealing evaluations.

a, Rapid haemostatic sealing of an ex vivo porcine aorta by the barnacle-glue-inspired paste. A heparinized porcine blood is used to ensure coagulation-independent haemostatic sealing. b, Images of a filtered porcine blood bath with a 100-µm mesh after 6 h continuous flow through a sealed ex vivo porcine aorta. c, Burst pressure of porcine aorta sealed by the barnacle-glue-inspired paste and commercially available products. d, Haemostatic sealing of a bleeding rat liver in vivo by Surgicel. e, Excised rat liver 2 weeks after haemostatic sealing by Surgicel. f, Haemostatic sealing of a bleeding rat liver in vivo by CoSeal. g, Excised rat liver 2 weeks after haemostatic sealing by CoSeal. Four independent experiments were conducted with similar results. h, Haemostatic sealing of a bleeding rat heart in vivo by Surgicel. i, Haemostatic sealing of a bleeding rat heart in vivo by CoSeal. Four independent experiments were conducted with similar results. Values in c represent the mean and the standard deviation (n = 3; independent samples). Statistical significance and p values are determined by two-sided Student t-test; *** p ≤ 0.001.

Source data

Supplementary information

Supplementary Information

Supplementary discussion, references, figures and video captions.

Reporting Summary

Supplementary Video 1

Overall process of adhesion formation between blood-covered tissues by the barnacle-glue-inspired paste.

Supplementary Video 2

Repelling of blood by the barnacle-glue-inspired paste applied on a porcine aorta.

Supplementary Video 3

Application of commercially available haemostatic agents (TachoSil and Veriset) to a bleeding aorta.

Supplementary Video 4

Rapid coagulation-independent haemostatic tissue sealing by the barnacle-glue-inspired paste.

Supplementary Video 5

Application of the commercially available haemostatic agents to a bleeding in vivo rat heart.

Supplementary Video 6

Rapid haemostatic tissue sealing of a bleeding in vivo rat heart by the barnacle-glue-inspired paste.

Supplementary Video 7

Application of a commercially available haemostatic agent (TachoSil) to a bleeding in vivo porcine liver.

Supplementary Video 8

Rapid haemostatic tissue sealing of a bleeding in vivo porcine liver by the barnacle-glue-inspired paste.

Supplementary Video 9

Rescue of a failed liver haemostasis with TachoSil by the barnacle-glue-inspired paste.

Source data

Source Data Fig. 2

Source Data for Fig. 2.

Source Data Fig. 3

Source Data for Fig. 3.

Source Data Fig. 4

Source Data for Fig. 4.

Source Data Fig. 5

Source Data for Fig. 5.

Source Data Fig. 6

Source Data for Fig. 6.

Source Data Fig. 7

Source Data for Fig. 7.

Source Data Extended Data Fig. 2

Source Data for Extended Data Fig. 2.

Source Data Extended Data Fig. 3

Source Data for Extended Data Fig. 3.

Source Data Extended Data Fig. 4

Source Data for Extended Data Fig. 4.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yuk, H., Wu, J., Sarrafian, T.L. et al. Rapid and coagulation-independent haemostatic sealing by a paste inspired by barnacle glue. Nat Biomed Eng 5, 1131–1142 (2021). https://doi.org/10.1038/s41551-021-00769-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-021-00769-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing