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

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.

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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.

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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

Affiliations

Authors

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 or 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

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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 (2021). https://doi.org/10.1038/s41551-021-00769-y

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