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.

  • Article
  • Published:

A multiphase transitioning peptide hydrogel for suturing ultrasmall vessels

Nature Nanotechnology volume 11, pages 95–102 (2016)Cite this article

Subjects

Abstract

Many surgeries are complicated by the need to anastomose, or reconnect, micrometre-scale vessels. Although suturing remains the gold standard for anastomosing vessels, it is difficult to place sutures correctly through collapsed lumen, making the procedure prone to failure. Here, we report a multiphase transitioning peptide hydrogel that can be injected into the lumen of vessels to facilitate suturing. The peptide, which contains a photocaged glutamic acid, forms a solid-like gel in a syringe and can be shear-thin delivered to the lumen of collapsed vessels (where it distends the vessel) and the space between two vessels (where it is used to approximate the vessel ends). Suturing is performed directly through the gel. Light is used to initiate the final gel–sol phase transition that disrupts the hydrogel network, allowing the gel to be removed and blood flow to resume. This gel adds a new tool to the armamentarium for micro- and supermicrosurgical procedures.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Conceptual design of the peptide hydrogel and its use in light-mediated suturing of ultrasmall vessels.
Figure 2: Molecular design of photosensitive APC1 gel.
Figure 3: Biophysical and mechanical characterization of the hydrogel.
Figure 4: Fibril morphology as a function of photolysis.
Figure 5: Assessment of vessel patency before and after gel-based anastomosis.
Figure 6: Perfusion of mouse lower limb after hydrogel-supported end-to-end anastomosis of the femoral artery.

Similar content being viewed by others

References

  1. Gardiner, M. D. & Nanchahal, J. Strategies to ensure success of microvascular free tissue transfer. J. Plastic Reconst. Aesth. Surg. 63, E665–E673 (2010).

    Article  CAS  Google Scholar 

  2. MacDonald, J. D. Learning to perform microvascular anastomosis. Skull Base 15, 229–240 (2005).

    Article  Google Scholar 

  3. Pratt, G. F. et al. Technology-assisted and sutureless microvascular anastomoses: evidence for current techniques. Microsurgery 32, 68–76 (2012).

    Article  Google Scholar 

  4. Alghoul, M. S. et al. From simple interrupted to complex spiral: a systematic review of various suture techniques for microvascular anastamoses. Microsurgery 31, 72–80 (2011).

    Article  Google Scholar 

  5. Bui, D. T. et al. Free flap reexploration: indications, treatment, and outcomes in 1193 free flaps. Plast. Reconstr. Surg. 119, 2092–2100 (2007).

    Article  CAS  Google Scholar 

  6. Disa, J. J., Cordeiro, P. G. & Hidalgo, D. A. Efficacy of conventional monitoring techniques in free tissue transfer: an 11-year experience in 750 consecutive cases. Plast. Reconstr. Surg. 104, 97–101 (1999).

    Article  CAS  Google Scholar 

  7. Nakayama, Y. & Matsuda, T. Photocurable surgical tissue adhesive glues composed of photoreactive gelatin and poly(ethylene glycol) diacrylate. J. Biomed. Mater. Res. 48, 511–521 (1999).

    Article  CAS  Google Scholar 

  8. Rickett, T. A. et al. Rapidly photo-cross-linkable chitosan hydrogel for peripheral neurosurgeries. Biomacromolecules 12, 57–65 (2011).

    Article  CAS  Google Scholar 

  9. Schneider, J. P. et al. Responsive hydrogels from the intramolecular folding and self-assembly of a designed peptide. J. Am. Chem. Soc. 124, 15030–15037 (2002).

    Article  CAS  Google Scholar 

  10. Nagy, K. J., Giano, M. C., Jin, A., Pochan, D. J. & Schneider, J. P. Enhanced mechanical rigidity of hydrogels formed from enantiomeric peptide assemblies. J. Am. Chem. Soc. 133, 14975–14977 (2011).

    Article  CAS  Google Scholar 

  11. Haines-Butterick, L. et al. Controlling hydrogelation kinetics by peptide design for three-dimensional encapsulation and injectable delivery of cells. Proc. Natl Acad. Sci. USA 104, 7791–7796 (2007).

    Article  CAS  Google Scholar 

  12. Pochan, D. J. et al. Thermally reversible hydrogels via intramolecular folding and consequent self-assembly of a de novo designed peptide. J. Am. Chem. Soc. 125, 11802–11803 (2003).

    Article  CAS  Google Scholar 

  13. Rajagopal, K., Ozbas, B., Pochan, D. J. & Schneider, J. P. Probing the importance of lateral hydrophobic association in self-assembling peptide hydrogelators. Eur. Biophys. J. 35, 162–169 (2006).

    Article  CAS  Google Scholar 

  14. Branco, M. C., Pochan, D. J., Wagner, N. J. & Schneider, J. P. The effect of protein structure on their controlled release from an injectable peptide hydrogel. Biomaterials 31, 9527–9534 (2010).

    Article  CAS  Google Scholar 

  15. Salick, D. A., Pochan, D. J. & Schneider, J. P. Design of an injectable beta-hairpin peptide hydrogel that kills methicillin-resistant Staphylococcus aureus. Adv. Mater. 21, 4120–4123 (2009).

    Article  CAS  Google Scholar 

  16. Sinthuvanich, C., Haines-Butterick, L. A., Nagy, K. J. & Schneider, J. P. Iterative design of peptide-based hydrogels and the effect of network electrostatics on primary chondrocyte behavior. Biomaterials 33, 7478–7488 (2012).

    Article  CAS  Google Scholar 

  17. Rughani, R. V., Branco, M. C., Pochan, D. J. & Schneider, J. P. De novo design of a shear-thin recoverable peptide-based hydrogel capable of intrafibrillar photopolymerization. Macromolecules 43, 7924–7930 (2010).

    Article  CAS  Google Scholar 

  18. Yan, C. Q. et al. Injectable solid hydrogel: mechanism of shear-thinning and immediate recovery of injectable beta-hairpin peptide hydrogels. Soft Matter 6, 5143–5156 (2010).

    Article  CAS  Google Scholar 

  19. Canepari, M., Nelson, L., Papageorgiou, G., Corrie, J. E. T. & Ogden, D. Photochemical and pharmacological evaluation of 7-nitroindolinyl-and 4-methoxy-7-nitroindolinyl-amino acids as novel, fast caged neurotransmitters. J. Neurosci. Methods 112, 29–42 (2001).

    Article  CAS  Google Scholar 

  20. Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nature Neurosci. 4, 1086–1092 (2001).

    Article  CAS  Google Scholar 

  21. Hutchinson, E. G., Sessions, R. B., Thornton, J. M. & Woolfson, D. N. Determinants of strand register in antiparallel beta-sheets of proteins. Protein Sci. 7, 2287–2300 (1998).

    Article  CAS  Google Scholar 

  22. Wouters, M. A. & Curmi, P. M. G. An analysis of side chain interactions and pair correlations within antiparallel beta-sheets—the differences between backbone hydrogen-bonded and non-hydrogen-bonded residue pairs. Prot. Struct. Funct. Genet. 22, 119–131 (1995).

    Article  CAS  Google Scholar 

  23. Huang, Y. et al. Microvascular anastomosis guidance and evaluation using real-time three-dimensional Fourier-domain Doppler optical coherence tomography. J. Biomed. Opt. 18, 111404 (2013).

    Article  Google Scholar 

  24. Huang, Y. et al. Evaluation of microvascular anastomosis using real-time, ultra-high-resolution, Fourier domain Doppler optical coherence tomography. Plast. Reconstr. Surg. 135, 711E–720E (2015).

    Article  CAS  Google Scholar 

  25. Zuman, P. & Shah, B. Addition, reduction, and oxidation reactions of nitrosobenzene. Chem. Rev. 94, 1621–1641 (1994).

    Article  CAS  Google Scholar 

  26. Papageorgiou, G., Ogden, D. & Corrie, J. E. T. An antenna-sensitized nitroindoline precursor to enable photorelease of L-glutamate in high concentrations. J. Org. Chem. 69, 7228–7233 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. The authors thank B. Bush for performing the atomic force microscopy analysis.

Author information

Authors and Affiliations

  1. Chemical Biology Laboratory, National Cancer Institute, Frederick, 21702, Maryland, USA

    Daniel J. Smith, Scott H. Medina, Katelyn J. Nagy-Smith & Joel P. Schneider

  2. Department of Chemistry and Biochemistry, University of Delaware, Newark, 19716, Delaware, USA

    Daniel J. Smith & Katelyn J. Nagy-Smith

  3. Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Gabriel A. Brat, Dedi Tong, Johanna Grahammer, Georg J. Furtmüller, Byoung Chol Oh & Gerald Brandacher

  4. Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, 21218, Maryland, USA

    Yong Huang

  5. Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Piotr Walczak

Authors
  1. Daniel J. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriel A. Brat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott H. Medina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dedi Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Johanna Grahammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Georg J. Furtmüller
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Byoung Chol Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Katelyn J. Nagy-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Piotr Walczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gerald Brandacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Joel P. Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.J.S., G.A.B., G.B. and J.P.S. conceived the research. D.J.S., S.H.M. and K.J.N.-S. were responsible for the synthesis, biophysical and rheological characterization of the materials. G.A.B., D.T., Y.H., J.G., G.J.F., B.C.O., P.W. and S.H.M. performed animal experiments. D.J.S., S.H.M., G.B. and J.P.S. wrote the manuscript.

Corresponding author

Correspondence to Joel P. Schneider.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 5276 kb)

Supplementary Movie 1

Supplementary Movie 1 (MOV 12529 kb)

Supplementary Movie 2

Supplementary Movie 2 (MOV 94039 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Smith, D., Brat, G., Medina, S. et al. A multiphase transitioning peptide hydrogel for suturing ultrasmall vessels. Nature Nanotech 11, 95–102 (2016). https://doi.org/10.1038/nnano.2015.238

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2015.238

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research