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Light-Activated Adhesive Seals Tissues

An easy way to repair vessels or attach devices to tissues would be welcomed by surgeons. An adhesive, for instance, can reconnect tissue and interface prosthetics, but currently available materials have limitations such as low strength, high toxicity, and most do not function well in wet environments. In response, Lang and colleagues developed a new biomaterial glue that is biocompatible, biodegradable, and easily manipulated. This material, called poly(glycerol sebacate acrylate) (PGSA), when combined with a photoinitiator, creates a solution that the authors called HLAA: hydrophobic light-activated adhesive. The HLAA is a thick gel that can be slathered on a tissue and then cross-linked within seconds by ultraviolet light, which is a unique feature that avoids stitches. The resulting bond is water-tight yet flexible and stays intact in the face of high pressure and flowing blood. The authors first tested their material in rats, showing that the HLAA could be used to attach a polymer patch to the heart and that the HLAA alone could seal up defects in the heart wall, performing as well as sutures. Lang et al. then moved into pigs, whose hearts beat at similar rates to humans (by contrast, rats have much higher heart rates). Lang et al. showed that the light-activated adhesive could attach a patch to the interventricular septum of a pig’s beating heart and that this patch remained in place even under higher than normal heart rates (induced by adrenaline). Additionally, the HLAA alone was able to immediately close up defects in the pig carotid artery without any bleeding complications.
The light-responsive adhesive performed well in several different in vivo scenarios, suggesting its broad applicability in the clinic, at least for cardiovascular surgeries and defects. As an added bonus, components of PGSA—namely, glycerol and sebacic acid—exist in the body and are readily metabolized. It is expected that this material could be translated soon to use in people.

Abstract

Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis.
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Supplementary Material

Summary

Materials and Methods
Fig. S1. Rheologic properties of the PGSA prepolymer.
Fig. S2. The adhesive strength of the HLAA to cardiac tissue varies with the degree of acrylation.
Fig. S3. UV light transmitted through multiple patch materials.
Fig. S4. FTIR evaluation of the HLAA.
Fig. S5. Adhesive strength of the HLAA.
Fig. S6. Approach for testing the adhesive strength of the HLAA or CA in the presence of flowing blood.
Fig. S7 HLAA cytocompatibility.
Fig. S8. Cardiac function over the course of the study in the in vivo biocompatibility study and LV wall defect model.
Fig. S9. Patch delivery system.
Movie S1. Closure of a transmural LV wall defect with an HLAA-coated patch.
Movie S2. The HLAA-coated patch resists supraphysiologic, highly dynamic conditions inside the chamber of the heart.

Resources

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Information & Authors

Information

Published In

Science Translational Medicine
Volume 6Issue 2188 January 2014
Pages: 218ra6
PubMed: 24401941

History

Received: 13 May 2013
Accepted: 5 November 2013

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Acknowledgments

We thank P. Hammer for critical comments throughout the project; K. Mullen, A. Nedder, and H. Yamauchi for assistance with the in vivo experiments; O. Miranda for assistance with the NMR; W. Fowle for assistance with SEM; and ADMET Inc. for providing an eXpert 7601 mechanical tester that was instrumental for this work. Funding: This work was supported by the Center for Integration of Medicine and Innovative Technology grant 11-315 and W81XWH-09-2-0001, the Technology Research Program grant of Boston Children’s Hospital, and NIH grant HL73647 to P.J.d.N. This work was also supported by the NIH grants GM086433 (to J.M.K.) and DE013023 (to R.L.). M.J.P. acknowledges the Portuguese Foundation for Science and Technology (fellowship SFR/BD/43013/2008) and the MIT-Portugal program (bioengineering focus area). N.L. acknowledges the German Research Foundation (DFG) for financial support (LA 2865/1-1). Author contributions: N.L., M.J.P., R.L., J.M.K., and P.J.d.N. developed the concept and designed the experiments. N.L., M.J.P., Y.L., and C.X. performed the adhesion tests. N.L., M.J.P., I.F., N.V.V., E.N.F., K.A., and A.F. performed the in vivo experiments. M.J.P. and Y.L. performed the synthesis and chemical characterization of the materials. N.L., M.J.P., I.F., E.D.O., S.W., and F.F. designed and characterized the devices for patch application. N.L. performed the echocardiography and analyzed the images. N.L., M.J.P., J.M.K., L.S.F., Y.L., and P.J.d.N. analyzed the data. N.L. and M.J.P. performed the statistical analysis. R.P. performed the histological analysis of tissue samples. N.L., M.J.P., J.M.K., and P.J.d.N. wrote the manuscript. All authors provided critical feedback on the manuscript. Competing interests: J.M.K. and R.L. hold equity in Gecko Biomedical, a company that has an option to license IP generated by J.M.K. and R.L. and that may benefit financially if the IP is licensed and further validated. The interests of J.M.K and R.L. were reviewed and are subject to a management plan overseen by their institutions in accordance with their conflict of interest policies. J.M.K., R.L., P.J.d.N., L.S.F., N.L., and M.J.P. have filed patents based on materials described in this manuscript.

Authors

Affiliations

Nora Lang*,
Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Maria J. Pereira*
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Biotechnology Innovation Center and Center of Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Yuhan Lee
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Ingeborg Friehs
Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Nikolay V. Vasilyev
Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Eric N. Feins
Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Klemens Ablasser
Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Eoin D. O’Cearbhaill§
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Chenjie Xu
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Assunta Fabozzo
Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Robert Padera
Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA.
Steve Wasserman
Department of Biological Engineering, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
Franz Freudenthal
Department of Pediatric Cardiology, Kardiozentrum, Obrajes, Calle 14, 669 La Paz, Bolivia.
Lino S. Ferreira
Biotechnology Innovation Center and Center of Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Robert Langer
Department of Chemical Engineering and the David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Jeffrey M. Karp [email protected]
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of Health Sciences and Technology, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Pedro J. del Nido [email protected]
Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Notes

*
These authors are first co-authors.
Present address: Department of Congenital Heart Defects and Pediatric Cardiology, Heart Center Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany.
These authors are second co-authors.
§
Present address: School of Mechanical & Materials Engineering, University College Dublin, Dublin 4, Ireland.
Present address: Division of Bioengineering, Department of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637457, Singapore.
¶Corresponding author. E-mail: [email protected] (J.M.K.); [email protected] (P.J.d.N.)

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Science Translational Medicine
Volume 6|Issue 218
January 2014
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Received:13 May 2013
Accepted:5 November 2013
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