Overcoming the translational barriers of tissue adhesives

For the past few decades, tissue sealants and adhesives have been developed as an alternative to sutures and staples to close and seal wounds or incisions. These materials are advantageous because of their ease of use, short application time and minimal tissue damage, making them suitable for minimally invasive procedures. However, there is a large gap between the amount of research into tissue adhesives and the number of products available. To bridge this gap, there is a need to better understand the challenges to clinical translation of tissue adhesives. In particular, adhesive design must be informed by a deep understanding of the target tissue’s surface characteristics and environment, which vary considerably among tissue types. Moreover, understanding and monitoring the long-term performance of a material post-implantation is crucial; this includes monitoring the chemical and physical properties of the implanted adhesives over time, tissue responses and the resultant changes in adhesion and cohesion. In addition, early-stage consideration of the unmet clinical need and the regulatory and development paths could lower the barriers in the development cost and effort, facilitating clinical translation. In this Review, we identify challenges in the development of tissue adhesives and provide design criteria to translate tissue-adhesive technologies into clinical practice.

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References

  1. Market Research Engine. Global wound closure products market expected to be worth US $ 15 billion by 2022 (Market Research Engine, 2018).
  2. Artzi, N. Sticking with the pattern for a safer glue. Sci. Transl Med.5, 205ec161 (2013). Google Scholar
  3. George, W. D. Suturing or stapling in gastrointestinal surgery: a prospective randomized study. Br. J. Surg.78, 337–341 (1991). Google Scholar
  4. Slieker, J. C., Daams, F., Mulder, I. M., Jeekel, J. & Lange, J. F. Systematic review of the technique of colorectal anastomosis. JAMA Surg.148, 190–201 (2013). Google Scholar
  5. Edmiston, C. E. et al. Microbiology of explanted suture segments from infected and noninfected surgical patients. J. Clin. Microbiol.51, 417–421 (2013). CASGoogle Scholar
  6. Owens, C. D. & Stoessel, K. Surgical site infections: epidemiology, microbiology and prevention. J. Hosp. Infect.70, 3–10 (2008). Google Scholar
  7. Matossian, C., Makari, S. & Potvin, R. Cataract surgery and methods of wound closure: a review. Clin. Ophthalmol.9, 921–928 (2015). Google Scholar
  8. Masket, S. et al. Hydrogel sealant versus sutures to prevent fluid egress after cataract surgery. J. Cataract Refract. Surg.40, 2057–2066 (2014). Google Scholar
  9. Lequaglie, C., Giudice, G., Marasco, R., Morte, A. D. & Gallo, M. Use of a sealant to prevent prolonged air leaks after lung resection: a prospective randomized study. J. Cardiothorac. Surg.7, 106 (2012). Google Scholar
  10. Lang, N. et al. A blood-resistant surgical glue for minimally invasive repair of vessels and heart defects. Sci. Transl Med.6, 218ra6 (2014). Google Scholar
  11. Sidle, D. M., Loos, B. M., Ramirez, A. L., Kabaker, S. S. & Maas, C. S. Use of BioGlue surgical adhesive for brow fixation in endoscopic browplasty. Arch. Facial Plast. Surg.7, 393–397 (2005). Google Scholar
  12. Petersen, B. et al. Tissue adhesives and fibrin glues. Gastrointest. Endosc.60, 327–333 (2004). Google Scholar
  13. Grand View Research. Surgical sealants and adhesives market analysis by type (natural or biological adhesives & sealants, synthetic & semi synthetic adhesives), by application, by region, and segment forecasts, 2018–2025 (Grand View Research, 2017).
  14. Cronkite, E. P., Lozner, E. L. & Deaver, J. M. Use of thrombin and fibrinogen in skin grafting: preliminary report. JAMA124, 976–978 (1944). Google Scholar
  15. Young, J. Z. & Medawar, P. B. Fibrin suture of peripheral nerves: measurement of the rate of regeneration. Lancet236, 126–128 (1940). Google Scholar
  16. Spotnitz, W. D. Fibrin sealant: past, present, and future: a brief review. World J. Surg.34, 632–634 (2010). Google Scholar
  17. Spotnitz, W. D. Fibrin sealant: the only approved hemostat, sealant, and adhesive – a laboratory and clinical perspective. ISRN Surg.2014, 203943 (2014). Google Scholar
  18. Gundry, S. R., Black, K. & Izutani, H. Sutureless coronary artery bypass with biologic glued anastomoses: preliminary in vivo and in vitro results. J. Thorac. Cardiovasc. Surg.120, 473–477 (2000). CASGoogle Scholar
  19. Chao, H.-H. & Torchiana, D. F. BioGlue: albumin/glutaraldehyde sealant in cardiac surgery. J. Card. Surg.18, 500–503 (2003). Google Scholar
  20. Singer, A. J., Perry, L. C. & Allen, R. L. Jr In vivo study of wound bursting strength and compliance of topical skin adhesives. Acad. Emerg. Med.15, 1290–1294 (2008). Google Scholar
  21. Leggat, P. A., Smith, D. R. & Kedjarune, U. Surgical applications of cyanoacrylate adhesives: a review of toxicity. ANZ J. Surg.77, 209–213 (2007). Google Scholar
  22. Pascual, G. et al. Cytotoxicity of cyanoacrylate-based tissue adhesives and short-term preclinical in vivo biocompatibility in abdominal hernia repair. PLOS ONE11, e0157920 (2016). Google Scholar
  23. Dumville, J. C. et al. Tissue adhesives for closure of surgical incisions. Cochrane Database Syst. Rev.28, CD004287 (2014). Google Scholar
  24. Oliva, N. et al. Personalizing biomaterials for precision nanomedicine considering the local tissue microenvironment. Adv. Healthc. Mater.4, 1584–1599 (2015). CASGoogle Scholar
  25. Bhagat, V. & Becker, M. L. Degradable adhesives for surgery and tissue engineering. Biomacromolecules18, 3009–3039 (2017). CASGoogle Scholar
  26. Artzi, N. et al. In vivo and in vitro tracking of erosion in biodegradable materials using non-invasive fluorescence imaging. Nat. Mater.10, 704–709 (2011). CASGoogle Scholar
  27. Oliva, N. et al. Regulation of dendrimer/dextran material performance by altered tissue microenvironment in inflammation and neoplasia. Sci. Transl Med.7, 272ra11 (2015). Google Scholar
  28. López-Guerra, D. et al. Postoperative bleeding and biliary leak after liver resection: a cohort study between two different fibrin sealant patches. Sci. Rep.9, 12001 (2019). Google Scholar
  29. Vakalopoulos, K. et al. Mechanical strength and rheological properties of tissue adhesives with regard to colorectal anastomosis: an ex vivo study. Ann. Surg.261, 323–331 (2015). Google Scholar
  30. Jue, B. & Maurice, D. M. The mechanical properties of the rabbit and human cornea. J. Biomech.19, 847–853 (1986). CASGoogle Scholar
  31. Khanafer, K. et al. Determination of the elastic modulus of ascending thoracic aortic aneurysm at different ranges of pressure using uniaxial tensile testing. J. Thorac. Cardiovasc. Surg.142, 682–686 (2011). Google Scholar
  32. Park, D. Y. et al. The use of microfluidic spinning fiber as an ophthalmology suture showing the good anastomotic strength control. Sci. Rep.7, 16264 (2017). Google Scholar
  33. Roy, C. K. et al. Self-adjustable adhesion of polyampholyte hydrogels. Adv. Mater.27, 7344–7348 (2015). CASGoogle Scholar
  34. Li, J. et al. Tough adhesives for diverse wet surfaces. Science357, 378–381 (2017). CASGoogle Scholar
  35. Liu, B. et al. Hydrogen bonds autonomously powered gelatin methacrylate hydrogels with super-elasticity, self-heal and underwater self-adhesion for sutureless skin and stomach surgery and E-skin. Biomaterials171, 83–96 (2018). CASGoogle Scholar
  36. Fan, H., Wang, J., Zhang, Q. & Jin, Z. Tannic acid-based multifunctional hydrogels with facile adjustable adhesion and cohesion contributed by polyphenol supramolecular chemistry. ACS Omega2, 6668–6676 (2017). CASGoogle Scholar
  37. Matsuda, M., Inoue, M. & Taguchi, T. Adhesive properties and biocompatibility of tissue adhesives composed of various hydrophobically modified gelatins and disuccinimidyl tartrate. J. Bioact. Compat. Polym.27, 481–498 (2012). Google Scholar
  38. Mizuta, R. & Taguchi, T. Enhanced sealing by hydrophobic modification of Alaska pollock-derived gelatin-based surgical sealants for the treatment of pulmonary air leaks. Macromol. Biosci.17, 1600349 (2017). Google Scholar
  39. Yoshizawa, K. & Taguchi, T. Bonding behavior of hydrophobically modified gelatin films on the intestinal surface. J. Bioact. Compat. Polym.29, 560–571 (2014). CASGoogle Scholar
  40. Matsuda, M., Inoue, M. & Taguchi, T. Enhanced bonding strength of a novel tissue adhesive consisting of cholesteryl group-modified gelatin and disuccinimidyl tartarate. J. Bioact. Compat. Polym.27, 31–44 (2012). CASGoogle Scholar
  41. Michel, R. et al. Interfacial fluid transport is a key to hydrogel bioadhesion. Proc. Natl Acad. Sci. USA116, 738–743 (2019). CASGoogle Scholar
  42. Rogers, A. C., Turley, L. P., Cross, K. S. & McMonagle, M. P. Meta-analysis of the use of surgical sealants for suture-hole bleeding in arterial anastomoses. Br. J. Surg.103, 1758–1767 (2016). CASGoogle Scholar
  43. Murdock, M. H. et al. Cytocompatibility and mechanical properties of surgical sealants for cardiovascular applications. J. Thorac. Cardiovasc. Surg.157, 176–183 (2019). Google Scholar
  44. Matthews, P. B. et al. Mechanical properties of surgical glues used in aortic root replacement. Ann. Thorac. Surg.87, 1154–1160 (2009). Google Scholar
  45. Natour, E., Suedkamp, M. & Dapunt, O. E. Assessment of the effect on blood loss and transfusion requirements when adding a polyethylene glycol sealant to the anastomotic closure of aortic procedures: a case–control analysis of 102 patients undergoing Bentall procedures. J. Cardiothorac. Surg.7, 105 (2012). Google Scholar
  46. Skorpil, J. et al. Effective and rapid sealing of coronary, aortic and atrial suture lines. Interact. Cardiovasc. Thorac. Surg.20, 720–724 (2015). Google Scholar
  47. Bhamidipati, C. M., Coselli, J. S. & LeMaire, S. A. BioGlue® in 2011: what is its role in cardiac surgery? J. Extra. Corpor. Technol.44, P6–P12 (2012). Google Scholar
  48. LeMaire, S. A. et al. Nerve and conduction tissue injury caused by contact with BioGlue. J. Surg. Res.143, 286–293 (2007). CASGoogle Scholar
  49. LeMaire, S. A. et al. BioGlue surgical adhesive impairs aortic growth and causes anastomotic strictures. Ann. Thorac. Surg.73, 1500–1506 (2002). Google Scholar
  50. Pasic, M., Unbehaun, A., Drews, T. & Hetzer, R. Late wound healing problems after use of BioGlue® for apical hemostasis during transapical aortic valve implantation. Interact. Cardiovasc. Thorac. Surg.13, 532–535 (2011). Google Scholar
  51. Fürst, W. & Banerjee, A. Release of glutaraldehyde from an albumin-glutaraldehyde tissue adhesive causes significant in vitro and in vivo toxicity. Ann. Thorac. Surg.79, 1522–1528 (2005). Google Scholar
  52. Park, J. S. et al. Risk factors of anastomotic leakage and long-term survival after colorectal surgery. Medicine95, e2890 (2016). Google Scholar
  53. Phillips, B. Reducing gastrointestinal anastomotic leak rates: review of challenges and solutions. Open Access Surg.9, 5–14 (2016). Google Scholar
  54. Bae, K.-B., Kim, S.-H., Jung, S.-J. & Hong, K.-H. Cyanoacrylate for colonic anastomosis; is it safe? Int. J. Colorectal Dis.25, 601–606 (2010). Google Scholar
  55. Vuocolo, T. et al. A highly elastic and adhesive gelatin tissue sealant for gastrointestinal surgery and colon anastomosis. J. Gastrointest. Surg.16, 744–752 (2012). Google Scholar
  56. Li, Y.-W. et al. Very early colorectal anastomotic leakage within 5 post-operative days: a more severe subtype needs relaparatomy. Sci. Rep.7, 39936 (2017). CASGoogle Scholar
  57. Hyman, N., Manchester, T. L., Osler, T., Burns, B. & Cataldo, P. A. Anastomotic leaks after intestinal anastomosis: it’s later than you think. Ann. Surg.245, 254–258 (2007). Google Scholar
  58. Silecchia, G. et al. The use of fibrin sealant to prevent major complications following laparoscopic gastric bypass: results of a multicenter, randomized trial. Surg. Endosc.22, 2492–2497 (2008). Google Scholar
  59. Slieker, J. C., Vakalopoulos, K. A., Komen, N. A., Jeekel, J. & Lange, J. F. Prevention of leakage by sealing colon anastomosis: experimental study in a mouse model. J. Surg. Res.184, 819–824 (2013). Google Scholar
  60. Trotter, J. et al. The use of a novel adhesive tissue patch as an aid to anastomotic healing. Ann. R. Coll. Surg. Engl.100, 230–234 (2018). CASGoogle Scholar
  61. Vakalopoulos, K. A. et al. Tissue adhesives in gastrointestinal anastomosis: a systematic review. J. Surg. Res.180, 290–300 (2013). CASGoogle Scholar
  62. Nordentoft, T., Pommergaard, H. C., Rosenberg, J. & Achiam, M. P. Fibrin glue does not improve healing of gastrointestinal anastomoses: a systematic review. Eur. Surg. Res.54, 1–13 (2014). Google Scholar
  63. Goulder, F. Bowel anastomoses: the theory, the practice and the evidence base. World J. Gastrointest. Surg.4, 208–213 (2012). Google Scholar
  64. Urbanavičius, L., Pattyn, P., Van de Putte, D. & Venskutonis, D. How to assess intestinal viability during surgery: a review of techniques. World J. Gastrointest. Surg.3, 59–69 (2011). Google Scholar
  65. Shogan, B. D. et al. Collagen degradation and MMP9 activation by Enterococcus faecalis contribute to intestinal anastomotic leak. Sci. Transl Med.7, 286ra68 (2015). Google Scholar
  66. Shogan, B. D. et al. Intestinal anastomotic injury alters spatially defined microbiome composition and function. Microbiome.2, 35 (2014). Google Scholar
  67. van Praagh, J. B. et al. Intestinal microbiota and anastomotic leakage of stapled colorectal anastomoses: a pilot study. Surg. Endosc.30, 2259–2265 (2016). Google Scholar
  68. Shakhsheer, B. et al. Morphine promotes colonization of anastomotic tissues with collagenase-producing Enterococcus faecalis and causes leak. J. Gastrointest. Surg.20, 1744–1751 (2016). Google Scholar
  69. Gaines, S., Shao, C., Hyman, N. & Alverdy, J. C. Gut microbiome influences on anastomotic leak and recurrence rates following colorectal cancer surgery. Br. J. Surg.105, e131–e141 (2018). CASGoogle Scholar
  70. Pommergaard, H. C., Rosenberg, J., Schumacher-Petersen, C. & Achiam, M. P. Choosing the best animal species to mimic clinical colon anastomotic leakage in humans: a qualitative systematic review. Eur. Surg. Res.47, 173–181 (2011). CASGoogle Scholar
  71. Nagel, S. J. et al. Spinal dura mater: biophysical characteristics relevant to medical device development. J. Med. Eng. Technol.42, 128–139 (2018). Google Scholar
  72. Protasoni, M. et al. The collagenic architecture of human dura mater. J. Neurosurg.114, 1723–1730 (2011). Google Scholar
  73. Hutter, G., von Felten, S., Sailer, M. H., Schulz, M. & Mariani, L. Risk factors for postoperative CSF leakage after elective craniotomy and the efficacy of fleece-bound tissue sealing against dural suturing alone: a randomized controlled trial. J. Neurosurg.121, 735–744 (2014). Google Scholar
  74. Esposito, F. et al. Fibrin sealants in dura sealing: a systematic literature review. PLOS ONE12, e0175619 (2016). Google Scholar
  75. Yu, F. et al. Current developments in dural repair: a focused review on new methods and materials. Front. Biosci.18, 1335–1343 (2013). CASGoogle Scholar
  76. Narotam, P. K., Qiao, F. & Nathoo, N. Collagen matrix duraplasty for posterior fossa surgery: evaluation of surgical technique in 52 adult patients. J. Neurosurg.111, 380–386 (2009). Google Scholar
  77. Spotnitz, W. D. in Musculoskeletal Tissue Regeneration (ed. Pietrzak, W. S.) 531–546 (Humana, 2008).
  78. Kim, K. D. et al. DuraSeal Exact is a safe adjunctive treatment for durotomy in spine: postapproval study. Global Spine J.9, 272–278 (2018). Google Scholar
  79. Kinaci, A. et al. Effectiveness of dural sealants in prevention of CSF leakage after craniotomy: a systematic review. World Neurosurg.118, 368–376 (2018). Google Scholar
  80. Van Doormaal, T. et al. Usefulness of sealants for dural closure: evaluation in an in vitro model. Oper. Neurosurg.15, 425–432 (2017). Google Scholar
  81. Lee, S.-H., Park, C.-W., Lee, S.-G. & Kim, W.-K. Postoperative cervical cord compression induced by hydrogel dural sealant (DuraSeal®). Korean J. Spine10, 44–46 (2013). Google Scholar
  82. Smyth, M. D. Hydrogel-induced cervicomedullary compression after posterior fossa decompression for Chiari malformation. J. Neurosurg. Pediatr.106, 302–304 (2007). Google Scholar
  83. Chenault, H. K. et al. Sealing and healing of clear corneal incisions with an improved dextran aldehyde-PEG amine tissue adhesive. Curr. Eye Res.36, 997–1004 (2011). CASGoogle Scholar
  84. Park, H. C., Champakalakshmi, R., Panengad, P. P., Raghunath, M. & Mehta, J. S. Tissue adhesives in ocular surgery. Expert. Rev. Ophthalmol.6, 631–655 (2011). Google Scholar
  85. Baker-Schena, L. Ocular sealants: one new option, but still room for innovation (EyeNet Magazine, 2014).
  86. Refojo, M. F. Current status of biomaterials in ophthalmology. Surv. Ophthalmol.26, 257–265 (1982). CASGoogle Scholar
  87. Sharma, A. et al. Fibrin glue versus N-butyl-2-cyanoacrylate in corneal perforations. Ophthalmology110, 291–298 (2003). Google Scholar
  88. Kasetsuwan, N. et al. Efficacy and safety of ethyl-2-cyanoacrylate adhesives for corneal gluing. Asian Biomed.7, 437–441 (2013). CASGoogle Scholar
  89. Bhatia, S. S. Ocular surface sealants and adhesives. Ocul. Surf.4, 146–154 (2006). Google Scholar
  90. Guhan, S. et al. Surgical adhesives in ophthalmology: history and current trends. Br. J. Ophthalmol.102, 1328–1335 (2018). Google Scholar
  91. Nallasamy, N., Grove, K. E., Legault, G. L., Daluvoy, M. B. & Kim, T. Hydrogel ocular sealant for clear corneal incisions in cataract surgery. J. Cataract Refract. Surg.43, 1010–1014 (2017). Google Scholar
  92. US Food and Drug Administration. ReSure® sealant. Summary of safety and effectiveness data (FDA, 2013).
  93. Wain, J. C. et al. Trial of a novel synthetic sealant in preventing air leaks after lung resection. Ann. Thorac. Surg.71, 1623–1629 (2001). CASGoogle Scholar
  94. Okereke, I., Murthy, S. C., Alster, J. M., Blackstone, E. H. & Rice, T. W. Characterization and importance of air leak after lobectomy. Ann. Thorac. Surg.79, 1167–1173 (2005). Google Scholar
  95. Malapert, G., Hanna, H. A., Pages, P. B. & Bernard, A. Surgical sealant for the prevention of prolonged air leak after lung resection: meta-analysis. Ann. Thorac. Surg.90, 1779–1785 (2010). Google Scholar
  96. Annabi, N. et al. Engineering a highly elastic human protein-based sealant for surgical applications. Sci. Transl Med.9, eaai7466 (2017). Google Scholar
  97. Fenn, S. L., Charron, P. N. & Oldinski, R. A. Anticancer therapeutic alginate-based tissue sealants for lung repair. ACS Appl. Mater. Interfaces9, 23409–23419 (2017). CASGoogle Scholar
  98. Santini, M. et al. Use of an electrothermal bipolar tissue sealing system in lung surgery. Eur. J. Cardiothorac. Surg.29, 226–230 (2006). Google Scholar
  99. US Food and Drug Administration. Premarket approval (PMA) for ProGEL pleural air leak sealant (FDA, 2010).
  100. Belda-Sanchís, J., Serra-Mitjans, M., Iglesias Sentis, M. & Rami, R. Surgical sealant for preventing air leaks after pulmonary resections in patients with lung cancer. Cochrane Database Syst. Rev.20, CD003051 (2010). Google Scholar
  101. ASTM International. ASTM F2392-04(2015). Standard test method for burst strength of surgical sealants (ASTM, 2015).
  102. ASTM International. ASTM F2458-05(2015), standard test method for wound closure Strength of tissue adhesives and sealants (ASTM, 2015).
  103. Ghobril, C. & Grinstaff, M. W. The chemistry and engineering of polymeric hydrogel adhesives for wound closure: a tutorial. Chem. Soc. Rev.44, 1820–1835 (2015). CASGoogle Scholar
  104. Annabi, N. et al. Surgical materials: current challenges and nano-enabled solutions. Nano Today9, 574–589 (2014). CASGoogle Scholar
  105. Annabi, N., Yue, K., Tamayol, A. & Khademhosseini, A. Elastic sealants for surgical applications. Eur. J. Pharm. Biopharm.95, 27–39 (2015). CASGoogle Scholar
  106. Duarte, A. P., Coelho, J. F., Bordado, J. C., Cidade, M. T. & Gil, M. H. Surgical adhesives: systematic review of the main types and development forecast. Prog. Polym. Sci.37, 1031–1050 (2012). CASGoogle Scholar
  107. Zhu, W., Chuah, Y. J. & Wang, D.-A. Bioadhesives for internal medical applications: a review. Acta Biomater.74, 1–16 (2018). CASGoogle Scholar
  108. Nair, L. S. & Laurencin, C. T. Biodegradable polymers as biomaterials. Prog. Polym. Sci.32, 762–798 (2007). CASGoogle Scholar
  109. Khanlari, S. & Dubé, M. A. Bioadhesives: a review. Macromol. React. Eng.7, 573–587 (2013). CASGoogle Scholar
  110. Marin, E., Briceño, M. I. & Caballero-George, C. Critical evaluation of biodegradable polymers used in nanodrugs. Int. J. Nanomed.8, 3071–3091 (2013). Google Scholar
  111. Caliceti, P. & Veronese, F. M. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)–protein conjugates. Adv. Drug Deliv. Rev.55, 1261–1277 (2003). CASGoogle Scholar
  112. Kean, T. & Thanou, M. Biodegradation, biodistribution and toxicity of chitosan. Adv. Drug Deliv. Rev.62, 3–11 (2010). CASGoogle Scholar
  113. Yamaoka, T., Tabata, Y. & Ikada, Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci.83, 601–606 (1994). CASGoogle Scholar
  114. Menovsky, T. et al. Massive swelling of Surgicel® Fibrillar™ hemostat after spinal surgery. case report and a review of the literature. Minim. Invasive Neurosurg.54, 257–259 (2011). CASGoogle Scholar
  115. Shazly, T. M. et al. Augmentation of postswelling surgical sealant potential of adhesive hydrogels. J. Biomed. Mater. Res. A95, 1159–1169 (2010). Google Scholar
  116. Buchowski, J., Good, C., Lenke, L. & Bridwell, K. Epidural spinal cord compression with neurologic deficit associated with intrapedicular application of FloSeal during pedicle screw insertion. Spine J.8, 120S–121S (2008). Google Scholar
  117. Pinkas, O. & Zilberman, M. Novel gelatin–alginate surgical sealants loaded with hemostatic agents. Int. J. Polym. Mater.66, 378–387 (2017). CASGoogle Scholar
  118. Unterman, S. et al. Hydrogel nanocomposites with independently tunable rheology and mechanics. ACS Nano11, 2598–2610 (2017). CASGoogle Scholar
  119. Barrett, D. G., Bushnell, G. G. & Messersmith, P. B. Mechanically robust, negative-swelling, mussel-inspired tissue adhesives. Adv. Healthc. Mater.2, 745–755 (2013). CASGoogle Scholar
  120. Cho, E., Lee, J. S. & Webb, K. Formulation and characterization of poloxamine-based hydrogels as tissue sealants. Acta Biomater.8, 2223–2232 (2012). CASGoogle Scholar
  121. Zhang, H. et al. On-demand and negative-thermo-swelling tissue adhesive based on highly branched ambivalent PEG–catechol copolymers. J. Mater. Chem. B3, 6420–6428 (2015). CASGoogle Scholar
  122. Feng, Q. et al. One-pot solvent exchange preparation of non-swellable, thermoplastic, stretchable and adhesive supramolecular hydrogels based on dual synergistic physical crosslinking. npg Asia Mater.10, e455 (2018). Google Scholar
  123. Li, C., Sajiki, T., Nakayama, Y., Fukui, M. & Matsuda, T. Novel visible-light-induced photocurable tissue adhesive composed of multiply styrene-derivatized gelatin and poly(ethylene glycol) diacrylate. J. Biomed. Mater. Res. B Appl. Biomater.66B, 439–446 (2003). CASGoogle Scholar
  124. Strong, M. J. et al. A pivotal randomized clinical trial evaluating the safety and effectiveness of a novel hydrogel dural sealant as an adjunct to dural repair. Oper. Neurosurg.13, 204–212 (2017). Google Scholar
  125. US Food and Drug Administration. Premarket approval (PMA) for adherus autospray dural sealant (FDA, 2015).
  126. Behrens, A. M. et al. Blood-aggregating hydrogel particles for use as a hemostatic agent. Acta Biomater.10, 701–708 (2014). CASGoogle Scholar
  127. Artzi, N., Shazly, T., Baker, A. B., Bon, A. & Edelman, E. R. Aldehyde-amine chemistry enables modulated biosealants with tissue-specific adhesion. Adv. Mater.21, 3399–3403 (2009). CASGoogle Scholar
  128. Hoang Thi, T. T., Lee, Y., Park, K. M. & Park, K. D. Enhanced tissue adhesiveness of injectable gelatin-based hydrogels using thiomer. Front. Bioeng. Biotechnol.https://doi.org/10.3389/conf.FBIOE.2016.01.01392 (2016).
  129. Li, S. Hydrolytic degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids. J. Biomed. Mater. Res.48, 342–353 (1999). CASGoogle Scholar
  130. Piskin, E. Biodegradable polymers as biomaterials. J. Biomater. Sci. Polym. Ed.6, 775–795 (1994). Google Scholar
  131. Laycock, B. et al. Lifetime prediction of biodegradable polymers. Prog. Polym. Sci.71, 144–189 (2017). CASGoogle Scholar
  132. Lyu, S. & Untereker, D. Degradability of polymers for implantable biomedical devices. Int. J. Mol. Sci.10, 4033–4065 (2009). CASGoogle Scholar
  133. Anderson, J. M., Rodrigues, A. & Chang, D. T. Foreign body reaction to biomaterials. Semin. Immunol.20, 86–100 (2007). Google Scholar
  134. Franz, S., Rammelt, S., Scharnweber, D. & Simon, J. Immune responses to implants – a review of the implications for the design of immunomodulatory biomaterials. Biomaterials32, 6692–6709 (2011). CASGoogle Scholar
  135. Kopeček, J. & Ulbrich, K. Biodegradation of biomedical polymers. Prog. Polym. Sci.9, 1–58 (1983). Google Scholar
  136. Li, Y., Rodrigues, J. & Tomas, H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chem. Soc. Rev.41, 2193–2221 (2012). CASGoogle Scholar
  137. Kong, H. J., Kaigler, D., Kim, K. & Mooney, D. J. Controlling rigidity and degradation of alginate hydrogels via molecular weight distribution. Biomacromolecules5, 1720–1727 (2004). CASGoogle Scholar
  138. Charriere, G., Bejot, M., Schnitzler, L., Ville, G. & Hartmann, D. J. Reactions to a bovine collagen implant: clinical and immunologic study in 705 patients. J. Am. Acad. Dermatol.21, 1203–1208 (1989). CASGoogle Scholar
  139. Cooperman, L. & Michaeli, D. The immunogenicity of injectable collagen. I. A 1-year prospective study. J. Am. Acad. Dermatol.10, 638–646 (1984). CASGoogle Scholar
  140. Pereira, M. J. N. et al. Combined surface micropatterning and reactive chemistry maximizes tissue adhesion with minimal inflammation. Adv. Healthc. Mater.3, 565–571 (2014). CASGoogle Scholar
  141. Sebesta, M. J. & Bishoff, J. T. Octylcyanoacrylate skin closure in laparoscopy. J. Endourol.17, 899–903 (2004). Google Scholar
  142. Epstein, N. Dural repair with four spinal sealants: focused review of the manufacturers’ inserts and the current literature. Spine J.10, 1065–1068 (2010). Google Scholar
  143. Tamariz, E. et al. Delivery of chemotropic proteins and improvement of dopaminergic neuron outgrowth through a thixotropic hybrid nano-gel. J. Mater. Sci. Mater. Med.22, 2097 (2011). CASGoogle Scholar
  144. Woo, W., Hong, S., Kim, T.-H., Baek, M.-Y. & Song, S.-W. Delayed pulmonary artery rupture after using BioGlue in cardiac surgery. Korean J. Thorac. Cardiovasc. Surg.50, 474–476 (2017). Google Scholar
  145. Gaffen, A. & Coleman, G. BioGlue surgical adhesive: reported incidents of chronic inflammation and foreign-body reactions. Can. Med. Assoc. J.175, 1013 (2006). Google Scholar
  146. Ngaage, D. L., Edwards, W. D., Bell, M. R. & Sundt, T. M. A cautionary note regarding long-term sequelae of biologic glue. J. Thorac. Cardiovasc. Surg.129, 937–938 (2005). Google Scholar
  147. Cuschieri, A. Tissue adhesives in endosurgery. Surg. Innov.8, 63–68 (2001). CASGoogle Scholar
  148. Lloris-Carsí, J. M., Barrios, C., Prieto-Moure, B., Lloris-Cejalvo, J. M. & Cejalvo-Lapeña, D. The effect of biological sealants and adhesive treatments on matrix metalloproteinase expression during renal injury healing. PLOS ONE12, e0177665 (2017). Google Scholar
  149. O’Leary, D. P., Wang, J. H., Cotter, T. G. & Redmond, H. P. Less stress, more success? Oncological implications of surgery-induced oxidative stress. Gut62, 461–470 (2013). Google Scholar
  150. Hillel, A. T. et al. Photoactivated composite biomaterial for soft tissue restoration in rodents and in humans. Sci. Transl Med.3, 93ra67 (2011). CASGoogle Scholar
  151. Reid, B. et al. PEG hydrogel degradation and the role of the surrounding tissue environment. J. Tissue Eng. Regen. Med.9, 315–318 (2015). CASGoogle Scholar
  152. Mouthuy, P.-A. et al. Biocompatibility of implantable materials: an oxidative stress viewpoint. Biomaterials109, 55–68 (2016). CASGoogle Scholar
  153. Tamariz, E. & Rios-Ramírez, A. in Biodegradation-Life of Science (eds Chamy, R. & Rosenkranz, F.) (IntechOpen, 2013).
  154. Conde, J., Oliva, N. & Artzi, N. Revisiting the ‘one material fits all’ rule for cancer nanotherapy. Trends Biotechnol.34, 618–626 (2016). CASGoogle Scholar
  155. Gül, N. et al. Surgery-induced reactive oxygen species enhance colon carcinoma cell binding by disrupting the liver endothelial cell lining. Gut60, 1076–1086 (2011). Google Scholar
  156. Duan, J. & Kasper, D. L. Oxidative depolymerization of polysaccharides by reactive oxygen/nitrogen species. Glycobiology21, 401–409 (2011). CASGoogle Scholar
  157. Xu, X., Jha, A. K., Harrington, D. A., Farach-Carson, M. C. & Jia, X. Hyaluronic acid-based hydrogels: from a natural polysaccharide to complex networks. Soft Matter8, 3280–3294 (2012). CASGoogle Scholar
  158. Xu, Q., He, C., Xiao, C. & Chen, X. Reactive oxygen species (ROS) responsive polymers for biomedical applications. Macromol. Biosci.16, 635–646 (2016). CASGoogle Scholar
  159. Soller, B. R. et al. Feasibility of non-invasive measurement of tissue pH using near-infrared reflectance spectroscopy. J. Clin. Monit.12, 387–395 (1996). CASGoogle Scholar
  160. Anderson, M., Moshnikova, A., Engelman, D. M., Reshetnyak, Y. K. & Andreev, O. A. Probe for the measurement of cell surface pH in vivo and ex vivo. Proc. Natl Acad. Sci. USA113, 8177–8181 (2016). CASGoogle Scholar
  161. Barar, J. & Omidi, Y. Dysregulated pH in tumor microenvironment checkmates cancer therapy. BioImpacts3, 149–162 (2013). Google Scholar
  162. Feng, L., Dong, Z., Tao, D., Zhang, Y. & Liu, Z. The acidic tumor microenvironment: a target for smart cancer nano-theranostics. Natl. Sci. Rev.5, 269–286 (2018). CASGoogle Scholar
  163. Lin, M.-H. et al. Monitoring the long-term degradation behavior of biomimetic bioadhesive using wireless magnetoelastic sensor. IEEE Trans. Biomed. Eng.62, 1838–1842 (2015). Google Scholar
  164. Cencer, M. et al. Effect of pH on the rate of curing and bioadhesive properties of dopamine functionalized poly(ethylene glycol) hydrogels. Biomacromolecules15, 2861–2869 (2014). CASGoogle Scholar
  165. Hong, S. et al. Hyaluronic acid catechol: a biopolymer exhibiting a pH-dependent adhesive or cohesive property for human neural stem cell engineering. Adv. Funct. Mater.23, 1774–1780 (2013). CASGoogle Scholar
  166. Kohane, D. S. & Langer, R. Biocompatibility and drug delivery systems. Chem. Sci.1, 441–446 (2010). CASGoogle Scholar
  167. Lei, K. et al. Non-invasive monitoring of in vivo degradation of a radiopaque thermoreversible hydrogel and its efficacy in preventing post-operative adhesions. Acta Biomater.55, 396–409 (2017). CASGoogle Scholar
  168. Prestwich, G. D. et al. What is the greatest regulatory challenge in the translation of biomaterials to the clinic? Sci. Transl Med.4, 160cm14 (2012). Google Scholar
  169. Krarup, P.-M., Nordholm-Carstensen, A., Jorgensen, L. N. & Harling, H. Anastomotic leak increases distant recurrence and long-term mortality after curative resection for colonic cancer: a nationwide cohort study. Ann. Surg.259, 930–938 (2014). Google Scholar
  170. Shao, H. & Stewart, R. J. Biomimetic underwater adhesives with environmentally triggered setting mechanisms. Adv. Mater.22, 729–733 (2010). CASGoogle Scholar
  171. Roche, E. T. et al. A light-reflecting balloon catheter for atraumatic tissue defect repair. Sci. Transl Med.7, 306ra149 (2015). Google Scholar
  172. Stam, M. A. W. et al. Sylys® surgical sealant: a safe adjunct to standard bowel anastomosis closure. Ann. Surg. Innov. Res.8, 6 (2014). Google Scholar
  173. Anseth, K. S. & Burdick, J. A. New directions in photopolymerizable biomaterials. MRS Bull.27, 130–136 (2002). CASGoogle Scholar
  174. Sabnis, A., Rahimi, M., Chapman, C. & Nguyen, K. T. Cytocompatibility studies of an in situ photopolymerized thermoresponsive hydrogel nanoparticle system using human aortic smooth muscle cells. J. Biomed. Mater. Res. A91, 52–59 (2009). Google Scholar
  175. Williams, C. G., Malik, A. N., Kim, T. K., Manson, P. N. & Elisseeff, J. H. Variable cytocompatibility of six cell lines with photoinitiators used for polymerizing hydrogels and cell encapsulation. Biomaterials26, 1211–1218 (2005). CASGoogle Scholar
  176. Pellenc, Q. et al. Preclinical and clinical evaluation of a novel synthetic bioresorbable, on-demand, light-activated sealant in vascular reconstruction. J. Cardiovasc. Surg.60, 599–611 (2019). Google Scholar
  177. Elvin, C. M. et al. The development of photochemically crosslinked native fibrinogen as a rapidly formed and mechanically strong surgical tissue sealant. Biomaterials30, 2059–2065 (2009). CASGoogle Scholar
  178. Fu, A., Gwon, K., Kim, M., Tae, G. & Kornfield, J. A. Visible-light-initiated thiol-acrylate photopolymerization of heparin-based hydrogels. Biomacromolecules16, 497–506 (2015). CASGoogle Scholar
  179. Tan, H. & Marra, K. G. Injectable, biodegradable hydrogels for tissue engineering applications. Materials3, 1746–1767 (2010). CASGoogle Scholar
  180. Li, L. et al. Biodegradable and injectable in situ cross-linking chitosan-hyaluronic acid based hydrogels for postoperative adhesion prevention. Biomaterials35, 3903–3917 (2014). CASGoogle Scholar
  181. Mo, X., Iwata, H., Matsuda, S. & Ikada, Y. Soft tissue adhesive composed of modified gelatin and polysaccharides. J. Biomater. Sci. Polym. Ed.11, 341–351 (2000). CASGoogle Scholar
  182. Tan, H., Chu, C. R., Payne, K. A. & Marra, K. G. Injectable in situ forming biodegradable chitosan–hyaluronic acid based hydrogels for cartilage tissue engineering. Biomaterials30, 2499–2506 (2009). CASGoogle Scholar
  183. Nair, D. P. et al. The thiol-Michael addition click reaction: a powerful and widely used tool in materials chemistry. Chem. Mater.26, 724–744 (2014). CASGoogle Scholar
  184. Lee, Y. et al. Thermo-sensitive, injectable, and tissue adhesive sol–gel transition hyaluronic acid/pluronic composite hydrogels prepared from bio-inspired catechol-thiol reaction. Soft Matter6, 977–983 (2010). CASGoogle Scholar
  185. Metters, A. & Hubbell, J. Network formation and degradation behavior of hydrogels formed by Michael-type addition reactions. Biomacromolecules6, 290–301 (2005). CASGoogle Scholar
  186. Nie, W., Yuan, X., Zhao, J., Zhou, Y. & Bao, H. Rapidly in situ forming chitosan/ε-polylysine hydrogels for adhesive sealants and hemostatic materials. Carbohydr. Polym.96, 342–348 (2013). CASGoogle Scholar
  187. Lamph, S. Regulation of medical devices outside the European Union. J. R. Soc. Med.105, 12–21 (2012). Google Scholar
  188. Mahdavi, A. et al. A biodegradable and biocompatible gecko-inspired tissue adhesive. Proc. Natl Acad. Sci. USA105, 2307–2312 (2008). CASGoogle Scholar
  189. Coover, H. W. Chemistry and performance of cyanoacrylate adhesives. J. Soc. Plast. Eng.15, 413–417 (1959). Google Scholar
  190. Tatooles, C. J. & Braunwald, N. S. The use of crosslinked gelatin as a tissue adhesive to control hemorrhage from liver and kidney. Surgery60, 857–861 (1966). CASGoogle Scholar
  191. Mintz, P. D. et al. Fibrin sealant: clinical use and the development of the University of Virginia Tissue Adhesive Center. Ann. Clin. Lab. Sci.31, 108–118 (2001). CASGoogle Scholar
  192. Ennker, J. et al. The impact of gelatin-resorcinol glue on aortic tissue: a histomorphologic evaluation. J. Vasc. Surg.20, 34–43 (1994). CASGoogle Scholar
  193. Kowanko, N. Adhesive composition and method. US Patent US5385606A (1993).
  194. Sawhney, A. S., Pathak, C. P. & Hubbell, J. A. Bioerodible hydrogels based on photopolymerized poly(ethylene glycol)-co-poly(α-hydroxy acid) diacrylate macromers. Macromolecules26, 581–587 (1993). CASGoogle Scholar
  195. FDA. Premarket Approval (PMA) for Dermabond®https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p960052 (1998).
  196. Barrows, T. H., Lewis, T. W. & Truong, M. T. Adhesive sealant composition. US Patent US5583114A (1994).
  197. Holowka, E. P. & Bhatia, S. K. Drug Delivery: Materials Design and Clinical Perspective (Springer, 2014).
  198. US Food and Drug Administration. Premarket approval (PMA) for BioGlue® (FDA, 2001).
  199. Zhang, J.-Y., Doll, B. A., Beckman, E. J. & Hollinger, J. O. Three-dimensional biocompatible ascorbic acid-containing scaffold for bone tissue engineering. Tissue Eng.9, 1143–1157 (2003). CASGoogle Scholar
  200. McDermott, M. K., Chen, T., Williams, C. M., Markley, K. M. & Payne, G. F. Mechanical properties of biomimetic tissue adhesive based on the microbial transglutaminase-catalyzed crosslinking of gelatin. Biomacromolecules5, 1270–1279 (2004). CASGoogle Scholar
  201. Bitton, R. & Bianco-Peled, H. Novel biomimetic adhesives based on algae glue. Macromol. Biosci.8, 393–400 (2008). CASGoogle Scholar
  202. US Food and Drug Administration. Premarket approval (PMA) for DuraSeal dural sealant system (FDA, 2005).
  203. US Food and Drug Administration. Premarket approval (PMA) for Ethicon OMNEX surgical sealant (FDA, 2010).
  204. US Food and Drug Administration. Premarket approval (PMA) for Cohera Medical TissuGlu (2015).
  205. Jito, J., Nitta, N. & Nozaki, K. Delayed cerebrospinal fluid leak after watertight dural closure with a polyethylene glycol hydrogel dural sealant in posterior fossa surgery: case report. Neurol. Med. Chir.54, 634–639 (2014). Google Scholar
  206. Sani, E. S. et al. Sutureless repair of corneal injuries using naturally derived bioadhesive hydrogels. Sci. Adv.5, eaav1281 (2019). CASGoogle Scholar
  207. Wuyts, F. L. et al. Elastic properties of human aortas in relation to age and atherosclerosis: a structural model. Phys. Med. Biol.40, 1577–1597 (1995). CASGoogle Scholar
  208. Annabi, N. et al. Engineering a sprayable and elastic hydrogel adhesive with antimicrobial properties for wound healing. Biomaterials139, 229–243 (2017). CASGoogle Scholar
  209. Helander, H. F. & Fändriks, L. Surface area of the digestive tract – revisited. Scand. J. Gastroenterol.49, 681–689 (2014). Google Scholar
  210. Lee, S., Pham, A. M., Pryor, S. G., Tollefson, T. & Sykes, J. M. Efficacy of Crosseal fibrin sealant (human) in rhytidectomy. Arch. Facial Plast. Surg.11, 29–33 (2009). CASGoogle Scholar
  211. Azuma, K. et al. Biological adhesive based on carboxymethyl chitin derivatives and chitin nanofibers. Biomaterials42, 20–29 (2015). CASGoogle Scholar
  212. Walgenbach, K. J., Bannasch, H., Kalthoff, S. & Rubin, J. P. Randomized, prospective study of TissuGlu® surgical adhesive in the management of wound drainage following abdominoplasty. Aesthetic Plast. Surg.36, 491–496 (2012). Google Scholar
  213. Kawai, H. et al. Usefulness of a new gelatin glue sealant system for dural closure in a rat durotomy model. Neurol. Med. Chir.54, 640–646 (2014). Google Scholar
  214. Lin, K. L. et al. DuraSeal as a ligature in the anastomosis of rat sciatic nerve gap injury. J. Surg. Res.161, 101–110 (2010). CASGoogle Scholar
  215. Assmann, A. et al. A highly adhesive and naturally derived sealant. Biomaterials140, 115–127 (2017). CASGoogle Scholar
  216. Florek, H.-J. et al. Results from a first-in-human trial of a novel vascular sealant. Front. Surg.2, 29 (2015). Google Scholar
  217. Coselli, J. S. et al. Prospective randomized study of a protein-based tissue adhesive used as a hemostatic and structural adjunct in cardiac and vascular anastomotic repair procedures. J. Am. Coll. Surg.197, 243–252 (2003). Google Scholar
  218. Kopelman, Y. et al. A gelatin-based prophylactic sealant for bowel wall closure, initial evaluation in mid-rectal anastomosis in a large animal model. J. Gastrointest. Dig. Syst.5, 1–6 (2015). Google Scholar
  219. Tjandra, J. J. & Chan, M. K. Y. A sprayable hydrogel adhesion barrier facilitates closure of defunctioning loop ileostomy: a randomized trial. Dis. Colon Rectum51, 956–960 (2008). Google Scholar
  220. Muto, G., D’Urso, L., Castelli, E., Formiconi, A. & Bardari, F. Cyanoacrylic glue: a minimally invasive nonsurgical first line approach for the treatment of some urinary fistulas. J. Urol.174, 2239–2243 (2005). CASGoogle Scholar
  221. Sanders, L., Stone, R., Webb, K., Mefford, T. & Nagatomi, J. Mechanical characterization of a bifunctional Tetronic hydrogel adhesive for soft tissues. J. Biomed. Mater. Res. A103, 861–868 (2015). Google Scholar

Acknowledgements

This work was supported by the Korea Institute for Advancement of Technology (N0002123) to Y.L., the MIT Deshpande Center and BioDevek to N.A. and the National Institutes of Health through the R01 grant HL095722 to J.M.K.