Abstract
Surgical adhesives are widely used in clinical practice but pose a significant risk of severe vascular embolism complications. Nevertheless, there are currently no non-invasive direct methods for precise detection of detached emboli. Herein, we show a CT-visualized method for hypersensitive detection of single millimeter vascular emboli from adhesive in vivo by simply doping BiOCl into surgical adhesives. As proof of concept, BiOCl-BioGlue with excellent CT imaging capability is fabricated and applied to repair ruptured vessels and liver in male rats. The location, morphology, and degradation process of BiOCl-BioGlue can be dynamically monitored by CT imaging for 42 days, and pulmonary emboli caused by BiOCl-BioGlue, with sizes as small as 1.2 mm, are successfully detected. Additionally, the high K-edge of Bi enables precise detection of pulmonary emboli in spectral CT imaging, unaffected by confounding calcifications. The proposed non-invasive detection strategy for adhesive emboli significantly enhances the biosafety of surgical adhesives.
Data availability
The data supporting the results in this study are available within the paper and its Supplementary Information. Source data are provided with this paper.
References
Ma, Z., Bao, G. & Li, J. Multifaceted design and emerging applications of tissue adhesives. Adv. Mater. 33, 2007663 (2021).
Taboada, G. M. et al. Overcoming the translational barriers of tissue adhesives. Nat. Rev. Mater. 5, 310–329 (2020).
Nam, S. & Mooney, D. Polymeric tissue adhesives. Chem. Rev. 121, 11336–11384 (2021).
Bach, A. G. et al. Imaging of nonthrombotic pulmonary embolism: biological materials, nonbiological materials, and foreign bodies. Eur. J. Radiol. 82, 120–141 (2013).
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. Brit. J. Surg. 103, 1758–1767 (2016).
Rubio Alvarez, J., Sierra Quiroga, J., de Alegria, A. M. & Delgado Dominguez, C. Pulmonary embolism due to biological glue after repair of type A aortic dissection. Interact. Cardiovasc. Thorac. Surg. 12, 650–651 (2011).
Dusick, J. R., Mattozo, C. A., Esposito, F. & Kelly, D. F. BioGlue® for prevention of postoperative cerebrospinal fluid leaks in transsphenoidal surgery: a case series. Surg. Neurol. 66, 371–376 (2006).
LeMaire, S. A. et al. The threat of adhesive embolization: BioGlue leaks through needle holes in aortic tissue and prosthetic grafts. Ann. Thorac. Surg. 80, 106–110 (2005).
Miyagi, T. et al. Coronary artery embolism caused by bioglue surgical adhesive after type A acute aortic dissection repair. JACC Case Rep. 3, 53–57 (2021).
Yamasaki, M., Abe, K., Nakamura, R., Tamaki, R. & Misumi, H. BioGlue cerebral embolism following acute type A aortic dissection repair. J. Am. Coll. Cardiol. 26, 289–292 (2022).
Tan, S. et al. Pulmonary CTA reporting: AJR expert panel narrative review. Am. J. Roentgenol. 218, 396–404 (2022).
Verbelen, T. et al. Clinical–radiological–pathological correlation in chronic thromboembolic pulmonary hypertension. Eur. Respir. Rev. 32, 230149 (2023).
Kosior, J. C. et al. Exploring reperfusion following endovascular thrombectomy. Stroke 50, 2389–2395 (2019).
Yokoi, M. et al. Intravascular ultrasound findings of bioglue surgical adhesive coronary embolism after ascending aorta replacement. JACC Cardiovasc. Interv. 14, 39–41 (2021).
Hamaguchi, Y., Enomoto, S., Kondo, H. & Tamura, T. In vivo optical coherence tomography visualisation of coronary artery embolism caused by BioGlue in a middle-aged woman with Marfan syndrome who underwent the Bentall procedure: a case report. Eur. Heart J. Case Rep. 7, 1–6 (2023).
Shin, K. et al. Multifunctional nanoparticles as a tissue adhesive and an injectable marker for image-guided procedures. Nat. Commun. 8, 15807 (2017).
Uman, S. et al. Imaging of injectable hydrogels delivered into myocardium with SPECT/CT. Adv. Healthc. Mater. 9, e2000294 (2020).
Dong, Y. C. et al. Ytterbium nanoparticle contrast agents for conventional and spectral photon-counting CT and their applications for hydrogel imaging. ACS Appl. Mater. Interfaces 14, 39274–39284 (2022).
Tian, M. et al. A transformable mucoadhesive microgel network for noninvasive multimodal imaging and radioprotection of a large area of the gastrointestinal tract. Adv. Mater. 35, e2303436 (2023).
Sahiner, N. et al. Hyaluronic acid (HA)-Gd(III) and HA-Fe(III) microgels as MRI contrast enhancing agents. Carbohyd. Polym. 277, 118873 (2022).
Xu, X. et al. 3D hollow porous radio-granular hydrogels for SPECT imaging-guided cancer intravascular brachytherapy. Adv. Funct. Mater. 33, 2215110 (2023).
Burns, M. W. N., Mattrey, R. F. & Lux, J. Microbubbles cloaked with hydrogels as activatable ultrasound contrast agents. ACS Appl. Mater. Interfaces 12, 52298–52306 (2020).
Farhoudi, N., Laurentius, L. B., Magda, J. J., Reiche, C. F. & Solzbacher, F. In vivo monitoring of glucose using ultrasound-induced resonance in implantable smart hydrogel microstructures. ACS Sens 6, 3587–3595 (2021).
Huang, D. et al. Injectable hydrogels with integrated ph probes and ultrasound-responsive microcapsules as smart wound dressings for visual monitoring and on-demand treatment of chronic wounds. Adv. Healthcare Mater. 13, 2303379 (2024).
Borum, R. M., Moore, C., Mantri, Y., Xu, M. & Jokerst, J. V. Supramolecular loading of DNA hydrogels with dye-drug conjugates for real-time photoacoustic monitoring of chemotherapy. Adv. Sci. 10, 2204330 (2023).
Shrestha, B. et al. Gold nanorods enable noninvasive longitudinal monitoring of hydrogels in vivo with photoacoustic tomography. Acta Biotheor. 117, 374–383 (2020).
Chen, Z. et al. A novel medically imageable intelligent cellulose nanofibril-based injectable hydrogel for the chemo-photothermal therapy of tumors. Chem. Eng. J. 431, 133255 (2022).
Braams, N. J. et al. Evolution of CT findings after anticoagulant treatment for acute pulmonary embolism in patients with and without an ultimate diagnosis of chronic thromboembolic pulmonary hypertension. Eur. Respir. J. 58, 2100699 (2021).
He, H., Long, Y., Frerichs, I. & Zhao, Z. Detection of acute pulmonary embolism by electrical impedance tomography and saline bolus injection. Am. J. Resp. Crit. Care 202, 881–882 (2020).
Rabin, O., Manuel Perez, J., Grimm, J., Wojtkiewicz, G. & Weissleder, R. An X-ray computed tomography imaging agent based on long-circulating bismuth sulphide nanoparticles. Nat. Mater. 5, 118–122 (2006).
Shu, G. et al. Metallic artifacts-free spectral computed tomography angiography based on renal clearable bismuth chelate. Biomaterials 305, 122422 (2024).
Zelepukin, I. V. et al. Polymer-coated BiOCl nanosheets for safe and regioselective gastrointestinal X-ray imaging. J. Control. Release 349, 475–485 (2022).
Wang, Y. et al. BSA-mediated synthesis of bismuth sulfide nanotheranostic agents for tumor multimodal imaging and thermoradiotherapy. Adv. Funct. Mater. 26, 5335–5344 (2016).
Liu, J. et al. Bismuth sulfide nanorods as a precision nanomedicine for in vivo multimodal imaging-guided photothermal therapy of tumor. ACS Nano 9, 696–707 (2015).
Lei, P. et al. Ultrafast synthesis of ultrasmall Poly(Vinylpyrrolidone)-protected bismuth nanodots as a multifunctional theranostic agent for in vivo dual-modal CT/photothermal-imaging-guided photothermal therapy. Adv. Funct. Mater. 27, 1702018 (2017).
Wu, S. et al. Harnessing X-Ray energy-dependent attenuation of bismuth-based nanoprobes for accurate diagnosis of liver fibrosis. Adv. Sci. 8, 2002548 (2021).
Ai, K. et al. Large-scale synthesis of Bi2S3 nanodots as a contrast agent for in vivo X-ray computed tomography imaging. Adv. Mater. 23, 4886–4891 (2011).
Yu, X. et al. Ultrasmall semimetal nanoparticles of bismuth for dual-modal computed tomography/photoacoustic imaging and synergistic thermoradiotherapy. ACS Nano 11, 3990–4001 (2017).
Griffith, D. M., Li, H., Werrett, M. V., Andrews, P. C. & Sun, H. Medicinal chemistry and biomedical applications of bismuth-based compounds and nanoparticles. Chem. Soc. Rev. 50, 12037–12069 (2021).
Li, H., Wang, R. & Sun, H. Systems approaches for unveiling the mechanism of action of bismuth drugs: new medicinal applications beyond helicobacter pylori infection. Acc. Chem. Res. 52, 216–227 (2019).
Shahbazi, M. A. et al. The versatile biomedical applications of bismuth-based nanoparticles and composites: therapeutic, diagnostic, biosensing, and regenerative properties. Chem. Soc. Rev. 49, 1253–1321 (2020).
Wang, X. et al. Ultrasmall BiOI quantum dots with efficient renal clearance for enhanced radiotherapy of cancer. Adv. Sci. 7, 1902561 (2020).
Guo, M. et al. Few-layer bismuthene for checkpoint knockdown enhanced cancer immunotherapy with rapid clearance and sequentially triggered one-for-all strategy. ACS Nano 14, 15700–15713 (2020).
Duan, M. et al. Phase-transitional bismuth-based metals enable rapid embolotherapy. Hyperth. Biomed. Imaging Adv. Mater. 34, 2205002 (2022).
Li, Z. et al. Multimodal imaging-guided antitumor photothermal therapy and drug delivery using bismuth selenide spherical sponge. ACS Nano 10, 9646–9658 (2016).
Liao, W. et al. Bi-DTPA as a high-performance CT contrast agent for in vivo imaging. Biomaterials 203, 1–11 (2019).
Tsilimigras, D. I. et al. The role of BioGlue in thoracic surgery: a systematic review. J. Thorac. Dis. 9, 568–576 (2017).
Li, J. et al. Emerging biopolymer-based bioadhesives. Macromol. Biosci. 22, 2100340 (2022).
Liang, Y., Xu, H., Li, Z., Zhangji, A. & Guo, B. Bioinspired Injectable self-healing hydrogel sealant with fault-tolerant and repeated thermo-responsive adhesion for sutureless post-wound-closure and wound healing. Nano-Micro Lett. 14, 185 (2022).
Peng, Z. G., Hidajat, K. & Uddin, M. S. Adsorption of bovine serum albumin on nanosized magnetic particles. J. Colloid Interf. Sci. 271, 277–283 (2004).
Goodsitt, M. M., Christodoulou, E. G. & Larson, S. C. Accuracies of the synthesized monochromatic CT numbers and effective atomic numbers obtained with a rapid kVp switching dual energy CT scanner. Med. Phys. 38, 2222–2232 (2011).
Greffier, J., Villani, N., Defez, D., Dabli, D. & Si-Mohamed, S. Spectral CT imaging: technical principles of dual-energy CT and multi-energy photon-counting CT. Diagn. Interv. Imaging 104, 167–177 (2023).
Lee, S. et al. Noise reduction approach in pediatric abdominal CT combining deep learning and dual-energy technique. Eur. Radiol. 31, 2218–2226 (2021).
Li, Y. et al. Spectral computed tomography with inorganic nanomaterials: state-of-the-art. Adv. Drug Deliv. Rev. 189, 114524 (2022).
Wang, Y. et al. Targeted imaging of damaged bone in vivo with gemstone spectral computed tomography. ACS Nano 10, 4164–4172 (2016).
FitzGerald, P. F. et al. CT image contrast of high-Z elements: phantom imaging studies and clinical implications. Radiology 278, 723–733 (2016).
Fält, T., Söderberg, M., Wassélius, J. & Leander, P. Material decomposition in dual-energy computed tomography separates high-Z elements from iodine, identifying potential contrast media tailored for dual contrast medium examinations. J. Comput. Assist. Tomogr. 39, 975–980 (2015).
Ouwendijk, R. et al. Vessel wall calcifications at multi–detector row CT angiography in patients with peripheral arterial disease: effect on clinical utility and clinical predictors. Radiology 241, 603–608 (2006).
Renker, M. et al. Evaluation of heavily calcified vessels with coronary CT angiography: comparison of iterative and filtered back projection image reconstruction. Radiology 260, 390–399 (2011).
Di Jiang, M. et al. The effect of coronary calcification on diagnostic performance of machine learning–based CT-FFR: a Chinese multicenter study. Eur. Radiol. 31, 1482–1493 (2021).
Acknowledgements
Ruihan Liu, Shuo Li and Xingyu Gao contributed equally to this work. This work was supported by the National Natural Science Foundation of China (82071982 (S.-K.S.), 82202830 (C.Z.), 82272052 (J.P.)), Natural Science Foundation of Tianjin City (19JCJQJC63700 (S.-K.S.), 23JCQNJC00620 (C.Z.)). Figure 1 and cartoon images in Figs. 2–5 were created with Biorender.com.
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R.L., Q.Z., X.C., and S.-K.S. conceived and designed the experiments. R.L., S.L., and X.G. performed the experiments. R.L., S.L., X.G., G.S., C.Z., and J.P. participated in data analysis. The manuscript was written by R.L., Q.Z., X.C., and S.-K.S. All authors discussed the results and commented on the paper.
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Liu, R., Li, S., Gao, X. et al. Hypersensitive detection of single millimeter vascular emboli from adhesive in vivo. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68534-w
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DOI: https://doi.org/10.1038/s41467-026-68534-w
