All data supporting the findings of this study are provided in the paper, the Extended Data and the Supplementary Information. Additional raw data generated in this study are available from the corresponding authors upon reasonable request.
The code that produced the findings of this study is available at GitHub (https://github.com/labofsoftbiomaterials/Engineered-blood-clot).
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This work was supported by the Canadian Institutes of Health Research (grants PJT-180232 and PJT-165995, J.L.), the New Frontiers in Research Fund—Exploration (grants NFRFE-2022-00348 and NFRFE-2018-00751, J.L. and C.K.) and the Natural Sciences and Engineering Research Council of Canada (grants RGPIN-2018-04146 and RGPIN-2024-04925, J.L.). J.L. acknowledges support from the Canada Research Chairs Program. X.Y. and R.L. acknowledge support from the United States National Science Foundation (grant CMMI-1752449). S.J. and Z.Y. acknowledge support from the FRQNT Doctoral Award. We thank R. Huo (McGill University) for helping with the burst pressure test, X. Li (McGill University) and L. Li (McGill University) for assistance with microscopy, and the Flow Cytometry Core Facility (McGill University) and the Advanced BioImaging Facility (ABIF, McGill University) for providing access to their facilities.
S.J., G.B., A. Nottegar and J.L. are inventors of a provisional patent application (PCT/CA2024/051494) that covers the design and application of tough cytogels. The other authors declare no competing interests.
Nature thanks Shige Wang, Malcolm Xing 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.
a, Agglutination of negatively charged cells, carrying polysaccharides (shown in cyan) on their surface and positively charged polymers through electrostatic interactions. b, Polymers carrying pendent hydrophobic groups (shown in purple) can insert into the lipid bilayers of cell membranes, thereby assembling cells. c, Polymers decorated with peptide ligands (e.g., RGD) can crosslink cells via receptor-ligand recognition. d, Cells surface-modified with reactive groups (e.g., azide) using metabolic labelling can be crosslinked by polymers carrying complementary reactive groups (e.g., DBCO)55. This method is not applicable to cells such as red blood cells lacking a nucleus and Golgi apparatus. e, Cells are initially modified with a click motif (e.g., TCO) on surface proteins using biocompatible covalent reactions and then bioorthogonally crosslinked by polymer linkers carrying complementary reactive groups (e.g., tetrazine). Figure created in BioRender; Jiang, S. https://BioRender.com/x9wwnmi (2026).
a, Intensity-hydrodynamic size distributions of HA-TZ variants with different hyaluronidase reaction time, measured by dynamic laser scattering (DLS). b, Measured hydrodynamic sizes of HA-TZ variants. Data are presented as mean ± SD (n = 4). c, Molecular weight distribution curves measured by gel permeation chromatography (GPC), plotted as dW/d log M (differential weight fraction per logarithmic molecular weight interval) versus log M (logarithm of molecular weight). Corresponding hyaluronidase reaction times are indicated. d, Time-sweep rheology of mixtures of modified RBCs and HA-TZ variants. HA20-TZ formed RBC cytogels, whereas HA40-TZ and HA60-TZ did not gel and remained viscous liquids under the same conditions. Insets show inverted-vial tests in which the non-gelling formulations flowed and ran down the vial wall upon inversion.
Finite element simulations of the lap shear test. a. Geometry of the simulated sample. b. The fracture of the RBC cytogel is characterized by a bi-linear cohesive zone mode, characterized by parameters: cohesive strength \({\sigma }_{\max }\), failure displacement \({\delta }_{f}\), and intrinsic cohesive energy \({\Gamma }_{0}\). c. Stress-stretch curves reproduced from Fig. 2j. RBC cytogels were subject to two cycles of loading and unloading at varying maximum stretches. The curves were smoothed. d. When a material point of the RBC cytogel is subject to loading and unloading, the mechanical work per volume U is defined as the area under the nominal stress-stretch curve. The energy dissipation per volume Ud is defined as the shaded area enclosed by the loading-unloading curve. e. The hysteresis ratio h = Ud/U plotted as functions of U for the RBC cytogel, tough gel, and porcine liver.
a, Finite element simulation and experimental results, reproduced from Fig. 2f. Insets are snapshots of the in-vitro (Top) and in-silico (Bottom) samples at different displacement. b, Finite element results with and without Mullins effect. The contour maps in a and b show energy dissipation per volume.
a, EBC consists of modified RBCs (red), HA-TZ (blue) and fibrin (green). The merged image reveals a connected RBC network interpenetrated with fibrin network. b, Control blood clot composed of unmodified RBCs (red), HA-TZ (blue) and fibrin (green), where RBCs are primarily trapped within the fibrin network as isolated clusters.
a, Stress-strain curves of native blood clots (NBC). b, Stress-strain curves of engineered blood clots (EBC) under 10%, 20% and 40% maximum strains. c, Quantitative recovery ratios calculated from the loading and unloading curves of the first cycle. Data are presented as mean ± SD.
A rat subcutaneous implantation model was utilized to evaluate tissue compatibility over a period of 28 days. Histological sections of the implants stained with H&E were captured at different time points. For each pair of images, the image on the right is the zoom-in view of the black dashed box in the image on the left. Scale bar, 200 μm (left) and 50 μm (right).
a, Glucose. b, Urea. c, Cholesterol. d, Lipase. e, Total protein. f, Globulin. g, Albumin/Globulin. h, Total bilirubin. i, Direct bilirubin. j, Indirect bilirubin. k, Alkaline phosphatase (ALP). l, γ-glutamyltransferase (GGT). m, Alanine aminotransferase (ALT). n, Aspartate aminotransferase (AST). o, Albumin level fluctuation over the implantation period. EBC showed minimal faster restoration of albumin production, which suggested that EBC promoted liver wound healing. Data are presented as mean ± SD (n = 6). 0.01 <*P < 0.05, 0.001 <**P < 0.01, ns denotes no significant difference.
a-b, Photos showing the implants of EBC and Floseal on the injured liver at different time points. Scale bar, 5 mm. c-d, Histological images showing the wound healing process of EBC and Floseal. Scale bars, 1 mm for the middle row, and 50 μm for the bottom row. EBC demonstrates nearly complete healing of the liver defect with minimal inflammation and fibrosis, while Floseal exhibits moderate fibrosis and scarring. Additionally, EBC exhibits anti-adhesion properties to the surrounding tissues, whereas Floseal samples resulted in organ adhesion in all the implants.
a, Schematic of the experimental design using genetically distinct Fischer 344 (donor) and Brown Norway (recipient) rats to assess immune compatibility of allogeneic EBCs. EBCs were prepared from donor blood and applied to standardized liver laceration wounds in recipients. b, Images and H&E-stained sections of injured livers, transient EBC residues at Day 5, tissue regeneration with minimal inflammatory infiltration at Day 14, and normal tissue architecture by Day 28. Scale bars: macroscopic images, 5 mm; 2.5×, 500 µm; 10×, 100 µm; 40×, 25 µm. Illustrations in a created in BioRender; Jiang, S. https://BioRender.com/x9wwnmi (2026).
This file contains Supplementary Schemes 1 and 2, Supplementary Figs. 1–30, Supplementary Tables 1–3, and additional references. This file includes data on the chemical characterization, mechanical properties, cytocompatibility, biodistribution, haematological analysis, and rat tail amputation haemorrhage model for the evaluation of cytogels and engineered blood clots.
Burst pressure tests of EBC, NBC, RBC cytogel and Floseal.
Haemostatic performance of EBC in rat liver incision haemorrhage model.
Haemostatic performance of Floseal in rat liver incision haemorrhage model.
Haemostatic performance of EBC in rat tail amputation haemorrhage model.
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Jiang, S., Bao, G., Yang, Z. et al. Engineering tough blood clots for rapid haemostasis and enhanced regeneration. Nature (2026). https://doi.org/10.1038/s41586-026-10412-y
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DOI: https://doi.org/10.1038/s41586-026-10412-y
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