Intravital three-dimensional bioprinting

ABSTRACT Fabrication of three-dimensional (3D) structures and functional tissues directly in live animals would enable minimally invasive surgical techniques for organ repair or

reconstruction. Here, we show that 3D cell-laden photosensitive polymer hydrogels can be bioprinted across and within tissues of live mice, using bio-orthogonal two-photon cycloaddition and

crosslinking of the polymers at wavelengths longer than 850 nm. Such intravital 3D bioprinting—which does not create by-products and takes advantage of commonly available multiphoton

microscopes for the accurate positioning and orientation of the bioprinted structures into specific anatomical sites—enables the fabrication of complex structures inside tissues of live

mice, including the dermis, skeletal muscle and brain. We also show that intravital 3D bioprinting of donor-muscle-derived stem cells under the epimysium of hindlimb muscle in mice leads to

the de novo formation of myofibres in the mice. Intravital 3D bioprinting could serve as an in vivo alternative to conventional bioprinting. Access through your institution Buy or subscribe

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FACILITATE HIGH-PERFORMANCE DIGITAL LIGHT PROCESSING-BASED BIOPRINTING OF FUNCTIONAL VOLUMETRIC SOFT TISSUES Article Open access 09 June 2022 GUIDING CELL MIGRATION IN 3D WITH

HIGH-RESOLUTION PHOTOGRAFTING Article Open access 23 May 2022 TRICOLOR VISIBLE WAVELENGTH-SELECTIVE PHOTODEGRADABLE HYDROGEL BIOMATERIALS Article Open access 29 August 2023 DATA AVAILABILITY

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw image data and the analysed data generated in this study are

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embryo. _Dev. Biol._ 392, 133–140 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by 2017 STARS-WiC grant of

University of Padova, Progetti di Eccellenza CaRiPaRo, TWINING of University of Padova, Oak Foundation Award (grant no. W1095/OCAY-14-191), ‘Consorzio per la Ricerca Sanitaria’ (CORIS) of

the Veneto Region, Italy (LifeLab Program) to N.E. and the STARS Starting Grant 2017 of University of Padova (grant code LS3-19613) to A.U. P.D.C. is supported by the National Institute for

Health Research (NIHR; grant no. NIHR-RP-2014-04-046). G.G.G. was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre Catalyst Fellowship. G.G.G., P.D.C. and N.E.

were supported by the Oak award W1095/OCAY-14-191. All research at Great Ormond Street Hospital NHS Foundation Trust and University College London Great Ormond Street Institute of Child

Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the National Health

Service, the NIHR or the Department of Health. We thank D. Moulding for technical support and S. Schiaffino for scientific advice and discussion. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS

* Department of Industrial Engineering, University of Padova, Padova, Italy Anna Urciuolo, Luca Brandolino, Cecilia Laterza, Monica Giomo & Nicola Elvassore * Veneto Institute of

Molecular Medicine, Padova, Italy Anna Urciuolo, Luca Brandolino, Paolo Raffa, Valentina Scattolini, Cecilia Laterza, Laura Brigo & Nicola Elvassore * Department of Women’s and

Children’s Health, University of Padova, Padova, Italy Anna Urciuolo, Paolo Raffa, Valentina Scattolini & Elisa Zambaiti * ONYEL Biotech, Padova, Italy Ilaria Poli * University College

London Great Ormond Street Institute of Child Health, London, UK Giovanni G. Giobbe, Giulia Selmin, Michael Magnussen, Paolo De Coppi & Nicola Elvassore * Department of Specialist

Paediatric and Neonatal Surgery, Great Ormond Street Hospital for Children, London, UK Paolo De Coppi * Department of Pharmaceutical and Pharmacological Science, University of Padova,

Padova, Italy Stefano Salmaso * Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, China Nicola Elvassore Authors * Anna Urciuolo View author

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Google Scholar CONTRIBUTIONS A.U. and N.E. designed the experiments. N.E. designed the photochemistry, I.P. synthesized and chemically characterized the coumarin polymers and S.S.

contributed to the chemical characterization of coumarin polymers. A.U. performed and analysed in vitro and in vivo experiments. L.Brandolino. and P.R. contributed to in vitro experiments.

V.S. contributed to the analysis of in vivo experiments. C.L. performed hydrogel injection into the brain and derived reporter cells and human ES cell-derived NSCs. G.G.G., E.Z., G.S. and

M.M. contributed to organoid experiments. G.G. and P.D.C. characterized human intestinal organoid cultures. L.Brigo. contributed to the design and interpretation of in vitro two-photon

crosslinking experiments. M.G. performed AFM analysis. A.U. and N.E. analysed the data and wrote the manuscript. N.E. supervised the project. CORRESPONDING AUTHOR Correspondence to Nicola

Elvassore. ETHICS DECLARATIONS COMPETING INTERESTS N.E. has an equity stake in ONYEL Biotech s.r.l. A.U. and N.E. are submitting a patent for the intravital 3D bioprinting (provisional

patent number 102020000008779). ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary methods, figures, tables and video captions. REPORTING SUMMARY SUPPLEMENTARY VIDEO 1 3D projection of _z_-stack images

showing a ‘LIFE’-shaped HCC–4-arm PEG 3D structure related to Supplementary Fig. 12c. SUPPLEMENTARY VIDEO 2 3D reconstruction of _z_-stack images showing an empty cuboidal-shaped HCC–8-arm

PEG 3D structure related to Supplementary Fig. 12e. SUPPLEMENTARY VIDEO 3 3D reconstruction of _z_-stack images showing a flower-shaped HCC–gel 3D structure related to Fig. 3d. SUPPLEMENTARY

VIDEO 4 3D reconstruction of _z_-stack images showing the maximum fabrication depth related to Fig. 3e. SUPPLEMENTARY VIDEO 5 Orthogonal 3D reconstruction of _z_-stack images showing a

cell-laden bioprinted structure related to Supplementary Fig. 18a. SUPPLEMENTARY VIDEO 6 Long-term 3D culture of MuSCs related to Fig. 4g. SUPPLEMENTARY VIDEO 7 3D reconstruction of

_z_-stack images showing object fabricated into a drop of HCC–gel/Matrigel related to Fig. 5a. SUPPLEMENTARY VIDEO 8 3D reconstruction of _z_-stack images showing objects fabricated into a

drop of HCC–gel/Matrigel in respect to hSIOs related to Supplementary Fig. 20a. SUPPLEMENTARY VIDEO 9 Intravital imaging related to Fig. 6b. SUPPLEMENTARY VIDEO 10 Intravital imaging related

to Fig. 6e. SUPPLEMENTARY VIDEO 11 3D reconstruction related to Fig. 6e. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Urciuolo, A., Poli, I.,

Brandolino, L. _et al._ Intravital three-dimensional bioprinting. _Nat Biomed Eng_ 4, 901–915 (2020). https://doi.org/10.1038/s41551-020-0568-z Download citation * Received: 22 July 2019 *

Accepted: 08 May 2020 * Published: 22 June 2020 * Issue Date: September 2020 * DOI: https://doi.org/10.1038/s41551-020-0568-z SHARE THIS ARTICLE Anyone you share the following link with will

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