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Engineered nascent living human tissues with unit programmability

Nature Materials volume 24, pages 143–154 (2025)Cite this article

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Abstract

Leveraging human cells as materials precursors is a promising approach for fabricating living materials with tissue-like functionalities and cellular programmability. Here we describe a set of cellular units with metabolically engineered glycoproteins that allow cells to tether together to function as macrotissue building blocks and bioeffectors. The generated human living materials, termed as Cellgels, can be rapidly assembled in a wide variety of programmable three-dimensional configurations with physiologically relevant cell densities (up to 108 cells per cm3), tunable mechanical properties and handleability. Cellgels inherit the ability of living cells to sense and respond to their environment, showing autonomous tissue-integrative behaviour, mechanical maturation, biological self-healing, biospecific adhesion and capacity to promote wound healing. These living features also enable the modular bottom-up assembly of multiscale constructs, which are reminiscent of human tissue interfaces with heterogeneous composition. This technology can potentially be extended to any human cell type, unlocking the possibility for fabricating living materials that harness the intrinsic biofunctionalities of biological systems.

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Fig. 1: Assembly of human-based living gel-like materials.
Fig. 2: Cellular engineering and assembly of cell-rich bioarchitectures.
Fig. 3: Cellgel bioarchitecture characterization.
Fig. 4: Cellgels present selective adhesion and biological self-healing properties.
Fig. 5: Modular fabrication of multicomponent Cellgel-based assemblies.
Fig. 6: In vivo analysis of Cellgel application for wound healing.

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Data availability

The raw RNA-sequencing data obtained in this study are available in the Gene Expression Omnibus (GEO) database under accession code GSE231507. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD042343. DAVID Bioinformatics tool is available at https://david.ncifcrf.gov/. The authors declare that all remaining data supporting the findings of this study are included within the article and Supplementary Information files. Source data are provided with this paper. Additional data are available from the corresponding authors upon request.

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Acknowledgements

This work was financed by the European Research Council Advanced Grant REBORN (grant agreement number H2020-ERC-AdG–883370) and within the scope of project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 and LA/P/0006/2020, financed by national funds through FCT/MEC (PIDDAC). P.L., B.S.M. and J.A.-P. acknowledge individual PhD fellowships from the Portuguese Foundation for Science and Technology (FCT) (SFRH/BD/141834/2018 (P.L.), 2021.08331.BD (B.S.M.) and 2023.04716.BD (J.A.-P.). V.M.G. acknowledges FCT for an assistant researcher contract (CEECIN/02106/2022). Transcriptomics library preparation and sequencing was conducted in IGC Genomic Facility, partially supported by LISBOA-01-0246-FEDER-000037 - Single cell HUB co-funded by Programa Operacional Regional Lisboa 2020. We acknowledge i3S Proteomics platform for conducting sample processing and mass spectrometry. We acknowledge i3S Animal facility for providing laboratory animal care and conducting the in vivo study.

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Authors and Affiliations

  1. CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Portugal

    Pedro Lavrador, Beatriz S. Moura, José Almeida-Pinto, Vítor M. Gaspar & João F. Mano

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  1. Pedro Lavrador
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  2. Beatriz S. Moura
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  3. José Almeida-Pinto
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Contributions

P.L., B.S.M., J.A.-P., V.M.G. and J.F.M. designed the experiments. P.L., B.S.M. and J.A.-P., conducted the experiments, analysed the data and prepared the figures. P.L., B.S.M., J.A.-P., V.M.G. and J.F.M. discussed results and wrote the paper. P.L., V.M.G. and J.F.M. conceptualized this work. V.M.G and J.F.M. supervised and acquired funding.

Corresponding authors

Correspondence to Vítor M. Gaspar or João F. Mano.

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Competing interests

P.L., B.S.M., V.M.G. and J.F.M. are inventors on a patent application (PCT/IB2023/062636), related to all the work covered in this article. J.A.-P. declares no competing interests.

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Nature Materials thanks Chao Zhong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Transient nature of azide-bearing motifs installed through metabolic glycoengineering.

a, Fluorescence microscopy of negative control and azide-bearing hASCs at 0 and 7 days post-glycoengineering. Blue channel, cell nuclei; green channel, cell-surface azides. Scale bars, 100 µm. b, Flow cytometry time-lapse evolution of azide-bearing motifs in hASCs cultured in standard medium (that is, absent of Ac4ManNAz). Normalized mean fluorescence intensity (MFI) is expressed following the correction of non-specific background from negative controls (that is, subtraction of MFI from native hASCs treated with DBCO-PEG4-Rhod110. Data represented as mean ± s.d., n = 4 replicates. c, Representative flow cytometry histogram plots of time lapse evolution of glycoengineered hASCs versus negative control. d, Micrograph of glycoengineered hASCs 7 days post-functionalization combined with the cell-tethering component (HA-DBCO) and unable to form Cellgel constructs. Scale bars, 5 mm.

Source data

Extended Data Fig. 2 Cellgels assembly with different microarchitectures.

Live/dead analysis of hASC-based Cellgels produced with different microarchitectures, namely toroids and hollow triangles. Living materials were matured for 7 days and demonstrate cytocompatible cell-to-cell bioorthogonal crosslinking regardless of construct shape. Green channel, calcein-AM (live cells); red channel, propidium iodide (dead cells). Scale bars, 500 µm (full constructs), 100 µm (close-ups).

Extended Data Fig. 3 Assembly of spheroidal-like Cellgel bead constructs.

Viability of spheroidal-like Cellgel beads during maturation. a, Top: micrograph of superhydrophobic surfaces used for generating hASC-based Cellgel beads. Scale bar, 1 cm. Inset represents Cellgel beads produced with different droplet sizes (1, 2 and 5 µL) to demonstrate the programmable volumetric control during fabrication. Bottom: brightfield microscopy of newly assembled bead constructs (2 µL, day 0). Scale bar, 500 µm. b, Live/dead analysis of bead constructs (2 µL) during maturation (3, 7 and 14 days). Green channel, calcein-AM (live cells); red channel, propidium iodide (dead cells). Scale bars, 200 µm. c, Quantification of live area (%) in microtissues over time. Data represented as mean ± s.d., n = 5 biological replicates.

Source data

Extended Data Fig. 4 Overview of Cellgels secreted proteins.

Proteomics analysis of Cellgels secretome following annotation of identified proteins in Matrisome Project database: core matrisome (collagens, glycoproteins, proteoglycans) and matrisome-associated proteins (ECM-affiliated proteins, ECM regulators and secreted factors).

Extended Data Fig. 5 Cellgels retain their selective bioadhesiveness post-maturation.

3D representation and micrographs of hybrid constructs two-stage assembly in different synthetic (PEGDA hydrogels) and tissue-mimetic (GelMA hydrogels) environments. Cellgels were initially matured for 24 h and modularly assembled with hydrogel blocks for 3 days. Upon contacting tissue-mimetic hydrogels, stable hybrids were formed. The Cellgel-based structures can be pushed along surfaces while successfully dragging the attached hydrogels underneath.

Extended Data Fig. 6 Additional characterization of Cellgels tissue adhesion.

a, 3D representation and micrograph of PDMS templates employed for Cellgel-tissue merging during tissue adhesion experiments. Scale bar, 5 mm. 3D representation measurements showed in mm. b, Characterization of adhesion failure time in multiple soft tissues (porcine skin, liver and heart) between Cellgel-tissue assemblies and tissue-on-tissue assemblies (negative control). Data represented as mean ± s.d., n = 10 Cellgel-tissue assemblies over 3 independent experiments. ****p < 0.0001, one-way ANOVA with Tukey’s multiple comparisons test. c, Demonstration of the stability of Cellgel-tissue interfaces while immersed in aqueous conditions (dPBS) and subjected to mechanical agitation. In contrast, tissue-on-tissue negative controls readily disassembled when immersed.

Source data

Supplementary information

Supplementary Information

Supplementary Figs. 1–34.

Reporting Summary

Supplementary Data 1

Full description of commercially available reagents and materials, including company name, catalogue numbers and CAS numbers.

Supplementary Data 2

Statistical source data for supplementary figures.

Supplementary Video 1

Demonstration of the experimental workflow for azide functionalization of cells via metabolic glycoengineering, as well as the manufacturing of Cellgel constructs.

Supplementary Video 2

Negative controls demonstrating no hASC-based Cellgel formation when combining (1) azide-bearing cells with non-functionalized hyaluronic acid or (2) native cells with HA-DBCO.

Supplementary Video 3

Demonstration of the transient nature of azide-bearing motifs installed in cell surfaces through metabolic glycoengineering. Glycoengineered cells are cultured for 1 week in standard culture medium (absent of Ac4ManNAz), leading to natural recycling of cell-surface sialosides, which negatively affects Cellgel assembly.

Supplementary Video 4

Proof-of-concept demonstration of fluid perfusability through the lumen of hollow tubular Cellgel constructs.

Supplementary Video 5

Demonstration of the ability of Cellgels to interpret the composition of their surroundings and interact specifically with cell-adhesive environments. Cellgels contacting bioinert synthetic constructs (PEGDA) failed to bridge together the two hydrogel blocks. However, GelMA–Cellgel–GelMA hybrid constructs remained stable following immersion in aqueous conditions.

Supplementary Video 6

Demonstration of the modular assembly of Cellgel–GelMA disks to produce hierarchical and spatially defined constructs. Cellgels can be matured for pre-determined periods and posteriorly stacked with cell-adhesive constructs, retaining the ability to form seamless hybrid structures. Cellgels could be pushed along surfaces while dragging the hydrogel blocks (GelMA) attached underneath, confirming their stable Cellgel-hydrogel interfaces.

Supplementary Video 7

Cellgels could be formed in situ following injection of precursor solutions into ex vivo porcine tissue defects. These cell-rich constructs remained merged to the filled cavities during mechanical handling.

Supplementary Video 8

Demonstration of the improved adhesiveness of Cellgel-glued tissues compared with tissue-stacked assemblies during extensional rheology analysis.

Supplementary Video 9

Demonstration of the stability of interfaces established in Cellgel tissues while immersed in aqueous conditions and subjected to mechanical agitation. In contrast, tissue-on-tissue assemblies (negative controls) readily disassembled when immersed.

Supplementary Video 10

As demonstrated through mechanical handling, self-healed Cellgels present a single seamless structure arising from the merging of two previously sliced constructs.

Supplementary Video 11

Demonstration of the implantation of Cellgels in a mouse excisional wound splinting model, followed by the subsequent protection of the wound site using a commercially available transparent film dressing (Tegaderm).

Source data

Source Data Fig. 2

Statistical source data for Fig. 2b,c.

Source Data Fig. 3

Statistical source data for Fig. 3f,g,k,l.

Source Data Fig. 4

Statistical source data for Fig. 4f,o,p.

Source Data Fig. 5

Statistical source data for Fig. 5d–j.

Source Data Fig. 6

Statistical source data for Fig. 6d,f–h.

Source Data Extended Data Fig. 1

Statistical source data for Extended Data Fig. 1b,c.

Source Data Extended Data Fig. 3

Statistical source data for Extended Data Fig. 3c.

Source Data Extended Data Fig. 6

Statistical source data for Extended Data Fig. 6b.

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Lavrador, P., Moura, B.S., Almeida-Pinto, J. et al. Engineered nascent living human tissues with unit programmability. Nat. Mater. 24, 143–154 (2025). https://doi.org/10.1038/s41563-024-01958-1

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