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Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing


Microporous annealed particle (MAP) scaffolds are flowable, in situ crosslinked, microporous scaffolds composed of microgel building blocks and were previously shown to accelerate wound healing. To promote more extensive tissue ingrowth before scaffold degradation, we aimed to slow MAP degradation by switching the chirality of the crosslinking peptides from l- to d-amino acids. Unexpectedly, despite showing the predicted slower enzymatic degradation in vitro, d-peptide crosslinked MAP hydrogel (d-MAP) hastened material degradation in vivo and imparted significant tissue regeneration to healed cutaneous wounds, including increased tensile strength and hair neogenesis. MAP scaffolds recruit IL-33 type 2 myeloid cells, which is amplified in the presence of d-peptides. Remarkably, d-MAP elicited significant antigen-specific immunity against the d-chiral peptides, and an intact adaptive immune system was required for the hydrogel-induced skin regeneration. These findings demonstrate that the generation of an adaptive immune response from a biomaterial is sufficient to induce cutaneous regenerative healing despite faster scaffold degradation.

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Fig. 1: d-MAP hydrogel degradation is enhanced in wounds of SKH1 hairless mice.
Fig. 2: d-MAP hydrogel induces neogenesis of hair follicles in full-thickness skin wounds in B6 mice.
Fig. 3: Peptide recognition by pattern recognition receptors is not required for myeloid cell recruitment.
Fig. 4: d-MAP induces antibody responses and the recruitment of myeloid cells via adaptive immunity.
Fig. 5: d-MAP requires an intact adaptive immunity to induce hair follicle neogenesis.
Fig. 6: d-MAP changes the wound fate from scar formation to regeneration by type 2 immune activation.

Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.


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We thank the National Institutes of Health F32EB018713-01A1 (D.R.G.), T32-GM008042 (M.M.A.), T32AR071307 (M.M.A), U01AR073159 (M.V.P.), R01NS094599 (T.S.), R01HL110592 (T.S.), R03AR073940 (P.O.S.), K08AR066545 (P.O.S.), Pew Charitable Trust (M.V.P.), LEO Foundation (M.V.P.), the National Science Foundation grant DMS1763272, Simons Foundation Grant (594598, QN) (M.V.P.), and the Presidential Early Career Award for Scientists and Engineers (N00014-16-1-2997) (D.D.) for funding. We thank S. C. Lesher-Perez and M. Bogumil for their assistance with MATLAB coding. We thank Y. Liu for assistance with running the endotoxin texts. We also thank the Advanced Light Microscopy and Spectroscopy at California NanoSystems Institute and Electron Microscopy Core Laboratory of the Brain Research Institute at UCLA and, particularly, for the significant help of M. Cilluffo.

Author information




D.R.G., P.O.S. and T.S. conceived the experiments. D.R.G., W.M.W., E.S., M.M.A. and J.K. carried out the microfluidic design and fabrication, and D.D.C. oversaw the microfluidic design and fabrication. D.R.G., M.M.A., C.-H.K., W.M.W, J.S.W., A.C.F., E.S., A.R., V.R. and P.O.S. performed the experiments. D.R.G., M.M.A., J.S.W., A.R., M.V.P., T.S. and P.O.S. analysed and interpreted the data. D.R.G., M.M.A., P.O.S. and T.S. wrote the manuscript and all the authors discussed the results and contributed to writing portions of the manuscript and editing the manuscript. D.R.G. and M.M.A. contributed equally to this work. The co-principal investigators are P.O.S. and T.S.

Corresponding authors

Correspondence to Tatiana Segura or Philip O. Scumpia.

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Competing interests

D.R.G., W.M.W., D.D.C., T.S., and P.O.S. have a financial interest in Tempo Therapeutics, which aims to commercialize MAP technology.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–5 and Supplementary Notes.

Reporting Summary

Source data

Source Data Fig. 1

Raw data for gel degradation and wound characterization.

Source Data Fig. 2

Figure 2 replicate images.

Source Data Fig. 3

Source data for cell infiltration and gene expression.

Source Data Fig. 4

Source data for antibody production and cell infiltration.

Source Data Fig. 5

Source data for wound characterization.

Source Data Supplementary Fig 2

Assessment of wound size.

Source Data Supplementary Fig 3

Quantification of F4/80+CD11b+ macrophages in the edge of L-MAP and D-MAP implant.

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Griffin, D.R., Archang, M.M., Kuan, CH. et al. Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing. Nat. Mater. 20, 560–569 (2021).

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