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A strain-programmed patch for the healing of diabetic wounds

Nature Biomedical Engineering volume 6, pages 1118–1133 (2022)Cite this article

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Abstract

Diabetic foot ulcers and other chronic wounds with impaired healing can be treated with bioengineered skin or with growth factors. However, most patients do not benefit from these treatments. Here we report the development and preclinical therapeutic performance of a strain-programmed patch that rapidly and robustly adheres to diabetic wounds, and promotes wound closure and re-epithelialization. The patch consists of a dried adhesive layer of crosslinked polymer networks bound to a pre-stretched hydrophilic elastomer backing, and implements a hydration-based shape-memory mechanism to mechanically contract diabetic wounds in a programmable manner on the basis of analytical and finite-element modelling. In mouse and human skin, and in mini-pigs and humanized mice, the patch enhanced the healing of diabetic wounds by promoting faster re-epithelialization and angiogenesis, and the enrichment of fibroblast populations with a pro-regenerative phenotype. Strain-programmed patches might also be effective for the treatment of other forms of acute and chronic wounds.

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Fig. 1: Strain-programmed patch for diabetic skin wounds.
Fig. 2: Design and mechanical properties of the strain-programmed patch.
Fig. 3: Mechanical modulation of human skin wounds.
Fig. 4: Evaluation of diabetic wound healing in a db/db mouse model.
Fig. 5: Immunofluorescence staining analysis of diabetic mouse wounds.
Fig. 6: Transcriptomic analysis of diabetic mouse wounds.
Fig. 7: Evaluation of diabetic wound healing in a human skin model.
Fig. 8: Accelerated diabetic wound healing of in vivo porcine skin.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The RNA-seq data are available from the Gene Expression Omnibus (GEO) database, with accession number GSE154132. Publicly available single-cell RNA-seq data were obtained from GEO (accession number, GSE141814). Additional raw datasets generated during the study are too large to be publicly shared, yet they are available from the corresponding authors on reasonable request.

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Acknowledgements

We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically K. Cormier and the Histology Core for the histological processing and analysis. This work was supported by Defense Advanced Research Projects Agency (DARPA) (5(GG0015670) to X.Z. and A.V.) and Department of Defense Congressionally Directed Medical Research Programs (CDMRP) (PR200524P1 to X.Z. and A.V.). A.V. received funding from the National Rongxiang Xu Foundation. G.T. received a George and Marie Vergottis Foundation Postdoctoral Fellowship. H.Y. acknowledges the financial support from Samsung Scholarship. H.R. acknowledges the financial support from Kwanjeong Educational Foundation Scholarship.

Author information

Author notes

  1. Hyunwoo Yuk

    Present address: SanaHeal, Inc., Boston, MA, USA

  2. Liu Wang

    Present address: CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China, Hefei, Anhui, China

  3. These authors contributed equally: Georgios Theocharidis, Hyunwoo Yuk, Heejung Roh, Liu Wang. These authors jointly supervised this work: Aristidis Veves, Xuanhe Zhao.

Authors and Affiliations

  1. Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Georgios Theocharidis, Ikram Mezghani, Brandon Sumpio, Zhuqing Li, Enya Wang, Lihong Chen, Navin Jayaswal & Aristidis Veves

  2. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Hyunwoo Yuk, Heejung Roh, Liu Wang, Jingjing Wu & Xuanhe Zhao

  3. Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen, China

    Jingjing Wu & Chuan Fei Guo

  4. Lincoln County Hospital, Northern Lincolnshire and Goole NHS Foundation Trust, Lincoln, Lincolnshire, UK

    Antonios Kafanas

  5. Division of Vascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Mauricio Contreras

  6. Cancer Research Institute, HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Xanthi-Leda Katopodi, Nikolaos Kalavros & Ioannis S. Vlachos

  7. Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA

    Christoph S. Nabzdyk

  8. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Ioannis S. Vlachos

  9. Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Xuanhe Zhao

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  1. Georgios Theocharidis
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Contributions

H.Y., G.T., A.V. and X.Z. designed the study. H.Y. conceived the idea and developed the materials and method for the strain-programmed patch. H.Y., H.R. and C.S.N. designed the in vitro and ex vivo experiment. H.Y. and H.R. conducted the in vitro and ex vivo experiment and analysis. L.W. and C.F.G. designed and conducted the theoretical and numerical modelling and analysis. H.Y. and J.W. designed and conducted the in vivo biocompatibility experiment. G.T., I.M., L.C. and A.V. designed and conducted the in vivo diabetic mouse wound healing experiment and analysis. G.T., M.C., B.S. and A.V. designed and conducted the in vivo diabetic porcine wound healing experiment. G.T., I.M., B.S., L.Z. and E.W. designed and conducted the in vivo diabetic humanized mice wound healing experiment. G.T., I.M., Z.L., E.W. and N.J. completed the flow cytometry, histology, immunofluorescence, gene expression and human skin ex vivo experiment analyses. A.K. performed histology assessment and scoring. X.-L.K., N.K. and I.S.V. performed sequencing analysis. H.Y. and G.T. prepared the figures. G.T., H.Y., X.Z. and A.V. wrote the manuscript with inputs from all authors.

Corresponding authors

Correspondence to Hyunwoo Yuk, Aristidis Veves or Xuanhe Zhao.

Ethics declarations

Competing interests

H.Y., H.R., X.Z., G.T. and A.V. are the inventors of a patent application (U.S. Application No. 63/148,901) that covers the design and mechanism of the strain-programmed patch for diabetic wound healing. H.Y., C.S.N. and X.Z. have a financial interest in SanaHeal, Inc., a biotechnology company focused on the development of medical devices for surgical sealing and repair. All other authors declare no competing interests.

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Nature Biomedical Engineering thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Rapid wet adhesion and on-demand detachment of the strain-programmed patch.

a, Rapid wet adhesion and on-demand detachment of the strain-programmed patch. b,c, Chemistry of the physical and covalent crosslinks for rapid wet adhesion (b) and on-demand detachment (c) of the strain-programmed patch.

Extended Data Fig. 2 Anisotropically strain-programmed patch.

a, Closure of an incisional wound on porcine skin by the anisotropically strain-programmed patch. b,c, Theoretical and experimental values of contraction (\(\lambda _{{{{\mathrm{patch}}}}}^{{{{\mathrm{shrink}}}}}\)) (b) and nominal contractile stress (c) generated by programmed strain release upon hydration of the anisotropically strain-programmed patch with varying \(\lambda _{{{{\mathrm{patch}}}}}^{{{{\mathrm{pre}}}}1}\). Values in b,c represent the mean and the standard deviation (n = 4; independent samples). Scale bars, 10 mm (a).

Extended Data Fig. 3 On-demand detachment of the strain-programmed patch.

a, On-demand detachment of the strain-programmed patch adhered on a porcine skin by application of a detachment solution. b, Interfacial toughness of the strain-programmed patch adhered on porcine skin 5 min after applying PBS or the detachment solution. Values in b represent the mean and the standard deviation (n = 3; independent samples). Statistical significance and p values are determined by two-sided t-test.

Extended Data Fig. 4 In vitro and in vivo biocompatibility of the strain-programmed patch.

a, Representative LIVE/DEAD assay images and the cell viability of mouse embryonic fibroblasts (mEFs) for control (DMEM) and the strain-programmed patch after 24-h culture. DMEM, Dulbecco’s modified eagle medium. b-f, Representative histological images for the subcutaneously implanted strain-programmed patch (b), Coseal (c), Dermabond cyanoacrylate (CA) adhesive (d), strain-programmed patch after on-demand detachment (e), and sham surgery (f) after 2 weeks post-implantation stained with hematoxylin and eosin (H&E). g, Degree of inflammation of various groups evaluated by a blinded pathologist (0, normal; 1, mild; 2, moderate; 3, severe; 4, very severe) after 2 weeks post-implantation. Skin side and implant side in the histological images are indicated by arrows. SM, skeletal muscle; FC, fibrous capsule. All experiments are repeated four biological replicates with similar results. Values in a,g represent the mean and the standard deviation (n = 4; independent samples). Statistical significance and p values are determined by two-sided t-test; ns, not significant; * p < 0.05. Scale bars, 200 µm (a-f).

Extended Data Fig. 5 Proliferation and apoptosis of the wound cells.

a,b, Quantification of proliferation marker Ki67+ cells in the dermis (a) and the epidermis (b) of day 5 (D5) wounds. c, Quantification of apoptosis marker active Caspase-3+ cells in the dermis of D5 wounds. d,e, Quantification of proliferation marker Ki67+ cells in the dermis (d) and the epidermis (e) of day 10 (D10) wounds. f, Quantification of apoptosis marker active Caspase-3+ cells in the dermis of D10 wounds. Values represent the mean and the standard deviation (n = 10 in a and b; n = 7 in c and f; n = 10 for TD Only, 8 for No Strain and 10 for Strain in d; n = 10 for TD Only, 8 for No Strain and 8 for Strain in e; independent samples). Statistical significance and p values are determined by one-way ANOVA followed by Tukey’s multiple comparison test; ns, not significant.

Extended Data Fig. 6 Flow-cytometric quantification of major immune cell populations and macrophage polarized states in D5 wounds.

a-m, Single-cell suspensions were generated from excised wound and peri-wound tissues and stained for the indicated cell surface proteins. Percentage of immune cells (a), neutrophils (b), monocytes (c), macrophages (d), dendritic cells (DCs) (e), and T-cells (f) and T-cell subsets (g,h). Percentage of macrophages expressing markers CD86 (i), CD80 (j), CD163 (k), CD206 (l), and CD301b (m). Each data point represents pooled cells from two mice (four wounds). Values represent the mean and the standard deviation (n = 6 for TD Only, 7 for No Strain and 7 for Strain; independent samples). Statistical significance and p values are determined by one-way ANOVA followed by Fisher’s least significant difference (LSD) post-hoc test; ns, not significant.

Extended Data Fig. 7 Flow-cytometric quantification of major immune cell populations and macrophage polarized states in D10 wounds.

a-m, Single-cell suspensions were generated from excised wound and peri-wound tissues and stained for the indicated cell surface proteins. Percentage of immune cells (a), neutrophils (b), monocytes (c), macrophages (d), dendritic cells (DCs) (e), and T-cells (f) and T-cell subsets (g,h). Percentage of macrophages expressing markers CD86 (i), CD80 (j), CD163 (k), CD206 (l), and CD301b (m). Each data point represents pooled cells from two mice (four wounds). Values represent the mean and the standard deviation (n = 6 for TD Only, 7 for No Strain and 7 for Strain; independent samples). Statistical significance and p values are determined by one-way ANOVA followed by Fisher’s least significant difference (LSD) post-hoc test; ns, not significant.

Extended Data Fig. 8 Ex vivo human skin wound-healing model with pre-tension.

a-c, Ex vivo human skin with speckles and corresponding digital image correlation (DIC) analysis results without pre-tension (a) and with pre-tension in x-direction (b) and in y-direction (c). ROI, region of interest. d,e, Representative images of an ex vivo human skin culture setup with pre-tension before (d) and after (e) the strain-programmed patch application. f, Quantification of the open wound length on day 4 (D4) post-injury. Values in f represent the mean and the standard deviation (n = 9 wounds for No Strain and 13 wounds for Strain from 2 individual patients’ skin; independent samples). Statistical significance and p values are determined by two-sided t-test. Scale bars, 5 mm (d,e).

Extended Data Fig. 9 Immunostaining analysis of diabetic in vivo wound healing of porcine skin.

a,b, Representative immunohistochemistry images for CD31 (a) and quantification of CD31 + vessels per unit area (b) on day 7 (D7). c,d, Representative immunohistochemistry images for CD31 (c) and quantification of CD31 + vessels per unit area (d) on day 14 (D14). e,f, Representative immunofluorescence images for αSMA (e) and quantification of αSMA + cells per unit area (f) on D7. g, Representative immunofluorescence images for αSMA on D14. In immunohistochemistry images, the NOVA Red peroxidase substrate chromogenic stain was used. In immunofluorescence images, blue fluorescence corresponds to cell nuclei stained with 4′,6-diamidino-2-phenylindole (DAPI); green fluorescence corresponds to the expression of αSMA. Experimental groups are Tegaderm (TD) only, no strain (\(\lambda _{{{{\mathrm{patch}}}}}^{{{{\mathrm{pre}}}}} = 1\)) and strain-programmed (\(\lambda _{{{{\mathrm{patch}}}}}^{{{{\mathrm{pre}}}}} = 1.3\)) patch for both D7 and D14. Values in b,d,f represent the mean and the standard deviation (n = 6; independent samples). Statistical significance and p values are determined by one-way ANOVA followed by Fisher’s least significant difference (LSD) post-hoc test; ns, not significant. Scale bars, 100 µm (a,c,e,g).

Extended Data Fig. 10 Accelerated diabetic in vivo wound healing of humanized mouse skin.

a, Schematic illustrations for the xenotransplantation procedure, diabetes induction, and experimental plan. W, week. b, Representative images from Day 5 wounds with Masson’s trichrome stain (MTS). Red triangles denote wound margins. c-g, Quantification of the wound closure expressed as % of open wound compared to Day 0 (c), the re-epithelialization expressed as % (d), the hyperproliferative epidermis (HPE) area (e), the number of CD31 + vessels per unit area (f), and the number of αSMA + cells per unit area (g) on Day 5. Values in c-g represent the mean and the standard deviation (n = 4 in c, f, g; n = 4 for No Strain and 3 for Strain in d and e; independent samples). Statistical significance and p values are determined by two-sided t-test. Scale bars, 5 mm (a); 250 µm (b). Parts of (a) were created with BioRender.com.

Supplementary information

Supplementary Information

Supplementary methods, discussion, figures, references and video captions.

Reporting Summary

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Supplementary Dataset 1

Complete lists of differentially expressed genes from RNA-seq data.

Supplementary Dataset 2

Complete list of the antibody cocktails for flow cytometry.

Supplementary Video 1

Rapid adhesion and closure of an ex vivo porcine skin wound by the strain-programmed patch.

Supplementary Video 2

Rapid adhesion and closure of an incisional skin wound by the anisotropically strain-programmed patch.

Supplementary Video 3

On-demand removal of the adhered patch from ex vivo porcine skin wound by applying a detachment solution.

Supplementary Video 4

Rapid adhesion and wound closure in diabetic mouse skin by the strain-programmed patch.

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Theocharidis, G., Yuk, H., Roh, H. et al. A strain-programmed patch for the healing of diabetic wounds. Nat. Biomed. Eng 6, 1118–1133 (2022). https://doi.org/10.1038/s41551-022-00905-2

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