Abstract
Wounds can become chronic if the biological processes that coordinate tissue repair, including immune cell activity and matrix remodelling, become dysregulated. Current treatments mainly focus on a wound’s physical properties, such as moisture and pressure, and do not restore the disrupted molecular pathways. Here we show a removable patch containing engineered human cells that continuously release native cytokines and that can accelerate healing in rodent and porcine full-thickness wounds. The patch is a polydimethylsiloxane structure that houses alginate-encapsulated human retinal epithelial cells engineered to secrete individual cytokines relevant to tissue repair. Once placed on the wound bed, the cells remain viable and locally release the cytokines over several days. Delivery of interleukin 10, interleukin 12 and transforming growth factor-beta accelerates wound healing in mice and pigs, with accompanying changes in gene expression linked to tissue repair, including pathways involved in skin development and collagen organization. This work suggests that localized, cell-based cytokine delivery may enable future wound treatments that directly modulate the cellular programs governing tissue repair.
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Data availability
Sequencing data for the murine scRNA-seq, murine bulk RNA-seq and pig bulk RNA-seq are available from the Sequence Read Archive with accession number PRJNA1436584. Any additional information is available from the corresponding author with reasonable request. Source data are provided with this paper.
References
Sawaya, A. P. et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat. Commun. 11, 4678 (2020).
Galiano, R. D. et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am. J. Pathol. 164, 1935–1947 (2004).
Khanna, S. et al. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS ONE 5, e9539 (2010).
Nussbaum, S. R. et al. An economic evaluation of the impact, cost, and medicare policy implications of chronic nonhealing wounds. Value Health 21, 27–32 (2018).
Rodrigues, M., Kosaric, N., Bonham, C. A. & Gurtner, G. C. Wound healing: a cellular perspective. Physiol. Rev. 99, 665–706 (2019).
De Rooij, L. et al. Negative pressure wound therapy does not decrease postoperative wound complications in patients undergoing mastectomy and flap fixation. Sci. Rep. 11, 9620 (2021).
Löndahl, M., Katzman, P., Nilsson, A. & Hammarlund, C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 33, 998–1003 (2010).
Patton, D. et al. A meta-review of the impact of compression therapy on venous leg ulcer healing. Int. Wound J. 20, 430–447 (2023).
Caravaggi, C. et al. HYAFF 11-based autologous dermal and epidermal grafts in the treatment of noninfected diabetic plantar and dorsal foot ulcers: a prospective, multicenter, controlled, randomized clinical trial. Diabetes Care 26, 2853–2859 (2003).
Edmonds, M. & European and Australian Apligraf Diabetic Foot Ulcer Study Group. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int. J. Low. Extrem. Wounds 8, 11–18 (2009).
Didomenico, L., Landsman, A. R., Emch, K. J. & Landsman, A. A prospective comparison of diabetic foot ulcers treated with either a cryopreserved skin allograft or a bioengineered skin substitute. Wounds 23, 184–189 (2011).
Cytokines in the balance. Nat. Immunol. 20, 1557 (2019).
Kohli, K., Pillarisetty, V. G. & Kim, T. S. Key chemokines direct migration of immune cells in solid tumors. Cancer Gene Ther. 29, 10–21 (2021).
Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).
King, A., Balaji, S., Le, L. D., Crombleholme, T. M. & Keswani, S. G. Regenerative wound healing: the role of interleukin-10. Adv. Wound Care 3, 315–323 (2014).
Kieran, I. et al. Interleukin-10 reduces scar formation in both animal and human cutaneous wounds: results of two preclinical and phase II randomized control studies. Wound Repair Regen. 21, 428–436 (2013).
Hamza, T., Barnett, J. B. & Li, B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int. J. Mol. Sci. 11, 789–806 (2010).
Xiao, T., Yan, Z., Xiao, S. & Xia, Y. Proinflammatory cytokines regulate epidermal stem cells in wound epithelialization. Stem Cell Res. Ther. 11, 232 (2020).
Barrientos, S., Stojadinovic, O., Golinko, M. S., Brem, H. & Tomic-Canic, M. PERSPECTIVE ARTICLE: Growth factors and cytokines in wound healing. Wound Repair Regen. 16, 585–601 (2008).
Hirshberg, J., Coleman, J., Marchant, B. & Rees, R. S. TGF-beta3 in the treatment of pressure ulcers: a preliminary report. Adv. Skin Wound Care 14, 91–95 (2001).
Roberts, N. J., Zhou, S., Diaz, L. A. & Holdhoff, M. Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget 2, 739–751 (2011).
Haicheur, N. et al. Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients. Clin. Exp. Immunol. 119, 28–37 (2000).
Cohen, J. IL-12 deaths: explanation and a puzzle. Science 270, 908 (1995).
Vazquez-Lombardi, R., Roome, B. & Christ, D. Molecular engineering of therapeutic cytokines. Antibodies 2, 426–451 (2013).
Darwin, E. & Tomic-Canic, M. Healing chronic wounds: current challenges and potential solutions. Curr. Dermatol. Rep. 7, 296–302 (2018).
Miranda, I. et al. Properties and applications of PDMS for biomedical engineering: a review. J. Funct. Biomater. 13, 2 (2022).
Lee, K. Y. & Mooney, D. J. Alginate: properties and biomedical applications. Prog. Polym. Sci. 37, 106–126 (2012).
Sieving, P. A. et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc. Natl Acad. Sci. USA 103, 3896–3901 (2006).
Dunn, L. et al. Murine model of wound healing. J. Vis. Exp. 2013, e50265 (2013).
Masson-Meyers, D. S. et al. Experimental models and methods for cutaneous wound healing assessment. Int. J. Exp. Pathol. 101, 21–37 (2020).
Singer, A. J. & McClain, S. A. Development of a porcine excisional wound model. Acad. Emerg. Med. 10, 1029–1033 (2003).
Nash, A. M. et al. Clinically translatable cytokine delivery platform for eradication of intraperitoneal tumors. Sci. Adv. 8, 1032 (2022).
Kauper, K. et al. Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases. Invest. Ophthalmol. Vis. Sci. 53, 7484–7491 (2012).
Eriksdotter-Jönhagen, M. et al. Encapsulated cell biodelivery of nerve growth factor to the basal forebrain in patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 33, 18–28 (2012).
Dunn, K. C., Aotaki-Keen, A. E., Putkey, F. R. & Hjelmeland, L. M. ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp. Eye Res. 62, 155–170 (1996).
Yousef, H., Ahangar, E. R. & Varacallo, M. Physiology, Thermal Regulation (StatPearls, 2023); https://www.ncbi.nlm.nih.gov/books/NBK499843/
Crum, R. J. et al. Transcriptomic, proteomic, and morphologic characterization of healing in volumetric muscle loss. Tissue Eng A 28, 941–957 (2022).
Zou, J. J. et al. Structure-function analysis of the p35 subunit of mouse interleukin 12. J. Biol. Chem. 270, 5864–5871 (1995).
Chen, L., Mirza, R., Kwon, Y., DiPietro, L. A. & Koh, T. J. The murine excisional wound model: contraction revisited. Wound Repair Regen. 23, 874–877 (2015).
Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293–304 (2023).
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495–502 (2015).
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902.e21 (2019).
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587.e29 (2021).
Jew, B. et al. Accurate estimation of cell composition in bulk expression through robust integration of single-cell information. Nat. Commun. 11, 1971 (2020).
Chen, J. et al. Complement factor D regulates collagen type I expression and fibroblast migration to enhance human tendon repair and healing outcomes. Front. Immunol. 14, 1225957 (2023).
Kuivaniemi, H. & Tromp, G. Type III collagen (COL3A1): gene and protein structure, tissue distribution, and associated diseases. Gene 707, 151–171 (2019).
Denigris, J., Yao, Q., Birk, E. K. & Birk, D. E. Altered dermal fibroblast behavior in a collagen V haploinsufficient murine model of classic Ehlers-Danlos syndrome. Connect. Tissue Res. 57, 1–9 (2016).
Park, A. C. et al. Deficits in Col5a2 expression result in novel skin and adipose abnormalities and predisposition to aortic aneurysms and dissections. Am. J. Pathol. 187, 2300–2311 (2017).
Theocharidis, G. et al. Type VI collagen regulates dermal matrix assembly and fibroblast motility. J. Invest. Dermatol. 136, 74–83 (2016).
Pyo, M. et al. HSP47, a collagen-specific chaperone protein, is a limiting factor for type I collagen secretion in aged skin. J. Dermatol. Sci. 86, e92 (2017).
Engelhardt, E. et al. Chemokines IL-8, GROα, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am. J. Pathol. 153, 1849–1860 (1998).
Ishi, S. et al. Cutaneous wound healing promoted by topical administration of heat-killed Lactobacillus plantarum KB131 and possible contribution of CARD9-mediated signaling. Sci. Rep. 13, 15917 (2023).
Ridiandries, A., Tan, J. T. M. & Bursill, C. A. The role of chemokines in wound healing. Int. J. Mol. Sci. 19, 3217 (2018).
Wietecha, M. S. et al. Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds. Nat. Commun. 11, 2604 (2020).
Wang, G. et al. Bacteria induce skin regeneration via IL-1β signaling. Cell Host Microbe 29, 777–791 (2021).
Jones, A. M. et al. The clinical significance and impact of interleukin 15 on keratinocyte cell growth and migration. Int. J. Mol. Med. 38, 679–686 (2016).
Hsu, J. Y. C. et al. Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. J. Neurosci. 26, 9841–9850 (2006).
Le, H. T. et al. Platelet factor 4 (CXCL4/PF4) upregulates matrix metalloproteinase-2 (MMP-2) in gingival fibroblasts. Sci. Rep. 12, 18636 (2022).
Gu, M. et al. Chemokine platelet factor 4 accelerates peripheral nerve regeneration by regulating Schwann cell activation and axon elongation. Neural Regen. Res. 19, 190–195 (2023).
Huguier, V. et al. Oncostatin M exerts a protective effect against excessive scarring by counteracting the inductive effect of TGFβ1 on fibrosis markers. Sci. Rep. 9, 2113 (2019).
DiPietro, L. A., Burdick, M., Low, Q. E., Kunkel, S. L. & Strieter, R. M. MIP-1alpha as a critical macrophage chemoattractant in murine wound repair. J. Clin. Invest. 101, 1693–1698 (1998).
Li, Y., Jalili, R. B. & Ghahary, A. Accelerating skin wound healing by M-CSF through generating SSEA-1 and -3 stem cells in the injured sites. Sci. Rep. 6, 28979 (2016).
Wang, J.-M. et al. Boosting UPR transcriptional activator XBP1 accelerates acute wound healing. PNAS Nexus 2, pgad050 (2023).
Wu, M. et al. Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. Am. J. Pathol. 175, 1041–1055 (2009).
Silva, W. N. et al. Macrophage-derived GPNMB accelerates skin healing. Exp. Dermatol. 27, 630–635 (2018).
Inoue, Y. et al. Macrophage-specific, mafb-deficient mice showed delayed skin wound healing. Int. J. Mol. Sci. 23, 9346 (2022).
Caley, M. P., Martins, V. L. C. & O’Toole, E. A. Metalloproteinases and wound healing. Adv. Wound Care 4, 225–234 (2015).
Hwang, S. J. et al. Human collagen alpha-2 type I stimulates collagen synthesis, wound healing, and elastin production in normal human dermal fibroblasts (HDFs). BMB Rep. 53, 539 (2020).
Xie, Z. et al. Gene set knowledge discovery with Enrichr. Curr. Protoc. 1, e90 (2021).
Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90–W97 (2016).
Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).
Browaeys, R., Saelens, W. & Saeys, Y. NicheNet: modeling intercellular communication by linking ligands to target genes. Nat. Methods 17, 159–162 (2019).
Shi, G. et al. Platelet factor 4 mediates vascular smooth muscle cell injury responses. Blood 121, 4417–4427 (2013).
Tantilertanant, Y. et al. Cyclic tensile force-upregulated IL6 increases MMP3 expression by human periodontal ligament cells. Arch. Oral Biol. 107, 104495 (2019).
Liu, M., Wilson, N. O., Hibbert, J. M. & Stiles, J. K. STAT3 Regulates MMP3 in heme-induced endothelial cell apoptosis. PLoS ONE 8, e71366 (2013).
Buka, R. J. et al. PF4 activates the c-Mpl–Jak2 pathway in platelets. Blood 143, 64–69 (2023).
Dinca, S. C. et al. Novel mechanism for OSM-promoted extracellular matrix remodeling in breast cancer: LOXL2 upregulation and subsequent ECM alignment. Breast Cancer Res. 23, 56 (2021).
Cuevas, E. P. et al. LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway. Sci. Rep. 7, 44988 (2017).
Kuo, T. Y. et al. Skin wound healing assessment via an optimized wound array model in miniature pigs. Sci. Rep. 12, 445 (2022).
Sakamoto, M. et al. Cultured human epidermis combined with meshed skin autografts accelerates epithelialization and granulation tissue formation in a rat model. Ann. Plast. Surg. 78, 651–658 (2017).
Matias, M. A., Saunus, J. M., Ivanovski, S., Walsh, L. J. & Farah, C. S. Accelerated wound healing phenotype in Interleukin 12/23 deficient mice. J. Inflamm. 8, 39 (2011).
Abu-Khalaf, J. M., Al-Ghussain, L. & Al-Halhouli, A. Fabrication of stretchable circuits on polydimethylsiloxane (PDMS) pre-stretched substrates by inkjet printing silver nanoparticles. Materials 11, 2377 (2018).
Denis, M. C. & Huber, B. T. Native and recombinant interleukin-2, two functionally distinct molecules. Mol. Immunol. 40, 279–286 (2003).
Li, Q. et al. Advances of hydrogel combined with stem cells in promoting chronic wound healing. Front. Chem. 10, 1038839 (2022).
Srifa, W. et al. Cas9-AAV6-engineered human mesenchymal stromal cells improved cutaneous wound healing in diabetic mice. Nat. Commun. 11, 2470 (2020).
Freedman, B. R. et al. Breakthrough treatments for accelerated wound healing. Sci. Adv. 9, eade7007 (2023).
Patil, P. et al. Reactive oxygen species–degradable polythioketal urethane foam dressings to promote porcine skin wound repair. Sci. Transl. Med. 14, eabm6586 (2022).
Notodihardjo, S. C. et al. A comparison of the wound healing process after the application of three dermal substitutes with or without basic fibzroblast growth factor impregnation in diabetic mice. J. Plast. Reconstr. Aesthet. Surg. 73, 1547–1555 (2020).
Larouche, J., Sheoran, S., Maruyama, K. & Martino, M. M. Immune regulation of skin wound healing: mechanisms and novel therapeutic targets. Adv. Wound Care 7, 209–231 (2018).
Barrientos, S., Stojadinovic, O., Golinko, M. S., Brem, H. & Tomic-Canic, M. Growth factors and cytokines in wound healing. Wound Repair Regen. 16, 585–601 (2008).
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
Beeton, C., Garcia, A. & Chandy, K. G. Drawing blood from rats through the saphenous vein and by cardiac puncture. J. Vis. Exp. https://doi.org/10.3791/266 (2007).
Bankhead, P. et al. QuPath: open source software for digital pathology imtypes of age analysis. Sci. Rep. 7, 16878 (2017).
Patel, H. et al. nf-core/rnaseq: nf-core/rnaseq v3.14.0 - Hassium Honey Badger. Zenodo https://doi.org/10.5281/zenodo.10471647 (2024).
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
Acknowledgements
This work was supported by Defense Advanced Research Projects Agency (D20AC00002) for O.V., T.C.-K., S.F.B. and B.N.B. We thank R. Crum and M. Lebaudy for their assistance with the canine surgery.
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C.C.S., E.L.K. and O.V. designed the studies. C.C.S., E.L.K, G.A., S.J., S.F., M.N.B., D.V., M.K. and G.M.D. conducted the experiments. R.G. designed the device form. C.C.S. and E.L.K. analysed data, carried out statistical analyses and prepared displays communicating datasets. O.V., T.C.-K., S.F.B. and B.N.B. provided advice and technical support throughout. O.V. supervised the study. C.C.S. wrote the paper with assistance from E.L.K, S.J., B.N.B., S.F.B. and O.V. All authors discussed the results and the preparation of the paper.
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C.C.S., T.C.K. and O.V. declare interests via patents filed by Rice University and Carnegie Mellon University on the wound patch described in this paper. C.C.S., T.C.K. and O.V. hold equity in and are cofounders of Curada Bio. The other authors declare no competing interests.
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Schreib, C.C., Kelley, E.L., Audia, G. et al. Cell-based cytokine patch for localized immunomodulation and accelerated healing in rodent and porcine wounds. Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-026-01687-7
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DOI: https://doi.org/10.1038/s41551-026-01687-7


