A strain-programmed patch for the healing of diabetic wounds.
Journal
Nature biomedical engineering
ISSN: 2157-846X
Titre abrégé: Nat Biomed Eng
Pays: England
ID NLM: 101696896
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
24
12
2021
accepted:
27
05
2022
pubmed:
6
7
2022
medline:
22
10
2022
entrez:
5
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35788686
doi: 10.1038/s41551-022-00905-2
pii: 10.1038/s41551-022-00905-2
doi:
Substances chimiques
Elastomers
0
Polymers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1118-1133Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL153857
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
Références
National Diabetes Statistics Report (Centers for Disease Control and Prevention, 2017).
Geiss, L. S. et al. Resurgence of diabetes-related nontraumatic lower extremity amputation in the young and middle-aged adult U.S. population. Diabetes Care 42, 50–54 (2019).
pubmed: 30409811
doi: 10.2337/dc18-1380
Boulton, A. J., Vileikyte, L., Ragnarson-Tennvall, G. & Apelqvist, J. The global burden of diabetic foot disease. Lancet 366, 1719–1724 (2005).
pubmed: 16291066
doi: 10.1016/S0140-6736(05)67698-2
Veves, A., Falanga, V., Armstrong, D. G., Sabolinski, M. L. & Apligraf Diabetic Foot Ulcer Study Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care 24, 290–295 (2001).
pubmed: 11213881
doi: 10.2337/diacare.24.2.290
Marston, W. A., Hanft, J., Norwood, P. & Pollak, R. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care 26, 1701–1705 (2003).
pubmed: 12766097
doi: 10.2337/diacare.26.6.1701
Wieman, T. J., Smiell, J. M. & Su, Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care 21, 822–827 (1998).
pubmed: 9589248
doi: 10.2337/diacare.21.5.822
Tecilazich, F., Dinh, T. & Veves, A. Treating diabetic ulcers. Expert Opin. Pharmacother. 12, 593–606 (2011).
pubmed: 21241210
doi: 10.1517/14656566.2011.530658
Tecilazich, F., Dinh, T. L. & Veves, A. Emerging drugs for the treatment of diabetic ulcers. Expert Opin. Emerg. Drugs 18, 207–217 (2013).
pubmed: 23687931
pmcid: 3697092
doi: 10.1517/14728214.2013.802305
Singer, A. J. & Clark, R. A. Cutaneous wound healing. N. Engl. J. Med. 341, 738–746 (1999).
pubmed: 10471461
doi: 10.1056/NEJM199909023411006
George Broughton, I., Janis, J. E. & Attinger, C. E. The basic science of wound healing. Plast. Reconstr. Surg. 117, 12S–34S (2006).
pubmed: 16799372
doi: 10.1097/01.prs.0000225430.42531.c2
Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).
pubmed: 18480812
doi: 10.1038/nature07039
Wong, V. W. et al. A mechanomodulatory device to minimize incisional scar formation. Adv. Wound Care 2, 185–194 (2013).
doi: 10.1089/wound.2012.0396
Eming, S. A., Martin, P. & Tomic-Canic, M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci. Transl. Med. 6, 265sr266 (2014).
doi: 10.1126/scitranslmed.3009337
Barnes, L. A. et al. Mechanical forces in cutaneous wound healing: emerging therapies to minimize scar formation. Adv. Wound Care 7, 47–56 (2018).
doi: 10.1089/wound.2016.0709
Harn, H. I. C. et al. The tension biology of wound healing. Exp. Dermatol. 28, 464–471 (2019).
pubmed: 29105155
doi: 10.1111/exd.13460
Falanga, V. Wound healing and its impairment in the diabetic foot. Lancet 366, 1736–1743 (2005).
pubmed: 16291068
doi: 10.1016/S0140-6736(05)67700-8
Loots, M. A. et al. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J. Investig. Dermatol. 111, 850–857 (1998).
pubmed: 9804349
doi: 10.1046/j.1523-1747.1998.00381.x
Brem, H. & Tomic-Canic, M. Cellular and molecular basis of wound healing in diabetes. J. Clin. Investig. 117, 1219–1222 (2007).
pubmed: 17476353
pmcid: 1857239
doi: 10.1172/JCI32169
Theocharidis, G. et al. Single cell transcriptomic landscape of diabetic foot ulcers. Nat. Commun. 13, 181 (2022).
pubmed: 35013299
pmcid: 8748704
doi: 10.1038/s41467-021-27801-8
Wang, J. H.-C., Thampatty, B. P., Lin, J.-S. & Im, H.-J. Mechanoregulation of gene expression in fibroblasts. Gene 391, 1–15 (2007).
pubmed: 17331678
pmcid: 2893340
doi: 10.1016/j.gene.2007.01.014
Gurtner, G. C. et al. Improving cutaneous scar formation by controlling the mechanical environment: large animal and phase I studies. Ann. Surg. 254, 217–225 (2011).
pubmed: 21606834
doi: 10.1097/SLA.0b013e318220b159
Li, J. et al. Tough adhesives for diverse wet surfaces. Science 357, 378–381 (2017).
pubmed: 28751604
pmcid: 5905340
doi: 10.1126/science.aah6362
Blacklow, S. et al. Bioinspired mechanically active adhesive dressings to accelerate wound closure. Sci. Adv. 5, eaaw3963 (2019).
pubmed: 31355332
pmcid: 6656537
doi: 10.1126/sciadv.aaw3963
Yuk, H. et al. Dry double-sided tape for adhesion of wet tissues and devices. Nature 575, 169–174 (2019).
pubmed: 31666696
doi: 10.1038/s41586-019-1710-5
Kelley, F. N. & Bueche, F. Viscosity and glass temperature relations for polymer‐diluent systems. J. Polym. Sci. 50, 549–556 (1961).
doi: 10.1002/pol.1961.1205015421
Frisch, H., Wang, T. & Kwei, T. Diffusion in glassy polymers. II. J. Polym. Sci. A‐2 7, 879–887 (1969).
doi: 10.1002/pol.1969.160070512
Mao, X., Yuk, H. & Zhao, X. Hydration and swelling of dry polymers for wet adhesion. J. Mech. Phys. Solids 137, 103863 (2020).
doi: 10.1016/j.jmps.2020.103863
Lendlein, A. & Langer, R. Biodegradable, elastic shape-memory polymers for potential biomedical applications. Science 296, 1673–1676 (2002).
pubmed: 11976407
doi: 10.1126/science.1066102
Mather, P. T., Luo, X. & Rousseau, I. A. Shape memory polymer research. Annu. Rev. Mater. Res. 39, 445–471 (2009).
doi: 10.1146/annurev-matsci-082908-145419
Meng, H. & Li, G. A review of stimuli-responsive shape memory polymer composites. Polymer 54, 2199–2221 (2013).
doi: 10.1016/j.polymer.2013.02.023
Chen, X., Yuk, H., Wu, J., Nabzdyk, C. S. & Zhao, X. Instant tough bioadhesive with triggerable benign detachment. Proc. Natl Acad. Sci. USA 117, 15497–15503 (2020).
pubmed: 32576692
pmcid: 7376570
doi: 10.1073/pnas.2006389117
Upton, D., Solowiej, K., Hender, C. & Woo, K. Stress and pain associated with dressing change in patients with chronic wounds. J. Wound Care 21, 53–61 (2012).
pubmed: 22584524
doi: 10.12968/jowc.2012.21.2.53
Than, U. T. T., Guanzon, D., Leavesley, D. & Parker, T. Association of extracellular membrane vesicles with cutaneous wound healing. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18050956 (2017).
Flynn, C., Taberner, A. & Nielsen, P. Mechanical characterisation of in vivo human skin using a 3D force-sensitive micro-robot and finite element analysis. Biomech. Model. Mechanobiol. 10, 27–38 (2011).
pubmed: 20429025
doi: 10.1007/s10237-010-0216-8
Berezovsky, A. B. et al. Primary contraction of skin grafts: a porcine preliminary study. Plast. Aesthet. Res. 25, 22–26 (2015).
Joodaki, H. & Panzer, M. B. Skin mechanical properties and modeling: a review. Proc. Inst. Mech. Eng. H 232, 323–343 (2018).
pubmed: 29506427
doi: 10.1177/0954411918759801
Grada, A., Mervis, J. & Falanga, V. Research techniques made simple: animal models of wound healing. J. Investig. Dermatol. 138, 2095–2105.e1 (2018).
pubmed: 30244718
doi: 10.1016/j.jid.2018.08.005
Scherer, S. S. et al. Wound healing kinetics of the genetically diabetic mouse. Wounds 20, 18–28 (2008).
pubmed: 25942757
Volk, S. W. & Bohling, M. W. Comparative wound healing—are the small animal veterinarian’s clinical patients an improved translational model for human wound healing research? Wound Repair Regen. 21, 372–381 (2013).
pubmed: 23627643
doi: 10.1111/wrr.12049
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).
pubmed: 26136050
pmcid: 5094847
doi: 10.1111/wrr.12338
Wang, X. T., McKeever, C. C., Vonu, P., Patterson, C. & Liu, P. Y. Dynamic histological events and molecular changes in excisional wound healing of diabetic DB/DB mice. J. Surg. Res. 238, 186–197 (2019).
pubmed: 30771688
doi: 10.1016/j.jss.2019.01.048
Hinz, B. Formation and function of the myofibroblast during tissue repair. J. Investig. Dermatol. 127, 526–537 (2007).
pubmed: 17299435
doi: 10.1038/sj.jid.5700613
Rinkevich, Y. et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 348, aaa2151 (2015).
pubmed: 25883361
pmcid: 5088503
doi: 10.1126/science.aaa2151
Mascharak, S. et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science 372, eaba2374 (2021).
pubmed: 33888614
pmcid: 9008875
doi: 10.1126/science.aba2374
Jiang, D. et al. Two succeeding fibroblastic lineages drive dermal development and the transition from regeneration to scarring. Nat. Cell Biol. 20, 422–431 (2018).
pubmed: 29593327
doi: 10.1038/s41556-018-0073-8
Shook, B. A. et al. Dermal adipocyte lipolysis and myofibroblast conversion are required for efficient skin repair. Cell Stem Cell 26, 880–895.e6 (2020).
pubmed: 32302523
pmcid: 7853423
doi: 10.1016/j.stem.2020.03.013
Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017).
pubmed: 28059714
pmcid: 5464786
doi: 10.1126/science.aai8792
Joshi, N. et al. Comprehensive characterization of myeloid cells during wound healing in healthy and healing-impaired diabetic mice. Eur. J. Immunol. 50, 1335–1349 (2020).
pubmed: 32306381
pmcid: 7496577
doi: 10.1002/eji.201948438
Mariani, E., Lisignoli, G., Borzi, R. M. & Pulsatelli, L. Biomaterials: foreign bodies or tuners for the immune response? Int. J. Mol. Sci. https://doi.org/10.3390/ijms20030636 (2019).
Krzyszczyk, P., Schloss, R., Palmer, A. & Berthiaume, F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front. Physiol. 9, 419 (2018).
pubmed: 29765329
pmcid: 5938667
doi: 10.3389/fphys.2018.00419
Gay, D. et al. Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing. Sci. Adv. 6, eaay3704 (2020).
pubmed: 32219160
pmcid: 7083618
doi: 10.1126/sciadv.aay3704
Acharya, P. S. et al. Fibroblast migration is mediated by CD44-dependent TGFβ activation. J. Cell Sci. 121, 1393–1402 (2008).
pubmed: 18397995
doi: 10.1242/jcs.021683
Ruiz-Ederra, J. & Verkman, A. Aquaporin-1-facilitated keratocyte migration in cell culture and in vivo corneal wound healing models. Exp. Eye Res. 89, 159–165 (2009).
pubmed: 19298815
pmcid: 3319399
doi: 10.1016/j.exer.2009.03.002
Xie, T. et al. Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. Cell Rep. 22, 3625–3640 (2018).
pubmed: 29590628
pmcid: 5908225
doi: 10.1016/j.celrep.2018.03.010
Stojadinovic, O. & Tomic-Canic, M. Human ex vivo wound healing model. Methods Mol. Biol. 1037, 255–264 (2013).
pubmed: 24029940
doi: 10.1007/978-1-62703-505-7_14
Gherardini, J., van Lessen, M., Piccini, I., Edelkamp, J. & Bertolini, M. Human wound healing ex vivo model with focus on molecular markers. Methods Mol. Biol. 2154, 249–254 (2020).
pubmed: 32314223
doi: 10.1007/978-1-0716-0648-3_21
Summerfield, A., Meurens, F. & Ricklin, M. E. The immunology of the porcine skin and its value as a model for human skin. Mol. Immunol. 66, 14–21 (2015).
pubmed: 25466611
doi: 10.1016/j.molimm.2014.10.023
Chen, K. et al. Disrupting biological sensors of force promotes tissue regeneration in large organisms. Nat. Commun. 12, 5256 (2021).
pubmed: 34489407
pmcid: 8421385
doi: 10.1038/s41467-021-25410-z
Martínez‐Santamaría, L. et al. The regenerative potential of fibroblasts in a new diabetes‐induced delayed humanised wound healing model. Exp. Dermatol. 22, 195–201 (2013).
pubmed: 23489422
doi: 10.1111/exd.12097
Ding, J. & Tredget, E. E. in Fibrosis. Methods in Molecular Biology Vol. 1627 (ed. Rittié, L.) 65–80 (Humana Press, 2017).
Démarchez, M., Hartmann, D. J., Herbage, D., Ville, G. & Pruniéras, M. Wound healing of human skin transplanted onto the nude mouse: II. An immunohistological and ultrastructural study of the epidermal basement membrane zone reconstruction and connective tissue reorganization. Dev. Biol. 121, 119–129 (1987).
pubmed: 3552786
doi: 10.1016/0012-1606(87)90145-X
Driver, V. R. et al. A clinical trial of Integra Template for diabetic foot ulcer treatment. Wound Repair Regen. 23, 891–900 (2015).
pubmed: 26297933
doi: 10.1111/wrr.12357
Baltzis, D., Eleftheriadou, I. & Veves, A. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv. Ther. 31, 817–836 (2014).
pubmed: 25069580
doi: 10.1007/s12325-014-0140-x
Castleberry, S. A. et al. Self-assembled wound dressings silence MMP-9 and improve diabetic wound healing in vivo. Adv. Mater. 28, 1809–1817 (2016).
pubmed: 26695434
doi: 10.1002/adma.201503565
Shibata, S. et al. Adiponectin regulates cutaneous wound healing by promoting keratinocyte proliferation and migration via the ERK signaling pathway. J. Immunol. 189, 3231–3241 (2012).
pubmed: 22904306
doi: 10.4049/jimmunol.1101739
Gao, M. et al. Acceleration of diabetic wound healing using a novel protease-anti-protease combination therapy. Proc. Natl Acad. Sci. USA 112, 15226–15231 (2015).
pubmed: 26598687
pmcid: 4679041
doi: 10.1073/pnas.1517847112
Brown, R. L., Breeden, M. P. & Greenhalgh, D. G. PDGF and TGF-alpha act synergistically to improve wound healing in the genetically diabetic mouse. J. Surg. Res. 56, 562–570 (1994).
pubmed: 8015312
doi: 10.1006/jsre.1994.1090
Smiell, J. M. et al. Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen. 7, 335–346 (1999).
pubmed: 10564562
doi: 10.1046/j.1524-475X.1999.00335.x
Leal, E. C. et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am. J. Pathol. 185, 1638–1648 (2015).
pubmed: 25871534
pmcid: 4450333
doi: 10.1016/j.ajpath.2015.02.011
Tellechea, A. et al. Topical application of a mast cell stabilizer improves impaired diabetic wound healing. J. Investig. Dermatol. 140, 901–911 e911 (2020).
pubmed: 31568772
doi: 10.1016/j.jid.2019.08.449
Stone, R. C. et al. A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaf8611 (2017).
Theocharidis, G. et al. Integrated skin transcriptomics and serum multiplex assays reveal novel mechanisms of wound healing in diabetic foot ulcers. Diabetes 69, 2157–2169 (2020).
pubmed: 32763913
pmcid: 7506837
doi: 10.2337/db20-0188
Asp, M., Bergenstrahle, J. & Lundeberg, J. Spatially resolved transcriptomes-next generation tools for tissue exploration. Bioessays 42, e1900221 (2020).
pubmed: 32363691
doi: 10.1002/bies.201900221
Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 17, 10–12 (2011).
doi: 10.14806/ej.17.1.200
Conesa, A. et al. A survey of best practices for RNA-seq data analysis. Genome Biol. 17, 13 (2016).
pubmed: 26813401
pmcid: 4728800
doi: 10.1186/s13059-016-0881-8
Cunningham, F. et al. Ensembl 2019. Nucleic Acids Res. 47, D745–D751 (2019).
pubmed: 30407521
doi: 10.1093/nar/gky1113
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
pubmed: 24227677
doi: 10.1093/bioinformatics/btt656
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).
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Yu, G., Wang, L.-G., Han, Y. & He, Q.-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287 (2012).
pubmed: 22455463
pmcid: 3339379
doi: 10.1089/omi.2011.0118
Newman, A. M. et al. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat. Biotechnol. 37, 773–782 (2019).
pubmed: 31061481
pmcid: 6610714
doi: 10.1038/s41587-019-0114-2
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
pubmed: 16199517
pmcid: 1239896
doi: 10.1073/pnas.0506580102