Biopolym. Cell. 2018; 34(3):171-195.
Regenerative therapy for the nonhealing cutaneous wounds
1Orlovska I. V., 1Yakovenko I. O., 1Haidak A. H., 2Zmejkoski D. Z., 1Kozyrovska N. O.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143
  2. Vinca Institute of Nuclear Sciences, University of Belgrade
    12-14, Mike Petrovića Str., Belgrade, Serbia


Regenerative medicine inspired by current advances in cellular biology, genetic engineering, synthetic biology, material sciences etc. is now making resistant diseases curable. Nowadays, chronic wound healing is possible due to cell-based regenerative technologies and recent non-cell therapeutic approaches. Here we review clinical applications of human stem cells, as well as cellular and tissue products as alternatives to the traditional therapy of nonhealing wounds. The cell-based technologies for tissue regeneration and bioengineering utilize stem cells that are either injected into blood stream or directly into the target area. Cell-free regeneration technologies require either stem cell products, i.e., secretomes or their separate components, extracellular membrane vesicles, or tissue products. The stem cell therapies are designed to replace critically absent components of wounded or degenerative tissue. The stem cell secretome can promote the repair of damaged tissues independently of parent cells. Extracellular membrane vesicles mimic and recapitulate the mechanisms of stem cells in tissue regeneration and therefore might be promising for chronic wound and severe burns healing. The tissue products traditionally remain efficient wound healing remedies along with emerging advanced technologies
Keywords: wound healing, cell and cell-free technologies, stem cells, secretomes, extracellular membrane vesicles, tissue product


[1] Watt SM, Pleat JM. Stem cells, niches and scaffolds: Applications to burns and wound care. Adv Drug Deliv Rev. 2018;123:82-106.
[2] Havran WL, Jameson JM. Epidermal T cells and wound healing. J Immunol. 2010;184(10):5423-8.
[3] Leavitt T, Hu M, Marshall C, Barnes L, Longaker M, Lorenz P. Stem cells and chronic wound healing: state of the art. Chronic Wound Care Manag Res. 2016, 3:7-27.
[4] Gottrup F, Apelqvist J, Price P; European Wound Management Association Patient Outcome Group. Outcomes in controlled and comparative studies on non-healing wounds: recommendations to improve the quality of evidence in wound management. J Wound Care. 2010;19(6):237-68.
[5] Gaur M, Dobke M, Lunyak VV. Mesenchymal stem cells from adipose tissue in clinical applications for dermatological indications and skin aging. Int J Mol Sci. 2017;18(1). pii: E208. doi:
[6] Na YK, Ban JJ, Lee M, Im W, Kim M. Wound healing potential of adipose tissue stem cell extract. Biochem Biophys Res Commun. 2017;485(1):30-34.
[7] Chen B, Li Q, Zhao B, Wang Y. Stem Cell-Derived extracellular vesicles as a novel potential therapeutic tool for tissue repair. Stem Cells Transl Med. 2017;6(9):1753-1758.
[8] Guo SC, Tao SC, Yin WJ, Qi X, Yuan T, Zhang CQ. Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics. 2017;7(1):81-96. doi:
[9] Valle-Prieto A, Conget PA. Human mesenchymal stem cells efficiently manage oxidative stress. Stem Cells Dev. 2010;19(12):1885-93.
[10] Li N, Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017;74(13):2345-2360.
[11] Shende P, Gupta H, Gaud RS. Cytotherapy using stromal cells: Current and advance multi-treatment approaches. Biomed Pharmacother. 2018;97:38-44.
[12] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-76.
[13] Lobo SE, Leonel LC, Miranda CM, Coelho TM, Ferreira GA, Mess A, Abrão MS, Miglino MA. The placenta as an organ and a source of stem cells and extracellular matrix: a review. Cells Tissues Organs. 2016;201(4):239-52. doi:
[14] Yoder MC. Endothelial stem and progenitor cells (stem cells): (2017 Grover Conference Series). Pulm Circ. 2018;8(1):2045893217743950.
[15] Mahla RS. Stem Cells applications in regenerative medicine and disease therapeutics. Int J Cell Biol. 2016;2016:6940283.
[16] Hyldig K, Riis S, Pennisi CP, Zachar V, Fink T. Implications of extracellular matrix production by adipose tissue-derived stem cells for development of wound healing therapies. Int J Mol Sci. 2017;18(6). pii: E1167.
[17] Omole AE, Fakoya AOJ. Ten years of progress and promise of induced pluripotent stem cells: historical origins, characteristics, mechanisms, limitations, and potential applications. PeerJ. 2018;6:e4370. doi: eCollection 2018.
[18] Bollini S, Silini AR, Banerjee A, Wolbank S, Balbi C, Parolini O. Cardiac Restoration Stemming From the Placenta Tree: Insights From Fetal and Perinatal Cell Biology. Front Physiol. 2018;9:385.
[19] Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7.
[20] Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing - A literature review. An Bras Dermatol. 2016;91(5):614-620. doi:
[21] Wong VW, Levi B, Rajadas J, Longaker MT, Gurtner GC. Stem cell niches for skin regeneration. Int J Biomater. 2012;2012:926059.
[22] Badiavas EV, Falanga V. Treatment of chronic wounds with bone marrow-derived cells. Arch Dermatol. 2003;139(4):510-6.
[23] Hyldig K, Riis S, Pennisi CP, Zachar V, Fink T. Implications of Extracellular Matrix Production by Adipose Tissue-Derived Stem Cells for Development of Wound Healing Therapies. Int J Mol Sci. 2017;18(6). pii: E1167.
[24] Chan XY, Black R, Dickerman K, Federico J, Lévesque M, Mumm J, Gerecht S. Three-Dimensional Vascular Network Assembly From Diabetic Patient-Derived Induced Pluripotent Stem Cells. Arterioscler Thromb Vasc Biol. 2015;35(12):2677-85. doi:
[25] Kim JY, Suh W. Stem cell therapy for dermal wound healing. Int J Stem Cells. 2010;3(1):29-31.
[26] Zeng X, Tang Y, Hu K, Jiao W, Ying L, Zhu L, Liu J, Xu J. Three-week topical treatment with placenta-derived mesenchymal stem cells hydrogel in a patient with diabetic foot ulcer: A case report. Medicine (Baltimore). 2017;96(51):e9212.
[27] Griffin MF, Butler PE, Seifalian AM, Kalaskar DM. Control of stem cell fate by engineering their micro and nanoenvironment. World J Stem Cells. 2015;7(1):37-50.
[28] Bello AB, Park H, Lee SH. Current approaches in biomaterial-based hematopoietic stem cell niches. Acta Biomater. 2018;72:1-15.
[29] Luo X, Zeng T, He S, Lin C. The Combined effects of bone marrow-derived mesenchymal stem cells and microporous porcine acellular dermal matrices on the regeneration of skin accessory cells in vivo. J Burn Care Res. 2018;39(4):481-490.
[30] Dash BC, Xu Z, Lin L, Koo A, Ndon S, Berthiaume F, Dardik A, Hsia H. Stem Cells and engineered scaffolds for regenerative wound healing. Bioengineering (Basel). 2018;5(1). pii: E23.
[31] Xavier Acasigua GA, de Olyveira GM, Manzine Costa LM, Braghirolli DI, Medeiros Fossati AC, Guastaldi AC, Pranke P, Daltro Gde C, Basmaji P. Novel chemically modified bacterial cellulose nanocomposite as potential biomaterial for stem cell therapy applications. Curr Stem Cell Res Ther. 2014;9(2):117-23.
[32] Rödling L, Schwedhelm I, Kraus S, Bieback K, Hansmann J, Lee-Thedieck C. 3D models of the hematopoietic stem cell niche under steady-state and active conditions. Sci Rep. 2017;7(1):4625.
[33] Matsumine H, Numakura K, Tsunoda S, Wang H, Matsumine R, Climov M, Giatsidis G, Sukhatme VP, Orgill DP. Adipose-derived aldehyde dehydrogenase-expressing cells promote dermal regenerative potential with collagen-glycosaminoglycan scaffold. Wound Repair Regen. 2017;25(1):109-119.
[34] Yi S, Ding F, Gong L, Gu X. Extracellular Matrix Scaffolds for Tissue Engineering and Regenerative Medicine. Curr Stem Cell Res Ther. 2017;12(3):233-246.
[35] He P, Zhao J, Zhang J, Li B, Gou Z, Gou M, Li X. Bioprinting of skin constructs for wound healing. Burns Trauma. 2018;6:5.
[36] Nolta JA. "Next-generation" mesenchymal stem or stromal cells for the in vivo delivery of bioactive factors: progressing toward the clinic. Transfusion. 2016;56(4):15S-7S.
[37] Fierro FA, Kalomoiris S, Sondergaard CS, Nolta JA. Effects on proliferation and differentiation of multipotent bone marrow stromal cells engineered to express growth factors for combined cell and gene therapy. Stem Cells. 2011;29(11):1727-37. PubMed Central
[38] Hourd P, Williams DJ. Scanning the horizon for high value-add manufacturing science: Accelerating manufacturing readiness for the next generation of disruptive, high-value curative cell therapeutics. Cytotherapy. 2018;20(5):759-767.
[39] Merkert S, Martin U. Targeted genome engineering using designer nucleases: State of the art and practical guidance for application in human pluripotent stem cells. Stem Cell Res. 2016;16(2):377-86.
[40] Santos DP, Kiskinis E, Eggan K, Merkle FT. Comprehensive Protocols for CRISPR/Cas9-based Gene Editing in Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol. 2016;38:5B.6.1-5B.6.60.
[41] Kim SI, Matsumoto T, Kagawa H, Nakamura M, Hirohata R, Ueno A, Ohishi M, Sakuma T, Soga T, Yamamoto T, Woltjen K. Microhomology-assisted scarless genome editing in human iPSCs. Nat Commun. 2018;9(1):939. doi:
[42] Kosaric N, Srifa W, Gurtner GC, Porteus MH. Abstract 100: Human Mesenchymal Stromal Cells Engineered to Overexpress PDGF-B Using CRISPR/Cas9/rAAV6-based Tools Improve Wound Healing. Plastic and Reconstructive Surgery Global Open. 2017;5(4 Suppl):74. doi:10.1097/01.GOX.0000516619.11665.84.
[43] Lau RWK, Wang B, Ricardo SD. Gene editing of stem cells for kidney disease modelling and therapeutic intervention. Nephrology (Carlton). 2018 May 30.
[44] Hu C, Li L. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J Cell Mol Med. 2018;22(3):1428-1442.
[45] Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998;4(5):594-600.
[46] Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mol Sci. 2017;18(9). pii: E1852.
[47] Cunningham CJ, Redondo-Castro E, Allan SM. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab. 2018 Jan 1:271678X18776802. doi:
[48] Walter MN, Wright KT, Fuller HR, MacNeil S, Johnson WE. Mesenchymal stem cell-conditioned medium accelerates skin wound healing: an in vitro study of fibroblast and keratinocyte scratch assays. Exp Cell Res. 2010;316(7):1271-81.
[49] Bartaula-Brevik S, Bolstad AI, Mustafa K, Pedersen T. Secretome of mesenchymal stem cells grown in hypoxia accelerates wound healing and vessel formation in vitro. Int J Stem Cell Res Ther. 2017; 4(1):1-9.
[50] Jun EK, Zhang Q, Yoon BS, Moon JH, Lee G, Park G, Kang PJ, Lee JH, Kim A, You S. Hypoxic conditioned medium from human amniotic fluid-derived mesenchymal stem cells accelerates skin wound healing through TGF-β/SMAD2 and PI3K/Akt pathways. Int J Mol Sci. 2014;15(1):605-28.
[51] Chen L, Xu Y, Zhao J, Zhang Z, Yang R, Xie J, Liu X, Qi S. Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. PLoS One. 2014;9(4):e96161.
[52] Chen J, Crawford R, Chen C, Xiao Y. The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng Part B Rev. 2013;19(6):516-28.
[53] Huang C, Jacobson K, Schaller MD. MAP kinases and cell migration. J Cell Sci. 2004;117(Pt 20):4619-28.
[54] Park SR, Kim JW, Jun HS, Roh JY, Lee HY, Hong IS. Stem Cell Secretome and Its Effect on Cellular Mechanisms Relevant to Wound Healing. Mol Ther. 2018;26(2):606-617.
[55] Abbasi-Malati Z, Roushandeh AM, Kuwahara Y, Roudkenar MH. Mesenchymal Stem Cells on Horizon: A New Arsenal of Therapeutic Agents. Stem Cell Rev. 2018;14(4):484-499. doi:
[56] Zhou BR, Xu Y, Guo SL, Xu Y, Wang Y, Zhu F, Permatasari F, Wu D, Yin ZQ, Luo D. The effect of conditioned media of adipose-derived stem cells on wound healing after ablative fractional carbon dioxide laser resurfacing. Biomed Res Int. 2013;2013:519126.
[57] Bermudez MA, Sendon-Lago J, Eiro N, Treviño M, Gonzalez F, Yebra-Pimentel E, Giraldez MJ, Macia M, Lamelas ML, Saa J, Vizoso F, Perez-Fernandez R. Corneal epithelial wound healing and bactericidal effect of conditioned medium from human uterine cervical stem cells. Invest Ophthalmol Vis Sci. 2015;56(2):983-92.
[58] Golebiewska EM, Poole AW. Platelet secretion: From haemostasis to wound healing and beyond. Blood Rev. 2015;29(3):153-62.
[59] Holzinger C, Zuckermann A, Kopp C, Schöllhammer A, Imhof M, Zwölfer W, Baumgartner I, Magometschnigg H, Weissinger E, Wolner E. Treatment of non-healing skin ulcers with autologous activated mononuclear cells. Eur J Vasc Surg. 1994;8(3):351-6.
[60] Sekhon UD, Gupta AS. Platelets and platelet-inspired biomaterials technologies in wound healing applications. ACS Biomaterials Science & Engineering. 2018; 4(4): 1176-92.
[61] Beer L, Zimmermann M, Mitterbauer A, Ellinger A, Gruber F, Narzt MS, Zellner M, Gyöngyösi M, Madlener S, Simader E, Gabriel C, Mildner M, Ankersmit HJ. Analysis of the Secretome of Apoptotic Peripheral Blood Mononuclear Cells: Impact of Released Proteins and Exosomes for Tissue Regeneration. Sci Rep. 2015;5:16662.
[62] Hacker S, Mittermayr R, Nickl S, Haider T, Lebherz-Eichinger D, Beer L, Mitterbauer A, Leiss H, Zimmermann M, Schweiger T, Keibl C, Hofbauer H, Gabriel C, Pavone-Gyöngyösi M, Redl H, Tschachler E, Mildner M, Ankersmit HJ. Paracrine Factors from Irradiated Peripheral Blood Mononuclear Cells Improve Skin Regeneration and Angiogenesis in a Porcine Burn Model. Sci Rep. 2016;6:25168. PubMed Central PMCID: PMC4850437.
[63] Simader E, Traxler D, Kasiri MM, Hofbauer H, Wolzt M, Glogner C, Storka A, Mildner M, Gouya G, Geusau A, Fuchs C, Eder C, Graf A, Schaden M, Golabi B, Aretin MB, Suessner S, Gabriel C, Klepetko W, Tschachler E, Ankersmit HJ. Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds: a randomized Phase 1 trial (MARSYAS I ). Sci Rep. 2017;7(1):6216.
[64] van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213-228. doi:
[65] Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255-89.
[66] Beer KB, Rivas-Castillo J, Kuhn K, Fazeli G, Karmann B, Nance JF, Stigloher C, Wehman AM. Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry. Proc Natl Acad Sci U S A. 2018;115(6):E1127-E1136.
[67] Shen L-M, Quan L, Liu J. Tracking exosomes in vitro and in vivo to elucidate their physiological functions: implications for diagnostic and therapeutic nanocarriers. ACS Appl Nano Mater. 2018, 1(6):2438–48.
[68] Boilard E. Extracellular vesicles and their content in bioactive lipid mediators: more than a sack of microRNA. J Lipid Res. 2018 Apr 20. pii: jlr.R084640.
[69] Laberge A, Arif S, Moulin VJ. Microvesicles: Intercellular messengers in cutaneous wound healing. J Cell Physiol. 2018;233(8):5550-5563.
[70] Fatima F, Nawaz M. Vesiculated long non-coding rnas: offshore packages deciphering trans-regulation between cells, cancer progression and resistance to therapies. Noncoding RNA. 2017;3(1). pii: E10.
[71] Silva AM, Teixeira JH, Almeida MI, Gonçalves RM, Barbosa MA, Santos SG. Extracellular Vesicles: Immunomodulatory messengers in the context of tissue repair/regeneration. Eur J Pharm Sci. 2017;98:86-95. doi:
[72] Yu Y, Gool E, Berckmans RJ, Coumans FAW, Barendrecht AD, Maas C, van der Wel NN, Altevogt P, Sturk A, Nieuwland R. Extracellular vesicles from human saliva promote hemostasis by delivering coagulant tissue factor to activated platelets. J Thromb Haemost. 2018;16(6):1153-1163.
[73] Cabral J, Ryan AE, Griffin MD, Ritter T. Extracellular vesicles as modulators of wound healing. Adv Drug Deliv Rev. 2018;129:394-406.
[74] Wu P, Zhang B, Shi H, Qian H, Xu W. MSC-exosome: A novel cell-free therapy for cutaneous regeneration. Cytotherapy. 2018;20(3):291-301.
[75] Golchin A, Hosseinzadeh S, Ardeshirylajimi A. The exosomes released from different cell types and their effects in wound healing. J Cell Biochem. 2018;119(7):5043-5052.
[76] Zhao B, Zhang Y, Han S, Zhang W, Zhou Q, Guan H, Liu J, Shi J, Su L, Hu D. Exosomes derived from human amniotic epithelial cells accelerate wound healing and inhibit scar formation. J Mol Histol. 2017;48(2):121-132.
[77] Shi Q, Qian Z, Liu D, Sun J, Wang X, Liu H, Xu J, Guo X. GMSC-derived exosomes combined with a chitosan/silk hydrogel sponge accelerates wound healing in a diabetic rat skin defect model. Front Physiol. 2017;8:904.
[78] Li X, Jiang C, Zhao J. Human endothelial progenitor cells-derived exosomes accelerate cutaneous wound healing in diabetic rats by promoting endothelial function. J Diabetes Complications. 2016;30(6):986-92.
[79] Zhang J, Chen C, Hu B, Niu X, Liu X, Zhang G, Zhang C, Li Q, Wang Y. Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling. Int J Biol Sci. 2016;12(12):1472-1487.
[80] Zhang B, Wu X, Zhang X, Sun Y, Yan Y, Shi H, Zhu Y, Wu L, Pan Z, Zhu W, Qian H, Xu W. Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway. Stem Cells Transl Med. 2015;4(5):513-22.
[81] Hu L, Wang J, Zhou X, Xiong Z, Zhao J, Yu R, Huang F, Zhang H, Chen L. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep. 2016;6:32993.
[82] Li W, Sahu D, Tsen F. Secreted heat shock protein-90 (Hsp90) in wound healing and cancer. Biochim Biophys Acta. 2012;1823(3):730-41.
[83] Fatima F, Ekstrom K, Nazarenko I, Maugeri M, Valadi H, Hill AF, Camussi G, Nawaz M. Non-coding RNAs in Mesenchymal Stem Cell-Derived Extracellular Vesicles: Deciphering Regulatory Roles in Stem Cell Potency, Inflammatory Resolve, and Tissue Regeneration. Front Genet. 2017;8:161. doi: eCollection 2017. Review.
[84] Bjørge IM, Kim SY, Mano JF, Kalionis B, Chrzanowski W. Extracellular vesicles, exosomes and shedding vesicles in regenerative medicine - a new paradigm for tissue repair. Biomater Sci. 2017;6(1):60-78.
[85] Adamiak M, Sahoo S. Exosomes in Myocardial Repair: Advances and Challenges in the Development of Next-Generation Therapeutics. Mol Ther. 2018;26(7):1635-1643. doi:
[86] Giebel B, Kordelas L, Börger V. Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig. 2017;4:84.
[87] Rufino-Ramos D, Albuquerque PR, Carmona V, Perfeito R, Nobre RJ, Pereira de Almeida L. Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases. J Control Release. 2017;262:247-258.
[88] Varon D, Shai E. Platelets and their microparticles as key players in pathophysiological responses. J Thromb Haemost. 2015;13 Suppl 1:S40-6.
[89] Tao SC, Guo SC, Zhang CQ. Platelet-derived Extracellular Vesicles: An Emerging Therapeutic Approach. Int J Biol Sci. 2017;13(7):828-834.
[90] Torreggiani E, Perut F, Roncuzzi L, Zini N, Baglìo SR, Baldini N. Exosomes: novel effectors of human platelet lysate activity. Eur Cell Mater. 2014;28:137-51.
[91] Guo SC, Tao SC, Yin WJ, Qi X, Yuan T, Zhang CQ. Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics. 2017;7(1):81-96.
[92] Jan AT. Outer Membrane Vesicles (OMVs) of Gram-negative Bacteria: A Perspective Update. Front Microbiol. 2017;8:1053.
[93] Tsatsaronis JA, Franch-Arroyo S, Resch U, Charpentier E. Extracellular Vesicle RNA: A Universal Mediator of Microbial Communication? Trends Microbiol. 2018;26(5):401-410.
[94] Shen Y, Giardino Torchia ML, Lawson GW, Karp CL, Ashwell JD, Mazmanian SK. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe. 2012;12(4):509-20. doi:
[95] Vanaja SK, Russo AJ, Behl B, Banerjee I, Yankova M, Deshmukh SD, Rathinam VAK. Bacterial Outer Membrane Vesicles Mediate Cytosolic Localization of LPS and Caspase-11 Activation. Cell. 2016;165(5):1106-1119.
[96] Baker S, Davitt C, Morici L. Gram-negative bacterial outer membrane vesicles inhibit growth of multidrug-resistant organisms and induce wound-healing cytokines. Open Forum Infect Dis. 2016, 3(1): 2242.
[97] Nieves W, Petersen H, Judy BM, Blumentritt CA, Russell-Lodrigue K, Roy CJ, Torres AG, Morici LA. A Burkholderia pseudomallei outer membrane vesicle vaccine provides protection against lethal sepsis. Clin Vaccine Immunol. 2014;21(5):747-54.
[98] Li Z, Clarke AJ, Beveridge TJ. Gram-negative bacteria produce membrane vesicles which are capable of killing other bacteria. J Bacteriol. 1998;180(20):5478-83.
[99] Kudryakova IV, Shishkova NA, Vasilyeva NV. Outer membrane vesicles of Lysobacter sp. XL1: biogenesis, functions, and applied prospects. Appl Microbiol Biotechnol. 2016;100(11):4791-801.
[100] Rani S, Ritter T. The Exosome - A Naturally Secreted Nanoparticle and its Application to Wound Healing. Adv Mater. 2016;28(27):5542-52.
[101] Gilligan KE, Dwyer RM. Engineering Exosomes for Cancer Therapy. Int J Mol Sci. 2017;18(6). pii: E1122.
[102] Armstrong JP, Holme MN, Stevens MM. Re-Engineering Extracellular Vesicles as Smart Nanoscale Therapeutics. ACS Nano. 2017;11(1):69-83.
[103] Tao SC, Guo SC, Zhang CQ. Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine. Adv Sci (Weinh). 2018;5(2):1700449.
[104] Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, Zhao Y, Liu H, Fu X, Han W. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 2015;13:308.
[105] Akao Y, Iio A, Itoh T, Noguchi S, Itoh Y, Ohtsuki Y, Naoe T. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther. 2011;19(2):395-9.
[106] Tao SC, Guo SC, Li M, Ke QF, Guo YP, Zhang CQ. Chitosan Wound Dressings Incorporating Exosomes Derived from MicroRNA-126-Overexpressing Synovium Mesenchymal Stem Cells Provide Sustained Release of Exosomes and Heal Full-Thickness Skin Defects in a Diabetic Rat Model. Stem Cells Transl Med. 2017;6(3):736-747.
[107] Xu N, Wang L, Guan J, Tang C, He N, Zhang W, Fu S. Wound healing effects of a Curcuma zedoaria polysaccharide with platelet-rich plasma exosomes assembled on chitosan/silk hydrogel sponge in a diabetic rat model. Int J Biol Macromol. 2018;117:102-107.
[108] Irvin J, Danchik C, Rall J, Babcock A, Pine M, Barnaby D, Pathakamuri J, Kuebler D. Bioactivity and composition of a preserved connective tissue matrix derived from human placental tissue. J Biomed Mater Res B Appl Biomater. 2018 Feb 13.
[109] Smiell JM, Treadwell T, Hahn HD, Hermans MH. Real-world Experience With a Decellularized Dehydrated Human Amniotic Membrane Allograft. Wounds. 2015;27(6):158-69.
[110] Zelen CM, Serena TE, Fetterolf DF. Dehydrated human amnion/chorion membrane allografts in patients with chronic diabetic foot ulcers: A long-term follow-up study. Wound Med. 2014, 4:1–4.
[111] Maan ZN, Rennert RC, Koob TJ, Januszyk M, Li WW, Gurtner GC. Cell recruitment by amnion chorion grafts promotes neovascularization. J Surg Res. 2015;193(2):953-962.
[112] Park JY, Lee J, Jeong M, Min S, Kim SY, Lee H, Lim Y, Park HJ. Effect of Hominis Placenta on cutaneous wound healing in normal and diabetic mice. Nutr Res Pract. 2014;8(4):404-9. doi:
[113] Singh N, Bhattacharyya D. Biochemical and functional analysis of corticotropin releasing factor purified from an aqueous extract of human placenta used as wound healer. J Pharm Biomed Anal. 2017;145:298-306.