Gene Therapy in Skin and Wound Healing

  • Kristo Nuutila
  • Mansher Singh
  • Elof Eriksson


Please check if the section headings are assigned to appropriate levels.


  1. 1.
    Kruse CR, Nuutila K, Lee CC, Kiwanuka E, Singh M, Caterson EJ, Eriksson E, Sørensen JA. The external microenvironment of healing skin wounds. Wound Repair Regen. 2015;23(4):456–64. Scholar
  2. 2.
    Nuutila K, Katayama S, Vuola J, Kankuri E. Human wound-healing research: issues and perspectives for studies using wide-scale analytic platforms. Adv Wound Care (New Rochelle). 2014;3(3):264–71.CrossRefGoogle Scholar
  3. 3.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21. Scholar
  4. 4.
    Cohen S, Elliot GA. The stimulation of epidermal keratinization by a protein isolated from the submaxillary gland of the mouse. J Invest Dermatol. 1963;40:1–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M. Clinical application of growth factors and cytokines in wound healing. Wound Repair Regen. 2014;22(5):569–78. Scholar
  6. 6.
    Wieman TJ, Smiell JM, 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. 1998;21(5):822–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Bielefeld KA, Amini-Nik S, Alman BA. Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci. 2013;70(12):2059–81. Scholar
  8. 8.
    Yao F, Eriksson E. Gene therapy in wound repair and regeneration. Wound Repair Regen. 2000;8(6):443–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6. Scholar
  10. 10.
    Kiwanuka E, Junker J, Eriksson E. Harnessing growth factors to influence wound healing. Clin Plast Surg. 2012;39(3):239–48. Scholar
  11. 11.
    Sun Y, Chen X, Xiao D. Tetracycline-inducible expression systems: new strategies and practices in the transgenic mouse modeling. Acta Biochim Biophys Sin (Shanghai). 2007;39(4):235–46.CrossRefGoogle Scholar
  12. 12.
    Karzenowski D, Potter DW, Padidam M. Inducible control of transgene expression with ecdysone receptor: gene switches with high sensitivity, robust expression, and reduced size. BioTechniques. 2005;39(2):191–2, 194, 196.CrossRefPubMedGoogle Scholar
  13. 13.
    Collins M, Thrasher A. Gene therapy: progress and predictions. Proc Biol Sci. 2015;282(1821):20143003. Scholar
  14. 14.
    Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;15(8):541–55. Scholar
  15. 15.
    Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46.CrossRefPubMedGoogle Scholar
  16. 16.
    Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. 2010;89(3):219–29. Scholar
  17. 17.
    Gill SE, Parks WC. Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol. 2008;40(6–7):1334–47.CrossRefPubMedGoogle Scholar
  18. 18.
    Widgerow AD. Chronic wound fluid--thinking outside the box. Wound Repair Regen. 2011;19(3):287–91.
  19. 19.
    Muller M, Trocme C, Lardy B, Morel F, Halimi S, Benhamou PY. Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing. Diabet Med. 2008;25(4):419–26. Scholar
  20. 20.
    Butzelaar L, Ulrich MM, Mink van der Molen AB, Niessen FB, Beelen RH. Currently known risk factors for hypertrophic skin scarring: a review. J Plast Reconstr Aesthet Surg. 2016;69(2):163–9. Scholar
  21. 21.
    Fujio K, Komai T, Inoue M, Morita K, Okamura T, Yamamoto K. Revisiting the regulatory roles of the TGF-β family of cytokines. Autoimmun Rev. 2016;15(9):917–22. Scholar
  22. 22.
    Branski LK, Pereira CT, Herndon DN, Jeschke MG. Gene therapy in wound healing: present status and future directions. Gene Ther. 2007;14(1):1–10.CrossRefPubMedGoogle Scholar
  23. 23.
    Khavari PA, Rollman O, Vahlquist A. Cutaneous gene transfer for skin and systemic diseases. J Intern Med. 2002;252(1):1–10.CrossRefPubMedGoogle Scholar
  24. 24.
    Branski LK, Gauglitz GG, Herndon DN, Jeschke MG. A review of gene and stem cell therapy in cutaneous wound healing. Burns. 2009;35(2):171–80. Scholar
  25. 25.
    Giatsidis G, Dalla Venezia E, Bassetto F. The role of gene therapy in regenerative surgery: updated insights. Plast Reconstr Surg. 2013;131(6):1425–35. Scholar
  26. 26.
    Appaiahgari MB, Vrati S. Adenoviruses as gene/vaccine delivery vectors: promises and pitfalls. Expert Opin Biol Ther. 2015;15(3):33751. Scholar
  27. 27.
    Kozarsky KF, Wilson JM. Gene therapy: adenovirus vectors. Curr Opin Genet Dev. 1993;3(3):499–503.CrossRefPubMedGoogle Scholar
  28. 28.
    Petrie NC, Yao F, Eriksson E. Gene therapy in wound healing. Surg Clin North Am. 2003;83(3):597–616, vii.CrossRefPubMedGoogle Scholar
  29. 29.
    Capasso C, Garofalo M, Hirvinen M, Cerullo V. The evolution of adenoviral vectors through genetic and chemical surface modifications. Virus. 2014;6(2):832–55. Scholar
  30. 30.
    Gaj T, Epstein BE, Schaffer DV. Genome engineering using Adeno associated virus: basic and clinical research applications. Mol Ther. 2016;24(3):458–64. Scholar
  31. 31.
    Eming SA, Krieg T, Davidson JM. Gene transfer in tissue repair: status, challenges and future directions. Expert Opin Biol Ther. 2004;4(9):1373–86.CrossRefPubMedGoogle Scholar
  32. 32.
    Hirsch T, Spielmann M, Yao F, Eriksson E. Gene therapy in cutaneous wound healing. Front Biosci. 2007;12:2507–18.CrossRefPubMedGoogle Scholar
  33. 33.
    Burton EA, Fink DJ, Glorioso JC. Gene delivery using herpes simplex virus vectors. DNA Cell Biol. 2002;21(12):915–36.CrossRefPubMedGoogle Scholar
  34. 34.
    Lachmann R. Herpes simplex virus-based vectors. Int J Exp Pathol. 2004;85(4):177–90.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ramamoorth M, Narvekar A. Non viral vectors in gene therapy- an overview. J Clin Diagn Res. 2015;9(1):GE01–6. Scholar
  36. 36.
    Wang W, Li W, Ma N, Steinhoff G. Non-viral gene delivery methods. Curr Pharm Biotechnol. 2013;14(1):46–60.PubMedGoogle Scholar
  37. 37.
    Alsaggar M, Liu D. Physical methods for gene transfer. Adv Genet. 2015;89:1–24. Scholar
  38. 38.
    Nayerossadat N, Maedeh T, Ali PA. Viral and nonviral delivery systems for gene delivery. Adv Biomed Res. 2012;1:27. Scholar
  39. 39.
    Gibot L, Rols MP. Gene transfer by pulsed electric field is highly promising in cutaneous wound healing. Expert Opin Biol Ther. 2016;16(1):67–77. Scholar
  40. 40.
    Wells DJ. Gene therapy progress and prospects: electroporation and other physical methods. Gene Ther. 2004;11(18):1363–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Hoeller D, Petrie N, Yao F, Eriksson E. Gene therapy in soft tissue reconstruction. Cells Tissues Organs. 2002;172(2):118–25.CrossRefPubMedGoogle Scholar
  42. 42.
    Davidson JM, Krieg T, Eming SA. Particle-mediated gene therapy of wounds. Wound Repair Regen. 2000;8(6):452–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Eriksson E, Yao F, Svensjö T, Winkler T, Slama J, Macklin MD, Andree C, McGregor M, Hinshaw V, Swain WF. In vivo gene transfer to skin and wound by microseeding. J Surg Res. 1998;78(2):85–91.CrossRefPubMedGoogle Scholar
  44. 44.
    Jeschke MG, Sandmann G, Finnerty CC, Herndon DN, Pereira CT, Schubert T, Klein D. The structure and composition of liposomes can affect skin regeneration, morphology and growth factor expression in acute wounds. Gene Ther. 2005;12(23):1718–24.CrossRefPubMedGoogle Scholar
  45. 45.
    Bleiziffer O, Eriksson E, Yao F, Horch RE, Kneser U. Gene transfer strategies in tissue engineering. J Cell Mol Med. 2007;11(2):206–23.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Felgner PL, Ringold GM. Cationic liposome-mediated transfection. Nature. 1989;337:387–8.CrossRefGoogle Scholar
  47. 47.
    Hengge UR, et al. Cytokine gene expression in epidermis with biological effects following injection of naked DNA. Nat Genet. 1995;10:161–6.CrossRefPubMedGoogle Scholar
  48. 48.
    Dang JM, Leong KW. Natural polymers for gene delivery and tissue engineering. Adv Drug Deliv Rev. 2006;58(4):487–99.CrossRefPubMedGoogle Scholar
  49. 49.
    Cam C, Segura T. Matrix-based gene delivery for tissue repair. Curr Opin Biotechnol. 2013;24(5):855–63. Scholar
  50. 50.
    Chandler LA, Doukas J, Gonzalez AM, Hoganson DK, Gu DL, Ma C, Nesbit M, Crombleholme TM, Herlyn M, Sosnowski BA, Pierce GF. FGF2-targeted adenovirus encoding platelet-derived growth factor-B enhances de novo tissue formation. Mol Ther. 2000;2(2):153–60.CrossRefPubMedGoogle Scholar
  51. 51.
    Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000;102(8):898–901.CrossRefPubMedGoogle Scholar
  52. 52.
    Toniatti C, Bujard H, Cortese R, Ciliberto G. Gene therapy progress and prospects: transcription regulatory systems. Gene Ther. 2004;11(8):649–57.CrossRefPubMedGoogle Scholar
  53. 53.
    Yao F, Pomahac B, Visovatti S, Chen M, Johnson S, Augustinova H, Svensjo T, Eriksson E. Systemic and localized reversible regulation of transgene expression by tetracycline with tetR-mediated transcription repression switch. J Surg Res. 2007;138(2):267–74.CrossRefPubMedGoogle Scholar
  54. 54.
    Gower RM, Shea LD. Biomaterial scaffolds for controlled, localized gene delivery of regenerative factors. Adv Wound Care (New Rochelle). 2013;2(3):100–6.CrossRefGoogle Scholar
  55. 55.
    Shepard JA, Wesson PJ, Wang CE, Stevans AC, Holland SJ, Shikanov A, Grzybowski BA, Shea LD. Gene therapy vectors with enhanced transfection based on hydrogels modified with affinity peptides. Biomaterials. 2011;32:5092.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Eming SA, Krieg T, Davidson JM. Gene therapy and wound healing. Clin Dermatol. 2007;25(1):79–92.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Nuutila K, Siltanen A, Peura M, Bizik J, Kaartinen I, Kuokkanen H, Nieminen T, Harjula A, Aarnio P, Vuola J, Kankuri E. Human skin transcriptome during superficial cutaneous wound healing. Wound Repair Regen. 2012;20(6):830–9. Scholar
  58. 58.
    Broughton G, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006;117(7 Suppl):12S–34S.CrossRefPubMedGoogle Scholar
  59. 59.
    Peng B, Chen Y, Leong KW. MicroRNA delivery for regenerative medicine. Adv Drug Deliv Rev. 2015;88:108–22. Scholar
  60. 60.
    Nelson CE, Gupta MK, Adolph EJ, Guelcher SA, Duvall CL. siRNA delivery from an injectable scaffold for wound therapy. Adv Wound Care (New Rochelle). 2013;2(3):93–9.CrossRefGoogle Scholar
  61. 61.
    Galeano M, Deodato B, Altavilla D, Cucinotta D, Arsic N, Marini H, Torre V, Giacca M, Squadrito F. Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse. Diabetologia. 2003;46(4):546–55.CrossRefPubMedGoogle Scholar
  62. 62.
    Galeano M, Deodato B, Altavilla D, Squadrito G, Seminara P, Marini H, Stagno d’Alcontres F, Colonna M, Calò M, Lo Cascio P, Torre V, Giacca M, Venuti FS, Squadrito F. Effect of recombinant adeno-associated virus vector-mediated vascular endothelial growth factor gene transfer on wound healing after burn injury. Crit Care Med. 2003;31(4):1017–25.Google Scholar
  63. 63.
    Kwon MJ, An S, Choi S, Nam K, Jung HS, Yoon CS, Ko JH, Jun HJ, Kim TK, Jung SJ, Park JH, Lee Y, Park JS. Effective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle vascular endothelial growth factor DNA and a cationic dendrimer. J Gene Med. 2012;14(4):272–8. Scholar
  64. 64.
    Sun L, Xu L, Chang H, Henry FA, Miller RM, Harmon JM, Nielsen TB. Transfection with aFGF cDNA improves wound healing. J Invest Dermatol. 1997;108(3):313–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Pereira CT, Herndon DN, Rocker R, Jeschke MG. Liposomal gene transfer of keratinocyte growth factor improves wound healing by altering growth factor and collagen expression. J Surg Res. 2007;139(2):222–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Escámez MJ, Carretero M, García M, Martínez-Santamaría L, Mirones I, Duarte B, Holguín A, García E, García V, Meana A, Jorcano JL, Larcher F, Del Río M. Assessment of optimal virus-mediated growth factor gene delivery for human cutaneous wound healing enhancement. J Invest Dermatol. 2008;128(6):1565–75. Scholar
  67. 67.
    Eming SA, Lee J, Snow RG, Tompkins RG, Yarmush ML, Morgan JR. Genetically modified human epidermis overexpressing PDGF-A directs the development of a cellular and vascular connective tissue stroma when transplanted to athymic mice--implications for the use of genetically modified keratinocytes to modulate dermal regeneration. J Invest Dermatol. 1995;105(6):756–63.CrossRefPubMedGoogle Scholar
  68. 68.
    Liechty KW, Nesbit M, Herlyn M, Radu A, Adzick NS, Crombleholme TM. Adenoviral-mediated overexpression of platelet-derived growth factor-B corrects ischemic impaired wound healing. J Invest Dermatol. 1999;113(3):375–83.CrossRefPubMedGoogle Scholar
  69. 69.
    Andree C, Swain WF, Page CP, Macklin MD, Slama J, Hatzis D, Eriksson E. In vivo transfer and expression of a human epidermal growth factor gene accelerates wound repair. Proc Natl Acad Sci U S A. 1994;91(25):1218892.CrossRefGoogle Scholar
  70. 70.
    Rosenthal FM, Cao L, Tanczos E, Kopp J, Andree C, Stark GB, Mertelsmann R, Kulmburg P. Paracrine stimulation of keratinocytes in vitro and continuous delivery of epidermal growth factor to wounds in vivo by genetically modified fibroblasts transfected with a novel chimeric construct. In Vivo. 1997;11(3):201–8.PubMedGoogle Scholar
  71. 71.
    Benn SI, Whitsitt JS, Broadley KN, Nanney LB, Perkins D, He L, Patel M, Morgan JR, Swain WF, Davidson JM. Particle-mediated gene transfer with transforming growth factor-beta1 cDNAs enhances wound repair in rat skin. J Clin Invest. 1996;98(12):2894–902.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Lee PY, Li Z, Huang L. Thermosensitive hydrogel as a Tgf-beta1 gene delivery vehicle enhances diabetic wound healing. Pharm Res. 2003;20(12):1995–2000.CrossRefPubMedGoogle Scholar
  73. 73.
    Kunugiza Y, Tomita N, Taniyama Y, Tomita T, Osako MK, Tamai K, et al. Acceleration of wound healing by combined gene transfer of hepatocyte growth factor and prostacyclin synthase with Shima Jet. Gene Ther. 2006;13:1143–52.CrossRefPubMedGoogle Scholar
  74. 74.
    Ha X, Li Y, Lao M, Yuan B, Wu CT. Effect of human hepatocyte growth factor on promoting wound healing and preventing scar formation by adenovirus-mediated gene transfer. Chin Med J. 2003;116:1029–33.PubMedGoogle Scholar
  75. 75.
    Hirsch T, Spielmann M, Velander P, Zuhaili B, Bleiziffer O, Fossum M, Steinstraesser L, Yao F, Eriksson E. Insulin-like growth factor-1 gene therapy and cell transplantation in diabetic wounds. J Gene Med. 2008;10:1247–52.CrossRefPubMedGoogle Scholar
  76. 76.
    Jeschke MG, Schubert T, Krickhahn M, Polykandriotis E, Klein D, Perez-Polo JR, et al. Interaction of exogenous liposomal insulin-like growth factor-I cDNA gene transfer with growth factors on collagen expression in acute wounds. Wound Repair Regen. 2005;13:269–77.CrossRefPubMedGoogle Scholar
  77. 77.
    Thanik VD, Greives MR, Lerman OZ, Seiser N, Dec W, Chang CC, Warren SM, Levine JP, Saadeh PB. Topical matrix-based siRNA silences local gene expression in a murine wound model. Gene Ther. 2007;14(17):1305–8.CrossRefPubMedGoogle Scholar
  78. 78.
    Nelson CE, Kim AJ, Adolph EJ, Gupta MK, Yu F, Hocking KM, Davidson JM, Guelcher SA, Duvall CL. Tunable delivery of siRNA from a biodegradable scaffold to promote angiogenesis in vivo. Adv Mater. 2014;26(4):607–14, 506. Scholar
  79. 79.
    Martin JR, Nelson CE, Gupta MK, Yu F, Sarett SM, Hocking KM, Pollins AC, Nanney LB, Davidson JM, Guelcher SA, Duvall CL. Local delivery of PHD2 siRNA from ROS-degradable scaffolds to promote diabetic wound healing. Adv Healthc Mater. 2016;5(21):2751–7. Scholar
  80. 80.
    Randeria PS, Seeger MA, Wang XQ, Wilson H, Shipp D, Mirkin CA, Paller AS. siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown. Proc Natl Acad Sci U S A. 2015;112(18):5573–8. Scholar
  81. 81.
    Kim HS, Son YJ, Yoo HS. Clustering siRNA conjugates for MMP-responsive therapeutics in chronic wounds of diabetic animals. Nanoscale. 2016;8(27):13236–44. Scholar
  82. 82.
    Yang X, Wang J, Guo SL, Fan KJ, Li J, Wang YL, Teng Y. MiR-21 promotes keratinocyte migration and re-epithelialization during wound healing. Int J Biol Sci. 2011;7:685–90.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Pastar I, Khan AA, Stojadinovic O, Lebrun EA, Medina MC, Brem H, Kirsner RS, Jimenez JJ, Leslie C, Tomic-Canic M. Induction of specific microRNAs inhibits cutaneous wound healing. J Biol Chem. 2012;287:29324–35.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Monaghan M, Browne S, Schenke-Layland K, Pandit A. A collagen-based scaffold delivering exogenous microRNA-29b to modulate extracellular matrix remodeling. Mol Ther. 2014;22:786–96.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K, Isner JM. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation. 1998;97:1114–23.CrossRefPubMedGoogle Scholar
  86. 86.
    Kim HJ, Jang SY, Park JL, Byun J, Kim DL, Do YS, Kim JM, Kim S, Kim BM, Kim WB, Kim DK. Vascular endothelial growth factor-induced angiogenic gene therapy in patients with peripheral artery disease. Exp Mol Med. 2004;36:336–44.CrossRefPubMedGoogle Scholar
  87. 87.
    Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J, Sawa Y, Matsuda H, Kaneda Y, Ogihara T. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension. 2004;44:203–9.CrossRefPubMedGoogle Scholar
  88. 88.
    Shigematsu H, Yasuda K, Sasajima T, Takano T, Miyata T, Ohta T, Tanemoto K, Obitsu Y, Iwai T, Ozaki S, Ogihara T, Morishita R, HGF Study Group. Transfection of human HGF plasmid DNA improves limb salvage in Buerger’s disease patients with critical limb ischemia. Int Angiol. 2011;30(2):140–9.PubMedGoogle Scholar
  89. 89.
    Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, Morishita R, Annex BH. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation. 2008;118(1):58–65. Scholar
  90. 90.
    Gu Y, Zhang J, Guo L, Cui S, Li X, Ding D, Kim JM, Ho SH, Hahn W, Kim S. A phase I clinical study of naked DNA expressing two isoforms of hepatocyte growth factor to treat patients with critical limb ischemia. J Gene Med. 2011;13(11):602–10. Scholar
  91. 91.
    Margolis DJ, Crombleholme T, Herlyn M. Clinical protocol: phase I trial to evaluate the safety of H5.020CMV.PDGF-B for the treatment of a diabetic insensate foot ulcer. Wound Repair Regen. 2000;8:480–93.CrossRefPubMedGoogle Scholar
  92. 92.
    Margolis DJ, Cromblehome T, Herlyn M, Cross P, Weinberg L, Filip J, Propert K. Clinical protocol. Phase I trial to evaluate the safety of H5.020CMV.PDGF-b and limb compression bandage for the treatment of venous leg ulcer: trial A. Hum Gene Ther. 2004;15:1003–19.CrossRefPubMedGoogle Scholar
  93. 93.
    Margolis DJ, Morris LM, Papadopoulos M, Weinberg L, Filip JC, Lang SA, Vaikunth SS, Crombleholme TM. Phase I study of H5.020CMV.PDGF-beta to treat venous leg ulcer disease. Mol Ther. 2009;17(10):1822–9. Scholar
  94. 94.
    Mulder G, Tallis AJ, Marshall VT, Mozingo D, Phillips L, Pierce GF, Chandler LA, Sosnowski BK. Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial. Wound Repair Regen. 2009;17(6):772–9. Scholar
  95. 95.
    Nikol S, Baumgartner I, Van Belle E, Diehm C, Visoná A, Capogrossi MC, Ferreira-Maldent N, Gallino A, Wyatt MG, Wijesinghe LD, Fusari M, Stephan D, Emmerich J, Pompilio G, Vermassen F, Pham E, Grek V, Coleman M, Meyer F, TALISMAN 201 Investigators. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther. 2008;16(5):972–8. Scholar
  96. 96.
    Comerota AJ, Throm RC, Miller KA, Henry T, Chronos N, Laird J, Sequeira R, Kent CK, Bacchetta M, Goldman C, Salenius JP, Schmieder FA, Pilsudski R. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: preliminary results of a phase I trial. J Vasc Surg. 2002;35(5):930–6.CrossRefPubMedGoogle Scholar
  97. 97.
    Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601. Scholar
  98. 98.
    Bennett SP, Griffiths GD, Schor AM, Leese GP, Schor SL. Growth factors in the treatment of diabetic foot ulcers. Br J Surg. 2003;90:133–46.CrossRefPubMedGoogle Scholar
  99. 99.
    Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer. 2000;7:165–97.CrossRefPubMedGoogle Scholar
  100. 100.
    Ramirez H, Patel SB, Pastar I. The role of TGFβ signaling in wound epithelialization. Adv Wound Care (New Rochelle). 2014;3(7):482–91.CrossRefGoogle Scholar
  101. 101.
    Peura M, Bizik J, Salmenperä P, Noro A, Korhonen M, Pätilä T, Vento A, Vaheri A, Alitalo R, Vuola J, Harjula A, Kankuri E. Bone marrow mesenchymal stem cells undergo nemosis and induce keratinocyte wound healing utilizing the HGF/c-Met/PI3K pathway. Wound Repair Regen. 2009;17(4):569–77. Scholar
  102. 102.
    Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, Wehland J, Birchmeier C, Birchmeier W. c-Met is essential for wound healing in the skin. J Cell Biol. 2007;177(1):151–62.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Seeger MA, Paller AS. The roles of growth factors in keratinocyte migration. Adv Wound Care (New Rochelle). 2015;4(4):213–24.CrossRefGoogle Scholar
  104. 104.
    Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83:835–70.CrossRefPubMedGoogle Scholar
  105. 105.
    Aydin F, Kaya A, Karapinar L, Kumbaraci M, Imerci A, Karapinar H, Karakuzu C, Incesu M. IGF-1 increases with hyperbaric oxygen therapy and promotes wound healing in diabetic foot ulcers. J Diabetes Res. 2013;2013:567834. Scholar
  106. 106.
    Aljuffali IA, Lin YK, Fang JY. Noninvasive approach for enhancing small interfering RNA delivery percutaneously. Expert Opin Drug Deliv. 2016;13(2):265–80. Scholar
  107. 107.
    Darby IA, Bisucci T, Hewitson TD, MacLellan DG. Apoptosis is increased in a model of diabetes-impaired wound healing in genetically diabetic mice. Int J Biochem Cell Biol. 1997;29:191–200.CrossRefPubMedGoogle Scholar
  108. 108.
    Beavers KR, Nelson CE, Duvall CL. MiRNA inhibition in tissue engineering and regenerative medicine. Adv Drug Deliv Rev. 2015;88:123–37. Scholar
  109. 109.
    Banerjee J, Sen CK. MicroRNAs in skin and wound healing. Methods Mol Biol. 2013;936:343–56.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Broderick JA, Zamore PD. MicroRNA therapeutics. Gene Ther. 2011;18(12):1104–10. Scholar
  111. 111.
    Fahs F, Bi X, Yu FS, Zhou L, Mi QS. New insights into microRNAs in skin wound healing. IUBMB Life. 2015;67(12):889–96. Scholar
  112. 112.
    Maurer B, Stanczyk J, Jüngel A, Akhmetshina A, Trenkmann M, Brock M, Kowal-Bielecka O, Gay RE, Michel BA, Distler JH, Gay S, Distler O. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 2010;62(6):1733–43. Scholar
  113. 113.
    Li D, Wang A, Liu X, Meisgen F, Grünler J, Botusan IR, Narayanan S, Erikci E, Li X, Blomqvist L, Du L, Pivarcsi A, Sonkoly E, Chowdhury K, Catrina SB, Ståhle M, Landén NX. MicroRNA-132 enhances transition from inflammation to proliferation during wound healing. J Clin Invest. 2015;125(8):3008–26. Scholar
  114. 114.
    Blume P, Driver VR, Tallis AJ, Kirsner RS, Kroeker R, Payne WG, Wali S, Marston W, Dove C, Engler RL, Chandler LA, Sosnowski BK. Formulated collagen gel accelerates healing rate immediately after application in patients with diabetic neuropathic foot ulcers. Wound Repair Regen. 2011;19(3):302–8. Scholar
  115. 115.
    Steed DL. Modifying the wound healing response with exogenous growth factors. Clin Plast Surg. 1998;25:397–405.PubMedGoogle Scholar
  116. 116.
    Robson MC, Mustoe TA, Hunt TK. The future of recombinant growth factors in wound healing. Am J Surg. 1998;176:80S–2S.CrossRefPubMedGoogle Scholar
  117. 117.
    Robson MC, Smith PD. Topical use of growth factors to enhance healing. In: Falanga V, editor. Cutaneous wound healing. London: Taylor & Francis; 2001. p. 379–98.Google Scholar
  118. 118.
    Li S, Huang L. Nonviral gene therapy: promises and challenges. Gene Ther. 2000;7(1):31–4.CrossRefPubMedGoogle Scholar
  119. 119.
    Whittam AJ, Maan ZN, Duscher D, Wong VW, Barrera JA, Januszyk M, Gurtner GC. Challenges and opportunities in drug delivery for wound healing. Adv Wound Care (New Rochelle). 2016;5(2):79–88.CrossRefGoogle Scholar
  120. 120.
    Lynch SE, Nixon JC, Colvin RB, Antoniades HN. Role of platelet-derived growth factor in wound healing: synergistic effects with other growth factors. Proc Natl Acad Sci U S A. 1987;84:7696–700.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Sprugel KH, McPherson JM, Clowes AW, Ross R. Effects of growth factors in vivo. I. Cell ingrowth into porous subcutaneous chambers. Am J Pathol. 1987;129:601–13.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Eid A, Mahfouz MM. Genome editing: the road of CRISPR/Cas9 from bench to clinic. Exp Mol Med. 2016;48(10):e265. Scholar
  123. 123.
    Wang M, Glass ZA, Xu Q. Non-viral delivery of genome-editing nucleases for gene therapy. Gene Ther. 2016;24(3):144. Scholar
  124. 124.
    Sessions JW, Armstrong DG, Hope S, Jensen BD. A review of genetic engineering biotechnologies for enhanced chronic wound healing. Exp Dermatol. 2016;26(2):179–85. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Kristo Nuutila
    • 1
    • 2
  • Mansher Singh
    • 3
  • Elof Eriksson
    • 4
  1. 1.Division of Plastic Surgery, Department of SurgeryBrigham & Women’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Faculty of Medicine, Department of Pharmacology, University of HelsinkiHelsinkiFinland
  3. 3.Department of General SurgeryBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  4. 4.Harvard Medical SchoolBostonUSA

Personalised recommendations