Principles of Gene Therapy in Reconstructive and Regenerative Surgery

  • Giorgio GiatsidisEmail author


In November 2017, a group of investigators from Germany and Italy, led by Michele De Luca, published on Nature a case report on the use of tissue-engineered, genetically-modified keratinocyte sheets, to regenerate the entire epidermis of a pediatric patient affected by junctional epidermolysis bullosa [1]. The gene therapy-edited cells showed a sustained survival in vivo (>21 months), offering the possibility of a cure where other conventional therapies are lacking or have failed. This groundbreaking report highlights the enormous progresses that the field of gene therapy has been achieving over the last few years and its increasing potential to be translated from a laboratory bench to the clinical care of patients. In reconstructive and regenerative surgery, gene therapies have been the focus of an increasing interest for the last two decades, either as stand-alone therapeutic strategies or as adjuvant methods to boost the effectiveness of other treatments (e.g., stem cells therapies or tissue engineered products) [2, 3]. Virtually every tissue that is routinely repaired by reconstructive and regenerative surgeries can be further enhanced by gene therapies. These include the skin, bones, tendons and fascias, nerves, muscles, soft tissues, and more.


  1. 1.
    Hirsch T, Rothoeft T, Teig N, et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. 2017;551(7680):327–32. Scholar
  2. 2.
    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
  3. 3.
    Tepper OM, Mehrara BJ. Gene therapy in plastic surgery. Plast Reconstr Surg. 2002;109(2):716–34. Accessed January 12, 2018.CrossRefPubMedGoogle Scholar
  4. 4.
    Baisch A, Riedel F. Hyperplastic scars and keloids: part II: surgical and non-surgical treatment modalities. HNO. 2006;54(12):981–92-4. Scholar
  5. 5.
    Xu B, Liu ZZ, Zhu GY, et al. Efficacy of recombinant adenovirus-mediated double suicide gene therapy in human keloid fibroblasts. Clin Exp Dermatol. 2008;33(3):322–8. Scholar
  6. 6.
    Mofazzal Jahromi MA, Sahandi Zangabad P, Moosavi Basri SM, et al. Nanomedicine and advanced technologies for burns: preventing infection and facilitating wound healing. Adv Drug Deliv Rev. 2018;123:33–64. Scholar
  7. 7.
    Mendoza-Garcia J, Sebastian A, Alonso-Rasgado T, Bayat A. Optimization of an ex vivo wound healing model in the adult human skin: functional evaluation using photodynamic therapy. Wound Repair Regen. 2015;23(5):685–702. Scholar
  8. 8.
    Balaji S, Lesaint M, Bhattacharya SS, et al. Adenoviral-mediated gene transfer of insulin-like growth factor 1 enhances wound healing and induces angiogenesis. J Surg Res. 2014;190(1):367–77. Scholar
  9. 9.
    Tollefson TT, Senders CW, Sykes JM. Changing perspectives in cleft lip and palate: from acrylic to allele. Arch Facial Plast Surg. 2008;10(6):395–400. Scholar
  10. 10.
    Icli B, Nabzdyk CS, Lujan-Hernandez J, et al. Regulation of impaired angiogenesis in diabetic dermal wound healing by microRNA-26a. J Mol Cell Cardiol. 2016;91:151–9. Scholar
  11. 11.
    Steinstraesser L, Lam MC, Jacobsen F, et al. Skin electroporation of a plasmid encoding hCAP-18/LL-37 host defense peptide promotes wound healing. Mol Ther. 2014;22(4):734–42. Scholar
  12. 12.
    Golas AR, Hernandez KA, Spector JA. Tissue engineering for plastic surgeons: a primer. Aesthet Plast Surg. 2014;38(1):207–21. Scholar
  13. 13.
    Whittam AJ, Maan ZN, Duscher D, et al. Challenges and opportunities in drug delivery for wound healing. Adv Wound Care. 2016;5(2):79–88. Scholar
  14. 14.
    Wackerhage H, Ratkevicius A. Signal transduction pathways that regulate muscle growth. Essays Biochem. 2008;44(1):99–108. Scholar
  15. 15.
    Ghali S, Dempsey MP, Jones DM, Grogan RH, Butler PE, Gurtner GC. Plastic surgical delivery systems for targeted gene therapy. Ann Plast Surg. 2008;60(3):323–32. Scholar
  16. 16.
    Liao J, Wei Q, Fan J, et al. Characterization of retroviral infectivity and superinfection resistance during retrovirus-mediated transduction of mammalian cells. Gene Ther. 2017;24(6):333–41. Scholar
  17. 17.
    Yi CG, Xia W, Zhang LX, et al. VEGF gene therapy for the survival of transplanted fat tissue in nude mice. J Plast Reconstr Aesthet Surg. 2007;60(3):272–8. Scholar
  18. 18.
    Sharma P, Wimalawansa SM, Gould GC, Johnson RM, Excoffon KJDA. Adeno-associated virus 5 transduces adipose-derived stem cells with greater efficacy than other adeno-associated viral serotypes. Hum Gene Ther Methods. 2016;27(6):219–27. Scholar
  19. 19.
    Tang JB, Chen CH, Zhou YL, McKeever C, Liu PY. Regulatory effects of introduction of an exogenous FGF2 gene on other growth factor genes in a healing tendon. Wound Repair Regen. 2014;22(1):111–8. Scholar
  20. 20.
    Jackson JD, McMorris AM, Roth JC, et al. Assessment of oncolytic HSV efficacy following increased entry-receptor expression in malignant peripheral nerve sheath tumor cell lines. Gene Ther. 2014;21(11):984–90. Scholar
  21. 21.
    Qiu L, Zhang L, Wang L, et al. Ultrasound-targeted microbubble destruction enhances naked plasmid DNA transfection in rabbit Achilles tendons in vivo. Gene Ther. 2012;19(7):703–10. Scholar
  22. 22.
    Delalande A, Gosselin M-P, Suwalski A, et al. Enhanced Achilles tendon healing by fibromodulin gene transfer. Nanomedicine. 2015;11(7):1735–44. Scholar
  23. 23.
    Liu PY, Tong W, Liu K, et al. Liposome-mediated transfer of vascular endothelial growth factor cDNA augments survival of random-pattern skin flaps in the rat. Wound Repair Regen. 2004;12(1):80–5. Scholar
  24. 24.
    Hirsch T, Spielmann M, Velander P, et al. Insulin-like growth factor-1 gene therapy and cell transplantation in diabetic wounds. J Gene Med. 2008;10(11):1247–52. Scholar
  25. 25.
    Seyed Jafari SM, Shafighi M, Beltraminelli H, Geiser T, Hunger RE, Gazdhar A. Improvement of flap necrosis in a rat random skin flap model by in vivo electroporation-mediated HGF gene transfer. Plast Reconstr Surg. 2017;139(5):1116e–27e. Scholar
  26. 26.
    Rezende FC, Gomes HC, Lisboa B, Lucca AF, Han SW, Ferreira LM. Electroporation of vascular endothelial growth factor gene in a unipedicle transverse rectus abdominis myocutaneous flap reduces necrosis. Ann Plast Surg. 2010;64(2):242–6. Scholar
  27. 27.
    Chávez MN, Schenck TL, Hopfner U, et al. Towards autotrophic tissue engineering: photosynthetic gene therapy for regeneration. Biomaterials. 2016;75:25–36. Scholar
  28. 28.
    Perisic T, Zhang Z, Foehr P, et al. Biodegradable poly (lactic acid-co-glycolic acid) scaffolds as carriers for genetically-modified fibroblasts. PLoS One. 2017;12(4):e0174860. Scholar
  29. 29.
    Alluri R, Jakus A, Bougioukli S, et al. 3D printed hyperelastic “bone” scaffolds and regional gene therapy: a novel approach to bone healing. J Biomed Mater Res A. 2017;106(4):1104–10. Scholar
  30. 30.
    Lu P, Zhang G-R, Cai Y-Z, et al. Lentiviral-encoded shRNA silencing of proteoglycan decorin enhances tendon repair and regeneration within a rat model. Cell Transplant. 2013;22(9):1507–17. Scholar
  31. 31.
    Lu P, Zhang GR, Song XH, Zou XH, Wang LL, Ouyang HW. Col V siRNA engineered tenocytes for tendon tissue engineering. PLoS One. 2011;6(6):e21154. Scholar
  32. 32.
    Nixon AJ, Watts AE, Schnabel LV. Cell- and gene-based approaches to tendon regeneration. J Shoulder Elb Surg. 2012;21(2):278–94. Scholar
  33. 33.
    Mo Y, Guo R, Zhang Y, Xue W, Cheng B, Zhang Y. Controlled dual delivery of angiogenin and curcumin by electrospun nanofibers for skin regeneration. Tissue Eng Part A. 2017;23(13–14):597–608. Scholar
  34. 34.
    Bougioukli S, Sugiyama O, Pannell W, et al. Gene therapy for bone repair using human cells: superior osteogenic potential of BMP-2 transduced mesenchymal stem cells derived from adipose tissue compared to bone marrow. Hum Gene Ther. 2017.
  35. 35.
    Wu G, Zhou B, Hu C, Li S. Gene expression of osteogenic factors following gene therapy in mandibular lengthening. J Craniofac Surg. 2015;26(2):378–81. Scholar
  36. 36.
    Zhang Q, Gong W, Ning B, Nie L, Wooley PH, Yang S-Y. Local gene transfer of OPG prevents joint damage and disease progression in collagen-induced arthritis. Sci World J. 2013;2013:1–8. Scholar
  37. 37.
    Tang Y, Wang B. Gene- and stem cell-based therapeutics for cartilage regeneration and repair. Stem Cell Res Ther. 2015;6(1):78. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wu YF, Mao WF, Zhou YL, Wang XT, Liu PY, Tang JB. Adeno-associated virus-2-mediated TGF-β1 microRNA transfection inhibits adhesion formation after digital flexor tendon injury. Gene Ther. 2016;23(2):167–75. Scholar
  39. 39.
    Tang JB, Zhou YL, Wu YF, Liu PY, Wang XT. Gene therapy strategies to improve strength and quality of flexor tendon healing. Expert Opin Biol Ther. 2016;16(3):291–301. Scholar
  40. 40.
    Tang JB, Wu YF, Cao Y, et al. Basic FGF or VEGF gene therapy corrects insufficiency in the intrinsic healing capacity of tendons. Sci Rep. 2016;6(1):20643. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Majewski M, Betz O, Ochsner PE, Liu F, Porter RM, Evans CH. Ex vivo adenoviral transfer of bone morphogenetic protein 12 (BMP-12) cDNA improves Achilles tendon healing in a rat model. Gene Ther. 2008;15(16):1139–46. Scholar
  42. 42.
    Hoyng SA, De Winter F, Gnavi S, et al. Gene delivery to rat and human Schwann cells and nerve segments: a comparison of AAV 1-9 and lentiviral vectors. Gene Ther. 2015;22(10):767–80. Scholar
  43. 43.
    Jiang W, Tang L, Zeng J, Chen B. Adeno-associated virus mediated SOD gene therapy protects the retinal ganglion cells from chronic intraocular pressure elevation induced injury via attenuating oxidative stress and improving mitochondrial dysfunction in a rat model. Am J Transl Res. 2016;8(2):799–810. Accessed January 12, 2018.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Zor F, Deveci M, Kilic A, et al. Effect of VEGF gene therapy and hyaluronic acid film sheath on peripheral nerve regeneration. Microsurgery. 2014;34(3):209–16. Scholar
  45. 45.
    Busuttil F, Rahim AA, Phillips JB. Combining gene and stem cell therapy for peripheral nerve tissue engineering. Stem Cells Dev. 2017;26(4):231–8. Scholar
  46. 46.
    O’Toole G, MacKenzie D, Lindeman R, et al. Vascular endothelial growth factor gene therapy in ischaemic rat skin flaps. Br J Plast Surg. 2002;55(1):55–8. Scholar
  47. 47.
    Moimas S, Manasseri B, Cuccia G, et al. AAV vector encoding human VEGF165-transduced pectineus muscular flaps increase the formation of new tissue through induction of angiogenesis in an in vivo chamber for tissue engineering: a technique to enhance tissue and vessels in microsurgically engineered tissue. J Tissue Eng. 2015;6:2041731415611717. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Huang N, Khan A, Ashrafpour H, et al. Efficacy and mechanism of adenovirus-mediated VEGF-165 gene therapy for augmentation of skin flap viability. Am J Physiol Heart Circ Physiol. 2006;291(1):H127–37. Scholar
  49. 49.
    Jung H, Gurunluoglu R, Scharpf J, Siemionow M. Adenovirus-mediated angiopoietin-1 gene therapy enhances skin flap survival. Microsurgery. 2003;23(4):374–80. Scholar
  50. 50.
    Michaels J, Dobryansky M, Galiano RD, et al. Ex vivo transduction of microvascular free flaps for localized peptide delivery. Ann Plast Surg. 2004;52(6):581–4. Accessed January 12, 2018.CrossRefPubMedGoogle Scholar
  51. 51.
    Dempsey MP, Hamou C, Michaels J, et al. Using genetically modified microvascular free flaps to deliver local cancer immunotherapy with minimal systemic toxicity. Plast Reconstr Surg. 2008;121(5):1541–53. Scholar
  52. 52.
    Agrawal VK, Copeland KM, Barbachano Y, et al. Microvascular free tissue transfer for gene delivery: in vivo evaluation of different routes of plasmid and adenoviral delivery. Gene Ther. 2009;16(1):78–92. Scholar
  53. 53.
    Michaels J, Levine JP, Hazen A, et al. Biologic brachytherapy: ex vivo transduction of microvascular beds for efficient, targeted gene therapy. Plast Reconstr Surg. 2006;118(1):54–65-8. Scholar
  54. 54.
    Ghali S, Bhatt KA, Dempsey MP, et al. Treating chronic wound infections with genetically modified free flaps. Plast Reconstr Surg. 2009;123(4):1157–68. Scholar
  55. 55.
    Pineda M, Moghadam F, Ebrahimkhani MR, Kiani S. Engineered CRISPR systems for next generation gene therapies. ACS Synth Biol. 2017;6(9):1614–26. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Plastic Surgery, Department of SurgeryBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

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