Challenges and Opportunities in Drug Delivery and Wound Healing

  • Matthias M. AitzetmüllerEmail author
  • Hans-Günther Machens
  • Dominik Duscher


Wound healing requires a convoluted systems biology interplay depending on the coordination of several cell types, intra- and extracellular mechanisms, proteins, and signaling pathways. Drugs meant to improve these interactions need to be delivered in a targeted and sustained fashion to effectively modulate the complex mechanisms involved in the response to injury. Specific drug delivery systems (DDS) are key for achieving this goal. An efficacious DDS prevents the wound from mechanical, oxidative, and enzymatic stress and from bacterial contamination and provides enough oxygen while maximizing localized and sustained drug delivery to the target tissue. In this chapter, we summarize the most promising recent advances in wound healing therapeutics with the corresponding delivery challenges and shed light on possible solutions for effective application.


Soft-tissue regeneration Regenerative medicine Wound healing Drug delivery Regeneration Skin barrier Local drug delivery 


  1. 1.
    Lindholm C, Searle R. Wound management for the 21st century: combining effectiveness and efficiency. Int Wound J. 2016;13(Suppl 2):5–15.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Lanman TH, Ingalls TH. Vitamin C deficiency and wound healing: an experimental and clinical study. Ann Surg. 1937;105(4):616–25.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Tiesler V, Coppa A, Zabala P, Cucina A. Scurvy-related morbidity and death among Christopher Columbus’ Crew at La Isabela, the First European Town in the New World (1494–1498): An Assessment of the Skeletal and Historical Information. Int J Osteoarchaeol. 2014;26(2):191–202.CrossRefGoogle Scholar
  4. 4.
    Grinnell F, Fukamizu H, Pawelek P, Nakagawa S. Collagen processing, crosslinking, and fibril bundle assembly in matrix produced by fibroblasts in long-term cultures supplemented with ascorbic acid. Exp Cell Res. 1989;181(2):483–91.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Clinical trials regarding wound healing and drug delivery system. Accessed 2 May 2017.
  6. 6.
    Deichmann W, Henschler D, Holmstedt B, Keil G. What is there that is not poison? A study of the Third Defense by Paracelsus. Arch Toxicol. 1986;58(4):207–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Saraswati S, Deskins DL, Holt GE, Young PP. Pyrvinium, a potent small molecule Wnt inhibitor, increases engraftment and inhibits lineage commitment of mesenchymal stem cells (MSCs). Wound Repair Regen. 2012;20(2):185–93.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Saraswati S, Alfaro MP, Thorne CA, Atkinson J, Lee E, Young PP. Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS One. 2010;5(11):e15521.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Lim M, Otto-Duessel M, He M, Su L, Nguyen D, Chin E, et al. Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium. ACS Chem Biol. 2014;9(3):692–702.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Antonijevic B, Stojiljkovic MP. Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin Med Res. 2007;5(1):71–82.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hom DB, Goding GS Jr, Price JA, Pernell KJ, Maisel RH. The effects of conjugated deferoxamine in porcine skin flaps. Head Neck. 2000;22(6):579–84.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Zarychanski R, Turgeon AF, McIntyre L, Fergusson DA. Erythropoietin-receptor agonists in critically ill patients: a meta-analysis of randomized controlled trials. Canad Med Assoc J. 2007;177(7):725–34.CrossRefGoogle Scholar
  13. 13.
    John MJ, Jaison V, Jain K, Kakkar N, Jacob JJ. Erythropoietin use and abuse. Indian J Endocrinol Metab. 2012;16(2):220–7.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Corwin HL, Parsonnet KC, Gettinger A. RBC transfusion in the ICU. Is there a reason? Chest. 1995;108(3):767–71.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Abraham E, MacIntyre NR, Shabot MM, Duh MS, Shapiro MJ. The CRIT study: Anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med. 2004;32(1):39–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ, EPO Critical Care Trials Group. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357(10):965–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Gunter CI, Bader A, Dornseifer U, Egert S, Dunda S, Grieb G, Wolter T, Pallua N, von Wild T, Siemers F, Mailänder P, Thamm O, Ernert C, Steen M, et al. A multi-center study on the regenerative effects of erythropoietin in burn and scalding injuries: study protocol for a randomized controlled trial. Trials. 2013;14:124.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Zhang Y, Chan HF, Leong KW. Advanced materials and processing for drug delivery: the past and the future. Adv Drug Deliv Rev. 2013;65(1):104–20.PubMedCrossRefGoogle Scholar
  19. 19.
    Weiser JR, Saltzman WM. Controlled release for local delivery of drugs: barriers and models. J Controlled Rel. 2014;190:664–73.CrossRefGoogle Scholar
  20. 20.
    Chu Y, Yu D, Wang P, Xu J, Li D, Ding M. Nanotechnology promotes the full-thickness diabetic wound healing effect of recombinant human epidermal growth factor in diabetic rats. Wound Repair Regen. 2010;18(5):499–505.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Jerome D. Advances in negative pressure wound therapy: the VAC instill. J Wound Ostomy Continence Nurs. 2007;34(2):191–4.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Wong VW, Rustad KC, Glotzbach JP, Sorkin M, Inayathullah M, Major MR, Longaker MT, Rajadas J, Gurtner GC. Pullulan hydrogels improve mesenchymal stem cell delivery into high-oxidative-stress wounds. Macromol Biosci. 2011;11(11):1458–66.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Zimmerlin L, Rubin JP, Pfeifer ME, Moore LR, Donnenberg VS, Donnenberg AD. Human adipose stromal vascular cell delivery in a fibrin spray. Cytotherapy. 2013;15(1):102–8.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Wainwright D, Madden M, Luterman A, Hunt J, Monafo W, Heimbach D, et al. Clinical evaluation of an acellular allograft dermal matrix in full-thickness burns. J Burn Care Rehab. 1996;17(2):124–36.CrossRefGoogle Scholar
  25. 25.
    Kim PJ, Heilala M, Steinberg JS, Weinraub GM. Bioengineered alternative tissues and hyperbaric oxygen in lower extremity wound healing. Clin Podiatr Med Surg. 2007;24(3):529–46.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Reyzelman A, Crews RT, Moore JC, Moore L, Mukker JS, Offutt S, Tallis A, Turner WB, Vayser D, Winters C, Armstrong DG. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study. Int Wound J. 2009;6(3):196–208.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Mostow EN, Haraway GD, Dalsing M, Hodde JP, King D, Group OVUS. Effectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. J Vasc Surg. 2005;41(5):837–43.CrossRefGoogle Scholar
  28. 28.
    Romanelli M, Dini V, Bertone MS. Randomized comparison of OASIS wound matrix versus moist wound dressing in the treatment of difficult-to-heal wounds of mixed arterial/venous etiology. Adv Skin Wound Care. 2010;23(1):34–8.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Scimeca CL, Bharara M, Fisher TK, Kimbriel H, Mills JL, Armstrong DG. An update on pharmacological interventions for diabetic foot ulcers. Foot Ankle Spec. 2010;3(5):285–302.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21.CrossRefGoogle Scholar
  31. 31.
    Smiell JM, Wieman TJ, Steed DL, Perry BH, Sampson AR, Schwab BH. 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. 1999;7(5):335–46.PubMedCrossRefGoogle Scholar
  32. 32.
    Rees RS, Robson MC, Smiell JM, Perry BH. Becaplermin gel in the treatment of pressure ulcers: a phase II randomized, double-blind, placebo-controlled study. Wound Repair Regen. 1999;7(3):141–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Senet P, Vicaut E, Beneton N, Debure C, Lok C, Chosidow O. Topical treatment of hypertensive leg ulcers with platelet-derived growth factor-BB: a randomized controlled trial. Arch Dermatol. 2011;147(8):926–30.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Nair DG, Miller KG, Lourenssen SR, Blennerhassett MG. Inflammatory cytokines promote growth of intestinal smooth muscle cells by induced expression of PDGF-Rbeta. J Cell Molec Med. 2014;18(3):444–54.CrossRefGoogle Scholar
  35. 35.
    Ingber DE. Mechanical control of tissue growth: function follows form. Proc Natl Acad Sci U S A. 2005;102(33):11571–2.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Ingber DE. The mechanochemical basis of cell and tissue regulation. Mech Chem Biosyst. 2004;1(1):53–68.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Nie B, Yue B. Biological effects and clinical application of negative pressure wound therapy: a review. J Wound Care. 2016;25(11):617–26.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Zhang YG, Wang X, Yang Z, Zhang H, Liu M, Qiu Y, Guo X. The therapeutic effect of negative pressure in treating femoral head necrosis in rabbits. PLoS One. 2013;8(1):e55745.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Li X, Liu J, Liu Y, Hu X, Dong M, Wang H, Hu D. Negative pressure wound therapy accelerates rats diabetic wound by promoting agenesis. Int J Clin Exp Med. 2015;8(3):3506–13.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Valente PM, Deva A, Ngo Q, Vickery K. The increased killing of biofilms in vitro by combining topical silver dressings with topical negative pressure in chronic wounds. Int Wound J. 2016;13(1):130–6.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Rowan MP, Niece KL, Rizzo JA, Akers KS. Wound penetration of cefazolin, ciprofloxacin, piperacillin, tazobactam, and vancomycin during negative pressure wound therapy. Adv Wound Care. 2017;6(2):55–62.CrossRefGoogle Scholar
  42. 42.
    Hadjipanayi E, Bauer AT, Moog P, Salgin B, Kuekrek H, Fersch B, Hopfner U, Meissner T, Schlüter A, Ninkovic M, Machens HG, Schilling AF. Cell-free carrier system for localized delivery of peripheral blood cell-derived engineered factor signaling: towards development of a one-step device for autologous angiogenic therapy. J Control Release. 2013;169(1–2):91–102.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9(1):11–5.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Dazzi F, Lopes L, Weng L. Mesenchymal stromal cells: a key player in ‘innate tolerance’? Immunology. 2012;137(3):206–13.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Rustad KC, Wong VW, Sorkin M, Glotzbach JP, Major MR, Rajadas J, Longaker MT, Gurtner GC. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials. 2012;33(1):80–90.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Shin L, Peterson DA. Human mesenchymal stem cell grafts enhance normal and impaired wound healing by recruiting existing endogenous tissue stem/progenitor cells. Stem Cells Transl Med. 2013;2(1):33–42.PubMedCrossRefGoogle Scholar
  47. 47.
    Kosaraju R, Rennert RC, Maan ZN, Duscher D, Barrera J, Whittam AJ, Januszyk M, Rajadas J, Rodrigues M, Gurtner GC. Adipose-derived stem cell-seeded hydrogels increase endogenous progenitor cell recruitment and neovascularization in wounds. Tissue Eng Part A. 2016;22(3–4):295–305.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Rennert RC, Rodrigues M, Wong VW, Duscher D, Hu M, Maan Z, Sorkin M, Gurtner GC, Longaker MT. Biological therapies for the treatment of cutaneous wounds: phase III and launched therapies. Expert Opin Biol Ther. 2013;13(11):1523–41.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Giri P, Ebert S, Braumann UD, Kremer M, Giri S, Machens HG, Bader A. Skin regeneration in deep second-degree scald injuries either by infusion pumping or topical application of recombinant human erythropoietin gel. Drug Des Devel Ther. 2015;9:2565–79.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Bader A, Ebert S, Giri S, Kremer M, Liu S, Nerlich A, Günter CI, Smith DU, Machens HG. Skin regeneration with conical and hair follicle structure of deep second-degree scalding injuries via combined expression of the EPO receptor and beta common receptor by local subcutaneous injection of nanosized rhEPO. Int J Nanomedicine. 2012;7:1227–37.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Boateng JS, Matthews KH, Stevens HN, Eccleston GM. Wound healing dressings and drug delivery systems: a review. J Pharm Sci. 2008;97(8):2892–923.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Ekenseair AK, Kasper FK, Mikos AG. Perspectives on the interface of drug delivery and tissue engineering. Adv Drug Deliv Rev. 2013;65(1):89–92.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Nusse R. Cell biology: relays at the membrane. Nature. 2005;438(7069):747–9.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Nusse R, Varmus HE. Wnt genes. Cell. 1992;69(7):1073–87.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X. LDL-receptor-related proteins in Wnt signal transduction. Nature. 2000;407(6803):530–5.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Bielefeld KA, Amini-Nik S, Alman BA. Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci. 2013;70(12):2059–81.CrossRefGoogle Scholar
  57. 57.
    Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, Jernigan KK, Meyers KC, Hang BI, Waterson AG, Kim K, Melancon B, Ghidu VP, Sulikowski GA, LaFleur B, Salic A, Lee LA, Miller DM 3rd, Lee E. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1alpha. Nat Chem Biol. 2010;6(11):829–36.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Semenza GL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev. 1998;8(5):588–94.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–72.CrossRefPubMedGoogle Scholar
  60. 60.
    Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–8.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Kimura H, Weisz A, Ogura T, Hitomi Y, Kurashima Y, Hashimoto K, D’Acquisto F, Makuuchi M, Esumi H. Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J Biol Chem. 2001;276(3):2292–8.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10(8):858–64.CrossRefPubMedGoogle Scholar
  63. 63.
    Kajiwara H, Luo Z, Belanger AJ, Urabe A, Vincent KA, Akita GY, Cheng SH, Mochizuki S, Gregory RJ, Jiang C. A hypoxic inducible factor-1 alpha hybrid enhances collateral development and reduces vascular leakage in diabetic rats. J Gene Med. 2009;11(5):390–400.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Sarkar K, Fox-Talbot K, Steenbergen C, Bosch-Marce M, Semenza GL. Adenoviral transfer of HIF-1alpha enhances vascular responses to critical limb ischemia in diabetic mice. Proc Natl Acad Sci U S A. 2009;106(44):18769–74.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Wetterau M, George F, Weinstein A, Nguyen PD, Tutela JP, Knobel D, Cohen Ba O, Warren SM, Saadeh PB. Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure. Wound Repair Regen. 2011;19(4):481–6.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, Nedeau A, Thom SR, Velazquez OC. Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Invest. 2007;117(5):1249–59.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Thangarajah H, Yao D, Chang EI, Shi Y, Jazayeri L, Vial IN, Galiano RD, Du XL, Grogan R, Galvez MG, Januszyk M, Brownlee M, Gurtner GC. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A. 2009;106(32):13505–10.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Bergeron RJ, Wiegand J, McManis JS, Bussenius J, Smith RE, Weimar WR. Methoxylation of desazadesferrithiocin analogues: enhanced iron clearing efficiency. J Med Chem. 2003;46(8):1470–7.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341(26):1986–95.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Botusan IR, Sunkari VG, Savu O, Catrina AI, Grunler J, Lindberg S, Pereira T, Ylä-Herttuala S, Poellinger L, Brismar K, Catrina SB. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A. 2008;105(49):19426–31.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Sundin BM, Hussein MA, Glasofer S, El-Falaky MH, Abdel-Aleem SM, Sachse RE, Klitzman B. The role of allopurinol and deferoxamine in preventing pressure ulcers in pigs. Plast Reconstr Surg. 2000;105(4):1408–21.PubMedGoogle Scholar
  72. 72.
    Verma RK, Garg S. Drug delivery technologies and future directions. Pharmaceut Technol On-Line. 2001;25(2):1–14.Google Scholar
  73. 73.
    Zhang L, Pornpattananangku D, Hu CM, Huang CM. Development of nanoparticles for antimicrobial drug delivery. Curr Med Chem. 2010;17(6):585–94.PubMedCrossRefGoogle Scholar
  74. 74.
    Duscher D, Neofytou E, Wong VW, Maan ZN, Rennert RC, Inayathullah M, Rodrigues M, Malkovskiy AV, Whitmore AJ, Walmsley GG, Galvez MG, Whittam AJ, Brownlee M, Rajadas J, Gurtner GC. Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proc Natl Acad Sci U S A. 2015;112(1):94–9.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Gavrilov K, Saltzman WM. Therapeutic siRNA: principles, challenges, and strategies. Yale J Biol Med. 2012;85(2):187–200.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Gao Z, Wang Z, Shi Y, Lin Z, Jiang H, Hou T, Wang Q, Yuan X, Zhao Y, Wu H, Jin Y. Modulation of collagen synthesis in keloid fibroblasts by silencing Smad2 with siRNA. Plast Reconstr Surg. 2006;118(6):1328–37.PubMedCrossRefGoogle Scholar
  77. 77.
    Gary DJ, Puri N, Won YY. Polymer-based siRNA delivery: perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery. J Control Release. 2007;121(1–2):64–73.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol. 2005;23(6):709–17.PubMedCrossRefGoogle Scholar
  79. 79.
    Dykxhoorn DM, Palliser D, Lieberman J. The silent treatment: siRNAs as small molecule drugs. Gene Ther. 2006;13(6):541–52.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Krebs MD, Jeon O, Alsberg E. Localized and sustained delivery of silencing RNA from macroscopic biopolymer hydrogels. J Am Chem Soc. 2009;131(26):9204–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Kanasty R, Dorkin JR, Vegas A, Anderson D. Delivery materials for siRNA therapeutics. Nat Mater. 2013;12(11):967–77.PubMedCrossRefGoogle Scholar
  82. 82.
    Liu X, Ma L, Liang J, Zhang B, Teng J, Gao C. RNAi functionalized collagen-chitosan/silicone membrane bilayer dermal equivalent for full-thickness skin regeneration with inhibited scarring. Biomaterials. 2013;34(8):2038–48.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Matthias M. Aitzetmüller
    • 1
    • 2
    Email author
  • Hans-Günther Machens
    • 1
  • Dominik Duscher
    • 3
  1. 1.Department of Plastic and Hand Surgery, Klinikum rechts der IsarTechnical University of MunichMunichGermany
  2. 2.Section of Plastic and Reconstructive Surgery, Department of Trauma, Hand and Reconstructive SurgeryWestfaelische Wilhelms, University of MuensterMuensterGermany
  3. 3.Department for Plastic Surgery and Hand Surgery, Division of Experimental Plastic SurgeryTechnical University of MunichMunichGermany

Personalised recommendations