Tissue-Engineered Wound Dressings for Diabetic Foot Ulcers

  • Sahar Rahmani
  • David J. MooneyEmail author
Part of the Contemporary Diabetes book series (CDI)


With the rise in the number of individuals suffering from diabetes, a greater number of patients are at risk of developing diabetic foot ulcers (DFUs). While traditional wound therapies can be successful at treating moderate DFUs when detected early, they often fall short in treating more severe cases which can lead to secondary ulcer formation or lower extremity amputations. To remedy this, a number of FDA-approved therapies have been developed and approved in the past two decades that take advantage of advances in biomaterials and tissue engineering to manufacture materials that have specific functionalities, and exploit active dressing materials that can enhance the wound healing process for these patients. Despite these advances, diabetic patients still suffer from slow healing wounds that often lead to further infections and delayed healing and/or amputations. Recent research in the wound healing field has focused on developing dressings with improved properties, especially the ability to encapsulate and release therapeutics over prolonged durations. These can potentially enhance the wound healing process by controlling cell migration and proliferation into the wound and provide a physiochemical environment conducive to healing. While many of these therapies are still undergoing clinical testing, or have yet to be tested for the treatment of DFUs, they provide a promising future.


Diabetes Diabetic foot ulcers (DFU) Wound healing Wound dressings Tissue engineering Biomaterials Drug delivery FDA approval Hydrogels Foams 


  1. 1.
    Moura LI, Dias AM, Carvalho E, de Sousa HC. Recent advances on the development of wound dressings for diabetic foot ulcer treatment--a review. Acta Biomater. 2013;9(7):7093–114.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. JAMA. 2015;314(10):1021–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol. 2006;24(4):237–46.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Mangiapane H. Cardiovascular disease and diabetes. Adv Exp Med Biol. 2012;771:219–28.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Bowling FL, Rashid ST, Boulton AJ. Preventing and treating foot complications associated with diabetes mellitus. Nat Rev Endocrinol. 2015;11(10):606–16.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Gupta SK, Singh SK. Diabetic foot: a continuing challenge. Adv Exp Med Biol. 2012;771:123–38.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Lim JZ, Ng NS, Thomas C. Prevention and treatment of diabetic foot ulcers. J R Soc Med. 2017;110(3):104–9.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Tabur S, Eren MA, Celik Y, Dag OF, Sabuncu T, Sayiner ZA, et al. The major predictors of amputation and length of stay in diabetic patients with acute foot ulceration. Wien Klin Wochenschr. 2015;127(1–2):45–50.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Tecilazich F, Dinh T, Veves A. Treating diabetic ulcers. Expert Opin Pharmacother. 2011;12(4):593–606.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Han G, Ceilley R. Chronic wound healing: a review of current management and treatments. Adv Ther. 2017;34(3):599–610.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of removable and irremovable cast walkers in the healing of diabetic foot wounds: a randomized controlled trial. Diabetes Care. 2005;28(3):551–4.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Cavanagh PR. Therapeutic footwear for people with diabetes. Diabetes Metab Res Rev. 2004;20(Suppl 1):S51–5.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Huang C, Leavitt T, Bayer LR, Orgill DP. Effect of negative pressure wound therapy on wound healing. Curr Probl Surg. 2014;51(7):301–31.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Hsu CR, Chang CC, Chen YT, Lin WN, Chen MY. Organization of wound healing services: the impact on lowering the diabetes foot amputation rate in a ten-year review and the importance of early debridement. Diabetes Res Clin Pract. 2015;109(1):77–84.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Andrews KL, Houdek MT, Kiemele LJ. Wound management of chronic diabetic foot ulcers: from the basics to regenerative medicine. Prosthetics Orthot Int. 2015;39(1):29–39.CrossRefGoogle Scholar
  17. 17.
    Steed DL. Debridement. Am J Surg. 2004;187(5A):71S–4S.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Boateng J, Catanzano O. Advanced therapeutic dressings for effective wound healing--a review. J Pharm Sci. 2015;104(11):3653–80.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    MacNeil S. Progress and opportunities for tissue-engineered skin. Nature. 2007;445(7130):874–80.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Dickinson LE, Gerecht S. Engineered biopolymeric scaffolds for chronic wound healing. Front Physiol. 2016;7:341.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    van der Veen VC, van der Wal MB, van Leeuwen MC, Ulrich MM, Middelkoop E. Biological background of dermal substitutes. Burns. 2010;36(3):305–21.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Malafaya PB, Silva GA, Reis RL. Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv Drug Deliv Rev. 2007;59(4–5):207–33.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Caruta BM. Polymeric materials: new research. New York: Nova Science Publishers; 2005. p. 146.Google Scholar
  24. 24.
    Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016;1:1–17.Google Scholar
  25. 25.
    Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol. 2008;58(2):185–206.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Hilton JR, Williams DT, Beuker B, Miller DR, Harding KG. Wound dressings in diabetic foot disease. Clin Infect Dis. 2004;39(Suppl 2):S100–3.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Hu S, Kirsner RS, Falanga V, Phillips T, Eaglstein WH. Evaluation of Apligraf persistence and basement membrane restoration in donor site wounds: a pilot study. Wound Repair Regen. 2006;14(4):427–33.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft Diabetic Foot Ulcer Study G. The efficacy and safety of dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701–5.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Hanft JR, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis. J Foot Ankle Surg. 2002;41(5):291–9.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Newton DJ, Khan F, Belch JJ, Mitchell MR, Leese GP. Blood flow changes in diabetic foot ulcers treated with dermal replacement therapy. J Foot Ankle Surg. 2002;41(4):233–7.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Driver VR, Lavery LA, Reyzelman AM, Dutra TG, Dove CR, Kotsis SV, et al. A clinical trial of Integra template for diabetic foot ulcer treatment. Wound Repair Regen. 2015;23(6):891–900.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs. 1997;21(11):1203–10.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Falanga V, Isaacs C, Paquette D, Downing G, Kouttab N, Butmarc J, et al. Wounding of bioengineered skin: cellular and molecular aspects after injury. J Invest Dermatol. 2002;119(3):653–60.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Veves A, Falanga V, Armstrong DG, Sabolinski ML, 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. 2001;24(2):290–5.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Landsman AS, Cook J, Cook E, Landsman AR, Garrett P, Yoon J, et al. A retrospective clinical study of 188 consecutive patients to examine the effectiveness of a biologically active cryopreserved human skin allograft (TheraSkin(R)) on the treatment of diabetic foot ulcers and venous leg ulcers. Foot Ankle Spec. 2011;4(1):29–41.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Kirsner RS, Falanga V, Eaglstein WH. The development of bioengineered skin. Trends Biotechnol. 1998;16(6):246–9.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Nicholas MN, Yeung J. Current status and future of skin substitutes for chronic wound healing. J Cutan Med Surg. 2017;21(1):23–30.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Armstrong SH, Ruckley CV. Use of a fibrous dressing in exuding leg ulcers. J Wound Care. 1997;6(7):322–4.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Foster L, Moore P, Clark S. A comparison of hydrofibre and alginate dressings on open acute surgical wounds. J Wound Care. 2000;9(9):442–5.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Bowler PG, Jones SA, Davies BJ, Coyle E. Infection control properties of some wound dressings. J Wound Care. 1999;8(10):499–502.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Thomas S, McCubbin P. An in vitro analysis of the antimicrobial properties of 10 silver-containing dressings. J Wound Care. 2003;12(8):305–8.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Jude EB, Apelqvist J, Spraul M, Martini J, Silver Dressing Study G. Prospective randomized controlled study of hydrofiber dressing containing ionic silver or calcium alginate dressings in non-ischaemic diabetic foot ulcers. Diabet Med. 2007;24(3):280–8.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Goodhead A. Clinical efficacy of Comfeel plus transparent dressing. Br J Nurs. 2002;11(4):284. 6-7PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Apelqvist J, Larsson J, Stenstrom A. Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc. Br J Dermatol. 1990;123(6):787–92.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Feldman DL, Rogers A, Karpinski RH. A prospective trial comparing biobrane, duoderm and xeroform for skin graft donor sites. Surg Gynecol Obstet. 1991;173(1):1–5.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Hogge J, Krasner D, Nguyen H, Harkless LB, Armstrong DG. The potential benefits of advanced therapeutic modalities in the treatment of diabetic foot wounds. J Am Podiatr Med Assoc. 2000;90(2):57–65.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Meaume S, Ourabah Z, Cartier H, Granel-Brocard F, Combemale P, Bressieux JM, et al. Evaluation of a lipidocolloid wound dressing in the local management of leg ulcers. J Wound Care. 2005;14(7):329–34.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Carter MJ, Tingley-Kelley K, Warriner RA 3rd. Silver treatments and silver-impregnated dressings for the healing of leg wounds and ulcers: a systematic review and meta-analysis. J Am Acad Dermatol. 2010;63(4):668–79.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Jensen JL, Seeley J, Gillin B. Diabetic foot ulcerations. A controlled, randomized comparison of two moist wound healing protocols: carrasyn hydrogel wound dressing and wet-to-moist saline gauze. Adv Wound Care. 1998;11(7 Suppl):1–4.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Diehm C, Lawall H. Evaluation of Tielle hydropolymer dressings in the management of chronic exuding wounds in primary care. Int Wound J. 2005;2(1):26–35.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Schulze HJ. Clinical evaluation of TIELLE* plus dressing in the management of exuding chronic wounds. Br J Community Nurs. 2003;8(11 Suppl):18–22.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Mellor J, Boothman S. TIELLE* hydropolymer dressings: wound responsive technology. Br J Community Nurs. 2003;8(11 Suppl):14–7.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Williams C, Young T. Allevyn adhesive. Br J Nurs. 1996;5(11):691–3.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Amione P, Ricci E, Topo F, Izzo L, Pirovano R, Rega V, et al. Comparison of Allevyn Adhesive and Biatain Adhesive in the management of pressure ulcers. J Wound Care. 2005;14(8):365–70.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Dinar S, Sen C, Unal C, Agir H, Iscen D. A new material for the standard burn model: Allevyn adhesive. Plast Reconstr Surg. 2006;117(2):717–8.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Winter GD. Epidermal wound healing under a new polyurethane foam dressing (Lyofoam). Plast Reconstr Surg. 1975;56(5):531–7.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Williams C. The benefits and application of the Lyofoam product range. Br J Nurs. 1999;8(11):745. 8-9PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Lasa CI Jr, Kidd RR 3rd, Nunez HA, Drohan WN. Effect of fibrin glue and opsite on open wounds in DB/DB mice. J Surg Res. 1993;54(3):202–6.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Foster AV, Eaton C, McConville DO, Edmonds ME. Application of OpSite film: a new and effective treatment of painful diabetic neuropathy. Diabet Med. 1994;11(8):768–72.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Czaja W, Krystynowicz A, Bielecki S, Brown RM Jr. Microbial cellulose--the natural power to heal wounds. Biomaterials. 2006;27(2):145–51.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Weindorf M, Korber A, Klode J, Dissemond J. Non-interventional study to investigate the efficacy and safety of Tegaderm Matrix in the treatment of patients with therapy-refractory chronic wounds. J Dtsch Dermatol Ges. 2012;10(6):412–20.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Ong CT, Zhang Y, Lim R, Samsonraj R, Masilamani J, Phan TH, et al. Preclinical evaluation of tegaderm supported nanofibrous wound matrix dressing on porcine wound healing model. Adv Wound Care (New Rochelle). 2015;4(2):110–8.CrossRefGoogle Scholar
  63. 63.
    Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen. 1999;7(4):201–7.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Edmonds M, European, Australian Apligraf Diabetic Foot Ulcer Study G. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds. 2009;8(1):11–8.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Zelen CM, Serena TE, Gould L, Le L, Carter MJ, Keller J, et al. Treatment of chronic diabetic lower extremity ulcers with advanced therapies: a prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost. Int Wound J. 2016;13(2):272–82.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Gentzkow GD, Iwasaki SD, Hershon KS, Mengel M, Prendergast JJ, Ricotta JJ, et al. Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care. 1996;19(4):350–4.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Omar AA, Mavor AI, Jones AM, Homer-Vanniasinkam S. Treatment of venous leg ulcers with dermagraft. Eur J Vasc Endovasc Surg. 2004;27(6):666–72.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Zelen CM, Gould L, Serena TE, Carter MJ, Keller J, Li WW. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J. 2015;12(6):724–32.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502–7.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Lee KY, Mooney DJ. Alginate: properties and biomedical applications. Prog Polym Sci. 2012;37(1):106–26.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Wong T, McGrath JA, Navsaria H. The role of fibroblasts in tissue engineering and regeneration. Br J Dermatol. 2007;156(6):1149–55.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Mansbridge JN, Liu K, Pinney RE, Patch R, Ratcliffe A, Naughton GK. Growth factors secreted by fibroblasts: role in healing diabetic foot ulcers. Diabetes Obes Metab. 1999;1(5):265–79.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Jackson WM, Nesti LJ, Tuan RS. Concise review: clinical translation of wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med. 2012;1(1):44–50.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007;13(6):1299–312.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Maharlooei MK, Bagheri M, Solhjou Z, Jahromi BM, Akrami M, Rohani L, et al. Adipose tissue derived mesenchymal stem cell (AD-MSC) promotes skin wound healing in diabetic rats. Diabetes Res Clin Pract. 2011;93(2):228–34.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Ojeh N, Pastar I, Tomic-Canic M, Stojadinovic O. Stem cells in skin regeneration, wound healing, and their clinical applications. Int J Mol Sci. 2015;16(10):25476–501.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Hachiya A, Sriwiriyanont P, Kaiho E, Kitahara T, Takema Y, Tsuboi R. An in vivo mouse model of human skin substitute containing spontaneously sorted melanocytes demonstrates physiological changes after UVB irradiation. J Invest Dermatol. 2005;125(2):364–72.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Liu Y, Luo H, Wang X, Takemura A, Fang YR, Jin Y, et al. In vitro construction of scaffold-free bilayered tissue-engineered skin containing capillary networks. Biomed Res Int. 2013;2013:561410.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Zhang X, Yang J, Li Y, Liu S, Long K, Zhao Q, et al. Functional neovascularization in tissue engineering with porcine acellular dermal matrix and human umbilical vein endothelial cells. Tissue Eng Part C Methods. 2011;17(4):423–33.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Marino D, Luginbuhl J, Scola S, Meuli M, Reichmann E. Bioengineering dermo-epidermal skin grafts with blood and lymphatic capillaries. Sci Transl Med. 2014;6(221):221ra14.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Huang S, Xu Y, Wu C, Sha D, Fu X. In vitro constitution and in vivo implantation of engineered skin constructs with sweat glands. Biomaterials. 2010;31(21):5520–5.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Hamdan S, Pastar I, Drakulich S, Dikici E, Tomic-Canic M, Deo S, et al. Nanotechnology-driven therapeutic interventions in wound healing: potential uses and applications. ACS Cent Sci. 2017;3(3):163–75.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Merrell JG, McLaughlin SW, Tie L, Laurencin CT, Chen AF, Nair LS. Curcumin-loaded poly(epsilon-caprolactone) nanofibres: diabetic wound dressing with anti-oxidant and anti-inflammatory properties. Clin Exp Pharmacol Physiol. 2009;36(12):1149–56.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Manjunatha K, Poojary B, Lobo PL, Fernandes J, Kumari NS. Synthesis and biological evaluation of some 1,3,4-oxadiazole derivatives. Eur J Med Chem. 2010;45(11):5225–33.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Li Y, Lee PI. Controlled nitric oxide delivery platform based on S-nitrosothiol conjugated interpolymer complexes for diabetic wound healing. Mol Pharm. 2010;7(1):254–66.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Masters KS, Leibovich SJ, Belem P, West JL, Poole-Warren LA. Effects of nitric oxide releasing poly(vinyl alcohol) hydrogel dressings on dermal wound healing in diabetic mice. Wound Repair Regen. 2002;10(5):286–94.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Sobotka L, Smahelova A, Pastorova J, Kusalova M. A case report of the treatment of diabetic foot ulcers using a sodium hyaluronate and iodine complex. Int J Low Extrem Wounds. 2007;6(3):143–7.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Shaw J, Hughes CM, Lagan KM, Stevenson MR, Irwin CR, Bell PM. The effect of topical phenytoin on healing in diabetic foot ulcers: a randomized controlled trial. Diabet Med. 2011;28(10):1154–7.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Xiao Y, Reis LA, Feric N, Knee EJ, Gu J, Cao S, Laschinger C, Londono C, Antolovich J, McGuigan AP, Radisic M. Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization. Proc Natl Acad Sci U S A. 2016;113(40):E5792–E801.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Damodaran G, Tiong WH, Collighan R, Griffin M, Navsaria H, Pandit A. In vivo effects of tailored laminin-332 alpha3 conjugated scaffolds enhances wound healing: a histomorphometric analysis. J Biomed Mater Res A. 2013;101(10):2788–95.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Masuda R, Mochizuki M, Hozumi K, Takeda A, Uchinuma E, Yamashina S, et al. A novel cell-adhesive scaffold material for delivering keratinocytes reduces granulation tissue in dermal wounds. Wound Repair Regen. 2009;17(1):127–35.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Halim AS, Khoo TL, Mohd Yussof SJ. Biologic and synthetic skin substitutes: an overview. Indian J Plast Surg. 2010;43(Suppl):S23–8.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Sethi KK, Yannas IV, Mudera V, Eastwood M, McFarland C, Brown RA. Evidence for sequential utilization of fibronectin, vitronectin, and collagen during fibroblast-mediated collagen contraction. Wound Repair Regen. 2002;10(6):397–408.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Clark RA, Lin F, Greiling D, An J, Couchman JR. Fibroblast invasive migration into fibronectin/fibrin gels requires a previously uncharacterized dermatan sulfate-CD44 proteoglycan. J Invest Dermatol. 2004;122(2):266–77.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Bielefeld KA, Amini-Nik S, Whetstone H, Poon R, Youn A, Wang J, et al. Fibronectin and beta-catenin act in a regulatory loop in dermal fibroblasts to modulate cutaneous healing. J Biol Chem. 2011;286(31):27687–97.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Han CM, Zhang LP, Sun JZ, Shi HF, Zhou J, Gao CY. Application of collagen-chitosan/fibrin glue asymmetric scaffolds in skin tissue engineering. J Zhejiang Univ Sci B. 2010;11(7):524–30.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Buchberger B, Follmann M, Freyer D, Huppertz H, Ehm A, Wasem J. The evidence for the use of growth factors and active skin substitutes for the treatment of non-infected diabetic foot ulcers (DFU): a health technology assessment (HTA). Exp Clin Endocrinol Diabetes. 2011;119(8):472–9.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Nicholas MN, Jeschke MG, Amini-Nik S. Methodologies in creating skin substitutes. Cell Mol Life Sci. 2016;73(18):3453–72.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Yamamoto A, Shimizu N, Kuroyanagi Y. Potential of wound dressing composed of hyaluronic acid containing epidermal growth factor to enhance cytokine production by fibroblasts. J Artif Organs. 2013;16(4):489–94.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Sun W, Lin H, Xie H, Chen B, Zhao W, Han Q, et al. Collagen membranes loaded with collagen-binding human PDGF-BB accelerate wound healing in a rabbit dermal ischemic ulcer model. Growth Factors. 2007;25(5):309–18.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Ulubayram K, Nur Cakar A, Korkusuz P, Ertan C, Hasirci N. EGF containing gelatin-based wound dressings. Biomaterials. 2001;22(11):1345–56.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Yang Y, Xia T, Zhi W, Wei L, Weng J, Zhang C, et al. Promotion of skin regeneration in diabetic rats by electrospun core-sheath fibers loaded with basic fibroblast growth factor. Biomaterials. 2011;32(18):4243–54.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Choi JS, Leong KW, Yoo HS. In vivo wound healing of diabetic ulcers using electrospun nanofibers immobilized with human epidermal growth factor (EGF). Biomaterials. 2008;29(5):587–96.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Kulkarni A, Diehl-Jones W, Ghanbar S, Liu S. Layer-by-layer assembly of epidermal growth factors on polyurethane films for wound closure. J Biomater Appl. 2014;29(2):278–90.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Lai HJ, Kuan CH, Wu HC, Tsai JC, Chen TM, Hsieh DJ, et al. Tailored design of electrospun composite nanofibers with staged release of multiple angiogenic growth factors for chronic wound healing. Acta Biomater. 2014;10(10):4156–66.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Akasaka Y, Ono I, Tominaga A, Ishikawa Y, Ito K, Suzuki T, et al. Basic fibroblast growth factor in an artificial dermis promotes apoptosis and inhibits expression of alpha-smooth muscle actin, leading to reduction of wound contraction. Wound Repair Regen. 2007;15(3):378–89.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Inoue S, Kijima H, Kidokoro M, Tanaka M, Suzuki Y, Motojuku M, et al. The effectiveness of basic fibroblast growth factor in fibrin-based cultured skin substitute in vivo. J Burn Care Res. 2009;30(3):514–9.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Tsuji-Saso Y, Kawazoe T, Morimoto N, Tabata Y, Taira T, Tomihata K, et al. Incorporation of basic fibroblast growth factor into preconfluent cultured skin substitute to accelerate neovascularisation and skin reconstruction after transplantation. Scand J Plast Reconstr Surg Hand Surg. 2007;41(5):228–35.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Kuroyanagi M, Yamamoto A, Shimizu N, Ishihara E, Ohno H, Takeda A, et al. Development of cultured dermal substitute composed of hyaluronic acid and collagen spongy sheet containing fibroblasts and epidermal growth factor. J Biomater Sci Polym Ed. 2014;25(11):1133–43.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Ferguson MW, O'Kane S. Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond Ser B Biol Sci. 2004;359(1445):839–50.CrossRefGoogle Scholar
  111. 111.
    Koria P, Yagi H, Kitagawa Y, Megeed Z, Nahmias Y, Sheridan R, et al. Self-assembling elastin-like peptides growth factor chimeric nanoparticles for the treatment of chronic wounds. Proc Natl Acad Sci U S A. 2011;108(3):1034–9.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Kwon MJ, An S, Choi S, Nam K, Jung HS, Yoon CS, et al. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Castleberry SA, Almquist BD, Li W, Reis T, Chow J, Mayner S, et al. Self-assembled wound dressings silence MMP-9 and improve diabetic wound healing in vivo. Adv Mater. 2016;28(9):1809–17.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Kim HS, Yoo HS. Matrix metalloproteinase-inspired suicidal treatments of diabetic ulcers with siRNA-decorated nanofibrous meshes. Gene Ther. 2013;20(4):378–85.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Breen AM, Dockery P, O'Brien T, Pandit AS. The use of therapeutic gene eNOS delivered via a fibrin scaffold enhances wound healing in a compromised wound model. Biomaterials. 2008;29(21):3143–51.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Gu DL, Nguyen T, Gonzalez AM, Printz MA, Pierce GF, Sosnowski BA, et al. Adenovirus encoding human platelet-derived growth factor-B delivered in collagen exhibits safety, biodistribution, and immunogenicity profiles favorable for clinical use. Mol Ther. 2004;9(5):699–711.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Choi JS, Kim HS, Yoo HS. Electrospinning strategies of drug-incorporated nanofibrous mats for wound recovery. Drug Deliv Transl Res. 2015;5(2):137–45.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Cam C, Segura T. Matrix-based gene delivery for tissue repair. Curr Opin Biotechnol. 2013;24(5):855–63.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Chandler LA, Gu DL, Ma C, Gonzalez AM, Doukas J, Nguyen T, et al. Matrix-enabled gene transfer for cutaneous wound repair. Wound Repair Regen. 2000;8(6):473–9.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Tellechea A, Silva EA, Min J, Leal EC, Auster ME, Pradhan-Nabzdyk L, et al. Alginate and DNA gels are suitable delivery systems for diabetic wound healing. Int J Low Extrem Wounds. 2015;14(2):146–53.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Guo DD, Hong SH, Jiang HL, Kim JH, Minai-Tehrani A, Kim JE, et al. Synergistic effects of Akt1 shRNA and paclitaxel-incorporated conjugated linoleic acid-coupled poloxamer thermosensitive hydrogel on breast cancer. Biomaterials. 2012;33(7):2272–81.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Molan, P. Honey based wound dressings. USRE42755E1, United States Patent and Trademark Office, December 9, 1999.
  123. 123.
    Inpanya P, Faikrua A, Ounaroon A, Sittichokechaiwut A, Viyoch J. Effects of the blended fibroin/aloe gel film on wound healing in streptozotocin-induced diabetic rats. Biomed Mater. 2012;7(3):035008.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Pereira R, Carvalho A, Vaz DC, Gil MH, Mendes A, Bartolo P. Development of novel alginate based hydrogel films for wound healing applications. Int J Biol Macromol. 2013;52:221–30.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Catanzano O, Straccia MC, Miro A, Ungaro F, Romano I, Mazzarella G, et al. Spray-by-spray in situ cross-linking alginate hydrogels delivering a tea tree oil microemulsion. Eur J Pharm Sci. 2015;66:20–8.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Altiok D, Altiok E, Tihminlioglu F. Physical, antibacterial and antioxidant properties of chitosan films incorporated with thyme oil for potential wound healing applications. J Mater Sci Mater Med. 2010;21(7):2227–36.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Muthukumar T, Prabu P, Ghosh K, Sastry TP. Fish scale collagen sponge incorporated with Macrotyloma uniflorum plant extract as a possible wound/burn dressing material. Colloids Surf B Biointerfaces. 2014;113:207–12.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Turner CT, McInnes SJ, Melville E, Cowin AJ, Voelcker NH. Delivery of Flightless I neutralizing antibody from porous silicon nanoparticles improves wound healing in diabetic mice. Adv Healthc Mater. 2017;6:2).Google Scholar
  129. 129.
    Randeria PS, Seeger MA, Wang XQ, Wilson H, Shipp D, Mirkin CA, et al. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    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
  131. 131.
    Das S, Singh G, Majid M, Sherman MB, Mukhopadhyay S, Wright CS, et al. Syndesome therapeutics for enhancing diabetic wound healing. Adv Healthc Mater. 2016;5(17):2248–60.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Wilgus TA. Immune cells in the healing skin wound: influential players at each stage of repair. Pharmacol Res. 2008;58(2):112–6.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Ting C, Bansal V, Batal I, Mounayar M, Chabtini L, El Akiki G, et al. Impairment of immune systems in diabetes. Adv Exp Med Biol. 2012;771:62–75.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Ahmed AS, Antonsen EL. Immune and vascular dysfunction in diabetic wound healing. J Wound Care. 2016;25(Suppl 7):S35–46.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Paulson School of Engineering and Applied SciencesHarvard UniversityCambridgeUSA
  2. 2.Wyss Institute for Biologically Inspired EngineeringHarvard UniversityBostonUSA

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