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The Diabetic Foot pp 155–172Cite as

Dermal Regeneration and Induction of Wound Closure in Diabetic Wounds

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Part of the book series: Contemporary Diabetes ((CDI))

Abstract

This chapter reviews the biological and mechanical role of the extracellular matrix (ECM) in cutaneous wound healing. The multiplicity of viewpoints expressed in the literature, the lack of standards in evaluating research and surgical outcomes, and poor data quality have made our analysis challenging. We attempt to deliver a clear, objective analysis given these constraints. We highlight how chronic wounds impair the architecture of the ECM leading to a loss of structural and biochemical cues and halt healing. We also discuss how ECM scaffolds can be used therapeutically to repair or temporarily replace lost ECM, triggering healing, tissue regeneration, and ultimately effective wound closure. We further analyze biological characteristics, design principles, scientific evidence, and future challenges in the use of ECM scaffolds to treat chronic (diabetic) wounds. In particular, we debate the difference between bioactive ECM scaffolds that possess a regenerative capacity as stand-alone product and do not require pre-application (or simultaneous applications) of cells, and biological matrices designed as delivery methods of cells and growth factors. We discuss the elements of an “induced regeneration” theory that is organ nonspecific. Finally, we review the process behind the conception and development of a specific example of successful ECM scaffolds currently used for the treatment of diabetic chronic wounds.

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References

  1. Zielins ER, Atashroo DA, Maan ZN, Duscher D, Walmsley GG, Hu M, Senarath-Yapa K, McArdle A, Tevlin R, Wearda T, Paik KJ, Duldulao C, Hong WX, Gurtner GC, Longaker MT. Wound healing: an update. Regen Med. 2014;9(6):817–30.

    CAS  PubMed  Google Scholar 

  2. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21.

    CAS  PubMed  Google Scholar 

  3. Rittié L. Cellular mechanisms of skin repair in humans and other mammals. J Cell Commun Signal. 2016;10(2):103–20.

    PubMed  PubMed Central  Google Scholar 

  4. Leavitt T, Hu MS, Marshall CD, Barnes LA, Lorenz HP, Longaker MT. Scarless wound healing: finding the right cells and signals. Cell Tissue Res. 2016;365(3):483–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Stappenbeck TS, Miyoshi H. The role of stromal stem cells in tissue regeneration and wound repair. Science. 2009;324(5935):1666–9.

    CAS  PubMed  Google Scholar 

  6. Tracy LE, Minasian RA, Caterson EJ. Extracellular matrix and dermal fibroblast function in the healing wound. Adv Wound Care (New Rochelle). 2016;5(3):119–36.

    Google Scholar 

  7. Maquart FX, Monboisse JC. Extracellular matrix and wound healing. Pathol Biol (Paris). 2014;62(2):91–5.

    CAS  Google Scholar 

  8. Pellowe AS, Gonzalez AL. Extracellular matrix biomimicry for the creation of investigational and therapeutic devices. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2016;8(1):5–22.

    CAS  PubMed  Google Scholar 

  9. Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle). 2015;4(3):119–36.

    Google Scholar 

  10. Godwin J, Kuraitis D, Rosenthal N. Extracellular matrix considerations for scar-free repair and regeneration: insights from regenerative diversity among vertebrates. Int J Biochem Cell Biol. 2014;56:47–55.

    CAS  PubMed  Google Scholar 

  11. Zgheib C, Xu J, Liechty KW. Targeting inflammatory cytokines and extracellular matrix composition to promote wound regeneration. Adv Wound Care (New Rochelle). 2014;3(4):344–55.

    Google Scholar 

  12. Volk SW, Iqbal SA, Bayat A. Interactions of the extracellular matrix and progenitor cells in cutaneous wound healing. Adv Wound Care (New Rochelle). 2013;2(6):261–72.

    Google Scholar 

  13. Wilgus TA. Growth factor-extracellular matrix interactions regulate wound repair. Adv Wound Care (New Rochelle). 2012;1(6):249–54.

    PubMed Central  Google Scholar 

  14. Schultz GS, Wysocki A. Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen. 2009;17(2):153–62.

    PubMed  Google Scholar 

  15. Ghatak S, Maytin EV, Mack JA, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Misra S. Roles of proteoglycans and glycosaminoglycans in wound healing and fibrosis. Int J Cell Biol. 2015;2015:834893.

    PubMed  PubMed Central  Google Scholar 

  16. Kirn-Safran C, Farach-Carson MC, Carson DD. Multifunctionality of extracellular and cell surface heparan sulfate proteoglycans. Cell Mol Life Sci. 2009;66(21):3421–34.

    CAS  PubMed  Google Scholar 

  17. Olczyk P, Mencner Ł, Komosinska-Vassev K. Diverse roles of heparan sulfate and heparin in wound repair. Biomed Res Int. 2015;2015:549417.

    PubMed  PubMed Central  Google Scholar 

  18. Coelho NM, McCulloch CA. Contribution of collagen adhesion receptors to tissue fibrosis. Cell Tissue Res. 2016;365(3):521–38.

    CAS  PubMed  Google Scholar 

  19. Law JX, Musa F, Ruszymah BH, El Haj AJ, Yang Y. A comparative study of skin cell activities in collagen and fibrin constructs. Med Eng Phys. 2016;38(9):854–61.

    PubMed  Google Scholar 

  20. Theocharidis G, Drymoussi Z, Kao AP, Barber AH, Lee DA, Braun KM, Connelly JT. Type VI collagen regulates dermal matrix assembly and fibroblast motility. J Invest Dermatol. 2016;136(1):74–83.

    CAS  PubMed  Google Scholar 

  21. Egbert M, Ruetze M, Sattler M, Wenck H, Gallinat S, Lucius R, Weise JM. The matricellular protein periostin contributes to proper collagen function and is downregulated during skin aging. J Dermatol Sci. 2014;73(1):40–8.

    CAS  PubMed  Google Scholar 

  22. Volk SW, Wang Y, Mauldin EA, Liechty KW, Adams SL. Diminished type III collagen promotes myofibroblast differentiation and increases scar deposition in cutaneous wound healing. Cells Tissues Organs. 2011;194(1):25–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Iorio V, Troughton LD, Hamill KJ. Laminins: roles and utility in wound repair. Adv Wound Care (New Rochelle). 2015;4(4):250–63.

    Google Scholar 

  24. Sawicka KM, Seeliger M, Musaev T, Macri LK, Clark RA. Fibronectin interaction and enhancement of growth factors: importance for wound healing. Adv Wound Care (New Rochelle). 2015;4(8):469–78.

    Google Scholar 

  25. Neuman MG, Nanau RM, Oruña-Sanchez L, Coto G. Hyaluronic acid and wound healing. J Pharm Pharm Sci. 2015;18(1):53–60.

    CAS  PubMed  Google Scholar 

  26. Aya KL, Stern R. Hyaluronan in wound healing: rediscovering a major player. Wound Repair Regen. 2014;22(5):579–93.

    PubMed  Google Scholar 

  27. McCarty SM, Percival SL. Proteases and delayed wound healing. Adv Wound Care (New Rochelle). 2013;2(8):438–47.

    Google Scholar 

  28. Jones EM, Cochrane CA, Percival SL. The effect of pH on the extracellular matrix and biofilms. Adv Wound Care (New Rochelle). 2015;4(7):431–9.

    Google Scholar 

  29. McCarty SM, Cochrane CA, Clegg PD, Percival SL. The role of endogenous and exogenous enzymes in chronic wounds: a focus on the implications of aberrant levels of both host and bacterial proteases in wound healing. Wound Repair Regen. 2012;20(2):125–36.

    PubMed  Google Scholar 

  30. Agren MS, Werthén M. The extracellular matrix in wound healing: a closer look at therapeutics for chronic wounds. Int J Low Extrem Wounds. 2007;6(2):82–97.

    PubMed  Google Scholar 

  31. Xue M, Le NT, Jackson CJ. Targeting matrix metalloproteases to improve cutaneous wound healing. Expert Opin Ther Targets. 2006;10(1):143–55.

    CAS  PubMed  Google Scholar 

  32. Moseley R, Stewart JE, Stephens P, Waddington RJ, Thomas DW. Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: lessons learned from other inflammatory diseases? Br J Dermatol. 2004;150(3):401–13.

    CAS  PubMed  Google Scholar 

  33. Ravanti L, Kähäri VM. Matrix metalloproteinases in wound repair (review). Int J Mol Med. 2000;6(4):391–407.

    CAS  PubMed  Google Scholar 

  34. Wells A, Nuschke A, Yates CC. Skin tissue repair: matrix microenvironmental influences. Matrix Biol. 2016;49:25–36.

    CAS  PubMed  Google Scholar 

  35. Arya AK, Tripathi R, Kumar S, Tripathi K. Recent advances on the association of apoptosis in chronic non healing diabetic wound. World J Diabetes. 2014;5(6):756–62.

    PubMed  PubMed Central  Google Scholar 

  36. Baltzis D, Eleftheriadou I, Veves A. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv Ther. 2014;31(8):817–36.

    CAS  PubMed  Google Scholar 

  37. Jhamb S, Vangaveti VN, Malabu UH. Genetic and molecular basis of diabetic foot ulcers: Clinical review. J Tissue Viability. 2016;25(4):229–36.

    PubMed  Google Scholar 

  38. Lioupis C. Effects of diabetes mellitus on wound healing: an update. J Wound Care. 2005;14(2):84–6.

    CAS  PubMed  Google Scholar 

  39. Xu F, Zhang C, Graves DT. Abnormal cell responses and role of TNF-α in impaired diabetic wound healing. Biomed Res Int. 2013;2013:754802.

    PubMed  PubMed Central  Google Scholar 

  40. Ayuk SM, Abrahamse H, Houreld NN. The role of matrix metalloproteinases in diabetic wound healing in relation to photobiomodulation. J Diabetes Res. 2016;2016:2897656.

    PubMed  PubMed Central  Google Scholar 

  41. Tsioufis C, Bafakis I, Kasiakogias A, Stefanadis C. The role of matrix metalloproteinases in diabetes mellitus. Curr Top Med Chem. 2012;12(10):1159–65.

    CAS  PubMed  Google Scholar 

  42. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–43.

    PubMed  Google Scholar 

  43. Turner NJ, Badylak SF. The use of biologic scaffolds in the treatment of chronic nonhealing wounds. Adv Wound Care (New Rochelle). 2015;4(8):490–500.

    Google Scholar 

  44. Chaudhary C, Garg T. Scaffolds: a novel carrier and potential wound healer. Crit Rev Ther Drug Carrier Syst. 2015;32(4):277–321.

    PubMed  Google Scholar 

  45. Nicholas MN, Jeschke MG, Amini-Nik S. Methodologies in creating skin substitutes. Cell Mol Life Sci. 2016;73(18):3453–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Widgerow AD. Bioengineered skin substitute considerations in the diabetic foot ulcer. Ann Plast Surg. 2014;73(2):239–44.

    CAS  PubMed  Google Scholar 

  47. Greaves NS, Iqbal SA, Baguneid M, Bayat A. The role of skin substitutes in the management of chronic cutaneous wounds. Wound Repair Regen. 2013;21(2):194–210.

    PubMed  Google Scholar 

  48. Yildirimer L, Thanh NT, Seifalian AM. Skin regeneration scaffolds: a multimodal bottom-up approach. Trends Biotechnol. 2012;30(12):638–48.

    CAS  PubMed  Google Scholar 

  49. Poinern GE, Fawcett D, Ng YJ, Ali N, Brundavanam RK, Jiang ZT. Nanoengineering a biocompatible inorganic scaffold for skin wound healing. J Biomed Nanotechnol. 2010;6(5):497–510.

    CAS  PubMed  Google Scholar 

  50. Langer A, Rogowski W. Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Serv Res. 2009;9:115.

    PubMed  PubMed Central  Google Scholar 

  51. Fang RC, Galiano RD. A review of becaplermin gel in the treatment of diabetic neuropathic foot ulcers. Biologics. 2008;2(1):1–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhong SP, Zhang YZ, Lim CT. Tissue scaffolds for skin wound healing and dermal reconstruction. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2(5):510–25.

    CAS  PubMed  Google Scholar 

  53. Yannas IV, Tzeranis DS, Harley BA, So PT. Biologically active collagen-based scaffolds: advances in processing and characterization. Philos Trans A Math Phys Eng Sci. 2010;368(1917):2123–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Badylak SF. The extracellular matrix as a scaffold for tissue reconstruction. Semin Cell Dev Biol. 2002;13(5):377–83.

    CAS  PubMed  Google Scholar 

  55. Bello YM, Falabella AF, Eaglstein WH. Tissue-engineered skin. Current status in wound healing. Am J Clin Dermatol. 2001;2(5):305–13.

    CAS  PubMed  Google Scholar 

  56. Yannas IV. Tissue and organ regeneration in adults. 2nd ed. New York: Springer; 2015.

    Google Scholar 

  57. Yannas IV. Tissue and organ regeneration in adults. New York: Springer; 2001.

    Google Scholar 

  58. Butler CE, Orgill DP. Simultaneous in vivo regeneration of neodermis, epidermis, and basement membrane. Adv Biochem Eng Biotechnol. 2005;94:23–41.

    PubMed  Google Scholar 

  59. Hatton MP, Rubin PA. Conjunctival regeneration. Adv Biochem Eng Biotechnol. 2005;94:125–40.

    PubMed  Google Scholar 

  60. Zhang M, Yannas IV. Peripheral nerve regeneration. Adv Biochem Eng Biotechnol. 2005;94:67–89.

    PubMed  Google Scholar 

  61. Soller EC, Tzeranis DS, Miu K, So PT, Yannas IV. Common features of optimal collagen scaffolds that disrupt wound contraction and enhance regeneration both in peripheral nerves and in skin. Biomaterials. 2012;33(19):4783–91.

    CAS  PubMed  Google Scholar 

  62. Yannas IV, Tzeranis D, So PT. Surface biology of collagen scaffold explains blocking of wound contraction and regeneration of skin and peripheral nerves. Biomed Mater. 2015;11(1):014106.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Tzeranis DS, Soller EC, Buydash MC, So PT, Yannas IV. In situ quantification of surface chemistry in porous collagen biomaterials. Ann Biomed Eng. 2016;44(3):803–15.

    PubMed  Google Scholar 

  64. Yannas IV, Lee E, Orgill DP, Skrabut EM, Murphy GF. Synthesis and characterization of a model extracellular matrix which induces partial regeneration of adult mammalian skin. Proc Natl Acad Sci U S A. 1989;86:933–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Yannas IV. Emerging rules for inducing organ regeneration. Biomaterials. 2013;34(2):321–30.

    CAS  PubMed  Google Scholar 

  66. Golas AR, Hernandez KA, Spector JA. Tissue engineering for plastic surgeons: a primer. Aesthetic Plast Surg. 2014;38(1):207–21.

    PubMed  Google Scholar 

  67. Nyame TT, Chiang HA, Leavitt T, Ozambela M, Orgill DP. Tissue-engineered skin substitutes. Plast Reconstr Surg. 2015;136(6):1379–88.

    CAS  PubMed  Google Scholar 

  68. Brantley JN, Verla TD. Use of placental membranes for the treatment of chronic diabetic foot ulcers. Adv Wound Care (New Rochelle). 2015;4(9):545–59.

    Google Scholar 

  69. Litwiniuk M, Grzela T. Amniotic membrane: new concepts for an old dressing. Wound Repair Regen. 2014;22(4):451–6.

    PubMed  Google Scholar 

  70. Silini AR, Cargnoni A, Magatti M, Pianta S, Parolini O. The long path of human placenta, and its derivatives, in regenerative medicine. Front Bioeng Biotechnol. 2015;3:162.

    PubMed  PubMed Central  Google Scholar 

  71. Peters WJ. Biological dressings in burns--a review. Ann Plast Surg. 1980;4(2):133–7.

    CAS  PubMed  Google Scholar 

  72. Iorio ML, Shuck J, Attinger CE. Wound healing in the upper and lower extremities: a systematic review on the use of acellular dermal matrices. Plast Reconstr Surg. 2012;130(5 Suppl 2):232S–41S.

    CAS  PubMed  Google Scholar 

  73. Yannas IV, Orgill DP, Burke JF. Template for skin regeneration. Plast Reconstr Surg. 2011;127(Suppl 1):60S–70S.

    CAS  PubMed  Google Scholar 

  74. Garfein ES, Orgill DP, Pribaz JJ. Clinical applications of tissue engineered constructs. Clin Plast Surg. 2003;30(4):485–98.

    PubMed  Google Scholar 

  75. Nyame TT, Chiang HA, Orgill DP. Clinical applications of skin substitutes. Surg Clin North Am. 2014;94(4):839–50.

    PubMed  Google Scholar 

  76. Heimbach DM, Warden GD, Luterman A, Jordan MH, Ozobia N, Ryan CM, Voigt DW, Hickerson WL, Saffle JR, DeClement FA, Sheridan RL, Dimick AR. Multicenter postapproval clinical trial of Integra dermal regeneration template for burn treatment. J Burn Care Rehabil. 2003;24(1):42–8.

    PubMed  Google Scholar 

  77. Yannas IV, Burke JF, Orgill DP, Skrabut EM. Wound tissue can utilize a polymeric template to synthesise a functional extension of skin. Science. 1982;215:174–6.

    CAS  PubMed  Google Scholar 

  78. Yannas IV, Burke JF, Orgill DP, Skrabut EM. Regeneration of skin following closure of deep wounds with a biodegradable template. Trans Soc Biomater. 1982;5:24–7.

    Google Scholar 

  79. Yannas IV, Orgill DP, Skrabut EM, Burke JF. Skin regeneration with a bioreplaceable polymeric template. In: Gebelein CG, editor. Polymeric materials and artificial organs. Washington, DC: American Chemical Society; 1984. p. 191–7.

    Google Scholar 

  80. Burke JF, Yannas IV, Quniby WC Jr, Bondoc CC, Jung WK. Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg. 1981;194:413–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Gottlieb ME. 127 in situ tissue engineering with Integra®-a new paradigm of surgical wound repair. Wound Repair Regen. 2005;13:A28–48.

    Google Scholar 

  82. Driver VR, Lavery LA, Reyzelman AM, Dutra TG, Dove CR, Kotsis SV, Kim HM, Chung KC. A clinical trial of Integra template for diabetic foot ulcer treatment. Wound Repair Regen. 2015;23(6):891–900.

    PubMed  Google Scholar 

  83. Spector JA, Glat PM. Hair-bearing scalp reconstruction using a dermal regeneration template and micrograft hair transplantation. Ann Plast Surg. 2007;59(1):63–6.

    CAS  PubMed  Google Scholar 

  84. Shores JT, Hiersche M, Gabriel A, Gupta S. Tendon coverage using an artificial skin substitute. J Plast Reconstr Aesthet Surg. 2012;65(11):1544–50.

    PubMed  Google Scholar 

  85. Davison SP, Sobanko JF, Clemens MW. Use of a collagen-glycosaminoglycan copolymer (Integra) in combination with adjuvant treatments for reconstruction of severe chest keloids. J Drugs Dermatol. 2010;9(5):542–8.

    PubMed  Google Scholar 

  86. Stiefel D, Schiestl C, Meuli M. Integra artificial skin for burn scar revision in adolescents and children. Burns. 2010;36(1):114–20.

    PubMed  Google Scholar 

  87. González Alaña I, Torrero López JV, Martín Playá P, Gabilondo Zubizarreta FJ. Combined use of negative pressure wound therapy and Integra® to treat complex defects in lower extremities after burns. Ann Burns Fire Disasters. 2013;26(2):90–3.

    PubMed  PubMed Central  Google Scholar 

  88. Menn ZK, Lee E, Klebuc MJ. Acellular dermal matrix and negative pressure wound therapy: a tissue-engineered alternative to free tissue transfer in the compromised host. J Reconstr Microsurg. 2012;28(2):139–44.

    PubMed  Google Scholar 

  89. Molnar JA, DeFranzo AJ, Hadaegh A, Morykwas MJ, Shen P, Argenta LC. Acceleration of Integra incorporation in complex tissue defects with subatmospheric pressure. Plast Reconstr Surg. 2004;113(5):1339–46.

    PubMed  Google Scholar 

  90. Climov M, Bayer LR, Moscoso AV, Matsumine H, Orgill DP. The role of dermal matrices in treating inflammatory and diabetic wounds. Plast Reconstr Surg. 2016;138(3 Suppl):148S–57S.

    CAS  PubMed  Google Scholar 

  91. Min JH, Yun IS, Lew DH, Roh TS, Lee WJ. The use of matriderm and autologous skin graft in the treatment of full thickness skin defects. Arch Plast Surg. 2014;41(4):330–6.

    PubMed  PubMed Central  Google Scholar 

  92. Bertolli E, Campagnari M, Molina AS, Macedo MP, Pinto CA, Cunha IW, Duprat Neto JP. Artificial dermis (Matriderm®) followed by skin graft as an option in dermatofibrosarcoma protuberans with complete circumferential and peripheral deep margin assessment. Int Wound J. 2015;12(5):545–7.

    PubMed  Google Scholar 

  93. De Angelis B, Gentile P, Agovino A, Migner A, Orlandi F, Delogu P, Cervelli V. Chronic ulcers: MATRIDERM(®) system in smoker, cardiopathic, and diabetic patients. J Tissue Eng. 2013;4:2041731413502663.

    PubMed  PubMed Central  Google Scholar 

  94. Böttcher-Haberzeth S, Biedermann T, Schiestl C, Hartmann-Fritsch F, Schneider J, Reichmann E, Meuli M. Matriderm® 1 mm versus Integra® Single Layer 1.3 mm for one-step closure of full thickness skin defects: a comparative experimental study in rats. Pediatr Surg Int. 2012;28(2):171–7.

    PubMed  Google Scholar 

  95. Schneider J, Biedermann T, Widmer D, Montano I, Meuli M, Reichmann E, Schiestl C. Matriderm versus Integra: a comparative experimental study. Burns. 2009;35(1):51–7.

    PubMed  Google Scholar 

  96. Harish V, Raymond AP, Maitz PK. Reconstruction of soft tissue necrosis secondary to cryoglobulinaemia. J Plast Reconstr Aesthet Surg. 2014;67(8):1151–4.

    PubMed  Google Scholar 

  97. Wosgrau AC, Jeremias Tda S, Leonardi DF, Pereima MJ, Di Giunta G, Trentin AG. Comparative experimental study of wound healing in mice: pelnac versus integra. PLoS One. 2015;10(3):e0120322.

    PubMed  PubMed Central  Google Scholar 

  98. Jeremias Tda S, Machado RG, Visoni SB, Pereima MJ, Leonardi DF, Trentin AG. Dermal substitutes support the growth of human skin-derived mesenchymal stromal cells: potential tool for skin regeneration. PLoS One. 2014;9(2):e89542.

    PubMed  Google Scholar 

  99. Eo S, Kim Y, Cho S. Vacuum-assisted closure improves the incorporation of artificial dermis in soft tissue defects: Terudermis(®) and Pelnac(®). Int Wound J. 2011;8(3):261–7.

    PubMed  PubMed Central  Google Scholar 

  100. Lee JW, Jang YC, Oh SJ. Use of the artificial dermis for free radial forearm flap donor site. Ann Plast Surg. 2005;55(5):500–2.

    CAS  PubMed  Google Scholar 

  101. Matsumoto Y, Ikeda K, Yamaya Y, Yamashita K, Saito T, Hoshino Y, Koga T, Enari H, Suto S, Yotsuyanagi T. The usefulness of the collagen and elastin sponge derived from salmon as an artificial dermis and scaffold for tissue engineering. Biomed Res. 2011;32(1):29–36.

    CAS  PubMed  Google Scholar 

  102. Tanihara M, Kajiwara K, Ida K, Suzuki Y, Kamitakahara M, Ogata S. The biodegradability of poly(Pro-Hyp-Gly) synthetic polypeptide and the promotion of a dermal wound epithelialization using a poly(Pro-Hyp-Gly) sponge. J Biomed Mater Res A. 2008;85((1):133–9.

    Google Scholar 

  103. Brigido SA, Boc SF, Lopez RC. Effective management of major lower extremity wounds using an acellular regenerative tissue matrix: a pilot study. Orthopedics. 2004;27(1 Suppl):s145–9.

    PubMed  Google Scholar 

  104. Martin BR, Sangalang M, Wu S, Armstrong DG. Outcomes of allogenic acellular matrix therapy in treatment of diabetic foot wounds: an initial experience. Int Wound J. 2005;2(2):161–5.

    PubMed  PubMed Central  Google Scholar 

  105. Brigido SA. The use of an acellular dermal regenerative tissue matrix in the treatment of lower extremity wounds: a prospective 16-week pilot study. Int Wound J. 2006;3(3):181–7.

    PubMed  PubMed Central  Google Scholar 

  106. Winters CL, Brigido SA, Liden BA, Simmons M, Hartman JF, Wright ML. A multicenter study involving the use of a human acellular dermal regenerative tissue matrix for the treatment of diabetic lower extremity wounds. Adv Skin Wound Care. 2008;21(8):375–81.

    PubMed  Google Scholar 

  107. 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.

    PubMed  PubMed Central  Google Scholar 

  108. Wainwright DJ, Bury SB. Acellular dermal matrix in the management of the burn patient. Aesthet Surg J. 2011;31(7 Suppl):13S–23S.

    PubMed  Google Scholar 

  109. Jung SN, Chung JW, Yim YM, Kwon H. One-stage skin grafting of the exposed skull with acellular human dermis (AlloDerm). J Craniofac Surg. 2008;19(6):1660–2.

    PubMed  Google Scholar 

  110. Deneve JL, Turaga KK, Marzban SS, Puleo CA, Sarnaik AA, Gonzalez RJ, Sondak VK, Zager JS. Single-institution outcome experience using AlloDerm® as temporary coverage or definitive reconstruction for cutaneous and soft tissue malignancy defects. Am Surg. 2013;79(5):476–82.

    PubMed  PubMed Central  Google Scholar 

  111. Carlson TL, Lee KW, Pierce LM. Effect of cross-linked and non-cross-linked acellular dermal matrices on the expression of mediators involved in wound healing and matrix remodeling. Plast Reconstr Surg. 2013;131(4):697–705.

    CAS  PubMed  Google Scholar 

  112. Askari M, Cohen MJ, Grossman PH, Kulber DA. The use of acellular dermal matrix in release of burn contracture scars in the hand. Plast Reconstr Surg. 2011;127(4):1593–9.

    CAS  PubMed  Google Scholar 

  113. Oh SJ, Kim Y. Combined AlloDerm® and thin skin grafting for the treatment of postburn dyspigmented scar contracture of the upper extremity. J Plast Reconstr Aesthet Surg. 2011;64(2):229–33.

    PubMed  Google Scholar 

  114. Maloney BP, Murphy BA, Cole HP 3rd. Cymetra. Facial Plast Surg. 2004;20(2):129–34.

    PubMed  Google Scholar 

  115. Karr JC. Retrospective comparison of diabetic foot ulcer and venous stasis ulcer healing outcome between a dermal repair scaffold (PriMatrix) and a bilayered living cell therapy (Apligraf). Adv Skin Wound Care. 2011;24(3):119–25.

    PubMed  Google Scholar 

  116. Kavros SJ, Dutra T, Gonzalez-Cruz R, Liden B, Marcus B, McGuire J, Nazario-Guirau L. The use of PriMatrix, a fetal bovine acellular dermal matrix, in healing chronic diabetic foot ulcers: a prospective multicenter study. Adv Skin Wound Care. 2014;27(8):356–62.

    PubMed  Google Scholar 

  117. Lullove E. Acellular fetal bovine dermal matrix in the treatment of nonhealing wounds in patients with complex comorbidities. J Am Podiatr Med Assoc. 2012;102(3):233–9.

    PubMed  Google Scholar 

  118. Rennert RC, Sorkin M, Garg RK, Januszyk M, Gurtner GC. Cellular response to a novel fetal acellular collagen matrix: implications for tissue regeneration. Int J Biomater. 2013;2013:527957.

    PubMed  PubMed Central  Google Scholar 

  119. Troy J, Karlnoski R, Downes K, Brown KS, Cruse CW, Smith DJ, Payne WG. The use of EZ Derm® in partial-thickness burns: an institutional review of 157 patients. Eplasty. 2013;13:e14.

    PubMed  PubMed Central  Google Scholar 

  120. Esteban-Vives R, Young MT, Ziembicki J, Corcos A, Gerlach JC. Effects of wound dressings on cultured primary keratinocytes. Burns. 2016;42(1):81–90.

    PubMed  Google Scholar 

  121. Burkey B, Davis W 3rd, Glat PM. Porcine xenograft treatment of superficial partial-thickness burns in paediatric patients. J Wound Care. 2016;25(2):S10–5.

    CAS  PubMed  Google Scholar 

  122. El-Khatib HA, Hammouda A, Al-Ghol A, Habib B. Al-Basti. Aldehyde-treated porcine skin versus biobrane as biosynthetic skin substitutes for excised burn wounds: case series and review of the literature. Ann Burns Fire Disasters. 2007;20(2):78–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Mostow EN, Haraway GD, Dalsing M, Hodde JP, King D, OASIS Venus Ulcer Study Group. 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.

    PubMed  Google Scholar 

  124. Cazzell SM, Lange DL, Dickerson JE Jr, Slade HB. The management of diabetic foot ulcers with porcine small intestine submucosa tri-layer matrix: a randomized controlled trial. Adv Wound Care (New Rochelle). 2015;4(12):711–8.

    Google Scholar 

  125. Shi L, Ronfard V. Biochemical and biomechanical characterization of porcine small intestinal submucosa (SIS): a mini review. Int J Burns Trauma. 2013;3(4):173–9.

    PubMed  PubMed Central  Google Scholar 

  126. Kim MS, Hong KD, Shin HW, Kim SH, Kim SH, Lee MS, Jang WY, Khang G, Lee HB. Preparation of porcine small intestinal submucosa sponge and their application as a wound dressing in full-thickness skin defect of rat. Int J Biol Macromol. 2005;36(1–2):54–60.

    CAS  PubMed  Google Scholar 

  127. Parmaksiz M, Elcin AE, Elcin YM. Decellularization of bovine small intestinal submucosa and its use for the healing of a critical-sized full-thickness skin defect, alone and in combination with stem cells, in a small rodent model. J Tissue Eng Regen Med. 2017;11(6):1754–65.

    CAS  PubMed  Google Scholar 

  128. Salgado RM, Bravo L, García M, Melchor JM, Krötzsch E. Histomorphometric analysis of early epithelialization and dermal changes in mid-partial-thickness burn wounds in humans treated with porcine small intestinal submucosa and silver-containing hydrofiber. J Burn Care Res. 2014;35(5):e330–7.

    PubMed  Google Scholar 

  129. Luo X, Kulig KM, Finkelstein EB, Nicholson MF, Liu XH, Goldman SM, Vacanti JP, Grottkau BE, Pomerantseva I, Sundback CA, Neville CM. In vitro evaluation of decellularized ECM-derived surgical scaffold biomaterials. J Biomed Mater Res B Appl Biomater. 2017;105(3):585–93.

    CAS  PubMed  Google Scholar 

  130. Rong JJ, Sang HF, Qian AM, Meng QY, Zhao TJ, Li XQ. Biocompatibility of porcine small intestinal submucosa and rat endothelial progenitor cells in vitro. Int J Clin Exp Pathol. 2015;8(2):1282–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Rosales MA, Bruntz M, Armstrong DG. Gamma-irradiated human skin allograft: a potential treatment modality for lower extremity ulcers. Int Wound J. 2004;1(3):201–6.

    PubMed  PubMed Central  Google Scholar 

  132. Cancio LC, Horvath EE, Barillo DJ, Kopchinski BJ, Charter KR, Montalvo AE, Buescher TM, Brengman ML, Brandt MM, Holcomb JB. Burn support for Operation Iraqi Freedom and related operations, 2003 to 2004. J Burn Care Rehabil. 2005;26(2):151–61.

    PubMed  Google Scholar 

  133. http://pl-s.com/WhatisGammaGraft.html.

  134. Kimmel H, Rahn M, Gilbert TW. The clinical effectiveness in wound healing with extracellular matrix derived from porcine urinary bladder matrix: a case series on severe chronic wounds. J Am Col Certif Wound Spec. 2010;2(3):55–9.

    PubMed  PubMed Central  Google Scholar 

  135. Rommer EA, Peric M, Wong A. Urinary bladder matrix for the treatment of recalcitrant nonhealing radiation wounds. Adv Skin Wound Care. 2013;26(10):450–5.

    PubMed  Google Scholar 

  136. Iorio T, Blumberg D. Short-term results of treating primary and recurrent anal fistulas with a novel extracellular matrix derived from porcine urinary bladder. Am Surg. 2015;81(5):498–502.

    PubMed  Google Scholar 

  137. Dorman RM, Bass KD. Novel use of porcine urinary bladder matrix for pediatric pilonidal wound care: preliminary experience. Pediatr Surg Int. 2016;32(10):997–1002.

    PubMed  Google Scholar 

  138. Monteiro IP, Gabriel D, Timko BP, Hashimoto M, Karajanagi S, Tong R, Marques AP, Reis RL, Kohane DS. A two-component pre-seeded dermal-epidermal scaffold. Acta Biomater. 2014;10(12):4928–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Navone SE, Pascucci L, Dossena M, Ferri A, Invernici G, Acerbi F, Cristini S, Bedini G, Tosetti V, Ceserani V, Bonomi A, Pessina A, Freddi G, Alessandrino A, Ceccarelli P, Campanella R, Marfia G, Alessandri G, Parati EA. Decellularized silk fibroin scaffold primed with adipose mesenchymal stromal cells improves wound healing in diabetic mice. Stem Cell Res Ther. 2014;5(1):7.

    PubMed  PubMed Central  Google Scholar 

  140. Greer N, Foman NA, MacDonald R, Dorrian J, Fitzgerald P, Rutks I, Wilt TJ. Advanced wound care therapies for nonhealing diabetic, venous, and arterial ulcers: a systematic review. Ann Intern Med. 2013;159(8):532–42.

    PubMed  Google Scholar 

  141. Landsman A, Taft D, Riemer K. The role of collagen bioscaffolds, foamed collagen, and living skin equivalents in wound healing. Clin Podiatr Med Surg. 2009;26(4):525–33.

    PubMed  Google Scholar 

  142. Woodroof A, Phipps R, Woeller C, Rodeheaver G, Naughton GK, Piney E, Hickerson W, Branski L, Holmes JH 4th. Evolution of a biosynthetic temporary skin substitute: a preliminary study. Eplasty. 2015;15:e30. eCollection 2015

    PubMed  PubMed Central  Google Scholar 

  143. Uccioli L, TissueTech Autograph System Italian Study Group. A clinical investigation on the characteristics and outcomes of treating chronic lower extremity wounds using the tissuetech autograft system. Int J Low Extrem Wounds. 2003;2(3):140–51.

    CAS  PubMed  Google Scholar 

  144. 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.

    CAS  PubMed  Google Scholar 

  145. Falanga V, Margolis D, Alvarez O, Auletta M, Maggiacomo F, Altman M, Jensen J, Sabolinski M, Hardin-Young J. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch Dermatol. 1998;134(3):293–300.

    CAS  PubMed  Google Scholar 

  146. Sabolinski ML, Alvarez O, Auletta M, Mulder G, Parenteau NL. Cultured skin as a ‘smart material’ for healing wounds: experience in venous ulcers. Biomaterials. 1996;17(3):311–20.

    CAS  PubMed  Google Scholar 

  147. Zelen CM, Serena TE, Gould L, Le L, Carter MJ, Keller J, Li WW. 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.

    PubMed  Google Scholar 

  148. Bowering CK. Dermagraft in the treatment of diabetic foot ulcers. J Cutan Med Surg. 1998;3(Suppl 1):S1–29–32.

    PubMed  Google Scholar 

  149. Marston WA. Dermagraft, a bioengineered human dermal equivalent for the treatment of chronic nonhealing diabetic foot ulcer. Expert Rev Med Devices. 2004;1(1):21–31.

    CAS  PubMed  Google Scholar 

  150. Papanas N, Eleftheriadou I, Tentolouris N, Maltezos E. Advances in the topical treatment of diabetic foot ulcers. Curr Diabetes Rev. 2012;8(3):209–18.

    CAS  PubMed  Google Scholar 

  151. Still J, Glat P, Silverstein P, Griswold J, Mozingo D. The use of a collagen sponge/living cell composite material to treat donor sites in burn patients. Burns. 2003;29(8):837–41.

    PubMed  Google Scholar 

  152. Santema TB, Poyck PP, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. 2016;2:CD011255.

    PubMed  Google Scholar 

  153. Ehrenreich M, Ruszczak Z. Update on tissue-engineered biological dressings. Tissue Eng. 2006;12(9):2407–24.

    CAS  PubMed  Google Scholar 

  154. Faglia E, Mantero M, Gino M, et al. A combined conservative approach in the treatment of a severe Achilles tendon region ulcer in a diabetic patient: a case report. Wounds. 1999;11(5):105–9.

    Google Scholar 

  155. Dalla Paola L, Cogo A, Deanesi W, Stocchiero C, Colletta VC. Using hyaluronic acid derivatives and cultured autologous fibroblasts and keratinocytes in a lower limb wound in a patient with diabetes: a case report. Ostomy Wound Manage. 2002;48(9):46–9.

    PubMed  Google Scholar 

  156. Harris PA, di Francesco F, Barisoni D, Leigh IM, Navsaria HA. Use of hyaluronic acid and cultured autologous keratinocytes and fibroblasts in extensive burns. Lancet. 1999;353(9146):35–6.

    CAS  PubMed  Google Scholar 

  157. Ilancheran S, Moodley Y, Manuelpillai U. Human fetal membranes: a source of stem cells for tissue regeneration and repair? Placenta. 2009;30(1):2–10.

    CAS  PubMed  Google Scholar 

  158. May SR. The effects of biological wound dressings on the healing process. Clin Mater. 1991;8(3–4):243–9.

    CAS  PubMed  Google Scholar 

  159. Zelen CM, Snyder RJ, Serena TE, Li WW. The use of human amnion/chorion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. 2015;32(1):135–46.

    PubMed  Google Scholar 

  160. Kesting MR, Wolff KD, Hohlweg-Majert B, Steinstraesser L. The role of allogenic amniotic membrane in burn treatment. J Burn Care Res. 2008;29(6):907–16.

    PubMed  Google Scholar 

  161. Lineen E, Namias N. Biologic dressing in burns. J Craniofac Surg. 2008;19(4):923–8.

    PubMed  Google Scholar 

  162. 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.

    PubMed  PubMed Central  Google Scholar 

  163. 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.

    PubMed  Google Scholar 

  164. Penny H, Rifkah M, Weaver A, Zaki P, Young A, Meloy G, Flores R. Dehydrated human amnion/chorion tissue in difficult-to-heal DFUs: a case series. J Wound Care. 2015;24(3):104; 106–9; 111.

    Google Scholar 

  165. Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, Kashefsky H, Owings TM, Nadarajah J, Grafix Diabetic Foot Ulcer Study Group. The efficacy and safety of Grafix(®) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014;11(5):554–60. https://doi.org/10.1111/iwj.12329.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Gibbons GW. Grafix®, a cryopreserved placental membrane, for the treatment of chronic/stalled wounds. Adv Wound Care (New Rochelle). 2015;4(9):534–44.

    Google Scholar 

  167. Regulski M, Jacobstein DA, Petranto RD, Migliori VJ, Nair G, Pfeiffer D. A retrospective analysis of a human cellular repair matrix for the treatment of chronic wounds. Ostomy Wound Manage. 2013;59(12):38–43.

    PubMed  Google Scholar 

  168. Kampmann A, Lindhorst D, Schumann P, Zimmerer R, Kokemüller H, Rücker M, Gellrich NC, Tavassol F. Additive effect of mesenchymal stem cells and VEGF to vascularization of PLGA scaffolds. Microvasc Res. 2013;90:71–9. https://doi.org/10.1016/j.mvr.2013.07.006.

    Article  CAS  PubMed  Google Scholar 

  169. Gelain F. Novel opportunities and challenges offered by nanobiomaterials in tissue engineering. Int J Nanomedicine. 2008;3(4):415–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Gil ES, Panilaitis B, Bellas E, Kaplan DL. Functionalized silk biomaterials for wound healing. Adv Healthc Mater. 2013;2(1):206–17.

    CAS  PubMed  Google Scholar 

  171. Liu X, Ma L, Gao C. RNAi functionalized scaffold for scarless skin regeneration. Organogenesis. 2013;9(2):76–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Norouzi M, Shabani I, Ahvaz HH, Soleimani M. PLGA/gelatin hybrid nanofibrous scaffolds encapsulating EGF for skin regeneration. J Biomed Mater Res A. 2015;103(7):2225–35.

    CAS  PubMed  Google Scholar 

  173. Mirdailami O, Soleimani M, Dinarvand R, Khoshayand MR, Norouzi M, Hajarizadeh A, Dodel M, Atyabi F. Controlled release of rhEGF and rhbFGF from electrospun scaffolds for skin regeneration. J Biomed Mater Res A. 2015;103(10):3374–85.

    CAS  PubMed  Google Scholar 

  174. Li B, Davidson JM, Guelcher SA. The effect of the local delivery of platelet-derived growth factor from reactive two-component polyurethane scaffolds on the healing in rat skin excisional wounds. Biomaterials. 2009;30(20):3486–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Sarkar A, Tatlidede S, Scherer SS, Orgill DP, Berthiaume F. Combination of stromal cell-derived factor-1 and collagen-glycosaminoglycan scaffold delays contraction and accelerates reepithelialization of dermal wounds in wild-type mice. Wound Repair Regen. 2011;19(1):71–9.

    PubMed  Google Scholar 

  176. Losi P, Briganti E, Errico C, Lisella A, Sanguinetti E, Chiellini F, Soldani G. Fibrin-based scaffold incorporating VEGF- and bFGF-loaded nanoparticles stimulates wound healing in diabetic mice. Acta Biomater. 2013;9(8):7814–21.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital—Harvard Medical School, Boston, MA, USA

    Giorgio Giatsidis MD & Dennis P. Orgill MD, PhD

  2. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Ioannis V. Yannas PhD

Authors
  1. Giorgio Giatsidis MD
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  2. Dennis P. Orgill MD, PhD
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  3. Ioannis V. Yannas PhD
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Correspondence to Dennis P. Orgill MD, PhD .

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Editors and Affiliations

  1. Rongxiang Xu, MD, Professor of Surgery, Harvard Medical School Director, The Rongxiang Xu, MD, Center for Regenerative Therapeutics Research Director, Joslin-Beth Israel Deaconess Foot Center Beth Israel Deaconess Medical Center, Boston, MA, USA

    Aristidis Veves

  2. Chief, Division of Podiatry, Beth Israel Deaconess Medical Center, Associate Professor of Surgery, Harvard Medical School, Co-director, Joslin-Bl Deaconess Diabetic Foot Center Consultant, Joslin Diabetes Center, Boston, MA, USA

    John M. Giurini

  3. Associate Professor of Surgery, Harvard Medical School, Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Joslin Diabetes Center, Boston, MA, USA

    Raul J. Guzman

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Conflict of Interest: I.V.Y. has participated in the founding of Integra LifeSciences, Plainsboro, NJ. He currently has no financial connection with the company and owns no stock of Integra LifeSciences.

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Giatsidis, G., Orgill, D.P., Yannas, I.V. (2018). Dermal Regeneration and Induction of Wound Closure in Diabetic Wounds. In: Veves, A., Giurini, J., Guzman, R. (eds) The Diabetic Foot. Contemporary Diabetes. Humana, Cham. https://doi.org/10.1007/978-3-319-89869-8_9

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