Wound Healing Kinetics of the Genetically Diabetic Mouse

  • 1/1/2008
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Author(s): 
Sandra Saja Scherer, MD;1 Giorgio Pietramaggiori, MD;1,2 Jasmine C. Mathews;1 Rodney Chan, MD;1 Paolo Fiorina, MD, PhD;3 Dennis P. Orgill MD, PhD1

Results

Wild type versus diabetic wound healing kinetics. Delayed wound closure in db/db mice with a 1.5-cm2 full-thickness wound on the dorsum was observed after 4–6 weeks, compared to their nondiabetic counterparts, who healed in 10–16 days.65 After 2–3 weeks, db/db mice showed almost no signs of healing with wound contraction of 10%–20%, while wild type animals at the same time point were almost healed. Similarly, in another study using db/db mice,32 4-mm to 6.0-mm db/db wounds on the dorsum of each animal healed in 27.75 days ± 1.49.32,49

In previous studies that corroborate these results, different sizes of full-thickness wounds in the db/db showed significant delay compared to their wild-type counterparts.26

However, in the authors’ experience, using a 1.5 cm2 excisional wound in db/db mice showed slightly faster wound closure, reaching 34% after only 9 days. On the same day, wild type animals showed 84% wound closure (Figure 4).26,65

Wound closure kinetics of the db/db mouse. Considering the 2 main mechanisms of wound healing—contraction and re-epithelialization—db/db mice were found to heal mainly by re-epithelialization (Figure 5, Table 1) during the first 10 days of the follow-up, and contraction in the last 2 weeks. Although it has been reported that contraction is the main wound healing deficiency of this animal model,65,68 the authors of the present study found that it plays a main role to facilitate complete wound closure that starts at the second week of the follow-up period. On day 10, wounds displayed a peak in new epithelial formation from the wound edges.30,31,69

One cm2 full-thickness wounds on the back of the diabetic mice reached 50% wound closure in 13.7 ± 2.9 days.30,31 Diabetic mice with 0.6-, 1.0-, and 1.5-cm2 full-thickness wounds, regardless of initial wound size, demonstrated similar delays in wound healing.26 Ninety percent closure was reached in 19.9 ± 8.6 days post wounding by 1.0 cm2 wounds in the diabetic mice and consistently reached 80% wound closure by day 21 (Figure 5).30,31

References: 

1. International Diabetes Federation. Available at: http://www.idf.org/home/index.cfm. Accessed 2006.
2. Galiano RD, Tepper OM, Pelo CR, et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am J Pathol. 2004;164(6):1935–1947.
3. Goulimari P, Kitzing TM, Knieling H, Brandt DT, Offermann S, Grosse R. Galpha12/13 is essential for directed cell migration and localized Rho-Dia1 function. J Biol Chem. 2005;280(51):42242–42251.
4. Gottrup F, Agren MS, Karlsmark T. Models for use in wound healing research: a survey focusing on in vitro and in vivo adult soft tissue. Wound Repair Regen. 2000;8(2):83–96.
5. Harrop AR, Ghahary A, Scott PG, Forsyth N, Uji-Friedland A, Tredget EE. Regulation of collagen synthesis and mRNA expression in normal and hypertrophic scar fibroblasts in vitro by interferon-gamma. J Surg Res. 1995;58(5):471–477.
6. MacDonald IM, Pannu R, Kovithavongs K, Peters C, Tredget EE, Ghahary A. Effect of retinoic acid on expression of transforming growth factor-beta by retinal pigment epithelial cells in culture. Can J Ophthalmol. 1995;30(6):301–305.
7. Woodley DT, Wynn KC, O'Keefe EJ. Type IV collagen and fibronectin enhance human keratinocyte thymidine incorporation and spreading in the absence of soluble growth factors. J Invest Dermatol. 1990;94(1):139–143.
8. Frank S, Stallmeyer B, Kämpfer H, Kolb N, Pfeilschifter J. Nitric oxide triggers enhanced induction of vascular endothelial growth factor expression in cultured keratinocytes (HaCaT) and during cutaneous wound repair. Faseb J. 1999;13(14):2002–2014.
9. Hager B, Bickenbach JR, Fleckman P. Long-term culture of murine epidermal keratinocytes. J Invest Dermatol. 1999;112(6):971–976.
10. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6(4):389–395.
11. Abdollahi A, Hahnfeldt P, Maercker C, et al. Endostatin’s antiangiogenic signaling network. Mol Cell. 2004;13(5):649–663.
12. Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA. Definition of two angiogenic pathways by distinct alpha v integrins. Science. 1995;270(5241):1500–1502.
13. Bettinger D, Gore D, Humphries Y. Evaluation of calcium alginate for skin graft donor sites. J Burn Care Rehabil. 1995;16(1):59–61.
14. Calderon M, Lawrence WT, Banes AJ. Increased proliferation in keloid fibroblasts wounded in vitro. J Surg Res. 1996;61(2):343–347.
15. Bell E, Ivarsson B, Merrill C. Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc Natl Acad Sci U S A. 1979;76(3):1274–1278.
16. Grinnell F. Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol. 1994;124(4):401–404.
17. Morykwas MJ. In vitro properties of crosslinked, reconstituted collagen sheets. J Biomed Mater Res. 1990;24(8):1105–1110.
18. Morykwas MJ, David LR, Schneider AM, et al. Use of subatmospheric pressure to prevent progression of partial-thickness burns in a swine model. J Burn Care Rehabil. 1999;20(1 Pt 1):15–21.
19. Morykwas MJ, Kennedy A, Argenta JP, Argenta LC. Use of subatmospheric pressure to prevent doxorubicin extravasation ulcers in a swine model. J Surg Oncol. 1999;72(1):14–17.
20. Buján J, Pascual G, Corrales C, Gomez-Gil V, Garcia-Honduvilla N, Bellon JM. Muscle-derived stem cells used to treat skin defects prevent wound contraction and expedite reepithelialization. Wound Repair Regen. 2006;14(2):216–223.
21. Reid RR, Mogford JE, Butt R, deGiorgio-Miller A, Mustoe TA. Inhibition of procollagen C-proteinase reduces scar hypertrophy in a rabbit model of cutaneous scarring. Wound Repair Regen. 2006;14(2):138–141.
22. Lee JP, Jalili RB, Tredget EE, Demare JR, Ghahary A. Antifibrogenic effects of liposome-encapsulated IFN-alpha2b cream on skin wounds in a fibrotic rabbit ear model. J Interferon Cytokine Res. 2005;25(10):627–631.
23. Said HK, Hijjawi J, Roy N, Mogford J, Mustoe T. Transdermal sustained-delivery oxygen improves epithelial healing in a rabbit ear wound model. Arch Surg. 2005;140(10):998–1004.
24. Lin MP, Marti GP, Dieb R, et al. Delivery of plasmid DNA expression vector for keratinocyte growth factor-1 using electroporation to improve cutaneous wound healing in a septic rat model. Wound Repair Regen. 2006;14(5):618–624.
25. Hata K, Fujitani M, Yasuda Y, et al. RGMa inhibition promotes axonal growth and recovery after spinal cord injury. J Cell Biol. 2006;173(1):47–58.
26. Chan RK, Liu PH, Pietramaggiori G, Ibrahim SI, Hechtman HB, Orgill DP. Effect of recombinant platelet-derived growth factor (Regranex) on wound closure in genetically diabetic mice. J Burn Care Res. 2006;27(2):202–205.
27. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–1743.
28. Ferrara N. VEGF as a therapeutic target in cancer. Oncology. 2005;69(Suppl 3):11–16.
29. Greenhalgh DG. Models of wound healing. J Burn Care Rehabil. 2005;26(4):293–305.
30. Pietramaggiori A, Kaipainen A, Ho D, et al. Trehalose lyophilized platelets for wound healing. Wound Repair Regen. 2007;15(2):213–220.
31. Pietramaggiori G, Kaipainen A, Czeczuga JM, Wagner CT, Orgill DP. Freeze-dried platelet-rich plasma shows beneficial healing properties in chronic wounds. Wound Repair Regen. 2006;14(5):573–580.
32. Sullivan SR, Underwood RA, Gibran NS, et al. Validation of a model for the study of multiple wounds in the diabetic mouse (db/db). Plast Reconstr Surg. 2004;113(3):953–960.
33. Falanga V, Schrayer D, Cha J, et al. Full-thickness wounding of the mouse tail as a model for delayed wound healing: accelerated wound closure in Smad3 knock-out mice. Wound Repair Regen. 2004;12(3):320–326.
34. Rerup CC. Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev. 1970;22(4):485–518.
35. Goodson WH 3rd, Hung TK. Studies of wound healing in experimental diabetes mellitus. J Surg Res. 1977;22(3):221–227.
36. Seifter E, Rettura G, Padawer J, Stratford F, Kambosos D, Levenson SM. Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin A. Ann Surg. 1981;194(1):42–50.
37. Cianfarani F, Zambruno G, Brogelli L, et al. Placenta growth factor in diabetic wound healing: altered expression and therapeutic potential. Am J Pathol. 2006;169(4):1167–1182.
38. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–432.
39. Goodson WH 3rd, Hunt TK. Wound collagen accumulation in obese hyperglycemic mice. Diabetes. 1986;35(4):491–495.
40. Chen H, Charlat O, Tartaglia LA, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996;84(3):491–495.
41. Coleman DL. Diabetes-obesity syndromes in mice. Diabetes. 1982;31(Suppl 1 Pt 2):1–6.
42. Kaplan MM, Young JB. Abnormal thyroid hormone deiodination in tissues of ob/ob and db/db obese mice. Endocrinology. 1987;120(3):886–893.
43. Stallmeyer B, Kampfer H, Podda M, Kaufmann R, Pfeilschifter J, Frank S. A novel keratinocyte mitogen: regulation of leptin and its functional receptor in skin repair. J Invest Dermatol. 2001;117(1):98–105.
44. Stallmeyer B, Pfeilschifter J, Frank S. Systemically and topically supplemented leptin fails to reconstitute a normal angiogenic response during skin repair in diabetic ob/ob mice. Diabetologia. 2001;44(4):471–479.
45. Man LX, Park JC, Terry MJ, et al. Lentiviral gene therapy with platelet-derived growth factor B sustains accelerated healing of diabetic wounds over time. Ann Plast Surg. 2005;55(1):81–86.
46. Obara K, Ishihara M, Fujita M, et al. Acceleration of wound healing in healing-impaired db/db mice with a photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2. Wound Repair Regen. 2005;13(4):390–397.
47. Mulder G. Electroporatic delivery of TGF-beta1 gene works synergistically with electric therapy to enhance diabetic wound healing in db/db mice. J Invest Dermatol. 2004;123(4):xi.
48. Lee PY, Chesnoy S, Huang L. Electroporatic delivery of TGF-beta1 gene works synergistically with electric therapy to enhance diabetic wound healing in db/db mice. J Invest Dermatol. 2004;123(4):791–798.
49. Muangman P, Muffley LA, Anthony JP, et al. Nerve growth factor accelerates wound healing in diabetic mice. Wound Repair Regen. 2004;12(1):44–52.
50. Thenen SW, Mayer J. Adipose tissue glycerokinase activity in genetic and acquired obesity in rats and mice. Proc Soc Exp Biol Med. 1975;148(4):953–957.
51. Hamann A, Matthaei S. Regulation of energy balance by leptin. Exp Clin Endocrinol Diabetes.1996;104(4):293–300.
52. Rahmouni K, Haynes WG, Morgan DA, Mark AL. Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension. 2003;41(3 Pt 2):763–767.
53. Kennedy WR, Wendelschafer-Crabb G, Johnson T. Quantitation of epidermal nerves in diabetic neuropathy. Neurology. 1996;47(4):1042–1048.
54. Pereira L, Matthes J, Schuster I, et al. Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. Diabetes. 2006;55(3):608–615.
55. Greer JJ, Ware DP, Lefer DJ. Myocardial infarction and heart failure in the db/db diabetic mouse. Am J Physiol Heart Circ Physiol. 2006;290(1):H146–H153.
56. Carley AN, Semeniuk LM, Shimoni Y, et al. Treatment of type 2 diabetic db/db mice with a novel PPARgamma agonist improves cardiac metabolism but not contractile function. Am J Physiol Endocrinol Metab. 2004;286(3):E449–E455.
57. Garris DR. Variable onset determinants and consequences of diabetes (db/db) obesity mutation expression: adrenergic promotion of utero-ovarian dysfunction. Horm Metab Res. 2004;36(5):312–318.
58. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269(5223):546–549.
59. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269(5223):543–546.
60. Stephens TW, Basinski M, Bristow PK, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 1995;377(6549):530–532.
61. Kieffer TJ, Heller RS, Leech CA, et al. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. Diabetes. 1997;46(6):1087–1093.
62. Mikhail AA, Beck EX, Shafer A, et al. Leptin stimulates fetal and adult erythroid and myeloid development. Blood. 1997;89(5):1507–1512.
63. Carlson MA, Longaker MT, Thompson JS. Wound splinting regulates granulation tissue survival. J Surg Res. 2003;110(1):304–309.
64. Reid RR, Said HK, Mogford JE, Mustoe TA. The future of wound healing: pursuing surgical models in transgenic and knockout mice. J Am Coll Surg. 2004;199(4):578–585.
65. Greenhalgh DG, Sprugel KH, Murray MJ, Ross R. PDGF and FGF stimulate wound healing in the genetically diabetic mouse. Am J Pathol. 1990;136(6):1235–1246.
66. Yannas I. Tissue and Organ Regeneration in Adults. New York, NY: Springer; 2001.
67. Michaels JT, Dobryansky M, Galiano RD, et al. Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor demonstration. Wound Repair Regen. 2005;13(5):506–512.
68. Klingbeil CK, Cesar LB, Fiddes JC. Basic fibroblast growth factor accelerates tissue repair in models of impaired wound healing. Prog Clin Biol Res. 1991;365:443–458.
69. Pietramaggiori G, Yang HJ, Scherer S, et al. Effects of poly-N-acetyl glucosamine (pGlcNAc) patch on wound healing in db/db mouse. J Trauma. In press.
70. Senter LH, Legrand EK, Laemmerhirt KE, Kiorpes TC. Assessment of full-thickness wounds in the genetically diabetic mouse for suitability as a wound healing model. Wound Repair Regen. 1995;3(3):351–358.

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