Combined Use of Acid Fibroblast Growth Factor, Granulocyte Colony-stimulating Factor and Zinc Sulphate Accelerates Diabetic Ulcer Healing

Abstract

Our previous studies demonstrated that topic application of recombinant human acid fibroblast growth factor (aFGF) significantly, but still not completely, improved in diabetic ulcer healing. To obtain a maximal therapy for diabetic ulcer healing, a combined protocol containing aFGF, anti-oxidative reagent zinc (Zn) and stem cell stimulator granulocyte colony-stimulating factor (G-CSF), i.e.: aFGF/G-CSF/zinc sulphate (ZnSO 4 ), was explored in the present study. Diabetes was induced by a single dose of streptozotocin (STZ, 55 mg/kg) in Sprague Dawley rats, and full thickness skin wound was made in diabetic rats at 2 months after diabetes onset. Diabetic ulcer rats were treated with aFGF, G-CSF, ZnSO 4 , aFGF/G-CSF/ZnSO 4 or vehicle control, respectively and 3, 6, 9, 12, 15, 18, 21 and 28 days later, therapeutic effects were evaluated by calculating ulcer area. On day 7, 14, 21 after treatment, rats were sacrificed to collect 2 pieces of dorsal skin from 3 different sites (wound center, edge and healed area) to perform histopathological examination. Results showed that treatment with aFGF/G-CSF/ZnSO 4 significantly enhanced ulcer healing compared with single drug treatment groups at different time points. Healing times for 100% of the wound in the aFGF/G-CSF/ZnSO 4 group was 20.00 ± 1.15 days, and significantly shorter than those in single treatment groups (p < 0.05). Histopathological and immunohistochemical analysis disclosed significant increases in capillary density, proliferating cells, the expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and the ratios of TIMP-1 to matrix metalloproteinase 1 (MMP-1) in aFGF/G-CSF/ZnSO 4 group as compared to other single treatments. Collectively, the combinative protocol of aFGF/G-CSF/ZnSO 4 significantly enhanced the therapeutic effect on diabetic ulcer wound, probably through the promotion of fibroblast proliferation and differentiation, enhancement of blood vessel regeneration, and up-regulation of TIMP-1 and down-regulation of MMP-1 expression in diabetic ulcer healing process.

How Effective are Nano-Based Dressings in Diabetic Wound Healing? A Comprehensive Review of Literature

“… 161 As the main component of metalloproteinase, Zn can participate in the formation of ECM and promote wound healing. 162 Li et al constructed a ZnO/Ag/PVP/PCL nanofiber to enhance tissue regeneration and wound healing, and found that this composite structure had better anti-inflammatory, antibacterial, skin regeneration and wound healing effects than traditional drugs or single metal nanofibers. 163 In addition to ZnO, TiO 2 , CeO 2 , Fe 2 O 3 and other emerging nanoparticles also play a certain role in skin wound healing.…”

Tratamiento complementario de heridas crónicas con factor de crecimiento estimulante de colonias de granulocitos. A propósito de dos casos clínicos.

“…(9) Posteriormente, diversos autores comenzaron a utilizar factor de crecimiento estimulante de colonias de granulocitos (G-CSF), primero en modelo animal y luego en pacientes con pie diabético infectado. (10)(11)(12)(13)(14)(15) El G-CSF, al igual que el GM-CSF, es un factor endógeno hematopoyético movilizador de células madre y progenitores hematopoyéticos de la médula ósea hacia la sangre periférica, los cuales pueden ser cuantificados mediante la determinación de células CD34+ en sangre periférica. (10,12) A nivel sistémico actúa regulando la supervivencia, proliferación y diferenciación terminal de las células precursoras de neutrófilos desde la médula a la sangre.…”

“…A su vez, estimula la función de neutrófilos maduros favoreciendo la quimiotaxis de éstos y mejorando su capacidad fagocítica. (10,12,17) Por otro lado, induce la proliferación de células endoteliales promoviendo la angiogénesis. (10) La eficacia del G-CSF ha sido evaluada en varios ensayos clínicos en pie diabético infectado, observándose mejoría en los parámetros de infección, así como disminución en la incidencia de amputación y de estadía hospitalaria en estos pacientes.…”

“…(10,12,17) Por otro lado, induce la proliferación de células endoteliales promoviendo la angiogénesis. (10) La eficacia del G-CSF ha sido evaluada en varios ensayos clínicos en pie diabético infectado, observándose mejoría en los parámetros de infección, así como disminución en la incidencia de amputación y de estadía hospitalaria en estos pacientes. (12)(13)(14) En contra posición a esto, Yönet y cols.…”