Therapeutic effect of the epidermal growth factor on diabetic foot ulcer and the underlying mechanisms

Zhang,Juanzi; Hu,Wenxian; Diao,Qixian; Wang,Zhaowei; Miao,Jin; Chen,Xiao; Xue,Zhijun

doi:10.3892/etm.2018.7133

Therapeutic effect of the epidermal growth factor on diabetic foot ulcer and the underlying mechanisms

Authors:
- Juanzi Zhang
- Wenxian Hu
- Qixian Diao
- Zhaowei Wang
- Jin Miao
- Xiao Chen
- Zhijun Xue
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Affiliations: Department of Vascular Surgery, The Affiliated Qingdao Hiser Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China, Department of General Surgery, The Affiliated Qingdao Hiser Hospital of Qingdao University, Qingdao, Shandong 266033, P.R. China
Published online on: December 24, 2018 https://doi.org/10.3892/etm.2018.7133
Pages: 1643-1648
Copyright : © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

The present study aimed to explore the therapeutic effect and underlying mechanism of epidermal growth factor (EGF) on the wound healing of diabetic foot ulcers (DFU). A total of 48 rabbits with DFU were randomly divided into 2 groups, comprising the treatment and control groups. Full‑thickness skin (10x10 mm) was excised from the thigh of each rabbit. The wounds in the treatment group were treated with 100 mg/l EGF once a day for 1 month. The control group received no treatment. At 20 days following treatment, new granulation tissues that formed beyond the edge of the wound were collected for subsequent analysis. Tissues from rabbits in the treatment group produced a greater number of fibroblasts, which exhibited a fibroblastic morphology when compared with those in the control group. In the treatment group, a larger number of these fibroblasts were observed as clusters, and there were numerous blood vessels when compared with the control group. The fibroblasts in the control group exhibited an irregular morphology, contained fewer organelles and the surrounding collagenous fibers were sparse. These fibroblasts also demonstrated a disordered arrangement and it was revealed that the wound healed at a slower rate compared with the treatment group. Endogenous EGF mRNA detection revealed that there was a significant difference (P<0.05) in the relative gray value of EGF mRNA between the treatment (103.27±4.27) and control (63.88±4.36) groups. In conclusion, EGF may accelerate the healing of DFU, and exogenous EGF treatment may upregulate the expression of EGF mRNA in newly generated tissues.

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1	Iraj B, Khorvash F, Ebneshahidi A and Askari G: Prevention of diabetic foot ulcer (DFU). Int J Prev Med. 4:373–376. 2013.PubMed/NCBI
2	Wojciechowski VV, Calina D, Tsarouhas K, Pivnik AV, Sergievich AA, Kodintsev VV, Filatova EA, Ozcagli E, Docea AO, Arsene AL, et al: A guide to acquired vitamin K coagulophathy diagnosis and treatment: The Russian perspective. Daru. 25:102017. View Article : Google Scholar : PubMed/NCBI
3	Asadi M, Alamdari DH, Rahimi HR, Aliakbarian M, Jangjoo A, Abdollahi A, Bahar MM, Azadmand A, Forghani N, Sadegh MN, et al: Treatment of life threatening wounds with a combination of allogenic platelet rich plasma, fibrin glue and collagen matrix, and a literature review. Exp Ther Med. 8:423–429. 2014. View Article : Google Scholar : PubMed/NCBI
4	Călina D, Docea AO, Roşu L, Zlatian O, Roşu AF, Anghelina F, Rogoveanu O, Arsene AL, Nicolae AC, Drăgoi CM, et al: Antimicrobial resistance development following surgical site infections. Mol Med Rep. 15:681–688. 2017. View Article : Google Scholar : PubMed/NCBI
5	Tănase A, Colita A, Ianosi G, Neagoe D, Branisteanu DE, Calina D, Docea AO, Tsatsakis A and Ianosi SL: Rare case of disseminated fusariosis in a young patient with graft vs. host disease following an allogeneic transplant. Exp Ther Med. 12:2078–2082. 2016. View Article : Google Scholar : PubMed/NCBI
6	Blumberg SN, Berger A, Hwang L, Pastar I, Warren SM and Chen W: The role of stem cells in the treatment of diabetic foot ulcers. Diabetes Res Clin Pract. 96:1–9. 2012. View Article : Google Scholar : PubMed/NCBI
7	Mcardle C, Lagan K, Spence S and McDowell D: Diabetic foot ulcer wound fluid: The effects of pH on DFU bacteria and infection. J Foot Ankle Res. 8 Suppl 1:A82015. View Article : Google Scholar
8	Buchberger B, Follmann M, Huppertz H and Wasem J: Health technology assessment (HTA) on the importance of growth factors for the treatment of diabetic foot ulcers (DFU). Das Gesundheitswesen. 72:491–501. 2010. View Article : Google Scholar
9	Sheehan P, Jones P, Caselli A, Giurini JM and Veves A: Percent change in wound area ofdiabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. 26:1879–1882. 2003. View Article : Google Scholar : PubMed/NCBI
10	Gilligan AM, Waycaster CR and Landsman AL: Wound closure in patients with DFU: A cost-effectiveness analysis of two cellular/tissue-derived products. J Wound Care. 24:149–156. 2015. View Article : Google Scholar : PubMed/NCBI
11	Singh K, Singh VK, Agrawal NK, Gupta SK and Singh K: Association of toll-like receptor 4 polymorphisms with diabetic foot ulcers and application of artificial neural network in DFU risk assessment in type 2 diabetes patients. Biomed Res Int. 2013:3186862013. View Article : Google Scholar : PubMed/NCBI
12	Mcdonnell J, Redekop K, Verboom P, Lovas K and Kalo Z: PDG15: The cost of treating diabetic foot ulcers (dfu) with apligraf in the Netherlands. Value Health. 4:5082001. View Article : Google Scholar
13	Hong JP, Jung HD and Kim YW: Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers. Ann Plast Surg. 56:394–398; discussion 399–400. 2006. View Article : Google Scholar : PubMed/NCBI
14	Robson MC: Invited discussion: Recombinant human epidermal growth factor (EGF) to enhance healing for diabetic foot ulcers. Ann Plast Surg. 56:399–400. 2006. View Article : Google Scholar
15	Choi JS, Leong KW and Yoo HS: In vivo wound healing of diabetic ulcers using electrospun nanofibers immobilized with human epidermal growth factor (EGF). Biomaterials. 29:587–596. 2008. View Article : Google Scholar : PubMed/NCBI
16	Mohan VK: Recombinant human epidermal growth factor (REGEN-D 150): Effect on healing of diabetic foot ulcers. Diabetes Res Clin Pract. 78:405–411. 2007. View Article : Google Scholar : PubMed/NCBI
17	Aktaş Ş, Baktıroğlu S, Demir L, Kılıçoğlu Ö, Topalan M, Güven E, Mirasoğlu B and Yanar F: Intralesional application of epidermal growth factor in limb-threatening ischemic diabetic foot ulcers. Acta Orthop Traumatol Turc. 50:277–283. 2016.PubMed/NCBI
18	Dumantepe M, Fazliogullari O, Seren M, Uyar I and Basar F: Efficacy of intralesional recombinant human epidermal growth factor in chronic diabetic foot ulcers. Growth Factors. 33:128–132. 2015. View Article : Google Scholar : PubMed/NCBI
19	Chen F, Lin L, Zhang HJ, Ye XX, Zhao WZ, Wang T and Yang XN: Roles of hepatocyte growth factor, c-Met and epidermal growth factor receptor in repair of colonic mucosa from patients with ulcerative colitis. Shiji Hua Ren Xiao Hua Za Zhi. 14:594–599. 2006.(In Chinese).
20	Chen F, Lin L, Zhang HJ and Wang T: Effect of epidermal growth factor receptor in the repair of colonic mucosa in patients with ulcerative colitis. Zhongguo Lin Chuang Kang Fu Za Zhi. 9:104–106. 2005.(In Chinese).
21	Sun L, Kwok E, Gopaluni B and Vahidi O: Pharmacokinetic-pharmacodynamic modeling of metformin for the treatment of type II diabetes mellitus. Open Biomed Eng J. 5:1–7. 2011. View Article : Google Scholar : PubMed/NCBI
22	Hu YH, Yun SF, Zhou SM and Tian XY: Influence of Sumianxin Anesthesia on Physiology in Rabbits. Zhongguo Bi Jiao Yi Xue Za Zhi. 16:475–478. 2006.(In Chinese).
23	Cao CY, Kang N, Yan L, Hu ZY, Shen ZH and Wang Q: Anesthetic effect of sumianxin II combined with chloral hydrate on rabbit. Zhongguo Bi Jiao Yi Xue Za Zhi. 24:25–18. 2014.(In Chinese).
24	Huang J: Scientific breeding management of experimental rabbits. Animal Husbandry Veterinarian of Zhejiang. 3:471995.
25	Li X, Liu W, Kou H, Zhou W, Li T, Dong B and Liang P: Experimental study of image-guided percutaneous microwave ablation in rabbit lung VX2 tumor model. Int J Clin Exp Pathol. 7:905–913. 2014.PubMed/NCBI
26	Yuan ZW, Pei LY, Qiu JL, et al: Anesthesia of commonly used experimental animals. Chinese J Comparative Medicine. 14:245–247. 2004.(In Chinese).
27	Pixin R and Shengfu D: Effects of epidermal growth factor (EGF) on circumflex function of isolated pulmonary artery in rats. Chinese J Pathophysiol. 2:173–176. 1994.(In Chinese).
28	Liu Y, Pei G and Jiang S: New porous beta-tricalcium phosphate as scaffold for bone tissue engineering. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 21:1123–1127. 2007.(In Chinese). PubMed/NCBI
29	Ertugrul BM, Buke C, Ersoy OS, Ay B, Demirez DS and Savk O: Intralesional epidermal growth factor for diabetic foot wounds: The first cases in Turkey. Diabetic Foot Ankle. 6:284192015. View Article : Google Scholar : PubMed/NCBI
30	Fan HJ, Yu JH, Cui GM, Zhang WY, Yang X and Dong QJ: Insulin pump for the treatment of diabetes in combination with ulcerative foot infections. J Biol Regul Homeost Agents. 30:465–470. 2016.PubMed/NCBI
31	Thomson SE, McLennan SV and Twigg SM: Growth factors in diabetic complications. Expet Rev Clin Immunol. 2:403–418. 2006. View Article : Google Scholar
32	Han HM, Guo L, Jiang LJ, Jiang XY, Lv YL, Pang JK, Bai ZM, Che WJ, Xu RH, Yu P and Li Q: A microarray study on the molecular mechanism for the therapeutic effect of Antidotal and Myogenic Ointment on the foot ulcer in diabetic rats. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 23:621–624. 2011.(In Chinese). PubMed/NCBI
33	Wan Y, Yang YJ, Li YS, Li XJ, Zhang W, Liu M and Tang HB: Effects of San-huang-sheng-fu oil on peripheral circulatory disorders and foot ulcers in diabetic rats and the mechanisms. Zhonghua Shao Shang Za Zhi. 32:168–175. 2016.(In Chinese). PubMed/NCBI
34	Demidova-Rice TN, Hamblin MR and Herman IM: Acute and impaired wound healing: Pathophysiology and current methods for drug delivery, part 2: Role of growth factors in normal and pathological wound healing: Therapeutic potential and methods of delivery. Adv Skin Wound Care. 25:349–370. 2012. View Article : Google Scholar : PubMed/NCBI
35	Jennings JA, Crews RM, Robinson J, Richelsoph K, Cole JA, Bumgardner JD, Yang Y and Haggard WO: Effect of growth factors in combination with injectable silicone resin particles on the biological activity of dermal fibroblasts: A preliminary in vitro, study. J Biomed Mater Res B Appl Biomater. 92:255–260. 2010. View Article : Google Scholar : PubMed/NCBI
36	Yuan N, Wang C, Wang Y, Yu T, Long Y, Zhang X and Ran X: Preparation of autologous platelet-rich gel for diabetic refractory dermal ulcer and growth factors analysis from it. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 22:468–471. 2008.(In Chinese). PubMed/NCBI
37	Zhou LS, Liao ZJ, Zhang Q, Luo M, Lu G and Zhang W: Bio-inductive effects of inorganic elements on skin wound healing. Zhonghua Shao Shang Za Zhi. 21:363–366. 2005.(In Chinese). PubMed/NCBI
38	Jiang XH, Zhou WM, He YZ, Wang Y, Lv B and Wang XM: Effects of lipopeptide carboxymethyl chitosan nanoparticles on Staphylococcus aureus biofilm. J Biol Regul Homeost Agents. 31:737–743. 2017.PubMed/NCBI
39	Buteică AS, Mihăescu DE, Grumezescu AM, Vasile BS, Popescu A, Călina D and Mihăiescu OM: The citotoxicity of (non)magnetic nanoparticles tested on Escherichia coli and Staphylococcus aureus. Dig J Nanomater Biostruct. 5:651–655. 2010.
40	Acosta JB, Savigne W, Valdez C, Franco N, Alba JS, del Rio A, López-Saura P, Guillén G, Lopez E, Herrera L and Férnandez-Montequín J: Epidermal growth factor intralesional infiltrations can prevent amputation in patients with advanced diabetic foot wounds. Int Wound J. 3:232–239. 2006. View Article : Google Scholar : PubMed/NCBI
41	Galkowska H, Wojewodzka U and Olszewski WL: Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound Repair Regen. 14:558–565. 2006. View Article : Google Scholar : PubMed/NCBI
42	Pedro A, López Saura, Jorge Berlanga Acosta, José I, Fernández Montequín, Carmen Valenzuelá Silva, Odalys González Díaz, William Savigne, Lourdes Morejoń Vega, Amauryś del Río Martín, Luis Herrera Martínez, et al: Intralesional human recombinant epidermal growth factor for the treatment of advanced diabetic foot ulcer: From proof of concept to confirmation of the efficacy and safety of the procedure. Zhur. Eksptl'. i Teoret. Fiz. 21:406–409. 2011.
43	Bennett SP, Griffiths GD, Schor AM, Leese GP and Schor SL: Growth factors in the treatment of diabetic foot ulcers. Br J Surg. 90:133–146. 2003. View Article : Google Scholar : PubMed/NCBI
44	Margolis DJ, Bartus C, Hoffstad O, Malay S and Berlin JA: Effectiveness of recombinant human platelet-derived growth factor for the treatment of diabetic neuropathic foot ulcers. Wound Repair Regen. 13:531–536. 2005. View Article : Google Scholar : PubMed/NCBI
45	Buchberger B, Follmann M, Freyer D, Huppertz H, Ehm A and 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. 119:472–479. 2011. View Article : Google Scholar : PubMed/NCBI
46	Galstyan GR, Ignatieva VI, Avksentieva MV and Dedov II: Pharmacoeconomic analysis of epidermal growth factor (HeberprotP^®) for the treatment of diabetic foot ulcers. Endocrine Surgery. 7:4–15. 2013. View Article : Google Scholar
47	Tuyet HL, Nguyen Quynh TT, Vo Hoang Minh H, Thi Bich DN, Do Dinh T, Le Tan D, Van HL, Le Huy T, Doan Huu H and Tran Trong TN: The efficacy and safety of epidermal growth factor in treatment of diabetic foot ulcers: The preliminary results. Int Wound J. 6:159–166. 2009. View Article : Google Scholar : PubMed/NCBI
48	Tiaka EK, Papanas N, Manolakis AC and Georgiadis GS: Epidermal growth factor in the treatment of diabetic foot ulcers: An update. Perspect Vasc Surg Endovasc Ther. 24:37–44. 2012. View Article : Google Scholar : PubMed/NCBI
49	Afshari M, Larijani B, Fadayee M, Farzaneh Darvishzadeh, Ghahary A, Pajouhi M, Bastanhagh MH, Baradar-Jalili R and Vassigh AR: Efficacy of topical epidermal growth factor in healing diabetic foot ulcers. Therapy. 2:759–765. 2016. View Article : Google Scholar
50	Lihuan D: Regenerated cellulose skin repair materials: preparation and performance. Zhongguo Zu Zhi Gong Cheng Yan Jiu. 19:6098–6103. 2015.(In Chinese).
51	Singla S, Singla S, Kumar A and Singla M: Role of epidermal growth factor in healing of diabetic foot ulcers. Indian J Surg. 74:451–455. 2012. View Article : Google Scholar : PubMed/NCBI
52	Gałkowska H and Olszewski W: Cellular and molecular basis of impaired healing of diabetic foot ulcers. Polish J Surg. 79:720–727. 2007. View Article : Google Scholar
53	Li Q, Wang Y and Yang L: Curative effect observation of recombinant human epidermal growth factor in treatment of oral ulcer in children with hand-foot-mouth disease. Erke Yao Xue Za Zhi. 23:533–547. 2015.(In Chinese).