Yara Tedavisinde Büyüme Hormonlarının Etkileri ve Uygulamaları
Özet
Yara iyileşmesi; enflamatuar, proliferatif ve remodelling fazlarından oluşan, hücreler ile büyüme hormonlarının rol oynadığı kompleks bir süreçtir. Bir ay içinde kapanmayan yaralar kronik yara olarak tanımlanır. Büyüme hormonları (EBF, VEBF, bFBF, TKBF, GM-CSF, IBF-1) peptid yapıda düzenleyiciler olup hücreler arası haberleşmeyi, proliferasyonu ve anjiogenezi sağlar. Kronik yaralarda bu hormonlar yetersiz kaldığından, dışarıdan tatbik edilmeleri yarayı akut faza geçirerek iyileşmeyi hızlandırır. Klinik kullanımda EBF (Heberprot enjeksiyon ve Regen-D krem) diyabetik ayak yaralarında epitelizasyonu artırır. Rekombinant VEBF (Telbermin) nöropatik ülserlerde, bFBF (Trafermin sprey) yanık ve venöz ülserlerde etkilidir. Rekombinant TKBF (Becaplermin jel) diyabetik ülserlerin iyileşmesini hızlandırırken, GM-CSF (Filgrastim) nötrofil aktivitesini artırıp amputasyon oranlarını düşürür. IBF-1 ise re-epitelizasyon sağlar ancak henüz ticari bir preparatı yoktur. Bu yapay hormonlar, kısa yarılanma ömürleri ve soğuk zincir gereksinimleri nedeniyle yüksek maliyetli olmalarına karşın, hastanede yatış sürelerini, nüksleri ve özellikle ampütasyon oranları ile maliyetlerini dramatik şekilde düşürdükleri için kar-maliyet analizlerinde konvansiyonel pansumanlara kıyasla oldukça efektif ve ekonomiktir.
Wound healing is a complex process consisting of inflammatory, proliferative, and remodeling phases, where cells and growth hormones play roles. Wound closure is expected within a month; wounds that do not heal within this period are defined as chronic wounds. Growth hormones (EGF, VEGF, bFBF, PDGF, GM-CSF, IGF-1) are peptide regulators that provide intercellular communication, proliferation, and angiogenesis. Since these hormones are insufficient in chronic wounds, their external application converts the wound into an acute phase and accelerates healing. In clinical use, EGF (Heberprot injection and Regen-D cream) increases epithelialization in diabetic foot ulcers. Recombinant VEGF (Telbermin) is effective in neuropathic ulcers, and bFBF (Trafermin spray) is effective in burns and venous ulcers. Recombinant PDGF (Becaplermin gel) accelerates the healing of diabetic ulcers, while GM-CSF (Filgrastim) increases neutrophil activity and reduces amputation rates. IGF-1 provides re-epithelialization, but no commercial preparation is available yet. Although these artificial hormones are costly due to short half-lives and cold chain requirements, they are highly effective and economical in cost-benefit analyses compared to conventional dressings, as they dramatically reduce hospital stay durations, recurrences, and especially amputation rates and their associated costs.
Referanslar
Janis JE, Kwon RK, Lalonde DH. A practical guide to wound healing. Plast Reconstr Surg 2010: 125(6):230e-44e.
Werdin F, Tenenhaus M, Rennekampff HO. Chronic wound care. Lancet. 2008 Nov 29;372(9653):1860-1862
Bennett N.T., Schultz G.S.: Growth factors and wound healing: biochemical properties of growth factors and their receptors. Am J Surg 1993; 165: pp. 728-737.
Stadelmann W.K., Digenis A.G., Tobin G.R.: Physiology and healing dynamics of chronic cutaneous wounds. Am J Surg 1998; 176: pp. 26S-38S.
Cohen S.: Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 1962; 237: pp. 1555-1562.
Brown G.L., Curtsinger L., Jurkiewicz M.J., et. al.: Stimulation of healing of chronic wounds by epidermal growth factor. Plast Reconstr Surg 1991; 88: pp. 189-194.
Kahraman M, Misir A, Kizkapan TB, Ozcamdalli M, Uzun E, Mutlu M. The Long-Term Outcomes Following the Application of Intralesional Epidermal Growth Factor in Patients With Diabetic Foot Ulcers. J Foot Ankle Surg. 2019 Mar;58(2):282-287Gomez-Villa R, Aguilar-Rebolledo F, Lozano-Platonoff A et. al. Epidermal growth factor in foot ulcers. Wound Repair Regen. 2014; 22: 497-503.
Berlanga-Acosta J, Gavilondo-Cowley J, Lopez-Saura P, González-López T, Castro-Santana MD, López-Mola E, Guillén-Nieto G, Herrera-Martinez L: Epidermal growth factor in clinical practice: a review of its biological actions, clinical indications and safety implications. Int Wound J. 2009; 6: pp. 331-346.
Gomez-Villa R, Aguilar-Rebolledo F, Lozano-Platonoff A et. al. Epidermal growth factor in foot ulcers. Wound Repair Regen. 2014; 22: 497-503.
Mohan VK. Recombinant human epidermal growth factor (REGEN-D 150): effect on healing of diabetic foot ulcers. Diabetes Res Clin Pract. 2007 Dec;78(3):405-11
Viswanathan V, Juttada U, Babu M. Efficacy of Recombinant Human Epidermal Growth Factor (Regen-D 150) in Healing Diabetic Foot Ulcers: A Hospital-Based Randomized Controlled Trial. Int J Low Extrem Wounds. 2020 Jun;19(2):158-164
Frank S., Hubner G., Breier G., et. al.: Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem 1995; 270: pp. 12607-12613.
Wartiovaara U, Salven P, Mikkola H, Lassila R, Kaukonen J, Joukov V et al. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 1988; 80: 171–175.
McCourt M, Wang JH, Sookhart S, Redmond HP. Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch Surg 1999; 134: 1325–1332.
Bates, D.O., PritchardJones, R.O. The role of vascular endothelial growth factor in wound healing. Lower Extremity Wounds 2003; 2: 107-120.
Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischaemia. Circulation 1998; 97: 1114–1123.
Hanft JR, Pollak RA, Barbul A, van Gils C, Kwon PS, Gray SM, Lynch CJ, Semba CP, Breen TJ. Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers. J Wound Care. 2008 Jan;17(1):30-2, 34-7
Reed JA, Albino AP, McNutt NS. Human cutaneous mast cells express basic fibroblast growth factor. Lab Invest 1995;72: 215–222
Barrientos, S., Brem, H., Canic, M.C., Golinko., M.S., and Stojadinovic, O. (2008). Growth factors and cytokines in wound healing, Wound Repair and Regeneration,16(5), 585–601
Hui, Q., Jin, Z., Li, X., Liu, C., and Wang, X.(2018). FGF Family: From Drug Development to Clinical Application. International Journal of Molecular Sciences, 19(7), 1875
Fu X, Shen Z, Chen Y, Xie J, Guo Z, Zhang M, Sheng Z. Randomised placebo-controlled trial of use of topical recombinant bovine basic fibroblast growth factor for second-degree burns. Lancet. 1998 Nov 21;352(9141):1661-4
Hayashida K., Akita S.: Quality of pediatric second-degree burn wound scars following the application of basic fibroblast growth factor: results of a randomized, controlled pilot study. Ostomy Wound Manag 2012; 58: pp. 32-36.
Hayashi M, Muramatsu H, Nakano M, Ito H, Inoie M, Tomizuka Y, Inoue M, Yoshimoto S. Experience of using cultured epithelial autografts for the extensive burn wounds in eight patients. Ann Plast Surg. 2014 Jul;73(1):25-9
Ichioka S, Ohura N, Nakatsuka T. The positive experience of using a growth factor product on deep wounds with exposed bone. J Wound Care. 2005 Mar;14(3):105-9
Ross R., Raines E.W., Bowen-Pope D.F.: The biology of platelet-derived growth factor. Cell 1986; 46: pp
Bowen-Pope D.F., Malpass T.W., Foster D.M., et. al.: Platelet-derived growth factor in vivo: levels, activity, and rate of clearance. Blood 1984; 64: pp. 458-469.
Martin P.I., Hopkinson-Woolley J., McCluskey J.: Growth factors and cutaneous wound repair. Prog Growth Factor Res 1992; 4: pp. 25-44.
Wieman T.J., Smiell J.M., Su Y.: Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care 1998; 21: pp. 822-827.
Louis D.N., Cavenee W.K.: Neoplasms of the central nervous system.DeVita V.T.Hellman S.Rosenberg S.A.Cancer: principles & practice of oncology.2001.Lippincott Williams & WilkinsPhiladelphia:pp. 2092.
Smith C.H., Allen M.H., Groves R.W., Barker J.N.: Effect of granulocyte macrophage-colony stimulating factor on Langerhans cells in normal and healthy atopic subjects. Br J Dermatol 1998; 139: pp. 239-246.
Cianfarani F., Tommasi R., Failla C.M., et. al.: Granulocyte/macrophage colony stimulating factor treatment of human chronic ulcers promotes angiogenesis asociated with de novo vascular endothelial growth factor transcription in the ulcer bed. Br J Dermatol 2006; 154: pp. 34-41.
Robson M., Kucukcelebi A., Carp S.S., et. al.: Effects of granulocyte-macrophage colony stimulating factor on wound contraction. Eur J Clin Microbiol Infect Dis 1994; 13: pp. 41-46.
Groves R.W., Schmidt-Lucke J.A.: Recombinant human GM-CSF in the treatment of poorly healing wounds. Adv Skin Wound Care 2000; 13: pp. 107-112.
Tavakkol A., Elder J.T., Griffiths C.E., et. al.: Expression of growth hormone receptor, insulin-like growth factor 1 (IGF-1) and IGF-1 receptor mRNA and proteins in human skin. J Invest Dermatol 1992; 99: pp. 343.
Ando Y., Jensen P.J.: Epidermal growth factor and insulin-like growth factor I enhance keratinocyte migration. J Invest Dermatol 1993; 100: pp. 633.
Semenova E., Koegel H., Hasse S., et. al.: Overexpression of mIGF-1 in keratinocytes improves wound healing and accelerates hair follicle formation and cycling in mice. Am J Pathol 2008; 173: pp. 1295.
Jeschke M.G., Herndon D.N.: The combination of IGF-I and KGF cDNA improves dermal and epidermal regeneration by increased VEGF expression and neovascularization. Gene Ther 2007; 14: pp. 1235.
Hirsch T., Spielmann M., Velander P., et. al.: Insulin-like growth factor-1 gene therapy and cell transplantation in diabetic wounds. J Gene Med 2008; 10: pp. 1247.
Romero Prada M, Roa C, Alfonso P, Acero G, Huérfano L, Vivas-Consuelo D. Cost-effectiveness analysis of the human recombinant epidermal growth factor in the management of patients with diabetic foot ulcers. Diabet Foot Ankle. 2018 Jun 26;9(1):1480249.
Gilligan AM, Waycaster CR, Motley TA. Cost-effectiveness of becaplermin gel on wound healing of diabetic foot ulcers. Wound Repair Regen. 2015 May-Jun;23(3):353-60.
