Angiogenesis is a vital component of the orchestrated wound healing cascade and tissue regeneration process, which has a therapeutic prominence in treatment of ischemic vascular diseases and certain cardiac conditions. Based on its eminence, several strategies using growth factors have been studied to initiate angiogenesis. However, growth factors are expensive and have short half-life. In this work, sustained release of triiodothyronine, which plays a crucial role in stimulating growth factors and other signaling pathways that are instrumental in initiating angiogenesis, has been attempted through electrospun polycaprolactone nanofibers. This delivery system enabled the slow and sustained delivery of triiodothyronine into the micro-environment, reducing seepage of excess into systemic circulation and eliminating the necessity of repeated dosage forms. It was observed that triiodothyronine-incorporated nanofibers exhibited favorable interaction with cells (phalloidin staining of actin filaments) and also enhanced the rate of endothelial proliferation, migration, and adhesion. The angiogenic potential of these nanofibers was further corroborated through chorioallantoic membrane and rat aortic ring assay (demonstrating cell sprouting area of 3.3 ± 0.71 mm2 compared to 1.2 ± 0.01 mm2 in control). The nanofiber matrix thus fabricated demonstrated a vibrant therapeutic potential to induce angiogenesis. Triiodothyronine also plays a significant role in wound healing independent of initiating angiogenesis. This further substantiates the positive impact of this delivery system as a dressing material for chronic wound therapeutics, ischemic vascular diseases, and certain cardiac conditions.
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Gurtner G, Werner S, Barrandon Y, Longaker M. Wound repair and regeneration. Nature. 2008;453(7193):314–21.
Diegelmann RF, Evans MC. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci. 2004;9:283–9.
Battegay EJ. Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med. 1995;73(7):333–46.
Davies NH, Schmidt C, Bezuidenhout D, Zilla P. Sustaining neovascularization of a scaffold through staged release of vascular endothelial growth factor-a and platelet-derived growth factor-BB. Tissue Eng Part A. 2012;18(1–2):26–34.
Li Z, Qu T, Ding C, Ma C, Sun H, Li S, et al. Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis. Acta Biomater. 2015;13:88–100.
Lai HJ, Kuan CH, Wu HC, Tsai JC, Chen TM, Hsieh DJ, et al. Tailored design of electrospun composite nanofibers with staged release of multiple angiogenic growth factors for chronic wound healing. Acta Biomater. 2014;10(10):4156–66.
Bai Y, Yin G, Huang Z, Liao X, Chen X, Yao Y, et al. Localized delivery of growth factors for angiogenesis and bone formation in tissue engineering. Int Immunopharmacol. 2013;16(2):214–23.
Zigdon-giladi H, Khutaba A, Elimelech R, Machtei EE, Srouji S. VEGF release from a polymeric nanofiber scaffold for improved angiogenesis. J Biomed Mater Res - Part A. 2017;105 A:2712–21.
Choi DH, Subbiah R, Kim IH, Han DK, Park K. Dual growth factor delivery using biocompatible core-shell microcapsules for angiogenesis. Small. 2013;9(20):3468–76.
Davis PJ, Davis FB, Mousa SA. Thyroid hormone-induced angiogenesis. Curr Cardiol Rev. 2009;5:12–6.
Rajagopalan V, Zhang Y, Pol C, Costello C, Seitter S, Lehto A, et al. Modified low-dose triiodo-L-thyronine therapy safely improves function following myocardial ischemia-reperfusion injury. Front Physiol. 2017;8:1–11.
Wang W, Guan H, Fang W, Zhang K, Gerdes AM, Iervasi G, et al. Free triiodothyronine level correlates with myocardial injury and prognosis in idiopathic dilated cardiomyopathy : evidence from cardiac MRI and SPECT/PET imaging. Sci Rep. 2016;6:1–9.
Luidens MK, Mousa SA, Davis FB, Lin H, Davis PJ. Thyroid hormone and angiogenesis. Vasc Pharmacol. 2010;52:142–5.
Tomanek RJ, Doty MK, Sandra A. Early coronary angiogenesis in response to thyroxine. Circ Res. 1998;82:587–93.
Davis FB, Mousa SA, Connor LO, Mohamed S, Lin H, Cao HJ, et al. Proangiogenic action of thyroid hormone is fibroblast growth factor – dependent and is initiated at the cell surface. Circ Res. 2004;94:1500–7.
Biro S, Yu Z-X, Fu Y-M, Smale G, Sasse J, Sanchez J, et al. Expression and subcellular distribution of basic fibroblast growth factor are regulated during migration of endothelial cells. Circ Res. 1993;74:485–94.
Yanagisawa-Miwa A, Uchida Y, Nakamura F, Tomaru T, Kido H, Kamijo T, et al. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science. 1992;257:1401–3.
Kassem R, Liberty Z, Babaev M, Trau H, Cohen O. Harnessing the skin-thyroid connection for wound healing: a prospective controlled trial in guinea pigs. Clin Exp Dermatol. 2012;37(8):850–6.
Satish A, Korrapati PS. Fabrication of a triiodothyronine incorporated nanofibrous biomaterial: its implications on wound healing. RSC Adv. 2015;5:83773–80.
Safer JD, Fraser LM, Ray S, Holick MF. Topical triiodothyronine stimulates epidermal proliferation , dermal thickening , and hair growth in mice and rats. Thyroid. 2001;11(8):717–24.
Safer JD. Thyroid hormone and wound healing. J Thyroid Res. 2013;2013:1–5.
Lin Y, Sun Z. Thyroid hormone potentiates insulin signaling and attenuates hyperglycemia and insulin resistance in a mouse model of type 2 diabetes. Br J Pharmacol. 2011;162(3):597–610.
Ghosal K, Manakhov A, Zajíčková L, Thomas S. Structural and surface compatibility study of modified electrospun poly(ε-caprolactone) (PCL) composites for skin tissue engineering. AAPS PharmSciTech. 2017;18:72–81.
Solano AGR, de Fátima Pereira A, Pinto FCH, Ferreira LGR, de Oliveira Barbosa LA, Fialho SL, et al. Development and evaluation of sustained-release etoposide-loaded poly(ε-caprolactone) implants. AAPS PharmSciTech. 2013;14(2):890–900.
Mofidfar M, Wang J, Long L, Hager CL, Vareechon C, Pearlman E, et al. Polymeric nanofiber/antifungal formulations using a novel co-extrusion approach. AAPS PharmSciTech. 2017;18(6):1917–24.
Satish A, Korrapati PS. Tailored release of triiodothyronine and retinoic acid from a spatio-temporally fabricated nanofiber composite instigating neuronal differentiation. Nanoscale. 2017;9:14565–80.
Madhaiyan K, Sridhar R, Sundarrajan S, Venugopal JR, Ramakrishna S. Vitamin B12 loaded polycaprolactone nanofibers: a novel transdermal route for the water soluble energy supplement delivery. Int J Pharm. 2013;444(1–2):70–6.
Janani I, Lakra R, Kiran MS, Korrapati PS. Selectivity and sensitivity of molybdenum oxide-polycaprolactone nano fiber composites on skin cancer: preliminary in-vitro and in-vivo implications. J Trace Elem Med Biol. 2018;49:60–71.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1–2):55–63.
Chandrakasan G, Torchia DA, Piez KA. Preparation of intact monomeric collagen from rat tail tendon and skin and the structure of the nonhelical ends in solution. J Biol Chem. 1976;251(19):6062–7.
Rajan N, Habermehl J, Cote M, Doillon CJ, Mantovani D. Preparation of ready-to-use, storable and reconstituted type I collagen from rat tail tendon for tissue engineering applications. Nat Protoc. 2006;1(6):2753–8.
Baker M, Robinson SD, Lechertier T, Barber PR, Tavora B, Amico GD, et al. Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc. 2011;7(1):89–104.
Krishnaswamy VR, Balaguru UM, Chatterjee S, Korrapati PS. Dermatopontin augments angiogenesis and modulates the expression of transforming growth factor beta 1 and integrin alpha 3 beta 1 in endothelial. Eur J Cell Biol. 2017;96(3):266–75.
Paneva D, Bougard F, Manolova N, Dubois P, Rashkov I. Novel electrospun poly(ε-caprolactone)-based bicomponent nanofibers possessing surface enriched in tertiary amino groups. Eur Polym J. 2008;44(3):566–78.
Marsac PJ, Li T, Taylor LS. Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26(1):139–51.
Yoshida K, Aiyama S, Uchida M, Kurabuchi S. Role of thyroid hormone in the initiation of EGF (epidermal growth factor) expression in the sublingual gland of the postnatal mouse. Anat Rec - Part A. 2005;284:585–93.
Lin H, Sun M, Tang H, Lin C, Luidens MK, Mousa SA, et al. L-thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Physiol. 2009;296:C980–91.
Antonini D, Sibilio A, Dentice M, Missero C. An intimate relationship between thyroid hormone and skin: regulation of gene expression. Front Endocrinol (Lausanne). 2013;4:1–9.
Solano AGR, de Fátima Pereira A, de Faria LGA, Fialho SL, de Oliveira Patricio PS, da Silva-Cunha A, et al. Etoposide-loaded poly(lactic-co-glycolic acid) intravitreal implants: in vitro and in vivo evaluation. AAPS PharmSciTech. 2018;19(4):1652–61.
Deryugina EI, Quigley JP. Chapter 2 Chick embryo chorioallantoic membrane models to quantify angiogenesis induced by inflammatory and tumor cells or purified effector molecules. Methods Enzymol. 2008;444:21–41.
Schlenker EH, Hora M, Liu Y, Redetzke RA, Morkin E, Gerdes AM. Effects of thyroidectomy, T4, and DITPA replacement on brain blood vessel density in adult rats. AJP Regul Integr Comp Physiol. 2008;294(5):R1504–9.
Liu X, Zheng N, Shi Y, Yuan J, Li L. Thyroid hormone induced angiogenesis through the integrin alpha v beta 3/protein kinase D/histone deacetylase 5 signaling pathway. J Mol Endocrinol. 2014;52:245–54.
The authors are grateful to the Director, CSIR – CLRI for his constant support. The research is carried out as a part of Ph.D. work registered in the University of Madras, Chennai. The first author would like to acknowledge the DST-INSPIRE programme, New Delhi for the research fellowship (IF130876).
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Satish, A., Korrapati, P.S. Nanofiber-Mediated Sustained Delivery of Triiodothyronine: Role in Angiogenesis. AAPS PharmSciTech 20, 110 (2019). https://doi.org/10.1208/s12249-019-1326-y
- wound healing