Silicone implants capable of the local, controlled delivery of triamcinolone for the prevention of fibrosis with minimized drug side effects

Beom Su Jeon; Byung Ho Shin; Beom Kang Huh; Byung Hwi Kim; Se-Na Kim; Han Bi Ji; Seung Ho Lee; Soo Im Kang; Jung Hee Shim; So Min Kang; Jae Chul Lee; Kyu Sang Lee; Chan Yeong Heo; Young Bin Choy

Journal of Industrial and Engineering Chemistry, Vol.63, 168-180, July, 2018

DOI10.1016/j.jiec.2018.02.013 Export Citation

Silicone implants capable of the local, controlled delivery of triamcinolone for the prevention of fibrosis with minimized drug side effects

Beom Su Jeon¹, Byung Ho Shin², Beom Kang Huh¹, Byung Hwi Kim², Se-Na Kim¹, Han Bi Ji¹, Seung Ho Lee³, Soo Im Kang⁴, Jung Hee Shim⁴, So Min Kang⁴, Jae Chul Lee⁴, Kyu Sang Lee⁵, Chan Yeong Heo^{1, 6, †}, and Young Bin Choy^{1, 2, †}

¹Interdisciplinary Program for Bioengineering, College of Engineering, Seoul National University, Seoul 08826, Republic of Korea
²Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
³Institute of Medical & Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea
⁴Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
⁵Department of Pathology, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
⁶Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul 03080, Republic of Korea

E-mail:,

We propose silicone implants capable of the local, controlled release of a glucocorticoid drug, triamcinolone acetonide (TA), for the prevention of fibrosis. The shells of these silicone implants were coated with two different loading amounts of TA, which could release the drug in a sustained manner for 12 weeks. The drug-loaded implants were inserted into the subcutaneous space in living rats, and the tissues were biopsied at scheduled times during 12 weeks. For the drug-coated implants, the capsule thickness and collagen density decreased compared with those of the non-coated implant. Because of the effect of TA, inflammation and the expression of pro-inflammatory cytokines were downregulated, thereby decreasing the number of monocytes during acute inflammation. This effect in turn decreased the number of macrophages at the later stage of inflammation, leading to the expression of less TGF-β and consequently fewer fibroblasts and myofibroblasts. Our findings also revealed that with an appropriate dose control, skin and muscle atrophy, major side effects of TA, could be avoided while still effectively reducing fibrosis. Therefore, we conclude that the local, sustained release of an appropriate dose of a glucocorticoid drug can be a promising strategy for safely preventing fibrosis around silicone implants.

Keywords:Controlled release;Fibrosis;Inflammation;Silicone implant;Triamcinolone

[References]

Champaneria MC, Wong WW, Hill ME, Gupta SC, World J. Surg., 36, 730 (2012)
Malahias M, Jordan D, Hughes L, Hindocha S, Juma A, Int. J. Surg. Open, 3, 1 (2016)
Headon H, Kasem A, Mokbel K, Arch. Plast. Surg., 42, 532 (2015)
Wahl S, Wong H, McCartney-Francis N, J. Cell. Biochem., 40, 193 (1989)
Anderson JM, Rodriguez A, Chang DT, Foreign Body React. Biomater., 86 (2008).
Cotran RS, Pober JS, J. Am. Soc. Nephrol., 1, 225 (1990)
Meng XM, Nikolic-Paterson DJ, Lan HY, Nat. Rev. Nephrol., 12, 325 (2016)
Wynn TA, Ramalingam TR, Nat. Med., 18, 1028 (2012)
Cain DW, Cidlowski JA, Nat. Rev. Immunol., 17, 233 (2017)
Cutroneo KR, Rokowski R, Counts DF, Coll. Relat. Res., 1, 557 (1981)
Lemperle G, Exner K, Aesthet. Plast. Surg., 17, 317 (1993)
Costagliola M, Atiyeh BS, Rampillon F, Aesthet. Surg. J., 33, 1008 (2013)
Schleimer R, Eur. J. Clin. Pharmacol., 45, S3 (1993)
Joyce D, Steer J, Abraham L, Inflamm. Res., 46, 447 (1997)
Amano Y, Lee SW, Allison AC, Mol. Pharmacol., 43, 176 (1993)
Anderson JM, Ann. Rev. Mater. Res., 31, 81 (2001)
Park S, Park M, Kim BH, Lee JE, Park HJ, Lee SH, Park CG, Kim MH, Kim R, Kim EH, J. Control. Release, 200, 125 (2015)
Schacke H, Docke WD, Asadullah K, Pharmacol. Ther., 96, 23 (2002)
Kumar GP, Tirupathirao N, Krishna TM, Int. J. Pharm. Res. Health Sci., 4, 1504 (2016)
Thakur A, Kadam RS, Kompella UB, Drug Metab. Dispos., 39, 771 (2011)
Zeplin PH, Larena-Avellaneda A, Schmidt K, Plast. Reconstr. Surg., 126, 266 (2010)
Ruiz-de-Erenchun R, de las Herrerias JD, Hontanilla B, Plast. Reconstr. Surg., 116, 1370 (2005)
Nair P, Duncan H, Ford TP, Luder H, Int. Endod. J., 41, 128 (2008)
Kim BH, Park M, Park HJ, Lee SH, Choi SY, Park CG, Han SM, Heo CY, Choy YB, Acta Biomater., 51, 209 (2017)
Lee JN, Park C, Whitesides GM, Anal. Chem., 75, 6544 (2003)
Khalil N, Bereznay O, Sporn M, Greenberg AH, J. Exp. Med., 170, 727 (1989)
Dolores W, Christian R, Harald N, Hildegunde P, Georg W, J. Autoimmun., 23, 81 (2004)
Diegelmann RF, Evans MC, Front. Biosci., 9, 283 (2004)
Minami E, Koh IHJ, Ferreira JCR, Waitzberg AFL, Chifferi V, Rosewick TF, Pereira MD, Saldiva PHN, de Figueiredo LFP, Plast. Reconstr. Surg., 118, 874 (2006)
Schillinger M, Exner M, Mlekusch W, Rumpold H, Ahmadi R, Sabeti S, Lang W, Wagner O, Minar E, Radiology, 227, 516 (2003)
Eming SA, Krieg T, Davidson JM, J. Investig. Dermatol., 127, 514 (2007)
Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J, J. Clin. Investig., 107, 1529 (2001)
Zhang K, Gharaee-Kermani M, McGarry B, Remick D, Phan SH, J. Immunol., 158, 954 (1997)
Shi C, Pamer EG, Nat. Rev. Immunol., 11, 762 (2011)
Johnston RB, N. Engl. J. Med., 318, 747 (1988)
Fernandez IE, Eickelberg O, Proc. Am. Thorac. Soc., 9, 111 (2012)
Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM, J. Biol. Chem., 282, 22910 (2007)
Luttikhuizen DT, Harmsen MC, Luyn MJV, Tissue Eng., 12, 1955 (2006)
Wynn T, J. Pathol., 214, 199 (2008)
Kyle DJ, Bayat A, Plast. Reconstr. Surg., 135, 1413 (2015)
Gabbiani G, J. Pathol., 200, 500 (2003)
Schoepe S, Schacke H, May E, Asadullah K, Exp. Dermatol., 15, 406 (2006)
Schakman O, Kalista S, Barbe C, Loumaye A, Thissen JP, Int. J. Biochem. Cell Biol., 45, 2163 (2013)
Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Am. J. Physiol. Heart Circ. Physiol., 293, H2210 (2007)
Mantovani A, Immunol. Today, 20, 254 (1999)
Leask A, Abraham DJ, Faseb J., 18, 816 (2004)
Wang AS, Armstrong EJ, Armstrong AW, Am. J. Surg., 206, 410 (2013)
Sconfienza LM, Murolo C, Callegari S, Calabrese M, Savarino E, Santi P, Sardanelli F, Eur. Radiol., 21, 575 (2011)
Catanuto G, Spano A, Pennati A, Riggio E, Farinella GM, Impoco G, Spoto S, Gallo G, Nava MB, J. Plast. Reconstr. Aesthet. Surg., 61, 314 (2008)

[Referenced By]

[1] Champaneria MC, Wong WW, Hill ME, Gupta SC, World J. Surg., 36, 730 (2012)

[2] Malahias M, Jordan D, Hughes L, Hindocha S, Juma A, Int. J. Surg. Open, 3, 1 (2016)

[3] Headon H, Kasem A, Mokbel K, Arch. Plast. Surg., 42, 532 (2015)

[4] Wahl S, Wong H, McCartney-Francis N, J. Cell. Biochem., 40, 193 (1989)

[5] Anderson JM, Rodriguez A, Chang DT, Foreign Body React. Biomater., 86 (2008).

[6] Cotran RS, Pober JS, J. Am. Soc. Nephrol., 1, 225 (1990)

[7] Meng XM, Nikolic-Paterson DJ, Lan HY, Nat. Rev. Nephrol., 12, 325 (2016)

[8] Wynn TA, Ramalingam TR, Nat. Med., 18, 1028 (2012)

[9] Cain DW, Cidlowski JA, Nat. Rev. Immunol., 17, 233 (2017)

[10] Cutroneo KR, Rokowski R, Counts DF, Coll. Relat. Res., 1, 557 (1981)

[11] Lemperle G, Exner K, Aesthet. Plast. Surg., 17, 317 (1993)

[12] Costagliola M, Atiyeh BS, Rampillon F, Aesthet. Surg. J., 33, 1008 (2013)

[13] Schleimer R, Eur. J. Clin. Pharmacol., 45, S3 (1993)

[14] Joyce D, Steer J, Abraham L, Inflamm. Res., 46, 447 (1997)

[15] Amano Y, Lee SW, Allison AC, Mol. Pharmacol., 43, 176 (1993)

[16] Anderson JM, Ann. Rev. Mater. Res., 31, 81 (2001)

[17] Park S, Park M, Kim BH, Lee JE, Park HJ, Lee SH, Park CG, Kim MH, Kim R, Kim EH, J. Control. Release, 200, 125 (2015)

[18] Schacke H, Docke WD, Asadullah K, Pharmacol. Ther., 96, 23 (2002)

[19] Kumar GP, Tirupathirao N, Krishna TM, Int. J. Pharm. Res. Health Sci., 4, 1504 (2016)

[20] Thakur A, Kadam RS, Kompella UB, Drug Metab. Dispos., 39, 771 (2011)

[21] Zeplin PH, Larena-Avellaneda A, Schmidt K, Plast. Reconstr. Surg., 126, 266 (2010)

[22] Ruiz-de-Erenchun R, de las Herrerias JD, Hontanilla B, Plast. Reconstr. Surg., 116, 1370 (2005)

[23] Nair P, Duncan H, Ford TP, Luder H, Int. Endod. J., 41, 128 (2008)

[24] Kim BH, Park M, Park HJ, Lee SH, Choi SY, Park CG, Han SM, Heo CY, Choy YB, Acta Biomater., 51, 209 (2017)

[25] Lee JN, Park C, Whitesides GM, Anal. Chem., 75, 6544 (2003)

[26] Khalil N, Bereznay O, Sporn M, Greenberg AH, J. Exp. Med., 170, 727 (1989)

[27] Dolores W, Christian R, Harald N, Hildegunde P, Georg W, J. Autoimmun., 23, 81 (2004)

[28] Diegelmann RF, Evans MC, Front. Biosci., 9, 283 (2004)

[29] Minami E, Koh IHJ, Ferreira JCR, Waitzberg AFL, Chifferi V, Rosewick TF, Pereira MD, Saldiva PHN, de Figueiredo LFP, Plast. Reconstr. Surg., 118, 874 (2006)

[30] Schillinger M, Exner M, Mlekusch W, Rumpold H, Ahmadi R, Sabeti S, Lang W, Wagner O, Minar E, Radiology, 227, 516 (2003)

[31] Eming SA, Krieg T, Davidson JM, J. Investig. Dermatol., 127, 514 (2007)

[32] Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J, J. Clin. Investig., 107, 1529 (2001)

[33] Zhang K, Gharaee-Kermani M, McGarry B, Remick D, Phan SH, J. Immunol., 158, 954 (1997)

[34] Shi C, Pamer EG, Nat. Rev. Immunol., 11, 762 (2011)

[35] Johnston RB, N. Engl. J. Med., 318, 747 (1988)

[36] Fernandez IE, Eickelberg O, Proc. Am. Thorac. Soc., 9, 111 (2012)

[37] Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM, J. Biol. Chem., 282, 22910 (2007)

[38] Luttikhuizen DT, Harmsen MC, Luyn MJV, Tissue Eng., 12, 1955 (2006)

[39] Wynn T, J. Pathol., 214, 199 (2008)

[40] Kyle DJ, Bayat A, Plast. Reconstr. Surg., 135, 1413 (2015)

[41] Gabbiani G, J. Pathol., 200, 500 (2003)

[42] Schoepe S, Schacke H, May E, Asadullah K, Exp. Dermatol., 15, 406 (2006)

[43] Schakman O, Kalista S, Barbe C, Loumaye A, Thissen JP, Int. J. Biochem. Cell Biol., 45, 2163 (2013)

[44] Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Am. J. Physiol. Heart Circ. Physiol., 293, H2210 (2007)

[45] Mantovani A, Immunol. Today, 20, 254 (1999)

[46] Leask A, Abraham DJ, Faseb J., 18, 816 (2004)

[47] Wang AS, Armstrong EJ, Armstrong AW, Am. J. Surg., 206, 410 (2013)

[48] Sconfienza LM, Murolo C, Callegari S, Calabrese M, Savarino E, Santi P, Sardanelli F, Eur. Radiol., 21, 575 (2011)

[49] Catanuto G, Spano A, Pennati A, Riggio E, Farinella GM, Impoco G, Spoto S, Gallo G, Nava MB, J. Plast. Reconstr. Aesthet. Surg., 61, 314 (2008)