莢膜攣縮是義乳植入手術中最常見再次手術的原因。植入物失敗及不適的原因和異物反應及纖維化莢膜有關，而這個纖維化的莢膜形成之中存在發炎反應及傷口癒合的機制。過去CD248被證實能調節發炎及纖維化反應，我們假說CD248在矽膠引起的莢膜形成扮演某種角色。
首先我們改良了小鼠的莢膜攣縮模型以建立CD248及莢膜攣縮的相關性。我們用蛋白質分析跟顯微鏡檢查來發掘CD248在模型裡的特徵。其次我們比較模型中正常小鼠及CD248基因缺失小鼠之間的表現差異去探討CD248可能扮演的角色。
我們發現CD248在植入物周邊的莢膜基質及血管周邊的纖維母細胞被表現。CD248在第四天被過度活化，並在第二十一天到五十六天之間降到穩定但仍活化的濃度。比較起來，正常小鼠較CD248基因缺失小鼠容易發展出較薄但卻較為纖維化的莢膜。
結論是，我們建立了一個有效的莢膜攣縮小鼠模型來研究CD248及莢膜攣縮的相關性。根據正常小鼠與CD248基因缺失小鼠莢膜的不同表現，我們猜測缺乏CD248表現αSMA的肌肉纖維母細胞會導致一個較不攣縮的莢膜，也因此CD248可以是治療莢膜攣縮的一個可能標的。

Capsular contracture is the most common reason for secondary breast implant surgery. The failure of implanted device and discomfort are related to the foreign body response. It consists of inflammatory events and wound-healing process which form a fibrotic capsule. Upregulated expression of CD248 was previously demonstrated to modulate inflammation and fibrosis. We hypothesized that CD248 play a role in silicone implant-related capsule formation.
First, we modified a murine capsular contracture model to establish the correlation between CD248 and capsular contracture. We characterized the timing and site for expression of CD248 by protein analysis and histologic examination in this model. Second, we compared difference of capsules between wild-type mice and CD248 knockout mice 42 days after silicone implantation to verify possible role of CD248 in silicone-related capsule formation.
CD248 was expressed in the peri-silicone implant capsule by stromal fibroblast and perivascular fibroblast. CD248 was overexpressed since day 4 and down to a constant level but still upregulated through day 21 to day 56 after silicone implantation. In comparison, wild-type mice tended to develop a thinner but more collagenous capsule than CD248 knockout mice.
In conclusion, we established an effective murine capsular contracture model to study the correlation between CD248 and capsular contracture. According to the different presentation of capsules between wild-type and CD248 knockout mice, we furtherly hypothesized CD248- αSMA+ myofibroblast contributes to a less contracted capsule. CD248 is therefore a potential therapeutic target in capsular contracture.

1. Atisha D, Alderman AK, Lowery JC, et al. Prospective analysis of long-term psychosocial outcomes in breast reconstruction: two-year postoperative results from the Michigan Breast Reconstruction Outcomes Study. Ann Surg 2008;247:1019-1028.
2. Jagsi R, Jiang J, Momoh AO, et al. Trends and variation in use of breast reconstruction in patients with breast cancer undergoing mastectomy in the United States. J Clin Oncol 2014;32:919-926.
3. Jagsi R, Jiang J, Momoh AO, et al. Complications After Mastectomy and Immediate Breast Reconstruction for Breast Cancer: A Claims-Based Analysis. Ann Surg 2016;263:219-227.
4. Spear SL, Murphy DK, Slicton A, et al. Inamed silicone breast implant core study results at 6 years. Plast Reconstr Surg 2007;120:8S-16S; discussion 17S-18S.
5. Cunningham B, McCue J. Safety and effectiveness of Mentor's MemoryGel implants at 6 years. Aesthetic Plast Surg 2009;33:440-444.
6. Spear SL, Murphy DK, Allergan Silicone Breast Implant USCCSG. Natrelle round silicone breast implants: Core Study results at 10 years. Plast Reconstr Surg 2014;133:1354-1361.
7. Hwang K, Sim HB, Huan F, et al. Myofibroblasts and capsular tissue tension in breast capsular contracture. Aesthetic Plast Surg 2010;34:716-721.
8. Adams WP, Jr. Capsular contracture: what is it? What causes it? How can it be prevented and managed? Clin Plast Surg 2009;36:119-126.
9. Embrey M, Adams EE, Cunningham B, et al. A review of the literature on the etiology of capsular contracture and a pilot study to determine the outcome of capsular contracture interventions. Aesthetic Plast Surg 1999;23:197-206.
10. Reid RR, Greve SD, Casas LA. The effect of zafirlukast (Accolate) on early capsular contracture in the primary augmentation patient: a pilot study. Aesthet Surg J 2005;25:26-30.
11. Bhardwaj U, Sura R, Papadimitrakopoulos F, et al. PLGA/PVA hydrogel composites for long-term inflammation control following s.c. implantation. Int J Pharm 2010;384:78-86.
12. Zimman OA, Toblli J, Stella I, et al. The effects of angiotensin-converting-enzyme inhibitors on the fibrous envelope around mammary implants. Plast Reconstr Surg 2007;120:2025-2033.
13. Gancedo M, Ruiz-Corro L, Salazar-Montes A, et al. Pirfenidone prevents capsular contracture after mammary implantation. Aesthetic Plast Surg 2008;32:32-40.
14. McLean AL, Talmor M, Harper A, et al. Expression of cyclooxygenase-2 in the periprosthetic capsule surrounding a silicone shell implant in the rat. Ann Plast Surg 2002;48:292-297.
15. Zeplin PH, Larena-Avellaneda A, Schmidt K. Surface modification of silicone breast implants by binding the antifibrotic drug halofuginone reduces capsular fibrosis. Plast Reconstr Surg 2010;126:266-274.
16. Zeplin PH, Larena-Avellaneda A, Jordan M, et al. Phosphorylcholine-coated silicone implants: effect on inflammatory response and fibrous capsule formation. Ann Plast Surg 2010;65:560-564.
17. Vieira VJ, d'Acampora AJ, Marcos AB, et al. Vascular endothelial growth factor overexpression positively modulates the characteristics of periprosthetic tissue of polyurethane-coated silicone breast implant in rats. Plast Reconstr Surg 2010;126:1899-1910.
18. Rettig WJ, Garin-Chesa P, Healey JH, et al. Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci U S A 1992;89:10832-10836.
19. St Croix B, Rago C, Velculescu V, et al. Genes expressed in human tumor endothelium. Science 2000;289:1197-1202.
20. Christian S, Winkler R, Helfrich I, et al. Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells. Am J Pathol 2008;172:486-494.
21. Valdez Y, Maia M, Conway EM. CD248: reviewing its role in health and disease. Curr Drug Targets 2012;13:432-439.
22. MacFadyen JR, Haworth O, Roberston D, et al. Endosialin (TEM1, CD248) is a marker of stromal fibroblasts and is not selectively expressed on tumour endothelium. FEBS Lett 2005;579:2569-2575.
23. Dolznig H, Schweifer N, Puri C, et al. Characterization of cancer stroma markers: in silico analysis of an mRNA expression database for fibroblast activation protein and endosialin. Cancer Immun 2005;5:10.
24. Bagley RG, Honma N, Weber W, et al. Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization. Microvasc Res 2008;76:180-188.
25. Lax S, Hou TZ, Jenkinson E, et al. CD248/Endosialin is dynamically expressed on a subset of stromal cells during lymphoid tissue development, splenic remodeling and repair. FEBS Lett 2007;581:3550-3556.
26. Maia M, de Vriese A, Janssens T, et al. CD248 and its cytoplasmic domain: a therapeutic target for arthritis. Arthritis Rheum 2010;62:3595-3606.
27. Brett E, Zielins ER, Chin M, et al. Isolation of CD248-expressing stromal vascular fraction for targeted improvement of wound healing. Wound Repair Regen 2017;25:414-422.
28. Tomkowicz B, Rybinski K, Foley B, et al. Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration. Proc Natl Acad Sci U S A 2007;104:17965-17970.
29. Smith SW, Croft AP, Morris HL, et al. Genetic Deletion of the Stromal Cell Marker CD248 (Endosialin) Protects against the Development of Renal Fibrosis. Nephron 2015;131:265-277.
30. Wilhelm A, Aldridge V, Haldar D, et al. CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism. Gut 2016;65:1175-1185.
31. Bartis D, Crowley LE, D'Souza VK, et al. Role of CD248 as a potential severity marker in idiopathic pulmonary fibrosis. BMC Pulm Med 2016;16:51.
32. Baker JL, Jr., Chandler ML, LeVier RR. Occurrence and activity of myofibroblasts in human capsular tissue surrounding mammary implants. Plast Reconstr Surg 1981;68:905-912.
33. Katzel EB, Koltz PF, Tierney R, et al. The impact of Smad3 loss of function on TGF-beta signaling and radiation-induced capsular contracture. Plast Reconstr Surg 2011;127:2263-2269.
34. Kim S, Ahn M, Piao Y, et al. Effect of Botulinum Toxin Type A on TGF-beta/Smad Pathway Signaling: Implications for Silicone-Induced Capsule Formation. Plast Reconstr Surg 2016;138:821e-829e.
35. Suresh Babu S, Valdez Y, Xu A, et al. TGFbeta-mediated suppression of CD248 in non-cancer cells via canonical Smad-dependent signaling pathways is uncoupled in cancer cells. BMC Cancer 2014;14:113.
36. Norris RE, Fox E, Reid JM, et al. Phase 1 trial of ontuxizumab (MORAb-004) in children with relapsed or refractory solid tumors: A report from the Children's Oncology Group Phase 1 Pilot Consortium (ADVL1213). Pediatr Blood Cancer 2018;65:e26944.
37. Huang HP, Hong CL, Kao CY, et al. Gene targeting and expression analysis of mouse Tem1/endosialin using a lacZ reporter. Gene Expr Patterns 2011;11:316-326.
38. Schoonjans F, Zalata A, Depuydt CE, et al. MedCalc: a new computer program for medical statistics. Comput Methods Programs Biomed 1995;48:257-262.
39. Baker JL, Jr., Mara JE, Douglas WM. Repair of concavity of thoracic wall with silicone elastomer implant. Case report. Plast Reconstr Surg 1975;56:212-215.
40. Malata CM, Feldberg L, Coleman DJ, et al. Textured or smooth implants for breast augmentation? Three year follow-up of a prospective randomised controlled trial. Br J Plast Surg 1997;50:99-105.
41. Collis N, Coleman D, Foo IT, et al. Ten-year review of a prospective randomized controlled trial of textured versus smooth subglandular silicone gel breast implants. Plast Reconstr Surg 2000;106:786-791.
42. Vieira VJ, D'Acampora A, Neves FS, et al. Capsular Contracture In Silicone Breast Implants: Insights From Rat Models. An Acad Bras Cienc 2016;88:1459-1470.
43. Isom C, Kapoor V, Wilson L, et al. Breast implant capsules are partially composed of bone marrow-derived cells. Ann Plast Surg 2007;58:377-380.
44. Katzel EB, Koltz PF, Tierney R, et al. A novel animal model for studying silicone gel-related capsular contracture. Plast Reconstr Surg 2010;126:1483-1491.
45. Christian S, Winkler R, Helfrich I, et al. Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells. Am J Pathol 2008;172:486-494.
46. Lax S, Hardie DL, Wilson A, et al. The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansion. Eur J Immunol 2010;40:1884-1889.
47. Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol 2008;20:86-100.
48. Hernandez-Pando R, Bornstein QL, Aguilar Leon D, et al. Inflammatory cytokine production by immunological and foreign body multinucleated giant cells. Immunology 2000;100:352-358.
49. Song E, Ouyang N, Horbelt M, et al. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol 2000;204:19-28.
50. Adams WP, Jr., Haydon MS, Raniere J, Jr., et al. A rabbit model for capsular contracture: development and clinical implications. Plast Reconstr Surg 2006;117:1214-1219; discussion 1220-1211.
51. Smahel J. Histology of the capsules causing constrictive fibrosis around breast implants. Br J Plast Surg 1977;30:324-329.
52. Bui JM, Perry T, Ren CD, et al. Histological characterization of human breast implant capsules. Aesthetic Plast Surg 2015;39:306-315.
53. Zelensky AN, Gready JE. The C-type lectin-like domain superfamily. FEBS J 2005;272:6179-6217.