術後沾黏是臨床上很嚴重的問題，不但造成病人需要二次手術來去除，倘若使病人出現慢性疼痛和女性不孕症，也會造成很大的經濟成本。沾黏是指兩個原本應該分開的組織或是器官互相連在一起，目前缺乏有效的預防及診斷方式。在臨床上最常使用的預防沾黏的方法為給予物理屏障，直接阻隔兩個傷口以防止直接碰觸，臨床上較常被使用的材料為透明質酸為基底的材料，因為此分子為天然化合物，可以在體內由酶進行分解，經由體內吸收，故可以避免需要將材料再次取出的問題。在物理屏障的使用上，出現三個問題，第一點天然分子的降解過於快速，第二點材料無法完全覆蓋不規則的損傷，第三點材料無法黏附在傷口表面上，還有一個現實面的問題為目前臨床使用的防止沾黏的材料過於昂貴。
本研究希望可以製備出一種價格較為低廉、可依照病患傷口需求而調控降解速度、材料可以完整覆蓋且容易黏附於傷口表面，故選用體內含量最豐富的蛋白質-白蛋白，不但擁有很好的生物相容性，也可以利用抽血的方式容易取得。本研究將白蛋白修飾上用酪胺(tyramine)或是甲基丙烯酸 2-氨基乙酯鹽酸鹽(2-Aminoethyl methacrylate hydrochloride, AEMA)，可利用化學交聯及光交聯的方式形成三維結構的水凝膠，可以藉由調控交聯劑的濃度或是照光時間，以調控水凝膠的機械性質，因此調控降解時間、藥物釋放的劑量，也可以製備出具圖樣化的水凝膠。
研究結果發現以白蛋白為基底的水凝膠，在材料鑑定中，證實具備動態調控機械性質及空間化的特性；在細胞實驗中，證實製備出可選擇性貼附的表面；體內降解實驗中，證實此水凝膠在體內存留的時間比可降解的天然高分子材料具有大範圍可調控的降解時間；腹腔模型實驗中，證實此水凝膠具有預防沾黏的特性。

Postoperative adhesion is a serious clinical problem, which not only causes the patient to need secondary surgery to remove, but also causes chronic pain and female infertility, which also causes great economic costs. Adhesion refers to two tissues or organs that should be separated from each other. There is currently no effective prevention and diagnosis method. The most commonly used method of preventing adhesion in the clinic is to give a physical barrier that directly blocks the two wounds to prevent direct contact. The material that is currently used more often is a hyaluronic acid-based material. Since this molecule is a natural compound, the problem of requiring the material to be removed again can be avoided. In the use of physical barriers, three problems arise. The first point of degradation of natural molecules is too fast, the second point of material cannot completely cover irregular damage, and the third point of material cannot adhere to the surface of the wound. There is also a real problem that the currently used anti-adhesive materials are too expensive.
This study focus on developing a material that is relatively inexpensive and has controllable mechanical and biodegrdation properties, easily fully coverage on wounds and tissue adhesive. Therefore, the most abundant protein-albumin in the body is selected, which not only has good biocompatibility, but also can be easily obtained by means of blood drawing. In this study, albumin was modified with tyramine or 2-Aminoethyl methacrylate hydrochloride (AEMA) to form a three-dimensional hydrogel by chemical crosslinking and photocrosslinking. The concentration of crosslinked reagents and light exposure time can adjust the mechanical properties of the hydrogel, thus regulating the degradation time and the dosage of drug release and can also prepare a patterned hydrogel.
The results showed that the albumin-based hydrogel have dynamic mechanical properties and spatialization characteristics in material identification. In cell experiments, it was confirmed that a selectively anti-adhesive surface was prepared; in vivo degradation experiments It was confirmed that the hydrogel stayed in the body for a longer period of time than other natural degradable polymer material; in the abdominal cavity model test, the hydrogel was confirmed to have the property of preventing adhesion.

1. Alpay, Z., G.M. Saed, and M.P. Diamond, Postoperative adhesions: From formation to prevention. Seminars in Reproductive Medicine, 2008. 26(4): p. 313-321.
2. Rojo, D. and P. Conget, Acellular derivatives of mesenchymal stem cells prevent peritoneal adhesions in an animal model. Journal of Surgical Research, 2018. 223: p. 198-206.
3. Imai, A. and N. Suzuki, Topical non-barrier agents for postoperative adhesion prevention in animal models. Eur J Obstet Gynecol Reprod Biol, 2010. 149(2): p. 131-5.
4. Tabibian, N., E. Swehli, A. Boyd, A. Umbreen, and J.H. Tabibian, Abdominal adhesions: A practical review of an often overlooked entity. Ann Med Surg (Lond), 2017. 15: p. 9-13.
5. Lee, J.E., S.M. Abuzar, Y. Seo, H. Han, Y. Jeon, E.J. Park, S.H. Baik, and S.J. Hwang, Oxaliplatin-loaded chemically cross-linked hydrogels for prevention of postoperative abdominal adhesion and colorectal cancer therapy. International Journal of Pharmaceutics, 2019. 565: p. 50-58.
6. Lih, E., S.H. Oh, Y.K. Joung, J.H. Lee, and D.K. Han, Polymers for cell/tissue anti-adhesion. Progress in Polymer Science, 2015. 44: p. 28-61.
7. Li, L., N. Wang, X. Jin, R. Deng, S.H. Nie, L. Sun, Q.J. Wu, Y.Q. Wei, and C.Y. Gong, Biodegradable and injectable in situ cross-linking chitosan-hyaluronic acid based hydrogels for postoperative adhesion prevention. Biomaterials, 2014. 35(12): p. 3903-3917.
8. van Goor, H., Consequences and complications of peritoneal adhesions. Colorectal Disease, 2007. 9: p. 25-34.
9. Hellebrekers, B.W. and T. Kooistra, Pathogenesis of postoperative adhesion formation. Br J Surg, 2011. 98(11): p. 1503-16.
10. Kamel, R.M., Prevention of postoperative peritoneal adhesions. Eur J Obstet Gynecol Reprod Biol, 2010. 150(2): p. 111-8.
11. Belluco, C., F. Meggiolaro, D. Pressato, A. Pavesio, E. Bigon, M. Dona, M. Forlin, D. Nitti, and M. Lise, Prevention of postsurgical adhesions with an autocrosslinked hyaluronan derivative gel. J Surg Res, 2001. 100(2): p. 217-21.
12. Moris, D., J. Chakedis, A.A. Rahnemai-Azar, A. Wilson, M.M. Hennessy, A. Athanasiou, E.W. Beal, C. Argyrou, E. Felekouras, and T.M. Pawlik, Postoperative Abdominal Adhesions: Clinical Significance and Advances in Prevention and Management. J Gastrointest Surg, 2017. 21(10): p. 1713-1722.
13. Risberg, B., Adhesions: preventive strategies. The European journal of surgery. Supplement.:= Acta chirurgica. Supplement, 1997(577): p. 32-39.
14. Sakari, T., R. Sjodahl, L. Pahlman, and U. Karlbom, Role of icodextrin in the prevention of small bowel obstruction. Safety randomized patients control of the first 300 in the ADEPT trial. Colorectal Dis, 2016. 18(3): p. 295-300.
15. Hong, M.K. and D.C. Ding, Seprafilm(R) Application Method in Laparoscopic Surgery. JSLS, 2017. 21(1).
16. Ward, B.C. and A. Panitch, Abdominal adhesions: current and novel therapies. J Surg Res, 2011. 165(1): p. 91-111.
17. De Laco, P.A., M. Stefanetti, D. Pressato, S. Piana, M. Donà, A. Pavesio, and L. Bovicelli, A novel hyaluronan-based gel in laparoscopic adhesion prevention: preclinical evaluation in an animal model. Fertility and sterility, 1998. 69(2): p. 318-323.
18. Zhang, Z., J. Ni, L. Chen, L. Yu, J. Xu, and J. Ding, Biodegradable and thermoreversible PCLA-PEG-PCLA hydrogel as a barrier for prevention of post-operative adhesion. Biomaterials, 2011. 32(21): p. 4725-36.
19. Haderermuller.
20. Jafari-Sabet, M., A. Shishegar, A.R. Saeedi, and S. Ghahari, Pentoxifylline Increases Antiadhesion Effect of Streptokinase on Postoperative Adhesion Formation: Involvement of Fibrinolytic Pathway. Indian J Surg, 2015. 77(Suppl 3): p. 837-42.
21. Ivarsson, M., L. Holmdahl, G. Franzen, and B. Risberg, Cost of bowel obstruction resulting from adhesions. The European journal of surgery= Acta chirurgica, 1997. 163(9): p. 679-684.
22. Schnuriger, B., G. Barmparas, B.C. Branco, T. Lustenberger, K. Inaba, and D. Demetriades, Prevention of postoperative peritoneal adhesions: a review of the literature. Am J Surg, 2011. 201(1): p. 111-21.
23. Singh, S.R., E. Bianchi, K. Boekelheide, M. Sigman, D.J. Lamb, S.J. Hall, and K. Hwang, Ghrelin Inhibits Post-Operative Adhesions via Blockage of the TGF-β Signaling Pathway. Plos One, 2016. 11(4).
24. Boland, G.M. and R.J. Weigel, Formation and prevention of postoperative abdominal adhesions. J Surg Res, 2006. 132(1): p. 3-12.
25. Hellebrekers, B.W., T.C. Trimbos-Kemper, J.B.M. Trimbos, J.J. Emeis, and T. Kooistra, Use of fibrinolytic agents in the prevention of postoperative adhesion formation. Fertility and sterility, 2000. 74(2): p. 203-212.
26. Rout, U.K. and M.P. Diamond, Role of plasminogen activators during healing after uterine serosal lesioning in the rat. Fertility and sterility, 2003. 79(1): p. 138-145.
27. Holmdahl, L., E. Eriksson, B.I. Eriksson, and B. Risberg, Depression of peritoneal fibrinolysis during operation is a local response to trauma. Surgery, 1998. 123(5): p. 539-544.
28. Bruggmann, D., G. Tchartchian, M. Wallwiener, K. Munstedt, H.R. Tinneberg, and A. Hackethal, Intra-abdominal adhesions: definition, origin, significance in surgical practice, and treatment options. Dtsch Arztebl Int, 2010. 107(44): p. 769-75.
29. Ghonge, N.P. and S.D. Ghonge, Computed tomography and magnetic resonance imaging in the evaluation of pelvic peritoneal adhesions: What radiologists need to know? The Indian journal of radiology & imaging, 2014. 24(2): p. 149.
30. Mershina, E., E. Vasilyeva, V. Sinitsyn, V. Lyadov, and V. Eghiev. Functional cine-MRI in detection of adhesive disease following ventral hernia repair. 2010. European Congress of Radiology 2010.
31. Buhmann-Kirchhoff, S., R. Lang, C. Kirchhoff, H.O. Steitz, K.W. Jauch, M. Reiser, and A. Lienemann, Functional cine MR imaging for the detection and mapping of intraabdominal adhesions: method and surgical correlation. European radiology, 2008. 18(6): p. 1215-1223.
32. Boland, G.M. and R.J. Weigel, Formation and prevention of postoperative abdominal adhesions. Journal of Surgical Research, 2006. 132(1): p. 3-12.
33. Cheong, Y., S. Laird, T. Li, J. Shelton, W. Ledger, and I. Cooke, Peritoneal healing and adhesion formation/reformation. Human reproduction update, 2001. 7(6): p. 556-566.
34. Brüggmann, D., G. Tchartchian, M. Wallwiener, K. Münstedt, H.-R. Tinneberg, and A. Hackethal, Intra-abdominal adhesions: definition, origin, significance in surgical practice, and treatment options. Deutsches Ärzteblatt International, 2010. 107(44): p. 769.
35. Gervin, A.S., C.L. Puckett, and D. Silver, Serosal hypofibrinolysis: a cause of postoperative adhesions. The American Journal of Surgery, 1973. 125(1): p. 80-88.
36. Heuer, G.J., R.T. Miller, and R. Matas, In memoriam: William Stewart Halsted 1852-1922. Archives of Surgery, 1925. 10(1): p. 293-305.
37. Yesildaglar, N. and P.R. Koninckx, Adhesion formation in intubated rabbits increases with high insufflation pressure during endoscopic surgery. Human Reproduction, 2000. 15(3): p. 687-691.
38. Ahmad, G., H. O'Flynn, A. Hindocha, and A. Watson, Barrier agents for adhesion prevention after gynaecological surgery. Cochrane Database of Systematic Reviews, 2015(4).
39. Arung, W., M. Meurisse, and O. Detry, Pathophysiology and prevention of postoperative peritoneal adhesions. World J Gastroenterol, 2011. 17(41): p. 4545-53.
40. Hosie, K., J.A. Gilbert, D. Kerr, C.B. Brown, and E.M. Peers, Fluid dynamics in man of an intraperitoneal drug delivery solution: 4% icodextrin. Drug Deliv, 2001. 8(1): p. 9-12.
41. Correa-Rovelo, J.M., G. Cleva Villanueva-López, R. Medina-Santillan, R. Carrillo-Esper, and A. Díaz-Girón-Gidi, Intestinal obstruction secondary to postoperative adhesion formation in abdominal surgery. Review literature. Cirugía y Cirujanos (English Edition), 2015. 83(4): p. 345-351.
42. Menzies, D., M.H. Pascual, M.K. Walz, J.J. Duron, F. Tonelli, A. Crowe, A. Knight, and A. Registry, Use of icodextrin 4% solution in the prevention of adhesion formation following general surgery: from the multicentre ARIEL Registry. Ann R Coll Surg Engl, 2006. 88(4): p. 375-82.
43. diZerega, G.S., Contemporary adhesion prevention. Fertility and Sterility, 1994. 61(2): p. 219-235.
44. Reijnen, M.M., E.M. Skrabut, V.A. Postma, J.W. Burns, and H. Van Goor, Polyanionic polysaccharides reduce intra-abdominal adhesion and abscess formation in a rat peritonitis model. Journal of Surgical Research, 2001. 101(2): p. 248-253.
45. Burns, J.W., K. Skinner, M.J. Colt, L. Burgess, R. Rose, and M.P. Diamond, A hyaluronate based gel for the prevention of postsurgical adhesions: evaluation in two animal species. Fertility and sterility, 1996. 66(5): p. 814-821.
46. Yeo, Y., C.B. Highley, E. Bellas, T. Ito, R. Marini, R. Langer, and D.S. Kohane, In situ cross-linkable hyaluronic acid hydrogels prevent post-operative abdominal adhesions in a rabbit model. Biomaterials, 2006. 27(27): p. 4698-705.
47. Johns, D.B., G.M. Keyport, F. Hoehler, and I.A.P.S. Group, Reduction of postsurgical adhesions with Intergel® adhesion prevention solution: a multicenter study of safety and efficacy after conservative gynecologic surgery. Fertility and sterility, 2001. 76(3): p. 595-604.
48. Sakai, S., K. Ueda, and M. Taya, Peritoneal adhesion prevention by a biodegradable hyaluronic acid-based hydrogel formed in situ through a cascade enzyme reaction initiated by contact with body fluid on tissue surfaces. Acta Biomater, 2015. 24: p. 152-8.
49. Chen, C.H., S.H. Chen, S.H. Mao, M.J. Tsai, P.Y. Chou, C.H. Liao, and J.P. Chen, Injectable thermosensitive hydrogel containing hyaluronic acid and chitosan as a barrier for prevention of postoperative peritoneal adhesion. Carbohydr Polym, 2017. 173: p. 721-731.
50. Sandoval, P., J.A. Jimenez-Heffernan, G. Guerra-Azcona, M.L. Perez-Lozano, A. Rynne-Vidal, P. Albar-Vizcaino, F. Gil-Vera, P. Martin, M.J. Coronado, C. Barcena, J. Dotor, P.L. Majano, A.A. Peralta, and M. Lopez-Cabrera, Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions. J Pathol, 2016. 239(1): p. 48-59.
51. Hu, M.H., K.C. Yang, Y.H. Sun, Y.C. Chen, S.H. Yang, and F.H. Lin, In situ forming oxidised hyaluronic acid/adipic acid dihydrazide hydrogel for prevention of epidural fibrosis after laminectomy. Eur Cell Mater, 2017. 34: p. 307-320.
52. Arabi, S.H., B. Aghelnejad, C. Schwieger, A. Meister, A. Kerth, and D. Hinderberger, Serum albumin hydrogels in broad pH and temperature ranges: characterization of their self-assembled structures and nanoscopic and macroscopic properties. Biomater Sci, 2018. 6(3): p. 478-492.
53. Day, Y.S. and D.G. Myszka, Characterizing a drug's primary binding site on albumin. Journal of pharmaceutical sciences, 2003. 92(2): p. 333-343.
54. Upadhyay, A., R. Kandi, and C.P. Rao, Injectable, Self-Healing, and Stress Sustainable Hydrogel of BSA as a Functional Biocompatible Material for Controlled Drug Delivery in Cancer Cells. ACS Sustainable Chemistry & Engineering, 2018. 6(3): p. 3321-3330.
55. Baler, K., R. Michael, I. Szleifer, and G.A. Ameer, Albumin hydrogels formed by electrostatically triggered self-assembly and their drug delivery capability. Biomacromolecules, 2014. 15(10): p. 3625-3633.
56. Aiyelabegan, H.T., S.S.Z. Zaidi, S. Fanuel, A. Eatemadi, M.T.K. Ebadi, and E. Sadroddiny, Albumin-based biomaterial for lung tissue engineering applications. International Journal of Polymeric Materials and Polymeric Biomaterials, 2016. 65(16): p. 853-861.
57. Park, K., Albumin: a versatile carrier for drug delivery. Journal of Controlled Release, 2012. 1(157): p. 3.
58. Ren, K., A. Dusad, R. Dong, and L. Quan, Albumin as a delivery carrier for rheumatoid arthritis. J Nanomed Nanotechol, 2013. 4(4): p. 176.
59. Liu, F., J. Mu, and B. Xing, Recent advances on the development of pharmacotherapeutic agents on the basis of human serum albumin. Current pharmaceutical design, 2015. 21(14): p. 1866-1888.
60. Sun, Y. and Y. Huang, Disulfide-crosslinked albumin hydrogels. Journal of Materials Chemistry B, 2016. 4(16): p. 2768-2775.
61. Taverna, M., A.L. Marie, J.P. Mira, and B. Guidet, Specific antioxidant properties of human serum albumin. Ann Intensive Care, 2013. 3(1): p. 4.
62. Arroyo, V., R. Garcia-Martinez, and X. Salvatella, Human serum albumin, systemic inflammation, and cirrhosis. J Hepatol, 2014. 61(2): p. 396-407.
63. Levitt, D.G. and M.D. Levitt, Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements. Int J Gen Med, 2016. 9: p. 229-55.
64. Allen, L.T., M. Tosetto, I.S. Miller, D.P. O'Connor, S.C. Penney, I. Lynch, A.K. Keenan, S.R. Pennington, K.A. Dawson, and W.M. Gallagher, Surface-induced changes in protein adsorption and implications for cellular phenotypic responses to surface interaction. Biomaterials, 2006. 27(16): p. 3096-108.
65. Andrade, J. and V. Hlady, Protein adsorption and materials biocompatibility: a tutorial review and suggested hypotheses, in Biopolymers/Non-Exclusion HPLC. 1986, Springer. p. 1-63.
66. Cai, Y. and D.K. Schwartz, Influence of Protein Surface Coverage on Anomalously Strong Adsorption Sites. ACS Appl Mater Interfaces, 2016. 8(1): p. 511-20.
67. Goh, S.C., Y. Luan, X. Wang, H. Du, C. Chau, H.E. Schellhorn, J.L. Brash, H. Chen, and Q. Fang, Polydopamine–polyethylene glycol–albumin antifouling coatings on multiple substrates. Journal of Materials Chemistry B, 2018. 6(6): p. 940-949.
68. Zhao, Z., R. Hu, H. Shi, Y. Wang, L. Ji, P. Zhang, and Q. Zhang, Design of ruthenium-albumin hydrogel for cancer therapeutics and luminescent imaging. J Inorg Biochem, 2019. 194: p. 19-25.
69. Baler, K., O.A. Martin, M.A. Carignano, G.A. Ameer, J.A. Vila, and I. Szleifer, Electrostatic unfolding and interactions of albumin driven by pH changes: a molecular dynamics study. J Phys Chem B, 2014. 118(4): p. 921-30.
70. Tada, D., T. Tanabe, A. Tachibana, and K. Yamauchi, Albumin-crosslinked alginate hydrogels as sustained drug release carrier. Materials Science and Engineering: C, 2007. 27(4): p. 870-874.
71. Zhou, Y., L. Gao, J. Peng, M. Xing, Y. Han, X. Wang, Y. Xu, and J. Chang, Bioglass Activated Albumin Hydrogels for Wound Healing. Adv Healthc Mater, 2018. 7(16): p. e1800144.
72. Borzova, V.A., K.A. Markossian, N.A. Chebotareva, S.Y. Kleymenov, N.B. Poliansky, K.O. Muranov, V.A. Stein-Margolina, V.V. Shubin, D.I. Markov, and B.I. Kurganov, Kinetics of Thermal Denaturation and Aggregation of Bovine Serum Albumin. PLoS One, 2016. 11(4): p. e0153495.
73. Scano, P., L.R. Cagliani, and R. Consonni, 1H NMR characterisation of the lipid fraction and the metabolite profiles of Fossa (pit) cheese. International Dairy Journal, 2019. 90: p. 39-44.
74. Tada, D., T. Tanabe, A. Tachibana, and K. Yamauchi, Drug release from hydrogel containing albumin as crosslinker. J Biosci Bioeng, 2005. 100(5): p. 551-5.