新型西罗莫司药物涂层疝补片的制备及动物实验研究
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摘要
目的通过化学反应将西罗莫司嫁接到聚丙烯(polypropylene,PP)补片表面,制备新型西罗莫司药物涂层聚丙烯(sirolimus drug-coated polypropylene,SRL-PP)补片,并将其应用于动物实验,研究新型补片抗粘连性能。方法将西罗莫司通过化学反应的方法嫁接到PP补片表面制备SRL-PP补片,与PP补片组(PP组)及聚乙二醇修饰的聚丙烯(polyethylene glycol modified polypropylene,PEG-PP)补片组(PEG-PP组)形成对照。对3组补片分别进行表征分析(红外光谱检测、接触角测量),检测其拉伸性能,并分别通过手术植入大鼠腹腔,通过观察大鼠腹腔内粘连情况、组织病理学改变等研究新型西罗莫司药物涂层补片抗粘连性能。结果红外光谱分析表明SRL-PP补片在波长1 643 cm–1(酰胺基)处有新的吸收峰出现,提示西罗莫司成功上载到补片表面;SRL-PP补片亲水性优良,为腹膜间皮细胞生长提供了有利条件;SRL-PP补片力学性能同PP补片及PEG-PP补片无明显差异;SRL-PP组的大鼠腹腔粘连程度[(1.00±0.58)分]明显低于PP组[(5.17±0.69)分]及PEG-PP组[(4.00±0.58)分],且SRL-PP组与PP组比较,差异有统计学意义(t=2.76,P<0.05);SRL-PP组粘连组织在炎性细胞数量及炎性细胞因子表达水平上均明显低于PP组和PEG-PP组。结论通过化学反应的方法成功将西罗莫司上载到PP补片表面,动物实验表明西罗莫司药物涂层补片可以明显减轻大鼠腹腔粘连,为其临床试验及应用提供了依据。
Objective To prepare a new sirolimus drug-coated polypropylene(SRL-PP) mesh by grafting he sirolimus onto the surface of the polypropylene(PP) mesh via chemical reaction, and to apply the new mesh to animal experiment to explore its anti-adhesion properties. Methods The sirolimus was grafted onto the surface of the mesh by chemical reaction to prepare the SRL-PP mesh, which was compared with the PP mesh and the polyethylene glycol modified polypropylene(PEG-PP) mesh. The three groups of meshes were respectively characterized(infrared spectroscopy test, contact angle measurement), and their tensile property was measured. These meshes were implanted into the abdominal cavity of the rats respectively. The anti-adhesion properties of the new sirolimus drug-coated mesh was studied by intraperitoneal adhesion and histopathological change in rats. Results The results of infrared spectrum analysis showed that there was a new absorption peak at the wavelength 1 643 cm–1(amide group) of SRL-PP mesh,suggesting that sirolimus drug was successfully uploaded onto the surface of the mesh; the SRL-PP mesh was excellent in hydrophilicity, which provided a favorable condition for the growth of peritoneal mesothelial cells. There was no significant difference in mechanical properties between SRL-PP mesh and PP mesh or PEG-PP mesh, which provided a good mechanical guarantee for clinical application. The degree of abdominal adhesion in SRL-PP mesh group(1.00±0.58)was significantly lower than that in PP mesh group(5.17±0.69) and PEG-PP mesh group(4.00±0.58), and the tD value between SRL-PP mesh group and PP mesh group was 2.76(P<0.05). The number of inflammatory cells and the expression of inflammatory cytokines in the adhesion tissue in SRL-PP mesh group were significantly lower than those in PP mesh group and PEG-PP mesh group. Conclusions The sirolimus is successfully loaded onto the surface in the PP mesh by chemical reaction. Animal experiment shows that the sirolimus drug-coated mesh can significantly reduce the abdominal adhesion of the rats, which provides a basis for clinical trial and application.
Objective To prepare a new sirolimus drug-coated polypropylene(SRL-PP) mesh by grafting he sirolimus onto the surface of the polypropylene(PP) mesh via chemical reaction, and to apply the new mesh to animal experiment to explore its anti-adhesion properties. Methods The sirolimus was grafted onto the surface of the mesh by chemical reaction to prepare the SRL-PP mesh, which was compared with the PP mesh and the polyethylene glycol modified polypropylene(PEG-PP) mesh. The three groups of meshes were respectively characterized(infrared spectroscopy test, contact angle measurement), and their tensile property was measured. These meshes were implanted into the abdominal cavity of the rats respectively. The anti-adhesion properties of the new sirolimus drug-coated mesh was studied by intraperitoneal adhesion and histopathological change in rats. Results The results of infrared spectrum analysis showed that there was a new absorption peak at the wavelength 1 643 cm–1(amide group) of SRL-PP mesh,suggesting that sirolimus drug was successfully uploaded onto the surface of the mesh; the SRL-PP mesh was excellent in hydrophilicity, which provided a favorable condition for the growth of peritoneal mesothelial cells. There was no significant difference in mechanical properties between SRL-PP mesh and PP mesh or PEG-PP mesh, which provided a good mechanical guarantee for clinical application. The degree of abdominal adhesion in SRL-PP mesh group(1.00±0.58)was significantly lower than that in PP mesh group(5.17±0.69) and PEG-PP mesh group(4.00±0.58), and the tD value between SRL-PP mesh group and PP mesh group was 2.76(P<0.05). The number of inflammatory cells and the expression of inflammatory cytokines in the adhesion tissue in SRL-PP mesh group were significantly lower than those in PP mesh group and PEG-PP mesh group. Conclusions The sirolimus is successfully loaded onto the surface in the PP mesh by chemical reaction. Animal experiment shows that the sirolimus drug-coated mesh can significantly reduce the abdominal adhesion of the rats, which provides a basis for clinical trial and application.
引文
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2Kingsnorth A,LeBlanc K.Hernias:inguinal and incisional.Lancet,2003,362(9395):1561-1571.
3Kamel RM.Prevention of postoperative peritoneal adhesions.Eur J Obstet Gynecol Reprod Biol,2010,150(2):111-118.
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7Hosseini A,Akhavan S,Menshaei M,et al.Effects of streptokinase and normal saline on the incidence of intra-abdominal adhesion 1 week and 1 month after laparotomy in rats.Adv Biomed Res,2018,7:16.
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9Sadava EE,Krpata DM,Gao Y,et al.Wound healing process and mediators:implications for modulations for hernia repair and mesh integration.J Biomed Mater Res Part A,2014,102(1):295-302.
10Poppas DP,Sung JJ,Magro CM,et al.Hydrogel coated mesh decreases tissue reaction resulting from polypropylene mesh implant:implication in hernia repair.Hernia,2016,20(4):623-632.
11Scheidback H,Tamme C,Tannapfel A,et al.In vivo studies comparing the biocompatibility of various polypropylene meshes and their handling properties during endoscopic total extraperitoneal(TEP)patchplasty:an experimental study in pigs.Surg Endosc,2004,18(2):211-220.
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13Laschke MW,H?ufel JM,Roller J,et al.Rapamycin,but not cyclosporine A,inhibits vascularization and incorporation of implanted surgical meshes.Transpl Int,2009,22(6):654-662.
14Shah PR,Kute VB,Patel HV,et al.Therapeutic drug monitoring of sirolimus.Clinical Queries:Nephrology,2015,4:44-49.
15Dilling DF,Nair A,Gries CJ,et al.Use of sirolimus in patients with lymphangioleiomyomatosis(LAM)on waiting lists for lung transplant(LTX).J Heart Lung Transplant,2018,37(4):s457.
16Lai ZW,Kelly R,Winans T,et al.Sirolimus in patients with clinically active systemic lupus erythematosus resistant to,or intolerant of,conventional medications:a single-arm,open-label,phase 1/2 trial.Lancet,2018,391(10126):1186-1196.
17任常,朱兰.盆腹腔手术后粘连的分类及评价方法.中华妇产科杂志,2012,47(4):317-318.
18Ye XL,Han XY,Wei B,et al.Ventral hernia repair in rat using nanofibrous polylactic acid/polypropylene meshes.Nanomedicine(Lond),2018,13(17):2187-2199.
19Grant S,Ramshaw B.Progress in synthetic prosthetic mesh for ventral hernia repair//LeBlanc K,Kingsnorth A,Sanders D.Management of abdominal hernias.5 ed.Springer,Cham,2018:173-178.
20Zhang C,Salick MR,Cordie TM,et al.Incorporation of poly(ethylene glycol)grafted cellulose nanocrystals in poly(lactic acid)electrospun nanocomposite fibers as potential scaffolds for bone tissue engineering.Mater Sci Eng C Mater Biol Appl,2015,49:463-471.
21Kong CY,Lai LL,Khoo AYY,et al.Inflammatory reaction to fish oil coated polypropylene mesh used for laparoscopic incisional hernia repair:a case report.BMC Surg,2016,16:8.
22Vermet G,Degoutin S,Chai F,et al.Cyclodextrin modified PLLAparietal reinforcement implant with prolonged antibacterial activity.Acta Biomater,2017,53:222-232.
23Bayhan Z,Zeren S,Kocak FE,et al.Antiadhesive and antiinflammatory effects of pirfenidone in postoperative intraabdominal adhesion in an experimental rat model.J Surg Res,2016,201(2):348-355.
24宋宇,张慧,刘瑞丽,等.钩藤碱通过抑Smad信号通路磷酸化减轻腹腔粘连发生的作用机制.药学学报,2017,52(2):229-235.
2Kingsnorth A,LeBlanc K.Hernias:inguinal and incisional.Lancet,2003,362(9395):1561-1571.
3Kamel RM.Prevention of postoperative peritoneal adhesions.Eur J Obstet Gynecol Reprod Biol,2010,150(2):111-118.
4Boland GM,Weigel RJ.Formation and prevention of postoperative abdominal adhesions.J Surg Res,2006,132(1):3-12.
5Sahbaz A,Aynioglu O,Isik H,et al.Bromelain:a natural proteolytic for intra-abdominal adhesion prevention.Int J Surg,2015,14:7-11.
6Coleman MG,McLain AD,Moran BJ.Impact of previous surgery on time taken for incision and division of adhesions during laparotomy.Dis Colon Rectum,2000,43(9):1297-1299.
7Hosseini A,Akhavan S,Menshaei M,et al.Effects of streptokinase and normal saline on the incidence of intra-abdominal adhesion 1 week and 1 month after laparotomy in rats.Adv Biomed Res,2018,7:16.
8Bryers JD,Giachelli CM,Ratner BD.Engineering biomaterials to integrate and heal:the biocompatibility paradigm shifts.Biotechnol Bioeng,2012,109(8):1898-1911.
9Sadava EE,Krpata DM,Gao Y,et al.Wound healing process and mediators:implications for modulations for hernia repair and mesh integration.J Biomed Mater Res Part A,2014,102(1):295-302.
10Poppas DP,Sung JJ,Magro CM,et al.Hydrogel coated mesh decreases tissue reaction resulting from polypropylene mesh implant:implication in hernia repair.Hernia,2016,20(4):623-632.
11Scheidback H,Tamme C,Tannapfel A,et al.In vivo studies comparing the biocompatibility of various polypropylene meshes and their handling properties during endoscopic total extraperitoneal(TEP)patchplasty:an experimental study in pigs.Surg Endosc,2004,18(2):211-220.
12Zhang Z,Zhang T,Li J,,et al.Preparation of poly(L-lactic acid)-modified polypropylene mesh and its antiadhesion in experimental abdominal wall defect repair.J Biome Mater Res B Appl Biomater,2014,102(1):12-21.
13Laschke MW,H?ufel JM,Roller J,et al.Rapamycin,but not cyclosporine A,inhibits vascularization and incorporation of implanted surgical meshes.Transpl Int,2009,22(6):654-662.
14Shah PR,Kute VB,Patel HV,et al.Therapeutic drug monitoring of sirolimus.Clinical Queries:Nephrology,2015,4:44-49.
15Dilling DF,Nair A,Gries CJ,et al.Use of sirolimus in patients with lymphangioleiomyomatosis(LAM)on waiting lists for lung transplant(LTX).J Heart Lung Transplant,2018,37(4):s457.
16Lai ZW,Kelly R,Winans T,et al.Sirolimus in patients with clinically active systemic lupus erythematosus resistant to,or intolerant of,conventional medications:a single-arm,open-label,phase 1/2 trial.Lancet,2018,391(10126):1186-1196.
17任常,朱兰.盆腹腔手术后粘连的分类及评价方法.中华妇产科杂志,2012,47(4):317-318.
18Ye XL,Han XY,Wei B,et al.Ventral hernia repair in rat using nanofibrous polylactic acid/polypropylene meshes.Nanomedicine(Lond),2018,13(17):2187-2199.
19Grant S,Ramshaw B.Progress in synthetic prosthetic mesh for ventral hernia repair//LeBlanc K,Kingsnorth A,Sanders D.Management of abdominal hernias.5 ed.Springer,Cham,2018:173-178.
20Zhang C,Salick MR,Cordie TM,et al.Incorporation of poly(ethylene glycol)grafted cellulose nanocrystals in poly(lactic acid)electrospun nanocomposite fibers as potential scaffolds for bone tissue engineering.Mater Sci Eng C Mater Biol Appl,2015,49:463-471.
21Kong CY,Lai LL,Khoo AYY,et al.Inflammatory reaction to fish oil coated polypropylene mesh used for laparoscopic incisional hernia repair:a case report.BMC Surg,2016,16:8.
22Vermet G,Degoutin S,Chai F,et al.Cyclodextrin modified PLLAparietal reinforcement implant with prolonged antibacterial activity.Acta Biomater,2017,53:222-232.
23Bayhan Z,Zeren S,Kocak FE,et al.Antiadhesive and antiinflammatory effects of pirfenidone in postoperative intraabdominal adhesion in an experimental rat model.J Surg Res,2016,201(2):348-355.
24宋宇,张慧,刘瑞丽,等.钩藤碱通过抑Smad信号通路磷酸化减轻腹腔粘连发生的作用机制.药学学报,2017,52(2):229-235.