离子束辅助沉积羟基磷灰石修饰的钛人工角膜实验研究
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摘要
目的
采用离子束辅助沉积(IBAD)技术在人工角膜钛支架表面快速沉积羟基磷灰石涂层;采用美国Lambda Research Corporation开发的光学设计软件OSLO进行人工角膜镜柱的设计和制作。组织病理学和分子学水平评价人工角膜纯钛支架经羟基磷灰石表面修饰后其生物相容性。通过体内动物实验观察人工角膜在动物体内的组织病理学改变。
方法
1.制备三襻式人工角膜纯钛支架,以此作为基底,使用电子束蒸发器和离子枪,在一定电压和电流的情况下对钛支架进行预清沈,并通过离子束轰击使磷酸钙蒸发剂在旋状的钛板上沉积形成磷酸钙膜制备HA-Ti人工角膜支架。按照几何光学原理,采用美国Lambda Research Corporation开发的光学设计软件进行镜柱设计,以聚甲基丙烯酸甲酯(PMMA)为原材料制作人工角膜柱镜。
2.80只SD大鼠随机分为2组,实验组右眼角膜基质层内植入HA-Ti人工角膜支架,对照组仅作角膜板层切口而不植入支架作为手术对照组,术后裂隙灯观察角膜水肿及新生血管产生情况。术后不同时间取材,进行HE染色、特殊染色、免疫组织化学染色、电镜以及RT-PCR检测,观察支架与组织愈合过程中炎症反应、组织修复及相关因子表达情况。
3.20只角膜碱烧伤的新西兰白兔,在角膜基质层间植入HA-Ti人工角膜支架(包括连接环)3个月后随机分为A、B两组,A组切除支架中央全层角膜后,旋入实验一中设计制作的人工角膜镜柱,B组则在植入后使用脱细胞真皮覆盖于角膜表面。术后观察前房炎症反应,同时行HE染色和免疫荧光染色。
结果
1.能量色散光谱镜显示通过IBAD形成的沉积膜中Ca的含量提高;与Kpro支架基底之间的结合力高于其他喷涂技术。根据光学设计软件,使用聚甲基丙烯酸甲酯,制作出直径为3.0 mm,长度为3.5 mm的人工角膜镜柱。
2.对照组术后早期角膜创口以急性炎细胞浸润为主,术后7d新生血管形成,术后28d角膜基本恢复正常。实验组角膜新生血管在术后7d增多,28d形成稳定。HE染色提示Kpro支架周围有纤维肉芽组织增生。苦味酸天狼星红染色显示实验组术后28d时角膜基质层出现绿色Ⅲ型胶原纤维。免疫组织化学染色显示实验组MMP-9、bFGF为阳性表达。扫描电镜结果显示HA-Ti支架表面被密集的细胞外基质及细胞紧密抓附,二者粘连紧密,愈合良好。RT-PCR扩增结果显示对照组和实验组的六对引物在各个时间点均有表达,扩增片段与设计片段一致。
3.新西兰白兔角膜碱烧伤后3个月角膜白斑和新生血管形成稳定。Kpro支架植入后均在观察期内稳定存留,无角膜溃疡、坏死融解及支架脱出发生。人工角膜镜柱与周围角膜组织愈合好。并发症方面A有2只兔子7d后出现镜柱周围角膜部分溶解;B未出现角膜溶解病例,两组各有1只兔子出现人工角膜后膜。两种并发症经SPSS10.0统计软件进行卡方检验,显示无统计学差异(p＞0.05)。房水检查结果显示,两组术后房水中的电解质(Na、K、Cl)、蛋白质、葡萄糖、碱性磷酸酶,与正常新西兰白兔前房水相比无明显改变。HE染色显示Kpro镜柱植入后早期角膜上皮水肿、增厚,基质层内急性炎细胞浸润明显,同时伴有大量新生血管;晚期Kpro支架所在区域有纤维肉芽组织形成,角膜与镜柱结合牢固。两组人工角膜镜柱植入术后在Kpro镜柱及支架植入周围组织中均可见Vimentin绿色强荧光的阳性表达。
结论
1.使用IABD技术在Ti支架表面形成的羟基磷灰石涂层,具有高Ca/P比,强粘附力的特点,适用于人工角膜的制备。
2.IBAD制备的HA-Ti支架经动物实验证实,其表面有纤维血管组织粘附、生长,支架与宿主角膜愈合好。
3.本课题设计制作的人工角膜在兔角膜中可以长期稳定存在,并发症的减少有赖于手术技术的提高及镜柱制作工艺的改良。
Objective
Adopt the Ion beam assisted deposition technique to quickly deposites hydroxyapatite on the support surface made by Titanium of the keratoprosthesi; Adopt the design software OSLO of the optics developed by Lambda Research Corporation of American for the design and creation of the artificial cornea mirror pillar.To evaluate the histocompatibility of Titanium frame of the keratoprosthesi with surface modification of hydroxyapatite at molecular level and through histopathology.To observe the histopathological change of artificial cornea inside the body of the animal body.
Method
1.Pure titanium with three loop-support was used as a substrate after machining into disk.The substrate surface was deposited with calcium phosphate membrane by ion beam assisted deposition(IBAD) method.Using the design software OSLO to design the artificial cornea mirror pillar made by Polymethylmecrylate(PMMA) which was produed by the professional technical persons on the Switzerland instrument lathe.
2.A total of 80 SD rabbits were respectively divided into two groups.Skirt of HA-Ti was inserted into the right corneal stroma of rabbits of experimental group as compared with control group which did not insert skirt.Slit lamp was used to observe the corneal edema and neovascularisation.On the 1d,7ds,14ds, 21 ds,28ds,90ds after surgery,histological materials were examined under light microscopy by HE dyeing,specialdyeing,immunohistochemistry dyeing and inspection with electro-microscopy and RT-PCR in order to know the inflammatory reaction,tissue repairment and expressing of relative factors during tissue healing process.
3.Twenty New Zealand white rabbits with cornea alkalis burn were random divided into 2 groups after the corneal transplanted with HA-Ti artificial cornea support(include conjunction wreath) for 3 months.After cutting off the central whole layer cornea of support,artificial cornea mirror pillar was inserted in group A.Acellular dermal matrix was put on the rabbits' corneal surface in group B. On the 7ds,28ds,90ds after surgery,the inflammatory reaction of anterchamper was inspected while HE dyeing and immunofluorescence dyeing were performed.
Result
1.By X-ray diffractometer and energy dispersive spectroscopy,we found the increase of Ca content and Ca/P ratio after adding extra CaO in the HA. Likewise,the Ca/P ratio in the depositing membrane and the combination of Hi membrane with Kpro support base were also increased.Cooperated with professional technicians,we produed artificial cornea mirror pillar of 3mm in diameter and 3.5 mm in length by PMMA using optic design software.
2.The matched control SD rats all appears the corneal stimulating symptom after surgery in different degree,new-born blood vessels appeared on the 7d.HE dyeing also showed neovasticulization appeared on the 7d,and decreased on the 14d.On the 28d,the epithelial layer of cornea lightly incrassation with irregular matrix fiber and indistinct vascularizatio and inflammatory reaction.The experimental SD rats were also appears the corneal stimulating symptom after surgery,new-born blood vessels distinctly increased on the 7 ds and stabilized on 21d with no Kpro exclusion.HE dyeing showed neovasticulization appeared on the 7d,and increased more on the 14d.On the 28d,the Kpro was surrounded by the fibrogranulomous tissue.GreenⅢ-type collagen fibers were also found on the 28d.As to immunohistochemitry,positive expressiong of MMP-9 appeared on the 7d and bFGF on the 28d.Electromicroscopy showed tightly attachment of extra-matrix and corneal cell with HA-Ti frame.RT-PCR found RNA level went up earlier than that of the experiment group.
3.The New Zealand white rabbits appeared severely earlier inflammatory reaction after cornea alkali buming which mitigated on the 7d and new vascularization increased.During the observing period,Kpro frame kept stabile without cornea ulcer,putrescence and frame emersion.The cornea edema completely fadeaway after 28d.Compared to the group A,the group B appeared apparent stimulous symptom and better healing of PMMA artificial conea mirror pillar with surrounding comea tissue on the 28d.Also,they had no cornea dissolution.According to the research of Aqueous humor,no distinct change of electrolyte(Na,K,Cl),protein,glucose,and alkalescence between the two groups and normal New Zealand white rabbits.
Conclusion
1.The PMMA coats deposited on the Ti frame was produed by IBAD method and have much characteristics:high Ca/P ratio,strong conglutination and easily preparation for artificial cornea.
2.The HA-Ti frame made by IBAD was confirmed by animal experiment that its surface was attached with a fiberous vascular tissues and healed better with host cornea.
3.The artificial cornea of this topic can stable exist over a long period of time in the rabbit cornea.The decrease of complications depends on the improvement of the mirror pillar creation craft.
采用离子束辅助沉积(IBAD)技术在人工角膜钛支架表面快速沉积羟基磷灰石涂层;采用美国Lambda Research Corporation开发的光学设计软件OSLO进行人工角膜镜柱的设计和制作。组织病理学和分子学水平评价人工角膜纯钛支架经羟基磷灰石表面修饰后其生物相容性。通过体内动物实验观察人工角膜在动物体内的组织病理学改变。
方法
1.制备三襻式人工角膜纯钛支架,以此作为基底,使用电子束蒸发器和离子枪,在一定电压和电流的情况下对钛支架进行预清沈,并通过离子束轰击使磷酸钙蒸发剂在旋状的钛板上沉积形成磷酸钙膜制备HA-Ti人工角膜支架。按照几何光学原理,采用美国Lambda Research Corporation开发的光学设计软件进行镜柱设计,以聚甲基丙烯酸甲酯(PMMA)为原材料制作人工角膜柱镜。
2.80只SD大鼠随机分为2组,实验组右眼角膜基质层内植入HA-Ti人工角膜支架,对照组仅作角膜板层切口而不植入支架作为手术对照组,术后裂隙灯观察角膜水肿及新生血管产生情况。术后不同时间取材,进行HE染色、特殊染色、免疫组织化学染色、电镜以及RT-PCR检测,观察支架与组织愈合过程中炎症反应、组织修复及相关因子表达情况。
3.20只角膜碱烧伤的新西兰白兔,在角膜基质层间植入HA-Ti人工角膜支架(包括连接环)3个月后随机分为A、B两组,A组切除支架中央全层角膜后,旋入实验一中设计制作的人工角膜镜柱,B组则在植入后使用脱细胞真皮覆盖于角膜表面。术后观察前房炎症反应,同时行HE染色和免疫荧光染色。
结果
1.能量色散光谱镜显示通过IBAD形成的沉积膜中Ca的含量提高;与Kpro支架基底之间的结合力高于其他喷涂技术。根据光学设计软件,使用聚甲基丙烯酸甲酯,制作出直径为3.0 mm,长度为3.5 mm的人工角膜镜柱。
2.对照组术后早期角膜创口以急性炎细胞浸润为主,术后7d新生血管形成,术后28d角膜基本恢复正常。实验组角膜新生血管在术后7d增多,28d形成稳定。HE染色提示Kpro支架周围有纤维肉芽组织增生。苦味酸天狼星红染色显示实验组术后28d时角膜基质层出现绿色Ⅲ型胶原纤维。免疫组织化学染色显示实验组MMP-9、bFGF为阳性表达。扫描电镜结果显示HA-Ti支架表面被密集的细胞外基质及细胞紧密抓附,二者粘连紧密,愈合良好。RT-PCR扩增结果显示对照组和实验组的六对引物在各个时间点均有表达,扩增片段与设计片段一致。
3.新西兰白兔角膜碱烧伤后3个月角膜白斑和新生血管形成稳定。Kpro支架植入后均在观察期内稳定存留,无角膜溃疡、坏死融解及支架脱出发生。人工角膜镜柱与周围角膜组织愈合好。并发症方面A有2只兔子7d后出现镜柱周围角膜部分溶解;B未出现角膜溶解病例,两组各有1只兔子出现人工角膜后膜。两种并发症经SPSS10.0统计软件进行卡方检验,显示无统计学差异(p＞0.05)。房水检查结果显示,两组术后房水中的电解质(Na、K、Cl)、蛋白质、葡萄糖、碱性磷酸酶,与正常新西兰白兔前房水相比无明显改变。HE染色显示Kpro镜柱植入后早期角膜上皮水肿、增厚,基质层内急性炎细胞浸润明显,同时伴有大量新生血管;晚期Kpro支架所在区域有纤维肉芽组织形成,角膜与镜柱结合牢固。两组人工角膜镜柱植入术后在Kpro镜柱及支架植入周围组织中均可见Vimentin绿色强荧光的阳性表达。
结论
1.使用IABD技术在Ti支架表面形成的羟基磷灰石涂层,具有高Ca/P比,强粘附力的特点,适用于人工角膜的制备。
2.IBAD制备的HA-Ti支架经动物实验证实,其表面有纤维血管组织粘附、生长,支架与宿主角膜愈合好。
3.本课题设计制作的人工角膜在兔角膜中可以长期稳定存在,并发症的减少有赖于手术技术的提高及镜柱制作工艺的改良。
Objective
Adopt the Ion beam assisted deposition technique to quickly deposites hydroxyapatite on the support surface made by Titanium of the keratoprosthesi; Adopt the design software OSLO of the optics developed by Lambda Research Corporation of American for the design and creation of the artificial cornea mirror pillar.To evaluate the histocompatibility of Titanium frame of the keratoprosthesi with surface modification of hydroxyapatite at molecular level and through histopathology.To observe the histopathological change of artificial cornea inside the body of the animal body.
Method
1.Pure titanium with three loop-support was used as a substrate after machining into disk.The substrate surface was deposited with calcium phosphate membrane by ion beam assisted deposition(IBAD) method.Using the design software OSLO to design the artificial cornea mirror pillar made by Polymethylmecrylate(PMMA) which was produed by the professional technical persons on the Switzerland instrument lathe.
2.A total of 80 SD rabbits were respectively divided into two groups.Skirt of HA-Ti was inserted into the right corneal stroma of rabbits of experimental group as compared with control group which did not insert skirt.Slit lamp was used to observe the corneal edema and neovascularisation.On the 1d,7ds,14ds, 21 ds,28ds,90ds after surgery,histological materials were examined under light microscopy by HE dyeing,specialdyeing,immunohistochemistry dyeing and inspection with electro-microscopy and RT-PCR in order to know the inflammatory reaction,tissue repairment and expressing of relative factors during tissue healing process.
3.Twenty New Zealand white rabbits with cornea alkalis burn were random divided into 2 groups after the corneal transplanted with HA-Ti artificial cornea support(include conjunction wreath) for 3 months.After cutting off the central whole layer cornea of support,artificial cornea mirror pillar was inserted in group A.Acellular dermal matrix was put on the rabbits' corneal surface in group B. On the 7ds,28ds,90ds after surgery,the inflammatory reaction of anterchamper was inspected while HE dyeing and immunofluorescence dyeing were performed.
Result
1.By X-ray diffractometer and energy dispersive spectroscopy,we found the increase of Ca content and Ca/P ratio after adding extra CaO in the HA. Likewise,the Ca/P ratio in the depositing membrane and the combination of Hi membrane with Kpro support base were also increased.Cooperated with professional technicians,we produed artificial cornea mirror pillar of 3mm in diameter and 3.5 mm in length by PMMA using optic design software.
2.The matched control SD rats all appears the corneal stimulating symptom after surgery in different degree,new-born blood vessels appeared on the 7d.HE dyeing also showed neovasticulization appeared on the 7d,and decreased on the 14d.On the 28d,the epithelial layer of cornea lightly incrassation with irregular matrix fiber and indistinct vascularizatio and inflammatory reaction.The experimental SD rats were also appears the corneal stimulating symptom after surgery,new-born blood vessels distinctly increased on the 7 ds and stabilized on 21d with no Kpro exclusion.HE dyeing showed neovasticulization appeared on the 7d,and increased more on the 14d.On the 28d,the Kpro was surrounded by the fibrogranulomous tissue.GreenⅢ-type collagen fibers were also found on the 28d.As to immunohistochemitry,positive expressiong of MMP-9 appeared on the 7d and bFGF on the 28d.Electromicroscopy showed tightly attachment of extra-matrix and corneal cell with HA-Ti frame.RT-PCR found RNA level went up earlier than that of the experiment group.
3.The New Zealand white rabbits appeared severely earlier inflammatory reaction after cornea alkali buming which mitigated on the 7d and new vascularization increased.During the observing period,Kpro frame kept stabile without cornea ulcer,putrescence and frame emersion.The cornea edema completely fadeaway after 28d.Compared to the group A,the group B appeared apparent stimulous symptom and better healing of PMMA artificial conea mirror pillar with surrounding comea tissue on the 28d.Also,they had no cornea dissolution.According to the research of Aqueous humor,no distinct change of electrolyte(Na,K,Cl),protein,glucose,and alkalescence between the two groups and normal New Zealand white rabbits.
Conclusion
1.The PMMA coats deposited on the Ti frame was produed by IBAD method and have much characteristics:high Ca/P ratio,strong conglutination and easily preparation for artificial cornea.
2.The HA-Ti frame made by IBAD was confirmed by animal experiment that its surface was attached with a fiberous vascular tissues and healed better with host cornea.
3.The artificial cornea of this topic can stable exist over a long period of time in the rabbit cornea.The decrease of complications depends on the improvement of the mirror pillar creation craft.
引文
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33.Han B,Dudenhoefer EJ,Dohlman CH.Keratoprosthesis:an update.Curr Opin Ophthalmol.2001;12(4):282-7.
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1.顾汉卿,徐国风.生物医学材料[M].天津:天津科技翻译出版公司,1993。
2.Sauli Kujala,Jorma Ryh.etal.Bone modeling controlled by a nickel titanium shape memory alloy intramedullary nail[J].Biomaterials,2002:2535-2543.
3.Van Noort R.Titanium:the implant of today[J].J Mater Sci,1987,22:3801-3811.
4.Ninomi M,Kuroda D,Fukunaga K,et al.Corrosion wear fraeture of new βtype biomedieal titanium alloys[J].Mater Sci Eng,1999,A263:193-199.
5.Feng Zhang,Xianghuai Liu,Yingjun Mao,et al.Artificial heart valves:improved hemocompatibility by titanium oxide coatings prepared by ion beam assisted depo sition[J].Surface and Coatings Techno logy,1998,103-104,146-150,
6.程宇航.人工关节用补给涂层材料[J].功能材料,1999,30(5):467.
7.Puleo DA,Nanci A.Understanding and controlling the bone-implant interface.Biomaterials,1999,20:2311-2321.
8.Brash JL,Horbett TA.Proteins at interfaces:an overview,in:Horbett TA,Brash JL.(Eds),Proteins at interfaces Ⅱ:Fundamentals and Applications.ACS symposium Series,Vol,602,American Chemical Society,Washington,DC,1995:1-23
9.Ratner BD.The blood compatibility catastrophe.J Biomed Mater Res,1993,27:283-287
10.中国标准出版社第一编辑室编.医疗器械生物学评价标准汇编.北京:中国标准出版社,2003.
11.Fabio Franceschini Mitri,Marcelo Yoshimoto,Sergio Allegrini Junior,et al.Histological findings in titanium implants coated with calcium phosphate ceramics installed in rabbit's tibias.Ann Anat,2005,187:93 - 98
12.Ooms EM,Egglezos EA,Wolke JGC,et al.Soft tissue response to injectable calcium phosphate cements.Biomaterials,2003,24:749- 757
13.Bogdanski D,Koller M,Muller D,et al.Easy assessment of the biocompatibility of Ni-Ti Alloys by in vitro cell culture experiments on a functionally graded Ni-Ni Ti-Ti material[J].Biomaterials,2002,23(23):4549-4555
14.Kapanen A,Kinnunen A,Ryhanen J,et al.TGF-betal secretionof ROS-17/2.8cultures on NiTi implant material[J].Biomaterials,2002,23(16):3341-3346
15.Hao L,Lawrence J,Li L.Manipulation of the osteoblast response to a Ti-6Al- 4V titanium alloy using a high power diode laser.Applied Surface science,2005,247:602-606
16.Gonzalez-Carrasco JL,Ciapetti G,Montealegregre MA,et al.Evaluation of mechanical properties and biological response of an alumina forming Ni free ferritic alloy.Biomaterials,2005,26:3861 - 3871
17.杨晓芳,奚廷斐.生物材料生物相容性评价研究进展.生物医学工程杂志,2001,18(1):123-128
18.Trentani L,Pelillo F,Pavesi FC,et al.Evaluation of the TiMo12- Zr6Fe2alloy for orthopaedic implants:in vitro biocompatibility study by using primary human fibroblasts and osteoblasts.Biomaterials,2002,23:2863 -2869
19.谢超,刘荷中,等.基因表达连续分析技术及应用研究的进展.国外医学分子生物学分册,2002,24(6):369-372。