具有形状记忆功能的D,L-聚乳酸基输卵管避孕材料的研究
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摘要
以聚乳酸大分子二醇为软段,己二异氰酸酯(HDI)和丁二胺(BDA)为硬段形成的聚乳酸基聚氨酯脲(PDLLA-PUU SMP)是一种新型的具有良好形状记忆性能和生物可降解性的智能高分子材料,可望用于加工形状记忆输卵管节育栓,实现无创植入,并随节育栓的降解,输卵管增生纤维组织可完全取代节育栓而阻塞输卵管。以输卵管上皮细胞为模型细胞,全面评价PDLLA-PUU SMP的短期和长期细胞毒性,并考查PDLLA-PUU SMP节育栓的避孕效果对于指导PDLLA-PUU SMP的优化制备,推进节育栓的进一步临床试验是不可缺少的。PDLLA-PUU SMP1K1.1是以数均分子量为2100的聚乳酸大分子二醇为软段,HDI和BDA为硬段,且HDI与大分子二醇摩尔比为1:1.1而合成的PDLLA-PUU。其Tg为38.08℃,在人体生理温度附近,就形状温度而言,非常适合用于加工输卵管节育器。因此,本研究考察了PDLLA-PUU SMP1K1.1的形状记忆性能和体外生物可降解性;以兔输卵管上皮细胞为模型细胞,采用聚合物膜共培养法评价了材料的细胞相容性,采用间接法考查材料降解液的细胞毒性,以评价材料的长期细胞毒性;并以新西兰兔为模型动物初步考查了材料的体内避孕效果。主要研究内容和结论如下:
(1)体外降解实验表明,对照组PDLLA的失重率和pH值变化存在加速阶段,呈现明显的酸致自催化降解现象;但在降解过程中,失重率以及介质的pH值下降缓慢,酸性环境导致的自催化降解现象减弱,说明PDLLA-PUU SMPs材料在降解过程中释放出的碱性二胺物质能够部分中和降解产物中的酸性物质。
(2)依次采用刮除法和反复差速贴壁法分离纯化得到了原代输卵管上皮细胞。倒置相差显微镜观察和免疫荧光染色鉴定结果表明,所得细胞具有明显的输卵管上皮细胞的生物学特征,可用于后续细胞实验。
(3)以PDLLA为对照,将PDLLA-PUU SMP1K1.1膜与兔输卵管上皮细胞复合培养,考察了细胞在材料表面的形态和增殖能力。结果表明,与对照组PDLLA膜相比,输卵管上皮细胞在形状记忆材料薄膜上具更好的形态和细胞增殖能力。
(4)输卵管上皮细胞在降解液中的培养结果表明:PDLLA-PUU SMP1K1.1在12周降解时间内,输卵管上皮细胞在各种浓度降解液中的增殖活力略低于阴性对照组,材料的细胞毒性为1级,表明PDLLA-PUU SMP1K1.1无明显的长期细胞毒性,是一种安全的生物可降解高分子材料,可用于加工输卵管节育器。
(5)采用自制模具将PDLLA-PUU SMP1K1.1加工成直径为2mm,长度为10mm的波形节育栓,并将其植入新西兰兔输卵管内。组织学观察结果表明,节育器植入3月后,兔输卵管的粘膜层大部分纤维化,增生纤维堵塞了大部分管腔,这时异物反应已基本完全消失,无明显的充血和水肿现象。而植入6月后,整个管腔几乎完全被增生纤维堵塞,可以完成避孕功能。
A novel poly(DL-lactic acid)-based poly(urethane-urea) (PDLLA-PUU) has been previously designed and prepared using PDLLA-based macrodiol as soft segments, hexamethylene diisocynate (HDI) and butanediamine (BDA) as hard segments. It has been proved of good shape memory properties and biodegradability. These properties make PDLLA-PUU suitable for oviduct contraceptive devices which may be non-invasively implanted into oviducts through vagina and uterus. Moreover, this PDLLA-PUU SMPs based oviduct contraceptive device may induce hyperplastic fibrous tissue with its degrading, and finally the oviduct is blocked by the fibrous tissue instead of the foreign device. Therefore, evaluating the short-term and long-term cytotoxicity by using oviduct epithelial cells as the model cell, and further in vivo examining the contraceptive effects are indispensable to both direct the modification of PDLLA-PUU SMP and push its clinical tests. PDLLA-PUU SMP1K1.1, a PDLLA-PUU with a soft segment of Mn=2100 and molar ratio of the macrodiol to HDI equal to 1:1.1, has a Tg of 38.08℃, which is close to the body temperature and thus suitable for the contraceptive device fabrication. In this study, the shape memory properties and degradability of PDLLA-PUU SMP1K1.1 were firstly determined, and then the short-term cytotoxicity was examined by co-culture of oviduct epithelial cells with PDLLA-PUU SMP1K1.1 films and long-term cytotoxicity by testing the cell viability in PDLLA-PUU SMP1K1.1 degradation products, and finally the contraceptive effect was preliminarily evaluated. The main work and conclusions are listed as follows:
(1) The weight loss ratio and pH value changes of PDLLA-PUU SMP1K1.1 during 12-week degradation were tested to characterize the in vitro degradation behavior by using PDLLA as controls. The results revealed that the weight loss ratio of PDLLA and pH value change of the medium decreased significantly, exhibiting obvious acid catalyzed auto-accelerating degradation. However, the weight loss ratio and pH value changes of SMPs decreased slowly and the weight loss ratio was less than 30% after degrading for 12-week, which may due to the existence of alkaline BDA during the degradation of SMPs which could partially neutralize the acidic degradation products of PDLLA segments.
(2) Scratch assay and then repetitive differential attachment methods were established to isolate and purify rabbit oviduct epithelial cells. Observations by inverted fluorescence microscope and identifications by immunofluorescence assays indicated that the obtained cells demonstrated typical morphology and biological characteristics of oviduct epithelial cells.
(3) The short-term cytotoxicity and cytocompatibility of PDLLA-PUU SMP1K1.1 were evaluated by detecting the cell morphology and viability of oviduct epithelial cells co-cultured on PDLLA-PUU SMP1K1.1 films. PDLLA films were employed as controls. The results indicated that the cells on PDLLA-PUU SMP1K1.1 exhibited much better cell morphology and higher viability, suggesting decreased cytotoxicity and improved cytocompatibility compared to PDLLA films.
(4) The cell viability of oviduct epithelial cells cultured in PDLLA-PUU SMP1K1.1 degrading products was measured. The results revealed that the viability of the cells cultured in the degrading products of various concentration was slightly lower than that in the negative control. The USP level is level 1, suggesting PDLLA-PUU SMP1K1.1 has no obvious long-term cytotoxicity and is safe for oviduct contraception.
(5) A series of oviduct contraceptive devices with a diameter of 2mm and a length of 10mm was fabricated from PDLLA-PUU SMP1K1.1 and their contraceptive effect was evaluated by implanting the devices into the isthmus of female New Zealand rabbits. The histopathologic changes of oviduct mucosa were observed. The results indicated that obvious fibrous hyperplasia tissues were induced after implantation of 3 month which blocked most of the oviduct and there was no observable synthetic polymer, and after implantation of 6 month, the oviduct was almost completely blocked. This shows that the PDLLA-PUU SMP1K1.1 based contraceptive devices are effective in oviduct contraception. A longer term in vivo test is on-going.
(1)体外降解实验表明,对照组PDLLA的失重率和pH值变化存在加速阶段,呈现明显的酸致自催化降解现象;但在降解过程中,失重率以及介质的pH值下降缓慢,酸性环境导致的自催化降解现象减弱,说明PDLLA-PUU SMPs材料在降解过程中释放出的碱性二胺物质能够部分中和降解产物中的酸性物质。
(2)依次采用刮除法和反复差速贴壁法分离纯化得到了原代输卵管上皮细胞。倒置相差显微镜观察和免疫荧光染色鉴定结果表明,所得细胞具有明显的输卵管上皮细胞的生物学特征,可用于后续细胞实验。
(3)以PDLLA为对照,将PDLLA-PUU SMP1K1.1膜与兔输卵管上皮细胞复合培养,考察了细胞在材料表面的形态和增殖能力。结果表明,与对照组PDLLA膜相比,输卵管上皮细胞在形状记忆材料薄膜上具更好的形态和细胞增殖能力。
(4)输卵管上皮细胞在降解液中的培养结果表明:PDLLA-PUU SMP1K1.1在12周降解时间内,输卵管上皮细胞在各种浓度降解液中的增殖活力略低于阴性对照组,材料的细胞毒性为1级,表明PDLLA-PUU SMP1K1.1无明显的长期细胞毒性,是一种安全的生物可降解高分子材料,可用于加工输卵管节育器。
(5)采用自制模具将PDLLA-PUU SMP1K1.1加工成直径为2mm,长度为10mm的波形节育栓,并将其植入新西兰兔输卵管内。组织学观察结果表明,节育器植入3月后,兔输卵管的粘膜层大部分纤维化,增生纤维堵塞了大部分管腔,这时异物反应已基本完全消失,无明显的充血和水肿现象。而植入6月后,整个管腔几乎完全被增生纤维堵塞,可以完成避孕功能。
A novel poly(DL-lactic acid)-based poly(urethane-urea) (PDLLA-PUU) has been previously designed and prepared using PDLLA-based macrodiol as soft segments, hexamethylene diisocynate (HDI) and butanediamine (BDA) as hard segments. It has been proved of good shape memory properties and biodegradability. These properties make PDLLA-PUU suitable for oviduct contraceptive devices which may be non-invasively implanted into oviducts through vagina and uterus. Moreover, this PDLLA-PUU SMPs based oviduct contraceptive device may induce hyperplastic fibrous tissue with its degrading, and finally the oviduct is blocked by the fibrous tissue instead of the foreign device. Therefore, evaluating the short-term and long-term cytotoxicity by using oviduct epithelial cells as the model cell, and further in vivo examining the contraceptive effects are indispensable to both direct the modification of PDLLA-PUU SMP and push its clinical tests. PDLLA-PUU SMP1K1.1, a PDLLA-PUU with a soft segment of Mn=2100 and molar ratio of the macrodiol to HDI equal to 1:1.1, has a Tg of 38.08℃, which is close to the body temperature and thus suitable for the contraceptive device fabrication. In this study, the shape memory properties and degradability of PDLLA-PUU SMP1K1.1 were firstly determined, and then the short-term cytotoxicity was examined by co-culture of oviduct epithelial cells with PDLLA-PUU SMP1K1.1 films and long-term cytotoxicity by testing the cell viability in PDLLA-PUU SMP1K1.1 degradation products, and finally the contraceptive effect was preliminarily evaluated. The main work and conclusions are listed as follows:
(1) The weight loss ratio and pH value changes of PDLLA-PUU SMP1K1.1 during 12-week degradation were tested to characterize the in vitro degradation behavior by using PDLLA as controls. The results revealed that the weight loss ratio of PDLLA and pH value change of the medium decreased significantly, exhibiting obvious acid catalyzed auto-accelerating degradation. However, the weight loss ratio and pH value changes of SMPs decreased slowly and the weight loss ratio was less than 30% after degrading for 12-week, which may due to the existence of alkaline BDA during the degradation of SMPs which could partially neutralize the acidic degradation products of PDLLA segments.
(2) Scratch assay and then repetitive differential attachment methods were established to isolate and purify rabbit oviduct epithelial cells. Observations by inverted fluorescence microscope and identifications by immunofluorescence assays indicated that the obtained cells demonstrated typical morphology and biological characteristics of oviduct epithelial cells.
(3) The short-term cytotoxicity and cytocompatibility of PDLLA-PUU SMP1K1.1 were evaluated by detecting the cell morphology and viability of oviduct epithelial cells co-cultured on PDLLA-PUU SMP1K1.1 films. PDLLA films were employed as controls. The results indicated that the cells on PDLLA-PUU SMP1K1.1 exhibited much better cell morphology and higher viability, suggesting decreased cytotoxicity and improved cytocompatibility compared to PDLLA films.
(4) The cell viability of oviduct epithelial cells cultured in PDLLA-PUU SMP1K1.1 degrading products was measured. The results revealed that the viability of the cells cultured in the degrading products of various concentration was slightly lower than that in the negative control. The USP level is level 1, suggesting PDLLA-PUU SMP1K1.1 has no obvious long-term cytotoxicity and is safe for oviduct contraception.
(5) A series of oviduct contraceptive devices with a diameter of 2mm and a length of 10mm was fabricated from PDLLA-PUU SMP1K1.1 and their contraceptive effect was evaluated by implanting the devices into the isthmus of female New Zealand rabbits. The histopathologic changes of oviduct mucosa were observed. The results indicated that obvious fibrous hyperplasia tissues were induced after implantation of 3 month which blocked most of the oviduct and there was no observable synthetic polymer, and after implantation of 6 month, the oviduct was almost completely blocked. This shows that the PDLLA-PUU SMP1K1.1 based contraceptive devices are effective in oviduct contraception. A longer term in vivo test is on-going.
引文
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[2] Kubba A, Guillebaud J, Anderson RA, et al. Contraception [J]. The Lancet, 2000, 356:1913-1919.
[3] Keder LM. New developments in contraception [J]. J Pediatr Adolesc Gynecol, 2002, 15:179-181.
[4] Saxena BB, Singh M, Gospin RM, et al. Efficacy of nonhormonal vaginal contraceptives from a hydrogel delivery system [J].Contraception, 2004, 70(3):213-219.
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