CN107376033B - 一种细胞移植增效保护装置及其制备方法 - Google Patents
一种细胞移植增效保护装置及其制备方法 Download PDFInfo
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Abstract
本发明属于医用移植装置及其制备技术领域，具体涉及一种细胞移植增效装置及其制备方法。它包括用高度生物相容性的GMP级材料聚DL‑丙交酯‑己内酯构建的移植块和细胞储存管道以及血管生成相关因子组合而成。本发明细胞移植装置可承载任何治疗用人体细胞，移植到皮下、肌肉、腹腔、肾包囊以及特定治疗部位。同时本发明移植装置可以促进血管在移植物储存管四周生成，不但可让移植物在移植部位发挥作用，其所分泌的治疗性物质还可经由周边血管到达全身起到相关疗效。本发明移植装置在移植过程可以适量增加或者去除移植物，故能简便、快捷、安全和有效地调节移植物的剂量。本发明结构简单，易于制作，能实现规模化生产，起到治疗相关疾病的作用。
Description
技术领域
本发明属于医用移植装置及其制备技术领域，涉及一种适合多种细胞的移植治疗增效保护装置及其制备技术，尤其涉及胰岛细胞移植增效保护装置及其制备技术。
背景技术
随着医学领域的开拓与发展，一种新型的治疗手段出现在人们的视野中。细胞移植利用某些具有特定功能的细胞的特性，采用生物工程方法获取或通过体外扩增、特殊培养等处理后，具有促进组织器官再生、集体康复等治疗功效以达到治疗某些疾病的目的，此方法也越来越受到科学家的关注。
如今细胞移植已运用到了许多疾病上，如自体软骨细胞移植技术修复关节软骨损伤、嗅鞘细胞移植治疗帕金森病、雪旺氏细胞移植修复脊髓损伤、胰岛细胞移植治疗糖尿病等，其中，糖尿病的治疗显得尤为重要。糖尿病是人类面临的一种重要健康问题，全世界约1.5亿人患糖尿病。不论是1型糖尿病还是2型糖尿病，其共同特征是由于胰岛β细胞缺陷或缺失导致胰岛素分泌绝对或相对不足，造成糖、脂、蛋白质以及水、电解质代谢紊乱。药物治疗和长期注射外源性胰岛素是目前糖尿病的主要治疗措施，但这些方法并不能从根本上解决糖尿病患者对胰岛素的依赖问题，也不能很好的防止糖尿病并发症的发生。胰岛细胞移植为糖尿病患者提供了更好的治疗途径。患者接受胰岛细胞移植治疗，80％的移植者1年后脱离外源性胰岛素，同时其糖、氨基酸、脂肪代谢恢复稳定，心血管系统并发症的发生和发展风险逐渐降低。
尽管细胞移植领域正在日新月异的发展，但面临最主要的几个问题仍然不可避免：1、免疫排斥反应仍是移植细胞丢失和导致远期效果差的主要原因；2、因为缺氧导致移植细胞不能够长期存活；3、移植多为全身性而不能充分在相关局部部位发挥作用；4、移植部位难以固定，移植物难以回收。因此，解决细胞移植过程中缺氧、缺少营养物质，免疫排斥反应，移植部位难以固定，移植物难以回收等问题是推动细胞移植临床应用的关键步骤。
发明内容
针对目前细胞移植存在的免疫排斥，移植部位缺少氧气、营养物质，移植细胞难以固定在目的部位发挥相关作用等问题，我们以高生物相容性材料为原料，开发一种新型的细胞移植增效保护装置及其制备方法，有利于细胞特定部位移植的固定、长期存活、增加和移除。用于治疗相关疾病，该移植增效保护装置也适合产业化生产。
为了实现本发明的目的，本发明采用如下技术方案：
一种细胞移植增效装置的制备方法，包括以下步骤：
(1)在聚DL-丙交酯-己内酯的氯仿溶液中加入NaCl，彻底搅拌均匀，待溶剂挥发完全后成型为长方体，用无菌蒸馏水冲洗多次，将NaCl溶解洗去，形成含有微孔结构的移植块；
(2)在移植块上打至少一个贯穿两相对侧壁的通孔，然后用与通孔直径大小相匹配的疏水性聚乙烯管插入通孔中，疏水性聚乙烯管的长度不小于通孔的长度；
(3)将插入疏水性聚乙烯管的移植块浸泡在包含人纤维蛋白原、血管内皮生长因子、表皮生长因子、凝血酶、青霉素-链霉素的CMRL培养基中，使纤维蛋白凝胶固化在移植块的微孔结构内。
所述的细胞移植增效装置的制备方法，步骤(1)中2-10％聚DL-丙交酯-己内酯的氯仿溶液中加入150-1000μMNaCl。
所述的细胞移植增效装置的制备方法，步骤(1)中移植块长度为10-15mm，宽度为15-20mm，厚度为4-6mm，体积为600-1800mm3。优选移植块长度为10mm，宽度为15mm，厚度为5mm，体积为750mm3。
所述的细胞移植增效装置的制备方法，步骤(2)的通孔孔径是0.4-1mm。优选是0.4mm。
所述的细胞移植增效装置的制备方法，所述人纤维蛋白原浓度为1-5mg/ml，血管内皮生长因子浓度为10-100ng/ml，表皮生长因子浓度为20-100ng/ml，凝血酶浓度为0.5-1％，青霉素-链霉素的浓度为1％。
一种细胞移植增效装置，是由上述的方法制备而成的。
本发明提供一种结构简单、加工容易、操作安全、使用方便的细胞移植装置及其制备方法。细胞通过装置内生成的血管与生物体相连，可以同时移植多个装置起到增幅或者协同作用。该装置可以移植到皮下、腹腔、肾脏等不同部位，后期替换、增加或者移除都很简单易行。而且因为有移植装置的保护和固定，所以移植细胞的丢失很少，血管没有直接进入到装置的通道中，免疫细胞也不会攻击胰岛细胞。
本发明细胞移植装置可承载任何治疗用人体细胞，移植到皮下、肌肉、腹腔、肾包囊以及特定治疗部位。同时本发明移植装置可以促进血管在移植物储存管四周生成，不但可让移植物在移植部位发挥作用，其所分泌的治疗性物质还可经由周边血管到达全身起到相关疗效。本发明细胞移植装置可预先促进毛细血管在细胞储存管周围生成，使移植细胞在移植早期便得到充分的血供、氧气和营养从而提高移植细胞在体内生存率和功能效率(其治疗性分泌物能迅速经血液循环到达全身或疾病部位发挥疗效)。本发明移植装置在移植过程可以适量增加或者去除移植物，故能简便、快捷、安全和有效地调节移植物的剂量。本发明解决了组织细胞的移植治疗的途径和移植位点，能有效地保护移植细胞，使其不受到免疫细胞的攻击，提高细胞的存活率，增强移植细胞的疗效，降低移植手术的难度和风险，更加可控回收移植细胞，节省了手术的时间和费用，保证了手术的安全性。本发明结构简单，易于制作，能实现规模化生产，起到治疗相关疾病的作用。
附图说明
图1为本发明移植装置；
图2为采用本发明装置皮下移植胰岛细胞；
图3为移植后糖尿病小鼠血糖检测；
图4为移植装置中的胰岛细胞insulin染色；
A是移植到本发明移植增效装置的胰岛细胞，B是本发明增效保护器的区域；
图5为肾被膜下移植胰岛细胞insulin染色；
A是移植到肾被膜下的胰岛细胞，B是聚集的淋巴细胞，C是坏死的组织细胞。
具体实施方式：
实施例1本发明移植增效装置的制备，使用：
4g聚DL-丙交酯-己内酯溶于50ml氯仿中，加入20g NaCl充分搅拌后移入无菌培养皿中，在超净工作台中待氯仿挥发干后得到移植块，用无菌蒸馏水冲洗移植块。移植块铸造成10×15×5mm，体积为750mm3。用孔径是0.4mm的空心铁管在支架侧面打孔，制作移植物储存管道，然后用疏水性聚乙烯管插入移植物储存管道。在2ml CMRL培养基中加入的2mg人纤维蛋白原、50ng血管内皮生长因子、100ng表皮生长因子、2ul1％青霉素-链霉素和20ul凝血酶，形成纤维蛋白凝胶，将移植装置浸泡于纤维蛋白凝胶中，使纤维蛋白凝胶固化在移植装置的微孔孔径内。
在皮下或腹壁等部位切一个小口，将移植装置放入近血管处、固定，缝合切口，等待移植装置内血管化，4周后在相同部位切开一个小口，将装置的疏水性聚乙烯管取出，为移植细胞提供通道，用23G汉密尔顿注射器将细胞注射入通道中。
实施例2糖尿病模型小鼠胰岛细胞的移植
第一组糖尿病模型小鼠在其背上腰部皮下移植入本发明移植装置，4周后待移植装置内血管化后，在小鼠背部移植装置上方做一个小切口，取出疏水性聚乙烯管，为胰岛细胞提供通道，用23G汉密尔顿注射器将1200个胰岛细胞注射入通道中，然后用聚DL-丙交酯-己内酯封住通道端口，缝合切口。第二组糖尿病模型小鼠在肾被膜下直接移植1200个胰岛细胞。第三组糖尿病模型小鼠不移植任何胰岛细胞作为对照。
实施例3糖尿病模型小鼠血糖检测
胰岛细胞移植后，一、二、三组糖尿病模型小鼠每周测定小鼠血糖水平，一直测到第十周，第三组糖尿病模型小鼠作为对照。实验结果显示，用本发明装置进行移植胰岛细胞后，糖尿病小鼠的血糖明显下降，并且10周内血糖能一直保持稳定水平。肾被膜移植组糖尿病小鼠初期的血糖明显下降并且保持稳定，但是后期血糖水平逐步升高波动也逐渐变大。未移植组糖尿病小鼠的血糖一直保持较高的血糖水平，并且血糖波动较大。
实施例4糖尿病模型小鼠病理检测
胰岛细胞移植后，一、二组糖尿病模型小鼠第十一周处死，分别对移植部位进行免疫组化insulin染色。实验结果显示，移植装置中的胰岛细胞附近未见淋巴细胞浸润，而肾被膜下的胰岛细胞有大量的淋巴细胞浸润，甚至有部分组织坏死，随着移植时间的推延，淋巴细胞的免疫作用，肾被膜下的胰岛细胞会逐渐减少。这可能是导致实施例3中肾被膜移植胰岛细胞小鼠后期检测到的血糖水平回升和波动较大的一个重要原因。实验结果说明，本发明移植装置能较好的保护胰岛细胞产生屏障作用，使免疫细胞不攻击移植的胰岛细胞。
Claims (8)
1.一种细胞移植增效装置的制备方法，其特征在于，包括以下步骤：
(1)在聚DL-丙交酯-己内酯的氯仿溶液中加入NaCl，彻底搅拌均匀，待溶剂挥发完全后成型为长方体，用无菌蒸馏水冲洗多次，将NaCl溶解洗去，形成含有微孔结构的移植块；
(2)在移植块上打至少一个贯穿两相对侧壁的通孔，然后用与通孔直径大小相匹配的疏水性聚乙烯管插入通孔中，疏水性聚乙烯管的长度不小于通孔的长度；
(3)将插入疏水性聚乙烯管的移植块浸泡在包含人纤维蛋白原、血管内皮生长因子、表皮生长因子、凝血酶、青霉素-链霉素的CMRL培养基中，使纤维蛋白凝胶固化在移植块的微孔结构内。
2.根据权利要求1所述的细胞移植增效装置的制备方法，其特征在于，步骤(1)中2-10％聚DL-丙交酯-己内酯的氯仿溶液中加入150-1000μMNaCl。
3.根据权利要求1所述的细胞移植增效装置的制备方法，其特征在于，步骤(1)中移植块长度为10-15mm，宽度为15-20mm，厚度为4-6mm，体积为600-1800mm3。
4.根据权利要求3所述的细胞移植增效装置的制备方法，其特征在于，步骤(1)中移植块长度为10mm，宽度为15mm，厚度为5mm，体积为750mm3。
5.根据权利要求1所述的细胞移植增效装置的制备方法，其特征在于，步骤(2)的通孔孔径是0.4-1mm。
6.根据权利要求5所述的细胞移植增效装置的制备方法，其特征在于，步骤(2)的通孔孔径是0.4mm。
7.根据权利要求1所述的细胞移植增效装置的制备方法，其特征在于，所述人纤维蛋白原浓度为1-5mg/ml，血管内皮生长因子浓度为10-100ng/ml，表皮生长因子浓度为20-100ng/ml，凝血酶浓度为0.5-1％，青霉素-链霉素的浓度为1％。
8.一种细胞移植增效装置，其特征在于，是由权利要求1-7任一项所述的方法制备而成的。
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Date of cancellation: 20231124 Granted publication date: 20190326 Pledgee: Jinzhou Branch of Hunan Ningxiang Rural Commercial Bank Co.,Ltd. Pledgor: HUNAN XENO LIFE SCIENCE Co.,Ltd. Registration number: Y2023980031055 |
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Denomination of invention: A cell transplantation enhancing protective device and its preparation method Effective date of registration: 20231129 Granted publication date: 20190326 Pledgee: Jinzhou Branch of Hunan Ningxiang Rural Commercial Bank Co.,Ltd. Pledgor: HUNAN XENO LIFE SCIENCE Co.,Ltd. Registration number: Y2023980068297 |