WO2016065684A1 - 辐照灭菌条件下维持骨形态发生蛋白-2活性的方法 - Google Patents

辐照灭菌条件下维持骨形态发生蛋白-2活性的方法 Download PDF

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WO2016065684A1
WO2016065684A1 PCT/CN2014/092094 CN2014092094W WO2016065684A1 WO 2016065684 A1 WO2016065684 A1 WO 2016065684A1 CN 2014092094 W CN2014092094 W CN 2014092094W WO 2016065684 A1 WO2016065684 A1 WO 2016065684A1
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bmp
irradiation
alp
unirradiated
activity
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亓洪昭
杨贤金
卢云峰
李朝阳
李雪
崔振铎
原续波
王思颖
汪亚运
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Tianjin University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
    • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
    • A61L2/08—Radiation

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  • the invention relates to the activity maintenance of the bone morphogenetic protein-2 (BMP-2) in the irradiation sterilization process, the irradiation object is BMP-2, and the irradiation source of 60 Co, 137 Cs, 192 Ir is used, and the irradiation dose is 0.01. -100kGy.
  • BMP-2 bone morphogenetic protein-2
  • Bone morphogenetic protein is widely used mainly because it induces the formation of bone and cartilage, can be used as a therapeutic agent for the treatment of fractures and periodontal defects, and can induce bone growth around implants and artificial prostheses.
  • Traditional gene knockout experiments have shown that bone morphogenetic proteins possess a variety of biological activities, such as early embryogenesis, multi-dimensional organ formation and other functions can be achieved by regulating cell proliferation, differentiation and apoptosis.
  • a series of human bone morphogenetic proteins have been shown to stimulate bone formation, and recombinant human bone morphogenetic proteins have also been applied.
  • BMP-2 has almost the same bone repairing ability as autologous bone and is considered to have the strongest osteoinductive activity.
  • Sterilization is required for the clinical use of BMP-2 and BMP-2 loaded medical devices.
  • BMP-2 BMP-2 loaded medical devices.
  • Ethylene oxide can chemically react with proteinaceous materials to inactivate BMP-2; autoclaving sterilizes BMP-2 and inactivates it.
  • Irradiation sterilization is an effective method for killing microorganisms on most substances by emitting radiation from radioactive materials.
  • the temperature is not significantly increased throughout the sterilization process, and it is a good sterilization method for heat sensitive compounds.
  • the invention adds the BMP-2 solution into the centrifuge tube, seals it with a sealing film, puts it into a thermos flask, fills it with ice, irradiates with 60 Co, 137 Cs, 192 Ir source rays, and sets the dose to be 0.01-100 kGy.
  • the dosage is set to 15-50 kGy; the irradiation process to BMP-2 is achieved.
  • the cells were then routinely cultured in DF12 complete medium to establish unirradiated BMP-2.
  • the group and irradiated BMP-2 group were tested for ALP content in each well after 7 days of cell culture.
  • the activity of BMP-2 was determined by the level of ALP, and the detection of BMP-2 activity was achieved.
  • the principle of detecting BMP-2 activity in the present invention is that ALP is an important index for cell differentiation into osteoblasts, BMP-2 activity is high, and the tendency of cells to differentiate into osteoblasts is obvious, and the ALP expression level is high, and the content of ALP can be high or low.
  • the level of BMP-2 activity was measured.
  • the invention has the advantages that the problem of deactivation in the process of BMP-2 irradiation sterilization is effectively solved, and the application prospect thereof is improved.
  • Figure 1 Changes in ALP content in cells after 60 Co-irradiation at 25 kGy;
  • Figure 2 Changes in ALP content in cells after 60 CoG irradiation at 50 kGy;
  • Figure 3 Changes in ALP content in cells after 60 Co-ray irradiation at 35 kGy.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.
  • Umbilical cord blood mesenchymal stem cells were routinely cultured in DF12 complete medium, and unirradiated BMP-2 group and irradiated BMP-2 group were established. The ALP content of each well was measured after 7 days of cell culture.

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Abstract

利用射线辐照维持BMP-2活性的方法。将BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用 60Co、 137Cs、 192Ir源射线辐照，设定剂量为0.01-100kGy；实现对BMP-2的辐照过程。有效解决了BMP-2辐照过程中失活问题，推动了负载BMP-2的医疗器械的研究发展，大大提高了其应用前景。

Description

一种辐照灭菌条件下维持骨形态发生蛋白-2活性的方法 技术领域
本发明涉及骨形态发生蛋白-2(BMP-2)辐照灭菌过程中的活性保持，其辐照对象为BMP-2，采用60Co、137Cs、192Ir发射源，辐照剂量为0.01-100kGy。
背景技术
骨形态发生蛋白(BMP)被广泛应用，主要是因为它可以诱导骨和软骨的形成，可作为治疗骨折和牙周缺陷的治疗剂，并能够在植入物和人工假体周围诱导骨生长。传统的基因剔除实验表明，骨形态发生蛋白拥有着多种多样的生物活性，比如在早期的胚胎发生、多方位的器官形成等方面都能通过调节细胞的增殖、分化和凋亡来实现功能。通过体外和体内试验，一系列人骨形态发生蛋白已经被证实可以刺激骨形成，同时重组人骨形成蛋白也被应用。至今，已经有超过20种BMP被鉴定和表征，他们都是转化生长因子β(TGF-β)超家族的成员。其中，BMP-2具有几乎和自体骨相当的骨修复能力，被认为具有最强的骨诱导活性。
灭菌是BMP-2及负载BMP-2医疗器械临床使用前必需的操作。但是现行的几种常规灭菌方式都会使BMP-2失去活性。环氧乙烷可与蛋白类物质发生化学反应而使BMP-2失活；高压蒸汽灭菌使BMP-2变性而失活。
辐照灭菌是通过放射性物质发出辐射线杀死大多数物质上的微生物的一种有效方法，在整个灭菌过程中，温度并不明显升高，对于热敏性化合物是很好的灭菌方式。
发明内容
本发明的目的在于射线辐照有效地对BMP-2灭菌同时维持其活性。
本发明的技术方案如下：
本发明将BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用60Co、137Cs、192Ir源射线辐照，设定剂量为0.01-100kGy，优选设定剂量为15-50kGy；实现对BMP-2的辐照过程。
然后将细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2 组、辐照的BMP-2组，细胞培养7天后检测每个孔ALP含量。通过ALP含量的高低来确定BMP-2的活性高低，实现对BMP-2活性的检测。
本发明检测BMP-2活性的原理是ALP是细胞向成骨细胞分化的重要指标，BMP-2活性高，细胞向成骨细胞分化的趋势明显，则ALP表达量高，通过ALP的含量高低可以检测BMP-2活性的高低。
本发明的优点在于有效解决了BMP-2辐照灭菌过程中失活问题，提高了其应用前景。
附图说明
图1：60Co射线25kGy辐照后细胞中ALP含量变化；
图2：60Co射线50kGy辐照后细胞中ALP含量变化；
图3：60Co射线35kGy辐照后细胞中ALP含量变化。
具体实施方法
下面通过例子对本发明专利进行进一步的阐述。
实施例1：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用60Co源射线辐照，设定剂量为0.01kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例2：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用137Cs源射线辐照，设定剂量为0.01kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表 达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例3：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用192Ir源射线辐照，设定剂量为0.01kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例4：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用60Co源射线辐照，设定剂量为100kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例5：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用137Cs源射线辐照，设定剂量为100kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例6：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用192Ir源射线辐照，设定剂量为100kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例7：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用60Co源射线辐照，设定剂量为25kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。实验结果如附图1所示。
实施例8：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用60Co源射线辐照，设定剂量为50kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。实验结果如附图2所示。
实施例9：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用60Co源射线辐照，设定剂量为35kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。实验结果如附图3所示。
实施例10：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用137Cs源射线辐照，设定剂量为25kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例11：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用192Ir源射线辐照，设定剂量为50kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例11：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用192Ir源射线辐照，设定剂量为28kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例12：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用60Co源射线辐照，设定剂量为15kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。
实施例13：
1.准备BMP-2溶液加入离心管中，用封口膜封好，放入保温瓶中，装满冰，用137Cs源射线辐照，设定剂量为15kGy。
2.脐带血间充质干细胞在DF12完全培养液中常规培养，分别设立未辐照的BMP-2组、辐照的BMP-2组。细胞培养7天后检测每个孔ALP含量。
3.通过对ALP含量的分析，我们可以看到，BMP-2辐照之后，其ALP表达量与未辐照的BMP-2的ALP表达量相近，并没有显著性差异，从而证明辐照之后BMP-2活性得到维持。

Claims (2)

  1. 利用射线辐照维持BMP-2活性的方法，其特征在于：射线发射源为60Co、137Cs或192Ir，辐照剂量为0.01-100kGy。
  2. 如权利要求书1所述的方法，其特征在于：辐照剂量为25-50kGy。
PCT/CN2014/092094 2014-10-27 2014-11-24 辐照灭菌条件下维持骨形态发生蛋白-2活性的方法 Ceased WO2016065684A1 (zh)

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Citations (3)

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WO2006007780A1 (fr) * 2004-07-22 2006-01-26 Fang Xu Matiere pour reparation d'os sous forme de gelatine injectable et son procede de preparation
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