CN107913436A - 作用于伤残组织原位的骨与软组织同步再生诱导剂 - Google Patents
作用于伤残组织原位的骨与软组织同步再生诱导剂 Download PDFInfo
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- CN107913436A CN107913436A CN201610878374.2A CN201610878374A CN107913436A CN 107913436 A CN107913436 A CN 107913436A CN 201610878374 A CN201610878374 A CN 201610878374A CN 107913436 A CN107913436 A CN 107913436A
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Abstract
本发明属于再生医学领域的原位再生诱导。该诱导剂为外用药，可于伤残的残余组织处同步诱导骨及肌肉、血管、皮肤等包绕骨的软组织的再生。再生组织量的多少与植入诱导剂的剂量相关。该诱导剂可用于增加断指/断肢残余部分的长度和厚度，实现了断指/断肢的不完全再生；还可用于其他骨缺损/骨不连接等创伤的再生治疗。在小鼠中节趾的切除实验中，在离体组织弃之不用的情况下，再生后中节趾的骨量可超过原趾的骨量。该诱导剂主要由生物材料组成，在再生过程中可被完全吸收、新/旧伤均适用。
Description
技术领域
本发明属于再生医学领域的原位再生诱导部分。本发明诱导的再生为多组织的器官性再生，既有骨组织的再生，也有肌肉、血管、包括皮肤等的骨周围软组织的再生。本发明可用于离体的残损，如断指/断肢的再生(一般指离体的原组织不可用的情况)；也可用于非离体的残损，如骨缺损/骨不连接的再生。
背景技术
蚯蚓、水蛭等低等生物有强大的再生能力，蜥蜴、蝾螈和青蛙等两栖动物的前后肢或尾巴切除后可完全再生。哺乳动物的再生能力弱，鹿茸等少量哺乳动物的附属器官可完全再生，人类和鼠(啮齿类)的末节指/趾(Phalange3，P3)有不完全的再生能力，即远端切除后可再生，但近端切除不可再生。中节指/趾(Phalange2，P2)等其余指/趾及上下肢切除后不可再生。本发明以细胞外基质(ECM)和骨形态蛋白(BMP)诱导残损组织的骨性再生，效果显著。
发明内容
本发明要解决的问题是：诱导无再生能力的断指/断肢的骨性再生，或将末节指的不完全再生转变为完全再生，或实现其它骨缺损/骨不连接的再生性修复。新/旧创伤均适用。
诱导剂组成：
a.细胞外基质(ECM，extracellular matrix)。
b.骨形态蛋白(BMP，bone morphogenetic protein)。
c.骨形态蛋白BMP的稀释液。
诱导剂制备：
1.将b用c液稀释成适当浓度，浓度范围0.01～1000μg/ml。
2.将稀释好的b液与a混合，混合比例为b∶a＝1∶1～1000。
3.将a与b的混合物塑形为拟再生的骨的形状。诱导剂制备完成。
4.制备环境清洁无菌，诱导剂的各组分在制备前需经无菌化处理。
诱导剂的效果：
小鼠P2(中节趾)切除实验表明，在被切除的原组织弃之不用的情况下，该诱导剂可在断趾残端诱发骨和肌肉、皮肤等软组织的同步再生，从而延长残趾的长度，也可增加残趾的厚度。再生的骨组织为带有孔隙结构的骨，骨表面凸凹不平，随着时间的推移，再生骨内的孔隙结构减少，骨表面趋于光滑。
附图说明
图1是正常鼠趾的外观图(腹侧面，即掌心侧)。
中间趾(“中指”)不做切除，两侧趾(“食指”和“无名指”)做切除，切除位置为两侧趾的第2条趾纹线，箭头表示切除位置。中间趾的第3条趾纹线与两侧趾的第二条趾纹线(箭头所示)平齐，故中间趾的第三条趾纹线可用作两侧趾再生长度的参照坐标。图1的标号说明：①切除位置。②切除位置
图2是小鼠中节趾P2切除后35天的外观及其透明标本图。
图2-1是外观图。
图2-2是透明标本图。
左侧趾(“无名指”)有诱导剂植入，右侧趾(“食指”)无诱导剂为对照趾。透明标本用于观察骨。单箭头表示切除位置，双箭头表示P2趾骨的长度。诱导剂趾骨的长度约为对照趾趾骨长度的2倍。图2-1、图2-2为同一样品，所用诱导剂为低剂量诱导剂。图2-1的标号说明：①诱导剂趾的切除位置。②切除后加诱导剂的再生趾。③未损伤的正常趾(“中指”)。④切除后不加诱导剂的对照趾。⑤对照趾的切除位置。图2-2的标号说明：①诱导剂趾的切除位置。②切除后加诱导剂的再生趾。③再生的P2骨的长度。④未损伤的正常趾(“中指”)。⑤切除后不加诱导剂的对照趾。⑥对照趾的切除位置。⑦对照趾P2骨的长度。
图3是过量再生的P2鼠趾micro-CT成像及透明标本图(不同样品)。
图3-1是micro-CT图(切除后50天)。
图3-2是透明标本图(切除后34天)。
图3-3是透明标本图(切除后35天)。
再生的P2趾骨与正常中间趾的P2趾骨长度相当，再生趾的厚度等于或大于正常中间趾。鼠的正常中间趾，相当于人的“中指”，其P2趾骨最长。以上表明再生P2趾的骨量大于原P2趾，为过量的鼠趾再生。单箭头表示切除位置，双箭头表示P2趾骨的长度。图3-1的标号说明：①诱导剂趾的切除位置。②再生的P2趾。③正常中间趾的P3骨。④正常中间趾的P2骨。图3-2的标号说明：①正常中间趾的P2骨的长度。②再生的P2骨的长度。③诱导剂趾的切除位置。图3-3的标号说明：①诱导剂趾的切除位置。②正常中间趾的P2骨的长度。③再生的P2骨的长度。
具体实施方法
1.ECM可购买或自制。
2.BMP可购买或自制。
3.诱导剂的使用方法：按上述“诱导剂制备”的方法制备诱导剂，将制备完成的诱导剂植入伤口，使其与残损的骨组织保持接触。
4.实施例：将ECM与BMP-2按照适当的比例混合(BMP∶ECM约为1∶10～100)。其中BMP-2的浓度为100μg/ml，BMP-2的稀释液为含5％海藻糖的磷酸盐缓冲液(PH＝7.2)。混合物塑形后植入在P2处切除的鼠趾残端。35天后，再生P2趾的长度超过原P2趾，厚度与原P2趾相当，再生趾的骨量超过原趾骨量，为过量的鼠趾再生。
Claims (9)
1.本诱导剂主要成分为ECM，ECM的特征为，以动物组织器官为原料所得的产物，它包括但不限于：取自小肠、气管、膀胱、骨的细胞外基质。
2.本诱导剂主要成分为ECM，ECM的特征为，非动物组织器官来源的细胞外基质。
3.本诱导剂主要成分为ECM，ECM的特征为，权利要求1或2经物理或化学方法处理后的产物，此类处理方法包括但不限于：冻干、粉碎、降解、交联化、凝胶化。
4.本诱导剂主要成分为BMP，BMP的特征为，BMP超家族的骨形成蛋白，它包括但不限于：BMP-2、BMP-3、BMP-3B/GDF-10、BMP-4、BMP-5、BMP-6、BMP-7/OP-1、BMP-8/OP-2、BMP-8B、BMP-9、BMP-10、BMP-11、BMP-12、BMP-13、BMP-14、CDMP-1、CDMP-2、CDMP-3、GDF-1、GDF-2、GDF-3、GDF-4、GDF-5/CDMP-1/BMP-14、GDF-6/CDMP-2/BMP-13、GDF-7/CDMP-3/BMP-12、GDF-8、GDF-9。
5.本诱导剂主要成分为BMP，BMP的特征为，通过BMP发挥骨生成作用的外源性添加物，它包括但不限于：BMP结合蛋白如Follistatin。
6.本诱导剂主要成分为BMP，BMP的特征为，具有权利要求4或5中蛋白的核心序列的肽链。
7.稀释液为纯水或中性缓冲液，稀释液中可添加无机盐或其他促骨生成的组分，它包括但不限于：含钙、磷、镁等离子的无机盐。
8.本诱导剂为外用药，通过植入组织的残损处的方式发挥作用并在再生过程中被完全吸收。
9.本诱导剂主要成分为ECM和BMP，ECM指权利要求1、2、3中的任一种，BMP指权利要求4、5、6中的任一种。
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| EP17857811.8A EP3524281A4 (en) | 2016-10-09 | 2017-09-19 | INDUCTOR FOR THE SYNCHRONOUS REGENERATION OF BONES AND SOFT PARTS, PRODUCTION METHODS THEREFOR AND USE THEREOF |
| JP2019538548A JP6936324B2 (ja) | 2016-10-09 | 2017-09-19 | 骨と軟組織を同調に再生する誘導剤、その調製方法、及びその使用 |
| PCT/CN2017/102270 WO2018064930A1 (zh) | 2016-10-09 | 2017-09-19 | 骨与软组织同步再生诱导剂及其制备方法和用途 |
| CN201780060982.5A CN110072566A (zh) | 2016-10-09 | 2017-09-19 | 骨与软组织同步再生诱导剂及其制备方法和用途 |
| US16/369,246 US11547780B2 (en) | 2016-10-09 | 2019-03-29 | Inducer for regeneration of bone and soft tissue, and method for making same and uses thereof |
| ZA201902097A ZA201902097B (en) | 2016-10-09 | 2019-04-03 | Inducer for regeneration of bone and soft tissue, and method for making same and uses thereof |
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| US20190224381A1 (en) | 2019-07-25 |
| US11547780B2 (en) | 2023-01-10 |
| JP6936324B2 (ja) | 2021-09-15 |
| CN110072566A (zh) | 2019-07-30 |
| EP3524281A4 (en) | 2020-06-03 |
| JP2019531170A (ja) | 2019-10-31 |
| EP3524281A1 (en) | 2019-08-14 |
| WO2018064930A1 (zh) | 2018-04-12 |
| ZA201902097B (en) | 2019-11-27 |
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