CN111407785A - 一种用于治疗股骨头坏死的复合脱细胞基质注射液及使用方法 - Google Patents
一种用于治疗股骨头坏死的复合脱细胞基质注射液及使用方法 Download PDFInfo
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- CN111407785A CN111407785A CN202010293104.1A CN202010293104A CN111407785A CN 111407785 A CN111407785 A CN 111407785A CN 202010293104 A CN202010293104 A CN 202010293104A CN 111407785 A CN111407785 A CN 111407785A
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Abstract
本发明公开了一种复合脱细胞基质注射液，所述复合脱细胞基质注射液作为股骨头坏死修复材料用于临床治疗。所述复合脱细胞基质注射液由生物脱细胞基质溶胶、骨髓间充质干细胞及当归寄生液复合而成，于术中注入股骨头与髋臼之间髋关节部位，可提供组织修复的微环境，促进骨髓间充质干细胞增殖分化为成骨细胞，诱导新生血管形成及新骨形成，并具有消炎镇痛的作用，可用于早中期非创伤性股骨头坏死的治疗。
Description
技术领域
本发明涉及一种复合脱细胞基质注射液的制法及其在股骨头坏死中的治疗应用，属于医用生物材料领域、组织工程修复领域。
背景技术
非创伤性股骨头坏死的致病因素主要分为两种：慢性酒精中毒、滥用激素类药物。酒精及激素使股骨头周围血液循环发生障碍，引起供血不足，从而使股骨头坏死、骨小梁断裂、股骨头塌陷，严重时可导致患者瘫痪。股骨头坏死分为四个时期: 
、
期为塌陷前期；
期为股骨头塌陷期，
期为股骨头塌陷发展至关节炎，在早、中期发现尚可治疗，发展至晚期则需开展人工髋关节置换术，给患者造成极大痛苦。
细胞外基质是由细胞合成分泌至细胞膜外、分布在细胞表面或之间的大分子，主要成分包括胶原蛋白、糖蛋白、黏蛋白等，其他成分有多糖（透明质酸、硫酸软骨素）、脂质及生长因子等。这些活性物质构成复杂的网络结构，在细胞增殖、分化、迁移和血管生成方面有着重要的作用。脱细胞基质液在体内可形成组织修复支架，充当细胞外基质，提供有利于干细胞生长分化的微环境，促进血管生成。
骨髓间充质干细胞（BMSCs）是未分化多潜能干细胞，在组织再生领域具有巨大应用潜力。BMSCs可分化为成骨细胞、软骨细胞、成肌细胞、脂肪细胞、成纤维细胞，同时也可介导骨矿化及新生血管生成。这些功能预示了BMSCs在治疗早中期股骨头坏死的应用前景。BMSCs具有免疫原性低，多向分化功能，易于分离、扩增，来源广泛等优点，在股骨头坏死治疗中应用越来越多。BMSCs单独植入治疗股骨头坏死虽然可以减轻症状，但由于缺乏良好的骨架材料，细胞存活时间短，治疗效果不显著。
当归寄生液具有抗氧化、抑制血栓形成、降低血液黏滞度的作用，具有增强免疫功能、加强巨噬细胞吞噬能力的作用，有明显的抗炎、抗渗出、抗增生作用。其成份为当归和槲寄生。其中，当归为血中之圣药，具有补血活血、化瘀止痛、生肌健骨的功效，现代药理研究已证明，有抗炎、清除氧自由基、保肝护肾、增强免疫功能等作用。槲寄生具益肝肾、强筋骨、祛风湿、通经络益血之功效。现代药理研究其能扩张血管、镇静中枢，同时有减少关节积液、改善关节骨端变性及骨质疏松状态、增宽狭窄的关节间隙等作用。
脱细胞基质液与BMSCs、当归寄生液按比例混合后，基质液将BMSCs及当归多糖包裹在内，其所含生长因子可诱导BMSCs分化再生，诱导BMSCs分化为骨组织，混合的基质液在体内可形成缓释体系，延长BMSCs的作用时间，也还可防止细胞随骨内压增加而流失，还具有促进新生血管形成的作用，血管生成和骨生成之间关系十分密切，在骨损伤修复中新生血管形成被视为重要因素之一。
专利（CN201910178248.X）公开了一种用于腔隙注射治疗缺血性股骨头坏死的人源脐带间充质干细胞注射液的制备方法，该注射液的软骨分化诱导剂包括葡萄糖异黄酮、骨形成蛋白-2、抗坏血酸、地塞米松、β-甘油磷酸钠，该类诱导剂不能固定间充质干细胞，无法提供再生微环境，干细胞在体内易流失。专利（CN201010152461.2）公开了一种治疗骨损伤细胞注射剂及其制备方法，该凝胶主要为泊洛沙姆凝胶，属于高分子聚合物，不利于肾脏排泄。
目前还未有脱细胞基质液、骨髓间充质干细胞及当归寄生液复合再生材料，构建组织修复微环境，用于股骨头坏死组织修复的相关报道。
发明内容
本发明提供了一种用于治疗股骨头坏死的复合脱细胞基质注射液及使用方法，通过将哺乳动物组织细胞外基质进行脱细胞处理和基质液化处理，制备出脱细胞基质液，消除了异种组织的免疫原性，保留细胞外基质活性成分，成为干细胞安全载体，并能够诱导干细胞分化及组织再生。BMSCs从骨髓中提取培养，当归寄生液为生产检验合格的市售产品，将脱细胞基质液与骨髓间充质干细胞的细胞液及当归寄生液混合摇匀后，注射于髋关节股骨窝关节腔内，该复合材料具有良好的治疗效果及安全性。
为了实现上述发明目的，本发明提供以下技术方案：
一种用于治疗股骨头坏死的复合脱细胞基质注射液，其特征在于，所述复合脱细胞基质注射液由异种哺乳动物组织经脱细胞处理得到的基质溶胶、骨髓间充质干细胞及当归寄生液复合而成，所述复合脱细胞基质注射液中组成成分的体积份为脱细胞基质溶胶0.8-1.2份、骨髓间充质干细胞液（细胞密度1×106～107个/ml，细胞活率>90%）0.8-1.2份和当归寄生注射液0.8-1.2份。
一种脱细胞基质液的制备方法，包括以下步骤：
（1）首先用PBS对动物组织进行清洗等预处理，经病毒灭活后粉碎；
（2）加入10%的氯化钠溶液浸泡摇床震荡处理2h，30℃/200rpm；
（3）过滤，将组织用纯化水清洗3次，30min/次，摇床震荡处理10min，30℃/200rpm；
（4）用3%碳酸钠溶液浸泡3小时脱脂，纯化水洗3次：10min/次，30℃/200rpm；
（5）用4%胰蛋白酶浸泡摇床3小时，纯化水洗3次：10min/次，30℃/200rpm；
（6）再经核酸酶降解细胞中核酸成分，充分清洗以除去去垢剂后得到脱细胞基质，经冻干后得到脱细胞基质粉；
（7）配制pH=2 HCl溶液、10×PBS溶液、1×PBS溶液、0.1mol/L NaOH溶液；
（8）按照1g基质粉/100ml HCl溶液/0.1g胃蛋白酶的比例进行酶解，酶解条件：200rpm/min、30℃、36h；
（9）36h后酶解液中加入按1g基质液/0.05g胃蛋白酶的比例进行二次酶解，酶解条件：200rpm/min、30℃、36h；
（10）过滤，除去未酶解基质；
（11）酶提取液中加入氯化钠固体颗粒至浓度为 4mol/L，4℃下盐析 36 h；
（12）盐析后过滤分离，沉淀用5倍量的3%的醋酸溶液溶解，然后再次盐析，纯化水冲洗沉淀数次，冻干；
（13）按照1g冻干粉/100ml pH=2 HCl溶液的比例将冻干粉进行复溶；
（14）按照12ml基质溶液加1.3ml 10×PBS加1.2ml 0.1mol/L NaOH溶液加5.5ml 1×PBS的比例在低温下混合，调节pH pH=7.3～7.5；
（15）过滤除菌后装入无菌注射器中，2-8℃低温保存。
骨髓间充质干细胞的提取及培养方法：
（1）BMSCs提取过程在层流无菌手术室进行，对患者进行局部麻醉后，选取患者双侧髂后上棘部位进行穿刺，用含有肝素抗凝液的注射器抽取骨髓血，将抽取的骨髓血打入医用无菌采血袋中；
（2）在无菌条件下，将采集袋中的自体骨髓血装入50ml离心管中，在2000r/min的转速下离心20min；
（3）离心完成后，去除离心管上层血浆，再用生理盐水稀释至30ml，并混合摇匀；
（4）将分离稀释后的骨髓细胞与20mlFicoll分离液，混合摇匀，1800r/min的转速下离心20min；
（5）离心后，用移液器小心吸取上层血浆与Ficoll分离液之间的白膜层细胞，用30ml生理盐水稀释吸取液，混合摇匀，1600r/min的转速下离心14min；
（6）离心后，用移液器吸取底部细胞，放入新的离心管中，加30ml生理盐水稀释，混合摇匀，1400r/min的转速下离心12min；
（7）再次吸取底部细胞，加30ml生理盐水稀释，混合摇匀，1200r/min的转速下离心10min；
（8）收取细胞加入无血清培养基，37℃，5%CO2条件下培养扩增至第3-5代使用。
一种复合脱细胞基质注射液的制备方法：
收集第3-5代BMSCs，按照0.8-1.2份脱细胞基质液、0.8-1.2份骨髓干细胞、0.8-1.2份当归寄生液的比例混合，细胞密度1×106～107个/ml（活率>90%），形成复合修复材料，以上制备全过程均在无菌环境中进行。
治疗方法：
患者患侧在上，侧膝卧位，术者对患侧髋部用碘付常规消毒3遍，采用10ml注射器用12cm注射针头，将复合脱细胞基质注射液混合摇匀，注射于患侧股骨关节腔内，股骨头与髋臼之间髋关节部位。注射液复温条件为25℃-37℃，1-2min，复温后需在3min内完全注射入体内。
本发明所述的复合脱细胞基质注射液中脱细胞基质液、骨髓间充质干细胞液和当归寄生注射液成分最优化体积比为，脱细胞基质液1.2份，骨髓间充质干细胞液1份，当归寄生注射液0.8份。
与现有发明相比，本发明具有以下优点：
（1）脱细胞基质液于25℃-37℃左右条件下，随着时间增加，体系粘弹性增加，转化为半流动态，从纯粘性液体转变成粘弹性水凝胶，在体内可形成组织修复支架，充当细胞外基质，提供有利于干细胞生长分化的微环境，促进血管生成，为股骨头再生提供生物支架及营养成分，其所含生长因子可诱导BMSCs分化再生，在体内可形成缓释体系，延长BMSCs的作用时间，有效提高细胞的存活率，材料本身可进行生物降解，可随人体代谢吸收排泄；
（2）本发明制得的脱细胞基质液制备过程中，采用的试剂温和，有效保留细胞外基质中活性结构蛋白、多糖及生长因子，可特异性引导骨组织的再生修复。所制备材料可扩张血管、促进血管化形成，以及消炎镇痛作用；
（3）本发明提供的治疗材料与方法无毒副作用、能加快全愈时间解除患者痛苦，通过股骨关节腔注射的方式可避免开创手术的风险，能促进早中期非创伤性股骨头坏死的组织功能恢复。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示实施例7动物造模后股骨头 X 线表现；
图2示实施例7模型动物治疗后第2周股骨头 X 线表现；
图3示实施例7模型动物治疗后第4周股骨头 X 线表现；
图4示实施例7模型动物治疗后第6周股骨头 X 线表现。
图5示手术中复合脱细胞基质注射液具体使用部位。
具体实施方式
下面结合本发明的具体实施例对本发明做进一步说明。
实施例1、复合脱细胞基质注射液的制备方法
脱细胞基质液的制备方法：（1）首先称取500g猪跟腱组织，用PBS对其进行清洗等预处理，经病毒灭活后粉碎；（2）加入2L 10%的氯化钠溶液浸泡摇床震荡处理2h，30℃/200rpm；（3）过滤，将组织用大量纯化水清洗3次，30min/次，摇床震荡处理10min，30℃/200rpm；（4）用2L 3%碳酸钠溶液浸泡3小时脱脂，纯化水洗3次：10min/次，30℃/200rpm；（5）用5L 4%胰蛋白酶浸泡摇床3小时，纯化水洗3次：10min/次，30℃/200rpm；（6）再经核酸酶降解细胞中核酸成分，充分清洗以除去去垢剂后得到脱细胞基质，经冻干后得到脱细胞基质粉；（7）配制pH=2 HCl溶液、10×PBS溶液、1×PBS溶液、0.1mol/L NaOH溶液；（8）按照1g基质粉/100mlHCl溶液/0.1g胃蛋白酶的比例进行酶解，酶解条件：200rpm/min、30℃、36h；（9）36h后酶解液中加入按1g基质液/0.05g胃蛋白酶的比例进行二次酶解，酶解条件：200rpm/min、30℃、36h；（10）过滤，除去未酶解基质；（11）酶提取液中加入氯化钠固体颗粒至浓度为 4mol/L，4℃下盐析 36 h；（12）盐析后过滤分离，沉淀用5倍量的3%的醋酸溶液溶解，然后再次盐析，纯化水冲洗沉淀数次，冻干；（13）按照1g冻干粉/100ml pH=2 HCl溶液的比例将冻干粉进行复溶；（14）按照12ml基质溶液加1.3ml 10×PBS加1.2ml 0.1mol/L NaOH溶液加5.5ml 1×PBS的比例在低温下混合，调节pH pH=7.3～7.5；（15）过滤除菌后装入无菌注射器中，2℃-8℃低温保存。
骨髓间充质干细胞的提取及培养方法：BMSCs提取过程在层流无菌手术室进行，对患者进行局部麻醉后，选取患者双侧髂后上棘部位进行穿刺，用含有肝素抗凝液的注射器抽取骨髓血200ml，将抽取的骨髓血打入医用无菌采血袋中；在无菌条件下，将采集袋中的自体骨髓血平均装入6个50ml离心管中，在2000r/min的转速下离心20min；离心完成后，去除离心管上层血浆，再用生理盐水稀释至30ml，并混合摇匀；将分离稀释后的骨髓细胞与20mlFicoll分离液，混合摇匀，1800r/min的转速下离心20min；离心后，用移液器小心吸取上层血浆与Ficoll分离液之间的白膜层细胞，用30ml生理盐水稀释吸取液，混合摇匀，1600r/min的转速下离心14min；离心后，用移液器吸取底部细胞，放入新的离心管中，加30ml生理盐水稀释，混合摇匀，1400r/min的转速下离心12min；再次吸取底部细胞，加30ml生理盐水稀释，混合摇匀，1200r/min的转速下离心10min；收取细胞加入无血清培养基，37℃，5%CO2条件下培养扩增至第3-5代使用。
当归寄生注射液：取生成检验合格的当归寄生注射液，备用。
取上述复合脱细胞基质注射液中组成成分脱细胞基质液1份、骨髓间充质干细胞液1份和当归寄生注射液1份，按照比例在手术时进行混合，装入10ml注射器中，复合为可注射的混合物。
实施例2、取实施例1中的复合脱细胞基质注射液中组成成分脱细胞基质液1.2份、骨髓间充质干细胞液1份和当归寄生注射液0.8份，按照比例在手术时进行混合，装入10ml注射器中，复合为可注射的混合物。
实施例3、取实施例1中的复合脱细胞基质注射液中组成成分脱细胞基质液0.8份、骨髓间充质干细胞液1份和当归寄生注射液1.2份，按照比例在手术时进行混合，装入10ml注射器中，复合为可注射的混合物。
实施例4、取实施例1中的复合脱细胞基质注射液中组成成分脱细胞基质液1份、骨髓间充质干细胞液1.2份和当归寄生注射液0.8份，按照比例在手术时进行混合，装入10ml注射器中，复合为可注射的混合物。
实施例5、将按比例混合后的可注射复合脱细胞基质液（1.2份脱细胞基质溶胶、1份骨髓间充质干细胞（细胞密度1×106～107个/ml，细胞活率>90%）及0.8份当归寄生注射液）于术中注入股骨头与髋臼之间髋关节部位，注射液复温条件为28℃，2min，复温后在3min内完全注射入体内。
实施例6、将按比例混合后的可注射复合脱细胞基质液（1.2份脱细胞基质溶胶、1份骨髓间充质干细胞（细胞密度1×106～107个/ml，细胞活率>90%）及0.8份当归寄生注射液）于术中注入股骨头与髋臼之间髋关节部位，注射液复温条件为35℃，2min，复温后在3min内完全注射入体内。
实施例7、有效性动物验证实验
实验方法：实验动物为普通级1月龄大白鼠，体重约280g，雌雄不限，共12只，6只左腿经过骨缘注射无水酒精，另6只左腿经过骨缘注射地塞米松造模2周。之后进行手术治疗，先用水合氯醛腹腔麻醉大白鼠，麻醉成功后将大白鼠俯卧位固定于手术台，剪除鼠毛，用安尔碘消毒左髋部3次，将复合脱细胞基质注射液0.5ml(0.1ml/min)缓慢注射至股骨头关节腔内。手术前肌肉注射苄星青霉素12万单位预防感染。术后在25℃空调房间里观察一天，第二天放回笼养。第1-3天观察2次/日，记录食量、精神状态和跛行程度。
主要观察：CT检查：实验动物分别在第2周，4周，6周行CT X 射线片检查，以水合氯醛腹腔麻醉后，双侧后肢八字形分开伸直，摄双侧髋关节正位片。
结果：第2周（图2），4周（图3）股骨头内骨坏死面积逐渐缩小，第6周（图4）股骨头骨密度均匀一致。
讨论：本动物实验通过研究复合脱细胞基质注射液，在股骨头坏死动物模型使用该生物复合材料诱导骨损伤区域血管再生及干细胞分化为成骨细胞，从而促进骨再生。该生物复合材料可提供力学稳定性和生物相容性，可模拟组织再生的最佳微环境，既可以保持病灶局部的干细胞浓度，也可诱导组织生长和组织再生特异性基因的活性信号表达，由于其骨诱导活性作为骨代用品。可注射的组织工程化干细胞复合脱细胞基质凝胶为早中期股骨头坏死提供了新的治疗方法。
Claims (5)
1.权利要求1：一种用于治疗股骨头坏死的复合脱细胞基质注射液，其特征在于，所述复合脱细胞基质注射液由异种哺乳动物组织经脱细胞处理得到的基质溶胶、骨髓间充质干细胞及当归寄生液复合而成，所述复合脱细胞基质注射液中组成成分的体积份为脱细胞基质溶胶0.8-1.2份、骨髓间充质干细胞液（细胞密度1×106～107个/ml，细胞活率>90%）0.8-1.2份和当归寄生注射液0.8-1.2份。
2.根据权利要求1所述的复合脱细胞基质注射液，其特征在于25℃-37℃条件下，随着时间增加，体系粘弹性增加，转化为半流动态，从纯粘性液体转变成粘弹性水凝胶，在体内可形成组织修复支架，提供有利于干细胞生长分化及组织再生的微环境。
3.根据权利要求1所述异种哺乳动物组织经脱细胞处理得到的基质溶胶，其特征在于，所述异种动物组织选自猪、牛、羊的心包膜、小肠粘膜下层、真皮、腹膜、韧带、跟腱、周围神经组织等。
4.一种脱细胞基质液的制备方法，其特征在于包括以下步骤：
（1）首先用PBS对动物组织进行清洗等预处理，经病毒灭活后粉碎；
（2）加入10%的氯化钠溶液浸泡摇床震荡处理2h，30℃/200rpm；
（3）过滤，将组织用纯化水清洗3次，30min/次，摇床震荡处理10min，30℃/200rpm；
（4）用3%碳酸钠溶液浸泡3小时脱脂，纯化水洗3次：10min/次，30℃/200rpm；
（5）用4%胰蛋白酶浸泡摇床3小时，纯化水洗3次：10min/次，30℃/200rpm；
（6）再经核酸酶降解细胞中核酸成分，充分清洗以除去去垢剂后得到脱细胞基质，经冻干后得到脱细胞基质粉；
（7）配制pH=2 HCl溶液、10×PBS溶液、1×PBS溶液、0.1mol/L NaOH溶液；
（8）按照1g基质粉/100ml HCl溶液/0.1g胃蛋白酶的比例进行酶解，酶解条件：200rpm/min、30℃、36h；
（9）36h后酶解液中加入按1g基质液/0.05g胃蛋白酶的比例进行二次酶解，酶解条件：200rpm/min、30℃、36h；
（10）过滤，除去未酶解基质；
（11）酶提取液中加入氯化钠固体颗粒至浓度为 4mol/L，4℃下盐析 36 h；
（12）盐析后过滤分离，沉淀用5倍量的3%的醋酸溶液溶解，然后再次盐析，纯化水冲洗沉淀数次，冻干；
（13）按照1g冻干粉/100ml pH=2 HCl溶液的比例将冻干粉进行复溶；
（14）按照12ml基质溶液加1.3ml 10×PBS加1.2ml 0.1mol/L NaOH溶液加5.5ml 1×PBS的比例在低温下混合，调节pH pH=7.3～7.5；
（15）过滤除菌后装入无菌注射器中，2℃-8℃低温保存。
5.一种用于治疗股骨头坏死的复合脱细胞基质注射液的使用方法：将按比例混合后的可注射复合脱细胞基质液（0.8-1.2份脱细胞基质溶胶、0.8-1.2份骨髓间充质干细胞（细胞密度1×106～107个/ml，细胞活率>90%）及0.8-1.2份当归寄生注射液）于术中注入股骨头与髋臼之间髋关节部位，注射液复温条件为25℃-37℃，1-2min，复温后需在3min内完全注射入体内。
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| CN116492508A (zh) * | 2023-02-28 | 2023-07-28 | 诺一迈尔（苏州）医学科技有限公司 | 一种促进关节软骨修复的可注射水凝胶及其制备方法 |
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| CN102232970A (zh) * | 2010-04-22 | 2011-11-09 | 董运海 | 一种治疗骨损伤细胞注射剂及其制备方法 |
| CN104971380A (zh) * | 2014-04-11 | 2015-10-14 | 烟台隽秀生物科技有限公司 | 一种脱细胞基质修复凝胶及其制备新方法 |
| CN107929726A (zh) * | 2017-11-23 | 2018-04-20 | 吉林省拓华生物科技有限公司 | 一种干细胞复方注射液及其在制备防治股骨头坏死药物中的应用 |
| CN110237303A (zh) * | 2019-06-27 | 2019-09-17 | 浙江大学医学院附属邵逸夫医院 | 天然组织来源的脱细胞骨膜基质凝胶材料的制备方法 |
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| CN114306749A (zh) * | 2022-01-06 | 2022-04-12 | 杭州倍荣生物科技有限公司 | 一种负载活细胞的胎盘脱细胞基质凝胶的制备及应用 |
| CN116492508A (zh) * | 2023-02-28 | 2023-07-28 | 诺一迈尔（苏州）医学科技有限公司 | 一种促进关节软骨修复的可注射水凝胶及其制备方法 |
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