CN111632068A - 一种犬、猫干细胞眼用制剂及其应用 - Google Patents
一种犬、猫干细胞眼用制剂及其应用 Download PDFInfo
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- CN111632068A CN111632068A CN202010609491.5A CN202010609491A CN111632068A CN 111632068 A CN111632068 A CN 111632068A CN 202010609491 A CN202010609491 A CN 202010609491A CN 111632068 A CN111632068 A CN 111632068A
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Abstract
一种犬、猫干细胞眼用制剂，涉及犬和猫干细胞技术领域，特别涉及一种犬和猫干细胞眼药水、眼用凝胶、眼膏的制备方法及其应用。本发明的犬、猫干细胞眼用制剂，其特征在于该制剂包括犬、猫MSCs，以及犬、猫干细胞分泌因子。本发明所述的干细胞及分泌因子眼用制剂可用于犬、猫常规眼科手术后，快速修复、重建和再生眼科各组织，恢复眼部功能和视力。对于角膜溃疡，视网膜疾病、干眼症，角膜炎，结膜炎，葡萄膜炎等有良好的治疗效果，对于早期的青光眼和白内障也具有一定的辅助治疗作用。
Description
技术领域
本发明涉及犬和猫干细胞技术领域，特别涉及一种犬和猫干细胞眼药水、眼用凝胶、眼膏的制备方法及其应用。
背景技术
间充质干细胞(MSCs)是存在于骨髓、脂肪、脐带或胎盘中的具有高度自我更新能力和多向分化潜能的成体干细胞，又称为基质干细胞或间充质祖细胞。MSCs具有向内、中、外3个胚层包括肌腱、韧带、肝细胞、角膜细胞、神经元细胞、心肌细胞和骨髓基质细胞分化发育的潜能；MSCs表达低水平的主要组织相容性复合物（MHC）Ⅰ类表面分子，不表达MHCⅡ类分子，具有低免疫原性和安全性；MSCs通过调控多种活性淋巴细胞（包括Ｔ细胞、Ｂ细胞、自然杀伤细胞、树突状细胞）发挥免疫调节作用。基于以上特点，MSCs在治疗眼表疾病、视网膜疾病、干眼症等眼科疾病方面显示出了巨大的优势。
MSCs还可以产生和分泌大量的生物活性因子，如干细胞生长因子 ( SCF )、神经生长因子 ( NGF )、基质细胞源性生长因子 ( SDF )、血管内皮细胞生长因子 ( VEGF )、碱性成纤维细胞生长因子 ( bFGF )、胰岛素样生长因子 ( IGF )、表皮生长因子( EGF )、白介素-6 与白介素-7( IL-6 与 IL-7 )、巨核细胞集落刺激因子( M-CSF )、肿瘤坏死因子 ( TNF )、干扰素 ( IFN ) 等80余种活性因子，这些干细胞活性因子具有支持干/祖细胞的增殖与分化、化学趋化、免疫调节、抗细胞凋亡、促进血管发生、抗瘢痕等功能。
MSCs通过自分泌或旁分泌的方式，改善眼部微环境，发挥眼部免疫调节作用，促进内源性干细胞向眼部受损部位进行迁移和分化，并作为种子细胞参与角膜、视网膜、泪腺等眼部受损组织修复与再生，挽救濒临凋亡的眼组织细胞，从而达到修复眼组织、恢复眼组织功能的目的。
发明内容
本发明提供了一种犬、猫干细胞眼用制剂，能够修复犬、猫眼组织、恢复眼组织功能。
本发明的犬、猫干细胞眼用制剂，该制剂包括犬、猫MSCs，以及犬、猫干细胞分泌因子、视黄酸、牛磺酸、洋地黄苷、七叶亭苷、二甲基亚砜、透明质酸、三氯叔丁醇、异槲皮苷和灭菌生理盐水。
上述犬、猫干细胞眼用制剂，其特征在于100ml该制剂中包含有以下的组分：
犬猫间充质干细胞：1×105～1×106个；
犬猫干细胞分泌因子：80ml～90ml；
视黄酸：0.5g～1g；
牛磺酸：4g～5g；
洋地黄苷：4mg～6mg；
七叶亭苷：9mg～11mg；
透明质酸：0.3g～2g；
异槲皮苷：0.2g～0.8g；
三氯叔丁醇：0.08g～0.1g；
二甲基亚砜：4ml～6ml；
其余量为灭菌生理盐水，并利用NaHCO3调节pH值至7.0～7.2。
上述的制剂包括眼药水、眼用凝胶或眼膏。
本发明的主要核心成份是犬、猫MSCs及干细胞分泌因子，且以保持犬、猫MSCs和干细胞分泌因子的活性和功效为前提，以上配方是经过大量的对比试验，不断优化各组分的种类和比例而得出的，任何一种组分的改变或比例的变化，都会导致犬、猫MSCs和干细胞分泌因子活性的降低或丧失。
所述的犬、猫MSCs是从犬、猫的骨髓、脂肪、脐带或胎盘中分离培养，其表面分子CD44强阳性，中国专利申请号201410405353.X公开了犬MSCs的获得方式，猫的获得同于犬。其中，本发明所述的犬、猫干细胞生长因子由共培养犬、猫骨髓间充质干细胞和造血干细胞时，由这两种干细胞共同分泌和释放出来的细胞因子和活性成份。MSCs及其分泌因子可以改善眼部环境，发挥眼部免疫调节作用，促进内源性干细胞向眼部受损部位进行迁移和分化，并作为种子细胞参与角膜、视网膜、泪腺等眼部受损组织修复与再生。视黄酸可以促进眼上皮细胞分化与生长，维持上皮组织的正常角化过程；减少皮脂腺管部位角化过程，促进腺管组织结构的正常化。牛磺酸是一种含硫氨基酸，为成熟视网膜中主要的氨基酸，能促进视网膜生长发育，缓解睫状肌痉挛，牛磺酸在房水和玻璃体中与还原性糖竞争性结合，使玻璃体中蛋白质避免糖化和氧化。洋地黄苷可以增强眼睫状肌的收缩力，特别是对伴有眼肌机能不全的情况；七叶亭苷能增强血管的封闭性，增加虹膜和睫状体中毛细血管的阻力，这两种成份的联合作用使视网膜的血流灌注得到改善。异槲皮苷维持干细胞的活性及干性，促进干细胞发挥再生和修复作用。二甲基亚砜保护MSCs及干细胞分泌因子，透明质酸可以促进伤口愈合，同时延长MSCs及干细胞分泌因子的作用效果。三氯叔丁醇抑制细菌生长，起到防腐的作用。
本发明所述的干细胞及分泌因子眼用制剂可用于犬、猫常规眼科手术后，快速修复、重建和再生眼科各组织，恢复眼部功能和视力。对于角膜溃疡，视网膜疾病、干眼症，角膜炎，结膜炎，葡萄膜炎等有较好的治疗效果，对于早期的青光眼和白内障也具有一定的辅助治疗作用。
附图说明
图1为本发明病例一检查结果；
图2为本发明病例一一阶段治疗效果；
图3为本发明病例一最终治疗效果；
图4为本发明病例二检查结果（1）；
图5为本发明病例二检查结果（2）；
图6为本发明病例二最终治疗效果；
图7为本发明实施例1毒副作用生理盐水组；
图8为本发明实施例1毒副作用培养基对照组；
图9为本发明实施例1毒副作用眼用制剂组；
图10为本发明实施例2毒副作用生理盐水组；
图11为本发明实施例2毒副作用培养基对照组；
图12为本发明实施例2毒副作用眼用制剂组；
图13为本发明MTT法测定不同时间段眼用制剂中间充质干细胞的活性结果。
具体实施方式
实施例1：
在本实施例中，配100ml犬、猫干细胞眼用制剂，其中包括：
犬猫间充质干细胞：1×105个；
犬猫干细胞分泌因子：80ml；
视黄酸：0.5g；
牛磺酸：4g；
洋地黄苷：4mg；
七叶亭苷：9mg；
透明质酸：0.3g；
异槲皮苷：0.2g；
三氯叔丁醇：0.08g；
二甲基亚砜：4ml；
其余量为灭菌生理盐水，并利用NaHCO3调节pH值至7.0～7.2。
本实施例所述制剂为眼用凝胶，该眼用凝胶加入酚红指示剂，呈粉红色。
采用本实施例所述眼用凝胶治疗病例一：
病患：加菲猫，8月龄，雄性，未去势，体重2.5kg。
主述：三天前家中猫打闹后，发现患猫右眼偶尔有羞明症状，患猫有抓挠眼部表现，主人没太在意，今早忽然发现右眼发白，眼表面有异样。
基本检测：右眼荧光阳性，荧光素钠角膜上皮下浸润着色。如图1所示。
诊断：角膜溃疡，角膜穿孔（外伤性）。
治疗：全天佩戴眼科伊丽莎白圈防自损，猫干细胞眼用制剂(眼用凝胶)3次/日，2滴/次。一周后复诊，如图2所示：
以猫干细胞眼用凝胶点眼方式继续巩固治疗。二周后复诊，如图3所示。
实施例2：
在本实施例中，配100ml犬、猫干细胞眼用制剂，其中包括：
犬猫间充质干细胞： 1×106个；
犬猫干细胞分泌因子： 90ml；
视黄酸：1g；
牛磺酸：5g；
洋地黄苷： 6mg；
七叶亭苷： 11mg；
透明质酸： 2g；
异槲皮苷： 0.8g；
三氯叔丁醇： 0.1g；
二甲基亚砜： 6ml；
其余量为灭菌生理盐水，并利用NaHCO3调节pH值至7.0～7.2。
本实施例所述制剂为眼药水，该眼药水加入酚红指示剂，呈粉红色。
采用本实施例所述眼药水治疗病例二：
病患：中华田园犬，8 岁，雄性，去势，体重5.0Kg。
主诉：3个月前，突然羞明、流泪、角膜变成白色。他院诊断为角膜溃疡。
基本检查：STT、右眼为15mm，左眼为10mm，IOP右眼为13mmHg，左眼为11mmHg，右眼荧光阳性，荧光素纳角膜上皮下浸润着色，裂隙灯及分泌物镜检，结膜正常，角膜中心岛屿状变性、溶解，其周边呈环形、角膜水肿、轻度隆起、溃疡部呈黄色、点眼局麻后，棉棒检查角膜上皮疏松呈泥状，溶解状态，角膜中心严重变性，镜检分泌物内大量葡萄球菌。如图4、图5所示。
诊断：顽固性角膜溃疡
鉴别诊断：浅表性角膜溃疡、糜烂性角膜溃疡、外伤异物、激素性角膜溃疡
治疗过程：实施阿尔杰刷清创术及角膜镜遮盖术联合内科点眼治疗。患犬左侧卧位，真空枕固定头部，使用0.05%聚维酮碘进行眼球消毒，5分钟后生理盐水冲洗，眼睑皮肤1%聚维酮磺消毒。使用开眼器，内外眦结膜处装置2根眼球固定线，使用阿尔杰刷由角膜中心向周围放射状进行疏松上皮清理，清理范围一定要大于染色剂着色边缘确定无疏松上皮残留后，装置15mm软角膜镜，闭合外眼角。2周后拆线，摘下角膜镜后观察，是否进行第二次清理治疗。
术后内科治疗：术后连续2周全天配戴眼科专用伊丽莎白圈以防自伤，犬用干细胞制剂(眼药水)滴眼液4次/日，3滴/次。
术后2周拆线，拆线后疏松上皮消失，角膜水肿消失，角膜表面光滑，但角膜仍有轻度混浊，患眼视觉功能恢复正常。拆线后继续内科治疗，犬干细胞眼药水调整为3次/日，2滴/次，3周后角膜痊愈。如图6所示。
对本发明实施例1和实施例2所述制剂分别进行毒副作用实验，对分离培养的犬猫间充质干细胞第15天换液时，分别加入生理盐水，培养基和实施例1和实施例2中眼用制剂，于第3天观察，如图7-9和图10-12所示，三者细胞形态未见异常及差别，表明实施例1和实施例2中的眼用试剂对体外培养的间充质细胞无毒副作用。
本申请在眼用制剂中加入异槲皮苷，经异槲皮苷处理后cBMSCs 的 CBX4 mRNA 表达水平增加，细胞状态依然保持“年轻态”，细胞衰老情况得以缓解。
各时间点不同处理组的 Ct 值如表1所示，数据显示各组不同时间点CBX 4 基因的 mRNA 表达水平存在一定的差异。
注：与对照组比较， * P<0.05差异显著， ** P<0.01差异极显著，n=3.
在长期保存后，利用细胞计数仪对眼用制剂的间充质干细胞进行了计数统计，发现随着时间的延长，眼药水中的间充质干细胞数量变化差异不显著，结果如表2所示：
同时，运用MTT法对眼用制剂中的干细胞测定其活性：将眼用制剂在室温下放置，分别于1个月，3个月，5个月，7个月，9个月后取样，测定眼药水中的间充质干细胞活性，发现随着时间的延长，眼药水中的间充质干细胞的活性差异不显著，即分别为90%，90%，92%，89%，88%。其结果如图13所示。
Claims (5)
1.一种犬、猫干细胞眼用制剂，其特征在于，所述制剂包括犬、猫MSCs、犬、猫干细胞分泌因子、视黄酸、牛磺酸、洋地黄苷、七叶亭苷、二甲基亚砜、透明质酸、三氯叔丁醇、异槲皮苷和灭菌生理盐水。
2.如权利要求1所述的一种犬、猫干细胞眼用制剂，其特征在于，100ml该制剂中，含有以下的组分：
犬猫间充质干细胞：1×105～1×106个；
犬猫干细胞分泌因子：80ml～90ml；
视黄酸：0.5g～1g；
牛磺酸：4g～5g；
洋地黄苷：4mg～6mg；
七叶亭苷：9mg～11mg；
透明质酸：0.3g～2g；
异槲皮苷：0.2g～0.8g；
三氯叔丁醇：0.08g～0.1g；
二甲基亚砜：4ml～6ml；
其余量为灭菌生理盐水，并利用NaHCO3调节pH值至7.0～7.2。
3.如权利要求2所述的一种犬、猫干细胞眼用制剂，其特征在于，100ml该制剂中，含有以下的组分：
犬猫间充质干细胞：1×105个；
犬猫干细胞分泌因子：80ml；
视黄酸：0.5g；
牛磺酸：4g；
洋地黄苷：4mg；
七叶亭苷：9mg；
透明质酸：0.3g；
异槲皮苷：0.2g；
三氯叔丁醇：0.08g；
二甲基亚砜：4ml；
其余量为灭菌生理盐水，并利用NaHCO3调节pH值至7.0～7.2。
4.如权利要求2所述的一种犬、猫干细胞眼用制剂，其特征在于，100ml该制剂中，含有以下的组分：
犬猫间充质干细胞： 1×106个；
犬猫干细胞分泌因子： 90ml；
视黄酸：1g；
牛磺酸：5g；
洋地黄苷： 6mg；
七叶亭苷： 11mg；
透明质酸： 2g；
异槲皮苷： 0.8g；
三氯叔丁醇： 0.1g；
二甲基亚砜： 6ml；
其余量为灭菌生理盐水，并利用NaHCO3调节pH值至7.0～7.2。
5.如权利要求1～4所述的一种犬、猫干细胞眼用制剂，其特征在，所述的制剂包括眼药水、眼用凝胶或眼膏。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1753683A (zh) * | 2002-12-20 | 2006-03-29 | 视可舒研究公司 | 预防和治疗不良眼部病症的眼用制剂 |
| CN106890193A (zh) * | 2017-04-21 | 2017-06-27 | 云南农业大学 | 一种犬、猫干细胞眼用制剂及其应用 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1753683A (zh) * | 2002-12-20 | 2006-03-29 | 视可舒研究公司 | 预防和治疗不良眼部病症的眼用制剂 |
| CN106890193A (zh) * | 2017-04-21 | 2017-06-27 | 云南农业大学 | 一种犬、猫干细胞眼用制剂及其应用 |
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| M.LI等: "Isoquercitrin promotes the osteogenic differentiation of osteoblasts and BMSCs via the RUNX2 or BMP pathway", 《CONNECT TISSUE RES》 * |
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