CN114072132A - 仿生组织黏附性水凝胶贴片及其用途 - Google Patents
仿生组织黏附性水凝胶贴片及其用途 Download PDFInfo
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- CN114072132A CN114072132A CN201980098290.9A CN201980098290A CN114072132A CN 114072132 A CN114072132 A CN 114072132A CN 201980098290 A CN201980098290 A CN 201980098290A CN 114072132 A CN114072132 A CN 114072132A
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- hydrogel
- patch
- hydrogel patch
- growth factor
- drug
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Abstract
本发明涉及一种邻苯二酚基或邻苯三酚基修饰的生物相容性及组织粘合力优秀的生物相容性聚合物水凝胶贴片以及利用其的药物递送、细胞移植和组织再生用途。上述邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物水凝胶贴片相比基于溶液的本体水凝胶,具有显著优秀的机械性质及组织粘合力,因此可以在体内长时间装载细胞和药物,并安全有效地将上述细胞和药物递送到靶部位。
Description
技术领域
本发明涉及一种邻苯二酚基(catechol groups)或邻苯三酚基(pyrogallolgroups)修饰的生物相容性及组织粘合力优秀的生物相容性聚合物水凝胶贴片以及利用其的药物递送、细胞移植和组织再生用途。
背景技术
为了有效地恢复因疾病或事故而受损的组织和器官,需要将药物和细胞有效地递送到体内和体外。为此进行了许多用于传递药物和细胞的研究,但是应用于实际临床中并显示出令人满意水平的治疗效果的系统的开发仍然不足。
对于细胞递送,现有技术中主要采用了直接注射的方法,但是此方法存在因注射时的压力而使细胞破坏、组织损伤以及出血的风险。为了克服这一限制,开发了基于聚合物贴片的细胞递送技术,但是为了将贴片附着在组织表面,仍然需要进一步采用缝合线(suture)或粘合剂(glue)等。另外,存在以下缺点:因缝合而可能对组织产生直接损伤,并且当使用粘合剂时,搭载细胞的贴片与组织之间不能完全粘附,从而将细胞递送到损伤组织的效率大大降低。并且,由于进一步的处理也会使手术时间变长,因此频繁发生由此导致的治疗效果下降的情况。
关于药物递送,现有的简单的给药方式(如经口给药)因药物的快速降解和扩散而存在药物滞留时间较短的问题,并且为了有效的治疗,必须注入大量的药物或增加药物的注入频率。
为了解决药物及细胞递送方法的问题,进行了利用水凝胶的递送方法的研究,但大部分是关于在水凝胶溶液中搭载药物或细胞,并通过交联来诱导凝胶形成的方式方面的研究。但上述方式是以将水凝胶注入到生物体内的形态来进行适用,因此可能因用户对水凝胶进行操作的熟练度而异的可能性较大,并且存在大大降低用户的便利性的问题。另外,通过注射来注入到生物体内,因此依然存在组织损伤和出血的风险,并且现有的水凝胶在较多的情况下在生物体内无法长期维持物性和粘合力。
为了克服现有技术中存在的如组织损伤可能性、用户使用不便、细胞及药物递送效率低等限制,本发明人通过对邻苯二酚基(catechol groups)或邻苯三酚基(pyrogallolgroups)修饰的透明质酸衍生物进行冷冻干燥来制备了药物及细胞递送效率和用户便利性显著优异的水凝胶贴片。
发明内容
发明所要解决的问题
本发明的目的在于,提供一种具有优秀的生物相容性、粘合力、机械性能及使用便利性的水凝胶贴片以及利用其的药物递送、细胞移植和组织再生方法。
用于解决问题的方案
为了达到上述目的,本发明的一个方面提供一种由邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物构成的水凝胶贴片。
本说明书中所使用的术语“邻苯二酚基”作为源自包含1,2-二羟基苯(dihydroxybenzene)(两个羟基(-OH)彼此相邻)的邻苯二酚类化合物的官能基,通过氧化反应而形成各种官能基(functional group)和共价交联(cross-linking)。上述邻苯二酚类化合物作为全部包含邻苯二酚及其衍生物的广义概念,优选地,除了上述邻苯二酚基以外进一步包含用于与上述生物相容性聚合物进行反应的末端官能基,但不限于此。上述邻苯二酚类化合物可以选自由邻苯二酚(catechol)、4-叔丁基邻苯二酚(4-tert-butylcatechol;TBC)、漆酚(urushiol)、茜素(alizarin)、多巴胺(dopamine)、盐酸多巴胺(dopamine hydrochloride)、3,4-二羟基苯丙氨酸(3,4-dihydroxyphenylalanine;DOPA)、咖啡酸(caffeic acid)、去甲肾上腺素(norepinephrine)(优选地,L-去甲肾上腺素)、肾上腺素(epinephrine)(优选地,L(-)-肾上腺素)、3,4-二羟基苯乙酸(3,4-dihydroxyphenylacetic acid;DOPAC)、异丙去甲肾上腺素(isoprenaline)、异丙肾上腺素(isoproterenol)(优选地,DL-异丙肾上腺素)及3,4-二羟基苯甲酸(3,4-dihydroxybenzoic acid)组成的组;本发明中使用了盐酸多巴胺(dopaminehydrochloride)作为邻苯二酚类化合物,此时,上述盐酸多巴胺的末端官能基中-NH2可以与上述生物相容性聚合物(尤其是透明质酸)进行反应。
此外,本说明书中所使用的术语“邻苯三酚基”作为源自包含1,2,3-三羟基苯(trihydroxybenzene)(三个羟基(-OH)彼此相邻)的邻苯三酚类化合物的官能基,通过氧化反应而形成各种官能基(functional group)和共价交联(crosslinking)。尤其,由于具有快速氧化的特征,因此在如人体内等具有较高氧浓度的环境中,数分钟内可以发生自然氧化,无需氧化剂处理,因此当将水凝胶贴片适用于实际临床中时,具有在没有额外的氧化剂处理的情况下即可适用的优点。上述邻苯三酚类化合物作为全部包含邻苯三酚及其衍生物的广义概念,优选地,除了上述邻苯三酚基以外进一步包含用于与上述生物相容性聚合物进行反应的末端官能基,但不限于此。上述邻苯三酚类化合物可以选自由邻苯三酚(pyrogallol)、5-羟基多巴胺(5-hydroxydopamine)、单宁酸(tannic acid)、没食子酸(gallic acid)、表没食子儿茶素(epigallocatechin)、表儿茶素没食子酸酯(epicatechingallate)、表没食子儿茶素没食子酸酯(epigallocatechin gallate)、2,3,4-三羟基苯甲醛(2,3,4-trihydroxybenzaldehyde)、2,3,4-三羟基苯甲酸(2,3,4-Trihydroxybenzoicacid)、3,4,5-三羟基苯甲醛(3,4,5-Trihydroxybenzaldehyde)、3,4,5-三羟基苯甲酰胺(3,4,5-Trihydroxybenzamide)、5-叔-丁基焦酚(5-tert-Butylpyrogallol)及5-甲基连苯三酚(5-Methylpyrogallol)组成的组,并且本发明中使用5-羟基多巴胺(5-hydroxydopamine)作为邻苯三酚类化合物,此时,上述5-羟基多巴胺末端官能基中的-NH2可以与上述生物相容性聚合物(尤其是透明质酸)进行反应。
本说明书中所使用的术语“水凝胶贴片(hydrogel patch)”是指由生物相容性聚合物构成并具有一定厚度的薄膜形态的结构物,且具有能够将其切割成所需形态来使用的优点。
本发明的一具体例中,上述生物相容性聚合物通过与存在于上述邻苯二酚类化合物或上述邻苯三酚类化合物的末端官能基进行反应而直接被修饰为上述邻苯二酚基或邻苯三酚基。上述生物相容性聚合物可以选自由透明质酸、肝素(Heparin)、纤维素(cellulose)、葡聚糖(dextran)、藻酸盐(alginate)、壳聚糖(Chitosan)、甲壳素(chitin)、胶原、明胶、硫酸软骨素(chondroitin sulfate)、果胶(pectin)、角蛋白(Keratin)及血纤维蛋白(fibrin)组成的组;优选透明质酸,此时,可以使上述透明质酸的末端官能基中的-COOH进行反应以便修饰为上述邻苯二酚基或邻苯三酚基。
本发明的一具体例中,相比由上述邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物构成的基于溶液的水凝胶(以下,记载为本体水凝胶(bulk hydrogel)),包含上述邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物的水凝胶贴片(以下,记载为水凝胶贴片)具有纳米纤维素基多孔性结构,并且由于具有优秀的溶胀性,因此也可以在生物体内环境中有效地装载细胞或药物。
另外,上述水凝胶贴片的机械性质及组织粘合力相比本体水凝胶更加优秀,从而可以在生物体内长期保持贴片结构,可以长时间附着在体内组织中,并且可以通过有效地移植干细胞、类器官(Organoid)等细胞来提高细胞植入率。
本发明的一具体例中,上述水凝胶贴片可以具有0.05mm至10.0mm的厚度,优选地,可以具有0.1mm至5.0mm的厚度,更优选地,可以具有1.6mm至5.0mm的厚度。
本发明的一具体例中,上述水凝胶贴片可以通过以下步骤来制造:
步骤(a),将邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物溶液倒在平坦的表面;及
步骤(b),将上述溶液在零下0.5℃至零下100℃的温度下进行冷冻干燥5小时至48小时。
本发明的一具体例中,上述步骤(a)是通过将HA-CA或HA-PG溶液以40μl、80μl或160μl的方式倒入8mm圆筒模具中来进行;针对上述HA-CA或HA-PG溶液,可以使用0.1至5%的浓度,优选地,可以使用0.5至3%的浓度。上述HA-CA或HA-PG溶液的容量分别用于制造厚度为0.8mm、1.6mm或3.2mm的高分子水凝胶贴片,因此可以轻松调节本发明的HA-CA或HA-PG水凝胶贴片的厚度。
本发明的一具体例中,上述步骤(b)是通过以下方法来进行:在零下0.5℃至零下100℃的温度下对邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物溶液进行冷冻干燥5小时至48小时,或者在零下50℃至零下100℃的温度下进行冷冻干燥12小时至36小时。如果对邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物溶液进行冷冻干燥,会在溶液的体积缩小的同时制得具有一定厚度的薄膜形态的水凝胶贴片。
本发明的另一个方面提供一种药物载体,其包含上述水凝胶贴片以及装载于水凝胶贴片的药物。
本发明的一具体例中,上述药物可以是蛋白质,如生长因子,例如可以选自由血管内皮生长因子(vascular endothelial growth factor,VEGF)、表皮生长因子(epidermalgrowth factor,EGF)、角质细胞生长因子(keratinocyte growth factor,KGF)、生长分化因子(growth and differentiation factor)、肝细胞生长因子(hepatocyte growthfactor,HGF)、血小板衍生生长因子(platelet-derived growth factor,PDGF)、转化生长因子(transforming growth factor,TGF)、血管生成素(angiopoietin)、促红细胞生成素(erythropoietin)、骨形态发生蛋白(bone morphogenic protein,BMP)、胰岛素样生长因子(insulin-like growth factor)、成纤维细胞生长因子(acidic and basic fibroblastgrowth factor)、粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor,GM-CSF)、脑衍生神经滋长因子(brain-derived neurotrophicfactor)、胶质细胞衍生神经营养因子(glial cell-derived neurotrophic factor)、神经生长因子(nerve growth factor)、基质细胞衍生因子-1(stromal cell-derived factor-1,SDF-1)、P物质(substance P,SP)、低氧诱导因子-1(Hypoxia-inducible factor-1,HIF-1)、Dickkopf-相关蛋白-1(Dickkopf-related protein-1,DKK-1)、白细胞介素(interleukin)、帕博利珠单抗(Pembrolizumab;产品名为可瑞达(Keytruda))、纳武单抗(nivolumab;产品名为欧狄沃(Opdivo))、阿特珠单抗(atezolizumab;产品名为泰圣奇(Tecentriq))、易普利姆玛(Ipilimumab;产品名为伊匹单抗(Yervoy))、博纳吐单抗(blinatumomab;产品名为倍利妥(Blincyto))、曲妥珠单抗(trastuzumab;产品名为赫赛汀(Herceptin))、西妥昔单抗(cetuximab);产品名为爱必妥(Erbitux))及贝伐珠单抗(bevacizumab;产品名为阿瓦斯汀(Avastin))组成的组。
另外,上述药物选自由阿西美辛(acemethacin)阿伐斯汀(acrivastine)、醛固酮(aldosterone)、安他唑啉(antazoline)、阿司咪唑(astemizole)、阿扎他定(azatadine)、氮卓斯汀(azelastine)、倍氯米松(beclomethasone)、倍他米松(betamethasone)、溴芬酸(bromfenac)、布可利嗪(buclizine)、卡洛芬(carprofen)、西替利嗪(cetirizine)、氯吡啉(Chloropyrilene)、氯苯那敏(chlorpheniramine)、氯马斯汀(clemastine)、色甘酸(cromolyn)、赛克利嗪(cyclizine)、赛庚啶(cyproheptadine)、地塞米松(dexamethasone)、美海屈林(diazolinum)、双氯芬酸(diclofenac)、苯海拉明(diphenhydramine)、依巴斯汀(ebastine)、依美斯汀(emedastine)、依匹斯汀(epinastine)、依托度酸(etodolac)、芬布芬(fenbufen)、苯氧布洛芬(fenoprofen)、非索非那定(fexofenadine)、氟氢可的松(fludrocortisone)、氟比洛芬(flurbiprofen)、氟米龙(fluorometholone)、羟嗪(hydroxyzine)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、酮洛芬(ketoprofen)、酮咯酸氨丁三醇(ketorolac tromethamine)、酮替芬(ketotifen)、左卡巴斯汀(levocabastine)、左西替利嗪(levocetirizine)、洛度沙胺(lodoxamide)、氯雷他定(loratadine)、氯替泼诺(loteprednol)、洛索洛芬(loxoprofen)、甲羟松(medrysone)、甲哌卡因(mepivacaine)、美喹他嗪(mequitazine)、甲吡吩嗪(methdilazine)、美沙吡林(metapyrilen)、萘丁美酮(nabumetone)、萘甲唑林(naphazoline)、萘普生(naproxen)、奈多罗米(nedocromil)、去甲阿司咪唑(norastemizole)、Norvastin、奥洛他定(olopatadine)、非尼达明(fenidamin)、苯肾上腺素(phenylephrine)、奥沙米特(oxatomide)、羟甲唑啉(oxymetazoline)、吡嘧司特(pemirolast)、苯吡胺(Pheniramin)、哌香豆司特(picumast)、泼尼松龙(prednisolone)、异丙嗪(promethazine)、利美索龙(rimexolone)、瑞吡司特(Repirinast)、孟鲁司特(montelukast)、舒林酸(sulindac)、舒洛芬(suprofen)、扎鲁司特(zafirlukast)、四氢唑林(tetrahydrozoline)、特非那定(terfenadine)、噻洛芬酸(tiaprofenic acid)、Tometim、曲尼司特(tranilast)、曲安西龙(triamcinolone)、三甲泼拉嗪(trimeprazine)、曲普利啶(triprolidine)、多奈哌齐(donepezil)、卡巴拉汀(rivastigmine)、加兰他敏(galantamine)、美金刚(memantine)、利多卡因(lidocaine)、氯胺酮(ketamine)、甲氨蝶呤(methotrexate)、环孢素(cyclosporine)、顺铂(cisplatinum)、卡培他滨(capecitabine)、奥沙利铂(Oxaliplatin)、阿霉素(doxorubicin;产品名为亚德里亚霉素(Adriamycin))、丝裂霉素-C(mitomycin-C)、正定霉素(daunomycin)、表阿霉素(epirubicin)、他莫昔芬(tamoxifen)、索拉非尼(sorafenib)、5-氟尿嘧啶(5-fluorouracil)、紫杉醇(paclitaxe)、右旋布洛芬(dexibuprofen)、吡罗昔康(poroxicam)、药学上可接受的它们的盐及其混合物组成的组。
本发明的一具体例中,上述药物载体还可以包含将水凝胶贴片和药物附着(交联)到所要递送的靶部位时所需的物质,例如,氧化剂,作为氧化剂可以使用高碘酸钠。当将氧化剂涂敷或喷射到水凝胶贴片时,邻苯二酚基被氧化,从而发生交联反应。
本发明的一具体例中,作为将药物装载于水凝胶贴片的方法,可以使用如下方法:通过混合邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物溶液和药物来制造水凝胶贴片,或者将药物涂敷在水凝胶贴片后,通过添加氧化剂,将药物交联到水凝胶贴片中。
本发明人通过混合邻苯二酚基修饰的透明质酸HA-CA水溶液和VEGF,并将其冷冻干燥来制造HA-CA水凝胶贴片,然后对药物释放状况及伤口愈合效果进行了确认。结果证实,在药物效果上,以包含药物的状态制作的HA-CA水凝胶贴片和在制作贴片后对药物进行交联的HA-CA水凝胶贴片之间并没有差异。另外,通过与HA-CA本体水凝胶进行比较来确认了HA-CA水凝胶贴片具有优秀的伤口愈合效果。
另外,本发明人通过使用HA-PG水凝胶贴片来将PDGF引入到诱发糖尿病的小鼠伤口中,并确认了伤口治疗效果。结果证实,在伤口治疗效果上,通过将PDGF预先混合到HA-PG聚合物溶液并进行冷冻干燥来制作的HA-PG水凝胶贴片与制作贴片后对PDGF进行交联的HA-PG水凝胶贴片之间并没有差异。另外,确认了与HA-PG本体水凝胶相比,在利用HA-PG水凝胶贴片来递送PDGF的情况下具有更加优秀的伤口治疗效果。
本发明的另一个方面提供了一种将药物或细胞递送到靶部位的方法,该方法包括如下步骤:
步骤(a),将药物或细胞与上述水凝胶贴片接触;及
当上述步骤(a)的水凝胶贴片中引入有邻苯二酚基时,可选地,步骤(b),将氧化剂与上述步骤(a)的水凝胶贴片接触。
本发明的一具体例中,将药物或细胞递送到上述靶部位的方法是由以下方式来进行:i)将水凝胶贴片附着到靶部位后进行步骤(a)和步骤(b);或者,ii)将药物或细胞与水凝胶贴片接触,并将水凝胶贴片附着到靶部位之后与氧化剂接触;或者,iii)经过上述步骤(a)和步骤(b)之后,将载有药物或细胞的水凝胶贴片附着到靶部位。
本发明的一具体例中,上述步骤(a)的药物可以使用与药物载体中使用的药物相同的药物,并且上述步骤(a)的细胞可以选自由干细胞、血管内皮细胞、骨细胞、软骨细胞、心肌细胞、肌细胞、表皮细胞、成纤维细胞、神经细胞、肝细胞、肠细胞、胃细胞、皮肤细胞、脂肪细胞、血液细胞、免疫细胞、细胞球体(Cell spheroid)及类器官(organoid)组成的组。
本说明书中所使用的术语,“细胞球体”是指由多个单细胞聚集而形成的球形形态的三维细胞聚集体。
本说明书中所使用的的术语,“类器官”是指从干细胞通过自我更新和自我组织化而形成的三维细胞聚集体(器官类似物);作为干细胞,可以使用成体干细胞(adult stemcell,ASC)、胚胎干细胞(embryonic stem cell,ESC)、诱导多能干细胞(inducedpluripotent stem cell,iPSC)、脂肪干细胞(adipose derived stem cell,ADSC)、间充质干细胞(mesenchymal stem cell,MSC)、胎盘源性干细胞(placental derived stem cell,PDSC)或神经干细胞(neural stem cell,NSC)等。通过模仿人体内环境来三维培养干细胞,因此能够类似地重现人体的生理活性功能,并可以通过从患者的组织构建器官类似物来进行基于患者遗传信息的疾病建模、药物筛选等。
本发明的一具体例中,上述步骤(b)的与氧化剂进行接触的步骤通过将氧化剂溶液涂敷或喷射到涂有药物或细胞的水凝胶贴片的方式来进行。
本发明人通过上述方法将间充质干细胞移植到缺血性心肌梗塞模型大鼠中,其结果证实,间充质干细胞的移植和植入效率增加,心脏功能改善,受损的心肌组织再生。另外,通过上述方法将VEGF引入到小鼠的背部伤口中,其结果证实,促进伤口恢复及皮肤组织的再生。因此,通过上述方法可以将药物和细胞有效地引入到靶部位。
本发明的一具体例中,将上述药物载体,或者药物或细胞递送到靶部位的方法可以用于治疗和改善如下疾病:阿尔茨海默症、脑卒中(stroke)、帕金森病、癫痫(epilepsy)、脑出血、脑梗塞、脑肿瘤、脑膜炎、脊髓损伤、皮肤伤口、湿疹、特应性皮炎、带状疱疹、脚气(皮肤癣菌病)、脂溢性皮炎、褥疮、银屑病、蜂窝织炎、毛囊炎、手足口病、汗疱疹(pompholyx)、疣、鸡眼(clavus)、胃损伤、胃溃疡、十二指肠溃疡、溃疡性肠炎、克罗恩病、骨缺损、骨质疏松症、软骨破裂、软骨软化症、肌肉损伤、韧带/肌腱损伤、筋膜炎、骨髓纤维化、关节炎、毒性弥漫性甲状腺肿(Grave's disease)、狼疮、白内障、青光眼、黄斑变性、视网膜损伤、肝硬变、酒精性肝病(脂肪肝)、肝硬化、肾功能衰竭、硅肺(silicosis)、囊肿性肺病、阻塞性肺疾病、慢性肺疾病、肺炎、肺纤维化、囊性纤维化、扁桃体结石、支气管扩张症、气管狭窄、声带/喉结节、牙周炎、口炎、口唇疱疹、高脂血症、高胆固醇血症、血脂异常症、周围血管病、下肢缺血、动脉硬化、心肌纤维化、心肌梗塞、心肌病、心力衰竭、心绞痛、胆管炎、胰腺炎、胃炎、反流性食管炎、食管狭窄症、食管憩室(esophagus diverticula)、食管肌瘤、特发性食道扩张症、普卢默-文森综合征(Plummer-Vinson syndrome)、食管静脉曲张、肝炎、中耳炎、支气管炎、甲状腺炎、结膜炎、血管炎、扁桃体炎、脊椎炎、肾盂肾炎、膀胱炎、扭伤(distortion)、胸膜炎、甲状腺癌、卵巢癌、宫颈癌、肺癌、胃癌、肝癌、乳腺癌、多发性骨髓瘤、消化道癌、胰腺癌、胆石症、胆囊炎、胆管癌、大肠癌、前列腺癌、淋巴瘤、骨与软组织肿瘤、头颈癌、血癌、食管癌、骨肉瘤、喉癌、糖尿病、糖尿病足溃疡、糖尿病性视网膜病变、糖尿病性肾病、糖尿病性神经病变或肥胖。
本发明的另一个方面提供一种模拟生物组织的结构体形成方法,该方法包括如下步骤:
步骤(a),用水凝胶贴片包裹一定形态的模具;
步骤(b),使干细胞与上述水凝胶贴片接触。
本发明的一具体例中,上述模拟生物组织的结构体形成方法可以是重复一次至多次进行步骤(a)和步骤(b)的方法。
本发明的一具体例中,上述步骤(b)的干细胞可以选自成体肝细胞、胚胎干细胞、诱导多能干细胞、脂肪干细胞、间充质干细胞、胎盘源性干细胞及神经干细胞,但不限于此。
本发明的一具体例中,当邻苯二酚基引入到上述步骤(a)的水凝胶贴片中时,上述步骤(b)可以通过将干细胞涂敷在水凝胶贴片之后与氧化剂进行接触的方法来进行,具体地,可以通过将氧化剂溶液滴落或喷射到水凝胶贴片的方式来进行。另外,当邻苯三酚基引入到上述步骤(a)的水凝胶贴片中时,上述步骤(b)可以通过将包含干细胞的溶液涂敷到水凝胶贴片的方法来进行。
本发明的一具体例中,上述生物组织可以是血管、皮肤或肝,但不限于此。
发明效果
本发明的邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物水凝胶贴片相比基于溶液的本体水凝胶,具有显著优秀的机械性质、粘合力,因此可以在体内长时间装载细胞和药物,并且可以安全地将上述细胞和药物递送到体内而不会发生组织损伤。另外,与本体水凝胶相比,上述邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物水凝胶贴片是具有一定厚度的薄膜形态,因此容易操作,使用步骤非常简单,并可以切割成所需的形态,从而便于使用。进一步地,邻苯二酚修饰的生物相容性聚合物水凝胶贴片可以将所需形态的模具包裹成单层或多层来制造多层的水凝胶贴片,并且可以通过使干细胞与其接触来形成与生物体内组织类似的结构体。
尤其,当在上述水凝胶贴片中修饰有邻苯三酚基时,在没有额外的氧化剂的情况下,也可以在生物体内自然氧化,因此在实际临床中可以方便地使用。
附图说明
图1是示意性地示出用邻苯二酚修饰的透明质酸(HA-CA)水凝胶贴片的制作过程(A)、具有不同厚度的HA-CA水凝胶贴片(B)和上述水凝胶贴片的使用方法(C)。
图2是对HA-CA本体水凝胶(A)和HA-CA水凝胶贴片(B)的细胞毒性及是三维培养与否进行确认的结果。
图3是对HA-CA水凝胶贴片(Patch)和HA-CA本体水凝胶(Gel)的溶胀度(A和B)、含水量(C)及通过透明质酸降解酶的降解速度(D)进行确认的结果。
图4是通过扫描电子显微镜来对HA-CA本体水凝胶和HA-CA水凝胶贴片的内部结构进行确认的结果。
图5是对HA-CA水凝胶贴片和HA-CA本体水凝胶的机械强度(A和B)、根据HA-CA水凝胶贴片的厚度的弹性模量(C)进行确认的结果。
图6是示出测量HA-CA水凝胶贴片和HA-CA本体水凝胶的组织粘合力的方法(A),并对用该方法测量的组织粘合力(B和C)和组织附着功(D)进行确认的结果。
图7是对HA-CA水凝胶贴片和HA-CA本体水凝胶的不锈钢粘合力(A和B)、附着功(C)进行确认的结果。
图8是通过使用HA-CA水凝胶贴片来将干细胞移植到肾脏、肝及肠之后,对水凝胶贴片的附着与否以及干细胞的植入与否进行确认的结果。
图9是通过HA-CA水凝胶贴片(MSC-patch)或注射方法(MSC-injection),将干细胞移植到诱发心肌梗塞的缺血组织后,对干细胞的植入与否进行确认的结果。
图10是通过HA-CA水凝胶贴片或注射方法,将干细胞移植到缺血性心肌梗塞模型大鼠中后,对左心室舒张期末直径(A)、左心室收缩期末直径(B)、心脏射血分数(C)及缩短分数(fractional shortening)(D)进行确认的结果。
图11是通过HA-CA水凝胶贴片或注射方法,将干细胞移植到缺血性心肌梗塞模型大鼠中后,通过TTC染色(A和B)、马松三色(Masson’s Trichrome)染色(C和D)来对损伤的心脏组织进行确认的结果。
图12是通过HA-CA水凝胶贴片或注射方法,将干细胞移植到缺血性心肌梗塞模型大鼠中后,通过小动脉特异性标志物(平滑肌肌动蛋白(smooth muscle actin,SMA))和毛细血管标志物CD31来对损伤部位进行染色的结果。
图13是通过使用HA-CA水凝胶贴片将用荧光标记的类器官移植到肝(A和B)、胃(C)及小肠(D)中之后,对细胞的植入与否进行确认的结果。
图14是多层结构的HA-CA水凝胶贴片的制作结果(A)以及利用其来对多层的生物体内结构进行模拟之后进行确认的结果。
图15是管状的多层HA-CA水凝胶贴片的制作结果(A)以及利用其来制作多层的血管模拟结构体(C)的结果。
图16是在模拟存在有透明质酸降解酶的生物体内环境的条件下,对HA-CA水凝胶贴片的药物释放状况进行确认的结果。
图17是通过在小鼠伤口模型中使用HA-CA水凝胶贴片来引入血管内皮生长因子(VEGF)后,根据时间的经过对伤口治疗效果进行确认的结果。
图18是通过在小鼠伤口模型中使用HA-CA水凝胶贴片来引入血管内皮生长因子VEGF后,对毛囊再生(A和C)、胶原的生成(B和D)及血管形成程度(E和F)进行确认的结果。
图19是通过在小鼠伤口模型中使用HA-CA水凝胶贴片或HA-CA本体水凝胶来引入药物之后,对伤口治疗效果进行确认的结果。
图20是通过在小鼠伤口模型中使用HA-CA水凝胶贴片或HA-CA本体水凝胶来引入药物之后,通过苏木精-伊红染色(A)、马松三色染色(B)来对伤口部位的再生程度进行确认的结果。
图21中A是示出邻苯三酚修饰的透明质酸(HA-PG)的分子结构,B是示出将HA-PG水凝胶贴片和HA-PG本体水凝胶进行凝胶化(gelation)的形态,C是示出不同厚度的HA-PG水凝胶贴片。
图22是对HA-PG水凝胶贴片(PG)和HA-PG本体水凝胶(PG)的细胞毒性与否进行确认的结果。
图23是对HA-PG水凝胶贴片(PG)和HA-CA本体水凝胶(PG)的溶胀度(A和B)及通过透明质酸降解酶的降解程度(C)进行确认的结果。
图24是通过扫描电子显微镜对HA-PG水凝胶贴片(PG)和HA-PG本体水凝胶(PG)的内部结构进行确认的结果。
图25是对HA-PG水凝胶贴片(PG)和HA-PG本体水凝胶(PG)的机械强度(A和B)、随HA-PG贴片厚度的弹性模量(C)进行确认的结果。
图26是对HA-PG水凝胶贴片(PG)和HA-CA本体水凝胶(PG)的组织粘合力(A和B)及附着功(C)进行确认的结果。
图27是通过使用HA-PG水凝胶贴片将干细胞移植到小肠(A)、肝(B)、肾脏(C)及胃(D)之后,对干细胞的植入与否进行确认的结果。
图28是通过使用HA-PG水凝胶贴片,对将荧光标记的类器官移植到小肠的示意性过程(A);移植了类器官的小肠(B);肝(C)和胃(D)中类器官的附着与否进行确认的结果。
图29是在糖尿病性小鼠伤口模型中适用HA-PG水凝胶贴片和人脂肪干细胞(humanadipose derived stem cell,hADSC)之后,对伤口的尺寸随时间经过的变化进行确认的结果。
图30是在糖尿病性小鼠伤口模型中适用HA-PG水凝胶贴片和hADSC之后,对伤口部位的毛囊再生(A)和胶原的生成(B)水平进行确认的结果。
图31是在糖尿病性小鼠伤口模型中适用HA-PG水凝胶贴片和血小板衍生生长因子(platelet-derived growth factor,PDGF)之后,根据时间的经过对伤口治疗效果进行确认的结果。
图32是用HA-PG水凝胶贴片制造与生物体内组织类似的多层结构之后进行确认的结果。
具体实施方式
以下,通过实施例对一个以上的具体例进行更加详细的说明。但是,这些实施例是用于示例性地说明一个以上的具体例,并且本发明的范围不限于这些是实施例。
制备例1
(1)HA-CA水凝胶贴片的制作
使用盐酸多巴胺(dopamine hydrochloride)将邻苯二酚修饰的透明质酸(catechol-functionalized hyaluronic acid;以下记载为HA-CA)以1%的浓度溶解在蒸馏水中,将1%的HA-CA溶液以40μl、80μl或160μl的方式倒入8mm圆筒模具中,然后在-80℃的温度下冷冻干燥过夜,由此制作厚度为0.8mm、1.6mm或3.2mm的HA-CA水凝胶贴片。由于所制作的HA-CA水凝胶贴片处于干燥的状态,因此容易储存,并且由于是薄膜形态,因此可以容易地切割成所需的形状,从而便于使用。
将切割成特定形状的HA-CA水凝胶贴片置于目标组织的表面上,并将所需的药物或细胞涂敷在贴片上。之后,将高碘酸钠(sodium periodate,NaIO4;氧化剂)喷洒在HA-CA水凝胶贴片上,使细胞或药物封装(encapsulated)在贴片上。
在以前的实验中,当HA-CA的浓度高于1%时,水凝胶贴片太硬导致细胞和药物无法有效地渗透到水凝胶贴片内部;当低于1%时,水凝胶贴片的结构无法得到充分的维持,从而导致细胞和药物的损失。另外,如果HA-CA水凝胶贴片的厚度太厚,则细胞和药物无法有效地渗透到水凝胶贴片内部;如果太薄,则难以操作水凝胶贴片,并且在涂敷氧化剂后存在水凝胶贴片的结构无法长时间维持的缺点。
实施例1-1至1-5中使用了厚度为1.6mm的HA-CA水凝胶贴片。
图1中A是示出HA-CA水凝胶贴片的制作过程,B是示出不同厚度的HA-CA水凝胶贴片,C是示意性地示出在目标组织中使用HA-CA水凝胶贴片的方法。
(2)HA-CA本体水凝胶的制作
通过将HA-CA溶解在磷酸盐缓冲生理盐水(Phosphate-buffered saline,PBS)中,并在此溶液中添加高碘酸钠溶液(HA-CA溶液:氧化剂溶液=3:1(v/v))来制备HA-CA本体水凝胶。在完成的HA-CA本体水凝胶中HA-CA的最终浓度为2%。所制造的HA-CA本体水凝胶用于结构分析和细胞毒性分析等。包含药物或细胞的HA-CA本体水凝胶是通过将HA-CA溶液与药物或细胞预先进行混合后,添加高碘酸钠溶液的方式来制作的。
实施例1-1:HA-CA水凝胶贴片的特性分析
(1)确认细胞毒性
将上述制备例中制作的HA-CA水凝胶贴片或HA-CA本体水凝胶放置在6-孔细胞培养板的底部,并种植人脂肪干细胞(human adipose derived stem cell,hADSC),然后培养7天。通过使用活/死细胞检测(美国英杰生命技术(Invitrogen))并根据制造商的协议,在培养的第0天、第3天及第7天确认了细胞存活率。
其结果可以证实,已验证生物相容性的HA-CA本体水凝胶无细胞毒性(图2的A),并且HA-CA水凝胶贴片也没有细胞毒性(图2的B)。另外,如XZ轴图中所示,可以发现HA-CA水凝胶贴片中细胞三维分布,而不是单层的方式分布。其结果意味着,即使将HA-CA本体水凝胶的剂型改变为HA-CA水凝胶贴片,透明质酸的生物相容性也可以保持原样,并且也可以进行细胞的三维培养。
(2)对溶胀度(swelling)及降解速度进行确认
将HA-CA水凝胶贴片或HA-CA本体水凝胶在与生物体内条件类似的37℃的PBS中浸泡7天,并在12小时、1天、3天和7天后测定了溶胀度。测定结果,HA-CA水凝胶贴片的溶胀度比HA-CA本体水凝胶略高4倍左右(图3的A),而HA-CA本体水凝胶的实际含水量高于HA-CA水凝胶贴片(图3的B和C)。
另外,在实际生物体内环境中存在各种降解酶,因此将HA-CA水凝胶贴片或HA-CA本体水凝胶浸泡在37℃的PBC中,并通过透明质酸降解酶来进行处理直至其降解。通过定期测量HA-CA水凝胶贴片和HA-CA本体水凝胶的重量来测量了随时间降解的程度。测量结果,通过透明质酸降解酶来处理HA-CA本体水凝胶后,在2小时内快速降解,并在6小时后完全降解,但是HA-CA水凝胶贴片在经过透明质酸降解酶处理的24小时之后仍有残留,这可以说明酶的降解速度较慢(图3的D)。
(3)内部结构的确认
使用扫描电子显微镜来对HA-CA水凝胶贴片和HA-CA本体水凝胶的内部结构进行了确认。其结果可以确认,HA-CA本体水凝胶具有微米(μm)大小的多孔性结构,而HA-CA水凝胶贴片示出了基于纳米纤维的多孔性结构(图4)。其结果意味着,相比HA-CA本体水凝胶,HA-CA水凝胶贴片具有更加紧凑的内部结构,并且通过纳米纤维结构而增加了邻苯二酚修饰的表面积,因此可以具有优秀的组织粘合力。
(4)机械强度的测量
使用流变仪在0.1Hz至10Hz之间的频率条件下测量了HA-CA水凝胶贴片和HA-CA本体水凝胶的弹性模量。测量结果,HA-CA水凝胶贴片和HA-CA本体水凝胶均显示出G’值高于G”值的结果,从而可以确认其内部结构由稳定的聚合物网络构成(图5的A)。
另外,HA-CA本体水凝胶的平均弹性模量约为260Pa,而HA-CA水凝胶贴片显示出约11kPa的弹性模量,从而可以确认增加了约50倍以上(图5的B)。对上述制备例1中制作的HA-CA水凝胶贴片的弹性模量进行了测量,其结果可以确认,随着贴片厚度的增加,弹性模量从0.8kPa显著增加到5kPa和14kPa(图5的C),弹性模量的增加意味着机械强度优秀。
上述实验结果意味着,与HA-CA本体水凝胶相比,HA-CA水凝胶贴片的机械强度显著优秀,并且通过调节HA-CA水凝胶贴片的厚度,可以轻松调节机械强度。
(5)生物组织粘合力的测量
在猪心脏组织上放置HA-CA水凝胶贴片后喷洒氧化剂或放置混合氧化剂并诱导交联的HA-CA本体水凝胶之后,利用附着有猪心脏组织的探针(probe)来按压后,放置10分钟。之后,通过粘合力测量仪来测量了HA-CA水凝胶贴片和HA-CA本体水凝胶的组织粘合力(图6的A)。
测量结果,HA-CA本体水凝胶具有约1.5N的粘合力,而HA-CA水凝胶贴片显示出约5.5N的粘合力,由此可知,组织粘合力提升了3.5倍以上(图6的B和C)。
另外,通过测量粘合力-拉伸长度图表(图6的B)的面积来计算对附着在猪心脏组织上的HA-CA本体水凝胶或HA-CA水凝胶贴片进行分离时所需的功的量(附着功)。其结果可以确认,与HA-CA本体水凝胶相比,HA-CA水凝胶贴片的组织附着功增加了8倍以上(图6的D)。
(6)粘合力的测量(不锈钢表面)
将HA-CA水凝胶贴片和HA-CA本体水凝胶放置在不锈钢(stainless steel)表面上,并以与上述实验例1-5相同的方法测量了粘合力。
测量结果,HA-CA本体水凝胶具有约12N的粘合力,而HA-CA水凝胶贴片显示出约30N的粘合力,由此可知,粘合力提升了2.5倍以上(图7的A和B)。
另外,通过测量粘合力-拉伸长度图表(图7的A)的面积来计算对附着在不锈钢表面上的HA-CA本体水凝胶或HA-CA水凝胶贴片进行分离时所需的附着功。其结果可以确认,与HA-CA本体水凝胶相比,HA-CA水凝胶贴片的附着功增加了5.5倍以上(图7的C)。
实施例1-2:对HA-CA水凝胶贴片的脏器粘附能力进行确认
由于生物体内环境是水分较多的状态,因此确认了本发明的HA-CA水凝胶贴片是否可以附着到各种脏器。对小鼠进行麻醉后进行开腹,并在肾脏、肝和肠上放置HA-CA水凝胶贴片,并滴落人脂肪干细胞(human adipose derived stemcells,hADSC)之后,喷洒氧化剂,并进行了缝合。24小时之后,处死小鼠,并对肾脏、肝和肠进行分离,通过肉眼来确认HA-CA水凝胶贴片的附着与否之后,制作组织切片并进行了苏木精-伊红染色。其结果可以看出,即使在24小时后,HA-CA水凝胶贴片也能很好地附着在水分较多的脏器表面。通过组织染色的结果也可以确认,HA-CA水凝胶贴片附着在肾脏、肝和肠上(图8)。
本结果意味着,HC-CA水凝胶贴片可以粘附在各种脏器和生物体内组织上,因此可以在各种脏器和组织上进行无创细胞移植。
实施例1-3:HA-CA水凝胶贴片的心肌梗塞治疗效果
(1)干细胞移植和植入效率的确认
现有的干细胞移植术主要是通过在受损组织中直接注射的方式来进行,但具有如下缺点:干细胞的递送和植入效率低,并且存在因注射而引起的出血和组织损伤的风险。与其相比,利用粘合性贴片的干细胞移植方法具有能够以将干细胞有效地无创移植到较宽的组织部位中的优点。因此,通过使用本发明的HA-CA水凝胶贴片来将干细胞移植之后,确认了结果。
对缺血性心肌梗塞模型小鼠进行麻醉后开胸,并将HA-CA水凝胶贴片放置在心脏上,然后滴落2×105个大鼠骨髓间充质干细胞(mesencymal stem cell;以下记载为MSC)。之后,将氧化剂喷射到HA-CA水凝胶贴片上以使MSC封装在HA-CA水凝胶贴片上。将手术部位进行缝合,并在移植MSC的第3天提取发生心肌梗塞的心脏组织,并根据本领域知晓的方法进行了苏木精-伊红染色。染色结果,可以确认包含MSC的HA-CA水凝胶贴片(MSC-贴片)牢固地附着在心脏组织表面上(图9的A),其结果意味着,HA-CA水凝胶贴片也可以稳定且很好地附着在跳动的心脏表面上,并保持附着力。
另外,将用荧光物质(Paul Karl Horan 26,PKH26)标记的MSC直接注入到大鼠中,或以与上述相同的方式使用HA-CA水凝胶贴片来进行移植。在MSC移植2周后进行跟踪的结果可以证实,利用HA-CA水凝胶贴片来移植到心脏外壁的MSC移动到受损的心脏组织内。与通过直接注射来进行的现有的MSC移植术(MSC-injection)相比,当利用HA-CA水凝胶贴片(MSC-贴片)时,MSC的植入和移动效率显著提高(图9的B)。
(2)通过超声心动图来评价心功能
对缺血性心肌梗塞模型大鼠进行麻醉后,通过结扎左心室冠状动脉来诱发了急性心肌梗塞。之后,将大鼠分为以下组并进行相关处理后比较了心肌梗塞的治疗效果。对照组(注射生理盐水,Saline);实验组1(仅附着HA-CA水凝胶贴片(仅贴片));实验组2(通过直接注射来移植MSC,MSC-注射);及实验组3(利用HA-CA水凝胶贴片来移植MSC,MSC-贴片)。进行实验4周后通过进行超声心动描记术(echocardiography)来评价了心功能改善的效果。
评价结果,可以确认,与对照组相比,实验组3中左心室收缩期末直径(leftventricle end-systolic dimension,LVIDs)有意义地减小,这意味着通过HA-CA水凝胶贴片来移植的MSC有效地减少了心脏组织的损伤,从而防止缺血性心脏的肥大(图10的B)。可以确认的是,与对照组相比,作为能够评价心脏收缩功能指标的射血分数(Ejectionfraction)在实验组3中也得到了提升(图10的C)。与对照组相比,左室缩短分数(Fractional shortenin)也在实验组3中得到了提升(图10的D)。
通过本实验的结果确认了,通过HA-CA水凝胶贴片来移植MSC,可以有效地治疗缺血性心肌梗塞。
(3)通过组织学分析来检查缺血组织
为了确认通过HA-CA水凝胶贴片来移植的MSC是否对损伤的心肌组织进行再生而进行了受损心脏的组织学分析。TTC染色(2,3,5-三苯基氯化四氮唑)仅将正常心肌组织染成红色,心肌梗塞导致的坏死组织不会被染色而显示出白色。
上述实验例3-2结束后对大鼠进行麻醉,并通过分离心肌组织来制作组织切片载片,然后根据本领域公知的方法进行TTC染色。进行的结果,实验组3(MSC-贴片)中几乎见不到白色部分,从而可以确认,与对照组(Saline)相比坏死组织面积(Infarct size)有意义地减少。另一方面,可以确认,在实验组1(仅贴片处理)中,尽管没有移植MSC,但显示出与实验组2(MSC-注射)类似水平的组织坏死抑制效果(图11的A和B)。
另外,从大鼠中分离出诱发心肌梗塞的心脏后,制作组织切片,并通过进行马松三色(Masson’s Trichrome)染色来确认了缺血导致的心脏组织的纤维化(fibrosis)程度。其结果可以确认,实验组3的纤维化抑制效果显著优秀,从而使正常的心肌组织得到很好的保持。实验组2与对照组相比,也显示出有意义的纤维化抑制效果(图11的C和D)。
通过本实验的结果确认了,HA-CA水凝胶贴片本身促进了有助于组织再生的生物体内细胞的移动和植入,并且可以通过提供细胞能够存活的空间来将缺血性疾病所导致的心肌组织的损伤降低到显著优于直接注射MSC的方法的水平。另外,可以确认,当使用HA-CA水凝胶贴片时,MSC的移植和植入效率显著优秀,因此可以有效地适用于实际心脏疾病的治疗当中。
(4)确认血管再生与否
确认了通过HA-CA水凝胶贴片移植的MSC是否再生了血管。具体地,通过小动脉特异性标志物(平滑肌肌动蛋白(smooth muscle actin,SMA))和毛细血管标志物CD31来对上述(3)的心脏组织切片载片进行了染色。
染色结果,可以确认,与对照组相比,实验组3(MSC-贴片)中再生了显著多的小动脉和毛细血管(图12的A和B)。通过此结果可以确认,与现有的MSC注入方式相比,利用HA-CA水凝胶贴片的MSC移植方法具有显著的效果。
实施例1-4:HA-CA水凝胶贴片的细胞移植及组织再生效果
(1)类器官的移植
现有的通过注射来注入细胞的方式难以有效地移植细胞球体(cell spheroid)或类器官(organoid)等大细胞团块。这是因为在移植过程中,存在通过注射针头时的压力会使细胞结构破坏和细胞死亡等问题。因此通过使用本发明的HA-CA水凝胶贴片来进行了细胞类器官的移植。
将小鼠进行麻醉后进行开腹,并将用Dil荧光来标记的细胞类器官置于肝、胃及小肠表面之后,通过以胶带形态贴上HA-CA水凝胶贴片,来将类器官固定于每个脏器的表面上。
类器官移植3天后分离胃和小肠,并在7天后分离肝脏,从而确认了类器官的附着与否。其结果可以确认,类器官成功附着到肝脏并与现有的肝组织整合在一起(图13的A和B)。
另外,可以确认类器官也成功附着到胃和小肠上(图13的C和D)。
(2)形成片(sheet)形态的多层结构
如皮肤、血管等生物体内组织形成为多层结构,因此通过本发明的HA-CA水凝胶贴片来制作了与生物体内组织类似的多层结构。
使用彩色墨水来制作红色和绿色的HA-CA水凝胶贴片,并通过在一个HA-CA水凝胶贴片上放置另一个HA-CA水凝胶贴片来形成多层贴片结构体。此时,没有使用额外的粘合剂,而是利用了HA-CA水凝胶贴片本身的粘合性。实验结果,可以制作形成为3层和5层的贴片结构体(图14的A)。
另外,通过重复进行以下方式来形成多层的三维细胞结构体:在一个HA-CA水凝胶贴片上放置用荧光物质标记的hADSC,并在其上放置另一个HA-CA水凝胶贴片,然后再次放置用荧光物质标记的hADSC。此时,每层使用了用不同荧光物质标记的hADSC。其结果可以确认,通过使用HA-CA水凝胶贴片,可以实现由多层片组成的组织结构(图14的B),其中上述多层片的每层上存在相互不同的细胞。
将圆筒形状的模具用红色和绿色的HA-CA水凝胶贴片进行包裹后,可以通过去除模具来制作管形态的多层HA-CA水凝胶贴片(图15的A),并且可以确认,由于其具有弹性,因此即使通过施加压力来改变形态,也可以再次恢复到原来的形态(图15的B)。在制作管形态的多层HA-CA水凝胶贴片时,在一层中附着人血管内皮细胞(HUVEC),在另一层中附着hADSC,结果可以制作与人体血管类似的结构。
实施例1-5:利用HA-CA水凝胶贴片的药物递送
(1)药物释放状况的确认
根据制备例1的方法制作了HA-CA水凝胶贴片,并将血管内皮生长因子(vascularendothelial growth factor;以下记载为VEGF)喷洒在贴片上,然后通过涂敷氧化剂来将VEGF封装在贴片上(贴片(CA)-VEGF实验组)。作为对比组,将HA-CA水溶液与VEGF混合后,通过冷冻干燥来制作HA-CA水凝胶贴片之后涂敷氧化剂(贴片(CA)-VEGF/FD实验组)。对比组是在实际临床中使用HA-CA水凝胶贴片时被认为便利性最优秀的药物递送形式。将包含VEGF的上述两种HA-CA水凝胶贴片浸泡在37℃的PBS中,并通过ELISA分析了根据有或无透明质酸降解酶(hyaluronidase)处理的VEGF释放状况。
分析结果可以确认,将VEGF一同进行冷冻干燥的HA-CA水凝胶贴片、额外引入VEGF的HA-CA水凝胶贴片均显示出类似的VEGF释放状况(图16)。另外,可以确认,由于邻苯二酚与蛋白质的各种亲核官能基的较强的结合,在没有降解酶的环境(-透明质酸降解酶)中难以发生VEGF的释放,相反,在模拟生物体内环境并用降解酶进行处理的环境(+透明质酸降解酶)中有效地释放了VEGF(图16)。
因此,当使用本发明的HA-CA水凝胶贴片时,可以将药物有效地递送到透明质酸降解酶的活性增加的伤口部位(如创伤),并可以提高伤口部位的治疗效果。
(2)评价小鼠创伤治疗效果
使用打孔器在小鼠的背部制造8mm的创伤后,放置HA-CA水凝胶贴片,并将FITC-BSA蛋白喷洒在贴片之后,通过涂敷氧化剂来将贴片进行交联。经过一定时间后,将该创伤部位的组织分离并进行染色,其结果可以确认,装载有FITC-BSA蛋白的HA-CA水凝胶贴片牢固地附着在创伤部位的肌肉层上(图17的A)。
使用打孔器在小鼠的背部制造8mm的创伤,并分为4组,从而确认了HA-CA水凝胶贴片的皮肤再生和创伤治疗效果:1.对照组(未处理);2仅适用HA-CA水凝胶贴片(仅贴片(CA));3.HA-CA水凝胶贴片上封装VEGF(贴片(CA)-VEGF);及4.通过将HA-CA溶液与VEGF混合后进行冷冻干燥来制作贴片后进行交联(冷冻干燥贴偏;贴片(CA)-VEGF/FD)。
进行确认的结果可以证实,将VEGF递送到创伤部位的贴片(CA)-VEGF组和贴片(CA)-VEGF/FD组中创伤的大小有意义地快速减小,并且上述两组显示出类似的创伤治疗效果(图17的B和C)。通过其结果可以确认,即使预先将药物装载于HA-CA水凝胶贴片之后进行冷冻干燥,药物的效果上并没有较大的差异,并且这可以提高用户的便利性。
为了评价创伤部位的皮肤再生水平,在实验的第12天,将创伤部位用苏木精-伊红进行染色,并确认了基于图像的定量分析。
进行确认的结果可以证实,将VEGF递送到创伤部位的贴片(CA)-VEGF组和贴片(CA)-VEGF/FD组中发生了较活跃的毛囊再生(图18的A和C)。另外,通过马松三色染色来确认了,在将VEGF递送到创伤部位的贴片(CA)-VEGF组和贴片(CA)-VEGF/FD组中,胶原再生也出现了增加(图18的B和D)。为了确认血管形成的效果,用毛细血管标志物CD31进行免疫染色,结果可以确认在将VEGF递送到创伤部位的贴片(CA)-VEGF组和贴片h(CA)-VEGF/FD组中形成有更多的血管(图18的E和F)。
(3)比较小鼠创伤治疗效果
使用打孔器在小鼠的背部制造8mm的创伤,并对HA-CA水凝胶贴片和HA-CA本体水凝胶的创伤治疗效果进行了比较。具体地,将VEGF预先混合到HA-CA溶液中后进行冷冻干燥,并将其再次溶解到PBS中,然后以HA-CA本体水凝胶的形态进行了交联(Freeze-driedbulk hydrogel;本体(CA)-VEGF/FD)。HA-CA水凝胶贴片是通过预先将VEGF与HA-CA溶液混合后以贴片形态冷冻干燥,然后用氧化剂将贴片进行交联的方式来制造(Freeze-driedpatch;贴片(CA)-VEGF/FD)。
观察16天创伤大小减小程度的结果,可以确认,与通过HA-CA本体水凝胶来递送VEGF的实验组(本体(CA)-VEGF/FD)相比,通过HA-CA水凝胶贴片来递送VEGF的实验组(贴片(CA)-VEGF/FD)中创伤大小快速减小(图19的A和B)。
为了确认创伤部位的皮肤再生程度,在实验的第16天,将小鼠处死,并将创伤部位用苏木精-伊红进行染色。其结果可以确认,与通过HA-CA本体水凝胶来递送VEGF的实验组(本体(CA)-VEGF/FD)相比,通过HA-CA水凝胶贴片来递送VEGF的实验组(贴片(CA)-VEGF/FD)中生成了较多的细胞,从而创伤部位发生了显著多的再生(图20的A)。另外,将创伤部位用马松三色来进行染色的结果,可以确认,在贴片(CA)-VEGF/FD实验组中发生了更多的胶原再生。上述实验结果意味着,即使由相同的物质制成,水凝胶贴片剂型比现有的基于溶液的本体水凝胶剂型具有更优秀的治疗效果。
制备例2
(1)HA-PG水凝胶贴片的制作
使用5-羟基多巴胺(5-hydroxydopamine)来将邻苯三酚修饰的透明质酸(pyrogallol-functionalized hyaluronic acid;以下记载为HA-PG)以1%的浓度溶解在蒸馏水中,将1%的HA-PG溶液分别以40μl、80μl或160μl的方式倒入8mm的圆筒模具中,然后在-80℃的温度下冷冻干燥过夜,由此制作了厚度为0.8mm、1.6mm、3.2mm的HA-PG水凝胶贴片。由于所制作的HA-PG水凝胶贴片处于干燥的状态,因此容易储存,并且由于是薄膜形态,因此可以轻松地切割成所需的形状,从而便于使用。
在以前的实验中,当HA-PG的浓度高于1%时,水凝胶贴片太硬导致细胞和药物无法有效地渗透到水凝胶贴片内部;当低于1%时,水凝胶贴片的结构无法得到充分的维持,从而导致细胞和药物的损失。另外,如果水凝胶贴片的厚度太厚,则细胞和药物无法有效地渗透到贴片内部;如果太薄,则难以操作水凝胶贴片,并且存在水凝胶贴片的结构无法长时间维持的缺点。实施例2-1至2-3中使用了厚度为1.6mm的HA-PG水凝胶贴片。
(2)HA-PG本体水凝胶的制作
通过将HA-PG溶解在磷酸盐缓冲生理盐水(Phosphate-buffered saline,PBS)中,并在此溶液中添加高碘酸钠溶液(HA-PG溶液:氧化剂溶液=3:1(v/v))来制备HA-PG本体水凝胶。在完成的HA-PG本体水凝胶中HA-PG的最终浓度为1%,并且所制造的HA-PG本体水凝胶用于结构分析。
细胞移植和药物递送实验中,使用了未经过高碘酸钠溶液处理的HA-PG本体水凝胶,以便在体内自然氧化。
图21中A是示出HA-PG的分子结构,B示出了将HA-PG水凝胶贴片和HA-PG本体水凝胶进行凝胶化(gelation)的形态,C示出了不同厚度的HA-PG水凝胶贴片。
实施例2-1:HA-PG水凝胶贴片的特性分析
(1)确认细胞毒性
将上述制备例中制作的HA-PG水凝胶贴片或HA-PG本体水凝胶放置在6-孔细胞培养板的底部,并种植人脂肪干细胞(human adipose derived stem cell,hADSC),然后培养7天。通过使用活/死细胞检测(美国英杰生命技术(Invitrogen))并根据制造商的协议,在培养的第0天、第3天及第7天确认了细胞存活率。
其结果可以确认,HA-PG本体水凝胶(凝胶(PG))和HA-PG水凝胶贴片(贴片(PG))均没有细胞毒性(图22)。其结果意味着,即使将HA-PG本体水凝胶的剂型改变为HA-PG水凝胶贴片,透明质酸的生物相容性也可以保持原样。
(2)对溶胀度(swelling)及降解速度进行确认
将HA-PG水凝胶贴片或HA-PG本体水凝胶在与生物体内条件类似的37℃的PBS中浸泡7天,并在9小时、1天、3天和7天后测量了溶胀度。测定结果,可以确认HA-PG水凝胶贴片的溶胀度比HA-PG本体水凝胶略高2倍左右(图23的A和B),其结果意味着,相比HA-PG本体水凝胶,HA-PG水凝胶贴片具有更加紧凑的内部结构。
另外,在实际生物体内环境中存在各种降解酶,因此将HA-PG水凝胶贴片或HA-PG本体水凝胶浸泡在37℃的PBC中,并通过透明质酸降解酶来进行处理直至其降解。通过定期测量HA-PG水凝胶贴片和HA-PG本体水凝胶的重量来测量了随时间降解的程度。测量结果,通过透明质酸降解酶来处理HA-PG本体水凝胶后快速降解,并在24小时之前完全降解,但是HA-PG水凝胶贴片在经过透明质酸降解酶处理的600小时之后仍有残留,这可以说明酶的降解速度较慢(图23的C)。
(3)内部结构的确认
通过扫描电子显微镜对HA-PG水凝胶贴片(贴片(PG))和HA-PG本体水凝胶(凝胶(PG))的内部结构进行了确认。其结果可以确认,HA-PG本体水凝胶具有微米(μm)大小的多孔性结构,而HA-PG水凝胶贴片示出了更加紧密的基于纳米纤维的多孔性结构(图24)。
其结果意味着,相比HA-PG本体水凝胶,HA-PG水凝胶贴片可以形成更加紧凑的内部结构,并且大大增加邻苯三酚修饰的聚合物的表面积,从而可以具有优秀的机械性能和粘附能力。
(4)机械强度的测量
使用流变仪在0.1Hz至10Hz之间的频率条件下测量了HA-PG水凝胶贴片(贴片(PG))和HA-PG本体水凝胶(凝胶(PG))的弹性模量。
测量结果,HA-PG水凝胶贴片和HA-PG本体水凝胶均显示出G’值高于G”值,从而可以确认其内部结构由稳定的聚合物网络构成(图25的A)。另外,HA-PG本体水凝胶的平均弹性模量约为1.5kPa,而HA-PG水凝胶贴片显示出约18kPa的弹性模量,从而可以确认增加了约10倍以上(图25的B)。对上述制备例1中制作的不同厚度HA-PG水凝胶贴片的弹性模量进行了测量,其结果可以确认,随着贴片厚度的增加,弹性模量从5kPa显著增加到27kPa和46kPa(图25的C),弹性模量的增加意味着机械强度优秀。
上述实验结果意味着,与HA-PG本体水凝胶相比,HA-PG水凝胶贴片的机械强度显著优秀,并且通过调节HA-PG水凝胶贴片的厚度,可以轻松调节机械强度。
(5)组织粘合力的测量
切开小鼠背部皮肤,并放置HA-PG水凝胶贴片(贴片(PG))或HA-PG本体水凝胶(凝胶(PG))后,通过体内溶解氧的自然氧化的方式来诱导贴片的交联(附着)。通过自然氧化来完全进行交联后(约5分钟之内)切除皮肤组织,并通过粘性测试(tack test)来测量从皮肤组织上剥离HA-PG本体水凝胶或HA-PG水凝胶贴片的力,从而比较了组织附着力。
测量结果,HA-PG本体水凝胶具有约1.6N的粘合力,而HA-PG水凝胶贴片显示出约4N的粘合力,由此可知,组织粘合力提升了2.5倍以上(图26的A和B)。
另外,通过测量粘合力-拉伸长度图表(图26的A)的面积来计算对附着在皮肤上的HA-PG本体水凝胶或HA-PG水凝胶贴片进行分离时所需的功的量(附着功)。其结果可以确认,与HA-PG本体水凝胶相比,HA-PG水凝胶贴片的组织附着功增加了2.5倍以上(图26的C)。
实施例2-2:HA-PG水凝胶贴片的细胞移植效果
(1)干细胞移植
对小鼠进行麻醉后开腹,并在小肠、肝和肾脏上放置HA-PG水凝胶贴片,并滴下用荧光标记的hADSC之后,进行了缝合。24小时之后,处死小鼠,并对肾脏、肝和肠进行分离,通过肉眼来确认HA-PG水凝胶贴片的附着与否,然后观察hADSC的植入与否。其结果可以看出,即使在24小时后,HA-PG水凝胶贴片也能很好地附着在水分较多的脏器表面,并且通过组织染色的结果也可以确认,HA-PG水凝胶贴片附着在小肠、肝及肾脏及胃上,并且hADSC也附着在其中。
本结果意味着,HC-PG水凝胶贴片在水分较多的生物体内环境中可以粘附在各种脏器和组织上,因此可以在各种脏器和组织上进行无创细胞移植。
(2)类器官移植
类器官具有如组织再生等优异的治疗效果,但由于其尺寸较大,因此尚未开发有效的移植方法。因此,确认了本发明的HC-PG水凝胶贴片是否能够用于类器官的移植当中。
将用Dil荧光标记的类器官放置在小肠、肝或胃上,并覆盖HC-PG水凝胶贴片,然后以自然氧化的方式使类器官固定在各组织的表面上(图28的A)。24小时后,通过对移植有类器官的组织进行分离并进行染色,结果可以发现,所移植的类器官成功附着在每个组织上并与现有的组织整合在一起(图28的B是小肠组织,C是肝,以及D是胃组织)。
通过上述实验结果可以发现,HC-PG水凝胶贴片通过体内溶解氧的自然氧化的方式来交联,因此可以通过将HC-PG水凝胶贴片和类器官贴在靶部位的一步法(one-step)来将尺寸较大的类器官牢固地固定在靶部位并进行移植。
(3)创伤治疗效果
糖尿病是由胰岛素分泌减少、胰岛素抵抗等原因引起的代谢性疾病,引起糖尿病视网膜病变、肾功能衰竭等多种并发症。尤其,糖尿病可以诱发糖尿病性足部溃疡(diabetic foot ulcers)等糖尿病性创伤(diabetic wounds),由于血液循环障碍、血液内较高的血糖水平等原因,糖尿病性创伤的治疗和组织再生比一般的创伤更加困难。因此,确认了本发明的HC-PG水凝胶贴片是否能够用于糖尿病创伤的治疗。
给小鼠禁食24小时,并将作为选择性地损伤胰岛β-细胞的药物的链脲佐菌素以100mg/kg的浓度施用于腹腔内,从而诱发糖尿病。经过2周后测量了血糖的变化,当血糖为300mg/dL以上时,判定为诱发了糖尿病。
使用打孔器在诱发糖尿病的小鼠的背部制造8mm的创伤,且分为以下6组,并将hADSC进行种植之后,确认了皮肤再生和创伤治疗效果:1.对照组(未处理);2.仅适用HA-PG本体水凝胶(仅凝胶(PG));3.仅适用HA-PG水凝胶贴片(仅贴片(PG));4.仅直接适用hADSC(仅hADSC);5.将HA-PG本体水凝胶和hADSC混合后进行适用(凝胶(PG)-hADSC);及6.将HA-PG水凝胶贴片放置在创伤部位并种植hADSC(贴片(PG)-hADSC)。
对创伤尺寸的变化观察了12天,其结果可以确认,在放置HA-PG水凝胶贴片和种植了hADSC的组(贴片(PG)-hADSC)中创伤尺寸以最快的速度减小(图29)。
进行实验的第12天,分离创伤部位的组织,确认了皮肤再生程度。用苏木精-伊红进行染色的结果,在放置HA-PG水凝胶贴片和种植了hADSC的组(贴片(PG)-hADSC)中发生了毛囊的再生,从而可以确认,与其他组相比,发生了成熟的组织再生(图30的A)。另外,马松三色的结果可以确认,在贴片(PG)-hADSC组中胶原的再生也最为活跃(图30的B和C)。
通过上述实验结果可以确认,当将HA-PG水凝胶贴片覆盖于创伤部位时,在无氧化剂处理的情况下以通过体液等体内含氧环境而自然氧化的方式交联,因此可以简单地进行细胞移植,并且可以防止由氧化剂引起的副作用,从而可以判断,HA-PG贴片是适合在临床上适用的剂型。另外,可以确认,本发明的HA-PG水凝胶贴片可以有效地适用于相比一般的创伤治疗和恢复更加困难且逐渐加深组织损伤的糖尿病性创伤治疗中。
实施例2-3:利用HA-PG水凝胶贴片的药物递送
通过与实施例2-3相同的方法来制造糖尿病性小鼠模型。使用打孔器在诱发糖尿病的小鼠的背部制造8mm的创伤,且分为6组,并涂敷血小板衍生生长因子(platelet-derived growth factor,PDGF)后,确认了皮肤再生和创伤治疗效果:对照组(未处理);仅适用HA-PG本体水凝胶(仅凝胶(PG));仅适用HA-PG水凝胶贴片(仅贴片(PG));在HA-PG本体水凝胶中PDGF的封装(凝胶(PG)-PDGF);在HA-PG水凝胶贴片中PDGF的封装(贴片(PG)-PDGF);及通过一同将PDGF和HA-PG溶液进行冷冻干燥来制造贴片后进行交联(Freeze-dried patch;贴片(PG)-PDGF/FD)。
对创伤尺寸的减小观察了10天,其结果可以确认,适用HA-PG水凝胶贴片的贴片(PG)-PDGF组和贴片(PG)-PDGF/FD组中,第10天创伤恢复约80%左右,而适用HA-PG本体水凝胶的组和对照组中创伤仅恢复60%左右(图31的A和B)。另外,贴片(PG)-PDGF组和贴片(PG)-PDGF/FD组在创伤治疗效果上并没有显著的差异,其结果意味着,即使预先将药物装载于HA-PG水凝胶贴片之后进行冷冻干燥,在药物的效果上也没有较大的差异。
实施例2-4:利用HA-PG水凝胶贴片来形成多层结构体
如皮肤、血管等生物体内组织形成为多层结构,因此通过本发明的HA-PG水凝胶贴片来制作了与生物体内组织类似的多层结构。
使用彩色墨水来制作红色和绿色的HA-PG水凝胶贴片,并通过在一个HA-PG水凝胶贴片上放置另一个HA-PG水凝胶贴片来形成多层贴片结构体。此时,没有使用额外的粘合剂,而是利用了HA-PG水凝胶贴片本身的粘合性。实验结果,可以制作形成为3层和5层的贴片结构体(图32)。
Claims (15)
1.一种水凝胶贴片,其包含:邻苯二酚基或邻苯三酚基修饰的生物相容性聚合物。
2.根据权利要求1中所述的水凝胶贴片,其中,
所述邻苯二酚基源自邻苯二酚类化合物,所述邻苯二酚类化合物选自由邻苯二酚、4-叔丁基邻苯二酚、漆酚、茜素、多巴胺、盐酸多巴胺、3,4-二羟基苯丙氨酸、咖啡酸、去甲肾上腺素、肾上腺素、3,4-二羟基苯乙酸、异丙去甲肾上腺素、异丙肾上腺素及3,4-二羟基苯甲酸组成的组,
所述邻苯三酚基时源自邻苯三酚类化合物,所述邻苯三酚类化合物选自由邻苯三酚、5-羟基多巴胺、单宁酸、没食子酸、表没食子儿茶素、表儿茶素没食子酸酯、表没食子儿茶素没食子酸酯、2,3,4-三羟基苯甲醛、2,3,4-三羟基苯甲酸、3,4,5-三羟基苯甲醛、3,4,5-三羟基苯甲酰胺、5-叔-丁基焦酚及5-甲基连苯三酚组成的组。
3.根据权利要求1中所述的水凝胶贴片,其中,
所述生物相容性聚合物选自由透明质酸、肝素、纤维素、葡聚糖、藻酸盐、壳聚糖、甲壳素、胶原、明胶、硫酸软骨素、果胶、角蛋白及血纤维蛋白组成的组。
4.根据权利要求1中所述的水凝胶贴片,其中,
所述水凝胶贴片具有0.05mm至10.0mm的厚度。
5.一种药物载体,其包含:
权利要求1所述的水凝胶贴片;及
装载于所述水凝胶贴片的药物。
6.根据权利要求5中所述的药物载体,其中,
所述药物选自由血管内皮生长因子、表皮生长因子、角质细胞生长因子、生长分化因子、肝细胞生长因子、血小板衍生生长因子、转化生长因子、血管生成素、促红细胞生成素、骨形态发生蛋白、胰岛素样生长因子、成纤维细胞生长因子、粒细胞-巨噬细胞集落刺激因子、脑衍生神经滋长因子、胶质细胞衍生神经营养因子、神经生长因子、基质细胞衍生因子-1、P物质、低氧诱导因子-1、Dickkopf-相关蛋白-1、白细胞介素、帕博利珠单抗、纳武单抗、阿特珠单抗、易普利姆玛、博纳吐单抗、曲妥珠单抗、西妥昔单抗及贝伐珠单抗组成的组。
7.根据权利要求5中所述的药物载体,其中,
所述药物选自由阿西美辛、阿伐斯汀、醛固酮、安他唑啉、阿司咪唑、阿扎他定、氮卓斯汀、倍氯米松、倍他米松、溴芬酸、布可利嗪、卡洛芬、西替利嗪、氯吡啉、氯苯那敏、氯马斯汀、色甘酸、赛克利嗪、赛庚啶、地塞米松、美海屈林、双氯芬酸、苯海拉明、依巴斯汀、依美斯汀、依匹斯汀、依托度酸、芬布芬、苯氧布洛芬、非索非那定、氟氢可的松、氟比洛芬、氟米龙、羟嗪、布洛芬、吲哚美辛、酮洛芬、酮咯酸氨丁三醇、酮替芬、左卡巴斯汀、左西替利嗪、洛度沙胺、氯雷他定、氯替泼诺、洛索洛芬、甲羟松、甲哌卡因、美喹他嗪、甲吡吩嗪、美沙吡林、萘丁美酮、萘甲唑林、萘普生、奈多罗米、去甲阿司咪唑、Norvastin、奥洛他定、非尼达明、苯肾上腺素、奥沙米特、羟甲唑啉、吡嘧司特、苯吡胺、哌香豆司特、泼尼松龙、异丙嗪、利美索龙、瑞吡司特、孟鲁司特、舒林酸、舒洛芬、扎鲁司特、四氢唑林、特非那定、噻洛芬酸、Tometim、曲尼司特、曲安西龙、三甲泼拉嗪、曲普利啶、多奈哌齐、卡巴拉汀、加兰他敏、美金刚、利多卡因、氯胺酮、甲氨蝶呤、环孢素、顺铂、卡培他滨、奥沙利铂、阿霉素、丝裂霉素-C、正定霉素、表阿霉素、他莫昔芬、索拉非尼、5-氟尿嘧啶、紫杉醇、右旋布洛芬、吡罗昔康、药学上可接受的它们的盐及其混合物组成的组。
8.一种将药物或细胞递送到靶部位的方法,其中,包括:
步骤(a),将药物或细胞与权利要求1所述的水凝胶贴片接触。
9.根据权利要求8中所述的将药物或细胞递送到靶部位的方法,其中,
所述步骤(a)的药物选自由血管内皮生长因子、表皮生长因子、角质细胞生长因子、生长分化因子、肝细胞生长因子、血小板衍生生长因子、转化生长因子、血管生成素、促红细胞生成素、骨形态发生蛋白、胰岛素样生长因子、成纤维细胞生长因子、粒细胞-巨噬细胞集落刺激因子、脑衍生神经滋长因子、胶质细胞衍生神经营养因子、神经生长因子、基质细胞衍生因子-1、P物质、低氧诱导因子-1、Dickkopf-相关蛋白-1、白细胞介素、帕博利珠单抗、纳武单抗、阿特珠单抗、易普利姆玛、博纳吐单抗、曲妥珠单抗、西妥昔单抗及贝伐珠单抗组成的组。
10.根据权利要求8中所述的将药物或细胞递送到靶部位的方法,其中,
所述步骤(a)的药物选自由阿西美辛、阿伐斯汀、醛固酮、安他唑啉、阿司咪唑、阿扎他定、氮卓斯汀、倍氯米松、倍他米松、溴芬酸、布可利嗪、卡洛芬、西替利嗪、氯吡啉、氯苯那敏、氯马斯汀、色甘酸、赛克利嗪、赛庚啶、地塞米松、美海屈林、双氯芬酸、苯海拉明、依巴斯汀、依美斯汀、依匹斯汀、依托度酸、芬布芬、苯氧布洛芬、非索非那定、氟氢可的松、氟比洛芬、氟米龙、羟嗪、布洛芬、吲哚美辛、酮洛芬、酮咯酸氨丁三醇、酮替芬、左卡巴斯汀、左西替利嗪、洛度沙胺、氯雷他定、氯替泼诺、洛索洛芬、甲羟松、甲哌卡因、美喹他嗪、甲吡吩嗪、美沙吡林、萘丁美酮、萘甲唑林、萘普生、奈多罗米、去甲阿司咪唑、Norvastin、奥洛他定、非尼达明、苯肾上腺素、奥沙米特、羟甲唑啉、吡嘧司特、苯吡胺、哌香豆司特、泼尼松龙、异丙嗪、利美索龙、瑞吡司特、孟鲁司特、舒林酸、舒洛芬、扎鲁司特、四氢唑林、特非那定、噻洛芬酸、Tometim、曲尼司特、曲安西龙、三甲泼拉嗪、曲普利啶、多奈哌齐、卡巴拉汀、加兰他敏、美金刚、利多卡因、氯胺酮、甲氨蝶呤、环孢素、顺铂、卡培他滨、奥沙利铂、阿霉素、丝裂霉素-C、正定霉素、表阿霉素、他莫昔芬、索拉非尼、5-氟尿嘧啶、紫杉醇、右旋布洛芬、吡罗昔康、药学上可接受的它们的盐及其混合物组成的组。
11.根据权利要求8中所述的将药物或细胞递送到靶部位的方法,其中,
所述步骤(a)的细胞选自由干细胞、血管内皮细胞、骨细胞、软骨细胞、心肌细胞、肌细胞、表皮细胞、成纤维细胞、神经细胞、肝细胞、肠细胞、胃细胞、皮肤细胞、脂肪细胞、血液细胞、免疫细胞、细胞球体及类器官组成的组。
12.根据权利要求8中所述的将药物或细胞递送到靶部位的方法,其中,
当所述步骤(a)的水凝胶贴片中有邻苯二酚基修饰时,还包括:
步骤(b),将氧化剂与所述步骤(a)的水凝胶贴片接触。
13.一种模拟生物组织的结构体的形成方法,其中,包括:
步骤(a),用权利要求1所述的水凝胶贴片包裹一定形态的模具;
步骤(b),使干细胞与所述水凝胶贴片接触。
14.根据权利要求13中所述的模拟生物组织的结构体的形成方法,其中,
所述步骤(b)的干细胞选自由成体干细胞、胚胎干细胞、诱导多能干细胞、脂肪干细胞、间充质干细胞、胎盘源性干细胞及神经干细胞组成的组。
15.根据权利要求13中所述的模拟生物组织的结构体的形成方法,其中,
当所述步骤(a)的水凝胶贴片中有邻苯二酚基修饰时,所述步骤(b)是通过将细胞涂敷在水凝胶贴片之后与氧化剂进行接触的步骤。
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CN114644766A (zh) * | 2022-03-24 | 2022-06-21 | 福建师范大学 | 一种温敏脱粘的湿态组织粘附水凝胶及其制备方法 |
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CN114773629A (zh) * | 2022-05-20 | 2022-07-22 | 昆明理工大学 | 用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法 |
CN114773629B (zh) * | 2022-05-20 | 2024-04-12 | 昆明理工大学 | 用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法 |
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EP3981393A4 (en) | 2023-07-19 |
US20220280442A1 (en) | 2022-09-08 |
JP2022540223A (ja) | 2022-09-14 |
WO2021006426A1 (ko) | 2021-01-14 |
EP3981393A1 (en) | 2022-04-13 |
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