CN113456897A - 生物材料及其用于促进组织再生的用途 - Google Patents
生物材料及其用于促进组织再生的用途 Download PDFInfo
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- CN113456897A CN113456897A CN202010245685.1A CN202010245685A CN113456897A CN 113456897 A CN113456897 A CN 113456897A CN 202010245685 A CN202010245685 A CN 202010245685A CN 113456897 A CN113456897 A CN 113456897A
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Abstract
本发明提供一种生物材料及其用于促进组织再生的用途,生物材料包含一生物可相容性高分子、一无机盐以及一降血糖药物。本发明生物材料的功效在于:可藉由调控造骨细胞‑专一性基因(osteoblast‑specific genes)(包括碱性磷酸酶(alkaline phosphatase,ALPP)基因、矮小相关转录因子2(runt‑related transcription factor 2,RUNX2)基因、osterix(SP7)基因、骨结合素(osteonectin,SPARC)基因、骨钙素(osteocalcin,BGLAP)基因、及第I型胶原蛋白α1(Collagen,type I,alpha 1,COL1A1)基因)的表现量来达到促进组织再生(例如骨骼组织再生)的功效,且人体实验也证实有效。
Description
技术领域
本发明涉及生物技术领域,具体涉及一种生物材料及其用于促进组织再生的用途。
背景技术
组织工程,是一门以细胞生物学和材料科学相结合,进行体外或体内建构组织或器官的新兴学科,其核心在于建立细胞与生物材料的三维空间复合体,用以对缺损组织进行形态、结构及功能三个方面的重建,并达到永久性替代。骨组织工程是指将分离的自体高浓度成骨细胞、骨髓基质干细胞或软骨细胞,经体外培养扩增后种植于某种细胞支架或细胞外基质上,然后将这种细胞杂化材料植入骨缺损部位,在生物材料逐步降解的同时,种植的成骨细胞不断增殖,从而达到修复骨组织缺损的目的。
用于骨缺损修复的材料主要有生物无机材料和有机高分子材料两大类。有机高分子材料中,由乳酸和羟基乙酸随机聚合而成的聚乳酸-羟基乙酸(poly(lactic-co-glycolic acid),PLGA)的研究较为广泛,其具有良好的生物相容性、生物可降解性以及降解速率可调节性等优点,而且,PLGA透过酯键水解降解为乳酸和羟基乙酸,最终降解为二氧化碳和水排出体外。
现有的技术主要采用加热技术使支架成形,这种高温的应用会使一些蛋白质类的药物变性,限制了载体药物的种类;同时,由于大型加热的装置较少,加热技术的选择也限制了支架的制作。虽然关于微球载药支架已经有了一些研究,但是微囊支架仍少见报导,微囊支架载体药物更是如此。此外,现有技术用于促进骨骼组织再生的方式往往有生物相容性差及效果不彰的缺点。
为了解决上述问题,本领域的技术人员亟需研发出具有促进组织再生(例如骨骼组织再生)效用的新颖医药品以造福有此需求的广大族群。
发明内容
有鉴于此,本发明的目的为提供一种用于促进骨骼组织再生的生物材料,包含一生物可相容性高分子、一无机盐以及一降血糖药物。
在本发明的一实施例中,该降血糖药物是选自于由下列所组成的群组:双胍(Biguanides)、胰岛素(insulin)、磺酰脲类(Sulfonylureas)、格列奈类(Meglitinides)、胰岛素增敏剂(Thiazolidinediones)、α-葡萄糖苷酶抑制剂(α-Glucosidaseinhibitors)、DPP-4抑制剂、SGLT2抑制剂及甲磺酸溴隐亭(Cycloset)。
在本发明的一实施例中,该双胍是二甲双胍(Metformin)。
在本发明的一实施例中,该磺酰脲类是选自于由下列所组成的群组:克吡噻(glipizide)、甘布若(glyburide)、葛立克拉(gliclazide)以及格列美脲(glimepiride)。
在本发明的一实施例中,该格列奈类是一利泊格(Repaglinide)或一替格利尼得(nateglinide)。
在本发明的一实施例中,该胰岛素增敏剂是一罗格列酮(rosiglitazone)或一皮利酮(pioglitazone)。
在本发明的一实施例中,该α-葡萄糖苷酶抑制剂是选自于由下列所组成的群组:阿卡波糖(acarbose)、米格列醇(miglitol)以及伏格列波糖(voglibose)。
在本发明的一实施例中,该DPP-4抑制剂是选自于由下列所组成的群组:西他列汀(sitagliptin)、沙格列汀(saxagliptin)、维格列汀(vildagliptin)、利拉利汀(linagliptin)以及阿格列汀(alogliptin)。
在本发明的一实施例中,该SGLT2抑制剂是一达格列净(dapagliflozin)或一卡格列净(canagliflozin)。
在本发明的一实施例中,该甲磺酸溴隐亭是一溴麦角隐亭(Bromocriptine)。
在本发明的一实施例中,该生物材料进一步包含一黏合成形剂,其中该黏合成形剂是一交联剂。
在本发明的一实施例中,该生物可相容性高分子具有一为1~50%(w/v)的浓度,该无机盐具有一为1~50%(w/v)的浓度,该降血糖药物具有一为1nM~1M的浓度,以及该黏合成形剂具有一为1~50wt%的浓度。
在本发明的一实施例中,该生物可相容性高分子是一多醣、一蛋白质或其组合。
在本发明的一实施例中,该多醣是选自于由下列所组成的群组:透明质酸(hyaluronic acid)、褐藻酸(alginate)、几丁聚醣(chitosan)及其任意组合。
在本发明的一实施例中,该蛋白质是一明胶(gelatin)、一胶原蛋白(collagen)或其组合。
在本发明的一实施例中,该无机盐是选自由下列所组成的群组:氢氧基磷灰石(hydroxyapatite,Hap)、磷酸三钙(tricalcium phosphate,TCP)、磷酸二钙(dicalciumphosphate,DCP)、磷酸二钙二水合物(dicalcium phosphate dihydrate,DCPD)、磷酸四钙(tetracalcium phosphate,TTCP)、碳酸盐、硝酸盐、硫酸盐、钾盐、钠盐以及镁盐。
在本发明的一实施例中,该生物可相容性高分子是呈一胶体、一支架、一球体、一粉体、或一薄膜的形式。
在本发明的一实施例中,该生物可相容性高分子是藉由一选自于下列所组成的群组中的酵素进行交联作用:谷氨酰胺转胺酶(Transglutaminase)、脂肪酶(Lipase)、胜肽酶(Peptidase)、转肽酶(Sortase)、氧化还原酶(Oxidoreductase)、酪胺酸酶(Tyrosinase)、多酚氧化酶(Polyphenoloxidase,PPO)、漆氧化酶(laccase)、过氧化物酶(peroxidase)、离胺酸氧化酶(Lysyl oxidase)以及胺氧化酶(amine oxidase)。
在本发明的一实施例中,该生物可相容性高分子或该无机盐的平均尺度为1nm至1mm。
本发明的另一目的为提供一种如前所述的生物材料用于制备一促进组织再生的医药品的用途。
在本发明的一实施例中,该促进组织再生是促进骨骼组织再生。
在本发明的一实施例中,该生物可相容性高分子具有一为1~50%(w/v)的浓度,该无机盐具有一为1~50%(w/v)的浓度,该降血糖药物具有一为1nM~1M的浓度,以及该黏合成形剂具有一为1~50wt%的浓度。
综上所述,本发明生物材料的功效在于:可藉由调控造骨细胞-专一性基因(osteoblast-specific genes)(包括碱性磷酸酶(alkaline phosphatase,ALPP)基因、矮小相关转录因子2(runt-related transcription factor 2,RUNX2)基因、osterix(SP7)基因、骨结合素(osteonectin,SPARC)基因、骨钙素(osteocalcin,BGLAP)基因、及第I型胶原蛋白α1(Collagen,type I,alpha 1,COL1A1)基因)的表现量来达到促进组织再生(例如骨骼组织再生)的功效,且人体实验也证实有效。
以下将进一步说明本发明的实施方式,下述所列举的实施例系用以阐明本发明,并非用以限定本发明的范围,任何熟习此技艺者,在不脱离本发明的精神和范围内,当可做些许更动与润饰,因此本发明的保护范围当视本发明权利要求范围所界定为准。
附图说明
图1a是本发明生物材料的一个显微结构图;
图1b是本发明生物材料的另一个显微结构图;
图2是本发明生物材料(以二甲双胍作为降血糖药物组分)在处理细胞之后第7天及第14天时调控造骨细胞-专一性基因上的效用的数据图;
图3是本发明生物材料(以胰岛素作为降血糖药物组分)在处理细胞之后第7天、第14天、第21天及第28天时调控造骨细胞-专一性基因上的效用的数据图;
图4a是对照组中无填充材料的骨缺损的电脑断层扫描图;
图4b是本发明生物材料在促进骨骼组织再生上的效用的电脑断层扫描图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面对本发明实施例的技术方案进行清楚、完整地描述。显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例。基于所描述的本发明的实施例,本领域普通技术人员所获得的所有其他实施例,都属于本发明保护的范围。
本文中所使用数值为近似值,所有实验数据皆表示在20%的范围内,较佳为在10%的范围内,最佳为在5%的范围内。
除非另有定义,本文中所有技术和科学用语与本发明所属领域中具有通常知识者所理解的含义相同。如在本申请中所使用的,以下术语具有如下意涵。
除非上下文中另有指定外,本文及申请专利范围所述单数格式的「一」、「一个」、「一种」及「该」包含复数指涉。本文中的用语例如:「一」、「该」、「一或多」、「复数」及「至少为一」可互相代换。
本文所述的「包含」、「包括」、「含有」、「囊括」、「具有」也可互相代换而不受限制。
除此之外,本文所述的「和/或」、「及/或」被用作特指表达两个特定特征或组合物的其一或全部。因此,用语「和/或」用于表达语句如「A和/或B」系包含「A和B」、「A或B」、「(单独)A」「(单独)B」的含意。相同的,用语「和/或」用于表达语句如「A、B和/或C」系包含如后所述的意涵:A、B和C;A、B或C;A或C;A或B;B或C;A和C;A和B;B和C;(单独)A;(单独)B;(单独)C。
依据本发明,数据以平均值±S.D.显示4个独立实验。
本文中所称的「降血糖药物」,系指存在于临床的降血糖药物,包括但不限于:双胍(Biguanides)、胰岛素(insulin)、磺酰脲类(Sulfonylureas)、格列奈类(Meglitinides)、胰岛素增敏剂(Thiazolidinediones)、α-葡萄糖苷酶抑制剂(α-Glucosidaseinhibitors)、DPP-4抑制剂、SGLT2抑制剂及甲磺酸溴隐亭(Cycloset)。依据本发明,双胍可为二甲双胍(Metformin);磺酰脲类可选自于由下列所组成的群组:克吡噻(glipizide)、甘布若(glyburide)、葛立克拉(gliclazide)以及格列美脲(glimepiride);格列奈类可为一利泊格(Repaglinide)或一替格利尼得(nateglinide);胰岛素增敏剂可为一罗格列酮(rosiglitazone)或一皮利酮(pioglitazone);α-葡萄糖苷酶抑制剂可选自于由下列所组成的群组:阿卡波糖(acarbose)、米格列醇(miglitol)以及伏格列波糖(voglibose);DPP-4抑制剂可选自于由下列所组成的群组:西他列汀(sitagliptin)、沙格列汀(saxagliptin)、维格列汀(vildagliptin)、利拉利汀(linagliptin)以及阿格列汀(alogliptin);SGLT2抑制剂可为一达格列净(dapagliflozin)或一卡格列净(canagliflozin);甲磺酸溴隐亭可为一溴麦角隐亭(Bromocriptine)。
依据本发明,降血糖药物具有一为1nM~1M的浓度。较佳地,降血糖药物具有一为1μM~1mM的浓度。更佳地,降血糖药物具有一为10μM~100μM的浓度。
本文中所称的降血糖药物系将上述的药物溶于一溶剂中,该溶剂可为任何极性或非极性溶剂,于较佳实施例中,该极性溶剂为水。
依据本发明,医药品可利用熟习此技艺者所详知的技术而被制造成一适合于非经肠道地(parenterally)、口服地(orally)或局部地(topically)投药的剂型,这包括,但不限于:注射品(injection)[例如,无菌的水性溶液(sterile aqueous solution)或分散液(dispersion)]、无菌的粉末(sterile powder)、锭剂(tablet)、片剂(troche)、口含锭(lozenge)、丸剂(pill)、胶囊(capsule)、分散性粉末(dispersible powder)或细颗粒(granule)、溶液、悬浮液(suspension)、乳剂(emulsion)、糖浆(syrup)、酏剂(elixir)、浓浆(slurry)、外部制剂(external preparation)以及类似物。
依据本发明,医药品可进一步包含有一被广泛地使用于药物制造技术的医药上可接受的载剂(pharmaceutically acceptable carrier)。例如,该医药上可接受的载剂可包含一或多种选自于下列的试剂:溶剂(solvent)、缓冲液(buffer)、乳化剂(emulsifier)、悬浮剂(suspending agent)、分解剂(decomposer)、崩解剂(disintegrating agent)、分散剂(dispersing agent)、黏结剂(binding agent)、赋形剂(excipient)、安定剂(stabilizingagent)、螯合剂(chelating agent)、稀释剂(diluent)、胶凝剂(gelling agent)、防腐剂(preservative)、润湿剂(wetting agent)、润滑剂(lubricant)、吸收延迟剂(absorptiondelaying agent)、脂质体(liposome)以及类似物。有关这些试剂的选用与数量是落在熟习此项技术的人士的专业素养与例行技术范畴内。
依据本发明,该医药上可接受的载剂包含有一选自于由下列所构成的群组中的溶剂:水、生理盐水(normal saline)、磷酸盐缓冲生理盐水(phosphate buffered saline,PBS)、含有醇的水性溶液(aqueous solution containing alcohol)以及它们的组合。
依据本发明,该医药品可以一选自于由下列所构成的群组中的非经肠道途径(parenteral routes)来投药:腹膜内注射(intraperitoneal injection)、皮下注射(subcutaneous injection)、表皮内注射(intraepidermal injection)、皮内注射(intradermal injection)、肌肉内注射(intramuscular injection)、静脉内注射(intravenous injection)以及病灶内注射(intralesional injection)。
依据本发明,医药品可利用熟习此技艺者所详知的技术而被制造成一适合于局部地施用于皮肤上的外部制剂(external preparation),这包括,但不限于:乳剂(emulsion)、凝胶(gel)、软膏(ointment)、乳霜(cream)、贴片(patch)、擦剂(liniment)、粉末(powder)、气溶胶(aerosol)、喷雾(spray)、乳液(lotion)、乳浆(serum)、糊剂(paste)、泡沫(foam)、滴剂(drop)、悬浮液(suspension)、油膏(salve)以及绷带(bandage)。
依据本发明,该外部制剂是藉由将本发明的医药品与一为熟习此项技艺者所详知的基底(base)相混合而被制备。
依据本发明,该基底可包含有一或多种选自于下列的添加剂(additives):水、醇(alcohols)、甘醇(glycol)、碳氢化合物(hydrocarbons)[诸如石油胶(petroleum,jelly)以及白凡士林(white petrolatum)]、蜡(wax)[诸如石蜡(paraffin)以及黄蜡(yellowwax)]、保存剂(preserving agents)、抗氧化剂(antioxidants)、界面活性剂(surfactants)、吸收增强剂(absorption enhancers)、安定剂(stabilizing agents)、胶凝剂(gelling agents)[诸如974P(974P)、微结晶纤维素(microcrystalline cellulose)以及羧基甲基纤维素(carboxymethylcellulose)]、活性剂(active agents)、保湿剂(humectants)、气味吸收剂(odor absorbers)、香料(fragrances)、pH调整剂(pH adjusting agents)、螯合剂(chelating agents)、乳化剂(emulsifiers)、闭塞剂(occlusive agents)、软化剂(emollients)、增稠剂(thickeners)、助溶剂(solubilizing agents)、渗透增强剂(penetration enhancers)、抗刺激剂(anti-irritants)、着色剂(colorants)以及推进剂(propellants)等。有关这些添加剂的选用与数量是落在熟习此项技术的人士的专业素养与例行技术范畴内。
实施例1.生物材料的制备及生物材料在调控造骨细胞-专一性基因(osteoblast-specific genes)上的效用评估
在本发明一实施例中,首先,配制1~50%(w/v)生物可相容性高分子溶液,生物可相容性高分子可使用蛋白质分子或是多醣分子,其中当生物可相容性高分子为蛋白质分子时,较佳为明胶溶液(Sigma-Aldrich)(明胶取自猪的皮肤,型号G1890(9000-70-8),Sigma-Aldrich),亦可以胶原蛋白(collagen)取代之;生物可相容性而当高分子为多醣分子时,多醣分子可为透明质酸(hyaluronic acid)、褐藻酸(alginate)、几丁聚醣(chitosan)或其组合。在本实施例中,生物可相容性高分子是呈一胶体、一支架、一球体、一粉体、或一薄膜的形式。
接着,对明胶溶液添加1~50%(w/v)氢氧基磷灰石(hydroxyapatite,Hap,型号677418(12167-74-7),Sigma-Aldrich),然后加入二甲双胍(Metformin,Sigma-Aldrich)(1,1-盐酸二甲双胍(1,1-Dimethylbiguanide hydrochloride)(型号D150959(1115-70-4),Sigma-Aldrich)到明胶溶液使二甲双胍形成50μM的浓度。在本实施例中,氢氧基磷灰石是一种无机盐,可以用磷酸三钙(tricalcium phosphate,TCP)、磷酸二钙(dicalciumphosphate,DCP)、磷酸二钙二水合物(dicalcium phosphate dihydrate,DCPD)、磷酸四钙(tetracalcium phosphate,TTCP)、碳酸盐、硝酸盐、硫酸盐、钾盐、钠盐或镁盐取代。在本实施例中,生物可相容性高分子或无机盐的平均尺度为1nm至1mm。
在本实施例中,二甲双胍是一种双胍(Biguanides)的降血糖药物。选择性地,降血糖药物可选自于由下列所组成的群组:胰岛素(insulin)、磺酰脲类(Sulfonylureas)、格列奈类(Meglitinides)、胰岛素增敏剂(Thiazolidinediones)、α-葡萄糖苷酶抑制剂(α-Glucosidase inhibitors)、DPP-4抑制剂、SGLT2抑制剂及甲磺酸溴隐亭(Cycloset)。
之后,添加1~50%wt%的酵素交联剂(Ajinomoto),并持续混合搅拌24小时。之后,灌模(模具型号为NuncTM Cell-Culture Treated Multidishes 24-well plates)进行冷冻干燥,得到本发明生物材料(干燥后为固体,在使用上也是以固体形式),其显微结构图显示于图1a和图1b,其中在图1b中的小白点(参见黑色箭头)即是降血糖药物,图1a和图1b为放大倍率(图1a为200倍放大倍率;图1b为3500倍放大倍率)的不同,图1a可以看到孔径大小适合骨骼生长,图1b则是可以看到降血糖药物的包覆。在本实施例中,酵素交联剂是一种黏合成形剂,可藉由一选自于下列所组成的群组中的酵素进行交联作用:谷氨酰胺转胺酶(Transglutaminase)、脂肪酶(Lipase)、胜肽酶(Peptidase)、转肽酶(Sortase)、氧化还原酶(Oxidoreductase)、酪胺酸酶(Tyrosinase)、多酚氧化酶(Polyphenoloxidase,PPO)、漆氧化酶(laccase)、过氧化物酶(peroxidase)、离胺酸氧化酶(Lysyl oxidase)以及胺氧化酶(amine oxidase)。
间叶干细胞(mesenchymal stem cells,MSCs)能分化成硬骨、软骨、脂肪和其他结缔组织或转分化为神经细胞、肝脏细胞等,称为单胚层多潜能干细胞。
接着,培养间叶干细胞(mesenchymal stromal cells,MSCs)(取自需要促进骨骼组织再生的病人,IRB编号为201904070RINA),然后将细胞分成对照组及实验组。将5%(v/v)生物材料以MGS微球(MGS microsphere)的形式添加至实验组的细胞中,至于对照组的细胞则未添加生物材料。接着,在处理细胞第3、7、14、21或28天后,收取细胞培养物并拿来进行基因表现分析。
在本实施例中,用来分析造骨细胞-专一性基因(osteoblast-specific genes)包括碱性磷酸酶(alkaline phosphatase,ALPP)基因、矮小相关转录因子2(runt-relatedtranscription factor 2,RUNX2)基因、osterix(SP7)基因、骨结合素(osteonectin,SPARC)基因、骨钙素(osteocalcin,BGLAP)基因、及第I型胶原蛋白α1(Collagen,type I,alpha 1,COL1A1)基因。
以Qiazol(Qiagen,Valencia,CA)对上面所得到的细胞培养物进行RNA的萃取,然后以随机六聚体(Random hexamer)(Vivantis Inc.,加州)以及反转录酶(Vivantis CatNo:RTPL12)将萃取出的RNA反转录为cDNA。接着,以cDNA作为模版,并且使用用来扩增标的基因的引子对(Biotools Co.,Ltd.,台北,中国台湾)以供成骨分化(osteogenicdifferentiation),包括ALPP、RUNX2、SP7、SPARC、BGLAP、COL1A1及GAPDH(作为内源性对照组),它们的核苷酸序列显示于下表1。在CFX Connect即时PCR侦测系统(CFX ConnectReal-Time PCR Detection System)(BioRed,CA,USA)中利用TOOLS 2X SYBR qPCR Mix(Biotools Co.,Ltd.,台北,中国台湾)来进行即时PCR,使以对标的基因进行扩增。
表1
PCR的参数如下:在95℃下变性(denaturation)3分钟,95℃20秒40循环,在60℃下黏合(annealing)30秒,及在72℃下延伸(elongation)30秒。透过使用甘油醛三磷酸脱氢酶(glyceraldehyde 3-phosphate dehydrogenase,GAPDH)作为内源性对照组(endogenouscontrol)来计算标的基因的表现,其中△Ct=Ct目标基因-CtGAPDH,△△Ct=△Ct实验样品-△Ct对照样品,倍数变化=2-△△Ct;对照组已作为内规化(标准化),也就是说令对照组为1倍,相较于实验组为对照组的多少倍,故在图式的呈现上便不会有对照组,只有实验组的表现,因为对照组为1,本实施例的结果显示于图2及图3。
图2是本发明生物材料在处理细胞之后第7天及第14天时调控造骨细胞-专一性基因上的效用的数据图,其中该生物材料所使用的降血糖药物为二甲双胍。由图2可见,以对照组进行标准化(normalized)之后,以本发明生物材料(以二甲双胍作为降血糖药物组分)处理间充质干细胞(MSCs)之后第7天及第14天时造骨细胞-专一性基因(包括ALPP、RUNX2、SP7、SPARC、BGLAP及COL1A1基因)的表现量被上调(upregulated)。
图3是本发明生物材料在处理细胞之后第7天、第14天、第21天及第28天时调控造骨细胞-专一性基因上的效用的数据图,其中该生物材料所使用的降血糖药物为胰岛素。由图3可见,以对照组进行标准化之后,以本发明生物材料(以胰岛素作为降血糖药物组分)处理间充质干细胞(MSCs)之后第7天、第14天、第21天及第28天时造骨细胞-专一性基因(包括ALPP、RUNX2、SP7、SPARC、BGLAP及COL1A1基因)的表现量被上调。
实施例2.本发明生物材料在促进骨骼组织再生上的效用评估
标准化手术程序以在大鼠模型中创建体内骨缺损部位。为了进行体内外科手术分析,从中国台湾大学医学院实验动物中心(Center for Laboratory Animals,College ofMedicine,National Taiwan University)获得了27只6周大公鼠,并透过腹膜内注射以1:2浓度的舒泰(Zoletil)及若朋(Rompum)(1mL/kg)麻醉。在无菌手术环境中,尺骨(ulna)上形成了单个骨缺损。从尺骨中部产生5mm的骨缺损(此为较一般骨缺损严重的骨缺损),然后用本发明生物材料(以二甲双胍作为降血糖药物组分)作为骨填充物填充骨缺损作为实验组。以没有填充任何材料单纯只有骨缺损作为对照组。植入骨移植物后,使用5-0可吸收缝线进行伤口闭合。在植入骨移植物之后第4周进行电脑断层扫描(CT scan),实验结果显示于图4a和图4b。
图4a是对照组中无填充材料的骨缺损的电脑断层扫描图,图4b是本发明生物材料(以二甲双胍作为降血糖药物组分)在促进骨骼组织再生上的效用的电脑断层扫描图。由图4a和图4b可见,与对照组(图4a)相较之下,用本发明生物材料(以二甲双胍作为降血糖药物组分)作为骨填充物的实验组(图4b)填充骨缺损可显著促进骨骼组织再生。
综上所述,本发明生物材料可藉由调控造骨细胞-专一性基因(osteoblast-specific genes)(包括碱性磷酸酶(alkaline phosphatase,ALPP)基因、矮小相关转录因子2(runt-related transcription factor 2,RUNX2)基因、osterix(SP7)基因、骨结合素(osteonectin,SPARC)基因、骨钙素(osteocalcin,BGLAP)基因、及第I型胶原蛋白α1(Collagen,type I,alpha 1,COL1A1)基因)的表现量来达到促进组织再生(例如骨骼组织再生)的功效,且人体实验也证实有效。
以上所述仅为举例性,而非为限制性者。任何未脱离本发明的精神与范畴,而对其进行的等效修改或变更,均应包含于本发明的权利要求保护范围中。
Claims (22)
1.一种用于促进骨骼组织再生的生物材料,其特征在于,包含一生物可相容性高分子、一无机盐以及一降血糖药物。
2.根据权利要求1所述的生物材料,其特征在于,该降血糖药物是选自于由下列所组成的群组:双胍、胰岛素、磺酰脲类、格列奈类、胰岛素增敏剂、α-葡萄糖苷酶抑制剂、DPP-4抑制剂、SGLT2抑制剂及甲磺酸溴隐亭。
3.根据权利要求2所述的生物材料,其特征在于,该双胍是二甲双胍。
4.根据权利要求2所述的生物材料,其特征在于,该磺酰脲类是选自于由下列所组成的群组:克吡噻、甘布若、葛立克拉以及格列美脲。
5.根据权利要求2所述的生物材料,其特征在于,该格列奈类是一利泊格或一替格利尼得。
6.根据权利要求2所述的生物材料,其特征在于,该胰岛素增敏剂是一罗格列或一皮利酮。
7.根据权利要求2所述的生物材料,其特征在于,该α-葡萄糖苷酶抑制剂是选自于由下列所组成的群组:阿卡波糖、米格列醇以及伏格列波糖。
8.根据权利要求2所述的生物材料,其特征在于,该DPP-4抑制剂是选自于由下列所组成的群组:西他列汀、沙格列汀、维格列汀、利拉利汀以及阿格列汀。
9.根据权利要求2所述的生物材料,其特征在于,该SGLT2抑制剂是一达格列净或一卡格列净。
10.根据权利要求2所述的生物材料,其特征在于,该甲磺酸溴隐亭是一溴麦角隐亭。
11.根据权利要求1所述的生物材料,其特征在于,包含一黏合成形剂,其中该黏合成形剂是一交联剂。
12.根据权利要求11所述的生物材料,其特征在于,该生物可相容性高分子具有一为1~50%(w/v)的浓度,该无机盐具有一为1~50%(w/v)的浓度,该降血糖药物具有一为1nM~1M的浓度,以及该黏合成形剂具有一为1~50wt%的浓度。
13.根据权利要求1所述的生物材料,其特征在于,该生物可相容性高分子是一多醣、一蛋白质或其组合。
14.根据权利要求13所述的生物材料,其特征在于,该多醣是选自于由下列所组成的群组:透明质酸、褐藻酸、几丁聚醣及其任意组合。
15.根据权利要求13所述的生物材料,其特征在于,该蛋白质是一明胶、一胶原蛋白或其组合。
16.根据权利要求1所述的生物材料,其特征在于,该无机盐是选自由下列所组成的群组:氢氧基磷灰石、磷酸三钙、磷酸二钙、磷酸二钙二水合物、磷酸四钙、碳酸盐、硝酸盐、硫酸盐、钾盐、钠盐以及镁盐。
17.根据权利要求1所述的生物材料,其特征在于,该生物可相容性高分子是呈一胶体、一支架、一球体、一粉体、或一薄膜的形式。
18.根据权利要求11所述的生物材料,其特征在于,该生物可相容性高分子是藉由一选自于下列所组成的群组中的酵素进行交联作用:谷氨酰胺转胺酶、脂肪酶、胜肽酶、转肽酶、氧化还原酶、酪胺酸酶、多酚氧化酶、漆氧化酶、过氧化物酶、离胺酸氧化酶以及胺氧化酶。
19.根据权利要求1所述的生物材料,其特征在于,该生物可相容性高分子或该无机盐的平均尺度为1nm至1mm。
20.一种如权利要求1至19中任一项所述的生物材料用于制备一促进组织再生的医药品的用途。
21.根据权利要求20所述的用途,其特征在于,该促进组织再生是促进骨骼组织再生。
22.根据权利要求21所述的用途,其特征在于,该生物可相容性高分子具有一为1~50%(w/v)的浓度,该无机盐具有一为1~50%(w/v)的浓度,该降血糖药物具有一为1nM~1M的浓度,以及该黏合成形剂具有一为1~50%wt%的浓度。
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