TWI742571B - 生物材料及其用於促進組織再生的用途 - Google Patents
生物材料及其用於促進組織再生的用途 Download PDFInfo
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- TWI742571B TWI742571B TW109109048A TW109109048A TWI742571B TW I742571 B TWI742571 B TW I742571B TW 109109048 A TW109109048 A TW 109109048A TW 109109048 A TW109109048 A TW 109109048A TW I742571 B TWI742571 B TW I742571B
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Abstract
本發明提供一種生物材料及其用於促進組織再生的用途,其中生物材料包含一生物可相容性高分子、一無機鹽以及一降血糖藥物。本發明生物材料可藉由調控造骨細胞-專一性基因的表現量來達到促進組織再生的功效。
Description
本發明是有關於一種生物材料及其用於促進組織再生的用途。
組織工程,是一門以細胞生物學和材料科學相結合,進行體外或體內建構組織或器官的新興學科,其核心在於建立細胞與生物材料的三維空間複合體,用以對缺損組織進行形態、結構及功能三個方面的重建,並達到永久性替代。骨組織工程是指將分離的自體高濃度成骨細胞、骨髓基質幹細胞或軟骨細胞,經體外培養擴增後種植於某種細胞支架或細胞外基質上,然後將這種細胞雜化材料植入骨缺損部位,在生物材料逐步降解的同時,種植的成骨細胞不斷增殖,從而達到修復骨組織缺損的目的。
用於骨缺損修復的材料主要有生物無機材料和有機高分子材料兩大類。有機高分子材料中,由乳酸和羥基乙酸隨機聚合而成的聚乳酸-羥基乙酸(poly(lactic-co-glycolic acid),PLGA)的研究較為廣泛,其具有良好的生物相容性、生物可降解性以及降解速率可調節性等優點,而且,PLGA透過酯鍵水解降解為乳酸和羥基乙酸,最終降解為二氧化碳和水排出體外。
現有的技術主要採用加熱技術使支架成形,這種高溫的應用會使一些蛋白質類的藥物變性,限制了載體藥物的種類;同時,由於大型加熱的裝置較少,加熱技術的選擇也限制了支架的製作。雖然關於微球載藥支架已經有了一些研究,但是微囊支架仍少見報導,微囊支架載體藥物更是如此。此外,現有技術用於促進骨骼組織再生的方式往往有生物相容性差及效果不彰的缺點。
為了解決上述問題,本領域的技術人員亟需研發出具有促進組織再生(例如骨骼組織再生)效用的新穎醫藥品以造福有此需求的廣大族群。
有鑑於此,本發明之目的為提供一種用於促進骨骼組織再生的生物材料,包含一生物可相容性高分子、一無機鹽以及一降血糖藥物。
在本發明的一實施例中,該降血糖藥物是選自於由下列所組成的群組:雙胍(Biguanides)、胰島素(insulin)、磺醯脲類(Sulfonylureas)、格列奈類(Meglitinides)、胰島素增敏劑(Thiazolidinediones)、α-葡萄糖苷酶抑制劑(α-Glucosidase inhibitors)、DPP-4抑制劑、SGLT2抑制劑及甲磺酸溴隱亭(Cycloset)。
在本發明的一實施例中,該雙胍是二甲雙胍(Metformin)。
在本發明的一實施例中,該磺醯脲類是選自於由下列所組成的群組:克吡噻(glipizide)、甘布若(glyburide)、葛立克拉(gliclazide)以及格列美脲(glimepiride)。
在本發明的一實施例中,該格列奈類是一利泊格(Repaglinide)或一替格利尼得(nateglinide)。
在本發明的一實施例中,該胰島素增敏劑是一羅格列酮(rosiglitazone)或一皮利酮(pioglitazone)。
在本發明的一實施例中,該α-葡萄糖苷酶抑制劑是選自於由下列所組成的群組:阿卡波糖(acarbose)、米格列醇(miglitol)以及伏格列波糖(voglibose)。
在本發明的一實施例中,該DPP-4抑制劑是選自於由下列所組成的群組:西他列汀(sitagliptin)、沙格列汀(saxagliptin)、維格列汀(vildagliptin)、利拉利汀(linagliptin)以及阿格列汀(alogliptin)。
在本發明的一實施例中,該SGLT2抑制劑是一達格列凈(dapagliflozin)或一卡格列淨(canagliflozin)。
在本發明的一實施例中,該甲磺酸溴隱亭是一溴麥角隱亭(Bromocriptine)。
在本發明的一實施例中,該生物材料進一步包含一黏合成形劑,其中該黏合成形劑是一交聯劑。
在本發明的一實施例中,該生物可相容性高分子具有一為1~50%(w/v)的濃度,該無機鹽具有一為1~50%(w/v)的濃度,該降血糖藥物具有一為1nM~1M的濃度,以及該黏合成形劑具有一為1~50wt%的濃度。
在本發明的一實施例中,該生物可相容性高分子是一多醣、一蛋白質或其組合。
在本發明的一實施例中,該多醣是選自於由下列所組成的群組:透明質酸(hyaluronic acid)、褐藻酸(alginate)、幾丁聚醣(chitosan)及其任意組合。
在本發明的一實施例中,該蛋白質是一明膠(gelatin)、一膠原蛋白(collagen)或其組合。
在本發明的一實施例中,該無機鹽是選自由下列所組成的群組:氫氧基磷灰石(hydroxyapatite,Hap)、磷酸三鈣(tricalcium phosphate,TCP)、磷酸二鈣(dicalcium phosphate,DCP)、磷酸二鈣二水合物(dicalcium phosphate dihydrate,DCPD)、磷酸四鈣(tetracalcium phosphate,TTCP)、碳酸鹽、硝酸鹽、硫酸鹽、鉀鹽、鈉鹽以及鎂鹽。
在本發明的一實施例中,該生物可相容性高分子是呈一膠體、一支架、一球體、一粉體、或一薄膜的形式。
在本發明的一實施例中,該生物可相容性高分子是藉由一選自於下列所組成之群組中的酵素進行交聯作用:谷氨醯胺轉胺酶(Transglutaminase)、脂肪酶(Lipase)、胜肽酶(Peptidase)、轉肽酶(Sortase)、氧化還原酶(Oxidoreductase)、酪胺酸酶(Tyrosinase)、多酚氧化酶(Polyphenoloxidase,PPO)、漆氧化酶(laccase)、過氧化物酶(peroxidase)、離胺酸氧化酶(Lysyl oxidase)以及胺氧化酶(amine oxidase)。
在本發明的一實施例中,該生物可相容性高分子或該無機鹽的的平均尺度為1nm至1mm。
本發明之另一目的為提供一種如前所述的生物材料用於製備一促進組織再生之醫藥品的用途。
在本發明的一實施例中,該促進組織再生是促進骨骼組織再生。
在本發明的一實施例中,該生物可相容性高分子具有一為1~50%(w/v)的濃度,該無機鹽具有一為1~50%(w/v)的濃度,該降血糖藥物具有一為1nM~1M的濃度,以及該黏合成形劑具有一為1~50wt%的濃度。
綜上所述,本發明生物材料之功效在於:可藉由調控造骨細胞-專一性基因(osteoblast-specific genes)(包括鹼性磷酸酶(alkaline phosphatase,ALPP)基因、矮小相關轉錄因子2(runt-related transcription factor 2,RUNX2)基因、osterix(SP7)基因、骨結合素(osteonectin,SPARC)基因、骨鈣素(osteocalcin,BGLAP)基因、及第I型膠原蛋白α1(Collagen,type I,alpha 1,COL1A1)基因)的表現量來達到促進組織再生(例如骨骼組織再生)的功效,且人體實驗也證實有效。
以下將進一步說明本發明的實施方式,下述所列舉的實施例係用以闡明本發明,並非用以限定本發明之範圍,任何熟習此技藝者,在不脫離本發明之精神和範圍內,當可做些許更動與潤飾,因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。
圖1是本發明生物材料的顯微結構圖。
圖2是本發明生物材料(以二甲雙胍作為降血糖藥物組分)在處理細胞之後第7天及第14天之時調控造骨細胞-專一性基因上的效用之數據圖。
圖3是本發明生物材料(以胰島素作為降血糖藥物組分)在處理細胞之後第7天、第14天、第21天及第28天之時調控造骨細胞-專一性基因上的效用之數據圖。
圖4是本發明生物材料在促進骨骼組織再生上的效用之電腦斷層掃描圖。
本文中所使用數值為近似值,所有實驗數據皆表示在20%的範圍內,較佳為在10%的範圍內,最佳為在5%的範圍內。
除非另有定義,本文中所有技術和科學用語與本發明所屬領域中具有通常知識者所理解的含義相同。如在本申請中所使用的,以下術語具有如下意涵。
除非上下文中另有指定外,本文及申請專利範圍所述單數格式之「一」、「一個」、「一種」及「該」包含複數指涉。本文中之用語例如:「一」、「該」、「一或多」、「複數」及「至少為一」可互相代換。
本文所述之「包含」、「包括」、「含有」、「囊括」、「具有」也可互相代換而不受限制。
除此之外,本文所述之「和/或」、「及/或」被用作特指表達兩個特定特徵或組合物的其一或全部。因此,用語「和/或」用於表達語句如「A和/或B」係包含「A和B」、「A或B」、「(單獨)A」「(單獨)B」之意。相同的,用語「和/或」用於表達語句如「A、B和/或C」係包含如後所述之意涵: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;(單獨)A;(單獨)B;(單獨)C。
依據本發明,數據以平均值±S.D.顯示4個獨立實驗。
本文中所稱之「降血糖藥物」,係指存在於臨床之降血糖藥物,包括但不限於:雙胍(Biguanides)、胰島素(insulin)、磺醯脲類(Sulfonylureas)、格列奈類(Meglitinides)、胰島素增敏劑(Thiazolidinediones)、α-葡萄糖苷酶抑制劑(α-Glucosidase inhibitors)、DPP-4抑制劑、SGLT2抑制劑及甲磺酸溴隱亭(Cycloset)。依據本發明,雙胍可為二甲雙胍(Metformin);磺醯脲類可選自於由下列所組成的群組:克吡噻(glipizide)、甘布若(glyburide)、葛立克拉(gliclazide)以及格列美脲(glimepiride);格列奈類可為一利泊格(Repaglinide)或一替格利尼得(nateglinide);胰島素增敏劑可為一羅格列酮(rosiglitazone)或一皮利酮
(pioglitazone);α-葡萄糖苷酶抑制劑可選自於由下列所組成的群組:阿卡波糖(acarbose)、米格列醇(miglitol)以及伏格列波糖(voglibose);DPP-4抑制劑可選自於由下列所組成的群組:西他列汀(sitagliptin)、沙格列汀(saxagliptin)、維格列汀(vildagliptin)、利拉利汀(linagliptin)以及阿格列汀(alogliptin);SGLT2抑制劑可為一達格列凈(dapagliflozin)或一卡格列淨(canagliflozin);甲磺酸溴隱亭可為一溴麥角隱亭(Bromocriptine)。
依據本發明,降血糖藥物具有一為1nM~1M的濃度。較佳地,降血糖藥物具有一為1μM~1mM的濃度。更佳地,降血糖藥物具有一為10μM~100μM的濃度。
本文中所稱之降血糖藥物係將上述之藥物溶於一溶劑中,該溶劑可為任何極性或非極性溶劑,於較佳實施例中,該極性溶劑為水。
依據本發明,醫藥品可利用熟習此技藝者所詳知的技術而被製造成一適合於非經腸道地(parenterally)、口服地(orally)或局部地(topically)投藥的劑型,這包括,但不限於:注射品(injection)[例如,無菌的水性溶液(sterile aqueous solution)或分散液(dispersion)]、無菌的粉末(sterile powder)、錠劑(tablet)、片劑(troche)、口含錠(lozenge)、丸劑(pill)、膠囊(capsule)、分散性粉末(dispersible powder)或細顆粒(granule)、溶液、懸浮液(suspension)、乳劑(emulsion)、糖漿(syrup)、酏劑(elixir)、濃漿(slurry)、外部製劑(external preparation)以及類似之物。
依據本發明,醫藥品可進一步包含有一被廣泛地使用於藥物製造技術之醫藥上可接受的載劑(pharmaceutically acceptable carrier)。例如,該醫藥上可接受的載劑可包含一或多種選自於下列的試劑:溶劑(solvent)、緩衝液(buffer)、乳化劑(emulsifier)、懸浮劑(suspending agent)、分解劑(decomposer)、崩解劑(disintegrating agent)、分散劑(dispersing agent)、黏結劑(binding agent)、賦形劑(excipient)、安定劑(stabilizing agent)、螯合劑(chelating agent)、稀釋劑(diluent)、膠凝劑(gelling agent)、防腐劑(preservative)、潤濕劑(wetting agent)、潤滑劑(lubricant)、吸收延遲劑(absorption delaying agent)、脂質體(liposome)以
及類似之物。有關這些試劑的選用與數量是落在熟習此項技術之人士的專業素養與例行技術範疇內。
依據本發明,該醫藥上可接受的載劑包含有一選自於由下列所構成之群組中的溶劑:水、生理鹽水(normal saline)、磷酸鹽緩衝生理鹽水(phosphate buffered saline,PBS)、含有醇的水性溶液(aqueous solution containing alcohol)以及它們的組合。
依據本發明,該醫藥品可以一選自於由下列所構成之群組中的非經腸道途徑(parenteral routes)來投藥:腹膜內注射(intraperitoneal injection)、皮下注射(subcutaneous injection)、表皮內注射(intraepidermal injection)、皮內注射(intradermal injection)、肌肉內注射(intramuscular injection)、靜脈內注射(intravenous injection)以及病灶內注射(intralesional injection)。
依據本發明,醫藥品可利用熟習此技藝者所詳知的技術而被製造成一適合於局部地施用於皮膚上的外部製劑(external preparation),這包括,但不限於:乳劑(emulsion)、凝膠(gel)、軟膏(ointment)、乳霜(cream)、貼片(patch)、擦劑(liniment)、粉末(powder)、氣溶膠(aerosol)、噴霧(spray)、乳液(lotion)、乳漿(serum)、糊劑(paste)、泡沫(foam)、滴劑(drop)、懸浮液(suspension)、油膏(salve)以及繃帶(bandage)。
依據本發明,該外部製劑是藉由將本發明的醫藥品與一為熟習此項技藝者所詳知的基底(base)相混合而被製備。
依據本發明,該基底可包含有一或多種選自於下列的添加劑(additives):水、醇(alcohols)、甘醇(glycol)、碳氫化合物(hydrocarbons)[諸如石油膠(petroleum,jelly)以及白凡士林(white petrolatum)]、蠟(wax)[諸如石蠟(paraffin)以及黃蠟(yellow wax)]、保存劑(preserving agents)、抗氧化劑(antioxidants)、界面活性劑(surfactants)、吸收增強劑(absorption enhancers)、安定劑(stabilizing agents)、膠凝劑(gelling agents)[諸如卡波普®974P(carbopol®974P)、微結晶纖維素(microcrystalline cellulose)以及羧基甲基纖維素(carboxymethylcellulose)]、活性劑(active agents)、保濕劑(humectants)、氣味吸收劑(odor absorbers)、香料(fragrances)、pH調整劑(pH adjusting agents)、螯合劑
(chelating agents)、乳化劑(emulsifiers)、閉塞劑(occlusive agents)、軟化劑(emollients)、增稠劑(thickeners)、助溶劑(solubilizing agents)、滲透增強劑(penetration enhancers)、抗刺激劑(anti-irritants)、著色劑(colorants)以及推進劑(propellants)等。有關這些添加劑的選用與數量是落在熟習此項技術之人士的專業素養與例行技術範疇內。
實施例1. 生物材料的製備及生物材料在調控造骨細胞-專一性基因(osteoblast-specific genes)上的效用評估
在本發明一實施例中,首先,配製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質分子或是多醣分子,其中當生物可相容性高分子為蛋白質分子時,較佳為明膠溶液(Sigma-Aldrich)(明膠取自豬的皮膚,型號G1890(9000-70-8),Sigma-Aldrich),亦可以膠原蛋白(collagen)取代之;生物可相容性而當高分子為多醣分子時,多醣分子可為透明質酸(hyaluronic acid)、褐藻酸(alginate)、幾丁聚醣(chitosan)或其組合。在本實施例中,生物可相容性高分子是呈一膠體、一支架、一球體、一粉體、或一薄膜的形式。
接著,對明膠溶液添加1~50%(w/v)氫氧基磷灰石(hydroxyapatite,Hap,型號677418(12167-74-7),Sigma-Aldrich),然後加入二甲雙胍(Metformin,Sigma-Aldrich)(1,1-鹽酸二甲雙胍(1,1-Dimethylbiguanide hydrochloride)(型號D150959(1115-70-4),Sigma-Aldrich)到明膠溶液使二甲雙胍形成50μM的濃度。在本實施例中,氫氧基磷灰石是一種無機鹽,可以磷酸三鈣(tricalcium phosphate,TCP)、磷酸二鈣(dicalcium phosphate,DCP)、磷酸二鈣二水合物(dicalcium phosphate dihydrate,DCPD)、磷酸四鈣(tetracalcium phosphate,TTCP)、碳酸鹽、硝酸鹽、硫酸鹽、鉀鹽、鈉鹽或鎂鹽取代之。在本實施例中,生物可相容性高分子或無機鹽的的平均尺度為1nm至1mm。
在本實施例中,二甲雙胍是一種雙胍(Biguanides)的降血糖藥物。選擇性地,降血糖藥物可選自於由下列所組成的群組:胰島素(insulin)、磺醯脲類(Sulfonylureas)、格列奈類(Meglitinides)、胰島素增敏劑(Thiazolidinediones)、α-葡萄糖苷酶抑制劑(α-Glucosidase inhibitors)、DPP-4抑制劑、SGLT2抑制劑及甲磺酸溴隱亭(Cycloset)。
之後,添加1~50% wt%之酵素交聯劑(Ajinomoto),並持續混合攪拌24小時。之後,灌模(模具型號為NuncTM Cell-Culture Treated Multidishes 24-well plates)進行冷凍乾燥,得到本發明生物材料(乾燥後為固體,在使用上也是以固體形式),其顯微結構圖顯示於圖1,其中在圖1中的小白點(參見紅色箭頭)即是降血糖藥物,上下兩張為放大倍率(上張為200倍放大倍率;下張為3500倍放大倍率)的不同,上圖可以看到孔徑大小適合骨骼生長,下圖則是可以看到降血糖藥物的包覆。在本實施例中,酵素交聯劑是一種黏合成形劑,可藉由一選自於下列所組成之群組中的酵素進行交聯作用:谷氨醯胺轉胺酶(Transglutaminase)、脂肪酶(Lipase)、胜肽酶(Peptidase)、轉肽酶(Sortase)、氧化還原酶(Oxidoreductase)、酪胺酸酶(Tyrosinase)、多酚氧化酶(Polyphenoloxidase,PPO)、漆氧化酶(laccase)、過氧化物酶(peroxidase)、離胺酸氧化酶(Lysyl oxidase)以及胺氧化酶(amine oxidase)。
間葉幹細胞(mesenchymal stem cells,MSCs)能分化成硬骨、軟骨、脂肪和其他結締組織或轉分化為神經細胞、肝臟細胞等,稱為單胚層多潛能幹細胞。
接著,培養間葉幹細胞(mesenchymal stromal cells,MSCs)(取自需要促進骨骼組織再生的病人,IRB編號為201904070RINA),然後將細胞分成對照組及實驗組。將5%(v/v)生物材料以MGS微球(MGS microsphere)的形式添加至實驗組的細胞中,至於對照組的細胞則未添加生物材料。接著,在處理細胞第3、7、14、21或28天後,收取細胞培養物並拿來進行基因表現分析。
在本實施例中,用來分析造骨細胞-專一性基因(osteoblast-specific genes)包括鹼性磷酸酶(alkaline phosphatase,ALPP)基因、矮小相關轉錄因子2(runt-related transcription factor 2,RUNX2)基因、osterix(SP7)基因、骨結合素(osteonectin,SPARC)基因、骨鈣素(osteocalcin,BGLAP)基因、及第I型膠原蛋白α1(Collagen,type I,alpha 1,COL1A1)基因。
以Qiazol(Qiagen,Valencia,CA)對上面所得到的細胞培養物進行RNA的萃取,然後以隨機六聚體(Random hexamer)(Vivantis Inc.,加州)以及反轉錄酶(Vivantis Cat No:RTPL12)將萃取出的RNA反轉錄為cDNA。接著,以cDNA
作為模版,並且使用用來擴增標的基因的引子對(Biotools Co.,Ltd.,台北,台灣)以供成骨分化(osteogenic differentiation),包括ALPP、RUNX2、SP7、SPARC、BGLAP、COL1A1及GAPDH(作為內源性對照組),它們的核苷酸序列顯示於下表1。在CFX Connect即時PCR偵測系統(CFX Connect Real-Time PCR Detection System)(BioRed,CA,USA)中利用TOOLS 2X SYBR qPCR Mix(Biotools Co.,Ltd.,台北,台灣)來進行即時PCR,俾以對標的基因進行擴增。
PCR的參數如下:在95℃下變性(denaturation)3分鐘,95℃ 20秒40循環,在60℃下黏合(annealing)30秒,及在72℃下延伸(elongation)30秒。透過使用甘油醛三磷酸脫氫酶(glyceraldehyde 3-phosphate dehydrogenase,GAPDH)作為內源性對照組(endogenous control)來計算標的基因的表現,其中△Ct=Ct目標基因-CtGAPDH,△△Ct=△Ct實驗樣品-△Ct對照樣品,倍數變化=2-△△Ct;對照組已作為內規化(標準化),也就是說令對照組為1倍,相較於實驗組為對照組的多少倍,故在圖式的呈現上便不會有對照組,只有實驗組的表現,因為對照組為1,本實施例的結果顯示於圖2及圖3。
圖2是本發明生物材料在處理細胞之後第7天及第14天之時調控造骨細胞-專一性基因上的效用之數據圖,其中該生物材料所使用的降血糖藥物為二甲雙胍。由圖2可見,以對照組進行標準化(normalized)之後,以本發明生物材料(以二甲雙胍作為降血糖藥物組分)處理間充質幹細胞(MSCs)之後第7天及第14天之時造骨細胞-專一性基因(包括ALPP、RUNX2、SP7、SPARC、BGLAP及COL1A1基因)的表現量被上調(upregulated)。
圖3是本發明生物材料在處理細胞之後第7天、第14天、第21天及第28天之時調控造骨細胞-專一性基因上的效用之數據圖,其中該生物材料所使用的降血糖藥物為胰島素。由圖3可見,以對照組進行標準化之後,以本發明生物材料(以胰島素作為降血糖藥物組分)處理間充質幹細胞(MSCs)之後第7天、第14天、第21天及第28天之時造骨細胞-專一性基因(包括ALPP、RUNX2、SP7、SPARC、BGLAP及COL1A1基因)的表現量被上調。
實施例2. 本發明生物材料在促進骨骼組織再生上的效用評估
標準化手術程序以在大鼠模型中創建體內骨缺損部位。為了進行體內外科手術分析,從國立臺灣大學醫學院實驗動物中心(Center for Laboratory Animals,College of Medicine,National Taiwan University)獲得了27隻6
周大公鼠,並透過腹膜內注射以1:2濃度的舒泰(Zoletil)及若朋(Rompum)(1mL/kg)麻醉。在無菌手術環境中,尺骨(ulna)上形成了單個骨缺損。從尺骨中部產生5mm的骨缺損(此為較一般骨缺損嚴重的骨缺損),然後用本發明生物材料(以二甲雙胍作為降血糖藥物組分)作為骨填充物填充骨缺損作為實驗組。以沒有填充任何材料單純只有骨缺損作為對照組。植入骨移植物後,使用5-0可吸收縫線進行傷口閉合。在植入骨移植物之後第4週進行電腦斷層掃描(CT scan),實驗結果顯示於圖4。
圖4是本發明生物材料(以二甲雙胍作為降血糖藥物組分)在促進骨骼組織再生上的效用之電腦斷層掃描圖。由圖4可見,與對照組(上圖)相較之下,用本發明生物材料(以二甲雙胍作為降血糖藥物組分)作為骨填充物的實驗組(下圖)填充骨缺損可顯著促進骨骼組織再生。
綜上所述,本發明生物材料可藉由調控造骨細胞-專一性基因(osteoblast-specific genes)(包括鹼性磷酸酶(alkaline phosphatase,ALPP)基因、矮小相關轉錄因子2(runt-related transcription factor 2,RUNX2)基因、osterix(SP7)基因、骨結合素(osteonectin,SPARC)基因、骨鈣素(osteocalcin,BGLAP)基因、及第I型膠原蛋白α1(Collagen,type I,alpha 1,COL1A1)基因)的表現量來達到促進組織再生(例如骨骼組織再生)的功效,且人體實驗也證實有效。
以上所述僅為舉例性,而非為限制性者。任何未脫離本發明之精神與範疇,而對其進行之等效修改或變更,均應包含於後附之申請專利範圍中。
<110> 美商威斯頓股份有限公司
<120> 生物材料及其用於促進組織再生的用途
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Claims (15)
- 一種用於促進骨骼組織再生的生物材料,包含一生物可相容性高分子、一無機鹽以及一降血糖藥物,其中該降血糖藥物是選自於由下列所組成的群組:雙胍(Biguanides)、磺醯脲類(Sulfonylureas)、格列奈類(Meglitinides)、胰島素增敏劑(Thiazolidinediones)、α-葡萄糖苷酶抑制劑(α-Glucosidase inhibitors)、DPP-4抑制劑、SGLT2抑制劑及甲磺酸溴隱亭(Cycloset);該生物可相容性高分子具有一為1~50%(w/v)的濃度,該無機鹽具有一為1~50%(w/v)的濃度,該降血糖藥物具有一為1nM~1M的濃度,以及該黏合成形劑具有一為1~50wt%的濃度;該生物可相容性高分子是一多醣、一蛋白質或其組合;該多醣是選自於由下列所組成的群組:褐藻酸(alginate)、幾丁聚醣(chitosan)及其任意組合;該蛋白質是一明膠(gelatin)、一膠原蛋白(collagen)或其組合;以及該無機鹽是選自由下列所組成的群組:氫氧基磷灰石(hydroxyapatite,Hap)、磷酸三鈣(tricalcium phosphate,TCP)、磷酸二鈣(dicalcium phosphate,DCP)、磷酸二鈣二水合物(dicalcium phosphate dihydrate,DCPD)、磷酸四鈣(tetracalcium phosphate,TTCP)、碳酸鹽、硝酸鹽、硫酸鹽、鉀鹽、鈉鹽以及鎂鹽。
- 如申請專利範圍第1項所述的生物材料,其中該雙胍是二甲雙胍(Metformin)。
- 如申請專利範圍第1項所述的生物材料,其中該磺醯脲類是選自於由下列所組成的群組:克吡噻(glipizide)、甘布若(glyburide)、葛立克拉(gliclazide)以及格列美脲(glimepiride)。
- 如申請專利範圍第1項所述的生物材料,其中該格列奈類是一利泊格(Repaglinide)或一替格利尼得(nateglinide)。
- 如申請專利範圍第1項所述的生物材料,其中該胰島素增敏劑是一羅格列酮(rosiglitazone)或一皮利酮(pioglitazone)。
- 如申請專利範圍第1項所述的生物材料,其中該α-葡萄糖苷酶抑制劑是選自於由下列所組成的群組:阿卡波糖(acarbose)、米格列醇(miglitol)以及伏格列波糖(voglibose)。
- 如申請專利範圍第1項所述的生物材料,其中該DPP-4抑制劑是選自於由下列所組成的群組: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)。
- 如申請專利範圍第1項所述的生物材料,其中該SGLT2抑制劑是一達格列凈(dapagliflozin)或一卡格列淨(canagliflozin)。
- 如申請專利範圍第1項所述的生物材料,其中該甲磺酸溴隱亭是一溴麥角隱亭(Bromocriptine)。
- 如申請專利範圍第1項所述的生物材料,進一步包含一黏合成形劑,其中該黏合成形劑是一交聯劑。
- 如申請專利範圍第1項所述的生物材料,其中該生物可相容性高分子是呈一膠體、一支架、一球體、一粉體、或一薄膜的形式。
- 如申請專利範圍第10項所述的生物材料,其中該生物可相容性高分子是藉由一選自於下列所組成之群組中的酵素進行交聯作用:谷氨醯胺轉胺酶(Transglutaminase)、脂肪酶(Lipase)、胜肽酶(Peptidase)、轉肽酶(Sortase)、氧化還原酶(Oxidoreductase)、酪胺酸酶(Tyrosinase)、多酚氧化酶(Polyphenoloxidase,PPO)、漆氧化酶(laccase)、過氧化物酶(peroxidase)、離胺酸氧化酶(Lysyl oxidase)以及胺氧化酶(amine oxidase)。
- 如申請專利範圍第1項所述的生物材料,其中該生物可相容性高分子或該無機鹽的平均尺度為1nm至1mm。
- 一種如申請專利範圍第1項至第13項中任一項所述的生物材料用於製備一促進組織再生之醫藥品的用途,其中該生物可相容性高分子具有一為1~50%(w/v)的濃度,該無機鹽具有一為1~50%(w/v)的濃度,該降血糖藥物具有一為1nM~1M的濃度,以及該黏合成形劑具有一為1~50% wt%的濃度。
- 如申請專利範圍第14項所述的用途,其中該促進組織再生是促進骨骼組織再生。
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US20160000974A1 (en) * | 2011-08-09 | 2016-01-07 | New Jersey Institute Of Technoloty | Composite Matrix for Bone Repair Applications |
US20170182080A1 (en) * | 2014-03-14 | 2017-06-29 | Bo Han | Functional scaffold for tissue repair and regeneration |
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