TWI827321B - 含有粒線體之組合物及其用於作為膠原蛋白增生促進劑之用途 - Google Patents
含有粒線體之組合物及其用於作為膠原蛋白增生促進劑之用途 Download PDFInfo
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Abstract
本發明係揭露一種粒線體用於促進傷口癒合及修復之用途，具體來說，當投予一定量之粒線體或含有一定量之粒線體的組合物至一傷口時，係能夠有效地達到促進傷口癒合或加速傷口修復之功效。
Description
本發明係有關於粒線體之第二用途，特別係指含有粒線體之組合物及其用於作為膠原蛋白增生促進劑之用途。
按，傷口癒合是一連續且精密之生物反應過程，其大致可分為幾個階段，包含有止血期、發炎期、增生期與組織重塑期，癒合時間之長短會受到外在或內在因素影響，亦即當傷者本身之血液循環不佳、年紀大、糖尿病或遭遇細菌感染，則傷口復原所需時間會增加。
對於傷口修復之治療，臨床上除了需要透過如抗生素等藥物控制傷口之感染狀況，更需要考慮對於其他合併症進行治療，如對於糖尿病患者則須進行血糖控制等。目前研究指出血小板活化後會釋放許多的生長因子，因此投予濃縮血小板血漿（PRP）至需要治療或改善之患部，逸能夠達到修復與改善之效果，然，由於在製備PRP之過程中需要使用抗凝劑，而這些抗凝劑其實會影響傷口的修復。
事實上，當傷口復原情形不佳、難以癒合、反覆發炎甚而持續惡化時，會導致慢性傷口感染，而後可能會發生組織壞死、截肢或危及生命等不良結果；因此，如何能夠促進傷口癒合一直以來都是臨床醫學上所欲解決之問題。
本發明之主要目的係在提供一種粒線體用於促進傷口修復及/或傷口癒合之用途，具體來說，由於粒線體係具有促進纖維母細胞進行細胞遷移並且增加膠原蛋白之表現，是以，藉由投予一定量之粒線體或含有一定量之粒線體的組合物之傷口，係能有效地達到促進傷口修復或傷口癒合之功效，進而能夠減少或改善傷口惡化或持續發炎之情形。
本發明之另一目的係在於提供一種組合物，其係含有粒線體與其他含有生長因子之物，而能大幅提升修復細胞、促進組織再生或改善細胞發炎之效率，以達到降低發炎相關併發症發生的機會。
緣是，為能達成上述目的，本發明係揭露一種組合物，其包含有一粒線體及一血液製品，其中，該血液製品中係含有至少一生長因子，例如富含血小板之血漿（PRP）、血漿、血清、富含血小板纖維蛋白(Platelet-Rich Fibrin)等。
於一實施例中，本發明係揭露一種粒線體用於製備修復傷口或促進傷口癒合之組合物之用途，藉由將該組合物投予一患部，係能夠提升患部癒合之效率。
於本發明之次一實施例中係將粒線體用於製備促進組織再生之組合物之用途，因此，藉由投予一定量之粒線體至一傷處，係能夠抑制或改善傷口處之發炎反應。藉以達到避免產生與發炎相關併發症之功效。
於本發明之一實施例中，該粒線體於該組合物中之含量為至少5~80μg，其中，又以該粒線體於該組合物中之含量為40μg以上為佳。
於本發明之另一實施例中，該粒線體係分離自一細胞，如脂肪幹細胞、間質幹細胞等，並且該細胞係可來自自體，亦可來自異體。
於本發明之一實施例中，該組合物中係更包含有一富含血小板纖維蛋白，其中，該粒線體於該組合物中之含量至少為15μg。
於本發明另一實施例中係揭露一種組合物，其包含有一粒線體及一富含血小板纖維蛋白（PRF），舉例來說，該粒線體之劑量為5~80μg，又以15~40μg為佳，而PRF之濃度為5體積百分比以上者為佳。
本發明係提供一種粒線體用於促進傷口癒合及修復之用途，意即當投予一定量之粒線體或含有其之組合物至一傷口時，其係能夠有效地達到促進傷口癒合及修復之功效，其中，本發明所揭粒線體之投予劑量為1-80μg，如1、2、4、5、10、15、20、25、30、40、50、60、65、70、80 μg等，又以投予劑量為15~40 μg者為佳；並且，為能達到較佳之治療或改善傷口修復或是促進傷口癒合之功效。
更進一步來說，本發明所揭粒線體係能搭配其他組成份製備為一組合物，而所搭配之組成份又以具有生長因子者為佳，又以含有生長因子之血液製品為佳，舉例來說，含有生長因子之血液製品係為富含血小板纖維蛋白（Platelet-rich fibrin，PRF）， 其包含有多種生長因子，如PDGF-AA（15.6-1000 pg/ml）、PDGF-AB（15.6-1000 pg/ml）、PDGF-BB（31.2-2000 pg/ml）、TGF- β1 （31.2-2000 pg/ml)、VEGF（31.2-2000 pg/ml）、EGF（ 31.2-2000 pg/ml)、IGF（31.2-2000 pg/ml）等。
本發明所稱「粒線體」，係指具功能性及結構完整之粒線體，其係得分離自非自體細胞或自體細胞，而細胞種類不限，包含但不限於脂肪幹細胞、間質幹細胞、骨骼肌細胞、肝臟細胞、腎臟細胞、纖維母細胞、神經細胞、皮膚細胞、血球細胞等。
本發明所稱「組合物」，係指至少含有一有效量粒線體之物，如醫藥品、藥用美容品等，並該組合物得依據使用方式或投予方式被製備為不同劑型，例如滴劑、乳劑、膏劑等，且得搭配不同組成份，如生長因子、PRF或是含有上述物質之血液製品等。
本發明所稱「血液製品」，係指以血液作為原料所製備而成之物，並且其內含有一定量之生長因子，例如分離自全血之富含血小板纖維蛋白（PRF）、添加有生長因子之血液、富含血小板之血漿（PRP）、血漿、血清等；而此所指「一定量」乃為本發明所屬技術領域之通常知識者依據周知常識可得之量。
本發明所稱「投予」，係指將本發明所揭粒線體接觸受損部位，而接觸受損部位之方法係不限於塗抹、滴入、注射、導入等，並且，得輔以外力加強或加速細胞吸收，例如超音波、震波、加熱等。
以下，為能證明本發明所揭技術特徵及其所能達成之功效，將茲舉若干實例並搭配圖式作詳細說明如後。
根據研究，人類皮膚纖維母細胞（Human skin fibroblast，CCD-966SK）是常被用於驗證傷口損傷之體外細胞模式，因此以下實例中將以CCD-966SK細胞作為傷口修復之體外細胞模式。
以下實例係以羟基脲（Hydroxyurea，下稱HU）作為細胞增生抑制劑。
實例一：CCD-966SK細胞培養
將CCD-966SK細胞培養於添加10％胎牛血清與/2 mM L-glutamine 之DMEM培養基（Dulbecco’s Modified Eagle’s Medium），並於37℃及5%二氧化碳之培養箱中進行培養，當細胞生長至8-9分滿時，將細胞培養基移除並以磷酸鹽緩衝液進行潤洗後，移除磷酸鹽緩衝液，再加入0.25%胰蛋白酶於37℃下反應5分鐘，而後加入細胞培養基中和胰蛋白酶並以1000rpm離心5分鐘，離心後移除上清液，再加入新的細胞培養液並進行細胞計數，依後續實例之需求進行細胞繼代培養。
實例二：製備富含血小板纖維蛋白
將10 ml之血液樣品置入未含有抗凝劑之離心管內，接著以700 rpm之轉速進行離心，取出上清液，此上清液即為液態之富含血小板纖維蛋白（Platelet-rich fibrin，以下簡稱PRF）。經驗證，PRF中係含有許多種之生長因子，包含有也被驗證過裡面含有多種的生長因子，其中又以PDGF-AA（15.6-1000 pg/ml）、PDGF-AB（15.6-1000 pg/ml）、PDGF-BB（31.2-2000 pg/ml）、TGF- β1 （31.2-2000 pg/ml)、VEGF（31.2-2000 pg/ml）、EGF（ 31.2-2000 pg/ml)、IGF（31.2-2000 pg/ml）。
為了以下實例之用，係將所製備好之PRF以5％體積加入細胞培養基或是所要注射之動物溶劑內，製備為體積百分濃度為5％之PRF溶液。
實例三：粒線體萃取
將人體脂肪幹細胞培養至細胞數量為1.5x10
8個細胞，以杜氏緩衝液（DPBS）沖洗細胞後移除杜氏緩衝液，再加入胰蛋白酶反應3分鐘後，加入幹細胞培養液（Keratinocyte SFM (1X)液體、bovine pituitary extract、10wt％胎牛血清）終止反應，而後，收集細胞後進行離心（600g、10分鐘），移除上清液，加入80毫升之IBC-1緩衝液（緩衝液（225mM甘露醇、75mM蔗糖、0.1mM EDTA、30 mMTris-HCl pH 7.4）至細胞中，進行均質後離心，得到之沈澱物即為粒線體（下稱粒線體沈澱物）。將粒線體沈澱物中加入1.5毫升IBC-1緩衝液及蛋白質分解酶抑制劑，並置於4℃，供以下實例使用。
實例四：細胞遷移試驗（一）
將實例一培養之CCD-966SK細胞以每孔2x10
4cells/0.25ml之細胞數培養於24孔盤中，培養24小時，確認細胞滿度達9分滿，以磷酸鹽緩衝液清洗並更換成不含有10%胎牛血清之細胞培養基培養8小時後，於細胞中間刮出一條固定寬度之直線傷口，將細胞培養液及懸浮之細胞移除而更換成含有10μM之HU的細胞培養液，並分別加入不同濃度（15μg、40μg）之粒線體培養24小時，24小時培養後進行細胞遷移之觀察與分析，結果如圖1A及圖1B所示。
由圖1A及圖1B可知，投予粒線體係能夠有效地促進纖維母細胞往損傷處移動，並且隨著投予粒線體之劑量增加，纖維母細胞移動之速度越快。更進一步來說，如圖1B所示，其係以未經任何粒線體處理之空白組作為計算細胞遷移之基準（100％），計算出經15μg粒線體處理之CCD-966SK細胞，其細胞遷移之比例為149.4±40.9％，並經40μg粒線體處理之CCD-966SK細胞，其細胞遷移之比例為160.4±26.1％。
由本實例之結果顯示，粒線體確實能夠促進纖維母細胞往傷口處移動，達到加速傷口癒合或促進傷口修復之效果。
實例五：膠原蛋白分泌試驗（一）
本實例之流程係如同實例四所示，惟，不同者在於，於添加不同濃度（15μg、40μg）之粒線體培養24小時後，分別收集細胞上清液並以水溶性總膠原蛋白測定試劑盒（Sircol™ Soluble Collagen AssayKit）進行膠原蛋白分泌檢測，結果如圖2所示。
由圖2之結果可知，空白組之膠原蛋白表現量為5.85±0.1μg/ml；經15μg粒線體處理之CCD-966SK細胞的膠原蛋白表現量為15.1±0.3μg/ml；經40μg粒線體處理之CCD-966SK細胞的膠原蛋白表現量為25.3±0.3μg/ml；由此顯示，於模擬細胞受損之情形下，經粒線體處理之CCD-966SK細胞能夠分泌較多膠原蛋白，並且，膠原蛋白之表現量係隨著投予粒線體劑量之增加而上升。
由此實例結果可知，粒線體確實能夠促進纖維母細胞的膠原蛋白表現量增加，以達到加速傷口癒合或促進傷口修復之效果。
實例六：細胞遷移試驗（二）
本實例之流程係大體等同於實例四，惟，不同者在於，於更換成含有10μM之HU的細胞培養液，並分別加入PRF（實例二所製備者）、15μg粒線體及5 vol % PRF、含有40μg粒線體及5 vol % PRFF後，培養24小時，培養完成後再觀察及分析細胞遷移之結果，結果如圖3A及圖3B所示。
由圖3A及圖3B可知，空白組中CCD-966SK細胞之細胞遷移比例為100％；將PRF處理之CCD-966SK細胞的細胞遷移比例為156.8±16.0％；經PRF與15μg粒線體處理之CCD-966SK細胞的細胞遷移比例為185.4±40.9％；經PRF與40μg粒線體處理之CCD-966SK細胞的細胞遷移比例為202.0±30.9％。
由上述結果顯示，雖然單純給予PRF能夠促進纖維母細胞的遷移，但是同時給予PRF及粒線體能夠明顯提升纖維母細胞遷移之比例，並且隨著粒線體劑量增加而能使細胞遷移之效果更佳，意即以一定量本發明所揭粒線體投予至傷口或是受損組織確實具有促進傷口復原之功效。
實例七：膠原蛋白分泌試驗（二）
本實例之流程大體上等同於實例五，惟，不同者在於，係PRF後，培養24小時，培養完成後，再分別收集細胞上清液並以水溶性總膠原蛋白測定試劑盒進行膠原蛋白分泌檢測，結果如圖4所示。
由圖4之結果可知，空白組之膠原蛋白表現量為5.85±0.1μg/ml；經PRF處理之CCD-966SK細胞的膠原蛋白表現量為342.51±15.84μg/ml；經PRF及15μg粒線體處理之CCD-966SK細胞的膠原蛋白表現量為1107.33±87.97μg/ml；經PRF及40μg粒線體處理之CCD-966SK細胞的膠原蛋白表現量為1413.4±158.72μg/ml。
由圖4之結果顯示，經PRF及粒線體共同處理之CCD-966SK細胞，其膠原蛋白表現量係明顯高於單獨經PRF處理之CCD-966SK細胞所分泌者，並且，膠原蛋白之表現量係隨著投予粒線體劑量之增加而上升。由此可知，本發明所揭粒線體投予至傷口或是受損組織確實具有促進傷口復原之功效，並且其促進傷口復原之能力係明顯高於PRF。
實例八：動物試驗
取若干隻8週大之C57BL/6公鼠，分別進行麻醉，再將之背部毛髮剃除，並以75%酒精進行背部消毒後，以消毒後之器具在各公鼠背部建立約直徑1公分之傷口，而後依不同條件進行傷口處理：空白組係為未經任何傷口處理；PRF組係為連續兩天將PRF滴於傷口上；PRF+粒線體組係為將PRF及15μg粒線體連續兩天直接滴於傷口上；並且於給藥過程中，盡量避免滴於其他正常皮膚上，滴完後靜置5-10分鐘確定傷口將處理之組合物吸收。於試驗第0天及第10天拍照觀察各小鼠傷口修復情況，如圖5所示。
由圖5之結果可知，相較於未給藥之空白組來說，不論是單獨投予PRF或是同時投予PRF及粒線體之傷口，其傷口復原之情形係較佳；而相較於單獨投予PRF之傷口復原情形，同時投予PRF及粒線體之傷口恢復狀況更好，意即於試驗第10天時，傷口幾乎已經完全癒合。
實例九：細胞增生率試驗
取以CCD-966SK細胞，於相同之條件下先培養4小時，再分別於細胞培養過程中給予不同劑量（0、1、15、40μg）之粒線體作為細胞培養基之補充劑培養24小時，更換含有阿爾瑪藍（alamar blue）之培養基作用3小時，而後以OD 530/595波長評估各組細胞生長效率，結果如圖6所示。
其中，各組之細胞培養基如下表1所示：
表1：各組細胞培養基組成
| 組別 | 對照組（0μg粒線體） | 粒線體1 μg組 | 粒線體15 μg組 | 粒線體40μg組 |
| 細胞培養基 | DEME/2 mM L-glutamine 10％胎牛血清 | DEME/2 mM L-glutamine 10％胎牛血清 1μg粒線體 | DEME/2 mM L-glutamine 10％胎牛血清 15μg粒線體 | DEME/2 mM L-glutamine 10％胎牛血清 40μg粒線體 |
由圖6之結果可知，分別以各條件培養初始之細胞數量為基礎（1倍），於培養24小時後，未添加粒線體者之細胞生長效率為1.16±0.08倍，添加1μg之粒線體者之細胞生長效率為1.17±0.06倍，添加15μg之粒線體者之細胞生長效率為1.28±0.08倍，添加40μg之粒線體者之細胞生長效率為1.31±0.07倍；於培養48小時後，未添加粒線體者之細胞生長效率為1.77±0.06倍，添加1μg之粒線體者之細胞生長效率為1.77±0.07倍，添加15μg之粒線體者之細胞生長效率為1.90±0.12倍，添加40μg之粒線體者之細胞生長效率為2.20±0.16倍。由圖6之結果顯示，於CCD-966SK細胞培養過程中添加粒線體係能夠觀察提高其生長效率，且隨著粒線體的濃度增加生長的效率也更提升，係能夠達到促進細胞增生、組織再生及修復之功效。
藉由上述實例中之細胞試驗與動物試驗之結果顯示，投予一定量之本發明所揭粒線體或是含有其之組合物至傷口，確實能夠促進傷口癒合，以達到加速傷口修復及避免傷口發炎或相關併發症發生之功效。
無
圖1A係為觀察CCD-966SK細胞以不同劑量之粒線體處理且進行細胞遷移試驗之結果。
圖1B係為統計分析經圖1A中經不同處理之CCD-966SK細胞進行細胞遷移之比例。
圖2係為檢測CCD-966SK細胞以不同劑量之粒線體處理後膠原蛋白分泌量之統計分析結果。
圖3A係為觀察CCD-966SK細胞以含有不同劑量粒線體之PRF處理且進行細胞遷移試驗之結果。
圖3B係為統計分析經圖3A中經不同處理之CCD-966SK細胞進行細胞遷移之比例。
圖4係為檢測CCD-966SK細胞以含有不同劑量粒線體之PRF處理後膠原蛋白分泌量之統計分析結果。
圖5係為小鼠傷口滴入含有不同劑量粒線體之PRF後，觀察其傷口復原情形之結果。
圖6係為CCD-966SK細胞以添加不同劑量粒線體之細胞培養基進行培養，分別計算其細胞生長效率之結果。
Claims (6)
- 一種粒線體及血液製品用於製備膠原蛋白分泌促進劑之用途。
- 如請求項1所述用途，其中，該血液製品中含有至少一生長因子。
- 如請求項2所述用途，其中，該血液製品係為一富含血小板纖維蛋白。
- 如請求項1所述用途，其中，該粒線體之劑量為1~80μg。
- 如請求項1所述用途，其中，該粒線體係分離自一幹細胞。
- 如請求項1所述用途，其中，該血液製品係以血液為原料所製備而成之物。
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| TW111141019A TW202308668A (zh) | 2020-03-20 | 2021-03-19 | 含有粒線體的組合物修復軟骨損傷或改善退化性關節炎的用途 |
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