TW202135838A - 粒線體用於治療及/或預防肌腱受損或其相關疾病之用途 - Google Patents
粒線體用於治療及/或預防肌腱受損或其相關疾病之用途 Download PDFInfo
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- TW202135838A TW202135838A TW110109767A TW110109767A TW202135838A TW 202135838 A TW202135838 A TW 202135838A TW 110109767 A TW110109767 A TW 110109767A TW 110109767 A TW110109767 A TW 110109767A TW 202135838 A TW202135838 A TW 202135838A
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Abstract
本發明係提供一種粒線體之第二用途，其係能夠用於治療肌腱受損相關疾病及預防由肌腱受損所引起之疾病。具體來說，本發明所揭粒線體係具有修復受損之肌腱細胞並且增加肌腱細胞癒合速率之功效，故透過投予一預定量之粒線體或是含有一預定量之粒線體至肌腱受損處，係能夠促進肌腱受損處傷口癒合，達到修復受損肌腱之功效，並進而預防因肌腱受損或發炎所導致關節疾病之發生。
Description
本發明係有關於一種粒線體之第二用途，特別係指一種粒線體用於治療及/或預防肌腱受損或其相關疾病之用途。
按，肌腱係為將骨骼與肌肉連結在一起之密集結締結締組織，能夠將肌肉力量傳遞到骨骼並且使關節運動，因此，於肌肉連接肌腱處或於肌腱連接骨頭處會承受較大機械載荷，導致上述區域較容易受傷而影響到肌腱之功能。肌腱損傷通常會發生在過度使用肌腱、長期重複相似的動作、反覆過度壓迫或發扯肌腱者上，造成肌腱發生撕裂傷，若無法癒合，會使肌腱彈性下降，無法承受拉力，此時，則會發生肌腱病變之情形，而依據發生部位之不同而使該部位無法使力或疼痛，如二頭肌腱炎、肩旋轉肌腱炎、膝蓋髕腱炎、跟腱炎、鈣化性肌腱炎、肱骨外上髁炎、肱骨內上髁炎、韌帶損傷、韌帶發炎等。
肌腱損傷之修復往往需要長時間治療或復健才能慢慢改善，為能增加治療效率，目前臨床上有將再生療法應用於肌腱、韌帶與肌肉損傷修補，如PRP（Platelet-rich plasma，富含血小板的血漿）增生療法，亦即透過將PRP投予至受傷之肌腱部位，能夠有效地促進肌腱受損處癒合，惟，並非所有肌腱受損之患者接受PRP增生療法皆有效，意即當患者本身凝血功能不佳或是肌腱受損過於嚴重時，PRP之治療效果有限。
基於肌腱和韌帶損傷是目前普遍存在之健康問題，因此，目前當務之急係為提供一種有效且能增加治療效率之方法或組合物。
本發明之主要目的係在於提供一種粒線體之第二用途，其係由於粒線體於一定量下係具有修復受損之肌腱細胞、改善或抑制肌腱細胞發炎反應及增加肌腱細胞癒合速率之能力，因此，當一個體具有肌腱受損相關疾病或是病徵時，能夠透過投予一定量之粒線體或含有其之組合物達到治療肌腱受損相關疾病或/及預防因肌腱受損所導致之關節疾病的功效。
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，而能大幅提升修復肌腱細胞或改善肌腱細胞發炎之效率，以達到降低與肌腱受損或發炎相關併發症發生的機會。
為能達成前述目的，於本發明之一實施例中係揭露一種組合物，其包含有一粒線體及一血液製品，而該血液製品中係含有至少一生長因子。
其中，該血液製品係為一富含血小板的血漿（PRP），而該富含血小板的血漿中含有多種生長因子，包含有PDGF-BB、IGF-1、TGF-β1、VEGF、 bFGF等。
舉例來說，本發明所揭組合物係包含有粒線體與富含血小板的血漿，其中，該粒線體之劑量為5~80μg，又以15~40μg為佳，而PRP之濃度為5體積百分比以上者為佳。
于本發明之另一實施例中係將粒線體用於製備治療肌腱受損相關疾病或預防關節疾病之組合物之用途，因此，藉由投予一定量之粒線體至一肌腱受損處，係能夠加速修復肌腱受損且改善肌腱發炎之情形，藉以達到治療肌腱受損關疾病或預防關節疾病之功效。
其中，該粒線體於該組合物之劑量為40μg以上。
為能增進治療肌腱受損相關疾病、預防關節疾病或韌帶損傷相關疾病之功效，於本發明之一實施例中，該組合物更包含有一富含血小板的血漿，其中，該富含血小板的血漿之濃度為5%以上，而又以富含血小板的血漿之濃度為5%以上與該粒線體之劑量為40μg以上所組成之組合物為佳。
於本發明之一實施例中，關節疾病或韌帶損傷相關疾病係由肌腱受損或肌腱發炎所引起者，如關節炎、關節腫脹、韌帶發炎、韌帶受損等。
於本發明之一實施例中，該肌腱受損相關疾病係為肌腱病變、肌腱炎或是任何具有肌腱發炎或腫脹之病徵的疾病，如二頭肌腱炎、肩旋轉肌腱炎、膝蓋髕腱炎、跟腱炎、鈣化性肌腱炎、肱骨外上髁炎、肱骨內上髁炎、韌帶損傷、韌帶發炎等。
於本發明之實施例中，該粒線體係得分離自一自體細胞或一異體細胞，並且，該粒線體係得分離自一幹細胞，例如脂肪肝細胞、間質幹細胞、CD34+造血幹細胞、間質幹細胞、骨隨幹細胞、臍帶幹細胞、羊膜幹細胞、羊水幹細胞、胎盤幹細胞、iPS、神經幹細胞。
本發明係揭露一種粒線體之第二用途，其係能夠用於治療肌腱受損相關疾病及預防由肌腱受損所引起之疾病。具體來說，本發明所揭粒線體係具有修復受損之肌腱細胞並且增加肌腱細胞癒合速率之功效，故透過投予一預定量之粒線體或是含有一預定量之粒線體至肌腱受損處，係能夠促進肌腱受損處傷口癒合，達到修復受損肌腱之功效，並進而預防因肌腱受損或發炎所導致關節疾病之發生。
一般來說，投予之粒線體劑量為5~80μg，如5、15、20、25、30、40、55、60、70、80 μg，並且，粒線體得於搭配不同組成份而製備為一組合物，其中，以粒線體搭配生長因子或含有生長因子之混合物為佳，例如粒線體與PRP或具有生長因子之組成份，如血液製品，混合成為一組合物。
更進一步來說，本發明所揭粒線體係得搭配其他組成份投予至傷處，如粒線體搭配富含血小板的血漿，係能夠大幅提升肌腱受損處之癒合速度。
本發明所稱「組合物」，係指包含有一有效量之粒線體之物，並得依據使用需求或使用方法而被製備為不同型態及劑型，且得搭配不同組成份、載體、賦形劑等。
本發明所指「粒線體」，係分離自一細胞，而所使用之分離技術或方法應要能維持粒線體結構及功能之完整性，依據本發明所屬技術領域者之通常知識者來說，分離技術或方法可為物理性或化學性。
本發明所指「細胞」，係指具有粒線體之細胞，如脂肪幹細胞、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「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的血漿（PRP）、添加有生長因子之血液等；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；舉例來說，本發明所揭PRP內之血小板數目至少為1000000顆/μl， 並其中包含有PDGF-BB（155.2±57.67 ng/ml）、IGF-1（236.07±222.1 ng/ml）、TGF-β1（488.76±240.77 ng/ml）、VEGF（242.29±97.64 ng/ml）、 bFGF（82.24±64.51 ng/ml）之生長因子；又如本發明所指血液製品之生長因子含量係至少為522.54 ng/ml，並其內得具有血小板，數目至少為1000000顆/μl。
本發明所稱「投予」，係指將本發明所揭粒線體接觸受損肌腱部位，而接觸受損肌腱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。
本發明所稱「肌腱受損相關疾病」，係指由肌腱撕裂、彈性下降、受力能力下降所產生之疾病，如肌腱炎，並由於肌腱係存在於肌肉與骨骼之間，因此，肌腱受損相關疾病係會發生於身體中具有肌腱之各部位，臨床上會依據肌腱所處位置而有不同適應症名稱，如二頭肌腱炎、肩旋轉肌腱炎、膝蓋髕腱炎、阿基里斯跟腱病、肩關節鈣化肌腱炎等。
本發明所稱「關節疾病」，其係指由肌腱發炎或受損所產生之疾病，意即當肌腱受損或發炎時，會影響到肌腱所處部位（即關節處）之動作能力，並且會隨著肌腱受損或發炎時間增加，而使關節病變或關節疾病發生機會大幅提升，例如若膝蓋處之肌腱受損，將會影響到膝蓋動作能力，如彎曲、行走等，因此，若能加速修復肌腱受損處，係能夠有效地預防因肌腱長期受損導致之關節疾病發生，如五十肩、退化性關節炎、膝關節炎等。
以下，為能驗證本發明所揭技術特徵之功效，將茲舉若干實例並搭配圖式作詳細說明如後。
下列實例中係以羟基脲（Hydroxyurea，HU）作為細胞增生抑制劑，進行細胞遷移試驗之用。
實例一：培養人類肌腱細胞
將人類肌腱細胞培養於TEN-1生長培養基（Tenocyte Growth Medium，zenbio），而人類肌腱細胞培養前，先於培養皿上以於250μg/ml之基底膠（matrixgel，廠牌: Corning，型號: 354234）進行塗布（coating）處理，處理1小時後，移除基底膠並以磷酸鹽緩衝液進行清洗，接著即可將人類肌腱細胞於已經塗布基底膠之TEN-1生長培養基、37℃培養箱中（5%二氧化碳環境中)進行培養，待人類肌腱細胞長至9分滿時，移除細胞培養基，並以磷酸鹽緩衝液進行清洗，移除磷酸鹽緩衝液，加入0.25%胰蛋白酶在37℃下反應5分鐘，反應結束後加入TEN-1生長培養基中和胰蛋白酶之作用，並以1000rpm離心5分鐘，離心後移除上清液，加入新的TEN-1生長培養基並進行細胞計數，以利進行後續實例之用。
實例二：製備PRP
取新鮮血液至含有抗凝劑之分離管內（廠牌: BD；型號: REF362761），以1500-2000g離心10分鐘後，血液樣品被分為四層，由下至上各層分別為呈紅色之紅血球層、分離膠、呈白色之buffy coat層（含有單核球細胞與血小板）及略為呈現黃色透明之血漿層，收集buffy coat與plasma，收集之buffy coat層與plasma層，並將所收集之buffy coat層與plasma層轉移至另一分離管內，以900g離心10分鐘，離心後將上層2/3之血漿移除，剩餘之產物均勻混勻後即為PRP。
本實例中所製備之PRP內血小板數目每μl大於1000000顆，並包含多種生長因子，如PDGF-BB（155.2±57.67 ng/ml）、IGF-1（236.07±222.1 ng/ml）、TGF-β1（488.76±240.77 ng/ml）、VEGF（242.29±97.64 ng/ml）、 bFGF（82.24±64.51 ng/ml）。
為了以下實例之用，係將所製備好之PRP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PRP溶液。
實例三：製備粒線體
將人體脂肪幹細胞培養至細胞數量為1.5x108
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：肌腱細胞損傷試驗（一）
將實例一中之人類肌腱細胞繼代後培養於24孔盤，以每孔5×104
cells/500μL之濃度培養8小時後，移除上清液並加入磷酸鹽緩衝液進行清洗，而後移除磷酸鹽緩衝液，於每孔加入體積500μL之TEN-1生長培養基並培養8小時，培養後以濃度為300μM之過氧化氫進行處理，反應4小時後將上清液移除，以磷酸鹽緩衝液進行清洗，接著依組別不同而分別以下列給藥條件進行處理：加入PRP、加入粒線體（40μg)、加入與粒線體（40μg)及PRP，而後各組分別進行培養24小時，培養結束後以磷酸鹽緩衝液清洗後，加入含有10% 阿爾瑪藍（alamar Blue）之TEN-1生長培養基（250μL/孔），在37℃環境下培養3~4小時，培養結束後進行螢光訊號測量（Excitation/Emission: 560/590 nm），結果如圖1所示。
由圖1之結果可知，未經過氧化氫處理之人類肌腱細胞（下稱空白組）的細胞存活率為100.4±1.83％；以過氧化氫處理後而未投予粒線體或/及PRP之人類肌腱細胞（下稱H2
O2
組）的細胞存活率為59.97±12.83％；以過氧化氫處理後而投予PRP之人類肌腱細胞（下稱H2
O2
/PRP組）的細胞存活率為80.12±9.19％；以過氧化氫處理後而投予粒線體之人類肌腱細胞（下稱H2
O2
/粒線體組）的細胞存活率為85.22±11.46％；以過氧化氫及粒線體處理後而投予粒線體及PRP之人類肌腱細胞（下稱H2
O2
/PRP/粒線體組）的細胞存活率為99.16±11.83％。
由上述結果顯示，H2
O2
組之細胞存活率係明顯較空白組下降，顯示過氧化氫確實會使人類肌腱細胞受損而導致肌腱細胞死亡；而投予粒線體或PRP之組別的細胞存活率係皆明顯高於過氧化氫組，並且，H2
O2
/粒線體組之細胞存活率係高於H2
O2
/PRP組，亦即粒線體與PRP雖然都可以改善肌腱細胞受損而減少細胞死亡，但是粒線體對於改善肌腱細胞受損之效果係較好；又，H2
O2
/PRP/粒線體組之細胞存活率係幾乎等於空白組，表示若於人類肌腱細胞損傷時，同時給予粒線體與PRP係不僅能夠改善人類肌腱細胞受損情形，更能夠修復受損之人類肌腱細胞，達到治療受損人類肌腱細胞或其相關疾病之功效。
實例五：肌腱細胞損傷試驗（二）
本實例之流程大致等同於實例四，惟，不同者在於除空白組外，各組人類肌腱細胞係先以濃度為300μM之tBHP（叔丁基過氧化氫，tert-butyl hydroperoxide）處理後，再依據給予各組不同給藥條件並進行培養，培養結束後進行螢光訊號測量（Excitation/Emission: 560/590 nm），結果如圖2所示。
由圖2之之結果可知，未經tBHP處理之人類肌腱細胞（下稱空白組）的細胞存活率為93.38±7.65％；以tBHP處理後而未投予粒線體或/及PRP之人類肌腱細胞（下稱tBHP組）的細胞存活率為63.3±16.03％；以tBHP處理後而投予PRP之人類肌腱細胞（下稱tBHP/PRP組）的細胞存活率為76.4±19.55％；以tBHP處理後而投予粒線體之人類肌腱細胞（下稱tBHP/粒線體組）的細胞存活率為90.2±11.09％；以tBHP/粒線體處理後而投予粒線體及PRP之人類肌腱細胞（下稱tBHP/PRP/粒線體組）的細胞存活率為97±2.29％。
由於tBHP組之細胞存活率係明顯較空白組下降，顯示tBHP確實會使人類肌腱細胞受損而導致肌腱細胞死亡；投予粒線體或/及PRP之組別的細胞存活率係皆明顯高於tBHP組，顯示粒線體與PRP皆可以改善人類肌腱細胞經tBHP誘導所產生之損傷情形，其中，又以單獨投予粒線體之改善效果優於單純投予PRP；而當於人類肌腱細胞經tBHP處理而產生受損情形時，同時投予粒線體與PRP係能夠使人類肌腱細胞受損情形幾乎消失，細胞存活率幾乎如同空白組，亦即於人類肌腱細胞受損之情形下，同時給予粒線體與PRP係能夠有效地改善及修復人類肌腱細胞，達到促進或加速治療受損人類肌腱細胞或其相關疾病之功效。
實例六：肌腱細胞遷移試驗
肌腱細胞以每5x104 cells/500μL之細胞數培養於24孔盤中，培養24小時後，於細胞滿度達9分滿時，先以磷酸鹽緩衝液清洗，接著於細胞中間刮出固定寬度之直線傷口，將TEN-1生長培養基及懸浮之細胞移除而更換成含有10μM之羟基脲之混合細胞培養液（90% DMEM/F12+10% TEN-1生長培養基），並依照試驗設計而分別以下列不同條件進行培養24小時：加入40μg粒線體、加入5％PRP、加入5％PRP及40μg粒線體，培養後進行傷口修復癒合之觀察與分析，結果如圖3所示。
由圖3A之結果可知，相較於未進行任何給藥處理之空白組來說，給予粒線體、PRP或PRP及粒線體之人類肌腱細胞具有較好之修復效果，並且，由圖3B之結果可知，空白組之細胞遷移數量為100±27.58顆細胞；粒線體處理組之細胞遷移數量為211.31±42.18顆細胞；PRP處理組之細胞遷移數量為221.6±56.61顆細胞；PRP及粒線體處理組細胞遷移數量為302.06±84.97顆細胞。
由圖3A及圖3B之結果顯示，單純給予粒線體予受損之人類肌腱細胞係能夠促進肌腱傷口癒合，並且其癒合效果係等同甚至優於單純給予PRP者，而若能同時投予粒線體與PRP至受損之人類肌腱細胞，係能使傷口癒合之速率加倍，亦即本案所揭粒線體或含有粒線體之組合物確實能夠促進或加速肌腱傷口癒合，以達到加速修復受損肌腱細胞或是治療肌腱病變之功效。
實例七：動物試驗
將12周大的雌性Sprague-Dawley（SD）大鼠飼養於為22±2℃及濕度介於50%-70%的環境中，並以二型膠原白酶（type 2 collagenase）誘導大鼠形成肌鍵損傷後，再以給予不同條件處理後觀察分析其肌腱強度。
詳言之，先麻醉各組大鼠後，將大鼠肩關節周圍的毛髮剃除乾淨並以70%酒精進行消毒，將二型膠原白酶以針頭及注射器以45度之角度注射至各大鼠喙突（coracoids）和鎖骨（clavicle）之間的棘上肌肌腱（Supraspinatus tendon）上，其中，須以80U/8ul/1 min的濃度與劑量在1分鐘的時間完成注射。進行及完成注射二型膠原蛋白酶之日為試驗第0天，於試驗第0天開始觀察及評估各大鼠肌腱損傷狀況；於試驗第3天分別依據組別給予不同投藥條件，包含有不給藥、給予粒線體（15μg）、給予PRP（5 vol %）、給予粒線體（15μg）及PRP（5 vol %）；於試驗第7天及第14天進行肌腱強度分；其中，本實例中係以立式自動測試儀（JSV-H1000）評估肌腱損傷狀況並分析肌腱強度，意即將試驗完成之各大鼠犧牲後，連同肱骨取下棘上肌腱，並將之設置於立式自動測試儀上，以10mm/min之速率進行測試，直到肌腱斷裂為止之受力即為大鼠肌腱最大強度。本實例之結果如表1及表2所示。
由表1之結果可知，投予二型膠原白酶至第3天時，確實會觀察到肌腱發炎與損傷之狀況，並且，肌腱強度也明顯下降，顯示二型膠原白酶確實會誘導肌腱發炎並腫脹，而至第7天與第14天時，觀察到肌腱發炎及腫脹現象均有改善，肌腱強度也逐漸提升，但仍僅有注射當日（第0天）之一半不到。而如表2所示，試驗第7天及第14天進行肌腱強度之結果可知，投予粒線體及/或PRP之大鼠肌腱發炎及受損情形係較未投予任何藥物者來得佳，並且肌腱強度恢復得亦較好，其中，又以同時與PRP及粒線體者之肌腱強度恢復更佳。
由此結果顯示，本發明所揭粒線體或含有粒線體之組合物，如粒線體與PRP組成之組合物，確實具有改善肌腱發炎或腫脹之能力，並且能夠促進肌腱修復之效率，於短時間內可以使受損肌腱恢復其受力能力及彈性，達到治療或預防肌腱受損相關疾病之功效。
表1：評估肌腱損傷模式大鼠之肌腱強度的結果（僅注射二型膠原白酶且未投予粒線體及/或PRP）
| 試驗天數 | 第0天 | 第3天 | 第7天 | 第14天 |
| 肌腱最大強度（N） | 33.32±2.13 | 5.32±1.21 | 9.13±1.19 | 16.13±2.06 |
表2：各組大鼠於試驗期間進行肌腱強度測試之結果
| 肌腱強度（N） | |||
| 試驗天數 | 第3天 | 第7天 | 第9天 |
| 膠原蛋白酶組（空白組） | 5.32±1.21 | 9.13±1.19 | 16.13±2.06 |
| PRP組 | 12.83±1.28 | 17.96±1.73 | |
| 粒線體組 | 13.27±1.36 | 18.28±1.94 | |
| 粒線體及PRP組 | 15.31±2.21 | 21.36±2.26 |
無
圖1係為人類肌腱細胞經過氧化氫處理後分別以不同投藥條件進行培養後，進行細胞存活率分析之結果。
圖2係為人類肌腱細胞經tBHP（叔丁基過氧化氫，tert-butyl hydroperoxide）處理後分別以不同投藥條件進行培養後，進行細胞存活率分析之結果。
圖3A係為觀察人類肌腱細胞經不同條件處理後進行細胞遷移試驗之結果。
圖3B係為統計分析人類肌腱細胞經不同條件處理後進行細胞遷移試驗之結果。
Claims (10)
- 一種組合物，其包含有一粒線體及一血液製品，其中，該血液製品中至少包含有下列任一生長因子：PDGF-BB、IGF-1、TGF-β1、VEGF及bFGF。
- 如請求項1所述組合物，其中，該血液製品係為一富含血小板的血漿（PRP）。
- 如請求項1所述組合物，其中，該粒線體之劑量為5~80μg。
- 一種將粒線體用於製備治療肌腱受損相關疾病之組合物之用途。
- 如請求項4所述將粒線體用於製備治療肌腱受損相關疾病之組合物之用途，其中，該肌腱受損相關疾病係為肌腱炎。
- 如請求項4所述將粒線體用於製備治療肌腱受損相關疾病之組合物之用途，其中，該肌腱受損相關疾病係具有肌腱發炎或腫脹之病徵。
- 如請求項4所述將粒線體用於製備治療肌腱受損相關疾病之組合物之用途，其中，該肌腱受損相關疾病係為肌腱病變。
- 如請求項4所述將粒線體用於製備治療肌腱受損相關疾病之組合物之用途，其中，該組合物更包含有一富含血小板的血漿。
- 一種將粒線體用於製備預防關節疾病或韌帶損傷相關疾病之組合物之用途，其中，該關節疾病或該韌帶損傷相關疾病係由肌腱受損或肌腱發炎所引起者。
- 如請求項9所述將粒線體用於製備預防關節疾病或韌帶損傷相關疾病之組合物之用途，其中，該組合物更包含有一富含血小板的血漿。
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| WO2019083201A2 (ko) * | 2017-10-24 | 2019-05-02 | 주식회사 엑소코바이오 | 지방줄기세포 유래의 엑소좀을 유효성분으로 포함하는 조성물의 신장 기능 개선 용도 |
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| KR20210035829A (ko) * | 2018-07-22 | 2021-04-01 | 미노비아 테라퓨틱스 리미티드 | 기능성 미토콘드리아가 풍부화된 줄기 세포를 사용한 미토콘드리아 증강 요법 |
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