TW214514B - - Google Patents
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- TW214514B TW214514B TW081102394A TW81102394A TW214514B TW 214514 B TW214514 B TW 214514B TW 081102394 A TW081102394 A TW 081102394A TW 81102394 A TW81102394 A TW 81102394A TW 214514 B TW214514 B TW 214514B
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- matrix
- tgf
- sister
- growth factor
- cartilage
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Description
五、發明説明 琎明夕坊術節圈 本發明係有闞治療及恢復软胥不全或損害。更特定言之 •本發明係有Μ治療軟骨不全或損害（可互換地用於本文 )，及有闞包含有一種或多種增殖劑以促進恢復细胞形成 新的穩定軟骨姐嫌之生物可降解之基質。本發明之姐合物 與方法，特別有用於治療骨關節炎及其他疾病及產生软骨 損傷之損傷。 背置技i· 闞節為一般骨酪中之骨相連之方法之一。正常Μ節之贵 之端由Μ節软#姐嫌覆蓋，其允許實用上有闞骨相互間無 摩擦之移劻[L. Weiss 編輯，Cell and Tissue Biology (畑胞班姐嫌生物畢）(Mauchen： Urban and Schvarzenburg, 1988) P.247] ° 闞節软费K特別结構之姐嫌為特性，其由埋於充滿蛋白 多糖、主要地第I型之膠原嫌維、其他蛋白質及水之细胞 間物霣（文獻中通常稱為“軟骨基質^ )中之特定的细胞 經濟部中央櫺準局A工消费合作社印51 (請先間讀背而之注意事項再填窩本頁) ______ —I L___ (软》细胞）姐成[Buck waiter等人“躕節的軟贵：損害 與恢復畑胞”，於 I η -ί u r g and Repair n f the Musruloskelftt. al Soft. Tissues (Park Ridge， 111.: Aierican Academy of Orthopaedic Surgeons Syaposiu», 1987) P.465 ]。软骨姐雄既不被神經支配亦 不被血管或淋巴糸统穿入。然而，於成人之成热闞節中， 在肋软骨下骨姐嫌之下•在贵姐雄與軟骨之間形成狹窄、 逋鑛之板，受神經支配且形成血管。在此骨板之下，母姐 本紙張尺度边用中β B家«準（CNS)T4規怙（2丨0父297公爹1 經濟部屮央榣準局A工消#合作杜印製
pt4Ui-"A 五、發明説明（2) 嫌形成小梁含有骨路於未成热闞節中•闞節软骨由只是原 始之骨小梁加強。關節中新月形姐嫌部分亦由其姐成類似 關節软骨之软费姐成[Beaupre, A等人，Clin. Or thop . Rel. Res. PP.72-76 (1986)]。 於软骨姐雄中可識別兩類型之不全或損客•亦即，完全 厚度（full-thickness)不全及表面不全*此兩不全差異不 只在於物理損害软骨之程度，亦在於各類型損害可引出恢 復反應之性質。 完全厚度損害擴展至肋软#下之骨，且可引起嚴重疼痛 因骨板含感貴神烴末稍。此不全一般由嚴重損傷或在退化 性闞節病之後期如骨闞節炎期間發生。完全厚度損害有時 可導致流血及自肋软#下之骨引發恢復反應[Buck waiter 等人“W節软骨：姐成、结構、對損傷之反應*及促進恢 愎之方法” ，於 Articular C a r t i lags and K n b s Join t. Function: R a s ΐ n Science and Arthrosnopy (New York: Raven Press, 1990) PP. 19-56]形成之恢復姐嫌為有血 管形成之谢維狀型软骨具不充分之生物结構性，而於長期 基礎上無法持縝[Buckwalter等人（1990)前述]。 闞節軟骨姐嫌中之表面不全限於软贵姐纗本身·此種不 全為周知的因彼等不會痊通•且願示無恢復反懕之傾向。 這些不舍在软骨表面可出現為裂隙，（divot或cleft)，或 彼等可於受影響之姐嫌具“蟹肉”外覲。彼等不會如於完 全厚度損害中所見之流血血管（血斑）*表面不全可不具 巳知原因，但通常彼等為等致軟骨姐嫌磨損之機械性失調 (請先閲讀背而之注悉事項#填寫本頁) 裝· 線· 本紙ΛΛ度边用中B B家《準(CNS) T 4規格(210X297公¢) - 4 _ 五、發明説明 Λ 6 Π 6 經濟部屮央標準局貝工消费合作杜印製 之结果。欐械性失調可由 形姐嫌之遷移於闢節内、 節鬆弛，闞節之排列錯亂 所引起。表面不全亦為退 微。因软贵姐嫌並無受神 9 版）（Philadelphia: PP. 266-272]或血管形形 而*雖然無痛*但表面不 度不全。 一般咸信，由於關節软 嫌並無接受充分或適當之 人· “兔子半月形繼維软 式” （30th Ann. Orthop. 1984) ; Webber 等人 * «L· (1985)]。建立理論為软 霣於充分量之典型地存在 恢復剌激劑如生長因素及 巳用來暴K損害之软骨 骨穿人或刮人肋软贵下之 • (1990)，前诚1。不幸 反應•通常與天然發生於 成期維吠型之软骨所觀察 物结構性而無法於長期之 (1990)，前诚 1 〇 對關節之損傷，例如破損之半月 半月板切除術、由破損勒帶之闞 •或骨折斷琨象，或由适傳疾病 化性闢節病如骨闞節炎之早期特 經支配[Ham’s Histology (第 J. Β· Lippincott公司（1987)， 成•所Μ表面不全並不疼痛。然 全並不痊癒且通常變性成完全厚
骨缺少血管 剌激來引出 骨之内在恢 Res . S〇c. Π r t. h 〇 d . R 贵姐嫌内之 於損害之有 血纖維蛋白 於恢復剌激 费Μ引起流 地·姐嫌對 引起流血之 到者可比較 基礎上持鑛 本紙張尺度边用中Ββ家楳毕(CNS)T4規怙（210X297公龙）-5- 先 閲 背 而 之 -注 意 事 項 填 % 木 頁 裝 结構，損害之軟骨姐 恢復反應[Webber等 後能力：细胞培養棋 ,Atlanta, Feb. es. . 2., PP. 36-42 软骨细胞正常地未暴 血管形成之姐嫌中之 凝塊。 之一方法包括經由軟 向[Buckvalter等人 此種外科損傷之恢復 完全厚度不全例如形 ，其顯現不充分之生 [Buckva 丨 ter 等人 訂 線 五、發明説明（4) 經濟部屮央梂準局貝工消1Ϊ-合作社印製 巳單離各種生長因子•且現在可利用供研究及生物《學 之應用[參見例如，Rizzino，A.，De v. Biol.，130. PP. 411-22 (1988)]。這些生長因子之一些•如轉化生長 因子/S (TGF-/S)，已烴報告於活體外胚胎之鼠間充質细胞 中促進軟# -特異性分子，如第II型膠原纖維素及软骨-特異性蛋白多糖之形成[例如Seyedin等人，Proc. H a 1.1 . A pad. Sc ? . USA. 8^., PP. 2267-71 (1985)； Seyedin 等人，J. Biol. Chea.. 2 61. PP. 5693-95 (1986); Seyedin等人，J. Biol. Chem.. 262. PP.1946-1949 (1987)]。 無數病人巳烴診斷為有骨關節炎•亦即為於彼等之M節 软贵中具有退化性不全或損害。無論如何*不管各種方法 聲明可於損害之软骨中引出恢復反應，這些治療無一受到 實霣之應用[Buckwalter等人（1990)，前诚;Knutson等 人· J . R ο η and Joint. S u r g .，6 8 - B . P.795 (198.β)； Knutson 等人 » .1 . Bone and Joint Sure. , 6 7 - B . P . 4 7 (1985) ; Knutson 等人，.Clin. Orthoo. , 191. P. 202 (1984) ； Marquet, Clin. Orthop. ,. 146 P.102 (1980)] 。且此等治療一般只提供暫時性解除。“软贵保護劑”之 全身性使用亦巳聲稱可停止贵闞節炎之渐進並導致解除疼 痛。然而*此等之劑並未顯示促進软骨姐嫌中損窖或不全 之恢復。 至今為止*遭受骨闞節炎之病人巳大部分經由使用«痛 劑及抗發炎劑針對症狀之解除。無可引發闞節软费中表面 (請先閲讀背而之注意事項再塡寫本頁) _-*_ ____ 本紙》•尺度遑用中B因家《準(CNS) T4規格(210x297公*) -6- 214514 Λ 6 Η 6 五、發明説明（5 ) 經濟部中央標準局β工消t合作杜印31 不全之恢復之治療，炊骨常常磨損至肋软骨下骨板。於此 期之病，亦即嚴重骨闞節焱*疼痛之不斷性及重大的機能 危害，常支配著整個闞節被切除而以金羼及/或塑膠之人 造關節取代。最近每年對膝蓋及锊部進行約五十萬個包括 W節切除術及Μ人造闞節取代之手術[參見例如Graves, E. J.,“ 1988 /概要；國立》院出院調査” ，Advarw»Pd Data From Vital and Health Statistics. 1 R . P P · 卜 12 (1990, 6月 19日）]。 因此，對於能引發恢復及再產生穏定之軟骨並防止表面 軟骨不全或損害之漸進成嚴重骨闞節炎之可信賴之治療软 骨不全之方法有需要。 琎明之《Ε要 本發明藉由提供能引發人及其他動物之软母損害之恢復 之有效治療方法與姐合物而解決有W上述之問題。本發明 方法及姐合物之使用亦防止損傷性損害及早期型之骨闞節 炎之漸進*不然會等致具不斷之疼痛及失去有效之闞節功 能之嚴重骨Μ節炎·而専致可能之W節切除術及取代。 一般概述•本發明恢復软骨不全之方法包括Μ本發明姐 合物充填或另外方式修飾软骨不全，姐合物包含（1)生物 可降解之基霣或基霣形成物質（2)增殖劑Μ促進基質與不 全區中恢復细胞之增質•及於某些具《實施例中· （3)向 化劑Μ吸引恢復细胞至基霣與不全區，及（4)於遘當釋放 糸统中之轉化因子，其將於«當時間釋放轉化因子Μ促進 基質或不全區之恢復佃胞之分化（亦即轉化）成能產生新 (請先閲讀背而之注意事項#塡寫本頁) 裝· 訂· 線. 本紙張尺度遑用中B國家《平(CNS)T4規格（210X297公*) -η- 五、發明説明 Λ 6 Η 6 經濟部中央標準局EX工消#合作社印製 的穗定软《姐嫌之软骨细胞。替代地，可將轉化因子於遘 當時間分開地加至不全部位。 發阴夕挂拥銳明 為了本發明可更完全了解，提供下列詳细說明，於說明 中用下列術語。 I Μ節内腔铕檢法--如本文所用，係指用關節内腔鏑 來檢査或對關節做外科術。 軟骨--如本文所用*係指一類型之结締姐嫌含有埋入 於包含膠原嫌絲（主要地第I型膠原伴陳其他软次要型 *例如第IX及XI型），各種蛋白多糖（例如硫酸软骨素 、硫酸角霣素及硫酸皮虜素蛋白多糖）、其他蛋白質及 水之畑胞間質（通常稱為“软母基質）中之軟#细胞。 如本文所用軟贵包括闞節及半月型軟胥。W節软骨蓋住 翮節内之掛部分之表面而允許於闞節中移動而無直接骨 對胥接觸，且因而防止Β損及損窖並列之贵表面。大部 分正常健康之闞節軟贵亦記述為“透明的”，亦即具特 徴之结冰玻璃外觀。半月形软骨通常發現於暴兹於振通 及移動之W節中。此種半月形软骨之位置包括顳骨下頜 的•胸#鎖骨的肩峰鎖讶的，腕及膝關節[Gray's Anatomy (Hew Yorks Bounty Books, 1977)]。 胞黏谏促谁因素--如本文所用，係指媒介细胞黏附 於细胞外物霣之任何化合物或姐合物•包括黏連蛋白及 其他肽，小如包含三肽Arg-Gly-Asp之四肽[ Ruoslathi 等人，Cell. 44. PP. 517-518 (1986) ] 〇 本紙張尺度A用18 »家《毕（CNS) f 4規格（210X297公-8- (請先閲讀背而之注意事項#填寫本頁) 裝- 訂· 線· 3 A 4 * 五、發明説明 如本文所用，係指於活S外向化測定中，能 吸引檷準品中细胞之任何化合物或姐合物，包括肽、蛋 白質、糖蛋白、及葡萄糖胺聚合糖鏈[例如Wahl等人· Proc. Natl. Acad. S f i . US A. 84. PP. 5788-92 (1987); Postlewaite 等人 * .1. R x d . Med. , 165. P P. 251-561 (1987); Moore等人，Tnt. .1. Tiss. Reac. JLL, PP. 30H7 (1989)]。 砍骨细胞--如本文所用•係指能製造軟贵姐纗姐份* 例如第II型软骨繼絲及孅維及蛋白多糖之细胞。 成雄維钿朐生#因隶（FGF) -- FGF多肽之族群之任何 成貝 [G i aenez-Ga 1 1 ego 等人 * Biochem. B i o p h v s .
Res. Commu n.，135. PP. 541-548 (1986); Thonas等人 ，Trends Biochem. Sci. , LL, PP. 8卜84 (1986)]或 經濟部中央橾準局貝工消费合作社印製 其衍生物，可得自 细胞，包括原發性 内皮细胞、成骨细 胞[Thomas等人· 合成及细胞分裂之 G i menez-Ga 1 1 ego J. Clin. Invest. FGFs可依彼等之等 (bFGF) ' FGF 〇 基質--如本文所 足夠大到能令细胞 (請先閱誚背而之注意事項孙填寫本頁) 天然，合成或重姐體來源•其在各種 成嫌維细胞、軟骨细胞、血管及角膜 胞、成肌细胞、.平滑肌及神經膠霣细 1986，前述1之活體外顯示刺激DHA 能力[對於測定，參見例如 等人，1986，前沭；Canalis等人， 81. PP. 1572-1577 (1988)]。 霣點（PU#類為酸性（aFGF)或驗性 用，係指多孔性混合物*為具有孔或 移留於基質之空間之固材或半固體生 本紙張尺度逍用中《困家楳準(CNS)肀4規格(210x297公;》) -9- Λ 6 Η 6 - 五、發明説明（。） 0 (請先閲誚背而之注意事項#填寫本頁) _______- · 物可降解之物質。術語基質包括形成基霣之物質•亦即 可在软骨内不全部位内形成基霣之物質。形成基質物質 可能需加聚合劑來形成基質，如加凝向_至含血孅維蛋 白原之溶液Μ形成向纖維蛋白基質。 携蕹（促有級分Μ }麵--如本文所用·係指包含肽蛋 白質及糖蛋白之,任何化合物或姐合物*其能在活體外剌 激细胞之增殖。活體外分析測定肽、多肽及其他化合物 之増殖（促有絲分裂> 活性乃熟知於技藝界[參見例如 C a n a 1 i s 等人，J. Clin. Invest., PP. 1572- 77 (1 988) ; Gimenez-Ga11 ego等人，Biochen. Biophys. Res. Commun.. 135. PP. 541-548 (1986); Rizzino ， “對轉化生長因子及促有躲分裂之肽之软瓊脂生長分析 ”，於 Methods Enzv no 1 . , 146 A (New York； Academic
Press, 1987), PP. 341 -52; Dickson 等人，“促细胞 分裂劑對於细胞之併入清除劑、從無到有及純粹的DN A 合成之前驅體之誘發作用之分析”於Methods Ε η z V π 〇 1 . , 14 6 A (New York； Academic Press, 1987), 經濟部中央標準局EX工消费合作社印製 PP. 329-40]。測定化合物或姐合物之增殖（促有絲分裂 )活性之一標準方法為活賵外澜定其在软瓊脂中引發非 烴轉化之细胞之固定獮立生長之能力〔例如，Rizzino ，1987 ·前述〕。其他促细哮分裂之活性分析系铳亦為 巳知〔例如 ’ Giiaenez-Gallego 等人 ’ 1986’ 前述 * Cana 1 is 等人，1988，前谏;D ickson 等人，1987，I 冰1。 本紙張尺度逍用中國B家樣準(CNS)肀4規格（210X2974*) - 1 〇 - Λ 6 It 6 〇1 五、發明説明（9 ) (請先閲請背而之注意事項再填寫本頁) 细胞--如本文所用，係指當暴®於適當剌激時* 將分化且轉化成軟骨细胞之細胞。恢復细胞包括間充質 细胞•成纖維细胞、成纖維细胞狀细胞、巨噬细胞及去 分化成軟骨 BL化因素--如本文所用，係指引發恢復细胞之分化成 软骨细胞之任何肽、多肽、蛋白質或任何其他化合物或 姐合物。化合物或姐合物引發或剌激由细胞產生软骨特 異性蛋白多糖及第I型膠原之能力*可藉由已知於技藝 界之活18外分析測定[Seyedin等人，P r 〇 c . Natl.
Acad. Sc i . USA. . &2., PP. 2267-71 (1985)； Seyedin 等人，Path. Immunol . Res. , L. PP. 3β-42 (1987)]° 經濟部t央櫺準局CX工消费合作社印製 轉化生長因素/3 (TGF-/9 )--TGF-/3多肽之族群之任何成 員[Derynck, R.等人》 Nature. 316. PP. 701-705 (1985); Roberts等人，“轉化生長因索- /9，於 Peptide growth factors and t. h r i r rfi^eptors T (B e r 1 i n : S p r i n g e r V e r* 1 a g，1 9 9 0 ) , P . 41 9 ]或其衍生物 ，得自天然、合成或重姐«來源，其於软瓊脂分析中，顯 現剌激正常鼠腎（NRK)细胞生長及形成群落之特性之TGF-/3能力•且由活體外引發或剌激由细胞產生软骨-特異性 之蛋白多糖及第II型膠原之能与之證據•其能引發恢復细 胞之轉化成软毋细胞[Seyedin等人，1985·前jLJ 。 本發明係有闢治療软骨不全或損害之姐合物及方法。本 發明之姐合物包含具有足夠大到能令恢復细胞移留於基霣 本《»尺度遑用中《國家«率(CNS) T4規格（210x297公ft) -H-
»6 五、發明説明（1Q) 之孔之生物可降解之基質。基質亦含有增殖劑Μ剌激基質 中之恢復细胞之增殖。較佳地，增殖劑亦供作向化劑以吸 引恢復细胞至基質。替代地·基質除增殖劑Μ外可含向化 劑。於本發明之一較佳具體實施例中，基質亦含有逋當濃 度之轉化因子，轉化因子為含在裡面或與釋放系统瞄合· 其在適當時間使釋放轉化因子Μ轉化基質中之增殖之恢復 佃胞成能產生穏定之软骨姐嫌之软骨细胞。基質亦可含细 胞黏附促進因子。 有用於本發明之方法與姐合物供充填或另外方式修飾軟 骨中之不全之基質物霣，包括血纖維蛋白原（Μ凝血酶活 化Μ於不全或損害中形成向孅維蛋白）、膠原、瓊脂糖（ Sepharose)、明膠及可形成具有足夠大到令恢復细胞移留 於其中之孔之基質，並令恢復细胞在基«中增殖，且其可 在恢復過程中降解並以软骨代替之任何其他生物可降解之 物質。
有用於本發明之姐合物與方法之基霣可預先形成或可當 場形成•例如薄由聚合化合物與姐合物如血纖維蛋白原K (請先閲讀背而之注意事項#填寫本頁) 經濟部屮央標準局ΕΧ工消ίί·合作社印製 原形填物 成酶 膠，充質 形血 ί 31將基 用凝 原海由之 使加 膝或或解 乃中 括珠質降 成其 包膠物可 形於 質明接均 之， 基、凝生。質液 之原成之物基溶 成膠形霣合 •之 形之他基-混中原 先飾其於之例白 預修何留述施蛋 可經任移上實維 。上，胞或體嫌 質學糖佃，具血 基化脂復質佳為 白}瓊恢物較地 蛋毛如令合之佳 維原質可姐明較 嫌膠物且之發質 血及膠處成本物 成綿凝全姐於質 形海成不質 基 本紙Λ尺度遑用中ΒΒ家楳毕(CNS)TM規格（210X297公;tt) -12- if A 4 f 4 6 » 五、發明説明（n) 經濟部屮央橾準局貝工消费合作社印31 以在使用前不久起始聚合作用。可使用每奄升緩衝水溶液 0.5-5*克之濃度之血嫌維蛋白原。較佳地•使用1毫克 /毫升之媛衝水溶液之血嫌維蛋白原溶液。此血嫌維蛋白 原溶液於不全區之聚合作用產生之基質具足夠大（例如約 50 - 200微米）之孔尺寸使恢復细胞自由的移留於基質並增 殖以充填基質所佔據之不全處之體積。較佳地，在應用前 不久•將充分量之凝血酶加至血纖維蛋白原溶液以令外科 轚在完成聚合作用以前有充分時間來存積物質於不全區。 典型地•凝血梅之濃度應為使聚合作用在幾分鐘（2-4 )内達成者，因暴B软骨於空氣一段長時間，已顯示會引 起損害[Mitchell 等人，J. Bone Joint Surg.，71A· PP. 89-95(1989)]。不應使用遇量之凝血因凝血醻具 裂解生長因子分子而使其失活之能力•可製備每毫升嫒街 水溶液· 10- 50 0單位且較佳地100單位之凝血_溶液供 加至血嫌維蛋白原溶液。於本發明之較佳具體實施例中* 在充填不全處前約200秒，將約20微升凝血酶（100單位/ 毫升）與各奄升之血纖維蛋白原溶液（1奄克/奄升）混 合。如加較低濃度之凝血豳•則聚合作用會發生更慢。要 重視的是，在2 - 4分鐘内達血纖維蛋白聚合作用所需之 凝血酶溶液之量只能大約地提供，因此依瓖境溫度、凝血 1$溶液湛度、血纖維蛋白原溶碎溫度等而定。充填不全處 之凝血»活化之基霣之聚合作用•易於賴由観拥外面的血 嫌維蛋白原溶液之樣品之凝血梅引發之聚合作用來監測。 較佳地•於本發明之姐合物與方法中，由自體的血纖維蛋 (請先閲誚背而之注意事項#填转木頁) 本紙张尺度逍用中as家«毕(CNS)T4規怙（210x297公货）-13- >Λ4 …_ 五、發明説明（12) Λ 6 Η 6 經濟部中央標準局貝工消费合作杜印9i 白原分子亦即來自與待治療之哺乳類同種之血液之血纗維 蛋白原分子形成血纖維蛋白原分子。亦可使用得自其同棰 之非免疫原之血纖維蛋白原。 當用膠原為基質物.質時，可製成充分黏之溶液*例如使 用Collagen-Vliess® ( w膠原毛”）或明膠-血液-琨 合物*而無須聚合劑。膠原基質亦可與K聚合劑活化之血 嫌維蛋白原溶液一起用，K致產生混合之基質。當其他生 物可降解之化合物用來形成基質時•亦可不需要聚合劑。 例如，亦可選擇瓊脂糖溶液*其在39 - 42 υ下為液體基質 溶液•而於35 - 38TC變成固Μ (亦即凝膠將）。瓊脂糖亦 應於致使充填软毋不全之凝膠具有可允許恢後细胞自由地 移留於基霣及不全區之網目尺寸之溻度。 於本發明之姐合物中，可將一種或多種增殖（促有絲分 裂）劑加至基霣溶液。蝤殖劑應以逋當之溻度範圏存在， Κ對於充填不全處之基質中之恢復细胞具增殖之作用（參 見實例節），較佳地*同一試劑懕亦對细胞具向化作用（ 如TGF-/S之情形）；然而，可用唯一地具有增殖作用之因 素。替代地•可使用兩不同之劑•各只具有那些特異性作 用之一（或為向化性或為增殖性）•來產生向化性细胞移 入·接著引發细胞增殖。 有用於本發明之姐合物與方毕供剌*恢復细胞之增殖之 增殖（促有錄分裂 > 劑包括轉化生長因子（"TGFs”）如TGF-ots及TGF-/9S;胰島素狀生長因子（"IGFI");酸性或_ 性成繼維佃胞生長因子（"FGFs”）；血小板衍生之生長因子 (請先閲讀背而之注意事項#填寫本頁) 裝- 訂_ 線. 本紙》尺度逍用中BB家«準(CNS)>P4規格（210x297公*) if Λ Λ 2 4 66 Λπ 五、發明説明（） 1 經濟部中央榣準局Α工消费合作社印製 (”PDGF”）；上皮生長因子（"EGF”）；及造血的生長因子， 如白细胞間素3 ("IL-3") [R izzino, 1987.前述； C a n a 1 i s 等人 » .前诚,19 8 8： Growth factors in biology and medirinp.(生物學與β學中之生長因子）C i b a Foundation SynDnsiui. 116 (New York： John Viley & Sons, 1985) ; Baserga, R.,編著，Cell growth and division (细胞生長與分裂） （Orford: IRL Press, 1985) ; Sporn, M. A .及 Roberts A . B.編著，Peptide growth f a f； t. n r s and their receptors (狀生長因子及其 受體），第 I 與 11 冊（B e r 1 i η : S p r i n g e r - V e r 1 a g . 1990)]。 然而·逭些特別實例並非限制性的。當由活體外 分析细增殖作用證明能剌澂细胞之增資之任何化合物或姐 合物*乃有用的作為本發明增殖劑。此等分析已知於技蕤 界[例如· Canal is等人，1988 ·前述; G i 通enez-Ga 1 1 ego 等人，1986，前诚 » Dickson 等人， 1987 ·前谏;Rizzino, 1987 ·前沭 1。 有用於本發明姐合物與方法供吸引恢復细胞之向化劑包 括，例如TGF-y8 s、FGFs (酸或性）、PDGF、腫掴壊死因 索（例如TNF-α、THF-3)及蛋白多糖降解產物*如葡萄 糖胺聚合糖鏈[Roberts等人（1990) ·前诚i Growth factors ΐ η h ι η 1 ο g γ and nedirine (生物學與 Β 學中之生 長因子） * Π i h a Foundation. Svaposiun. 116 (H e V York· John Viley & Sons» 1985); R. Baserga 編著， Cell growth and division (细胞生長與分裂） (請先閲讀背而之注意事項#填寫本頁) 線- 本紙張尺度遑用中《困家楳準(CNS> T4規格(210X297公;«:) -15- η 6 ^14' 4hli. 五、發明説明 ih 先 閲 背 而 之 注 意 事 項 *孙 填 寫 本 頁 (Oxford: IRL Press, 1985)]。測定多肽與其他化合物之 向化能力之分析巳知於技藝界[例如* Postlewaite等人 * 1987 ·前诚:Wahl等人，1987，前谏;Moore等人， 1989，前诚 1 〇 於本發明之較佳具體貢施例中·基質含TGF-/8為堆殖劑 且為向化劑。特定言之· TGF-；3 I或TGF-/3 II可用為增殖 劑及向化劑。其他TGF-;9型式（例如TGF-y8 III、TGF-/9 IV 、TGF-y9V等）或具TGF-/3活性之多肽[參見Roberts, 1990，前述]，以及將來可被檢測之此物之其他型式及其 他生長因子亦可用有於此目的。供作增殖劑及向化劑之用 ，將TGF-y3分子K較佳地2 - 50奄微克/毫升基質溶液， 且更佳地2 - 10奄微克/亳升基質溶液之濃度溶解或懸浮 於基質。要了解的是可剌瀨恢復佃胞增殖之TGF-/S之較佳 濃度可依待治療之特別動物而異。 經濟部屮央標準局CS工消费合作社印製 轉化因子亦可存在於基質溶液中·致使恢復细胞已移留 於基質後，轉化因子將Μ足Μ促進恢復细胞分化（亦即轉 化）成形成新的穩定軟贵姐嫌之软骨细胞之濃度·釋放於 不全部位内。若轉化因子可抑制或干擾增殖覿之有效性， 則轉化因子釋於之迪時特別重要[參見Roberts等人 (1990) ·前诚 1 〇 有用於本發明之姐合物與方法之轉化因子包括可引發恢 復细胞分化成製$软骨特異性蛋白多糖及第I型曄原之软 骨细胞之任何呔、多肽、蛋白質或任何其他化合物或姐合 物。化合物或姐合物引發或剌激於细胞中產生软骨-特異 本紙》尺度边用中a B家楳準(CNS)甲4規格(210X297公;St) - 1 6 - 2 五、發明説明U 15 Λ 6 Β 6 經濟部屮央樣準局CS工消伢合作杜印製 性蛋白多糖及第I型膠原之能力可用已知於技蕤界之分析 法測定[例如· Seyedin等人，1985，上述;Seyedin等 人，198 7，前诚有用於本發明姐合物與方法之轉化因 子包括，例如TGF-/3s、TGF-cts及FGFs (酸性或鐮性）。 此等轉化因子可單用或併用。此外* TGF-/3可與EG F併用 0 適時之釋放轉化因子可賴由·包装轉化因子於適當釋放糸 统中或與其一起包裝來達成•有用於本發明姐合物與方法 之釋放系統包括脂質體、生物可腐蝕之聚合物、基於碳水 化合物之觸覺小體、化學性聯接於硫酸肝素蛋白多糖之纖 維如膠原或因子自發性地结合於其上之其他此等分子，及 滲透唧简。釋放系统如脂質雅、生物可腐胜之聚合物、具 结合之轉化因子之纖維及含轉化劑之基於碳水化合物之觸 覺小體，可與用來充填不全處之基質溶液混合。此等系统 於技藝界中為已知且可利用[參見P. Johnson及J. G. Lloyd-Jones 編著，Drug Delivery Systems (蔡物釋放 系統）（C h i c h e s t e r，E n g 1 a n d : E 1 1 i s Η 〇 r w ο 〇 d 公司， 1987)]。脂質 IS 可依 Kin 等人於 Biochem. Biophys. Acta. PP. 339-348 (1983)中之方法製備。其他脂質 體製佾方法亦可使用•剌激軟骨细胞合成软骨姐嫌組份可 與轉化因子包含於釋放糸铳。 於本發明之較佳具《實施例中•基質合作為增殖與向化 劑之TGF-/3，及含包裝於釋放糸统作為轉化因子之TGF-/3 。特定言之，TGF-/3 I或TGF-II可用為增殖及向化劑並作 (請先閲讀背而之注意事項再填寫本頁) 裝· 線· 本紙張尺度遑用中Β B家樣爭(CNS) T 4規格(210x297公*) -17- 2 - 五、發明説明（16) Λ 6 It 6 經濟部t央楳準局貝工消费合作杜印製 為轉化因子。其他TGF-/3型式（例如TGF-/3III 、TGF-iS IV、TGF-y9V等）或具TGF-；S活性之多肽（參見Roberts, 19 90，前诫)亦可用於此目的，K及將來可檢测之此物之 其他型式•及其他生長因子。 於較佳具體實施例中，TGF-冷湄度較佳為2 - 50奄微克 /毫升之基質溶液*且較佳地2 - 10¾微克/毫升之基質 溶液，用為增殖劑及為向化劑。實質上較高濃度之TGF-yS 亦Μ後來可釋放之型式存在於基霣姐合物中作為轉化因子 。較佳地，TGF-/S之後來濃度大於20 0毫微克/奄升之基 質，且較佳地大於500奄微克/ ¾升之基質。要重視的是 • TGF-卢引發恢復细胞分化之較佳濃度可隨待治療之特別 動物而異。 必箱交錯暴霣恢復细胞於兩濃度範圍之TGF-/9 *因TGF-/8於相當高湄度（例如大於200 «微克/奄升之基質溶液 )不只轉化恢復细胞成软骨细胞，但亦將抑制恢復细胞之 向化性吸引；而於相當低之濃度（例如2 -10«微克/奄 升），TGF-/9吸引恢復细胞並剌激彼等之增殖•但將不會 引發恢復细胞轉化成產生软骨姐嫌之軟骨细胞。 於本發明之較佳具«實砲例中*為了要得到趙化性及增 殖•接著轉化之順序，TGF-/3 K自由態、未烴包膠之型式 ，及Μ經包膠或其他方式隔離：ί：型式存在於基質中。較佳 地•為了吸引及引發在基霣與不全區中之恢復细胞之增殖 之目的，將TGF-/Q分子以2 -10毫微克/ ¾升之基霣溶液 之濃度溶解或懸浮於基質中。為促進基質中之恢復细胞轉 (請先閲請背而之注意事項#填寫木頁) 裝· 線· 本紙張尺度边用+ BH家«準(CNS)T4規格(210x297公-18- A Λ 1 1 Γ〆 6 » 五、發明説明（17) 經濟部中央櫺準局貝工消费合作社印製 化成软骨细胞，TGF-/9子亦根據Kin等· 1983，前谏中之 方法，Μ大於200奄微克/毫升之基質溶液之溻度•且較 佳地以大於500毫微克/ ¾升之澴度，Κ隔戆於多泡脂質 體中存在於基質內。當受吸引之恢復细胞已移留於基質時 *使負載TGF-J3之脂質體分裂，並開始降解基霣。於基霣 之降解期間，恢復细胞攝食及/或降解脂質體，造成.TGF-足以引發恢復细胞轉化成软骨细胞之濃度釋放。 向化及增殖對轉化澹度之TGF-/9所需之兩階段釋放，亦 可藉合併轉化濃度之TGF-/S與生物可腐蝕之聚合物來達成 。替代地，泵且較佳地•植入之滲透泵可用來控制不全區 及基霣中TGF-/3之濃度。於本發明之此具體》施例中，泵 控制基質中TGF-/3之濃度，亦即泵可以最初之向化及埔殖 剌激壤度及Μ後來之轉化溻度釋放TGF-/9。較佳地，大約 在手術後1至2遇由泵釋放轉化澹度之TGF-J8。轉化因素 之釋故於不全«積内*較好是局限於不全部位中之基質。 本發明組合物中之增殖劑及轉化因子（當使用時），及 應用於生物可降解之基質内之不全部位。彼等之存在因此 限於很局限之部位。如此為之以避免彼等自由注入或输入 Μ節間隙。此種自由输注可產生剌激滑膜细胞而產生Μ節 滲出之不利影響。 黏連蛋白或任何含胺基酸序列Arg-Gly-Asp之其他化合 物•包括小如四肽之肽，可用為佃胞黏附促進因子 [Ruoslathi等人，1986，前诚]，為了促進恢復细胞之最 初黏附於存積於不全部位之基霣。血纖維蛋白及某些B原 (請先W讀背而之注意事項冉塡寫本頁) 本紙張尺度边用中a a家«毕（CNS) Τ4規格（210x297公Λ) -jg- Αί 21 4 i if 66 ΛΒ 五、發明説明（12) 1〇 經濟部中央標準局貝工消#合作杜印製 基霣早巳含此序列[Ruos lathi等人，1986，前诚]。當使 用其他生物可降解之基質時，可將此種细胞黏附促進因子 在使用基質修飾不全處K前，與基質物料混合。含 Arg-Gly-Asp之肽亦可化學性偶聯於基質物料（例如於其 期維或網目），或偶脚於加至基霣之化合物如白蛋白。 上文所述之姐合物有用於動物之軟骨姐撖内之選擇之不 全處或損害處引發軟骨形成。 本發明之方法允許治療動物包括人之耽骨不全*此方法 只單鈍地投藥•且限於局限在受影響之Μ節區。整個治療 可Μ單一之瞄節内腔耪檢法或打開之外科方法進行。 要進行根捶本發明之治療軟骨不全或損害之方法•將不 全或損害確認、準備好Κ根據本發明之生物可降解之基質 姐合物修飾。«殖（促有絲分裂）劑乃Μ剌激於基質與不 全或攢害處之中之恢復细胞增殖之適當溻度存在於基質姐 合物中。於此濃度下，若所用之因子且有有關细胞增殖與 趨化性之合併之作用（如同TGF-/3於2-10毫微克/毫升 之基質），則相同之劑亦可供作向化劑。替代地，兩不同 之劑可存在於基質中，一具特異性增殖作用，而另一者具 特異性向化作用。於替代性具施例中•於不全區以生 物可降解之基質修飾後，可將增殖劑且若須要，及向化劑 直接注射入經基質充填之不全區内。 於《後之步驟中，將於基質中之恢復细胞於迪當時間， 蘗露於足Μ轉化恢復细胞成可產生穩定软骨姐嫌之濃度之 轉化因子。此乃賴由包含含轉化因子之通當釋放系统於如 (請先閲讀背而之注意事項再填寫本頁) 裝- 訂‘ 線< 本紙》尺度遑用中ΒΗ家«準(CHS)>P4規格(210X297公*) . -20- 6 %ν 五、發明説明 上述之基質中 直接注射於烴 生物可降解之 细胞利用。可 促進於此時點 動物之软骨 開之外科單纯 软母不全亦可 經濟部中央標準局B3：工消费合作杜印製 描）、 檷記· 一旦 以促進 及基質 邊緣之 學•以 質〇 除了 化學處 之钦骨 致使彼 或與基 相互作 蛋白或 制凝血 X -光 或藉由 巳鑑定 不全處 物«之 形狀或 更能保 上述機 置亦可 蛋白多 等可與 質之血 用。於 其他生 _活性 來達成。 基質充真 基質於不 將其他因 合成软骨 不全或損 檢査不全 藉由使用 檢査、核 已知於技 不全處， 生理上保 能力。較 將其切去 留本文所 替代地 之不全 全區後 子加至 基質姐 害在闞 或損害 霣腦之 磁共振 e界之 外科翳 留本文 佳地， 下部代 述之治 *轉化 區來输 約1至 釋放系 份》 節內腔 時，可 肋之X 顧像術 任何其 可選擇 所述治 不全處 替具有 療法中 劑可藉由於逋當時間 送。應使在最初植入 2週，轉化濃度可供 統或直接注射，以更 鏡檢檢査 容易地Μ 光斷層攝 (MRI)、 他方法鑑 外醫地修 療法中所 具有或使 平的或淺 所加之溶 關節或在打 目視鑑別。 影術（CAT掃 滑液或血清 定。 飾不全處· 加入之溶液 其成具垂直 的凹面幾何 液及基霣物 械處置可增進基質對不全部位之黏附Μ外， 促進基質黏附，此種處置包括使不全表面上 糖之表面層退化，以暴Κ软骨之膠原級絲， 基霣之眵原纖絲（當使用膠原之基質時）· 纖維蛋白孅絲（當使用血期維蛋白基質時） 軟»表面上之蛋白多糖不僅易於干擾血纖維 .物可降解之基質黏附於软骨，而且局部地抑 。有利地，蛋白多糖降解產物對恢復细胞亦 (請先H1讀背而之注意事項典填寫木頁) 本紙»尺度边用中《Β家楳毕(CNS)T4規格（210X297公¢) -21 - 五、發明説明 可具向化作用[Moore, Λ 6 It 6 R .等人，T n t. - J . T i s s . 經濟部中央橒準局工消费合作杜印製
Reac.. xi(6). PP. 301-307 (1989)]。 再者*基質之黏附於不全之軟骨·亦可薄使用血纖維蛋 白膠（亦即向因子XIII或血纖維蛋白穩定因子）促進，Μ 增進基質之嫌絲之化學结合於不全表面上之软#膠原期絲 [參見Gibble等人，Transfusion. 3018). PP. 741-47 (1990)]。轉毅胺醢胺酶可用於同一作用[參見，例如 Ichinose等人 * J. Biol. Chen.. 2fiS(23) PP. 13411-14 (1990); “轉毅胺釀胺酶* ”編著：V. A. Ha j jar*及L. Lorand, MartinusNijhoff出版者（Boston, 1984)]。其他 可促進细胞外物質之黏附之化合物亦可使用。 根據本發明方法之一具體實施f，將不全處之表面藉由 用滅菌吸收劑薄紙吸乾不全區來乾煉•並將不全處體積充 « Μ滅菌酶溶液歷2 - 10分鐘之一段時間，K降解存在於 砍骨表面上及局部地在由不全處表面約1至2微米深内之 蛋白多糖。各種酶可單用或併用於滅菌嫒衝之水溶液中以 降解蛋白多糖。溶液之出懕加以調節使酶活性最佳。 有用於降解本發明方法中之蛋白多糖之酶包括軟骨素酶 AC、玻尿酸IS、爾蛋白酶、胰蛋白酶、胰凝乳蛋白酶、木 瓜蛋白_、鍵徽蛋白海、基質溶解素（st「omelysin)及 Staph V8蛋白_。特別之»或_之混合物之通當濃度將梅 溶液之活性而定。 於本發明之較佳具«實施例中，以1單位/奄升之濃度 之软#素酶之滅菌溶液充填不全處’並令消化作用進行4 (請先Ml讀背而之注意事項#填寫本頁) 裝< 訂· 線. 本紙》尺度遑用+ β國家《毕(CNS> T4規格(2丨0乂 297公货> -22- 五、發明説明（21) 經濟部屮央標準局貝工消费合作社印製 分鐘。软骨素_ ABC之較佳濃度藉由Μ電子顯微鏑檢査已 經Μ各種湄度之_如實例1中所述處理各種時間之兔W節 軟骨姐織來決定。所用之任何其他酶應Μ致使只有降解表 面蛋白多糖下至約1 - 2微米之深度之濃度下歷一段時間 來使用。 晦溶液所懕用之時間量應保持使佔優勢地於修復區中之 蛋白多糖產生降解為最小。對於以1單位/奄升之濃度之 軟骨素_ ABC ，消化期間多於10分鐘，可造成在不全區外 面之蛋白多糖不必要且可能地有害的降解。再者，消化時 間大於10分鐮過度地增進此遇程之總共時間。以過程之總 時間應保持至最少•尤其是在開放之關節内腔鏡檢法期間 ，因软骨會被暴露於空氣而損害[Mitchell等人（1989)· 前述1 。為了埴些原因，於本發明方法之具體霣施例中包 含由胸促消化之降解蛋白多糖步驟，少於10分鐘之消化時 間為佳*且少於5分鐘之濟化時間最佳。 根據本發明方法•於梅已自不全之表面降解蛋白多糖後 ，W溶液應自不全區除去。梅溶液之去除可藉由使用装有 细的吸引尖端之吸氣器、接著Μ棉質物吸乾來生效。替代 地溶液可單藉由Κ柿質物吸乾去除。 去除_溶液之後•不全處應徹底濟洗•較好以滅菌生理 鹽水（例如0.15MNaCl>洗3辛。然後應將垤清洗之不全 部位乾燥。滅菌妙布或棉霣物可用來乾嫌不全部位。 替代地•或除了酶處理步驟以外，不全部位可K化合物 如血嫌維蛋白膠或轉毅胺醯胺_修飾•促進基霣之黏附於 (請先閩讀背而之注意事項洱填寫本頁) 本紙張尺度边用中a B家榫準(CNS) «Ρ 4規格(210X297公*) -23- A Λ % 息 6 9} - 五、發明説明（22! 經濟部屮央標準局员工消费合作社印31 不全部 之後清 於不全 根據 物修飾 致使形 及向化 統中之 、向化 包裝於 重新塑 软骨细 若基 烴基霣 之較佳 修飾不 毫微克 全區以 殖及翡 於不 形•只 基質充 並结束 若轉 位。於 洗與乾 部位。 本發明 之後， 成平面 劑。用 轉化因 劑（其 或與釋 造细胞 胞之濃 質不含 充填之 濃度於 全處後 /毫升 防止暴 節滲出 全部位 要基霣 填之不 闞節内 化因子 較佳具體實施例中，在不全部位巳在_處理 燥後，將血纖維蛋白膠或轉穀胺皤胺酶應用 之方法•不全 較佳地Μ基霣 。姐合物包含 於此步驟之姐 子。於最佳之 可為與增殖劑 放系铳聯合， 間物質之時， 度釋放轉化因 增殖及向化劑 不全區Κ _送 發明之此具餳 ，將 TGF->9 局 基霣之濃度。 霣滑膜之细胞 0 Μ基質姐合物 巳固化）•且 全部位後•可 腔鏡檐法或開 不以逋當釋放 部位以本 姐合物充 基質物質 合物亦可 本發明方 相同）及 在恢復细 釋放糸统 子。較佳 *則可將 促進恢復 賞腌例中 部注射於 注射應局 於生長因 文所述之 填不全處 及增殖劑 含包裝於 法中，基 轉化因子 胞移留於 Κ可轉化 之姐合物 此等之劑 细胞之趨 。較佳地 基質中Μ 限於經基 子，其可 本發明姐合 至其邊緣， 且若須要* 適當釋放系 質含埸殖劑 ，轉化因子 基質巳開始 恢復细胞成 記述於上。 直接注射於 化性與增殖 •在Κ基質 提供2 - 10 霣充填之不 導致细胞增 修飾之後且於血級維蛋白之情 若須要•已將增殖劑注射於烴 將關節被膜及皮虜切口閉合， 放之外科。 糸统存在於基質中•可將轉化 本紙張尺度遑用中ΒΒ家«準(CNS)T4規格(210X297公货）-24- (請先閲讀背而之注意事項#填寫本頁) __5_
A6 B6 {請先《讀背面之注意事項再瑱窵本筲) 因子於手術後約1 - 2遇，直接加於基霣内，例如賴由注 射或薄由滲透泵，以足K轉化恢復细胞成软贵细胞之瀠度 。較佳地，於發明之此具體實施例中*在手術後約1週， 將TGF-/3直接加入基質，Μ提供高於200毫微克/毫升， 且最佳地方於500奄微克/ ¾升之基質。 本文所述供恢復Μ節软母不全之方法•當不全未擴展至 炊骨下之毋時最有效，本文所述方法亦可用於恢復半月形 軟贵姐嫌不全。 、 為了使本文所述之發明可更完全了解，陳述下列實例。 應該了解的是這些實例乃供例證之目的，而無論如何不應 *被解釋為限制本發明。 窖例1 豳瀨Μ番白名埔之去除 為了促進及增進沿關節軟骨姐嫌之表面不全表面，可將 表面軟骨基質内之蛋白多糖分子_促性地去除*以暴兹膠 原孅絲之網狀姐嫌於外來應用之基質並使恢復细胞通移。 各種蛋白酶降解及葡萄糖胺聚合糖之酶適宜用為此目的· 但應控制出條件Μ提供各《最高之活性。 於此實例中，吾等試驗軟骨素梅ABC (0.5-5單位/毫升 )及胰蛋白_(〇.5 - 4%)使產生蛋白多糖去除之能力。 使用得自剛宰殺之兔（得自當地屠夫）之膝關節。將機械 性產生之表面软册不全暴霹於酶溶液歷4分鐘之期間。再 K吸收劑薄紙去除溶液，並Μ生理邇水檄底清洗不全部位 ，此程序後，立刻將软骨姐織固定於2!S(V/V)(雅積比） 戊二醛溶液（M0.05M二甲胂酸納緩衝，PH7.4)，含 甲 4(210X 297公潘） 25 A6 B6 五、發明説明（) 0.7；Uw/v)(重量體積比）六胺三氯化釕（RHT)， 供姐嫌學 檢査。固定後媒液由1%RHT-四氧化嫌溶液（M0.1M二甲 胂酸納缓衝）姐成。將姐織於分等级之乙酵組中脫水再埋 入Ερο η 812中。切薄片、以醋酸雙氧轴及檸樺酸鉛染色， 再於電子顯微鏑中檢査。於這些切片中· RHT -固定（亦即 沈澱）之蛋白多耱顯現為呈暗色染色之顆粒。去除蛋白多 糖之表面曆不多於1 -2微米厚度之酶濃度定義為最佳的 (_之較深穿透會影響在下面之耽贵细胞）。發現软骨素 酶於約1單位/ ¾升之溻度為最佳活性。胰蛋白酶經發現 於約2. 5%之澹度為最佳活性。其他葡萄糖胺聚合糖_或 蛋白酶之最佳活性可Μ類似方法測定。若緩衝液為非毒性 且其最高緩衝能力發生於接近最大酶活性所須之出值•則 任何嫒衝液皆可與酶聯用。 奮俐2 某S對羌而不令宙之馱附袢 研究薄由控制之_消化表面软骨蛋白多糖，促進基質沿 不全表面黏附之可能性。藉由平面刀切剌於三隻成热之兔 膝W節中製造不全。這些不全處不加處理。不全處Μ 血雄維蛋白基質充填，在充填不全處Μ前約200秒，藉由 混合20微升凝血_溶液（100單位/奄升之含水級街液）與 各奄升之血纖維蛋白原溶液（1奄克/毫升之含水媛衝液 )形成血嫌維蛋白基質。1個月後播牲兔子，檢査膝鼷節 來定血鑲維蛋白黏附於不全部位之程度。將结果與兔子之 不全處在充填Κ血纖維蛋白基霣Μ前，已Μ軟贵素® ABC 處理（1單位/奄升歷4分鐘）者（參見實例3、4與5 ......................................................«...............................ir..............................Sf (請先Μ讀背面之注意事項再填窵本页) _-26 - 甲 4(210X 297公簷） A6 B6 五、發明说明（） )所達到之结果比較。 存積於未以酶處理之不全區之血纖維蛋白基霣，顯現黏 附於不全表面之親和力低。_處理之後，血纖維蛋白基質 之黏著力（間接地賴由躉度黏附之機械強度，亦即《由測 試可Μ鑷子之尖端手動地推開基質之容易度，及間接地藉 由記下在整個實驗中基質成功地保持黏性之不全處之數目 來決定）顯著增加。基霣對於無酶處理之不全表面之低親 和力，可能由於基質黏附被蛋白多糖分子之局部抑制及血 纖維蛋白聚合作用之抑制。這些作用皆可用酶去除沿不全 表面區之表面蛋白多醣來防止。 奮例3 牛苒闵；之腱用於不佘邰位以檯批你》钿胞 «路於不仝面肉之1&1化#刺瀚及引琎恢ariffl胞攢葙 測試各種生長因子在刺激恢復细胞之向化通移至不全區 Μ達成治通不全處之有用性。 所用之生長因子包括a)上皮生長因子（EGF) , b)_性成 纘維畑胞生長因子（bPGF)，c)胰島素狀生長因子I(IGF I)，d)人生長激素（hGH)及e)轉化生長因子-/9 (TGF-/3 ) Μ 5 - 10毫微克/奄升間之濃度。 將埴些因子各個如實例2所述於软骨素_ABC處理及清 洗後，局部應用於膝中產生之不全區。總共使用1〇隻動物 。各生長因子能向化性地吸引或局部性地剌激至不全表面 之恢復细胞之增殖，足K完全蓋住不全表面。然而，畑胞 只存在於不全之表面，並無恢復细胞之增殖足以充填不全 «積之例子。 27 {請先聞碛背面之注意事項再填坏本页) 肀 4(210X297 公省) A6 B6 五、發明说明（） (咸信蛋白多耱降解產物本身，亦即無添加任何其他之 劑*運用充分的向化作用來吸引恢復细胞至不全處。 Moor*e, A. R.等人於[Int. ，1. Tiss. Rp.ar.. XT(b). PP. 30 1 - 1 07, 1 989]中已顯示蛋白多糖降解產物本身具向 化作用）。 g Μ 4. 裁留於生物可降解基瞀中乏半层闵芊之應用 於不令部位以提供恢搛油朐《I路於不令K肉 夕向仆；刺激及引琎体檀钿睢遒箱 因在實例3之條件下局部應用生長因子，無一例引發足 以充填不全體積之恢復细胞增殖，重複實驗使用相同生長 因子，但此次將生長因子截留於生物可降解之基質。所用 之生物可降解之基質為血纖維蛋白、膠原及瓊脂糖，將含 生長因子之充分量之基質應用來完全充填不全體積。在充 填不全處之前約200秒賴由混合20微升凝血_溶液（100單 位/毫升之埋®水溶液：Verona丨酷酸逋緩衝液’ PH7.0)與各奄升之血嫌維蛋白原溶液（1奄克/毫升之緩 衝水溶液：Tris, pH 7.4，0.1M NaCl)形成血雄 維蛋白基霣。對於膠原基質，使用c〇lagen_vliess<ft或明 膠-血液-混合物製造充分黏性之溶液。對於瓊脂糖基霣 ，以璞脂糖之液體溶液於39 - 42 υ下充填不全處。經冷卻 (35 - 28 (請先聞讀背面之注意事項再填寫本頁) 甲 4(210X297 乂 溲） 發明説明 27 A 6 It 6 38¾ ) •瓊脂糖基質於不全處中形成。 30隻兔子（各類型基質及生長因子2隻）用於此實驗。 於存積之基質保持黏附於不全處之所有例中，不全處變成 完全為成纖維细胞狀恢復细胞所留住。此情形經發現早在 手術後8至10天即已存在，直至手術後4遇，於恢復姐嫌 之结構姐嫌中無進一步之變化發生了生物可降解之基 質變成為恢復细胞重新塑造及由鬆散、结締姐織型之细胞 外基質·代替。 此姐嫌之轉化成軟骨姐嫌並未發生。 竇俐5 裁留於牛物1可路鏟夕某«之牛異闵孑夕瘭用 於不令部份批你徇佃睢播玆於末全IS肉 (請先閲請背而之注今" 裝 订_ 經濟部中央標準局κχ工消份合作社印製 夕曲务•刺浦》引％体街《η睢捎葙 接菪於箪二睡段賴由麻蒔的，届铺轉协MMhW孑 播世不令捕枋^_Mh成播明的1»得 不全體積内之基質完全充填Μ恢復细胞接著應用生長因 子·且這些緬胞能重新塑造存積之基質（參見實例4)之 觀察，促使研究引入於包膠型式（例如脂質體）中之轉化 因子（如TGF-/3) ·當基質完全為恢復细胞所留住，開始 重新塑造细胞間结構時*可自其釋放轉化因子。 將TGF-ySM低濃度（例如2:10«微克/奄升）混合於 血纽維蛋白原溶液（1毫克/毫升）内•為了促進最初之 向化及增殖作用之目的。根據KU等人（1983) 之方法 ，亦將TGF-iS包膠於脂質《内。將含TGF-/3之這些脂霣糖 線 本紙Λ尺度逍用中國國家«準(CNS)T4規格（210X297公*) -29- i 9 五、發明説叻（28) Λ 6 Β 6 經濟部屮央標準扃貝工消费合作社印製 Μ當脂質體破裂放出TGF-/3，足以提供每《升血纖維蛋白 原100 - 1000毫微克之較高濃度之濃度加於同一血纖維蛋 白原溶液，供促進恢復细胞之轉化成軟骨细胞及當移留於 血孅維蛋白基質之恢復细胞已開始重新塑造细胞間物質時 之第二階段期間•轉化基質充垓之不全處成软骨之目的。 將其中如實例2製造表面膝關節软骨不全之10隻成热_^ 子，賴由應用此含自由態及脂質體包膠之TGF-冷血潘維蛋 白原之混合物於不全部位來«理。於此系列實驗之各種實 驗中，自由態TGF-/3之濃度維持於由2 - 10毫微克/毫升 之血纖維蛋白原之範圍*而包膠之TGF-/S之澹度加Μ變化 以提供（依TGF-/9自脂質«釋故而定）於100與1000奄微 克TGF-/3/«升之血孅維蛋白原之間之灞度於100亳微克 步驟中。透明软骨姐嫌之形成發生於所有例中之處理部位 。最再現性之结果於200毫微克Μ上之包膠之TGF-yS/奄 升之血纖维蛋白原溶液*且較佳地500奄微克Μ上之TGF-/3毫升之血纖維蛋白原溶液之濃度得到。 g俐R 姐埔鼸仆之時點夕澜亩 於此實驗中，使一姐6隻成热兔子受到膝外科Μ製造如 實例2之表面不全。應用對表面不全恢復之完全處理計畫 •亦即Μ软骨素_ ABC «理（1單元/ «升歷4分鐘）· 接著以含自由態70厂-/3(〜2-10毫微克/«升）及脂質 «I包膠之TGF-/8 (〜800¾微克/«升）之血纖維蛋白基霣 (1«克/奄升之血缅維蛋白原溶液•每奄升血纖維蛋白 本紙張尺度遑用中《國家《準(CNS) T4規格（210x297公；!η -30- (請先閲請背而之注'>;'#8午4,?木頁) 裝' 訂- 線- A6 B6 五、發明説明（） {請先W讀背面之注意事項再填寫本页) 原溶液，20微升100單位/奄升之凝血素）充填不全部位。 於手術後8、10及12天犧牲3雙兔子，刺下之3隻於20、 24及28天播牲。原成纖維细胞狀之恢復细胞姐嫌之轉化成 透明钦骨姐嫌發生於此動物横式之第12天與2 4天之間。此 乃基於姐嫌學檢査決定。於第8至12天，鬆散之嫌維狀恢 復细胞仍存在（懕用之血嫌維蛋白基質為部分或完全地重 新被塑造），而於20天及其後，不全之間隙為部分或完全 為透明软贵姐嫌所充填。 . 啻俐7 •打· 飲得你指葙庠之腱用於诛侏豬《忒 將用於前並兔横式中之實驗程序應用於較大之動物棋式 ，迷你豬。於4隻成热迷你豬（2-4歲大· 80-110磅） ，籍由Μ平面刀於膝蓋骨溝内及内側骨果狀突上切割，創 造表面不全（0.6毫米寬| 0.6奄米深及約10 - 15奄米長） 。再以軟贵素IS ABC處理不全處（1單位/毫升歷4分鐘 *如前述對兔子所用）。除去酶溶液，將不全處乾嫌、Μ 生理鹽水淸洗、再乾埭。不全部位再Μ血孅维蛋白原基質 溶液充填，用於此實驗之血纖維蛋白原基質溶液含每毫升 2 - 6毫撤克之自由態TGP-/3，及每奄升血纖維蛋白原溶 液1500 - 2000毫微克之脂質體包膠之TGF-Θ。在充填不全 處Μ前，如上面兔子實驗中所述，將凝血酶加至基質溶液 〇 手術後6遇犧牲迷你豬，並μ姐嫌學上檢査基質充填之 不全部位。所有部位顯示痊通，亦即於處理部位形成透明 軟贵姐嫌。 甲 4(210X 297公羶） 31
Claims (1)
- 1 ·—棰可用於治療或修復软骨不全或損害之B藥姐合物， 其包括： 生物可降解之基質或形成基質之物«，其係用來修飾 軟骨不全或損害區*及 通當濃度之增殖劑，Μ刺激於基霣及不全或損害區中 之修復细胞之增殖， 與输送系铳聯合之轉化因子*其係以通當濃度存在· 使轉化因子输送至基霣及不全區中之修復细胞時，使修 復细胞轉化成產生软骨姐嫌之软骨细胞。 2. 根據申請専利範圃第1項之醫蕖姐合物，其進一步包括 遇當濃度之向化劑，Κ吸引修復佃胞至基質及不全區。 3. 根據申謫專利範圃第2項之》蕖姐合物，其中向化劑係 選自由TGF-;8(轉化生長因子-/3)、FGF(成纖維细胞生 長子）、PDGF(血小板衍生之生長因子）、THF-a (腫 癯壊死因子-a)、TNF->3 (鼷瘤壞死因子-/9 >及蛋白多 難降解產物所姐成之族群。 4. 根據申謫専利範園第1或2項之翳蕖姐合物*其中增殖 經濟部中央橾準局印裝 (請先閲讀背面之注意事硕再填寫本頁) 劑係遘自由TGF-/3(轉化生長因子-yS)、FGF(成纖維细 胞生長因子）、IGF I(類胰島素生長因子I)、PDGF( 血小板衍生之生長因子）、EGF (上皮生長因子）、 TGF-a(轉化生長因子-a)、 人生長激素及造血生長因 子所姐成之族群。 5· 根據申請專利範圃第1或2項之醫蕖姐合物•其中轉化 甲 4(210X297 公省） A B c D 214514 六、申請專利範® (請先閱讀背面之注意事項再填寫本百} 因子係選自由TGF-yS(轉化生長因子-/3)、TGF-a (轉 化生長因子- a)、FGF (成嫌維细胞生長因子）和其混合 物、和TGF-/3(轉化生長因子-/3)及EGF(上皮生長因子 )之姐合所姐成之族群。 6. 根據申請專利範圍第1或2項之B藥姐合物，其中用來 充填不全區之生物可降解基質係埋自由血纖維蛋白、膠 原、明膠、瓊脂釀或其混合物所姐成之族群。 7. 根據申請専利範圍第2項之B蕖姐合物，其中增殖劑、 向化劑及轉化因子係選自由TGF-/9 (轉化生長因子- /3) 所姐成之族群。 8. 根據申請專利範圃第1或2項之》藥姐合物•其中轉化 因子為一種或多種轉化因子之混合物。 9. 根據申請專利範園第7項之翳藥姐合物，其中於基質中 之增殖劑及向化劑為TGF-/S(轉化生長因子-/3)，其係 JbT2 - 50奄微克/奄升之澹度存在，而轉化因子為與通 當檐送系統聯合之TGF-々（轉化生長因子-/3)，其於基 質中提供大於200 «微克/¾升之濃度。 10. 根據申誚專利範園第1或2項之醫蕖姐合物•其中轤送 系统係遘自由脂霣Μ、生物可腐姓之聚合物、化學聯接 於肝素硫酸酯蛋白多醣之膠原纖維，及基於碳水化合物 之小艚所姐成之族群。 經濟部中央搮準局印裝 11. 一種可用於治療或修復軟骨不全或損害之》藥姐合物， 其包括： 一種纖維蛋白基質，»加凝血_至纖維蛋白原溶液中 -2-甲 4(210X297 公;¥) ^14514 B7 C7 _D7_ 六、申請專利苑® 而形成在纖維蛋白原溶液中濃度為2 -10奄微克/奄升 之TGF-/9 (轉化生長因子-召），及 包膠於脂質體中且在孅維蛋白原溶液中濃度大於2 〇〇 奄微克/奄升之TGF-/3 (轉化生長因子_/3)。 12. 根據申請專利範圍第1或2項之醫蕖姐合物*其進一步 包括细胞附著促進因子，其包括三肽Arg-Gly-Asp 。 13. 根據申請專利範園第1項之Η藥姐合物，其可用於生產 治療軟费表面不全之藥物。 (請先閑讀背面之注免事项再填宵本頁) 經濟部中央標準局印製 甲 4(210X297公廣） 21糾4 第八---三九四號專利申請案 中々補充説明^ ( 81年..i g .月）_ 照片1: 關節表面不全之示意圖。 照片2 : 兔子關節中未經治療且未修復之表面不耷之姐織切片照 片。此切片是在切開不全處12週後取得。 照片3 : 兔子關節中未修復之表面不全之姐織切片照片，呈現一 種典型之结果，其係K軟骨素梅ABC, ( 1單位/毫升、， 歷時4分鐘）處理，Μ去除表面蛋白多釀，再Μ生理食 ~ 鹽水輕洗，1個月後取得此切片。可観察到有一些细晦 _ 附著不全處之表面上*但無软胥再生之證據。 照片4: 兔子關節中未修復之表面不全之姐雄切片照片，呈現一 棰典型之结果，其係Κ軟骨素_ ABC (1單位/奄升* 歷時4分鐘）處理，再根據本案實例3之步驟，M5-1〇奄微克/毫升之濃度局部施予生長因子TGF-/3至不全 處，3 - 4週後取得此切片。在不全處之表面上可觀察 到细胞*但细胞之增殖不足以填滿不全處。未觀察到不 全處有修復現象。 .- * * · 照片5 : 兔子醞節中未修復之表面不全之姐嫌切片照片，圼現一 種典型之结果•其係K软骨素酶ABC (1單位/毫升· 歷時4分鐘）處理，再根據本案實例4之步驟含5 -10毫微克/毫升TGF-/3之纖維蛋白基霣填充不全處， 3 - 4週後取得此切片。此基質重新成型，且被鬆散之 结締姐織取代，但未観察到有軟骨形成。 照片6和7 :二隻不同兔子表面不全充分修復處之組織切片哼片，其 係Κ软骨素酶ABC處理，再根據本系實例5之步驟，Κ 含2 -10毫微克/毫升之自由TGF-y8和〜800毫微克/ sh\0008.g 214514 .毫升包覆於脂質體中之TGF-/3之纖維蛋白基質填充不# 處，6週後進行檢視。該等照片顯示不全處已完全被成 热透明軟骨姐織填滿*恢復軟骨層之完整。 照片8和9 :二隻不同兔子表面不全充分修復處之組織切片照片，其 係Μ照片6和7中所述之方法治療二隻兔子，一年後進 行檢視。該等照片顯示成熟透明軟骨於進行治療一年後 仍繼纊存在。 * 照片10和u :迷你豬膝關節充分修復後之表面不全處之姐織切片照片 ' ，其係Κ本案實例7之步驟處理，5 - 6週後進行檢辑 __ 。該等照片呈現二隻不同迷你豬中三個不同不全處之结 果。其係以軟骨素_ ABC (1單位，歷時4分鐘）處理 不全處，再Μ含2 - 6毫微克/毫升之自由TGF-/3和〜 800毫微克/毫升包覆於脂質體中之TGF-/3之纖維蛋白 基質填充。該等不全處已被成熟透明軟骨組織填滿。 sh\0008 · g
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|---|---|---|---|
| US07/648,274 US5206023A (en) | 1991-01-31 | 1991-01-31 | Method and compositions for the treatment and repair of defects or lesions in cartilage |
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| TW214514B true TW214514B (zh) | 1993-10-11 |
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| TW081102394A TW214514B (zh) | 1991-01-31 | 1992-03-28 |
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| KR (1) | KR100235391B1 (zh) |
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| TW (1) | TW214514B (zh) |
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-
1991
- 1991-01-31 US US07/648,274 patent/US5206023A/en not_active Expired - Lifetime
-
1992
- 1992-01-28 NZ NZ260125A patent/NZ260125A/en unknown
- 1992-01-29 IL IL10079992A patent/IL100799A/en not_active IP Right Cessation
- 1992-01-30 AT AT92906351T patent/ATE121943T1/de not_active IP Right Cessation
- 1992-01-30 AU AU14128/92A patent/AU667032B2/en not_active Ceased
- 1992-01-30 JP JP4505748A patent/JPH06505258A/ja not_active Withdrawn
- 1992-01-30 HK HK98105693A patent/HK1006416A1/zh not_active IP Right Cessation
- 1992-01-30 ES ES92906351T patent/ES2072144T3/es not_active Expired - Lifetime
- 1992-01-30 KR KR1019930702276A patent/KR100235391B1/ko not_active Expired - Fee Related
- 1992-01-30 CA CA002101556A patent/CA2101556C/en not_active Expired - Fee Related
- 1992-01-30 DK DK92906351.9T patent/DK0569541T3/da active
- 1992-01-30 WO PCT/US1992/000840 patent/WO1992013565A1/en not_active Ceased
- 1992-01-30 EP EP92906351A patent/EP0569541B1/en not_active Expired - Lifetime
- 1992-01-30 DE DE69202332T patent/DE69202332T2/de not_active Expired - Fee Related
- 1992-01-31 ZA ZA92726A patent/ZA92726B/xx unknown
- 1992-01-31 CN CN92101431A patent/CN1056083C/zh not_active Expired - Fee Related
- 1992-03-28 TW TW081102394A patent/TW214514B/zh active
- 1992-11-23 US US07/979,904 patent/US5368858A/en not_active Expired - Lifetime
-
1993
- 1993-07-28 IE IE920309A patent/IE67515B1/en not_active IP Right Cessation
- 1993-07-30 NO NO932748A patent/NO307735B1/no not_active IP Right Cessation
-
2004
- 2004-04-07 JP JP2004113680A patent/JP2004230184A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ZA92726B (en) | 1992-11-25 |
| AU1412892A (en) | 1992-09-07 |
| DE69202332T2 (de) | 1996-01-04 |
| JPH06505258A (ja) | 1994-06-16 |
| DK0569541T3 (da) | 1995-07-10 |
| CN1064813A (zh) | 1992-09-30 |
| NO932748D0 (no) | 1993-07-30 |
| ATE121943T1 (de) | 1995-05-15 |
| NZ260125A (en) | 1997-07-27 |
| US5206023A (en) | 1993-04-27 |
| NO307735B1 (no) | 2000-05-22 |
| WO1992013565A1 (en) | 1992-08-20 |
| DE69202332D1 (de) | 1995-06-08 |
| IL100799A0 (en) | 1992-09-06 |
| HK1006416A1 (zh) | 1999-02-26 |
| CA2101556C (en) | 2002-07-23 |
| NO932748L (no) | 1993-09-29 |
| AU667032B2 (en) | 1996-03-07 |
| IE920309A1 (en) | 1992-07-29 |
| JP2004230184A (ja) | 2004-08-19 |
| CN1056083C (zh) | 2000-09-06 |
| IL100799A (en) | 1996-10-16 |
| CA2101556A1 (en) | 1992-08-01 |
| EP0569541A1 (en) | 1993-11-18 |
| KR100235391B1 (ko) | 1999-12-15 |
| US5368858A (en) | 1994-11-29 |
| IE67515B1 (en) | 1996-04-03 |
| ES2072144T3 (es) | 1995-07-01 |
| EP0569541B1 (en) | 1995-05-03 |
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