TW200800240A - Hair follicle graft from tissue engineered skin - Google Patents
Hair follicle graft from tissue engineered skin Download PDFInfo
- Publication number
- TW200800240A TW200800240A TW095143289A TW95143289A TW200800240A TW 200800240 A TW200800240 A TW 200800240A TW 095143289 A TW095143289 A TW 095143289A TW 95143289 A TW95143289 A TW 95143289A TW 200800240 A TW200800240 A TW 200800240A
- Authority
- TW
- Taiwan
- Prior art keywords
- graft
- cells
- hair
- hair follicle
- tissue engineered
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
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Description
200800240 九、發明說明： 【發明所屬之技術領域】 本發明係關於得自組織工程皮膚之毛囊移植物。 【先前技術】 毛髮脫落可因諸多病症而發生，且可能影響到任何人·· 男人、婦女及兒童。毛髮脫落病症包括（但不限於）全禿（亦 即所有頭髮脫落）、普禿（亦即全身毛髮脫落）、斑禿（亦即毛 丈片狀脫落）及雄激素遺傳禿髮（亦即男性型禿髮）。市售治 ⑩ 療儿頭症之藥物包括敏樂定（minoxidil)、非那雄安 (finasteride)、皮質類固醇及蒽三酚。然而，通常當停止用 藥時任何由藥物所致之新生毛髮生長亦會停止。 更主動之毛髮恢復方法包括毛髮移植及頭皮縮減手術。 毛髮移植必須自頭後部切下一全厚頭皮組織條且將該切下 之頭皮組織分割成數百個"毛囊單元移植物”（各含有一至數 根毛髮）且將該等移植物植入藉由在頭皮禿髮部分中製造 刺破創口所形成的接受部位中。毛髮移植不形成新生毛 • 囊’且通常並非所有移植出之毛囊都能成功移植。頭皮縮 減手術（其已不再流行）旨在以手術方式縮減受檢者頭上之 • 儿髮皮膚區域。毛髮移植及頭皮縮減手術皆造價昂貴且令 人疼痛。此外，二者皆有感染及留有疤痕之可能危險。 吾人已知在毛囊中之特定細胞（包括表皮幹細胞及真皮 孔頭細胞）具有誘導毛囊再生之能力。已嘗試探索該等細胞 之誘導能力，包括將真皮乳頭細胞直接注入表皮中及移植 攜帶具有不同增殖及分化特性之表皮細胞的拔除毛髮。以 116598.doc 200800240 往企圖產生毛囊再生之各種嘗試皆未能產生可靠、可再生 及良好美容結果。 【發明内容】 在一實施例中，本發明提供毛髮移植物，其包含（a)包含 組織工程表皮層、組織工程真皮層及毛囊祖細胞的組織工 程皮膚及（b)—腳架，其中該支片至少為2毫米厚。 在其他實施例中，本發明提供製造及使用本發明之毛髮 移植物的方法。
【實施方式】 本發明提供用於形成毛囊之新穎移植物，該移植物包含 一層包含組織工程表皮層及組織工程真皮層之組織工程皮 膚及生物吸收性支片上的毛囊祖細胞。組織工程皮膚本身 適合移植。然而，其極薄且難以使用慣用毛髮移植技術操 作。支片為組織工程皮膚提供牢固性及穩定性，以便可容 易地操作移植物。 可藉由熟習此項技術者已知的任何合適方法製備組織工 程皮膚。舉例而言，人類新生包皮組織可用作在培養基中 操作且接種於諸如膠原蛋白凝膠之支片上的人類真皮纖維 母細胞源以提供組織工程真皮層。可自相同新生組織或拔 除毛囊獲得表皮角質細胞。如美國專利第6,73()，513號、第 M73,6G现、帛6,548，G58號、帛5,968,546鼓其巾所引用 之參考中所揭示（其教示内容以引用的方式併入本文中），可 自拔除毛囊產生組織工程表皮層。可分別製備組織工程真 皮層及組織卫程表皮層，且隨後予以組裝成組織工程皮 116598.doc 200800240 膚，且使毛囊祖細胞分散於其中並合適地爽於兩個組裝層 之間。可不使用支片來製備組織工程真皮及表皮層，例如 藉由Pouliot等人在⑽如/⑽，2〇〇2年6月15曰； 73(11)·· 1751.7及其中所引用的參考中所描述之方法（其教示 以引用之方式併入本文中）。 在一實施例中，將含有毛囊祖細胞之組織工程皮膚置於 合適厚度之生物吸收性支片以形成一構造物，且將其進一 步活體内培養直至活皮膚構造物牢固地附著於生物吸收性 支片上。在另一實施例中，將組織工程真皮層置於生物吸 收性支片上。將毛囊祖細胞置於真皮層上且隨後將組織工 程表皮層皇於毛囊祖細胞頂部上以形成一構造物。或者， 組織工程真皮層可形成於生物吸收性支片上。隨後將毛囊 祖細胞置於真皮層上且將組織工程表皮層置於毛囊袓細胞 頂部。 在另一實施例中’可在雙層支片上製備組織工程真皮 層’該雙層支片包含人造皮膚移植物之底層，諸如Integra Dermal Regeneration Template™(Integra NeuroSciences, Plainsboro, New Jersey)，其中已移除矽橡膠層且以膠原蛋 白上層替代。隨後以真皮纖維母細胞接種膠原蛋白塗層且 活體外培養。 合適地，毛囊祖細胞可為間葉幹細胞、真皮乳頭細胞、 真皮鞘細胞、毛囊表皮幹細胞（亦稱作”凸出”細胞）或其任何 組合。合適地，在置於組織工程皮膚前將祖細胞聚集或凝 結在一起。聚集體之尺寸合適地為約1〇至約500微米，或約 116598.doc 200800240 20至約200微米或約3〇至約6〇微米。 隨後將包含含有毛囊祖細胞及生物吸收性支片之組織工 程皮膚的構造物切成適於植入皮膚之移植物。切割該構造 物以使得形成表皮層面對一方向且支片面對相反方向X之= 植物。使切割物之尺寸及形狀最佳化，以便僅極少浪費戋 完全不浪費構造物，且使最長之向度垂直於組織層。合適 地，將移植物切割成等於單個毛髮移植物、毛囊單元移= 物或改質毛囊單元移植物之尺寸。一般地，該等移植物之 表面積為約1至約9平方毫米，或約2至約8平方毫米，或約4 至約6平方毫米。該厚度合適地約與頭皮皮膚之厚度相同。 合適地，移植物為至少約2毫米厚，或至少約5毫米厚、或 至、、力8耄米厚、或至少約丨〇毫米厚。如本文所用之"厚，，係 用來描述移植物之高度，亦即移植物的2轴。 生物吸收性支片為可含有或承載活細胞且將其固持於所 要組態持續一段時間之無細胞毒性的結構或物質。術語，，生 物吸收性係指人體可將其分解為可自人體排出或在其中 代谢之無毒性副產物的任何材料。用於此支片之合適生物 吸收性材料包括（但不限於）聚（乳酸）、聚（乙醇酸）、聚（碳酸 三亞甲酯）、聚（碳酸二甲基三亞曱基酯）、聚（胺基酸）、酪 胺酸源聚（碳酸酯）、聚（碳酸酯）、聚（己内酯）、聚（對二氧環 己酮）、聚（酯）、聚（酯-醯胺）、聚（酐）、聚（鄰酯）、膠原蛋白、 明膠、血清白蛋白、蛋白質、多醣 '黏多醣、碳水化合物、 葡糖胺聚糖、聚（乙一醇）、聚（丙二醇）、聚（丙烯酸酯）、聚（甲 基丙烯酸1曰）、聚（乙烯醇）、玻糖醛酸、硫酸軟骨素、肝素、 116598.doc 200800240 硫酸皮膚素、多功能蛋白聚糖（versican)、共聚物、摻合物 及聚合物之混合物及含有生物吸收性鍵的寡聚物。 舉例而言，藉由以縮合劑（合適地丨_乙基-3-(3_二曱基胺基 丙基）奴化二醯亞胺（"EDC"))處理將玻糖駿酸轉化為不可之 交聯材料（"HAX")。或者，可藉由酯化（例如，玻糖醛酸之 苄基Sg )將玻糖醛啤轉化成不可溶材料，且將其用以製備該 生物吸收性支片。合適地，因為所得產物隨後當酯鍵水解 時轉化回可溶解之玻糖醛酸，所以使用交酯化交聯ΗΑχ。 醋鍵之水解在幾天之内活體内發生。可使用各種交聯劑， 其包含（但不限於）脂族二胺、二胺基酸酯（諸如離胺酸之烷 基酯）及胺末端化聚（乙二醇）。 可使用（例如）生物吸收性材料之表面改質、接合聚合、共 聚合或將至少一部分與形成該生物吸收性支片中所使用之 生物可吸收材料摻合來使各種分子部分與生物吸收性支片 結合。可與生物吸收性支片結合之部分包括（但不限於）生長 因子、細胞附著結合位點部分、血管生成因子、細胞發信 分子、其他小分子（例如增強毛囊再生之藥物，諸如莫希德 (monoxidil))、糖蛋白（例如硫酸軟骨素、硫酸皮膚素及多功 能蛋白聚糖）、其他生物活性分子或其組合。 使至少一部分與生物吸收性支片結合，可合適地有利於 各種類型毛囊袓細胞之間的經改良結合及/或毛囊再生過 私中之經改良細胞功能、細胞聚集或細胞發生。可在生物 吸收性支片之降解過程中釋放諸如生長因子及血管生成因 子的附著部分且促進血管生成新生毛囊。高分子量部分（諸 116598.doc -10- 200800240 如蛋白質、糖蛋白）及其他生物聚合物（諸如膠原蛋白、昆布 胺酸及纖維結合蛋白）之附著可與生物吸收性支片共價或 靜電結合以合適地提供較大實體整體性、細胞附著能力或 生物活性。 舉例而言’生物活性分子與Hax結構之結合合適地增強 所得支片之效能，例如可使用含有細胞附著結構域胺基酸 序列Arg-Gly-Asp(RGD)之肽的結合來增強真皮乳頭細胞與 支片的附著。
術浯生長因子"係指可促進細胞增殖及細胞分化之天然 存在的蛋白質v生長因子對調控諸多細胞過程而言為重要 的適用於本發明之熟知生長因子包括（但不限於）粒細胞集 落刺激因子r，G-CSF，，）、粒細胞_巨噬細胞集落刺激因子 ("GM-CSF”）、神經生長因子（"NGF")、神經生長素、血小板 何生生長因子（"PDGF")、紅血球生成素（"Ep〇”）、血小扳生 成素（"TPO”）、肌肉抑制素（"GDF_8")、生長分化因子 ("GDF9")、鹼性纖維母細胞生長因子（，，bFGF”或⑺^")、 表皮生長因子（"EGF")、胎盤源生長因子（"plgdf")及肝細 胞生長因子（"hgf")。 類似地，術語”血管生成因子"係指可促進血管生成之天 然存在蛋白質。對本發明而言，合適血管生成因子包括（作 不限於）血管内皮生長因子（"VEGF")、内皮細胞刺激Μ生 士因子（"ESAF”)及存在於創口流體中之任何非有絲分 管生成因子。 在細胞-細胞/細胞·基 術語"細胞附著結合位點部分，，係指 116598.doc -11 - 200800240 :::作用及細胞流通中發揮作用的蛋白質。合適細胞附 者結合位點部分之實例包括（但不限於）整合素、㈣素、細 胞黏附分子（，”）、選擇素、纖維結合蛋白及包括合成纖 維結合蛋白·模㈣結合位_如咖胺基酸序列）之纖維 結合蛋白片段。
術語"細胞發信分子"係指涉及傳輸細胞之間的資訊之化 學物質。自藉由跨越細胞間之間隙、與另一細胞中之受體 相互作用及激發該細胞中之反應來發送信號的細胞中釋放 該等分子。細胞發信分子天然地為支配驗性細胞活性及協 調細胞作狀複雜通信系統之部分。其包括氧化氮及各種 甾類。 術語"生物活性分子"係指具有有利於毛囊再生及成活之 藥理學活性的任何分子。合適生物活性分子可包括（但不限 於）細胞發信促效劑或拮抗劑。 在本發明之另一實施例中，使用類似於慣用毛囊單元所 用技術之技術將移植物手工植入所要植入位點中所形成的 創口中。或者，可使用”黏貼及放置"之接枝方法植入毛髮 移植物與生物吸收性支片的組合。在"黏貼及放置，，方法 中，以中空針或管之尖端刺破皮膚，該中空針或管亦用作 以生物吸收性支片作為外鞘的毛髮移植物之容器。隨後將 管插入創口中且抵靠推桿抽取該管，該推桿防止移植物離 開該管且確保移植物的正確安置。該”黏貼及放置”方法之 修正可使用諸如Choi移植器之工具，其需要在插入管及放 置移植物之前以尖狀器械使皮膚破裂。 116598.doc -12- 200800240 在本發明之另一實施例中’用於為組織工程毛囊祖細胞 接種之皮膚提供足夠厚度的支片與用以形成組織工程真皮 層之支片相同。因此，用於此目的之支片可具有各向同性 結構以使得表面經設計用於接受真皮纖維母細胞及促進其 增殖且成熟為組織工程真皮層，其中該支片之本體為經設 計以在植入時使組織快速向内生長的多孔結構。舉例而 言，可藉由以膠原蛋白或其他合適生物聚合物或細胞相容 物貝塗佈待以真皮細胞接種之高度多孔合成或交聯生物聚 合物支片的表面來製備用於此目的之合適支片。在真皮皮 膚細胞與支片表面匯合後，將毛囊祖細胞或其聚集體置於 真皮組織均等物上部且使其附著。將組織工程表皮層置於 毛囊祖細胞頂部以完成構造物之形成。在浸沒於培養基中 時進一步培養構造物且隨後將其移至空氣介面以使表皮成 熟以完成組織工程皮膚之形成（如在製造組織工程皮膚領 域中的標準實踐）。 在本卷明之另一實施例中，為組織工程毛囊祖細胞接種 之皮膚提供厚度的支片亦可用作提供有利作用之向移植物 添加其他細胞的載具。該等細胞可包括（例如）脂肪細胞、前 月曰肪、浪胞内皮細胞及骨髓細胞。合適地，該等額外細胞 可為自需要毛髮移植物之患者獲得之自體細胞。因此，移 植物之組織工程皮膚組份可得自於新生包皮；毛囊祖細胞 可得自於需要毛髮恢復之患者的頭皮活組織檢I;及補充 細胞視情況亦可得自於患者。使用該等添加細胞（其產生重 要有利生長因子）避免需要上文提及之生長因子或補充其 116598.doc • 13 - 200800240 效用。内皮乡田胞、脂肪細胞及前脂肪細胞可得自於（例如） 自患者腹部脂肪所移除之抽取脂肪且可（例如）藉由抽吸患 者之髖骨而獲得骨髓細胞。 可藉由任何合適技術在所要植入部位中製造創口。舉例 而吕，可使用尖狀器械（諸如解剖刀、套管針或針頭）製造創 口，或藉由雷射或衝壓來之製造創口。合適地，針頭為18 或19號針頭。可藉由適當調節附著於裝備有為此目的製造 之螺紋扣件之手柄的矛型刀片之突出長度來預定創口深 度。舉例而言，特定設計具有四邊矛型尖端之sp9〇& sp9i 刀片（Swann-Morton Surgical，Sheffield，υκ)以允許在形成 供毛囊移植物植入之受體部位時控制深度及角度。 可在植入毛髮移植物之前、期間或之後將保護劑置於創 口中。術語”保護劑"係指用於保護細胞免於移植相關之創 傷或免於由創口癒合之炎性過程的損害之暫時持續的任何 物質。可將許多市售及臨床上可用之物質用作保護劑。合 適保護劑包括（但不限於）膠原蛋白、玻糖醛酸及硫酸軟骨素 溶液。一種合適保護劑為來自其中植入毛髮移植物之受檢 者的自體血清。可藉由自該受檢者抽取少量全血且藉由離 心移除細胞來獲得自體血清。使用自體血清之優點包括經 由與該血清相關之天然凝血特性來為毛髮移植物提供錯 定。同樣，自體血清可含有養分分子及其他自然有利之因 子以進一步為毛囊再生供養。 可使用本發明之移植物及方法在需要新生毛髮之受檢者 的任何區域上形成新生毛囊及新生毛髮。合適地，可利用 116598.doc -14- 200800240 本發明之移植物及方法來在受檢者頭皮或眉毛區域產生新 生毛髮。受檢者可為任何哺乳動物。合適地，受檢者為人 應瞭解本發明在應用中不限於在下文描述中所闡述或在 下文附圖中所說明之構造物細節及組件的配置。本發明可 具有其他實施例且可以各種方式實踐或進行。同樣，應瞭 解本文所使用之習語及術語為描述之目的且不應將其認為 係限制性的。本文使用”包括"、”包含"或„具有，，及其變體意 欲涵蓋其後所列舉之條目及其均等物以及額外條目。 除非文章内容另有明確說明，否則如本說明書及所附申 請專利範圍中所使用，單數形式，，一，，及”該，，包括複數指代 物。除非文章内容另有明確說明，否則亦應注意通常所使 用之術語"或”包括”及/或，，之意義。在本說明書中所提及之 所有公開案、專利及專利申請案表明在本發明所屬領域中 一般技術的水準。所有公開案、專利及專利申請案係以引 用的方式明確地併入本文中，併入程度正如以引用的方式 特定地或單獨地說明各單獨公開案或專利申請案。若本揭 示案與所併入之專利、公開案及參考文獻衝突時，本揭示 案應佔主導。 亦應特定瞭解本文所列舉之任何數字範圍包括下限值至 上限值的所有值，亦即認為在該中請案中明確陳述在所列 舉出之最小值與最大值之間的數值之所有可能組合。舉例 而吕，若濃度範圍表述為1%至50%,則其意欲表示在該說 明書中明確列舉出諸如2%至40〇/〇、10〇/。至30〇/〇或1%至3%等 116598.doc -15- 200800240 的值。 ，供下列實心幫料-步理解本發明。所使用之該等 特定材料、方法及條件意欲說明本發明且不限制本發明之 範疇。 實例 實例1 : 自於新生Φ S包皮組織獲得及培養人類真皮纖維母細 胞。將經培養之細胞接種於具有矽橡膠薄膜襯底之生物吸 收性支片上。在不干擾下部血管之條件下自nu/仙小鼠切除 塊月部皮膚。將經接種之支片植入創口上且原位血供應 維持經接種之支片的發育能力。適當痊癒時間過後，移除 聚矽氧橡膠襯底且將毛囊祖細胞輸送至血管化上皮組織均 等物上。毛囊祖細胞經表皮層遮蓋。使創口癒合且形成新 生毛囊。 實例2 : 人類真皮纖維母細胞及角質細胞係得自新生嬰兒包皮組 織且將其根據由Auger及Germain教授所研發之程序（參見
Pouliot，等人，2002 年 6 月 15 日· 73(11):175 1-7及其引用之參考文獻）培養以產生單獨組織工 程真皮及表皮層。以無菌DMEM/F12培養基無菌沖洗諸如由
Integra Life Sciences，Inc. (Plainsboro，New Jersey)所售之 包含膠原蛋白及葡糠胺聚糖之多孔真皮再生模板（5 mm厚） 且將其在細胞培養恆溫箱中培育直至組織工程真皮層及真 皮再生模板附著。將真皮乳頭細胞置於真皮層頂部且使其 116598.doc -16- 200800240 附著。仔細地將包含一片角質細胞之組織工程表皮層轉移 至經乳頭細胞接種之真皮組織上以完成組織工程真皮層與 表皮層的組裝’其中真皮乳頭細胞夾於其間。進一步培養 該構造物直至其擁有足夠完整性，且隨後根據標準程序將 其與曝硌於空氣之表皮層一起培養以誘導成熟皮膚的形 成。隨後將該構造物轉移至操作間，其中患者經麻醉且以 矛型刀片對其手術形成用於移植物之受體部位，當前毛囊 移植的慣用做法亦是如此。同時，技術人員使用適當放大 工具及手術工具工作將組織工程構造物切割成約〖至2 mm 寬且藉由將表皮表面切片至支片底部製備的"長條"。隨後 將長條切割成1至2 mm寬之塊以產生一般為lxlx5 mm的移 植物。隨後將該等移植物裝入包含管及推桿組件的ch〇i植 入器中。移植物"頭端，，先進入以使得表皮表面與推桿接觸 且支片底部位於管的開口端。技術人員隨後將管插入接受 部位且在推動推桿時移除管以恰如外科醫生所計劃的來放 置忒移植物。適當植入之移植物將使其表皮層與周圍表皮 接觸且支片底部將位於皮下脂肪之層面。活體外起始之毛 囊再生過程將在活體内繼續以使得將在3至6個月内在植入 部位可觀察到新生毛髮。 實例3 : 除在即將與組織工程真皮層結合前將前脂肪細胞及血管 内皮細胞添加至多孔支片外，如在實例2中所描述製備及植 入組織工程移植物。所有其他步驟如上所述。 實例4 : 116598.doc -17- 200800240 除首先以人類膠原蛋白溶解於0.005M乙酸中之溶液塗佈 該支片且隨後將其浸泡且以缓衝培養基沖洗以使膠原蛋白 不溶以外，如在實例2中所描述製備及植入組織工程移植 物。隨後將人類包皮纖維母細胞直接接種於經膠原蛋白塗 佈之支片上且將其培養直至形成組織工程真皮層。如前文 所述進行以乳頭細胞接種且以角質細胞之表皮片分層的隨 後步驟。
116598.doc 18-
Claims (1)
- 200800240 十、申請專利範圍： 1· 一種毛髮移植物，其包含“）具有一組織工程表皮層、一 組織工程真皮層及毛囊祖細胞之組織工程皮膚；及（b)— 支片，其中該移植物至少為約2毫米厚。 2·如請求項1之移植物，其中該毛囊祖細胞係位於該真皮層 與表皮層之間。 3·如請求項1之移植物，其中該移植物之表皮層的表面面積 為約1至約9平方毫米。 4·如請求項1之移植物，其中一部份係與該支片結合。 5.如請求項4之移植物，其中該部分係選自由以下各物組成 之群··生長因子、血管生成因子、細胞附著結合位點部 分、細胞發信分子、多肽、糖蛋白及生物活性分子。 6·如請求項1之移植物，其中其他細胞係與該支片結合。 7·如請求項6之移植物，其中該等其他細胞係選自由以下各 物組成之群··脂肪細胞、前脂肪細胞、血管内皮細胞及 骨髓細胞。 8.如請求項1之移植物，其中該等毛囊祖細胞包含真皮乳頭 細胞。 9·如凊求項1之移植物，其中該等毛囊祖細胞係聚集的。 1〇·種製備毛髮移植物之方法，其包含： a) 將一組織工程真皮層置於一生物吸收性支片上； b) 將毛囊袓細胞置於該組織工程真皮層上； c) 將一組織工程表皮層置於該等毛囊祖細胞上以形成一 構造物； 116598.doc 200800240 , r Μ d) 使該構造物在活體外成熟；及 e) 將該構造物切割成可植入之移植物。 1 L 一種植入毛髮移植物之方法，其包含在一受檢者皮膚中 形成一創口且將如請求項1之移植物植入該創口中。116598.doc -2- 200800240 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式： (無） 116598.doc
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| US8492112B2 (en) | 2011-01-18 | 2013-07-23 | National Taiwan University | Method for the manufacture of microtissues for inducing the growth of a hair follicle |
Also Published As
| Publication number | Publication date |
|---|---|
| AR057629A1 (es) | 2007-12-05 |
| US20100178683A1 (en) | 2010-07-15 |
| US9023380B2 (en) | 2015-05-05 |
| WO2007062386A3 (en) | 2007-11-01 |
| WO2007062386A2 (en) | 2007-05-31 |
| US20070148138A1 (en) | 2007-06-28 |
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