CN1330316C - 通过施加超高静水压力的移植用生物体组织的处理方法 - Google Patents
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Abstract
本发明提供一种移植用生物体组织的处理方法，是在介质中对可用于移植的动物来源组织施加超高静水压力。通过该处理，在保持构造和生物体力学性质完整的状态下可以将结缔组织从含有细胞的其他成分中分离。
Description
技术领域
本发明涉及一种完成从移植用的生物来源组织的供体细胞的破坏、细胞的死灭和病毒的失活的技术。
背景技术
通过用戊二醛这样的固定剂对生物体组织进行化学处理，或者通过除去生物体组织中的细胞成分，而制作成的移植用组织片，这被广泛地应用于临床。例如，在心脏瓣膜置换术中，异种生物体瓣膜是指用戊二醛固定化猪的心脏瓣膜或牛的心脏瓣膜以降低免疫原性。这种异种生物体瓣膜在抗凝固性方面具有优势，但如果用于年轻人，只有大约5至10年的耐久性，通常适用于60岁以上的高龄人群。欧美从1985年开始，而日本国内也从近几年开始建立了通过冷冻保存的组织库，由尸体提供的冷冻保存同种瓣膜正用于临床。这种同种瓣膜与机械瓣膜比较具有抗血栓性，与异种生物体瓣膜比较具有耐久性，并且与这二者相比较，在抗感染性方面也具有优势。然而，提供数量绝对不够是个大问题。另外，有报道年轻人在移植后比较早期出现功能不全的病例，提示与免疫反应强烈相关。对年轻人有效的Ross手术的特点是，把患者自身的肺动脉瓣置换移植到主动脉瓣的位置上，再用冷冻保存的同种瓣膜重新构建缺损的肺动脉瓣，而移植到主动脉瓣位置上的自身的肺动脉瓣会随着患者的成长逐渐增大。与此相比，更不必说机械瓣膜和异种生物体瓣膜，就连冷冻保存的同种瓣膜也没有成长性，所以，很多儿科患者都需要重新移植。最近为了解决这些问题，出现了关于通过除去同种瓣膜中来源于供体的细胞来减弱抗原性而降低免疫反应的关联性，从而提高瓣膜的耐久性和自体化的研究的报道。美国CryoLife公司发表了通过名为SynerGraft的药液处理的细胞除去方法，报道了在移植后几个月内自体细胞向组织内浸润而自体组织化。另外，德国的Hannover医科大学的Haverich等的小组将作为表面活性剂的TritonX-100或作为蛋白质分解酶的胰蛋白酶(tripsin)溶液用于除去细胞。然而，只通过仅仅利用过去的表面活性剂或者药液的清洗工序，除去组织片内部的细胞成分以及细菌或病毒是通过药液从表面的扩散或浸润进行的，所以不够充分。另外，因为具有这样的限制，在对大块的组织片的处理中，很难完全地除去细胞或细菌、病毒。另外，用化学方法处理时，为了达到充分的效果，有必要提高处理的程度，这样就会产生埋入后的钙化和处理试剂等的问题。而且，通过在硬膜移植中的BSE和CJD的感染已经很明确了，确保移植组织的安全性是极其重要的，可是用现在的化学药液处理并不能保证使组织内的病毒完全失活。另外，在处理过程中的污染所导致的来自移植用组织的感染事故也经常发生。
发明内容
本发明的目的是为了改善如上所述的以往技术的问题点。即，首先第一是完成用药液处理不能完成的除去大块组织内部的细胞成分及细胞、病毒，第二是进行不破坏组织的生物体力学特性的处理过程，第三是简便而快速地对组织进行灭菌。
本发明为了解决上述课题进行了潜心研究，结果是考虑利用高压条件细胞膜的破坏、细菌的死灭、病毒的失活，用作移植用的生物来源组织的处理方法。
本发明提供一种移植用生物体组织的处理方法，其特征在于，通过在介质中对可移植的动物来源组织施加超高静水压力后，在保持构造及生物体力学性质完整的状态下，可以将结缔组织从含有细胞的其它成分分离。
附图说明
图1是表示猪心脏瓣膜组织的组织断面照片。左图是用表面活性剂处理24小时、右图是用高压处理10000个大气压10分钟，用表面活性剂处理时在组织深部内(左下方)细胞核的残存。
图2是表示猪心脏瓣膜组织的组织断面照片。左图是用表面活性剂处理24小时、右图是用高压处理10000个大气压10分钟，二者均没有出现组织松散等，胶原组织保存良好。
图3是表示猪心脏瓣膜叶的断裂强度的处理时间依赖性。左图是用表面活性剂处理、右图是用高压10000个大气压处理，用细胞表面活性剂处理时断裂强度有随着处理时间的延长而增加的倾向，而高压处理时没有出现变化。
图4是表示猪心脏瓣膜叶的弹性率的处理时间依赖性。左图是用表面活性剂处理、右图是用高压10000个大气压处理。用表面活性剂处理时弹性率有随着处理时间的延长而增加的倾向，而高压处理时没有出现变化。
图5是表示预先感染了常见菌的血管组织经高压处理后培养一天的结果。可见用1000个大气压处理的细胞的增殖造成的培养基混浊，而用5000个大气压以上处理时没有出现。
具体实施方式
这里所用的高压是指从5000个大气压到15000个大气压左右的范围，在食品领域的研究中，早已显示出可以灭菌。另外，也有报道造成细菌的破坏及病毒的失活。可却没有综合考虑这些而提出把它作为移植用处理法的先例。全面考虑这些主要因素，而且，重新设定各个主要因素的条件范围以及新的处理温度范围，开发了新的移植用生物来源组织的处理方法。施加超高静水压力可以使用神户制钢所制造的Dr.CHEF等装置。或者也可以使用光工学制造的超高压实验装置。二者都把处理组织放置在小腔内，把液体作为介质，可以施加静水压力达到15000个大气压左右。另外，同时可以通过控制腔外壳的温度来控制腔内的温度。与食品领域不同，移植用生物体组织的情况为了不改变生物体力学特性，有必要防止构成基质的变性，还必须避免施加高压时温度到达冰点以下和40℃以上。药液处理的时候，细胞核的除去是通过细胞表明活性剂的从表面的扩散及浸润，所以除去组织深部的细胞需要长时间处理。对于超高压处理，可以用30分钟这样的短时间完全破坏组织内的细胞并除去。而且，能够进行均质的处理直到细胞片的内部。应用领域及用途：
1)移植用动物来源软组织
例如：来源于脑死亡或心脏死亡的供体的移植用软组织处理。或者来源于猪、牛等异种动物的移植用软组织处理。能够飞跃提高除去细胞成分的清洗处理工序的效率。另外，还能达到大幅度减少具有抗原性的物质的目的。
2)移植用动物来源硬组织
例如：与上述一样，能够进行骨、软骨、牙齿等硬组织处理。
3)医疗用生物组织的处理
例如：能够用于对动物及植物来源的组织中含有细胞的组织的细胞破坏处理。
所述的介质是水、高张液、低张液、表面活性剂溶液、或酶溶液。
实施例
1.从食用猪养殖场买进猪心脏，在4℃条件下搬运。摘出心脏时的热缺血时间为20分钟以内。摘出肺动脉瓣、血管，用Hank’s液清洗。把供体细胞放入神户制钢所制造的Dr.CHEF装置中，在37℃下施加1000～10000个大气压的静水压力10～30分钟。处理后，用PBS液清洗除去。把处理后的标本的组织断面用HE及EVG染色并置光学显微镜下观察，由此进行组织学评价。对于生物体力学特性，是把高压处理后的心脏瓣膜叶切割成宽3mm、长约15mm的短册状，用力学试验机(tensilon)进行拉伸试验，测定断裂时使用的张力。用测定后的切割片的重量和密度求得瓣膜的厚度，通过应力歪斜性来计算弹性率。对于组织的感染性，是在对预先感染了常见菌的血管组织进行高压处理后，通过培养评价细菌增殖能力而进行的。如图1所示，其结果是在通过超高压处理而使脱细胞化的猪肺动脉瓣膜叶组织中，能完全地除去细胞直到组织深部。与之相比，在用表面活性剂处理后的肺动脉瓣膜叶断面，对于数百μm厚的瓣膜叶内，在浸润处理6小时以后细胞核不被染色，可瓣膜叶基部的心肌组织内细胞的核即使在处理24小时以后，距表面1mm以外仍被染色。另外，如图2所示，即使在超高压处理以后也可以保存瓣膜叶内的胶原纤维和弹性纤维。从生物体力学特性来看，正常猪的肺动脉瓣膜叶的密度约为1.05，与血管壁的值大致相等。以瓣膜叶的血管壁切线方向作为基准0°，如果研究力学特性的各向异性，则具有在90°方向上是柔软且微弱的、而在0°方向上是坚硬且强大的特性。如图3及图4所示，在用超高压进行脱细胞化处理时，对力学特性完全没有影响。与此相对，通过表面活性剂处理，强度、弹性管组织进行高压处理，如图4所示，在施加5000个以上的大气压的情况下，无细菌感染发生。
Claims (7)
1.一种移植用生物体组织的处理方法，其特征在于，通过在含水的液体介质中对可用于移植的动物来源组织施加超高静水压力，在保持构造及生物体力学特性完整的状态下可以将结缔组织从包括细胞的其它成分分离，所述超高静水压力为5000-15000个大气压。
2.如权利要求1所述的方法，其特征在于，处理的组织是含有血管、心脏瓣膜、角膜、羊膜或硬膜的软组织。
3.如权利要求1所述的方法，其特征在于，处理的组织是含有骨、软骨、或牙齿的硬组织。
4.如权利要求1所述的方法，其特征在于，处理的组织是含有心脏、肾脏、肝脏、胰脏、骨、脑的脏器或其一部分。
5.如权利要求1所述的方法，其特征在于，施加超高静水压力是在0℃～4℃的温度下实施的。
6.如权利要求1所述的方法，其特征在于，所述的介质是水、高张液、低张液、表面活性剂溶液、或酶溶液。
7.如权利要求1～6中任意一项所述的方法，其特征在于，包含在处理后通过清洗从组织中除去被破坏的细胞的工序。
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| JP2002264470A JP4092397B2 (ja) | 2002-09-10 | 2002-09-10 | 超高静水圧印加による移植用生体組織の処理方法 |
| JP264470/2002 | 2002-09-10 |
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| CN1691950A CN1691950A (zh) | 2005-11-02 |
| CN1330316C true CN1330316C (zh) | 2007-08-08 |
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| JP (1) | JP4092397B2 (zh) |
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| CN (1) | CN1330316C (zh) |
| AU (1) | AU2003262030B2 (zh) |
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| JP5050197B2 (ja) * | 2006-07-31 | 2012-10-17 | 財団法人ヒューマンサイエンス振興財団 | 生物由来スキャフォールドの作製方法 |
| WO2008111530A1 (ja) | 2007-03-09 | 2008-09-18 | National University Corporation, Tokyo Medical And Dental University | 脱細胞化軟組織の調製方法、移植片、及び培養部材 |
| WO2011022369A2 (en) * | 2009-08-18 | 2011-02-24 | Lifecell Corporation | Method for processing tissues |
| WO2012141454A2 (en) * | 2011-04-12 | 2012-10-18 | Hans Biomed. Cor. | Graft materials derived from mammalian cartilage |
| KR101269618B1 (ko) * | 2011-04-12 | 2013-06-05 | 한스바이오메드 주식회사 | 포유류의 연골조직에서 유래한 생체이식재 |
| JPWO2014065017A1 (ja) | 2012-10-26 | 2016-09-08 | 株式会社ジェイ・エム・エス | 人工血管、および、人工血管の製造方法 |
| KR102339700B1 (ko) | 2013-05-07 | 2021-12-14 | 케이엠 바이올로직스 가부시키가이샤 | 입자상 탈세포화 조직을 포함하는 하이브리드 겔 |
| EP3556406B1 (en) | 2013-05-07 | 2021-12-22 | National University Corporation Tokyo Medical and Dental University | Method for producing particulate decellularized tissue |
| JP6433901B2 (ja) | 2013-08-14 | 2018-12-05 | 国立研究開発法人理化学研究所 | 光透過性に優れた生物材料を調製するための組成物およびその利用 |
| JP6271298B2 (ja) * | 2014-02-28 | 2018-01-31 | 国立大学法人 東京医科歯科大学 | 脱細胞組織の製造方法 |
| NL2012797B1 (en) * | 2014-05-09 | 2016-02-24 | Tournois Dynamic Innovations B V | Bone material process. |
| JP6666898B2 (ja) * | 2015-02-27 | 2020-03-18 | 株式会社Adeka | 脱細胞化組織 |
| US11033661B2 (en) | 2015-03-12 | 2021-06-15 | Adeka Corporation | Anti-adhesion material and substitute biomembrane using decellularized tissue |
| CN105944142B (zh) * | 2016-05-09 | 2018-07-13 | 拜欧迪赛尔（北京）生物科技有限公司 | 一种脱细胞肌腱或韧带支架的制备方法 |
| JPWO2018221402A1 (ja) * | 2017-05-30 | 2020-04-30 | 株式会社Adeka | 移植用脱細胞化材料の製造方法及び当該材料を含む生体適合性材料からなる移植片組成物 |
| JP7472142B2 (ja) | 2019-08-01 | 2024-04-22 | Ｋｍバイオロジクス株式会社 | 生体適合性高分子を用いた組織の線維化抑制剤 |
| CN115554472B (zh) * | 2022-09-22 | 2023-08-18 | 舩本诚一 | 一种用于移植的生物组织处理方法 |
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| WO2002014480A2 (en) * | 2000-08-16 | 2002-02-21 | Duke University | Decellularized tissue engineered constructs and tissues |
| WO2002049681A1 (de) * | 2000-12-20 | 2002-06-27 | Auto Tissue Gmbh | Verfahren zur dezellularisierung von fremdmaterial zur herstellung von bioprothesen |
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| US5333626A (en) * | 1991-12-31 | 1994-08-02 | Cryolife, Inc. | Preparation of bone for transplantation |
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| IL139708A0 (en) * | 2000-11-15 | 2002-02-10 | Amiel Gilad | Process of decellularizing biological matrices and acellular biological matrices useful in tissue engineering |
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- 2003-09-09 EP EP03795344A patent/EP1541157B1/en not_active Expired - Lifetime
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| WO2002014480A2 (en) * | 2000-08-16 | 2002-02-21 | Duke University | Decellularized tissue engineered constructs and tissues |
| WO2002049681A1 (de) * | 2000-12-20 | 2002-06-27 | Auto Tissue Gmbh | Verfahren zur dezellularisierung von fremdmaterial zur herstellung von bioprothesen |
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| Publication number | Publication date |
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| JP2004097552A (ja) | 2004-04-02 |
| CA2507498A1 (en) | 2004-03-25 |
| WO2004024170A1 (ja) | 2004-03-25 |
| AU2003262030A1 (en) | 2004-04-30 |
| KR100869685B1 (ko) | 2008-11-21 |
| KR20050047109A (ko) | 2005-05-19 |
| EP1541157A4 (en) | 2009-06-24 |
| US20060110720A1 (en) | 2006-05-25 |
| CN1691950A (zh) | 2005-11-02 |
| JP4092397B2 (ja) | 2008-05-28 |
| CA2507498C (en) | 2012-06-05 |
| EP1541157B1 (en) | 2012-11-14 |
| AU2003262030B2 (en) | 2008-09-11 |
| EP1541157A1 (en) | 2005-06-15 |
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