JP2016193896A - Platelet separation substrate and production method of platelet preparations - Google Patents
Platelet separation substrate and production method of platelet preparations Download PDFInfo
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本発明は、巨核球と血小板とを含む細胞懸濁液から血小板を分離するための分離基材および当該分離基材を用いた血小板製剤の製造方法に関する。 The present invention relates to a separation substrate for separating platelets from a cell suspension containing megakaryocytes and platelets, and a method for producing a platelet preparation using the separation substrate.
血小板製剤は、骨髄抑制や急性白血病、再生不良性貧血や骨髄異形成症候群等の患者に投与するものである。現行の血小板製剤は、ボランティアからの献血に完全に依存している。しかしながら、超高齢化社会の到来に伴い献血可能年齢層の人口が減少し続けており、２０２７年には日本における必要献血延べ人数が約５４５万人に対して約８５万人の献血延べ人数が不足すると予測されている（非特許文献１）。血小板の保存期間は約４日間とされており、血小板製剤を長期且つ大量に備蓄することは極めて困難であり、継続的に新鮮な血小板製剤を得ることが強く望まれている。つまり、現行の献血に完全に依存した血小板製剤では、将来的な血液の供給不足を解消することは極めて困難である。 The platelet preparation is administered to patients with myelosuppression, acute leukemia, aplastic anemia, myelodysplastic syndrome, and the like. Current platelet products rely entirely on blood donation from volunteers. However, with the advent of a super-aging society, the population of age groups that can donate blood continues to decline. In 2027, the total number of blood donations in Japan is about 850,000 compared to about 5.45 million. It is predicted to be insufficient (Non-Patent Document 1). The preservation period of platelets is about 4 days, and it is extremely difficult to store a large amount of platelet preparation for a long time, and it is strongly desired to obtain a fresh platelet preparation continuously. In other words, it is extremely difficult to eliminate the future shortage of blood supply with platelet preparations completely dependent on current blood donation.
上記課題を解決する一つの手法として、血小板を産生する巨核球を幹細胞から分化させ、大量培養することで、献血に依存せずに血小板製剤を製造する技術が研究されている。この技術の特徴として、患者由来（自家）細胞はもちろん、ヒト血小板抗原（ＨＰＡ）が適合するボランティア由来（他家）細胞を用いて血小板を産生できることが挙げられる。また現行の血小板製剤は白血球が含まれるためヒト白血球抗原（ＨＬＡ）が適合しない場合、重篤な副作用が懸念されるが、幹細胞由来の血小板を製造できれば白血球や赤血球が含まれることはないため、上記副作用のリスクを払拭することができる。 As one technique for solving the above problems, a technique for producing a platelet preparation without depending on blood donation by differentiating megakaryocytes producing platelets from stem cells and culturing them in large quantities has been studied. A feature of this technique is that platelets can be produced using not only patient-derived (autologous) cells but also volunteer-derived (other family) cells that are compatible with human platelet antigen (HPA). In addition, since the current platelet preparation contains leukocytes and human leukocyte antigen (HLA) is not compatible, serious side effects are feared, but if stem cells derived platelets can be produced, leukocytes and erythrocytes are not included, The risk of the above side effects can be eliminated.
しかしながら、幹細胞から分化させ目的の細胞を得ようとした場合、ほとんどの場合、目的の細胞以外に未分化な幹細胞等が混在した状態となる。よって得られた細胞を治療に用いるためには、目的の細胞を分離する必要がある。例えば巨核球から分化させた血小板を製剤化する場合、巨核球と血小板を分離する必要がある。 However, when trying to obtain target cells by differentiating from stem cells, in most cases, undifferentiated stem cells and the like are mixed in addition to the target cells. Therefore, in order to use the obtained cells for treatment, it is necessary to isolate the target cells. For example, when formulating platelets differentiated from megakaryocytes, it is necessary to separate megakaryocytes and platelets.
血液から血小板を分離する方法としては遠心分離が一般的に用いられている（特許文献１）。遠心分離は現行の血小板製剤の精製にも用いられている。また、白血球と血小板を高精度に分離するため、濾材表面の白血球との親和性を向上させ、吸着分離する技術も報告されている（特許文献２）。 Centrifugation is generally used as a method for separating platelets from blood (Patent Document 1). Centrifugation is also used to purify current platelet products. In addition, in order to separate leukocytes and platelets with high accuracy, a technique for improving the affinity with the leukocytes on the surface of the filter medium and adsorbing and separating has been reported (Patent Document 2).
血液から血小板を分離する方法として一般的に用いられる遠心分離は、密度が近似する細胞同士を分離することが難しい。一方、吸着分離法では、目的の細胞を吸着させ最終的に回収する方法や目的の細胞以外の細胞を吸着させ目的の細胞のみを回収する方法があり、効率よく純度の高い細胞液を回収できる一方で、表面性状が近似する細胞同士（例えば巨核球と血小板）を分離することが難しい。そのため、これらの手法は、密度も表面性状もともに近似する血小板と巨核球を効率的に分離する手法としては不十分であった。本発明は、巨核球と、巨核球から産生された血小板との効率的な分離を実現することを課題とする。 Centrifugation generally used as a method for separating platelets from blood is difficult to separate cells having similar densities. On the other hand, in the adsorption separation method, there are a method of adsorbing target cells and finally recovering them, or a method of recovering only target cells by adsorbing cells other than the target cells, and can efficiently collect highly pure cell fluid. On the other hand, it is difficult to separate cells having similar surface properties (for example, megakaryocytes and platelets). Therefore, these methods are insufficient as a method for efficiently separating platelets and megakaryocytes that have similar densities and surface properties. An object of the present invention is to achieve efficient separation of megakaryocytes and platelets produced from the megakaryocytes.
上記課題を解決するための本発明は、巨核球と血小板とを含む細胞懸濁液から血小板を分離するための分離基材であって、分離前の該懸濁液が流入する側に配置された通気度（ｃｃ／ｃｍ２／ｓｅｃ）が２５以上５５以下である第１の多孔質体と、該第１の多孔質体に連続して流出側に配置された通気度が１０以上２０以下である第２の多孔質体とからなる血小板分離基材である。 The present invention for solving the above problems is a separation substrate for separating platelets from a cell suspension containing megakaryocytes and platelets, and is disposed on the side into which the suspension before separation flows. The first porous body having an air permeability (cc / cm 2 / sec) of 25 or more and 55 or less, and the air permeability continuously disposed on the outflow side of the first porous body is 10 or more and 20 or less. It is a platelet separation base material which consists of a 2nd porous body which is.
本発明によれば、巨核球と血小板とを効率的に分離することでき、培養細胞由来の血小板製剤の製造に寄与する。 According to the present invention, megakaryocytes and platelets can be efficiently separated, which contributes to the production of a platelet preparation derived from cultured cells.
本発明において多孔質体とは、小さな空隙を多数内部に有する構造体であり、例えば繊維構造体、スポンジ体、多孔膜及びこれらの積層体、ビーズ充填カラムからなる群より選択されるいずれかで構成されるものが挙げられる。なお、本発明において、多孔質体の通気度とは、フラジール法（ＪＩＳ Ｌ１９１３）によって測定した値であるものとする。 In the present invention, the porous body is a structure having a large number of small voids inside, for example, any one selected from the group consisting of a fiber structure, a sponge body, a porous film and a laminate thereof, and a bead-filled column. What is composed is mentioned. In the present invention, the air permeability of the porous body is a value measured by the Frazier method (JIS L1913).
繊維構造体とは繊維が絡み合って一つの構造をなしているものであり、例えば、織物、編物、組紐、不織布および繊維をカラムに充填したものが挙げられるが、作製の容易性の点から特に不織布が好ましい。不織布の製法としては乾式法、湿式法、スパンボンド法、メルトブロー法、エレクトロスピニング法、ニードルパンチ法などが挙げられるが、生産性と汎用性の点から湿式法とメルトブロー法、エレクトロスピニング法が特に好ましい。 The fiber structure is a structure in which fibers are entangled to form one structure, and examples thereof include woven fabrics, knitted fabrics, braids, non-woven fabrics, and fibers filled in columns, but particularly from the viewpoint of ease of production. Nonwoven fabric is preferred. Nonwoven fabric production methods include dry methods, wet methods, spunbond methods, meltblowing methods, electrospinning methods, needle punching methods, etc. preferable.
スポンジ体とは全体に無数の孔を有するものであり、具体的には、焼結多孔質プラスチック、合成樹脂スポンジ等が挙げられる。スポンジ体の製法としては相分離法、発泡法、放射線やレーザー光などを照射するエッチング法、ポロジェン法、凍結乾燥法などが挙げられる。 The sponge body has innumerable pores as a whole, and specific examples thereof include sintered porous plastic and synthetic resin sponge. Examples of the method for producing a sponge body include a phase separation method, a foaming method, an etching method in which radiation or laser light is irradiated, a porogen method, a freeze drying method, and the like.
多孔膜とは平膜に無数の孔を有するものであり、例えばレーザー穿孔したポリカーボネート膜が挙げられる。 The porous film has a myriad of pores in a flat film, and examples thereof include a laser-perforated polycarbonate film.
ビーズ充填カラムとは、カラム内にビーズを充填させることでビーズ間に空隙を形成したものであり、本明細書においては多孔質体に含めるものとする。ビーズの粒径は均一であるものが望ましく、ビーズの粒径によってビーズ間の空隙を孔径として制御し易い。 The bead packed column is a column in which voids are formed by filling beads in the column, and in this specification, it is included in the porous body. It is desirable that the bead particle size is uniform, and it is easy to control the gap between the beads as the pore size depending on the bead particle size.
本発明の血小板分離基材は、分離前の巨核球と血小板とを含む細胞懸濁液が流入する側に配置された第１の多孔質体と、第１の多孔質体に連続して流出側に配置された第２の多孔質体多孔質体とからなる。そして、第１の多孔質体の通気度（ｃｃ／ｃｍ２／ｓｅｃ）が２５以上５５以下であり、第２の多孔質体の通気度が１０以上２０以下である。 The platelet separation substrate of the present invention includes a first porous body arranged on the side into which a cell suspension containing megakaryocytes and platelets before separation flows, and a continuous flow out of the first porous body. And a second porous body disposed on the side. And the air permeability (cc / cm < 2 > / sec) of a 1st porous body is 25 or more and 55 or less, and the air permeability of a 2nd porous body is 10 or more and 20 or less.
本発明者らは、鋭意検討した結果、多孔質体の通気度が１０以上２０以下であると、血小板は巨核球よりも早く当該多孔質体を通過できることを見出した。ここで、巨核球と血小板を効率的に分離するためには、多孔質体の処理厚みを拡大することで、両者の通過速度の差を大きくすることが考えられる。しかし、通気度が１０以上２０以下の多孔質体の処理厚みを単純に拡大した場合、巨核球の目詰まりが起こり分離時に巨核球と血小板にかかる圧力が大きくなって巨核球が破砕して不要成分が増大する、血小板機能（凝集能や表面抗原）が劣化する等の問題がある。そのため、本発明においては、流入側に通気度（ｃｃ／ｃｍ２／ｓｅｃ）が２５以上５５以下であるもう一つの多孔質体（第１の多孔質体）を積層する。流入側にこのような多孔質体を設置することで、分離時の圧力上昇を抑えることができる。 As a result of intensive studies, the present inventors have found that when the porous body has an air permeability of 10 or more and 20 or less, platelets can pass through the porous body earlier than megakaryocytes. Here, in order to efficiently separate megakaryocytes and platelets, it is conceivable to increase the difference in passage speed between the two by increasing the treatment thickness of the porous body. However, when the treatment thickness of a porous material having an air permeability of 10 to 20 is simply increased, clogging of megakaryocytes occurs and the pressure applied to the megakaryocytes and platelets during separation increases and the megakaryocytes are crushed and unnecessary There are problems such as increase in components and deterioration of platelet function (aggregation ability and surface antigen). Therefore, in the present invention, another porous body (first porous body) having an air permeability (cc / cm 2 / sec) of 25 to 55 is laminated on the inflow side. By installing such a porous body on the inflow side, an increase in pressure during separation can be suppressed.
本発明の多孔質体は、例えば多孔質体として不織布を用いる場合、平均孔径が２５以上５５以下である第１の不織布と、平均孔径が１０以上２０以下である第２の不織布を独立して製造した後、これらを積層することで作製することができる。この場合、懸濁液が多孔質体を通過する際に層間が剥離しない限り積層法は特に限定されないが、縁を熱もしくは超音波で溶着する方法、縁をゴム製のリングで押さえながら圧力で挟み込む方法、ニードルパンチ法で層間を密着させる方法などが挙げられる。 For example, when the nonwoven fabric is used as the porous body of the porous body of the present invention, the first nonwoven fabric having an average pore diameter of 25 to 55 and the second nonwoven fabric having an average pore diameter of 10 to 20 are independently used. After manufacturing, it can produce by laminating | stacking these. In this case, the laminating method is not particularly limited as long as the layer does not peel when the suspension passes through the porous body, but the edge is welded with heat or ultrasonic waves, the pressure is applied while pressing the edge with a rubber ring. Examples thereof include a sandwiching method and a method of closely contacting the layers by a needle punch method.
上記第１の多孔質体および第２の多孔質体の厚みは特に限定しないが、機械的強度と精密な構造を維持するため、それぞれ５μｍ以上５ｍｍ以下が好ましく、５０μｍ以上２．５ｍｍ以下が特に好ましい。 The thicknesses of the first porous body and the second porous body are not particularly limited, but are preferably 5 μm or more and 5 mm or less, particularly 50 μm or more and 2.5 mm or less in order to maintain mechanical strength and a precise structure. preferable.
巨核球及び巨核球から産生された血小板が含まれる懸濁液を本発明の分離基材に通過させることで、巨核球は分離基材に捕捉され、血小板は通過するため、血小板のみを分離して血小板製剤を製造することができる。また本発明の血小板分離基材は、血小板を分離回収した後、基材内に捕捉された巨核球を、分離時の送液方向と逆方向へ送液することで、巨核球を回収することもできる。 By passing a suspension containing megakaryocytes and platelets produced from megakaryocytes through the separation substrate of the present invention, the megakaryocytes are captured by the separation substrate and the platelets pass through, so only the platelets are separated. In this way, a platelet preparation can be produced. In addition, the platelet separation substrate of the present invention collects megakaryocytes by separating and collecting platelets, and then feeding megakaryocytes captured in the substrate in a direction opposite to the liquid feeding direction during separation. You can also.
〔製造例〕
不織布Ａ：メルトブロー法により作製したポリプロピレン製の不織布（通気度１５．３ｃｃ／ｃｍ２／ｓ）を直径２５ｍｍにポンチで刳り抜いた。（平均繊維径：２．０μｍ、厚み：０．２５ｍｍ、目付：３０ｇ／ｍ２）
不織布Ｂ：メルトブロー法により作製したポリプロピレン製の不織布（通気度１６．８ｃｃ／ｃｍ２／ｓ）を直径２５ｍｍにポンチで刳り抜いた。（平均繊維径：2.0μm、厚み：0.24mm、目付：30g/m2）
不織布Ｃ：メルトブロー法により作製したポリプロピレン製の不織布（通気度２８．０ｃｃ／ｃｍ２／ｓ）を直径２５ｍｍにポンチで刳り抜いた。（平均繊維径：2.0μm、厚み：0.33mm、目付：30g/m2）
不織布Ｄ：メルトブロー法により作製したポリプロピレン製の不織布（通気度４３．７ｃｃ／ｃｍ２／ｓ）を直径２５ｍｍにポンチで刳り抜いた。（平均繊維径：２．３μｍ、厚み：０．１９ｍｍ、目付：２０ｇ／ｍ２）
［実施例１］
分離基材として、不織布Ａ３枚、不織布Ｄ３枚を、縁をゴム製のＯ−リングで押さえながら圧力で挟み込むことにより積層したものを用いた。この分離基材をミリポア社製シリンジタイプホルダーへ、ホルダー入り口側（流入側）が不織布Ｄとなるようにセットした。予め、リンゲル液で分離基材及びホルダー内部を洗浄した後、ホルダー内部の気泡を除去した。ｉＰＳ細胞から分化誘導した巨核球から血小板を産生させた後の巨核球及び血小板の懸濁液を、リンゲル液が充填されたホルダー内の分離基材に、ローラーポンプを用いて１３．３ｍｌ／ｍｉｎで送液した。分離前後の巨核球数及び血小板数はＦＡＣＳを用いて計測し、巨核球通過率と血小板回収率を下記式より算出した。
[Production example]
Nonwoven fabric A: A polypropylene nonwoven fabric (air permeability 15.3 cc / cm 2 / s) produced by the melt blow method was punched out to a diameter of 25 mm with a punch. (Average fiber diameter: 2.0 μm, thickness: 0.25 mm, basis weight: 30 g / m 2 )
Nonwoven fabric B: A polypropylene nonwoven fabric (air permeability 16.8 cc / cm 2 / s) produced by the melt blow method was punched out to a diameter of 25 mm with a punch. (Average fiber diameter: 2.0 μm, thickness: 0.24 mm, basis weight: 30 g / m 2 )
Nonwoven fabric C: A nonwoven fabric made of polypropylene (air permeability 28.0 cc / cm 2 / s) produced by a melt blow method was punched out with a punch to a diameter of 25 mm. (Average fiber diameter: 2.0 μm, thickness: 0.33 mm, basis weight: 30 g / m 2 )
Nonwoven fabric D: A nonwoven fabric made of polypropylene (air permeability 43.7 cc / cm 2 / s) produced by the melt blow method was punched out with a punch to a diameter of 25 mm. (Average fiber diameter: 2.3 μm, thickness: 0.19 mm, basis weight: 20 g / m 2 )
[Example 1]
As the separation substrate, a laminate of 3 sheets of nonwoven fabric A and 3 sheets of nonwoven fabric D that was sandwiched by pressure while pressing the edges with rubber O-rings was used. The separation substrate was set in a syringe type holder manufactured by Millipore so that the holder entrance side (inflow side) was a nonwoven fabric D. The separation substrate and the inside of the holder were washed in advance with Ringer's solution, and then the bubbles inside the holder were removed. The suspension of megakaryocytes and platelets after producing platelets from megakaryocytes induced to differentiate from iPS cells was applied to a separation substrate in a holder filled with Ringer's solution at 13.3 ml / min using a roller pump. Liquid was sent. The number of megakaryocytes and platelets before and after separation were measured using FACS, and the megakaryocyte passage rate and platelet recovery rate were calculated from the following formulas.
巨核球通過率（％）＝（分離後巨核球数）／（分離前巨核球数）×１００
血小板回収率（％）＝（分離後血小板数）／（分離前血小板数）×１００
［実施例２］
分離基材として不織布Ａ２枚、不織布Ｄ１枚を、実施例１と同様に不織布Ｄが流入側となるようにセットし、分離を行った。
Megakaryocyte passage rate (%) = (number of megakaryocytes after separation) / (number of megakaryocytes before separation) × 100
Platelet recovery rate (%) = (platelet number after separation) / (platelet number before separation) × 100
[Example 2]
Separation was performed by setting two non-woven fabrics A and one non-woven fabric D as separation substrates so that the non-woven fabric D was on the inflow side in the same manner as in Example 1.
［実施例３］
分離基材として不織布Ａ１枚、不織布Ｄ２枚を、実施例１と同様に不織布Ｄが流入側となるようにセットし、分離を行った。
[Example 3]
Separation was performed by setting one non-woven fabric A and two non-woven fabrics D as separation substrates so that the non-woven fabric D was on the inflow side in the same manner as in Example 1.
［実施例４］
分離基材として不織布Ａ１枚、不織布Ｂ１枚、不織布Ｃ１枚を、実施例１と同様に流入側から不織布Ｃ、不織布Ｂ、不織布Ａの順になるようにセットし、分離を行った。
[Example 4]
In the same manner as in Example 1, the non-woven fabric A, the non-woven fabric B, and the non-woven fabric C1 were set as the separation base material in the order of the non-woven fabric C, the non-woven fabric B, and the non-woven fabric A from the inflow side.
［実施例５］
分離基材として不織布Ａ２枚、不織布Ｃ１枚を、実施例１と同様に不織布Ｃが流入側となるようにセットし、分離を行った。
[Example 5]
Separation was performed by setting two nonwoven fabrics A and one nonwoven fabric C as separation substrates so that the nonwoven fabric C was on the inflow side in the same manner as in Example 1.
［実施例６］
分離基材として不織布Ａ１枚、不織布Ｃ２枚を、実施例１と同様に不織布Ｃが流入側となるようにセットし、分離を行った。
[Example 6]
Separation was performed by setting one non-woven fabric A and two non-woven fabrics C as separation substrates so that the non-woven fabric C would be on the inflow side in the same manner as in Example 1.
［比較例１］
分離基材として不織布Ｄを３枚積層したものを用いた以外は実施例１と同様に分離を行った。
[Comparative Example 1]
Separation was performed in the same manner as in Example 1 except that a laminate of three nonwoven fabrics D was used as the separation substrate.
［比較例２］
分離基材として不織布Ｄを６枚積層したものを用いた以外は実施例１と同様に分離を行った。
[Comparative Example 2]
Separation was performed in the same manner as in Example 1 except that a laminate of 6 nonwoven fabrics D was used as the separation substrate.
各実施例、比較例で作製した分離基材の巨核球通過率と血小板回収率の数値を表１に示す。 Table 1 shows numerical values of the megakaryocyte passage rate and platelet recovery rate of the separation base materials prepared in each Example and Comparative Example.
Claims (4)
A method for separating platelets, comprising passing a cell suspension containing megakaryocytes and platelets through the platelet separation substrate according to any one of claims 1 to 3.
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| JP2015072339 | 2015-03-31 | ||
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| JP2016193896A true JP2016193896A (en) | 2016-11-17 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018169060A1 (en) * | 2017-03-16 | 2018-09-20 | 富士フイルム株式会社 | Method for separating megakaryocytes from platelets, and platelet separation kit |
| WO2018207564A1 (en) * | 2017-05-12 | 2018-11-15 | 富士フイルム株式会社 | Separation substrate, cell separation filter and platelet producing method |
| WO2019164227A1 (en) * | 2018-02-20 | 2019-08-29 | 고려대학교 산학협력단 | Multi-column for isolating exosomes and exosome isolation method |
-
2016
- 2016-03-30 JP JP2016068096A patent/JP2016193896A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018169060A1 (en) * | 2017-03-16 | 2018-09-20 | 富士フイルム株式会社 | Method for separating megakaryocytes from platelets, and platelet separation kit |
| WO2018207564A1 (en) * | 2017-05-12 | 2018-11-15 | 富士フイルム株式会社 | Separation substrate, cell separation filter and platelet producing method |
| CN110603316A (en) * | 2017-05-12 | 2019-12-20 | 富士胶片株式会社 | Separation substrate, cell separation filter, and method for producing platelets |
| JPWO2018207564A1 (en) * | 2017-05-12 | 2020-02-27 | 富士フイルム株式会社 | Separation substrate, cell separation filter, and method for producing platelets |
| US11512275B2 (en) | 2017-05-12 | 2022-11-29 | Fujifilm Corporation | Separation substrate, cell separation filter, and method for producing platelet |
| WO2019164227A1 (en) * | 2018-02-20 | 2019-08-29 | 고려대학교 산학협력단 | Multi-column for isolating exosomes and exosome isolation method |
| CN111770931A (en) * | 2018-02-20 | 2020-10-13 | 高丽大学校产学协力团 | Multi-column for separating exosomes and exosome separation method |
| CN111770931B (en) * | 2018-02-20 | 2023-08-25 | 高丽大学校产学协力团 | Multi-column for separating exosomes and exosome separation method |
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