JPWO2007105805A1 - Blood characteristic measurement probe, circulatory system artificial organ and artificial lung - Google Patents
Blood characteristic measurement probe, circulatory system artificial organ and artificial lung Download PDFInfo
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
- A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
- A61B5/14552—Details of sensors specially adapted therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
- A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
- A61B5/14557—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases specially adapted to extracorporeal circuits
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2205/00—General characteristics of the apparatus
- A61M2205/33—Controlling, regulating or measuring
- A61M2205/3306—Optical measuring means
Abstract
血液中に第１の波長λ１（８０５±３０ｎｍ）及び第２の波長λ２（６６０±６０ｎｍ）の近赤外光を照射する光照射部（３）と、前記血液に照射された近赤外光の反射光の受光部（４）を有し、この光照射部（３）と受光部（４）はほぼ並列に配置され、光照射部（３）の先端部（７）の中心（７Ｃ）と受光部（４）の先端部（８）の中心（８Ｃ）の間隔（ＳＤ）を０．９〜３．０ｍｍにしたものを、光送受信部（２）とし、発光素子（１３）及び受光素子（１４）を含む電子回路部（３０）から分離して設け、前記光照射部（３）および前記受光部（４）がそれぞれ照射用光ファイバ（５）および受光用光ファイバ（６）により構成され、シース（２１）で液密的に被覆された血液特性測定プローブ（１）。A light irradiation unit (3) for irradiating the blood with near-infrared light having a first wavelength λ1 (805 ± 30 nm) and a second wavelength λ2 (660 ± 60 nm); and the near-infrared light irradiated on the blood The light irradiator (3) and the light receiver (4) are arranged substantially in parallel, and the center (7C) of the tip (7) of the light irradiator (3). And the center (8C) of the tip part (8) of the light receiving part (4) with an interval (SD) of 0.9 to 3.0 mm as the light transmitting / receiving part (2), the light emitting element (13) and the light receiving part Provided separately from the electronic circuit part (30) including the element (14), the light irradiation part (3) and the light receiving part (4) are respectively provided by an irradiation optical fiber (5) and a light receiving optical fiber (6). A blood property measuring probe (1) constructed and liquid-tightly covered with a sheath (21).
Description
本発明は、血液に近赤外光を投光（照射）し、血液中の赤血球に含まれるヘモグロビンの反射光の強度を測定することにより、複数の血液特性を同時に計測可能とした血液特性計測プローブ、及び、この血液特性計測プローブを内部に設置した循環器系人工臓器及び人工肺に関する。特に、当該血液特性計測プローブの測定データに基づいて、酸素ガス流量及び／又は血液流量を制御し、自動適正化できる循環器系人工臓器、人工肺、及びこれらの関連機器全般に関する。 The present invention is a blood characteristic measurement capable of simultaneously measuring a plurality of blood characteristics by projecting (irradiating) near-infrared light to blood and measuring the intensity of reflected light of hemoglobin contained in red blood cells in the blood. The present invention relates to a probe, and a circulatory system artificial organ and an artificial lung in which the blood characteristic measurement probe is installed. In particular, the present invention relates to a circulatory system artificial organ, an artificial lung, and related devices in general that can control and automatically optimize an oxygen gas flow rate and / or a blood flow rate based on measurement data of the blood characteristic measurement probe.
人工心臓等循環器系人工臓器内における血液特性値、例えば、ヘマトクリット値、酸素飽和度などの測定、評価は、人工心臓が拍出する血液流量を、生体組織の酸素消費量に応じて自動制御するための指標として用いられる。これらの計測は、光を用いた非侵襲的な方法であり、多波長の光源を血液（赤血球）に照射し、その反射光強度比から酸素飽和度の推定を行う方法である。例えば、人工心臓の血液流量の制御は、体循環と肺循環の異なる血液の酸素飽和度を比較し、生体の酸素消費量を推定・算出することにより、行われる。
一方、人工心臓の長期使用における臨床においては、人工心臓内の血栓が剥離し、塞栓症を誘発する問題があることが報告されている。そこで、人工心臓内の血液が淀みやすい部位などの血液流れ、および血栓の形成を常時モニタリングすることにより、大きな血栓が出来る前に、抗凝固剤の投与を行ったり、また瞬間的にポンプの流量を上げ、淀み流れをウオッシュアウト（ｗａｓｈｏｕｔ）し、事前に血栓の拡大を防ぐことができる。しかしながら、従来、人工心臓用に開発されてきた血液特性計測センサは、人工心臓の血液流入・流出口の血液特性を計測するための形状や機構を有するものであるため、人工心臓内部の血栓形成を直接モニタリングすることはできない。
また、人工心臓の開発過程における血栓形成部位の計測実験においても、当該人工心臓の動作中に、血栓生成の有無をモニタリングすることは困難であり、実験終了後に、その人工心臓そのものを分解目視するしか、血栓の有無を確認する方法が無かった。
以上のごとく、人工心臓の開発コストの低減や、臨床への応用をより安全に可能とするには、人工心臓を動作中に、その内部の任意の部位で、流動する血液中のヘモグロビン濃度、ヘマトクリット値、血栓形成状態、及び酸素飽和度をリアルタイムで計測するセンサの開発が、必要不可欠となる。これら４つの血液特性の測定項目は、いずれも重要不可欠であり、全てが測定可能であってこそ始めて人工心臓等の循環器系人工臓器の実用化を完全に成し遂げることができる。
一方、重症心不全や呼吸不全患者に使用されるＰＣＰＳ（Ｐｅｒｃｕｔａｎｅｏｕｓ Ｃｉｒｃｕｌａｔｏｒｙ Ｐｕｌｍｏｎａｒｙ Ｓｙｓｔｅｍ、経皮的心肺補助装置）、ＥＣＭＯ（Ｅｘｔｒａ Ｃｏｒｐｏｒａｌ Ｍｅｍｂｒａｎｅ Ｏｘｙｇｅｎａｔｏｒ、体外式膜型人工肺）、ＩＮＶＯＸ（Ｉｎｔｒａ Ｖｅｎｏｕｓ ＯＸｙｇｅｎａｔｏｒ、静脈型人工肺）、及び一般の開心術における呼吸補助装置（人工肺）などは、病院などの専門のスタッフや機器を備えた環境下での使用が大前提である。そのため、これらの呼吸補助装置など体外循環装置においては、その酸素（空気）ガス流量や血液循環量などの制御は、常に、ＭＥ（Ｍｅｄｉｃａｌ Ｅｎｇｉｎｅｅｒｉｎｇ）技師などの人的操作によって行われている。そのため、従来から、これらＭＥ技師の負担軽減を行うためにこれら体外循環装置における血液流量等の自動制御や、溶血を低減するための様々な研究が行われている。
しかしながら、ガス流量や血液循環量を制御する指標となる血液特性の計測は、未だ、主として採血による侵襲的な計測方法に頼っている。確かに、採血による血液特性の計測は、非常に精度が高く、信頼の出来る値であるが、一方で、宗教的に採血が困難な患者の存在、女性、小児、高齢者では侵襲の負荷が高くなること、病院スタッフならびに患者へ血液経由の感染症のリスクが高くなること、長期モニタリングでは、病院スタッフへの所謂ヒヤリハット（医療現場におけるニアミス、ニアアクシデントの総称）誘発の原因になることが想定されること等の諸問題を多く残している。
また、加えて、近年の背景としてこれら、人工肺の応用は、専門的な設備の整った環境から、より日常生活に近い環境、例えば、被災地やＳＡＲＳ（Ｓｅｖｅｒｅ Ａｃｕｔｅ Ｒｅｓｐｉｒａｔｏｒｙ Ｓｙｎｄｒｏｍｅ、重症急性呼吸器症候群）対策などの伝染病に対する経皮的呼吸補助への応用が期待されている。このような場合、従来の人工肺では、生体状態に応じて適切にガス交換を行えるように、人工肺への酸素、二酸化炭素ガスの供給をＭＥ技師の判断で行う必要がある。そのため、人工肺自体が、採血することなく血液特性をモニタリングできる機能を備えなければ、上述したような日常生活に近い環境における人工肺の使用は実現困難となる。
さらに、重症呼吸不全における生体肺へのブリッジユースやデスティネーションセラピーにおける臨床応用として、携帯型人工肺や埋め込み型人工肺の開発に対する期待は非常に高く、近年の抗血栓材の開発や数値流体解析技術（Ｃｏｍｐｕｔａｔｉｏｎａｌ Ｆｌｕｉｄ Ｄｙｎａｍｉｃｓ）の発展により、血栓が生じにくい人工肺が開発されつつある。特に、埋め込みや携帯型を考慮した人工肺では、人工肺内のガス交換特性はもとより、人工肺内の血液流動状態をモニタリングし、血栓に対する安全性を考慮することが必要不可欠となる。更には、能動的なガス交換では酸素ガスの過剰によるアシドーシスや、抗凝固剤の使用量に関する安全性について、従来の人工肺とは異なる特殊性を有するため、酸素飽和度測定や抗凝固剤の調整に関するより細やかな扱いが要求される。それらのきめ細やかな調整により、ある一定のパフォーマンス（人工肺機能）を常に引き出すことが、人工肺自身に望まれる。
携帯および埋め込みを想定した人工肺の開発および臨床応用における、血栓形成に関する問題は、人工心臓と同様に、未だに解決出来ていない。上記したように、従来、人工肺の血栓低減に関する研究開発段階において、血栓形成部位の確認は、人工肺を分解目視する方法により実施されている。一部、超音波やレーザードップラーなどを使用しての血液流路内の血栓塊計測などの手段も開発されているが、この様な血栓塊の計測では、剥離した血栓の計測が可能なだけであり、人工肺内の血栓の形成過程及び血栓の形成状態などをリアルタイムで計測することすら出来ない。最近の研究報告によれば、人工肺の血栓形成は、小さな血栓塊が中空糸束に集まり、大きな血栓が形成されていくメカニズムによるものと考えられている。そのため、血栓に関する問題を解決するには、中空糸近傍の血液の流動状態をリアルタイムにモニタリングすることで、血栓形成過程を詳細に解明することが必須である。
一方、人工肺（膜型肺）の更なる小型化と高ガス交換能化を目指すには、中空糸膜近傍の血液流れ、および血液酸素飽和度を計測する必要がある。従来の採血による人工肺内の酸素飽和度測定方法では、そもそも、人工肺内部における酸素飽和度の分布が分からないため、中空糸膜面積に対するガス交換能効率が正しく計測できない。そのため、人工肺の開発および臨床応用に際して、人工肺内の任意の部位における、血液特性がリアルタイムに計測できることが強く望まれている。
更には、人工肺の安全性や耐久性を向上させるには、人工肺の開発段階もしくは臨床での使用中に、人工肺内の血液の流れに依存する局所的なヘマトクリット値の計測が必要になる。特に、埋め込み、携帯などを考慮した人工肺は、人工心臓などの流れの速い人工臓器と異なるため、血栓が形成される確率が高い。そのため、人工肺内部の流れの淀みやすい部分を、常にモニタリングし、血栓が出来やすい条件になった時には、強制的に流すなどの自己診断が可能な機能を有する必要がある。
（従来の技術）
これら問題点を解決するため、従来、幾つかの研究がなされてきた。
例えば、特公平７−１２７４（特許文献１）は、ヘモグロビン濃度測定方法に関するものであって、血液に、ヘモグロビンの酸素化状態によってその光吸収率が変化しない波長の光を照射して反射光強度Ｅを測定し、ヘモグロビン濃度〔Ｈｂ〕を、〔Ｈｂ〕＝ＡＥ２＋ＢＥ＋Ｃ、（Ａ、Ｂ、Ｃは係数）なる式で求めるものである。当該方法は、従来のように光を透過させるために必要な処理、即ち赤血球を破壊したり、蒸留水で数百倍に薄めたりする面倒がなく、測定者は反射光強度を計測するだけで上記式にしたがい、容易にヘモグロビン濃度を測定することができるとする。
また、特公平０７−１１３６０４号公報（特許文献２）は、上記方法の改良に関するヘモグロビン測定装置に関するものであって、血液中のヘモグロビンの酸素飽和度により吸光係数がほぼ変化しない波長の光を血液中に照射する第１の光照射手段および第２の光照射手段と、血液中に照射された光の血液からの反射光強度を検出する検出手段と、第１の反射光強度信号または第２の反射光強度信号を用いる補正係数演算手段と、これにより補正反射光強度比を演算する補正反射光強度比演算手段と、出力される補正反射光強度比を用いて血液中のヘモグロビン濃度を演算するヘモグロビン濃度演算手段を有する装置が開示されている。
特許文献２においては、光照射手段の光照射部と光検出手段の光検出部を有するセンサープローブの具体例がその第１図及び第２図に記載されており、発光用の第１または第２の光ファイバの端面により形成される第１及び第２の光照射部と受光用の光ファイバの端面により形成される光検出部との中心間の距離は、それぞれ０．２５ｍｍ及び０．５０ｍｍであり、両者間の距離が異なるように設けられており、これにより、測定する血液を溶血させる必要なく、かつ連続的にヘモグロビン濃度を正確かつ簡単に測定することができるとする。
また特公平０６−２９８５０号公報（特許文献３）は、酸素飽和度測定装置に関するものであって、第１の波長の光を血液中に照射する第１の光照射機能と、酸素化ヘモグロビンと還元ヘモグロビンとの吸光係数がほぼ等しい第２の波長の光を照射する第２の光照射機能と、第２の波長と同じ波長の光を照射する第３の光照射機能とを備えた光照射手段と、これらから特定の距離に設けられた反射光強度を検出する検出手段と、第３の反射光強度信号を用いて、ヘモグロビン濃度等に起因する測定誤差の補正値（Ｃｌ）の補正値演算手段と、補正値（Ｃｌ）を用いて、第１の反射光強度信号（Ｉ１）の補正値（Ｉ１−Ｃｌ）および第２の反射光強度信号（Ｉ２）の補正値（Ｉ２−Ｃｌ）を演算し、当該補正値（Ｉ１−Ｃｌ）と（Ｉ２−Ｃｌ）とを用いる補正反射光強度比演算手段と、これらによる酸素飽和度演算手段とを有し、さらに、第２と第３の反射光強度信号比に基づく、第１の補正値演算手段と、これから出力される第１の補正値及び第３の反射光強度信号（Ｉ３）とに基づいて、第２の補正値（Ｃｌ）を演算する第２の補正値演算手段とを有する技術が記載されている。この補正演算手段を採用することにより、酸素飽和度の低い領域においてもヘマトクリット値の影響を受けることなく正確な酸素飽和度の値を得ることができるとする。
特許文献３においても、光照射手段の光照射部および光検出手段の光検出部を有する、特許文献２と同様な形態の、センサープローブの具体例が第１図及び第２図に記載されている。光ファイバの端面により形成される第１及び第２の光照射部と受光用のファイバの端面により形成される光検出部との中心間の距離は、同様にそれぞれ０．２５ｍｍ及び０．５０ｍｍである。
しかしながら、後記詳述するように、ヘマトクリット値と反射強度の相関を実施的に直線関係で得るためには、本発明により規定されているとおり、当該距離は、０．９ｍｍ以上に設定することが必須であり、０．９ｍｍ未満では、データの信頼性が著しく低下するものである。
ＡＳＡＩＯ Ｊｏｕｒｎａｌ、５１（１）：１１０−１１５、２００５（非特許文献１）においては、フローセル内を通過する血液の血栓形成過程を光センサ（プローブ）の反射光強度および振幅変化から計測できることが示されている。この血栓形成過程の検出手段は、センサ表面を流れる赤血球形状変化および濃度変化によって変化する散乱光強度を周波数解析することにより、血栓の形成過程を検出するのである。
しかしながら、非特許文献１の方法においては、光センサの発光―受光距離（本発明における発光部先端の光照射部と受光部先端の光検出部の間隔：ＳＤに相当）が０．２５ｍｍであるため、反射光は、ヘマトクリット値Ｈｃｔが５０％において、最大になるような特性となる。すなわち、Ｈｃｔが５０％前後で変動する場合には、光センサの検出範囲においてＨｃｔが増加しているのか、減少しているのかを判断することは困難である。
また、光源がピーク波長６３２ｎｍを使用しているため、酸素飽和度により計測する散乱光強度の値が大きく変化してしまう。また、本光センサのプローブは、入射光が単波長の光源であるため、赤血球の動きを定性的に測定はできるが、酸素飽和度やヘマトクリットなどの物性を測定することはできないという問題もあった。
（発明が解決しようとする課題）
上記の例のように、血液に光を照射してその反射光強度により、血液特性を計測する提案は多数なされている。しかしながら、これらはいずれも、血液特性の中の酸素飽和濃度またはヘモグロビン濃度のみを測定可能とするものでしかない。すなわち、酸素飽和度の計測は、２波長以上の反射光強度から計測される方法が主であり、血液の酸素飽和度の影響を受けずにヘモグロビン濃度を精度よく計測することが、酸素飽和度計測の基本となる。しかしながら、従来の２波長光源による酸素飽和度計測システムにおいて、血液の希釈が行われるような状況下では、酸素飽和度を正しく計測できないことがある。
また、血液特性計測装置は、センサの構造や計測方法により、血液循環回路内に別途、フローセルを設け、そのフローセル内を流れる血液特性を計測する方法や、または、血液回路内に、直接センサを組み込む方法で行われている。そのため、血液循環回路の血液充填量の増加や血液特性計測のための電気的配線が増え、血液循環回路周辺を複雑化する要因となる。更には、従来の血液特性計測システムは、計測対象項目に応じた単独設計および信号解析アルゴリズムを導入しているため、同時に複数の情報を計測するには、適していない。
一方、埋め込みや携帯型を想定した循環器系人工臓器においては、生体の活動量に適した血液流量および血液への酸素供給が要求される。これまで提案された方法は、上記のように血液の酸素飽和度およびヘマトクリット値の計測に重点を置かれたものであり、また循環器系人工臓器の血液流出及び流入口における血液特性を計測することを目的とするものであったため、センサの設置は比較的容易であった。
しかしながら、人工肺などの中空糸膜を用いた人工臓器においては、血液の性状変化や、装置の個体差などにより、人工肺内部の中空糸近傍の血液流れは大きく変化しうるものであり、血栓やガス交換能の低下をもたらす。そのため、従来のような単に血液流入出口の特性を計測するシステムでは、人工肺の血液特性計測に適用するには全く不十分である。
また、急性呼吸不全の治療では、数週間程度の呼吸補助において、人工肺の血漿漏出や血栓形成などによる人工肺の性能低下などが生じ、しばしば人工肺の交換を余儀なくされている。このような問題を解決し、より人工肺の安全性を考慮した使用環境を提供するには、人工肺内の複数の部位で血栓の形成部位や血液の流れ方などをリアルタイムにモニタリングすることが必要不可欠となる。
現在のところ、人工肺の開発段階においては、血栓やガス交換の有効膜面積の向上を目指すには、人工肺内部の中空糸膜近傍の微小な血液流れの解析が不可能であるため、より良い製品の開発に至っていないのが現状である。
また、体外循環用人工肺においては、血液リザーバー内に血液特性、酸素飽和度、ヘモグロビン量などを計測するためのセンサを内蔵したものが使用されているが、用途が開心術などの短期間の使用を対象としているため、長期間使用しなければならない携帯型及び埋め込み型人工肺への応用は困難である。さらに、従来の血栓塊の測定方法は、血液流路内を通過する血栓塊の計測しか行えないことや装置が高価で大掛かりになるなどの問題点がある。Measurement and evaluation of blood characteristic values, such as hematocrit value and oxygen saturation, in circulatory system artificial organs such as artificial hearts, etc., automatically control the blood flow rate of the artificial heart according to the oxygen consumption of living tissue It is used as an index for These measurements are non-invasive methods using light, and are methods of irradiating blood (red blood cells) with a multi-wavelength light source and estimating the oxygen saturation from the reflected light intensity ratio. For example, the blood flow of the artificial heart is controlled by comparing the oxygen saturation of blood with different body circulation and pulmonary circulation, and estimating / calculating the oxygen consumption of the living body.
On the other hand, it has been reported that there is a problem that the thrombus in the artificial heart peels off and induces embolism in clinical use in the long-term use of the artificial heart. Therefore, by constantly monitoring the blood flow in the artificial heart where blood easily stagnate, and the formation of thrombus, an anticoagulant is administered before a large thrombus is formed, and the flow rate of the pump is instantaneous. And wash out the stagnation flow to prevent the thrombus from spreading in advance. However, blood characteristic measuring sensors that have been developed for artificial hearts have a shape and mechanism for measuring blood characteristics at the blood inflow / outflow of the artificial heart. Cannot be monitored directly.
It is also difficult to monitor the presence or absence of thrombus during the operation of the artificial heart even in the measurement experiment of the thrombus formation site in the development process of the artificial heart. However, there was no method for confirming the presence or absence of blood clots.
As described above, in order to reduce the development cost of an artificial heart and to make it safer for clinical application, the hemoglobin concentration in the flowing blood at any site inside the artificial heart during operation, The development of sensors that measure the hematocrit value, thrombus formation state, and oxygen saturation in real time is indispensable. The measurement items for these four blood characteristics are all indispensable. Only when all the measurement items are measurable, the practical use of a circulatory system artificial organ such as an artificial heart can be achieved completely.
On the other hand, PCPS (Percutaneous Circulatory Pulmonary System, percutaneous cardiopulmonary assist device) used for patients with severe heart failure and respiratory failure, ECMO (Extra Corporate Membrane Oxygenator, Intravenous type oxygenator) Artificial lungs) and respiratory assistance devices (artificial lungs) in general open heart surgery are premised on use in an environment equipped with specialized staff and equipment such as hospitals. Therefore, in extracorporeal circulation devices such as these breathing assistance devices, the oxygen (air) gas flow rate and blood circulation amount are always controlled by a human operation such as a ME (Medical Engineering) engineer. For this reason, conventionally, various studies have been conducted to automatically control the blood flow rate in these extracorporeal circulation devices and reduce hemolysis in order to reduce the burden on these ME engineers.
However, the measurement of blood characteristics as an index for controlling the gas flow rate and the blood circulation volume still relies mainly on an invasive measurement method by blood collection. Certainly, the measurement of blood characteristics by blood collection is highly accurate and reliable, but on the other hand, the presence of patients who are difficult to collect blood religiously, women, children, and elderly people are invasive. It is assumed that the risk of infectious diseases via blood increases to hospital staff and patients, and that long-term monitoring may cause so-called near-miss (generic name for near misses and near accidents) in hospital staff. Many problems remain.
In addition, as a background in recent years, these artificial lungs have been applied to environments closer to everyday life from environments equipped with specialized equipment, such as disaster areas, SARS (Severe Act Respiratory Syndrome, severe acute respiratory Syndrome) Expected to be applied to percutaneous respiratory assistance for infectious diseases such as countermeasures. In such a case, in the conventional oxygenator, it is necessary to supply oxygen and carbon dioxide gas to the oxygenator at the discretion of the ME engineer so that gas exchange can be appropriately performed according to the biological state. Therefore, if the oxygenator itself does not have a function of monitoring blood characteristics without collecting blood, it is difficult to use the oxygenator in an environment close to everyday life as described above.
Furthermore, there are very high expectations for the development of portable oxygen implants and implantable oxygenators for clinical use in bridging use and destination therapy for living lungs in severe respiratory failure. Recent developments in antithrombotic materials and numerical fluid analysis With the development of technology (Computational Fluid Dynamics), artificial lungs that are less prone to thrombus are being developed. In particular, in the case of an artificial lung considering implantation or portable type, it is indispensable to monitor the blood flow state in the artificial lung as well as the gas exchange characteristics in the artificial lung and consider the safety against thrombus. Furthermore, in active gas exchange, acidosis due to excess oxygen gas and safety related to the amount of anticoagulant used are different from conventional artificial lungs, so oxygen saturation measurement and anticoagulant More detailed handling regarding adjustment is required. It is desirable for the oxygenator itself to always bring out a certain performance (artificial lung function) by fine adjustment.
The problems related to thrombus formation in the development and clinical application of artificial lungs intended to be carried and implanted have not been solved as in the case of artificial hearts. As described above, conventionally, in the research and development stage related to the reduction of thrombus in an artificial lung, confirmation of a thrombus formation site has been carried out by a method of visualizing the artificial lung. Some measures such as measurement of thrombus in the blood flow path using ultrasound, laser Doppler, etc. have been developed, but such measurement of thrombus is only possible to measure the detached thrombus. Therefore, it is impossible to even measure the thrombus formation process and the thrombus formation state in the artificial lung in real time. According to recent research reports, thrombus formation in an artificial lung is thought to be due to a mechanism in which small thrombus aggregates gather in a hollow fiber bundle and large thrombus is formed. Therefore, in order to solve the problems related to thrombus, it is essential to elucidate the thrombus formation process in detail by monitoring the blood flow state in the vicinity of the hollow fiber in real time.
On the other hand, in order to further reduce the size of the artificial lung (membrane type lung) and increase the gas exchange capacity, it is necessary to measure the blood flow in the vicinity of the hollow fiber membrane and the blood oxygen saturation. In the conventional method for measuring oxygen saturation in an artificial lung by blood collection, the distribution of oxygen saturation in the oxygenator is not known in the first place, and therefore the gas exchange capacity efficiency with respect to the hollow fiber membrane area cannot be measured correctly. Therefore, in the development and clinical application of an artificial lung, it is strongly desired that blood characteristics at an arbitrary site in the artificial lung can be measured in real time.
Furthermore, in order to improve the safety and durability of the oxygenator, it is necessary to measure the local hematocrit value depending on the blood flow in the oxygenator during the development of the oxygenator or during clinical use. Become. In particular, an artificial lung taking into account implantation, carrying, etc. is different from a fast-flowing artificial organ such as an artificial heart, so that there is a high probability that a thrombus will be formed. Therefore, it is necessary to constantly monitor the stagnation part of the flow inside the artificial lung, and to have a function capable of self-diagnosis, such as forcible flow when a condition where thrombosis is likely to occur.
(Conventional technology)
In order to solve these problems, several studies have been made in the past.
For example, Japanese Patent Publication No. 7-1274 (Patent Document 1) relates to a method for measuring hemoglobin concentration, and irradiates blood with light having a wavelength that does not change its light absorption rate depending on the oxygenated state of hemoglobin. E is measured, and the hemoglobin concentration [Hb] is obtained by the following equation: [Hb] = AE 2 + BE + C (A, B, and C are coefficients). This method does not have the trouble of processing to transmit light as in the past, that is, destroying red blood cells or diluting it several hundred times with distilled water, and the measurer only measures the reflected light intensity. It is assumed that the hemoglobin concentration can be easily measured according to the above formula.
Japanese Examined Patent Publication No. 07-113604 (Patent Document 2) relates to a hemoglobin measuring apparatus related to the improvement of the above method, and uses light having a wavelength at which the extinction coefficient does not substantially change due to the oxygen saturation of hemoglobin in the blood. A first light irradiating means and a second light irradiating means for irradiating the light, a detecting means for detecting a reflected light intensity from the blood of the light irradiated into the blood, a first reflected light intensity signal or a second Correction coefficient calculation means using the reflected light intensity signal, corrected reflected light intensity ratio calculation means for calculating the corrected reflected light intensity ratio, and hemoglobin concentration in blood using the corrected reflected light intensity ratio that is output An apparatus having a hemoglobin concentration calculating means is disclosed.
In Patent Document 2, a specific example of a sensor probe having a light irradiation part of a light irradiation means and a light detection part of a light detection means is described in FIGS. The distances between the centers of the first and second light irradiating portions formed by the end faces of the two optical fibers and the light detecting portion formed by the end faces of the light receiving optical fibers are 0.25 mm and 0.50 mm, respectively. It is assumed that the distance between the two is different, so that the hemoglobin concentration can be measured accurately and simply continuously without the need to hemolyze the blood to be measured.
Japanese Examined Patent Publication No. 06-29850 (Patent Document 3) relates to an oxygen saturation measuring apparatus, and includes a first light irradiation function for irradiating blood with a first wavelength of light, oxygenated hemoglobin, Light irradiation provided with a second light irradiation function for irradiating light with a second wavelength that has substantially the same extinction coefficient as that of reduced hemoglobin, and a third light irradiation function for irradiating light with the same wavelength as the second wavelength Correction value (Cl) for a measurement error caused by a hemoglobin concentration or the like using a means, a detection means for detecting reflected light intensity provided at a specific distance from the means, and a third reflected light intensity signal Using the calculation means and the correction value (Cl), the correction value (I1-Cl) of the first reflected light intensity signal (I1) and the correction value (I2-Cl) of the second reflected light intensity signal (I2) And the correction values (I1-Cl) and (I2-Cl) A corrected reflected light intensity ratio calculating means using the above, an oxygen saturation calculating means based on these, a first correction value calculating means based on the second and third reflected light intensity signal ratios, and an output from now on And a second correction value calculating means for calculating a second correction value (Cl) based on the first correction value and the third reflected light intensity signal (I3). . By adopting this correction calculation means, it is assumed that an accurate oxygen saturation value can be obtained without being affected by the hematocrit value even in a region where the oxygen saturation is low.
Also in patent document 3, the specific example of the sensor probe of the form similar to patent document 2 which has the light irradiation part of a light irradiation means and the light detection part of a light detection means is described in FIG. 1 and FIG. Yes. The distances between the centers of the first and second light irradiating portions formed by the end face of the optical fiber and the light detecting portion formed by the end face of the light receiving fiber are similarly 0.25 mm and 0.50 mm, respectively. is there.
However, as will be described in detail later, in order to obtain a correlation between the hematocrit value and the reflection intensity in a practically linear relationship, the distance may be set to 0.9 mm or more as defined by the present invention. It is essential, and if it is less than 0.9 mm, the reliability of the data is significantly reduced.
ASAIO Journal, 51 (1): 110-115, 2005 (Non-Patent Document 1) shows that the thrombus formation process of blood passing through the flow cell can be measured from the reflected light intensity and amplitude change of the optical sensor (probe). Has been. The thrombus formation detection means detects the thrombus formation process by frequency analysis of the intensity of scattered light that changes due to changes in the shape and concentration of red blood cells flowing on the sensor surface.
However, in the method of Non-Patent Document 1, the light emission-light reception distance of the optical sensor (the interval between the light irradiation part at the front end of the light emitting part and the light detection part at the front end of the light receiving part in the present invention: equivalent to SD) is 0.25 mm. Therefore, the reflected light has such characteristics that it becomes maximum when the hematocrit value Hct is 50%. That is, when Hct fluctuates around 50%, it is difficult to determine whether Hct is increasing or decreasing in the detection range of the optical sensor.
Further, since the light source uses a peak wavelength of 632 nm, the value of the scattered light intensity measured by the oxygen saturation level changes greatly. In addition, since the probe of this optical sensor is a light source with a single wavelength of incident light, it can qualitatively measure the movement of red blood cells, but it cannot measure physical properties such as oxygen saturation and hematocrit. It was.
(Problems to be solved by the invention)
As in the above example, many proposals have been made to irradiate blood with light and measure blood characteristics based on the intensity of reflected light. However, all of these can only measure the oxygen saturation concentration or the hemoglobin concentration in the blood characteristics. In other words, the oxygen saturation is mainly measured from reflected light intensity of two wavelengths or more, and it is possible to accurately measure the hemoglobin concentration without being affected by the blood oxygen saturation. It becomes the basis of measurement. However, in a conventional oxygen saturation measurement system using a two-wavelength light source, the oxygen saturation may not be measured correctly under circumstances where blood is diluted.
In addition, the blood characteristic measuring device is provided with a flow cell separately in the blood circulation circuit depending on the sensor structure and measurement method, or a method for measuring the blood characteristic flowing in the flow cell, or a sensor directly in the blood circuit. It is done in a way that incorporates it. For this reason, an increase in the blood filling amount of the blood circulation circuit and an increase in electrical wiring for measuring blood characteristics increase the complexity of the periphery of the blood circulation circuit. Furthermore, the conventional blood characteristic measurement system is not suitable for measuring a plurality of pieces of information at the same time because a single design and a signal analysis algorithm corresponding to the measurement target item are introduced.
On the other hand, in a circulatory system artificial organ that is assumed to be implanted or portable, a blood flow rate suitable for the amount of activity of the living body and oxygen supply to the blood are required. The methods proposed so far are focused on the measurement of blood oxygen saturation and hematocrit as described above, and measure blood characteristics at the blood outflow and inlet of circulatory system artificial organs. Therefore, the installation of the sensor was relatively easy.
However, in an artificial organ using a hollow fiber membrane such as an artificial lung, the blood flow in the vicinity of the hollow fiber inside the artificial lung can be greatly changed due to changes in blood properties or individual differences between devices, and thrombus. And decrease gas exchange capacity. Therefore, a conventional system that simply measures the characteristics of blood inflow / outlet is not sufficient for application to blood characteristics measurement of an artificial lung.
Moreover, in the treatment of acute respiratory failure, the performance of the artificial lung is reduced due to plasma leakage of the artificial lung, thrombus formation, etc. in the respiratory assistance for several weeks, and the artificial lung is often replaced. In order to solve these problems and provide a use environment that takes into account the safety of the oxygenator, it is necessary to monitor in real time the thrombus formation site and blood flow at multiple sites in the oxygenator Indispensable.
At present, in the development stage of artificial lungs, it is impossible to analyze the minute blood flow near the hollow fiber membrane inside the artificial lung to improve the effective membrane area for thrombus and gas exchange. At present, good products have not been developed.
In addition, extracorporeal oxygenators have built-in sensors that measure blood characteristics, oxygen saturation, hemoglobin content, etc. in the blood reservoir. Since it is intended for use, it is difficult to apply to portable and implantable oxygenators that must be used for a long time. Furthermore, the conventional method for measuring a thrombus has problems that it can only measure a thrombus that passes through the blood flow path and that the apparatus is expensive and large.
本発明は上記の問題点を解決するためになされたものであって、本発明によれば、以下のごとく、基本的な血液特性たる酸素飽和度をヘモグロビン濃度変化に大きな影響を受けずに、光学的に計測しうる血液特性計測プローブが提供される。
１． 血液中に第１の波長λ１（８０５±３０（７７５〜８３５）ｎｍ）及び／又は第２の波長λ２（６６０±６０（６００〜７２０）ｎｍ）の近赤外光を照射する光照射部（３）と、前記血液に照射された近赤外光の反射光の受光部（４）を有し、
前記光照射部（３）と前記受光部（４）は略並列に配置され、
前記光照射部（３）先端の光照射先端部（７）の中心（７Ｃ）と前記受光部（４）先端の光検出部（８）の中心（８Ｃ）の間隔（ＳＤ）を０．９〜３．０ｍｍにしたものを少なくとも光送受信部（２）として含むことを特徴とする血液特性測定プローブ（１）。
２． 前記光送受信部（２）における前記光照射部（３）は１本または２本以上の照射用光ファイバ（５）より構成され、また前記受光部（４）は、少なくとも１本以上の受光用光ファイバ（６）より構成されていることを特徴とする前記１に記載の血液特性測定プローブ（１）。
３． 前記照射用光ファイバ（５）は発光素子（１３）に接続され、受光用光ファイバ（６）は受光素子（１４）に接続され、
前記照射用光ファイバ（５）と受光用光ファイバ（６）を含む前記光送受信部（２）が、前記発光素子（１３）と前記受光素子（１４）を含む電子回路部（３０）とから分離されていることを特徴とする前記１または２に記載の血液特性測定プローブ（１）。
４． 前記照射用光ファイバ（５）と受光用光ファイバ（６）を含む前記光送受信部（２）が、シース（２１）で液密的に被覆されていることを特徴とする前記１から３のいずれかに記載の血液特性測定プローブ（１）。
５． 血液中に照射した近赤外光の第１の波長λ１（８０５±３０（７７５〜８３５）ｎｍ）の反射光強度を測定することにより、当該血液中のヘマトクリット値、ヘモグロビン濃度、血栓形成状況を計測可能であり、
当該血液中に照射した近赤外光の第１の波長λ１（８０５±３０（７７５〜８３５）ｎｍ）及び第２の波長λ２（６６０±６０（６００〜７２０）ｎｍの反射光強度を測定することにより、当該血液中の酸素飽和度を計測可能であることを特徴とする前記１から４のいずれかに記載の血液特性測定プローブ（１）。
また本発明よれば、循環器系人工臓器、特に人工肺において、本発明の血液特性計測プローブを装着し、当該計測プローブにより人工臓器内を流れる血液特性をモニターできる携帯型・埋め込み型を含む人工肺が提供される。
６． 血液を内部に流通させる循環器系人工臓器において、前記１から５のいずれかに記載の血液特性測定プローブ（１）を内部に配置してなることを特徴とする循環器系人工臓器。
７． ヘモグロビン濃度、ヘマトクリット値、酸素飽和濃度、血栓形成状況の全てを同時に計測可能であることを特徴とする前記６に記載の循環器系人工臓器。
８． 前記６または７に記載の循環器系人工臓器において、当該人工臓器の複数の箇所に、前記１から前記５のいずれかに記載の血液特性計測プローブを配置することにより、同時に複数部位の血液特性を計測可能であることを特徴とする前記循環器系人工臓器。
９． 中空糸膜を備えた循環器系人工臓器において、当該中空糸膜内に前記１から５のいずれかに記載の血液特性計測プローブを編み込んだことを特徴とする前記６から８のいずれかにに記載の循環器系人工臓器。
１０． 埋め込み型もしくは携帯型であることを特徴とする前記６から９のいずれかに記載の循環器系人工臓器。
１１． 前記１から５のいずれかに記載の血液特性測定プローブより得た情報を、有線もしくは無線によって転送し、循環器系人工臓器へのガス流量及び／又は血液流量を当該情報を基にアルゴリズム構築によって適正化できることを特徴とする循環器系人工臓器。
１２． 前記６から前記１１のいずれかに記載の循環器系人工臓器が人工肺であることを特徴とする前記循環器系人工臓器。The present invention has been made to solve the above problems, and according to the present invention, the oxygen saturation, which is a basic blood characteristic, is not greatly affected by changes in hemoglobin concentration, as described below. A blood characteristic measurement probe that can be optically measured is provided.
1. A light irradiation unit for irradiating near-infrared light having a first wavelength λ1 (805 ± 30 (775-835) nm) and / or a second wavelength λ2 (660 ± 60 (600-720) nm) into blood ( 3) and a light receiving part (4) for the reflected light of the near-infrared light irradiated on the blood,
The light irradiation part (3) and the light receiving part (4) are arranged substantially in parallel,
The distance (SD) between the center (7C) of the light irradiation tip (7) at the tip of the light irradiation part (3) and the center (8C) of the light detection part (8) at the tip of the light receiving part (4) is 0.9. A blood characteristic measurement probe (1) comprising at least 3.0 mm as an optical transmission / reception unit (2).
2. The light irradiating part (3) in the light transmitting / receiving part (2) is composed of one or more irradiating optical fibers (5), and the light receiving part (4) is at least one for receiving light. 2. The blood characteristic measurement probe (1) according to (1) above, comprising an optical fiber (6).
3. The irradiation optical fiber (5) is connected to the light emitting element (13), the light receiving optical fiber (6) is connected to the light receiving element (14),
The optical transmission / reception unit (2) including the irradiation optical fiber (5) and the light receiving optical fiber (6) includes the light emitting element (13) and the electronic circuit unit (30) including the light receiving element (14). 3. The blood property measurement probe (1) according to 1 or 2, which is separated.
4). The optical transmitter / receiver (2) including the irradiation optical fiber (5) and the light receiving optical fiber (6) is liquid-tightly covered with a sheath (21). The blood characteristic measurement probe (1) according to any one of the above.
5. By measuring the intensity of reflected light at the first wavelength λ1 (805 ± 30 (775-835) nm) of near-infrared light irradiated into blood, the hematocrit value, hemoglobin concentration, and thrombus formation status in the blood can be determined. Is measurable,
The reflected light intensity of the first wavelength λ1 (805 ± 30 (775-835) nm) and the second wavelength λ2 (660 ± 60 (600-720) nm) of the near infrared light irradiated into the blood is measured. Thus, the blood characteristic measurement probe (1) according to any one of (1) to (4), wherein the oxygen saturation level in the blood can be measured.
In addition, according to the present invention, in a circulatory system artificial organ, particularly an artificial lung, the artificial blood vessel including a portable type and an implantable type that can be mounted with the blood characteristic measurement probe of the present invention and can monitor the blood characteristic flowing through the artificial organ with the measurement probe. A lung is provided.
6). A circulatory prosthetic organ that circulates blood inside, wherein the blood characteristic measurement probe (1) according to any one of 1 to 5 is disposed therein.
7). 7. The circulatory system artificial organ according to 6 above, wherein all of hemoglobin concentration, hematocrit value, oxygen saturation concentration, and thrombus formation status can be measured simultaneously.
8). In the circulatory system artificial organ according to 6 or 7, the blood characteristic measurement probes according to any one of 1 to 5 described above are arranged at a plurality of locations of the artificial organ, so that blood characteristics of a plurality of sites can be simultaneously obtained. It is possible to measure the circulatory system artificial organ.
9. In any one of 6 to 8 above, the blood characteristic measurement probe according to any one of 1 to 5 described above is knitted into the hollow fiber membrane in a circulatory system artificial organ provided with a hollow fiber membrane. The circulatory system artificial organ described.
10. 10. The circulatory system artificial organ according to any one of 6 to 9, which is an implantable type or a portable type.
11. The information obtained from the blood characteristic measurement probe according to any one of 1 to 5 above is transferred by wire or wirelessly, and the gas flow rate and / or blood flow rate to the circulatory organ prosthesis is constructed by constructing an algorithm based on the information. A circulatory prosthesis that can be optimized.
12 12. The circulatory system artificial organ according to any one of 6 to 11, wherein the circulatory system artificial organ is an artificial lung.
第１図は、本発明の血液特性測定プローブの概略説明図であり、第２図は、本発明の血液特性測定プローブの概略図であり、（Ａ）は斜視図、（Ｂ）は側面図、（Ｃ）は正面図であり、第３図は本発明の血液特性測定プローブを装着した人工肺の概略説明図であり、第４図は血液に照射した光の波長と光吸収係数の相関を、血液酸素飽和度１００％の場合（ＨｂＯ２（酸素化ヘモグロビン））と酸素飽和度０％の場合（Ｈｂ（還元ヘモグロビン））について示したグラフである。
第５図は、光照射先端部の中心（７Ｃ）と光検出部（８）の中心（８Ｃ）の間隔（ＳＤ）を変えた場合、ヘマトクリット値と反射光強度（相対反射率）の関係についての数値解析結果を示すグラフであり、第６図は、反射光強度とヘマトクリット値との相関を示すグラフであり、第７図は、２波長（８３０／７３０ｎｍと８３０／６６０ｎｍ）における反射光比（Ｒｅｆｌｅｃｔｅｄ ｌｉｇｈｔ ｉｎｔｅｎｓｉｔｙ）とＯＳ（酸素飽和度；Ｏｘｙｇｅｎ Ｓａｔｕｒａｔｉｏｎ）との計測結果の相関を示すグラフである。第８図は、血栓形成過程ならび剥離と反射光強度の相関について実験するためのウサギを含む閉鎖回路による実験装置の説明図であり、第９図は、第８図で使用するフローセル内の流速分析及び血液特性プローブの設置位置を示す図であり、第１０図は第９図に示した実験装置において、血栓形成過程から剥離までの各過程における反射光強度（Ｂａｃｋｓｃａｔｔｅｒｅｄ ｌｉｇｈｔ ｉｎｔｅｎｓｉｔｙ）の変化を示す図（波長８１０ｎｍ）であり、第１１図は、人工肺に装着するための血液特性測定プローブの反射光強度と酸素飽和度の計測結果を示すグラフであり、第１２図は、血液特性測定プローブを人工肺に装着し，酸素飽和度を計測したとき計測結果を示す図である。
図において、１、１Ａ、１Ｂ、１Ｃ、１１は血液特性測定プローブ、２は光送受信部、３は光照射部、４は受光部、５は照射用光ファイバ、６は受光用光ファイバ、７は光照射先端部、７Ｃは光照射先端部の中心、８は光検出部、８Ｃは光検出部の中心、１３は発光素子（発光ダイオード等）、１４は受光素子（フォトダイオード等）、２１はシース、３０は電子回路部、５０は人工肺、５１はハウジング、５２は人工肺の血液入口、５３は血液出口、５４は中空糸膜（束）、５５は血液ポンプ、５６は（電磁）バルブ、５７は（ガスボンベ）連結管、５８は無線送信部、６０は受信機を備えた演算処理制御装置、６１はＣＰＵ、６２は記憶装置、６３はディスプレイ等の表示手段、６４は無線受信部、７０は閉鎖回路、７１はフローセル、７２はローラポンプをそれぞれ示す。FIG. 1 is a schematic explanatory view of a blood characteristic measuring probe of the present invention, FIG. 2 is a schematic view of a blood characteristic measuring probe of the present invention, (A) is a perspective view, and (B) is a side view. , (C) is a front view, FIG. 3 is a schematic explanatory diagram of an artificial lung equipped with the blood characteristic measurement probe of the present invention, and FIG. 4 is a correlation between the wavelength of light irradiated on blood and the light absorption coefficient. Is a graph showing a case where the blood oxygen saturation is 100% (HbO 2 (oxygenated hemoglobin)) and a case where the oxygen saturation is 0% (Hb (reduced hemoglobin)).
FIG. 5 shows the relationship between the hematocrit value and the reflected light intensity (relative reflectance) when the distance (SD) between the center (7C) of the light irradiation tip and the center (8C) of the light detector (8) is changed. FIG. 6 is a graph showing the correlation between the reflected light intensity and the hematocrit value, and FIG. 7 is the reflected light ratio at two wavelengths (830/730 nm and 830/660 nm). It is a graph which shows the correlation of the measurement result of (Reflected light intensity) and OS (oxygen saturation; Oxygen Saturation). FIG. 8 is an explanatory diagram of an experimental apparatus using a closed circuit including a rabbit for experimenting on the correlation between the thrombus formation process and peeling and reflected light intensity, and FIG. 9 shows the flow velocity in the flow cell used in FIG. FIG. 10 is a view showing the installation position of the analysis and blood characteristic probe, and FIG. 10 shows the change in reflected light intensity (Backscattered light intensity) in each process from the thrombus formation process to detachment in the experimental apparatus shown in FIG. FIG. 11 is a graph showing measurement results of reflected light intensity and oxygen saturation of a blood characteristic measurement probe to be attached to an artificial lung, and FIG. 12 is a blood characteristic measurement probe. It is a figure which shows a measurement result when mounting | wearing an artificial lung and measuring oxygen saturation.
In the figure, 1, 1A, 1B, 1C, 11 are blood characteristic measuring probes, 2 is an optical transceiver, 3 is a light irradiator, 4 is a light receiver, 5 is an optical fiber for irradiation, 6 is an optical fiber for light reception, 7 Is the light irradiation tip, 7C is the center of the light irradiation tip, 8 is the light detection part, 8C is the center of the light detection part, 13 is a light emitting element (light emitting diode, etc.), 14 is a light receiving element (photodiode, etc.), 21 Is a sheath, 30 is an electronic circuit unit, 50 is an artificial lung, 51 is a housing, 52 is a blood inlet of the artificial lung, 53 is a blood outlet, 54 is a hollow fiber membrane (bundle), 55 is a blood pump, and 56 is (electromagnetic) Valve, 57 (gas cylinder) connecting pipe, 58 a wireless transmission unit, 60 an arithmetic processing control device provided with a receiver, 61 a CPU, 62 a storage device, 63 a display means such as a display, 64 a wireless reception unit , 70 is a closed circuit, 71 is a flow cell, 2 shows a roller pump, respectively.
以下、本発明を実施するための最良の形態を、図面を参照しながら詳細に説明する。
（血液特性測定プローブの構成）
本発明の血液特性測定プローブ１は、概略的に説明すると、図１に例示するように、血液中に第１の波長λ１（８０５±３０ｎｍ（６００〜７２０ｎｍ））及び／又は第２の波長λ２（６６０±６０ｎｍ（７７５〜８３５ｎｍ））の近赤外光を照射する光照射部３と、血液に照射された近赤外光の反射光の受光部４を備えた、光送受信部２を少なくとも含むものであり、この光送受信部２は、発光素子１３と受光素子１４を含む電子回路部３０とから分離されて設けられていることを特徴とする。
そしてより詳しくは、この光送受信部２における光照射部３は、１本または２本以上の照射用光ファイバ５より構成され、また前記受光部４は、少なくとも１本以上の受光用光ファイバ６より構成されており、この照射用光ファイバ５は発光素子１３に接続され、受光用光ファイバ６は受光素子１４に接続されているのである。
（光送受信部）
そして、図２の（Ａ）〜（Ｃ）に示されているように、本発明の血液特性測定プローブ１は、当該光送受信部２における光照射部３と、受光部４の配置（ｃｏｎｆｉｇｕｒａｔｉｏｎ）として、前記光照射部３と前記受光部４は略並列に配置され、前記光照射部３先端の光照射先端部７の中心７Ｃと前記受光部４先端の光検出部８の中心８Ｃの間隔（ＳＤ、Ｓｅｐａｒａｔｅ Ｄｉｓｔａｎｃｅ）（以下単に「光照射部３−受光部４間隔」ということがある。）を０．９〜３．０ｍｍにしたことを特徴としている。なお、図では、受光部４の周囲に複数の光照射部３を配置しているが、光照射部３の周囲に複数の受光部４を配置するようにしてもよい。
本発明のプローブにおいて、ＳＤが０．９ｍｍ以上であることが好ましいのは、当該血液特性測定プローブ１を使用した実験例において、第５図の数値解析の結果より明らかなごとく、２０％以上のヘマトクリット値の領域において、その増加と反射光強度の関係に高い線形性が得られることが推定されたからである。
なお、第５図において、各曲線において、ａはＳＤが０．３ｍｍ、ｂはＳＤが０．６ｍｍ、ｃはＳＤが０．９ｍｍ、ｄはＳＤが１．２ｍｍ、ｅはＳＤが１．５ｍｍ、ｆはＳＤが１．８ｍｍの場合である。
なおＳＤが、３．０ｍｍを超えるように、あまり大きすぎる場合は、反射光が散乱あるいは減衰するため好ましくない。
（近赤外光波長）
第４図は血液に照射した光の波長と光吸収係数の相関関係を、ＨｂＯ２（酸素化ヘモグロビン）とＨｂ（還元ヘモグロビン）について示したグラフである
第４図から、ヘモグロビン濃度を正しく計測するには、血液の酸素飽和度の影響が少ない第１の波長（λ１）（８０５±３０（７７５〜８３５）ｎｍ）を使用することが適切であると考えられる。すなわち、λ１としては、所謂″ｉｓｏｂｅｓｔｉｃｗａｖｅｌｅｎｇｔｈ″近傍の波長が選択される。
また、同様に第４図から、血液の酸素飽和濃度を測定するためには、第２の波長（λ２）（６６０±６０（６００〜７２０）ｎｍ）が使用される。波長λ２の近赤外光の吸光度は、ヘモグロビンが酸化状態であれば極めて高くなるため、当該λ２（６６０±６０ｎｍ）の近赤外光の反射光強度を測定することによって血液の酸素飽和濃度を正確に測定可能である。
（電子回路部）
電子回路部３０における発光素子１３には、ＬＥＤ（Ｌｉｇｈｔ Ｅｍｉｔｔｉｎｇ Ｄｉｏｄｅ）やＬＤ（Ｌａｓｅｒ Ｄｉｏｄｅ）が好適に使用され、受光素子１４には、フォトダイオード（フォトトランジスタともいう）が好適に使用される。ここで発光素子１３であるＬＥＤ等の波長は、計測すべき血液特性によって適宜選択して使用される。当該受光素子１４で捕らえられた反射光は信号電圧に変換され、アンプシステム（図示せず）によって増幅される。当該増幅信号は、後述するように、演算制御装置に送られてそのＣＰＵ（中央演算装置）による演算処理に付されて、血液特性値が測定され、また、その結果は、ＬＣＤ等のディスプレイに表示させることができる。
（シース）
光送受信部２における光照射部３は、上記したように、１本または２本以上の照射用光ファイバ５より構成され、また前記受光部４は、少なくとも１本以上の受光用光ファイバ６より構成されている。そして、照射用光ファイバ５と受光用光ファイバ６を含む光送受信部２は、第１図−第２図に示されているように、シース２１で液密的に被覆されている。
本発明の血液特性測定プローブ１は、後記するように、例えば人工臓器の血液回路中に挿入して使用されるものであるから、シース２１は柔軟性があり滅菌可能で、使い捨て可能な材料で形成するのが好ましい。使い捨て可能な材料は特に限定されないが、通常適当な高分子材料が選択使用される。かかる高分子材料としては、例えばポリエチレン、ポリプロピレン等のポリオレフィン、ポリウレタン、ポリアミド、ポリエチレンテレフタレート、塩化ビニル樹脂、フッ素樹脂、ＰＭＭＡ等が好ましい、なお、照射する近赤外線の波長に吸収が少ない材料が望ましい。
被覆される光照射部３における照射用光ファイバ５の本数としては、一本の照射用光ファイバ５に血液中に第１の波長λ１（８０５±３０ｎｍ）及び第２の波長λ２（６６０±６０ｎｍ）の近赤外光を照射する機能を付与しても良いし、二本以上の照射用光ファイバ５を配置してそれぞれに、第１の波長λ１と第２の波長λ２を照射する機能を付与しても良い。
本発明の血液特性測定プローブ１は、上記した特定の波長λ１、λ２を血液に照射し、その反射光強度を測定することにより、血液中のヘモグロビン濃度、ヘマトクリット値、血栓形成状況、及び酸素飽和濃度の諸血液特性を同時に測定可能である。
（ヘモグロビン濃度の測定方法）
すでに述べたように、第４図から、ヘモグロビン濃度を正しく計測するには、血液の酸素飽和度の影響が少ない波長λ１（８０５±３０ｎｍ）の近赤外光を使用することが適切であると考えられ、この波長λ１を照射しその反射光強度（Ｒｅｆｌｅｃｔｅｄ ｌｉｇｈｔ ｉｎｔｅｎｓｉｔｙ）を測定することにより、ヘモグロビン濃度は容易に求められる。
（ヘマトクリット値の計測方法）
ヘマトクリット値の計測も、同様にして血液中に近赤外光を照射し、その反射光強度を測定することにより行われる。照射光波長としては、ヘモグロビンの酸化状態に吸光度が影響を受けない波長λ１（８０５±３０ｎｍ）が好適に使用される。
ヘマトクリット値と反射光強度には波長によって若干異なるが、後記実施例２の結果（λ１＝８３０ｎｍ）を示した第６図のごとく、ヘマトクリット値と反射光強度には強い直線的に相関関係が存在する。したがって、当該関係式を使用することにより、反射光強度から、ヘマトクリット値は容易に測定可能である。
なお、第６図は、酸素飽和度が０〜１００％、ヘマトクリット値が２０〜５０％における血液特性の計測結果の一例で、ＬＥＤの波長λ１を８３０ｎｍとし、光照射部３−受光部４間隔（ＳＤ、Ｓｅｐａｒａｔｅ Ｄｉｓｔａｎｃｅ）を２．１ｍｍとした時のヘモグロビン濃度と反射光強度の関係を示している。
（血栓形成状況の計測方法）
血栓とは、局所的なヘマトクリット値の異常な増加である。血栓が成長すると血管内の正常な血流を妨げることになり、種々の症状の原因となる因子である。また、血栓は人工心肺等の人工臓器の血液回路中でも、長時間動作させた場合、血流がよどむ部位（例えば人工肺の場合は中空糸膜）において、生成しうるものであり、一旦血栓が形成・生長した場合は、当該臓器が正常に動作しなくなる大きな原因となる。
このように、例えば人工臓器の動作中においても血流中における血栓の形成状況を連続的に監視・確認することは重要である。血栓形成状況を確認可能とする計測方法としては、好ましくは血液中に近赤外光を照射し、その反射光強度を測定することである。血栓は、上記したように、局所的なヘマトクリト値の増加として把握されるので、血栓の形成・成長に伴って赤血球の吸光度は上昇し、反射光の強度は低下することになる。
具体的には、第５図に示したように、ヘマトクリット濃度が２０％以上の領域において、ヘマトクリット値と反射光強度（Ｒｅｌａｔｉｖｅ ｒｅｆｌｅｃｔａｎｃｅ）は線形的に低下する関係がある（ただし、ＳＤが０．９ｎｍ以上の場合）。したがって、血液中に照射した近赤外光の反射光強度を測定することで、血栓形成状況を確認することが可能である。ヘマクリット値を測定する場合の近赤外線の波長としては、ヘモグロビンの酸化状態によって吸光度が影響を受けない波長λ１（８０５±３０ｎｍ）の近赤外光が好適に使用される。
なお、同じヘマトクリット値を示す血栓であっても、その形成メカニズムが、血液流れの影響の差異により、凝集か凝固に区別され、血栓生成の原因及び生成血栓の性状（特性）が異なることになる。より的確に血栓の形成原因を究明し、これに対処するためには、その形成メカニズムに関する情報を得る必要がある。その判断方法の一つとして、反射光強度を周波数解析することにより、血液の流動の血栓生成に及ぼす影響を考慮することが可能となる。周波数解析方法には、ＦＦＴ解析やフラクタル解析などが有効であると考えられる。
（酸素飽和濃度の計測方法）
血液の酸素飽和濃度を計測する計測方法は、血液中に２種類以上の波長の近赤外光を照射し、その反射光強度を測定すること可能である。
すなわち、第４図に示したように、波長λ２（６６０ｎｍ）前後の近赤外光を血液に照射したときの吸光度（光吸収係数）は、ヘモグロビンが酸化状態であれば極めて高くなる。よって、６６０ｎｍ前後の近赤外光の反射光強度を測定することによって血液の酸素飽和濃度を測定することが可能である。ただし、上述したとおり、近赤外光を血液に照射したときの吸光度は、そのヘモグロビン濃度、ヘマトクリット値によって大きく異なる。このため、ヘモグロビンの酸化状態に吸光度が影響を受けない波長λ１（８０５±３０ｎｍ）の近赤外光の反射光強度を同時に測定し、ヘモグロビン濃度、ヘマトクリット値を算出し、これらの影響を補正することで、血液の酸素飽和濃度を正確に求めることが可能である。
その計測結果の一例を第７図に示す。第７図は、後記する実施例３のデータであるが、２波長における反射光比、８３０／７３０ｎｍと８３０／６６０ｎｍによる酸素飽和度（ＯＳ；Ｏｘｙｇｅｎ Ｓａｔｕｒａｔｉｏｎ）の計測結果を示したものである。
酸素飽和度と反射光強度の関係は、一般的には直線線形による予測方法も可能であるが、ここでは、図に示すように２次線形として整理することにより、より高い相関性を得ることが確認された。
これらの反射光強度とヘモグロビン酸素飽和度の相関関係に関し、３次元の拡散理論を適用し、本発明の血液特性計測プローブが創出されたものである。
（循環器系人工臓器（人工肺））
また本発明よれば、循環器系人工臓器、特に人工肺において、上記した本発明の血液特性計測プローブ１を内部に装着し、当該計測プローブにより人工臓器内を流れる血液のヘモグロビン濃度、ヘマトクリット値、血栓形成状況、及び酸素飽和濃度のすべての血液特性を計測できる。
また、当該循環器系人工臓器において、当該人工臓器の複数の箇所に、本発明の血液特性計測プローブ１を配置することにより、同時に複数部位の血液特性を計測可能である。
さらに、中空糸膜を備えた循環器系人工臓器において、当該中空糸膜内に本発明の血液特性計測プローブを編み込むことができる。当該循環器系人工臓器は、好ましくは、埋め込み型もしくは携帯型のものである。
本発明においては、後記詳述するように、血液特性測定プローブ１より得た血液特性に関する情報（測定データ）を、有線もしくは無線によって演算制御装置に転送する。当該演算制御装置は、ＲＯＭ及びＲＡＭからなる記憶装置を備え、当該データを、ＲＡＭに格納するとともに、ＲＯＭにはＯＳプログラム及びすでに述べた反射光強度データからモグロビン濃度、ヘマトクリット値、血栓形成状況、及び酸素飽和濃度のすべての血液特性を算出するプログラムが格納されており、これにしたがって送信した計測データからただちにこれらの諸血液特性値が算出される。
また、これらの血液特性値に基づいて、これらを適正値に制御するために、循環器系人工臓器への酸素ガス流量及び／又は血液流量を制御する構築アルゴリズム（制御プログラム）がＲＯＭに格納されており、当該演算制御装置は、当該制御プログラムにより、当該測定データにもとづき、人工臓器へのガスや血液流量を最適な範囲に自動制御し、適正化する制御システムを構築することができる。
本発明の血液特性測定プローブを内部に装着した人工肺においては、上記のような制御システムを構築することにより、被災地などでの経皮的呼吸補助、携帯型人工肺による社会復帰などが可能となる。また、病院内での使用においても、ＭＥ技師の仕事量の軽減や、患者のＱＯＬ（Ｑｕａｌｉｔｙ ｏｆ Ｌｉｆｅ）の向上に寄与する。さらには、埋め込み型人工肺もしくは携帯型人工肺のより早期の実用化を可能とする。
本発明においては、人工臓器へのガスや血液流量を最適な範囲に制御し、適正化する目的を達成するためには、ヘモグロビン濃度、ヘマトクリット値、血栓形成状況及び酸素飽和濃度の全てを計測可能であることが望ましい。この場合、一つの血液特性計測プローブにより、上記全ての項目が測定可能のようにするものであってもよいし、複数の血液特性プローブを備え、各々の項目を役割分担して、それぞれ別の独立した血液特性計測プロープで測定するようにしてもよい。
本発明の循環器系人工臓器においては、上記したように、当該人工臓器の複数の箇所に、本発明の血液特性計測プローブ１をそれぞれ配置することにより、同時に複数部位の血液特性を計測可能である。このように、人工肺内の複数の箇所、特に、血液流が変化したり、特定の部位において、ある血液特性値を保持することが要求される部位に、血液特性計測プローブを装着し、同時に複数部位の血液特性を計測することが好ましい。
例えば、流速が遅くなり血栓形成が予測される部位に、血栓形成状況を常時監視（モニター）可能な、本発明の血液特性計測プローブを設置し、または、ガス交換部前後に血液の酸素飽和濃度を測定し、当該酸素飽和濃度が基準値に達しているか否かを確認するための血液特性計測プローブを設置することにより、人工心肺を総合的に管理することが可能である。
さらに、本発明においては、上記したように中空糸膜を備えた循環器系人工臓器において、当該中空糸膜内に、本発明の血液特性計測プローブを編み込むことができる。本発明のプローブは、第１図−第２図に示したように、光照射部と光受光部は光ファイバにより形成され、柔軟なシースで被覆された極細で柔軟な先端を有するものであるから、当該プローブを人工肺の中空糸内に一緒に編み込むことが可能となる。かくして、本発明によれば、従来不可能であった、人工肺の内部の血液特性をリアルタイムでモニターすることができ、人工肺内部の管理を実施することが可能となる。
（循環器系人工臓器内の流動解析方法）
循環器系人工臓器を最適に設計し、解析、操作するには、基礎データとして当該臓器内の血液の流動状態の詳細な実測データが必要である。
このためには、当該臓器内部に液体を満たして流動させ、本発明の血液特性測定プローブを臓器内部に挿入してその位置で光照射部３から光照射し、その反射光を受光部４で受ける状態にしておく。定常状態において、当該受光部４が受ける反射光に対し、これを吸収、遮蔽、散乱等何らかの影響を及ぼす物質（液体または微小粒子でもよい）を、トレーサーとして、流路の上流において少なくとも１ショット（すなわちパルスとして）液中に流し、流路の下流において当該トレーサー濃度の時間的変化（応答）（または当該トレーサーによる反射光の変化）を血液特性測定プローブにより検出、測定する。これは、化学工学の分野で周知のパルス（デルタ）応答解析であって、当該物質（トレーサー）の到達時間、流速、濃度、分布の少なくとも１つ、より正確には、トレーサー濃度の時間的変化（応答曲線の形状）を解析し、流動を表現するモデルと対応させることにより、例えば中空糸膜を配置した循環器系人工臓器内の流動解析を行うことができる。
（循環器系人工臓器（人工肺）へのプローブ装着）
第３図は、血液特性計測プローブ１を内部に配置、装着した循環器系人工臓器（人工肺）５０の概略図である。以下人工肺５０の例について、プローブを取り付け血液特性の計測を実施する方法を説明する。
当該人工肺５０において、５１はハウジング、５２は人工肺への血液入口、５３は血液出口、５４は中空糸膜（束）、５５はローラポンプまたは遠心ポンプ等の血液ポンプ、５６は（電磁）バルブ、５７は（ガスボンベ）連結管である。入口５２より流入した酸素飽和度の低い血液（還元ヘモグロビン：Ｈｂ）は、中空糸膜５４と接触することにより、ガスボンベ連結管５７からバルブ５６をへて供給された空気（又は酸素）と接触し、酸素飽和度の高い血液（酸素化ヘモグロビン：ＨｂＯ２）となり、５３から流出する。
この場合、第３図に示すように、人工肺５０内における血液の流れの遅い低速部位（例えば第３図においては、血液出口５３と反対側の部位で、ハウジング５１の右上の部分）には、血栓を生じやすいと予想される。
また人工肺５０の血液流入口５２と血液流出口５３では、当然のことながら人工肺における最も重要な因子として酸素飽和濃度の数値を計測し、酸素飽和度が所定の値以上に確保していることを常にモニターし管理する必要がある。これらの部位に、例えば三個の測定用プローブ１Ａ、１Ｂ及び１Ｃを図のように取り付ける。
なお、後記詳述するように、５８は無線送信部、６０は受信機を備えた演算処理制御装置、６１はＣＰＵ、６２は記憶装置、６３はディスプレイ等の表示手段、６４は無線受信部である。
また第３図に示すように、各プローブ１Ａ、１Ｂ、１Ｃからの情報（測定データ）は埋め込み型または装着型無線送信部５８を介して、データ処理及び演算処理のために、受信機を備えた演算処理制御装置６０の（埋め込み型または装着型の）無線受信部６４に送信されるシステムにすることが好ましい。
演算処理制御装置６０は、中央演算装置（ＣＰＵ）６１、記憶装置６２、表示手段６３、無線受信部６４等を含んでいる。また、記憶装置６２は、ＲＯＭ及びＲＡＭからなり、各プローブからの測定データを、ＲＡＭに格納し記録するとともに、ＲＯＭにはＯＳプログラム及びすでに述べた反射光強度データからモグロビン濃度、ヘマトクリット値、血栓形成状況、及び酸素飽和濃度のすべての血液特性を算出するプログラムが格納されており、当該プログラムにより諸血液特性値が算出される。
以上のごとくして、無線によって転送された各プローブ１Ａ、１Ｂ、１Ｃの情報（各部位１Ａ、１Ｂ、１Ｃにおける血液特性データ）は、演算処理制御装置で演算処理され、その結果は表示手段６３、たとえばＬＥＤディスプレイにリアルタイムで表示される。
また、これらの各プローブ１Ａ、１Ｂ、１Ｃが検出した情報（血液特性値）に基づいて、これらを適正値に制御するために、循環器系人工臓器への酸素（空気）ガス流量及び／又は血液流量を制御する構築アルゴリズム（制御プログラム）がＲＯＭに格納されており、当該演算処理制御装置は、当該制御プログラムにより、当該測定データにもとづき、人工臓器５０へのガス流量や血液流量を最適な範囲に自動制御し、適正化する制御システムを構築することができる。
具体的には、たとえば（ｉ）血栓が一定以上形成され始めると、ポンプの回転数を増加させる等して血液流速を上昇させ、（ｉｉ）酸素飽和度は、酸素ガスの過剰によるアシドーシスを生じず、かつ酸欠にならないように９０％〜１００％を保つようガス流量を調製する。この様な手法を用いることにより長期間血栓が形成されず、酸素飽和度を適正値に保つことが可能な携帯型人工肺を実現することが可能である。
（発明の効果）
（Ａ）本発明の血液特性計測プローブは、以下の有利な特徴または効果を有する。
（ａ１）本発明のプローブにおいては、その先端の血液特性の計測部位（光照射部３と受光部４を含む光送受信部）は、発光素子や受光素子を含む電子回路部と分離されている構造（ｃｏｎｆｉｇｕｒａｔｉｏｎ）であるため、当該血液の流れに変化をもたらすような機構や形状のものではない。また、光照射部３と受光部４を含む光送受信部は、発光用光ファイバ５と受光用光ファイバ６により構成されているので、容易に任意の位置に設置できるような構造であって、計測対象となる循環器系人工臓器の製造段階で容易に設置することが可能となる。
（ａ２）また発光用光ファイバ５と受光用光ファイバ６は、それぞれ発光素子１３および受光素子１４に接続され、光送受信部２と電気回路部３０が分離できるため、高価な発光素子、受光素子を含む電気回路部は繰返し使用が可能であり、光ファイバからなる光送受信部２のみをディスポーサブル（使い捨て）として使用することができる。
（ａ３）さらには、発光用光ファイバ５と受光用光ファイバ６で導光（照射）を行うため、同時にヘモグロビン濃度、ヘマトクリット値、酸素飽和濃度、血栓形成状況等の複数の血液特性を多点で計測することが可能となる。
（Ｂ）本発明による血液特性計測プローブを装着した循環器系人工臓器、携帯型・埋め込み型を含む人工肺は、以下の有利な効果を有する。
（ｂ１）人工肺内の血液の流入口や流出口といった、比較的流れが遅い部位における血液特性の計測には、第１の波長λ１（８０５±３０（７７５〜８３５）ｎｍ）及び／又は第２の波長λ２（６６０±６０（６００〜７２０）ｎｍ）の近赤外光を照射する光照射部３とこの近赤外光の反射光の受光部４を直接人工肺内の血液流路の壁面に埋め込み、または外部から装着して、血液特性の計測を行うことができる。
（ｂ２）本発明の血液特性測定プローブを人工肺内に設置して人工肺内用血液特性測定プローブとして使用する場合、当該プローブの先端（光送受信部２）は、光ファイバを主体として構成されているものであって、このような細径で比較的柔軟な構造の光ファイバを柔軟性あるシース２１で覆い、人工肺（膜型人工肺）を構成する中空糸束（中空糸膜）（ここで血液と酸素が中空糸膜を通して接触し血液に酸素が移動する。）の製作段階において、容易に織り込むことが可能であり、計測対象となる中空糸束における計測位置を、随意に決定することが出来る。
（ｂ３）発光用光ファイバ５先端の光照射部７から発する光の散乱特性を直接計測することにより、血液特性測定プローブ近傍の様々な血液特性を容易に、かつ、リアルタイムで、長期に渡り計測することが実現できる。そのため、人工肺の開発段階はもとより、臨床現場における人工肺の安全性能の更なる向上が期待される。
（ｂ４）採血による血液特性計測ではなく、血液に光照射し、その光散乱特性を受光して反射光強度を直接計測するシステムであるため、採血による患者の侵襲がない。また採血を伴うシステムの場合大きな問題となる患者、病院スタッフへの感染の予防に大きく貢献する。
（ｂ５）ガス流量、血液流量調節装置と、本血液特性測定プローブの測定データを連動させることで人工肺に対するＭＥ技師の操作を大きく減少させられる。このことは、携帯型・埋め込み型人工肺を実現する上で極めて有効である。
（ｂ６）中空糸束内に配置する血液特性計測プローブは、血液の流れを妨げないような直径及び少なくとも２本１組で構成される発光用光ファイバ５と受光用光ファイバ６の二本以上で構成され、当該血液特性計測プローブを人工肺内の随意の位置に設置することで、人工肺を動作させている状態において、リアルタイムに中空糸束内の血液の様々な情報を同時に多数取得することができる。
（ｂ７）計測された光信号を従来の血液光特性と組み合わせることで、血液特性機能を多数計測するアルゴリズムを構築し、当該アルゴリズムを考慮した血液流量、ガス流量コントロールモジュールを作成することができる。
（ｂ８）内部に液体を満たして流動させ、受光部４が受ける反射光に何らかの影響を及ぼす物質を少なくとも１ショット液中に流し、その物質の到達時間、流速、濃度、分布の少なくとも１つを分析することで、中空糸膜を配置した循環器系人工臓器内の流動解析が可能になる。また、そのような、流動解析システムを構築することができる。Hereinafter, the best mode for carrying out the present invention will be described in detail with reference to the drawings.
(Configuration of blood characteristic measurement probe)
The blood characteristic measuring probe 1 of the present invention will be described briefly. As illustrated in FIG. 1, the blood has a first wavelength λ1 (805 ± 30 nm (600 to 720 nm)) and / or a second wavelength λ2. At least an optical transmission / reception unit 2 including a light irradiation unit 3 that irradiates near infrared light of (660 ± 60 nm (775 to 835 nm)) and a light receiving unit 4 of reflected light of the near infrared light irradiated to blood The optical transmitting / receiving unit 2 is provided separately from the light emitting element 13 and the electronic circuit unit 30 including the light receiving element 14.
More specifically, the light irradiating unit 3 in the optical transmitting / receiving unit 2 includes one or two or more irradiation optical fibers 5, and the light receiving unit 4 includes at least one light receiving optical fiber 6. The irradiation optical fiber 5 is connected to the light emitting element 13, and the light receiving optical fiber 6 is connected to the light receiving element 14.
(Optical transceiver)
As shown in FIGS. 2A to 2C, the blood characteristic measurement probe 1 of the present invention is configured by the light irradiation unit 3 and the light receiving unit 4 in the optical transmission / reception unit 2. As described above, the light irradiation unit 3 and the light receiving unit 4 are arranged substantially in parallel, and the distance between the center 7C of the light irradiation front end 7 at the front end of the light irradiation unit 3 and the center 8C of the light detection unit 8 at the front end of the light receiving unit 4 is as follows. (SD, Separate Distance) (hereinafter simply referred to as “light irradiation unit 3 -light receiving unit 4 interval”) is set to 0.9 to 3.0 mm. In the figure, a plurality of light irradiation units 3 are arranged around the light receiving unit 4, but a plurality of light receiving units 4 may be arranged around the light irradiation unit 3.
In the probe of the present invention, it is preferable that the SD is 0.9 mm or more, in the experimental example using the blood characteristic measurement probe 1, as apparent from the result of numerical analysis in FIG. This is because it has been estimated that high linearity is obtained in the relationship between the increase and the reflected light intensity in the hematocrit region.
In FIG. 5, in each curve, a is 0.3 mm SD, b is 0.6 mm SD, c is 0.9 mm, d is 1.2 mm, and e is 1.5 mm. , F is the case where SD is 1.8 mm.
In addition, when SD is too large so that it may exceed 3.0 mm, since reflected light is scattered or attenuated, it is not preferable.
(Near infrared wavelength)
FIG. 4 is a graph showing the correlation between the wavelength of light irradiated on blood and the light absorption coefficient for HbO 2 (oxygenated hemoglobin) and Hb (reduced hemoglobin). FIG. 4 correctly measures the hemoglobin concentration. For this, it is considered appropriate to use the first wavelength (λ1) (805 ± 30 (775-835) nm) that is less affected by the oxygen saturation of blood. That is, as λ1, a wavelength in the vicinity of the so-called “isobestic wavelength” is selected.
Similarly, from FIG. 4, the second wavelength (λ2) (660 ± 60 (600 to 720) nm) is used to measure the oxygen saturation concentration of blood. Since the absorbance of near-infrared light having a wavelength of λ2 is extremely high when hemoglobin is in an oxidized state, the oxygen saturation concentration of blood is determined by measuring the reflected light intensity of the near-infrared light of λ2 (660 ± 60 nm). It can be measured accurately.
(Electronic circuit part)
For the light emitting element 13 in the electronic circuit unit 30, an LED (Light Emitting Diode) or an LD (Laser Diode) is preferably used, and for the light receiving element 14, a photodiode (also referred to as a phototransistor) is preferably used. Here, the wavelength of the LED or the like that is the light emitting element 13 is appropriately selected and used depending on blood characteristics to be measured. The reflected light captured by the light receiving element 14 is converted into a signal voltage and amplified by an amplifier system (not shown). As will be described later, the amplified signal is sent to an arithmetic control device and subjected to arithmetic processing by the CPU (central processing unit) to measure blood characteristic values, and the result is displayed on a display such as an LCD. Can be displayed.
(sheath)
As described above, the light irradiation unit 3 in the optical transmission / reception unit 2 includes one or more irradiation optical fibers 5, and the light receiving unit 4 includes at least one light reception optical fiber 6. It is configured. The optical transmission / reception unit 2 including the irradiation optical fiber 5 and the light receiving optical fiber 6 is liquid-tightly covered with a sheath 21 as shown in FIGS.
As will be described later, the blood characteristic measuring probe 1 of the present invention is used by being inserted into a blood circuit of an artificial organ, for example. Therefore, the sheath 21 is a flexible, sterilizable, disposable material. Preferably formed. The disposable material is not particularly limited, but an appropriate polymer material is usually selected and used. As such a polymer material, for example, polyolefins such as polyethylene and polypropylene, polyurethane, polyamide, polyethylene terephthalate, vinyl chloride resin, fluororesin, PMMA, and the like are preferable, and materials that absorb less in the wavelength of near infrared rays to be irradiated are preferable.
The number of the irradiation optical fibers 5 in the light irradiation unit 3 to be coated is such that the first wavelength λ1 (805 ± 30 nm) and the second wavelength λ2 (660 ± 60 nm) in the blood in one irradiation optical fiber 5. ) Or a function of irradiating the first wavelength λ1 and the second wavelength λ2 to each of the two or more irradiation optical fibers 5. May be given.
The blood characteristic measurement probe 1 of the present invention irradiates blood with the above-mentioned specific wavelengths λ1 and λ2 and measures the intensity of reflected light, thereby measuring blood hemoglobin concentration, hematocrit value, thrombus formation status, and oxygen saturation. Various blood characteristics of concentration can be measured simultaneously.
(Measurement method of hemoglobin concentration)
As already described, from FIG. 4, it is appropriate to use near-infrared light having a wavelength λ1 (805 ± 30 nm) that is less affected by oxygen saturation of blood in order to correctly measure the hemoglobin concentration. The hemoglobin concentration can be easily obtained by irradiating this wavelength λ1 and measuring the reflected light intensity (Reflected light intensity).
(Measurement method of hematocrit value)
Similarly, the hematocrit value is measured by irradiating the blood with near infrared light and measuring the intensity of the reflected light. As the irradiation light wavelength, a wavelength λ1 (805 ± 30 nm) at which the absorbance is not affected by the oxidation state of hemoglobin is preferably used.
Although the hematocrit value and reflected light intensity differ slightly depending on the wavelength, there is a strong linear correlation between the hematocrit value and reflected light intensity as shown in FIG. 6 showing the result of Example 2 (λ1 = 830 nm) described later. To do. Therefore, by using the relational expression, the hematocrit value can be easily measured from the reflected light intensity.
FIG. 6 shows an example of a blood characteristic measurement result when the oxygen saturation is 0 to 100% and the hematocrit value is 20 to 50%. The wavelength λ1 of the LED is 830 nm, and the interval between the light irradiation part 3 and the light receiving part 4 is shown. The relationship between hemoglobin concentration and reflected light intensity when (SD, Separate Distance) is 2.1 mm is shown.
(Measurement method of thrombus formation status)
A thrombus is an abnormal increase in local hematocrit. When a thrombus grows, it interferes with the normal blood flow in the blood vessel, and is a factor causing various symptoms. In addition, blood clots can be generated even in blood circuits of artificial organs such as heart-lung machines at sites where blood flow stagnate (for example, hollow fiber membranes in the case of artificial lungs) when operated for a long time. In the case of formation / growth, the organ becomes a major cause of malfunction.
Thus, for example, it is important to continuously monitor and confirm the state of thrombus formation in the bloodstream even during operation of the artificial organ. The measurement method that enables confirmation of the thrombus formation status is preferably to irradiate blood with near infrared light and measure the reflected light intensity. As described above, the thrombus is grasped as an increase in the local hematocrit value. Therefore, as the thrombus is formed and grown, the absorbance of the red blood cell increases and the intensity of the reflected light decreases.
Specifically, as shown in FIG. 5, in the region where the hematocrit concentration is 20% or more, the hematocrit value and the reflected light intensity (relative reflectance) are linearly decreased (however, the SD is 0. 0). 9 nm or more). Therefore, it is possible to confirm the thrombus formation status by measuring the reflected light intensity of the near infrared light irradiated into the blood. As the near-infrared wavelength when measuring the hematocrit value, near-infrared light having a wavelength λ1 (805 ± 30 nm) in which the absorbance is not affected by the oxidation state of hemoglobin is preferably used.
In addition, even if the blood clots have the same hematocrit value, the formation mechanism is distinguished by aggregation or coagulation due to the difference in the influence of blood flow, and the cause of thrombus generation and the properties (characteristics) of the generated thrombus are different. . In order to investigate the cause of thrombus formation more accurately and cope with it, it is necessary to obtain information on the formation mechanism. As one of the determination methods, it is possible to consider the influence of blood flow on thrombus generation by frequency analysis of reflected light intensity. For frequency analysis methods, FFT analysis, fractal analysis, etc. are considered effective.
(Measurement method of oxygen saturation concentration)
The measuring method for measuring the oxygen saturation concentration of blood can irradiate blood with near infrared light having two or more wavelengths and measure the reflected light intensity.
That is, as shown in FIG. 4, the absorbance (light absorption coefficient) when the blood is irradiated with near-infrared light having a wavelength of about λ2 (660 nm) is extremely high if hemoglobin is in an oxidized state. Therefore, it is possible to measure the oxygen saturation concentration of blood by measuring the reflected light intensity of near-infrared light around 660 nm. However, as described above, the absorbance when blood is irradiated with near-infrared light varies greatly depending on the hemoglobin concentration and the hematocrit value. For this reason, the reflected light intensity of near-infrared light having a wavelength λ1 (805 ± 30 nm) whose absorbance is not affected by the oxidation state of hemoglobin is simultaneously measured, the hemoglobin concentration and the hematocrit value are calculated, and these effects are corrected. Thus, it is possible to accurately obtain the oxygen saturation concentration of blood.
An example of the measurement result is shown in FIG. FIG. 7 shows data of Example 3 to be described later, and shows the measurement result of the oxygen saturation (OS) by the reflected light ratio at two wavelengths, 830/730 nm and 830/660 nm.
The relationship between oxygen saturation and reflected light intensity can generally be predicted by linear linearity, but here, a higher correlation can be obtained by arranging it as a second-order linear as shown in the figure. Was confirmed.
The blood characteristic measurement probe of the present invention has been created by applying a three-dimensional diffusion theory to the correlation between the reflected light intensity and the hemoglobin oxygen saturation.
(Cardiovascular artificial organ (artificial lung))
Further, according to the present invention, in a circulatory system artificial organ, particularly an artificial lung, the blood characteristic measurement probe 1 of the present invention described above is mounted inside, and the hemoglobin concentration, hematocrit value of blood flowing in the artificial organ by the measurement probe, Thrombus formation status and all blood characteristics of oxygen saturation can be measured.
In the circulatory system artificial organ, the blood characteristic measurement probe 1 of the present invention is arranged at a plurality of locations of the artificial organ, so that blood characteristics at a plurality of sites can be measured simultaneously.
Furthermore, in a circulatory system artificial organ provided with a hollow fiber membrane, the blood characteristic measurement probe of the present invention can be knitted into the hollow fiber membrane. The circulatory system artificial organ is preferably implantable or portable.
In the present invention, as will be described in detail later, information (measurement data) related to blood characteristics obtained from the blood characteristic measurement probe 1 is transferred to the arithmetic and control unit by wire or wirelessly. The arithmetic and control unit includes a storage device including a ROM and a RAM, and stores the data in the RAM. The ROM stores the moglobin concentration, hematocrit value, thrombus formation status from the OS program and the reflected light intensity data described above, In addition, a program for calculating all blood characteristics of oxygen saturation concentration is stored, and these blood characteristic values are calculated immediately from the measurement data transmitted in accordance with the program.
In addition, a construction algorithm (control program) for controlling the oxygen gas flow rate and / or blood flow rate to the circulatory prosthetic organ is stored in the ROM in order to control them to appropriate values based on these blood characteristic values. The arithmetic and control unit can construct a control system that automatically controls and optimizes the gas and blood flow rate to the artificial organ within the optimum range based on the measurement data by the control program.
In the artificial lung equipped with the blood characteristic measurement probe of the present invention, by constructing the control system as described above, percutaneous respiration assistance in a stricken area, etc., social rehabilitation with a portable artificial lung, etc. are possible It becomes. Further, even in use in a hospital, it contributes to reducing the workload of ME engineers and improving the quality of life (QOL) of patients. In addition, it enables early use of an implantable oxygenator or a portable oxygenator.
In the present invention, all of hemoglobin concentration, hematocrit value, thrombus formation status and oxygen saturation concentration can be measured in order to achieve the objective of controlling and optimizing the gas and blood flow to the artificial organ within the optimum range. It is desirable that In this case, one blood characteristic measurement probe may be used so that all the above items can be measured, or a plurality of blood characteristic probes are provided, each of which is divided into roles, You may make it measure with an independent blood characteristic measurement probe.
In the circulatory system artificial organ of the present invention, as described above, the blood characteristic measurement probes 1 of the present invention are arranged at a plurality of locations of the artificial organ, respectively, so that blood characteristics at a plurality of sites can be measured simultaneously. is there. In this way, a blood characteristic measurement probe is attached to a plurality of locations in the oxygenator, particularly where the blood flow changes or a specific region is required to maintain a certain blood property value, It is preferable to measure blood characteristics at a plurality of sites.
For example, the blood characteristic measurement probe of the present invention that can constantly monitor (monitor) the thrombus formation status at a site where the flow rate is slow and thrombus formation is predicted, or the oxygen saturation concentration of blood before and after the gas exchange unit It is possible to comprehensively manage the heart-lung machine by installing a blood characteristic measurement probe for measuring whether or not the oxygen saturation concentration has reached a reference value.
Furthermore, in the present invention, the blood characteristic measurement probe of the present invention can be knitted into the hollow fiber membrane in the circulatory system artificial organ provided with the hollow fiber membrane as described above. As shown in FIGS. 1 and 2, the probe of the present invention has an ultrafine and flexible tip formed by an optical fiber in the light irradiation part and the light receiving part and covered with a flexible sheath. Therefore, the probe can be knitted together in the hollow fiber of the artificial lung. Thus, according to the present invention, it is possible to monitor the blood characteristics inside the oxygenator, which has been impossible in the past, in real time, and to manage the inside of the oxygenator.
(Flow analysis method in circulatory organs)
In order to optimally design, analyze, and manipulate a circulatory system artificial organ, detailed measurement data of the blood flow state in the organ is required as basic data.
For this purpose, the organ is filled with a fluid and flowed, the blood characteristic measurement probe of the present invention is inserted into the organ, light is irradiated from the light irradiation unit 3 at that position, and the reflected light is received by the light receiving unit 4. Keep it ready. In a steady state, the reflected light received by the light receiving unit 4 absorbs, shields, or scatters a substance that may have some effect (may be liquid or fine particles) as a tracer, and at least one shot upstream of the flow path ( That is, it flows in the liquid (as a pulse), and a temporal change (response) of the tracer concentration (or a change in reflected light by the tracer) is detected and measured by the blood characteristic measurement probe downstream of the flow path. This is a well-known pulse (delta) response analysis in the field of chemical engineering, in which at least one of the arrival time, flow rate, concentration, and distribution of the substance (tracer), more precisely, the temporal change of the tracer concentration By analyzing (the shape of the response curve) and making it correspond to the model expressing the flow, for example, the flow analysis in the circulatory system artificial organ in which the hollow fiber membrane is arranged can be performed.
(Probe attachment to circulatory system artificial organ (artificial lung))
FIG. 3 is a schematic diagram of a circulatory system artificial organ (artificial lung) 50 in which the blood characteristic measurement probe 1 is disposed and mounted. Hereinafter, a method for measuring blood characteristics by attaching a probe to an example of the artificial lung 50 will be described.
In the oxygenator 50, 51 is a housing, 52 is a blood inlet to the oxygenator, 53 is a blood outlet, 54 is a hollow fiber membrane (bundle), 55 is a blood pump such as a roller pump or a centrifugal pump, and 56 is (electromagnetic). A valve 57 is a (gas cylinder) connecting pipe. The blood with low oxygen saturation (reduced hemoglobin: Hb) flowing from the inlet 52 comes into contact with the air (or oxygen) supplied from the gas cylinder connecting pipe 57 to the valve 56 by contacting with the hollow fiber membrane 54. , Blood with high oxygen saturation (oxygenated hemoglobin: HbO 2 ) flows out of 53.
In this case, as shown in FIG. 3, there is a low-speed part of the artificial lung 50 where the blood flow is slow (for example, the part on the opposite side of the blood outlet 53 in the upper part of the housing 51 in FIG. 3). Expected to be prone to blood clots.
In addition, the blood inlet 52 and the blood outlet 53 of the oxygenator 50 naturally measure the value of the oxygen saturation concentration as the most important factor in the oxygenator, and ensure that the oxygen saturation is above a predetermined value. There is a need to constantly monitor and manage this. For example, three measurement probes 1A, 1B, and 1C are attached to these parts as shown in the figure.
As described in detail later, 58 is a wireless transmission unit, 60 is an arithmetic processing control device provided with a receiver, 61 is a CPU, 62 is a storage device, 63 is a display means such as a display, and 64 is a wireless reception unit. is there.
Further, as shown in FIG. 3, information (measurement data) from each probe 1A, 1B, 1C is provided with a receiver for data processing and arithmetic processing via an embedded or wearable wireless transmitter 58. It is preferable to use a system that transmits to the wireless receiving unit 64 (embedded type or mounted type) of the arithmetic processing control device 60.
The arithmetic processing control device 60 includes a central processing unit (CPU) 61, a storage device 62, a display means 63, a wireless reception unit 64, and the like. The storage device 62 includes a ROM and a RAM, and the measurement data from each probe is stored and recorded in the RAM. The ROM stores the moglobin concentration, hematocrit value, thrombus from the OS program and the reflected light intensity data described above. A program for calculating all blood characteristics of the formation status and oxygen saturation concentration is stored, and various blood characteristic values are calculated by the program.
As described above, the information of each probe 1A, 1B, 1C transferred by radio (blood characteristic data in each part 1A, 1B, 1C) is arithmetically processed by the arithmetic processing control device, and the result is displayed on the display means 63. For example, it is displayed in real time on an LED display.
Further, based on information (blood characteristic values) detected by the probes 1A, 1B, and 1C, in order to control them to appropriate values, the oxygen (air) gas flow rate to the circulatory system artificial organ and / or A construction algorithm (control program) for controlling the blood flow rate is stored in the ROM, and the arithmetic processing control device uses the control program to optimize the gas flow rate and blood flow rate to the artificial organ 50 based on the measurement data. A control system that automatically controls and optimizes the range can be constructed.
Specifically, for example, (i) when a thrombus begins to form over a certain level, the blood flow rate is increased by increasing the number of rotations of the pump, etc. (ii) the oxygen saturation causes acidosis due to excess oxygen gas The gas flow rate is adjusted so as to maintain 90% to 100% so as not to run out of oxygen. By using such a technique, it is possible to realize a portable oxygenator that does not form a thrombus for a long period of time and can maintain oxygen saturation at an appropriate value.
(The invention's effect)
(A) The blood characteristic measurement probe of the present invention has the following advantageous features or effects.
(A1) In the probe of the present invention, the blood characteristic measurement site at the tip thereof (the optical transmission / reception unit including the light irradiation unit 3 and the light receiving unit 4) is separated from the electronic circuit unit including the light emitting element and the light receiving element. Since it is a configuration, it does not have a mechanism or shape that causes a change in the blood flow. In addition, the optical transmission / reception unit including the light irradiation unit 3 and the light receiving unit 4 is composed of the light emitting optical fiber 5 and the light receiving optical fiber 6, so that it can be easily installed at any position, It can be easily installed at the manufacturing stage of the circulatory prosthetic organ to be measured.
(A2) The light-emitting optical fiber 5 and the light-receiving optical fiber 6 are connected to the light-emitting element 13 and the light-receiving element 14, respectively, and the optical transmission / reception unit 2 and the electric circuit unit 30 can be separated. The electric circuit unit including the can be used repeatedly, and only the optical transmitting / receiving unit 2 made of an optical fiber can be used as a disposable (disposable).
(A3) Furthermore, since light is guided (irradiated) by the light-emitting optical fiber 5 and the light-receiving optical fiber 6, a plurality of blood characteristics such as hemoglobin concentration, hematocrit value, oxygen saturation concentration, thrombus formation status, etc. It becomes possible to measure with.
(B) Cardiovascular artificial organs and portable / implantable artificial lungs equipped with the blood characteristic measurement probe according to the present invention have the following advantageous effects.
(B1) For measurement of blood characteristics at a relatively slow flow site such as a blood inlet or outlet of blood in an artificial lung, the first wavelength λ1 (805 ± 30 (775-835) nm) and / or the first The light irradiation unit 3 that irradiates near infrared light having a wavelength λ2 of 2 (660 ± 60 (600 to 720) nm) and the light receiving unit 4 that reflects reflected light of the near infrared light are directly connected to the blood flow path in the artificial lung. Blood characteristics can be measured by embedding in a wall surface or mounting from the outside.
(B2) When the blood characteristic measurement probe of the present invention is installed in an artificial lung and used as a blood characteristic measurement probe for use in an artificial lung, the tip of the probe (optical transmission / reception unit 2) is mainly composed of an optical fiber. A hollow fiber bundle (hollow fiber membrane) that constitutes an artificial lung (membrane-type artificial lung) by covering an optical fiber having such a small diameter and a relatively flexible structure with a flexible sheath 21. Here, blood and oxygen come into contact with each other through the hollow fiber membrane, and oxygen moves to the blood.) In the manufacturing stage, the measurement position in the hollow fiber bundle to be measured is arbitrarily determined. I can do it.
(B3) By directly measuring the scattering characteristics of the light emitted from the light irradiation section 7 at the tip of the light-emitting optical fiber 5, various blood characteristics in the vicinity of the blood characteristic measurement probe can be easily measured in real time over a long period of time. Can be realized. Therefore, further improvement of the safety performance of the oxygenator in the clinical field is expected as well as the stage of developing the oxygenator.
(B4) It is not a blood characteristic measurement by blood collection, but is a system that directly irradiates blood with light, receives its light scattering characteristics, and directly measures the reflected light intensity, so there is no patient invasion by blood collection. In addition, it greatly contributes to the prevention of infection to patients and hospital staff, which is a major problem in the case of a system involving blood collection.
(B5) The operation of the ME engineer on the artificial lung can be greatly reduced by linking the gas flow rate and blood flow rate control device and the measurement data of the blood characteristic measurement probe. This is extremely effective in realizing a portable / implantable oxygenator.
(B6) The blood characteristic measurement probe disposed in the hollow fiber bundle has two or more light emitting optical fibers 5 and light receiving optical fibers 6 each having a diameter that does not hinder blood flow and at least two pairs. By installing the blood characteristic measurement probe at an arbitrary position in the oxygenator, a large number of various pieces of information on the blood in the hollow fiber bundle can be simultaneously acquired in real time while the oxygenator is in operation. be able to.
(B7) By combining the measured optical signal with the conventional blood optical characteristics, an algorithm for measuring a large number of blood characteristic functions can be constructed, and a blood flow rate and gas flow rate control module can be created in consideration of the algorithm.
(B8) The inside is filled with a liquid to flow, and a substance that has some influence on the reflected light received by the light receiving unit 4 is caused to flow in at least one shot liquid, and at least one of the arrival time, flow velocity, concentration, and distribution of the substance is determined. By analyzing, it becomes possible to analyze the flow in the circulatory system artificial organ in which the hollow fiber membrane is arranged. Moreover, such a flow analysis system can be constructed.
以下、本発明の具体的な実施の態様を、実施例により説明する。
〔実施例１〕
（血栓形成過程ならび剥離と反射光強度の相関）
第８図に示すように生体（ウサギ）に、フローセル７１を接続し、ローラポンプ７２によって血液７３（酸素飽和度９９±０．５％）を循環する閉鎖回路７０を作製した。当該閉鎖回路７０において、血液の循環を継続したところ、循環時間が長くなるにつれ、回路内の流速が遅い部分に血栓が生じた。
第９図は、第８図で使用するフローセル内の流速分析及び血液特性プローブの設置位置を示す図であるが、図に示すように、フローセル７１内には低流速部位Ｌ１と高流速部位Ｌ２が存在し、血栓は通常この低流速部位Ｌ１において形成される。その低流速部位Ｌ１に波長λ１（８１０ｎｍ）の発光部３および受光部４を有する（血栓形成状態を計測する）血液特性測定プローブ１を取り付けた。
この状態において、循環時間と反射光強度の相関について、経時変化を測定した。第１０図に実験結果の一例を示す。血栓が形成される前（Ａ）では、ローラポンプ７２の周期に応じて反射光強度は周期的に変動している。しかしながら、血液循環時間Ｔが増加するにつれ、血栓が低流速部Ｌ１において形成され（Ｂ）、反射光強度の振幅および平均値が減衰していく（Ｃ）。これは赤血球同士が凝固し、最後には血液特性測定プローブ１が検出可能な領域にある赤血球群（血栓塊）を検出することになるが、当該血栓塊は、流れの影響を受けずにそのままの形を維持しているからである。
そして、外部からフローセル７１に強制的な振動を加えると（Ｄ点）、実験開始直後と同じような反射光強度の振幅と平均値なることが確認された（Ｅ）。これは、血液特性測定プローブ１を覆っていた血栓塊が剥離するとともに、血液特性測定プローブ１で測定される反射光強度がローラポンプ７２で流れる血液の状態を測定しているからである。
〔実施例２〕
（ヘマトクリット値と反射光強度の相関）
ヘマトクリット値が異なる複数のヘパリン加牛血液を準備し、リン酸緩衝生理食塩液により、牛血をヘマトクリット値が１０〜８０％、酸素飽和度は０〜１００％となるように調整した。本ヘパリン化加牛血を収容した透明セルに、酸化ヘモグロビン（ＨｂＯ２）の吸光度が低い波長λ１（８３０ｎｍ）の近赤外光照射部３（光度１２００ｍｃｄ、順方向電流２０ｍＡ）を６個を円状に、および、それらの中心部に受光部４が１個となるように配設した本発明の血液特性測定プローブ１を取り付けた。
上記調整した、それぞれの異なるヘマトクリット値を有する試料に対し、プローブ１により不反射光強度を測定し、ヘマトクリット値と反射光強度の相関関係を得る。ヘマトクリット値と反射光強度の相関性を血液特性測定プローブ１により測定する場合、すでに述べたように、測定に使用する当該プローブの照射部３−受光部４間距離であるＳＤ間隔が大きな影響を及ぼす因子となる。そこで、測定に先立ち、まず３次元拡散理論により、反射光強度とヘマトクリット値の関係について、数値解析を行ったところ、第５図に示す結果が得られた。図より、ＳＤ値が０．９ｍｍ以上であれば、計測対象となるヘマトクリット２０％以上において、反射光強度とヘマトクリット値の関係に線形性が得られることが確認された。
以上の結果に基づき、ＳＤを２．１ｍｍに設計した血液特性測定プローブ１を使用して、上記調整した試料により、ヘマトクリット値と反射光強度の相関を計測した。計測結果を第６図に示した。実験結果から、ヘマトクリット値と反射光の強度には強い相関が存在することが見いだされた。以上の結果から、反射光強度を測定することで、２０％以上のヘマトクリット値を正確に求めることが可能となることが確認された。
〔実施例３〕
（酸素飽和度と反射光強度の相関）
ＳＤを２．１ｍｍに設計した血液特性測定プローブ１（光源波長：８３０、７３０、６６０ｎｍを内蔵）により、実施例２と同様な血液特性について反射光強度の計測を行った。結果を第７図に示す。図は、２波長（λ１／λ２）（８３０／７３０ｎｍと８３０／６６０ｎｍ）における反射光強度比Ｒ（Ｒｅｆｌｅｃｔｅｄ ｌｉｇｈｔ ｉｎｔｅｎｓｉｔｙ）とＯＳ（酸素飽和度；Ｏｘｙｇｅｎ Ｓａｔｕｒａｔｉｏｎ）との相関を示すグラフとして表現されている。各実験結果より、反射光強度比Ｒに対する酸素飽和度ＯＳは、２次の線形近似により、０．９５以上の高い相関性を得ることが確認された。
〔実施例４〕
（人工肺に取り付けられた血液特性測定プローブにおける酸素飽和度と反射光強度の相関）
貯血槽、血液特性測定プローブが設置されたフローセルを人工心肺回路（川澄化学工業社製）で接続し、ローラポンプによって血液を循環する閉鎖回路（図示せず）を作製し、当該閉鎖回路内に３７℃のヘパリン加牛血液を循環させた。
当該回路に血液特性測定プローブ設置し、血液特性を測定した。血液特性測定プローブは、実施例１で使用したものと同様な形状とし、照射光波長λ１（８１０ｎｍ）、λ２（６４５ｎｍ）である測定プローブをそれぞれフローセルに設置し、測定を実施した。結果は第１１図に示すように、酸素飽和度ＯＳと反射光強度比Ｒ（８１０／６４５ｎｍ）は、０．９７以上の高い相関係数を得ることが確認された。
そこで、血液特性測定プローブ（照射光波長λ１（８１０ｎｍ）、λ２（６４５ｎｍ））を、人工肺モデル（第３図）に示すように、人工肺の壁面に設置をして、酸素飽和度と反射光強度の相関について計測する実験を行った。この測定実験は、貯血槽と人工肺モデルを人工心肺回路で接続し、ローラポンプによって血液を循環する閉鎖回路を作製し、当該閉鎖回路内に３７℃のヘパリン加牛血液を循環させた。循環回路内の酸素飽和度は、人工肺モデルへ酸素ガスおよび二酸化炭素ガスを流すことで調整を行った。結果は第１２図に示す。図から、酸素飽和度ＯＳと反射光強度比（８１０／６４５ｎｍ）は、０．６８以上であることが確認された。
なお、第１１図〜第１２図において、「Ｒ８１０」とは波長λ１（＝８１０ｎｍ）の光を照射した時の反射光強度であり、「Ｒ６４５」とは波長λ２（＝６４５ｎｍ）の光を照射した時の反射光強度である。図は、この比（Ｒ８１０／Ｒ６４５）、その平方根「ｓｑｒｔ（Ｒ８１０／Ｒ６４５）」、及び自然対数「ｌｎ（Ｒ８１０／Ｒ６４５）」と酸素飽和度（ＯＳ）との相関を示したものである。図から、自然対数「ｌｎ（Ｒ８１０／Ｒ６４５）」で酸素飽和度（ＯＳ）を相関させるのがその傾きから最も誤差が少ないと推定される。Hereinafter, specific embodiments of the present invention will be described by way of examples.
[Example 1]
(Correlation between thrombus formation process and peeling and reflected light intensity)
As shown in FIG. 8, a closed circuit 70 in which a flow cell 71 was connected to a living body (rabbit) and blood 73 (oxygen saturation 99 ± 0.5%) was circulated by a roller pump 72 was produced. In the closed circuit 70, when blood circulation was continued, as the circulation time became longer, a thrombus occurred in a portion where the flow rate in the circuit was slow.
Figure 9 is a view showing a flow rate analysis and the installation position of the blood characteristics probe in the flow cell used in FIG. 8, as shown in FIG, high flow rate region in the flow cell 71 with low flow region L 1 L 2 is present and a thrombus is usually formed at this low flow rate site L 1 . As the low flow rate region L 1 having a light emitting portion 3 and the light receiving portion 4 of the wavelength .lambda.1 (810 nm) (measuring thrombus formation state) fitted with a blood characteristic measuring probe 1.
In this state, the change with time of the correlation between the circulation time and the reflected light intensity was measured. FIG. 10 shows an example of the experimental results. Before the thrombus is formed (A), the reflected light intensity varies periodically according to the cycle of the roller pump 72. However, as the blood circulation time T increases, thrombus is formed at low flow rates section L 1 (B), the amplitude and the mean value of the reflected light intensity decays (C). This means that red blood cells coagulate and finally a red blood cell group (thrombus mass) in a region where the blood property measurement probe 1 can be detected is detected. It is because it maintains the shape.
When forced vibration was applied to the flow cell 71 from the outside (D point), it was confirmed that the amplitude and average value of the reflected light intensity were the same as immediately after the start of the experiment (E). This is because the thrombus that has covered the blood characteristic measuring probe 1 is peeled off and the reflected light intensity measured by the blood characteristic measuring probe 1 measures the state of blood flowing through the roller pump 72.
[Example 2]
(Correlation between hematocrit value and reflected light intensity)
A plurality of heparinized bovine bloods having different hematocrit values were prepared, and the bovine blood was adjusted with a phosphate buffered saline so that the hematocrit value was 10 to 80% and the oxygen saturation was 0 to 100%. In a transparent cell containing the heparinized calf blood, 6 pieces of near-infrared light irradiation unit 3 (luminous intensity 1200 mcd, forward current 20 mA) having a wavelength λ1 (830 nm) where the absorbance of oxyhemoglobin (HbO 2 ) is low are circular. The blood characteristic measurement probe 1 of the present invention, which is arranged in a shape and so that there is one light receiving portion 4 at the center, is attached.
The non-reflected light intensity is measured by the probe 1 for the adjusted samples having different hematocrit values, and a correlation between the hematocrit value and the reflected light intensity is obtained. When the correlation between the hematocrit value and the reflected light intensity is measured by the blood characteristic measurement probe 1, the SD interval which is the distance between the irradiation unit 3 and the light receiving unit 4 of the probe used for the measurement has a great influence as described above. It becomes a factor to affect. Therefore, prior to the measurement, first, a numerical analysis was performed on the relationship between the reflected light intensity and the hematocrit value by the three-dimensional diffusion theory, and the result shown in FIG. 5 was obtained. From the figure, it was confirmed that when the SD value is 0.9 mm or more, linearity is obtained in the relationship between the reflected light intensity and the hematocrit value when the hematocrit to be measured is 20% or more.
Based on the above results, the correlation between the hematocrit value and the reflected light intensity was measured with the above-adjusted sample using the blood characteristic measurement probe 1 designed with an SD of 2.1 mm. The measurement results are shown in FIG. From the experimental results, it was found that there is a strong correlation between the hematocrit value and the intensity of the reflected light. From the above results, it was confirmed that it is possible to accurately obtain a hematocrit value of 20% or more by measuring the reflected light intensity.
Example 3
(Correlation between oxygen saturation and reflected light intensity)
The reflected light intensity was measured for blood characteristics similar to those of Example 2 with a blood characteristic measurement probe 1 (with built-in light source wavelengths: 830, 730, and 660 nm) designed to have an SD of 2.1 mm. The results are shown in FIG. The figure is expressed as a graph showing the correlation between the reflected light intensity ratio R (Reflected light intensity) at two wavelengths (λ1 / λ2) (830/730 nm and 830/660 nm) and OS (oxygen saturation). Yes. From each experimental result, it was confirmed that the oxygen saturation OS with respect to the reflected light intensity ratio R has a high correlation of 0.95 or higher by the second-order linear approximation.
Example 4
(Correlation between oxygen saturation and reflected light intensity in blood characteristic measurement probe attached to oxygenator)
A blood cell and a flow cell in which a blood characteristic measurement probe is installed are connected by an artificial cardiopulmonary circuit (manufactured by Kawasumi Chemical Industry Co., Ltd.), and a closed circuit (not shown) for circulating blood by a roller pump is produced. Circulating heparinized cattle blood at 37 ° C.
A blood characteristic measurement probe was installed in the circuit, and blood characteristics were measured. The blood characteristic measurement probe had the same shape as that used in Example 1, and the measurement probes having the irradiation light wavelengths λ1 (810 nm) and λ2 (645 nm) were installed in the flow cell, respectively. As a result, as shown in FIG. 11, it was confirmed that the oxygen saturation OS and the reflected light intensity ratio R (810/645 nm) obtain a high correlation coefficient of 0.97 or more.
Therefore, blood characteristic measurement probes (irradiation light wavelengths λ1 (810 nm), λ2 (645 nm)) are placed on the wall of the artificial lung as shown in the artificial lung model (FIG. 3), and the oxygen saturation and reflection are measured. An experiment was conducted to measure the correlation of light intensity. In this measurement experiment, a blood reservoir and an artificial lung model were connected by an artificial cardiopulmonary circuit, a closed circuit for circulating blood by a roller pump was produced, and heparinized cow blood at 37 ° C. was circulated in the closed circuit. The oxygen saturation in the circulation circuit was adjusted by flowing oxygen gas and carbon dioxide gas through the artificial lung model. The results are shown in FIG. From the figure, it was confirmed that the oxygen saturation OS and the reflected light intensity ratio (810/645 nm) were 0.68 or more.
In FIGS. 11 to 12, “R810” is the intensity of reflected light when irradiated with light of wavelength λ1 (= 810 nm), and “R645” is irradiated with light of wavelength λ2 (= 645 nm). It is the reflected light intensity at the time. The figure shows the correlation between this ratio (R810 / R645), its square root “sqrt (R810 / R645)”, and the natural logarithm “ln (R810 / R645)” and the oxygen saturation (OS). From the figure, it is estimated that correlating oxygen saturation (OS) with the natural logarithm “ln (R810 / R645)” has the least error from the slope.
本発明の血液特性測定プローブは、その先端の血液特性の計測部位（近赤外光照射部等）は、発光素子や受光素子を含む電子回路部と分離されている構造であり、血液の流れを乱すような形状のものでなく、また、光ファイバにより構成されているので、容易に任意の位置に設置でき、また、光ファイバからなる光送受信部のみをディスポーサブル（使い捨て）として使用することができる。
また、発明の血液特性計測プローブを装着した循環器系人工臓器、携帯型・埋め込み型を含む人工肺においては、流れが遅く血栓が生じやすい部位などに光送受信部を血液流路壁面に装着することが可能であり、人工肺（膜型人工肺）を構成する中空糸膜の製作段階において、血栓が生じやすい膜中に容易に織り込むことが出来るため、計測対象となる中空糸束における計測位置を、随意に決定することができる。すなわち、これらの産業上の利用可能性は、非常に大きい。The blood characteristic measurement probe of the present invention has a structure in which a blood characteristic measurement site (near infrared light irradiation part or the like) at the tip is separated from an electronic circuit part including a light emitting element and a light receiving element. In addition, it is configured by an optical fiber, so that it can be easily installed at an arbitrary position, and only an optical transmission / reception unit made of an optical fiber can be used as a disposable (disposable). it can.
In addition, in an artificial lung including a circulatory system artificial organ and a portable / implantable type equipped with the blood characteristic measurement probe of the invention, an optical transmission / reception unit is attached to the blood flow channel wall surface at a site where flow is slow and thrombosis is likely to occur. In the production stage of the hollow fiber membrane that constitutes the artificial lung (membrane type artificial lung), it can be easily woven into the membrane that is prone to thrombus, so the measurement position in the hollow fiber bundle to be measured Can be determined at will. That is, the industrial applicability is very large.
Claims (12)
前記光照射部（３）と前記受光部（４）は略並列に配置され、
前記光照射部（３）先端の光照射先端部（７）の中心（７Ｃ）と前記受光部（４）先端の光検出部（８）の中心（８Ｃ）の間隔（ＳＤ）を０．９〜３．０ｍｍにしたものを少なくとも光送受信部（２）として含むことを特徴とする血液特性測定プローブ（１）。A light irradiation unit for irradiating near-infrared light having a first wavelength λ1 (805 ± 30 (775-835) nm) and / or a second wavelength λ2 (660 ± 60 (600-720) nm) into blood ( 3) and a light receiving part (4) for the reflected light of the near-infrared light irradiated on the blood,
The light irradiation part (3) and the light receiving part (4) are arranged substantially in parallel,
The distance (SD) between the center (7C) of the light irradiation tip (7) at the tip of the light irradiation part (3) and the center (8C) of the light detection part (8) at the tip of the light receiving part (4) is 0.9. A blood characteristic measurement probe (1) comprising at least 3.0 mm as an optical transmission / reception unit (2).
前記照射用光ファイバ（５）と受光用光ファイバ（６）を含む前記光送受信部（２）が、前記発光素子（１３）と前記受光素子（１４）を含む電子回路部（３０）とから分離されていることを特徴とする請求項１または請求項２に記載の血液特性測定プローブ（１）。The irradiation optical fiber (5) is connected to the light emitting element (13), the light receiving optical fiber (6) is connected to the light receiving element (14),
The optical transmission / reception unit (2) including the irradiation optical fiber (5) and the light receiving optical fiber (6) includes the light emitting element (13) and the electronic circuit unit (30) including the light receiving element (14). The blood characteristic measuring probe (1) according to claim 1 or 2, wherein the blood characteristic measuring probe (1) is separated.
当該血液中に照射した近赤外光の第１の波長λ１（８０５±３０（７７５〜８３５）ｎｍ）及び第２の波長λ２（６６０±６０（６００〜７２０）ｎｍの反射光強度を測定することにより、当該血液中の酸素飽和度を計測可能であることを特徴とする請求項１から請求項４のいずれかに記載の血液特性測定プローブ（１）。By measuring the intensity of reflected light at the first wavelength λ1 (805 ± 30 (775-835) nm) of near-infrared light irradiated into blood, the hematocrit value, hemoglobin concentration, and thrombus formation status in the blood can be determined. Is measurable,
The reflected light intensity of the first wavelength λ1 (805 ± 30 (775-835) nm) and the second wavelength λ2 (660 ± 60 (600-720) nm) of the near infrared light irradiated into the blood is measured. Thus, the blood characteristic measurement probe (1) according to any one of claims 1 to 4, wherein the oxygen saturation in the blood can be measured.
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| JP2008505210A JP4944093B2 (en) | 2006-03-10 | 2007-03-09 | Blood characteristic measurement probe, circulatory system artificial organ and artificial lung |
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| JP2008505210A JP4944093B2 (en) | 2006-03-10 | 2007-03-09 | Blood characteristic measurement probe, circulatory system artificial organ and artificial lung |
| PCT/JP2007/055302 WO2007105805A1 (en) | 2006-03-10 | 2007-03-09 | Blood characteristics measuring probe, cardiovascular system artificial organ and artificial lung |
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| EP3193957B1 (en) * | 2014-08-29 | 2019-04-10 | Fresenius Kabi Deutschland GmbH | Tubing set for use in a blood processing apparatus |
| EP3193956B1 (en) * | 2014-08-29 | 2018-11-07 | Fresenius Kabi Deutschland GmbH | A blood processing apparatus comprising a holder device for a measurement device |
| CN106794289B (en) * | 2014-08-29 | 2019-07-12 | 费森尤斯卡比德国有限公司 | Blood processing apparatus including measuring device |
| JP6799245B2 (en) * | 2016-02-25 | 2020-12-16 | 国立研究開発法人産業技術総合研究所 | How to measure changes in the amount of fibrin in blood |
| CN110554087A (en) * | 2019-09-18 | 2019-12-10 | 哈尔滨工业大学 | Device for detecting blood clots |
| JP2023056972A (en) * | 2021-10-08 | 2023-04-20 | 日機装株式会社 | Blood purification device |
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| EP0336985B1 (en) * | 1988-04-09 | 1993-01-27 | Hewlett-Packard GmbH | Method for manufacturing an optical probe |
| JPH0257239A (en) * | 1988-08-23 | 1990-02-27 | Terumo Corp | Probe for optical sensor |
| JPH0318742A (en) * | 1989-06-16 | 1991-01-28 | Terumo Corp | Instrument for measuring saturation degree of oxygen |
| WO2001017422A1 (en) * | 1999-09-08 | 2001-03-15 | Optoq Ab | Method and apparatus for detecting blood characteristics including hemoglobin |
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