JP2011142929A - Low-invasive neoangiogenesis measuring device - Google Patents
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本発明は、医療分野、特に臓器移植や再生医療の分野において、移植手術後の臓器周辺における栄養血管網の新生過程や、糖尿病患者の末梢血管障害の治療効果を定量的に評価、診断するための低侵襲血管新生計測装置に関する。 The present invention is for quantitatively evaluating and diagnosing the therapeutic effect of a nutritional vascular network around the organ after transplantation surgery and peripheral vascular disorders in diabetic patients in the medical field, particularly organ transplantation and regenerative medicine. The present invention relates to a minimally invasive angiogenesis measuring apparatus.
近年、病気や事故によって失われた体の細胞や組織、臓器などの再生や機能回復を、細胞移植や組織移植することで実現する再生医療の研究開発が進んでおり、再生骨や再生軟骨、再生皮膚、再生角膜、再生心筋、再生腎臓、再生肝臓などが研究対象となっている。
これら再生組織や再生臓器を生体内へ移植した後、長期間安定して機能させるためには、酸素や栄養を供給できるような栄養血管網を、再生組織や再生臓器に誘導する必要がある。
そのため、再生組織や再生臓器を生体に移植した後、再生組織や再生臓器周辺の栄養血管網の新生度を評価することが重要である。
In recent years, research and development of regenerative medicine that realizes regeneration and functional recovery of body cells, tissues, organs etc. lost due to illness or accident by cell transplantation or tissue transplantation has progressed, and regenerative bone, regenerated cartilage, Research subjects include regenerated skin, regenerated cornea, regenerated myocardium, regenerated kidney, and regenerated liver.
In order to function stably for a long period of time after transplanting these regenerated tissues and organs into the living body, it is necessary to induce a nutrient vascular network that can supply oxygen and nutrients to the regenerated tissues and organs.
Therefore, it is important to evaluate the degree of newness of the nutrient vascular network around the regenerated tissue or organ after transplanting the regenerated tissue or organ into the living body.
すなわち、こうした臓器移植に際しては、移植手術時に主要な血管は接続されるが、臓器移植の正否は、移植手術後、移植された臓器周辺における栄養血管網の新生度が大きく影響する。
主要血管の接続が成功しても、その後栄養血管網が健全に新生されなければ、結局移植された臓器に栄養が補給されず、最悪の場合壊死してしまう。
したがって、移植手術後、臓器周辺における栄養血管網の新生状況を正確に計測し、投薬治療、再手術の要否を的確に診断することが非常に重要である。
このことは、糖尿病患者の末梢血管障害の治療効果を定量的に診断する上でもまったく同様である。
That is, in such organ transplantation, main blood vessels are connected at the time of transplantation surgery, but the correctness of organ transplantation is greatly influenced by the newness of the nutritional vascular network around the transplanted organ after transplantation surgery.
Even if the connection of the main blood vessels is successful, if the nutritional vascular network is not born again after that, the transplanted organ will not be replenished, and in the worst case, it will be necrotic.
Therefore, after transplantation surgery, it is very important to accurately measure the new state of the nutritional vascular network around the organ and accurately diagnose the necessity of medication and reoperation.
This is exactly the same in quantitatively diagnosing the therapeutic effect of peripheral vascular disorders in diabetic patients.
従来、血液中の成分濃度を計測する装置として、下記特許文献１にみられるように、生体を撮像して得られる生体画像中の血管像に基づいて血液に含まれる成分濃度を算出することが知られている。 Conventionally, as an apparatus for measuring the concentration of a component in blood, as seen in Patent Document 1 below, calculating the concentration of a component contained in blood based on a blood vessel image in a living body image obtained by imaging a living body Are known.
また、脳表面を含む複数部位の血流量の変化を計測する装置として、下記特許文献２にみられるように、複数の光照射プローブと複数の光検出プローブで、検出光量のマッピングを行うことが知られている。 Further, as a device for measuring changes in blood flow in a plurality of parts including the brain surface, mapping of detected light amounts can be performed with a plurality of light irradiation probes and a plurality of light detection probes as seen in Patent Document 2 below. Are known.
さらに下記特許文献３には、300〜700nmの波長領域を使用した生体情報計測装置が、下記特許文献４には、３種類以上の光の吸収度合いの違いにより血液量を計測する血液量測定装置が、下記特許文献５には、所定波長の光を血液流路中に照射して、ヘマトクリットまたは酸素飽和度を求める血液特性計測装置が示されている。 Furthermore, the following Patent Document 3 discloses a biological information measuring device using a wavelength region of 300 to 700 nm, and the following Patent Document 4 describes a blood volume measuring device that measures a blood volume based on differences in the degree of absorption of three or more types of light. However, Patent Document 5 below discloses a blood characteristic measuring device that irradiates light of a predetermined wavelength into a blood flow path to obtain hematocrit or oxygen saturation.
これらの計測装置では、測定部位における血液の成分濃度や血液量は計測できるものの、臓器周辺における栄養血管網の新生度を計測することはできず、病理標本による侵襲を伴う検査や、血管造影剤による血管造影、超音波エコーを用いた画像診断技術などを使用して、生体内の血管を画像化することにより、非侵襲での検査方法が行われている。 Although these measuring devices can measure the blood component concentration and blood volume at the measurement site, they cannot measure the degree of neovascularization of the nutrient vascular network around the organ. A non-invasive examination method is performed by imaging a blood vessel in a living body using angiography based on the above, an image diagnostic technique using ultrasonic echoes, and the like.
しかし、病理標本検査や血管造影検査は、被験者に大きな負担を掛けるものであり、これを定期的に行うと、被験者の健康を阻害するおそれが生じる。
また、超音波エコーを用いた画像診断技術では、画像分解能に制限があるため、細かい細動脈や毛細血管などの細い血管網までは評価することは困難である。
そこで、非侵襲あるいは低侵襲で被験者に負担を与えず、しかも簡便な計測装置により高精度に栄養血管網の新生度や末梢血管障害の治療効果の計測を可能にすることが強く求められている。
However, pathological specimen examination and angiography examination place a heavy burden on the subject. If this is performed regularly, the health of the subject may be impaired.
In addition, in image diagnostic techniques using ultrasonic echoes, it is difficult to evaluate even fine blood vessels such as fine arterioles and capillaries because image resolution is limited.
Therefore, there is a strong demand to enable measurement of the degree of neovascularization of the vascular network and the therapeutic effect of peripheral vascular disorders with high accuracy by a simple measurement device that is non-invasive or minimally invasive and does not burden the subject. .
そこで、上記の課題を解決するため、本発明の低侵襲血管新生計測装置においては、次のような技術的手段を講じた。すなわち、
（１）新生血管の新生度を計測する装置において、生体組織透過性が高い近赤外光を新生血管測定部位に照射するための発光部と、該発光部から照射された近赤外光が、前記新生血管測定部位において散乱反射して得られる反射近赤外光を受光するための受光部と、前記発光部から照射された近赤外光と前記受光部で受光した反射近赤外光とに基づいて、前記新生血管測定部位における近赤外光の減衰率を演算する減衰率演算部と、該減衰率に基づいて、前記新生血管測定部位における血液量を演算する血液量演算手段と、該血液量を記録する記録部と、前記血液量の時間経過に応じた変化率に基づいて、前記新生血管測定部位内における新生血管の新生度を評価する血管新生度評価手段とを備えた。
Therefore, in order to solve the above-described problems, the following technical means have been taken in the minimally invasive angiogenesis measuring device of the present invention. That is,
(1) In an apparatus for measuring the degree of neovascularization, a light emitting unit for irradiating a neovascular measurement site with near infrared light having high biological tissue permeability, and a near infrared light irradiated from the light emitting unit A light receiving unit for receiving reflected near infrared light obtained by scattering and reflecting at the neovascularization measurement site, near infrared light emitted from the light emitting unit, and reflected near infrared light received by the light receiving unit And an attenuation rate calculation unit for calculating the near infrared light attenuation rate at the neovascular measurement site, and a blood volume calculation means for calculating the blood volume at the neovascular measurement site based on the attenuation rate. And a recording unit for recording the blood volume, and an angiogenesis evaluation means for evaluating the neovascularization degree in the new blood vessel measurement site based on the rate of change of the blood volume over time. .
（２）新生血管の新生度を計測する装置において、生体組織透過性の高い近赤外光を新生血管測定部位に照射するための発光部と、該発光部から照射された近赤外光が、前記新生血管測定部位を透過して得られる透過近赤外光を受光するための受光部と、前記発光部から照射された近赤外光と前記受光部で受光した反射近赤外光とに基づいて、前記新生血管測定部位における近赤外光の減衰率を演算する減衰率演算部と、該減衰率に基づいて、前記新生血管測定部位における血液量を演算する血液量演算手段と、該血液量を記録する記録部と、前記血液量の時間経過に応じた変化率に基づいて、前記新生血管測定部位内における新生血管の新生度を評価する血管新生度評価手段とを備えた。 (2) In an apparatus for measuring the degree of neovascularization, a light emitting unit for irradiating a neovascular measurement site with near-infrared light having high biological tissue permeability, and a near-infrared light emitted from the light emitting unit A light receiving unit for receiving transmitted near-infrared light obtained by passing through the neovascularization measurement site, near-infrared light emitted from the light-emitting unit, and reflected near-infrared light received by the light-receiving unit, An attenuation rate calculation unit for calculating an attenuation rate of near-infrared light in the neovascular measurement site, and a blood volume calculation means for calculating a blood volume in the neovascular measurement site based on the attenuation rate, A recording unit that records the blood volume, and an angiogenesis degree evaluation unit that evaluates the degree of neovascularization in the neovascularization measurement site based on the rate of change of the blood volume over time.
（３）上記の低侵襲血管新生計測装置において、前記発光部は、酸化ヘモグロビンと還元ヘモグロビンの等吸収点となる波長を前記新生血管測定部位に照射するようにした。 (3) In the above-mentioned minimally invasive angiogenesis measuring device, the light emitting unit irradiates the neovascular measurement site with a wavelength that is an isosbestic point of oxyhemoglobin and reduced hemoglobin.
（４）上記の低侵襲血管新生計測装置において、ひとつの発光部から照射された近赤外光の前記反射近赤外光あるいは前記透過近赤外光を、複数の受光部で受光するようにした。 (4) In the above-mentioned minimally invasive angiogenesis measuring device, the reflected near-infrared light or the transmitted near-infrared light of the near-infrared light emitted from one light-emitting unit is received by a plurality of light-receiving units. did.
（５）上記の低侵襲血管新生計測装置において、前記血管新生度評価手段は、前記発光部から異なる距離に設置した２つの受光部の検出値に基づいて、深さの異なる血液量の差分を求め、浅部における毛細血管の血液量変化を補償する手段を備えた。 (5) In the above-mentioned minimally invasive angiogenesis measuring device, the angiogenesis degree evaluation means calculates a difference in blood volume at different depths based on detection values of two light receiving units installed at different distances from the light emitting unit. Means for compensating for changes in blood volume of capillaries in the shallow portion were provided.
（６）上記の低侵襲血管新生計測装置において、前記受光部として近赤外線カメラを用い、前記血管新生度評価手段が該近赤外線カメラの出力に基づいて画像処理を行うことにより、前記血管新生度評価手段が前記新生血管測定部位における新生血管の新生度を評価するようにした。 (6) In the above-mentioned minimally invasive angiogenesis measuring device, a near-infrared camera is used as the light-receiving unit, and the angiogenesis-evaluating means performs image processing based on the output of the near-infrared camera, whereby the angiogenesis degree The evaluation means evaluates the degree of neovascularization at the neovascular measurement site.
（７）上記の低侵襲血管新生計測装置において、前記発光部は複数波長の近赤外光を前記新生血管測定部位に時間差をつけて照射し、前記減衰率演算部は、それぞれの照射タイミング毎の波長の減衰率から前記新生血管測定部位内における近赤外光の減衰率を演算するようにした。 (7) In the above-described minimally invasive angiogenesis measurement device, the light-emitting unit irradiates the neovascularization measurement site with a plurality of wavelengths of near-infrared light with a time difference, and the attenuation rate calculation unit is configured for each irradiation timing. The attenuation rate of near-infrared light in the neovascularization measurement site is calculated from the attenuation rate of the wavelength.
（８）上記の低侵襲血管新生計測装置において、前記発光部は複数波長の近赤外光を前記新生血管測定部位に照射するとともに、前記受光部は分光器を備え、前記減衰率演算部が、前記分光器により分光分析された近赤外光の減衰率を演算するようにした。 (8) In the above-mentioned minimally invasive angiogenesis measuring device, the light emitting unit irradiates the neovascularized measurement site with a plurality of wavelengths of near infrared light, the light receiving unit includes a spectroscope, and the attenuation rate calculating unit The attenuation rate of near-infrared light spectrally analyzed by the spectroscope is calculated.
（９）上記の低侵襲血管新生計測装置において、前記発光部と前記受光部が２つの組からなり、前記減衰率演算部は、一方の組により前記新生血管測定部位における近赤外光の減衰率を演算するとともに、他方の組により、前記新生血管測定部位の近傍にある基準部位における近赤外光の減衰率を演算し、前記血管新生度評価手段は、前記新生血管測定部位における近赤外光の減衰率に基づいて演算された血液量の変化率と、前記基準部位における近赤外光の減衰率に基づいて演算された血液量の変化率とを比較することにより、前記新生血管測定部位内における新生血管の新生度を評価するようにした。 (9) In the above-described minimally invasive angiogenesis measuring device, the light emitting unit and the light receiving unit are composed of two sets, and the attenuation rate calculating unit attenuates near-infrared light at the neovascular measurement site by one set. And calculating the rate of near-infrared light attenuation at a reference site in the vicinity of the new blood vessel measurement site by the other set. By comparing the change rate of the blood volume calculated based on the attenuation rate of external light and the change rate of the blood volume calculated based on the attenuation rate of near-infrared light at the reference site, the new blood vessel The degree of neovascularization in the measurement site was evaluated.
本発明によれば、次のような効果を奏することができる。
（１）生体外から近赤外線を測定部位に照射するため、非侵襲あるいは低侵襲で血管新生度の計測評価が可能となる。
（２）新生血管網を画像化するのではなく、血液量として評価するため、細動脈や毛細血管などの極めて細い新生血管網の新生度を計測評価することができ、造影剤を使用する必要もない。
（３）新生血管網の測定部位近傍に基準点を取るため、患者の生理状態の変動や日内変動の影響を軽減することができる。
（４）受光部に近赤外線カメラを用いることで、一度に広範囲の血管新生度を計測評価することができる。
According to the present invention, the following effects can be achieved.
(1) Since the near-infrared ray is irradiated from outside the living body, measurement and evaluation of the degree of neovascularization can be performed in a non-invasive or minimally invasive manner.
(2) Since the neovascular network is not imaged but is evaluated as a blood volume, it is possible to measure and evaluate the degree of neovascular network such as arterioles and capillaries, and use a contrast medium Nor.
(3) Since the reference point is set in the vicinity of the measurement site of the neovascular network, it is possible to reduce the influence of fluctuations in the physiological state of the patient and fluctuations within the day.
(4) By using a near-infrared camera for the light receiving unit, it is possible to measure and evaluate a wide range of angiogenesis at a time.
以下、本発明の実施例を、図面を参照しつつ説明する。 Embodiments of the present invention will be described below with reference to the drawings.
［第１実施例］
図1は本発明の第１実施例の基本ブロック図を示すものであり、ＬＥＤまたは半導体レーザー素子からなる発光素子とこれを駆動する駆動回路からなる発光部１ａ、１ｂと、この発光部１ａ、１ｂから照射された近赤外光が、測定部位内において散乱反射して得られる反射近赤外光を受光するためのフォトダイオードあるいはフォトトランジスタからなる素子及びその出力を増幅する増幅回路からなる受光部２ａ、２ｂを備えている。
[First embodiment]
FIG. 1 shows a basic block diagram of a first embodiment of the present invention. A light emitting element 1a, 1b comprising a light emitting element made of an LED or a semiconductor laser element and a drive circuit for driving the light emitting element, and the light emitting part 1a, Light reception comprising an element composed of a photodiode or phototransistor for receiving reflected near infrared light obtained by scattering and reflecting near-infrared light irradiated from 1b in the measurement site and an amplification circuit for amplifying the output thereof Part 2a, 2b is provided.
例えば、生体内の近赤外光が到達する範囲に植え込まれた、鼻や耳の再生軟骨や指の再生骨、再生皮膚などを対象に、発光部１ａ、１ｂから、生体の窓と呼ばれ、血液中のヘモグロビンに吸収される以外は、生体組織に対しては透過性が高い600〜1000nmの近赤外光を新生血管測定部位、及びその周辺の基準部位に照射し、新生血管測定部位内及び基準部位を散乱反射して得られた近赤外光をフォトダイオードあるいはフォトトランジスタを使用した受光部２ａ、２ｂでそれぞれ受光する。 For example, from the light emitting units 1a and 1b to the regenerated cartilage of the nose and the ear, the regenerated bone of the finger, the regenerated skin, etc., which are implanted in the range where the near infrared light reaches in the living body, it is called a living body window. In addition to being absorbed by hemoglobin in the blood, the near-infrared light of 600 to 1000 nm, which is highly permeable to living tissue, is irradiated to the neovascularization measurement site and its surrounding reference site to measure the neovascularization Near-infrared light obtained by scattering and reflecting the inside of the part and the reference part is received by the light receiving parts 2a and 2b using photodiodes or phototransistors.
そして、発光部１ａ、１ｂの信号と受光部２ａ、２ｂの信号に基づいて演算部５で新生血管測定部位内のヘモグロビンによる近赤外光の減衰率から、ランベルト・ベールの法則を利用して血液量を算出し、記録部６で計測値を保存する。
また、生体の日内変動や生理状態による変動の影響を補償するため、ほぼ同等の生体組織である新生血管測定部の近傍でも血液量を計測し、記録部で計測値を保存する。最後に評価部７で、新生血管の新生開始時からの新生血管測定部とその近傍の血液量の変化を差分することで、新生血管の新生度を評価する。
Based on the signals of the light emitting units 1a and 1b and the signals of the light receiving units 2a and 2b, the calculation unit 5 uses the Lambert-Beer law from the attenuation rate of near-infrared light due to hemoglobin in the neovascularization site. The blood volume is calculated, and the measured value is stored in the recording unit 6.
In addition, in order to compensate for the effects of daily fluctuations in the living body and fluctuations due to physiological conditions, the blood volume is measured in the vicinity of the neovascularization measurement section, which is a substantially equivalent biological tissue, and the measurement value is stored in the recording section. Finally, the evaluation unit 7 evaluates the neovascularization degree of the new blood vessel by subtracting the change in the blood volume in the vicinity of the new blood vessel measurement unit from the start of the new blood vessel.
すなわち、発光部１ａの発光素子及び受光部２ａの受光素子は、新生血管測定部位である、再生治療を行った部分の直上付近に密着されるものであり、減衰率演算部３ａにより、発光部１ａの発光強度と受光部２ａの受光強度とに基づいて、新生血管測定部位における近赤外光の減衰率が演算される。 That is, the light-emitting element of the light-emitting unit 1a and the light-receiving element of the light-receiving unit 2a are in close contact with the vicinity of the neovascular measurement site, where the regenerative treatment has been performed. Based on the light emission intensity of 1a and the light reception intensity of the light receiving unit 2a, the near infrared light attenuation rate at the neovascularization measurement site is calculated.
一方、発光部１ｂの発光素子及び受光部２ｂの受光素子は、移植された臓器の周辺であって、ほぼ同等の生体組織を有し、移植手術とは直接関わりなく、細動脈や毛細血管が健全に巡らされている基準部位に密着されるものであり、同様に、減衰率演算部３ｂにより、発光部１ｂの発光強度と受光部２ｂの受光強度とに基づいて、基準部位における近赤外光の減衰率が演算される。 On the other hand, the light-emitting element of the light-emitting unit 1b and the light-receiving element of the light-receiving unit 2b are around the transplanted organ and have almost the same living tissue. Similarly, it is in close contact with a reference region that is soundly circulated. Similarly, the near-infrared light at the reference region is calculated by the attenuation factor calculation unit 3b based on the light emission intensity of the light emitting unit 1b and the light reception intensity of the light receiving unit 2b. The light attenuation rate is calculated.
各減衰率演算部３ａ、３ｂで演算された各減衰率は、血液量演算部５により新生血管測定部位における血液量を演算し、記録部６に計測日時とともに記録する。
同様に、血液量演算部５は基準部位における血液量を演算し、記録部６に計測日時とともに記録する。
The respective attenuation rates calculated by the respective attenuation rate calculation units 3a and 3b are calculated by the blood volume calculation unit 5 to calculate the blood volume at the new blood vessel measurement site and recorded in the recording unit 6 together with the measurement date and time.
Similarly, the blood volume calculation unit 5 calculates the blood volume at the reference site and records it in the recording unit 6 together with the measurement date and time.
血管新生度評価部７は、記録された新生血管測定部位における血液量及び基準部位における血液量に基づいて、手術後からの経過時間に応じた両者の血液量の変化率を求め、その差分に基づいて、正常な血液新生が行われた場合の変化率と比較し、細動脈や毛細血管が健全に新生しているか否かを評価する。 Based on the recorded blood volume at the new blood vessel measurement site and the blood volume at the reference site, the angiogenesis degree evaluation unit 7 obtains the rate of change of both blood volumes according to the elapsed time after the operation, Based on this, it is compared with the rate of change when normal hematopoiesis is performed, and it is evaluated whether or not arterioles and capillaries are born healthy.
なお、この実施例では、血管新生度評価部７が、手術後からの経過時間に応じた新生血管測定部位の血液量の変化率と、基準部位における血液量の変化率の差分に基づいて、正常な血液新生が行われたか否かを評価しているが、これは、計測時の被験者の脈拍変動や体調等により左右するため、新生血管による影響のない基準部位における血液量の変化と新生血管測定部位における血液量の変化を比較することにより、被験者の脈拍変動や体調等による影響を排除するためである。
このような被験者の脈拍変動や体調等による影響が少ない場合は、必ずしも基準部位における血液量の変化率を求める必要はない。
In this embodiment, the angiogenesis degree evaluation unit 7 is based on the difference between the change rate of the blood volume at the neovascularization measurement site according to the elapsed time after the operation and the change rate of the blood volume at the reference site. We are evaluating whether or not normal hematopoiesis has occurred, but this depends on the subject's pulse fluctuation and physical condition at the time of measurement. This is because the change in blood volume at the blood vessel measurement site is compared to eliminate the influence of the subject's pulse fluctuation, physical condition, and the like.
When there is little influence by such a subject's pulse fluctuation, physical condition, etc., it is not necessarily required to obtain the rate of change in blood volume at the reference site.
図２に、血管新生度を評価する評価部の構成例を示す。
新生血管測定部位において、細動脈や毛細血管の新生が進むにつれ、その密度が高くなり、血液量が増大していく。一方、この発光部１ａから新生血管測定部位に照射された近赤外光は、血液中の赤血球に含まれるヘモグロビンに対し吸収性の高い波長を有しているため、細動脈や毛細血管の新生につれ、新生血管測定部位内での吸収量が増加し、散乱反射する反射近赤外光が減少することになる。
したがって、減衰率演算部３ａにより、発光部１ａからの発光強度と受光部２ａで検出される受光強度に基づいて減衰率を演算すれば、血液量演算部５により血液量を求めることができ、移植手術後の経過時間に応じた血液量の変化率を求めることができる。
FIG. 2 shows a configuration example of the evaluation unit that evaluates the degree of neovascularization.
As arterioles and capillaries are newly developed at the new blood vessel measurement site, the density increases and the blood volume increases. On the other hand, the near-infrared light irradiated to the neovascular measurement site from the light emitting part 1a has a wavelength that is highly absorbed by hemoglobin contained in red blood cells in the blood, and therefore, neovascularization of arterioles and capillaries. As a result, the amount of absorption in the new blood vessel measurement site increases, and the reflected near-infrared light scattered and reflected decreases.
Therefore, if the attenuation rate is calculated based on the light emission intensity from the light emitting unit 1a and the light reception intensity detected by the light receiving unit 2a by the attenuation rate calculating unit 3a, the blood volume calculating unit 5 can determine the blood volume. The change rate of the blood volume according to the elapsed time after the transplant operation can be obtained.
同様に、発光部１ｂからの発光強度と受光部２ｂで検出される受光強度に基づいて、基準部位における血液量の変化率を求め、両者の差をとれば、基準部位における血液量の変化率と比較した新生血管測定部位における血液量の変化率と、血管新生診断マップにおける良好な血液量の変化率と比較することにより、新生血管測定部位において、細動脈や毛細血管の新生が健全に進行しているか否かを診断することが可能になる。 Similarly, based on the light emission intensity from the light emitting unit 1b and the light reception intensity detected by the light receiving unit 2b, the rate of change in blood volume at the reference site is obtained. Compared with the rate of change in blood volume at the neovascularization site compared to the rate of change in blood volume at the neovascularization diagnostic map, the arteriole and capillary neovascularization progresses smoothly at the neovascularization site. It is possible to diagnose whether or not
図３に、本実施例による血管新生計測装置をラットに用いた場合の実験結果を示す。
本実験では、図４に示すように、半導体レーザー素子を使用した発光部から発光用光ファイバを通じて計測部位に近赤外光を照射し、浅部受光用光ファイバと深部受光用の光ファイバを通じて受光部により近赤外光を受光する。
なお、浅部受光用光ファイバと深部受光用の光ファイバは、その受光部が光源から半径方向に異なる距離にその先端が設置され、反射角に応じて浅部及び深部からの近赤外光を受光し、浅部の再生に関与しない毛細血管の血液量変化を補償する。
FIG. 3 shows the experimental results when the angiogenesis measuring apparatus according to this example is used in rats.
In this experiment, as shown in FIG. 4, the measurement region is irradiated with near-infrared light through a light-emitting optical fiber from a light-emitting unit using a semiconductor laser element, and then passed through a shallow light-receiving optical fiber and a deep light-receiving optical fiber. Near infrared light is received by the light receiving unit.
In addition, the optical fiber for receiving the shallow part and the optical fiber for receiving the deep part have their light receiving parts disposed at different distances in the radial direction from the light source, and near infrared light from the shallow part and the deep part depending on the reflection angle. And compensates for changes in blood volume in capillaries not involved in shallow regeneration.
また、新生血管の測定部位の近傍に、血液量の基準部位を設け、同様の発光部及び受光部により、基準部位の血液量変化を求めた。
なお、血液量変化は赤血球数密度の変化として計測し、血管新生開始時、３日目、５日目の計測を行った。そして、５日間の赤血球数密度の変化の計測結果と５日目の実験終了時の病理標本結果による血管新生度合いの結果をまとめた。
In addition, a blood volume reference site was provided in the vicinity of the new blood vessel measurement site, and a change in the blood volume of the reference site was determined using the same light emitting unit and light receiving unit.
The change in blood volume was measured as a change in red blood cell number density, and measurement was performed on the third and fifth days at the start of angiogenesis. Then, the results of the degree of angiogenesis based on the measurement results of the change in red blood cell number density during 5 days and the pathological specimen results at the end of the experiment on the 5th day were summarized.
その結果、本実施例により赤血球密度が、基準部位と比較して平均9.49×104個/mm3増加したことが計測されたラット（血管誘導ゲルを使用）については、組織染色で血管誘導ゲルを使用して、血管新生が良好に進行していることが確認できた。
一方、基準部位と比較した赤血球密度の増加が平均5.90×104個/mm3にとどまったラットについては、血管誘導ゲルを使用したものの、組織染色部位で血管新生が不良と評価され、さらに血管誘導ゲルを使用しないラットについては、基準部位と比較した赤血球密度の増加が平均1.58×104個/mm3と計測された。
本試験の結果、本実施例により計測された赤血球密度の増加が、血管新生度を非侵襲で評価する上で有用なパラメータになることが確認された。
As a result, in the rat (using a blood vessel induction gel) in which the red blood cell density was measured to increase by an average of 9.49 × 10 4 cells / mm 3 compared to the reference site according to this example, the blood vessel induction gel was obtained by tissue staining. It was confirmed that angiogenesis was progressing satisfactorily.
On the other hand, in rats where the increase in the red blood cell density compared to the reference site averaged 5.90 × 10 4 cells / mm 3 on average, the angiogenesis was evaluated at the tissue stained site, although the blood vessel induction gel was used. For rats that did not use the induction gel, the increase in red blood cell density compared to the reference site was measured to average 1.58 × 10 4 cells / mm 3 .
As a result of this test, it was confirmed that the increase in red blood cell density measured by this example was a useful parameter for non-invasive evaluation of the degree of neovascularization.
［第２実施例］
図５は本発明の第２実施例の基本ブロック図を示すものであり、１つの発光部１ｃに対し、２つの受光素子２ｃ、２ｄを使用した例を示す。
この発光部１ｃは、新生血管測定部位及び基準部位の双方に照射し得るよう広角な発光素子を備えており、減衰率演算部３ｃ、３ｄの双方に発光部１ｃの発光強度が入力される点を除いて、他の構成は実施例１と同様である。
[Second Embodiment]
FIG. 5 shows a basic block diagram of the second embodiment of the present invention, and shows an example in which two light receiving elements 2c and 2d are used for one light emitting portion 1c.
The light emitting unit 1c includes a wide-angle light emitting element that can irradiate both the neovascular measurement site and the reference site, and the light emission intensity of the light emitting unit 1c is input to both the attenuation rate calculation units 3c and 3d. Except for, other configurations are the same as those in the first embodiment.
［第３実施例］
図６は本発明の第３実施例の基本ブロック図を示すものであり、受光素子として近赤外カメラを用いた例である。
生体内の近赤外光が到達する範囲に植え込まれた、鼻や耳の再生軟骨や指の再生骨、再生皮膚などを対象に、LEDまたは半導体レーザー素子を使用したひとつの発光部１ｄから第２実施例と同様に、近赤外光を新生血管測定部位及び基準部位の双方に照射し、新生血管測定部位内を散乱反射して得られた近赤外光を、近赤外光の受光感度を有するＣＣＤカメラにより撮像する。そして、実施例１と同様に、撮影された画像中の各画素の血液量を画像処理により求め、新生血管の新生開始時からの新生血管の測定部位と基準部位の血液量変化の差から血管新生度を評価する。
[Third embodiment]
FIG. 6 shows a basic block diagram of a third embodiment of the present invention, which is an example using a near infrared camera as a light receiving element.
From a single light emitting unit 1d using an LED or a semiconductor laser device for the regenerated cartilage of the nose and ears, the regenerated bone of the finger, the regenerated skin, etc., which are implanted within the reach of near-infrared light in the living body. Similar to the second embodiment, near infrared light obtained by irradiating both the new blood vessel measurement site and the reference site with near infrared light and scattering and reflecting in the new blood vessel measurement site is used as the near infrared light. Imaging is performed by a CCD camera having light receiving sensitivity. Then, as in Example 1, the blood volume of each pixel in the captured image is obtained by image processing, and the blood vessel is determined from the difference in blood volume change between the measurement site of the new blood vessel and the reference site from the start of the new blood vessel. Assess the degree of newborn.
図７に、各実施例で使用する計測プローブの例を示す。
図７に示すプローブは、生体組織に密着させるフレキシブルシートに発光素子である発光用ＬＥＤ、受光素子である受光用ＬＥＤを配列したものである。このプローブは、特に第２実施例に使用されるものであり、フレキシブルシートにおける発光用ＬＥＤ、受光用ＬＥＤの配列に基づいて、新生血管の測定部位と基準部位を含め、広範囲の部位について、血液量を測定し、血管新生度を評価することが可能である。
FIG. 7 shows an example of a measurement probe used in each embodiment.
The probe shown in FIG. 7 is obtained by arranging a light emitting LED, which is a light emitting element, and a light receiving LED, which is a light receiving element, on a flexible sheet that is in close contact with a living tissue. This probe is used particularly in the second embodiment. Based on the arrangement of the light emitting LED and the light receiving LED on the flexible sheet, this probe is used for a wide range of sites including a measurement site and a reference site of a new blood vessel. It is possible to measure the amount and evaluate the degree of angiogenesis.
図８は、計測対象が生体外から近赤外光の到達しない部位にある、再生心筋や再生骨、再生軟骨、再生腎臓、再生肝臓などの大規模な新生血管の新生度を出来るだけ少ない侵襲で評価する際の生体内への適用例を示す。 FIG. 8 shows an invasion that minimizes the degree of neovascularization of large-scale new blood vessels, such as regenerated myocardium, regenerated bone, regenerated cartilage, regenerated kidney, and regenerated liver, where the measurement target is in a region where near infrared light does not reach from outside the body. An example of application to a living body at the time of evaluation is shown.
生体外から近赤外光の到達しない深い狭い部位の血管新生を評価する場合、体表面より生体内の再生部位近傍まで、事前に留置されたカテーテルを通じて挿入したプローブを利用する。
ここで使用するプローブは、図９に示されるように弾力性のある合成樹脂の中に、発光用光ファイバと受光用光ファイバが埋め込まれており、その先端が血管新生部位あるいは基準部位に密着され、それぞれの末端は、外部に設置された機器内の発光部、受光部に接続されている。そして、発光部から発光用光ファイバを通じて、新生血管測定部位に近赤外光を照射し、新生血管測定部位内を散乱反射して得られた近赤外光を、受光用光ファイバを通じて受光部で受光する。他の構成は実施例１と同様である。
When evaluating angiogenesis in a deep and narrow site where near infrared light does not reach from outside the living body, a probe inserted through a catheter placed in advance from the body surface to the vicinity of the regenerating site in the living body is used.
As shown in FIG. 9, the probe used here has a light-emitting optical fiber and a light-receiving optical fiber embedded in an elastic synthetic resin, and its tip is in close contact with an angiogenesis site or a reference site. Each end is connected to a light emitting unit and a light receiving unit in an external device. Then, the near-infrared light obtained by irradiating near-infrared light to the neovascular measurement site from the light-emitting unit through the light-emitting optical fiber and scattering and reflecting the inside of the neovascularization measurement site is received through the optical fiber for light-receiving. Receive light at. Other configurations are the same as those of the first embodiment.
また、図１０に示されるように内視鏡の先端中央にＣＣＤカメラを設け、新生血管測定部位内を散乱反射して得られた近赤外光をＣＣＤカメラにより撮像し、得られた画像中の各画素の血液量を画像処理により求め、新生血管の新生開始時からの新生血管の測定部位と基準部位の血液量変化の差から血管新生度を評価することができる。 Further, as shown in FIG. 10, a CCD camera is provided at the center of the tip of the endoscope, and near-infrared light obtained by scattering and reflecting inside the neovascularization site is imaged by the CCD camera, and in the obtained image The blood volume of each pixel can be obtained by image processing, and the degree of angiogenesis can be evaluated from the difference in blood volume change between the measurement site of the new blood vessel and the reference site from the start of new blood vessel neovascularization.
以上、各実施例では、発光部から照射された近赤外光が、新生血管の測定部位及び基準部位内において散乱反射して得られる反射近赤外光を受光することにより血液量を計測したが、測定部位によっては、受光部により透過した透過近赤外光を受光することにより血液量を計測してもよい。この場合は、受光部は、新生血管の測定部位及び基準部位を挟んで発光部に相対するよう被験者に密着させる。 As mentioned above, in each Example, the blood volume was measured by receiving the reflected near-infrared light obtained by the near-infrared light irradiated from the light emission part being scattered and reflected in the measurement part and the reference part of the new blood vessel. However, depending on the measurement site, the blood volume may be measured by receiving transmitted near-infrared light transmitted by the light receiving unit. In this case, the light receiving unit is brought into close contact with the subject so as to face the light emitting unit across the measurement site and the reference site of the new blood vessel.
以上のとおり、本発明によれば、生体組織透過性の高い近赤外光を測定部位内に照射するための発光部と、測定部位内において得られる反射近赤外光あるいは透過赤外光を受光するための受光部を設け、新生血管測定部位とその近傍の基準部位の血液量を測定するという簡便な構成で、血管の新生度を簡単にしかも高精度に計測することができるので、患者の再生臓器の再生度あるいは糖尿病患者の末梢血管障害の治療効果を、定期的かつ定量的に診断する診断機器として広く利用されることが期待できる。 As described above, according to the present invention, the light emitting unit for irradiating the measurement site with near-infrared light having high biological tissue permeability, and the reflected near-infrared light or transmission infrared light obtained in the measurement site are used. With a simple configuration of providing a light-receiving unit for receiving light and measuring the blood volume at the neovascularization measurement site and the reference site in the vicinity, the neovascularization level can be measured easily and with high accuracy. It can be expected to be widely used as a diagnostic device for periodically and quantitatively diagnosing the degree of regenerative organ regeneration or the therapeutic effect of peripheral vascular disorders in diabetic patients.
１ａ〜１ｄ 発光部
２ａ〜２ｄ 受光部
３ａ、３ｂ 減衰率演算部
５ 演算部
DESCRIPTION OF SYMBOLS 1a-1d Light-emitting part 2a-2d Light-receiving part 3a, 3b Attenuation factor calculation part 5 Calculation part
Claims (9)
生体組織透過性の高い近赤外光を新生血管測定部位に照射するための発光部と、
該発光部から照射された近赤外光が、前記新生血管測定部位において散乱反射して得られる反射近赤外光を受光するための受光部と、
前記発光部から照射された近赤外光と前記受光部で受光した反射近赤外光とに基づいて、前記新生血管測定部位における近赤外光の減衰率を演算する減衰率演算部と、
該減衰率に基づいて、前記新生血管測定部位における血液量を演算する血液量演算手段と、
該血液量を記録する記録部と、
前記血液量の時間経過に応じた変化率に基づいて、前記新生血管測定部位内における新生血管の新生度を評価する血管新生度評価手段とを備えたことを特徴とする低侵襲血管新生計測装置。 In a device for measuring the degree of neovascularization,
A light emitting unit for irradiating a neovascular measurement site with near-infrared light having high biological tissue permeability;
A light-receiving unit for receiving reflected near-infrared light obtained by scattering and reflecting near-infrared light emitted from the light-emitting unit at the neovascularization site;
Based on the near-infrared light emitted from the light-emitting unit and the reflected near-infrared light received by the light-receiving unit, an attenuation rate calculating unit that calculates the attenuation rate of the near-infrared light in the neovascular measurement site;
Blood volume calculating means for calculating the blood volume at the neovascularization site based on the attenuation rate;
A recording unit for recording the blood volume;
A minimally invasive angiogenesis measurement device comprising: an angiogenesis degree evaluation means for evaluating the degree of neovascularization in the neovascularization measurement site based on a rate of change of the blood volume over time. .
生体組織透過性の高い近赤外光を新生血管測定部位に照射するための発光部と、
該発光部から照射された近赤外光が、前記新生血管測定部位を透過して得られる透過近赤外光を受光するための受光部と、
前記発光部から照射された近赤外光と前記受光部で受光した反射近赤外光とに基づいて、前記新生血管測定部位における近赤外光の減衰率を演算する減衰率演算部と、
該減衰率に基づいて、前記新生血管測定部位における血液量を演算する血液量演算手段と、
該血液量を記録する記録部と、
前記血液量の時間経過に応じた変化率に基づいて、前記新生血管測定部位内における新生血管の新生度を評価する血管新生度評価手段とを備えたことを特徴とする低侵襲血管新生計測装置。 In a device for measuring the degree of neovascularization,
A light emitting unit for irradiating a neovascular measurement site with near-infrared light having high biological tissue permeability;
A near-infrared light irradiated from the light-emitting part, a light-receiving part for receiving transmitted near-infrared light obtained by transmitting through the neovascularization site;
Based on the near-infrared light emitted from the light-emitting unit and the reflected near-infrared light received by the light-receiving unit, an attenuation rate calculating unit that calculates the attenuation rate of the near-infrared light in the neovascular measurement site;
Blood volume calculating means for calculating the blood volume at the neovascularization site based on the attenuation rate;
A recording unit for recording the blood volume;
A minimally invasive angiogenesis measurement device comprising: an angiogenesis degree evaluation means for evaluating the degree of neovascularization in the neovascularization measurement site based on a rate of change of the blood volume over time. .
前記発光部は、酸化ヘモグロビンと還元ヘモグロビンの等吸収点となる波長を前記新生血管測定部位に照射することを特徴とする低侵襲血管新生計測装置。 In the minimally invasive angiogenesis measuring device of Claim 1 or 2,
The said light emission part irradiates the said neovascular measurement site | part with the wavelength used as the equiabsorption point of oxyhemoglobin and deoxyhemoglobin, The minimally invasive neovascularization measurement apparatus characterized by the above-mentioned.
ひとつの発光部から照射された近赤外光の前記反射近赤外光あるいは前記透過近赤外光を、複数の受光部で受光するようにしたことを特徴とする低侵襲血管新生計測装置。 In the minimally invasive angiogenesis measuring device of Claim 1 thru | or 3,
A minimally invasive angiogenesis measuring apparatus, wherein a plurality of light receiving parts receive the reflected near infrared light or the transmitted near infrared light of the near infrared light emitted from one light emitting part.
前記血管新生度評価手段は、前記発光部から異なる距離に設置した２つの受光部の検出値に基づいて、深さの異なる血液量の差分を求め、浅部における毛細血管の血液量変化を補償する手段を備えたことを特徴とする低侵襲血管新生計測装置。 The minimally invasive angiogenesis measuring device according to claim 4,
The angiogenesis degree evaluation means obtains a difference in blood volume at different depths based on detection values of two light receiving units installed at different distances from the light emitting unit, and compensates for blood volume changes in capillaries in the shallow part. A minimally invasive angiogenesis measuring device comprising means for performing
前記受光部として近赤外線カメラを用い、前記血管新生度評価手段が該近赤外線カメラの出力に基づいて画像処理を行うことにより、前記血管新生度評価手段が前記新生血管測定部位における新生血管の新生度を評価することを特徴する低侵襲血管新生計測装置。 In the minimally invasive angiogenesis measuring device of Claim 1 thru | or 3,
A near-infrared camera is used as the light-receiving unit, and the angiogenesis-evaluating means performs image processing based on the output of the near-infrared camera, so that the angiogenesis-evaluating means is a neovascularization at the new blood vessel measurement site. A minimally invasive angiogenesis measuring device characterized by evaluating the degree.
前記発光部は複数波長の近赤外光を前記新生血管測定部位に時間差をつけて照射し、前記減衰率演算部は、それぞれの照射タイミング毎の波長の減衰率から前記新生血管測定部位内における近赤外光の減衰率を演算することを特徴とする低侵襲血管新生計測装置。 The minimally invasive angiogenesis measuring device according to claim 1,
The light emitting unit irradiates a plurality of wavelengths of near-infrared light with a time difference to the neovascularization measurement site, and the attenuation rate calculation unit calculates the wavelength within the neovascularization measurement site from the wavelength attenuation rate at each irradiation timing. A minimally invasive angiogenesis measuring device that calculates the attenuation rate of near-infrared light.
前記発光部は複数波長の近赤外光を前記新生血管測定部位に照射するとともに、前記受光部は分光器を備え、前記減衰率演算部が、前記分光器により分光分析された近赤外光の減衰率を演算することを特徴とする低侵襲血管新生計測装置。 The minimally invasive angiogenesis measuring device according to claim 1,
The light emitting unit irradiates near-infrared light having a plurality of wavelengths to the neovascularization measurement site, the light receiving unit includes a spectroscope, and the attenuation rate calculation unit is subjected to spectroscopic analysis by the spectroscope. A minimally invasive angiogenesis measuring device characterized by calculating an attenuation rate of the blood vessel.
前記発光部と前記受光部が２つの組からなり、前記減衰率演算部は、一方の組により前記新生血管測定部位における近赤外光の減衰率を演算するとともに、他方の組により、前記新生血管測定部位の近傍にある基準部位における近赤外光の減衰率を演算し、
前記血管新生度評価手段は、前記新生血管測定部位における近赤外光の減衰率に基づいて演算された血液量の変化率と、前記基準部位における近赤外光の減衰率に基づいて演算された血液量の変化率とを比較することにより、前記新生血管測定部位内における新生血管の新生度を評価するようにしたことを特徴とする低侵襲血管新生計測装置。 The minimally invasive angiogenesis measuring device according to claim 1,
The light emitting unit and the light receiving unit are composed of two sets, and the attenuation rate calculation unit calculates the attenuation rate of near-infrared light at the neovascularization measurement site by one set, and the new set by the other set. Calculate the near-infrared light attenuation rate at the reference site in the vicinity of the blood vessel measurement site,
The angiogenesis degree evaluation means is calculated based on the blood volume change rate calculated based on the near-infrared light attenuation rate at the neovascular measurement site and the near-infrared light attenuation rate at the reference site. A minimally invasive angiogenesis measuring apparatus characterized in that the degree of neovascularization in the neovascularization measurement site is evaluated by comparing the rate of change in blood volume.
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