JP2004016489A - Testing apparatus of subcutaneous contaminant substance - Google Patents

Testing apparatus of subcutaneous contaminant substance Download PDF

Info

Publication number
JP2004016489A
JP2004016489A JP2002175875A JP2002175875A JP2004016489A JP 2004016489 A JP2004016489 A JP 2004016489A JP 2002175875 A JP2002175875 A JP 2002175875A JP 2002175875 A JP2002175875 A JP 2002175875A JP 2004016489 A JP2004016489 A JP 2004016489A
Authority
JP
Japan
Prior art keywords
subcutaneous
detection unit
skin contact
contact surface
skin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2002175875A
Other languages
Japanese (ja)
Inventor
Hiroyuki Kasano
笠野 宏之
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Polytronics Ltd
Original Assignee
Polytronics Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Polytronics Ltd filed Critical Polytronics Ltd
Priority to JP2002175875A priority Critical patent/JP2004016489A/en
Publication of JP2004016489A publication Critical patent/JP2004016489A/en
Pending legal-status Critical Current

Links

Images

Landscapes

  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
  • Measuring And Recording Apparatus For Diagnosis (AREA)

Abstract

<P>PROBLEM TO BE SOLVED: To provide a biological power generation apparatus which has simple structure and which is inexpensive, disposable and has safety by avoiding using of an external power source as to a testing apparatus of a subcutaneous contaminant substance of an inverse iontophoresis type. <P>SOLUTION: A metal Al or a metal having a normal electrode potential lower than that or a semiconductor B2 is conduct-connected with a detection part 3 of the subcutaneous contaminant substance. When the subcutaneous contaminant substance is alkaline,the metal 1 is selected. Electrodes conduct-connected with the detection part 3 and the other electrodes are conduct-connected with each other in a non skin contact area, and the detection part 3 and a counter electrode are spatially separated and skin-contacted. Inverse iontophoresis is elicited and the subcutaneous contaminant substance oozes onto the detection part 3 by a closed circuit current including a subcutaneous area to be reacted and detected. <P>COPYRIGHT: (C)2004,JPO

Description

【0001】
【発明の属する技術分野】
本発明は、生体皮下に含有される物質の検査装置、特に、皮下体液に含有される生体物質の抽出と量的検査に好適な装置に関する。
【0002】
【従来の技術】
近年成人病の急増に伴って、体内に含まれる特定の生体物質を抽出して分析することにより疾病の予防、診断、治療を行う臨床検査が重要視され、分析技術の向上がはかられている。
生体から特定含有物質を抽出するには、一般に患者の新鮮な血液または排泄物を利用する。含有物質の内特に生理活性物質の定量分析が必要な場合には、血液の抽出が必要とされる。例えば糖尿病の場合、一次判定は尿中に排泄された血糖の有無で行うが、治療の目安を知るために患者に対しては空腹時、満腹時の血糖値測定を血液採取によって行う必要がある。
血液採取は、その量にかかわりなく侵襲的方法で行われるため、患者の苦痛やウイルス・細菌感染等の危険をさけることができない。
【0003】
最近、非侵襲的方法を用いて生体内の特定含有物質濃度を知る試みが行われている。例えば、指の皮膚を透過した赤外線を分析することによって特定化学物質により吸収量を知るという試みが血糖値などに対して行われているが、かく乱要因が多く、いまだ実用化には至っていない。
【0004】
この中にあって、イオントフォレシス(電界印加によるイオン性物質の電気泳動)の作用を利用して皮下体液を非侵襲的に滲出せしめ、この体液分析から血糖値を知る方法が開発されている。イオントフォレシスは、通常イオン性薬剤を経皮吸収させるために用いられるDDSの一手法であるが、体液採取は逆イオントフォレシスを利用するものである。即ち、皮下体液のpHは7.2〜7.5程度の弱アルカリ性であることから、皮接した2枚の電極間に直流電源を接続し、電源の負極側に接続した電極板と皮膚との間にセンサを密着させて通電すれば、体液は負極側に吸い寄せられ表皮上に配置されたセンサまで滲出して検知される仕組みである。
【0005】
体液には、血管外に滲出した血液成分も含まれており、体液中の特定物質濃度はその血中濃度と一定の相関関係を示す。よって、あらかじめこの相関関係を測定しておけば、この方法によって例えば血糖値を知りうる。
【0006】
【発明が解決しようとする課題】
逆イオントフォレシス法は、皮侵襲的方法で体液を採取し、直接分析することによって特定物質の血中濃度を知るもので、定量性が高く実用化が有望である。しかし、従来の直流電源接続法においては、コスト上電源、制御部位のみならず電極板に至るまで繰り返し再利用される。この結果、センサは取り替えても電極板の汚染が次回測定時に混入するおそれがある。また、携帯型であるため、装置小型化の必要上2枚の電極板間隔が狭くなり、生体の発汗等によって電極間短絡の危険を生ずる。電極間短絡によって大電流が流れるならば、皮膚は焼損する。従って安全回路を具備する必要があり、さらに装置のコストアップと大型化につながる。
また、電源の正極側に接続した電極板下の皮膚には、皮内通電によってOH ̄イオンが溜まりアルカリ化するため、装置の長時間皮接によって皮膚トラブルが発生する危険を避けることができない。
【0007】
本発明の目的は、低コストで使い捨てができ、かつ皮接使用時安全性の高い逆イオントフォレシス型の皮下含有物質検査装置を提供することにある。
【0008】
【課題を解決するための手段】
本発明は、金属Aと、これより標準単極電位の低い金属または半導体Bと、皮下含有物質を検出する、導電性の検知部とを備えて成り、
該検知部は皮接面を持ち、この皮接面以外の部位で前記AまたはBのいずれか一方に接触し、
検知部に接触していないAまたはBの他方は皮接面を持ち、且つAとBとは皮接面以外の部位で導電に接続し、
前記検知部の皮接面と、AとBとの一方が持つ皮接面とを同時に皮接することによって発生する化学電池起電力を利用して皮下含有物質を電気的に検知部に抽出し認識する皮下含有物質検査装置を開示する。
【0009】
更に本発明は、検知部は複数に分割されて複数の皮接面を持ち、皮接面を持つAまたはBの一方は、各分割検知部の周囲に相互に分離されて配置されており、各分割検知部の周囲のAまたはBとは、相互に独立して検知可能とする皮下含有物質検査装置を開示する。
【0010】
更に本発明は、各分割検知部の周囲のAまたはBの一方と他方との導電接続系路にスイッチを設け、各スイッチを選択的に切り替えるようにした皮下含有物質検査装置を開示する。
【0011】
更に本発明は、各分割検知部の周囲に配置された皮接面を持つのAまたはBの一方と他方との導電接続系路にスイッチを設け、各スイッチを選択的に切り替えるようにした皮下含有物質検査装置を開示する。
【0012】
更に本発明は、検知部は、二重酵素センサとする皮下含有物質の検査装置を開示する。
【0013】
更に本発明は、被検知部位に接触可能な、複数区分された第1の皮接面を持つ含有物質の検知部と、
この検知部に接触した導電性海綿体と、
この海綿体に接触した金属Aと、
被検知部位に接触可能な第2の皮接面を持ち、上記金属Aと導電接続され、更に、金属Aよりも標準単極電位の低い金属又は半導体Bと、
を備える皮下含有物質の検査装置を開示する。
【0014】
【発明の実施の形態】
本発明は、金属Aとこれより標準単極電位の低い金属または半導体Bとを有し、更にAまたはBに導電接続する検知部を有する。
このAとBとを同時に皮接することで皮膚を電解質とする化学電池を形成し、AとBとの電子親和力差に基づいて発電する。特にBがn型半導体である場合、皮接面にショットキー障壁が形成され、界面の電界領域から過剰正孔が皮膚側にドリフトアウトする。この結果、電極下の皮内で生ずるpH変化(アルカリ化)が緩和される。AとBとから成る化学電池の起電力は、第一義的には材料組み合わせによって決まり、従来技術では不可欠であった外部電源を用いることなく皮内通電が可能となる。
従って、本発明の技術によって逆イオントフォレシスによる体液等の皮外抽出が可能となる。
【0015】
AとBとを構成の主要部とする化学電池は、電解質作用を示す皮膚が発汗や濡水等で抵抗ゼロとなれば、直ちに酸化還元反応を停止するので発電が自動停止し、過電流を流すことなく安全性が高い。
【0016】
AとBとを持つ構成体はメッキや蒸着などの薄膜形成技術を利用すれば安価に作ることができ、使い捨て可能なのでウイルスや細菌の感染を避けることができる。また、皮膚の汚染が次回の測定時に混入する危険もない。
【0017】
AまたはBに導電接続して配置される検知部は、例えば抽出された皮下含有物質と反応して発色を行い、あるいは特定の化合物形成を行う試薬が塗布された導電性シートである。予め発色度や特定の化合物形成量と抽出物質の関係が測定されていれば、検知部で採取されたデータを検量することによって皮下含有物質濃度が求められる。検知部としては、例えば、後述するような二重酵素センサやグルコース脱水素酵素センサ、鉄イオン検出センサがあるが、皮下含有物質の検出目的に応じて種々のセンサがある。
【0018】
検知部の一例としては、前記検出シートの他に中空細針を備えたセルを有しており、中空部を脱気後この細針を少なくとも表皮角質層以深まで貫通せしめると、皮下含有物質の皮外抽出は各段に容易になる。高抵抗の皮脂層、角質層による電位降下(化学電池の内部損失)を1/10以下に抑制できるので、逆イオントフォレシスが一層有効に行い得るのみでなく毛細管現象を利用して体液抽出をより効果的に進めうるためである。このとき、セル内を軽く負圧にしておけば、さらにサイフォン効果が加わって体液抽出は各段に加速される。
【0019】
上記したAとBとを構成の主要部とする化学電池は直流起電力を惹起するが、この場合皮下物質の抽出は主に毛穴を通じて行われると考えられる。然るに、この直流起電力をパルス化すれば、エレクトロポレーションと称される細胞電位の反転がパルス周期にあわせて生じ、反転時に皮下物質が細胞を貫通して電極板方向に上昇すると考えられており、抽出により効果的といえる。
勿論、AとBとで形成される化学電池を昇圧するごとく、即ちA側に負極、B側に正極を接続するごとくして外部回路に補助電源を挿入すれば、動作マージンがより大きくなるため逆イオントフォレシスが加速されて生ずる。
【0020】
以上の説明では、検知部を皮下含有物質の検出の機能例としたが、それ以外に、検出だけに止まらずに、皮下含有物質の特定化を行ったり、皮下含有物質の量の特定化を行ったりすることも可能である。これにはこうした特定化手段を検知部に代わり、または検知部に重ねて、または検知部につなげて、設ける。特定化手段には、化学的反応、物質的反応、電気的反応等を利用したシートやレイヤや部材等、または電子回路(IC)の利用等がある。かかる発明によれば、検出のみでなく更に特定化という測定の最終目的まで1つのデバイスで達成可能となる。
以下、本発明を具体的に沿ってより詳しく述べる。
【0021】
(その1)図1(i)、(ii)は、本発明の一実施例における皮下含有物質検査装置の主要構成部を示す図である。(i)は装置の皮接面側である上面図を、また(ii)はそのM−M′断面図を示す。
図において、1は金属A、2は半導体B、3は検知部、4は海綿体、5は絶縁物を表す。この検査装置は、皮接面と反対側の面に例えば図1(ii)に点線表示したような絆創膏10を外側にはり付け、検査時、(i)に示した上面を皮膚に皮接面として接触させ、その上で外側にはり付けた絆創膏10で検査装置全体を皮膚に接着固定させ、皮下含有物質の検出を行う。(ii)では表面2a、3aがこの皮接面となる。
図示された検査装置においては、金属(A)1は底面全体にわたって形成された25×25mmサイズのアルミ箔(厚さ0.05mm)に蒸着された金層(厚さ0.3μm)、半導体(B)2は上面の周縁部及び中央部に形成したものであって、幅3mmで図示した6分割(この分割は分割部20、21、22…による)した形状に加工されたアルミ箔(厚さ0.05mm)に亜鉛を蒸着後表面を高温蒸気で酸化して形成した酸化亜鉛(亜鉛過剰)層、検知部3は左右2つに30、31として分割されており、それぞれ透水性プラスチックフィルムに固定化された二重酵素(グルコースオキシターゼ/ペルオオキシターゼ)センサである。一方、海綿体4は生理的食塩水を含侵させた海綿様プラスチック層であり、絶縁物5はポリエチレンなどの柔軟性のある絶縁体層である。装置の厚みは約1.5mmで可撓性を有しており、使い捨ての構造になっている。
【0022】
検知部3を左右に30、31として二分割したのは、検知部3の表面に印加される電界強度をできるだけ均一にするためであり、これにより表面電流密度の均一性を高めた。金属1(皮接時プラス電極として働く)は図1(ii)に示すように検知部3の裏面全体を覆っているが、金属又は半導体2(皮接時マイナス電極として作用)は、図1(i)、(ii)に示すように検知部3を検知可能に作動させるため、検知部3の2分した部位30、31のそれぞれの周囲に配置した。これによって、左半分及び右半分にそれぞれ存在する検知部3の部位30、31に対して周りを囲むマイナス極からの距離を短くでき、検知能力の向上をはかれる。 一方、金属又は半導体2を6分割したのは、生体皮膚の抵抗値が局所的に、また経時的に大きく変化していることから、開口部に配置された検知部3に出来るだけ均等に通電するためである。これによって、半導体2を分割しない場合に比べ、装置皮接面積のうち最も抵抗値の低い領域への電流の集中を少なくでき、検知部3のセンサ機能の向上がはかれる。
【0023】
金属Aと半導体例えばn型半導体Bとは、非皮接面(皮接面2a、3aではない部位との意)で導電接続している。例えば、端部10A〜10F等でAとBとの導電接続をはかっている。海綿体4は、金属Aと検知部3とを導電接触させ、かつ検知部3に導電性を与える役割を果たしている。かくして、半導体Bの2a−皮膚−検知部3の表面3aに滲出したを介しての内部の海面様プラスチック層4含有生理食塩水−金属A−半導体Bの電気系路が形成され、検知部3に皮下体液の抽出を可能にする。
【0024】
この装置を、例えば人体上腕部皮膚に絆創膏で皮接すると、金を正極、酸化亜鉛を負極とする化学電池が起動して、金電極から電子が海綿体4に、また正孔が酸化亜鉛から皮内に注入される。海綿体4に注入された電子は、検知部3を経て皮膚面に達することにより皮膚の酸性度をさらに高める。一方、皮内に注入された正孔は、負極領域から正極側へ体液(pH7.4)をドリフトせしめる。この結果、電気的作用によって皮下体液は正極側表皮上へ引き上げられる。表皮上に滲出した皮下体液は、検知部3に配合された酵素のうちまず上層のグルコースオキシターゼ(GOD)に接触し、皮下体液中の糖(D−グルコース)が

Figure 2004016489
なる反応を惹起する。生成したHは、下層のペルオキシターゼ(POD)に接して
Figure 2004016489
なる反応を惹起する。キノン色素は赤色を呈するので、感知部3の酵素固定部は赤く着色する。
所定経過後、検査装置を上腕部から取り外し検知部3を取り出す。この検知部3を測定装置(図示せず)の測定部位に装着し、その後で検知部3の着色部位に赤色光を照射して透過光から505nmの吸光度を測定する。予め作成してある吸光度vs.血糖値の標準試料を用いて比色法でグルコース濃度が算出される。皮下体液中と血中におけるグルコース濃度には一定の相関関係があるので、この実施例の装置によって非侵襲的に血糖値を知ることができる。
【0025】
次に上記した実施例と同じ原理を用いて、ひとつの検査装置で複数個の皮下体液サンプルを得る方法について述べる。これは、例えば同一人が空腹時、満腹時、就寝前及び起床時に血糖値の変化を知りたい場合などに用いて有用である。
【0026】
図2は、用いられる装置の一例の構成を示す断面図である。(i)は皮接面図、(ii)はそのM−M′断面図を示す。図における各番号は上記図1と同じである。10は、選択スイッチを示す。また、( )で示す数字は、2の各断片に対応している。
選択スイッチ10は非皮接面に配置されており、(i)で図示した2の各断片(1)−(8)を三片ずつまとめて非皮接面で1に接続する機能を有している。
【0027】
図2の装置サイズは、36×36mmであり、図2(i)で示すように4分割された検知部3の各サイズは、12×12mmである。選択スイッチ10を除いた装置の構成材料は、図1の場合と全く同じである。
この装置を絆創膏によって上腕部に皮接すると、金/酸化亜鉛の化学電池が起動して皮下体液を皮膚上へ吸い上げるが、その吸い上げ領域は選択スイッチ10によって指定される。各酸化亜鉛電極片に接続した導線に図示したような(1)〜(8)の番号付けを行うと、選択スイッチ10が(1)、(2)、(3)の3導線と金電極の接続を行った場合、図2(A)の右上の皮接面となる開口部位置のみに皮下体液が滲出し、その位置にある検知部によって酵素反応が選択的におきる。他の皮接面となる開口部位置には、それを囲む電極回路が切断されているため皮下体液が上昇してこない。
所定時間経過後、一旦選択スイッチをオフにすればすべての酸化亜鉛電極片と金電極との接続が遮断されるため皮下体液はどの開口部位置にも滲出してこなくなる。次の採取時刻がくれば、再び選択スイッチ10をオンにすることによって酸化亜鉛電極片(接続導線)(3)、(4)、(5)と金電極が接続され、図の右下開口部のみに皮下体液が滲出してくる。
【0028】
以下同様にして、左下及び右上の皮接面である開口部にそれぞれ独立して皮下体液を滲み出させ、そのときの血糖値に対応した酵素反応着色を得ることができる。そして、すべての検知反応終了後、装置を取り外し、検知部3を取り出す。検知部3のセンサには4箇所に別々のデータが載っており、これを順に光測定器で解析することによってそれぞれの血糖値がひとつの装置で固定できるのである。装置取り外し後装着部位の皮膚には何の損傷も認められなかった。
【0029】
図1及び図2で示した装置を利用すれば、皮下含有物質の抽出と経皮投薬を同時に行い得る。例えば図2の装置において、左下の開口部のみ検知部3の配置を止め、代わりにインスリンを分散した導電性ゲルを配置しておく。まず、装置皮接後、酸化亜鉛電極片(接続導線)(1)、(2)、(3)を選択スイッチ10によって金電極1に接続すると同時に酸化亜鉛電極片(接続導線)(5)、(6)、(7)を金電極1に接続する。この操作によって右上の開口部では逆イォントフォレシスが惹起して皮下体液の抽出が行われると同時に、左下の開口部ではイォントフォレシスが惹起してインスリンの皮下浸透を生ずる。前記したように酸化亜鉛電極片の金電極への接続を選択的に行うことによって、右上、右下、左上のそれぞれ開口部位に配置された検知部で所定時間の皮下体液抽出が行われるが、この間酸化亜鉛電極片(接続導線)(5)、(6)、(7)と金電極との接続を持続すれば、インスリンの体内浸透は持続する。実施例(その3)で述べる技術を援用すれば、非皮接領域において酸化亜鉛電極片(接続導線)(5)、(6)、(7)を束ねた上でここに電圧可変補助電源をさらに接続することによってインスリンの皮内浸透量を可変にすることもできる。
【0030】
(その2)図3は、本発明の別の実施例における皮下物質検査装置の構成概略を示す図である。(i)は上面図(皮接面図)、(ii)はそのM−M′断面図である。理解を容易にするために図は部分的に誇張して描かれており、実寸図に対応するものではない。
【0031】
図において、1は金属A、2は金属または半導体B、3は検知部、4は海綿体、5は絶縁体、6は逆止弁、7は中空細針である。
1は厚さ0.05mmの導電性プラスチックシート上にメッキされた白金膜(膜厚1μm)、2は厚さ0.05mmに圧延された錫シートで表面は希塩酸で軽く酸化されSnOxが形成されている。3は透水性プラスチック板の一表面にグルコース脱水素酵素(GDH)が固定されたものである。4はスポンジ様多孔体、5は可撓性プラスチック、6は装置内部から外部への一方的排気を可能にする逆止弁、7はプラスチック製の外径150μm、長さ1.5mmの中空細針(中空部径80μm)であり、使用前は滅菌処理後生理的食塩水が約半分の長さまで充填されている。
【0032】
この検査装置を例えば絆創膏などで皮膚に固定する。図3(i)の面が皮膚に圧接されると細針7が皮内に侵襲し、同時に生理的食塩水が皮内に注入される。一方、圧接時に海綿体4が圧迫されるため装置内の空気は逆止弁を経て装置外へ排出される。装置が絆創膏などで固定し皮膚に装着されると、排気後の装置内は海綿体4の再誇張によって軽い負圧状態を保つ(逆止弁6の働きで外部から空気が装置内に入ることはない)。
【0033】
装置の皮接によって白金を正極、酸化錫を負極とする化学電池が起動し、発生した電力と毛細管現象によって皮下体液は急速に装置内に滲出する。負圧はサイフォン効果をもたらすため、前実施例に比べて電池起電力は0.5V以上低いにもかかわらず1/10以下の短時間の内に検知部が作動する。体液が検知部のグルコース脱水素酵素に接触すると、体液に含有されているDグルコースとの間でグルコース+NADP(ニコチンアミドアデニンジヌクレオチドりん化合物)

GDH
グルコノラクトン+NADPH(還元ニコチンアミドアデニンジヌクレオチド燐酸)
なる反応を惹起する。
所定時間を経て装置を取り外し、検知部を取り出す。細針は径が細いため、取り外しても全く出血やウイルス感染の心配はない。また、装置取り外し後装着部位の皮膚には何の損傷も認められなかった。
反応した酵素膜に紫外光を照射して反射光のスペクトルを測定する。NADPHが0.1mM生成すると340nmの吸光度は0.630上昇するという関係を利用して皮下体液中に含有されているグルコース量を同定することができる。本装置は、前実施例同様安価に製造できるので使い捨て可能である。
この方法は、髄液採取にも利用できる。この場合細針7は絶縁膜でコーティングされた金属針とし、長さも骨髄に達する程度にする。
【0034】
(その3)図4は、本発明のさらに別の一実施例における装置の構成概略を示す図である。図4(i)は皮接面側の平面図、(ii)は(i)のM−M′断面図である。
図において1は金属A、2は金属B、3は検知部、4は海綿体、5は絶縁体、8はパルス化装置、9は補助電源を示す。
1は銅フィルム(厚さ0.05mm)に圧着された金箔、2は鉄であって厚さ0.05mmに圧延された板の一部にステンレス細針2A(外径100μm、長さ2mm)を導電接着したもので使用前に消毒しておく。3は透水性プラスチック板表面に水に不溶の鉄イオン検出剤、例えば8−ヒドロキシー7−ヨードー5−キノリンスルホン算を塗布したもの、4は吸水性プラスチックスポンジ、5は可撓性プラスチック、8は通電電流をパルス化する装置、9は補助電源(電圧E)であるが8の駆動用にも用いられ金箔側が負極に、鉄側が正極に接続される。
【0035】
この装置を絆創膏などで皮接すると、皮接に伴ってステンレス細針が皮内に侵襲するが、針が細く痛みは通常全く感じない。皮接によって金箔と鉄から成る化学電池を起動して発電するが、同時に皮膚を介して電気的閉回路が形成されるので、補助電源9からの電流も流れる。電流はパルス化装置8によってデューティ比30%、パルス幅30μsecの単極性パルスに変換されて閉回路を流れる。ステンレス針は、皮膚抵抗の大部分を占める皮脂層、角質層による通電損失をなくするので、装置全体からみれば図1、2に示した装置に比べて通電損失を半分減らすことができる。この装置の装着によって、金箔電極下の皮膚内から体液が滲出し、吸水性プラスチック4にリザーブされる。
【0036】
補助電源の印加電圧Eを大きくすれば、それに比例して体液滲出速度が大きくなる。この装置はパルス電流を用いているのでエレクトロポレーションを利用することができ、直流を用いた場合よりも効果的に皮下体液を採取することができる。
吸水性プラスチック4にリザーブされた皮下体液は検知部3の試薬と反応して発色させる。従って、所定時間経過後この装置を取り外して検知部を取り出せば、比色法を用いて皮下体液含有の鉄イオン濃度を同定することができる。
装置取り外しに時に細針の径が細いので皮膚の侵襲部位は直ちに閉じ、出血や感染の心配は全くない。補助電源やパルス化装置などの電気系以外は安価に形成できるため使い捨て可能である。
【0037】
(その4)以上の実施例においては、装置の検知部3が皮下含有物質を検知するセンサ機能を持つ場合のみについて述べたが、本発明では上記したように、検知のみにとどまらず検知物質を量的に特定する機能を持つ装置を付与することも可能である。
図5は、経時的に血糖値をモニターすることが出来る本発明の一実施例の装置について、その構成概略を示す図である。図5(i)は上面図(皮接面図)、(ii)はそのM−M’断面に装置裏面の電気的配線を付加した図である。
図において、1は金メッシュ電極、2は表面に高さ1−2mmの突起を複数個有する酸化亜鉛半導体電極、3はGOD(またはグルコースデヒドロゲナーゼ)固定化酵素膜であって導電性溶液が含浸されている。GODまたはグルコースデヒドロゲナーゼは電極1側に固定されている。5は柔軟性を持つ絶縁性プラスチック、6はプラスチック製逆止弁、9は偏侍電源、11は微小電流計、12は表面に厚さ3μ珊の白金をメツ・キした鉄フィルム(中央に逆止弁6を装着)、13は12を接着したベローズ、14はパヅキン、15は絶縁性プラスチック接合部、16は空室である。
【0038】
微小電流計11は記録計(図示せず)に接続されており、変化量が経時的に記録される仕組みである。この装置においては、パッキン14より皮接面側(金メッシュ電極1を含む皮接面側構成部位)は使い捨て、パッキン14を含む非皮接面側は更新した皮接面側構成部位と共に再利用される構造になっている。使い捨て部位と再利用部位の接続はネジまたは嵌合によって行われる。
さて、この装置を伴創膏等によって例えば上腕部に圧接すると、金/酸化亜鉛の化学電池が起動して皮下体液が電気的に皮外へ瀞出せしめられる。同時にベローズ13が圧縮されて空室16内の空気は逆止弁6を経て外に排出される。この結果、空室16内は負圧状態になる。ついで、補助電源9のスイッチを入れる。この操作によってE、に接続された微小電源11及ぴ記録計も作動をはじめる。
【0039】
酸化亜鉛半導体電極2上に設けられた複数個の突起2Bは、非侵襲的に皮膚を強く圧迫する。この結果、装置皮接部位の皮膚は引き伸ぱされ、汗腺や毛穴が広がる。皮下体液は、汗腺や毛穴を通じて皮膚上に湾出するので、これによって逆イオントフォレシスによる皮下体液疹出が加速される。実際、同一サイズ、同一材料を用いた実施例1の装置と比較すると、皮接3時間後の皮下体液採取量は、本実施例の揚合2−2.5倍に増加していることが認められた。
皮膚上に溶出した体液は、GOD(またはグルコースデヒドロゲナーゼ)固定化酵素膜3に吸収され、その裏面に固定化されたGODまたはグルコースデヒドロゲナーゼと体液中のグルコースが反応して過酸化水素を生成する。生成した過酸化水素ガスは、負圧状態の空室16内に進入し、白金膜に到達する。ここで、白金の触媒作用により発生機の酸素を遊離するが、このとき電子を白金旗に放出するため白金膜の抵抗値が変化する(通電電流が増加する)。放出電子数は、反応グルコース濃度に比例するので、微小電流計11によって通電電流値の増加を測定すれぽ、皮下体液中のグルコース濃度が特定できる。
3の酵素膜は少なくとも12時間は安定に反応するので、通電電流の変化を経時的に記録計で記録すれば、血糖値の変化を経時的に知ることが出来る。
【0040】
本実施例では、汗腺や毛穴を広げるための突起を半導体電極2上に設けたが、突起は酵素固定膜3側に設けることも出来る。この場合、突起は中空の体液通過孔を有し、酵素固定化膜3上に密着配置された絶縁性膜の一部として設けられることになる。
【0041】
以上、実施例を用いて本発明を詳細に述べたが、本発明はこれらにとどまることなく本発明の権利の範囲内でさまざまな改変を行いうることは自明であろう。例えば、反応時間を決めるタイマーを付設することもできる。
あるいは、前記実施例のすべてにおいて検知部の上下に化学電池を構成する2枚の電極板を配置した構造を開示したが、検知部の皮接面積より広く取るために検知部に直接導電接触した電極と対向電極とを皮膚に対して並行配置し非皮接領域で両電極を導電接続した装置構造も本発明の範疇に属する。
また、皮外抽出すべき皮下含有物質が酸性である場合には、前記した各実施例でAとBとの配置を逆にして用いなければならない。
【0042】
【発明の効果】
以上説明したように、本発明によって、患者に苦痛や感染、皮膚損傷の危険を与えることなく、皮下含有物質の抽出検知が手軽に行えるようになった。また、本発明の装置は構成が簡単であり、患者が携行使用後その都度使い捨てができるという大きな利点がある。
【図面の簡単な説明】
【図1】本発明のそれぞれの別の実施例を説明するための装置構成の概略を示す図である。
【図2】本発明のそれぞれの別の実施例を説明するための装置構成の概略を示す図である。
【図3】本発明のそれぞれの別の実施例を説明するための装置構成の概略を示す図である。
【図4】本発明のそれぞれの別の実施例を説明するための装置構成の概略を示す図である。
【図5】本発明の実施例を説明するための装置構成の概略を示す図である。
【符号の説明】
1  金属
2 金属または半導体
3 検知部
4 海綿体
5 絶縁体
6 逆止弁
7 中空細針
8 パルス化装置
9 補助電源
10 選択スイッチ[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an apparatus for examining a substance contained in a subcutaneous body of a living body, and particularly to an apparatus suitable for extracting and quantitatively examining a biological substance contained in a subcutaneous body fluid.
[0002]
[Prior art]
With the rapid rise of adult diseases in recent years, clinical tests for preventing, diagnosing, and treating diseases by extracting and analyzing specific biological substances contained in the body have been emphasized, and analysis techniques have been improved. I have.
Extraction of a specific contained substance from a living body generally utilizes fresh blood or excretion of a patient. When quantitative analysis of a physiologically active substance among the contained substances is required, blood extraction is required. For example, in the case of diabetes, the primary determination is made based on the presence or absence of blood glucose excreted in urine, but it is necessary to perform blood glucose measurement on an empty stomach and a full stomach for a patient in order to know the standard of treatment. .
Since blood collection is performed in an invasive manner regardless of the volume, it is not possible to prevent the patient from suffering or the risk of viral or bacterial infection.
[0003]
Recently, attempts have been made to determine the concentration of a specific contained substance in a living body using a non-invasive method. For example, attempts have been made to determine the amount of absorption by a specific chemical substance by analyzing infrared light that has passed through the skin of a finger, but this has not yet been put to practical use because of many disturbing factors.
[0004]
Among them, a method has been developed in which the subcutaneous body fluid is non-invasively exuded using the action of iontophoresis (electrophoresis of an ionic substance by applying an electric field), and the blood glucose level is determined from this body fluid analysis. . Iontophoresis is a technique of DDS that is usually used for percutaneous absorption of ionic drugs, while body fluid collection utilizes reverse iontophoresis. That is, since the pH of the subcutaneous body fluid is weakly alkaline of about 7.2 to 7.5, a DC power supply is connected between the two electrodes in contact with each other, and an electrode plate connected to the negative electrode side of the power supply, the skin, and the like. When a sensor is brought into close contact with the sensor and energized, the body fluid is drawn to the negative electrode side and exudes to the sensor disposed on the epidermis to be detected.
[0005]
The body fluid also contains blood components that have oozed out of blood vessels, and the specific substance concentration in the body fluid shows a certain correlation with the blood concentration. Therefore, if this correlation is measured in advance, for example, the blood sugar level can be known by this method.
[0006]
[Problems to be solved by the invention]
The reverse iontophoresis method is a technique in which a body fluid is collected by a skin invasive method and directly analyzed to determine the blood concentration of a specific substance, and is highly quantitative and promising for practical use. However, in the conventional DC power supply connection method, not only power supply and control parts but also electrode plates are repeatedly reused due to cost. As a result, even if the sensor is replaced, contamination of the electrode plate may be mixed in the next measurement. In addition, since the device is portable, the interval between the two electrode plates is reduced due to the necessity of miniaturization of the device, and there is a danger of a short circuit between the electrodes due to sweating of a living body or the like. If a large current flows due to a short circuit between the electrodes, the skin is burned. Therefore, it is necessary to provide a safety circuit, which leads to an increase in cost and size of the device.
In addition, since OH ̄ ions accumulate and become alkaline in the skin under the electrode plate connected to the positive electrode side of the power supply due to intradermal conduction, the danger of causing skin trouble due to long-time skin contact of the device cannot be avoided.
[0007]
An object of the present invention is to provide a reverse iontophoresis type subcutaneous substance inspection apparatus which can be disposable at low cost and has high safety at the time of skin use.
[0008]
[Means for Solving the Problems]
The present invention comprises a metal A, a metal or semiconductor B having a lower standard monopolar potential, and a subcutaneous substance, and a conductive detector.
The detection unit has a skin contact surface, and comes into contact with either A or B at a site other than the skin contact surface,
The other of A or B not in contact with the detection unit has a skin contact surface, and A and B are electrically connected at a portion other than the skin contact surface,
The subcutaneous substance is electrically extracted and recognized by the detection unit using the electromotive force of the chemical battery generated by simultaneously skinning the skin contact surface of the detection unit and the skin contact surface of one of A and B. A subcutaneous substance inspection apparatus is disclosed.
[0009]
Further, according to the present invention, the detection unit is divided into a plurality and has a plurality of skin contact surfaces, and one of A and B having the skin contact surface is arranged separately from each other around the divided detection unit, A subcutaneous-substance-containing substance inspection apparatus that enables detection independently of A or B around each divided detection unit is disclosed.
[0010]
Furthermore, the present invention discloses a subcutaneous substance inspection apparatus in which a switch is provided in a conductive connection path between one and the other of A or B around each split detection unit, and each switch is selectively switched.
[0011]
Further, the present invention provides a subcutaneous device in which a switch is provided in a conductive connection path between one and the other of A or B having a skin contact surface disposed around each division detection unit, and each switch is selectively switched. Disclosed is an apparatus for inspecting contained substances.
[0012]
Furthermore, the present invention discloses an apparatus for testing a substance contained under the skin, wherein the detection unit is a double enzyme sensor.
[0013]
Further, the present invention, a detection unit for a contained substance having a plurality of divided first skin contact surfaces capable of contacting a detection site,
A conductive sponge body in contact with the detection unit,
Metal A in contact with the spongy body,
A metal or semiconductor B having a standard monopolar potential lower than the metal A, having a second skin contact surface capable of contacting the detected part, and being conductively connected to the metal A;
An apparatus for testing a substance containing subcutaneous substances comprising:
[0014]
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention includes a metal A and a metal or semiconductor B having a lower standard monopolar potential than the metal A, and further includes a detection unit electrically connected to A or B.
By simultaneously contacting A and B with each other, a chemical battery using the skin as an electrolyte is formed, and power is generated based on the difference in electron affinity between A and B. In particular, when B is an n-type semiconductor, a Schottky barrier is formed on the skin contact surface, and excess holes drift out from the electric field region at the interface to the skin side. As a result, a pH change (alkalization) occurring in the skin under the electrode is reduced. The electromotive force of the chemical battery composed of A and B is primarily determined by the combination of materials, and enables intracutaneous energization without using an external power supply, which is indispensable in the prior art.
Therefore, the technique of the present invention enables extracorporeal extraction of body fluids and the like by reverse iontophoresis.
[0015]
The chemical battery having A and B as the main components of the configuration, when the skin showing the electrolyte action becomes zero resistance due to sweating or wetting, immediately stops the oxidation-reduction reaction, so that the power generation is automatically stopped, and the overcurrent is reduced. High safety without shedding.
[0016]
The structure having A and B can be manufactured at a low cost by using a thin film forming technique such as plating or vapor deposition, and can be disposable, so that infection of viruses and bacteria can be avoided. Further, there is no danger of contamination of the skin during the next measurement.
[0017]
The detection unit arranged to be conductively connected to A or B is, for example, a conductive sheet coated with a reagent that forms a color by reacting with the extracted subcutaneous substance or forms a specific compound. If the relationship between the degree of color formation or the amount of a specific compound formed and the extracted substance is measured in advance, the concentration of the subcutaneous substance can be determined by calibrating the data collected by the detection unit. Examples of the detection unit include a double enzyme sensor, a glucose dehydrogenase sensor, and an iron ion detection sensor, which will be described later, and various sensors depending on the purpose of detecting the substance contained in the subcutaneous region.
[0018]
As an example of the detection unit, a cell having hollow fine needles in addition to the detection sheet is provided.When the fine needle is pierced to at least the depth of the stratum corneum of the epidermis after deaeration of the hollow portion, a substance containing a subcutaneous substance is obtained. Extra-dermal extraction is facilitated in each step. Since the potential drop (internal loss of the chemical battery) due to the high-resistance sebum and stratum corneum can be suppressed to 1/10 or less, not only can reverse iontophoresis be performed more effectively, but also bodily fluid extraction can be performed by utilizing the capillary phenomenon. This is because it can proceed more effectively. At this time, if the inside of the cell is set to a slightly negative pressure, the siphon effect is further added and the body fluid extraction is accelerated to each stage.
[0019]
The above-described chemical battery having A and B as main components causes a DC electromotive force. In this case, it is considered that extraction of the subcutaneous substance is mainly performed through pores. However, if this DC electromotive force is pulsed, it is considered that the reversal of the cell potential called electroporation occurs in accordance with the pulse cycle, and at the time of the reversal, the subcutaneous substance penetrates the cells and rises toward the electrode plate. It can be said that extraction is more effective.
Of course, if the auxiliary power supply is inserted into the external circuit as if the voltage of the chemical battery formed by A and B is increased, that is, the negative electrode is connected to the A side and the positive electrode is connected to the B side, the operation margin becomes larger. Reverse iontophoresis is caused by acceleration.
[0020]
In the above description, the detection unit has been described as an example of the function of detecting subcutaneous substances, but in addition to the detection, it is also necessary to specify subcutaneous substances or specify the amount of subcutaneous substances. It is also possible to go. For this purpose, such a specifying means is provided instead of the detection unit, overlapped with the detection unit, or connected to the detection unit. The specification means includes a sheet, a layer, a member, or the like using a chemical reaction, a material reaction, an electric reaction, or the like, or the use of an electronic circuit (IC). According to the invention, not only detection but also the final purpose of measurement of further specification can be achieved with one device.
Hereinafter, the present invention will be described in more detail specifically.
[0021]
(Part 1) FIGS. 1 (i) and 1 (ii) are diagrams showing main components of a subcutaneous substance inspection apparatus according to an embodiment of the present invention. (I) is a top view on the skin contact surface side of the device, and (ii) is a cross-sectional view along line MM ′.
In the figure, 1 is a metal A, 2 is a semiconductor B, 3 is a sensing part, 4 is a spongy body, and 5 is an insulator. In this inspection apparatus, for example, a bandage 10 as shown by a dotted line in FIG. 1 (ii) is attached to the outside on the surface opposite to the skin contact surface, and at the time of inspection, the upper surface shown in FIG. Then, the entire inspection apparatus is adhered and fixed to the skin with the adhesive bandage 10 adhered to the outside, and the substance contained under the skin is detected. In (ii), the surfaces 2a and 3a are the skin contact surfaces.
In the illustrated inspection apparatus, the metal (A) 1 has a size of 25 × 25 mm formed over the entire bottom surface. 2 A gold layer (thickness 0.3 μm) deposited on a size aluminum foil (thickness 0.05 mm), the semiconductor (B) 2 is formed at the peripheral portion and the central portion of the upper surface, and is shown in a width of 3 mm. Zinc oxide was formed by vapor-depositing zinc on an aluminum foil (thickness: 0.05 mm) processed into a shape divided into six parts (the division was made by the divided parts 20, 21, 22,...) And then oxidizing the surface with high-temperature steam. The zinc excess layer and the detection unit 3 are divided into two parts, 30 and 31, on the left and right sides, and are double enzyme (glucose oxidase / peroxidase) sensors immobilized on a water-permeable plastic film. On the other hand, the sponge body 4 is a sponge-like plastic layer impregnated with physiological saline, and the insulator 5 is a flexible insulator layer such as polyethylene. The device has a thickness of about 1.5 mm and is flexible and has a disposable structure.
[0022]
The reason why the detection unit 3 is divided into two parts, 30 and 31, is to make the electric field intensity applied to the surface of the detection unit 3 as uniform as possible, thereby improving the uniformity of the surface current density. 1 (ii) covers the entire back surface of the detection unit 3 while the metal or semiconductor 2 (acts as a negative electrode when in contact with the skin) as shown in FIG. As shown in (i) and (ii), in order to operate the detection unit 3 so as to be detectable, the detection unit 3 is disposed around each of the divided portions 30 and 31 of the detection unit 3. This makes it possible to shorten the distance from the surrounding negative pole to the portions 30 and 31 of the detection unit 3 existing in the left half and the right half, respectively, and to improve the detection capability. On the other hand, the metal or semiconductor 2 is divided into six parts, because the resistance value of the skin of the living body changes locally and greatly over time, so that the detection unit 3 disposed in the opening is energized as uniformly as possible. To do that. As a result, compared to the case where the semiconductor 2 is not divided, the concentration of current in the region having the lowest resistance value in the device skin contact area can be reduced, and the sensor function of the detection unit 3 can be improved.
[0023]
The metal A and the semiconductor, for example, the n-type semiconductor B, are electrically conductively connected on a non-skin contact surface (meaning a portion other than the skin contact surfaces 2a and 3a). For example, conductive connections between A and B are made at the ends 10A to 10F. The spongy body 4 plays a role of bringing the metal A and the detection unit 3 into conductive contact and giving conductivity to the detection unit 3. In this way, an electric path of the saline-metal A-semiconductor B containing the sea-surface-like plastic layer 4 is formed through the surface of the semiconductor B 2a-skin-exuded on the surface 3a of the detection unit 3 and the detection unit 3 Enables the extraction of subcutaneous body fluids.
[0024]
When this device is, for example, skin-contacted to the upper arm skin of a human body with a bandage, a chemical battery using gold as a positive electrode and zinc oxide as a negative electrode starts, electrons from the gold electrode to the spongy body 4, and holes from the zinc oxide. It is injected intradermally. The electrons injected into the corpus cavernosum 4 reach the skin surface via the detection unit 3 to further increase the acidity of the skin. On the other hand, the holes injected into the skin cause body fluid (pH 7.4) to drift from the negative electrode region to the positive electrode side. As a result, the subcutaneous body fluid is pulled up onto the positive electrode side epidermis by the electric action. The subcutaneous bodily fluid exuded on the epidermis first comes in contact with the upper layer of glucose oxidase (GOD) among the enzymes incorporated in the detection unit 3, and the sugar (D-glucose) in the subcutaneous bodily fluid is removed.
Figure 2004016489
Cause a reaction. Generated H 2 O 2 Is in contact with the underlying peroxidase (POD)
Figure 2004016489
Cause a reaction. Since the quinone dye exhibits a red color, the enzyme-fixed portion of the sensing unit 3 is colored red.
After a predetermined time elapses, the inspection device is removed from the upper arm and the detection unit 3 is taken out. The detection unit 3 is mounted on a measurement site of a measuring device (not shown), and thereafter, the colored site of the detection unit 3 is irradiated with red light to measure the absorbance at 505 nm from the transmitted light. Absorbance vs. previously prepared. The glucose concentration is calculated by a colorimetric method using a blood glucose standard sample. Since there is a certain correlation between the glucose concentration in the subcutaneous body fluid and the blood, the blood glucose level can be known non-invasively by the apparatus of this embodiment.
[0025]
Next, a method for obtaining a plurality of subcutaneous body fluid samples with one test device using the same principle as the above-described embodiment will be described. This is useful, for example, when the same person wants to know a change in blood sugar level when he is hungry, when he is full, before going to bed and when he wakes up.
[0026]
FIG. 2 is a cross-sectional view showing the configuration of an example of the device used. (I) is a skin contact view, and (ii) is a sectional view taken along line MM '. The numbers in the figure are the same as those in FIG. Reference numeral 10 denotes a selection switch. The numbers shown in parentheses correspond to the respective fragments of 2.
The selection switch 10 is arranged on the non-skin contact surface, and has a function of connecting the three pieces (1) to (8) shown in FIG. ing.
[0027]
The device size in FIG. 2 is 36 × 36 mm 2 As shown in FIG. 2 (i), each size of the detection unit 3 divided into four is 12 × 12 mm 2 It is. The constituent materials of the apparatus excluding the selection switch 10 are exactly the same as those in FIG.
When the device is placed in skin contact with the upper arm with a bandage, a gold / zinc oxide chemical battery is activated to draw up subcutaneous body fluid onto the skin, and the area to be sucked up is designated by the selection switch 10. When the conductors connected to the respective zinc oxide electrode pieces are numbered (1) to (8) as shown in the figure, the selection switch 10 switches the three conductors (1), (2) and (3) and the gold electrode When the connection is made, the subcutaneous bodily fluid oozes only at the opening position which is the upper right skin contact surface in FIG. 2 (A), and the enzymatic reaction is selectively caused by the detection unit at that position. The subcutaneous body fluid does not rise at the position of the opening serving as the other skin contact surface because the electrode circuit surrounding the opening is cut off.
If the selection switch is once turned off after a lapse of a predetermined time, the connection between all the zinc oxide electrode pieces and the gold electrode is cut off, so that the subcutaneous body fluid does not seep into any opening position. When the next sampling time comes, the selection switch 10 is turned on again to connect the zinc oxide electrode pieces (connection wires) (3), (4), and (5) to the gold electrodes, and the lower right opening in the figure Only subcutaneous body fluids seep out.
[0028]
In the same manner as above, subcutaneous body fluids can be independently oozed into the openings at the lower left and upper right skin contact surfaces, respectively, and enzymatic reaction coloring corresponding to the blood sugar level at that time can be obtained. Then, after all the detection reactions are completed, the device is removed and the detection unit 3 is taken out. Separate data is placed on the sensor of the detection unit 3 at four places, and by analyzing the data sequentially with an optical measuring device, each blood glucose level can be fixed by one device. After the device was removed, no damage was observed on the skin at the mounting site.
[0029]
If the apparatus shown in FIGS. 1 and 2 is used, the extraction of the subcutaneous substance and the transdermal administration can be performed simultaneously. For example, in the apparatus of FIG. 2, the arrangement of the detection unit 3 is stopped only in the lower left opening, and a conductive gel in which insulin is dispersed is arranged instead. First, after the device is in contact with the device, the zinc oxide electrode pieces (connection wires) (1), (2), and (3) are connected to the gold electrode 1 by the selection switch 10 and the zinc oxide electrode pieces (connection wires) (5), (6) and (7) are connected to the gold electrode 1. By this operation, reverse iontophoresis is induced in the upper right opening to extract subcutaneous body fluid, and at the same time, iontophoresis is induced in the lower left opening to cause subcutaneous penetration of insulin. By selectively performing the connection of the zinc oxide electrode piece to the gold electrode as described above, the subcutaneous body fluid extraction is performed for a predetermined period of time at the detection unit disposed at the upper right, lower right, and upper left opening portions, During this time, if the connection between the zinc oxide electrode pieces (connection wires) (5), (6), (7) and the gold electrode is maintained, insulin permeates the body. If the technique described in the embodiment (Part 3) is employed, the zinc oxide electrode pieces (connection wires) (5), (6), and (7) are bundled in the non-skin contact area, and a voltage-variable auxiliary power supply is provided here. Further, the amount of insulin permeated into the skin can be made variable by connecting.
[0030]
(Part 2) FIG. 3 is a view schematically showing a configuration of a subcutaneous substance inspection apparatus according to another embodiment of the present invention. (I) is a top view (skin-contacting view), and (ii) is a sectional view taken along line MM ′. The drawings are partially exaggerated for ease of understanding, and do not correspond to actual drawings.
[0031]
In the figure, 1 is a metal A, 2 is a metal or semiconductor B, 3 is a detecting portion, 4 is a spongy body, 5 is an insulator, 6 is a check valve, and 7 is a hollow fine needle.
1 is a platinum film (1 μm thick) plated on a conductive plastic sheet having a thickness of 0.05 mm, and 2 is a tin sheet rolled to a thickness of 0.05 mm, the surface of which is lightly oxidized with dilute hydrochloric acid to form SnOx. ing. Reference numeral 3 denotes a water-permeable plastic plate having glucose dehydrogenase (GDH) fixed on one surface. 4 is a sponge-like porous body, 5 is a flexible plastic, 6 is a check valve which allows one-way exhaust from the inside to the outside of the device, 7 is a plastic thin outer diameter of 150 μm and a length of 1.5 mm. Needle (hollow diameter: 80 μm), which is sterilized before use and filled with physiological saline to about half the length.
[0032]
This inspection device is fixed to the skin with, for example, a bandage. When the surface of FIG. 3 (i) is pressed against the skin, the fine needle 7 invades the skin, and at the same time, physiological saline is injected into the skin. On the other hand, since the corpus cavernosum 4 is squeezed at the time of pressing, the air in the apparatus is discharged out of the apparatus via the check valve. When the device is fixed with a bandage and attached to the skin, the interior of the device after evacuation maintains a light negative pressure due to the re-exaggeration of the corpus cavernosum 4 (the air from the outside enters the device by the action of the check valve 6). No).
[0033]
The chemical battery with platinum as the positive electrode and tin oxide as the negative electrode is activated by skin contact of the device, and the subcutaneous body fluid rapidly exudes into the device due to the generated power and capillary action. Since the negative pressure causes a siphon effect, the detection section operates within a short time of 1/10 or less even though the battery electromotive force is 0.5 V or more lower than in the previous embodiment. When the body fluid comes into contact with the glucose dehydrogenase in the detection unit, glucose + NADP (nicotinamide adenine dinucleotide phosphorus compound) is exchanged with D glucose contained in the body fluid.

GDH
Gluconolactone + NADPH (reduced nicotinamide adenine dinucleotide phosphate)
Cause a reaction.
After a predetermined time, the device is removed, and the detection unit is removed. Since the fine needle has a small diameter, there is no fear of bleeding or virus infection even if it is removed. Further, no damage was observed on the skin at the mounting site after the device was removed.
The reacted enzyme film is irradiated with ultraviolet light, and the spectrum of the reflected light is measured. The amount of glucose contained in the subcutaneous body fluid can be identified using the relationship that the absorbance at 340 nm increases by 0.630 when 0.1 mM of NADPH is generated. This device can be manufactured inexpensively as in the previous embodiment, and is disposable.
This method can also be used for cerebrospinal fluid collection. In this case, the fine needle 7 is a metal needle coated with an insulating film, and the length is set so as to reach the bone marrow.
[0034]
(Part 3) FIG. 4 is a view showing a schematic configuration of an apparatus according to still another embodiment of the present invention. FIG. 4 (i) is a plan view on the skin contact surface side, and (ii) is a sectional view taken along line MM ′ of (i).
In the figure, 1 is a metal A, 2 is a metal B, 3 is a detecting portion, 4 is a spongy body, 5 is an insulator, 8 is a pulser, and 9 is an auxiliary power supply.
1 is a gold foil pressed on a copper film (thickness 0.05 mm), 2 is iron, a part of a plate rolled to a thickness of 0.05 mm, and a stainless fine needle 2A (outside diameter 100 μm, length 2 mm) Disinfect before use with conductive adhesive. 3 is a water-permeable plastic plate surface coated with a water-insoluble iron ion detector, for example, 8-hydroxy-7-iodo-5-quinoline sulfone, 4 is a water-absorbing plastic sponge, 5 is a flexible plastic, and 8 is a flexible plastic. 9 is a device for pulsing a current flow, and 9 is an auxiliary power supply (voltage E B ), But is also used for driving 8, with the gold foil side connected to the negative electrode and the iron side connected to the positive electrode.
[0035]
When this device is in skin contact with a plaster or the like, the stainless fine needle invades the skin with the skin contact, but the needle is thin and usually no pain is felt. The chemical battery made of gold foil and iron is activated by skin contact to generate electric power, but at the same time, an electric closed circuit is formed through the skin, so that the electric current from the auxiliary power supply 9 also flows. The current is converted by the pulsing device 8 into a unipolar pulse having a duty ratio of 30% and a pulse width of 30 μsec and flows through a closed circuit. Since the stainless needle eliminates the electricity loss due to the sebum layer and the stratum corneum which occupy most of the skin resistance, the electricity loss can be reduced by half compared to the apparatus shown in FIGS. By mounting this device, bodily fluid oozes out of the skin under the gold foil electrode and is reserved in the water-absorbing plastic 4.
[0036]
Applied voltage E of auxiliary power supply B Is increased, the body fluid exudation rate increases in proportion to it. Since this device uses a pulse current, it can use electroporation, and can collect a subcutaneous body fluid more effectively than when using a direct current.
The subcutaneous body fluid reserved in the water-absorbent plastic 4 reacts with the reagent of the detection unit 3 to form a color. Therefore, if the device is removed after a predetermined time elapses and the detection unit is taken out, the iron ion concentration in the subcutaneous body fluid can be identified using a colorimetric method.
Since the diameter of the fine needle is small at the time of removal of the device, the invasion site of the skin is immediately closed, and there is no fear of bleeding or infection. Other than the electric system such as the auxiliary power supply and the pulsing device, it can be formed at low cost and is disposable.
[0037]
(Part 4) In the above embodiments, only the case where the detection unit 3 of the device has a sensor function of detecting a subcutaneous substance is described. However, in the present invention, as described above, the detection substance is not limited to detection only. It is also possible to provide a device having a function of specifying quantitatively.
FIG. 5 is a diagram schematically showing the configuration of an apparatus according to an embodiment of the present invention, which can monitor a blood glucose level over time. FIG. 5 (i) is a top view (skin contact surface view), and FIG. 5 (ii) is a view in which electrical wiring on the back surface of the device is added to the MM ′ cross section.
In the figure, 1 is a gold mesh electrode, 2 is a zinc oxide semiconductor electrode having a plurality of protrusions having a height of 1-2 mm on the surface, and 3 is a GOD (or glucose dehydrogenase) immobilized enzyme membrane, which is impregnated with a conductive solution. ing. GOD or glucose dehydrogenase is fixed on the electrode 1 side. 5 is an insulating plastic having flexibility, 6 is a check valve made of plastic, 9 is an uneven power supply, 11 is a micro ammeter, and 12 is an iron film whose surface is made of platinum with a thickness of 3 μm. 13 is a bellows to which 12 is adhered, 14 is a packing, 15 is an insulating plastic joint, and 16 is an empty room.
[0038]
The microammeter 11 is connected to a recorder (not shown), and has a mechanism in which the amount of change is recorded with time. In this apparatus, the skin contact surface side (the skin contact surface side component portion including the gold mesh electrode 1) from the packing 14 is disposable, and the non-skin contact surface side including the packing 14 is reused together with the updated skin contact surface side component portion. It is structured to be. The connection between the disposable part and the reusable part is made by screws or fitting.
When this device is pressed against the upper arm, for example, with an accompanying plaster or the like, a gold / zinc oxide chemical battery is activated and the subcutaneous body fluid is electrically discharged outside the skin. At the same time, the bellows 13 is compressed, and the air in the vacant space 16 is discharged outside through the check valve 6. As a result, the inside of the empty room 16 is in a negative pressure state. Then, the auxiliary power supply 9 is turned on. By this operation, E B , The micro power supply 11 and the recorder are also started to operate.
[0039]
The plurality of protrusions 2B provided on the zinc oxide semiconductor electrode 2 strongly press the skin non-invasively. As a result, the skin at the device skin contact site is stretched, and the sweat glands and pores are expanded. Subcutaneous bodily fluid rushes onto the skin through sweat glands and pores, thereby accelerating the subcutaneous bodily eruption due to reverse iontophoresis. In fact, when compared with the device of Example 1 using the same size and the same material, the amount of subcutaneous body fluid collected 3 hours after skin contact is increased to 2-2.5 times the value of this example. Admitted.
The body fluid eluted on the skin is absorbed by the GOD (or glucose dehydrogenase) immobilized enzyme membrane 3, and the GOD or glucose dehydrogenase immobilized on the back surface reacts with glucose in the body fluid to generate hydrogen peroxide. The generated hydrogen peroxide gas enters the negative pressure chamber 16 and reaches the platinum film. Here, the oxygen of the generator is released by the catalytic action of platinum, but at this time, electrons are released to the platinum flag, so that the resistance value of the platinum film changes (current supply current increases). Since the number of emitted electrons is proportional to the concentration of the reactive glucose, the increase in the value of the supplied current can be measured by the microammeter 11 to determine the glucose concentration in the subcutaneous body fluid.
Since the enzyme film of No. 3 reacts stably for at least 12 hours, the change in the blood glucose level can be known over time by recording the change in the supplied current over time with a recorder.
[0040]
In the present embodiment, the projections for expanding the sweat glands and pores are provided on the semiconductor electrode 2. However, the projections may be provided on the enzyme fixing film 3 side. In this case, the projection has a hollow bodily fluid passage hole, and is provided as a part of an insulating film closely arranged on the enzyme-immobilized film 3.
[0041]
As described above, the present invention has been described in detail with reference to the embodiments. However, it is obvious that the present invention can be variously modified without departing from the scope of the present invention. For example, a timer for determining a reaction time can be provided.
Alternatively, in all of the above embodiments, the structure in which the two electrode plates constituting the chemical battery are disposed above and below the detection unit has been disclosed, but in order to make the detection unit wider than the skin contact area of the detection unit, a direct conductive contact is made with the detection unit. An apparatus structure in which an electrode and a counter electrode are arranged in parallel with the skin and both electrodes are conductively connected in a non-skin contact area also belongs to the category of the present invention.
Further, when the subcutaneous substance to be extracutaneously extracted is acidic, the arrangement of A and B in each of the above-mentioned embodiments must be reversed.
[0042]
【The invention's effect】
As described above, according to the present invention, extraction and detection of a substance contained in the subcutaneous region can be easily performed without giving a patient a risk of pain, infection, or skin damage. Further, the device of the present invention has a great advantage in that the device is simple in construction and can be disposable each time the patient uses the device.
[Brief description of the drawings]
FIG. 1 is a diagram showing an outline of a device configuration for explaining another embodiment of the present invention.
FIG. 2 is a diagram showing an outline of a device configuration for explaining another embodiment of the present invention.
FIG. 3 is a diagram showing an outline of a device configuration for explaining another embodiment of the present invention.
FIG. 4 is a diagram showing an outline of a device configuration for explaining another embodiment of the present invention.
FIG. 5 is a diagram showing an outline of a device configuration for explaining an embodiment of the present invention.
[Explanation of symbols]
1 metal
2 Metal or semiconductor
3 Detector
4 spongy bodies
5 Insulator
6 Check valve
7 hollow fine needle
8 Pulsing device
9 Auxiliary power supply
10 Selection switch

Claims (10)

金属Aと、これより標準単極電位の低い金属または半導体Bと、皮下含有物質を検出する、導電性の検知部とを備えて成り、
該検知部は皮接面を持ち、この皮接面以外の部位で前記AまたはBのいずれか一方に接触し、
検知部に接触していないAまたはBの他方は皮接面を持ち、且つAとBとは皮接面以外の部位で導電接続し、
前記検知部の皮接面と、AとBとの一方が持つ皮接面とを同時に皮接することによって発生する化学電池起電力を利用して皮下含有物質を電気泳動的に検知部に抽出し認識する皮下含有物質検査装置。
Comprising a metal A, a metal or semiconductor B having a lower standard monopolar potential, and a subcutaneous substance, and a conductive detector,
The detection unit has a skin contact surface, and comes into contact with either A or B at a site other than the skin contact surface,
The other of A and B not in contact with the detection unit has a skin contact surface, and A and B are conductively connected at a portion other than the skin contact surface,
The subcutaneous substance is electrophoretically extracted to the detection unit by utilizing the electromotive force of the chemical cell generated by simultaneously skinning the skin contact surface of the detection unit and the skin contact surface of one of A and B. Recognition device for subcutaneous substances.
前記検知部が、少なくとも表皮角質層を貫通する程度の長さを有する1本以上の中空細針を備えており、前記皮接が細針による軽侵襲までを含む請求項第1項記載の皮下含有物質検査装置。The subcutaneous according to claim 1, wherein the detection unit includes one or more hollow fine needles having a length at least penetrating the stratum corneum of the epidermis, and the skin contact includes light invasion by the fine needle. Contained substance inspection device. 前記皮接面を持つAまたはBの一方が細針状をなし皮接時軽侵襲して用いられる請求項1または2記載の皮下含有物質検査装置。The subcutaneous substance inspection device according to claim 1 or 2, wherein one of A and B having the skin contact surface has a fine needle shape and is used by lightly invading at the time of skin contact. 前記AとBとの導電接続系路に通電電流のパルス化装置を設けた請求項1乃至3記載のいずれかの皮下含有物質検査装置。The subcutaneous substance inspection device according to any one of claims 1 to 3, further comprising a current-current pulsing device provided in the conductive connection path between A and B. 前記AとBとの導電接続系路に補助電源を設けた請求項1乃至4記載のいずれかの皮下含有物質検査装置。The subcutaneous substance inspection apparatus according to any one of claims 1 to 4, wherein an auxiliary power supply is provided in the conductive connection path between A and B. 検知部に接触した前記AまたはBの一方の領域を使用時負圧に保つ請求項1乃至5記載のいずれかの皮下含有物質検査装置。The subcutaneous substance inspection apparatus according to any one of claims 1 to 5, wherein one of the areas A and B in contact with the detection unit is maintained at a negative pressure during use. 検知部は複数に分割されて複数の皮接面を持ち、皮接面を持つAまたはBの一方は、各分割検知部の周囲に相互に分離されて配置されており、各分割検知部の周囲のAまたはBとは、相互に独立して検知可能とする請求項1の皮下含有物質検査装置。The detection unit is divided into a plurality and has a plurality of skin contact surfaces, and one of A or B having the skin contact surface is arranged separately from each other around the division detection unit, The subcutaneous substance inspection device according to claim 1, wherein the surrounding A or B can be detected independently of each other. 各分割検知部の周囲に配置された皮接面を持つのAまたはBの一方と他方との導電接続系路にスイッチを設け、各スイッチを選択的に切り替えるようにした請求項7の皮下含有物質検査装置。8. A subcutaneous content according to claim 7, wherein a switch is provided in a conductive connection path between one and the other of A or B having a skin contact surface disposed around each divided detection unit, and each switch is selectively switched. Material inspection device. 検知部の皮接面、または検知部に接触していないAまたはBの皮接面に非侵襲的な突起を1個以上設けた請求項1または4乃至8記載のいずれかの皮下含有物質検査装置。9. The subcutaneous substance inspection according to claim 1, wherein one or more non-invasive projections are provided on the skin contact surface of the detection part or on the skin contact surface of A or B not in contact with the detection part. apparatus. 被検知部位に接触可能な、複数区分された第1の皮接面を持つ皮下含有物質を検出する検知部と、
この検知部に接触した導電性海綿体と、
この海綿体に接触した金属Aと、
被検知部位に接触可能な第2の皮接面を持ち、上記金属Aと導電接続され、更に、金属Aよりも標準単極電位の低い金属又は半導体Bと、
を備える皮下含有物質の検査装置。
A detection unit that detects a subcutaneous-containing substance having a plurality of divided first skin contact surfaces, which can be in contact with the detection site;
A conductive sponge body in contact with the detection unit,
Metal A in contact with the spongy body,
A metal or semiconductor B having a standard monopolar potential lower than the metal A, having a second skin contact surface capable of contacting the detected part, and being conductively connected to the metal A;
An inspection device for a subcutaneous substance, comprising:
JP2002175875A 2002-06-17 2002-06-17 Testing apparatus of subcutaneous contaminant substance Pending JP2004016489A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2002175875A JP2004016489A (en) 2002-06-17 2002-06-17 Testing apparatus of subcutaneous contaminant substance

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2002175875A JP2004016489A (en) 2002-06-17 2002-06-17 Testing apparatus of subcutaneous contaminant substance

Publications (1)

Publication Number Publication Date
JP2004016489A true JP2004016489A (en) 2004-01-22

Family

ID=31174403

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2002175875A Pending JP2004016489A (en) 2002-06-17 2002-06-17 Testing apparatus of subcutaneous contaminant substance

Country Status (1)

Country Link
JP (1) JP2004016489A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1839567A1 (en) * 2005-01-19 2007-10-03 Sysmex Corporation Analyzer and cartridge for extracting analyte
JP2012515563A (en) * 2008-06-30 2012-07-12 ネマウラ ファーマ リミテッド Patch for reverse iontophoresis
WO2017186783A1 (en) * 2016-04-26 2017-11-02 The University Of Bath Multiplexed transdermal extraction and detection devices for non-invasive monitoring of substances and methods of use
CN110389163A (en) * 2018-04-16 2019-10-29 潘新宇 Noninvasive dynamics monitoring device based on multisensor pixel array

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1839567A1 (en) * 2005-01-19 2007-10-03 Sysmex Corporation Analyzer and cartridge for extracting analyte
EP1839567A4 (en) * 2005-01-19 2009-11-11 Sysmex Corp Analyzer and cartridge for extracting analyte
JP2012515563A (en) * 2008-06-30 2012-07-12 ネマウラ ファーマ リミテッド Patch for reverse iontophoresis
WO2017186783A1 (en) * 2016-04-26 2017-11-02 The University Of Bath Multiplexed transdermal extraction and detection devices for non-invasive monitoring of substances and methods of use
CN109414227A (en) * 2016-04-26 2019-03-01 巴斯大学 Multiplexing for non-invasive monitoring substance is percutaneously extracted and detection device and its application method
US11278218B2 (en) 2016-04-26 2022-03-22 The University Of Bath Multiplexed transdermal extraction and detection devices for non-invasive monitoring of substances and methods of use
CN110389163A (en) * 2018-04-16 2019-10-29 潘新宇 Noninvasive dynamics monitoring device based on multisensor pixel array

Similar Documents

Publication Publication Date Title
JP3155523B2 (en) Biosensor, ion permeation sampling system and method of using the same
US5954685A (en) Electrochemical sensor with dual purpose electrode
US8046043B2 (en) Extraction device, analyzer, extraction method, and analysis method
CA2332112C (en) Monitoring of physiological analytes
EP1117461B1 (en) Kit and method for quality control testing of an iontophoretic sampling system
JP3328290B2 (en) Ion introduction sampling apparatus and method
JP3507437B2 (en) Collection assembly for transdermal sampling systems
JP5680156B2 (en) In vivo component measuring method and in vivo component measuring device
JP2004294242A (en) Percutaneous anatyte extracting system, analyte analyzing system, percutaneous analyte extracting method and analyte analyzing method
JP2004016489A (en) Testing apparatus of subcutaneous contaminant substance
WO2006077750A1 (en) Analyzer and cartridge for extracting analyte

Legal Events

Date Code Title Description
A621 Written request for application examination

Free format text: JAPANESE INTERMEDIATE CODE: A621

Effective date: 20050608

A977 Report on retrieval

Free format text: JAPANESE INTERMEDIATE CODE: A971007

Effective date: 20070727

A131 Notification of reasons for refusal

Free format text: JAPANESE INTERMEDIATE CODE: A131

Effective date: 20070807

A02 Decision of refusal

Free format text: JAPANESE INTERMEDIATE CODE: A02

Effective date: 20080115